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Fitzpatrick’s Dermatology in General Medicine

LOWELL A. GOLDSMITH, MD, MPH

Emeritus Professor of Dermatology University of North Carolina School of Medicine Chapel Hill, North Carolina Dean Emeritus University of Rochester School of Medicine and Dentistry Rochester, NY

STEPHEN I. KATZ, MD, PhD

Fellow, American Academy of Dermatology Schaumburg, IL; Past President, Society of Investigative Dermatology Cleveland, OH; Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases National Institutes of Health Bethesda, MD

BARBARA A. GILCHREST, MD

Chair Emerita and Professor of Dermatology Department of Dermatology Boston University School of Medicine Boston, MA

AMY S. PALLER, MD

Walter J. Hamlin Professor and Chair of Dermatology Professor of Pediatrics Feinberg School of Medicine Northwestern University Chicago, IL

DAVID J. LEFFELL, MD

David Paige Smith Professor of Dermatology and Surgery Chief, Section of Dermatologic Surgery and Cutaneous Oncology Department of Dermatology Yale University School of Medicine New Haven, CT

KLAUS WOLFF, MD, FRCP Professor of Dermatology Chairman Emeritus Department of Dermatology Medical University of Vienna Vienna, Austria

Fitzpatrick’s Dermatology in General Medicine Eighth Edition EDITORS LOWELL A. GOLDSMITH, MD, MPH STEPHEN I. KATZ, MD, PhD BARBARA A. GILCHREST, MD AMY S. PALLER, MD DAVID J. LEFFELL, MD KLAUS WOLFF, MD, FRCP

New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto

Copyright © 2012 by The McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-171755-7 MHID: 0-07-171755-2 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-166904-7, MHID: 0-07-166904-3. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at [email protected]. Previous editions copyright © 2008, 2003, 1999, 1993, 1987, 1979, 1971 by The McGraw-Hill Companies, Inc. Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGraw-Hill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvii Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxxi Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxxiii

Volume One PART 1  INTRODUCTION Section 1. General Considerations    1 The Epidemiology and Burden of Skin Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Martin A. Weinstock, MD, PhD & Mary-Margaret Chren, MD

Section 3. Overview of Biology, Development, and Structure of Skin   7 Development and Structure of Skin. . . . . . . . . . . . 58 David H. Chu, MD, PhD   8 Genetics in Relation to the Skin . . . . . . . . . . . . . . . 75 John A. McGrath, MD, FRCP & W. H. Irwin McLean, FRSE, FMedSci   9 Racial Considerations: Skin of Color. . . . . . . . . . . 91 Kavitha K. Reddy, MD, Yolanda M. Lenzy, MD, MPH, Katherine L. Brown, MD, MPH, & Barbara A. Gilchrest, MD

 ART 2  Disorders Presenting in P Skin and Mucous Membranes

   2 Evidence-Based Dermatology. . . . . . . . . . . . . . . . . . 9 Michael Bigby, MD, Rosamaria Corona, DSc, MD, & Moyses Szklo, MD, MPH, DrPH

Section 4. Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

   3 Global Health in Dermatology. . . . . . . . . . . . . . . . 15 Roderick J. Hay, DM, FRCP, FRCPath, FMedSci

  10 Innate and Adaptive Immunity in the Skin. . . . 105 Robert L. Modlin, MD, Lloyd S. Miller, MD, PhD, Christine Bangert, MD, & Georg Stingl, MD

   4 Public Health in Dermatology. . . . . . . . . . . . . . . . . 21 Hywel C. Williams, MSc, PhD, FRCP, Sinéad M. Langan, MRCP, MSc, PhD, & Carsten Flohr, BM, BCh (Hons), MA, Mphil, MRCPCH, MSc, PhD

Section 2. Approach to Dermatologic Diagnosis   5 Structure of Skin Lesions and Fundamentals of Clinical Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . 26 Amit Garg, MD, Nikki A. Levin, MD, PhD, & Jeffrey D. Bernhard, MD, FRCP (Edin)   6 Basic Pathologic Reactions of the Skin. . . . . . . . . . 42 Martin C. Mihm Jr., MD, FACP, Abdul-Ghani Kibbi, MD, FAAD, FACP, George F. Murphy, MD & Klaus Wolff, MD, FRCP

  11 Cytokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Ifor R. Williams, MD, PhD & Thomas S. Kupper, MD, FAAD   12 Chemokines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142 Anke S. Lonsdorf, MD & Sam T. Hwang, MD, PhD   13 Allergic Contact Dermatitis. . . . . . . . . . . . . . . . . . 152 Mari Paz Castanedo-Tardan, MD & Kathryn A. Zug, MD   14 Atopic Dermatitis (Atopic Eczema). . . . . . . . . . . 165 Donald Y.M. Leung, MD, PhD, Lawrence F. Eichenfield, MD, & Mark Boguniewicz, MD   15 Nummular Eczema, Lichen Simplex Chronicus, and Prurigo Nodularis. . . . . . . . . . . . 182 Susan Burgin, MD

  16 Vesicular Palmoplantar Eczema . . . . . . . . . . . . . . 187 Daven N. Doshi, MD, Carol E. Cheng, MD, & Alexa B. Kimball, MD, MPH   17 Autosensitization Dermatitis. . . . . . . . . . . . . . . . . 194 Donald V. Belsito, MD   18 Psoriasis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Johann E. Gudjonsson, MD, PhD & James T. Elder, MD, PhD   19 Psoriatic Arthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . 232 Dafna D. Gladman, MD, FRCPC & Vinod Chandran, MBBS, MD, DM

Contents

  20 Reactive Arthritis. . . . . . . . . . . . . . . . . . . . . . . . . . . 243 John D. Carter, MD   21 Pustular Eruptions of Palms and Soles . . . . . . . . 253 Ulrich Mrowietz, MD   22 Seborrheic Dermatitis. . . . . . . . . . . . . . . . . . . . . . . 259 Chris D. Collins, MD, FAAD & Chad Hivnor, MD   23 Exfoliative Dermatitis. . . . . . . . . . . . . . . . . . . . . . . 266 Jane Margaret Grant-Kels, MD, Flavia Fedeles, MD, MS, & Marti J. Rothe, MD   24 Pityriasis Rubra Pilaris. . . . . . . . . . . . . . . . . . . . . . 279 Daniela Bruch-Gerharz, MD & Thomas Ruzicka, Prof. Dr. med. Dr. h.c.   25 Parapsoriasis and Pityriasis Lichenoides. . . . . . . 285 Gary S. Wood, MD, Chung-Hong Hu, MD & Rosemarie Liu, MD   26 Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296 Mazen S. Daoud, MD & Mark R. Pittelkow, MD   27 Lichen Nitidus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312 Mazen S. Daoud, MD & Mark R. Pittelkow, MD

  32 Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome). . . . . . . . . . . . . . . . . . . . . . . . . . 362 Philip R. Cohen, MD, Herbert Hönigsmann, MD, & Razelle Kurzrock, MD, FACP   33 Pyoderma Gangrenosum. . . . . . . . . . . . . . . . . . . . 371 Frank C. Powell, FRCPI, FAAD, Bridget C. Hackett, MB BCh, BAO, MRCPI, & Daniel Wallach, MD   34 Granuloma Faciale. . . . . . . . . . . . . . . . . . . . . . . . . . 380 David A. Mehregan, MD & Darius R. Mehregan, MD   35 Subcorneal Pustular Dermatosis (Sneddon– Wilkinson Disease). . . . . . . . . . . . . . . . . . . . . . . . . . 383 Franz Trautinger, MD & Herbert Hönigsmann, MD   36 Eosinophils in Cutaneous Diseases . . . . . . . . . . . 386 Kristin M. Leiferman, MD & Margot S. Peters, MD

Section 6. Inflammatory Diseases Based on Abnormal Humoral Reactivity and Other Inflammatory Diseases   37 Humoral Immunity and Complement. . . . . . . . . 401 Lela A. Lee, MD   38 Urticaria and Angioedema. . . . . . . . . . . . . . . . . . . 414 Allen P. Kaplan, MD   39 Erythema Multiforme. . . . . . . . . . . . . . . . . . . . . . . 431 Jean-Claude Roujeau, MD

  28 Graft-Versus-Host Disease. . . . . . . . . . . . . . . . . . . 316 Edward W. Cowen, MD, MHSc

  40 Epidermal Necrolysis (Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis). . . . . 439 L. Valeyrie-Allanore, MD & Jean-Claude Roujeau, MD

  29 Skin Disease in Acute and Chronic Immunosuppression. . . . . . . . . . . . . . . . . . . . . . . . 330 Benjamin D. Ehst, MD, PhD & Andrew Blauvelt, MD

  41 Cutaneous Reactions to Drugs . . . . . . . . . . . . . . . 449 Neil H. Shear, MD, FRCPC & Sandra R. Knowles, BScPhm

Section 5. Inflammatory Diseases Based on Neutrophils and Eosinophils vi

  31 Regulation of the Production and Activation of Eosinophils. . . . . . . . . . . . . . . . . . . . 351 Kristin M. Leiferman, MD, Lisa A. Beck, MD, & Gerald J. Gleich, MD

  30 Regulation of the Production and Activation of Neutrophils . . . . . . . . . . . . . . . . . . . 345 Steven M. Holland, MD

  42 Pityriasis Rosea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 Andrew Blauvelt, MD   43 Erythema Annulare Centrifugum and Other Figurate Erythemas. . . . . . . . . . . . . . . . . . . . . . . . . 463 Walter H.C. Burgdorf, MD   44 Granuloma Annulare . . . . . . . . . . . . . . . . . . . . . . . 467 Julie S. Prendiville, MB, FRCPC

  59 Pemphigoid Gestationis (Herpes Gestationis). . . 630 Jeff K. Shornick, MD, MHA

  45 Epidermal Stem Cells . . . . . . . . . . . . . . . . . . . . . . . 473 Rebecca J. Morris, PhD

  60 Epidermolysis Bullosa Acquisita. . . . . . . . . . . . . . 634 David T. Woodley, MD & Mei Chen, PhD

  46 Epidermal Growth and Differentiation. . . . . . . . 478 Pierre A. Coulombe, PhD, Stanley J. Miller, MD, & Tung-Tien Sun, PhD

  61 Dermatitis Herpetiformis. . . . . . . . . . . . . . . . . . . . 642 Arash Ronaghy, MD, PhD, Stephen I. Katz, MD, PhD, & Russell P. Hall III, MD

  47 Skin as an Organ of Protection. . . . . . . . . . . . . . . 486 Ehrhardt Proksch, MD, PhD & Jens-Michael Jensen, MD

  62 Inherited Epidermolysis Bullosa. . . . . . . . . . . . . . 649 M. Peter Marinkovich, MD

  48 Irritant Contact Dermatitis. . . . . . . . . . . . . . . . . . . 499 Antoine Amado, MD, Apra Sood, MD, & James S. Taylor, MD, FAAD

Section 9. Disorders of the Dermal Connective Tissue

  49 The Ichthyoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 507 Philip Fleckman, MD & John J. DiGiovanna, MD   50 Inherited Palmoplantar Keratodermas . . . . . . . . 538 Mozheh Zamiri, BSc (Hons), MBChB, MRCP, MD, Maurice A. M. van Steensel, MD, PhD, & Colin S. Munro, MD, FRCP (Glasg)   51 Acantholytic Disorders of the Skin. . . . . . . . . . . . 550 Susan Burge, OBE, DM, FRCP & Alain Hovnanian, MD, PhD   52 Porokeratosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563 Grainne M. O’Regan, MRCPI & Alan D. Irvine, MD, FRCP, FRCPI

Section 8. Disorders of Epidermal and Dermal–Epidermal Adhesion and Vesicular and Bullous Disorders   53 Epidermal and Epidermal–Dermal Adhesion. . . . 569 Leena Bruckner-Tuderman, MD & Aimee S. Payne, MD, PhD   54 Pemphigus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586 Aimee S. Payne, MD, PhD & John R. Stanley, MD   55 Paraneoplastic Pemphigus. . . . . . . . . . . . . . . . . . . 600 Grant J. Anhalt, MD & Daniel Mimouni, MD   56 Bullous Pemphigoid . . . . . . . . . . . . . . . . . . . . . . . . 608 Donna A. Culton, MD, PhD, Zhi Liu, PhD, & Luis A. Diaz, MD   57 Cicatricial Pemphigoid. . . . . . . . . . . . . . . . . . . . . . 617 Kim B. Yancey, MD   58 Linear Immunoglobulin A Dermatosis and Chronic Bullous Disease of Childhood . . . . . . . . 623 Caroline L. Rao, MD & Russell P. Hall III, MD

  63 Collagens, Elastic Fibers, and Other Extracellular Matrix Proteins of the Dermis. . . . . . . . . . . . . . . . 666 Thomas Krieg, MD, Monique Aumailley, Manuel Koch, PhD, Mon-Li Chu, PhD, & Jouni Uitto, MD, PhD

Contents

Section 7. Disorders of Epidermal Differentiation and Keratinization

  64 Morphea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692 Stephanie Saxton-Daniels, MD & Heidi T. Jacobe, MD, MSCS   65 Lichen Sclerosus. . . . . . . . . . . . . . . . . . . . . . . . . . . . 702 Ulrich R. Hengge, MD, MBA   66 Dermal Hypertrophies and Benign Fibroblastic/Myofibroblastic Tumors . . . . . . . . . 707 Christine J. Ko, MD   67 Anetoderma and Other Atrophic Disorders of the Skin. . . . . . . . . . . . . . . . . . . . . . . . 718 Catherine Maari, MD & Julie Powell, MD, FRCPC   68 Ainhum and Pseudoainhum. . . . . . . . . . . . . . . . . 724 Robert T. Brodell, MD & Stephen E. Helms, MD   69 Acquired Perforating Disorders . . . . . . . . . . . . . . 727 Julia S. Minocha, MD & Bethanee J. Schlosser, MD, PhD

Section 10. Disorders of Subcutaneous Tissue   70 Panniculitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 732 Iris K. Aronson, MD, Patricia M. Fishman, MD, & Sophie M. Worobec, MD, FAAD   71 Lipodystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755 Abhimanyu Garg, MD

Section 11. Disorders of Melanocytes   72 Biology of Melanocytes. . . . . . . . . . . . . . . . . . . . . . 765 Hee-Young Park, PhD & Mina Yaar, MD

vii

  73 Albinism and Other Genetic Disorders of Pigmentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781 Thomas J. Hornyak, MD, PhD   74 Vitiligo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792 Stanca A. Birlea, MD, PhD, Richard A. Spritz, MD & David A. Norris, MD

Contents

  75 Hypomelanoses and Hypermelanoses . . . . . . . . 804 Hilde Lapeere, MD, PhD, Barbara Boone, MD, PhD, Sofie De Schepper, MD, PhD, Evelien Verhaeghe, MD, Mireille Van Gele, PhD, Katia Ongenae, MD, PhD, Nanja Van Geel, MD, PhD, Jo Lambert, MD, PhD, & Lieve Brochez, MD, PhD

Section 12. Disorders of the Oral and Genital Integument   76 Biology and Pathology of the Oral Cavity. . . . . . 827 Sook-Bin Woo, DMD   77 Diseases and Disorders of the Male Genitalia . . . 852 Christopher B. Bunker, MD, FRCP   78 Diseases and Disorders of the Female Genitalia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878 Lynette J. Margesson, MD, FRCPC & F. William Danby, MD, FRCPC, FAAD

PART 3  Disorders of the Skin Appendages Section 13. Disorders of the Sebaceous Glands   79 Biology of Sebaceous Glands. . . . . . . . . . . . . . . . . 893 Amanda M. Nelson, PhD & Diane M. Thiboutot, MD   80 Acne Vulgaris and Acneiform Eruptions. . . . . . . 897 Andrea L. Zaenglein, MD, Emmy M. Graber, MD, & Diane M. Thiboutot, MD   81 Rosacea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918 Michelle T. Pelle, MD   82 Perioral Dermatitis. . . . . . . . . . . . . . . . . . . . . . . . . . 925 Leslie P. Lawley, MD & Sareeta R.S. Parker, MD

Section 14. Disorders of the Eccrine and Apocrine Glands   83 Biology of Eccrine and Apocrine Glands. . . . . . . 929 Theodora M. Mauro, MD

viii

  84 Disorders of the Eccrine Sweat Glands and Sweating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936 Robert D. Fealey, MD & Adelaide A. Hebert, MD

  85 Disorders of the Apocrine Sweat Glands. . . . . . . 947 Christos C. Zouboulis, MD, PhD & Fragkiski Tsatsou, MD, MSc, BSc

Section 15. Disorders of the Hair and Nails   86 Biology of Hair Follicles. . . . . . . . . . . . . . . . . . . . . 960 George Cotsarelis, MD & Vladimir Botchkarev, MD, PhD   87 Keratosis Pilaris and Other Inflammatory Follicular Keratotic Syndromes. . . . . . . . . . . . . . . 973 Paradi Mirmirani, MD & Maureen Rogers, MBBS, FACD   88 Hair Growth Disorders. . . . . . . . . . . . . . . . . . . . . . 979 Nina Otberg, MD & Jerry Shapiro, MD, FRCPC, FAAD   89 Biology of Nails and Nail Disorders. . . . . . . . . . 1009 Antonella Tosti, MD & Bianca Maria Piraccini, MD, PhD

PART 4  Disorders Due to the Environment Section 16. Disorders Due to Ultraviolet Radiation   90 Fundamentals of Cutaneous Photobiology and Photoimmunology. . . . . . . . . . . . . . . . . . . . . . . . . 1031 Irene E. Kochevar, PhD, Charles R. Taylor, MD, & Jean Krutmann, MD   91 Abnormal Responses to Ultraviolet Radiation: Idiopathic, Probably Immunologic, and Photoexacerbated. . . . . . . . . . . . . . . . . . . . . . . . . . 1049 Travis W. Vandergriff, MD & Paul R. Bergstresser, MD   92 Abnormal Responses to Ultraviolet Radiation: Photosensitivity Induced by Exogenous Agents. . . . . . . . . . . . . . . . . . . . . . . . . 1066 Henry W. Lim, MD

Section 17. Skin Changes Due to Other Physical and Chemical Factors   93 Thermoregulation . . . . . . . . . . . . . . . . . . . . . . . . . 1075 Dean L. Kellogg, Jr., MD, PhD   94 Cold Injuries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079 Gérald E. Piérard, MD, PhD, Pascale Quatresooz, MD, PhD, & Claudine Piérard-Franchimont, MD, PhD

  95 Thermal Injuries. . . . . . . . . . . . . . . . . . . . . . . . . . . 1089 Robert L. Sheridan, MD   96 Skin Problems in Amputees. . . . . . . . . . . . . . . . . 1095 Calum C. Lyon, MA, FRCP & Michael H. Beck, FRCP, MBChB   97 Skin Problems in Ostomates . . . . . . . . . . . . . . . . 1104 Calum C. Lyon, MA, FRCP & Michael H. Beck, FRCP, MBChB   98 Corns and Calluses . . . . . . . . . . . . . . . . . . . . . . . . 1111 Thomas M. DeLauro, DPM & Nicole M. DeLauro, DPM

100 Decubitus (Pressure) Ulcers . . . . . . . . . . . . . . . . 1121 Jennifer G. Powers, MD, Lillian Odo, MD, & Tania J. Phillips, MD, FRCP, FRCPC 101 Body Art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129 Anne Laumann, MBChB, MRCP(UK), FAAD

PART 5  Neurocutaneous and Psychocutaneous Aspects of Skin Disease

109 Aging of Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213 Mina Yaar, MD & Barbara A. Gilchrest, MD

PART 7  NEOPLASIA Section 20. Carcinogenesis 110 Genome Instability, DNA Repair, and Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227 Thomas M. Rünger, MD, PhD & Kenneth H. Kraemer, MD 111 Chemical Carcinogenesis. . . . . . . . . . . . . . . . . . . 1239 Adam B. Glick, PhD & Andrzej A. Dlugosz, MD 112 Ultraviolet Radiation Carcinogenesis . . . . . . . . 1251 Masaoki Kawasumi, MD, PhD & Paul Nghiem, MD, PhD

Section 21. Epidermal and Appendageal Tumors 113 Epithelial Precancerous Lesions. . . . . . . . . . . . . 1261 Karynne O. Duncan, MD, John K. Geisse, MD & David J. Leffell, MD

Section 18. Neurocutaneous and Psychocutaneous Skin Disease

114 Squamous Cell Carcinoma. . . . . . . . . . . . . . . . . . 1283 Douglas Grossman, MD, PhD & David J. Leffell, MD

102 Neurobiology of the Skin. . . . . . . . . . . . . . . . . . . 1137 Martin Steinhoff, MD, PhD & Thomas A. Luger, MD

115 Basal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . 1294 John A. Carucci, MD, PhD, David J. Leffell, MD & Julia S. Pettersen, MD

103 Pathophysiology and Clinical Aspects of Pruritus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146 Gil Yosipovitch, MD & Tejesh S. Patel, MBBS (Lon), BSc (Hons)

116 Basal Cell Nevus Syndrome . . . . . . . . . . . . . . . . 1304 Anthony E. Oro, MD, PhD & Jean Y. Tang, MD, PhD

104 Psychocutaneous Skin Disease . . . . . . . . . . . . . . 1158 Evan Rieder, MD & Francisco A. Tausk, MD 105 Cutaneous Manifestations of Drug Abuse. . . . . 1166 Haley Naik, MD & Richard Allen Johnson, MDCM 106 Skin Signs of Physical Abuse. . . . . . . . . . . . . . . . 1177 Howard B. Pride, MD

PART 6 SKIN CHANGES ACROSS THE SPAN OF LIFE Section 19. From Birth to Old Age 107 Neonatal, Pediatric, and Adolescent Dermatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1185 Mary Wu Chang, MD

Contents

  99 Sports Dermatology. . . . . . . . . . . . . . . . . . . . . . . . 1115 Dirk M. Elston, MD

108 Skin Changes and Diseases in Pregnancy. . . . . 1204 Julie K. Karen, MD & Miriam Keltz Pomeranz, MD

117 Keratoacanthoma. . . . . . . . . . . . . . . . . . . . . . . . . . 1312 Lorenzo Cerroni, MD & Helmut Kerl, MD 118 Benign Epithelial Tumors, Hamartomas, and Hyperplasias. . . . . . . . . . . . . 1319 Valencia D. Thomas, MD, Nicholas R. Snavely, MD, Ken K. Lee, MD & Neil A. Swanson, MD 119 Appendage Tumors and Hamartomas of the Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1337 Divya Srivastava, MD & R. Stan Taylor, MD 120 Merkel Cell Carcinoma. . . . . . . . . . . . . . . . . . . . . 1362 Andrew Tegeder, MS, Olga Afanasiev, BA, & Paul Nghiem, MD, PhD 121 Mammary and Extramammary Paget’s Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1371 Sherrif F. Ibrahim, MD, PhD, Roy C. Grekin, MD, & Isaac M. Neuhaus, MD

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Section 22. Melanocytic Tumors 122 Benign Neoplasias and Hyperplasias of Melanocytes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1377 James M. Grichnik, MD, PhD, Arthur R. Rhodes, MD, MPH, & Arthur J. Sober, MD 123 Atypical (Dysplastic) Melanocytic Nevi. . . . . . 1410 James M. Grichnik, MD, PhD & Margaret A. Tucker, MD

Contents

124 Cutaneous Melanoma. . . . . . . . . . . . . . . . . . . . . . 1416 Evans C. Bailey, MD, PhD, Arthur J. Sober, MD, Hensin Tsao, MD, PhD, Martin C. Mihm Jr, MD, FACP, & Timothy M. Johnson, MD

Section 23. Tumors and Hyperplasias of the Dermis and Subcutaneous Fat 125 Malignant Fibrous, Fibrohistiocytic, and Histiocytic Tumors of the Dermis. . . . . . . . . . . . 1445 Jürgen C. Becker, MD, PhD, Bernadette Liegl-Atzwanger, MD & Selma Ugurel, MD 126 Vascular Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 1456 Erin F. Mathes, MD & Ilona J. Frieden, MD 127 Neoplasias and Hyperplasias of Muscular and Neural Origin. . . . . . . . . . . . . . . . 1470 Lucile E. White, MD, Ross M. Levy, MD, & Murad Alam, MD, MSci

134 Systemic Autoinflammatory Diseases. . . . . . . . 1584 Chyi-Chia Richard Lee, MD, PhD & Raphaela Goldbach-Mansky, MD, MHS 135 Xanthomatoses and Lipoprotein Disorders. . . . 1600 Ernst J. Schaefer, MD & Raul D. Santos, MD, PhD 136 Fabry Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1613 Atul B. Mehta, MD, FRCP, FRCPath & Catherine H. Orteu, MBBS, BSc, MD, FRCP 137 Lipoid Proteinosis and Heritable Disorders of Connective Tissue. . . . . . . . . . . . . . 1624 Jonathan A. Dyer, MD 138 Cutaneous Mineralization and ­Ossification. . . . 1649 Janet A. Fairley, MD 139 Hereditary Disorders of Genome Instability and DNA Repair. . . . . . . . . . . . . . . . . 1654 Thomas M. Rünger, MD, PhD, John J. DiGiovanna, MD, & Kenneth H. Kraemer, MD 140 Tuberous Sclerosis Complex . . . . . . . . . . . . . . . . 1671 Thomas N. Darling, MD, PhD 141 The Neurofibromatoses. . . . . . . . . . . . . . . . . . . . 1680 Robert Listernick, MD & Joel Charrow, MD

128 Kaposi’s Sarcoma and Angiosarcoma. . . . . . . . 1481 Erwin Tschachler, MD

142 Ectodermal Dysplasias. . . . . . . . . . . . . . . . . . . . . 1691 Alanna F. Bree, MD, Nnenna Agim, MD, & Virginia P. Sybert, MD

129 Neoplasms of Subcutaneous Fat. . . . . . . . . . . . . 1489 Thomas Brenn, MD, PhD, FRCPath

143 Genetic Immunodeficiency Diseases. . . . . . . . . 1703 Ramsay L. Fuleihan, MD & Amy S. Paller, MD

Volume Two PART 8  THE SKIN IN SYSTEMIC DISEASE

Section 25. Skin Manifestations of Bone Marrow or Blood Chemistry Disorders 144 Hematologic Diseases. . . . . . . . . . . . . . . . . . . . . . 1726 Warren W. Piette, MD

Section 24. Skin in Nutritional, Metabolic, and Heritable Disease

145 Cutaneous Lymphoma. . . . . . . . . . . . . . . . . . . . . 1745 Marc Beyer, MD & Wolfram Sterry, Prof. Dr.

130 Cutaneous Changes in Nutritional Disease. . . . 1499 Melinda Jen, MD & Albert C. Yan, MD

146 Inflammatory Diseases That Simulate Lymphomas: Cutaneous Pseudolymphomas. . . . . . . . . . . . . . . 1767 Gary S. Wood, MD

131 Cutaneous Changes in Errors of Amino Acid Metabolism. . . . . . . . . . . . . . . . . . . . 1525 Peter H. Itin, MD

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133 Amyloidosis of the Skin. . . . . . . . . . . . . . . . . . . . 1574 Helen J. Lachmann, MD, FRCP & Philip N. Hawkins, PhD, FRCP, FRCPath, FMedSci

132 The Porphyrias. . . . . . . . . . . . . . . . . . . . . . . . . . . . 1538 David R. Bickers, MD & Jorge Frank, MD, PhD

147 Cutaneous Langerhans Cell Histiocytosis. . . . . 1782 Carlo Gelmetti, MD 148 Non-Langerhans Cell Histiocytosis . . . . . . . . . . 1795 Carlo Gelmetti, MD

149 Mastocytosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1809 Michael D. Tharp, MD

Section 26. Skin Manifestations of Internal Organ Disorders 150 The Skin and Disorders of the Alimentary Tract, the Hepatobiliary System, the Kidney, and the Cardiopulmonary System. . . . . . . . . . . 1819 Graham A. Johnston, MBChB, FRCP & Robin A.C. Graham-Brown, BSc, MB, FRCP, FRCPCH

152 Sarcoidosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1869 Richard M. Marchell, MD, Bruce Thiers, MD, & Marc A. Judson, MD 153 Cutaneous Manifestations of Internal Malignant Disease: Cutaneous Paraneoplastic Syndromes. . . . . . . . . . . . . . . . . . 1880 Christine A. DeWitt, MD, Lucinda S. Buescher, MD, & Stephen P. Stone, MD

Section 27. The Skin in Vascular and Connective Tissue and Other Autoimmune Disorders 154 Mechanisms of Autoimmune Disease. . . . . . . . 1901 Insoo Kang, MD & Joseph Craft, MD 155 Lupus Erythematosus. . . . . . . . . . . . . . . . . . . . . . 1909 Melissa I. Costner, MD & Richard D. Sontheimer, MD 156 Dermatomyositis. . . . . . . . . . . . . . . . . . . . . . . . . . 1926 Richard D. Sontheimer, MD, Christopher B. Hansen, MD, & Melissa I. Costner, MD 157 Scleroderma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1942 P. Moinzadeh, MD, Christopher P. Denton, PhD, FRCP, T. Krieg, MD, & Carol M. Black, MD, FRCP, FMedSci 158 Scleredema and Scleromyxedema. . . . . . . . . . . . 1957 Roger H. Weenig, MD, MPH & Mark R. Pittelkow, MD 159 Relapsing Polychondritis. . . . . . . . . . . . . . . . . . . 1962 Camille Francès, MD 160 Rheumatoid Arthritis, Rheumatic Fever, and Gout . . . . . . . . . . . . . . . . . . . . . . . . . . . 1965 Warren W. Piette, MD

Section 28. The Skin in Inflammatory and Other Vascular Disorders 162 Endothelium in Inflammation and Angiogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1986 Peter Petzelbauer, MD, Robert Loewe, MD, & Jordan S. Pober, MD, PhD 163 Cutaneous Necrotizing Venulitis . . . . . . . . . . . . 2003 Nicholas A. Soter, MD 164 Systemic Necrotizing Arteritis. . . . . . . . . . . . . . . 2013 Peter A. Merkel, MD, MPH & Paul A. Monach, MD, PhD

Contents

151 Diabetes Mellitus and Other Endocrine Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1840 Andrea A. Kalus, MD, Andy J. Chien, MD, PhD, & John E. Olerud, MD

161 Sjögren’s Syndrome. . . . . . . . . . . . . . . . . . . . . . . . 1976 Gabor Illei, MD, PhD, MHS & Stamatina Danielides, MD

165 Erythema Elevatum Diutinum . . . . . . . . . . . . . . 2029 Nneka I. Comfere, MD & Lawrence E. Gibson, MD 166 Adamantiades–Behçet Disease. . . . . . . . . . . . . . 2033 Christos C. Zouboulis, MD, PhD 167 Kawasaki Disease. . . . . . . . . . . . . . . . . . . . . . . . . . 2042 Anne H. Rowley, MD 168 Pigmented Purpuric Dermatoses . . . . . . . . . . . . 2049 Theresa Schroeder Devere, MD & Anisha B. Patel, MD 169 C  ryoglobulinemia and Cryofibrinogenemia. . . . . . . . . . . . . . . . . . . . . . . . 2055 Holger Schmid, MD, MSc PD & Gerald S. Braun, MD 170 Raynaud Phenomenon. . . . . . . . . . . . . . . . . . . . . 2065 John H. Klippel, MD 171 Malignant Atrophic Papulosis (Degos Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . 2072 Dan Lipsker, MD, PhD 172 Vascular Malformations. . . . . . . . . . . . . . . . . . . . 2076 Laurence M. Boon, MD, PhD & Miikka Vikkula, MD, PhD 173 Cutaneous Changes in Peripheral Arterial Vascular Disease. . . . . . . . . . . . . . . . . . . 2094 Veerendra Chadachan, MD Steven M. Dean, DO, FACP, RPVI, & Robert T. Eberhardt, MD, FACC, FSVM, RPVI 174 Cutaneous Changes in Peripheral Venous and Lymphatic Insufficiency. . . . . . . . . 2110 Craig N. Burkhart, MD, Chris Adigun, MD, & Claude S. Burton, MD

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PART 9  Disease Due to Microbial Agents, Infestations, Bites, and Stings Section 29. Bacterial Disease 175 G  eneral Considerations of Bacterial Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2121 Noah Craft, MD, PhD, DTMH

Contents

176 S  uperficial Cutaneous Infections and Pyodermas. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2128 Noah Craft, MD, PhD, DTMH 177 G  ram-Positive Infections Associated with Toxin Production. . . . . . . . . . . . . . . . . . . . . . 2148 Jeffrey B. Travers, MD, PhD & Nico Mousdicas, MBChB, MD 178 N  on-Necrotizing Infections of the Dermis and Subcutaneous Fat: Cellulitis and Erysipelas. . . . . . . . . . . . . . . . . . . . 2160 Adam D. Lipworth, MD, Arturo P. Saavedra, MD, PhD, MBA, Arnold N. Weinberg, MD, & Richard Allen Johnson, MDCM 179 Necrotizing Soft Tissue Infections: Necrotizing Fasciitis, Gangrenous Cellulitis, and Myonecrosis . . . . . . . . . . . . . . . . . 2169 Adam D. Lipworth, MD, Arturo P. Saavedra, MD, PhD, MBA, Arnold N. Weinberg, MD, & Richard Allen Johnson, MDCM

187 Lyme Borreliosis. . . . . . . . . . . . . . . . . . . . . . . . . . . 2263 Meera Mahalingam, MD, PhD, FRCPath, Jag Bhawan, MD, Daniel B. Eisen, MD, & Linden Hu, MD

Section 30. Fungal Diseases 188 Superficial Fungal Infection. . . . . . . . . . . . . . . . . 2277 Stefan M. Schieke, MD & Amit Garg, MD 189 Yeast Infections: Candidiasis, Tinea (Pityriasis) Versicolor, and Malassezia (Pityrosporum) Folliculitis. . . . . . . . . . 2298 Roopal V. Kundu, MD & Amit Garg, MD 190 Deep Fungal Infections. . . . . . . . . . . . . . . . . . . . . 2312 Roderick J. Hay, DM, FRCP, FRCPath, FMedSci

SECTION 31. Viral and Rickettsial Diseases 191 G  eneral Considerations of Viral Diseases. . . . . 2329 L. Katie Morrison, MD, Ammar Ahmed, MD, Vandana Madkan, MD, Natalia Mendoza, MD, MS, & Stephen Tyring, MD, PhD 192 E  xanthematous Viral Diseases. . . . . . . . . . . . . . . 2337 Leah T. Belazarian, MD, Mayra E. Lorenzo, MD, PhD, Andrea L. Pearson, MD, Susan M. Sweeney, MD, & Karen Wiss, MD

180 Gram-Negative Coccal and Bacillary Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2178 Myron S. Cohen, MD, William A. Rutala, BS, MS, PhD, MPH, & David J. Weber, MD, MPH

193 H  erpes Simplex . . . . . . . . . . . . . . . . . . . . . . . . . . . 2367 Adriana R. Marques, MD & Jeffrey I. Cohen, MD

181 The Skin in Infective Endocarditis, Sepsis, Septic Shock, and Disseminated Intravascular Coagulation . . . . . . . . . . . . . . . . . . 2194 Laura Korb Ferris, MD, PhD & Joseph C. English, MD

195 Poxvirus Infections . . . . . . . . . . . . . . . . . . . . . . . . 2402 Caroline Piggott, MD, Sheila Fallon Friedlander, MD, & Wynnis Tom, MD

182 Bartonellosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2201 Timothy G. Berger, MD & Francisco G. Bravo, MD 183 Miscellaneous Bacterial Infections with Cutaneous Manifestations. . . . . . . . . . . . . . . . . . 2210 Scott A. Norton, MD, MPH, MS

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186 Leprosy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2253 Delphine J. Lee, MD, PhD, FAAD, Thomas H. Rea, & Robert L. Modlin, MD

194 V  aricella and Herpes Zoster. . . . . . . . . . . . . . . . . 2383 Kenneth E. Schmader, MD & Michael N. Oxman, MD

196 Human Papilloma Virus Infections . . . . . . . . . . 2421 Elliot J. Androphy, MD & Reinhard Kirnbauer, MD 197 H  uman T-Lymphotropic Viruses . . . . . . . . . . . . 2434 Erwin Tschachler, MD

184 Tuberculosis and Infections with Atypical Mycobacteria. . . . . . . . . . . . . . . . . . . . . . 2225 Aisha Sethi, MD

198 C  utaneous Manifestations of Human Immunodeficiency Virus Disease. . . . . . . . . . . . 2439 Lily Changchien Uihlein, MD, JD, Arturo P. Saavedra, MD, PhD, MBA, & Richard Allen Johnson, MDCM

185 Actinomycosis, Nocardiosis, and ­ Actinomycetoma . . . . . . . . . . . . . . . . . . . . . . . . . . 2241 Francisco G. Bravo, MD, Roberto Arenas, MD, & Daniel Asz Sigall, MD

199 T  he Rickettsioses, Ehrlichioses, and Anaplasmoses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2456 Sandra A. Kopp, MD, Analisa V. Halpern, MD, Justin J. Green, MD & Warren R. Heymann, MD

SECTION 32. Sexually Transmitted Diseases 200 S  yphilis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2471 Kenneth A. Katz, MD, MSc, MSCE 201 E  ndemic (Nonvenereal) Treponematoses. . . . . 2493 Nadine Marrouche, MD & Samer H. Ghosn, MD 202 Chancroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2501 Stephan Lautenschlager, MD

204 Granuloma Inguinale . . . . . . . . . . . . . . . . . . . . . . 2510 Abdul-Ghani Kibbi, MD, FAAD, FACP, Ruba F. Bahhady, MD, & Myrna El-Shareef, MD 205 G  onorrhea, Mycoplasma, and Vaginosis. . . . . . 2514 Ted Rosen, MD

SECTION 33. Infestations, Bites, and Stings 206 Leishmaniasis and Other Protozoan Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2527 Joelle M. Malek, MD & Samer H. Ghosn, MD 207 Helminthic Infections . . . . . . . . . . . . . . . . . . . . . . 2544 Kathryn N. Suh, MD & Jay S. Keystone, MD, MSc(CTM), FRCPC 208 Scabies, Other Mites, and Pediculosis . . . . . . . . 2569 Craig N. Burkhart, MD & Craig G. Burkhart, MD, MPH 209 Bites and Stings of Terrestrial and Aquatic Life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2578 Jennifer S. Daly, MD & Mark Jordan Scharf, MD 210 Arthropod Bites and Stings . . . . . . . . . . . . . . . . . 2599 Robert A. Schwartz, MD, MPH & Christopher J. Steen, MD

PART 10  Occupational Skin Diseases and Skin Diseases Due to Biologic Warfare SECTION 34. Occupational Skin Diseases 211 O  ccupational Skin Diseases Due to Irritants and Allergens . . . . . . . . . . . . . . . . . . . . . 2611 Golara Honari, MD, James S. Taylor, MD, FAAD, & Apra Sood, MD

SECTION 35. The Skin in Bioterrorism and Biologic Warfare 213 C  utaneous Manifestations of Biologic, Chemical, and Radiologic Attacks . . . . . . . . . . . 2633 Scott A. Norton, MD, MPH, MSc

PART 11  THERAPEUTICS

Contents

203 Lymphogranuloma Venereum. . . . . . . . . . . . . . . 2505 Rim S. Ishak, MD & Samer H. Ghosn, MD

212 O  ccupational Noneczematous Skin Diseases Due to Biologic, Physical, and Chemical Agents: Introduction. . . . . . . . . . 2622 Paul X. Benedetto, MD, James S. Taylor, MD, FAAD, & Apra Sood, MD

SECTION 36. Topical Therapy 214 P  rinciples of Topical Therapy . . . . . . . . . . . . . . . 2643 Aieska De Souza, MD, MS & Bruce E. Strober, MD, PhD 215 P  harmacokinetics and Topical ­ Applications of Drugs. . . . . . . . . . . . . . . . . . . . . . 2652 Hans Schaefer, PhD, Thomas E. Redelmeier, MD Gerhard J. Nohynek, PhD, DABT, & Jürgen Lademann, Prof. Dr. rer. nat. Dr.-Ing. habil. 216 T  opical Corticosteroids. . . . . . . . . . . . . . . . . . . . . 2659 Isabel C. Valencia, MD & Francisco A. Kerdel, MD 217 Topical Retinoids. . . . . . . . . . . . . . . . . . . . . . . . . . 2665 Anna L. Chien, MD, John J. Voorhees, MD, FRCP, & Sewon Kang, MD 218 Topical Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . 2673 Mark W. Bonner, MD & William D. James, MD 219 Topical Antifungal Agents. . . . . . . . . . . . . . . . . . 2677 Whitney A. High, MD, JD, MEng & James E. Fitzpatrick, MD 220 T  opical and Intralesional Cytotoxic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2685 Aieska De Souza, MD, MS, Megan M. Moore, MD, & Bruce E. Strober, MD, PhD 221 T  opical Immunomodulators . . . . . . . . . . . . . . . . 2690 Edward M. Esparza, MD, PhD & Robert Sidbury, MD, MPH 222 O  ther Topical Medications. . . . . . . . . . . . . . . . . . 2697 Craig N. Burkhart, MD & Kenneth A. Katz, MD, MSc, MSCE 223 Photoprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . 2707 Henry W. Lim, MD

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SECTION 37. Systemic Therapy 224 Systemic Glucocorticoids. . . . . . . . . . . . . . . . . . . 2714 Victoria P. Werth, MD 225 Dapsone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2721 Joni G. Sago, MD & Russell P. Hall III, MD 226 Aminoquinolines. . . . . . . . . . . . . . . . . . . . . . . . . . 2726 Susannah E. McClain, MD, Jeffrey R. LaDuca, MD, PhD & Anthony A. Gaspari, MD

Contents

227 Cytotoxic and Antimetabolic Agents. . . . . . . . . 2735 Whitney A. High, MD, JD, MEng & James E. Fitzpatrick, MD 228 Retinoids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2759 Anders Vahlquist, MD, PhD & Jean-Hilaire Saurat, MD 229 Antihistamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . 2767 Robert A. Wood, MD 230 Antibiotics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2776 Christopher C. Gasbarre, DO, FAAD, Steven K. Schmitt, MD, & Kenneth J. Tomecki, MD 231 Antiviral Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . 2787 Dirk M. Elston, MD 232 Oral Antifungal Agents. . . . . . . . . . . . . . . . . . . . . 2796 Reza Jacob, MD & Nellie Konnikov, MD 233 I mmunosuppressive and ­ Immunomodulatory Drugs. . . . . . . . . . . . . . . . . 2807 Jeffrey P. Callen, MD 234 I mmunobiologicals, Cytokines, and Growth Factors in Dermatology. . . . . . . . . . . . . 2814 Stephen K. Richardson, MD & Joel M. Gelfand, MD, MSCE 235 Antiangiogenic Agents. . . . . . . . . . . . . . . . . . . . . 2827 Ricardo L. Berrios, MD, Michael Y. Bonner, BA, Jonathan Hofmekler, BSc, & Jack L. Arbiser, MD, PhD 236 Drug Interactions. . . . . . . . . . . . . . . . . . . . . . . . . . 2834 Stephen E. Wolverton, MD

SECTION 38. Physical Treatments 237 Phototherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2841 Jennifer A. Cafardi, MD, Brian P. Pollack, MD, PhD, & Craig A. Elmets, MD

xiv

238 Photochemotherapy and ­Photodynamic Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2851 Herbert Hönigsmann, MD, Rolf-Markus Szeimies, MD, PhD, & Robert Knobler, MD 239 Lasers and Flashlamps in ­Dermatology. . . . . . 2869 Michael Landthaler, MD, Wolfgang Bäumler, PhD, & Ulrich Hohenleutner, MD 240 Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2890 Roy H. Decker, MD, PhD, & Lynn D. Wilson, MD, MPH

SECTION 39. Complementary and Alternative Dermatology 241 C  omplementary and Alternative Medicine in Dermatology. . . . . . . . . . . . . . . . . . . 2899 Alan Dattner, MD

SECTION 40. Surgery in Dermatology 242 A  natomy and Approach in ­Dermatologic Surgery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2905 Sumaira Z. Aasi, MD & Brent E. Pennington, MD 243 E  xcisional Surgery and Repair, Flaps, and Grafts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2921 Jessica M. Sheehan, MD, Melanie Kingsley, MD, & Thomas E. Rohrer, MD 244 M  ohs Micrographic Surgery . . . . . . . . . . . . . . . . 2950 Joseph Alcalay, MD & Ronen Alkalay, MD, MBA 245 N  ail Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2956 Robert Baran, MD 246 C  ryosurgery and Electrosurgery. . . . . . . . . . . . . 2968 Justin J. Vujevich, MD & Leonard H. Goldberg, MD, FRCP 247 Surgical Complications. . . . . . . . . . . . . . . . . . . . . 2977 Richard G. Bennett, MD 248 M  echanisms of Wound Repair, Wound Healing, and Wound Dressing. . . . . . . . . . . . . . 2984 Vincent Falanga, MD, FACP & Satori Iwamoto, MD, PhD 249 T  reatment for Varicose and ­Telangiectatic Leg Veins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2997 Robert A. Weiss, MD & Margaret A. Weiss, MD

SECTION 41. Cosmetic Dermatology 250 C  osmetics and Skin Care in ­ Dermatology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3009 Leslie Baumann, MD 251 A  blative Lasers, Chemical Peels, and Dermabrasion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3021 Elizabeth L. Tanzi, MD & Tina S. Alster, MD

254 S  oft Tissue Augmentation. . . . . . . . . . . . . . . . . . 3044 Lisa M. Donofrio, MD 255 B  otulinum Toxin. . . . . . . . . . . . . . . . . . . . . . . . . . . 3053 Richard G. Glogau, MD 256 H  air Transplantation and Alopecia ­ Reduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3061 Walter P. Unger, MD, Robin H. Unger, MD, & Mark A. Unger, MD, CCFP Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I-1

Contents

252 C  osmetic Applications of Nonablative Lasers and Other Light Devices . . . . . . . . . . . . . 3032 Elliot T. Weiss, MD, Anne M. Chapas, MD, & Roy G. Geronemus, MD

253 Liposuction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3041 William G. Stebbins, MD, Aimee L. Leonard, MD, & C. William Hanke, MD, MPH, FACP

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Contributors

Sumaira Z. Aasi, MD

Elliot J. Androphy, MD

Christine Bangert, MD

Chris Adigun, MD

Grant J. Anhalt, MD

Robert Baran, MD

Associate Professor, Department of Dermatology, Yale University, New Haven, CT [242]

Department chair Dermatology at Indiana University School of Medicine Indianapolis, IN [196]

Department of Dermatology, Medical University of Vienna, Vienna, Austria [10]

Professor, Department of Dermatology and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD [55]

Honorary Professor, Department of Dermatology, Nail Disease Center, Cannes, France [245]

Jack L. Arbiser, MD, PhD

Professor, Department of Dermatology, Emory University School of Medicine, Atlanta, GA [235]

Chief Executive Officer, Cosmetic Dermatology, Baumann Cosmetic and Research Institute, Miami Beach, FL [250]

Assistant Professor, Department of Dermatology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX [142]

Roberto Arenas, MD

Lisa A. Beck, MD

Ammar Ahmed, MD

Iris K. Aronson, MD

Physician (PGY-3), Department of Dermatology, UNC-Chapel Hill, Chapel Hill, NC [174]

Olga K. Afanasiev, BA

Department of Dermatology, University of Washington School of Medicine, Seattle, WA [120]

Nnenna Agim, MD

Resident Physician, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX [191]

Murad Alam, MD, MSci

Associate Professor, Departments of Dermatology, Otolaryngology, and Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL [127]

Professor, Department of Dermatology, University of Mexico, Mexico, DF [185] Associate Professor, Department of Dermatology, University of Illinois College of Medicine, Chicago, IL [70]

Daniel Asz-Sigall, MD

Resident, Dermatology, Cutaneous Oncology and Dermatologic Surgery, Department of Dermatology, ABC Hospital, Mexico City, Mexico [185]

Joseph Alcalay, MD

Monique Aumailley

Ronen Alkalay, MD, MBA

Wolfgang Bäumler, PhD

Director, Mohs Surgery Unit, Assuta Medical Center, Tel Aviv, Israel [244] Mohs Unit, Assuta Medical Hospital, Tel Aviv, Israel [244]

Tina S. Alster, MD

Director, Laser Surgery, Washington Institute of Dermatologic Laser Surgery, Washington, DC [251]

Antoine Amado, MD

Resident in Dermatology, Dermatology and Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH [48]

Professor, Center for Biochemistry, Cologne, Germany [63] Professor, Department of Dermatology, University of Regensburg, Germany [239]

Ruba F. Bahhady, MD

Resident (PGY-4), Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon [204]

Evans C. Bailey, MD, PhD

Lecturer, Department of Dermatology, University of Michigan, Ann Arbor, MI [124]

Leslie Baumann, MD

Associate Professor of Dermatology and Medicine, Department of Dermatology and Medicine, University of Rochester School of Medicine, Rochester, NY [31]

Michael H. Beck, FRCP, MBChB

Honorary Clinical Lecturer, Occupational and Environmental Health Group, University of Manchester, Manchester, UK [96, 97]

Jürgen C. Becker, MD, PhD

Professor, Division of General Dermatology, Medical University of Graz, Graz, Austria [125]

Leah T. Belazarian, MD

Assistant Professor of Medicine and Pediatrics, Department of Medicine, Division of Dermatology, University of Massachusetts Medical School, Worcester, MA [192]

Donald V. Belsito, MD

Clinical Professor, Medicine (Dermatology), University of Missouri, Kansas City, MO [17]

Paul X. Benedetto, MD

Resident Physician, Department of Dermatology, Cleveland Clinic Foundation, Cleveland, OH [212]

Richard G. Bennett, MD

Clinical Professor, Dermatology, University of Southern California, Los Angeles, CA [247]

Timothy G. Berger, MD

Professor, Department of Dermatology, University of California, San Francisco, San Francisco, CA [182]

Paul R. Bergstresser, MD

Professor, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX [91]

Jeffrey D. Bernhard, MD, FRCP (Edin) Contributors

Professor Emeritus, University of Massachusetts Medical School, Worcester, MA [5]

Ricardo L. Berrios, MD

Post-Doctoral Fellow, Department of Dermatology, School of Medicine, Emory University, Atlanta, GA [235]

Marc Beyer, MD

Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany [145]

Jag Bhawan, MD

Professor, Department of Dermatology and Pathology, Boston University School of Medicine, Boston, MA [187]

David R. Bickers, MD

Carl Truman Nelson Professor, Department of Dermatology, Columbia University Medical Center, New York, NY [132]

Michael Bigby, MD

Associate Professor, Department of Dermatology, Harvard Medical School, Boston, MA [2]

Stanca A. Birlea, MD, PhD

Instructor, Dermatology and Human Medical Genetics Program, School of Medicine, University of Colorado Denver, Aurora, CO [74]

Carol M. Black, MD, FRCP, FMedSci

Professor, Centre for Rheumatology, University College London, London, UK [157]

Georgia Dermatology Warner Robins, GA [218]

Michael Y. Bonner, BA

Research Associate, Department of Dermatology, School of Medicine, Emory University, Atlanta, GA [235]

Laurence M. Boon, MD, PhD

Center for Vascular Anomalies Division of Plastic Surgery St Luc University Hospital, Brussels, Belgium [172]

Barbara Boone, MD, PhD

Dermatologist, Ghent University Hospital, Ghent, Belgium [75]

Vladimir Botchkarev, MD, PhD

Professor, Centre for Skin Sciences, University of Bradford and Bradford, UK [86]

Gerald S. Braun, MD

Department of Nephrology and Clinical Immunology, University Hospital, RWTH University of Aachen, Aachen, Germany [169]

Francisco G. Bravo, MD

Professor, Department of Dermatology, University Hospital of Düsseldorf, Düsseldorf, Germany [24]

Leena Bruckner-Tuderman, MD Professor, Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany [53]

Lucinda S. Buescher, MD

Associate Professor, Division of Dermatology, Southern Illinois University, Springfield, IL [153]

Christopher B. Bunker, MD, FRCP

Professor, Department of Dermatology, University College London Hospitals, London, UK [77]

Walter H.C. Burgdorf, MD

Lecturer, Department of Dermatology, Ludwig Maximilian University, Munich, Germany [43]

Susan Burge, OBE DM FRCP

Consultant Dermatologist, Oxford University Hospitals, Oxford, UK [51]

Susan Burgin, MD

Alanna F. Bree, MD

Craig G. Burkhart, MD, MPH

Thomas Brenn, MD, PhD, FRCPath

Craig N. Burkhart, MD

Pediatric Dermatologist, Dermatology Specialists of Houston, Bellaire, TX [142]

Consultant Dermatopathologist, Department of Pathology, Western General Hospital, Edinburgh, UK [129]

Lieve Brochez, MD, PhD

Professor, Department of Dermatology, Ghent University Hospital, Ghent, Belgium [75]

Robert T. Brodell, MD

Professor, Department of Dermatology, Oregon Health & Science University, Portland, OR [29, 42]

Mark Boguniewicz, MD

Katherine L. Brown, MD, MPH

Professor, Department of Pediatrics, Division of Allergy-Immunology, National Jewish Health, Denver, CO [14]

Daniela Bruch-Gerharz, MD

Associate Professor, Department of Pathology, Universidad Peruana Cayetano Heredia, Lima, Peru [182, 185]

Professor of Internal Medicine and Clinical Professor of Dermatopathology in Pathology, Department of Internal Medicine and Pathology, Northeastern Ohio Universities College of Medicine and Pharmacy, Rootstown, OH [68]

Andrew Blauvelt, MD

xviii

Mark W. Bonner, MD

Dermatology Resident, Department of Dermatology, Boston University, Boston, MA [9]

Assistant Professor, Department of Dermatology, Harvard Medical School, Boston, MA [15] Clinical Professor, Department of Medicine, College of Medicine, University of Toledo, Toledo, OH [208] Assistant Professor, Department of Dermatology, The University of North Carolina at Chapel Hill, Chapel Hill, NC [174, 208, 222]

Claude S. Burton, MD

Professor, Department of Dermatology, Duke University School of Medicine, Durham, NC [174]

Jennifer A. Cafardi, MD

Assistant Professor, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL [237]

Jeffrey P. Callen, MD

Professor of Medicine (Dermatology), Department of Medicine, University of Louisville, Louisville, KY [233]

John D. Carter, MD

Associate Professor, Department of Internal Medicine, Division of Rheumatology, University of South Florida College of Medicine, Tampa, FL [20]

John A. Carucci, MD, PhD

Associate Professor, Department of Dermatology, Weill Cornell Medical College, New York, NY [115]

Mari Paz Castanedo-Tardan, MD

Lorenzo Cerroni, MD

Associate Professor, Department of Dermatology, Medical University of Graz, Graz, Austria [117]

Veerendra Chadachan, MD

Vascular Medicine Program, Boston University Medical Center, Boston MA, USA Consultant, Department of General Medicine Vascular Medicine and Hypertension Section, Tan Tock Seng Hospital, Singapore [173]

Vinod Chandran, MBBS, MD, DM

Clinical Research Fellow, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto, ON, Canada [19]

Mary Wu Chang, MD

Associate Clinical Professor, Department of Dermatology, Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT [107]

Anne M. Chapas, MD

Clinical Assistant Professor, Department of Dermatology, New York University School of Medicine, New York, NY [252]

Joel Charrow, MD

Professor, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL [141]

Mei Chen, PhD

Professor and Director of Research, Department of Dermatology, University of Southern California, Los Angeles, CA [60]

Carol E. Cheng, MD

Department of Dermatology, Massachusetts General Hospital, Boston, MA [16]

Melissa I. Costner, MD

Anna L. Chien, MD

George Cotsarelis, MD

Assistant Professor, Division of Dermatology, University of Washington School of Medicine, Seattle, WA [151] Assistant Professor, Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD [217]

Mary-Margaret Chren, MD Professor, Department of Dermatology, University of California, San Francisco, San Francisco, CA [1]

David H. Chu, MD, PhD

Division of Dermatology and Cutaneous Surgery, Scripps Clinic Medical Group, La Jolla, CA [7]

Mon-Li Chu, PhD

Professor, Department of Dermatology & Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA [63]

Clinical Associate Professor, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX [155, 156] Professor, Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA [86]

Pierre A. Coulombe, PhD

E.V. McCollum Professor and Chair, Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD [46]

Edward W. Cowen, MD, MHSc

Head, Dermatology Consultation Service, Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD [28]

Joseph Craft, MD

Chief, Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD [193]

Paul B. Beeson Professor of Medicine and Professor of Immunobiology, Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, CT [154]

Myron S. Cohen, MD

Noah Craft, MD, PhD, DTMH

Philip R. Cohen, MD

Donna A. Culton, MD, PhD

Chris D. Collins, MD, FAAD

Jennifer S. Daly, MD

Jeffrey I. Cohen, MD

Associate Vice Chancellor and Professor of Medicine, Microbiology and Immunology, Departments of Medicine and Epidemiology, University of North Carolina, Chapel Hill, NC [180] Clinical Associate Professor, Department of Dermatology, MD Anderson Cancer Center, University of Texas, Houston, TX [32] Professor of Clinical Dermatology US Army & Air Force Dermatology Brooke Army Medical Center, Wilford Hall Medical Center San Antonio, TX [22]

Nneka I. Comfere, MD

Assistant Professor, Department of Medicine, Divisions of Dermatology and Adult Infectious Disease, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA [175, 176] Resident Physician, Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC [56] Professor, Department of Medicine, University of Massachusetts Medical School, Worcester, MA [209]

F. William Danby, MD, FRCPC, FAAD

Assistant Professor, Department of Dermatology, Mayo Clinic College of Medicine, Rochester, MN [165]

Adjunct Assistant Professor, Department of Surgery (Section of Dermatology), Dartmouth Medical School, Hanover, NH [78]

Rosamaria Corona, DSc, MD

Stamatina Danielides, MD

Attending Physician, Division of Immunodermatology, Istituto Dermopatico dell’Immacolata, Rome, Italy [2]

Contributors

Postdoctoral Research Fellow, Section of Dermatology, DartmouthHitchcock Medical Center, Dartmouth Medical School, Lebanon, NH [13]

Andy J. Chien, MD, PhD

Sjögren’s Syndrome Clinic Gene Therapy and Therapeutics Branch, National Institute of Dental and Craniofacial Research National Institutes of Health Bethesda, MD [161]

xix

Mazen S. Daoud, MD

Christine A. DeWitt, MD

Daniel B. Eisen, MD

Thomas N. Darling, MD, PhD

Luis A. Diaz, MD

Myrna El Shareef, MD

Alan Dattner, MD

John J. DiGiovanna, MD

James T. Elder, MD, PhD

Private Practice, Dermatology and Dermatopathology, Advanced Dermatology Specialties, Fort Myers, FL [26, 27] Associate Professor, Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, MD [140]

Contributors

Chief Scientific Officer, Founder and CEO, www.holisticdermatology.com, New York, NY [241]

Sofie De Schepper, MD, PhD Professor, Department of Dermatology, Ghent University Hospital, Ghent, Belgium [75]

Aieska De Souza, MD, MS

Dermatopharmacology Fellow, Department of Dermatology, New York University Langone Medical Center, New York, NY [214, 220]

Steven M. Dean, DO, FACP, RPVI

Associate Professor of Internal Medicine, Department of Cardiovascular Medicine, The Ohio State University College of Medicine, Columbus, OH [173]

Roy H. Decker, MD, PhD

Assistant Professor, Department of Therapeutic Radiology, Yale School of Medicine, Yale University, New Haven, CT [240]

Nicole M. DeLauro, DPM

Associate Physician, Podiatric Medicine and Surgery, Foot and Ankle Center of New Jersey, Plainfield, NJ [98]

Thomas M. DeLauro, DPM

Professor, Departments of Medicine and Surgery, New York College of Podiatric Medicine, New York, NY [98]

Christopher P. Denton, PhD, FRCP

Professor of Experimental Rheumatology, Centre for Rheumatology, University College London, London, UK [157]

Theresa Schroeder Devere, MD

Assistant Professor, Department of Dermatology, Oregon Health & Science University, Portland, OR [168]

xx

Assistant Professor, Division of Dermatology, Georgetown University Hospital, Washington, DC [153] Professor and Chairman, Department of Dermatology, University of North Carolina, Chapel Hill, NC [56] Staff Clinician, DNA Repair Section, Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD [49, 139]

Andrzej A. Dlugosz, MD

Poth Professor of Cutaneous Oncology, Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI [111]

Lisa M. Donofrio, MD

Associate Clinical Professor, Department of Dermatology, Yale School of Medicine, Yale University, New Haven, CT [254]

Daven N. Doshi, MD

Resident, Department of Dermatology, Albert Einstein College of Medicine, Bronx, NY [16]

Karynne O. Duncan, MD

Private Practice, Saint Helena, CA [113]

Jonathan A. Dyer, MD

Assistant Professor, Departments of Dermatology and Child Health, School of Medicine, University of Missouri, Columbia, MO [137]

Robert T. Eberhardt, MD, FACC, FSVM, RPVI Associate Professor, Department of Medicine, Boston University School of Medicine, Boston, MA [173]

Benjamin D. Ehst, MD, PhD

Assistant Professor, Department of Dermatology, Oregon Health & Science University, Portland, OR [29]

Lawrence F. Eichenfield, MD

Professor, Departments of Pediatrics and Medicine (Dermatology), University of California, San Diego, San Diego, CA [14]

Associate Clinical Professor, Dermatology, University of California, Davis, Sacramento, CA [187] Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon [204] Professor, Department of Dermatology, University of Michigan Medical School, Ann Arbor, MI [18]

Craig A. Elmets, MD

Professor and Chair, Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL [237]

Dirk M. Elston, MD

Director, Department of Dermatology, Geisinger Medical Center, Danville, PA [99, 231]

Joseph C. English, MD

Associate Professor, Department of Dermatology, University of Pittsburgh, Pittsburgh, PA [181]

Edward M. Esparza, MD, PhD

Resident, Division of Dermatology, University of Washington, Seattle, WA [221]

Janet A. Fairley, MD

Professor and Head, Department of Dermatology, University of Iowa, Iowa City, IA [138]

Vincent Falanga, MD, FACP

Professor, Departments of Dermatology and Biochemistry, Boston University School of Medicine, Boston, MA [248]

Robert D. Fealey, MD

Consultant, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN [84]

Flavia Fedeles, MD, MS

Intern, Internal Medicine, Hospital of St Raphael, New Haven, CT [23]

Laura Korb Ferris, MD, PhD

Assistant Professor, Department of Dermatology, School of Medicine, University of Pittsburgh, Pittsburgh, PA [181]

Patricia M. Fishman, MD

Assistant Professor, Department of Pathology, University of Illinois at Chicago, Chicago, IL [70]

James E. Fitzpatrick, MD

Professor and Vice Chair, Department of Dermatology, University of Colorado, Denver, CO [219, 227]

Philip Fleckman, MD

Professor, Medicine (Dermatology), University of Washington, Seattle, WA [49]

Senior Lecturer (Associate Professor) and Honorary Consultant Dermatologist, St John’s Institute of Dermatology, St Thomas’s Hospital and King’s College London, London, UK [4]

Camille Francès, MD

Professor, Department of Dermatology-Allergology, Hôpital Tenon, Paris, France [159]

Jorge Frank, MD, PhD

Professor, Department of Dermatology, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands [132]

Ilona J. Frieden, MD

Associate Staff Physician, Department of Dermatology, Cleveland Clinic, Cleveland, OH [230]

Anthony A. Gaspari, MD

Shapiro Professor, Department of Dermatology, University of Maryland School of Medicine, Baltimore, MD [226]

John K. Geisse, MD

Clinical Professor, Department of Dermatology, University of California, San Francisco, San Francisco, CA [113]

Joel M. Gelfand, MD, MSCE

Assistant Professor of Dermatology and Epidemiology, Departments of Dermatology, Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA [234]

Carlo Gelmetti, MD

Full Professor, Department of Anesthesia, Intensive Care and Dermatologic Sciences, Università degli Studi di Milano, Milano, Italy [147, 148]

Roy G. Geronemus, MD

Director, Dermatology, Laser & Skin Surgery Center of New York, New York, NY [252]

Adam B. Glick, PhD

Associate Professor, Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Department of Dermatology, Hershey Medical Center, The Pennsylvania State University, University Park, PA [111]

Richard G. Glogau, MD

Clinical Professor, Department of Dermatology, University of California, San Francisco, San Francisco, CA [255]

Raphaela Goldbach-Mansky, MD, MHS

Acting Chief, National Institute of Arthritis and Musculoskeletal and Skin Diseases Intramural Research Program, Translational Autoinflammatory Disease Section, The National Institutes of Health, Bethesda, MD [134]

Leonard H. Goldberg, MD, FRCP

Medical Director, DermSurgery Associates, PA, Houston, TX [246]

Emmy M. Graber, MD

Assistant Professor of Dermatology, Department of Dermatology, Boston University Medical Center, Boston, MA [80]

Samer H. Ghosn, MD

Robin A.C. Graham-Brown, BSc, MB, FRCP, FRCPCH

Professor, Departments of Pediatrics and Medicine (Dermatology), School of Medicine, University of California, San Diego, San Diego, CA [195]

Lawrence E. Gibson, MD

Jane Margaret Grant-Kels, MD

Ramsay L. Fuleihan, MD

Associate Professor, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL [143]

Chair Emerita and Professor of Dermatology, Department of Dermatology, Boston University School of Medicine, Boston, MA [9, 109]

Abhimanyu Garg, MD

Dafna D. Gladman, MD, FRCPC

Professor, Department of Dermatology and Pediatrics, School of Medicine, University of California, San Francisco, San Francisco, CA [126]

Sheila Fallon Friedlander, MD

Professor, Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX [71]

Amit Garg, MD

Associate Professor, Department of Dermatology, Boston University School of Medicine, Boston, MA [5, 188, 189]

Assistant Professor, Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon [201, 203, 206] Professor, Department of Dermatology, Mayo Clinic College of Medicine, Rochester, MN [165]

Barbara A. Gilchrest, MD

Professor, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto, ON, Canada [19]

Gerald J. Gleich, MD

Professor of Dermatology and Medicine, Department of Dermatology, School of Medicine, University of Utah, Salt Lake City, UT [31]

Contributors

Carsten Flohr, BM, BCh (Hons), MA, Mphil, MRCPCH, MSc, PhD

Christopher C. Gasbarre, DO, FAAD

Consultant Dermatologist, Department of Dermatology, University Hospitals of Leicester, Leicester, UK [150] Professor and Chair, Department of Dermatology, University of Connecticut Health Center, Farmington, CT [23]

Justin J. Green, MD

Department of Dermatology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Wood Johnson Medical School, Camden, NJ [199]

Roy C. Grekin, MD

Professor, Department of Dermatology, University of California, San Francisco School of Medicine, San Francisco, CA [121]

James M. Grichnik, MD, PhD Professor, Department of Dermatology, Miller School of Medicine, Miami, FL [122, 123]

xxi

Douglas Grossman, MD, PhD

Associate Professor, Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, UT [114]

Johann E. Gudjonsson, MD, PhD

Assistant Professor, Department of Dermatology, University of Michigan, Ann Arbor, MI [18]

Bridget C. Hackett, MB BCh, BAO, MRCPI Contributors

Department of Dermatology, Mater Misericordiae University Hospital, Dublin, Ireland [33]

Russell P. Hall III, MD

J Lamar Callaway Professor and Chair, Department of Dermatology, Duke University Medical Center, Durham, NC [58, 61, 225]

Analisa V. Halpern, MD

Chung-Hong Hu, MD

Warren R. Heymann, MD

Linden Hu, MD

Professor, Hautzentrum Prof. Hengge, Düesseldorf, NRW, Germany [65]

Professor of Medicine and Pediatrics, Head, Division of Dermatology, Robert Wood Johnson Medical School at Camden, University of Medicine & Dentistry of New Jersey, Camden, NJ [199]

Whitney A. High, MD, JD, MEng Associate Professor, Department of Dermatology, University of Colorado Denver Health Sciences Center, Denver, CO [219, 227]

Chad Hivnor, MD

Associate Program Director, San Antonio Uniformed Services Health Education Consortium, San Antonio, TX [22]

Assistant Professor, Department of Medicine, Division of Dermatology, Cooper University Hospital, Rowan University, Camden, NJ [199]

Jonathan Hofmekler, BSc

C. William Hanke, MD, MPH, FACP

Ulrich Hohenleutner, MD

Visiting Professor of Dermatology, University of Iowa Carver College of Medicine, Iowa City, IA [253]

Christopher B. Hansen, MD

Assistant Professor, Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT [156]

Philip N. Hawkins, PhD, FRCP, FRCPath, FMedSci

Professor of Medicine, Centre for Amyloidosis and Acute Phase Proteins, University College London Medical School, London, UK [133]

Roderick J. Hay, DM, FRCP, FRCPath, FMedSci

Chairman, International Foundation for Dermatology, London, UK [3, 190]

Adelaide A. Hebert, MD

Professor, Department of Dermatology, University of Texas Medical School at Houston, Houston, TX [84]

Stephen E. Helms, MD

Associate Professor, Department of Medicine, Northeastern Ohio Universities College of Medicine, Rootstown, OH [68]

xxii

Ulrich R. Hengge, MD, MBA

Associate Researcher, Department of Dermatology, School of Medicine, Emory University, Atlanta, GA [235] Professor, Klinik und Poliklinik für Dermatologie, Universitätsklinikum Regensburg, Regensburg, Germany [239]

Steven M. Holland, MD

Chief, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD [30]

Golara Honari, MD

Attending Physician, Dermatology and Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, [211]

Herbert Hönigsmann, MD

Professor of Dermatology, Emeritus Chairman, Department of Dermatology, Medical University of Vienna, Vienna, Austria [32, 35, 238]

Thomas J. Hornyak, MD, PhD

Investigator, Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD [73]

Alain Hovnanian, MD, PhD Departments of Genetics and Dermatology, University René Descartes, Paris, France [51]

Department of Dermatology University of Wisconsin Madison, WI [25] Associate Professor, Department of Medicine, School of Medicine, Tufts University, Boston, MA [187]

Sam T. Hwang, MD, PhD

Chair and Professor, Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI [12]

Sherrif F. Ibrahim, MD, PhD

Procedural Dermatology Fellow, Department of Dermatology, University of California, San Francisco, San Francisco, CA [121]

Gabor Illei, MD, PhD, MHS

Head, Sjögren’s Syndrome Clinic, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD [161]

Alan D. Irvine, MD, FRCP, FRCPI

Consultant Dermatologist, Paediatric Dermatology, Our Lady’s Children’s Hospital, Dublin, Ireland [52]

Rim S. Ishak, MD

Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon [203]

Peter H. Itin, MD

Professor, Department of Dermatology, School of Medicine, University of Basel, Basel, Switzerland [131]

Satori Iwamoto, MD, PhD

Assistant Professor, Department of Dermatology and Skin Surgery, Boston University School of Medicine, Boston, MA [248]

Reza Jacob, MD

Resident, Department of Dermatology, Boston University School of Medicine, Boston, MA [232]

Heidi T. Jacobe, MD, MSCS

Assistant Professor, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX [64]

William D. James, MD

Paul R. Gross Professor, Department of Dermatology, School of Medicine, University of Pennsylvania, Philadelphia, PA [218]

Melinda Jen, MD

Pediatric Dermatology Fellow, Division of Pediatric and Adolescent Dermatology, Rady Children’s Hospital, University of California, San Diego, San Diego, CA [130]

Jens-Michael Jensen, MD

Department of Dermatology, Venereology and Allergy, University of Kiel, Kiel, Germany [47]

Richard Allen Johnson, MDCM

Timothy M. Johnson, MD

Professor, Department of Dermatology, University of Michigan, Ann Arbor, MI [124]

Graham A. Johnston, MBChB, FRCP

Consultant, Department of Dermatology, Leicester Royal Infirmary, Leicester, Leicestershire, UK [150]

Marc A. Judson, MD

Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Medical University of South Carolina, Charleston, SC [152]

Andrea A. Kalus, MD

Assistant Professor, Division of Dermatology, University of Washington School of Medicine, Seattle, WA [151]

Insoo Kang, MD

Associate Professor of Medicine, Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, CT [154]

Sewon Kang, MD

Noxell Professor and Chairman, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD [217]

Allen P. Kaplan, MD

Clinical Professor, Department of Medicine, Medical University of South Carolina, Charleston, SC [38]

Julie K. Karen, MD

Clinical Assistant Professor, Department of Dermatology, New York University Langone School of Medicine, New York, NY [108]

STD Control Officer and Senior Physician, Health and Human Services Agency, County of San Diego, San Diego, CA [200, 222]

Stephen I. Katz, MD, PhD

Fellow, American Academy of Dermatology, Schaumburg, IL; Past President, Society of Investigative Dermatology, Cleveland, OH; Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD [61]

Masaoki Kawasumi, MD, PhD

Department of Medicine, Division of Dermatology, University of Washington, Seattle, WA [112]

Dean L. Kellogg, Jr., MD, PhD

Professor, Department of Medicine, University of Texas Health Science Center, San Antonio, TX [93]

Francisco A. Kerdel, MD

Robert Knobler, MD

Associate Professor, Department of Dermatology, Medical University of Vienna, Vienna, Austria [238]

Sandra R. Knowles, BScPhm

Lecturer, Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada [41]

Christine J. Ko, MD

Associate Professor, Department of Dermatology, Yale School of Medicine, Yale University, New Haven, CT [66]

Manuel Koch, PhD

Associate Professor, Institute for Oral and Musculoskeletal Biology, Medical Faculty, Center for Dental Medicine, University of Cologne, Cologne, Germany [63]

Irene E. Kochevar, PhD

Professor, Department of Dermatology, Harvard Medical School, Boston, MA [90]

Director, Dermatology Inpatient Unit, Department of Dermatology, University of Miami Hospital, Miami, FL [216]

Nellie Konnikov, MD

Helmut Kerl, MD

Sandra A. Kopp, MD

Jay S. Keystone, MD, MSc(CTM), FRCPC

Kenneth H. Kraemer, MD

Professor of Dermatology, Chairman Emeritus, Department of Dermatology, Medical University of Graz, Graz, Austria [117]

Professor, Department of Medicine, University of Toronto, Toronto, ON, Canada [207]

Abdul-Ghani Kibbi, MD, FAAD, FACP

Professor and Chair, Department of Dermatology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon [6, 204]

Alexa B. Kimball, MD, MPH

Professor, Department of Dermatology, Boston University School of Medicine, Boston, MA [232] Resident Physician, Department of Dermatology, Robert Wood Johnson Medical School at Camden, University of Medicine & Dentistry of New Jersey, Camden, NJ [199] Chief, DNA Repair Section, Dermatology Branch, National Cancer Institute, Bethesda, MD [110, 139]

T. Krieg, MD

Department of Dermatology, University of Cologne, Cologne, Germany [63, 157]

Jean Krutmann, MD

Associate Professor, Department of Dermatology, Harvard Medical School, Boston, MA [16]

Univ.- Professor Dr. med., Institut für Umweltmedizinische Forschung (IUF), Düsseldorf, NRW, Germany [90]

Reinhard Kirnbauer, MD

Roopal V. Kundu, MD

Associate Professor, Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases (DIAID), Medical University of Vienna, Vienna, Austria [196]

John H. Klippel, MD

President and Chief Executive Officer, Arthritis Foundation, Atlanta, GA [170]

Contributors

Assistant Professor, Department of Dermatology, Harvard Medical School, Boston, MA [105, 178, 179, 198]

Kenneth A. Katz, MD, MSc, MSCE

Assistant Professor, Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL [189]

Thomas S. Kupper, MD, FAAD Thomas B. Fitzpatrick Professor, Department of Dermatology, Harvard Medical School, Boston, MA [11]

xxiii

Razelle Kurzrock, MD, FACP

Chair and Professor, Investigational Cancer Therapeutics, MD Anderson Cancer Center, University of Texas, Houston, TX [32]

Helen J. Lachmann, MD, FRCP

Senior Lecturer/Honorary Consultant, National Amyloidosis Centre, University College London Medical School, London, UK [133]

Jeffrey N. Lackey, MD Contributors

Staff Dermatologist, Kimbrough Ambulatory Care Center, Fort George G. Meade, MD [213]

Jürgen Lademann, Prof. Dr. rer. nat. Dr.-Ing. habil.

Department of Dermatology, Center of Experimental and Applied Cutaneous Physiology (CCP), Charité - Universitätsmedizin Berlin, Berlin, Germany [215]

Jeffrey R. LaDuca, MD, PhD Reflections Dermatology, Skaneateles, NY [226]

Jo Lambert, MD, PhD

Professor, Department of Dermatology, Ghent University Hospital, Ghent, Belgium [75]

Michael Landthaler, MD

Department of Dermatology, University of Regensburg, Regensburg, Germany [239]

Sinéad M. Langan, MRCP, MSc, PhD

Visiting Scholar, Department of Dermatology, University of Pennsylvania, Philadelphia, PA [4]

Hilde Lapeere, MD, PhD

Department of Dermatology, University Hospital Ghent, Ghent, Belgium [75]

Anne Laumann, MBChB, MRCP(UK), FAAD

Associate Professor of Dermatology, Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL [101]

Stephan Lautenschlager, MD

Associate Professor, Outpatient Clinic of Dermatology & Venereology, City Hospital Triemli, Zürich, Switzerland [202]

Leslie P. Lawley, MD

xxiv

Assistant Professor of Dermatology and Pediatrics, Department of Dermatology, School of Medicine, Emory University, Atlanta, GA [82]

Chyi-Chia Richard Lee, MD, PhD Staff Clinician, Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD [134]

Delphine J. Lee, MD, PhD, FAAD

Dirks/Dougherty Laboratory for Cancer Research, Director, Department of Translational Immunology, John Wayne Cancer Institute, Santa Monica, CA [186]

Ken K. Lee, MD

Associate Professor, Department of Dermatology, Director of Dermatologic Surgery, Oregon Health and Science University, Portland, OR [118]

Lela A. Lee, MD

Professor, Departments of Dermatology and Medicine, School of Medicine, University of Colorado Denver, Denver, CO [37]

David J. Leffell, MD

David Paige Smith Professor of Dermatology and Surgery, Chief, Section of Dermatologic Surgery and Cutaneous Oncology Department of Dermatology, Yale School of Medicine, Yale University, New Haven, CT [113, 114, 115]

Kristin M. Leiferman, MD

Professor, Department of Dermatology, University of Utah, Salt Lake City, UT [31, 36]

Yolanda M. Lenzy, MD, MPH Clinical Dermatologist, Family Dermatology of Massachusetts, Brookline, MA [9]

Aimee L. Leonard, MD

Private Practice, New England Dermatology & Laser Center, Springfield, MA [253]

Donald Y.M. Leung, MD, PhD

Professor, Department of Pediatrics, School of Medicine, University of Colorado Denver, Denver, CO [14]

Nikki A. Levin, MD, PhD

Associate Professor, Department of Medicine, Division of Dermatology, University of Massachusetts Medical School, Worcester, MA [5]

Ross M. Levy, MD

Attending Physician, Division of Dermatology, North Shore University Health System, Skokie, IL [127]

Bernadette Liegl-Atzwanger, MD

Institute of Pathology, Medical University Graz, Graz, Austria [125]

Henry W. Lim, MD

Chairman and C.S. Livingood Chair, Department of Dermatology, Henry Ford Hospital, Detroit, MI [92, 223]

Dan Lipsker, MD, PhD

Professor, Department of Dermatology, Université de Strasbourg, Faculté de Médecine, Strasbourg, France [171]

Adam D. Lipworth, MD

Instructor, Department of Dermatology, Harvard Medical School, Harvard University, Boston, MA [178, 179]

Robert Listernick, MD

Professor, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL [141]

Rosemarie Liu, MD

Private Practice Skin, Cancer Surgery Center Fairfax, VA [25]

Zhi Liu, PhD

Professor, Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC [56]

Robert Loewe, MD

Associate Professor, Department of Dermatology, Medical University of Vienna, Vienna, Austria [162]

Anke S. Lonsdorf, MD

Department of Dermatology, University Hospital of Heidelberg, Heidelberg, Germany [12]

Mayra E. Lorenzo, MD, PhD Instructor, Department of Dermatology, Harvard Medical School, Boston, MA [192]

Thomas A. Luger, MD

Professor and Chairman, Department of Dermatology, University of Münster, Münster, Germany [102]

Calum C. Lyon, MA, FRCP

Department of Dermatology, York Hospital, York, North Yorkshire, UK [96, 97]

Catherine Maari, MD

Susannah E. McClain, MD

Daniel Mimouni, MD

Vandana Madkan, MD

John A. McGrath, MD, FRCP

Julia S. Minocha, MD

Meera Mahalingam, MD, PhD, FRCPath

W. H. Irwin McLean, FRSE, FMedSci

Paradi Mirmirani, MD

Assistant Professor, Department of dermatology, University of Montreal, Montreal, QC, Canada [67] Dermatologist, Center for Clinical Studies, Dermatological Association of Texas, Houston, TX [191]

Joelle M. Malek, MD

Chief Resident, Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon [206]

Richard M. Marchell, MD

Assistant Professor, Department of Dermatology, Medical University of South Carolina, Charleston, SC [152]

Lynette J. Margesson, MD, FRCPC

Assistant Professor of Obstetrics and Gynecology and Medicine (Dermatology), Section of Dermatology, Department of Obstetrics and Gynecology, Dartmouth Medical School, Hanover, NH [78]

M. Peter Marinkovich, MD

Associate Professor, Department of Dermatology, Stanford University School of Medicine, Stanford, CA [62]

Adriana R. Marques, MD

National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD [193]

Nadine Marrouche, MD

Department of Dermatology, American University of Beirut Medical Center, Beirut, Lebanon [201]

Erin F. Mathes, MD

Department of Dermatology, University of California, San Francisco, San Francisco, CA [126]

Theodora M. Mauro, MD

Service Chief, Dermatology, San Francisco VA Medical Center, San Francisco, CA [83]

Professor, St John’s Institute of Dermatology, Guy’s Campus, King’s College London, London, UK [8]

Dermatology and Genetic Medicine University of Dundee, Dundee, UK [8]

Darius R. Mehregan, MD

Associate Professor and Hermann Pinkus Chair, Department of Dermatology, Wayne State University, Detroit, MI [34]

David A. Mehregan, MD

Associate Professor, Department of Dermatology, School of Medicine, Wayne State University, Detroit, MI [34]

Atul B. Mehta, MD, FRCP, FRCPath

Professor, Department of Haematology, Royal Free Hospital, University College London School of Medicine, London, UK [136]

Natalia Mendoza, MD, MS

Assistant Professor, Department of Research and Dermatology, Universidad El Bosque, Bogotá, Colombia [191]

Peter A. Merkel, MD, MPH

Senior Lecturer, Department of Dermatology, Beilinson Campus, Rabin Medical Center, Petah-Tikva, Israel [55] Clinical Research Fellow, Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL [69] Department of Dermatology, The Permanente Medical Group, Vallejo, CA [87]

Robert L. Modlin, MD

Klein Professor of Dermatology, and Professor of Microbiology, Immunology and Molecular Genetics, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA [10, 186]

P. Moinzadeh, MD

Department of Dermatology, University of Cologne, Cologne, Germany [157]

Paul A. Monach, MD, PhD

Assistant Professor, Department of Medicine, Section of Rheumatology, Vasculitis Center, Boston University School of Medicine, Boston, MA [164]

Megan M. Moore, MD

Department of Dermatology, The Permanente Medical Group, Walnut Creek, CA [220]

Professor of Medicine, Section of Rheumatology, Clinical Epidemiology Unit, Boston University School of Medicine, Boston, MA [164]

Rebecca J. Morris, PhD

Martin C. Mihm, MD, FACP

L. Katie Morrison, MD

Director, Melanoma Program in Dermatology, Department of Dermatology, Brigham and Women’s Hospital, Boston, MA [6, 124]

Lloyd S. Miller, MD, PhD

Assistant Professor, Division of Dermatology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA [10]

Stanley J. Miller, MD

Associate Professor, Departments of Dermatology and OtolaryngologyHead and Neck Surgery, Johns Hopkins Hospital, Baltimore, MD [46]

Contributors

Professor of Dermatology and Pathology and Laboratory Medicine, Dermatopathology Section, Department of Dermatology, Boston University School of Medicine, Boston, MA [187]

Resident, Department of Dermatology, University of Maryland Medical System, Baltimore, MD [226]

Professor, Laboratory of Stem Cells and Cancer, The Hormel Institute, University of Minnesota, Austin, MN [45] Department of Dermatology, University of Texas Health Sciences Center, Houston, TX [191]

Nico Mousdicas, MBChB, MD

Associate Professor, Department of Dermatology, Indiana University, Indianapolis, IN [177]

Ulrich Mrowietz, MD

Associate Professor, Psoriasis Center, Department of Dermatology, Campus Kiel, University Medical Center Schleswig-Holstein, Kiel, Germany [21]

xxv

Colin S. Munro, MD, FRCP (Glasg)

Katia Ongenae, MD, PhD

George F. Murphy, MD

Grainne M. O’Regan, MRCPI

Professor, Alan Lyell Centre for Dermatology, Southern General Hospital, Glasgow, UK [50]

Professor of Pathology, Harvard Medical School Director, Program in Dermatopathology, Brigham and Women’s Hospital, Boston MA [6]

Haley Naik, MD Contributors

Department of Dermatology, Massachusetts General Hospital, Boston, MA [105]

Amanda M. Nelson, PhD

Department of Dermatology, College of Medicine, The Pennsylvania State University, Hershey, PA [79]

Isaac M. Neuhaus, MD

Assistant Professor, Department of Dermatology, University of California, San Francisco, San Francisco, CA [121]

Paul Nghiem, MD, PhD

Associate Professor, Departments of Medicine and Dermatology, University of Washington, Seattle, WA [112, 120]

Gerhard J. Nohynek, PhD, DABT

Scientific Director, Worldwide Safety Department, L’Oreal R&D, Asnières, France [215]

David A. Norris, MD

Professor and Chairman, Department of Dermatology, School of Medicine, University of Colorado Denver, Denver, CO [74]

Scott A. Norton, MD, MPH, MSc

Professor of Dermatology, Division of Dermatology, Department of Medicine, Georgetown University Hospital, Washington, DC [183, 213]

Lillian Odo, MD

Associate Professor, Department of Dermatology, University of Santo Amaro, São Paulo, SP, Brazil [100]

John E. Olerud, MD

Professor, Medicine, Division of Dermatology, University of Washington, Seattle, WA [151]

xxvi

Professor, Department of Dermatology, University Hospital Ghent, Ghent, Belgium [75] Department of Paediatric Dermatology, Our Lady’s Children’s Hospital, Dublin, Ireland [52]

Anthony E. Oro, MD, PhD

Andrea L. Pearson, MD

Resident Physician, Department of Dermatology, University of Massachusetts Medical School, Worcester, MA [192]

Michelle T. Pelle, MD

Attending Physician, Department of Medicine, Scripps Mercy Hospital, San Diego, CA [81]

Associate Professor, Program in Epithelial Biology, School of Medicine, Stanford University, Stanford, CA [116]

Brent E. Pennington, MD

Catherine H. Orteu, MBBS, BSc, MD, FRCP

Department of Dermatology, Mayo Clinic, Rochester, MN [36]

Consultant Dermatologist, Department of Dermatology, Royal Free Hospital, London, UK [136]

Nina Otberg, MD

Hair Clinic, Skin and Laser Center Berlin, Potsdam, Germany [88]

Michael N. Oxman, MD

Professor of Medicine and Pathology, University Of California, San Diego, San Diego, CA [194]

Amy S. Paller, MD

Walter J. Hamlin Professor and Chair of Dermatology, Professor of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL [143]

Hee-Young Park, PhD

Associate Professor, Department of Dermatology, Boston University School of Medicine, Boston, MA [72]

Sareeta R.S. Parker, MD

Associate Clinical Professor, Department of Dermatology, School of Medicine, Emory University, Atlanta, GA [82]

Nashville Skin & Cancer, Nashville, TN [242]

Margot S. Peters, MD

Julia S. Pettersen, MD

Department of Dermatology, Yale School of Medicine New Haven, CT [115]

Peter Petzelbauer, MD

Professor of Microvascular Research, Department of Dermatology, Medical University of Vienna, Vienna, Austria [162]

Tania J. Phillips, MD, FRCP, FRCPC

Professor of Dermatology, Department of Dermatology, Boston University School of Medicine, Boston, MA [100]

Gérald E. Piérard, MD, PhD

Chief, Dermatopathology Service, Department of Dermatology, University Hospital of Liège, Liège, Belgium [94]

Claudine Piérard-Franchimont, MD, PhD

Professor, Department of Dermatopathology, University Hospital of Liège, Liège, Belgium [94]

Anisha B. Patel, MD

Warren W. Piette, MD

Tejesh S. Patel, MBBS (Lon), BSc (Hons)

Caroline Piggott, MD

Resident, Department of Dermatology, Oregon Health & Science University, Portland, OR [168]

Dermatology Resident, Department of Medicine, Division of Dermatology, University of Tennessee Health Science Center, Memphis, TN [103]

Aimee S. Payne, MD, PhD

Assistant Professor, Department of Dermatology, University of Pennsylvania, Philadelphia, PA [53, 54]

Chair, Division of Dermatology, John H. Stroger Jr. Hospital of Cook County, Chicago, IL [144, 160] Resident, Department of Dermatology, University of California, San Diego, San Diego, CA [195]

Bianca Maria Piraccini, MD, PhD

Researcher, Department of Dermatology, University of Bologna, Bologna, Italy [89]

Mark R. Pittelkow, MD

Professor, Departments of Dermatology and Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Medical School, Rochester, MN [26, 27, 158]

Jordan S. Pober, MD, PhD

Professor and Vice Chair, Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT [162]

Brian P. Pollack, MD, PhD

Miriam Keltz Pomeranz, MD

Assistant Professor, Department of Dermatology, Duke University, Durham, NC [58]

Thomas H. Rea, MD

Emeritus Professor, Department of Dermatology, Keck School of Medicine, University of Southern California, Los Angeles, CA [186]

Kavitha K. Reddy, MD

Resident, Department of Dermatology, Boston University School of Medicine, Boston, MA [9]

Thomas E. Redelmeier, MD

Dermatology Department Charite Hospital/Humboldt University, Berlin, Berlin, Germany [215]

Jean-Claude Roujeau, MD Department of Dermatology Hôpital Henri Mondor Université Paris XII Créteil Paris, France [39, 40]

Anne H. Rowley, MD

Professor, Departments of Pediatrics, and Microbiology— Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL [167]

Thomas M. Rünger, MD, PhD Professor of Dermatology and Pathology, Department of Dermatology, Boston University School of Medicine, Boston, MA [110, 139]

William A. Rutala, BS, MS, PhD, MPH

Clinical Assistant Professor, Department of Dermatology, New York University School of Medicine, New York, NY [108]

Arthur R. Rhodes, MD, MPH

Frank C. Powell, FRCPI, FAAD

Stephen K. Richardson, MD

Thomas Ruzicka, Prof. Dr. med. Dr. h.c.

Evan Rieder, MD

Arturo P. Saavedra, MD, PhD, MBA

Associate Professor, Department of Dermatology, University College Dublin, Dublin, Ireland [33]

Julie Powell, MD, FRCPC

Associate Clinical Professor, and Director of Pediatric Dermatology, Department of Pediatrics, Division of Dermatology, CHU Sainte-Justine University of Montreal, Montreal, QC, Canada [67]

Jennifer G. Powers, MD

Resident, Department of Dermatology, Boston University School of Medicine, Boston, MA [100]

Julie S. Prendiville, MB, FRCPC Clinical Professor, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada [44]

Howard B. Pride, MD

Associate, Departments of Dermatology and Pediatrics, Geisinger Medical Center, Danville, PA [106]

Ehrhardt Proksch, MD, PhD

Professor, Department of Dermatology, University of Kiel, Kiel, Germany [47]

Pascale Quatresooz, MD, PhD

Lecturer Senior Registrar, Department of Dermatopathology, University Hospital of Liège, Liège, Belgium [94]

Professor, Department of Dermatology, Rush Medical College, Rush University, Chicago, IL [122] Clinical Assistant Professor, Department of Dermatology, Florida State College of Medicine, Tallahassee, FL [234] Department of Psychiatry, New York University School of Medicine, New York, NY [104]

Maureen Rogers, MBBS, FACD

Professor, Department of Medicine, University of North Carolina, Chapel Hill, NC [180]

Head and Professor, Department of Dermatolgy and Allergology, Ludwig Maximilian University, Munich, Germany [24]

Assistant Professor, Department of Dermatology, Harvard Medical School, Boston, MA [178, 179, 198]

Emeritus Consultant, Department of Dermatology, Royal Alexandra Hospital for Children, Sydney, Australia [87]

Joni G. Sago, MD

Thomas E. Rohrer, MD

Director, Lipid Clinic, Heart Institute (InCor), University of São Paulo Medical School Hospital, São Paulo, Brazil [135]

Clinical Associate Professor of Dermatology, Brown University, Alpert School of Medicine, Providence, RI [243]

Arash Ronaghy, MD, PhD

Dermatology Associates of Kingsport, Kingsport, TN [225]

Raul D. Santos, MD, PhD

Jean-Hilaire Saurat, MD

Research Associate, Department of Dermatology, Duke University, Durham, NC [61]

Professor, Swiss Center for Human Applied Toxicology, University Medical Center, Geneva, Switzerland [228]

Ted Rosen, MD

Stephanie Saxton-Daniels, MD

Marti J. Rothe, MD

Ernst J. Schaefer, MD

Professor, Department of Dermatology, Baylor College of Medicine, Houston, TX [205] Associate Professor of Dermatology, Department of Dermatology, University of Connecticut Health Center, Farmington, CT [23]

Contributors

Assistant Professor of Dermatology and Pathology/Laboratory Medicine, Emory University, Winship Cancer Institute and the Atlanta VA Medical Center, Atlanta, GA [237]

Caroline L. Rao, MD

Department of Dermatology, The University of Texas Southwestern Medical Center, Dallas, TX [64]

Senior Scientist and Director Lipid Metabolism Laboratory Jean Mayer USDA HNRCA at Tufts University, Boston, MA [135]

xxvii

Hans Schaefer, PhD

Professor, Retired [215]

Mark Jordan Scharf, MD

Clinical Professor of Medicine, Division of Dermatology, University of Massachusetts Medical School, Worcester, MA [209]

Stefan M. Schieke, MD

Robert L. Sheridan, MD

Associate Professor, Department of Surgery, Harvard Medical School, Boston, MA [95]

Jeff K. Shornick, MD, MHA Private Practice [59]

Robert Sidbury, MD, MPH

Department of Dermatology, Boston University School of Medicine, Boston, MA [188]

Associate Professor, Department of Pediatrics, Division of Dermatology, Seattle Children’s Hospital, Seattle, WA [221]

Bethanee J. Schlosser, MD, PhD

Nicholas R. Snavely, MD

Contributors

Assistant Professor, Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL [69]

Kenneth E. Schmader, MD

Professor and Chief, Department of Medicine-Geriatrics, Division of Geriatrics, Duke University Medical School, Durham, NC [194]

Holger Schmid, MD, MSc PD

Department of Internal Medicine, Ludwig Maximilian University, Munich, Germany [169]

Steven K. Schmitt, MD

Head, Section of Bone and Joint Infections, Department of Infectious Disease, Cleveland Clinic, Cleveland, OH [230]

Department of Dermatology Oregon Health & Science University Portland, OR [118]

Arthur J. Sober, MD

Professor, Department of Dermatology, Harvard Medical School, Boston, MA [122, 124]

Richard D. Sontheimer, MD

Professor, Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT [155, 156]

Apra Sood, MD

Associate Staff, Department of Dermatology, Cleveland Clinic, Cleveland, OH [48, 211, 212]

Nicholas A. Soter, MD

Professor and Head, Department of Dermatology, New Jersey Medical School, Newark, NJ [210]

Professor of Dermatology, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY [163]

Aisha Sethi, MD

Richard A. Spritz, MD

Robert A. Schwartz, MD, MPH

Assistant Professor, Department of Dermatology, University of Chicago, Chicago, IL [184]

Jerry Shapiro, MD, FRCPC, FAAD

Clinical Professor, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, Canada [88]

Neil H. Shear, MD, FRCPC

Professor, Department of Dermatology & Pharmacology, University of Toronto, Toronto, ON, Canada [41]

Jessica M. Sheehan, MD

Mohs Surgeon and Dermatologist, Northshore Center for Medical Aesthetics, Northbrook, IL [243]

Director, Human Medical Genetics Program, School of Medicine, University of Colorado Denver, Aurora, CO [74]

Divya Srivastava, MD

Assistant Professor, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX [119]

John R. Stanley, MD

Professor, Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA [54]

William G. Stebbins, MD

Department of Dermatology, Laser and Skin Surgery Center of Indiana, Carmel, IN [253]

Christopher J. Steen, MD

xxviii

Private Practice, Portland, ME [210]

Martin Steinhoff, MD, PhD Full Professor, Department of Dermatology, University of California, San Francisco, San Francisco, CA [102]

Wolfram Sterry, Prof. Dr.

Professor and Chairman, Department of Dermatology, Venereology and Allergology, Charité Universitätsmedizin Berlin, Berlin, Germany [145]

Georg Stingl, MD

Professor, Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Vienna, Austria [10]

Stephen P. Stone, MD

Professor, Division of Dermatology, Southern Illinois University School of Medicine, Springfield, IL [153]

Bruce E. Strober, MD, PhD

Assistant Professor, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY [214, 220]

Kathryn N. Suh, MD

Assistant Professor, Medicine and Pediatrics, University of Ottawa, Ottawa, ON, Canada [207]

Tung-Tien Sun, PhD

Professor, Departments of Cell Biology, Pharmacology and Urology, School of Medicine, New York University, New York, NY [46]

Neil A. Swanson, MD

Professor and Chair, Department of Dermatology, Oregon Health and Science University Portland, OR [118]

Susan M. Sweeney, MD

Assistant Professor, Division of Dermatology, University of Massachusetts Medical School, Worcester, MA [192]

Virginia P. Sybert, MD

Clinical Professor, Department of Medicine, Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA [142]

Rolf-Markus Szeimies, MD, PhD Professor and Chairman, Department of Dermatology and Allergology, Klinikum Vest Academic Teaching Hospital, Recklinghausen, Germany [238]

Moyses Szklo, MD, MPH, DrPH Professor, Departments of Epidemiology and Medicine, Johns Hopkins Schools of Public Health and Medicine, Baltimore, MD [2]

Jean Y. Tang, MD, PhD

Assistant Professor, Dermatology, Stanford University, Redwood City, CA [116]

Elizabeth L. Tanzi, MD

Co-Director, Washington Institute of Dermatologic Laser Surgery, Washington, DC [251] Professor, Department of Dermatology, University of Rochester, Rochester, NY [104]

Charles R. Taylor, MD

Associate Professor, Department of Dermatology, Harvard Medical School, Boston, MA [90]

James S. Taylor, MD, FAAD

Consultant Dermatologist, Department of Dermatology, Dermatology and Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH [48, 211, 212]

R. Stan Taylor, MD

Professor, Department of Dermatology, University of Texas Southwestern, Dallas, TX [119]

Andrew R. Tegeder, MS

Division of Dermatology, University of Washington School of Medicine, Seattle, WA [120]

Michael D. Tharp, MD

The Clark W. Finnerud, MD Professor and Chair, Department of Dermatology, Rush University Medical Center, Chicago, IL [149]

Diane M. Thiboutot, MD

Professor, Department of Dermatology, College of Medicine, The Pennsylvania State University, Hershey, PA [79, 80]

Bruce H. Thiers, MD

Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, SC [152]

Valencia D. Thomas, MD

Assistant Professor, Department of Dermatology, Section of Dermatologic Surgery & Cutaneous Oncology, Yale University School of Medicine, New Haven, CT [118]

Assistant Professor, Departments of Pediatrics and Medicine (Dermatology), University of California, San Diego, San Diego, CA [195]

Kenneth J. Tomecki, MD

Lily Changchien Uihlein, MD, JD

Resident, Department of Dermatology, Harvard Medical School, Boston, MA [198]

Jouni Uitto, MD, PhD

Vice Chairman, Department of Dermatology, Cleveland Clinic, Cleveland, OH [230]

Professor and Chair, Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, PA [63]

Antonella Tosti, MD

Mark A. Unger, MD, CCFP

Professor, Department of Dermatology & Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL [89]

Franz Trautinger, MD

Professor and Head, Department of Dermatology and Venereology, Landesklinikum St. Poelten St. Poelten, Austria [35]

Jeffrey B. Travers, MD, PhD

Professor of Dermatology, Pharmacology and Toxicology, Departments of Dermatology, Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN [177]

Hensin Tsao, MD, PhD

Associate Professor, Department of Dermatology, Harvard Medical School, Boston, MA [124]

Fragkiski Tsatsou, MD, MSc, BSc

Dermatology Resident, Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany [85]

Erwin Tschachler, MD

Private Practice, Toronto, ON, Canada [256]

Robin H. Unger, MD

Clinical Professor, Department of Dermatology, Mount Sinai School of Medicine, New York, NY [256]

Walter P. Unger, MD

Clinical Professor, Department of Dermatology, Mt. Sinai School of Medicine, New York, NY [256]

Anders Vahlquist, MD, PhD

Professor, Department of Medical Sciences, Uppsala University, Uppsala, Sweden [228]

Isabel C. Valencia, MD

Dermatopathology, Dermpath Diagnostics Bay Area, Tampa, FL [216]

L. Valeyrie-Allanore, MD

Department of Dermatology, Université Paris XII, Cedex, France [40]

Nanja van Geel, MD, PhD

Professor, Department of Dermatology, Ghent University Hospital, Ghent, Belgium [75]

Professor of Dermatology and Venereology, Department of Dermatology, Medical University of Vienna, Vienna, Austria [128, 197]

Mireille Van Gele, PhD

Margaret A. Tucker, MD

Maurice A.M. van Steensel, MD, PhD

Director, Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD [123]

Department of Dermatology, Ghent University Hospital, Ghent, Belgium [75]

Professor, Dermatology, Maastricht University Medical Center, Maastricht, The Netherlands [50]

Stephen Tyring, MD, PhD

Travis W. Vandergriff, MD

Selma Ugurel, MD

Evelien Verhaeghe, MD

Clinical Professor, Department of Dermatology, University of Texas Health Science Center, Houston, TX [191] Professor, Department of Dermatology, University of Würzburg, Würzburg, Germany [125]

Contributors

Francisco A. Tausk, MD

Wynnis Tom, MD

Chief Resident, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX [91] Department of Dermatology, Ghent University Hospital, Ghent, Belgium [75]

xxix

Miikka Vikkula, MD, PhD

Lucile E. White, MD

Sophie M. Worobec, MD, FAAD

John J. Voorhees, MD, FRCP

Hywel C. Williams, MSc, PhD, FRCP

Mina Yaar, MD

Maitre de Recherces du F.N.R.S. Human Molecular Genetics (GEHU) Christian de Duve Institute, Université catholique de Louvain, Brussels, Belgium [172] Professor, Department of Dermatology, University of Michigan, Ann Arbor, MI [217]

Justin J. Vujevich, MD Contributors

Director, Mohs Surgery, Vujevich Dermatology Associates, PC, Pittsburgh, PA [246]

Daniel Wallach, MD

Senior Lecturer, Department of Dermatology, Hôpital TarnierCochin, Paris, France [33]

David J. Weber, MD, MPH

Professor of Medicine, Pediatrics, and Epidemiology, University of North Carolina, Chapel Hill, NC [180]

Roger H. Weenig, MD, MPH Adjunct Assistant Professor, Department of Dermatology, University of Minnesota, Minneapolis, MN [158]

Arnold N. Weinberg, MD

Professor, Infectious Disease Unit, Department of Medicine, Harvard Medical School, Boston, MA [178, 179]

Martin A. Weinstock, MD, PhD Professor, Departments of Dermatology and Community Health, Brown University, Providence, RI [1]

Elliot T. Weiss, MD

Laser & Skin Surgery Center of New York, New York and Southampton, NY [252]

Margaret A. Weiss, MD

Department of Dermatology Johns Hopkins University School of Medicine, Baltimore, MD [249]

Robert A. Weiss, MD

Professor of Dermato-Epidemiology, Centre of Evidence-Based Dermatology, University of Nottingham, Nottingham, UK [4]

Ifor R. Williams, MD, PhD

Associate Professor, Department of Pathology, School of Medicine, Emory University, Atlanta, GA [11]

Lynn D. Wilson, MD, MPH

Professor, Vice Chairman and Clinical Director, Therapeutic Radiology, Yale School of medicine, Yale University, New Haven, CT [240]

Karen Wiss, MD

Professor, Department of Medicine (Dermatology) and Pediatrics, University of Massachusetts Medical School, Worcester, MA [192]

Klaus Wolff, MD, FRCP

Professor of Dermatology, Chairman Emeritus, Department of Dermatology, Medical University of Vienna, Vienna, Austria [6]

Stephen E. Wolverton, MD

Theodore Arlook Professor of Clinical Dermatology, Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN [236]

Sook-Bin Woo, DMD

Associate Professor, Department of Oral Medicine, Infection and Immunology, Harvard School of Dental Medicine, Boston, MA [76]

Gary S. Wood, MD

Johnson Professor and Chairman, Department of Dermatology, University of Wisconsin School of Medicine and Public Health, Madison, WI [25, 146]

Associate Professor, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD [249]

Robert A. Wood, MD

Victoria P. Werth, MD

David T. Woodley, MD

Professor, Department of Dermatology, University of Pennsylvania School of Medicine, Philadelphia, PA [224]

xxx

Pearland Dermatology and DermSurgery Associates, The Methodist Hospital, Houston, TX [127]

Professor, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD [229] Professor, Department of Dermatology, The Keck School of Medicine, University of Southern California, Los Angeles, CA [60]

Associate Professor, Department of Dermatology, Chicago School of Medicine, University of Illinois, Chicago, IL [70] Professor, Department of Dermatology, Boston University School of Medicine, Boston, MA [72, 109]

Albert C. Yan, MD

Associate Professor, Departments of Pediatrics and Dermatology, School of Medicine, University of Pennsylvania, Philadelphia, PA [130]

Kim B. Yancey, MD

Professor and Chair, Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX [57]

Gil Yosipovitch, MD

Professor, Department of Dermatology, Wake Forest University School of Medicine, Winston Salem, NC [103]

Andrea L. Zaenglein, MD

Associate Professor, Departments of Dermatology and Pediatrics, Penn State Milton S. Hershey Medical Center, Hershey, PA [80]

Mozheh Zamiri, BSc (Hons), MBChB, MRCP, MD

Specialist Registrar, Alan Lyell Centre for Dermatology, Southern General Hospital, Glasgow, Scotland [50]

Christos C. Zouboulis, MD, PhD

Professor and Director, Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Dessau, Germany [85, 166]

Kathryn A. Zug, MD

Professor, Section of Dermatology, Dartmouth Medical School, Hanover, NH [13]

Melanie Kingsley, MD

Assistant Professor of Dermatology, Director of Cosmetic Dermatology and Laser Surgery, Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN [243]

PREFACE

New knowledge drives medical progress and improves patient care. The rapid growth of this knowledge in skin diseases and skin biology makes publication of the eighth edition of Fitzpatrick’s Dermatology in General Medicine (DIGM) particularly timely. Forty years ago, the first edition of “Fitz” was a critical textbook devoted to providing a comprehensive knowledge of dermatology. The relevance of dermatology to general medicine and the basic science foundations of the specialty were defining elements of the new text. This edition, more than ever, reinforces those earlier goals and is designed to be easily accessible to those interested in the clinical and basic science of dermatology. This reference text also highlights the relevance of dermatology to general internal medicine and other disciplines of medicine and surgery. It is written for experienced clinicians and skin biologists worldwide as well as for those in training. The online edition adds further textual and illustrative detail to almost all chapters and provides extensive and robust literature citations, many with online links, which are especially useful for those who seek an in-depth understanding of a particular topic. The accompanying CD-ROM contains the figures from the print edition in an easily downloaded format for slide production. Because of the explosion of new knowledge relevant to dermatology and cutaneous biology, chapters have been extensively revised and new chapters have been

added on global dermatologic health, ethnic, and racial considerations for normal and diseased skin, and stem cell science. Medical and surgical therapeutics sections have been greatly expanded to reflect the increased importance of procedural dermatology. Twenty percent of the chapters have new authorship, drawing from expertise around the world. These authors provide new perspectives and guarantee that the content of the book remains fresh and vital. Schematic diagrams of clinical and basic science mechanisms and clinical care algorithms have been revised to allow rapid intuitive guidance while retaining accuracy and critical detail. This edition is enhanced with additional clinical figures and new tables that permit a “quick look” at key points in each chapter. Finally, the Parts of the book are designated with different colors, thus allowing the reader to easily find sections of interest. Validated, well-synthesized, and critically interpreted information is essential to improve the care of patients, to prevent skin disease, and to advance cutaneous biology. The current editors of DIGM have striven to fulfill these goals of the original text. Lowell A. Goldsmith Stephen I. Katz Barbara A. Gilchrest Amy S. Paller David J. Leffell Klaus Wolff

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ACKNOWLEDGMENTS

We thank and salute the nearly 500 authors who contributed to the creation of this new and vibrant eighth edition of Fitzpatrick’s Dermatology in General Medicine (DIGM). The eighth edition of this classic text reflects the amazing growth in new knowledge in basic and clinical sciences related to the skin and to its relationship with other organ systems. The authors have worked assiduously to integrate this new information within the context of established knowledge. The authors, all respected experts in their disciplines, wrote some of the most extensively referenced chapters available either in print or online. We are deeply grateful to them and their staff for their commitment to this text. Their expertise has created chapters that continue to define the comprehensiveness of this textbook. We are deeply grateful to our families, who appreciated the importance and immensity of our task. They recognized and accepted that editing this textbook demanded many hours of time and evenings spent with a computer screen rather than with them. We thank them for their support during this all-consuming effort. The editors were supported by talented and dedicated staff, Renate Kosma, Jacy Bernal, Jaime Zagami, Nilda Reyes, and Grace Camire, each of whom handled the

correspondence with over 50 authors. The debt that we owe to these individuals cannot be calculated. Many readers of previous editions and dermatology residents from several training programs painstakingly reviewed and critiqued the seventh edition and provided extremely useful advice on improving the content and the presentation for this new edition. The staff at McGraw-Hill Medical made this text their highest priority. They were led by our ever vigilant and talented editor, Anne M. Sydor, and our project manager for manuscript production and completion, Sarah M. Granlund; and a most professional production team led by Robert Pancotti and Sherri Souffrance in New York and by Sandhya Joshi in India. A major hallmark and the fresh look for this eighth edition are the hundreds of new figures that required meticulous attention by authors and a creative design and art team at Dragonfly Media Group. For their talented and effective partnership we are forever grateful.

Lowell A. Goldsmith Stephen I. Katz Barbara A. Gilchrest Amy S. Paller David J. Leffell Klaus Wolff

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Introduction

PA RT

General Considerations

Chapter 1 :: T  he Epidemiology and Burden of Skin Disease :: Martin A. Weinstock & Mary-Margaret Chren Scientists in health-related fields focus on phenomena at different levels. For laboratory scientists, the focus is at the molecular, cellular, or organ system level; for clinical scientists, the focus is on the patient; and for public health practitioners, the focus is on the population. Epidemiology is the basic science of public health. Epidemiology has many subdivisions and offshoots. Often the epidemiology of a disease in a clinical review refers primarily to its frequency and distribution in the population and estimates of its morbidity and mortality. These data are derived by descriptive epidemiology. Case-control, cohort, and cross-sectional studies may seek to identify risk factors and causes of disease and form the core of analytical epidemiology. Evaluations of public health interventions (experimental epidemiology) constitute the third major branch of classic epidemiology. The basic principles of epidemiology have found broad application in many areas, including understanding the public health implications of naturally occurring and synthetic compounds (molecular epidemiology), the complex interactions of genetic and environmental factors in disease (genetic epidemiology), the formulation of better diagnostic and treatment strategies for patients based on available evidence (clinical epidemiology), and the structuring of health care delivery for better outcomes and greater efficiency (health services research). The reader is referred to other sources for a more detailed discussion of various topics in dermatoepidemiology.1–3

TYPES OF EPIDEMIOLOGIC STUDIES Three of the many types of epidemiologic studies are mentioned here because of their prominence in epidemiologic research. The randomized, controlled trial is a particularly rigorous type of study appropriate to the evaluation of public health interventions. In general, the intervention is performed on a random sample of the study population, and the entire study population is then observed for the occurrence of the outcome in question. The random assignment of intervention allows the more rigorous application of many statistical techniques and reduces the potential for bias. Elimination of biases permits these studies to evaluate the efficacy and impact of an intervention more accurately than trials that do not assign the intervention randomly. Standards for reporting have been published4 (http://www.consort-statement.org, accessed Jul 7, 2010) and adopted by leading dermatology journals to improve assessment of their validity and their use in subsequent systematic reviews5 (see Chapter 2). When evaluating risk factors for disease, it is frequently impossible to assign the risk factor randomly. Hence, inference is based on observational studies. In classical cohort studies, a group with exposure to the risk factor and a group without are chosen and observed over time. Occurrences of the study outcome

1

1

Section 1 :: General Considerations

2

are counted and compared between groups. Although more vulnerable to bias than randomized trials, cohort studies, in which exposure to the risk factor is known well before the study outcome is knowable, avoid some potentially serious biases. In a cohort study, the incidence of the study outcome can be measured directly in each group, and the relative risk can be measured directly as the ratio of the incidence between the two groups. Cohort studies often are quite expensive to conduct because they require following a large population over time and may be impossible if the outcome being studied is uncommon. Hence, observational studies often use the case-control approach, in which cases with the outcome being studied and appropriate controls are investigated to determine their past exposure to the risk factor. Relative risks can be estimated by this approach, although incidence of the disorder cannot. Readers are referred to standard texts for more detail regarding epidemiologic study designs.6 Case-control and cohort study methods in dermatology also have been reviewed.7–9

BIAS AND CONFOUNDING The problem with inference from observational studies is that one may be led to draw erroneous conclusions. In particular, an association that is found between an exposure and a disease may be an artifact due to one or more of the many forms of bias or confounding. Proper inference regarding cause and effect requires understanding these possible artifacts and their potential impacts.10 Selection bias occurs when factors that lead to selection of the study population affect the likelihood of the outcomes or exposures evaluated. For example, a casecontrol study of cutaneous lymphoma may recruit its cases from sources that typically include a high proportion of referred patients. If controls are recruited from a local clinic population, their socioeconomic status and location of residence may be substantially different from those of the cases simply due to the method of recruitment. Under these circumstances, an association of cutaneous lymphoma with occupation may be noted. It then becomes important to note that the observed association may be due not to a carcinogenic chemical in the workplace but rather to the method by which cases and controls were selected. Similarly, if one were conducting a cohort study of the effect of breast-feeding on the risk of atopic dermatitis, it would be important to select breast-fed and bottle-fed infants from similar environments. Information bias occurs when the assessment of exposure or outcome may differ between the groups being compared. People who were exposed to a publicized environmental toxin may be more likely to seek care for minor symptoms or signs (and hence be more likely to be diagnosed and treated) than those who were not so exposed, even if the exposure had no biologic effect. Similarly, people who are diagnosed with a disease may be more likely to recall past exposures than healthy controls.

Confounding occurs when an observed association (or lack thereof) between exposure and disease is due to the influence of a third factor on both the exposure and the disease. For example, people who use sunscreens may have more intense sun exposure than those who do not, and intense sun exposure is one cause of melanoma. Hence, observational studies may mistakenly conclude that sunscreen use is a cause of melanoma when the observed association is due to sunscreen use serving as an indicator of a lifestyle involving intense sun exposure.

CAUSAL INFERENCE Key issues in the public health arena often must rely on observational data for inferring cause and effect; in these situations, the validity and generalizability of the individual studies and of the totality of the evidence must be carefully examined. The following criteria generally are applied for causal inference when an association is found. Although they are described for inferring causality between an exposure and a disease, they are more generally applicable to epidemiologic causal inference.

TIME SEQUENCE The exposure must precede the disease. This concept is simple and obvious in the abstract but sometimes difficult to establish in practice because the onset of disease may precede the diagnosis of disease by years, and the timing of exposure is often not well defined.

CONSISTENCY ON REPLICATION Replication of the observed association is key and provides the strongest evidence if the replications are many and diverse and with consistent results. The diversity of the replications refers to varied contexts as well as to study designs with different potential weaknesses and strengths.

STRENGTH OF ASSOCIATION True causal relationships may be strong (i.e., high relative risk) or weak, but artifactual associations are unlikely to have a high relative risk. If the association between factors x and y is due to the association of both with confounding variable z, the magnitude of the association between x and y always will be less than the magnitude of the association of either with z.

GRADED ASSOCIATION Also described as biologic gradient, this criterion refers to an association of the degree of exposure with occurrence of disease, in addition to an overall association of presence of exposure with disease. This dose-response relation may take many forms, as degree of exposure

may, for example, refer to intensity, duration, frequency, or latency of exposure.

COHERENCE

INVESTIGATION OF DISEASE OUTBREAKS Although outbreaks of disease vary tremendously, use of a standard framework for investigation is important to address the public health issues efficiently (see Chapter 4). The Centers for Disease Control and Prevention has outlined this framework as a series of ten steps, which are described in more detail at http:// www.cdc.gov. 1. Preparation. Before initiating fieldwork,

background information on the disease must be gathered, and appropriate interinstitutional and interpersonal contacts should be made. 2. Confirm the outbreak. Publicity, population changes, or other circumstances may lead to an inaccurate perception that more cases than expected have occurred. Hence, local or regional data should be sought to confirm the existence of an increased frequency of disease. 3. Confirm the diagnosis. Symptoms and signs of persons affected should be determined and laboratory findings confirmed, perhaps with the assistance of reference laboratories. 4. Establish a case definition, and find cases. Careful epidemiologic investigation will involve precise and simple case definitions that can be applied in the field. Efforts to find and count additional

DESCRIPTIONS OF DISEASE IN POPULATIONS: MEASURES OF DISEASE BURDEN

The Epidemiology and Burden of Skin Disease

Experimental support is critical when feasible. As noted in Section “Types of Epidemiologic Studies,” the strongest inferences derive from results of randomized trials, although other experimental designs and quasiexperimental designs may contribute useful evidence. More detailed discussions of these issues are available.11,12

::

EXPERIMENT

1

Chapter 1

Coherence refers to plausibility based on evidence other than the existence of an association between this exposure and this disease in epidemiologic studies. Coherence with existing epidemiologic knowledge of the disease in question (e.g., other risk factors for the disease and population trends in its occurrence) and other disorders (including but not limited to related disorders) supports inference. Coherence with existing knowledge from other fields, particularly those relevant to pathogenesis, is critically important when those fields are well developed. It may involve direct links, which are preferred, or analogy. Just as observations in the laboratory assume greater significance when their relevance is supported by epidemiologic data, the reverse is equally true.

cases beyond those reported initially are key to defining the scope of the outbreak. 5. Establish the descriptive epidemiology. The cases can now be characterized in terms of time, including development of an epidemic curve that describes the changes in magnitude of the outbreak; place, including mapping the distribution of cases; and person, the demographic and potential exposure characteristics of cases. 6. Develop hypotheses. On the basis of the data gathered in steps 1 through 5 and the input of other individuals, plausible hypotheses about causality can be developed for further evaluation. 7. Conduct analytical epidemiologic investigations. If the data gathered do not yet clearly prove a hypothesis, cohort and case-control investigations can be conducted to verify or disprove the hypotheses. 8. Revise hypotheses and obtain additional evidence as needed. Steps 6 and 7 are repeated, each building on prior iterations, to establish the causal chain of events. 9. Implement control measures. As soon as the causal chain of events is understood, prevention and control measures are initiated. 10. Communicate results. An outbreak investigation is not complete until the results have been appropriately communicated to the relevant communities.

No single number can completely describe the burden of skin disease because that burden has many dimensions and because the term skin disease itself is rather ambiguous. Many disorders with substantial morbidity or mortality, such as melanoma or lupus erythematosus, affect multiple organ systems. The degree of skin involvement may vary widely from patient to patient and within the same patient from time to time. Diseases not typically treated by dermatologists, such as thermal burns, often are excluded from estimates of the burden of skin disease even though they primarily involve the skin. In addition, some diseases treated most often by dermatologists may be classified in a different category by funding agencies or others [e.g., melanoma is classified as an oncologic disorder as opposed to a disease of the skin by the National Institutes of Health and by the International Classification of Diseases, (http://www.who.int/classifications/apps/ icd/icd10online/, accessed Jul 7, 2010) even though it almost always arises in the skin]. Organ systems are interrelated, and the overlap is sufficiently great that any definition of skin disease is necessarily arbitrary, and any global estimate of the public health burden of these diseases is therefore open to challenge. Typical

3

1

measures of disease burden are discussed in the following sections.

MORTALITY

Section 1 :: General Considerations

Mortality is a critical measure of disease impact. Death certification is universal in the United States, and the International Classification of Diseases code of the underlying cause of each death is recorded. For the year 2006, there were 16,163 deaths reported as due to “skin disease” in the United States, of which most were due to melanoma (Table 1-1). Additional major causes included other skin cancers (primarily keratinocyte carcinomas), infections of the skin, and skin ulcers (primarily decubitus ulcers). Bullous disorders represented less than 2% of these deaths. The total number of skin disease deaths, of course, depends critically on the definition of skin disease, as noted in Section “Descriptions of Disease in Populations: Measures of Disease Burden.” In addition to the total number of deaths, mortality typically is expressed as an age-adjusted rate to facilitate comparisons among populations with different age distributions. Statements of age-adjusted rates of mortality (or other results standardized by age) should be accompanied by an indication of the standard used in the adjustment to avoid potentially misleading inferences. For example, when 1998 melanoma mortality rates are estimated using the 2000 US population standard, the result is 50% higher than when the 1940 US standard population is used (1.8 vs. 1.2 per 100,000 per year for women and 4.1 vs. 2.7 per 100,000 per year for men). Similarly, when years of potential life lost are reported, the reader must be wary of different definitions that may be applied. In one analysis, a decline in years lost from melanoma was noted by one definition that was not observed with another.13

TABLE 1-1

Skin Disease Deaths, United States, 2006 Disease

Deaths (n)

Cancers   Melanoma   Genital   Lymphoma   Other cancers

12,301 8,441 1,126 91a 2,643a (primarily basal and squamous cell carcinoma)

Ulcers

1,496

Infections

1,793

Bullous disorders

269

Other causes

304

Total a

4

16,163

We estimate that approximately one-half of keratinocyte carcinoma deaths are misclassified squamous cell carcinomas arising from mucosal surfaces in the head and neck16 and that cutaneous lymphoma deaths are underestimated by a factor of 2 (see text). [Adapted from http://wonder.cdc.gov/ (verified Apr 27, 2010).]

Careful analyses of mortality include assessment of the validity of the data. Melanoma mortality statistics appear to be reasonably accurate.14,15 However, deaths from keratinocyte carcinomas are overestimated by a factor of 2 (mostly due to the erroneous inclusion of mucosal squamous cell carcinomas of the head and neck region),16,17 and conventional estimates of deaths from cutaneous lymphoma miss about half of the actual deaths.18

INCIDENCE Incidence refers to the number of new cases of a disorder. Mortality is low for most skin diseases; hence, incidence may be a more useful measure for the assessment of burden of skin disease. However, many features of skin diseases make their incidence difficult to measure. For example, for many skin disorders, there are no diagnostic laboratory tests, and, in fact, some disorders may evade physician diagnosis (e.g., allergic reactions). Incidence for reportable communicable diseases in the United States is published periodically based on reports to health departments, although underreporting of skin diseases due to failure to present for medical care or to misdiagnosis is a concern (Table 1-2). Incidences of melanoma and cutaneous lymphoma have been published based on data from a system of nationwide cancer registries, yet underreporting remains a potential concern with these data.19,20 Special surveys have been conducted and administrative datasets analyzed to estimate incidence of other disorders, such as keratinocyte carcinomas, although a system of sentinel registries would improve nationwide assessment.21,22 For some diseases unlikely to evade medical detection due to their severity, such as toxic epidermal necrolysis, efforts to estimate incidence have met with considerable success.23,24 Specific contexts that permit more accurate incidence estimates include the workplace; for example, where occupational skin disease is a prevalent problem.25

COHORT PATTERNS Cohort patterns of changes in mortality or incidence typically are observed when exposures determined in childhood predict frequency of disease throughout the life span. A classic example is melanoma mortality, for which sun exposure in childhood is an important determinant. A birth cohort is defined as the group of individuals born within a defined (e.g., 10-year) period. Melanoma mortality generally increases as a power function of age within a birth cohort. Until recent decades, each successive birth cohort had higher risk than its predecessor; hence, the curves of mortality versus age were shifted upward. Thus, the crosssectional relationship of mortality versus age and the increase in mortality risk during most of the twentieth century followed a cohort pattern. For many countries in the past several decades a decline in melanoma mortality has been observed in younger age groups

1

TABLE 1-2

New Cases of Selected Reportable Diseases in the United States 1940

1950

1960

1970

1980

—

—

Anthrax

76

49

23

2

Congenital rubella

—

—

—

77

Congenital syphilis

—

—

—

—

Diphtheria

15,536

5,796

918

Gonorrhea

175,841

286,746

0

44

— 291,162

Hansen disease Lyme disease Measles

—

41,595

40,758

39,202

1

0

1

0

50

11

9

0

—

3,865

529

227

435

3

4

1

0

258,933

600,072

1,004,029

690,169

358,995

229,315

54

129

223

198

91

72

—

—

—

—

—

17,730

26,739

319,124

441,703

47,351

13,506

27,786

86

132

1

3

2

13

18

2

6

1

457

464

204

380

1,163

651

495

2,276

Syphilis (primary and secondary)

—

23,939

16,145

21,982

27,204

50,223

5,979

12,195

Toxic shock syndrome

—

—

—

—

—

322

135

66

102,984c

121,742c

55,494

37,137

27,749

25,701

16,377

9,795

132

151

179

203

227

249

281

304

Rocky Mountain spotted fever

Tuberculosisb US population (millions) a

NA = data not available. Reporting criteria changed in 1975. c Data include newly reported active and inactive cases. Adapted from Weinstock MA, Boyle MM: Statistics of interest to the dermatologist. In: The Year Book of Dermatology and Dermatologic Surgery, 2009, edited by B Theirs, PG Lang. Philadelphia, Elsevier Mosby, 2009, p. 53-68. b

despite an increase in older age groups, suggesting a lower baseline in these mortality-versus-age curves for recent cohorts and hence a likely future decline in overall melanoma mortality.

PREVALENCE Prevalence refers to the proportion of the population affected by a disorder. Because many skin diseases are nonlethal yet chronic, prevalence is a particularly important measure of frequency in dermatology. Population-based data on prevalence of skin disease for the United States were obtained in the first Health and Nutrition Examination Survey, which was conducted in the early 1970s.26 Despite its limitations, this study was notable because the sample was representative of the general US population, the number surveyed was large (over 20,000), and the entire surveyed population was examined by physicians (primarily dermatology residents), so the resulting estimates were not dependent on patients’ ability or inclination to seek medical care. Indeed, one of the findings of the survey was that nearly one-third of those examined

The Epidemiology and Burden of Skin Disease

Plague

—

2008

::

NAa

2000

Chapter 1

Acquired immunodeficiency syndrome

1990

had one or more skin conditions judged to be significant enough to merit a visit to a physician. The most common conditions and their age- and gender-specific prevalence are indicated in Table 1-3 and Fig. 1-1. A similar survey in the United Kingdom of over 2,000 Londoners in 1975 noted that almost one-quarter of adults had a skin condition serious enough to warrant medical care.27 Other efforts have focused on obtaining prevalence estimates of specific conditions with special surveys.28,29

LIFETIME RISK Lifetime risks for certain disorders are quoted commonly, although their validity can be questioned. Lifetime risk can be measured only in retrospect, and even then it reflects competing causes of mortality in addition to incidence. It is commonly quoted for disorders such as cutaneous malignancies that are changing substantially in incidence, yet those changes are frequently ignored in its calculation, and, in any case, projections of future changes are quite speculative and may be misleading.30

5

1

Prevalence rates for the four leading types of significant skin pathology

TABLE 1-3

Prevalence of Skin Conditions—United States, 1971–1974a

Section 1 ::

Female

Dermatophytosis

131

34

81

Acne (vulgaris and cystic)

  74

66

70

Seborrheic dermatitis

  30

26

28

Atopic dermatitis/eczema

  20

18

19

Verruca vulgaris

  9

 6

 8

Malignant tumors

  6

 5

 6

Psoriasis

  6

 5

 6

Vitiligo

  6

 4

 5

Herpes simplex

  4

 5

 4

General Considerations

a

Cases per 1,000 population. From Skin conditions and related need for medical care among persons 1–74 years, United States, 1971–1974. Vital Health Stat [11], No. 212, US Department of Health, Education, and Welfare, November 1978.

NUMBER OF PHYSICIAN VISITS Number of physician visits for a condition is one practical measure of its frequency that may reflect its incidence, prevalence, and severity, as well as access to health care. Table 1-4 lists frequencies of dermatologist and other physician outpatient visits for some of the

Diseases of sebaceous glands Dermatophytoses

250 Rate per 1000 persons

Male

Both Sexes

300

Tumors Seborrheic dermatitis

200 150 100 50 0 10

20

30 40 Age in years

50

60

70

Figure 1-1  Prevalence rates for the four leading types of significant skin pathology among persons 1–74 years, by age, in the United States, 1971–1974. most common skin conditions. A feature of this measure of disease frequency is its direct relation to expenditures for care of the disease.

OTHER MEASURES OF MORBIDITY: CONCEPTUAL ISSUES The consequences of skin disease for a population (or the burden of disease) are complex; a practical conceptu-

TABLE 1-4

Visits to Non-Federal Office-Based Physicians in the United States, 2006a Type of Physician Diagnosis

All Physicians b

2,217 (8.8%)

Eczematous dermatitis

3,183 (12.6%)

5,377 (0.6%)

8,560 (1.0%)

Warts

1,041 (4.1%)

1,361 (0.2%)

2,401 (0.3%)

Skin cancer

2,672 (10.6%)

928 (0.1%)

3,599 (0.4%)

Fungal infections Hair disorders Actinic keratosis Benign neoplasm of the skin All disorders

692 (2.7%) b

b

1,759 (0.2%)

3,274 (0.4%)

737 (0.1%) 2,002 (0.2%)

741 (2.9%)

b

1,571 (0.2%)

2,432 (9.6%)

b

2,717 (0.3%)

1,293 (5.1%)

b

25,256 (100%)

876,698 (100%)

2,170 (0.2%) 901,954 (100%)

Estimates in thousands. Figure does not meet standard of precision. Note: Percentage of total visits is in parentheses. Adapted from Weinstock MA, Boyle MM: Statistics of interest to the dermatologist. In: The Year Book of Dermatology and Dermatologic Surgery, 2009, edited by B Theirs, PG Lang. Philadelphia, Elsevier Mosby, 2009, p. 53-68.

b

6

Other

Acne vulgaris

Psoriasis

a

Dermatologistb

Components of burden of disease

Effects on Health

Costs

Mortality

Effect on well-being

Direct

Impairment

Disability

Handicap

Indirect

Like all assays, measures of the nonfatal consequences of diseases must be accurate. For example, they must be reliable in that the variability in results among sub-

The Epidemiology and Burden of Skin Disease

OTHER MEASURES OF MORBIDITY: ISSUES IN QUANTIFICATION

A significant challenge for the development of clinimetric measures is developing a consensus among clinicians about the specific features of an individual disease that are important to include in such measures. Substantial progress in the empiric derivation of these features has been made for disease severity measures in certain skin diseases.34,35 The extent to which a specific skin disease disrupts the skin itself is related both to the percentage of body surface area involved and to physical signs of the eruption, such as the amount of induration and the degree of scale. Given the pleomorphism of skin eruptions, most dermatologic severity-of-disease measures are disease-specific, and for common skin conditions, multiple instruments are often available. Among the most studied instruments to measure clinical severity of disease are the Psoriasis Area and Severity Index (PASI)36 and the Severity Scoring of Atopic Dermatitis (SCORAD) index.37 With the PASI, severity of disease is assessed by judgment of the degree of involvement of four body regions with signs of erythema, induration, and desquamation. The SCORAD index combines an assessment of disease area with six clinical signs of disease intensity (scales to measure pruritus and sleep loss also can be included). Standardized reviews of severity measures can be helpful for informing a consensus as well as focusing futures studies; such reviews have recently been published of 20 measures of atopic dermatitis38 and 53 measures of psoriasis.39

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alization is contained in Fig. 1-2. Broadly, components of burden of skin disease are those related to effects on health or costs. Aspects of health include mortality and effects on well-being, including those related to the impairment, disability, or handicap a disease causes. For example, a patient with psoriasis may have thickening and scaling of the palms (a bodily impairment), which may cause disability (e.g., use of the hands), dysfunction (role at work), and effects on quality of life. Costs are either direct (for which funds can be paid) or indirect (for which charges are not routinely assigned, such as lost income because of disease).31 The measurement of burden of skin disease is challenging, in part because these conditions typically do not cause mortality and do not result in changes in easily measured laboratory tests. The most important gauges of skin disease status and progression (i.e., the physical examination and patients’ reports) can be difficult to measure and compile; in most cases patients’ reports of the effects of skin disease on their activities and well-being are crucial for determining the overall consequences of those diseases. The measurement challenges are heightened because people understand and value these aspects of health quite differently due to age, gender, cultural conceptions, or access to health care. The measurement of nonfatal consequences of disease is the subject of much international scientific and political attention (http://www.who.int/healthinfo/ global_burden_disease/en/, accessed Mar 5, 2010, and Chapter 3). An important point for dermatology is that patients’ experiences of illness may not be adequately assessed with global measures that focus on single aspects of health, or which were developed without substantial input from patients.32 For example, skin diseases that are visible and affect appearance may result in social stigma and mood changes, which would not be measured with metrics that are based on dysfunction.

CLINICAL SEVERITY OF DISEASE

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Chapter 1

Figure 1-2  Components of burden of disease.

jects who truly differ should be greater than the variability when a stable subject is examined repeatedly. The measures must have evidence of validity, which refers to the extent to which an instrument measures what it is supposed to measure and does not measure something else. Health outcome measures also must demonstrate responsiveness, the ability to detect clinical change. Furthermore, even when an accurate instrument exists, the clinical significance or interpretability of scores or changes in scores often cannot be judged until the tool is used widely and scores are available for many patients with disease of varying severity.33

PATIENT-REPORTED OUTCOMES As noted above, patients’ reports of their experiences of disease and health care are particularly important for assessing the course of chronic diseases (like most skin diseases). Table 1-5 includes typical aspects of patients’ experience that are measured in health care research. The effects of disease on patients’ quality of life can be assessed with generic instruments (which permit comparisons of effects in patients with different diseases), skin-specific instruments (which permit comparisons of patients with different skin diseases), and, more uncommonly, condition-specific instruments (which permit comparisons of patients with the same skin disease). Although more specific instruments may assess aspects of a disease that would be missed with

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TABLE 1-5

Typical Instruments Used to Measure Patient Reports Domain

Typical Instrument(s)

Comment

Overall quality of life

Medical Outcomes Study Short-Form instruments (SF-36)40 and (SF-12)41

36 or 12 items; commonly used in clinical research; interpretable scores

Skin-related quality of life

Dermatology Life-Quality Index42

10 items, most commonly used, focuses on functioning 29 or 16 items, focuses on emotional effects, symptoms, and functioning

Skindex-2943, Skindex-1644

Section 1

Patient-Oriented Eczema Measure (POEM)45, SelfAdministered Psoriasis Area and Severity Index (SAPASI)46

Correlate well with clinician measures

Symptoms: pruritus

Itch Severity Scale47, Pruritus-Specific Quality-of-Life Instrument48

Demonstrate promising measurement properties

Patient satisfaction

Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey49

Correlates with adherence, quality of life, and quality of care

Patient preferences

Utilities50, Willingness to Pay51

Correlations among different measures of preferences can be weak

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Disease-specific severity

General Considerations

8

generic tools, both generic and specific tools contribute unique information to a “snapshot” of a patient’s overall health-related quality of life. Substantial progress has been made in the development and testing of patients’ reports of the effects of their skin diseases on their activities and quality of life. Although quality of life is the patient-reported outcome most often measured, patients’ reports of symptoms, satisfaction with health care, and preferences for health states are other examples. Data continue to be accumulated about the performance of these instruments (including the use of sophisticated psychometric methods and the interpretation of their scores52). On a national level, to develop a core set of questions and metrics and to create item banks and repositories of items that perform well using modern analytic techniques, the National Institutes of Health has recently initiated the Patient-Reported Measurement Information System (PROMIS, http://www.nihpromis.org/). A utility is a numeric measure of the value a patient places on a given health state compared with other health states. In the measurement of utilities, a variety of procedures are used (such as visual analog scales and time tradeoff exercises) to assign a numerical value (or utility) to health states. This value reflects patients’ preferences for the health states, in which 1.0 represents perfect health and 0.0 represents death. Utilities are advantageous because they permit the incorporation of patient preferences into medical care decisions. Also, because they describe improvements in morbidity with a single weighted metric, utilities are used for the evaluation of complex tradeoffs such as the calculation of cost-effectiveness, in which the costs of treatments are compared with the values of the health states they make possible. However, utilities are controversial because they can be difficult to measure and can vary among patients in unpredictable ways. An increasing number of studies exist that formally measure utilities of patients with skin diseases.50

COSTS Costs of skin disease depend on the perspective from which they are measured, because the costs to insurers and patients may be quite different from the overall cost to society. Because most skin diseases are chronic and are cared for in the outpatient setting, estimation of both their monetary and intangible costs is difficult. Costs for individual skin conditions have been calculated53, and therapies have been evaluated in relation to their benefits and effectiveness.54 In addition, overall direct and indirect cost to payers, patients, and society of 22 skin diseases have been reported.55

QUALITY OF CARE IN DERMATOLOGY Health services research uses many scientific methods from epidemiology, clinical epidemiology, and the quantitative social sciences to study and improve the quality of health care. From the perspective of health services research, access to care, the processes involved in the provision of care, the particular therapeutic interventions, as well as patient and provider characteristics, are all determinants of the quality of care. Studies of both the effectiveness of care (i.e., outcomes of health care as it is usually practiced) and the efficacy of interventions (i.e., the results of interventions implemented in the idealized circumstances of a randomized clinical trial) are important. Many of the examples cited earlier demonstrate a sharpened focus in dermatology on accurate measurement of the clinical encounter. This capacity to measure the progress of chronic diseases and their care will permit rigorous efforts to evaluate and improve the quality of that care.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Barzilai DA et al: Dermatoepidemiology. J Am Acad Der­ matol 52:559, quiz 574, 2005 10. Sackett DL: Bias in analytic research. J Chron Dis 32:51, 1979 12. Hill AB: Environment and disease: Association or causation? Proc R Soc Med 58:295, 1965

38. Schmitt J, Langan S, Williams HC: What are the best outcome measurements for atopic eczema? A systematic review. J Allergy Clin Immunol 120(6):1389-1398, 2007 39. Spuls PI et al: How good are clinical severity and outcome measures for psoriasis?: Quantitative evaluation in a systematic review. J Invest Dermatol 130(4):933-943, 2010 52. Both H et al: Critical review of generic and dermatologyspecific health-related quality of life instruments. J Invest Dermatol 127(12):2726-2739, 2007 55. Bickers DR et al: The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol 55(3):490-500, 2006

EBM is predicated on asking clinical questions, finding the best evidence to answer the questions, critically appraising the evidence, applying the evidence to the treatment of specific patients, and saving the critically appraised evidence. The EBM approach is most appropriate for frequently encountered conditions. Results from well-designed clinical studies involving intact patients are at the pinnacle of the hierarchy of evidence used to practice EBM. Recommendations about treatment, diagnosis, and avoidance of harm should take into account the validity, magnitude of effect, precision, and applicability of the evidence on which they are based.

WHAT IS “THE BEST EVIDENCE?” The acceptance of evidence-based medicine (EBM) in the specialty of dermatology has been slow and reluctant. The term and principles are understood by few and misunderstood by many. EBM is perceived as an attempt to cut costs, impose rigid standards of

Evidence-Based Dermatology

Evidence-based medicine (EBM) is the use of the best current evidence in making decisions about the care of individual patients.

care, and restrict dermatologists’ freedom to exercise individual judgment. Practicing EBM in dermatology is hampered by the continued belief among dermatologists that clinical decisions can be guided by an understanding of the pathophysiology of disease, logic, trial and error, and nonsystematic observation.7,8 It is hampered also by a lack of sufficient data in many areas. As with EBM in general, therapy is often primarily emphasized; however, evidence-based approaches to diagnosis and avoidance or evaluation of harm are also important considerations. Practicing EBM is predicated on finding and using the best evidence. Potential sources of evidence include knowledge regarding the etiology and pathophysiology of disease, logic, personal experience, the opinions of colleagues or experts, textbooks, articles published in journals, and systematic reviews. An important principle of EBM is that the quality (strength) of evidence is based on a hierarchy. The precise hierarchy of evidence depends on the type of question being asked (Table 2-1).9 This hierarchy consists of results of welldesigned studies (especially if the studies have findings of similar magnitude and direction, and if there is statistical homogeneity among studies), results of case series, expert opinion, and personal experience, in descending order.6,8 The hierarchy was created to encourage the use of the evidence that is most likely to be accurate and useful in clinical decision-making. The ordering in this hierarchy has been widely discussed, actively debated, and sometimes hotly contested.10 A systematic review is an overview that answers a specific clinical question; contains a thorough, unbiased search of the relevant literature; uses explicit criteria for assessing studies; and provides a structured presentation of the results. A systematic review that uses quantitative methods to summarize results is a meta-analysis.11,12 A meta-analysis provides an objective and quantitative summary of evidence that is

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EVIDENCE-BASED MEDICINE AT A GLANCE

Chapter 2

Chapter 2 :: Evidence-Based Dermatology :: Michael Bigby, Rosamaria Corona, & Moyses Szklo

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Table 2-1

Grades of Evidencea,b Grade

A

Level of Evidence

Therapy/Harm

Diagnosis

1a

Systematic review (with homogeneityc) of RCTs

1b

Individual RCT (with narrow confidence intervals)

1c

All or noned

Systematic review (with homogeneity) of level 1 (see column 2) diagnostic studies, or a CPG validated on a test set. Independent blind comparison of an appropriate spectrum of consecutive patients, all of whom have been evaluated by both the diagnostic test and the reference standard. Very high sensitivity or specificity.

Section 1

2a 2b

Systematic review (with homogeneity) of cohort studies Individual cohort study [including low-quality RCT (e.g., 1.5 kilobases (kb) in size and is ideal for screening compact genes where more than one exon can be amplified together using genomic DNA as the template. All these techniques detect sequence changes such as truncating and missense mutations as well as polymorphisms; however, the protein truncation test screens only for truncating mutations and is predicted to have a sensitivity of >95% and can be used for RNA or DNA fragments in excess of 3 kb. Whichever approach is taken, having identified a difference in the patient’s DNA compared with the control sample, the next stage is to determine how this segregates within a particular family and also whether it is pathogenic or not. Very recently, great advances have been made in DNA sequencing technology, with the emergence of “next generation sequencing” (NGS) technology. Currently, it is quite feasible to carry out whole exome sequencing in an individual using NGS, i.e., sequencing of all the protein-encoding exons in the genome, in a matter of days and for only a few thousand dollars. It is expected that whole genome sequencing, at a cost of $1,000 or less will be a commonplace in 2–3 years. This incredible new technology is set to revolutionize human genetics once more, and in particular,

will facilitate identification of mutated genes in small kindreds that are not tractable by genetic linkage methods. These advances will also impact on diagnosis—in the near future it may be faster and cheaper to sequence a patient’s whole genome rather than to do targeted sequencing of specific genes or regions.

GENE MUTATIONS AND POLYMORPHISMS Within the human genome, the genetic code of two healthy individuals may show a number of sequence dissimilarities that have no relevance to disease or phenotypic traits. Such changes within the normal population are referred to as polymorphisms (Fig. 8-2). Indeed, even within the coding region of the genome, clinically irrelevant substitutions of one bp, known as SNPs, are common and occur approximately once every 250 bp.14 Oftentimes, these SNPs do not change the amino acid composition; for example, a C-to-T transition in the third position of a proline codon (CCC to CCT) still encodes for proline, and is referred to as a silent mutation. However, some SNPs do change the nature of the amino acid; for example, a C-to-G transversion at the second position of the same proline codon (CCC to CGC) changes the residue to arginine. It then becomes necessary to determine whether a missense change such as this represents a nonpathogenic polymorphism or a pathogenic mutation. Factors favoring the latter include the sequence segregating only with the disease phenotype in a particular family, the amino acid change occurring within an evolutionarily conserved residue, the substitution affecting the function of the encoded protein (size, charge, conformation, etc.), and the nucleotide switch not being detectable in at least 100 ethnically matched control chromosomes. Nonpathogenic polymorphisms do not always involve single nucleotide substitutions; occasionally, deletions and insertions may also be nonpathogenic. A mutation can be defined as a change in the chemical composition of a gene. A missense mutation changes one amino acid to another. Mutations may also be insertions or deletions of bases, the consequences of which will depend on whether this disrupts the normal reading frame of a gene or not, as well as nonsense mutations, which lead to premature termination of translation (see Fig. 8-2). For example, a single nucleotide deletion within an exon causes a shift in the reading frame, which usually leads to a downstream stop codon, thus giving a truncated protein, or often an unstable mRNA that is readily degraded by the cell. However, a deletion of three nucleotides (or multiples thereof) will not significantly perturb the overall reading frame, and the consequences will depend on the nature of what has been deleted. Nonsense mutations typically, but not exclusively, occur at CpG dinucleotides, where methylation of a cytosine nucleotide often occurs. Inherent chemical instability of this modified cytosine leads to a high rate of mutation to thymine. Where this alters the codon (e.g., from CGA to TGA), it will change an arginine residue to a stop codon. Nonsense mutations

Examples of nucleotide sequence changes

A A G G A C A G A G G C A G C

T G A G G C

B

T G A G G C

Figure 8-2  Examples of nucleotide sequence changes resulting in a polymorphism and a nonsense mutation. A. Two adjacent codons are highlighted. The AGG codon encodes arginine and the CAG codon encodes glutamine. B. The sequence shows two homozygous nucleotide substitutions. The AGG codon now reads AGT (i.e., coding for serine rather than arginine). This is a common sequence variant in the normal population and is referred to as a nonpathogenic missense polymorphism. In contrast, the glutamine codon CAG now reads TAG, which is a stop codon. This is an example of a homozygous nonsense mutation. C. This sequence is from one of the parents of the subject sequenced in B and shows heterozygosity for both the missense polymorphism AGG > AGT and the nonsense mutation CAG > TAG, indicating that this individual is a carrier of both sequence changes.

usually lead to a reduced or absent expression of the mutant allele at the mRNA and protein levels. In the heterozygous state, this may have no clinical effect [e.g., parents of individuals with Herlitz junctional EB are typically carriers of nonsense mutations in one of the laminin 332 (laminin 5) genes but have no skin fragility themselves; see Chapter 62], but a heterozygous nonsense mutation in the desmoplakin gene, for example, can result in the autosomal dominant skin disorder, striate palmoplantar keratoderma (see Chapter 50). This phenomenon is referred to as haploinsufficiency (i.e., half the normal amount of protein is insufficient for function).

Genetics in Relation to the Skin

A G G A C A G A G N N A G C

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C

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Chapter 8

A G G A C A G A G T T A G C T G A G G C

Apart from changes in the coding region that result in frameshift, missense, or nonsense mutations, approximately 15% of all mutations involve alterations in the gene sequence close to the boundaries between the introns and exons, referred to as splice site mutations. This type of mutation may abolish the usual acceptor and donor splice sites that normally splice out the introns during gene transcription. The consequences of splice site mutations are complex; sometimes they lead to skipping of the adjacent exon, and other times they result in the generation of new mRNA transcripts through utilization of cryptic splice sites within the neighboring exon or intron. Mutations within one gene do not always lead to a single inherited disorder. For example, mutations in the ERCC2 gene may lead to xeroderma pigmentosum (type D), trichothiodystrophy, or cerebrofacioskeletal syndrome, depending on the position and type of mutation. Other transacting factors may further modulate phenotypic expression. This situation is known as allelic heterogeneity. Conversely, some inherited diseases can be caused by mutations in more than one gene (e.g., non-Herlitz junctional EB; see Chapter 62) and can result from mutations in either the COL17A1, LAMA3, LAMB3, or LAMC2 genes. This is known as genetic heterogeneity. In addition, the same mutation in one particular gene may lead to a range of clinical severity in different individuals. This variability in phenotype produced by a given genotype is referred to as the expressivity. If an individual with such a genotype has no phenotypic manifestations, the disorder is said to be nonpenetrant. Variability in expression reflects the complex interplay between the mutation, modifying genes, epigenetic factors, and the environment and demonstrates that interpreting what a specific gene mutation does to an individual involves more than just detecting one bit of mutated DNA in a single gene.

MENDELIAN DISORDERS There are approximately 5,000 human single-gene disorders and, although the molecular basis of less than one-half of these has been established, understanding the pattern of inheritance is essential for counseling prospective parents about the risk of having affected children. The four main patterns of inheritance are (1) autosomal dominant, (2) autosomal recessive, (3) X-linked dominant, and (4) X-linked recessive. For individuals with an autosomal dominant disorder, one parent is affected, unless there has been a de novo mutation in a parental gamete. Males and females are affected in approximately equal numbers, and the disorder can be transmitted from generation to generation; on average, half the offspring will have the condition (Fig. 8-3). It is important to counsel affected individuals that the risk of transmitting the disorder is 50% for each of their children, and that this is not influenced by the number of previously affected or unaffected offspring. Any offspring that are affected will have a 50% risk of transmitting the mutated gene to the next generation, whereas for any unaffected offspring, the risk of the next generation being affected

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Section 3 :: Overview of Biology, Development, and Structure of Skin

82

is negligible, providing that the partner does not have the autosomal dominant condition. Some dominant alleles can behave in a partially dominant fashion. The term semidominant is applied when the phenotype in heterozygous individuals is less than that observed for homozygous subjects. For example, ichthyosis vulgaris is a semidominant disorder in which the presence of one or two mutant profilaggrin gene (FLG) alleles can strongly influence the clinical severity of the ichthyosis. In autosomal recessive disorders, both parents are carriers of one normal and one mutated allele for the same gene and, typically, they are phenotypically unaffected (Fig. 8-4). If both of the mutated alleles are

transmitted to the offspring, this will give rise to an autosomal recessive disorder, the risk of which is 25%. If one mutated and one wild-type allele is inherited by the offspring, the child will be an unaffected carrier, similar to the parents. If both wild-type alleles are transmitted, the child will be genotypically and phenotypically normal with respect to an affected individual. If the mutations from both parents are the same, the individual is referred to as a homozygote, but if different parental mutations within a gene have been inherited, the individual is termed a compound heterozygote. For someone who has an autosomal recessive condition, be it a homozygote or compound heterozygote, all offspring will be carriers of one of the mutated alleles but will be unaffected because of inheritance of a wildtype allele from the other, clinically and genetically unaffected, parent. This assumes that the unaffected parent is not a carrier. Although this is usually the case in nonconsanguineous relationships, it may not hold true in first-cousin marriages or other circumstances where there is a familial interrelationship. For example, if the partner of an individual with an autosomal recessive disorder is also a carrier of the same mutation, albeit clinically unaffected, then there is a 50% chance of the offspring inheriting two mutant alleles and therefore also inheriting the same autosomal recessive disorder. This pattern of inheritance is referred to as pseudodominant. In X-linked dominant inheritance, both males and females are affected, and the pedigree pattern may resemble that of autosomal dominant inheritance (Fig. 8-5). However, there is one important difference. An affected male transmits the disorder to all his daughters and to none of his sons. X-linked dominant inheritance has been postulated as a mechanism in incontinentia pigmenti (see Chapter 75), Conradi–Hünermann syndrome, and focal dermal hypoplasia (Goltz syndrome), conditions that are almost always limited to females. In most X-linked dominant

Autosomal recessive pattern of inheritance

X-linked dominant pattern of inheritance

Figure 8-4  Pedigree illustration of an autosomal recessive pattern of inheritance. Key observations include: the disorder affects both males and females; there are mutations on both inherited copies of the gene; the parents of an affected individual are both heterozygous carriers and are usually clinically unaffected; autosomal recessive disorders are more common in consanguineous families. Filled circle indicates affected female; half-filled circles/ squares represent clinically unaffected heterozygous carriers of the mutation; unfilled circles/squares represent unaffected individuals.

Figure 8-5  Pedigree illustration of an X-linked dominant pattern of inheritance. Key observations include: affected individuals are either hemizygous males or heterozygous females; affected males will transmit the disorder to their daughters but not to their sons (no male-to-male transmission); affected females will transmit the disorder to half their daughters and half their sons; some disorders of this type are lethal in hemizygous males and only heterozygous females survive. Filled circles indicate affected females; filled squares indicate affected males; unfilled circles/squares represent unaffected individuals.

Autosomal dominant pattern of inheritance

Figure 8-3  Pedigree illustration of an autosomal dominant pattern of inheritance. Key observations include: the disorder affects both males and females; on average, 50% of the offspring of an affected individual will be affected; affected individuals have one normal copy and one mutated copy of the gene; affected individuals usually have one affected parent, unless the disorder has arisen de novo. Importantly, examples of male-to-male transmission, seen here, distinguish this from X-linked dominant and are therefore the best hallmark of autosomal dominant inheritance. Filled circles indicate affected females; filled squares indicate affected males; unfilled circles/ squares represent unaffected individuals.

X-linked recessive pattern of inheritance

Aberrations in chromosomes are common. They occur in about 6% of all conceptions, although most of these lead to miscarriage, and the frequency of chro-

Genetics in Relation to the Skin

CHROMOSOMAL DISORDERS

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disorders with cutaneous manifestations, affected males may be aborted spontaneously or die before implantation (leading to the appearance of female-tofemale transmission). Most viable male patients with incontinentia pigmenti have a postzygotic mutation in NEMO and no affected mother; occasionally, males with an X-linked dominant disorder have Klinefelter syndrome with an XXY genotype. X-linked recessive conditions occur almost exclusively in males, but the gene is transmitted by carrier females, who have the mutated gene only on one X chromosome (heterozygous state). The sons of an affected male will all be normal (because their single X chromosome comes from their clinically unaffected mother) (Fig. 8-6). However, the daughters of an affected male will all be carriers (because all had to have received the single X chromosome from their father that carries the mutant copy of the gene). Some females show clinical abnormalities as evidence of the carrier state (such as in hypohidrotic ectodermal dysplasia; see Chapter 142); the variable extent of phenotypic expression can be explained by lyonization, the normally random process that inactivates either the wild-type or mutated X chromosome in each cell during the first weeks of gestation and all progeny cells.15 Other carriers may not show manifestations because the affected region on the X chromosome escapes lyonization (as in recessive X-linked ichthyosis) or the selective survival disadvantage of cells in which the mutated X chromosome is activated (as in the lymphocytes and platelets of carriers of Wiskott–Aldrich syndrome; see Section “Mosaicism”).

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Chapter 8

Figure 8-6  Pedigree illustration of an X-linked recessive pattern of inheritance. Key observations include: usually affects only males but females can show some features because of lyonization (X-chromosome inactivation); transmitted through female carriers, with no male-to-male transmission; for affected males, all daughters will be heterozygous carriers; female carrier will transmit the disorder to half her sons, and half her daughters will be heterozygous carriers. Dots within circles indicate heterozygous carrier females who may or may not display some phenotypic abnormalities; filled squares indicate affected males; unfilled circles/squares represent unaffected individuals.

mosomal abnormalities in live births is about 0.6%. Approximately two-thirds of these involve abnormalities in either the number of sex chromosomes or the number of autosomes; the remainder is chromosomal rearrangements. The number and arrangement of the chromosomes is referred to as the karyotype. The most common numerical abnormality is trisomy, the presence of an extra chromosome. This occurs because of nondisjunction, when pairs of homologous chromosomes fail to separate during meiosis, leading to gametes with an additional chromosome. Loss of a complete chromosome, monosomy, can affect the X chromosome but is rarely seen in autosomes because of nonviability. A number of chromosomal disorders are also associated with skin abnormalities, as detailed in Table 8-2. Structural aberrations (fragility breaks) in chromosomes may be random, although some chromosomal regions appear more vulnerable. Loss of part of a chromosome is referred to as a deletion. If the deletion leads to loss of neighboring genes this may result in a contiguous gene disorder, such as a deletion on the X chromosome giving rise to X-linked ichthyosis (see Chapter 49) and Kallman syndrome. If two chromosomes break, the detached fragments may be exchanged, known as reciprocal translocation. If this process involves no loss of DNA it is referred to as a balanced translocation. Other structural aberrations include duplication of sections of chromosomes, two breaks within one chromosome leading to inversion, and fusion of the ends of two broken chromosomal arms, leading to joining of the ends and formation of a ring chromosome. Chromosomal anomalies may be detected using standard metaphase cytogenetics but newer approaches, such as SNP arrays and comparative genomic hybridization arrays, can also be used for karyotyping. Array-based cytogenetic tools do not rely on cell division and are very sensitive in detecting unbalanced lesions as well as copy number-neutral loss of heterozygosity. These new methods have become commonplace in diagnostic genetics laboratories. A further possible chromosomal abnormality is the inheritance of both copies of a chromosome pair from just one parent (paternal or maternal), known as uniparental disomy.16 Uniparental heterodisomy refers to the presence of a pair of chromosome homologs, whereas uniparental isodisomy describes two identical copies of a single homolog, and meroisodisomy is a mixture of the two. Uniparental disomy with homozygosity of recessive alleles is being increasingly recognized as the molecular basis for several autosomal recessive disorders, and there have been more than 35 reported cases of recessive diseases, including junctional and dystrophic EB (see Chapter 62), resulting from this type of chromosomal abnormality. For certain chromosomes, uniparental disomy can also result in distinct phenotypes depending on the parental origin of the chromosomes, a phenomenon known as genomic imprinting.17,18 This parent-of-origin, specific gene expression is determined by epigenetic modification of a specific gene or, more often, a group of genes, such that gene transcription is altered, and only one inherited copy of the relevant imprinted gene(s) is expressed in the embryo. This means that,

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TABLE 8-2

Chromosomal Disorders with a Skin Phenotype Chromosomal Abnormality

Section 3

General Features

Skin Manifestations

Trisomy 21

Down syndrome

Small head with flat face Nose short and squat Ears small and misshapen Slanting palpebral fissures Thickened eyelids Eyelashes short and sparse Shortened limbs, lax joints Fingers short, sometimes webbed Hypoplastic iris, lighter outer zone (Brushfield’s spots)

1–10 year: dry skin, xerosis, lichenification 10+ year: increased frequency of atopic dermatitis, alopecia areata, single crease in palm and fifth finger Other associations: skin infections, angular cheilitis, geographic tongue, blepharitis, red cheeks, folliculitis, seborrheic dermatitis, boils, onychomycosis, fine hypopigmented hair, vitiligo, delayed dentition and hypoplastic teeth, acrocyanosis, livedo reticularis, cutis marmorata, calcinosis cutis, palmoplantar keratoderma, pityriasis rubra pilaris, syringomas, elastosis perforans serpiginosa, anetoderma, hyperkeratotic form of psoriasis, collagenoma, eruptive dermatofibromas, urticaria pigmentosa, leukemia cutis, keratosis follicularis spinulosa decalvans

Trisomy 18

Edwards syndrome

Severe mental deficiency Abnormal skull shape Small chin, prominent occiput Low-set, malformed ears “Rocker bottom” feet Short sternum Malformations of internal organs Only 10% survive beyond first year

Cutis laxa (neck), hypertrichosis of forehead and back, superficial hemangiomas, abnormal dermatoglyphics, single palmar crease, hyperpigmentation, ankyloblepharon filiforme adnatum

Trisomy 13

Patau syndrome

Mental retardation Sloping forehead due to forebrain maldevelopment (holoprosencephaly) Microphthalmia or anophthalmia Cleft palate/cleft lip Low-set ears “Rocker bottom” feet Malformations of internal organs Survival beyond 6 months is rare

Vascular anomalies (especially on forehead) Hyperconvex nails Localized scalp defects Cutis laxa (neck) Abnormal palm print (distal palmar axial triradius)

Chromosome 4, short arm deletion

Microcephaly Mental retardation Hypospadias Cleft lip/palate Low-set ears, preauricular pits

Scalp defects

Chromosome 5, short arm deletion

Mental retardation Microcephaly Cat-like cry Low-set ears, preauricular skin tag

Premature graying of hair

Chromosome 18, long arm deletion

Hypoplasia of midface Sunken eyes Prominent ear antihelix Multiple skeletal and ocular abnormalities

Eczema in 25% of cases

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45 XO

Turner syndrome

Early embryonic loss; prenatal ultrasound findings of cystic hygroma, chylothorax, ascites and hydrops Short stature, amenorrhea Broad chest, widely spaced nipples Wide carrying angle of arms Low misshapen ears, high arched palate Short fourth/fifth fingers and toes Skeletal abnormalities, coarctation of aorta

Redundant neck skin and peripheral edema Webbed neck, low posterior hairline Cutis laxa (neck, buttocks) Hypoplastic, soft upturned nails Increased incidence of keloids Increased number of melanocytic nevi and halo nevi Failure to develop full secondary sexual characteristics Lymphatic hypoplasia/lymphedema

47 XXY

Klinefelter syndrome

No manifestations before puberty Small testes, poorly developed secondary sexual characteristics Infertility Tall, obese, osteoporosis

May develop gynecomastia Sparse body and facial hair Increased risk of leg ulcers Increased incidence of systemic lupus erythematosus

48 XXYY

Similar to Klinefelter syndrome

Multiple cutaneous angiomas Acrocyanosis, peripheral vascular disease

47 XYY

Phenotypic males (tall) Mental retardation Aggressive behavior

Severe acne

49 XXXXY

Low birth weight Slow mental and physical development Large, low-set, malformed ears Small genitalia

Hypotrichosis (variable)

Fragile X syndrome

Mental retardation Mild dysmorphism Hyperextensible joints, flat feet

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during development, the parental genomes function unequally in the offspring. The most common examples of genomic imprinting are Prader–Willi (OMIM #176270) and Angelman (OMIM #105830) syndromes, which can result from maternal or paternal uniparental disomy for chromosome 15, respectively. Three phenotype abnormalities commonly associated with uniparental disomy for chromosomes with imprinting are (1) intrauterine growth retardation, (2) developmental delay, and (3) reduced stature.19

MITOCHONDRIAL DISORDERS

Genetics in Relation to the Skin

For Mendelian disorders, identifying genes that harbor pathogenic mutations has become relatively straightforward, with hundreds of disease-associated genes being discovered through a combination of linkage, positional cloning, and candidate gene analyses.

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COMPLEX TRAIT GENETICS

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Chapter 8

In addition to the 3.3 billion bp nuclear genome, each cell contains hundreds or thousands of copies of a further 16.5-kb mitochondrial genome, which is inherited solely from an individual’s mother. This closed, circular genome contains 37 genes, 13 of which encode proteins of the respiratory chain complexes, whereas the other 24 genes generate 22 transfer RNAs and two ribosomal RNAs used in mitochondrial protein synthesis.20 Mutations in mitochondrial DNA were first reported in 1988, and more than 250 pathogenic point mutations and genomic rearrangements have been shown to underlie a number of myopathic disorders and neurodegenerative diseases, some of which show skin manifestations, including lipomas, abnormal pigmentation or erythema, and hypo- or hypertrichosis.21 Mitochondrial DNA mutations are very common in somatic mammalian cells, more than two orders of magnitude higher than the mutation frequency in nuclear DNA.22 Mitochondrial DNA has the capacity to form a mixture of both wild-type and mutant DNA within a cell, leading to cellular dysfunction only when the ratio of mutated to wild-type DNA reaches a certain threshold. The phenomenon of having mixed mitochondrial DNA species within a cell is known as heteroplasmy. Mitochondrial mutations can induce, or be induced by, reactive oxygen species, and may be found in, or contribute to, both chronologic aging and photoaging.23 Somatic mutations in mitochondrial DNA have also been reported in several premalignant and malignant tumors, including malignant melanoma, although it is not yet known whether these mutations are causally linked to cancer development or simply a secondary bystander effect as a consequence of nuclear DNA instability. Indeed, currently there is little understanding of the interplay between the nuclear and mitochondrial genomes in both health and disease. Nevertheless, it is evident that the genes encoded by the mitochondrial genome have multiple biologic functions linked to energy production, cell proliferation, and apoptosis.24

By contrast, for complex traits, such as psoriasis and atopic dermatitis, these traditional approaches have been largely unsuccessful in mapping genes influencing the disease risk or phenotype because of low statistical power and other factors.25,26 Complex traits do not display simple Mendelian patterns of inheritance, although genes do have an influence, and close relatives of affected individuals may have an increased risk. To dissect out genes that contribute and influence susceptibility to complex traits, several stages may be necessary, including establishing a genetic basis for the disease in one or more populations; measuring the distribution of gene effects; studying statistical power using models; and carrying out marker-based mapping studies using linkage or association. It is possible to establish quantitative genetic models to estimate the heritability of a complex trait, as well as to predict the distribution of gene effects and to test whether one or more quantitative trait loci exist. These models can predict the power of different mapping approaches, but often only provide approximate predictions. Moreover, low power often limits other strategies such as transmission analyses, association studies, and familybased association tests. Another potential pitfall of association studies is that they can generate spurious associations due to population admixture. To counter this, alternative strategies for association mapping include the use of recent founder populations or unique isolated populations that are genetically homogeneous, and the use of unlinked markers (so-called genomic controls) to assign different regions of the genome of an admixed individual to particular source populations. In addition, and relevant to several studies on psoriasis, linkage disequilibrium observed in a sample of unrelated affected and normal individuals can also be used to fine-map a disease susceptibility locus in a candidate region. In recent years, advances in the identification of many millions of SNPs across the entire genome, as well as major advances in gene chip technology that allows up to 2 million SNPs to be typed in a given individual for a few hundred dollars, coupled with high powered computation, have led to the current era of genomewide association studies (GWAS).27 This has become the predominant technology for tacking complex traits, with GWAS having already been performed for psoriasis, atopic eczema, vitiligo, and alopecia areata. GWAS for other dermatological complex traits are underway. A typical GWAS design involves collecting DNA from a well-phenotyped case series of the condition of choice, preferably from an ethnically homogenous population. Normally, 2,000 or more cases are required versus 3,000 ethnically matched random population controls. Correct clinical ascertainment of the cases is paramount and so GWAS represents a great opportunity for close cooperation between physicians and scientists. These 5,000 or more individuals are genotyped for 500,000 to 2 million SNPs, generating billions of data points. For each SNP across the genome, a statistical test is performed and a P value derived. If an SNP is closely linked to a disease susceptibility gene, then a particular genotype will be greatly enriched in the case series compared to the general unselected

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population. The P values are plotted along each chromosome (“Manhattan plot”) and where disease susceptibility loci exist, there are clusters of strong association. Typically, P values of 10−10 or lower are indicative of a true locus, although this generally has to be replicated in a number of other case-control sets for confirmation. Although SNP-based GWAS is currently the weapon of choice in complex trait genetics, it has limitations. If a causative lesion in a susceptibility locus is very heterogeneous, i.e., if there are multiple mutations or other changes that cause the susceptibility, then the locus is poorly identified by GWAS. Furthermore, across the entire field of complex trait genetics, relatively few causative genes have emerged (the role of the filaggrin gene in atopic dermatitis, below, being a notable exception). In the majority of cases, there is currently little clue about what defect the associated SNPs are linked to that actually causes the disease susceptibility. However, recently, a conventional genetics approach has revealed fascinating new insight into the pathophysiology of one particular complex trait, namely atopic dermatitis (eczema). This finding emanated from the discovery that the disorder ichthyosis vulgaris was due to loss-of-function mutations in the gene encoding the skin barrier protein filaggrin (see Chapters 14 and 49).28 To dermatologists, the clinical association between this condition and atopic dermatitis is well known, and the same loss-of-function mutations in filaggrin have subsequently been shown to be a major susceptibility risk factor for atopic dermatitis, as well as asthma associated with atopic dermatitis, but not asthma alone.4 This suggests that asthma in individuals with atopic dermatitis may be secondary to allergic sensitization, which develops because of the defective epidermal barrier that allows allergens to penetrate the skin to make contact with antigenpresenting cells. Indeed, transmission–disequilibrium tests have demonstrated an association between filaggrin gene mutations and extrinsic atopic dermatitis associated with high total serum immunoglobulin E levels and concomitant allergic sensitizations.29 These recent data on the genetics of atopic dermatitis demonstrate how the study of a “simple” genetic disorder can also provide novel insight into a complex trait. Therefore, Mendelian disorders may be useful in the molecular dissection of more complex traits.30

MOSAICISM

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The presence of a mixed population of cells bearing different genetic or chromosomal characteristics leading to phenotypic diversity is referred to as mosaicism. There are several different types of mosaicism, including single gene, chromosomal, functional, and revertant mosaicism.31 Multiple expression patterns are recognized.32 Mosaicism for a single gene, referred to as somatic mosaicism, indicates a mutational event occurring after fertilization. The earlier this occurs, the more likely it is that there will be clinical expression of a disease phenotype as well as involvement of gonadal tissue (gonosomal mosaicism); for example, when individuals with

segmental neurofibromatosis subsequently have offspring with full-blown neurofibromatosis (see Chapter 141). However, in general, if the mutation occurs after generation of cells committed to gonad formation, then the mosaicism will not involve the germ line, and the reproductive risk of transmission is negligible. Gonosomal mosaicism refers to involvement of both gonads and somatic tissue, but mosaicism can occur exclusively in gonadal tissue, referred to as gonadal mosaicism. Clinically, this may explain recurrences among siblings of autosomal dominant disorders such as tuberous sclerosis or neurofibromatosis, when none of the parents has any clinical manifestations and gene screening using genomic DNA from peripheral blood samples yields no mutation. Segmental mosaicism for autosomal dominant disorders is thought to occur in one of two ways: either there is a postzygotic mutation with the skin outside the segment and genomic DNA being normal (type 1), or there is a heterozygous genomic mutation in all cells that is then exacerbated by loss of heterozygosity within a segment or along the lines of Blaschko (type 2). This pattern has been described in several autosomal dominant disorders, including Darier disease, Hailey–Hailey disease (see Chapter 51), superficial actinic porokeratosis (see Chapter 52), and tuberous sclerosis (see Chapter 140). The lines of Blaschko were delineated over 100 years ago; the pattern is attributed to the lines of migration and proliferation of epidermal cells during embryogenesis (i.e., the bands of abnormal skin represent clones of cells carrying a mutation in a gene expressed in the skin).33 Apart from somatic mutations [either in dominant disorders, such as epidermolytic ichthyosis (formerly called bullous congenital ichthyosiform erythroderma) leading to linear epidermolytic ichthyosis (epidermal nevus of the epidermolytic hyperkeratosis type) (see Chapter 49), or in conditions involving mutations in lethal dominant genes such as in McCune– Albright syndrome], mosaicism following Blaschko’s lines is also seen in chromosomal mosaicism and functional mosaicism (random X-chromosome inactivation through lyonization). Monoallelic expression on autosomes (with random inactivation of either the maternal or paternal allele) is also feasible, and probably underdocumented.34 Chromosomal mosaicism results from nondisjunction events that occur after fertilization. Clinically, this is found in the linear mosaic pigmentary disorders (hypomelanosis of Ito (see Chapter 75) and linear and whorled hyperpigmentation). It is important to point out that hypomelanosis of Ito is not a specific diagnosis but may occur as a consequence of several different chromosomal abnormalities that perturb various genes relevant to skin pigmentation, which has led to the term “pigmentary mosaicism” to describe this group of disorders. Functional mosaicism relates to genes on the X chromosome, because during embryonic development in females, one of the X chromosomes, either the maternal or the paternal, is inactivated. For X-linked dominant disorders, such as focal dermal hypoplasia (Goltz syndrome) or incontinentia pigmenti (see Chapter 75), females survive because of the presence of some cells in which the X chromosome without the mutation is

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EPIGENETICS

Genetics in Relation to the Skin

Disease phenotypes reflect the result of the interaction between a particular genotype and the environment, but it is evident that some variation, for example, in monozygotic twins, is attributable to neither. Additional influences at the biochemical, cellular, tissue, and organism levels occur, and these are referred to as epigenetic phenomena.38 Single genes are not solely responsible for each separate function of a cell. Genes may collaborate in circuits, be mobile, exist in plasmids and cytoplasmic organelles, and can be imported by nonsexual means from other organisms or as synthetic products. Even prion proteins can simulate some gene properties. Epigenetic effects reflect chemical modifications to DNA that do not alter DNA sequence but do alter the probability of gene transcription. Mammalian DNA methylation machinery is made up of two components: (1) DNA methyltransferases, which establish and maintain genome-wide DNA methylation patterns, and (2) the methyl-CpG-binding proteins, which are involved in scanning and interpreting the methylation patterns. Analysis of any changes in these processes is known as epigenomics.39 Examples of modifications include direct covalent modification of DNA by methylation of cytosines and alterations in proteins that bind to DNA. Such changes may affect DNA accessibility to local transcriptional complexes as well as influencing chromatin structure at regional and genome-wide levels, thus providing a link between genome structure and regulation of transcription. Indeed, epigenome analysis is now being carried out in parallel with gene expression to identify genome-wide methylation patterns and profiles of all human genes. For example, there is considerable interindividual variation in cytosine methylation of CpG dinucleotides within the major histocompatibility complex (MHC) region genes, although whether this has any bearing on the expression of skin disorders such as psoriasis remains to be seen. New sensitive and quantitative methylation-specific polymerase chain reaction-based assays can identify epigenetic anomalies in cancers such as melanoma.40 DNA hypermethylation contributes to gene silencing by preventing the binding of activating transcription factors and by attracting repressor complexes that induce the formation of inactive chromatin structures. With regard to melanoma, such changes may impact on several biologic processes, including cell cycle control, apoptosis, cell signaling, tumor cell invasion, metastasis, angiogenesis, and immune recognition. A further but as yet unresolved issue is whether there is heritability of epigenetic characteristics. Likewise, it is unclear whether environmentally induced changes in epigenetic status, and hence gene transcription and phenotype, can be transmitted through more than one generation. Such a phenomenon might account for the cancer susceptibility of grandchildren

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Figure 8-7  Revertant mosaicism in an individual with non-Herlitz junctional epidermolysis bullosa. The subject has loss-of-function mutations on both alleles of the type XVII collagen gene, COL17A1, but spontaneous genetic correction of the mutation in some areas has led to patches of normal-appearing skin (areas within black marker outline) that do not blister. (From Jonkman MF et al: Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion. Cell 88:543, 1997, with permission.)

ation. This phenomenon is known as epigenetic mosaicism; such events may be implicated in tumorigenesis but have not been associated with any genetic skin disorder.

Chapter 8

active and able to function. For males, these X-linked dominant disorders are typically lethal, unless associated with an abnormal karyotype (e.g., Klinefelter syndrome; 47, XXY) or if the mutation occurs during embryonic development. For X-linked recessive conditions, such as X-linked recessive hypohidrotic ectodermal dysplasia (see Chapter 142), the clinical features are evident in hemizygous males (who have only one X chromosome), but females may show subtle abnormalities due to mosaicism caused by X-inactivation, such as decreased sweating or reduced hair in areas of the skin in which the normal X is selectively inactivated. There are 1,317 known genes on the X chromosome, and most undergo random inactivation but a small percentage (approximately 27 genes on Xp, including the steroid sulfatase gene, and 26 genes on Xq) escape inactivation. Revertant mosaicism, also known as natural gene therapy, refers to genetic correction of an abnormality by various different phenomena including back mutations, intragenic crossovers, mitotic gene conversion, and second site mutations.35,36 Indeed, multiple different correcting events can occur in the same patient. Such changes have been described in a few genes expressed in the skin, including the keratin 14, laminin 332, collagen XVII, collagen VII, and kindlin-1 (fermitin family homolog 1) genes in different forms of EB (Fig. 8-7; see Chapter 62). The clinical relevance of the conversion process depends on several factors, including the number of cells involved, how much reversal actually occurs, and at what stage in life the reversion takes place. Attempts have been made to culture reverted keratinocytes and graft them to unreverted sites,37 a pioneering approach that may have therapeutic potential for some patients. Apart from mutations in nuclear DNA, mosaicism can also be influenced by environmental factors, such as viral DNA sequences (retrotransposons) that can be incorporated into nuclear DNA, replicate, and activate or silence genes through methylation or demethyl-

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of individuals who have been exposed to diethylstilbestrol, but this has not been proved. However, germ line epimutations have been identified in other human diseases, such as colorectal cancers characterized by microsatellite instability and hypermethylation of the MLH1 DNA mismatch repair gene, although the risk of transgenerational epigenetic inheritance of cancer from such a mutation is not well established and probably small. Over the course of an individual’s lifespan, epigenetic mutations (affecting DNA methylation and histone modifications) may occur more frequently than DNA mutations, and it is expected that, over the next decade, the role of epigenetic phenomena in influencing phenotypic variation will gradually become better understood.41

HISTOCOMPATABILITY ANTIGEN DISEASE ASSOCIATION Human leukocyte antigen (HLA) molecules are glycoproteins that are expressed on almost all nucleated cells. The HLA region is located on the short arm of chromosome 6, at 6p21, referred to as the MHC. There are three classic loci at HLA class I: (1) HLA-A, (2) HLA-B, and (3) HLA-Cw, and five loci at class II: (1) HLA-DR, (2) HLA-DQ, (3) HLA-DP, (4) HLA-DM, and (5) HLA-DO. The HLA molecules are highly polymorphic, there being many alleles at each individual locus. Thus, allelic variation contributes to defining a unique “fingerprint” for each person’s cells, which allows an individual’s immune system to define what is foreign and what is self. The clinical significance of the HLA system is highlighted in human tissue transplantation, especially in kidney and bone marrow transplantation, where efforts are made to match at the HLA-A, -B, and -DR loci. MHC class I molecules, complexed to certain peptides, act as substrates for CD8+ T-cell activation, whereas MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4+ T helper cells (see Chapter 10). Therefore, MHC molecules are central to effective adaptive immune responses. Conversely, however, genetic and epidemiologic data have implicated these molecules in the pathogenesis of various autoimmune and chronic inflammatory diseases. Several skin diseases, such as psoriasis (see Chapter 18), psoriatic arthropathy (central and peripheral), dermatitis herpetiformis, pemphigus, reactive arthritis syndrome (see Chapter 20), and Behçet disease (see Chapter 166), all show an association with inheritance of certain HLA haplotypes (i.e., there is a higher incidence of these conditions in individuals and families with particular HLA alleles). However, the molecular mechanisms by which polymorphisms in HLA molecules confer susceptibility to certain disorders are still unclear. This situation is further complicated by the fact that, for most diseases, it is unknown which autoantigens (presented by the disease-associated MHC molecules) are primarily involved. For many diseases, the MHC class association is the main genetic association. Nevertheless, for most of the MHC-associated

diseases, it has been difficult to unequivocally determine the primary disease-risk gene(s), owing to the extended linkage disequilibrium in the MHC region. However, recent genetic and functional studies support the long-held assumption that common MHC class I and II alleles themselves are responsible for many disease associations, such as the HLA cw6 allele in psoriasis. Of practical clinical importance is the strong genetic association between certain HLA alleles and the risk of adverse drug reactions. For example, in Han Chinese and some other Asian populations, HLAB*1502 confers a greatly increased risk of carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis. Therefore, screening for HLAB*1502 before starting carbamazepine in patients from high-risk populations is recommended or required by regulatory agencies.42

GENETIC COUNSELING The National Society of Genetic Counselors (http:// www.nsgc.org) has defined genetic counseling as “the process of helping people understand and adapt to the medical, psychological and familial implications of genetic contributions to disease.” Genetic counseling should include: (1) interpretation of family and medical histories to assess the chance of disease occurrence or recurrence; (2) education about inheritance, testing, management, prevention, resources, and research; and (3) counseling to promote informed choice and adaptation to the risk or condition.43 Once the diagnosis of an inherited skin disease is established and the mode of inheritance is known, every dermatologist should be able to advise patients correctly and appropriately, although additional support from specialists in medical genetics is often necessary. Genetic counseling must be based on an understanding of genetic principles and on a familiarity with the usual behavior of hereditary and congenital abnormalities. It is also important to be familiar with the range of clinical severity of a particular disease, the social consequences of the disorder, the availability of therapy (if any), and the options for mutation detection and prenatal testing in subsequent pregnancies at risk for recurrence (one useful site is http:// www.genetests.com). A key component of genetic counseling is to help parents, patients, and families know about the risks of recurrence or transmission for a particular condition. This information is not only practical but often relieves guilt and can allay rather than increase anxiety. For example, it may not be clear to the person that he or she cannot transmit the given disorder. The unaffected brother of a patient with an X-linked recessive disorder such as Fabry disease (see Chapter 136), X-linked ichthyosis (see Chapter 49), Wiskott–Aldrich syndrome (see Chapter 143), or Menkes syndrome (see Chapter 88) need not worry about his children being affected or even carrying the abnormal allele, but he may not know this. Prognosis and counseling for conditions such as psoriasis in which the genetic basis is complex or still

PRENATAL DIAGNOSIS

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:: Genetics in Relation to the Skin

In recent years, there has been considerable progress in developing prenatal testing for severe inherited skin disorders (Fig. 8-8). Initially, ultrastructural examination of fetal skin biopsies was established in a limited number of conditions. In the late 1970s, the first diagnostic examination of fetal skin was reported for epidermolytic hyperkeratosis and Herlitz junctional EB (see Chapter 62).46,47 These initial biopsies were performed with the aid of a fetoscope to visualize the

fetus. However, with improvements in sonographic imaging, biopsies of fetal skin are now taken under ultrasound guidance. The fetal skin biopsy samples obtained during the early 1980s could be examined only by light microscopy and transmission electron microscopy. However, the introduction of a number of monoclonal and polyclonal antibodies to various basement membrane components during the mid-1980s led to the development of immunohistochemical tests to help complement ultrastructural analysis in establishing an accurate diagnosis, especially in cases of EB.48 Fetal skin biopsies are taken during the midtrimester. For disorders such as EB, testing at 16 weeks’ gestation is appropriate. However, for some forms of ichthyosis, the disease-defining structural pathology may not be evident at this time, and fetal skin sampling may need to be deferred until 20 to 22 weeks of development. Nevertheless, since the early 1990s, as the molecular basis of an increasing number of genodermatoses has been elucidated, fetal skin biopsies have gradually been superseded by DNA-based diagnostic screening using fetal DNA from amniotic fluid cells or samples of chorionic villi; the latter are usually taken at 10 to 12 weeks’ gestation (i.e., at the end of the first trimester).49,50 In addition, advances with in vitro fertilization and embryo micromanipulation have led to the feasibility of even earlier DNA-based assessment through preimplantation genetic diagnosis, an approach first

Chapter 8

unclear is more difficult (see Chapter 18). Persons can be advised, for example, that if both parents have psoriasis, the probability is 60% to 75% that a child will have psoriasis; if one parent and a child of that union have psoriasis, then the chance is 30% that another child will have psoriasis; and if two normal parents have produced a child with psoriasis, the probability is 15% to 20% for another child with psoriasis.44 Ongoing discoveries in other diseases, such as melanoma genetics, can also impact on genetic counseling. The identification of family-specific mutations in the CDKN2A and CDK4 genes, as well as risk alleles in the MC1R and OCA2 genes and other genetic variants, allow for more accurate and informative patient and family consultations.45

A

C

B

Figure 8-8  Options for prenatal testing of inherited skin diseases. A. Fetal skin biopsy, here shown at 18 weeks’ gestation. B. Chorionic villi sampled at 11 weeks’ gestation. C. Preimplantation genetic diagnosis. A single cell is being extracted from a 12-cell embryo using a suction pipette.

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successfully applied in 1990, for risk of recurrence of cystic fibrosis.51 Successful preimplantation testing has also been reported for severe inherited skin disorders.52 This is likely to become a more popular, though still technically challenging, option for some couples, in view of recent advances in amplifying the whole genome in single cells and the application of multiple linkage markers in an approach termed preimplantation genetic haplotyping.53 This approach has been developed and applied successfully for Herlitz junctional epidermolysis bullosa.54 For some disorders, alternative less invasive methods of testing are now also being developed, including analysis of fetal DNA or RNA from within the maternal circulation and the use of three-dimensional ultrasonography. In the current absence of effective treatment for many hereditary skin diseases, prenatal diagnosis can provide much appreciated information to couples at risk of having affected children, although detailed and supportive genetic counseling is also a vital element of all prenatal testing procedures.

GENE THERAPY The field of gene therapy can be subdivided in different ways.55 First, there are approaches aimed at treatment of recessive genetic diseases where homozygous or compound heterozygous loss-of-function mutations lead to complete absence or complete functional ablation of a vital protein. These types of diseases are amenable to gene replacement therapy, and it is this form of gene therapy that has tended to predominate because it is generally technically more feasible than treatment of dominant genetic conditions.56 In dermatology, these include diseases such as lamellar ichthyosis (see Chapter 49), where in most cases, there is hereditary absence of transglutaminase-1 activity in the outer epidermis, or the severe Hallopeau–Siemens form of recessive dystrophic EB, where there is complete absence of type VII collagen expression due to recessive mutations.57 The second form of gene therapy, in broad terms, is aimed at treatment of dominant-negative genetic disorders and is known as gene inhibition therapy. Here, there is a completely different type of problem to be tackled because these patients already carry one normal copy of the gene and one mutated copy. The disease results because an abnormal protein product produced by the mutant allele, dominant-negative mutant protein, binds to and inhibits the function of the normal protein produced by the wild-type allele. In many cases, it can be shown from the study of rare recessive variants of dominant diseases that one allele is sufficient for normal skin function, and so if a means could be found of specifically inhibiting the expression of the mutant allele, this should be therapeutically beneficial. However, finding a gene therapy agent that is capable of discriminating the wild-type and mutant alleles, which can differ by as little as one bp of DNA, is challenging and, until recently has resulted in little success. A typical dominant-negative genetic skin disease is EB simplex (see Chapter 62), caused by mutations in either of the genes encoding keratins 5 or 14. The vast major-

ity of cases are caused by dominant-negative missense mutations, changing only a single amino acid, carried in a heterozygous manner on one allele.58 Gene therapy approaches can also be broadly subdivided according to whether they involve in vivo or ex vivo strategies.55 Using an in vivo approach, the gene therapy agent would be applied directly to the patient’s skin or another tissue. A disadvantage of the skin as a target organ for gene therapy is that it is a barrier tissue that is fundamentally designed to prevent entry of foreign nucleic acid in the form of viruses or other pathogenic agents. This is an impediment to in vivo gene therapy development but is not insurmountable due to developments in liposome technology and other methods for cutaneous macromolecule delivery.59 In an ex vivo approach, a skin biopsy would be taken, keratinocytes or fibroblasts would be grown and expanded in culture, treated with the gene therapy agent, and then grafted onto or injected back into the patient. The skin is a good organ system for both these approaches because it is very accessible for in vivo applications. In addition, the skin can be readily biopsied, and cell culture and regrafting of keratinocytes can be adapted for ex vivo gene therapy. Gene replacement therapy systems have been developed for lamellar ichthyosis (see Chapter 49) and the recessive forms of EB (see Chapter 62), among other diseases. These mostly consist of expressing the normal complementary DNA encoding the gene of interest from some form of gene therapy vector adapted from viruses that can integrate their genomes stably into the human genome. Therefore, such viral vectors can lead to long-term stable expression of the replacement gene.60 Early studies tended to use retroviral vectors or adeno-associated viral vectors, but these have a number of limitations. For example, retroviruses only transduce dividing cells and therefore fail to target stem cells; consequently, gene expression is quickly lost due to turnover of the epidermis through keratinocyte differentiation. Furthermore, there have been some safety issues in small-scale human trials for both retroviral and adeno-associated viral vectors. Lentiviral vectors, derived from short integrating sequences found in a number of immunodeficiency viruses, have the advantage of being able to stably transduce dividing and nondividing cells, with close to 100% efficiency and at low copy number. These may be the current vectors of choice, but they also have potential problems because their preferred integration sites in the human genome are currently ill defined and may lead to concerns about safety. However, with a wide variety of vectors under development and testing, it should become clear in future years which vectors are effective and safe for human use. Ultimately, like all novel therapeutics, animal testing can only act as a guide because the human genome is quite different and may react differently to foreign DNA integration, so that phase I, II, and III human trials or adaptations thereof will ultimately have to be performed to determine efficacy and safety. Currently, small-scale clinical trials are ongoing for junctional EB and are planned for a number of other genodermatoses, mainly concentrating on the more severe recessive conditions.

and was shown to have an excellent toxicity profile in rodents, as per a small molecule drug. This facilitated FDA approval for a double blind split body Phase 1b clinical trial in a single volunteer with PC. The trial was successful, with a number of objective measures showing statistically significant clinical improvement. This study, funded by the patient advocacy organization PC Project (www.pachyonychia.org), was the first in human siRNA trial using a mutation-specific gene silencing approach and only the fifth siRNA trial in humans. This personalized medicine strategy gives hope for patients with incurably dominant genodermatoses and future trials in EB simplex are currently in the planning stages.

KEY REFERENCES Full reference list available at www.DIGM8.com

Racial Considerations: Skin of Color

1. Hsu F et al: The UCSC known genes. Bioinformatics 22:1036, 2006 2. Tsongalis GJ, Silverman LM: Molecular diagnostics: A historical perspective. Clin Chim Acta 369:188, 2006 15. Happle R: X-chromosome inactivation: Role in skin disease expression. Acta Paediatr Suppl 95:16, 2006 39. Callinan PA, Feinberg AP: The emerging science of epigenomics. Hum Mol Genet 15:R95, 2006 56. Ferrari S et al: Gene therapy in combination with tissue engineering to treat epidermolysis bullosa. Expert Opin Biol Ther 6:367, 2006

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Chapter 9

Treatment of dominant-negative disorders has recently started to receive a great deal of attention with the discovery of the RNA inhibition pathway in humans and the finding that small synthetic double-stranded RNA molecules of 19 to 21 bp, known as short inhibitory RNA (siRNA), can efficiently inhibit expression of human genes in a sequence-specific, user-defined manner.58,61 There is currently a great deal of attention being focused on development of siRNA inhibitors to selectively silence mutant alleles in dominant-negative genetic diseases, such as the keratin disorders—EB simplex and pachyonychia congenita (PC). Currently, the big challenge in this rapidly evolving new field is finding an effective, noninvasive method to get siRNA through the stratum corneum and into keratinocytes or other target cells. A number of groups are working on means of delivering siRNA to skin and other organ systems, and there is currently much optimism about these developing into clinically applicable agents in the near future. In particular, a great deal of rapid progress has been made in PC in recent years. Following development of reporter gene methodology to rapidly screen many different siRNA species, two siRNAs were identified that could specifically and potently silence mutant keratin K6a mRNA differing from the wild-type mRNA by only a single nucleotide, i.e., these siRNAs represent allelespecific gene silencing agents. Following a battery of preclinical studies in cells and animal models to show efficacy, the K6a mutation-specific siRNA was manufactured to Good Manufacturing Practice standards

Chapter 9 :: Racial Considerations: Skin of Color :: K  avitha K. Reddy, Yolanda M. Lenzy, Katherine L. Brown, & Barbara A. Gilchrest SKIN OF COLOR AT A GLANCE Race and ethnicity are closely related but distinct factors that may influence skin disease prevalence or presentation. The Fitzpatrick skin phototype classification was developed to convey risk of photodamage in white skin and is often less useful in describing skin of color. The complex polygenic basis for variation in human skin, hair, and eye color has been partially elucidated. The structure and function of skin of color is similar or identical to that of white (Caucasian) skin, other than differences related to pigmentation.

Differences in the character of hair among whites, Asians, and Africans relate to shape of the hair follicle and thickness of the cuticle layer. African hair displays low tensile strength and easy breakage. This fragility may be compounded by chemical or heat application, apparently predisposing to several types of alopecia. Postinflammatory hyper- or hypopigmentation is often prominent and long lasting in skin of color; preventive and therapeutic measures should be considered in the plan of care.

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Figure 9-1  A spectrum of human pigmentary variation observed among Boston medical trainees. (Photograph by Michael Krathen, MD.)

Section 3

RACIAL AND ETHNIC INFLUENCES ON SKIN DISEASE AND THERAPY

:: Overview of Biology, Development, and Structure of Skin

In the United States and worldwide, myriad cutaneous phenotypes characterize mankind. Most striking is the range of skin and hair color (Fig. 9-1). The Census Bureau estimates that half of the US population will be of non-European descent by the year 2050.1 There are currently more than 95 million persons in the United State2 and billions of individuals worldwide categorized as having “skin of color.” There has been increasing awareness of racial and ethnic influences (see Table 9-1) on skin biology and on diagnosis and treatment of skin disease. The literature regarding “skin of color” primarily focuses on promoting awareness of normal and abnormal skin conditions in a patient regardless of skin phenotype. It seeks to identify risks and benefits of treatments in diverse skin types, to develop effective treatments for common dermatoses in skin of color, recognizing the importance of individualized therapy, and to avoid stereotyping and generalization.

DEFINING SKIN OF COLOR In defining skin of color, it is important to consider the reasons for doing so. Many have questioned the

common propensity of medical practitioners to state a patient’s race among the first few words, as a primary identifier. The skin type, color, or ethnic background of most patients may be better suited to the physical examination or to relevant points in the history. The International Committee of Medical Journal Editors’ Uniform Requirements for Manuscripts Submitted to Biomedical Journals recommends that authors using variables such as race or ethnicity should “define how they measured the variables and justify their relevance.”6 The Journal of the American Academy of Dermatology similarly suggests that authors inclined to submit racial, ethnic, or skin color descriptors in manuscripts ask themselves a series of questions regarding whether such identification is important to the understanding or pedagogical value of the manuscript, whether the patient would self-identify in the same way and how this is known, whether the descriptor used could be open to racist interpretation, and what the evidence is that the descriptor plays a role in the entities described.7 Most would argue that “nonwhite” skin is “skin of color.” However, there is a diverse array of phenotypes within the nonwhite and white spectra, and two categories are inadequate to describe them. The most commonly used classification system in dermatologic practice is the Fitzpatrick phototype,8,9 designed to provide an estimate of skin cancer and photoaging risk, in which individuals are assigned a number

TABLE 9-1

Race Versus Ethnicity

92

Term

Derivation

Current Usage or Implication

Race

6%); shows increased efficacy in combination therapy with 0.01% fluocinonide cream and 0.05% tretinoin Hydroquinone derivative; inhibits tyrosinase and DHICA113 Active ingredient glabridin decreases tyrosinase activity and has anti-inflammatory effects114 Potent tyrosinase inhibition115 Product should be stable for efficacy Also provides anti-inflammatory effect Inhibits tyrosinase transcription and glycosylation; normalizes epidermal melanin distribution Fungal derivative; inhibits tyrosinase Inhibits conversion of protyrosinase to tyrosinase116 Flavanoid compounds with antioxidant activity; oral treatment (25 mg TID) may improve melasma117 Amide of niacin (B3), inhibits melanosome transfer to keratinocytes118 Soybean trypsin inhibitor (STI) and Bowman-Birk inhibitor (BBI) inhibit cleavage of PAR-2, reducing melanosome transfer Reduce corneocyte adhesion

a

Reported mechanism of action, based on data of varying strength.

and can be less expensive than other options. Branded products include Veil Cover Cream, Keromask, Dermacolor, and Dermablend. These and the many other marketed formulations must be judged by the user on the basis of esthetics, cost, and other factors of importance to the individual. Referral to a professional makeup artist or camouflage makeup therapist for application demonstration and education regarding proper use can provide significant benefit.

PROCEDURAL DERMATOLOGY IN SKIN OF COLOR. Superficial and medium depth chemical peels,

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Special Considerations

when appropriately selected and performed, are appropriate for Fitzpatrick skin types IV–VI. Specific choices regarding chemical agent depend on the efficacy, safety, desired depth of peel, and the physician’s preference and experience. Microdermabrasion is appropriate for all skin types, is often used for acne and other types of facial scarring, and is a good option for those unable to tolerate peels or extensive recovery times. Laser treatment in patients with skin of color should be selected with the knowledge that epidermal mela-

nin can act as a competitive chromophore. Inadvertent absorption of laser energy by epidermal melanin can lead to scarring and dyspigmentation.

PATIENT INDIVIDUALIZATION The spectrum of human phenotypes results from a combination of genetic and environmental influences. Complexities of racial and ethnic contributors to disease susceptibility, clinical presentation, and therapeutic response are still poorly understood. Because there is on average greater genetic diversity between any two individuals (85–90%) than between races (10–15%),129 and because genes determining pigmentation make up an exceedingly small proportion of the genome, it is desirable that race not be overemphasized in determining a dermatologic plan of care. The welcome movement toward considering skin types as a continuous spectrum rather than dichotomously as white and nonwhite may one day render obsolete the term “skin of color.”

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

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Chapter 9 ::

1. US Interim Projections by Age, Sex, Race and Hispanic Origin, 2000–2050. US Census Bureau, http://www. census.gov/population/www/projections/usinterimproj/ natprojtab01a.pdf, accessed August 30, 2011 10. Taylor SC: Skin of color: Biology, structure, function, and implications for dermatologic disease. J Am Acad Dermatol 46(2 Suppl. Understanding):S41-S62, 2002 21. Sturm RA: Molecular genetics of human pigmentation diversity. Hum Mol Genet 18(R1):R9-R17, 2009 24. Lamason RL et al: SLC24A5, a putative cation exchanger, affects pigmentation in zebrafish and humans. Science (New York, N.Y.) 310(5755):1782-1786, 2005 26. Rees JL. Genetics of hair and skin color. Ann Rev Genet 37:67-90, 2003 30. Wolfram LJ: Human hair: A unique physicochemical composite. J Am Acad Dermatol 48(Suppl. 6):S106-S114, 2003

31. McMichael AJ: Hair breakage in normal and weathered hair: Focus on the Black patient. J Investig Dermatol Symp Proc/Soc Investig Dermatol, Inc. 12(2):6-9, 2007 41. Bernard BA: Hair shape of curly hair. J Am Acad Dermatol 48(Suppl. 6):S120-S126, 2003 42. Thibaut S et al: Human hair shape is programmed from the bulb. Br J Dermatol 152(4):632-638, 2005 57. Kelly AP: Pseudofolliculitis barbae and acne keloidalis nuchae. Dermatol Clin 21(4):645-653, 2003 120. Ries L, Eisner M, Kosary C: SEER Cancer Statistics Review, 1975–2001. Bethesda, MD, National Cancer Institute, 2004 123. Stevens NG, Liff JM, Weiss NS: Plantar melanoma: Is the incidence of melanoma of the sole of the foot really higher in blacks than whites? Int J Cancer 45(4):691-693, 1990 126. Criscione VD, Weinstock MA: Incidence of cutaneous T-cell lymphoma in the United States, 1973–2002. Arch Dermatol 143(7):854-859, 2007 129. Myles S et al: Identifying genes underlying skin pigmentation differences among human populations. Hum Genet 120(5):613-621, 2007

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Disorders Presenting PA RT in Skin and Mucous Membranes Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

Chapter 10 :: I nnate and Adaptive Immunity in the Skin :: Robert L. Modlin, Lloyd S. Miller, Christine Bangert, & Georg Stingl Innate And Adaptive Immunity At a Glance Innate immune responses are used by the host to immediately defend itself; determine the quality and quantity of many adaptive immune responses;

include cells such as monocytes/ macrophages, dendritic cells, natural killer cells, and polymorphonuclear leukocytes. Adaptive immune responses have memory;

are short lived;

have specificity;

have no memory;

are long lasting;

include physical barriers (skin and mucosal epithelia);

in skin, are initiated by dendritic antigenpresenting cells in the epidermis (Langerhans cells) and by dermal dendritic cells;

include soluble factors such as complement, antimicrobial peptides, chemokines, and cytokines;

The human immune system is comprised of two distinct functional parts: (1) innate and (2) adaptive. These two components have different types of recognition receptors and differ in the speed in which they respond to a potential threat to the host (Fig. 10-1).

are executed by T lymphocytes and antibodies produced by B lymphocytes/plasma cells.

Cells of the innate immune system, including macrophages and dendritic cells (DCs), use pattern recognition receptors encoded directly by the germ line DNA, respond to biochemical structures commonly shared by a variety of different pathogens, and elicit a rapid

2

4

The immune response

Innate response

Foreign pathogen

Section 4

Rapid response Pattern recognition receptorsgerm-line encoded - CD14, mannose and scavenger Cytokines, costimulatory molecules-instructive role for adaptive response Direct response for host defense - Phagocytosis - Antimicrobial activity

Adaptive response

Slow response Recognition - initially low affinity receptors Gene rearrangement Clonal expansion Response - T and B cells with receptors encoded by fully rearranged genes Memory

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Figure 10-1  The immune system of higher vertebrates uses both innate and adaptive immune responses. These immune responses differ in the way they recognize foreign antigens and the speed with which they respond; yet, they complement each other in eradicating foreign pathogens.

response against these pathogens, although no lasting immunity is generated. In contrast, cells of the adaptive immune system, T and B lymphocytes, bear specific antigen receptors encoded by rearranged genes, and in comparison to the innate response, adaptive immunity develops more slowly. A unique feature of the adaptive immune response is its ability to generate and retain memory; thus, it has the capability of providing a more rapid response in the event of subsequent immunologic challenge. Although the innate and adaptive immune responses are distinct, they interact and can each influence the magnitude and type of their counterpart. Together, the innate and adaptive immune systems act in synergy to defend the host against infection and cancer. This chapter describes the roles of the innate and adaptive immune response in generating host defense mechanisms in skin.

INNATE IMMUNE RESPONSE Immune mechanisms that are used by the host to immediately defend itself are referred to as innate immunity. These include physical barriers such as the skin and mucosal epithelium; soluble factors such as complement, antimicrobial peptides, chemokines, and cytokines; and cells, including monocytes/macrophages, DCs, natural killer cells (NK cells), and polymorphonuclear leukocytes (PMNs) (Fig. 10-2). Our present understanding of innate immunity is based on the studies of Elie Metchnikoff who, in 1884, published studies on the water flea Daphnia and its interaction with a yeast-like fungus.1 He demonstrated that cells of the water flea, which he termed “phagocytes,” were attracted to and engulfed the foreign spores, which were subsequently “killed and destroyed.” Thus, Metchnikoff described the key direct functions of cells of the innate immune system:

(1) rapid detection of microbes, (2) phagocytosis, and (3) antimicrobial activity. In addition to this direct role in host defense, the innate immune system has an indirect role in instructing and determining the type of adaptive T and B cell responses. Finally, by inducing inflammation, the innate immune response can also induce tissue injury.

PHYSICAL AND CHEMICAL BARRIERS2 Physical structures prevent most pathogens and environmental toxins from harming the host. The skin and the epithelial lining of the respiratory, gastrointestinal, and the genitourinary tracts provide physical barriers between the host and the external world. Skin, once thought to be an inert structure, plays a vital role in protecting the individual from the external environment. The epidermis impedes penetration of microbial organisms, chemical irritants, and toxins; absorbs and blocks solar and ionized radiation; and inhibits water loss (see Chapter 47).

MOLECULES OF THE INNATE IMMUNE SYSTEM COMPLEMENT.3 (See eFig. 10-2.1 in online edition;

see also Chapter 37). One of the first innate defense mechanisms that awaits pathogens that overcome the epithelial barrier is the alternative pathway of complement. Unlike the classical complement pathway that requires antibody triggering, the lectin-dependent pathway as well as the alternative pathway of complement activation can be spontaneously activated by microbial surfaces in the absence of specific antibodies (see eFig. 10-2.1 in online edition). In this way, the host defense mechanism is activated immediately

4

The innate immune response in skin

Pathogens

UV radiation

Irritants

1. Antimicrobial response: • defensins • cathelicidins/psoriasin • reactive oxygen intermediates

KC

NK cell

T cell response (Th1, Th2, Treg, Th17)

Figure 10-2  The innate immune response in skin. In response to exogenous factors, such as foreign pathogens, ultraviolet (UV) radiation, and chemical irritants, innate immune cells [granulocytes, mononuclear phagocytes, natural killer (NK) cells, keratinocytes] mount different types of responses including (1) release of antimicrobial agents; (2) induction of inflammatory mediators, such as cytokines, chemokines, neuropeptides, and eicosanoids; and (3) initiation and modulation of the adaptive immune response. DDC = dermal dendritic cell; KC = keratinocyte; LC = Langerhans cell; MHC II = major histocompatibility complex class II; Th1 = type I T cells; Th2 = type II T cells; Th17 = type 17 T cells; T reg = regulatory T cells.

after encountering the pathogen without the 5–7 days required for antibody production.

Antimicrobial Peptides.4 Antimicrobial pep-

tides serve as an important evolutionarily conserved innate host defense mechanism in many organisms. They typically are positively charged and are amphipathic, possessing both hydrophobic and hydrophilic surfaces. The antimicrobial activity of these peptides is thought to relate to their ability to bind membranes of microbes (through their hydrophobic surface) and form pores in the membrane, leading to microbial killing. There are numerous antimicrobial peptides identified in various human tissues and secretions. This section will focus on antimicrobial peptides identified in resident skin cells, including human b-defensins (HBD-1, HBD-2, HBD-3), cathelicidin (LL-37), psoriasin, and RNase 7, which have all been demonstrated to be produced by keratinocytes, and dermcidin, which is secreted in human sweat. In addition, there are numer-

ous other antimicrobial peptides that are produced by cells that infiltrate the skin and may participate in cutaneous innate immune responses.5 b-Defensins are cysteine-rich cationic low-molecular-weight antimicrobial peptides. The first human b-defensin, HBD-1, is constitutively expressed in the epidermis and is not transcriptionally regulated by inflammatory agents. HBD-1 has antimicrobial activity against Gram-negative bacteria and appears to play a role in keratinocyte differentiation. A second human b-defensin, HBD-2, was discovered in extracts of lesions from psoriasis patients.6 Unlike HBD-1 expression, HBD-2 expression is inducible by components of microbes, including Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans.6 Not only can components of microbes stimulate expression of HBD2, but proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interleukin 1 (IL-1) can also induce HBD-2 transcription in keratinocytes.6 When tested for antimicrobial activity, HBD-2 was effective

Innate and Adaptive Immunity in the Skin

Macrophage

::

LC/DDC

3. influence adaptive immune response: • activation of T cells

Chapter 10

2. Inflammatory response: • cytokines • chemokines • neuropeptides • eicosanoids

MHC II

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Section 4 :: Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

108

against Gram-negative bacteria such as Escherichia coli and P. aeruginosa and has a weak bacteriostatic effect against Gram-positive bacteria such as S. aureus.6 HBD-3 is another b-defensin that was first isolated from extracts of lesions from psoriasis patients.7 Contact with TNF-a and with bacteria was found to induce HBD-3 messenger RNA expression in keratinocytes. In addition, HBD-3 demonstrated potent bactericidal activity against S. aureus and vancomycin-resistant Enterococcus faecium. Therefore, HBD-3 is among the first human b-defensins in skin to demonstrate effective antimicrobial activity against Gram-positive bacteria. The localization of human b-defensins to the outer layer of the skin and the fact the b-defensins have antimicrobial activity against a variety of microbes suggest that human b-defensins are an essential part of cutaneous innate immunity. Furthermore, evidence indicating that human b-defensins attract DCs and memory T cells via CC chemokine receptor 6 (CCR6)8 provides a link between the innate and the adaptive immunity in skin. Cathelicidins are cationic peptides with a structurally variable antimicrobial domain at the C-terminus. Whereas in mammals like pigs or cattle a variety of cathelicidin genes exists, men (and mice) possess only one gene. The human precursor protein hCAP18 (human cathelicidin antimicrobial protein 18) is produced by skin cells, including keratinocytes, mast cells, neutrophils, and ductal cells of eccrine glands. Neutrophil proteases (i.e., proteinase 3) process hCAP18 into the effector molecule LL-37 (named LL-37 for the 37-amino acid active antimicrobial peptide liberated from the C-terminus of the protein), which plays an important role in cutaneous host defense because of its pronounced antibacterial,9,10 antifungal,11 and antiviral12,13 activities. LL-37 further contributes to innate immunity by attracting mast cells and neutrophils via formyl peptide receptor-like 1 and by inducing mediator release from the latter cells via a G protein-dependent, immunoglobulin (Ig) E-independent mechanism.14 It has now been shown that LL-37 is secreted into human sweat, where it is cleaved by a serine protease-dependent mechanism into its peptides RK-31 or KS-30. Interestingly, these components display an even more potent antimicrobial activity than intact LL-37.15 One of the most important inducers of LL-37 expression is vitamin D, which can be triggered by Toll-like receptor (TLR) activation of the vitamin D receptor and vitamin D-1-hydroxylase genes, leading to enhanced antimicrobial killing.16,17 In atopic dermatitis (see Chapter 14), LL-37 is downregulated, probably due to the effect of the T2 cytokines IL-4 and IL-13, which renders atopic skin more susceptible to skin infections with, for example, S. aureus, vaccinia virus (eczema vaccinatum), or herpes simplex virus (HSV) (eczema herpeticum).10,12,13 Furthermore, patients with rosacea have been found to possess high levels of aberrantly processed forms of cathelicidin peptides (due to posttranslational processing by stratum corneum tryptic enzyme), which contributes to the increased inflammation in the skin.18 Cathelicidin can also form complexes with self-DNA, which promotes activation of TLR9 on plasmacytoid

dendritic cells in the dermis, resulting in enhanced cutaneous inflammation that contributes to psoriasis pathogenesis.19 Another important human antimicrobial peptide has now been identified, psoriasin (S100A7),20 which elicits its antimicrobial effect by permeabilization of bacterial membranes.21 It is secreted predominantly by keratinocytes and plays a major role in killing the common gut bacterium E. coli. In fact, in vivo treatment of human skin with antipsoriasin antibodies results in the massive growth of E. coli.20 Furthermore, expression of psoriasin by keratinocytes has been shown to occur via TLR5 stimulation by E. coli flagellin.22 In addition to antimicrobial activity, psoriasin also functions as a chemoattractant for CD4 cells and neutrophils.23 RNase 7 was originally isolated from the stratum corneum from healthy human skin.24 RNase 7 has potent ribonuclease activity but also broad-spectrum antimicrobial activity against S. aureus, P. acnes, P. aeruginosa, E. coli, and C. albicans. RNase 7 production can be induced in cultured human keratinocytes by IL-1b, IFN-g, and bacterial challenge. Interestingly, high expression of RNase 7 in human skin confers protection against S. aureus cutaneous infection.25 Dermcidin is an antimicrobial peptide that is expressed by human sweat glands.26 Dermcidin goes through postsecretory proteolytic processing in sweat that gives rise to anionic and cationic dermcidin peptides that are secreted onto the skin surface. These dermcidin peptides have broad antimicrobial activity against S. aureus, E. coli, E. faecalis, and C. albicans. Although the mechanism of action of dermcidin activity is unknown, it does not involve pore formation like other antimicrobial peptides.27

PATTERN RECOGNITION RECEPTORS. How do the cells of the innate immune system recognize foreign pathogens? One way that pathogens can be recognized and destroyed by the innate immune system is via receptors on phagocytic cells. Unlike adaptive immunity, the innate immune response relies on a relatively small set of germ line-encoded receptors that recognize conserved molecular patterns that are shared by a large group of pathogens. These are usually molecular structures required for survival of the microbes and therefore are not subject to selective pressure. In addition, pathogen-associated molecular patterns are specific to microbes and are not expressed in the host system. Therefore, the innate immune system has mastered a clever way to distinguish between self and nonself and relays this message to the adaptive immune system. Of key importance was the discovery of the Tolllike receptors (TLRs), named after the Drosophila Toll gene whose protein product, Toll, participates in innate immunity and in dorsoventral development in the fruit fly.30,31 The importance of Toll signaling in mammalian cells was confirmed by the demonstration that the transmembrane leucine-rich protein TLR4 is involved in lipopolysaccharide (LPS) recognition.32 In addition to TLRs, there exist a variety of other molecules that sense the presence of pathogens. These include the NOD proteins (see below), triggering

Toll-Like Receptors.38 There is now substan-

SsRNA LPS

CpG DNA

ds RNA

Flagellin

Profilin (?)

Lipoproteins

X?

TLR9

TLR5

TLR7

TLR8

TLR4

TLR3

TLR 2/6

TLR11

TLR 1/2

TLR10 TRIF IRF3

NF-κB pathway

Influence adaptive response Cytokine production Costimulatory molecules

Cell mediated immunity Humoral immunity

Innate and Adaptive Immunity in the Skin

Toll-like receptors and host defense

4

::

tial evidence to support a role for mammalian TLRs in innate immunity (Fig. 10-3). First, TLRs recognize pathogen-associated molecular patterns present in a variety of bacteria, fungi, and viruses. Second, TLRs are expressed at sites that are exposed to microbial threats. Third, the activation of TLRs induces signaling pathways that, on the one hand, stimulate the produc-

tion of antimicrobial effector molecules, and, on the other, promote the expression of costimulatory molecules and the release of cytokines and, as a result, the augmentation of the adaptive response. Fourth, TLRs directly activate host defense mechanisms that then combat the foreign invader. Experiments performed in the Modlin laboratory39 and others40 led to the exciting finding that microbial lipoproteins trigger host responses via TLR2, requiring the acyl functions for activity. Subsequently, triacylated lipoproteins were found to activate TLR2/1 heterodimers,41 whereas diacylated lipoproteins were found to activate TLR2/6 heterodimers.42 For recognition of bacteria, the TLR system is redundant: TLR9 is activated by unmethylated DNA sequences (CpG dinucleotides) found in bacterial DNA43 and TLR5 activated by bacterial flagellin.44 Specific TLRs are involved in viral recognition: TLR3 is activated by viral derived double-stranded RNA45 and TLR7 and TLR8 by virus-derived single-stranded RNA.46 The finding that different TLRs have distinct patterns of expression, particularly on monocytes, macrophages, dendritic cells, B cells, endothelia, and epithelia, suggests that each TLR could trigger a specific host response. Furthermore, TLRs are expressed in specific

Chapter 10

receptors expressed on myeloid cell (TREM) proteins,33 the family of Siglec molecules,34 and a group of C-type lectin receptors.35 The latter are prominently expressed on antigen-presenting cells (APCs) as, for instance, dectin-1 and DC-SIGN [DC-specific intercellular adhesion molecule 3 (ICAM-3) grabbing nonintegrin], which is actually expressed on tissue macrophages.36 They are able to mediate efficient binding of microorganisms; facilitate phagocytosis; and induce activation of signaling pathways that result in antimicrobial activity. Members of the TREM protein family function as amplifiers of innate responses. Extreme examples of the consequences of microbe activation of TREM proteins are life-threatening septicemia and the deadly hemorrhagic fevers caused by Marburg and Ebola virus infection.37

Immunomodulatory genes

Tissue injury Apoptosis Septic shock

Direct antimicrobial response Reactive oxygen intermediates

Figure 10-3  Toll-like receptors (TLRs) mediate innate immune response in host defense. Activation of TLRs by specific ligands induces (1) cytokine release and costimulatory molecules that instruct the type of adaptive immune response; (2) direct antimicrobial response; and (3) tissue injury. CpG DNA = immunostimulatory cytosine- and guanine-rich sequences of DNA; dsRNA = double-stranded RNA; LPS = lipopolysaccharide; NF-kB = nuclear factor kB; ssRNA = single-stranded RNA; X = ligand unknown.

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Section 4 ::

subcellular compartments: TLR7, 8, and 9 are located in endosomes, where they encounter microbial pathogens in the endocytic pathway. The other TLRs are expressed on the cell surface and detect microbial ligands in the extracellular environment. The expression of TLRs on cells of the monocyte/ macrophage lineage is consistent with the role of TLRs in modulating inflammatory responses via cytokine release. Because these cells migrate into sites that interface with the environment—lung, skin, and gut—the location of TLR-expressing cells would situate them to defend against invading microbes. TLR expression by adipocytes, intestinal epithelial cells, and dermal endothelial cells supports the notion that TLRs serve a sentinel role with regard to invading microorganisms. The regulation of TLR expression is critical to their role in host defense, yet few factors have been identified that modulate this process. IL-4 acts to downregulate TLR expression,47 which suggests that T helper 2 (T2) adaptive immune responses might inhibit TLR activation.

Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

DETAILED STUDIES OF TLR Tlr-Induced Cytokine Release. TLR activation of a variety of cell types has been shown to trigger release of both proinflammatory and immunomodulatory cytokines.48–52 TLR activation of monocytes and DC induces IL-12 and IL-18, required for generation of a Th1 response, and IL-1b, IL-6, IL-23, involved in the generation of a Th17 response, as well as the ­anti-inflammatory IL-10.53–56 The relative induction of specific cytokine patterns determines the type of adaptive T-cell response (see Chapter 11). MF and DC Differentiation. TLRs can regulate

phagocytosis either through enhancing endosomal fusion with the lysosomal compartment57 or through induction of a phagocytic gene program including multiple scavenger receptors.58 Activation of TLRs on monocytes leads to the induction of IL-15 and IL15R, triggering differentiation into CD209+ MF36 with microbicidal activity.59 Activation of TLRs on monocytes also induces GM-CSF and GM-CSFR, triggering differentiation into immature DC with the capacity to release cytokines and efficiently present antigen to T cells.36 In addition, activation of TLRs on immature DC leads to further maturation with enhanced T-cell stimulatory capacity.60

TLR-Induced Antimicrobial Activity. In Dro-

110

sophila, Toll is critical for host defense. The susceptibility of mice with spontaneous mutations in TLRs to bacterial infection indicates that mammalian TLRs play a similar role. Activation of TLR2 by microbial lipoproteins induces activation of the inducible nitric oxide (NO) synthase (NOS-II or iNOS) promoter,39 which leads to the production of NO, a known antimicrobial agent. There is strong evidence that TLR2 activation leads to killing of intracellular Mycobacterium tuberculosis in both mouse and human macrophages.54 In mouse macrophages, bacterial lipoprotein activation of TLR2 leads to a NO-dependent killing of intracellular tubercle bacilli. In human monocytes and alveolar macro-

phages, bacterial lipoproteins similarly activate TLR2 to kill intracellular M. tuberculosis; however, this occurs by an antimicrobial pathway that is NO-independent. Instead, a key antimicrobial mechanism for TLR-activated human monocytes involves induction of the 25-hydroxyvitamin D3-1a-hydroxylase (CYP27b1), which converts the 25D into the active 1,25D form, upregulation and activation of the vitamin D receptor (VDR), and downstream induction of the antimicrobial peptide cathelicidin.16,59,61–63 The ability of TLR2/1 activation to upregulate expression of CYP27b1 and the VDR is IL-15 dependent.36 Simultaneous triggering of IL-1b activity and activation of the VDR induces HBD2, also required for antimicrobial activity. Activation of TLRs 3, 4, 7, 8, and 9 leads to induction of antiviral activity, dependent on type I IFN secretion and involving specific signaling pathways.64 Two TLR-mediated pathways have been identified: type I IFN production occurs through a MyD88-independent pathway in response to TLR3 and TLR4 activation,65 and, following stimulation with agonists of TLRs 7, 8, and 9, through a MyD88-dependent pathway.66 The activation of TLRs can also be detrimental, leading to tissue injury. The administration of LPS to mice can result in manifestations of septic shock, which is dependent on TLR4.32 Evidence suggests that TLR2 activation by Propionibacterium acnes induces inflammatory responses in acne vulgaris, which lead to tissue injury.67 Aliprantis et al demonstrated that microbial lipoproteins induce features of apoptosis via TLR2.40 Thus, microbial lipoproteins have the ability to elicit both TLR-dependent activation of host defense and tissue pathology. This dual signaling pathway is similar to TNF receptor and CD40 signaling, which leads to both nuclear factor-kB activation and apoptosis.68,69 In this manner, it is possible for the immune system to use the same molecules to activate host defense mechanisms and then, by apoptosis, to downregulate the response from causing tissue injury. Activation of TLR can lead to the inhibition of the major histocompatibility complex (MHC) class II antigen presentation pathway, which can downregulate immune responses leading to tissue injury but may also contribute to immunosuppression.70 Finally, Toll activation has been implicated in bone destruction.52 The critical biologic role of TLRs in human host defense can be deduced from the finding that TLR4 mutations are associated with LPS hyporesponsiveness in humans.71 By inference, one can anticipate that humans with genetic alterations in TLR may have increased susceptibility to certain microbial infections. Furthermore, it should be possible to exploit the pathway of TLR activation as a means to endorse immune responses in vaccines and treatments for infectious diseases as well as to abrogate responses detrimental to the host.

Cells of the Innate Immune System PHAGOCYTES. Two key cells of the innate immune system are characterized by their phagocytic function:

Effector Functions of Phagocytes. Activation

influence macrophage differentiation: IFN-g treatment results in “classically activated” macrophages, with antimicrobial activity, whereas in contrast IL-4 or IL-13 triggers differentiation into “alternatively activated” macrophages, which contribute to humoral and antiparasite immunity.82,83 Cytokines produced by the innate immune response also induce distinct macrophage differentiation programs.84 IL-10 induces the phagocytic program in macrophages, leading to the uptake of lipids and bacteria. In contrast, IL-15 induces a macrophage antimicrobial program. These data establish that the innate immune response, by selectively inducing IL-10 versus IL-15, differentially programs macrophages for phagocytosis versus antimicrobial responses that largely determines the outcome of infection. Phagocytic cells of the innate immune system can also be activated by cells of the adaptive immune system. CD40 is a 50-kDa glycoprotein present on the surface of B cells, monocytes, DCs, and endothelial cells. The ligand for CD40 is CD40L, a type II membrane protein of 33 kDa, preferentially expressed on activated CD4+ T cells and mast cells. CD40−CD40 ligand interaction plays a crucial role in the development of effec-

How Do NK Cells Discriminate Between Normal and Transformed or PathogenInfected Tissue? All nucleated cells express the

MHC class I molecules. NK cells have receptors, termed killer inhibitory receptors, which recognize the self-MHC class I molecules. This recognition results in the delivery of a negative signal to the NK cell that paralyzes it. If a nucleated cell loses expression of its MHC class I molecules, however, as often happens after malignant transformation or virus infection, the NK cell, on encountering it, will become activated and kill it. In addition, NK cells have activating receptors that bind MHC-like ligands on target cells. One such receptor is NKGD2, which binds to the human nonclassic MHC class I chain-related A and B molecules, MICA and MICB.87 MICA and MICB are not expressed in substantial amounts on normal tissues, but are overexpressed on carcinomas.88 NK cells are able to kill MICA/MICB-bearing tumors, which suggests a role for NKGD2 in immune surveillance. Another cell type that, at least in mice, could serve a similar function is the IFN-producing killer DC, which shares several features with DCs and NK cells.89,90 Their human equivalent has yet to be identified.

KERATINOCYTES. Once thought to only play a role in maintaining the physical barrier of the skin, keratinocytes, the predominant cells in the epidermis, can participate in innate immunity by mounting

Innate and Adaptive Immunity in the Skin

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Natural Killer Cells. NK cells appear as large granular lymphocytes. In humans, the vast majority of these cells exhibit the CD3−, CD56+, CD16+, CD94+, and CD161+ phenotype. Their function is to survey the body looking for altered cells, be they transformed or infected with viruses (e.g., cytomegalovirus), bacteria (e.g., Listeria monocytogenes), or parasites (e.g., Toxoplasma gondii). These pathogens are then killed directly via perforin/granzyme- or Fas/Fas ligand (FasL)-dependent mechanisms or indirectly via the secretion of cytokines (e.g., IFN-g).

4

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of phagocytes by pathogens induces several important effector mechanisms, for example, triggering of cytokine production. A number of important cytokines are secreted by macrophages in response to microbes, including IL-1, IL-6, TNF-a, IL-8, IL-12, and IL-10 (see also Chapter 11). Another important defense mechanism triggered in phagocytes in response to pathogens is the induction of direct antimicrobial responses. Phagocytic cells such as PMNs and macrophages recognize pathogens, engulf them, and induce antimicrobial effector mechanisms to kill the pathogens. The induction and/or release of toxic oxygen radicals, lysosomal enzymes, and antimicrobial peptides leads to direct killing of microbial organisms.4 Similarly, activation of TLRs on macrophages induces these various antimicrobial pathways as already discussed above.

tor functions. CD4+ T cells activate macrophages and monocytes to produce TNF-a, IL-1, IL-12, interferon-g (IFN-g), and NO via CD40–CD40L interaction. CD40L has also been shown to rescue circulating monocytes from apoptotic death, thus prolonging their survival at the site of inflammation. In addition, CD40–CD40L interaction during T-cell activation by APCs results in IL-12 production. Therefore, it can be concluded that CD40–CD40L interactions between T cells and macrophages play a role in maintenance of T1-type cellular responses and mediation of inflammatory responses. Other studies have established a role for CD40–CD40L interactions in B-cell activation, differentiation, and Ig class switching.85 In addition, CD40–CD40L interaction leads to upregulation of B7.1 (CD80) and B7.2 (CD86) on B cells. This costimulatory activity induced on B cells then acts to amplify the response of T cells. These mechanisms underscore the importance of the interplay between the innate and the adaptive immune system in generating an effective host response.

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macrophages and PMNs. These cells have the capacity to take up pathogens, recognize them, and destroy them. Some of the functions of these cells are regulated via TLRs and complement receptors as outlined earlier. PMNs are normally not present in skin; however, during inflammatory processes, these cells migrate to the site of infection and inflammation, where they are the earliest phagocytic cells to be recruited. These cells have receptors that recognize pathogens directly (see Pattern Recognition Receptors), and due to their expression of FcgRIII/CD16 and C3bR/CD35, can phagocytose microbes coated with antibody and with the complement component C3b. As a consequence, granules (containing myeloperoxidase, elastase, lactoferrin, collagenase, and other enzymes) are released, and microbicidal superoxide radicals (O2−) are generated (see Chapter 30).

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an immune and/or inflammatory response through secretion of cytokines and chemokines, arachidonic acid metabolites, complement components, and antimicrobial peptides. Keratinocytes of unperturbed skin produce only a few of these mediators, such as the cytokines IL-1, IL-7, and transforming growth factor-b (TGF-b), constitutively. Resident keratinocytes contain large quantities of preformed and biologically active IL-1a as well as immature IL-1b in their cytoplasm.91 The likely in vivo role of this stored intracellular IL-1 is that of an immediate initiator of inflammatory and repair processes after epidermal injury. IL-7 is an important lymphocyte growth factor that may have a role in the survival and proliferation of the T lymphocytes of human skin. Some evidence exists for the IL-7-driven propagation of lymphoma cells in Sézary syndrome. TGF-b, in addition to its growth-regulating effects on keratinocytes and fibroblasts, modulates the inflammatory as well as the immune response92 and is important for LC development (see in Langerhans Cells).93 On delivery of certain noxious, or at least potentially hazardous, stimuli (e.g., hypoxia, trauma, nonionizing radiation, haptens, or other rapidly reactive chemicals like poison ivy catechols, silica, LPS, and microbial toxins), the production and/or release of many cytokines is often dramatically enhanced. The biologic consequences of this event are manifold and include the initiation of inflammation (IL-1, TNF-a, IL-6, members of the chemokine family), the modulation of LC phenotype and function (IL-1, GM-CSF, TNF-a, IL-10, IL-15), T-cell activation (IL-15, IL-18),94,95 T-cell inhibition (IL10, TGF-b),96 and skewing of the lymphocytic response in either the type 1 (IL-12, IL-18),97 type 2 (thymic stromal lymphopoietin),98 or Th17 (IL-23) direction.99 In some cases, keratinocytes may also play a role in amplifying inflammatory signals in the epidermis originating from numerically minor epidermal cell subsets. One prominent example is the induction of proinflammatory cytokines such as TNF-a in keratinocytes by LC-derived IL-1b in the initiation phase of allergic contact dermatitis.100 In the presence of a robust stimulus, keratinocyte-derived cytokines may be released into the circulation in quantities that cause systemic effects. During a severe sunburn reaction, for example, serum levels of IL-1, IL-6, and TNF-a are clearly elevated and probably responsible for the systemic manifestations of this reaction, such as fever, leukocytosis, and the production of acute-phase proteins.101 There is also evidence that the ultraviolet (UV) radiation-inducible cytokines IL-6 and IL-10 can induce the production of autoantibodies and thus be involved in the exacerbation of autoimmune diseases such as lupus erythematosus. The fact that secreted products of keratinocytes can reach the circulation could conceivably also be used for therapeutic purposes. The demonstration by Fenjves et al102 that grafting of apolipoprotein E genetransfected human keratinocytes onto mice results in the detection of apolipoprotein E in the circulation of the mouse supports the feasibility of such an approach. Some of the innate functions of keratinocytes can be elicited by TLR activation, since keratinocytes express TLRs 1–6 and 9. Thus, by sensing microbial pathogens

via TLRs, keratinocytes may act as first-responders in cutaneous innate immunity. Activation of TLRs leads to keratinocyte production of proinflammatory cytokines (including TNF-a and IL-8), antimicrobial peptides (HBD-2 and HBD-3), and reactive oxygen mediators (iNOS).103–105 Activation of TLR3 and TLR9 on keratinocytes induces production of type I interferon (IFN-a/b), which may be important in promoting antiviral immune responses.105 Lastly, these TLR-mediated responses can be enhanced via danger signals such as toxins, irritants, UV light, purines generated during an infection (P2×7 receptor activation), and activation of other pattern-recognition receptors (NOD1 and NOD2), which all promote inflammasome-mediated activation of caspase-1 that results in cleavage of pro-IL‑1b into its active form.106 Another important function of keratinocytes is the production/secretion of factors governing the influx and efflux of leukocytes into and out of the skin. Two good examples are the chemokines thymus and activation-regulated chemokine (TARC; CC chemokine ligand 17, or CCL17) and cutaneous T cell-attracting chemokine (CTACK)/CCL27 and their corresponding receptors CCR4 and CCR10, selectively expressed on skin-homing T lymphocytes. Blocking of both chemokines drastically inhibits the migration of T cells to the skin in a murine model of contact hypersensitivity (CHS).107 KC-derived macrophage inflammatory protein 3a (MIP-3a)/CCL20 also plays an important role in leukocyte recruitment to the epidermis. Its secretion is triggered or enhanced by IL-17 and its counterreceptor CCR6 is present on LC precursors and certain T cells.108–110 The T17 cytokines, IL-17, IL-21, and IL-22 also modulate other keratinocyte innate immune functions. For example, IL-17 and IL-22 promote keratinocyte production of antimicrobial peptides, including HBD-2, cathelicidin, and psoriasin.111,112 In addition, IL-21 and IL-22 induce keratinocyte proliferation, leading to epidermal hyperplasia and acanthosis as seen in psoriasis.113,114 The demonstration of cytokine receptors on and cytokine responsiveness of keratinocytes established that the functional properties of these cells can be subject to regulation by cells of the immune system. As a consequence, keratinocytes express, or are induced to express, immunologically relevant surface moieties that can be targeted by leukocytes for stimulatory or inhibitory signal transduction. In addition to cytokines, keratinocytes secrete other factors such as neuropeptides, eicosanoids, and reactive oxygen species. These mediators have potent inflammatory and immunomodulatory properties and play an important role in the pathogenesis of cutaneous inflammatory and infectious diseases as well as in aging. Keratinocytes synthesize complement and related receptors including the C3b receptor [complement receptor 1 (CR1), CD35], the Epstein-Barr virus receptor CR2 (C3d receptor, CD21), the C5a receptor (CD88), the membrane cofactor protein (CD46), the decayaccelerating factor (CD55), and complement protectin (CD59). CD59 may protect keratinocytes from attack by complement. Its engagement by CD2 stimulates the

secretion of proinflammatory cytokines from keratinocytes. Membrane cofactor (CD46) is reported to be a receptor for M protein of group A Streptococci and for measles virus.115 Its ligation induces proinflammatory cytokines in keratinocytes such as IL-1a, IL-6, and GMCSF.

ADAPTIVE IMMUNE RESPONSE

LYMPHOCYTES

T-Cell Antigen Receptor (TCR). The T-cell anti-

gen receptor (TCR) is a complex of molecules consisting of an antigen-binding heterodimer (a/b or g/d chains) that is noncovalently linked with five CD3 subunits [(1) g, (2) d, (3) e, (4) ζ, or (5) h). The TCR chains have amino acid sequence homology with structural similarities to Ig heavy and light chains. The genes encoding TCR molecules are encoded as clusters of gene segments (V, J, D, C, or constant) that rearrange during T-cell maturation (eFig. 10-3.1 in online edition). Together with the addition of nucleotides at the junction of rearranged gene segments, this recombinatorial process, which involves the enzymes recombinase activating gene 1 and 2, results in a heterogeneity and diversity of the antigen recognition unit that is broad enough to allow for a successful host defense. TCR a/b or TCR g/d molecules must be paired with CD3 molecules to be inserted into the T-cell surface membrane117 (see Fig. 10-4). The TCR chains form the actual antigenbinding unit, whereas the CD3 complex mediates signal transduction, which results in either productive activation or nonproductive silencing of the T lymphocyte. Most T cells express a/b TCRs, which typically bind antigenic peptides presented by MHC molecules. ∼/b T cells includes Th1, Th2, Immunity provided by a Th17 and T reg responses (see Section “Functionality”).

Innate and Adaptive Immunity in the Skin

B CELLS. B cells mature in the fetal liver and adult bone marrow. They produce antibody-protein complexes that bind specifically to particular molecules defined as antigens. As a consequence of recombinatorial events in different Ig gene segments (V or variable; D or diversity; J or joining), each B cell produces a different antibody molecule (eFig. 10-3.1 in online edition). Some of this antibody is present on the surface of the B cell, conferring the unique ability of that B cell to recognize a specific antigen. B cells then differentiate into plasma cells, the actual antibody-producing and -secreting cells. Plasma-cell secreted Ig comprise the dimer IgA, the monomers IgD, IgE, and IgG as well as the pentamer IgM that mediate humoral immune responses. In general, antibodies bind to microbial agents and neutralize them or facilitate uptake of the pathogen by phagocytes that destroy them. Briefly, IgA can be found in mucosal tissues, saliva, tears, or breast milk and prevents colonization by various pathogens. IgD functions mainly as an antigen receptor on B cells and, as recently discovered, activates mast cells and basophils to produce antimicrobial factors.116 IgE binds to allergens on mast cells and basophils and can thereby trigger histamine release and allergic reactions including anaphylaxis and urticaria. In addition, some evidence exists that it can protect against parasitic and helminthic infections. IgG provides the majority of antibody responses that contribute to the immune defense against extracellular pathogens. It is the only antibody that is capable of crossing the placenta in order to protect the fetus. Finally, IgM is available either surface-bound on B cells or as secreted form and eliminates microbes

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Three subsets of lymphocytes exist in the human immune system: B cells, T cells, and NK cells (see Section “Cells of the Innate Immune System”). The adaptive immune response is mediated by T and B lymphocytes. The unique role of these cells is the ability to recognize antigenic specificities in all their diversity. All lymphocytes derive from a common bone marrow stem cell. This finding has been exploited in various clinical settings, with attempts to restore the entire lymphocyte pool by bone marrow or stem cell transplantation.

T CELLS. T cells mature in the thymus, where they are selected to live or to die. Those T cells that will have the capacity to recognize foreign antigens are positively selected and can enter the circulation. Those T cells that react to self are negatively selected and destroyed. T cells have the unique ability to direct other cells of the immune system. They do this, in part, by releasing cytokines. For example, T cells contribute to cell-mediated immunity (CMI), required to eliminate intracellular pathogens, by releasing cytokines that activate macrophages and other T cells. T cells release cytokines that activate NK cells and permit the growth, differentiation, and activation of B cells. T cells can be classified and subdivided in different ways: (1) on the basis of the T cell receptor; (2) on the basis of the accessory molecules CD4 and CD8; (3) on the basis of their virginity, i.e., their activation status (naive, memory, effector T cells); and (4) on the basis of their functional role in the immune response, which is often linked to the cytokine secretion property of the respective cell population. We have used the abbreviations Th1 and Th2 to distinguish CD4+ helper T cell subtypes but, as discussed below, many of the functional attributes, including cytokine production, of Th cells are not as clearly defined as previously thought and some cytokine profiles are also attributable to CD8+ cytotoxic T cells (Tc) (see Section “Functionality”).

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The strength and the type of the innate response determines both the quantity and quality of an adaptive response initiated by dendritic APCs in the epidermis (LCs) and dermis (dermal DCs or DDCs) and executed by T lymphocytes and antibodies.

in the early stages of humoral immunity before there is sufficient IgG production. Antibodies are also responsible for mediating certain pathologic conditions in skin. In particular, antibodies against self-antigens (mostly IgG, but also IgA) lead to autoimmune disease, typified in the pathogenesis of pemphigus and bullous pemphigoid (see Chapter 37 for more details about B cells and antibody production).

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T-cell differentiation Antigen Dendritic cell

Naive T-cell IFN-γ IL-2 LY-α

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IFNs, IL-12

IL-6, IL-21

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IL-4 IL-5 IL-6 IL-13

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TGF-β, IL-2 TGF-β IL-4

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GATA-3

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IL-1-β IL-23 TGF-β IL-6

Th9 IL-9 IL-10

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Th17 RORC

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IL-17A IL-17F

IL-22 IL-26

Figure 10-4  Schematic view of events governing and occurring in T-cell differentiation. Depending on the type and activation status of the antigen-presenting dendritic cells (DCs) and on the type and amounts of cytokines secreted by these and/or other cells, naive T cells will expand and differentiate into various directions, i.e., Th1 cells, Th2 cells, Th9 cells, Th17 cells, Th22 cells, T reg cells, and Tfh cells. They exhibit different types of transcription factors (e.g., T-bet, GATA-3, RORC, FoxP3, Bcl-6) and secrete different types of cytokines.

In contrast, only a small subset of T cells express g/d TCRs. These T cells have the capacity to directly bind pathogen-derived glycoproteins or nonclassical MHC molecules. It has been shown that g/d T cells in men and mice predominantly display a tissue-associated TCR repertoire as well as a memory phenotype, both probably due to chronical stimulation by nonpeptide antigens within the tissue. Importantly, they act early during immune response and are therefore termed “innate-like effectors.” Previous studies conducted in mice infected with Listeria monocytogenes or Nippostrongylus brasiliensis revealed that g∼/d T cells discriminate early between these pathogens and react by IFN-g ∼/b T-cell responses versus IL-4 production, skewing a in a Th1 or Th2 direction, respectively.118 Meanwhile, growing evidence exists that human and murine g∼/d T cells also have the capacity to produce IL-17 during bacterial or viral infections and thereby significantly contribute to the early innate immune defense.119–121 CD4+ Helper T Cells. The original observation that CD4+ T cells are critical for helping B cells to produce antibodies by triggering their differentiation into plasma cells in the humoral response coined the term “T helper cells” (Th cells). During the past years these lymphocytes have been characterized extensively. To our current knowledge, CD4+ T cells represent a heterogeneous cell population with diverse function depending on environmental requirements that play a central role in humoral and cell-mediated immunity. Effector CD4+ T cells protect against pathogens mainly by their production of Th1, Th2, or Th17 cytokines (i.e., IFN-g, IL-4, IL-17) and influence immune responses through both “helper” and “effector” functions. In

contrast, regulatory CD4+ T cells have the capacity to downregulate disproportionate effector responses to (self-) antigen (see Section “Functionality”). CD8+ Cytotoxic T Cells. In responding to an intracellular pathogen (e.g., a virus) the T cell must lyse the infected cell. To do so, it must be able to recognize and respond to antigenic peptides encoded by this pathogen and displayed on the cell surface. For this to occur, antigens arising in the cytosol are cleaved into small peptides by a complex of proteases, called the proteasome. The peptide fragments are then transported from the cytosol into the lumen of the endoplasmic reticulum, where they associate with MHC class I molecules. These peptide–class I complexes are exported to the Golgi apparatus and then to the cell surface (see Section “General Principles of Antigen Presentation”). The maturation of a CD8+ T cell to a killer T cell requires not only the display of the antigenic signal but also the delivery of helper signals from CD4+ T cells, for which the functional interaction between CD40 on the APC and CD40L on the CD8+ T cell can substitute.

VIRGINITY Naive T Cells. After

positive selection in the thymus, mature T cells with low affinity for self-peptide/ MHC molecules are released into the blood stream and form the long-lived pool of naive T cells. In order to survive, naive T cells require IL-7 signaling and a low level of self-reactivity entertained by constant TCR engagement with self-p/MHC molecules.145

T Helper 1/T Helper 2 Paradigm. T cells that produce IL-2, IFN-g, and TNF are termed Th1 cells. They are the main carriers of cell-mediated immunity (CMI). Other T cells produce IL-4, IL-5, IL-6, IL-13, and IL-15. These are termed Th2 cells and are primarily responsible for extracellular immunity (see below).160,161 Many factors influence whether an uncommitted T cell develops into a mature Th1 or Th2 cell. The cytokines IL-12 and IL-4, acting through signal transducer and activator of transcription (STAT) 4 and 6, respectively, are key determinants of the outcome, as are antigen dose, level of costimulation, and genetic modifiers. Certain transcription factors have causal roles in the gene-expression programs of Th1 and Th2 cells. For example, the T-box transcription factor T-bet is centrally involved in Th1 development, inducing both transcriptional competence of the IFN-g locus and selective responsiveness to the growth factor IL-12.162 By contrast, the zinc-finger transcription factor GATA-3 seems to be crucial for inducing certain key attributes of Th2 cells, such as the transcriptional competence of the Th2 cytokine cluster, which includes the genes encoding IL-4, IL-5, and IL-13.163,164 In murine models of intracellular infection, resistant versus susceptible immune responses appear to be regulated by these two T-cell subpopulations.165–167 Th1 cells, primarily by the release of IFN-g, activate macrophages to kill or inhibit the growth of the pathogen and trigger cytotoxic T-cell responses, which results in mild or self-curing disease. In contrast, Th2 cells facili-

Th17 Cells. Not every T-cell-mediated immune response and/or disease can be easily explained by the T1/T2 paradigm. Certain T-cell subpopulations are characterized by the secretion of IL-17. These cells are therefore termed Th17 cells. It was originally assumed that Th1 and Th17 cells arise from a common T1 precursor, but it now appears that Th17 cells are a completely separate and early lineage of effector CD4+ T cells produced directly from naive CD4+ T cells. This was proven by the identification of the Th17-specific transcription factor ROR (RAR-related orphan nuclear receptor) that regulates the expression of IL-17, IL-23R, and CCR6 in Th17 cells.170 The expression of CCR6 is unique for Th17 cells amongst T cells and regulates their migration into epithelial sites depending on its ligand CCL20.171 Recently, it has been demonstrated that Th17 cells may originate from a small subset of CD4+ T cells bearing the NK-cell-associated C-type lectin NKP-1A (CD161), which are present in cord blood and newborn thymus.172 Differentiation of human Th17 cells strongly depends on IL-23, a member of the IL-12 family, as well as on IL-1b, IL-6, and low doses of TGF-b173,174; murine Th17-lineage commitment is mainly induced by IL-6 and TGF-b. Importantly, the induction of Th17 cells from naive precursors may be inhibited by IFN-g and IL-4, using a cross-regulatory mechanism between Th1, Th2, and Th17 cells. One of the main physiological roles of Th17 cells is to promote protection against fungi, protozoa, viruses, and various extracellular bacteria, but Th17 cells have also been

169

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tate humoral responses and inhibit some cell-mediated immune responses, which results in progressive infection. These cytokine patterns are cross-regulatory. The Th1 cytokine IFN-g downregulates Th2 responses. The Th2 cytokines IL-4 and IL-10 downregulate both Th1 responses and macrophage function. The result is that the host responds in an efficient manner to a given pathogen by making either a Th1 or Th2 response. Sometimes, the host chooses an inappropriate cytokine pattern, which results in clinical disease. Of particular interest to immunologists is the delineation of factors that influence the T-cell cytokine pattern. The innate immune response is one important factor involved in determining the type of T-cell cytokine response. The ability of the innate immune response to induce the development of a Th1 response is mediated by release of IL-12, a 70-kDa heterodimeric protein.168 For example, in response to various pathogens, APCs including DCs and macrophages release IL-12, which acts on NK cells to release IFN-g. The presence of IL-12, IL-2, and IFN-g, with the relative lack of IL-4, facilitates Th1 responses. In contrast, in response to allergens or extracellular pathogens, mast cells or basophils release IL-4, which in the absence of IFN-g leads to differentiation of T cells along the Th2 pathway. It is intriguing to speculate that keratinocytes may also influence the nature of the T-cell cytokine response. Keratinocytes can produce IL-10, particularly after exposure to UVB radiation.96 The released IL-10 can specifically downregulate T1 responses, thus facilitating the development of Th2 responses.

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With regard to the functional capacities of various T-cell subsets, it was originally assumed that CD4+ cells predominantly subserve helper ­functions and that CD8+ cells act as killer cells. Many exceptions to this rule are now known to exist; for example, both CD4+ and CD8+ regulatory cells are found, but CD4+ cells are still commonly referred to as helper T cells (Th cells) and CD8+ cells as cytotoxic T cells (Tc cells). During an immune response, naive Th/Tc cells can differentiate into several functional classes of cells: (1) Th1 cells (type 1 T cells); (2) Th2 cells (type 2 T cells); (3) Th17 cells; (4) natural killer T cells (NKT); (5) regulatory T cells (T reg); and (6) T follicular helper (Tfh) cells (Fig. 10-4). Originally, all these T-cell subsets have mainly been defined as CD4+ Th cells. In the meantime we have learned that both CD4+ Th and CD8+ Tc cells can produce cytokines allowing their classification into these distinct T-cell subsets. The functional commitment of effector T-cell populations is controlled by the expression of lineage-specific transcription factors, but individual T cells can also express cytokines that are not lineage-specific. It therefore remains to be determined whether T cells display heterogeneity within a lineage or whether each distinct cytokine-expression pattern already reflects a separate lineage. It seems that T cells, although already polarized, still possess a high degree of functional plasticity that allows further differentiation depending on various factors such as the strength of antigenic signaling, cytokines, or interactions with other cells encountered in their microenvironment.155

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Functionality.

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linked to a growing list of autoimmune and inflammatory diseases such as neuroinflammatory disorders, asthma, lupus erythematosus, rheumatoid arthritis, Crohn’s disease and, most notably, psoriasis.99,175 Very recent evidence exists that Th17 cells might also play a role in antitumor immunity.176 Importantly, IL-17 expression is not restricted to CD4+ cells only, but has also been detected in CD8+ T cells.177 Th17 cells exert their function by producing effector cytokines including IL-17A, IL-17F, IL-22, and IL-26. Whereas IL-17 is believed to contribute to the pathogenesis of these diseases by acting as potent proinflammatory mediator, IL-22 has been described as a multifunctional cytokine with inflammatory as well as protective properties. In vitro stimulation of normal keratinocytes with IL-22, for example, results in inhibition of keratinocyte differentiation followed by epidermal hyperplasia and upregulated expression of proinflammatory genes in these cells.178

Regulatory T Cells. An important type of immunomodulatory T cells that controls immune responses are the so-called regulatory T cells (T reg cells), formerly known as T suppressor cells.181 T reg cells are induced by immature APCs/DCs and play key roles in maintaining tolerance to self-antigens in the periphery. Loss of T reg cells is the cause of organ-specific autoimmunity in mice that results in thyroiditis, adrenalitis, oophoritis/orchitis, etc. T reg cells are also critical for controlling the magnitude and duration of immune responses to microbes. Under normal circumstances, the initial antimicrobial immune response results in the elimination of the pathogenic microorganism and is then followed by an activation of T reg cells to suppress the antimicrobial response and prevent host injury. Some microorganisms (e.g., Leishmania parasites, mycobacteria) have developed the capacity to induce an immune reaction in which the T reg component dominates the effector response. This situation prevents elimination of the microbe and results in chronic infection. The best-characterized T reg subset is the CD4+/ CD25+/CTLA-4+/GITR+ (glucocorticoid-induced TNF receptor family-related gene)/FoxP3+ lymphocytes.182 The transcription factor FoxP3 is specifically linked to the suppressor function, as evidenced by the findings that mutations in the FoxP3 gene cause the fatal autoimmune and inflammatory disorder of scurfy in mice and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) in humans. The cytokines TGF-b and IL-10 are thought to be the main mediators of suppression. During the past years the situation has become even more complicated, because, at least under certain conditions, subsets with different phenotypes have been associated with regulatory functions such as CD4+, CD8+, and NKT cells. Accordingly, the existence of T reg cells coexpressing IL-17 and FoxP3 has been described.183 CD8+ cells can also be activated to become suppressor cells by antigenic peptides that are presented in the context of an MHC class Ib molecule [Qa1 in mice; human leukocyte antigen E (HLA-E) in humans]. CD8+ T reg cells suppress T cells that have

intermediate affinity for self or foreign antigens and are primarily involved in self–nonself discrimination. In addition, recent data provides evidence for a suppressive function of human FoxP3-, TGf-b-producing g/d T cells.184

T Follicular Helper (Tfh) Cells. Tfh cells represent a distinct subset of CD4+ T cells found in limited numbers, especially in B-cell areas of lymph nodes and spleen. Homing and long-term residency in B-cell follicles of these newly described T cells is secured by their surface expression of CXCR5. They have a crucial role in orchestrating T-cell-dependent effector and memory B-cell responses, produce IL-21 and express inducible T-cell costimulator (ICOS) and programed cell death 1 (PD-1) as costimulatory and coinhibitory molecules, respectively. Specific differentiation of Tfh cells was associated to the transcription factor Bcl6 as well as to the cytokines IL-6 and IL-21.185–187 Lymphocytes in Normal and Diseased Skin. As opposed to normal mouse skin,

in which a resident population of dendritic epidermal T cells uniformly equipped with a nonpolymorphic, canonical g∼d TCR exists, the lymphocytes of normal human skin are mainly located in the dermis and predominantly express the a∼b TCR rather than the g/d TCR. While the majority of epidermal T cells exhibit the CD8+/CD4− phenotype, dermal T cells are mainly CD4+/CD8−, belong to the CD45RO memory population, express the addressins CLA (cutaneous lymphocyte antigen) and CCR4 which they use for skinhoming purposes,188 and are largely devoid of CCR7 and L-selectin, i.e., addressins promoting the homing of lymphocytes to the lymphoid organs.152,189 This situation is true also for homeostatic conditions which means that a cutaneous pool of effector memory cells is already in place when danger is imminent. Some of these effector memory T cells have a rather long life span and have been found in different skin conditions, for example, at sites of HSV infection of mice 190,191 and men192 as well as in clinically resolved, hyperpigmented fixed drug eruptions.193 Normal human skin contains approximately 1 million T cells per cm2, 2%–3% of which reside within the epidermis,194 primarily in the basal and suprabasal layers. The T cells of the dermis are preferentially clustered around postcapillary venules of the superficial plexus high in the papillary dermis and are often situated just beneath the dermal–epidermal junction and within, or in close proximity to, adnexal appendages such as hair follicles and eccrine sweat ducts. The process of T-cell trafficking to the skin is guided by a series of receptor–ligand interactions between cells. It is of note that DCs are capable of imprinting homing receptor expression on T cells,195 which means that T cells programed by skin and/or skin-derived DCs will preferentially return to the skin. One such moiety is the glycoprotein cutaneous lymphocyte antigen (CLA) that defines a subset of memory T cells that home to skin. It is a glycosylated form of P-selectin– glycoprotein ligand 1 that is expressed constitutively

on all human peripheral blood T cells. The level of CLA on cells is regulated by an enzyme, a (1,3)-fucosyltransferase VII, which modifies P-selectin glycoprotein ligand 1. In this manner, CLA+ cells bind to both E-selectin and P-selectin, whereas CLA− cells bind P-selectin, but not E-selectin.196,197 The chemokine– chemokine receptor system is the other major regulator and coordinator of leukocyte migration to the skin (see Chapter 12).

Innate and Adaptive Immunity in the Skin

While lymphocytes are the only cells capable of recognizing antigenic moieties, the recognition process per se, at least as far as T cells are concerned, is dependent on the presence of antigen-presenting cells (APC). Unlike B cells, T cells cannot recognize soluble protein antigen per se; their antigen receptor (TCR) is designed to recognize antigen-derived peptides bound to MHC locus-encoded molecules expressed by APCs. Most CD8+ T cells, destined to become cytotoxic T cells, recognize the endogenous antigen in association with MHC class I molecules.216 Because most nucleated cells transcribe and express MHC class I genes and gene products, it is evident that many cell types can serve as APCs for MHC class I-restricted antigen presentation and/or as targets for MHC class I-dependent attack by T cells. For the antigen-specific activation of CD4+ T cells, exogenous antigen-derived peptides are usually presented in the context of MHC class II molecules.216 In this situation, peptides are generated in the endocytic, endosomal/lysosomal pathway and are bound to MHC class II molecules. The resulting MHC-peptide complex is expressed at the APC surface for encounter by the TCR of CD4+ T cells. In the MHC class II-dependent antigen presentation pathway, dendritic cells (DCs), including Langerhans cells (LCs) and dermal dendritic cells (DDCs), B cells, and activated monocytes/macrophages are the major APC populations. Among these, DCs act as professional APC, i.e., are capable of migration and stimulating antigenspecific responses in naive, resting T cells.

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Antigen Presenting Cells

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Skin Homing of Memory T Cells. Of particular importance for skin homing of memory T cells, independent of their polarization, is the interaction of CCL17 and CCL22 with CCR4 and of CCL27 with its counterreceptor CCR10 on CLA+ T cells. CCL17 is synthesized by activated keratinocytes, DCs and endothelial cells of the skin, while CCL22 is mainly of macrophage and DC origin. The CCR10 ligand, CCR27, appears to be exclusively produced by epidermal keratinocytes.198 Although it was originally assumed that functionally different T-cell subsets can be distinguished from each other by their chemokine receptor expression pattern and their responsiveness to the respective chemokines, the situation is less clear now. Reportedly, T1 cells selectively bear CXCR3 and CCR5, T2 cells preferentially exhibit CCR8 and CCR3, and T17 as well as T reg express CCR6, allowing them to respond to the keratinocyte- and endothelial cellderived chemokine CCL20.199,200 From all that has been said so far, one can surmise that the accumulation of T cells in skin is not stochastic. This is indeed the case as exemplified by the dominance of CD8+ T cells in skin lesions, but not in the peripheral blood of patients with lepromatous leprosy201 as well as by the clonality of the T-cell population in cutaneous T-cell lymphoma, in which a single V gene usage is found to predominate in different skin lesions from the same individual.202,203 A limited TCR V gene usage has also been reported to be present in skin lesions of leprosy,204 psoriasis,205 basal cell carcinoma, and countless other reactions in which T cells are present. The most direct indication of relevant T-cell populations in skin is determination of the number of antigenspecific T cells. It has been documented that 1 in 1,000 to 1 in 10,000 T cells in the peripheral blood, but only 1 in 50 to 1 in 100 T cells recognize the antigen causing the disease at sites of inflammation.206,207 Thus, there is as much as a 100-fold enrichment of antigen-reactive T cells at the site of cutaneous inflammation. With regard to survival and/or expansion of T cells of human skin/epidermis, it appears that IL-2, IL-7, and IL-15 play important roles.208 Notably, the latter two T-cell growth factors can be produced by human epidermal cells, and all of them are frequently overexpressed in T cell-rich skin lesions, for example, in patients with tuberculoid leprosy. For a long period of time, the Th1/Th2 paradigm was used to explain the pathogenesis and, more often, the course of infectious, inflammatory and, even, neoplastic skin diseases. Leprosy and leishmaniasis are outstanding examples of diseases in which the clinical manifestations are decisively determined by the dominance of either Th1

or Th2 cells. With the identification of new functionbased T-cell subpopulations (e.g., T0 cells, Th17 cells, Th22 cells), this classification is too rigid and no longer tenable. In fact, we come to realize that the T-cell pathogenesis of certain diseases that we had originally considered to belong into either the Th1 (e.g., psoriasis, allergic contact dermatitis) or the Th2 world (atopic dermatitis) is very complex and sometimes even stagespecific. Th17 and/or Th22 cells are apparently major players in psoriasis158 and allergic contact dermatitis.177 In atopic dermatitis, the acute lesions harbor not only Th2, but also Th17 and Th22 cells; in the chronic stage, however, Th1 cells seem to predominate. In syphilis, perhaps not only Th1 cells, but also CD8+IFN-g-producing Th17 cells do confer immunologic resistance to T. pallidum.209,210 Th17 cells may also be important in the pathogenesis of Borrelia burgdorferi-induced Lyme arthritis, which was long attributed to be a solely Th1 cell-mediated response.211,212 In patients with cutaneous T cell lymphoma (CTCL), Th2 responses dominate the inflammatory infiltrate of the skin, especially at late stages.213 In early lesions, however, infiltrating CD3+CD45RO+CLA+CCR4+ T cells also express IFN-g and IL-17 (see Chapter 145). In basal cell carcinomas the presence of a Th2-dominated environment with an increased expression of IL-4 and IL-10 as well as tumor-surrounding T reg cells may be responsible for tumor growth214 (see Chapter 115). In alopecia areata, recent data suggest a role for Th1 cells.215

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pH < 5

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Figure 10-5  Antigen-processing pathways. The intracellular antigen-processing pathways for major histocompatibility complex (MHC) class I, MHC class II, and CD1 presentation are shown. The MHC class I pathway involves the processing of cytoplasmic proteins, whereas the MHC class II pathway involves the processing of exogenous proteins. The CD1 pathway regulates the processing and presentation of self-glycosphingolipids and bacterial lipoglycans. DN T cell = double-negative (CD4−/CD8−) T cell; ER = endoplasmic reticulum; MIIC = MHC class II lysosomal peptide-loading compartment; NKT cell = natural killer T cell; TAP = transporter associated with antigen processing; TCR = T-cell receptor.

General Principles of Antigen Presentation. (Fig. 10-5) Major Histocompatibility Complex Class I-Restricted Antigen Presentation: Classic Pathway.217,218 Immediately after their biosynthesis,

MHC class I heavy and light (b2-microglobulin) chains are inserted into the membranes of the endoplasmic reticulum. The third subunit of the functional MHC class I complex is the peptide itself. The major sources of peptides for MHC class I loading are cytosolic proteins, which can be targeted for their rapid destruction through the catalytic attachment of ubiquitin. These cytosolic proteins can be self-proteins, viral particles, or neoantigens (altered self-proteins). Cytosolic proteinaceous material undergoes enzymatic digestion by the proteasome to yield short peptide chains of 8–12 amino acids, an appropriate length for MHC class I binding. In its basic conformation, the proteasome is a

constitutively active “factory” for self-peptides. IFN-g, by replacing or adding certain proteasomal subunits, induces “immunoproteasomes,” presumably to finetune the degradation activity and specificity to the demands of the immune response. The processed peptides are translocated to the endoplasmic reticulum by the transporter associated with antigen processing (TAP), an MHC-encoded dimeric peptide transporter. With the aid of chaperons (calnexin, calreticulin, tapasin), MHC class I molecules are loaded with peptides, released from the endoplasmic reticulum, and transported to the cell surface. Several infectious agents with relevance to skin biology have adopted strategies to subvert MHC class I presentation, and thus the surveillance of cell integrity, by interfering with defined molecular targets. Important examples of such interference are the inhibition of proteasomal function by the Epstein–Barr virus-encoded EBNA-1 protein, the competition for peptide–TAP interactions by a herpes

simplex virus protein, and the retention or destruction of MHC class I molecules by adenovirus- and human cytomegalovirus-encoded products.

Alternative Pathway (Cross-Presentation).

Dendritic Cells. DCs are the only APC capable of interacting with naive T cells. Depending on the DC activation status (i.e., mature versus immature), this cellular contact will result in either productive or nonproductive T-cell responses. Originally, DCs were identified in peripheral lymphoid organs in mice (lymphoid DC).227 A few years later the presence of DC in nonlymphoid tissue (nlDC) was first demonstrated as evidenced by the expression of Fc and C3 receptors as well as MHCII antigens on epidermal LC.228–230 This finding anchored LC as cells of the immune system. DCs populate nearly every mammalian tissue under homeostatic (indigenous DC) and inflammatory (inflammatory DC) conditions (Fig. 10-6). Both indigenous and inflammatory DCs ultimately derive from

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Besides peptides, self-glycosphingolipids and bacterial lipoglycans may also act as T-cell-stimulatory ligands. Molecules that bind and present these moieties belong to the family of nonpolymorphic, MHC class I- and IIrelated CD1 proteins. CD1 molecules are structurally close to MHC class I molecules, but functionally related to MHC class II molecules. In the skin, members of the CD1 family are expressed mainly by LCs and DDCs. The CD1 isoforms CD1a, CD1b, CD1c, and CD1d sample both recycling endosomes of the early endocytic system and late endosomes and lysosomes to which lipid antigens are delivered. Unlike in the MHC class II pathway, antigen loading in the CD1 pathway occurs in a vacuolar acidification-independent fashion. T cells expressing a Va24-containing canonic TCR, NKT cells, and CD4−/ CD8− T cells include the most prominent subsets of CD1-restricted T cells. CD1-restricted T cells play important roles in host defense against microbial infections. Accordingly, human subjects infected with M. tuberculosis showed stronger responses to CD1c-mediated presentation of a microbial lipid antigen than control subjects, and activation of CD1d-restricted NKT cells with a synthetic glycolipid antigen resulted in improved immune responses to several infectious pathogens. Thus, the CD1 pathway of antigen presentation and glycolipid-specific T cells may provide protection during bacterial and parasite infection, probably by the secretion of proinflammatory cytokines, the direct killing of infected target cells, and B cell help for Ig production.

Innate and Adaptive Immunity in the Skin

class II molecules predominantly bind peptides within endosomal/lysosomal compartments. Sampling peptides in these subcellular organelles allow class II molecules to associate with a broad array of peptides derived from proteins targeted for degradation after internalization by fluid phase or receptor-mediated endocytosis, macropinocytosis, or phagocytosis. One of the striking structural differences between MHC class I and class II molecules is the conformation of their peptide-binding grooves. Whereas MHC class I molecules have binding pockets to accommodate the charged termini of peptides and thus selectively ­associate with short peptides, the binding sites of MHC class II molecules are open at both ends. Thus, MHC class II molecules bind peptides with preferred lengths of 15–22 amino acids but can also associate with longer moieties. An important chaperone for MHC II molecules and responsible for the correct folding and the functional stability of MHC II molecules is the type II transmembrane glycoprotein invariant chain (Ii; CD74). Ii also prevents class II molecules from premature loading by peptides intended for binding to MHC class I molecules in the endoplasmic reticulum and participates in the sorting of MHC II toward the endocytic pathway.222 Depending on the cell type and the activation status of a cell, the half-life

CD1-Dependent Antigen Presentation.225,226

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Major Histocompatibility Complex216Class II-Restricted Antigen Presentation. MHC

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Under certain conditions, exogenous antigen can reach the MHC class I presentation pathway. Significant evidence for this cross-presentation first came from in vivo experiments in mice demonstrating that viral, tumor, and MHC antigens can be transferred from MHC-mismatched donor cells to host bone marrowderived APCs to elicit antigen-specific cytotoxic T-cell responses that are restricted to self-MHC molecules.219 In vitro studies have defined that exosomes (i.e., small secretory vesicles of approximately 100 nm in diameter secreted by various cell types, including tumor cells), heat shock proteins, immune complexes, and apoptotic cells (taken up via CD36 and avb3 or avb5 integrins) can all serve as vehicles for the delivery of antigen to DCs in a manner that permits the cross-presentation of antigen. In all in vitro systems in which a direct comparison has been made, DCs, including LCs, but not monocytes/macrophages, were capable of cross-presentation.220,221 Three distinct pathways are currently exploited by which antigen can access MHC class I molecules of DCs: (1) a recycling pathway for MHC class I in which antigen is loaded in the endosome; (2) a pathway by which retrograde transport of the antigen from the endosome to the endoplasmic reticulum facilitates entry into the classic MHC class I antigen presentation pathway; and (3) an endosome to the cytosol transport pathway, which again allows antigen processing via the classic MHC class I antigen presentation pathway.

of class II–peptide complexes varies from a few hours to days. It is particularly long (more than 100 hours) on DCs that have matured into potent immunostimulatory cells of lymphoid organs on encounter with an inflammatory stimulus in nonlymphoid tissues. The very long retention of class II–peptide complexes on mature DCs ensures that only the peptides generated at sites of inflammation will be displayed in lymphoid organs for T cell priming. Cytokines have long been known to regulate antigen presentation by DCs. In fact, proinflammatory (TNF-a, IL-1, IFN-g) and antiinflammatory (IL-10, TGF-b1) cytokines regulate presentation in MHC class II molecules in an antagonistic fashion. Mechanistically, regulatory effects include the synthesis of MHC components and proteases, and the regulation of endolysosomal acidification.223,224

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KEY CD8+ T cell

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KC

Figure 10-6  Resident and passenger leukocytes of the skin. Unperturbed skin: under homeostatic, steady-state conditions, the skin harbors only limited numbers of leukocytes. They consist mainly of dendritic cells (Langerhans cells in the epidermis and dermal dendritic cells in the dermis) and, to a lesser extent, of T cells in the epidermis (largely CD8+) and dermis (largely CD4+) and a few mononuclear phagocytes and mast cells. Granulocytes, NK cells, B cells, and inflammatory dendritic cells are essentially absent. Perturbed skin: upon delivery of exogenous (e.g., microorganisms, chemical irritants, ultraviolet radiation) and perhaps endogenous danger signals, resident skin cells such as keratinocytes become activated and, as a consequence, initiate an inflammatory tissue response arising mainly from circulating, but probably also resident leukocytes. KC = keratinocyte; LC = Langerhans cells; DDC = dermal dendritic cells; pDC = plasmacytoid dendritic cells; IDSC = inflammatory dendritic skin cells; NK cell = natural killer cells. hematopoietic stem and progenitor cells (HSPC) in the bone marrow. HSPCs give rise to progenitor cells that can further differentiate into one or more DC subsets.231,232 DC precursors can be found in multiple locations throughout the body such as the bone marrow, the thymus as well as the peripheral lymphoid organs including the blood.233–235 These blood-derived DC precursors populate nonlymphoid tissues and organs using specific chemokine receptor–ligand pathways (e.g., CCR2-CCL2, CCR5-CCL5, CCR6-CCL20).236–239 Upon arrival in the periphery, they either undergo a process of differentiation or maintain their density by self-renewal.234 Inflammatory DCs are mainly mobilized into the tissues from peripheral blood precursors upon receipt of danger signals. They probably do not constitute a DC subpopulation per se, but rather represent an activated state of a given DC. Within the periphery, differentiated DCs accumulate in extravascular areas and survey their surroundings for microbial invasion, always prepared for antigen capture. Under homeostatic conditions, the overwhelming majority of DCs are in an immature state that allows them to efficiently take up antigen (e.g., serum proteins, extracellular matrix components, dead cells) with the help of specific receptor sites (e.g., Langerin, macrophage mannose receptor, C-type lectin receptor DEC-205, low-affinity IgG receptor CD32/FcgRII,

high-affinity IgE receptor FceRI, the thrombospondin receptor CD36, DC-SIGN), but does not endow them with immunostimulatory properties for naive resting T cells. DCs apparently increase their efficacy in antigenuptake by repetitively extending and retracting their dendrites through intercellular spaces (dSEARCH: dendrite surveillance extension and retracting cycling habitude).240 Antigen-engulfment triggers DC maturation, which is followed by DC detachment from neighboring cells and trafficking to draining lymph nodes dependent on CCR7 signaling.241–243 DC trafficking from nonlymphoid to lymphoid tissues occurs, in a limited fashion, also under homeostatic conditions,244,245 but is much more enhanced upon the delivery of danger signals. During this journey, DCs have to overcome several obstacles such as vessel walls, connective tissue, basement membranes, or other anatomical barriers. To be capable of traveling, DCs are equipped with distinct proteolytic enzymes such as matrix metalloproteinase 2 (MMP-2) and MMP-9 that lead to the degradation of extracellular matrix proteins.246–248 Interstitial DC migration is partly controlled by tissue inhibitors of metalloproteinases (TIMPs), which inhibit MMP activity under nondanger conditions. However, upon maturation of DCs, TIMP expression is downregulated and MMPs exert their function.249 In the LN, DCs rapidly extend their dendrites in a “probing” way thereby

we find several APC including epidermal Langerhans cells (LC) and dermal dendritic cells278 (DDC). LCs and DDCs are lineage-negative (Lin−), bone marrowderived leukocytes, which phenotypically and functionally resemble other DCs present in most, if not all, lymphoid and nonlymphoid tissues.279 As gatekeepers of the immune system, they control the response to events perturbing tissue/skin homeostasis. In other species such as mice an additional DC subset has been described recently, namely CD103+CD207+ cells, which in humans have yet to be identified.280–282 Healthy skin also harbors other cells which at least theoretically could subserve APC function, such as basophils and mast cells. While these cells have been shown to play a role in the modulation of cutaneous immune responses, their functions as APC remain to be defined. Under inflammatory conditions, DC types that are not residents of the normal cutaneous environment appear in the skin. These include DCs from the plasmacytoid lineage, so-called plasmacytoid DC (pDCs) and inflammatory dendritic skin cells (IDSC), which originate from myeloid precursors and phenotypically resemble myeloid DCs (mDC) of the peripheral blood.

Innate and Adaptive Immunity in the Skin

Dendritic Cells of Normal and Diseased Skin. In essentially unperturbed normal human skin

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Mechanisms responsible for the tolerance-inducing property of nonactivated DCs, although not entirely understood, include (1) a reduced expression of MHCantigen complexes263 and costimulatory molecules264 on the cell surface; (2) expression of the coinhibitory receptor ligands programed cell death-ligand 1 (PDL1/B7-H1) and, to a lesser extent, PD-L2 (B7-DC)265–267; (3) the secretion of immunosuppressive cytokines such as IL-10,268 which fits well to the finding of T reg induction by UV-irradiated, IL-10-producing T reg cells269; (4) the expression of immunoinhibitory enzymes such as indoleamine 2,3-dioxygenase270; and (5) the receipt of signals interfering with the maturation and migration of DCs, for example, neuropeptides such as CGRP271 and vasoactive intestinal peptide,272 or the engagement of the CD47/SHPS-1 signal transduction cascade.273,274 It appears that these different factors are not equally operative in all situations. LCs, for example, can activate self-antigen-specific CD8 T cells in the steady state, which leads to chronic skin disease,275 and, at the same time, LCs are dispensable for276 or can even downregulate277 the induction of CHS.

Chapter 10

establishing physical contacts with adjacent T cells, as in vivo two-photon intravital microscopy of inguinal lymph nodes of mice has revealed.250,251 The display of MHC-peptide complexes on the DC surface delivers the “first signal” to T cells thereby starting communication, i.e., the triggering of the TCR by the APC-bound peptide-MHC complex. Upon activation, DCs display an upregulated and prolonged surface expression of MHCII as compared with nonactivated APC. Although this event may be sufficient to induce the proliferation of primed T cells, it is insufficient for the productive activation of naive T cells. The occurrence of the latter requires the receipt of “second signals,” which are also delivered by professional APCs. In fact, antigen-specific T cells that encounter MHC-expressing cells that cannot deliver second signals (e.g., MHC class II-induced keratinocytes, endothelial cells, fibroblasts) enter a state of anergy.252 Second signals, which include secreted cytokines and membrane-bound costimulatory molecules, determine the magnitude and quality of primary and secondary T-cell responses. Upon contact with the DC-derived cytokine IL-12, for example, T cells turn into type 1 IFN-g-producing cells, whereas DC-derived IL-23 may skew T-cell responses in the type 17 direction (see Section “Functionality”). Upon danger stimuli, DCs produce a variety of additional cytokines such as IL-1b, TNF-a, TGF-b, or IL-6 that all have the potential to polarize distinct T-cell responses. Costimulatory molecules on DCs are upregulated during the process of maturation induced by surface receptors triggered by ligands secreted or presented by other somatic cells or, alternatively, by microbial products (danger signals).253 The best-defined costimulatory molecules are the two members of the B7 family, B7.1/CD80 and B7.2/CD86. LCs/DCs in situ do not express or express only minute amounts of these costimulatory molecules, but greatly upregulate these moieties during maturation. Other costimulatory molecules include the ICAM-1 that binds to LFA-1 and LFA-3, the ligand of T cell-expressed CD2. Other important ligand–receptor pairs that positively affect T-cell activation by DCs include heat-stable antigen CD24/CD24L, CD40/CD40L, CD70/CD27L, OX40 (CD134)/OX40L, and receptor activator of nuclear factor kB (RANK)/RANKL. Another costimulatory molecule of great importance is the membrane-bound glycoprotein CD83. It is significantly upregulated during DC maturation and enhances CD8+ T cell proliferation upon binding to an as yet unknown CD83 ligand on T cells whose expression is strictly dependent on CD28mediated costimulation.254,255 Recent evidence suggests that DCs/LCs themselves can actively induce immune tolerance. The main mechanism to maintain immune tolerance is deletion of T cells with high affinity to self-peptide/ MHC complexes in the thymus by inducing apoptosis (negative selection). Another variation of tolerance is T cell-anergy induced by contact with APC that do not provide second signals. Finally, DCs, at least in their immature state, preferentially activate T reg cells.256 When antigen is targeted to these nonactivated DCs in vivo, antigen-specific hyporesponsiveness occurs.257–261 This finding has therapeutic implications for the treatment of autoimmune diseases.262

Langerhans Cells.283

In 1868, the medical student Paul Langerhans, driven by his interest in the anatomy of skin nerves, identified a population of dendritically shaped cells in the suprabasal regions of the epidermis after impregnating human skin with gold salts.284 These cells, which later were found in virtually all stratified squamous epithelia of mammals, are now eponymously referred to as Langerhans cells (Fig. 10-7). The expression of the Ca2+-dependent lectin Langerin (CD207) is currently the single best feature discriminating LCs from other cells. Langerin is a transmembrane molecule associated with and sufficient to form Birbeck granules, the prototypic, and cell type-defining organelles of LCs (see Fig. 10-7). Birbeck granules are

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A

B

Figure 10-7  A. Langerhans cells in a sheet preparation of murine epidermis as revealed by antimajor histocompatibility complex class II (fluorescein isothiocyanate) immunostaining. B. Electron micrograph of a Langerhans cell in human epidermis. Arrows denote Birbeck granules. N = nucleus. (From Stingl G: New aspects of Langerhans cell functions. Int J Dermatol 19:189, 1980, with permission.) Inset: High-power electron micrograph of Birbeck granules. The curved arrows indicate the zipper-like fusion of the fuzzy coats of the vesicular portion of the granule. The delimiting membrane envelops two sheets of particles attached to it and a central lamella composed of two linear arrays of particles. (From Wolff K: The fine structure of the Langerhans cell granule. J Cell Biol 35:466, 1967, with permission.) ­ entilaminar cytoplasmic structures frequently disp playing a tennis racket shape at the ultrastructural level. The additional presence of Langerin on the cell surface coupled with its binding specificity for mannose suggests that Langerin is involved in the uptake of mannose-containing pathogens by LCs. However, the disruption of the Langerin gene in experimental animals does not result in a marked loss in LC functionality.285 Additional molecules besides Langerin allow the identification of LCs within normal unperturbed epidermis. These include CD1a; the MHC class II antigens HLA-DR, HLA-DQ, and HLA-DP; and CD39, a membrane-bound, formalin-resistant, sulfhydryl-dependent adenosine triphosphatase (ATPase). The tissue distribution of LC varies regionally in human skin. On head, face, neck, trunk, and limb skin, the LC density ranges between 600 and 1,000/mm2. Comparatively low densities (approximately 200/mm2) are encountered in palms, soles, anogenital and sacrococcygeal skin, and the buccal mucosa. The density of human LCs decreases with age, and LC counts in skin with chronic actinic damage are significantly lower than those in skin not exposed to UV light (Fig. 23-7). HLADR+/ATPase+ DCs can be identified in the human epidermis by 6–7 weeks of estimated gestational age. These cells must originate from hemopoietic progenitor

cells in the yolk sac or fetal liver, the primary sites of hemopoiesis during the embryonic period. Until week 14 of estimated gestational age (EGA), these cells acquire the full phenotypic profile of LC in a stepwise fashion.286 The relative numeric stability of LC counts during later life must be achieved by a delicate balance of LC generation and immigration into the epidermis and LC death and emigration from the epidermis. Within the epidermis, LCs are anchored to surrounding keratinocytes by E-cadherin-mediated homotypic adhesion.287 This anchoring and the display of TGF-b1 also prevent terminal differentiation and migration, thus securing intraepidermal residence for the cells under homeostatic conditions. Two nonmutually exclusive pathways of LC repopulation of the epidermis may exist: (1) LC division within the epidermis, and (2) the differentiation of LCs from skin-resident or blood-borne precursors. Evidence for the first possibility is the demonstration of cycling/ mitotic LCs in the epidermis,288 although it remains to be established whether this cell division alone suffices for maintaining the epidermal LC population. The observation that the half-life of LCs within unperturbed murine epidermis is around 2–3 months289 suggests a significant turnover of the epidermal LC population even under noninflammatory conditions. In seeming contradiction stands the observation that the LC

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:: Innate and Adaptive Immunity in the Skin

peptides, have lost their capacity to process and present native protein antigens.298 Upon perturbance of skin homeostasis (e.g., TLR ligation, contact with chemical haptens, hypoxia), LCs gain access to antigen/allergen encountering the epidermis by distending their dendrites through epidermal tight junctions, thereby demonstrating strikingly remarkable cooperation between keratinocytes and LC.299 After a few hours, LCs begin to enlarge, to display increased amounts of surface-bound MHC class II molecules, and to migrate downward in the dermis, where they enter afferent lymphatics and, finally, reach the T-cell zones of draining lymph nodes.300 During this process, LCs undergo phenotypic changes similar to those that occur in single epidermal cell cultures,301 i.e., downregulation of molecules or structures responsible for antigen uptake and processing as well as for LC attachment to keratinocytes (e.g., Fc receptors, E-cadherin) and upregulation of moieties required for active migration and stimulation of robust responses of naive T cells (e.g., CD40, CD80, CD83, CD86). The mechanisms governing LC migration are becoming increasingly clear. TNF-a and IL-1b (in a caspase 1-dependent fashion) are critical promoters of this process, whereas IL-10 inhibits its occurrence. Increased cutaneous production and/or release of the proinflammatory cytokines are probably one of the mechanisms by which certain immunostimulatory compounds applied to or injected into the skin [e.g., imiquimod, unmethylated cytosine–phosphate–guanosine (CpG) oligonucleotides] accelerate LC migration. Another example is the topical application of contact sensitizers (e.g., dinitrofluorobenzene), which leads to the activation of ­certain protein tyrosine kinases, the modification of cellular content and structure of intracytoplasmic organelles (increase in coated pits and vesicles, endosomes and lysosomes, Birbeck granules), and increased in situ motility of these cells.302 Interestingly, Cumberbatch et al303 reported that, in psoriasis, LCs are impaired in their migratory capacity. This was somewhat unexpected in view of the remarkable overexpression of TNF-a in psoriatic skin. These investigators also found that the failure of TNF-a and/or IL-1b to induce LC migration from uninvolved skin was not attributable to an altered expression of receptors for these cytokines. An important hurdle for emigrating LCs is the basement membrane. During their downward journey, LCs probably attach to it via a6-containing integrin receptors and produce proteolytic enzymes such as type IV collagenase (MMP-9) to penetrate it and to pave their way through the dense dermal network into the lymphatic system. IL-16 also induces LC mobilization. This process could perhaps be operative in atopic dermatitis. In this disease, DCs of lesional skin exhibit surface IgE bound to high-affinity Fc receptors (FceRI), and allergen-mediated receptor cross-linking results in enhanced IL-16 production. Evidence is accumulating that DC migration occurs in an active, directed fashion. Osteopontin is a chemotactic protein that is essential in this regard. It initiates LC emigration from the epidermis and attracts LCs to draining nodes by interacting with an N-terminal epitope of the CD44 molecule.304 The entry into and active transport of cutaneous DCs

Chapter 10

population of human skin grafted onto a nude mouse remains rather constant for the life of the graft, despite epidermal proliferation and the absence of circulating precursors for human LCs. Moreover, epidermal LCs in mice whose bone marrow was lethally irradiated and subsequently transplanted are only partially replaced by LCs of donor origin,290 whereas DCs in other organs are efficiently exchanged for donor DCs.238 Together, these observations suggest that a precursor cell population resides in the dermis that is engaged constantly in the self-renewal of the epidermal LC population under noninflammatory conditions. The prime candidate LC precursors are dermal CD14+/CD11c+ cells that have the potential to differentiate in vitro into LCs in a TGFb1-dependent fashion.291 Under inflammatory conditions (e.g., UV radiation exposure, graft-versus-host disease), an additional pathway of epidermal LC recruitment becomes operative. In this situation, LC precursors enter the tissue, and their progeny populate the epidermis in a fashion dependent on chemoattraction mediated by LCexpressed chemokine receptors CCR2 and CCR6,239 the ligands of which are secreted by endothelial cells and keratinocytes. Thus, CCR6 and its ligand MIP3a/CCL20 may be essential for epidermal LC localization in vivo, as postulated previously in studies of LCs differentiated from human progenitor cells in vitro.108 The action of MIP-3a/CCL20 may be assisted or replaced under noninflammatory situations by the chemokine BRAK/CXCL14, which is constitutively produced by keratinocytes.292 The differentiation stage of the biologically relevant circulating LC precursors entering inflamed skin in vivo remains to be resolved. However, evidence exists that common myeloid progenitors, granulocyte–macrophage progenitors, monocytes, and even common lymphoid progenitors can give rise to the emergence of an epidermal LC population in experimental animals.293,294 Compelling evidence exists from in vitro and in vivo studies that LCs play a pivotal role in the induction of adaptive immune responses against antigens introduced into and/or generated in the skin (immunosurveillance). This is best illustrated by the early observation that LC-containing, but not LC-depleted, epidermal cell suspensions pulse-exposed to either soluble protein antigens or haptens elicit a genetically restricted, antigen-specific, proliferative T cell response.295 Inaba et al296 found that freshly isolated LCs (“immature” LCs) can present soluble antigen to primed MHC class II-restricted T cells but are only weak stimulators of naive, allogeneic T cells. In contrast, LCs purified from epidermal cell suspensions after a culture period of 72 hours or LCs purified from freshly isolated murine epidermal cells and cultured for 72 hours in the presence of GM-CSF and IL-1 (“mature” LC) are extremely potent stimulators of primary T cell-proliferative responses to alloantigens,296 soluble protein antigens,297 and haptens.297 Immature LCs, however, far excel cytokine-activated LCs in their capacity to take up and process native protein antigens.298 Accordingly, immature rather than mature LCs express antigen uptake receptors. Mature LCs, although fully capable of presenting preprocessed

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within lymphatic vessels appears to be mediated by MCPs binding to CCR2 and by secondary lymphoidorgan chemokine/CCL21 produced by lymphatic endothelial cells of the dermis and binding to CCR7 on maturing LCs and DDCs.242,305 Interestingly, CCL21 expression is upregulated in irritant and allergic contact dermatitis, which implicates its regulated impact on DC emigration from the skin.306

Section 4 :: Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

Dermal Dendritic Cells. Like resident LCs in the epidermis, dermal dendritic cells (DDCs) constitute another resident DC subpopulation in normal and inflamed skin that is capable of activating the immune system upon receipt of danger signals. Located primarily in the vicinity of the superficial vascular plexus, DDCs have been identified by their surface expression of CD1b, CD1c (BDCA-1), CD11c, CD36, CD205, MHCII, as well as the subunit A of the clotting proenzyme factor XIII (FXIIIa).307 They can be distinguished from LCs by the absence of Langerin expression and lack of Birbeck granules. Based on the positive reactivity for FXIIIa, DDCs from dermal single-cell suspensions were originally classified into at least three different subsets: (1) CD1a−/CD14− cells, (2) CD1a−/CD14− cells, and (3) CD1a−/CD14+ cells. Many assays conducted with DDCs during the past years revealed that they possess functional features of both macrophages and DCs, i.e., the capacity of efficient phagocytosis on the one hand as well as antigen-presenting, migratory and T-cell-stimulating capacities on the other hand.308,309 LC Versus DDC in Skin Immunity. (Fig. 10-8). What is the function of LCs/DDCs in normal skin? Is there a natural flux of LCs/DDCs to the regional lymph nodes? If so, what are the consequences of such an occurrence? Evidence exists that melanin granules captured in the skin accumulate in the regional lymph nodes but not in other tissues. The further observation of only very few melanin granule-containing cells in TGF-b1−/− mice suggests that, under steady-state conditions, epidermal and/or dermal antigens are carried to the regional lymph nodes by TGF-b1-dependent cells (most likely LCs/ DDCs) only. It appears that T lymphocytes encountering such APCs in vivo are rendered unresponsive in an antigen-specific manner.259 It is therefore conceivable that immature resident skin DC, i.e., LCs and DDCs, are endowed with tolerogenic skills inhibiting inflammatory T-cell responses in the steady state and, consequently, that absence of pathogenic T-cell autoimmunity and/or lack of reactivity against seemingly innocuous environmental compounds (e.g., aeroallergens) in the periphery is primarily the consequence of an active immune response rather than the result of its nonoccurrence. In the past few years, there has been a heavy debate about the relative sensitizing capacity of LCs versus DDCs in skin-derived immune responses. This discussion was initiated by seemingly controversial results obtained with different types of LC-depleted mice undergoing contact sensitization. Inflammatory Dendritic Cells.309 DCs

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appearing in inflamed skin can be subdivided into two major subpopulations, i.e., (1) inflammatory den-

dritic epidermal/dermal cells (IDECs/IDDCs) and (2) plasmacytoid dendritic cells (pDCs). The former ones will be referred to as inflammatory dendritic skin cells (IDSCs).

Inflammatory Dendritic Skin Cells (IDSC).

It is still unclear whether IDSCs represent a subpopulation of myeloid DCs which, upon danger stimuli, are recruited to the sites of inflammation from the blood, or whether indigenous DDCs are converted into specialized IDSCs that have the capacity to adapt their function according to the kind of danger signal delivered. Supporting the idea of circulating DC precursors infiltrating the skin upon danger signals, potential precursor cells including pre-DCs320,321 or hematopoietic precursor cells234 have been identified. Much work on the identification and characterization of epidermal and/or dermal inflammatory DC populations in various skin diseases has lately been provided by different groups.322–325 In the dermis of psoriatic lesions, the number of CD11c+ DCs is 30-fold increased as compared to normal skin.325,326 In contrast to steady-state DDC, these dermal CD11c+ DCs are CD1c−, but produce a number of proinflammatory cytokines (e.g., TNF-a. ) and inducible oxide synthetase (iNOS) and were therefore termed TIP-DCs (TNF-a∼ and iNOS-producing DCs). Initially identified in 2003 in a murine model of Listeria monocytogenes infection,327 they have been located in the lamina propria of human gut328 as well as in imiquimod-treated human basal cell carcinoma.324 Imiquimod and the other imidazoquinolines as ligands of TLR7/8 induce strong inflammation and, ultimately, regression of viral acanthomas and other superficial skin neoplasms.329 Upon treatment, TIP-DCs are abundantly present around regressing tumor cell islands330 and, interestingly, can express molecules of the lytic machinery such as perforin, granzyme B, and TRAIL, suggesting their cytotoxic potential. In psoriasis, TIP-DC have the capacity to prime T cells to become Th1, Th17, and a mixture of Th1/Th17 cells, which simultaneously produce IFN-g and IL-17325 and may contribute to the pathogenesis of the disease. In addition, their pathogenic role is indicated by downregulation of TNF-a, iNOS, and other cytokines they produce, namely, IL-20 and IL-23, upon effective psoriasis treatment.331 Recent work also identified TRAIL on CD11c+ CD1c− TIP-DCs in psoriasis, proposing a proinflammatory, cell-damaging interaction with keratinocytes that express activating TRAIL receptors (death receptor 4 and decoy receptor 2).332 In the epidermis of atopic dermatitis (AD) skin, the emergence of inflammatory dendritic epidermal cells (IDECs) has been well documented.333 They are characterized by the expression of CD1a, CD1b, CD1c, CD11c, FceRI, CD23, HLA-DR, CD11b, CD206 (MMR/ macrophage mannose receptor), and CD36.333,334 In situ staining of costimulatory molecules on epidermal CD1a+ DC in AD skin showed that mainly cells with the phenotype of IDEC display CD80 and CD86, whereas Langerin+ CD1a+ epidermal LC are almost devoid of these molecules.335 CD86 signaling is critical for the stimulatory capacity of IDEC. Evidence exists that, upon engagement of FceRI on IDEC, an immune

The mechanisms operative in the initiation, expression, and downregulation of skin-derived immune responses

Afferent phase

Efferent phase

Perturbation Ag

4

Homeostasis Ag

Danger signals

Ag

Cytokines Ag

KC

Ag

LC

LC

Epidermis

LC KC

Dermis

DDC

Anergic T cell

DDC

Ag

Naive T cells

Treg cell TCR

Lymph node Endothelial cells

Afferent lymphatic vessel Mature LC/DDC Naive T cells

Clonal expansion Effector T cells

Figure 10-8  The mechanisms operative in the initiation, expression, and downregulation of skin-derived immune responses. Induction of T cell immunity via the skin: Antigens administered to or occurring in the skin (microbial products, haptens, etc.) will be picked up, engulfed, processed and presented by dendritic antigen-presenting cells in the epidermis (LC = Langerhans cells) and/or the dermis (DDC = dermal dendritic cells). When danger signals, particularly those reaching beyond the dermal–epidermal junction, are present at the time of antigenic exposure, these DC will undergo a process of maturation as evidenced by an enhanced expression of MHC antigens, costimulatory molecules (CD80, CD86, CD40, CD83, etc.), and immunostimulatory cytokines (IL-1b, IL-6, IL-12, IL-23) as well as their enhanced emigration from the skin to the paracortical areas of the draining lymph nodes. At this site, the skin-derived DCs provide activation stimuli to the naive resting T cells surrounding them. This occurs in an antigen-specific fashion and thus results in the expansion of the respective clone(s). T cells thus primed begin to express skin-homing receptors (e.g., CLA) as well as receptors for various chemoattractants that promote their attachment to dermal microvascular endothelial cells of inflamed skin and, ultimately, their entry into this tissue. Elicitation of T-cell-mediated tissue inflammation and pathogen clearance: on receipt of a renewed antigenic stimulus by activated skin DCs or other APCs, the skin-homed T cells expand locally and display the effector functions needed for the elimination of the pathogen. Downregulation and prevention of cutaneous T cell immunity: In the absence of danger signals (tissue homeostasis), antigen-loaded skin DCs leave their habitat and migrate toward the draining lymph node. These cells or, alternatively, resident lymph node DCs that had picked up antigenic moieties from afferent lymphatics present this antigen in a nonproductive fashion, i.e., they induce antigen-specific T-cell unresponsiveness or allow the responding T cell(s) to differentiate into immunosuppressive T regulatory cells. The latter may limit antigen-driven clonal T-cell expansion during primary immune reactions in lymph nodes and during secondary immune reactions at the level of the peripheral tissue. Such events can result in the downregulation of both desired (antitumor, antimicrobial) and undesired (hapten-specific, autoreactive) immune responses. Ag = antigen; T = T naive cell; T* = anergic T cell; TCR = T-cell receptor; T reg = regulatory T cells; EM T cells = effector memory T cells.

response triggered by these cells is skewed into the Th1 direction.336 Recent work also located a substantial number of CD1a+ CD11c+ Langerin-DC within the dermis of AD lesions. Interestingly, these cells showed an upregulation of the chemokines CCL17 and CCL18 and can thereby provide a Th2 polarizing environment.323 Importantly, this subset of IDSC does not produce

Innate and Adaptive Immunity in the Skin

Immature LC/DDC

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Cytokines Chemokines

Chapter 10

DDC

iNOS or TNF-a, thus confirming the presence of different inflammatory DC subsets in different cutaneous pathologies.

Plasmacytoid Dendritic Cells.337

pDCs are DCs that are characterized by a highly developed endoplasmic reticulum, which results in their plasma

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cell-like appearance.338 Functionally, pDCs display a unique ability to produce up to 1,000 times more natural IFNs than any other blood mononuclear cell in response to TLR ligands and thus were also named principal type 1 IFN-producing cells.339

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

Section 4 :: Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

3. Gasque P: Complement: A unique innate immune sensor for danger signals. Mol Immunol 41:1089, 2004 5. Schauber J, Gallo RL: Antimicrobial peptides and the skin immune defense system. J Allergy Clin Immunol 122:261, 2008 38. Akira S et al: Pathogen recognition and innate immunity. Cell 124:783, 2006 75. Martinon F et al: The inflammasomes: Guardians of the body. Annu Rev Immunol 27:229, 2009 117. von Boehmer H: Selection of the T-cell repertoire: Receptor-controlled checkpoints in T-cell development. Adv Immunol 84:201, 2004 151. Surh CD, Sprent J: Homeostasis of naive and memory T cells. Immunity 29:848, 2008 169. Korn T et al: IL-17 and Th17 cells. Annu Rev Immunol 27:485, 2009

Chapter 11 :: Cytokines :: Ifor R. Williams & Thomas S. Kupper CYTOKINES AT A GLANCE Cytokines are polypeptide mediators that function in communication between hematopoietic cells and other cell types. Cytokines often have multiple biologic activities (pleiotropism) and overlapping biologic effects (redundancy). Primary cytokines, such as interleukin 1 and tumor necrosis factor-α, are sufficient on their own to trigger leukocyte influx into tissue. Most cytokines signal through either the nuclear factor-κB or the Jak/STAT signaling pathways.

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179. Bendelac A et al: The biology of NKT cells. Annu Rev Immunol 25:297, 2007 182. Shevach EM: Mechanisms of foxp3+ T regulatory cellmediated suppression. Immunity 30:636, 2009 186 Schaerli P et al: CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med 192:1553, 2000 189. Sallusto F, Mackay CR: Chemoattractants and their receptors in homeostasis and inflammation. Curr Opin Immunol 16:724, 2004 207. Modlin RL et al: Learning from lesions: Patterns of tissue inflammation in leprosy. Proc Natl Acad Sci U S A 85:1213, 1988 218. Hammer GE et al: The final touches make perfect the peptide-MHC class I repertoire. Immunity 26:397, 2007 253. Matzinger P: An innate sense of danger. Ann N Y Acad Sci 961:341, 2002 258. Steinman RM et al: Dendritic cell function in vivo during the steady state: A role in peripheral tolerance. Ann N Y Acad Sci 987:15, 2003 274 Seiffert K, Granstein RD: Neuroendocrine regulation of skin dendritic cells. Ann N Y Acad Sci 1088:195, 2006 283. Romani N et al: Langerhans cells and more: Langerinexpressing dendritic cell subsets in the skin. Immunol Rev 234:120, 2010 309. Zaba LC et al: Resident and “inflammatory” dendritic cells in human skin. J Invest Dermatol 129:302, 2009 337. Lande R, Gilliet M: Plasmacytoid dendritic cells: Key players in the initiation and regulation of immune responses. Ann N Y Acad Sci 1183:89, 2010

Cytokine-based therapeutics now in use include recombinant cytokines, inhibitory monoclonal antibodies, fusion proteins composed of cytokine receptors and immunoglobulin chains, topical immunomodulators such as imiquimod, and cytokine fusion toxins.

THE CONCEPT OF CYTOKINES When cells and tissues in complex organisms need to communicate over distances greater than one cell diameter, soluble factors must be employed. A subset of these factors is most important when produced or released transiently under emergent conditions. When faced with an infection- or injury-related challenge, the host must orchestrate a complex and carefully choreographed series of steps. It must mobilize certain circulating white blood cells precisely to the relevant injured area (but not elsewhere) and guide other leukocytes involved in host defense, particularly T and B cells, to specialized lymphatic tissue remote from the infectious lesion but sufficiently close to contain antigens from the relevant pathogen. After a limited period of time in this setting (i.e., lymph node), antibodies produced by B cells and effector-memory T cells, can be released into the circulation and will localize at the site of infection. Soluble factors produced by resident tissue cells at the site of injury, by leukocytes and platelets that are recruited to the site of injury, and by memory T cells ultimately recruited to the area, all conspire to generate an evolving and effective response to a challenge to host defense. Most important, the level of this response must be appropriate to the challenge and the duration

A simple concept that continues to be extremely useful for discussion of cytokine function is the concept of “primary” and “secondary” cytokines.6 Primary cytokines are those cytokines that can, by themselves, initiate all the events required to bring about leukocyte infiltration in tissues. IL-1 (both α and β forms) and tumor necrosis factor (TNF; includes both TNF-α and TNF-β) function as primary cytokines, as do certain other cytokines that signal through receptors that trigger the nuclear factor κB (NF-κB) pathway. IL-1 and TNF are able to induce cell adhesion molecule expression on endothelial cells [selectins as well as immunoglobulin superfamily members such as intercellular adhesion molecule 1 (ICAM-1) and vascular cellular adhesion molecule 1 (VCAM-1)], to stimulate a variety of cells to produce a host of additional cytokines, and to induce expression of chemokines that provide a chemotactic gradient allowing the directed migration of specific leukocyte subsets into a site of inflammation (see Chapter 12). Primary cytokines can be viewed as part of the innate immune system (see Chapter 10), and in fact share signaling pathways with the so-called Toll-like receptors (TLRs), a family of receptors that recognize molecular patterns characteristically associated with microbial products.7 Although other cytokines sometimes have potent inflammatory activity, they do not duplicate this full repertoire of activities. Many qualify as secondary cytokines whose production is induced after stimulation by IL-1 and/or TNF family molecules. The term secondary does not imply that they are less important or less active than primary cytokines; rather, it indicates that their spectrum of activity is more restricted.

Cytokines

The first cytokines described had distinct and easily recognizable biological activities, exemplified by IL-1, IL-2, and the interferons (IFNs). The term cytokine was first coined by Cohen in 1975, to describe several such

PRIMARY AND SECONDARY CYTOKINES

4

::

CLASSIFICATIONS OF CYTOKINES

activities released into the supernatant of an epithelial cell line.2 Prior to this, such activities had been thought to be the exclusive domain of lymphocytes (lymphokines) and monocytes (monokines) and were considered a function of the immune system. Keratinocyte cytokines were first discovered in 1981,3 and the list of cytokines produced by this epithelial cell rivals nearly any other cell type in the body.4,5 The number of molecules that can be legitimately termed cytokines continues to expand and has brought under the cytokine rubric molecules with a broad range of distinct biological activities. The progress in genomic approaches has led to identification of novel cytokine genes based on homologies to known cytokine genes. Making sense of this plethora of mediators is more of a challenge than ever, and strategies to simplify the analysis of the cytokine universe are sorely needed.

Chapter 11

of the response must be transient; that is, long enough to decisively eliminate the pathogen, but short enough to minimize damage to healthy host tissues. Much of the cell-to-cell communication involved in the coordination of this response is accomplished by cytokines. Cytokines (which include the large family of chemokines, discussed in Chapter 12) are soluble polypeptide mediators that play pivotal roles in communication between cells of the hematopoietic system and other cells in the body.1 Cytokines influence many aspects of leukocyte function including differentiation, growth, activation, and migration. While many cytokines are substantially upregulated in response to injury to allow a rapid and potent host response, cytokines also play important roles in the development of the immune system and in homeostatic control of the immune system under basal conditions. The growth and differentiation effects of cytokines are not limited to leukocytes, although we will not discuss soluble factors that principally mediate cell growth and differentiation of cells other than leukocytes in this chapter. The participation of cytokines in many parts of immune and inflammatory responses has prompted the examination of a variety of cytokines or cytokine antagonists (primarily antibodies and fusion proteins) as agents for pharmacologic manipulation of immune-mediated diseases. Only a few classes of effective cytokine drugs have emerged from the lengthy pathway of clinical trials to achieve FDA approval and widespread therapeutic use, but some of these drugs are now valuable therapeutics in dermatology. This chapter discusses these approved drugs and other promising biological agents still in clinical trials. General features of cytokines are their pleiotropism and redundancy. Before the advent of a systematic nomenclature for cytokines, most newly identified cytokines were named according to the biologic assay that was being used to isolate and characterize the active molecule (e.g., T-cell growth factor for the molecule that was later renamed interleukin 2, or IL-2). Very often, independent groups studying quite disparate bioactivities isolated the same molecule that revealed the pleiotropic effects of these cytokines. For example, before being termed interleukin 1 (IL-1), this cytokine had been variously known as endogenous pyrogen, lymphocyte-activating factor, and leukocytic endogenous mediator. Many cytokines have a wide range of activities, causing multiple effects in responsive cells and a different set of effects in each type of cell capable of responding. The redundancy of cytokines typically means that in any single bioassay (such as induction of T-cell proliferation), multiple cytokines will display activity. In addition, the absence of a single cytokine (such as in mice with targeted mutations in cytokine genes) can often be largely or even completely compensated for by other cytokines with overlapping biologic effects.

T-CELL SUBSETS DISTINGUISHED BY PATTERN OF CYTOKINE PRODUCTION Another valuable concept that has withstood the test of time is the assignment of many T-cell-derived cytokines into groups based on the specific helper T-cell

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IL-12

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IL-4

TGF-β1 IL-23 IL-6

TGF-β1

C m yto at ki ur ne e s CD m 4 ade T ce by lls

Development of CD4 helper T-cell subsets

U na ndi ive ffe CD ren 4 tiat T ed ce ll Cy CD to 4 kin de es ve in lo flu pm en en cin t g

4

Th1

IFN-γ,LT-α

Th2

IL-4, IL-5, IL-13

Th17

IL-17

Treg

TGF-β1, IL10

FoxP3

Figure 11-1  Cytokines control the development of specific CD4 helper T-cell subsets. The cytokine milieu at the time of activation of naive undifferentiated CD4 T cells has a profound influence on the ultimate pattern of cytokine secretion adopted by fully differentiated T cells. Subsets of effector CD4 T cells with defined patterns of cytokine secretion include T helper 1 (Th1), Th2, and Th17 cells. Regulatory CD4 T cells (Treg cells) express the FoxP3 transcription factor, and their effects are mediated in part by their production of transforming growth factor-β1 (TGFβ1) and/or interleukin 10 (IL-10). IFN = interferon; LT = lymphotoxin. (Adapted from Tato CM, O’Shea JJ: What does it mean to be just 17? Nature 441:166, 2006.)

subsets that produce them (Fig. 11-1). The original two helper T-cell subsets were termed Th1 and Th2.8 Commitment to one of these two patterns of cytokine secretion also occurs with CD8 cytotoxic T cells and γ/δ T cells. Dominance of type 1 or type 2 cytokines in a T-cell immune response has profound consequences for the outcome of immune responses to certain pathogens and extrinsic proteins capable of serving as allergens. Over two decades after the original description of the Th1 and Th2 subsets, strong evidence has emerged that there are other functionally significant patterns of cytokine secretion by T cells. Most prominent among these newer T-cell lineages are Th17 cells and regulatory T cells (or Treg cells for short). The Th17 subset is distinguished by production of a high level of IL-17, but many Th17 cells also secrete IL-21 and IL-22. Th17 cells promote inflammation, and there is consistent evidence from human autoimmune diseases and mouse models of these diseases that IL-17-producing cells are critical effectors in autoimmune disease.9 A subset of T cells known as Treg cells has emerged as a crucial subset involved in the maintenance of peripheral self-

tolerance.10 Two of the most distinctive features of Treg cells are their expression of the FoxP3 transcription factor and production of transforming growth factor-β (TGF-β), a cytokine that appears to be required for Treg cells to limit the excess activity of the proinflammatory T-cell subsets.11 IL-10 is also a significant contributor to the suppressive activity of Treg cells, particularly at some mucosal interfaces.12 Additional proposed helper T-cell subsets are follicular helper T cells (Tfh) that specialize in providing B cell help in germinal centers, Th9 cells distinguished by high levels of IL-9 production that function in antiparasite immunity along with Th2 cells, and Th22 cells associated with skin inflammation that produce Th22, but not other Th17-associated cytokines. Not only does each of these T-cell subsets exhibit distinctive patterns of cytokine production, cytokines are key factors in influencing the differentiation of naive T cells into these subsets. IL-12 is the key Th1-­promoting factor, IL-4 is required for Th2 differentiation, and IL-6, IL-23, and TGF-β are involved in promoting Th17 development.

STRUCTURAL CLASSIFICATION OF CYTOKINES Not all useful classifications of cytokines are based solely on analysis of cytokine function. Structural biologists, aided by improved methods of generating homogenous preparations of proteins and establishment of new analytical methods (e.g., solution magnetic resonance spectroscopy) that complement the classical X-ray crystallography technique, have determined the three-dimensional structure of many cytokines. These efforts have led to the identification of groups of cytokines that fold to generate similar three-dimensional structures and bind to groups of cytokine receptors that also share similar structural features. For example, most of the cytokine ligands that bind to receptors of the hematopoietin cytokine receptor family are members of the four-helix bundle group of proteins. Four-helix bundle proteins have a shared tertiary architecture consisting of four antiparallel α-helical stretches separated by short connecting loops. The normal existence of some cytokines as oligomers rather than monomers was discovered in part as the result of structural investigations. For example, interferon-γ (IFN-γ) is a four-helix bundle cytokine that exists naturally as a noncovalent dimer. The bivalency of the dimer enables this ligand to bind and oligomerize two IFN-γ receptor complexes, thereby facilitating signal transduction. TNF-α and TNF-β are both trimers that are composed almost exclusively of β-sheets folded into a “jelly roll” structural motif. Ligand-induced trimerization of receptors in the TNF receptor family is involved in the initiation of signaling.

SIGNAL TRANSDUCTION PATHWAYS SHARED BY CYTOKINES To accomplish their effects, cytokines must first bind with specificity and high affinity to receptors on the cell surfaces of responding cells. Many aspects of the

4

TABLE 11-1

Major Families of Cytokine Receptors

IL-1R, type I

NF-κB activation via TRAF6

TNF receptor family

TNFR1

NF-κB activation involving TRAF2 and TRAF5 Apoptosis induction via “death domain” proteins

Hematopoietin receptor family (class I receptors)

IL-2R

Activation of Jak/STAT pathway

IFN/IL-10 receptor family (class II receptors)

IFN-γR

Activation of Jak/STAT pathway

Immunoglobulin superfamily

M-CSF R

Activation of intrinsic tyrosine kinase

TGF-β receptor family

TGF-βR, types I and II

Activation of intrinsic serine/threonine kinase coupled to Smad proteins

Chemokine receptor family

CCR5

Seven transmembrane receptors coupled to G proteins

CCR = CC chemokine receptor; IFN = interferon; IL = interleukin; Jak = Janus kinase; M-CSF = macrophage colony-stimulating factor; NF-κB = nuclear factor κB; STAT = signal transducer and activator of transcription; TGF = transforming growth factor; TNF = tumor necrosis factor; TRAF = tumor necrosis factor receptor-associated factor.

pleiotropism and redundancy manifested by cytokines can be understood through an appreciation of shared mechanisms of signal transduction mediated by cell surface receptors for cytokines. In the early years of the cytokine biology era, the emphasis of most investigative work was the purification and eventual cloning of new cytokines and a description of their functional capabilities, both in vitro and in vivo. Most of the cytokine receptors have now been cloned, and many of the signaling cascades initiated by cytokines have been described in great detail. The vast majority of cytokine receptors can be classified into a relatively small number of families and superfamilies (Table 11-1), the members of which function in an approximately similar fashion. Table 11-2 lists the cytokines of particular relevance for cutaneous biology, including the major sources, responsive cells, features of interest, and clinical relevance of each cytokine. Most cytokines send signals to cells through pathways that are very similar to those used by other cytokines binding to the same class of receptors. Individual cytokines often employ several downstream pathways of signal transduction, which accounts in part for the pleiotropic effects of these molecules. Nevertheless, we propose here that a few major signaling pathways account for most effects attributable to cytokines. Of particularly central importance are the NF-κB pathway and the Jak/STAT pathway, described in the following sections.

NUCLEAR FACTOR kB, INHIBITOR OF kB, AND PRIMARY CYTOKINES A major mechanism contributing to the extensive overlap between the biologic activities of the primary cytokines IL-1 and TNF is the shared use of the NF-κB

signal transduction pathway. IL-1 and TNF use completely distinct cell surface receptor and proximal signaling pathways, but these pathways converge at the activation of the NF-κB transcription factor. NF-κB is of central importance in immune and inflammatory processes because a large number of genes that elicit or propagate inflammation have NF-κB recognition sites in their promoters.13 NF-κB-regulated genes include cytokines, chemokines, adhesion molecules, nitric oxide synthase, cyclooxygenase, and phospholipase A2. In unstimulated cells, NF-κB heterodimers formed from p65 and p50 subunits are inactive because they are sequestered in the cytoplasm as a result of tight binding to inhibitor proteins in the IκB family (Fig. 11-2). Signal transduction pathways that activate the NF-κB system do so through the activation of an IκB kinase (IKK) complex consisting of two kinase subunits (IKKα and IKKβ) and a regulatory subunit (IKKγ). The IKK complex phosphorylates IκBα and IκBβ on specific serine residues, yielding a target for recognition by an E3 ubiquitin ligase complex. The resulting polyubiquitination marks this IκB for rapid degradation by the 26S proteasome complex in the cytoplasm. Once IκB has been degraded, the free NF-κB (which contains a nuclear localization signal) is able to pass into the nucleus and induce expression of NF-κBsensitive genes. The presence of κB recognition sites in cytokine promoters is very common. Among the genes regulated by NF-κB are IL-1β and TNF-a. This endows IL-1b and TNF-a with the capacity to establish a positive regulatory loop that favors persistent inflammation. Cytokines besides IL-1 and TNF that activate the NF-κB pathway as part of their signal transduction mechanisms include IL-17 and IL-18. Proinflammatory cytokines are not the only stimuli that can activate the NF-κB pathway. Bacterial products

Cytokines

IL-1 receptor family

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Example

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Receptor Family

Major Signal Transduction Pathway(s) Leading to Biologic Effects

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TABLE 11-2

Cytokines of Particular Relevance for Cutaneous Biology

Section 4

Responsive Cells

Features of Interest

Clinical Relevance

IL-1α

Epithelial cells

Infiltrating leukocytes

Active form stored in keratinocytes

IL-1Ra used to treat rheumatoid arthritis

IL-1β

Myeloid cells

Infiltrating leukocytes

Caspase 1 cleavage required for activation

IL-1Ra used to treat rheumatoid arthritis

IL-2

Activated T cells

Activated T cells, Treg cells

Autocrine factor for activated T cells

IL-2 fusion toxin targets CTCL

IL-4

Activated Th2 cells, NKT cells

Lymphocytes, endothelial cells, keratinocytes

Causes B-cell class switching and Th2 differentiation

—

IL-5

Activated Th2 cells, mast cells

B cells, eosinophils

Regulates eosinophil response to parasites

Anti-IL-5 depletes eosinophils

IL-6

Activated myeloid cells, fibroblasts, endothelial cells

B cells, myeloid cells, hepatocytes

Triggers acute-phase response, promotes immunoglobulin synthesis

Anti-IL-6R used to treat rheumatoid arthritis

IL-10

T cells, NK cells

Myeloid and lymphoid cells

Inhibits innate and acquired immune responses

—

IL-12

Activated APCs

Th1 cells

Promotes Th1 differentiation, shares p40 subunit with IL-23

Anti-p40 inhibits Crohn’s disease and psoriasis

IL-13

Activated Th2 cells, nuocytes

Monocytes, keratinocytes, endothelial cells

Mediates tissue responses to parasites

—

IL-17

Activated Th17 cells

Multiple cell types

Mediates autoimmune diseases

Potential drug target in autoimmune disease

IL-22

Activated Th17 cells and Th22 cells

Keratinocytes

Induces cytokines and antimicrobial peptides

Contributes to psoriasis

IL-23

Activated dendritic cells

Memory T cells, Th17 cells

Directs Th17 differentiation, mediates autoimmune disease

Anti-p40 inhibits Crohn’s disease and psoriasis

IL-25

Activated Th2 cells, mast cells

Th17 cells

Promotes Th2 differentiation, inhibits Th17 cells

—

IL-27

Activated APCs

Th1 cells

Promotes Th1 differentiation

—

IL-35

Treg cells

Th17 cells and Treg cells

Inhibits Th17 cells and expands Treg cells

—

TNF-α

Activated myeloid, lymphoid, and epithelial cells

Infiltrating leukocytes

Mediates inflammation

Anti-TNF-α effective in psoriasis

IFN-α and IFN-β

Plasmacytoid dendritic cells

Most cell types

Major part of innate antiviral response

Elicited by topical imiquimod application

IFN-γ

Activated Th1 cells, CD8 T cells, NK cells, dendritic cells

Macrophages, dendritic cells, naive T cells

Macrophage activation, specific isotype switching

IFN-γ used to treat chronic granulomatous disease

TSLP

Epithelial cells including keratinocytes

Dendritic cells, B cells, Th2 cells

Promotes Th2 differentiation

Involved in atopic diseases

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Cytokine Major Sources

Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

APC = antigen-presenting cell; CTCL = cutaneous T-cell lymphoma; IFN = interferon; IL = interleukin; NK = natural killer; NKT = natural killer T cell; Th = T helper; TNF = tumor necrosis factor; Treg = T regulatory; TSLP = thymic stromal lymphopoietin.

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Activation of nuclear factor κB (NF-κB)

IL-1 TNF 1

Agonist binding to cell surface receptor

2

Receptor

3 Induction of IκB kinase activity

Cytoplasm Phosphorylation and ubiquitination of IκB

IκB

Ub

IκB

IκB

4

p65

::

NF-κB

5

Nucleus NF-κB

6

NF-κB release and nuclear translocation

Gene

GGGRNNYYCC

κB site

NF-κB

Cytokines

NF-κB complex with IκB

Degradation of IκB by 26S proteasome

Chapter 11

P

p50

Ub Ub

Transcription of NF-κBresponsive genes

Figure 11-2  Activation of nuclear factor κB (NF-κB)-regulated genes after signaling by receptors for primary cytokines or by Toll-like receptors (TLRs) engaged by microbial products. Under resting conditions, NF-κB (a heterodimer of p50 and p65 subunits) is tightly bound to an inhibitor called IκB that sequesters NF-κB in the cytoplasm. Engagement of one of the TLRs or the signal transducing receptors for interleukin 1 (IL-1) or tumor necrosis factor (TNF) family members leads to induction of IκB kinase activity that phosphorylates IκB on critical serine residues. Phosphorylated IκB becomes a substrate for ubiquitination, which triggers degradation of IκB by the 26S proteasome. Loss of IκB results in release of NF-κB, which permits it to move to the nucleus and activate transcription of genes whose promoters contain κB recognition sites. Ub = ubiquitin.

(e.g., lipopolysaccharide, or LPS), oxidants, activators of protein kinase C (e.g., phorbol esters), viruses, and ultraviolet (UV) radiation are other stimuli that can stimulate NF-κB activity. TLR4 is a cell surface receptor for the complex of LPS, LPS-binding protein, and CD14. The cytoplasmic domain of TLR4 is similar to that of the IL-1 receptor type 1 (IL-1R1) and other IL-1R family members and is known as the TIR domain (for Toll/IL-1 receptor).14 When ligand is bound to a TIR domain-containing receptor, one or more adapter proteins that also contain TIR domains are recruited to the complex. MyD88 was the first of these adapters to be identified; the other known adapters are TIRAP (TIR domain-containing adapter protein), TRIF (TIR domain-containing adapter inducing IFN-β), and TRAM (TRIF-related adapter molecule). Engagement

of the adapter, in turn, activates one or more of the IL-1R-associated kinases (IRAK1 to IRAK4) that then signal through TRAF6, a member of the TRAF (TNF receptor-associated factor) family, and TAK1 (TGFβ-activated kinase) to activate the IKK complex.15

JAK/STAT PATHWAY A major breakthrough in the analysis of cytokinemediated signal transduction was the identification of a common cell surface to nucleus pathway used by the majority of cytokines. This Jak/STAT pathway was first elucidated through careful analysis of signaling initiated by IFN receptors (Fig. 11-3), but was subsequently shown to play a role in signaling by all

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Figure 11-3  Participation of Jak (Janus kinase) and STAT (signal transducer and activator of transcription) proteins in interferon-γ (IFN-γ) signaling. Binding of human IFN-γ (a dimer) to its receptor brings about oligomerization of receptor complexes composed of α and β chains. The nonreceptor protein tyrosine kinases Jak1 and Jak2 are activated and phosphorylate critical tyrosine residues in the receptor such as the tyrosine at position 440 of the α chain (Y440). STAT1α molecules are recruited to the IFN-γ receptor based on the affinity of their Src homology 2 (SH2) domains for the phosphopeptide sequence around Y440. Receptor-associated STAT1α molecules then dimerize through reciprocal SH2-phosphotyrosine interactions. The resulting STAT1α dimers translocate to the nucleus and stimulate transcription of IFN-γ-regulated genes.

cytokines that bind to members of the hematopoietin receptor family.16 The Jak/STAT pathway operates through the sequential action of a family of four nonreceptor tyrosine kinases (the Jaks or Janus family kinases) and a series of latent cytosolic transcription factors known as STATs (signal transducers and activators of transcription). The cytoplasmic portions of many cytokine receptor chains are noncovalently associated with one of the four Jaks [Jak1, Jak2, Jak3, and tyrosine kinase 2 (Tyk2)]. The activity of the Jak kinases is upregulated after stimulation of the cytokine receptor. Ligand binding to the cytokine receptors leads to the association of two or more distinct cytokine receptor subunits and brings the associated Jak kinases into close proximity with each other. This promotes cross-phosphorylation or autophosphorylation reactions that in turn fully activate the kinases. Tyrosines in the cytoplasmic tail of the cytokine receptor as well as tyrosines on other associated and newly recruited proteins are also phosphorylated. A subset of the newly phosphorylated

tyrosines can then serve as docking points for attachment of additional signaling proteins bearing Src homology 2 (SH2) domains. Cytoplasmic STATs possess SH2 domains and are recruited to the phosphorylated cytokine receptors via this interaction. Homodimeric or heterodimeric STAT proteins are phosphorylated by the Jak kinases and subsequently translocate to the nucleus. In the nucleus they bind recognition sequences in DNA and stimulate transcription of specific genes, often in cooperation with other transcription factors. The same STAT molecules can be involved in signaling by multiple different cytokines. The specificity of the response in these instances may depend on the formation of complexes involving STATs and other transcription factors that then selectively act on a specific set of genes.

INTERLEUKIN 1 FAMILY OF CYTOKINES (INTERLEUKINS 1a, 1b, 18, 33) IL-1 is the prototype of a cytokine that has been discovered many times in many different biologic assays. Distinct genes encode the α and β forms of human IL-1, with only 26% homology at the amino acid level. Both IL-1s are translated as 31-kDa molecules that lack a signal peptide, and both reside in the cytoplasm. This form of IL-1α is biologically active, but 31-kDa IL-1b must be cleaved by caspase 1 (initially termed interleukin-1b-converting enzyme) in a multiprotein cytoplasmic complex called the inflammasome to generate an active molecule.17 In general, IL-1β appears to be the dominant form of IL-1 produced by monocytes, macrophages, Langerhans cells, and dendritic cells, whereas IL-1α predominates in epithelial cells, including keratinocytes. This is likely to relate to the fact that epithelial IL-1α is stored in the cytoplasm of cells that comprise an interface with the external environment. Such cells, when injured, release biologically active 31-kDa IL-1α and, by doing so, can initiate inflammation.6 However, if uninjured, these cells will differentiate and ultimately release their IL-1 contents into the environment. Leukocytes, including dendritic and Langerhans cells, carry their cargo of IL-1 inside the body, where its unregulated release could cause significant tissue damage. Thus, biologically active IL-1β release from cells is controlled at several levels: IL-1β gene transcription, caspase 1 gene transcription, and availability of the adapter proteins that interact with caspase 1 in the inflammasome to allow the generation of mature IL-1β. IL-1β stimulates the egress of Langerhans cells from the epidermis during the initiation of contact hypersensitivity, a pivotal event that leads to accumulation of Langerhans cells in skin-draining lymph nodes. Studies of mice deficient in IL-1α and IL-1β genes suggest that both molecules are important in contact hypersensitivity, but that IL-1α is more critical. Active forms of IL-1 bind to the IL-1R1 or type 1 IL-1 receptor.14 This is the sole signal-transducing receptor for IL-1, and its cytoplasmic domain has

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cell types in skin, including keratinocytes, Langerhans cells, and monocytes. IL-18 induces proliferation, cytotoxicity, and cytokine production by Th1 and natural killer (NK) cells, mostly synergistically with IL-12. The IL-18 receptor bears striking similarity to the IL-1 receptor.14 The binding chain (IL-18R) is an IL-1R1 homolog, originally cloned as IL-1Rrp1. IL-18R alone is a low-affinity receptor that must recruit IL-18RAcP (a homolog of IL-1RAcP). As for IL-1, both chains of the IL-18 receptor are required for signal transduction. Although there is no IL-18 homolog of IL-1ra, a molecule known as IL-18-binding protein binds to soluble mature IL-18 and prevents it from binding to the IL18R complex. More recently, it has become clear that there is a family of receptors homologous to the IL-1R1 and IL-18R molecules,14 having in common a TIR motif (Fig. 11-4). All of these share analogous signaling pathways initiated by the MyD88 adapter molecule. One of these receptors, originally known as ST2, was initially characterized as a gene expressed by Th2 cells, but not by Th1 cells. The description of a natural ligand for ST2 designated IL-33 has added a new member to the IL-1 family that shares characteristic features of other cytokines in the family, such as a requirement for

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little homology with other cytokine receptors, showing greatest homology with the Toll gene product identified in Drosophila. A second cell surface protein, the IL-1R accessory protein, or IL-1RAcP, must associate with IL-1R1 for signaling to occur. When IL-1 engages the IL-1R1/IL-1RAcP complex, recruitment of the MyD88 adapter occurs, followed by interactions with one or more of the IRAKs. These kinases in turn associate with TRAF6. Stepwise activation and recruitment of additional signaling molecules culminate in the induction of IKK activity. The net result is the activation of a series of NF-κB-regulated genes. A molecule known as the IL-1 receptor antagonist, or IL-1ra, can bind to IL-1R1 but does not induce signaling through the receptor. This IL-1ra exists in three alternatively spliced forms, and an isoform produced in monocytes is the only ligand for the IL-1R1 that both contains a signal peptide and is secreted from cells. Two other isoforms of IL-1ra, both lacking signal peptides, are contained within epithelial cells. The function of IL-1ra seems to be as a pure antagonist of IL-1 ligand binding to IL-1R1, and binding of IL-1ra to IL-1R1 does not induce the mobilization of IL-1RAcP. Consequently, although both IL-1α/β and IL-1ra bind with equivalent affinities to IL-1R1, the association of IL-1R1 with IL-1RAcP increases the affinity for IL-1α/β manyfold while not affecting the affinity for IL-1ra. This is consistent with the observation that a vast molar excess of IL-1ra is required to fully antagonize the effects of IL-1. The biologic role of IL-1ra is likely to be in the quenching of IL-1-mediated inflammatory responses, and mice deficient in IL-1ra show exaggerated and persistent inflammatory responses. A second means of antagonizing IL-1 activity occurs via expression of a second receptor for IL-1, IL-1R2. This receptor has a short cytoplasmic domain and serves to bind IL-1α/β efficiently, but not IL-1ra. This 68-kDa receptor can be cleaved from the cell surface by an unknown protease and released as a stable, soluble 45-kDa molecule that retains avid IL-1-binding function. By binding the functional ligands for IL-1R1, IL-1R2 serves to inhibit IL-1-mediated responses. It is likely that IL-1R2 also inhibits IL-1 activity by associating with IL-1RAcP at the cell surface and removing and sequestering it from the pool available to associate with IL-1R1. Thus, soluble IL-1R2 binds to free IL-1, whereas cell surface IL-1R2 sequesters IL-1RAcP. Expression of IL-1R2 can be upregulated by a number of stimuli, including corticosteroids and IL-4. However, IL-1R2 can also be induced by inflammatory cytokines, including IFN-γ and IL-1, probably as a compensatory signal designed to limit the scale and duration of the inflammatory response. Production of IL-1R2 serves to make the producing cell and surrounding cells resistant to IL-1-mediated activation. Interestingly, some of the most efficient IL-1-producing cells are also the best producers of the IL-1R2. IL-18 was first identified based on its capacity to induce IFN-γ. One name initially proposed for this cytokine was IL-1γ, because of its homology with IL-1α and IL-1β. Like IL-1β, it is translated as an inactive precursor molecule of 23 kDa and is cleaved to an active 18-kDa species by caspase 1. It is produced by multiple

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Figure 11-4  The interleukin 1 receptor (IL-1R) family and Toll-like receptors (TLRs) use a common intracellular signaling pathway. Receptors for cytokines in the IL-1 family (typified by the IL-1 and IL-18 receptors) share a common signaling domain with the TLRs (TLR1 to TLR11) called the Toll/IL-1 receptor (TIR) domain. The TIR domain receptors interact with TIR domain-containing adapter proteins such as MyD88 that couple ligand binding to activation of IL-1R-associated kinase (IRAK) and ultimately activation of nuclear factor κB (NF-κB). IL-1RAcP = IL-1R accessory protein; TRAF = tumor necrosis factor receptor-associated factor.

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processing by caspase 1 to release a mature form of the ligand.18 IL-33 stimulation of Th2 cells promotes their production of the characteristic Th2 cytokines IL-4, IL-5, and IL-10.19 IL-1R1, IL-18R, IL-33R (ST2), the TLRs, and their ligands are all best viewed as elements of the innate immune system that signal the presence of danger or injury to the host. When IL-1 produced by epidermis was originally identified, it was noted that both intact epidermis and stratum corneum contained significant IL-1 activity, which led to the concept that epidermis was a shield of sequestered IL-1 surrounding the host, waiting to be released on injury. More recently, it was observed that high levels of the IL-1ra coexist within keratinocytes; however, repeated experiments show that in virtually all cases, the amount of IL-1 present is sufficient to overcome any potential for inhibition mediated by IL-1ra. Studies have now shown that mechanical stress to keratinocytes permits the release of large amounts of IL-1 in the absence of cell death. Release of IL-1 induces expression of endothelial adhesion molecules, including E-selectin, ICAM-1, and VCAM-1, as well as chemotactic and activating chemokines. This attracts not only monocytes and granulocytes but a specific subpopulation of memory T cells that bear cutaneous lymphocyte antigen on their cell surface. Memory T cells positive for cutaneous lymphocyte antigen are abundant in inflamed skin, comprising the majority of T cells present. Therefore, any injury to the skin, no matter how trivial, releases IL-1 and attracts this population of memory T cells. If they encounter their antigen in this microenvironment, their ­activation and subsequent cytokine production will amplify the inflammatory response. This has been proposed as the basis of the clinical observation of inflammation in ­response to trauma, known as the Koebner reaction. Several biologics that act by inhibiting IL-1 function have been developed for clinical use including recombinant IL-1Ra (anakinra), antibody to IL-1β (canakinumab), and an IgG Fc fusion protein that includes the ligand binding domains of the type I IL-1R and IL-1RAcP (rilonacept, also known as IL-1 Trap). All of these agents are efficacious in countering the IL-1-induced inflammation associated with a group of rare autoinflammatory diseases called the cryopyrin-associated periodic syndromes (CAPS). Anakinra was initially US Food and Drug Administration (FDA) approved as a therapy for adult rheumatoid arthritis. IL-1 inhibition is also being tested as a therapy for gout, an inflammatory arthritis triggered by uric acid-mediated activation of inflammasomes that generate IL-1β.

TUMOR NECROSIS FACTOR: THE OTHER PRIMARY CYTOKINE

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TNF-α is the prototype for a family of related signaling molecules that mediate their biologic effects through a family of related receptor molecules. TNF-α was initially cloned on the basis of its ability to mediate two interesting biologic effects: (1) hemorrhagic necrosis of malignant tumors, and (2) inflammation-associated

cachexia. Although TNF-α exerts many of its biologically important effects as a soluble mediator, newly synthesized TNF-α exists as a transmembrane protein on the cell surface. A specific metalloproteinase known as TNF-α-converting enzyme (TACE) is responsible for most TNF-α release by T cells and myeloid cells. The closest cousin of TNF-α is TNF-β, also known as lymphotoxin α (LT-α). Other related molecules in the TNF family include lymphotoxin β (LT-β) that combines with LT-α to form the LT-α1β2 heterotrimer; Fas ligand (FasL); TNF-related apoptosis-inducing ligand (TRAIL); receptor activator of NF-κB ligand (RANKL); and CD40 ligand (CD154). Although some of these other TNF family members have not been traditionally regarded as cytokines, their structure (all are type II membrane proteins with an intracellular N-terminus and an extracellular C-terminus) and signaling mechanisms are closely related to those of TNF. The soluble forms of TNF-α, LT-α, and FasL are homotrimers, and the predominant form of LT-β is the membrane-bound LT-α1β2 heterotrimer. Trimerization of TNF receptor family members by their trimeric ligands appears to be required for initiation of signaling and expression of biologic activity. The initial characterization of TNF receptors led to the discovery of two receptor proteins capable of binding TNF-α with high affinity. The p55 receptor for TNF (TNFR1) is responsible for most biologic activities of TNF, but the p75 TNF receptor (TNFR2) is also capable of transducing signals (unlike IL-1R2, which acts solely as a biologic sink for IL-1). TNFR1 and TNFR2 have substantial stretches of close homology and are both present on most types of cells. Nevertheless, there are some notable differences between the two TNFRs. Unlike cytokine receptors from several of the other large families, TNF signaling does not involve the Jak/ STAT pathway. TNF-α evokes two types of responses in cells: (1) proinflammatory effects, and (2) induction of apoptotic cell death (Fig. 11-5). The proinflammatory effects of TNF-α that include upregulation of adhesion molecule expression and induction of secondary cytokines and chemokines, stem in large part from activation of NF-κB and can be transduced through both TNFR1 and TNFR2. Induction of apoptosis by signaling through TNFR1 depends on a region known as a death domain that is absent in TNFR2, as well as interactions with additional proteins with death domains within the TNFR1 signaling complex. Signaling initiated by ligand binding to TNFR1, Fas, or other death domain-containing receptors in the TNF family eventually leads to activation of caspase 8 or 10 and the nuclear changes and DNA fragmentation characteristic of apoptosis. At least two TNFR family members (TNFR1 and the LT-β receptor) also contribute to the normal anatomic development of the lymphoid system. Mice deficient in TNF-α lack germinal centers and follicular dendritic cells. TNFR1 mutant mice show the same abnormalities plus an absence of Peyer’s patches. Mice with null mutations in LT-α or LT-β have further abnormalities in lymphoid organogenesis and fail to develop peripheral lymph nodes.

Contrasting outcomes of signaling through tumor necrosis factor receptor 1(TNFR1)

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Figure 11-5  Two contrasting outcomes of signaling through tumor necrosis factor receptor 1 (TNFR1). Engagement of TNFR1 by trimeric tumor necrosis factor-α (TNF-α) can trigger apoptosis and/or nuclear factor κB (NF-κB) activation. Both processes involve the adapter protein TNFRassociated death domain (TRADD), which associates with TNFR1 via interactions between “death domains” (D.D.) on both proteins. For NF-κB activation, TNFR-associated factor 2 (TRAF2) and receptor-interacting protein (RIP) are required. Induction of apoptosis occurs when the death domain-containing protein Fas-associated death domain protein (FADD) associates with TRADD. FADD also contains a “death effector domain” (D.E.D.) that interacts with caspase 8 to initiate the apoptotic process. Cys = cysteine. (Adapted from Yuan J: Transducing signals of life and death. Curr Opin Cell Biol 9:247, 1997; and Nagata S: Apoptosis by death factor. Cell 88:355, 1997.)

TNF-α is an important mediator of cutaneous inflammation, and its expression is induced in the course of almost all inflammatory responses in skin. Normal human keratinocytes and keratinocyte cell lines produce substantial amounts of TNF-α after stimulation with LPS or UV light. Cutaneous inflammation stimulated by irritants and contact sensitizers is associated with strong induction of TNF-α production by keratinocytes. Exposure to TNF-α promotes Langerhans cell migration to draining lymph nodes, allowing for sensitization of naive T cells. One molecular mechanism that may contribute to TNF-α-induced migration of Langerhans cells toward lymph nodes is reduced expression of the E-cadherin adhesion molecule after exposure to TNF-α. Induction of CC chemokine receptor 7 on both epidermal and dermal antigen-presenting cells correlates with movement

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into the draining lymphatics. The predominant TNFR expressed by keratinocytes is TNFR1. Autocrine signaling loops involving keratinocyte-derived TNF-α and TNFR1 lead to keratinocyte production of a variety of TNF-inducible secondary cytokines. The central role of TNF-α in inflammatory diseases, including rheumatoid arthritis and psoriasis, has become evident from clinical studies. Clinical drugs that target the TNF pathway include the humanized antiTNF-α antibody infliximab, the fully human anti-TNF-α antibody adalumimab, and the soluble TNF receptor etanercept. Drugs in this class are FDA approved for the treatment of several autoimmune and inflammatory diseases, including Crohn’s disease and rheumatoid arthritis. These three anti-TNF drugs are also FDA approved for the treatment of psoriasis and psoriatic arthritis (see Chapter 234). This class of drugs also has the potential to be valuable in the treatment of other inflammatory dermatoses. Paradoxically, they are not effective against all autoimmune diseases—multiple sclerosis appears to worsen slightly after treatment with these agents. The TNF antagonists are powerful immunomodulating drugs, and appropriate caution is required in their use. Cases of cutaneous T-cell lymphoma initially thought to represent psoriasis have rapidly progressed to fulminant disease after treatment with TNF antagonists. TNF antagonists can also allow the escape of latent mycobacterial infections from immune control, with a potentially lethal outcome for the patient.

IL-17 FAMILY OF CYTOKINES IL-17 (also known as IL-17A) was the first described member of a family of related cytokines that now ­includes IL-17B through F. IL-17A and IL-17F have similar proinflammatory activities, bind to the same heterodimeric receptor composed of the IL-17RA and IL-17RC receptor chains, and act to promote recruitment of neutrophils and induce production of antimicrobial peptides. These IL-17 species normally function in immune defense against pathogenic species of extracellular bacteria and fungi. Signaling by IL-17A and IL-17F depends on STAT3; mutations in STAT3 associated with the hyper-IgE syndrome block IL-17 signaling and lead to recurrent skin infections with Staphylococcus aureus and Candida albicans. Less is ­currently known about the actions of IL-17B, C, and D. IL-17E, also known as IL-25, is a product of Th2 cells and mast cells that signals through IL-17RB. A total of five receptor chains for IL-17 family cytokines have been identified, but how each of these individual receptor chains associates to form receptors for all the members of the IL-17 family remains to be worked out. These IL-17 receptor chains are homologous to each other, but display very limited regions of homology to the other major families of cytokine receptors. Recent expansion of interest in Th17 cells and the entire IL-17 family is closely linked to observations that the immunopathology of autoimmune disease in human patients and mouse models is often associated with an inappropriate expansion of Th17 cells. Thus, the cytokines produced by Th17 cells and the receptors that

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transduce these signals may turn out to be useful targets for therapies designed to dampen autoimmunity.

LIGANDS OF THE CLASS I (HEMATOPOIETIN RECEPTOR) FAMILY OF CYTOKINE RECEPTORS

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The hematopoietin receptor family (also known as the class I cytokine receptor family) is the largest of the cytokine receptor families and comprises a number of structurally related type I membrane-bound glycoproteins. The cytoplasmic domains of these receptors associate with nonreceptor tyrosine kinase molecules, including the Jak kinases and src family kinases. After ligand binding and receptor oligomerization, these associated nonreceptor tyrosine kinases phosphorylate intracellular substrates, which leads to signal transduction. Most of the multiple-chain receptors in the hematopoietin receptor family consist of a cytokine-specific α chain subunit paired with one or more shared receptor subunits. Five shared receptor subunits have been described to date: (1) the common γ chain (γc), (2) the common β chain shared between the IL-2 and IL-15 receptors; (3) a distinct common β chain shared between the granulocyte-macrophage colony stimulating factor (GM-CSF), IL-3, and IL-5 receptors; (4) the IL-12Rβ2 chain shared by the IL-12 and IL-23 receptors; and (5) finally the glycoprotein 130 (gp130) molecule, which participates in signaling by IL-6 and related cytokines.

CYTOKINES WITH RECEPTORS THAT INCLUDE THE gc CHAIN The receptor complexes using the γc chain are the IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21 receptors. Two of these receptors, IL-2R and IL-15R, also use the IL-2Rβc chain. The γc chain is physically associated with Jak3, and activation of Jak3 is critical to most signaling initiated through this subset of cytokine receptors.20

INTERLEUKIN 2 AND INTERLEUKIN 15. IL-2 and IL-15 can each activate NK cells and stimulate proliferation of activated T cells. IL-2 is a product of activated T cells, and IL-2R is largely restricted to lymphoid cells. The IL-15 gene is expressed by nonlymphoid tissues, and its transcription is induced by UVB radiation in keratinocytes and fibroblasts and by LPS in monocytes and dendritic cells. Multiple isoforms of IL-15Rα are found in various hematopoietic and nonhematopoietic cells. The IL-2R and IL-15R complexes of lymphocytes incorporate up to three receptor chains, whereas most other cytokine receptor complexes have two. The affinities of IL-2R and IL-15R for their respective ligands can be regulated, and to some extent, IL-2 and IL-15 compete with each other. The highest affinity receptor complexes for each ligand (approximately 10−11 M) consist of the IL-2Rβc and γc chains, as well as their respective α chains (IL-2Rα,

also known as CD25, and IL-15Rα). γc and IL-2Rβc without the α chains form a functional lower affinity receptor for either ligand (10−8 to 10−10 M). Although both ligands transmit signals through the γc chain, those signals elicit overlapping but distinct responses in various cells. Activation of naive CD4 T cells by T-cell receptor and costimulatory molecules induces expression of IL-2, IL-2Rα, and IL-2Rβc, which leads to vigorous proliferation. Prolonged stimulation of T-cell receptor and IL-2R leads to expression of FasL and activation-induced cell death. Although IL-2 signaling facilitates the death of CD4 T cells in response to sustained exposure to antigen, IL-15 inhibits IL-2mediated activation-induced cell death as it stimulates growth. Similarly, IL-15 promotes proliferation of memory CD8 T cells, whereas IL-2 inhibits it. IL-15 is also involved in the homeostatic survival of memory CD8 T cells, NK cells, and NK T cells. These contrasting biologic roles are illustrated by mice deficient in IL-2 or IL-2Rα that develop autoimmune disorders, and mice deficient in IL-15 or IL-15Rα, which have lymphopenia and immune deficiencies. Thus, IL-15 appears to have an important role in promoting effector functions of antigen-specific T cells, whereas IL-2 is involved in reining in autoreactive T cells.21

INTERLEUKIN 4 AND INTERLEUKIN 13. IL-4 and IL-13 are products of activated Th2 cells that share limited structural homology (approximately 30%) and overlapping but distinct biologic activities. A specific receptor for IL-4, which does not bind IL13, is found on T cells and NK cells. It consists of IL4Rα (CD124) and γc and transmits signals via Jak1 and Jak3. A second receptor complex that can bind either IL-4 or IL-13 is found on keratinocytes, endothelial cells, and other nonhematopoietic cells. It consists of IL-13Rα1 and IL-4Rα and transmits signals via Jak1 and Jak2. These receptors are expressed at low levels in resting cells, and their expression is increased by various activating signals. Curiously, exposure of monocytes to IL-4 or IL-13 suppresses expression of IL-4Rα and IL-13Rα1, whereas the opposite effect is observed in keratinocytes. Both signal transduction pathways appear to converge with the activation of STAT6, which is both necessary and sufficient to drive Th2 differentiation. IL-13Rα2 is a cell surface receptor homologous to IL-13Rα1 that specifically binds to IL13 but is not known to transmit any signals.20 The biologic effects of engagement of the IL-4 receptor vary depending on the specific cell type, but most pertain to its principal role as a growth and differentiation factor for Th2 cells. Exposure of naive T cells to IL-4 stimulates them to proliferate and differentiate into Th2 cells, which produce more IL-4, which in turn leads to autocrine stimulation that prolongs Th2 responses. Thus the expression of IL-4 early in the immune response can initiate a cascade of Th2 cell development that results in a predominately Th2 response. The genes encoding IL-4 and IL-13 are located in a cluster with IL-5 that undergoes structural changes during Th2 differentiation that are associated with increased expression. Although naive T cells can make low levels of IL-4 when activated, IL-4

is also produced by activated NK T cells. Mast cells and basophils also release preformed IL-4 from secretory ­granules in response to FcεRI-mediated signals. A prominent activity of IL-4 is the stimulation of class switching of the immunoglobulin genes of B cells. Nuocytes and natural helper cells are recently identified populations of innate immune effector cells that provide an early source of IL-13 during helminth infection. As critical factors in Th2 differentiation and effector function, IL-4 and IL-13 are mediators of atopic immunity. In addition to controlling the behavior of effector cells they also act directly on resident tissue cells, such as in inflammatory airway reactions.22

that could act as a growth factor for B- and T-lineage cells. The TSLP receptor consists of the IL-7Rα and a second receptor chain (TSLPR) homologous to but distinct from the γc chain. TSLP has attracted interest because of its ability to prime dendritic cells to become stronger stimulators of Th2 cells. This activity may permit TSLP to foster the development of some types of allergic diseases.26,27

INTERLEUKIN 9 AND INTERLEUKIN 21. IL-9 is

The receptors for IL-3, IL-5, and GM-CSF consist of unique cytokine-specific α chains paired with a common β chain known as IL-3Rβ or βc (CD131). Each of these factors acts on subsets of early hematopoietic cells.28 IL-3, which was previously known as multilineage colony-stimulating factor, is principally a product of CD4+ T cells and causes proliferation, differentiation, and colony formation of various myeloid cells from bone marrow. IL-5 is a product of Th2 CD4+ cells and activated mast cells that conveys signals to B cells and eosinophils. IL-5 has a costimulatory effect on B cells in that it enhances their proliferation and immunoglobulin expression when they encounter their cognate antigen. In conjunction with an eosinophilattracting chemokine known as CC chemokine ligand 11 or eotaxin, IL-5 plays a central role in the accumulation of eosinophils that accompanies parasitic infections and some cutaneous inflammatory processes. IL-5 appears to be required to generate a pool of eosinophil precursors in bone marrow that can be rapidly mobilized to the blood, whereas eotaxin’s role is focused on recruitment of these eosinophils from blood into specific tissue sites. GM-CSF is a growth factor for myeloid progenitors produced by activated T cells, phagocytes, keratinocytes, fibroblasts, and vascular endothelial cells. In addition to its role in early hematopoiesis, GM-CSF has potent effects on macrophages and dendritic cells. In vitro culture of fresh Langerhans cells in the presence of GM-CSF promotes their transformation into mature dendritic cells with maximal immunostimulatory potential for naive T cells. The effects of GM-CSF on dendritic cells probably account for the dramatic ability of GM-CSF to evoke therapeutic antitumor immunity when tumor cells are engineered to express it.29,30

Cytokines

function of IL-7, IL-7Rα (CD127), γc, or Jak3 in mice or humans cause profound immunodeficiency as a result of T- and NK-cell depletion.20 This is principally due to the indispensable role of IL-7 in promoting the expansion of lymphocytes and regulating the rearrangement of their antigen receptor genes. IL-7 is a potent mitogen and survival factor for immature lymphocytes in the bone marrow and thymus. The second function of IL-7 is as a modifier of effector cell functions in the reactive phase of certain immune responses. IL-7 transmits activating signals to mature T cells and certain activated B cells. Like IL-2, IL-7 has been shown to stimulate proliferation of cytolytic T cells and lymphokine-activated killer cells in vitro and to enhance their activities in vivo. IL-7 is a particularly significant cytokine for lymphocytes in the skin and other epithelial tissues. It is expressed by keratinocytes in a regulated fashion, and this expression is thought to be part of a reciprocal signaling dialog between dendritic epidermal T cells and keratinocytes in murine skin. Keratinocytes release IL-7 in response to IFN-γ, and dendritic epidermal T cells secrete IFN-γ in response to IL-7. An IL-7-related cytokine using one chain of the IL-7 receptor as part of its receptor is thymic stromal lymphopoietin (TSLP). TSLP was originally identified as a novel cytokine produced by a thymic stromal cell line

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INTERLEUKIN 7 AND THYMIC STROMAL LYMPHOPOIETIN. Mutations abrogating the

CYTOKINES WITH RECEPTORS USING THE INTERLEUKIN 3 RECEPTOR b CHAIN Chapter 11

a product of activated Th2 cells exposed to TGF-β that acts as an autocrine growth factor as well as a mediator of inflammation.23 It is also produced by mast cells in response to IL-10 or stem cell factor. It stimulates proliferation of T and B cells and promotes expression of immunoglobulin E by B cells. It also exerts proinflammatory effects on mast cells and eosinophils. IL-9-deficient mice exhibit deficits in mast cell and goblet cell differentiation. IL-9 can be grouped with IL-4 and IL-13 as cytokines that function as effectors of allergic inflammatory processes and may play an important role in asthma and allergic disorders. IL21 is also a product made by the Th2, Th17, and Tfh lineages that signals through a receptor composed of a specific α chain (IL-21R) homologous to the IL-4R α chain and γc.24 Absence of an intact IL-21 receptor is associated with impaired Th2 responses.25

4

INTERLEUKIN 6 AND OTHER CYTOKINES WITH RECEPTORS USING GLYCOPROTEIN 130 Receptors for a group of cytokines including IL-6, IL-11, IL-27, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 interact with a hematopoietin receptor family member, gp130, which does not appear to interact with any ligand by itself. The gp130 molecule is recruited into signaling complexes with other receptor chains when they engage their cognate ligands.

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IL-6 is the most thoroughly characterized of the cytokines that use gp130 for signaling and serves as a paradigm for discussion of the biologic effects of this family of cytokines. IL-6 is yet another example of a highly pleiotropic cytokine with multiple effects. A series of different names (including IFN-β2, B-cell stimulatory factor 2, plasmacytoma growth factor, cytotoxic T cell differentiation factor, and hepatocyte-stimulating factor) were used for IL-6 before it was recognized that a single molecular species accounts for all of these activities. IL-6 acts on a wide variety of cells of hematopoietic origin. IL-6 stimulates immunoglobulin secretion by B cells and has mitogenic effects on B lineage cells and plasmacytomas. IL-6 also promotes maturation of megakaryocytes and differentiation of myeloid cells. Not only does it participate in hematopoietic development and reactive immune responses, but IL-6 is also a central mediator of the systemic acute-phase response. Increases in circulating IL-6 levels stimulate hepatocytes to synthesize and release acute-phase proteins. There are two distinct signal transduction pathways triggered by IL-6. The first of these is mediated by the gp130 molecule when it dimerizes on engagement by the complex of IL-6 and IL-6Rα. Homodimerization of gp130 and its associated Jak kinases (Jak1, Jak2, Tyk2) leads to activation of STAT3. A second pathway of gp130 signal transduction involves Ras and the mitogen-activated protein kinase cascade and results in phosphorylation and activation of a transcription factor originally designated nuclear factor of IL-6. IL-6 is an important cytokine for skin and is subject to dysregulation in several human diseases, including some with skin manifestations. IL-6 is produced in a regulated fashion by keratinocytes, fibroblasts, and vascular endothelial cells as well as by leukocytes infiltrating the skin. IL-6 can stimulate the proliferation of human keratinocytes under some conditions. Psoriasis is one of several inflammatory skin diseases in which elevated expression of IL-6 has been described. Human herpesvirus 8 produces a viral homolog of IL-6 that may be involved in the pathogenesis of human herpes virus-8-associated diseases, including Kaposi sarcoma and body cavity-based lymphomas. The other cytokines using gp130 as a signal transducer have diverse bioactivities. IL-11 inhibits production of inflammatory cytokines and has shown some therapeutic activity in patients with psoriasis. Exogenous IL-11 also stimulates platelet production and has been used to treat thrombocytopenia occurring after chemotherapy. IL-27 is discussed in the next section with the IL-12 family of cytokines.

INTERLEUKIN 12, INTERLEUKIN 23, INTERLEUKIN 27, AND INTERLEUKIN 35: PIVOTAL CYTOKINES REGULATING T HELPER 1 AND T HELPER 17 RESPONSES 138

IL-12 is different from most other cytokines in that its active form is a heterodimer of two proteins, p35 and p40. IL-12 is principally a product of antigen-

presenting cells such as dendritic cells, monocytes, macrophages, and certain B cells in response to bacterial components, GM-CSF, and IFN-γ. Activated keratinocytes are an additional source of IL-12 in skin. Human keratinocytes constitutively make the p35 subunit, whereas expression of the p40 subunit can be induced by stimuli including contact allergens, phorbol esters, and UV radiation. IL-12 is a critical immunoregulatory cytokine that is central to the initiation and maintenance of Th1 responses. Th1 responses that are dependent on IL-12 provide protective immunity to intracellular bacterial pathogens. IL-12 also has stimulatory effects on NK cells, promoting their proliferation, cytotoxic function, and the production of cytokines, including IFN-γ. IL-12 has been shown to be active in stimulating protective antitumor immunity in a number of animal models.31 Two chains that are part of the cell surface receptor for IL-12 have been cloned. Both are homologous to other β chains in the hematopoietin receptor family and are designated β1 and β2. The β1 chain is associated with Tyk2 and the β2 chain interacts directly with Jak2. The signaling component of the IL-12R is the β2 chain. The β2 chain is expressed in Th1 but not Th2 cells and appears to be critical for commitment of T cells to production of type 1 cytokines. IL-12 signaling induces the phosphorylation of STAT1, STAT3, and STAT4, but it is STAT4 that is essential for induction of a Th1 response. IL-23 is a heterodimeric cytokine in the IL-12 family that consists of the p40 chain of IL-12 in association with a distinct p19 chain. IL-23 has overlapping activities with IL-12, but also induces proliferation of memory T cells. Interest in IL-23 has been sparked by the observation that IL-23 promotes the differentiation of T cells producing IL-17 (Th17 subset). The IL-23 receptor consists of two chains: (1) the IL-12Rβ1 chain that forms part of the IL-12 receptor and (2) a specific IL-23 receptor.32 The third member of the IL-12 family to be discovered was IL-27. IL-27 is also a heterodimer and consists of a subunit called p28 that is homologous to IL-12 p35 and a second subunit known as EBI3 that is homologous to IL-12 p40. IL-27 plays a role in the early induction of the Th1 response. The IL-27 receptor consists of a receptor called WSX-1 that associates with the shared signal-transducing molecule gp130.32,33 The newest member of the IL-12 family is IL-35. The IL-35 heterodimer is composed of the p35 chain of IL-12 associated with the IL-27β chain EBI3. In contrast to the other IL-12 family cytokines, IL-35 is selectively made by Treg cells, promotes the growth of Treg cells, and suppresses the activity of Th17 cells.34 The IL-12 family of cytokines has emerged as a promising new target for anticytokine pharmacotherapy. The approach that has been developed the furthest to date is targeting both IL-12 and IL-23 with monoclonal antibodies directed against the p40 subunit that is part of both cytokines. Ustekinumab is an antihuman p40 monoclonal antibody that has shown therapeutic activity against psoriasis comparable to that of TNF inhibitors and has received FDA approval for the treatment of psoriasis.35 The development of

anti-p40 therapies is several years behind anti-TNF-α drugs, but development of additional anti-p40 biologics for clinical use is anticipated.

LIGANDS OF THE CLASS II FAMILY OF CYTOKINE RECEPTORS A second major class of cytokine receptors with common features includes two types of receptors for IFNs, IL-10R, and the receptors for additional IL-10- related cytokines including IL-19, IL-20, IL-22, IL-24, and IL-26.

:: Cytokines

IFNs were one of the first families of cytokines to be characterized in detail. The IFNs were initially subdivided into three classes: (1) IFN-α (the leukocyte IFNs), (2) IFN-β (fibroblast IFN), and (3) IFN-γ (immune IFN). The α and β IFNs are collectively called type I IFNs, and all of these molecules signal through the same two-chain receptor (the IFN-αβ receptor).36 The second IFN receptor is a distinct two-chain receptor specific for IFN-γ. Both of these IFN receptors are present on many cell types within skin as well as in other tissues. Each of the chains comprising the two IFN receptors is associated with one of the Jak kinases (Tyk2 and Jak1 for the IFN-αβR, and Jak1 and Jak2 for the IFN-γR). Only in the presence of both chains and two functional Jak kinases will effective signal transduction occur after IFN binding. A new class of IFNs known as IFN-γ or type III IFNs has now been identified that has a low degree of homology with both type I IFNs and IL-10.37 The current members of this class are IL-28A, IL-28B, and IL-29. Although the effects of these cytokines are similar to those of the type I IFNs, they are less potent. These type III IFNs use a shared receptor that consists of the β chain of the IL-10 receptor associated with an IL-28 receptor α chain. Viruses, double-stranded RNA, and bacterial products are among the stimuli that elicit release of the type I IFNs from cells. Plasmacytoid dendritic cells have emerged as a particularly potent cellular source of type I IFNs. Many of the effects of the type I IFNs directly or indirectly increase host resistance to the spread of viral infection. Additional effects mediated through IFNαβR are increased expression of major histocompatibility complex (MHC) class I molecules and stimulation of NK cell activity. Not only does it have well-known antiviral effects, but IFN-α also can modulate T-cell responses by favoring the development of a Th1 type of T-cell response. Finally, the type I IFNs also inhibit the proliferation of a variety of cell types, which provides a rationale for their use in the treatment of some types of cancer. Forms of IFN-α enjoy considerable use clinically for indications ranging from hairy cell leukemia, various cutaneous malignancies, and papillomavirus infections (see Chapter 196). Some of the same conditions that respond to therapy with type I IFNs

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Chapter 11

INTERFERONS: PROTOTYPES OF CYTOKINES SIGNALING THROUGH A JAK/STAT PATHWAY

also respond to topical immunomodulatory agents like imiquimod. This synthetic imidazoquinoline drug is an agonist for the TLR7 receptor, whose natural ligand is single-stranded RNA. Imiquimod stimulation of cells expressing TLR7 elicits local release of large amounts of type I IFNs from plasmacytoid dendritic cells, which can trigger clinically useful antiviral and tumor inhibitory effects against genital warts, superficial basal cell carcinoma, and actinic keratoses. Resiquimod is a related synthetic compound that activates both TLR7 and TLR8, eliciting a slightly different spectrum of cytokines.38 Production of IFN-γ is restricted to NK cells, CD8 T cells, and Th1 CD4 T cells. Th1 cells produce IFN-γ after engagement of the T-cell receptor, and IL-12 can provide a strong costimulatory signal for T-cell IFNγ production. NK cells produce IFN-γ in response to cytokines released by macrophages, including TNF-γ, IL-12, and IL-18. IFN-γ has antiviral activity, but it is a less potent mediator than the type I IFNs for induction of these effects. The major physiologic role of IFN-γ is its capacity to modulate immune responses. IFN-γ induces synthesis of multiple proteins that play essential roles in antigen presentation to T cells, including MHC class I and class II glycoproteins, invariant chain, the Lmp2 and Lmp7 components of the proteasome, and the TAP1 and TAP2 intracellular peptide transporters. These changes increase the efficiency of antigen presentation to CD4 and CD8 T cells. IFN-γ is also required for activation of macrophages to their full antimicrobial potential, enabling them to eliminate microorganisms capable of intracellular growth. Like type I IFNs, IFN-γ also has strong antiproliferative effects on some cell types. Finally, IFN-γ is also an inducer of selected chemokines (CXC chemokine ligands 9 to 11) and an inducer of endothelial cell adhesion molecules (e.g., ICAM-1 and VCAM-1). Because of the breadth of IFN-γ’s activities, it comes the closest of the T-cell cytokines to behaving as a primary cytokine.

INTERLEUKIN 10: AN “ANTIINFLAMMATORY” CYTOKINE IL-10 is one of several cytokines that primarily exert regulatory rather than stimulatory effects on immune responses. IL-10 was first identified as a cytokine produced by Th2 T cells that inhibited cytokine production after activation of T cells by antigen and antigenpresenting cells. IL-10 exerts its action through a cell surface receptor found on macrophages, dendritic cells, neutrophils, B cells, T cells, and NK cells. The ligand-binding chain of the receptor is homologous to the receptors for IFN-α/β and IFN-γ, and signaling events mediated through the IL-10 receptor use a Jak/ STAT pathway. IL-10 binding to its receptor activates the Jak1 and Tyk2 kinases and leads to the activation of STAT1 and STAT3. The effects of IL-10 on antigenpresenting cells such as monocytes, macrophages, and dendritic cells include inhibition of expression of class II MHC and costimulatory molecules (e.g., B7–1, B7–2) and decreased production of T cell-stimulating cytokines (e.g., IL-1, IL-6, and IL-12). At least four viral

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genomes harbor viral homologs of IL-10 that transmit similar signals by binding to the IL-10R.39 A major source of IL-10 within skin is epidermal keratinocytes. Keratinocyte IL-10 production is upregulated after activation; one of the best-characterized activating stimuli for keratinocytes is UV irradiation. UV radiation-induced keratinocyte IL-10 production leads to local and systemic effects on immunity. Some of the well-documented immunosuppressive effects that occur after UV light exposure are the result of the liberation of keratinocyte-derived IL-10 into the systemic circulation. IL-10 also plays a dampening role in other types of cutaneous immune and inflammatory responses, because the absence of IL-10 predisposes mice to exaggerated irritant and contact sensitivity responses.

NOVEL INTERLEUKIN 10-RELATED CYTOKINES: INTERLEUKINS 19, 20, 22, 24, AND 26 A series of cytokines related to IL-10 have been identified and shown to engage a number of receptor complexes with shared chains.40 IL-19, IL-20, and IL-24 transmit signals via a complex consisting of IL-20Rα and IL-20Rβ. IL-22 signals through a receptor consisting of IL-22R and IL-10Rβ. The receptors for these IL-20 family cytokines are preferentially expressed on epithelial cells including keratinocytes. Increased expression of these cytokines and their receptors is associated with psoriasis. The IL-20 family cytokines have profound effects on the proliferation and differentiation of human keratinocytes in culture.41 Transgenic mice overexpressing IL-20, IL-22, or IL-24 develop epidermal hyperplasia and abnormal keratinocyte differentiation.42 All of these findings point to a significant role for these cytokines in the epidermal changes associated with cutaneous inflammation. T cells producing IL-22 that elaborate a distinct set of cytokines from Th1, Th2 and Th17 cells have been isolated from the epidermis of patients with psoriasis and other inflammatory skin disorders. The IL-22 produced by these T cells promotes keratinocyte proliferation and epidermal acanthosis.43,44

TRANSFORMING GROWTH FACTOR-b FAMILY AND ITS RECEPTORS TGF-β1 was first isolated as a secreted product of virally transformed tumor cells capable of inducing normal cells in vitro to show phenotypic characteristics associated with transformation. Over 30 additional members of the TGF-β family have now been identified. They can be grouped into several families: the prototypic TGF-βs (TGF-β1 to TGF-β3), the bone morphogenetic proteins, the growth/differentiation factors, and the activins. The TGF name for this family of molecules is somewhat of a misnomer, because TGF-β has anti-

proliferative rather than proliferative effects on most cell types. Many of the TGF-β family members play an important role in development, influencing the differentiation of uncommitted cells into specific lineages. TGF-β family members are made as precursor proteins that are biologically inactive until a large prodomain is cleaved. Monomers of the mature domain of TGFβ family members are disulfide linked to form dimers that strongly resist denaturation. Participation of at least two cell surface receptors (type I and type II) with serine/threonine kinase activity is required for biologic effects of TGF-β.45 Ligand binding by the type II receptor (the true ligand-binding receptor) is associated with the formation of complexes of type I and type II receptors. This allows the type II receptor to phosphorylate and activate the type I receptor, a “transducer” molecule that is responsible for downstream signal transduction. Downstream signal transmission from the membrane-bound receptors in the TGF-β receptor family to the nucleus is primarily mediated by a family of cytoplasmic Smad proteins that translocate to the nucleus and regulate transcription of target genes. TGF-β has a profound influence on several types of immune and inflammatory processes. An immunoregulatory role for TGF-β1 was identified in part through analysis of TGF-β1 knockout mice that develop a wasting disease at 20 days of age associated with a mixed inflammatory cell infiltrate involving many internal organs. This phenotype is now appreciated to be a result in part of the compromised development of regulatory T cells when TGF-β1 is not available. Development of cells in the dendritic cell lineage is also perturbed in the TGF-β1-deficient mice, as evidenced by an absence of epidermal Langerhans cells and specific subpopulations of lymph node dendritic cells. TGFβ-treated fibroblasts display enhanced production of collagen and other extracellular matrix molecules. In addition, TGF-β inhibits the production of metalloproteinases by fibroblasts and stimulates the production of inhibitors of the same metalloproteinases (tissue inhibitors of metalloproteinase, or TIMPs). TGF-β may contribute to the immunopathology of scleroderma through its profibrogenic effects.46

CHEMOKINES: SECONDARY CYTOKINES CENTRAL TO LEUKOCYTE MOBILIZATION Chemokines are a large superfamily of small cytokines that have two major functions. First, they guide leukocytes via chemotactic gradients in tissue. Typically, this is to bring an effector cell to where its activities are required. Second, a subset of chemokines has the capacity to increase the binding of leukocytes via their integrins to ligands at the endothelial cell surface, which facilitates firm adhesion and extravasation of leukocytes in tissue. The activities of this important class of cytokines are sufficiently complex that they are the subject of a separate chapter (Chapter 12).

CYTOKINE NETWORK— THERAPEUTIC IMPLICATIONS AND APPLICATIONS

4

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

:: Cytokines

1. Oppenheim JJ: Cytokines: Past, present, and future. Int J Hematol 74:3, 2001 3. Luger TA et al: Epidermal cell (keratinocyte)-derived thymocyte-activating factor (ETAF). J Immunol 127:1493, 1981 4. Kupper TS: The activated keratinocyte: A model for inducible cytokine production by non-bone marrow-derived cells in cutaneous inflammatory and immune responses. J Invest Dermatol 94:146S, 1990 5. Albanesi C, Pastore S: Pathobiology of chronic inflammatory skin diseases: Interplay between keratinocytes and immune cells as a target for anti-inflammatory drugs. Curr Drug Metab 11:210, 2010 6. Kupper TS: Immune and inflammatory processes in cutaneous tissues. Mechanisms and speculations. J Clin Invest 86:1783, 1990 7. Beutler B: Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol Rev 227:248, 2009 9. O’Quinn DB et al: Emergence of the Th17 pathway and its role in host defense. Adv Immunol 99:115, 2008 10. Josefowicz SZ, Rudensky A: Control of regulatory T cell lineage commitment and maintenance. Immunity 30:616, 2009 15. Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nat Immunol 11:373, 2010 16. O’Shea JJ, Murray PJ: Cytokine signaling modules in inflammatory responses. Immunity 28:477, 2008 17. Martinon F, Mayor A, Tschopp J: The inflammasomes: Guardians of the body. Annu Rev Immunol 27:229, 2009 27. Ziegler SF, Artis D: Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11:289, 2010 35. Griffiths CE et al: Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 362:118, 2010 43. Eyerich S et al: Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 119:3573, 2009 44. Fujita H et al: Human Langerhans cells induce distinct IL22-producing CD4+ T cells lacking IL-17 production. Proc Natl Acad Sci U S A 106:21795, 2009

Chapter 11

This chapter has attempted to bring some degree of order and logic to the analysis of a field of human biology that continues to grow at a rapid rate. Although many things may change in the world of cytokines, certain key concepts have stood the test of time. Principal among them is the idea that cytokines are emergency molecules, designed to be released locally and transiently in tissue microenvironments. When cytokines are released persistently, the result is typically chronic disease. One potential way to treat such diseases is with cytokine antagonists or other drugs that target cytokines or cytokine-mediated pathways. Cytokines and cytokine antagonists are being used therapeutically by clinicians, and development of additional agents continues. With certain notable exceptions, systemic cytokine therapy has been disappointing and is often accompanied by substantial morbidity. In contrast, local and transient administration of cytokines may yield more promising results. An example of this approach is the transduction of tumor cells to express GM-CSF to create the therapeutic cancer vaccines that are capable of boosting antitumor immune responses.30 Conversely, multiple biologics that specifically block cytokine activity have been developed and approved for clinical use. Antibodies and TNF ­receptor–Fc fusion proteins are FDA-approved antagonists of TNF-α activity that are highly effective at inducing durable remissions in psoriasis (see Chapters 18 and 234). Antibodies against the p40 subunit shared by IL-12 and IL-23 are also active in treating psoriasis. An IL-1 receptor-Fc fusion protein, an antibody to IL-1β, and recombinant IL-1Ra are all effective therapy for patients with the cryopyrin-associated periodic syndromes. IL-1Ra is FDA-approved for treatment of adult rheumatoid arthritis. A class of pharmacologic agents that inhibits the production of multiple T cellderived cytokines is the calcineurin inhibitors. Tacrolimus and pimecrolimus both bind to the immunophilin FK-506 binding protein-12 (FKBP-12), producing complexes that bind to calcineurin, a calcium-dependent phosphatase that acts on proteins in the nuclear factor of activated T-cells (NFAT) family to promote their nuclear translocation and activation of cytokine genes (including IL-2, IL-4, and IFN-γ)47 (see Chapters 221 and 233). Finally, fusion toxins linked to cytokines, such as the IL-2 fusion protein denileukin diftitox, exploit the

cellular specificity of certain cytokine–receptor interactions to kill target cells (see Chapter 234). Denileukin diftitox is FDA approved for the treatment of cutaneous T-cell lymphoma and has also shown therapeutic activity in other types of lymphoid malignancies.48 Each of the aforementioned approaches is still relatively new and open to considerable future development. An understanding of cytokines by clinicians of the future is likely to be central to effective patient care.

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Chapter 12 :: Chemokines :: Anke S. Lonsdorf & Sam T. Hwang CHEMOKINES AT A GLANCE Chemokines and their receptors are vital mediators of cellular trafficking. Most chemokines are small proteins with molecular weights in the 8- to 10-kDa range.

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Chemokines are synthesized constitutively in some cells and can be induced in many cell types. Chemokines play roles in inflammation, angiogenesis, neural development, cancer metastasis, hematopoiesis, and infectious disease. In skin, chemokines play important roles in atopic dermatitis, psoriasis, melanoma, melanoma metastasis, and some viral (including retroviral) infections. Promising therapeutic applications of chemokines include the prevention of T-cell arrest on activated endothelium or blocking infection of T cells by human immunodeficiency virus 1 using CC chemokine receptor 5 analogs.

INTRODUCTION The skin is an organ in which the migration, influx, and egress of leukocytes occur in both homeostatic and inflammatory processes. Chemokines and their receptors are accepted as vital mediators of cellular trafficking. Since the discovery of the first chemoattractant cytokine or chemokine in 1977, 50 additional new chemokines and 17 chemokine receptors have been discovered. Most chemokines are small proteins with ­molecular weights in the 8–10 kDa range and are synthesized constitutively in some cells and can be induced in many cell types by cytokines. Initially associated only with recruitment of leukocyte subsets to inflammatory sites,1 it has become clear that chemokines play roles in angiogenesis, neural development, cancer metastasis, hematopoiesis, and infectious diseases. This chapter will focus primarily on the function of chemokines in inflammatory conditions, but will also touch upon the role of these molecules in other settings as well. An overview of the structure of chemokines and chemokine receptors will be provided that will detail the molecular signaling pathways initiated by the binding of a chemokine to its cognate receptor. Expression pat-

terns of chemokine receptors will be detailed because of the many types of immune cells that potentially can be recruited to skin under inflammatory conditions. Individual chemokine receptors will be highlighted in regard to biologic function, including facilitation of migration of effector T cells into the skin and the egress of antigen-presenting cells out of the skin. Finally, the roles of chemokines and their receptors in several cutaneous diseases—atopic dermatitis, psoriasis, cancer, and infectious disease—provide a better idea of the diversity of chemokine function in skin.

STRUCTURE OF CHEMOKINES Chemokines are grouped into four subfamilies based on the spacing of amino acids between the first two cysteines. The CXC chemokines (also called α-chemokines) show a C–X–C motif with one nonconserved amino acid between the two cysteines. The other major subfamily of chemokines lacks the additional amino acid and is termed the CC subfamily (or β-chemokines). The two remaining subfamilies contain only one member each: the C subfamily is represented by lymphotactin, and fractalkine is the only member of the CXXXC (or CX3C) subfamily. Chemokines can also be assigned to one of two broad and, perhaps, overlapping functional groups. One group (e.g., RANTES, MIP-1α/β LARC, etc.) mediates the attraction and recruitment of immune cells to sites of active inflammation while other (e.g., SLC and SDF-1) appear to play a role in constitutive or homeostatic migration pathways.2 The complexity and redundancy in the nomenclature of chemokines has led to the proposal for a systematic nomenclature for chemokines based on the type of chemokine (C, CXC, CX3C, or CC) and a number based on the order of discovery as proposed by Zlotnik and Yoshie.2 For example, stromal-derived factor-1 (SDF-1), a CXC chemokine, has the systematic name CXCL12. Because both nomenclatures are still in wide use, the original names (abbreviated in most cases) as well as systematic names will be used interchangeably throughout the chapter. Table 12-1 provides a list of chemokine receptors of interest in skin that are discussed in this chapter as well as the major chemokine ligands that bind to them. Chemokines are highly conserved and have similar secondary and tertiary structure. Based on crystallography studies, a disordered amino terminus followed by three conserved antiparallel β-pleated sheets is a common structural feature of chemokines. Fractalkine is unique in that the chemokine domain sits atop a mucin-like stalk tethered to the plasma membrane via a transmembrane domain and short cytoplasmic tail.30 Although CXC and CC chemokines form multimeric structures under conditions required for structural studies, these associations may be relevant only when

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TABLE 12-1

Chemokine Receptors in Skin Biology Chemokine Receptor

Chemokine Ligand

Expression Pattern

Comments

References

T, Mo, DC, NK, B

Migration of DC and monocytes; strongly upregulated in T cells by IL-2

12

CCR2

MCP-1 (CCL2),-3,-4 (CCL13)

T, Mo

Migration of T cells to inflamed sites; replenish LC precursors in epidermis; involved in skin fibrosis via MCP-1

3–5

CCR3

Eotaxin (CCL11) >RANTES, MCP-2 (CCL8),3,4

Eo, Ba, Th2, K

Migration of Th2 T cells and “allergic” immune cells

6,7

CCR4

TARC (CCL17), MDC (CCL22)

T (benign and malignant)

Expression in Th2 > Th1 cells; highly expressed on CLA+ memory T cells; TARC expression by keratinocytes may be important in atopic dermatitis; may guide trafficking of malignant as well as benign inflammatory T cells

8–12

CCR5

RANTES, MIP-1α,β (CCL3,4)

T, Mo, DC

Marker for Th1 cells; migration to acutely inflamed sites; may be involved in transmigration of T cells through endothelium; major HIV-1 fusion coreceptor

3,13

CCR6

LARC (CCL20)

T, DC, B

Expressed by memory, not naive, T cells; possibly involved in arrest of memory T cells to activated endothelium and recruitment of T cells to epidermis in psoriasis

76,77,82

CCR7

SLC (CCL21), ELC (CCL19)

T, DC, B, melanoma cells

Critical for migration of naive T cells and “central memory” T cells to secondary lymphoid organs; required for mature DC to enter lymphatics and localize to lymph nodes; facilitates nodal metastasis

14–18

CCR9

Thymus-expressed chemokine (CCL25)

T, melanoma cells

Associated with melanoma small bowel metastases

19

CCR10

CTACK (CCL27)

T (benign and malignant), melanoma cells

Preferential response of CLA+ T cells to CTACK in vitro; may be involved in T cell (benign as well as malignant) homing to epidermis, where CTACK is expressed; survival of melanoma is skin

20–23

CXCR1,2

IL-8 (CXCL8), MGSA/ GRO α (CXCL1), ENA-78 (CXCL5)

N, NK, En, melanoma cells

Recruitment of neutrophils (e.g., epidermis in psoriasis); may be involved in angiogenesis; melanoma growth factor

24–26

CXCR3

IP-10 (CXCL10), Mig (CXCL9), I-TAC (CXCL11)

T

Marker for Th1 Cells and may be involved in T cell recruitment to epidermis in CTCL; induces arrest of activated T cells on stimulated endothelium

27,28

CXCR4

SDF-1α,β (CXCL12)

T, DC, En, melanoma cells

Major HIV-1 fusion coreceptor; involved in vascular formation; involved in melanoma metastasis to lungs

3,29

CX3CR1

Fractalkine (CX3CL1)

T, Mo, MC, NK

May be involved in adhesion on activated T cells, Mo, NK cells to activated endothelium

30,31

::

MIP-1α (CCL3), RANTES (CCL5), MCP-3 (CCL7)

Chapter 12

CCR1

Chemokines

GRO = growth regulated oncogene; MGSA = melanoma growth stimulatory activity; Mig = monokine-induced by IFN-γ; I-TaC = interferoninducible T-cell alpha chemoattractant; SDF = stromal-derived factor; MCP = monocyte chemattractant protein; MIP = macrophage inflammatory protein; RANTES = regulated upon activation, normal T cell expressed and secreted; IL-8 = interleukin-8; TARC = thymus and activationregulated chemokine; LARC = liver and activation-regulated chemokine (also known as MIP-3α); SLC = secondary lymphoid-tissue chemokine; MDC = macrophage-derived chemokine; CTACK = cutaneous T cell attracting chemokine; T = T cells; Mo = monocytes; DC = dendritic cells; Eo = eosinophils; Ba = basophils; B = B cells; En = endothelial cells; Th1,2 = T helper 1,2 cell; N = neutrophils; MC = mast cells; NK = natural killer cells; CLA = cutaneous lymphocyte-associated antigen; HIV = human immunodeficiency virus.

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Chemokine receptor-mediated signaling pathways

CK Plasma membrane

αs β GDP

β

γ

RAMP RGS

Section 4

GRK

GTP

ER

Pl3K Rho, Rac

PKC

Ca2+ flux

PTK MaPK

:: Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

144

PLC

PTK

αs

γ

Cytoskeletal changes and gene transcription

Chemotaxis, adhesion, polarization, and cell proliferation

Degradation

Figure 12-1  Chemokine receptor-mediated signaling pathways. RAMP = receptor-activity-modifying protein; RGS = regulator of G-protein signaling; GRK = G-protein coupled receptor kinase; DG = 1,2-diacylglycerol; PLC = phospholipase C; PIP2 = phosphatidylinositol-4,5-bisphosphate; IP3 = inositol-1,4,5-triphosphate; PKC = protein kinase C; CK = chemokine; PTX = pertussis toxin; ER = endoplasmic reticulum; PTK = protein tyrosine kinase(s); MAPK = Mitogen activated protein kinase.

chemokines associate with cell-surface components such as glycosaminoglycans (GAGs) or proteoglycans. Since most chemokines have a net positive charge, these proteins tend to bind to negatively charged carbohydrates present on GAGs. Indeed the ability of positively charged chemokines to bind to GAGs is thought to enable chemokines to preferentially associate with the lumenal surface of blood vessels despite the presence of shear forces from the blood that would otherwise wash the chemokines away.

CHEMOKINE RECEPTORS AND SIGNAL TRANSDUCTION Chemokine receptors are seven transmembrane spanning membrane proteins that couple to intracellular heterotrimeric G-proteins containing α, β, and γ subunits.2 They represent a part of a large family of G-­protein coupled receptors (GPCR), including rhodopsin, that have critical biologic functions. Leukocytes express several Gα protein subtypes: s, i, and q, while the β and γ subunits each have 5 and 11 known subtypes, respectively. This complexity in the formation of the heterotrimeric G-protein may account for specificity in the action of certain chemokine receptors. Normally G-proteins are inactive when GDP is bound, but they are activated when the GDP is exchanged for

GTP (Fig. 12-1). After binding to a ligand, chemokine receptors rapidly associate with G-proteins, which in turn increases the exchange of GTP for GDP. Pertussis toxin is a commonly used inhibitor of GPCR that irreversibly ADP-ribosylates Gα subunits of the αi class and subsequently prevents most chemokine receptormediated signaling. Activation of G-proteins leads to the dissociation of the Gα and Gβγ subunits (Fig. 12-1). The Gα subunit has been observed to activate protein tyrosine kinases and mitogen-activated protein kinase, leading to cytoskeletal changes and gene transcription. The Gα subunit retains GTP, which is slowly hydrolyzed by the GTPase activity of this subunit. This GTPase activity is both positively and negatively regulated by GTPaseactivating proteins [also known as regulator of G-protein signaling (RGS) proteins]. The Gβγ dimer initiates critical signaling events in regard to chemotaxis and cell adhesion. It activates phospholipase C (PLC)32 leading to formation of diacylglycerol (DAG) and inositol triphosphate [Ins(1,4,5)P3]. Ins(1,4,5)P3 stimulates Ca2+ entry into the cytosol, which along with DAG, activates protein kinase C isoforms. While the Gβγ subunits have been shown to be critical for chemotaxis, the Gαι subunit has no known role in chemotactic migration. There is also evidence that binding of chemokine receptors results in the activation of other intracellular effectors including Ras and Rho, phosphatidylinositol3-kinase [PI(3)K].33

THE MULTISTEP MODEL OF LEUKOCYTE RECRUITMENT In order for leukocytes to adhere and migrate to peripheral tissues, they must overcome the pushing force of the vascular blood stream as they bind to activated

Chemokines

Generally speaking, chemokines are thought to play at least three different roles in the recruitment of host defense cells, predominantly leukocytes, to sites of inflammation.34 First, they provide the signal or signals required to cause leukocytes to come to a complete stop (i.e., arrest) in blood vessels at inflamed sites such as skin. Second, chemokines have been shown to have a role in the transmigration of leukocytes from the lumenal side of the blood vessel to the ablumenal side. Third, chemokines attract leukocytes to sites of inflammation in the dermis or epidermis following transmigration. Keratinocytes and endothelial cells are a rich source of chemokines when stimulated by appropriate cytokines. In addition, chemokines and their receptors are known to play critical roles in the emigration of resident skin dendritic cells (i.e., Langerhans cells and dermal dendritic cells) from the skin to draining lymph nodes (LN) via afferent lymphatic vessels, a process that is essential for the development of acquired immune responses. This section will be divided into three subsections. The first will introduce basic concepts of how all leukocytes arrest in inflamed blood vessels prior to transmigration by introducing the multistep model of leukocyte recruitment. The second will detail mechanisms of T cell migration, while the final subsection will focus on the mechanisms by which chemokines mediate the physiological migration of DC from the skin to regional LN.

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endothelial cells at local sites of inflammation. According to the multistep or cascade model of leukocyte recruitment (Fig. 12-2), one set of homologous adhesion molecules termed selectins mediates the transient attachment of leukocytes to endothelial cells while another set of adhesion molecules termed integrins and their receptors (immunoglobulin superfamily members) mediates stronger binding (i.e., arrest) and transmigration.35 The selectins (E-, L-, and P-selectins) are members of a larger family of carbohydrate-binding proteins termed lectins. The selectins bind their respective carbohydrate ligands located on protein scaffolds and thus mediate the transient binding or “rolling” of leukocytes on endothelial cells. The skin-associated vascular selectin known as E-selectin is upregulated on endothelial cells by inflammatory cytokines such as tumor necrosis factor (TNF)-α and binds to sialyl Lewis x-based carbohydrates. E-selectin ligands form distinct epitopes known as the cutaneous lymphocyte-associated antigen (CLA). CLA is expressed by 10%–40% of memory T cells and has been suggested as a marker for skinhoming T cells.36 At least two chemokine receptors (CCR10 and CCR4) show preferential expression in CLA+ memory T cells.8,20 While E-selectin is likely to be an important component of skin-selective homing, there is also evidence to suggest that L-selectin is involved in T cell migration to skin.37,38 In the second phase of this model, leukocyte integrins such as those of the β2 family must be “turned on” or activated from their resting state in order to bind to their counter receptors such as intercellular adhesion molecule-1 (ICAM-1) that are expressed by endothelial cells. A vast array of data suggest that the binding of chemokines to leukocyte chemokine receptors plays a critical role in activating both β1 and β2 integrins.33,39 Activation of chemokine receptors leads to a complex signaling cascade (Fig. 12-1) that causes a conformational change in individual integrins that leads to increases in the affinity and avidity of individual leukocyte integrins for their ligands. Furthermore, later steps of migration (i.e., transmigration or diapedesis) have been shown to be dependent on chemokines as well in selective cases.13 In the case of neutrophils, their ability to roll on inflamed blood vessels likely depends on their expression of L-selectin and E-selectin ligands while their arrest on activated endothelia likely depends on their expression of CXCR1 and CXCR2 as described below for wound healing. Integrin activation via chemokine-mediated signals appears to be more complex in T cells, which appear to use multiple chemokine receptors, and is described in more detail below.

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RhoA and protein kinase C appear to play a role in integrin affinity changes, while PI(3)K may be critical for changes in the avidity state of LFA-1. Other proteins have been found that regulate the synthesis, expression, or degradation of G-protein coupled receptors. For example, receptor-activity-modifying proteins (RAMPS) act as chaperones of seven transmembrane spanning receptors and regulate surface expression as well as the ligand specificity of chemokine receptors (Fig. 12-1). Importantly, after chemokine receptors are exposed to appropriate ligands, they are frequently internalized, leading to an inability of the chemokine receptor to mediate further signaling. This downregulation of chemokine function, which has been termed “desensitization,” occurs because of phosphorylation of Ser/Thr residues in the C-terminal tail by proteins termed GPCR kinases (GRK) and subsequent internalization of the receptor (Fig. 12-1). Desensitization may be an important mechanism for regulating the function of chemokine receptors by inhibiting cell migration as leukocytes arrive at the primary site of inflammation.

CHEMOKINE-MEDIATED MIGRATION OF T CELLS Antigen-inexperienced T cells are termed naive and can be identified by expressing three cell surface proteins: CD45RA (an isoform of the pan-leukocyte marker), L-selectin, and the chemokine receptor CCR7. These T cells migrate efficiently to secondary LN,

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ICAMs VCAM Tissue

Figure 12-2  Multistep model of leukocyte recruitment. Leukocytes, pushed by the blood stream, first transiently bind or “roll” on the surface of activated endothelial cells via rapid interactions with P-, E-, or L-selectin. Chemokines are secreted by endothelial cells and bind to proteoglycans that present the chemokine molecules to chemokine receptors on the surface of the leukocyte. After chemokine receptor ligation, intracellular signaling events lead to a change in the conformation of integrins and changes in their distribution on the plasma membrane resulting in “Integrin Activation.” These changes result in high affinity/avidity binding of integrins to endothelial cell intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecule-(VCAM)-1 in a step termed “Firm Adhesion,” which is then followed by transmigration of the leukocyte between endothelial cells and into tissue.

where they may make contact with antigen-bearing dendritic cells from the periphery. Once activated by dendritic cells presenting antigen, T cells then express CD45RO, are termed “memory” T cells, and appear to express a variety of adhesion molecules and chemokine receptors, which facilitate their extravasation from blood vessels to inflamed peripheral tissue. A specific subset of CCR7−, L-selectin memory T cells has been proposed to represent an effector memory T cell subset that is ready for rapid deployment at peripheral sites in terms of their cytotoxic activity and ability to mobilize cytokines.14 Although chemokines are both secreted and soluble, the net positive charge on most chemokines allows them to bind to negatively charged proteoglycans such as heparin sulfate that are present on the lumenal surface of endothelial cells, thus allowing them to be presented to T cells as they roll along the lumenal surface (Fig. 12-2). After ligand binding, chemokine receptors send intracellular signals that lead to increases in the affinity and avidity of T-cell integrins such as LFA-1 and VLA-4 for their endothelial receptors ICAM-1 and VCAM-1, respectively.40 Only a few chemokine receptors (CXCR4, CCR7, CCR4, and CCR6) are expressed at sufficient levels on resting peripheral blood T cells to mediate this transition. With activation and IL-2 stimulation, increased numbers of chemokine receptors (e.g., CXCR3) are expressed on activated T cells, mak-

ing them more likely to respond to other chemokines. In several different systems, inhibition of specific chemokines produced by endothelial cells or chemokine receptors found on T cells dramatically influences T cell arrest in vivo and in vitro.41 CXCR3 serves as a receptor for chemokine ligands Mig, IP-10, and I-Tac. All three of these chemokines are distinguished from other chemokines by being highly upregulated by interferon-γ. Resting T cells do not express functional levels of CXCR3, but upregulate this receptor with activation and cytokines such as IL-2. Once expressed on T cells, CXCR3 is capable of mediating arrest of memory T cells on activated endothelial cells.27 The expression of its chemokine ligands is strongly influenced by the cytokine interferon-γ, which synergistically works with proinflammatory cytokines such as TNF-α to increase expression of these ligands by activated endothelial cells27 and epithelial cells. In general, activation of T cells by cytokines such as IL-2 is associated with the enhanced expression of CCR1, CCR2, CCR5, and CXCR3. Just as Th1 and Th2 (T cell) subsets have different functional roles, it might have been predicted that these two subsets of T cells would express different chemokine receptors. Indeed, CCR49,42,43 and CCR36 are associated with Th2 cells in vitro while Th1 cells are associated with CCR5 and CXCR3.44

and function of skin-homing T cells in inflammatory disease models.51,52

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CHEMOKINES IN THE TRAFFICKING OF DENDRITIC CELLS FROM SKIN TO REGIONAL LYMPH NODES

:: Chemokines

Antigen-presenting cells, including dendritic cells (DC) of the skin, are critical initiators of immune responses and their trafficking patterns are thought to influence immunological outcomes. Their mission includes taking up antigen at sites of infection or injury and bringing these antigens to regional LN where they both present antigen and regulate the responses of T and B cells. Skin-resident DCs are initially derived from hematopoietic bone marrow progenitors53 and migrate to skin during the late prenatal and newborn periods of life. Under resting (steady state) conditions, homeostatic production by keratinocytes of CXCL14 (receptor unknown) may be involved in attracting CD14+ DC precursors to the basal layer of the epidermis.54 Similarly, Langerhans cells (LC) as well as CD1c+ LC precursors are strongly chemoattracted to keratinocyte-derived CCL20.55 Under inflammatory conditions, when skin-resident DC and LC leave the skin in large numbers, keratinocytes release a variety of chemokines, including CCL2 and CCL7 (via CCR2)4 and CCL20 (via CCR6),56 which may attract monocytelike DC precursors to the epidermis in order to replenish the LC population. When activated by inflammatory cytokines (e.g., TNF-α and IL-1β), lipopolysaccharide, or injury, skin DC, including LC, leave the epidermis, enter afferent lymphatic vessels, and migrate to draining regional LN where they encounter both naive and memory T cells. Chemokines guide the DC on this journey. Activated DC specifically upregulate expression of CCR7, which binds to secondary lymphoid tissue chemokine (SLC/CCL21), a chemokine expressed constitutively by lymphatic endothelial cells15,57 (eFig. 12-2.1 in online edition). SLC guides DC into dermal lymphatic vessels and helps retain them in SLC-rich regional draining LN (Fig. 12-3).58 Interestingly, naive T cells also strongly express CCR7 and use this receptor to arrest on high endothelial venules.59 The importance of the CCR7 pathway is demonstrated by LC from CCR7 knockout mouse that demonstrate poor migration from the skin to regional LN16 and by the observation that antibodies to SLC block migration of DC from the periphery to LN.15 Thus, CCR7 and its ligands facilitate the recruitment of at least two different kinds of cells—naive T cells and DC—to the LN through two different routes under both inflammatory16 and resting conditions.58 After DC reach the LN, they must interact with T cells to form a so-called “immunological synapse” that is critical for T cell activation. Activated DC secrete a number of chemokines, including macrophagederived chemokine (MDC),60 which attracts T cells to the vicinity of DC and promotes adhesion between the two cell types.61,62 CCR5 (via CCL3/4) has also been identified as mediating recruitment of naive CD8+ T

Chapter 12

In some instances, chemokine receptors may be regarded as functional markers that characterize distinct T helper cell subsets while also promoting their recruitment to inflammatory sites characterized by “allergic” or “cell-mediated” immune responses, respectively. When T cells are activated in vitro in the presence of Th1-promoting cytokines, CXCR3 and CCR5 appear to be highly expressed, while in the presence of Th2-promoting cytokines, CCR4, CCR8, and CCR3 expression predominates. In rheumatoid arthritis, a Th1-predominant disease, many infiltrating T cells express CCR5 and CXCR345 whereas, in atopic disease, CCR4 expressing T cells may be more frequent.9 CCR6 has recently been described as a marker for a newly characterized T-helper subset, expressing the hallmark effector cytokines IL-17 and IL-22.46 These so-called Th17 cells play a central role in the pathogenesis of psoriasis and other chronic inflammatory autoimmune diseases.47 However, in normal skin, the majority of skin resident T cells also coexpress CCR6, suggesting that CCR6 and CCL20 interactions regulate T cell infiltration in the skin under inflammatory as well as homeostatic conditions.48 While certain chemokine receptors characterize distinct T-cell subsets, flexible regulation of their expression may increase the migratory potential of circulating T cells to diverse tissues. For example, under some conditions, both Th1 and Th2 type T cells can express CCR4.43 Similarly, T regulatory cells (Treg) and Th17 cells share chemokines receptors with other T cell lineages but may alter their chemokine receptor expression profiles, depending on the microenvironment in which they are activated.49 The epidermis is a particularly rich source of chemokines, including RANTES, MIP-3a (CCL20), MCP-1, IP-10, IL-8, LARC, and TARC, which likely contribute to epidermal T cell migration. Keratinocytes from patients with distinctive skin diseases appear to express unique chemokine expression profiles. For instance, keratinocytes derived from patients with atopic dermatitis synthesized mRNA for RANTES at considerably earlier time points in response to IL-4 and TNF-α in comparison to healthy individuals and psoriatic patients.50 Keratinocytes derived from psoriatic patients synthesized higher levels of IP-10 with cytokine stimulation as well as higher constitutive levels of IL-8,50 a chemokine known to recruit neutrophils. IL-8 may contribute to the large numbers of neutrophils that localize to the suprabasal and cornified layers of the epidermis in psoriasis. IP-10 may serve to recruit activated T cells of the Th1 helper phenotype to the epidermis and has been postulated to have a role in the recruitment of malignant T cells to the skin in cutaneous T cell lymphomas.28 CTACK/CCL27 is selectively and constitutively expressed in the epidermis, and its expression is only marginally increased under inflammatory conditions.21 Interestingly, CTACK has been reported to preferentially attract CLA+ memory T cells in vitro21 and has been demonstrated to play a role in the recruitment

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BCZ

TCZ

SLC

ELC SLC

Lymph node

Lymphatic vessel

Figure 12-3  Trafficking of epidermal Langerhans cells to regional lymph nodes. Langerhans cells are activated by a variety of stimuli including injury, infectious agents, and cytokines such as IL-1α and TNF-α. Having sampled antigens, the activated LC downregulate E-cadherin and strongly upregulate CCR7. Sensing the CCR7-ligand, SLC (●), produced by lymphatic endothelial cells, the LC migrate into lymphatic vessels, passively flow to the lymph nodes, and stop in the T-cell zones (TCZ) that are rich in two CCR7 ligands, SLC and ELC. Note that chemokines also contribute to the recruitment of LC under both resting and inflammatory conditions. BCZ, B-cell zones.

cells to aggregates of antigen-specific CD4+ T cells and DC.63 Therefore, chemokines orchestrate a complex series of migration patterns bringing both DC and T cells to the confines of the LN, where expression of chemokines by DC themselves appears to be a direct signal for binding of the T cell (Fig. 12-3).

CHEMOKINES IN DISEASE ATOPIC DERMATITIS

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Atopic dermatitis is a prototypical Th2-mediated, allergic skin disease with multifactorial genetic and environmental factors involved in its pathogenesis. Although multiple chemokines have been associated with the atopic phenotype, the roles of CCR4 and CCR10 in AD have been particularly well documented.64 Clinical data from humans as well as experimental data

in the NC/Nga mouse model of atopic dermatitis suggest that the Th2-associated chemokine receptor, CCR4, in conjunction with its ligand, TARC/CCL17, may play a role in recruiting T cells to atopic skin. In patients with atopic dermatitis, CLA+CCR4+CCR10+ lymphocytes were found to be increased in the peripheral blood and in lesional skin compared to controls.9 Moreover, serum levels of TARC/CCL17 and CTACK/ CCL27 in atopic dermatitis patients were significantly higher than concentrations found in healthy or psoriatic controls and correlated with disease severity.10 CCL18, whose receptor is currently unknown, has been reported to be expressed at higher levels in the skin of patients with atopic disease compared to psoriasis.65 CCL18 is produced by antigen-presenting cells and attracts CLA+ memory T cells to the skin.66 Elevated levels of CCL18 can be found in the skin and sera of patients with AD but show a significant decrease after therapy.67 Of note, CCL18 and another chemokine, CCL1 (produced by mast cells and endothelial cells), are elicited in volunteer skin after topical challenge with dust mite allergen and Staphylococcal superantigen.65,68 The recruitment of eosinophils to skin is a frequently observed finding in allergic skin diseases, including atopic dermatitis and cutaneous drug reactions, and likely is mediated by chemokines. Eotaxin/CCL11 was initially isolated from the bronchoalveolar fluid of guinea pigs after experimental allergic inflammation and binds primarily to CCR3, a receptor expressed by eosinophils,69 basophils, and Th2 cells.6 Injection of eotaxin into the skin promotes the recruitment of eosinophils while anti-eotaxin antibodies delay the dermal recruitment of eosinophils in the late-phase allergic reaction in mouse skin.70 Immunoreactivity and mRNA expression of eotaxin and CCR3 are both increased in lesional skin and serum of patients with atopic dermatitis, but not in nonatopic controls.71,72 Eotaxin has also been shown to increase proliferation of CCR3expressing keratinocytes in vitro.73 Finally, expression of eotaxin (and RANTES) by dermal endothelial cells has been correlated with the appearance of eosinophils in the dermis in patients with onchocerciasis that experience allergic reactions following treatment with ivermectin.74 The observations above suggest that production of eotaxin and CCR3 may contribute to the recruitment of eosinophils and Th2 lymphocytes in addition to stimulating keratinocyte proliferation.

PSORIASIS Psoriasis is characterized by hyperplasia of the epidermis (acanthosis) and a prominent dermal and epidermal inflammatory infiltrate, typically resulting in thickened, hyperkeratotic plaques. The inflammatory infiltrate of psoriatic skin is predominantly composed of Th1- and Th17-polarized memory T cells, as well as neutrophils, macrophages, and increased numbers of dendritic cells.75 As shown in eFig. 12-3.1 in online edition and reviewed by others,64 there is a growing body of evidence supporting a central role for chemokines in regulating the complex events leading to psoriatic

Chemokines

Chemokines may play a role in tumor formation and immunity in several distinct ways, including the control of angiogenesis and the induction of tumor immune responses.85 CXC chemokines that express a three-amino-acid motif consisting of glu-leu-arg (ELR) immediately preceding the CXC signature are angiogenic while most non-ELR CXC chemokines, except SDF-1, are angiostatic. Interestingly, it is not clear that ELR− chemokines actually bind to chemokine receptors in order to reduce angiogenesis. It has been proposed that they act by displacing growth factors from

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proteoglycans. In any event, the balance between ELR+ versus ELR− chemokines is thought to contribute to the complex regulation of angiogenesis at tumor sites. IL-8, a prototypical ELR+ chemokine, can be secreted by melanoma cells and has been detected in conjunction with metastatic dissemination of this cancer,86 which may be related to its ability to attract circulating tumor cells to primary tumors and to influence leukocyte and endothelial cell recruitment.87,88 IL-8 may also act as an autocrine growth factor for melanoma24 as well as several other types of cancer. Although CXCR1 and CXCR2 bind IL-8 in common, several other ELR+ CXC chemokines also bind to and activate CXCR2. Tumors, including melanoma, have long been known to secrete chemokines that can attract a variety of leukocytes. The question arises as to why this is not deleterious to the tumor itself. Breast cancers, for instance, are known to secrete macrophage chemotactic protein-1 (MCP-1), a chemokine that attracts macrophages through CCR2. Higher tissue levels of MCP-1 correlate with increasing number of macrophages within the tissue. While chemokines secreted by tumor cells do lead to recruitment of immune cells, this does not necessarily lead to increased clearance of the tumor.89 Inflammatory cells such as macrophages may actually play a critical role in cancer invasion and metastasis. Firstly, MCP-1 may increase expression of macrophage IL-4 through an autocrine feedback loop and possibly skew the immune response from Th1 to Th2. Interestingly, MCP-1-deficient mice show markedly reduced dermal fibrosis following dermal challenge with bleomycin, a finding of possible relevance to the pathogenesis of conditions such as scleroderma.5 Secondly, macrophages may promote tumor invasion and metastasis.90 The antitumor effects of specific chemokines may occur by a variety of mechanisms. ELR− CXCR3 ligands such as IP-10 are potently antiangiogenic and may act as downstream effectors of IL-12-induced, NK cell-dependent angiostasis.91 Of note, some cancer cells can synthesize LARC, attracting immature DC that express CCR6.92 Experimentally, LARC has been transduced into murine tumors, where it attracts DC in mice and suppresses tumor growth in experimental systems.93 Lastly, chemokines produced by tumor cells may attract CD4+CD25+ T regulatory cells (Tregs) that suppress host antitumor cytolytic T cells.94 Tumor metastasis is the most common cause of mortality and morbidity in cancer. With skin cancers such as melanoma, there is a propensity for specific sites such as brain, lung, and liver, as well as distant skin sites. Cancers may also metastasize via afferent lymphatics and eventually reach regional draining LN. The discovery of nodal metastasis often portends a poor prognosis for the patient. In fact, the presence of nodal metastases is one of the most powerful negative predictors of survival in melanoma.95 Chemokines may play an important role in the sitespecific metastases of cancers of the breast and of melanoma96 (Fig. 12-4). Human breast cancer as well as melanoma lines express the chemokine receptors CXCR4

Chapter 12

skin inflammation. Chemokines, including CCL2076 and CCL178 mediate the arrest of effector memory T cells on endothelial cells that synthesize these chemokines.77 In addition, both CCL17 and CCL20 can be synthesized by keratinocytes, possibly contributing to T cell migration to the epidermis. While psoriasis has traditionally been considered a classical Th1-associated disease, accumulating evidence points to an important pathogenetic contribution of Th17 cells, which strongly express CCR6.79 Th17 cells, their signature effector cytokines IL-17 and IL-22, as well as high levels of IL-23, a major growth and differentiation factor for Th17 cells, are abundant in psoriatic skin lesions.80 Recent research suggests that CCR6 and its ligand, CCL20, are important mediators of psoriasis since both CCL20 as well as CLA+CCR6+ skin-homing Th17 cells are found in abundance in lesional psoriatic skin.80,81 Moreover, CCR6-deficient mice failed to develop psoriasis-like inflammation82 in response to intradermal IL-23 injections, a murine model for human psoriasis83 (eFig. 12-3.2 in online edition). Interestingly, CCR6 was required for both T cell dependent as well as T cell independent skin inflammation in this model.82 Neutrophils found in the epidermis of psoriatic skin are probably attracted there by high levels of IL-8, which would act via CXCR1 and CXCR2. In addition to attracting neutrophils, IL-8 is an ELR+ CXC chemokine that is known to be angiogenic, and it may also attract endothelial cells. This may lead to the formation of the long tortuous capillary blood vessels in the papillary dermis that are characteristic of psoriasis. Moreover, keratinocytes also express CXCR2 and thus may be autoregulated by the expression of CXCR2 ligands in the skin. Of note, an IL-8/CXCL8-producing population of memory T cells that express CCR6 has been isolated from patients with acute generalized exanthematous pustulosis (AGEP), a condition induced most commonly by drugs (e.g., aminopenicillins) and characterized by small intraepidermal or subcorneal sterile pustules.84 Similar T cells have been isolated from patients with Behçet’s disease and pustular psoriasis.78 It is possible that this subpopulation of T cells contributes to neutrophil accumulation in the stratum corneum (Munro’s abscesses) in psoriasis and other inflammatory skin disorders characterized by neutrophil-rich infiltrates in the absence of frank infection.

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Lymphatic vessel

Figure 12-4  Chemokine receptors in melanoma progression and metastasis. Chemokine receptors play distinct roles in melanoma metastasis.96 CCR10 may enhance survival of primary melanoma tumors and skin metastases. CCR7, CCR10, and, possibly, CXCR4 may contribute to lymph node metastasis. CXCR4 appears to be involved in primary tumor development and metastasis at distant organ sites such as the lungs. CCR9 has been implicated in melanoma small bowel metastasis in patients.

and CCR7, whereas normal breast epithelial cells and melanocytes do not appear to express these receptors.97 CXCR4 is expressed in over 23 different solid and hematopoietic cancers. Broad expression of this receptor may be due to its regulation by hypoxia, a condition common to growing tumors, via the hypoxia inducible factor-1α transcription factor.98 Notably stromal fibroblasts within human cancers express the CXCR4 ligand, CXCL12, which stimulates tumor growth as well as angiogenesis.99 In several different animals of breast cancer97 and melanoma metastasis,29 inhibition of CXCR4 with antibodies or peptides resulted in dramatically reduced metastases to distant organs. Expression of CCR7 by cancer cells, including gastric carcinoma and melanoma, appears to be critical for invasion of afferent lymphatics and LN metastasis. CCR7-transfected B16 murine melanoma cells were found to metastasize with much higher efficiency to regional LN compared to control B16 cells after inoculation into the footpad of mice,17 but CCR7 also directly stimulates primary B16 tumor development as well.100 CCR9 may also play a role in melanoma metastasis to the small bowel, which shows high expression of the CCR9 ligand, CCL25.19 CCR10 is highly expressed by melanoma primary tumors22 and is correlated with nodal metastasis in melanoma patients101 and in experimental animal models (eFig. 12-4.1 in online edition).22 Engagement of CCR10 by CTACK results in activation (via phosphorylation) of

the phosphatidylinositol 3-kinase (PI3K) and Akt signaling pathways, leading to antiapoptotic effects in melanoma cells.22 Because CTACK is constitutively produced by keratinocytes, it may act as a survival factor for both primary as well as secondary (metastatic) melanoma tumors that express CCR10. In fact, CCR10-activated melanoma cells become resistant to killing by melanoma antigen-specific T cells (eFig. 12-4.1 in online edition).22 Interestingly, CCR4,11 CXCR4,102 and CCR1023,103 have been implicated in the trafficking and/or survival of malignant T (lymphoma) cells to skin. Thus, a limited number of specific chemokine receptors appear to play distinct, nonredundant roles in facilitating cancer progression and metastasis (summarized in Fig. 12-4).

INFECTIOUS DISEASES Although chemokines and chemokine receptors may have evolved as a host response to infectious agents, recent data suggest infectious organisms may have coopted chemokine- or chemokine receptor-like molecules to their own advantage in selected instances. A variety of microorganisms express chemokine receptors, including US28 by cytomegalovirus and Kaposi’s sarcoma herpes virus (or human herpes virus-8) G-protein coupled receptor (GPCR). In the case of KSHV GPCR, this receptor is able to promiscuously

neutropenia and abnormal neutrophil morphology. The nearly universal presence of HPV infections associated with this syndrome can involve multiple common, as well as genital, wart subtypes (eFig. 12-4.2 in online edition) and suggest a critical role for normal CXCR4 function in immunological defense against this common human pathogen.

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:: Chemokines

The skin is rich in cells (keratinocytes, fibroblasts, endothelial cells, and immune cells) that are able to produce chemokines. Chemokines not only orchestrate the migration of inflammatory cells but also play roles in angiogenesis, cancer metastasis, and cellular proliferation. Other unanticipated biologic roles may ultimately be discovered. Just two of the promising therapeutic applications of chemokines (or molecules that mimic chemokines) may be in (1) preventing undesirable migration into the skin by preventing arrest of T cells or other inflammatory cells on activated endothelium, and (2) blocking the infection of dendritic cells and T cells by HIV-1 virus using CCR5 analogs. Signaling pathways are just beginning to be understood, and further work needs to be done to understand the regulation of these receptors, the specificity of intracellular activities, and the mechanism by which chemokine receptors work in the face of multiple chemokines present in many inflammatory sites.

Chapter 12

bind several chemokines. More importantly, it is constitutively active and may work as a growth promoter in Kaposi’s sarcoma.104 The human immunodeficiency virus (HIV)-1, the causative agent of the acquired immunodeficiency syndrome (AIDS), is an enveloped retrovirus that enters cells via receptor-dependent membrane fusion (see Chapter 198). CD4 is the primary fusion receptor for all strains of HIV-1 and binds to HIV-1 proteins, gp120 and gp41. However, different strains of HIV-1 have emerged that preferentially use CXCR4 (T-tropic) or CCR5 (M-tropic) or either chemokine receptor as a coreceptor for entry. While other chemokine coreceptors can potentially serve as coreceptors, most clinical HIV-1 strains are primarily dual-tropic for either CCR5 or CXCR4.3 The discovery of a 32-base pair deletion (D32) in CCR5 in some individuals that leads to low levels of CCR5 expression in T cells and dendritic cells and correlates with a dramatic resistance to HIV-1 infection demonstrated a clear role for CCR5 in the pathogenesis of HIV-1 infection.105 Interestingly, the frequency of D32 mutations in humans is surprisingly high, and the complete absence of CCR5 in homozygotes has only been associated with a more clinically severe form of sarcoidosis. Otherwise, these individuals are healthy. In fact, there is an association of less severe autoimmune diseases in patients with these mutations.106 LC reside in large numbers in the genital mucosa and may be one of the first initial targets of HIV-1 infection.107 Since infected (activated) LC likely enter dermal lymphatic vessels and then localize to regional LN as described earlier, the physiologic migratory pathway of LC may also coincidentally lead to the transmission of HIV-1 to T cells within secondary lymphoid organs. CCR5 is expressed by immature or ­resting LC in the epidermis and is the target of CCR5 analogs of RANTES that block HIV infection.108 Already, an FDAapproved small molecule inhibitor of CCR5, maraviroc, is available for use in treatment of HIV disease and may show fewer adverse effects than certain reverse transcriptase inhibitors.109 CXCR4 antagonists may also be of clinical utility with T- or dual-tropic viruses.110 A newly described autosomal dominant genetic syndrome comprised of warts (human papilloma virus (HPV)-associated), hypogammaglobulinemia, infections, and myelokathexis (WHIM) is the result of an activating mutation (deletion) in the cytoplasmic tail of the CXCR4 receptor or in yet unidentified downstream regulators of CXCR4 function.111,112 Bacterial infections are common because myelokathexis is associated with

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Charo IF, Ransohoff RM: The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354(6):610-621, 2006 2. Zlotnik A, Yoshie O: Chemokines: A new classification system and their role in immunity. Immunity 12(2):121127, 2000 29. Murakami T et al: Expression of CXC chemokine receptor (CXCR)-4 enhances the pulmonary metastatic potential of murine B16 melanoma cells. Cancer Res 62:73287334, 2002 34. Homey B: Chemokines and inflammatory skin diseases. Adv Dermatol 21:251-277, 2005 58. Ohl L et al: CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21(2):279-288, 2004 82. Hedrick MN et al: CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 119(8): 2317-2329, 2009

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Chapter 13 :: Allergic Contact Dermatitis :: Mari Paz Castanedo-Tardan & Kathryn A. Zug ALLERGIC CONTACT DERMATITIS AT A GLANCE

Section 4 :: Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

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Allergic contact dermatitis (ACD) is a cell-mediated (type IV), delayed type, hypersensitivity reaction caused by skin contact with an environmental allergen. Prior sensitization to a chemical is required for allergy to develop. The clinical manifestation of ACD is an eczematous dermatitis. The acute phase is characterized by pruritus, erythema, edema, and vesicles usually confined to the area of direct exposure. Recurrent contact to the allergen in a sensitized individual will result in chronic disease, characterized by lichenified erythematous plaques with variable hyperkeratosis and fissuring that may spread beyond the areas of direct exposure. Itch and swelling are key components of the history and can be a clue to allergy. The hands, feet, and face (including the eyelids) are some of the common sites for ACD. Patch testing is fundamental for the identification of causal allergens and is indicated for patients with persistent or recurrent dermatitis in whom ACD is suspected.

Avoidance is the mainstay of treatment for ACD. Educating patients about avoidance of the allergen and its potentially related substances, and providing suitable alternatives are crucial to a good outcome.

As the largest organ in the human body, the skin is a complex and dynamic organ that serves among many other purposes, the function of maintaining a physical and immunologic barrier to the environment. Therefore, the skin is the first line of defense after exposure to a variety of chemicals. Allergic contact dermatitis (ACD) accounts for at least 20% or more of the new incident cases in the subgroup of contact dermatitides (irritant contact dermatitis accounts for the remaining 80%).1 ACD, as the name implies, is an adverse cutaneous inflam-

matory reaction caused by contact with a specific exogenous allergen to which a person has developed allergic sensitization. More than 3,700 chemicals have been implicated as causal agents of ACD in humans.2 Following contact with an allergen, the skin reacts immunologically, giving the clinical expression of eczematous inflammation. In ACD the severity of the eczematous dermatitis can range from a mild, short-lived condition to a severe, persistent, chronic disease. Appropriate allergen identification through proper epicutaneous patch testing has been demonstrated to improve quality of life as measured by standard tools,3 as it allows for appropriate avoidance of the inciting allergen and possibly sustained remission of this potentially debilitating condition. Recognition of the presenting signs and symptoms, and appropriate patch testing are crucial in the evaluation of a patient with suspected ACD.

EPIDEMIOLOGY A small but substantial number of studies have investigated the prevalence of contact allergy in the general population and in unselected subgroups of the general population. In 2007, Thyssen and colleagues4 performed a retrospective study that reviewed the main findings from previously published epidemiological studies on contact allergy in unselected populations including all age groups and most publishing countries (mainly North America and Western Europe). Based on these heterogeneous published data collected between 1966 and 2007, the median prevalence of contact allergy to at least one allergen in the general population was 21.2%. Additionally, the study found that the most prevalent contact allergens in the general population were nickel, thimerosal, and fragrance mix. Importantly, the prevalence of contact allergy to specific allergens differs between various countries5,6 and the prevalence to a specific allergen is not necessarily static, as it is influenced by changes and developments in the regional environment, exposure patterns, regulatory standards, and societal customs and values. On a final note about epidemiology, contact allergy caused by ingredients found in personal care products (cosmetics, toiletries) is a well-known problem, with approximately 6% of the general population estimated to have a cosmetic-related contact allergy.19,20 Contact allergy to ingredients in personal care products will be further discussed in this chapter.

AGE Over the past decade, multiple studies have recognized contact dermatitis as an important cause of childhood dermatitis, and a common diagnosis among

children; being equally as likely in childhood as in adulthood,21,22 although the most common allergens identified differ between the age groups. On the other hand, although fragrance mix allergy is an important sensitizer in all ages, certain studies, such as the 2001 Augsburg study, which was based on adults aged 28–75 years, have shown a significant increase in fragrance mix allergy with increasing age.23 Similarly, Magnusson et al24 demonstrated a high prevalence rate (4.7%) of Myroxylon pereirae (balsam of Peru—a marker for fragrance allergy) sensitization among 65-year-old Swedish patients. Similarly, a recent Danish study demonstrated the prevalence allergy to preservatives being higher among those aged 41–60 years.25

Allergic contact dermatitis represents a classic cellmediated, delayed (type IV) hypersensitivity reac-

Allergic Contact Dermatitis

ETIOLOGY AND PATHOGENESIS

tion. Such immunological reaction, results from exposure and subsequent sensitization of a genetically susceptible host, to an environmental allergen, which on reexposure triggers a complex inflammatory reaction. The resulting clinical picture is that of erythema, edema, and papulo-vesiculation, usually in the distribution of contact with the instigating allergen, and with pruritus as a major symptom Fig. 13-1.35 To mount such reaction, the individual must have sufficient contact with a sensitizing chemical, and then have repeated contact with that substance later. This is an important distinction to irritant contact dermatitis (ICD) in which no sensitization reaction takes place, and the intensity of the irritant inflammatory reaction is proportional to the dose—concentration and amount of the irritant. In ACD, only minute quantities of an allergen are necessary to elicit overt allergic reactions. There are two distinct phases in the development of ACD: the sensitization phase and the elicitation phase.36

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Because very few studies have looked at the induction of allergic contact sensitization in men and women under controlled circumstances, gender differences in the development of ACD are largely unknown. When the human repeat-insult patch testing method was used to assess induction rates for ten common allergens, women were more often sensitized to seven of the ten allergens studied.26 With regard to frequency, Thyssen and colleagues found that the median prevalence of contact allergy among the general population was 21.8% in women versus 12% in men. When looking specifically at nickel sensitivity, the same study showed that the prevalence was much higher among women than men (17.1% in woman vs. 3% in men). This might be due to the fact that numerous studies have demonstrated that pierced ears are a significant risk factor for development of nickel allergy.27–31 Thus, the higher prevalence of nickel allergy in women may be explained by the higher median prevalence of pierced ears in women in comparison with men (81.5% in women vs. 12% in men) of the population studied. The role of race, if any, in the development of ACD to some potent allergens such as para-phenylenediamine (PPD), remains controversial.32,33 Limited studies have suggested lower sensitizations rates to nickel and neomycin in African Americans compared to Caucasians. With regard to the patch-test protocol, the evaluation of positive reactions may be slightly more difficult in darker skin types (Fitzpatrick types V and VI), as erythema may not be as obvious, posing the risk of overlooking a mild positive allergic reaction. However, the edema and papules/vesicles are usually obvious and palpable; therefore palpation of the patch-test site can help to detect allergic reactions in patients with darker skin types. Finally, the darker the skin, the more difficult it is to mark the patch-test site after removal. For very dark skin, a florescent marking ink is probably best, the markings being located by a Wood’s light in a darkened room.34

Figure 13-1  Erythematous papules and vesicles are characteristics of contact allergy in the acute stage.

Chapter 13

GENDER AND RACE

4

SENSITIZATION PHASE Most environmental allergens are small, lipophilic molecules with a low molecular weight (10% BSA

Day treatment center Modified Goeckerman

Mild 20% body surface area involvement).341 However, obesity does not appear to have a role in defining the onset of psoriasis.341

SMOKING. Smoking (more than 20 cigarettes daily) has also been associated with more than a twofold increased risk of severe psoriasis.342 Unlike obesity, smoking appears to have a role in the onset of psoriasis.341 Recently, a gene–environment interaction has been identified between low activity of the cytochrome P450 gene CYP1A1 and smoking in psoriasis.343 INFECTION. An association between streptococcal throat infection and guttate psoriasis has been repeatedly confirmed.300,343 Streptococcal throat infections have also been demonstrated to exacerbate preexisting chronic plaque psoriasis.227 Severe exacerbation of psoriasis can be a manifestation of human immunodeficiency virus (HIV) infection.345 Like psoriasis in general, HIV-associated psoriasis has a strong association with HLA-Cw6.345 Interestingly, the prevalence of psoriasis in HIV infection is no higher than in the general population (1%– 2% of patients),346,347 indicating that this infection is not a trigger for psoriasis but rather a modifying agent. Psoriasis is increasingly more severe with progression of immunodeficiency but can remit in the terminal phase.348,349 This paradoxical exacerbation of psoriasis may be due to loss of regulatory T cells and increased activity of the CD8 T-cell subset.300 Psoriasis exacerbation in HIV disease may be effectively treated with antiretroviral therapy.350 Psoriasis has also been associated with hepatitis C infection.351 DRUGS. Medications that exacerbate psoriasis include antimalarials, β blockers, lithium, nonsteroidal anti-inflammatory drugs, IFNs-α and -γ, imiquimod, angiotensin-converting enzyme inhibitors, and gemfibrozil.352 Imiquimod acts on pDCs and stimulates IFNα production,147 which then strengthens both innate and Th1 immune responses. Exacerbations and onset of psoriasis have been described in patients receiving TNF inhibitor therapy. The majority of these cases are palmoplantar pustulosis, but about one-third develop chronic plaque psoriasis.353 Lithium has been proposed to cause exacerbation by interfering with calcium release within keratinocytes, whereas β blockers are thought to interfere with intracellular cyclic adenosine monophosphate levels.352 The mechanisms by which the remaining medications exacerbate psoriasis are largely unknown. Patients with active or unstable psoriasis should receive advice when traveling to countries where antimalarial prophylaxis is needed.

TREATMENT GENERAL CONSIDERATIONS A broad spectrum of antipsoriatic treatments, both topical and systemic, is available for the management of psoriasis. As detailed in Tables 18-3–18-6, it

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TABLE 18-3

Topical Treatments for Psoriasis359 Topical Steroids

Vitamin D Analogs

Tazarotene

Calcineurin Inhibitors

Bind to vitamin D receptors, influencing the expression of many genes. Promote keratinocyte differentiation.

Metabolized to tazarotenic acid, its active metabolite,361 which binds to retinoic acid receptors. Normalizes epidermal differentiation, exhibits a potent antiproliferative effect, and decreases epidermal proliferation.

Bind to FK506-binding protein (FKBP) and inhibit calcineurin, decreasing the activation of the transcription factor, NF-AT, with resultant decrease in cytokine transcription, including IL-2.

Dosing

10,000-fold range of potency. Highpotency steroids are applied to affected areas twice daily for 2–4 weeks and then intermittently (weekends).

Calcipotriene, 0.005%, to affected areas twice daily. Often used alternating with topical steroids (i.e., vitamin D analogs on weekdays, topical steroids on weekends).

Available in 0.05% and 0.1% formulations, both as cream and gels. Apply every night to affected area.

Application to affected areas twice daily.

Efficacy

Very effective as short-term treatment.

Efficacy is increased by combination with topical steroids. Can be combined with various other therapies.

Efficacy is increased by combination with topical steroids.361

Effective for treatment of facial and flexural psoriasis269 but minimally for chronic plaque psoriasis.268

Safety

Suppression of the hypothalamic– pituitary–adrenal axis (higher risk in children). Atrophy of the epidermis and dermis. Formation of striae. Tachyphylaxis.258

Development of irritation at the site of application is common.258 Isolated reports of hypercalcemia in patients who applied excessive quantities.363

When used as monotherapy, significant proportion of patients develop irritation at the site of application.364

Burning sensation at the site of application. Case reports of development of lymphoma.

Contraindications

Hypersensitivity to the steroid, active skin infection.

Hypercalcemia, vitamin D toxicity.

Pregnancy, hypersensitivity to tazarotene.

Use only with caution for treatment of children younger than the age of 2 years.

Remarks/longterm use

Long-term use increases risk of side effects.

Calcipotriol is well tolerated and continues to be clinically effective with minimum of adverse effects in long-term use.365,366

Combination of steroid with tazarotene may reduce atrophy seen with superpotent topical steroids.362 If added during phototherapy, the ultraviolet doses should be reduced by one-third.258

Due to anecdotal reports of association with malignancy, this class of medications recently received a black-box warning by the US Food and Drug Administration.

Pregnancy category

C

C

X

C

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Bind to glucocorticoid receptors, inhibiting the transcription of many different AP-1- and NF-κBdependent genes, including IL-1 and TNF-α.

Chapter 18

Mechanism of action

Psoriasis

AP = activator protein; IL = interleukin; NF = nuclear factor; NF-AT = nuclear factor of activated T cells.

is notable that most if not all of these treatments are immunomodulatory. When choosing a treatment regimen (see Fig. 18-6) it is important to reconcile the extent and the measurable severity of the disease with the patient’s own perception of his or her disease. In

this context, it is notable that a recent study found that 40% of patients felt frustrated with the ineffectiveness of their current therapies, and 32% reported that treatment was not aggressive enough.350 As psoriasis is a chronic condition, it is important to know the safety

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TABLE 18-4

Phototherapy of Psoriasis385 Psoralen and UVA Light (PUVA)

Excimer Laser (308 nm)

Dosing

Dosage based on either the Fitzpatrick skin type or MED. Determine MED. Initial treatment at 50% of MED followed by three to five treatments weekly. Lubricate before treatment. Treatments 1–20; increase by 10% of initial MED. Treatments ≥21; increase as ordered by physician.385 Maintenance therapy after >95% clearance: 1×/week for 4 weeks, keep dose the same 1×/2 weeks for 2 weeks, decrease dose by 25% 1×/4 weeks, 50% of highest dose.385

The dosage may be administered according to the Fitzpatrick skin type.437 Initial treatment at 50% of MED followed by three to five treatments weekly. Treatment 1–10 increase dose by 25% of initial MED. Treatments 11–20; increase by 10% of initial MED. Treatments ≥21; increase as ordered by physician.385

Dose based on MPD is recommended. If MPD testing is impractical, a regimen based on skin type may be used. Initial dose 0.5–2.0 J/cm2, depending on skin type (or MPD). Treat twice weekly, increments of 40% per week until erythema, then maximum 20% per week. No further increments once 15 J/ cm2 is reached.369

The dose of energy delivered is guided by the patient’s skin type and thickness of plaque. Further doses are adjusted based on response to treatment or development of side effects.385 Treatment usually given twice weekly.

Efficacy

>70% improvement in a split body study after 4 weeks of treatment. Nine out of eleven patients showed clearance.368 More effective than BB-UVB.274,275,368

47% improvement in a split body study after 4 weeks, only 1 out of 11 patients showed clearance.367

Induces remission in 70%– 90% of patients.370–373 Less convenient than NB-UVB but may be more effective.278

High response rates. In one study, 85% of patients showed a ≥90% improvement in PASI after average 7.2 weeks of treatment438 While in another study showed greater than 75% improvement in 72% of patients in an average of 6.2 treatments.439

Safety

Photodamage, polymorphic light eruption, increased risk of skin aging and skin cancers although lower than that for PUVA.374

Photodamage, polymorphic light eruption, increased risk of skin aging and skin cancers.

Photodamage, premature skin aging, increased risk of melanoma and nonmelanoma skin cancers, ocular damage. Eye protection required with oral psoralens.

Erythema, blisters, hyperpigmentation and erosions. Long-term side effects not yet clear but likely similar to NB-UVB.

Contraindications

Absolute:   Photosensitivity disorders.

Absolute:  Photosensitivity disorders. Relative:  Photosensitizing medications, melanoma, and nonmelanoma skin cancers.

Absolute:  Light-sensitizing disorder, lactation, melanoma. Relative:  Age cord blood) T-cell replete graft Unrelated donor Donor leukocyte infusion Interruption or rapid tapering of immunosuppression

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BOX 28-1  Major Risk Factors for the Development of GraftVersus-Host Disease

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Chapter 28

Approximately 50,000 hematopoietic stem cell transplantation (HCT) procedures are performed worldwide each year for an expanding array of hematologic malignancies and marrow failure syndromes, metabolic disorders, and immunodeficiencies. HCT may utilize autologous, syngeneic, or allogeneic donor hematopoietic stem cell (HC). During autologous transplantation the patient’s own HC are returned to the patient following preparative chemotherapy. Syngeneic transplantation is the transfer of HC between identical twins. Allogeneic HCT (allo-HCT) is the transfer of HC from a related (nonidentical) or unrelated donor to a recipient. Graft-versus-host disease (GVHD) is the primary cause of nonrelapse-related morbidity and mortality in allo-HCT and also rarely occurs following transplantation of solid organs or transfusion of blood products. Transplantation regimens have advanced rapidly since the first successful allo-HCT was performed in 1968.1 Peripheral blood, rather than bone marrow, is now the primary source of donor HC at many transplant centers, and reduced intensity (nonmyeloablative) conditioning has permitted older patients and others who would not tolerate myeloablative chemotherapy a chance for cure with HCT. More recently, umbilical cord blood has gained prominence as a stem cell source in both pediatric and adult HCT. Donor leukocyte infusions (DLI), the administration of additional donor HC to the recipient weeks or even months after HCT, are also frequently utilized to augment graft-versus-malignancy effect. These evolving trends in HCT, in conjunction with other known donor/recipient risk variables (Box 28-1), contribute to a wide range of reported GVHD incidence. Nevertheless, the degree of HLA-mismatch between donor and recipient remains the single most important predictor of GVHD.2 Acute GVHD develops in approximately 40% of fully matched sibling donor HCT, whereas 80% of mismatched unrelated HCT result in acute GVHD.3,4 Risk estimates of chronic GVHD also vary widely and confounding factors such as improving early posttransplant survival may be influencing

the apparent trend in increasing chronic GVHD incidence.5 The most significant additional risk factor for chronic GVHD is a history of antecedent acute GVHD.5 Skin involvement is often the first indicator of acute GVHD (81%), followed by gastrointestinal (54%) and liver disease (50%).6 Similarly, the majority of patients who develop chronic GVHD manifest skin symptoms at some point in their disease course. The risk of chronic skin involvement is increased by the use of peripheral blood HCT (PB-HCT) compared with bone marrow HCT (BM-HCT). At one center, approximately 90% of patients who developed chronic GVHD following PB-HCT manifested skin symptoms.7 In most published reports, the incidence of sclerotic versus nonsclerotic chronic skin manifestations has not been differentiated. Although sclerotic involvement is less common than “lichenoid” GVHD and tends to occur later post-HCT, sclerotic features, particularly deepseated fascial changes, may have an insidious onset, and “lichenoid” involvement is not a prerequisite to the development of sclerotic features. In one series of 196 patients post-HCT, only 7 (3.6%) developed sclerotic manifestations (mean 2.0 years after HCT).8 In a review of 133 patients who survived at least 4 months after allo-HCT, the 5-year cumulative incidence of sclerotic GVHD was 10.5% (15.5% among patients with chronic GVHD). In this series, only 21% manifested “lichenoid” changes prior to the onset of skin sclerosis.9 In a referral setting for patients with primarily refractory disease at the NIH, 81/110 (74%) consecutive patients had skin involvement, 58/110 (53%) of whom had sclerotic manifestations.10

ETIOLOGY AND PATHOGENESIS In 1966, Billingham proposed three basic requirements for GVHD: (1) immunocompetent transplanted cells, (2) host antigens recognizable by the transplanted cells and lacking in the donor, and (3) a host incapable of mounting an immune response to the transplanted cells.11 The immunocompetent cells are now known to be T-cells, which target human leukocyte antigens (HLAs) expressed on host tissues. GVHD still develops in 40% of recipients of HLA-identical grafts, however. In this setting, GVHD is due to mismatch of key minor histocompatibility antigens (e.g., HY, HA-3).12 Tissue damage from the recipient’s underlying disease, infection, and pretransplant conditioning also plays a key role in induction of the inflammatory response through pro-inflammatory cytokine production and antigen-presenting cell (APC) activation.13,14 Following activation of host APCs, T-cell activation and differentiation drives the response in acute GVHD. This appears to be primarily a Th1-driven process with massive release of interferon-γ, interleukin-2 (IL2), and TNF-α.14 Genetic polymorphisms in tumor necrosis factor (TNF)-α, interleukin-10, interferon-γ, and transforming growth factor (TGF)-β have been linked to increased risk and severity of GVHD.15–17 Although many therapies for acute GVHD target IL-2 or its receptor (CD25), these approaches (calcineurin inhibitors, daclizumab) may have the unintended

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consequence of adversely impacting the CD4+CD25+ regulatory T-cell population.14,18 Decreased T-regulatory cells are associated with severity of acute GVHD and poor response to GVHD treatment.19 The final effector phase of acute GVHD is characterized by cell damage via cytotoxic T-cells, natural killer cells, and soluble inflammatory mediators, including TNF-α, interferon γ, and interleukin-1.14 In comparison to acute GHVD, the pathophysiology of chronic GVHD is less well understood. Features of alloimmunity and autoimmunity and the broad spectrum of disease manifestations implicate multiple immunological pathways beyond T-cell alloreactivity. In fact, in contrast to acute GVHD, T-cell depletion of the graft does not necessarily reduce the incidence of chronic disease.20 Murine models of GVHD have demonstrated both Th1 and Th2 responses, depending on the setting; however, these models typically demonstrate specific aspects of GVHD, but do not recapitulate the full breadth of immunological and clinical abnormalities seen in human disease.21 The role of B-cell function in chronic GVHD has garnered renewed interest following the success of the anti-CD20 antibody rituximab in chronic GVHD.22 Autoantibody formation (e.g., antinuclear antibody, anti-ds DNA antibody) is a frequent finding in chronic GVHD, although the antibodies lack the specificity of typical autoimmune disease. B-cells may play several key roles in facilitating the T-cell response in chronic GVHD. Acting as APCs, B-cells prime T-cells to respond to minor histocompatibility antigens (mHA), and high-titers of antibodies directed against mHA are associated with cGVHD.23,24 Similarly, soluble levels of B-cell activating factor of the TNF family (BAFF), a cytokine which inhibits apoptosis of B-cells and promotes differentiation into plasma cells, correlate with cGVHD activity. 25,26 The mechanisms responsible for chronic GVHDinduced fibrosis in the skin and elsewhere (e.g., bronchiolitis obliterans) remains uncertain. A two-phase model has been proposed in which the innate pathway is activated through toll-like receptors, leading to an alloreactive T-cell response. This is followed by a fibrotic phase driven by platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR), which in turn activates TGF-β.21 TGF-β is a potent profibrotic cytokine, capable of stimulating collagen production, abrogating metalloproteinase activity, and sensitizing fibroblasts to a constitutive-activated state via autocrine signaling.27 Furthermore, stimulatory antibodies directed against PDGFR have been identified by one group in patients with chronic GVHD as well as patients with systemic sclerosis.28,29 This has led to significant interest in imatinib mesylate, a multikinase inhibitor with potent activity against PDGFR signaling (and other receptors), for the treatment of GVHD-related fibrosis.30,31 However, to date, detection of PDGFR antibodies in sclerotic skin disease has not been replicated by other groups,32 and administration of imatinib prior to the onset of GVHD does not appear to eliminate the risk of developing skin sclerosis.33 The mechanism of action of imatinib therefore, remains unclear, and other mechanisms, including T-cell

inhibition34 and inhibition of fibrosis via “nonclassic” pathways downstream of TGF-β, such as cellular Abelson (c-Abl) may be relevant.27

CLINICAL FINDINGS HISTORY Accurate diagnosis of acute GVHD requires clinicopathologic correlation. Because the skin eruption (and histology) may be nonspecific at the time of first presentation, a careful history is invaluable. Key donor/ recipient characteristics include degree of HLA-match, use of related versus unrelated donor, and T-cell depletion of the graft. Reduced-intensity conditioning may delay the onset of acute GVHD symptoms beyond the 100-day period.35 The timing of neutrophil engraftment, new medication exposures, and evidence of other organ involvement (e.g., elevated total bilirubin, diarrhea) provide additional data for clinicopathologic correlation. Features of acute GVHD following recent blood transfusion should raise concern for transfusionassociated GVHD (TA-GVHD). TA-GVHD is an often fatal sequelae of administration of cellular blood products to immunocompromised HCT recipients, and therefore all blood products in these patients are now irradiated. TA-GVHD may also occur following transfusion of unirradiated blood products to children with congenital immunodeficiency, including Wiskott— Aldrich and ataxia-telangiectasia, as well as in the immunocompetent setting. In the latter scenario, the diagnosis may be easily missed. TA-GVHD in the immunocompetent setting follows transfusion of an unirradiated blood product that contains donor lymphocytes that are homozygous for the HLA haplotype of the recipient. A history of blood product transfusion from a relative or genetically similar population is an important feature. For example, in Japan, the estimated risk of randomly receiving blood from a homozygous donor is 1 in 874.36 In this form of TA-GVHD, the donor lymphocytes in the blood product are not recognized as foreign, leading to a GVHD reaction similar to classic acute GVHD. Beginning 10 days after transfusion, fever and skin rash (histologically consistent with GVHD) develops, followed by liver dysfunction and diarrhea. Death from pancytopenia usually occurs within several weeks.37 As with acute disease, a new diagnosis of chronic GVHD is best made based on history, cutaneous examination, and histology. A previous history of acute GVHD is the single greatest risk factor for chronic disease. Because acute symptoms may develop after 100 days posttransplant and chronic symptoms may develop before then, the revised classification of acute and chronic GVHD symptoms includes additional subtypes of GVHD with overlapping features or timing of acute and chronic symptoms (Fig. 28-1).38 Recent tapering of immunosuppressant medication or DLI given to augment the graft-versus-malignancy response are two common triggers of skin activity. DLI, in particular may present with an acute GVHD skin eruption consistent

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Revised classification of acute and chronic GVHD

GVHD manifestation

cGVHD diagnostic feature, or distinctive feature (if bx proven)

aGVHD feature

≤ 100 days post-HCT

Persistent aGVHD

Recurrent aGVHD

Additional aGVHD feature

Delayed aGVHD

No features of aGVHD

Overlap syndrome

Classic cGVHD

CUTANEOUS LESIONS Acute GVHD initially presents with erythematousdusky macules and papules of the volar and plantar surfaces and ears that may rapidly become a diffuse morbilliform exanthema (Fig. 28-2A and 28-2B; Box 28-2). Very early involvement may manifest as erythema limited to hair follicles (Fig. 28-2C). Pruritus is variable and is not useful to distinguish acute GVHD from other causes. Erythroderma may develop, and, in

severe cases, spontaneous bullae with skin sloughing resembling toxic epidermal necrolysis. Widespread erythrodermic involvement, particularly the presence of skin sloughing portends a very poor prognosis. In contrast to chronic disease, postinflammatory pigmentary changes following acute GVHD are uncommon. In appreciation of the tremendous variability in clinical presentation of chronic skin GVHD, it is no longer useful to dichotomize chronic GVHD of the skin into either “lichenoid” or “sclerodermoid” categories. In the transplant community, the term “lichenoid” has been utilized to denote any involvement of the skin in which erythema or scaling is present; however,

Graft-Versus-Host Disease

with acute GVHD rather than the papulosquamous eruption of chronic disease (Fig. 28-2D). Cutaneous or systemic infection may also induce a flare of skin GVHD, as will drug exanthems, which can result in a diagnostic challenge given the clinical and histologic similarities between viral exanthem, drug eruption, and GVHD.39 Important clues to sclerotic and fascial disease includes a history of edema of an extremity, muscle cramping, decreased flexibility, and complaints of skin tightness, particularly at the waistband and brassiere-line.10 Although GVHD in other organ systems may not necessarily flare in synchrony with skin involvement, the presence of other organ system involvement is helpful when the cutaneous features are nondiagnostic. Common GVHD symptoms include oral and ocular sicca and oral pain, particularly with spicy foods. Also common, but less specific, are symptoms of fatigue, poor appetite, and weakness. Dysphagia may indicate the presence of esophageal strictures or webbing. Bronchiolitis obliterans manifests as dry cough, wheezing, and dyspnea, but requires pulmonary function tests and computerized tomography (CT) scans to rule out infection and other etiologies. Finally, it is important to remember that despite the phenotypic variability in chronic GVHD of the skin, not every skin manifestation in a patient after HCT is due to GVHD, so a careful dermatologic history to detect other possible diagnoses is prudent.

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Figure 28-1  Revised classification of acute and chronic GVHD. (Adapted from Filipovich AH et al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11(12):945-956, 2005.)

Chapter 28

Classic aGVHD

> 100 days post-SCT

BOX 28-2  Acute GVHD Organ System Manifestations SKIN

Erythema of palms, soles, ears Perifollicular erythema Generalized exanthem Bullae/necrolysis

GASTROINTESTINAL

Abdominal pain Anorexia Ileus Mucositis Vomiting Secretory diarrhea

LIVER Endothelialitis Pericholangitis Cholestatic hyperbilirubinemia

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A

B

C

D

Figure 28-2  Spectrum of acute graft-versus-host skin manifestations. Acute cutaneous graft-versus-host reaction. Erythematous macules involving the ears (A), palms (B), and soles are characteristic of early cutaneous involvement. C. Follicular graft-versus-host disease. Perifollicular invovlement is an early manifestation of skin involvement. D. GVHDassociated necrolysis. Acute GVHD with bullae formation and skin sloughing following donor leukocyte for relapsed acute lymphoblastic leukemia 10 months following allogeneic HCT.

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“lichenoid” is a histologic pattern, not a clinical one, and, therefore, usage of it is best reserved to pathologic description. Futhermore, although chronic GVHD may resemble lichen planus (Fig. 28-3), other patterns are frequently observed, such as poikiloderma (Fig. 28-4) and skin lesions resembling lupus erythematosus, keratosis pilaris, or psoriasis.40 Postinflammatory hyperpigmentation is common following the resolution of

epidermal involvement, particularly in darkly pigmented individuals, and may persist for many months after the skin disease becomes quiescent. The fibrotic changes of chronic GVHD are also remarkably variable, and the term “sclerodermoid” is an inadequate descriptor of the varied sclerotic tissue abnormalities in the dermis, subcutaneous tissue, and fascia (Fig. 28-5). As in systemic sclerosis, an

4

Figure 28-4  Poikilodermic chronic GVHD. Hypopigmentation, hyperpigmentation, and erythema on the chest and proximal arms.

Chapter 28

Figure 28-3  Lichen planus-like chronic GVHD. Reticulate violaceous plaques with dry scale on the posterior neck and upper back.

:: Graft-Versus-Host Disease

A

C

B

D

Figure 28-5  Clinical spectrum of sclerotic GVHD skin manifestations. A. Guttate white plaques on the upper back resembling lichen sclerosus. B. Morphea-like sclerotic plaques at sites of previous indwelling line placement near the clavicle (isotopic response). C. Diffuse dermal sclerosis resembling scleroderma on the anterior torso with patchy hyperpigmentation. D. Subcutaneous fibrosis of chronic GVHD. There is prominent rippling with a firm nodular texture extending along the medial arm resembing eosinophilic fasciitis. There is associated decreased range of motion at the elbow.

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edematous phase may herald the onset of skin fibrosis, but fingers and toes are usually spared and the typical acral to proximal progression characteristic of systemic sclerosis is not seen in chronic GVHD. In constrast to systemic sclerosis, facial involvement is rarely involved in sclerotic-type GVHD. As mentioned above, fibrosis may occur primarily in the upper dermis, through the full-thickness of dermis, or in the subcutaneous fat and fascia. Early superficial fibrotic involvement resembles lichen sclerosus, often manifesting as porcelain-white atrophic plaques on the upper back (Fig. 28-5A). A common pattern of GVHD-associated fibrosis involves patchy sclerotic plaques with hypo- and hyperpigmentation mimicking morphea. Sclerosis of this type may exhibit an isomorphic response, localizing to the sites of minor skin trauma, particularly the waistband area, or may develop at sites of previous scar formation (Fig. 28-5B).41 Diffuse dermal involvement may result in a “pipe-stem” appearance of the lower extremities with marked reduction in limb volume and overlying shiny hidebound skin with loss of hair resembling scleroderma (Fig. 28-5C). Deeper involvement of the subcutaneous fat results in irregular hyperpigmented sclerotic plaques with intervening areas of edematous skin closely resembling deep morphea/morphea profunda.42 Bullae may develop at sites of fibrosis, particularly on the lower legs, as a result of dermal edema, as has been described in bullous morphea profunda.43 Patchy hyperpigmentation (“leopard spots”) may be visible prior to the diagnosis of dermal sclerotic involvement.44 Primary involvement of the subcutaneous fat and fascia results in a diffuse firm, rippled pattern to the skin resembling eosinophilic fasciitis (Fig. 28-5D).45 Features of overlying epidermal GVHD involvement and pigmentary changes may be absent. Fascial involvement is often most visible on the medial arms and thighs and be accentuated by abduction and supination of the arm. Prominent “grooving” demarcating fascial bundles and along the path of superficial vessels may be observed. Careful palpation of the skin is helpful in detecting deep-seated irregularities in skin texture and differentiation from cellulite. Dermal fibriosis or fascial involvement without overlying dermal thickening may lead to progressive loss of joint range of motion and contracture formation. Nail involvement in chronic GVHD typically results in longitudinal ridging and thin, easily broken nails. Partial or complete anonychia and dorsal pterygium formation may occur. Other unusual skin sequelae of chronic GVHD include milia formation, porokeratosis, often on the buttock area,46 angioma formation at sites of skin sclerosis,47 nipple hyperkeratosis,48 vitiligo,49 and alopecia, either diffuse or focal areas of alopecia areata.50 Different manifestations of sclerotic and and nonsclerotic skin disease may be present in the same individual, making accurate quantification of disease activity challenging. The chronic GVHD NIH Consensus Development Project provided more precise terminology for organ system involvement and defined features specific for diagnosis of chronic GVHD in the setting of HCT (Box 28-3). Diagnostic cutaneous features of GVHD include poikiloderma, lichen-planuslike lesions, and sclerotic skin changes.38

RELATED PHYSICAL FINDINGS Acute GVHD is primarily a disorder of the skin, GI tract, and liver (Box 28-2), typically presenting with skin rash, new onset elevation of total bilirubin, and/ or voluminous diarrhea. By contrast, chronic GVHD is remarkably diverse in its breadth of organ system manifestations (Box 28-3). The most frequently affected sites are skin and nails, oral mucosa, eyes, liver, lungs, and marrow (usually thrombocytopenia).5 Esophageal webs/strictures, vagino-vulvar disease, myositis, nephrotic syndrome, and pericarditis are less frequent sequelae of chronic disease. Mucosal disease is second only to skin involvement in frequency in chronic GVHD. Mucoceles are common, as are erosions, lichen-planus-like changes with Wickham’s striae, and sicca symptoms. Dryness and violaceous erythema of the lips are common. Genital involvement significantly impairs sexual function and quality of life and may be overlooked if a specific examination and directed questions regarding genital symptoms are not undertaken. Involvement of the penis may induce phimosis. Vulvo-vaginal involvement presents as erythema, erosions/fissures, vestibulitis, vaginal stenosis, labial resorption, or complete agglutination of the introitus leading to hematocolpos (Fig. 28-6).51

Figure 28-6  Severe chronic GVHD of the vulva. The labia minora are partially resorbed with residual vulvitis and atrophic mucosa. Surrounding reticulate hyperpigmentation of the nonmucosal skin is consistent with postinflammatory changes of chronic GVHD.

BOX 28-3  Signs and Symptoms of Chronic GVHD Based on NIH Consensus Criteria

:: Graft-Versus-Host Disease

OTHER ORGAN SYSTEM INVOLVEMENT Cardiovascular Pericardial effusion Cardiac conduction abnormality Cardiomyopathy Ophthalmologic Blepharitis Cicatricial conjunctivitis Confluent punctuate keratopathy Keratoconjunctivitis sicca Photophobia Gastrointestinal Esophageal weba Esophageal stricture/stenosisa Exocrine pancreatic insufficiency Hematopoeitic Eosinophilia Hypo-/hypergammaglobulinemia Lymphopenia Thrombocytopenia Hepatic Elevated total bilirubin Elevated alkaline phosphatase Elevated transaminases Musculoskeletal Arthralgia Arthritis Edema Myalgia Myositis/polymyositis Neurologic Peripheral neuropathy Pulmonary Bronchiolitis obliterans +/− organizing pneumoniaa Pleural effusion Renal Nephrotic syndrome Rheumatologic Autoantibodies Myasthenia gravis

Chapter 28

SKIN AND MUCOSAL INVOLVEMENT Skin Alopecia Angiomatous papules Bullae Erythema Hypo- or hyperpigmentation Ichthyosis-like Keratosis-pilaris-like Lichen planus-likea Lichen sclerosus-likea Maculopapular Morphea-likea Poikilodermaa Scleroderma-likea Sweat impairment Ulceration Nails Brittleness Longitudinal ridging or splitting Onycholysis Pterygium unguis Subcutaneous tissue Fasciitisa Panniculitis Oral mucosa Erythema Gingivitis Hyperkeratotic plaquesa Lichen planus-likea Mucocele Mucosal atrophy Mucositis Pseudomembrane Restriction of oral opening from sclerosisa Ulcer Xerostomia Genital mucosa Lichen planus-likea Vulvar erosions/fissures Vaginal scarring/stenosisa

4

a

Diagnostic features of cGVHD based on NIH Consensus Criteria. Other signs and symptoms listed are not considered sufficient to establish a diagnosis of chronic GVHD without further testing or evidence of other organ system involvement. The most common GVHD manifestations are shown in bold. Adapted from Filipovich AH et al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graftversus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11(12):945-956, 2005.

HISTOPATHOLOGY. The histological grading scale for acute GVHD is shown in Table 28-1. The hallmark feature of acute GVHD is the presence of necrotic keratinocytes accompanied by a dermal lymphocytic infiltrate (usually sparse) and basal vacu-

olar alteration (Fig. 28-7). Early GVHD involvement with follicular erythema correlates with involvement limited to the hair follicle. Subepidermal cleft formation (Grade III) is indicative of more severe involvement, whereas complete separation of epidermis

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TABLE 28-1

Histologic Grading of Acute GVHD Histologic Grading Scheme for Acute Cutaneous Graft-Versus-Host Reaction

Section 4 ::

Grade

Description

0

Normal skin or changes not referable to graftversus-host disease

1

Basal vacuolization of the dermalepidermal junction

2

Basal vacuolization, necrotic epidermal cells, lymphocytes in the dermis and/or epidermis

3

Subepidermal cleft formation plus grade 2 changes

4

Separation of epidermis from dermis plus grade 2 changes

Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

Adapted from Lerner KG et al: Histopathology of graft-versus-host reaction (GVHR) in human recipients of marrow from HLA-matched sibling donors. Transplantation 18:367, 1974.

from dermis (Grade IV) correlates with clinical findings resembling toxic epidermal necrolysis. Grade IV involvement may be impossible to differentiate histologically from drug-induced toxic epidermal necrolysis and requires careful clinical correlation. The presence of eosinophils has been used in the past to argue against a diagnosis of GVHD; however, the presence of scattered eosinophils may lead to a false diagnosis of drug eruption52 and, unless very large numbers of eosinophils are present, this feature cannot be used as a reliable indicator of a drug hypersensitivity reaction.53 Engraftment syndrome is a poorly understood phenomenon at the time of neutrophil engraftment following autologous-HCT or allo-HCT characterized by a nonspecific erythematous skin eruption, fever, and pulmonary edema.54 Histologi-

A

324

Figure 28-7  Histopathologic features of acute cutaneous graft-versus-host disease, Grade II. Inflammation of the upper dermis is present, with extension of lymphocytes into the dermis and interface change. cally, it may not be possible to distinguish engraftment rash from early (Grade I) acute GVHD. Epidermal changes in chronic GVHD may be indistinguishable from those of acute disease (Fig. 28-8A). Acanthosis and wedge-shaped hypergranulosis may be seen. Sclerotic involvement of the upper dermis may resemble lichen sclerosus, with atrophy, hyperkeratosis, follicular plugging, and pale, homogenized appearance of the upper dermis collagen (Fig. 28-8B).45 If epidermal changes of GVHD are not present, dermal fibrosis with thickened collagen bundles and loss of periadnexal fat involvement may be indistinguishable from morphea/scleroderma. Subcutaneous and fascial involvement accordingly demonstrates changes in the fat septae and fascia, including thickening, edema, and fibrosis. Variable lymphocytes, histiocytes, and eosinophils may be seen.45 Histology of involvement of the oral mucosa reflects similar interface changes as those seen in epidermal GVHD, but without associated acanthosis.55 Lymphocytic infiltration of the salivary glands resembles changes seen in Sjögren’s syndrome.

B

Figure 28-8  Histologic features of epidermal and sclerotic-type chronic cutaneous graft-versus-host disase. A. Histopathologic features of a lichen planus-like reaction. Acanthosis, hypergranulosis, hyperkeratosis, and pointed rete ridges are present. The inflammatory infiltrate is less dense than that usually seen in idiopathic lichen planus. B. Sclerotic-type GVHD. There is mild, compact hyperkeratosis or the epidermis with keratin plugging. There is hyalinization of the collagen throughout the dermis with loss of appendegeal structures.

LABORATORY TESTS

4

Suspicion of subcutaneous sclerotic and fascial disease and myositis may be confirmed by magnetic resonance imaging, particularly in cases in which definitive sclerotic changes are not observed or when a fascial or muscle biopsy is deferred.45,59,60

DIFFERENTIAL DIAGNOSIS See Box 28-4.

COMPLICATIONS

:: Graft-Versus-Host Disease

Skin erosions and ulceration due to chronic GVHD may lead to secondary infection. Sclerotic changes resulting in restriction in joint function lead to functional disability and joint contractures. Restrictive lung disease may result from sclerotic involvement of the torso. HCT survivors are at increased risk for melanoma61 and nonmelanoma62 skin cancer due to previous exposure to ionizing radiation, GVHD-associated immunodysregulation, and immunosuppressive treatment for GVHD. The risk of cutanous squamous cell carcinoma (SCC) may also be increased by long-term treatment with voriconazole, a potent photosensitizer, which may be employed for antifungal treatment or prophylaxis.63 Multiple SCC have also been reported after PUVA for GVHD.64

Chapter 28

Diagnosis of acute GVHD skin involvement is based on histopathologic correlation, particularly exclusion of drugs and infectious causes. The presence of a normal leukocyte count is indicative of engraftment but no specific laboratory testing is diagnostic. Liver function testing and total bilirubin levels and quantification of diarrhea volume are used in conjunction with skin disease to stage the disease (Table 28-2). Although autoimmune markers are seen in the majority of patients after alloHCT, their presence is generally not specific for the development of chronic GVHD manifestations, with the possible exception of sclerotic disease. In one study, elevated ANA titer was detected in 70% of patients with limited chronic disease and 94% of patients with extensive chronic disease compared to 23.5% of patients who did not develop chronic GVHD.56 The presence of more than one autantibody also correlated with risk of extensive disease (p = 0.04); however, ANA titer does not correlate with disease severity. In this study, the presence of a nucleolar ANA pattern also indicated a potential association with sclerotic disease (p = 0.06).56 In another multivariate analysis limited to sclerotic-type chronic GVHD patients, the presence of autoantibodies and serum eosinophilia were both associated with increased risk of sclerotic-type chronic GVHD.9 Identifying specific biomarkers of disease activity is an area of research emphasis in acute and chronic GVHD.57 Plasma levels of elafin, a protease secreted in response to IL-1 and TNF-α, was recently identified as a candidate marker capable or differentiating acute GVHD skin from rashes of other etiologies. In this study, immunohistochemical staining of skin biopsies for elafin also discriminated acute GVHD from drug exanthem, suggesting a potential diagnostic application of this biomarker.58

SPECIAL TESTS (INCLUDING IMAGING STUDIES)

PROGNOSIS/CLINICAL COURSE Although the presence of GVHD is associated with decreased risk of malignancy relapse, GVHD is also a cause of significant morbidity and mortality, particularly

TABLE 28-2

Staging and Grading of Acute GVHD Clinical and Laboratory Manifestations Stage

Skin

Liver

Gut

1

Rash 1,500 mL/day

4

Erythroderma w/bullae formation

Bilirubin >15 mg/dL

Severe abdominal pain with or without ileus

I

Stages 1–2

None

None

II

Stage 3

Stage 1

Stage 1

Stages 2–3

Stages 2–4

Grade

III IV

Stage 4

Stage 4

Adapted from Przepiorka D et al: 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 15(6):825-828, 1995.

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BOX 28-4  Differential Diagnosis of Graft-versus-Host Disease

BOX 28-5  Systemic Treatment of Acute Cutaneous GVHD

Acute GVHD

FIRST LINE Corticosteroids (IV methylprednisone 2 mg/kg/ day)112,113 Tacrolimus (usually on prophylactic treatment)114 Cyclosporine (usually on prophylactic treatment)115

Drug eruption Rash of engraftment syndrome Transient acantholytic dermatosis Toxic epidermal necrolysis (for Stage IV disease) Viral exanthem Chronic GVHD

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Epidermal involvement Drug eruption Lichen planus Pityriasis lichenoides chronica Psoriasis Sclerotic involvement Eosinophilic fasciitis Lichen sclerosus Morphea Nephrogenic systemic fibrosis Radiation dermatitis Systemic sclerosis

in patients who develop refractory disease. A number of systemic risk factors portend a poor prognosis, including a history of progressive involvement from acute to chronic GVHD,65 thrombocytopenia (fewer than 100,000 cells/mL),66 elevated bilirubin,67 older age, gastrointestinal symptoms, and lack of response to therapy at 6 months.68 The two primary dermatologic features associated with poor prognosis are extensive (>50%) skin involvement69 and “lichenoid” skin histology.65

TREATMENT MANAGEMENT OF ACUTE GVHD Treatment of acute GVHD is usually undertaken in the hospital, given the proximity to the date of HCT and the need for close observation. Patients with mild (Grade I) skin involvement without hepatic or gastrointestinal symptoms may respond to high-potency topical steroids. However, more severe skin involvement or the presence of internal organ involvement necessitates treatment with systemic corticosteroids (methylprednisone 2 mg/kDa/day). Patients with skin sloughing require meticulous skin care, infection surveillance, and fluid management similar to toxic epidermal necrolysis. Approximately 50% of patients respond to systemic corticosteroids—however, those who require salvage therapy typically receive one or more immunosuppressive agents, including calcineurin inhibitors (tacrolimus, cyclosporine), mycophenolate mofetil, and sirolimus, which are of variable success (Box 28-5).70 Phototherapy (PUVA,71 NB-UVB,72

SECOND LINE

Mycophenolate mofetil116,117 Etanercept74,118 Infliximab119,120 Denileukin diftitox121 Pentostatin122 Antithymocyte globulin123,124

OTHER SALVAGE THERAPY

Extracorporeal photopheresis125,126 Alefacept127 Mesenchymal stem cell therapy76,77 Anti-CD25 antibodies Daclizumab128 Inolimomab129 Baxiliximab130,131 ABX-CBL (anti-CD147)132 Anti-CD3 (visilizumab)133 Anti-CD52 (alemtuzumab)134,135 Psoralen plus UVA (PUVA)71,136 Narrowband-UVB72 Ultraviolet A1 (340–400 nm)73

UVA173) has also been used in small series for acute GVHD, but is logistically challenging in the inpatient setting and should be administered cautiously to avoid inducing erythema. Extracorporeal photopheresis (ECP), anti-TNF–α therapy, and multipotent mesenchymal stromal cells (MSC) are additional strategies that have shown recent success for the treatment of acute skin GVHD. In a review of salvage therapies for acute GVHD, 60%– 76% of patients with skin involvement responded to ECP; however, responses decreased with increasing skin severity.70 Levine et al74 demonstrated complete remission (CR) of skin symptoms in 81% of patients treated with steroids and etanercept compared to steroids alone (CR = 47%). Similarly, infliximab has also shown variable success in acute treatment-refractory skin GVHD (33%–60%).70 Finally, preliminary reports of the success of MSC, bone marrow-fibroblast derived cells capable of differentiation into adipocytes, chondrocytes, and osteoblasts, in patients with refractory acute GVHD has generated significant interest in this novel therapy.75–77 In a 2008 study, 39/55 (71%) of participants with steroid-resistant acute GVHD sustained a complete or partial response to MSC infusion.77 Responses were seen regardless of MSC source (HLAmatched, haploidentical, or third party unmatched

donors), and immunogenicity was not observed. The immunomodulatory mechanism of MSC is unclear, but may be through induction of regulatory T-cells.78,79 Several MSC studies are underway for the treatment or prophylaxis of acute and chronic GVHD as well as for other chronic conditions, including Crohn’s disease, multiple sclerosis, systemic sclerosis, and lupus erythematosus.

MANAGEMENT OF CHRONIC GVHD

TABLE 28-3

Systemic Treatment of Chronic Cutaneous GVHD Type of Chronic Skin Involvement Treatment First line  Prednisone PO 1 mg/ kg/day   Tacrolimus   Cyclosporine

Sc137

Ns137

Sc138 Not specified139

Ns138

Sc100,140

Ns100,140

Nsa141 Sc117

Ns117

Sc142 Sc143,144

Ns142 Ns143,144

Sc22,145 Scb89 Sc91 Ns90 Sc97,98

Ns22,145 Nsb89 Ns91

Not specified146 Sc147 Sc30,31 Sc44 Sc149 Not specified118,150 Sc104 Sc107 Not specified151,152 Not specified153 Sc154

Ns98

Graft-Versus-Host Disease

Other   Daclizumab   Methotrexate   Imatinib mesylate   Azathioprine   Clofazamine   Etanercept   Etretinate  Mesenchymal stem cells   Thalidomide   Alefacept  Total lymphoid irradiation

Nonsclerotic

::

Second line  Extracorporeal photopheresis   Hydroxychloroquine  Mycophenolate mofetil   Pentostatin  Rapamycin (sirolimus)   Rituximab   PUVA   UVB   NBUVB   UVA1

Sclerotic Features

Chapter 28

Among the myriad topical, phototherapy-based, and systemic treatments that have been used in patients with chronic GVHD who cannot be tapered from systemic corticosteroids or who are steroid-refractory, no single treatment has demonstrated proven superiority (Table 28-3). Determination of a preferred second-line agent has been complicated by poor understanding of the disease process and a lack of high-quality clinical trials. The need to spur clinical trial development in the field of chronic GVHD was acknowledged by the chronic GVHD NIH Consensus Project, which included a standardized system of organ system assessments and recommendations for clinical trial design80 Unfortunately, validated measures of cutaneous disease activity are still lacking, and the most common skin assessments tools, body surface estimates and use of Rodnan scoring (derived from systemic sclerosis trials) are not applicable for all manifestations of chronic GVHD skin activity.81 Ideally, dermatologic collaboration in future therapeutic trials will permit better quantification of cutaneous disease response. The dermatologist should play a key role in the multidisciplinary approach to chronic GVHD management, beginning with careful assessment of the subtype and extent of skin involvement. Together with an understanding of other organ system activity, infection risk, relapse risk, and GVHD prognostic risk factors, a decision regarding the appropriateness of topical, physical (e.g., phototherapy), and systemic therapy can then be made. If systemic therapy is prescribed by the transplant physician, periodic dermatologic monitoring is advised to differentiate adverse drug reactions or other new skin disease from GVHD,82 to assess cutaneous disease response, and to monitor for infection and skin malignancy. Nonsclerotic lichen-planus like and other papulosquamous chronic GVHD manifestations may respond well to topical steroid treatment and serve to reduce exposure to systemic immunosuppression.83 Topical emollients and antipruritic agents may provide relief of pruritus and skin irritation; however, oral antihistamines may worsen sicca symptoms in patients with oral and ocular dryness. Choi and Nghiem84 described a response to topical tacrolimus 0.1% ointment in 13/18 patients with chronic GVHD; however, all patients eventually required other therapy to control their skin disease. Subsequent reports have also described response to topical pimecrolimus 1% cream.85,86 Topical calcineurin inhibitors are particularly useful for treatment of areas at high risk of skin atrophy, such as the face (including the lips) and intertriginous surfaces.

4

Ns147,148

Ns149

Ns154

Sc: sclerotic skin disease; Ns: Nonsclerotic skin disease. a Sclerotic and nonsclerotic disease treated in this study; however, sclerotic disease did not respond. b Bath-PUVA.

Topical tacrolimus may not be tolerable at sites of significant inflammation or erosions. Hydroquinone in combination with tretinoin and topical dexamethasone has anecdotally been reported to improved periocular lichenoid type chronic GVHD and hyperpigmentation.87 Topical tretinoin may also benefit milia formation following GVHD skin activity. Phototherapy may be of benefit for both sclerotic and nonsclerotic chronic GVHD, but data are limited to anecdotal cases and a small number of noncontrolled case series. Vogelsang88 described improvement in 31/40 patients treated with PUVA.88 Three patients in this series had skin sclerosis—two demonstrated

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transient benefit, but developed severe phototoxicity, and the third did not respond to treatment. Smaller series with PUVA-bath (6 patients),89 narrow-band UVB (10 patients, pediatric),90 and UVB (5 patients),91 have also described chronic GHVD responses, primarily in patients with “lichenoid” disease. Over the last several years, however, there has been growing experience with UVA1 for sclerotic skin conditions, suggesting potential application in chronic GVHD. Longer wavelength UVA1 (340–400 nm) does not require psoralen ingestion/topical application and penetrates deeper into the dermis than full spectrum UVA. Several reports have described skin softening following UVA1 treatment of lichen sclerosus,92 localized morphea,93–95 and sclerotic-type GVHD.73,96–98 Wetzig et al73 used medium-dose UVA-1 phototherapy in seven patients with lichenoid GVHD and three with sclerotic GVHD. All three patients with sclerotic GVHD demonstrated partial response or improvement. Ständer et al97 described softening of skin lesions, improved joint mobility, and healing of skin erosions in five adult patients with medium-dose UVA-1 and one child treated with low-dose UVA-1. Calzavara Pinton et al98 described five patients with sclerotic involvement treated with MD UVA-1 therapy leading to complete resolution in three patients and partial response in two patients. UVA-1 may accentuate pigmentary abnormalities.99 Although UVA-1 is not yet widely available in the Unites States, it appears to be well tolerated, acceptable for pediatric use,96 and is not associated with persistent photosensitivity or potential gastrointestinal issues that may occur with oral psoralen use. Phototherapy may be appropriate for patients with limited epidermal or sclerotic disease in whom systemic therapy is not otherwise warranted (e.g., without internal organ system involvement), or in whom systemic immunosuppressive therapy is contraindicated (e.g., active infection); however further controlled trials are needed to directly compare phototherapy modalites and to determine the optimum dose and treatment schedule. Skin cancer risk assessment and concurrent use of photosensitizing medications should also be considered. Multiple squamous cell carcinomas have been reported following PUVA treatment for chronic GVHD 64 and the risk of melanoma is elevated in patients following HSCT.61 Photosensitizing medication use is common, including voriconazole therapy, which may further increase the risk of squamous cell carcinoma formation in the setting of chronic GVHD.63 Extracorporeal photopheresis (ECP) is another option for patients with cutaneous disease, particularly patients with extensive or sclerotic involvement. During ECP, the white cell compartment of the blood is removed from the patient via pheresis, mixed with 8-methyoxypsoralen, irradiated with UVA light, and then returned to the patient. In a retrospective review of 71 chronic GVHD patients who were treated with ECP, 59% of patients with cutaneous involvement responded, including 67% of those patients categorized as sclerotic involvement.100 ECP may be particularly useful for patients with deep-seated sclerotic involvement of the subcutaneous tissue and fascia.

Although GVHD-related fasciitis resembles eosinophilic fasciitis (EF), in contrast to EF, it does not respond well to steroid therapy and may result in significant long-term functional disability. Several case reports describe successful use of ECP for EF,101 and GVHD-related fasciitis.41,102,103 ECP is a time-consuming procedure and requires a dedicated pheresis center which is not available at all medical facilities. As with phototherapy, the optimal frequency and duration of ECP treatment is unclear. Typically, intensive treatment (2× weekly or every other week) is initiated, followed by an attempt to decrease frequency if a response is achieved. Limited data are available supporting the use of systemic retinoids for chronic GVHD. Marcellus et al104 reported improvement in 20/27 evaluable patients with sclerotic disease treated with etretinate; however, six patients could not tolerate the treatment due to scaling or skin breakdown. Ghoreschi et al105 described PUVA-bath treatment in 14 patients with sclerotic-type GVHD, five of whom received concurrent treatment with isotretinoin 10–20 mg/daily. Overall improvement was reported in 7/14 patients; however, skin ulceration was a significant issue in both PUVA-bath only and combination treatment groups, and the small sample size precluded statistical comparison between groups.105 Further prospective studies are needed to determine the tolerability and efficacy of systemic retinoid therapy. Imatinib mesylate, a multikinase inhibitor with activity against bc-abl, c-kit, PDGFR, and other kinases, has been reported to benefit patients with sclerotic GVHD in a small number of case reports.30,31,106 The drug is generally well tolerated in the setting of treatment for chronic myelogenous leukemia; however, the tolerability and efficacy of the drug in chronic GVHD is an area of ongoing clinical trial investigation. Common side effects include peripheral and periorbital edema, myalgia, and fatigue. Second generation agents with similar targeted tyrosine kinase inhibitory activity (nilotinib, dasatinib) also hold potential as therapeutic options for sclerotic disease, as does the use of MSC, based on the experience with acute GVHD. Recently, a single case of sclerotic-type GVHD was reported with a response to MSC therapy.107

TREATMENT OF CHRONIC ORAL AND VULVO-VAGINAL DISEASE Limited oral mucosal disease can be controlled with application of high-potency topical corticosteroid gel (fluocinonide gel 0.05%, clobestasol gel 0.05%). Refractory lesions may respond to intralesional triamcinolone injection (0.3–0.4 mL/L cm2).83 Topical application of tacrolimus 0.1% ointment may also be used;108 however, systemic absorption has been reported109 and, therefore, serum tacrolimus levels are reasonable following initiation of intra-oral treatment. Generalized oral disease can significantly impair oral intake and quality of life and often result in the need for systemic intervention. Corticosteroid rinses (dexamethasone 0.5 mg/mL; prednisolone 15 mg/mL) are beneficial

Full reference list available at www.DIGM8.com DVD contains references and additional content

PREVENTION GVHD prevention begins prior to transplantation with the selection of the most closely HLA-matched donor, the GVHD prophylaxis regimen and, in some cases, manipulation of the T-cell content of the graft. T-cell depletion is accomplished through ex vivo T-cell negative selection or enrichment of the CD34+ stem cell population, or through in vivo treatment with anti-T-cell therapy. The benefits of T-cell depletion, however, are offset by higher rates of graft failure, cancer relapse, and infection.14 Prophylactic immunosuppressive therapy is initiated concomitantly with the administration of the hematopoietic graft, but, as with T-cell depletion, such therapy must be balanced with potential for diminished graft-versus-leukemia/ lymphoma effect and long-term infection risks. In general, available strategies for the prevention of acute GVHD are rarely effective in the prevention of chronic GVHD, emphasizing the distinct pathophysiology of these two GVHD manifestations. Ideally, personalized

14. Ferrara JLM et al: Graft-versus-host disease. The Lancet 373(9674):1550-1561, 2009 38. Filipovich AH et al: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 11(12):945-956, 2005 40. Hymes SR et al: Cutaneous manifestations of chronic graft-versus-host disease. Biol Blood Marrow Transplant 12(11):1101-1113, 2006 45. Schaffer JV et al: Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: Expanding the sclerodermoid spectrum. J Am Acad Dermato 53(4):591-601, 2005 80. Pavletic SZ et al: Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplan 12(3):252-266, 2006 83. Couriel D et al: Ancillary therapy and supportive care of chronic graft-versus-host disease: National institutes of health consensus development project on criteria for clinical trials in chronic Graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 12(4):375-396, 2006

Graft-Versus-Host Disease

KEY REFERENCES

4

::

immunogenomics will evolve to allow careful titration of T-cell graft content and prophylactic immunosuppression to maximize graft acceptance and graft-versus-leukemia effect and at the same time minimize infection risk and other complications associated with long-term immunosuppression. Similar to solid-organ transplantation, skin cancer screening and patient education regarding photoprotective measures is a key preventive strategy in patients with chronic GVHD.83 Patients are also at elevated risk of systemic infection, and therefore, implementation of preventive infectious disease recommendations and careful monitoring for cutaneous infection, particularly in patients with chronic skin erosions/ulcerations, is prudent.83 Finally, patient education regarding early signs of skin sclerosis and fascial involvement, including skin tightness, edema, muscle cramping, and range of motion restriction, may facilitate early diagnosis and initiation of treatment.

Chapter 28

for widespread involvement and should be swished in the mouth 4–6 minutes 4–6 times daily.83 Cyclosporine and azathioprine rinses may also be used for refractory disease, but require pharmacy compounding. As mentioned above, patients with salivary gland disease should avoid oral antihistamines as well as other xerogenic medications (SSRIs, tricyclic antidepressants). Dental hygiene is very important in patients with decreased salivary function and home fluoride treatment is frequently recommended. Salivary stimulants (e.g., sugar-free gum) and sialogogue therapy (cevimeline, pilocarpine) are recommended for patients with severe salivary gland dysfunction.83 Although sclerotic involvement of perioral skin involvement is uncommon, in this setting aggressive systemic therapy is indicated. Genital erosions and fissures associated with chronic vulvo-vaginal disease may be treated with clobetastol proprionate ointment nightly, which should be tapered to a maintenance level of 2–3 times weekly. If estrogen is not contraindicated, hormone replacement via topical cream, vaginal ring, or oral replacement may improve genital skin integrity. Limited vaginal scarring/synechiae can be treated with dilators or manual lysing; however, thick vaginal scarring may require surgical intervention.110

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Chapter 29 :: S  kin Disease in Acute and Chronic Immunosuppression :: Benjamin D. Ehst & Andrew Blauvelt SKIN DISEASE IN ACUTE AND CHRONIC IMMUNOSUPPRESSION AT A GLANCE

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Skin manifestations in patients who have hematologic malignancies, have undergone bone marrow transplantation, or are immunosuppressed by drugs are common and varied. Many of these skin diseases occur in immunocompetent individuals as well. In patients with acute immunosuppression, infections occur that are normally controlled by neutrophils and macrophages. In patients who have long-term immunosuppression, T-cell function is impaired and skin diseases are often similar to those seen in patients with human immunodeficiency virus infection. Salient dermatologic features particularly associated with immunosuppression are important diagnostic signs and indicators for therapy.

Impairment of the body’s immune system results from a variety of causes, including natural aging, ultraviolet radiation, diabetes, malnutrition, cancer, and iatrogenic suppression. While few skin conditions appear solely in immunocompromised individuals, clinical presentations may be morphologically atypical, follow unusual clinical courses, or prove harder to treat than in individuals with intact immunity. This chapter focuses on dermatologic manifestations in immunosuppressed patients without human immunodeficiency virus (HIV) disease, predominantly in those with immunosuppression induced by drugs, conditions surrounding solid organ and bone marrow transplantation, and hematologic malignancy. Skin manifestations of HIV disease are described in Chapter 198. Other chapters cover graft-versus-host disease (see Chapter 28), skin signs associated with primary immunodeficiency disorders (see Chapter 143), and detailed side effects of medications, including corticosteroids, cancer chemotherapeutic agents, immunosuppressants, and cytokines (see Chapters 224, 227, 233, and 234). The salient clinical features particularly associated with immunosuppression are emphasized here. While a variety of inflammatory skin diseases and paraneoplastic processes occur in the setting of

immunosuppression, infections, and malignancy are most commonly seen and are discussed herein. When approaching an immunocompromised patient, it is helpful to determine the time frame of the immune loss as well as the specific immune defect. This chapter is divided into two major subsections based on this concept: acute immunosuppression and chronic immunosuppression. When patients are acutely immunosuppressed, usually from iatrogenic ablation of the immune system or from acute leukemia, infections occur that are normally controlled by innate immunity, which typically involve neutrophils and macrophages. In chronically immunosuppressed individuals, such as organ transplant patients and those taking corticosteroids on a long-term basis, T-cell function is impaired, and diseases will often be similar to those observed in HIV disease. Thus, it is helpful to understand the underlying immune defects associated with the medical conditions of each patient (Table 29-1), because it helps to focus the history taking and physical examination toward skin manifestations of specific pathogens. In ill-immunosuppressed patients, disease often manifests in the skin. Appropriate evaluation and diagnosis of skin lesions are critical to the overall health of these individuals, because the skin is often a window to more severe systemic illness. In particular, unusual presentations of infection with typical pathogens and infections with rare opportunistic pathogens are common in these patients. Diagnosis is also made more difficult by the variety of organisms that share similar morphologies and the wide variety of morphologic presentations of a single organism (Table 29-2). This makes prompt clinical evaluation and extensive use of skin biopsy and culture necessary to make an accurate diagnosis and initiate prompt treatment to obviate significant morbidity and mortality.

ACUTE IMMUNOSUPPRESSION The prototype of an acutely immunosuppressed patient needing dermatologic evaluation is the neutropenic patient undergoing chemotherapy around the time of hematopoietic transplantation. Pancytopenia and neutropenia in particular predispose to invasive infections caused by gram-negative and -positive bacteria and the fungal organisms Candida and Aspergillus.1 These complications from many cancer therapies often pose a more immediate threat to survival than the malignancy itself. In the past two decades, overall mortality due to infection among patients undergoing hematopoietic transplantation has decreased significantly with the use of better prophylaxis and nonmyeloablative regimens, but still represents an ongoing risk to survival. The causes of infection-related death

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TABLE 29-1

Opportunistic Infections that are Commonly Associated with Specific Underlying Immune Defects Common Bacterial Pathogens

Common Viral Pathogens

Common Fungal Pathogens

Defective cellmediated immunity

Organ transplantation, metastatic cancer, Hodgkin disease, glucocorticoid, or cyclosporine therapy

Listeria, Salmonella, Nocardia, Mycobacterium aviumintracellulare, M. tuberculosis, Legionella

Cytomegalovirus, herpes simplex virus, varicella zoster virus

Candida, Cryptococcus, Histoplasma, Coccidioides

Defective humoral immunity

Multiple myeloma, chronic lymphocytic leukemia

Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis

Enteroviruses

—

Neutropenia

Cancer chemotherapy, acute leukemia, adverse drug reaction

Aerobic Gram-negative bacteria; Staphylococcus aureus, Streptococcus viridans, Staphylococcus epidermidis

Herpes simplex virus

Candida, Aspergillus

Defective neutrophil function

Chronic granulomatous disease, myeloperoxidase deficiency

Catalase-positive bacteria: S. aureus, Escherichia coli

—

Candida

Hyposplenism

Splenectomy, hemolytic anemia

S. aureus, Streptococcus

—

Candida

Defective complement components

Congenital or acquired deficiencies

S. pneumoniae (C2, C3, C5 alternate), H. influenzae (C2, C3, alternate), S. aureus (C5), Enterobacteriaceae (C5), Salmonella(alternate), N. meningitidis (C6–C8)

—

—

Skin barrier disruption

Intravascular catheters, decubitus ulcers, burns

Staphylococcus, M. fortuitum, Gram-negative bacteria, anaerobes

—

Candida, Aspergillus, Mucor

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Usual Conditions

Cutaneous Morphologies and Associated Organisms in Immunosuppressiona

Bacteria   Pseudomonas aeruginosa   Streptococcus viridians   Staphylococcus sp.   Aeromonas hydrophilia   Nocardia spp.   Vibrio vulnificus Fungi   Aspergillus sp.   Zygomycetes organisms   Fusarium sp.   Cryptococcus neoformans   Histoplasma capsulatum   Coccidioides immitis Viruses   Herpes simplex virus   Varicella zoster virus   Cytomegalovirus a

Ecthymatous Lesions

Morbilliform Eruption

X X X

X X X

Vesicles

Erythemas (Cellulitic Patches and Plaques)

Ulcers

Skin Disease in Acute and Chronic Immunosuppression

TABLE 29-2

Organism

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Immune Defect

X X X

X (facial)

X X

X

X (facial)

X (necrotic) X (necrotic)

X X

X X (mucosal)

X X

X X X (mucosal)

X (hemorrhagic)

X X X

Each organism has a wide variety of presentations, and not all are included in this table.

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have remained relatively stable, with death due to bacterial infections being the most common (36%), followed by deaths due to infection by viruses (31%), fungi (28%), and parasites (5%).2,3 Infections in the acute period following solid organ transplantation are less opportunistic and tend to reflect the usual nosocomial pathogens associated with surgical procedures and hospitalization.4

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Bacteria are responsible for most infections during acute neutropenic episodes. Empiric antimicrobial therapy for fever and neutropenia was first introduced in the 1970s when 60%–70% of infections were due to Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Klebsiella species. Dramatic shifts have occurred since that time, such that over 50% of bacterial infections in cancer patients are now caused by Gram-positive organisms, and 75%–80% in patients that are bacteremic.5,6 The use of indwelling intravascular catheters, medications predisposing to mucositis, and prophylactic fluoroquinolones are all thought to play a role in the shift to Gram-positive organisms, such as coagulase-negative staphylococci, Staphylococcus aureus, Enterococcus species, and viridians group streptococci.7 The emergence of drug-resistant organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, as well as polymicrobial infections also complicates the situation.6 Routine cellulitis from staphylococcal and streptococcal organisms is a common manifestation of skin infection in the acutely immunocompromised host. Muted clinical signs and symptoms can be found in this population, so care must be taken to rule out deeper involvement as occurs in necrotizing fasciitis.8 Bacteremia may result from skin and soft-tissue infections such as folliculitis, furuncles, and wound infections. Bone marrow transplant patients and other patients with neutropenia are prone to streptococcal bacteremia and may develop facial flushing, a widespread erythematous, petechial or purpuric eruption of macules and papules, and desquamation of the palms and soles.9 Staphylococcal scalded-skin syndrome, which typically occurs in children (see Chapter 177), can occur in immunosuppressed adults.10 Ecthyma gangrenosum is one of the more specific clinical signs of bacteremia and is characterized by a painful erythematous to dusky nodule or plaque that rapidly develops a central pustule or hemorrhagic vesicle, followed by necrosis (Fig. 29-1). The groin, perianal area, and axillae are the most common locations. There may be one or many lesions. Classically described in patients with Pseudomonas septicemia, it is now recognized that other bacterial and fungal organisms, including S. aureus, Aeromonas hydrophilia, Serratia marcescens, K. pneumoniae, E. coli, Aspergillus, and Mucor species, can also cause similar lesions.11,12 Necrosis is secondary to underlying focal vasculitis, which can be observed in skin biopsy specimens. Diagnosis is made by culture of the organism from skin or blood.

Figure 29-1  Ecthyma gangrenosum secondary to Pseudomonas aeruginosa infection in a bone marrow transplant patient. Patients with neutropenia, cystic fibrosis, or extensive burns are particularly susceptible to systemic P. aeruginosa infection (see Chapter 180).13 The mortality rate of P. aeruginosa bacteremia in transplant patients is high at upwards of 40%.14 Other cutaneous manifestations of P. septicemia may appear initially as grouped vesicles, cellulitis, subcutaneous nodules, petechiae, purpura, or folliculitis.15 Progression to ulcerative and necrotic lesions that are more characteristic of ecthyma gangrenosum may occur. Primary cutaneous infection, usually at the site of a medical procedure, can also cause ecthyma gangrenosum-like lesions. As is common with other infections in neutropenic patients, primary lesions can lead to bacteremia and should be treated aggressively.

FUNGAL INFECTIONS In the acute transplant setting, invasive fungal infections are less common than bacterial infection, but cause much greater mortality. Mortality rates range from 40% to close to 100%, especially when treatment is delayed.16 Prolonged neutropenia is a significant risk factor and recovery from disseminated fungal infections is rare unless neutropenia resolves. Candidiasis and aspergillosis represent the two most common invasive fungal infections that occur in patients who are undergoing cytotoxic chemotherapy or stem cell transplantation or who have acute myeloproliferative disorders.17 However, they are not unique to the neutropenic patient and are encountered in settings such as surgical and neonatal intensive care units, and in patients with cell-mediated immune dysfunction such as those undergoing long-term immunosuppression after solid organ transplantation. Additional risk factors for opportunistic fungal infection include hyperalimentation, antibiotic use, hyperglycemia, corticosteroid use, and central venous catheter use. Other fungal organisms causing infection in hosts with acute neutropenia include Trichosporum species, Fusarium species, and organisms in the Zygomycetes class.18

CANDIDIASIS.

Skin Disease in Acute and Chronic Immunosuppression

ASPERGILLOSIS. While aspergillosis remains the second most common cause of opportunistic fungal infection in immunosuppressed patients as a whole, it has now surpassed Candida as the most common cause of invasive fungal infection in hematopoietic stem cell transplant patients and certain hematologic malignancies.15,16,20 Incidence rates vary in different immunosuppressed groups, but may reach 25% in acute leukemia and organ transplant patients.28 Persistent neutropenia and neutrophil dysfunction are risk factors for disseminated infection. Infection rates are also high for patients undergoing allogeneic stem cell transplantation, and risk factors in this group are expanded to include immunosuppression for graft-versus-host disease prophylaxis, graft-versus-host disease itself, and other infectious diseases, especially cytomegalovirus (CMV) infection. Invasive infection with Aspergillus was classically seen during acute periods of neutropenia, but shifts in conditioning regimens and other strategies to promote earlier engraftment have led to infections after 30–40 days posttransplantation.20 This observation emphasizes that immune defenses other than those mediated by granulocytes are important for protection against invasive fungal infections, and against Aspergillus infections in particular. The incidence of invasive aspergillosis is also increasing in nonclassic immunocompromised hosts such as critically ill patients in the intensive care unit. Environmental factors also clearly contribute to the development of aspergillosis, especially in primary cutaneous disease. These include hospital construction (which increases spore counts in ventilation systems), the use of indwelling catheters (which provide portals of entry for organisms), and contamination of tape and arm boards used to secure catheters. Mortality rates have improved with the introduction of newer antifungal agents, but remain higher than 50% in stem cell and organ transplant recipients.28,29 A. fumigatus is the most common cause of disseminated infections, although emerging strains of A. flavus, A. niger, and A. terreus are accounting for more disease.20 Reports suggest that A. flavus is associated most commonly with primary cutaneous disease.30 A. terreus is more likely to be resistant to amphotericin B, and multiple tri-azole resistant A. fumigatus has been described.28 Primary cutaneous aspergillosis often develops at paronychial locations, sites of intravenous catheters, or under areas of occlusion. Lesions initially appear as

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Figure 29-2  Early cutaneous lesion of disseminated candidiasis in a neutropenic patient after chemotherapy for non-Hodgkin lymphoma.

with a scalpel or small-diameter curette for slide examination and can be an invaluable aid in making a rapid diagnosis in an acutely ill patient. The treatment of choice for presumed disseminated candidiasis is usually intravenous liposomal amphotericin B, although the new class of echinocandins are also being evaluated.25,26 Culture results are again important since C. glabrata, C. albicans, C. tropicalis, and C. parapsilosis are showing resistance to fluconazole, and C. krusei is naturally resistant.22 Newer azoles, including voriconazole and posaconazole, are effective against Candida species, although breakthrough infections with resistant C. glabrata have already been reported with voriconazole (see Chapter 232).27

Chapter 29

Candidiasis (see Chapter 189) remains the most common opportunistic fungal infection worldwide, although its role in invasive infections is changing in certain immunosuppressed populations.19 Candida species still account for more than half of invasive fungal infections in solid organ transplant recipients, but aspergillosis has become more common in hematopoietic stem cell transplant recipients.20–22 Historically, most candidal infections were due to Candida albicans, but there has been an emergence of other organisms in recent years, including C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis.17 In certain populations of patients with hematologic malignancy or stem cell transplantation, non-C. albicans species now predominate, so awareness of local and regional patterns of infection is important.20,23 The classic triad of fever, myalgias, and erythematous skin lesions in a septic patient not responding to antibiotic therapy is highly suggestive of disseminated candidiasis. Fungi may seed numerous organs, causing myositis, meningitis, endocarditis, pneumonitis, cerebritis, esophagitis, bursitis, osteomyelitis, arthritis, and endophthalmitis. Cutaneous lesions are present in only 5%–10% of individuals with disseminated candidiasis.15,24 Lesions are characteristically painless, nonblanching, discrete, erythematous macules, papules, or nodules (Fig. 29-2) and may develop central purpuric, pustular, or necrotic changes. Involvement is usually generalized, but occasional patients have very few lesions limited to the proximal extremities. The major clinical differential diagnosis includes infections caused by other opportunistic pathogens and drug eruptions. Histologically, periodic acid-Schiff-positive yeast forms are seen in the dermis, usually in association with vascular damage and mild inflammation. Candida can be grown from sterile skin lesion samples in approximately 50% of patients. Tissue scrapings from dermal skin can be obtained at the time of biopsy

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Figure 29-3  Ecthymatous lesion of primary cutaneous aspergillosis in a child after bone marrow transplantation. (Used with permission from Jonathan Alexander, MD, Portland, OR.) small cellulitic areas and progress quickly to necrotic ulcers with black eschars (Fig. 29-3) due to the angioinvasive nature of the organism. In patients with Aspergillus sinusitis, necrotic ulcers with black eschars can occur in the anterior nares and on the nasal septum, palate, and skin overlying the nasal bridge. MRI may be useful in diagnosing the underlying sinusitis, and prior treatment with amphotericin B does not exclude the diagnosis as surgical treatment may be needed in this setting.31–33 Pulmonary, and less often primary cutaneous or sinus, infection can easily become invasive and lead to disseminated disease in immunocompromised hosts. Patients with disseminated aspergillosis often present with unremitting fever despite antibiotic use. The central nervous system, heart, kidneys, and gastrointestinal tract may also be involved. Cutaneous manifestations of disseminated aspergillosis are uncommon, occurring in only 5%–10% of patients.30 Lesions begin as single or multiple painful, erythematous papules, nodules, or plaques. They rapidly expand and develop central hemorrhagic vesicles or bullae, then eschar. In tissue sections, diagnosis can be made by demonstration of nonpigmented septated hyphae that branch at acute angles. Blood culture results often are not positive or reliable because Aspergillus is found commonly as a laboratory contaminant. Voriconazole has become the first-line agent for treatment of invasive aspergillosis. Alternatives include caspofungin, liposomal amphotericin B, itraconazole, and posaconazole.29 Surgical removal of isolated lesions of primary cutaneous aspergillosis can be attempted, although this may not necessarily prevent secondary disseminated infection in patients with persistent neutropenia.

ZYGOMYCOSIS. Zygomycosis is the third most common opportunistic fungal infection in immunosuppressed hosts, and may account for closer to 50% of invasive fungal infections in certain populations such as renal transplant patients.18 The term zygomycosis is used to describe a group of fungal infections caused by ubiquitous Zygomycetes found in soil and decaying matter. Infections in humans are mostly caused by the order Mucorales (mucormycosis) and include the genera of Mucor, Rhizopus, Absidia, Rhizomucor, and Cunninghamella. The term zygomycosis is now preferred over mucormycosis because it is broader and more relevant when organisms are not identifiable. Like aspergillosis, zygomycosis is rare in individuals without underlying immunodeficiency or predisposing conditions. Host defenses usually prevent the germination of spores unless the inoculation is too great, as in trauma or surgical wounds. Chronic medical conditions that affect macrophage function, such as diabetes or corticosteroid-induced immunosuppression, lead to an inability to inhibit spore germination, and these patients are at increased risk of infection. Additional risk factors besides immunosuppression include iron overload, burns, intravenous illicit drug use, and malnourishment. Recently, the use of voriconazole in immunosuppressed patients with presumed or diagnosed aspergillosis may account for part of the increase in zygomycotic infections.27 Primary infection can occur by inhalation, by direct inoculation into damaged skin, or by ingestion. Patients with prolonged neutropenia present most often with pulmonary disease and dissemination. The mortality rate in these individuals is very high, approaching 100%.34 Diabetic patients with sustained hyperglycemia and metabolic acidosis are predisposed to primary rhinocerebral (66%) and pulmonary (16%) infections.35 Malnutrition and gastrointestinal disease predispose patients to primary gastrointestinal tract infection. Wounds and burn injuries predispose to primary cutaneous infection. Each type of primary infection can lead to hematogenous spread and disseminated infection of numerous organs (especially the brain). The clinicopathologic hallmarks of cutaneous zygomycosis are vascular invasion, ischemic infarction, and necrosis, which result in painful erythematous nodules and plaques that ulcerate rapidly and form central black eschars.34 Clinical manifestations of primary cutaneous disease can range from necrotic papules to cellulitis, to subcutaneous nodules with rapid extension and dissemination especially in neutropenic patients.36 Rhinocerebral zygomycosis typically begins with facial edema and erythema (Fig. 29-4), bloody nasal discharge, and ulceration of the palate or nasal septum. Within a few days, necrotic skin lesions, headache, focal neurologic defects, exophthalmos, and altered vision develop and can progress to seizures, stupor, coma, and death. Disseminated disease from a noncutaneous primary site infrequently presents with skin findings.36 Diagnosis of zygomycosis is usually made by demonstration of nonseptated hyphae (with branching at right angles) within infected tissue. The treatment of choice for disseminated disease is lipid preparations of

TRICHOSPORONOSIS.

VIRAL INFECTIONS

FUSARIOSIS. Fusarium is a filamentous mold found in soil and plants belonging to the fungal group of hyalohyphomycoses. Disseminated infections are found in severely immunocompromised individuals, whereas immunocompetent patients have localized lesions at areas of skin breakdown. Neutropenic patients are particularly susceptible to infection and rapid dissemination.31 The source of infection in patients undergoing acute immunosuppressive therapy is often the skin, especially from cellulitis developing at the site of onychomycosis, local trauma, or insect bites. Nasal sinuses are another source of primary infection that can lead to dissemination following acute immunosuppression.18 In disseminated disease, patients present with multiple painful erythematous papules and nodules, some with central necrosis. Lesions are often at different stages of development, and a specific presentation of papules evolving into target-like lesions with a ring of normalappearing skin and an outer rim of erythema has been observed.31 Skin lesions in disseminated disease often precede fungemia and are found in approximately 75% of patients making dermatologic evaluation valuable.8 The mortality rate in patients who are persistently neutropenic is about 80%, compared with 30% in patients whose immune systems recover. Disease in solid organ transplant recipients may occur later than in patients with hematologic malignancies. Newer triazole antifungals such as voriconazole have some efficacy against infection with Fusarium species, for which treatment options have traditionally been limited. Surgical resection of localized skin infection is useful. Granulocyte transfusions may also play a role in treatment.18

Skin Disease in Acute and Chronic Immunosuppression

intravenous amphotericin B and surgical debridement. Some advocate the addition of posaconazole. If possible, reversal or removal of underlying predisposing conditions should be attempted.18

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Figure 29-4  Rapidly progressing zygomycosis in a man with diabetes.

Viral infections are predominantly associated with defects in cellular immune function and are not typically expected to cause problems in patients whose main immunologic defect is neutropenia.4 The most common viral infection that occurs in patients who are undergoing induction chemotherapy for lymphoma or an acute leukemia or who are in the first few weeks after a hematopoietic stem cell transplantation is reactivation of latent herpes simplex virus (HSV) infection (see Chapter 193).37 Clinical presentations in acutely immunosuppressed patients include an increased severity of oral mucositis, intraoral ulcers outside of the gingival margin, and necrotizing gingivitis. Pneumonitis can occur from either contiguous spread from the oropharynx or from viremia.37 Antiviral prophylaxis with acyclovir is very effective in preventing disease during chemotherapy and following hematologic and solid organ transplantation. When disease does occur in transplant patients, approximately 10% of cases are resistant to acyclovir because of a mutation in the gene coding for thymidine kinase, which is the enzyme required for efficacy of acyclovir, valacyclovir, and famciclovir (see Chapter 231).38 The treatment of choice in these patients is foscarnet, although reports of resistance to both agents is increasing.37,39,40 Reactivation of varicella zoster virus (VZV) (see Chapter 194) usually occurs 3 months or longer after transplantation and is relatively rare in the acutely immunosuppressed patient. VZV infection in adults with leukemia or after solid organ transplantation is rarely primary, but more often represents reactivation of latent virus. In this setting, patients are at increased risk for both skin and systemic dissemination of virus (Fig. 29-5).41 Before the use of antiviral prophylaxis in bone marrow transplantation, disseminated primary varicella or zoster infection was associated with mortality rates of 30%.42

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Trichosporon beigelii, a yeast-like organism that causes white piedra in the tropics, may produce acute systemic infection in immunosuppressed patients, most commonly in the setting of neutropenia.31 Trichosporon is an emerging pathogen in organ transplant recipients as well.18 Patients with disseminated trichosporonosis are acutely ill. They may have fever, hypotension, pulmonary infiltrates, renal involvement, and hepatosplenomegaly. Skin lesions occur in 30% of patients and appear similar to cutaneous lesions of disseminated candidiasis (multiple red papules that may ulcerate). Definitive diagnosis is made by culture, and the treatment of choice is fluconazole or itraconazole; amphotericin B resistance is common.18

CHRONIC IMMUNOSUPPRESSION Patients with chronic immunosuppression include those that are iatrogenically immunosuppressed because they are taking medications that impair the

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Figure 29-5  Disseminated varicella zoster virus in a patient after induction chemotherapy.

:: Inflammatory Disorders Based on T-Cell Reactivity and Dysregulation

immune system and those with chronic diseases that are associated with immune dysfunction, such as diabetes mellitus. Moreover, individuals with cancer often have immune system defects before aggressive cytotoxic, radiation, or surgical therapy.43 For example, tumors can secrete immunosuppressive factors (e.g., transforming growth factor-β1 and interleukin-10) or induce T-cell anergy, which help them evade normal immune responses and lead to further systemic immunosuppression. The population of patients taking long-term immunosuppressive medications is growing as solid organ transplantation becomes a therapeutic option for many human diseases and the survival of patients in the short and long term has improved. These individuals require lifelong therapy with immunosuppressive drugs to maintain function of the transplanted organ. Cyclosporine, tacrolimus, sirolimus, prednisone, mycophenolate mofetil, azathioprine (see Chapters 227 and 233), and the newer agents daclizumab and basiliximab are the drugs used most commonly to prevent graft-versus-host disease, predominately by inhibiting cell-mediated immunity (i.e., T-cell function).44 Humoral immunity (i.e., B-cell function) remains relatively intact in these patients. Thus, opportunistic diseases in most transplant patients are dominated by viral and fungal infections, intracellular bacterial infections, and virus-associated malignancies—conditions that are controlled predominantly by cell-mediated immune mechanisms in immunocompetent hosts.

and severity, with the highest incidence (up to 5%) seen in recipients of hematopoietic stem cell transplants. One-third present with catheter-related infections, although skin lesions are rare in this population. Skin involvement is the most commonly reported manifestation of nontuberculous mycobacterial infections in solid organ recipients except lung and heart transplant recipients, who are more likely to have pulmonary involvement. One-third of these patients have localized or disseminated cutaneous disease and the rapid growing species M. chelonae, M. fortuitum, and M. abscessus are most commonly isolated.45,46 Median time to infection varies depending on the type of transplant, ranging from 4 months posttransplant in stem cell recipients, to 30 months in heart recipients. Atypical mycobacterial infections in the skin are characterized by diverse morphologies, including reddish brown nodules and plaques (eFig. 29-5.1 in online edition), abscesses (Fig. 29-6), and ulcers.47 M. aviumintracellulare and M. haemophilum commonly cause disseminated infection, which can involve the lungs, lymph nodes, liver, spleen, bone marrow, and skin. Organisms can be identified by special stains or by culture of specimens from affected skin. Specific antimycobacterial antibiotic treatment regimens are complex and depend on the mycobacterial species, results of sensitivity testing, extent and severity of disease, and presence or absence of underlying immune defects.45,46 M. tuberculosis infection is a common worldwide problem, especially in individuals with impaired immunity. For example, individuals receiving highdose corticosteroids are prone to active pulmonary tuberculosis. Cutaneous tuberculosis is usually more common in the setting of immunosuppression. Specifically, scrofuloderma (tuberculous lymphadenitis with extension to overlying skin) and numerous cutaneous lesions of miliary tuberculosis may occur more commonly in patients with underlying immune defects.48

BACTERIAL INFECTIONS

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MYCOBACTERIAL INFECTIONS. Atypical mycobacteria (see Chapter 184) are ubiquitous organisms found in soil and water. The most common organisms in this group include Mycobacterium marinum, M. chelonae, M. fortuitum, M. abscessus, M. kansasii, M. haemophilum, and M. avium-intracellulare. Before the epidemic of acquired immunodeficiency syndrome (AIDS), most cases occurred in persons with underlying pulmonary disease. However, nontuberculous mycobacterial infections after transplantation are increasing in frequency

Figure 29-6  Mycobacterium chelonae infection in a patient receiving long-term, high-dose glucocorticoid treatment.

NOCARDIOSIS. Nocardia species (see Chapter 185)

Skin Disease in Acute and Chronic Immunosuppression

OTHER BACTERIAL INFECTIONS. (See Chapters 177–180.) Cellulitis caused by Streptococcus pyogenes, Streptococcus pneumoniae, or S. aureus may progress rapidly and cause necrotizing fasciitis in immunosuppressed patients (Fig. 29-8). Solid organ recipients also may develop recurrent cellulitis of the elbow, a condition termed “transplant elbow” that has been attributed to staphylococcal infection.8,57 Individuals with underlying complement deficiencies (loss of late-phase components C5–C9) or alcoholism are susceptible to infection with Neisseria meningitidis.58 Patients have acute septicemia, meningitis, disseminated intravascular coagulation, and widespread petechiae and purpura (Fig. 29-9). Persons with underlying hepatic disease (commonly alcoholic cirrhosis or hepatitis) are prone to infection with Vibrio vulnificus, a Gram-negative bacillus commonly found in seawater, shellfish, clams, and oysters.59 Infection occurs by ingestion of contaminated seafood or by direct cutaneous inoculation after contact with contaminated seawater. Patients classically present with rapidly evolving septicemia and painful cellulitis, bullae, or ulcers on the lower extremities (Fig. 29-10). Aeromonas can cause a similar picture in immunosuppressed patients.15,60 Capnocytophaga canimorsus is a commensal bacterium found in the saliva of dogs and cats that is transmitted to humans by bites or scratches. Hosts particularly ­susceptible to septicemia and widespread organ

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Figure 29-7  Nocardiosis in a man with glioblastoma.

BACILLARY ANGIOMATOSIS. Bacillary angiomatosis (see Chapter 182) is caused by infection with the bacterium Bartonella henselae or B. quintana and usually occurs in AIDS patients and other immunocompromised hosts.55 Cutaneous lesions appear as painful, dome-shaped vascular papules and nodules (often resembling pyogenic granulomas). Disseminated infection may occur and involve the liver, spleen, bone marrow, and brain. Fever and lymphadenopathy may be present. Patients often have a history of scratches or bites by cats, the natural reservoir for B. henselae and B. quintana. Diagnosis is made by demonstration of pleomorphic bacilli in tissue specimens with Warthin– Starry silver stain. Preferred treatments include oral erythromycin or azithromycin, or doxycycline.56

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are ubiquitous filamentous bacteria found in soil. While N. asteroides was historically considered the most common species associated with human disease, the recent availability of molecular diagnostics has allowed recategorization such that infections are now reported with a variety of species, including N. farcinica, N. nova, N. brasiliensis, N. asteroids sensu strictu, and N. cyriacigeorgica, among others.49 Species identification is important as some show more virulence and antimicrobial resistance than others (e.g., N. farcinica), and infection patterns may differ (e.g., N. brasiliensis is often the cause of primary cutaneous disease). Infection can be seen in immunocompetent hosts, but the majority of infections (60%) involve patients with immune compromise, particularly those receiving long-term corticosteroid therapy (the most important risk factor), solid organ or bone marrow transplant recipients, cancer patients, AIDS patients, intravenous drug users, and individuals with chronic pulmonary disease.50,51 Infections in patients treated with rituximab and tumor necrosis factor-α inhibitors have also been reported. In transplant patients, the mean onset of infection is 9 months after transplantation, although it can occur as early as 1 month afterward. Before the use of cyclosporine to prevent rejection, infection rates were much higher in transplant recipients, and this decline is attributed to decreased use of corticosteroids.49 Most cases of nocardiosis in transplant patients (approximately 80%) present as primary pulmonary disease and dissemination occurs in up to 40% of cases. The brain is commonly involved with disseminated infection, while approximately a third of cases show cutaneous involvement. Rarely, the skin is the primary location of infection.49 Several types of skin lesions have been described, including lower extremity subcutaneous nodules with pustules (Fig. 29-7), erythema nodosum-like disease, abscesses with sinus tract formation, mycetoma, sporotrichoid nodules, and cellulitis.8,52,53 Diagnosis is based on demonstration of Gram-positive, partially acid-fast, branching bacilli in tissue or tissue exudates, or is determined by tissue culture, although it often takes several weeks for organisms to grow. Molecular techniques may now aid in identification as well. The treatment of choice

remains trimethoprim-sulfamethoxazole (TMP-SMX); however, the severely ill or those with cerebral or disseminated infection may benefit from the addition of amikacin and/or imipenem. Numerous other antibiotics have been reported to be efficacious as well, such as linezolid, minocycline, other carbapenems, and third-generation cephalosporins. In addition, incision and drainage of cutaneous abscesses should be performed.50 The duration of treatment and the use of long-term prophylactic therapy to prevent primary or recurrent disease in transplant patients or patients on chronic corticosteroids are currently under debate. For instance, breakthrough infections in solid organ and hematopoietic transplant patients receiving traditional thrice weekly doses of TMP-SMX have occurred, and general resistance to sulfonamides is increasing.51,54

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Figure 29-8  Early (A) and late [after surgical debridement (B)] lesions of necrotizing fasciitis caused by Streptococcus ­pyogenes in an intravenous drug abuser with underlying Job syndrome. involvement include alcoholics, asplenic patients, and those taking glucocorticosteroids. Skin lesions occur commonly and include widespread macules, papules, purpura, and gangrene. Septicemia carries a mortality rate of 10%–50%.61,62 In immunosuppressed patients, Salmonella species have been associated with cutaneous abscesses and necrotizing fasciitis of the head and neck.63

FUNGAL INFECTIONS CANDIDIASIS. Although mucocutaneous candidiasis (see Chapter 189) is less serious than disseminated

Figure 29-9  Acute meningococcemia in a man with acquired complement deficiency.

candidiasis in the setting of acute immunosuppression (as described earlier), it is a significant source of morbidity in hosts with chronic cell-mediated immune dysfunction. Studies in organ transplant recipients suggest rates of oral candidiasis anywhere between 7% and 64%, depending on the type of transplant and the location of the study population.41,64 Patients with chronic mucocutaneous candidiasis have specific underlying immune deficits in fighting candidal infections, including alterations in dendritic cells and the T helper type 17 cells (Th17), and usually have chronic widespread disease without systemic involvement.65–67 Patients with oral mucosal candidiasis most commonly have pseudomembranous, white, friable plaques that leave a raw, erythematous undersurface when scraped. Less common oral lesions include erythematous or atrophic plaques as well as angular cheilitis. Esophageal involvement should be suspected in any patient with oral candidiasis complaining of pain or difficulty swallowing. Moist intertriginous areas are common locations of cutaneous lesions and are characterized by tender erythematous papules and plaques, often with satellite pustules. Onychomycosis and paronychia caused by Candida species are common in patients with chronic mucocutaneous candidiasis. For mucocutaneous disease, topical therapy with nystatin or clotrimazole and oral fluconazole are the treatments of choice. Prophylactic treatment with fluconazole is

Figure 29-10  Vibrio vulnificus infection in an alcoholic patient after minor trauma sustained while swimming in the ocean.

superficial nail plate scrapings. These conditions should prompt a search for underlying immune deficiency.31,69

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Skin Disease in Acute and Chronic Immunosuppression

DERMATOPHYTOSIS. Dermatophytoses (see Chapter 188) are common uncomplicated infections in normal hosts, but immunosuppressed patients may have widespread, aggressive infection that can be resistant to topical and systemic therapy.31,69 The overall incidence of dermatophyte infection is likely not higher in immunocompromised patients compared to normal hosts.70 Specific presentations seen in immunocompromised patients include multiple lesions, a wide distribution, tinea capitis in adults, and Majocchi granuloma. Manifestations more suggestive of immunosuppression include both white superficial onychomycosis and proximal subungual onychomycosis. In the former, the surfaces of affected nails have a white, chalky appearance (Fig. 29-11), and hyphae are observed readily in

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often recommended for patients at high risk for infection, such as those who have recently undergone organ transplant surgery, although as noted before resistance to this agent is increasing.68

Chapter 29

Figure 29-11  White superficial onychomycosis in a renal transplant patient receiving cyclosporine.

CRYPTOCOCCOSIS. Cryptococcus neoformans (see Chapter 190) is a yeast-like encapsulated fungus that is ubiquitous and is found commonly in soil enriched with bird feces. Primary infection is almost always via the respiratory tract by inhalation of airborne spores and usually is asymptomatic in healthy individuals. Organ transplant recipients are now the population at highest risk of developing disseminated disease, because improved antiretroviral agents have decreased the incidence in those with HIV disease.71 Patients receiving high-dose systemic corticosteroids are another group susceptible to hematogenous spread and disseminated infection, while incidences in those with diabetes mellitus, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, and Hodgkin disease are lower. Cryptococcal disease in hematopoietic stem cell transplant recipients is very rare.72 The central nervous system is most commonly involved during dissemination, although infection may occur in many organs including the lungs, bone marrow, heart, liver, spleen, kidneys, thyroid, lymph nodes, adrenal glands, and skin. Cutaneous lesions occur in up to 20% of patients with disseminated infection, however, skin lesions may be present in two-thirds of organ transplant patients receiving tacrolimus.73 In transplant patients, erythematous, edematous, warm, painful plaques on the extremities (clinically indistinguishable from bacterial cellulitis) have been reported most frequently (Fig. 29-12A).74 Umbilicated papules (resembling molluscum contagiosum), nodules, pustules, vesicles, and ulcers also may occur (Fig. 29-12B).75 Oral mucosal cryptococcal nodules and ulcerations also have been described. Lesions may be isolated or multiple and can be quite painful.

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Figure 29-12  Cellulitis and subsequent necrosis (A) and molluscum-like lesions (B) of cutaneous cryptococcosis. (Used with permission from Jonathan Alexander, MD, Portland, OR and Yale Residents’ slide collection, respectively.)

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Although primary skin disease may occur in the absence of pulmonary infection, diagnosis of cutaneous cryptococcosis always warrants an investigation for systemic infection, especially because disseminated disease may not always be evident clinically.76 Cerebrospinal fluid can be assessed for cryptococcal polysaccharide antigens. Budding encapsulated yeasts can be identified readily in skin biopsy specimens as well as in material obtained by a scraping of skin lesions. The yeast stain red with periodic acid-Schiff and mucicarmine stains and black with methenamine silver stain. India ink can be used to accentuate the capsule in a skin scraping. Cryptococcus can be isolated in culture of cutaneous tissue. The treatment of choice for cryptococcosis is a lipid formulation of amphotericin B with or without flucytosine. Fluconazole is used as alternative primary treatment and is the treatment of choice for prophylaxis in individuals at high risk for recurrent infection.77

HISTOPLASMOSIS. Histoplasma capsulatum (see Chapter 190) is a dimorphic fungus found in soil endemic to the central and eastern regions of the United States. As with cryptococcosis, inhalation of airborne spores causes primary pulmonary infection that usually leads to self-limited disease in otherwise healthy individuals. Disseminated disease is rare and most often occurs in individuals with deficiencies in cell-mediated immunity. In addition to pneumonia, immunosuppressed hosts may show fever, renal failure, central nervous system involvement, hepatosplenomegaly, lymphadenopathy, and myelosuppression.78 Mucocutaneous lesions occur in 5%–25% of patients with disseminated infection and may be an initial sign of disease. The head and neck region are favored and the oropharynx is the most common site. Mucosal lesions present with nodules or plaques that progress to ulcers with indurated borders. Skin findings are diverse and include molluscum-like papules, acneiform papules and pustules, and cellulitis.15,79 The organism grows very slowly in culture so diagnosis is best achieved by direct examination of tissue. Numerous small, oval, yeast-like fungi can be seen within the cytoplasm of dermal macrophages. Antigen testing is also available, but cross-reaction can occur with blastomycosis and other fungal infections (though not with cryptococcus). The treatment of choice for disseminated histoplasmosis in an immunosuppressed host is intravenous amphotericin B. For patients who are not acutely ill, oral itraconazole may be used; itraconazole is also recommended for immunosuppressed patients to prevent recurrent disease.78 COCCIDIOIDOMYCOSIS. Coccidioides immitis (see Chapter 190), the causative agent of coccidioidomycosis, is endemic to soil in the southwestern United States, and infection is usually acquired through inhalation of spores, which causes pulmonary disease.78 Although progressive primary infection may occur in immunosuppressed patients, reactivation of a prior, clinically unapparent infection is more common. The risks of dissemination and fatal infection are greater

among men, pregnant women, non-Caucasians, and immunosuppressed patients with defects in cell-mediated immunity. Thus, disseminated coccidioidomycosis can occur in any immunocompromised patient who lives or has lived previously in an endemic area. Immunosuppressed patients with disseminated disease may have fever, pneumonia, bone involvement, skin lesions, and/or meningitis. Mortality remains high at around 30%, but has improved with targeted prophylaxis in the organ transplant population.80 Primary cutaneous lesions of coccidioidomycosis are extremely rare and usually resolve in healthy individuals, whereas lesions persist in immunocompromised patients. Morphologies are varied and include multiple verrucous papules, abscesses, and ulcerated papules and plaques. Nonspecific findings seen in systemic disease include erythema multiforme, urticaria, a maculopapular rash, and erythema nodosum.15 Definitive diagnosis of coccidioidomycosis is made by culture or demonstration of characteristic endosporulating spherules in smears or biopsy specimens. Serologic studies may prove helpful, but may give false-negative results in the immunocompromised. In disseminated infections in immunosuppressed hosts, treatments for life-threatening disease include amphotericin B until infection is controlled, followed by itraconazole or fluconazole. Immunosuppressed patients with meningeal disease may require lifelong therapy.81

BLASTOMYCOSIS. Blastomyces dermatitidis (see Chapter 190) is endemic to the soil of the Ohio and Mississippi river valleys. Infection is acquired through inhalation of spores. Immunosuppressed patients are prone to disseminated disease involving the lungs, bone, genital tract, and skin, although infection in this population is still rare. Skin is the most common extrapulmonary site of involvement.15,78 Lesions appear as verrucous or ulcerated plaques with serpiginous borders located on the head, neck, or distal extremities. Ulcerative lesions begin as subcutaneous nodules and pustules.82 Diagnosis is made on demonstration of broad-based, budding, thick-walled yeasts in exudates or skin scrapings from the edges of lesions or by tissue culture. In life-threatening disseminated infection, intravenous amphotericin B is the treatment of choice, whereas less severe disease is treated with oral itraconazole.83 OTHER FUNGAL INFECTIONS. Alternaria is a common saprophytic fungus that can cause opportunistic infection in the setting of organ transplantation, Cushing syndrome, autoimmune bullous disease, and lymphoproliferative disorder. Over half of the patients reported to have cutaneous alternariosis were taking systemic corticosteroids, and secondary increased skin fragility has been implicated as a risk factor. There are two routes of infection: traumatic inoculation and secondary colonization of a preexisting skin lesion. Presentations include indurated plaques, ulcers, and pustules.84,85 Penicillium marneffei is a dimorphic fungus that is endemic to Southeast Asia (see Chapter 190). Most infections are associated with HIV disease, but cases

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in immunosuppressed patients residing or traveling to endemic areas have occurred.86 Tinea versicolor and folliculitis caused by Pityrosporum ovale (also known as Malassezia furfur; see Chapter 189) may be more prevalent, widespread, and persistent in immunosuppressed hosts. In addition, Pityrosporum has been reported to cause indwelling catheter-associated fungemia in immunosuppressed hosts, especially in those receiving parenteral lipid preparations.8

VIRAL INFECTIONS Chapter 29 ::

Figure 29-13  Severe chronic herpes simplex infection in a patient receiving long-term, high-dose glucocorticoids for autoimmune disease.

Figure 29-14  Severe recurrent varicella zoster virus infection in a child with acute lymphocytic leukemia.

Skin Disease in Acute and Chronic Immunosuppression

HERPES VIRUS INFECTION. Herpes viruses (see Chapters 193 and 194) include HSV-1, HSV-2, VZV, CMV, Epstein–Barr virus (EBV), human herpes virus 6 (HHV-6), HHV-7, and Kaposi sarcoma-associated herpes virus (KSHV or HHV-8). Infections are most prevalent in patients with acquired defects in cell-mediated immunity. Herpes viruses infect hosts for life and remain dormant in the nuclei of latently infected cells. Suppression of immunity often leads to reactivation (i.e., a latent to lytic switch). Recurrent HSV-1, HSV-2, and VZV infections are common in cancer and posttransplant patients, with the majority experiencing reactivation with at least one of these three viruses. Clinically apparent HSV outbreaks occur in up to 68% of organ transplant patients not on prophylaxis.87 Herpes zoster (recurrent VZV infection) is most likely to occur during the first year after transplantation with a 20–100-fold increased incidence in immunocompromised patients (approximately 10% incidence).37,88 Although presentations can be identical to those in immunocompetent hosts, lesions atypical in morphology and distribution often occur. For example, in immunosuppressed hosts recurrent lesions due to HSV or VZV may be isolated, nondermatomal, disseminated, necrotic, ulcerative, or verrucous (Figs. 29-13 and 29-14). In the mouth, chronic recurrent HSV infection can form white plaques and can be confused clinically with candidiasis. Lesions can occur in atypical locations, such as the tongue. Severe pain often is associated with both skin and oral lesions, and postherpetic pain is common. Protracted clinical courses of recurrent HSV or VZV infection are also more common in the setting of immunosuppression. In short, any painful, eroded lesion in an immunocompromised patient, regardless of its distribution or age, should be evaluated for both HSV and VZV by Tzanck preparation, immunofluorescence testing for viral antigen, polymerase chain reaction testing, and/ or viral culture. Importantly, systemic infection involving the lungs, central nervous system, liver, heart, and gastrointestinal tract may occur. Treatment with systemic acyclovir or a related antiherpesviral drug is always necessary. Prophylactic treatment to prevent recurrent episodes should be considered for individual patients if warranted. Foscarnet is the drug of choice for acyclovir-resistant viruses.37 Reactivation and recurrent disease associated with CMV are major causes of morbidity and mortality in patients with marked immunosuppression, occurring in 20%–60% of transplant recipients depending

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on the type of transplant and other risk factors.37,89 Disease is most commonly caused by reactivation of preexisting CMV infection, although CMV may be transmitted from donor to host in solid organ transplantation. CMV also exerts indirect effects in transplant patients, contributing to an increase in graft loss and risk of other opportunistic infections. CMV retinitis, gastroenteritis, hepatitis, and pneumonitis are the most common clinical disease manifestations. Cutaneous lesions can occur in 10%–20% of patients and are varied and nonspecific, including ulcers, papules, vesicles, petechiae, and morbilliform eruptions. Oral ulcers caused by CMV, particularly on the lateral aspects of the tongue, are most common. Painful, punched-out perianal ulcers have been reported and coinfection with HSV can occur. Tzanck preparations of specimens from the bases of ulcers may show multinucleated giant cells, and CMV-infected dermal endothelial cells may be seen in tissue sections by routine microscopy, appearing as large cells with intranuclear inclusions surrounded by clear halos (owl-eye nuclei). In addition, CMV can be cultured from infected skin. The treatment of choice for systemic CMV disease is intravenous ganciclovir, although intravenous foscarnet, cidofovir, or CMV immunoglobulin also may be effective.37,41 Prophylaxis of at-risk transplant patients is routine.39 HHV-6 and HHV-7, herpes viruses closely related to CMV, can also cause widespread multiorgan infection in immunosuppressed individuals. Disease itself is usually mild, but indirect effects of viral reactivation may allow other infections to occur and contribute to allograft failure.90 Unlike the other herpes virus infections, EBV and KSHV infections are associated with malignancies in the setting of immunosuppression. Specifically, chronic reactivated EBV infection is associated with non-Hodgkin lymphoma and other lymphoproliferative disorders, whereas chronic KSHV infection is associated with Kaposi sarcoma (KS), primary effusion lymphoma, and the plasmablastic variant of Castleman disease. Their neoplastic potential is discussed further later. Oral hairy leukoplakia is a unique presentation of EBV reactivation within oral mucosal epithelial cells, classically seen in patients with AIDS, but also seen in other immunosuppressed individuals (see Chapter 198).37 Lesions appear as adherent, white, corrugated plaques on the lateral aspects of the tongue. Histologically, there is hyperkeratosis and vacuolated suprabasal epithelial cells. Oral hairy leukoplakia may respond to topical podophyllin or high-dose acyclovir, although it is usually asymptomatic and does not require treatment. It has been regarded as a poor prognostic indicator in HIV-infected individuals, but the clinical significance of oral hairy leukoplakia in transplant patients is not known.

HUMAN PAPILLOMAVIRUS INFECTION.

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Warts (see Chapter 196) caused by human papillomavirus (HPV) infection are a common problem in posttransplant patients and in others receiving long-term immunosuppressive drug therapy. The prevalence of warts increases with longer duration of immune com-

promise, with up to 95% of individuals affected 5 years after transplant surgery.91 In this setting, lesions may be numerous, persistent, and difficult to eradicate. The morphology of the lesions may be typical or atypical. Atypical lesions appear as scaly macules and plaques, occur more commonly in sun-exposed areas, and are associated with HPV types observed in patients with epidermodysplasia verruciformis (e.g., HPV types 5 and 8). Several studies have reported that systemic retinoids (i.e., isotretinoin or acitretin) can prevent or decrease wart formation and prevent a variety of premalignant and malignant cutaneous lesions in posttransplant patients. In these patients, the association between HPV infection and cutaneous genital and nongenital squamous cell carcinoma (SCC) is complex, as discussed later.

HUMAN POLYOMAVIRUS INFECTION. Polyomaviruses are small double-stranded DNA viruses found in a variety of species including humans. The first two described, BK virus (BKV) and JC virus (JCV), were identified in the 1970s and cause nephropathy in kidney transplant patients and progressive multifocal leukoencephalopathy in immunosuppressed individuals, respectively. Neither produce skin lesions.92 In 2008, another polyomavirus was identified in tumors from patients with the neuroendocrine tumor Merkel cell carcinoma (MCC; see Chapter 120 and later in this chapter), subsequently termed Merkel cell polyomavirus (MCPyV).93 MCPyV can be found in 24%–89% of MCC with the highest rates in North American and European populations. Integration of the virus into MCC tumor genomes suggests a direct oncogenic role of MCPyV.94 Risk factors for MCC include advanced age and excessive sun exposure, and the incidence is greatly increased in the setting of immunosuppression, especially in organ transplant recipients.95 PARASITIC INFESTATIONS: CRUSTED SCABIES Crusted (or Norwegian or keratotic) scabies infestation (see Chapter 208) typically occurs in the settings of mental deficiency, malnutrition, or immunosuppression. Clinically, patients present with multiple widespread, thick, gray, or yellowish scaly plaques (eFig. 29-14.1 in online edition), with numerous mites present within lesions. Unlike in common scabies, pruritus may be minimal. Several courses of treatment with topical permethrin, as well as keratolytics, may be necessary to cure patients. Oral ivermectin is useful in these patients.96

CANCER NONMELANOMA SKIN CANCER. Nonmelanoma skin cancer (NMSC; see Chapters 114 and 115) is the most common malignancy in adult solid organ transplant patients and causes significant morbidity and mortality. The overwhelming majority of these neoplasms are SCCs; however, the incidence of basal cell carcinomas and other cutaneous malignancies is

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Chapter 29 ::

Figure 29-15  Caucasian renal transplant patient with warts, actinic keratoses, and squamous cell carcinomas. (Used with permission from Jonathan Alexander, MD, Portland, OR.) sis on monitoring of potentially premalignant lesions (e.g., actinic keratoses, porokeratosis, leukoplakia) for morphologic changes and initiation of treatment as indicated. Ideally, patients would be treated for precancerous lesions before transplant surgery. All transplant patients should be advised to maximize sun precautions.115 Oral retinoids, especially acitretin, have been used successfully to decrease the occurrence of new SCCs and actinic keratoses in transplant patients, but can be difficult to tolerate.116 A range of dosages has been used, and good effects with minimal side effects have been reported at daily dosages of 0.2– 0.4 mg/kg/day.117 It is a common clinical observation that when the medication is discontinued, numerous cancerous lesions arise (described as a rebound effect).118 Thus, when retinoids are considered for prophylaxis of NMSC, they should be considered as a long-term treatment. Recent studies have demonstrated that voriconazole, an oral broad-spectrum antifungal frequently used for the long-term management of chronically immunosuppressed patients, is associated with photosensitivity, accelerated photoaging, pseudoporphyria cutanea tarda, aggressive squamous cell carcinoma and melanoma. This accelerated cancer risk occurs in both children and adults. Thus, strict photoprotective measures should be recommended when voriconazole is used for prevention or treatment of fungal diseases.119,120

MELANOMA. The incidence of melanoma (see Chapter 124) and widespread atypical melanocytic nevi may be increased in transplant recipients and in other immunosuppressed patients.97 In particular, children who have had transplants appear to be at higher risk for the development of melanoma (15% of all skin cancers) compared with adults (6% of all skin cancers).121 Most melanomas arise from precursor nevi

Skin Disease in Acute and Chronic Immunosuppression

also increased.97 For SCC, the risk may be 200 times higher in transplant patients than in the general population and increases exponentially with length of immunosuppression.98,99 The cumulative incidence is a staggering 80% after 20 years of immunosuppressive therapy in renal transplant patients residing in Australia with its large amount of ultraviolet exposure.100 The incidence of other epithelial proliferative diseases, including actinic keratoses, keratoacanthomas, porokeratosis, appendageal tumors, and sebaceous carcinomas, is greatly increased as well. The pathogenesis of NMSC in posttransplant patients is multifactorial and has been studied and reviewed extensively.99,101–103 Prior history of NMSC was the most important predictor of risk in one comprehensive study.104 The distribution of lesions and the populations at highest risk suggest that sun exposure is one of the most important risk factors.105 Risk also increases with age and is greater for those with fair skin type, those living near the equator, and those with documented histories of significant sun exposure. In addition, gene mutations in the tumor suppressor gene p53 characteristic of those caused by ultraviolet radiation are found within NMSC in transplant patients.106,107 The commonly used immunosuppressive medications, including azathioprine and the calcineurin inhibitors cyclosporine and tacrolimus, are not only directly carcinogenic, but their additional effects on the immune system diminish immune surveillance mechanisms that potentially serve to eradicate precancerous lesions. On the other hand, sirolimus which blocks the mammalian target of rapamycin (m-TOR) pathway, has chemoprotective effects, including blocking tumor growth and angiogenesis.108 Switching from a calcineurin inhibitor to sirolimus-based therapy reduces the rates of internal malignancies and skin cancer in renal transplant patients.109 The role of HPV infection in organ transplant recipients is unclear. HPV is known to cause cervical and anal SCC and can be detected in cutaneous cancers of transplant patients (Fig. 29-15). Furthermore, epidermodysplasia verruciformis-associated HPV types (5, 8, and others) have been detected in cutaneous SCC, and there is suspicion that infections by these viruses may occur at an increased rate in immunosuppressed patients. However, asymptomatic infection has been identified in the general population, and thus it is unclear whether these HPV types are transcriptionally active and pathogenic in forming skin cancers in the setting of immunosuppression.103,110–112 Importantly, SCC in posttransplant patients can be clinically aggressive leading to increased morbidity and mortality than in the normal population. Local invasion, recurrence after primary treatment, and distant metastases are not uncommon and are all associated with a higher rate of mortality in organ transplant recipients.113,114 Oral mucosal leukoplakia and oral SCC also occur more commonly in immunocompromised individuals.99 Lip lesions are particularly common, which suggests a pathogenic role for sunlight in lesion formation. Careful and regular examination of skin and oral mucosa by both patients and dermatologists is required for all transplant patients, with an empha-

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in these patients. Melanomas have also been reported to originate from donor organs causing metastatic disease in graft recipients.122

LYMPHOMA. Lymphoproliferative disorders (see Chapter 145) are common devastating complications following transplantation and are often related to EBV-mediated proliferation of B-cells. Extranodal involvement is common, including involvement of the gastrointestinal tract, lungs, central nervous system, the transplanted organ, and skin.4,123 Cutaneous lesions present as violaceous macules to firm papules and plaques, similar to presentation in immunocompetent individuals. Lymphoma with purely cutaneous involvement is rare after transplantation. Most reported cases represent lymphomas of B-cell origin and are occasionally CD30+. The presence of EBV is often detected. Prognosis is generally better if there is cutaneous involvement alone, perhaps due to the ease of detection.37,124 Cutaneous T-cell lymphomas account for 30% of cases of cutaneous lymphomas in transplant patients. EBV is not associated with development in these patients. Clinical presentation is similar to that in nontransplant patients, except that there is an increased incidence of erythroderma. Prognosis is also worse than for cutaneous T-cell lymphoma in the general population.125 KAPOSI SARCOMA. The occurrence of KS (see Chapter 128) is increased in patients receiving immunosuppressive therapy after organ transplantation, with an incidence of 0.5%–5%. Risk factors in transplant recipients include male sex and Mediterranean, Jewish, Arabic, Caribbean, or African descent, as in the classic form of the disease.37,126 All cases of KS, regardless of clinical or geographic setting, are associated with KSHV infection. The vast majority of patients with posttransplant KS are KSHV seropositive before transplantation. Rarely, posttransplant KS can occur when KSHV-infected organs are transplanted into KSHV seronegative recipients.126,127 Clinically, skin lesions of posttransplant KS are identical to other forms of KS. As in classic KS, transplantassociated disease is found most commonly on the lower legs and feet, although the groin and oral cavity are also common locations. Typically, early KS lesions are deep red to violaceous macules or patches. With time, lesions develop into papules, plaques, nodules, or tumors. Visceral involvement occurs in 25% of renal transplant patients and 50% of those with heart or lung transplants.128 Reduction in immunosuppressive treatment often causes disease regression, although these patients remain at risk for developing KS at a later time if immunosuppressive therapy is reinstituted. Recently, regression of KS lesions in transplant patients after switching to a sirolimus-based regimen have been reported.129 Additional treatments include local excision or radiation therapy, intralesional therapy, and systemic chemotherapy. MERKEL CELL CARCINOMA. MCC (see Chapter 120) is an unusual, aggressive skin cancer of neuroendocrine cells (Fig. 29-16). The incidence of MCC

Figure 29-16  Merkel cell carcinoma on the scalp of a heart transplant patient. (Used with permission from ­Jonathan Alexander, MD, Portland, OR.) is increased and the cancer presents at a younger age in transplant recipients.95 Sentinel lymph node biopsy is becoming part of the standard of care in this population due to the high rate of lymph node metastases. Wide surgical resection and adjuvant radiation is recommended. The mortality rate is high at 56% at 2 years after diagnosis, which is nearly twice the rate for immunocompetent individuals. Less than 10% of individuals with distant metastasis survive longer than 3 years. There are early suggestions that MCC tumors positive for MCPyV DNA convey a better disease course than those lacking evidence of viral oncogenesis.92,130,131

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 4. Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357(25):2601-2614, 2007 7. Feld R: Bloodstream infections in cancer patients with febrile neutropenia. Int J Antimicrob Agents 32(Suppl. 1):S30-S33, 2008 15. Lopez FA, Sanders CV: Dermatologic infections in the immunocompromised (non-HIV) host. Infect Dis Clin North Am 15(2):671-702, xi, 2001 18. Kubak BM, Huprikar SS: Emerging & rare fungal infections in solid organ transplant recipients. Am J Transplant 9(Suppl. 4):S208-S226, 2009 31. Mays SR, Bogle MA, Bodey GP: Cutaneous fungal infections in the oncology patient: Recognition and management. Am J Clin Dermatol 7(1):31-43, 2006 37. Tan HH, Goh CL: Viral infections affecting the skin in organ transplant recipients: Epidemiology and current management strategies. Am J Clin Dermatol 7(1):13-29, 2006 57. Wolfson JS, Sober AJ, Rubin RH: Dermatologic manifestations of infections in immunocompromised patients. Medicine (Baltimore) 64(2):115-133, 1985 97. Vajdic CM, van Leeuwen MT: Cancer incidence and risk factors after solid organ transplantation. Int J Cancer 125(8):1747-1754, 2009 114. Ulrich C et al: Skin cancer in organ transplant recipients– where do we stand today? Am J Transplant 8(11):21922198, 2008 128. Farge D: Kaposi’s sarcoma in organ transplant recipients. The Collaborative Transplantation Research Group of Ile de France. Eur J Med 2(6):339-343, 1993

Inflammatory Diseases Based on Neutrophils and Eosinophils

Chapter 30 :: R  egulation of the Production and Activation of Neutrophils :: Steven M. Holland REGULATION OF THE PRODUCTION AND ACTIVATION OF NEUTROPHILS AT A GLANCE Human bone marrow commits enormous resources to the creation of neutrophils, producing approximately 1011 daily with a circulating half-life of approximately 7.5 hours and tissue survival for 1–2 days. Neutrophils are absolutely required for the prevention of infection and are not yet amenable to significant external replacement therapy. The neutrophil not only plays a central role in host defense, it can be responsible for significant tissue damage as well. The pathophysiology of the neutrophil indicates pathways, which can be exploited to enhance protection from infection. Selective abrogation of those pathways that are injurious in certain settings is also possible. Regulation of neutrophil responses in the skin is a major concern.

NEUTROPHILS This section presents an overview of neutrophil biology and function and uses a few well-characterized defects of myeloid function as illustrations.

ONTOGENY AND DEVELOPMENT Similar to other components of the hematopoietic system, the neutrophil is ultimately derived from a pluripotent hematopoietic stem cell. The development of

the myeloid stem cell is largely determined by ambient cytokines and reflected in its surface markers, morphology, and functional characteristics. The myeloblast is fully committed to the neutrophil lineage and is the first morphologically distinct cell in neutrophil development. Subsequent stages of neutrophil development occur under the influence of granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF). Four to six days are required for maturation through the mitotic phase to the myelocyte, and 5–7 days more for the myelocyte to develop into a mature neutrophil, including the metamyelocyte and band stages, before emerging as a fully developed neutrophil. Development of neutrophils through the myelocyte stage normally occurs exclusively in the bone marrow, which is composed of approximately 60% developing neutrophils. The mature neutrophil measures 10–12 μm and has a highly condensed, segmented, multilobulated nucleus, usually with three to five lobes. Although 1011 neutrophils are generated daily, this number can rise tenfold in the setting of infection. The calculated circulating granulocyte pool is 0.3 × 109 cells/kg blood and the marginated pool is 0.4 × 109 cells/kg blood, comprising only 3% and 4% of the total granulocyte pool, respectively. The bone marrow releases 1.5 × 109 cells/kg blood/day to this pool but keeps 8.8 × 109 cells/kg blood in the marrow in reserve. An additional reserve of immature and less competent neutrophils, 2.8 × 109 cells/kg blood, is also available. G-CSF is critically important for neutrophil production.1 Mice deficient in G-CSF show reduced neutrophil numbers and cannot upregulate neutrophil numbers in response to infection. Interestingly, G-CSF production is under the influence of IL-17, a cytokine of importance in regulation of epithelial defenses.

BIOLOGIC FUNCTIONS GRANULE CONTENT AND FUNCTION. (Table 30-1.) Neutrophils are characterized by cytoplasmic granules and partially condensed nuclei. Granules are first found at the promyelocyte stage.2 Primary (azurophilic) granules are the first to arise, measure

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TABLE 30-1

Human Neutrophil Components Primary Granules

Secondary Granules

Other Cytoplasmic Organelles

Neutrophil   Galectin-10

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346

Enzymes  Bactericidal/permeability-increasing protein   Defensins   Lysozyme   Myeloperoxidase   Elastase   Cathepsin G   Proteinase 3   Azurocidin   Phospholipase A2   5-Lipoxygenase   Cyclooxygenase Acid hydrolases   Cathepsin B   Cathepsin D   β-Glycerophosphatase   β-Glucuronidase   N-acetyl-β-glucosamine   α-Mannosidase

  p15s   Lysozyme

  Proteinase 3

  Cathepsin B   Cathepsin D

approximately 0.8 μm in diameter, and contain numerous antimicrobial products including lysozyme, myeloperoxidase, and defensins.3 Primary granules are only synthesized at the promyelocyte stage. The promyelocyte gives rise to the myelocyte, the last cell of the neutrophil lineage with proliferative potential. Therefore, cytokines or agents that increase total neutrophil production must act at or before the myelocyte stage. The smaller eosinophilic secondary (specific) granules appear during the myelocyte stage. These granules measure about 0.5 μm in diameter and contain lactoferrin, collagenase, gelatinase, vitamin B12-binding protein, and complement receptor 3 (CR3; CD11b/CD18). gp91phox and p22phox comprise the specific granule component cytochrome b558, defects in which cause chronic granulomatous disease (CGD), characterized by infections with particular catalase-producing bacteria. Gelatinase also cleaves and potentiates the activity of the chemokine interleukin-8 (IL-8). Because primary granules are synthesized early and distributed to daughter cells during division, they are eventually outnumbered by about 3:1 by the specific granules, which are produced throughout the myelocyte stage. Granules fuse in a sequential fashion with incoming phagocytic vacuoles, such as those containing ingested bacteria. Secondary granules fuse to the phagosome within the first 30 seconds after ingestion and release their enzymes, many of which function best at neutral or alkaline pH. By 3 minutes after ingestion, the primary granules have fused to the phagolysosome leading to rapid lowering of the intravacuolar pH. For objects too

Cathepsin B Cathepsin D β-Glycerophosphatase β-Glucuronidase N-acetyl-β-glucosamine α-Mannosidase

large to be ingested, or certain stimuli, degranulation to the cell surface occurs with release of granule contents into the surrounding environment. This can be inferred by detection of lactoferrin levels in blood. An example of disordered granule biogenesis is Chédiak–Higashi syndrome (CHS), a rare autosomal recessive disorder with abnormal pigmentation due to a generalized abnormality of primary granule and lysosome formation (see Chapter 143).

NEUTROPHIL-SPECIFIC GRANULE DEFICIENCY. Neutrophil-specific granule deficiency is a

rare, autosomal recessive condition clinically characterized by a profound susceptibility to bacterial infections. There is a paucity or absence of neutrophil-specific granules, specific granule proteins (e.g., lactoferrin) and their respective messenger RNAs, and very low levels of the primary granule products defensins and their messenger RNAs. Specific granule deficiency is due to loss of the transcriptional factor CCAAT/enhancer binding protein e (CEBPe), which is essential in normal myeloid development. Acquired abnormalities of neutrophil granules are seen in some myeloid leukemias, in which primary granule contents may be aberrantly accumulated (e.g., Auer rods in acute myelogenous leukemia).

TISSUE TRAFFICKING CHEMOATTRACTANTS AND CHEMOTAXIS.

Metchnikoff discovered over a century ago that

ment of chemokine receptor blockers for treatment of HIV infection (maraviroc and vicriviroc).

:: Regulation of the Production and Activation of Neutrophils

ADHESION. Neutrophils exist as free-flowing (those which are sampled on blood drawing) and marginated cells (those which are attached to the endothelium or are traversing the lung, skin, or other tissues). Neutrophils rolling along the endothelium recognize sites of activation (e.g., chemokine expression), adhere to those sites, and traverse the endothelium to enter the tissue and fight infection. Leukocyte physical interaction with endothelium and other leukocytes is mediated by integrins, selectins, and intercellular adhesion molecules (ICAMs; Fig. 30-1). Elaboration of chemoattractants or display of activation markers on endothelium triggers leukocyte high affinity binding by β2 integrins, heterodimeric surface molecules largely stored in the secondary granules of neutrophils that are displayed on the cell surface upon leukocyte activation. There are three β2 integrin heterodimers comprised of different α chains, CD11a, -b, and -c, and a common β chain, CD18. Each CD11/ CD18 complex has separate and overlapping activities. CD11a/CD18 [leukocyte function-associated molecule 1 (LFA-1)] binds to other leukocytes and mediates tight adhesion to the endothelium through ICAM-1 and ICAM-2. CD11b/CD18 (Mac-1, Mo-1, or CR3) binds to the inactivated form of the third component of complement (C3bi) and thereby facilitates complement-mediated phagocytosis. CD11b/CD18 also binds to bacteria directly, to fibrinogen, and to endothelium through ICAM-1. The divalent cations Ca2+ and Mg2+/Mn2+ mediate adhesion through β2 integrin “A” domains containing a metal ion-dependent adhesion site. CD11b/CD18 may also induce the expression of the β1 integrin very late antigen 6 [VLA-6 (CD49f/CD29)], derived from neutrophilic granules, to aid in tissue infiltration. The integrin-associated protein (CD47), expressed on neutrophils and endothelial and epithelial cells, is also involved in the transendothelial and transepithelial migration of neutrophils.4 Metalloproteinases may be involved in cleavage of L-selectin, allowing neutrophil migration through the basement membrane. Absence of CD18 causes lack of CD18/CD11 heterodimers and is called leukocyte adhesion deficiency type 1 (LAD1). Neutrophils lacking CD18 roll normally along the endothelium but are unable to stick to the vessel wall or exit the circulation after chemotactic stimulation. Absence of LFA-1 (CD11a/CD18) makes neutrophils unable to bind tightly to and traverse activated endothelium to infected areas. Therefore, LAD1 patients have chronic neutrophil leukocytosis, partly from inability of neutrophils to bind tightly to endothelium and exit the circulation, thus leading to a reduction in the marginated pool and an increase in the circulating pool of neutrophils. Poor neutrophil penetration to sites of bacterial invasion leads to necrotic ulcers that lack neutrophils on biopsy. Absence of Mac-1 (CD18/CD11b or CR3) leads to inability to perform complement-mediated phagocytosis, although antibody-mediated phagocytosis remains intact.

5

Chapter 30

­ eutrophils move toward very slight gradients of n chemical signals, now termed chemoattraction. The “classic” chemoattractants are N-formylmethionylleucyl-phenylalanine (fMLF), complement factor 5a (C5a), leukotriene B4, and platelet-activating factor (PAF). More recently, chemokines (chemoattractant cytokines), a class of small (9.6) protein of 452 amino acids and approximately 58 kDa. Sequence homology to lipopolysaccharide (LPS)-binding protein, a critical endotoxin binding acute-phase reactant, suggests that it acts by directly binding to LPS. BPI is cytotoxic to Gram-negative bacteria at concentrations as low as 10−9 M, but much less effective against Gram-positive organisms. Binding to LPS leads to insertion of BPI into the outer membrane of the organism and eventual insertion into the inner membrane. Arrest of bacterial growth is solely dependent on the N-terminal half of the molecule. The C-terminal fragment serves as an anchor to the membrane. BPI appears to act inside the phagolysosome. Not all Gram-negative rods are sensitive to BPI, especially Burkholderia (Pseudomonas) cepacia and Serratia marcescens, pathogens in patients who lack oxidative killing. Defensins are small (38°C (4) Association with an underlying hematologic (most commonly acute myelogenous leukemia) or visceral malignancy (most commonly carcinomas of the genitourinary organs, breast, and gastrointestinal tract), inflammatory disease (Crohn’s disease and ulcerative colitis) or pregnancy, or preceded by an upper respiratory (streptococcosis) or gastrointestinal (salmonellosis and yersiniosis) infection or vaccination (5) Excellent response to treatment with systemic corticosteroids or potassium iodide (6) Abnormal laboratory values at presentation (three of four): erythrocyte sedimentation rate >20 mm/hour; positive C-reactive protein; >8,000 leukocytes; >70% neutrophils

(A)  Abrupt onset of painful erythematous plaques or nodules (B) Histopathologic evidence of a dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis (C)  Pyrexia >38°C (D) Temporal relationship between drug ingestion and clinical presentation or temporally related recurrence after oral challenge

Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome)

471,474,476,477,482,487, 489,490,492,493,505,506

::

More than 1,000 cases of Sweet syndrome have been reported since Sweet’s original paper.1–509 The distribution of Sweet syndrome cases is worldwide and there is no racial predilection.1,2,12,16–20,30,31 The dermatosis presents in three clinical settings.13,15 Diagnostic criteria for classical or idiopathic Sweet syndrome were proposed by Su and Liu in 1986 and modified by von den Driesch in 1994 (Table 32-1).11–14 It may be associated with infection (upper respiratory tract or gastrointestinal tract), inflammatory bowel disease, or pregnancy.13,15 Two studies have noted a seasonal preference for the onset of Sweet syndrome for either autumn or spring in 70% of 42 patients.416 or autumn.496

5

Chapter 32

Acute febrile neutrophilic dermatosis was originally described by Dr. Robert Douglas Sweet in the August– September 1964 issue of the British Journal of Dermatology. The cardinal features of “a distinctive and fairly severe illness” that had been encountered in eight women during the 15-year period from 1949 to 1964 were summarized. Although the condition was originally known as the Gomm–Button disease “in eponymous honor of the first two patients” with the disease in Dr. Sweet’s department, “Sweet’s syndrome” has become the established eponym for this acute febrile neutrophilic dermatosis.1–10

Classical Sweet syndrome most commonly occurs in women between the ages of 30 to 60 years. However, classical Sweet syndrome also occurs in younger adults and children.32–48,405,415,445,447,453 The youngest Sweet syndrome patients are brothers who developed the dermatosis at 10 and 15 days of age.46 Several investigators consider it appropriate to distinguish between the classical form and the malignancyassociated form of this disease since the onset or recurrence of many of the cases of Sweet syndrome are temporally associated with the discovery or relapse of cancer.15,49–60 Recently, the investigators of a comprehensive review of 66 pediatric Sweet syndrome patients observed that 44% of 30 children between 3 and 18 years of age had an associated hematologic malignancy.405,447 Malignancy-associated Sweet syndrome in adults does not have a female predominance and is most often associated with acute myelogenous leukemia.61,62 In Sweet syndrome patients with dermatosis-related solid tumors, carcinomas of the genitourinary organs, breast, and gastrointestinal tract are the most frequently occurring cancers.1,2,63–66 Criteria for drug-induced Sweet syndrome were established by Walker and Cohen in 1996 (Table 32-1).13 This variant of the dermatosis is most frequently observed to occur in association with the administration of granulocyte-colony stimulating factor (G-CSF).1,2,13,67,68 However, several other medications have also been implicated in eliciting drug-induced Sweet syndrome (eTable 32-1.1 in online edition).11,13,17,39,41,69–124,401,402,422,427–429,436,437,439,446,455,456,463,464,468,469

(E) Temporally related resolution of lesions after drug withdrawal or treatment with systemic corticosteroids

a

The presence of both major criteria (1 and 2) and two of the four minor criteria (3, 4, 5, and 6) is required in order to establish the diagnosis of classical Sweet syndrome; the patients with malignancy-associated Sweet syndrome are included with the patients with classical Sweet syndrome in this list of diagnostic criteria. b All five criteria (A, B, C, D, and E) are required for the diagnosis of drug-induced Sweet syndrome. Adapted with permission from Walker DC, Cohen PR: Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: Case report and review of drug induced Sweet syndrome. J Am Acad Dermatol 34:918-923, 1996.

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ETIOLOGY AND PATHOGENESIS The pathogenesis of Sweet syndrome may be multifactorial and remains to be definitively determined. A condition, similar to Sweet syndrome, presenting as a sterile neutrophilic dermatosis, has been described in a female standard poodle dog after treatment with the nonsteroidal anti-inflammatory drug firocoxib and in multiple dogs temporally associated with the administration of carprofen.403 Sweet syndrome may result from a hypersensitivity reaction to an eliciting bacterial, viral, or tumor antigen.2,127 A septic process is suggested by the accompanying fever and peripheral leukocytosis. Indeed, a febrile upper respiratory tract bacterial infection or tonsillitis may precede skin lesions by 1–3 weeks in patients with classic Sweet syndrome. Also, patients with Yersinia enterolitica intestinal infection-associated Sweet syndrome have improved with systemic antibiotics.2,77,125–127 The systemic manifestations of Sweet syndrome resemble those of familial Mediterranean fever. Recently, the simultaneous occurrence of both conditions has been observed.421 Also, in a patient with chronic myelogenous leukemia-associated Sweet syndrome, the causative gene mutation for familial ­Mediterranean fever was detected.448 Hence, the pathogenesis for these conditions may be similar. Leukotactic mechanisms, dermal dendrocytes, circulating autoantibodies, immune complexes, human leukocyte antigen (HLA) serotypes, and cytokines have all been postulated to contribute to the pathogenesis of Sweet syndrome. Complement does not appear to be essential to the disease process. In some patients antibodies to neutrophilic cytoplasmic antigens (ANCAS) have been demonstrated;430 however, these are likely to represent an epiphenomenon.2 Cytokines—directly and/or indirectly—may have an etiologic role in the development of Sweet syndrome symptoms and lesions.2,21–23 Elevated serum levels of granulocyte-colony stimulating factor and interleukin-6 were detected in a patient with myelodysplastic syndrome-associated Sweet syndrome who was not receiving a drug.128 Detectable levels of intraarticular synovial fluid granulocyte macrophage-colony stimulating factor has also been observed in an infant with classical Sweet syndrome.44 Another study demonstrated that the serum G-CSF level was significantly higher in individuals with active Sweet syndrome than in dermatosis patients with inactive Sweet syndrome.129 And, a recent study showed that the level of endogenous G-CSF was closely associated with Sweet syndrome disease activity in a patient with acute myelogenous leukemia-associated Sweet syndrome and neutrophilic panniculitis.461 Significantly elevated levels of helper T-cell type 1 cytokines (interleukin-2 and interferon-γ) and normal levels of a helper T-cell type 2 cytokine (interleukin-4) have been seen in the sera of Sweet syndrome patients.130 In a patient with neuro-Sweet disease presenting with recurrent encephalomeningitis, serial measurements of cerebral spinal fluid interleukin-6, interferon-γ, interleukin-8, and IP10 [which is also

referred to as the chemokine (C–X–C motif) ligand 10 (CXCL10)] were elevated as compared to levels in control subjects with neurologic disorders and also correlated with total cerebral spinal fluid cell counts; this data suggests an important role of the helper T-cell type 1 cell (whose cytokines include interferon-γ and IP10) and interleukin-8 (a specific neutrophil chemoattractant) in the pathogenesis of neuro-Sweet disease.478 Other studies showed decreased epidermal staining for interleukin-1 and interleukin-6 and postulated that this was due to the release of these cytokines into the dermis.131 In summary, G-CSF, granulocyte macrophage colony stimulating factor, interferon-γ, interleukin-1, interleukin-3, interleukin-6, and interleukin-8 are potential cytokine candidates in the pathogenesis of Sweet syndrome.2,13,21–23,44,128–132

CLINICAL FINDINGS HISTORY Sweet syndrome patients may appear dramatically ill. The skin eruption is usually accompanied by fever and leukocytosis. However, the skin disease can follow the fever by several days to weeks or be concurrently present with the fever for the entire episode of the dermatosis. Arthralgia, general malaise, headache, and myalgia are other Sweet syndrome associated symptoms (Table 32-2).1,2,23

CUTANEOUS LESIONS Skin lesions of Sweet syndrome typically appear as tender, red or purple–red, papules or nodules. The eruption may present as a single lesion or multiple lesions that are often distributed asymmetrically (Fig. 32-1).

Figure 32-1  Unilateral lesions of Sweet syndrome around the eye and upper lip consisting of plaques and pseudovesicular papules suggesting herpes simplex.

5

TABLE 32-2

Clinical Features in Patients with Sweet Syndrome Clinical Form Characteristic Epidemiology   Women  Prior upper respiratory tract infection   Recurrencec

Drug Inducedb (%)

80 75–90

  50   16

59 20

  71   21

30

  69

41

  67

80–90 12–56

  88   26

79 34

100   21

17–72

   7

15

  21

80 50 30 Infrequent 2

  89   63   42   49   12

97 52 33 48  3

  71   43   50   36    7

80 90

  47 100

60 95

  38 100

Infrequent Infrequent 11–50

  82   68   15

83 50  7

100   50    0

a

Percentages for classical, hematologic malignancy, and solid tumor associated Sweet’s syndrome from Cohen PR, Kurzrock R: Sweet’s syndrome and cancer. Clin Dermatol 11:149-157, 1993. Copyright 1993, Elsevier Science Publishing Co., Inc., New York, NY. b Percentages for drug-induced Sweet’s syndrome from Walker DC, Cohen PR: Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: Case report and review of drug induced Sweet’s syndrome. J Am Acad Dermatol 34:918-923, 1996. Copyright 1996, American Academy of Dermatology, Inc., Mosby-Year Book, Inc., St. Louis, MO. c Recurrence following oral rechallenge testing in the patients with drug-induced Sweet’s syndrome. d Temperature greater than 38°C. e Neutrophil count greater than 6000 cells/uL. f Erythrocyte sedimentation rate greater than 20 mm/hour. g Hemoglobin less than 13 g/dL in men and less than 12 g/dL in women. h Platelet count less than 150,000/uL or greater than 500,000/uL. i This includes hematuria, proteinuria, and renal insufficiency.

The pronounced edema in the upper dermis of the lesions results in their transparent, vesicle-like appearance and has been described as an “illusion of vesiculation” (Fig. 32-2). In later stages, central clearing may lead to annular or arcuate patterns. The lesions may appear bullous, become ulcerated, and/or mimic the morphologic features of pyoderma gangrenosum in patients with malignancy-associated Sweet syndrome.133,134 The lesions enlarge over a period of days to weeks. Subsequently, they may coalesce and form irregular sharply bordered plaques (Fig. 32-3). They usually resolve, spontaneously or after treatment, without scarring. Lesions associated with recurrent episodes of Sweet syndrome occur in one-third to two-thirds of patients.1,2,135,136 Cutaneous pathergy, also referred to as skin hypersensitivity, is a dermatosis-associated feature.1,2 It occurs when Sweet syndrome skin lesions appear at

sites of cutaneous trauma.458,496 These include the locations where procedures have been performed such as biopsies,20 injection sites,431 intravenous catheter placement,20 and venipuncture.12,17,20,37,137,138 They also include sites of insect bites and cat scratches,20 areas that have received radiation therapy,139–141,138,484 and places that have been contacted by sensitizing antigens.137,142,420 In addition, in some Sweet syndrome patients, lesions have been photodistributed or localized to the site of a prior phototoxic reaction (sunburn).13,20,98,143–145 Sweet syndrome lesions have also rarely been located on the arm affected by postmastectomy lymphedema.100,146,419,505 Sweet syndrome can present as a pustular dermatosis.147 The lesions appear as tiny pustules on the tops of the red papules or eythematous-based pustules. Some of the patients previously described as having the

Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome)

Laboratory findings   Neutrophiliae  Elevated erythrocyte sedimentation ratef   Anemiag  Abnormal platelet counth  Abnormal renal functioni

Solid Tumora (%)

::

Lesion location   Upper extremities   Head and neck   Trunk and back   Lower extremities  Oral mucous membranes

Hematologic Malignancya (%)

Chapter 32

Clinical symptoms   Feverd  Musculoskeletal involvement  Ocular involvement

Classicala (%)

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5

The cutaneous lesions of subcutaneous Sweet syndrome usually present as erythematous, tender dermal nodules on the extremities.4,8,12,17,99,119,164–185 When the lesions are located on the legs, they often mimic erythema nodosum.170 Since Sweet syndrome can present concurrently21,125,187–189 or sequentially170 with erythema nodosum,17,21,187,190,509 tissue evaluation of one or more new dermal nodules may be necessary to establish the correct diagnosis—even in a patient whose Sweet syndrome has previously been biopsy-confirmed.1,2,4

RELATED PHYSICAL FINDINGS Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

Figure 32-2  Multiple confluent papules and plaques of Sweet syndrome that at first sight give the illusion of vesiculation but are solid on palpation. (From Honigsmann et al: Akute febrile neutrophile Dermatose. Wien Klin Wochenschr 91:842, 1979, with permission.) “pustular eruption of ulcerative colitis” are perhaps more appropriately included in this clinical variant of Sweet syndrome.1,148 “Neutrophilic dermatosis of the dorsal hands” or “pustular vasculitis of the dorsal hands” refers to a localized, pustular variant of Sweet syndrome when the clinical lesions are predominantly restricted to the dorsal aspect of the hands.3,149–154 The lesions from this latter group of individuals are similar to those of Sweet syndrome in morphology and rapid resolution after systemic corticosteroids and/or dapsone therapy was initiated. In addition, many of the individuals with this form of the disease also had concurrent lesions that were located on their oral mucosa, arm, leg, back, and/ or face.3,155–163,425,435,440,442,457,462,470,495,497

A

366

EXTRACUTANEOUS MANIFESTATIONS. (eTable 32-2.1 in online edition.) Extracutaneous manifestations of Sweet syndrome may include the bones, central nervous system, ears, eyes, kidneys, intestines, liver, heart, lung, mouth, muscles, and spleen.12,16,17,20,25,26,32,33,44,73,75,101,117,138,139, 165,202,203,205,212–257,407,408,410,433,444,450,452,459,465,468,475,478,481,486,599 The incidence of ocular involvement (such as conjunctivitis) is variable in classical Sweet syndrome and uncommon in the malignancy-associated and drug-induced forms of the dermatosis; however, it may be the presenting feature of the condition. Mucosal ulcers of the mouth occur more frequently in Sweet syndrome patients with hematologic disorders and are uncommon in patients with classical Sweet syndrome23,26,102,117,203,252; similar to extracutaneous manifestations of Sweet syndrome occurring at other sites, the oral lesions typically resolve after initiation of treatment with systemic corticosteroids.1,2 In children, dermatosis-related sterile osteomyelitis has been reported. ASSOCIATED DISEASES. (eTable 32-2.2 in online edition.) Several conditions have been observed to occur either before, concurrent with, or following the diagnosis of Sweet syndrome. Therefore, the development of Sweet syndrome may be etiologically related to Behcet’s disease, cancer, erythema nodosum, infections, inflammatory bowel disease, pregnancy, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, and thyroid

B

Figure 32-3  Acute febrile neutrophilic dermatosis. Typical lesion consisting of coalescing, plaque-forming papules. A. Bright-red lesions on the neck. B. Lesion on the dorsum of the right-hand exhibiting the “relief of a mountain range” feature. (From Honigsmann H, Wolff K: Acute febrile neutrophilic dermatosis (Sweet’s syndrome). In: Major Problems in Dermatology, vol 10, Vasculitis, edited by K Wolff, RK Winkelmann, consulting editor A Rook. London, Lloyd-Luke, 1980, p. 307, with permission.)

5

disease. The association between Sweet syndrome and the other conditions (eTable 32-2.2 in online edition) remains to be estab­lished.1,2,5,11–20,30,36–43,69–126,158–161,164,166,

186–190,195,214,231,236,259–339,400,402,406,410,411,415,417,418,421–424,426–429,434, 436–442,445,446,448,449,452–456,459,460,463,464,466–469,471–477,479,480,482,483,487–490, 492–494,496,497,500,502–504,508,509

ASSOCIATED NEUTROPHILIC DERMATOSES.

HISTOPATHOLOGY Evaluation of a lesional skin biopsy is helpful when the diagnosis of Sweet syndrome is suspected. Lesional

Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome)

LABORATORY TESTS

tissue should also be submitted for bacterial, fungal, mycobacterial, and possibly viral cultures since the pathologic findings of Sweet syndrome are similar to those observed in cutaneous lesions caused by infectious agents.1,2 A diffuse infiltrate of mature neutrophils is characteristically present in the papillary and upper reticular dermis (Fig. 32-4); however, it can also involve the epidermis or adipose tissue. “Histiocytoid” Sweet syndrome refers to the setting in which the hematoxylin and eosin-stained infiltrate of immature myeloid cells are “histiocytoid-appearing” and are therefore initially misinterpreted as histiocytes.201,412–414,436,443,445,460,474 The dermal inflammation is usually dense and diffuse; however, it can also be perivascular or demonstrate “secondary” changes of leukocytoclastic vasculitis believed to be occurring as an epiphenomenon and not representative of a “primary” vasculitis,3,192,193 Neutrophilic spongiotic vesicles194 or subcorneal pustules12,80,167,195,196 result from exocytosis of neutrophils into the epidermis.12,17,80,167,194,195,197 When the neutrophils are located either entirely or only partially in the subcutaneous fat, the condition is referred to as “subcutaneous Sweet syndrome”.4,8,12,17,99,119,164–184,451,461,493,497 Edema in the dermis, swollen endothelial cells, dilated small blood vessels, and fragmented neutrophil nuclei (referred to as karyorrhexis or leukocytoclasia) may also be present (Fig. 32-5). Fibrin deposition or neutrophils within the vessel walls (changes of “primary” leukocytoclastic vasculitis) are usually absent and the overlying epidermis is normal.1,2,23,167,168 However, the spectrum of pathologic changes described in cutaneous lesions of Sweet syndrome has expanded to include concurrent leukemia cutis, vasculitis, and variability of the composition or the location of the inflammatory infiltrate.3,191,491,496 Lymphocytes or histiocytes may be present in the inflammatory infiltrate of Sweet syndrome lesi ons.11,104,167,168,198–200,504 Eosinophils have also been noted in the cutaneous lesions from some patients with either idiopathic11,167,168,195,202–204,212 or drug-induced84,107,110,111

::

CONCURRENT LEUKEMIA CUTIS. In patients with hematologic disorders, Sweet syndrome may present as a paraneoplastic syndrome (signaling the initial discovery of an unsuspected malignancy), a drug-induced dermatosis (following treatment with either all-trans-retinoic acid, bortezomib, G-CSF, or imatinib mesylate), or a condition whose skin lesions concurrently demonstrate leukemia cutis.1 Acute leukemia (myelocytic and promyelocytic) is the most frequent hematologic dyscrasia associated with leukemia cutis (characterized by abnormal neutrophils) and Sweet syndrome (consisting of mature polymorphonuclear leukocytes) being present in the same skin lesion.1,70,71,93,109,165,205–211,497 Myelodysplastic syndrome and myelogenous leukemia (either chronic or not otherwise specified) are the other associated hematologic disorders that have been associated with concurrent Sweet syndrome and leukemia cutis.109 “Secondary” leukemia cutis, in which the circulating immature myeloid precursor cells are innocent bystanders that have been recruited to the skin as the result of an inflammatory oncotactic phenomenon stimulated by the Sweet syndrome lesions has been suggested as one of the hypotheses to explain concurrent Sweet syndrome and leukemia cutis in the same lesion.165,206,207 Alternatively, “primary” leukemia cutis, in which the leukemic cells within the skin constitutes the bonified incipient presence of a specific leukemic infiltrate is another possibility.207 Finally, it is possible that the atypical cells of leukemia cutis developed into mature neutrophils of Sweet syndrome as a result of G-CSF therapy-induced differentiation of the sequestered leukemia cells in patients with “primary” leukemia cutis who were being treated with this agent.205

Figure 32-4  Histopathologic presentation of acute febrile neutrophilic dermatosis (Sweet syndrome) demonstrates massive edema of the papillary dermis and a dense diffuse infiltrate of mature neutrophils throughout the upper dermis (hematoxylin and eosin stain). (From Cohen PR et al: Sweet’s syndrome in patients with solid tumors. Cancer 72:2723-2731, 1993, with permission.)

Chapter 32

An inflammatory infiltrate of mature polymorphonuclear leukocytes is the unifying characteristic of ­neutrophilic dermatoses of the skin and mucosa. ­Concurrent or sequential occurrence of Sweet syndrome with either erythema elevatum diutinum,340 neutrophilic eccrine hidradenitis,6 pyoderma gangrenosum,9,231,269,341,342,430,483,497 subcorneal pustular dermatosis,6,9 and/or vasculitis3,192,231 has been observed. Although these conditions can display similar clinical and pathologic features, the location of the neutrophilic infiltrate helps to differentiate them.6,120,499

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A

Figure 32-5  Characteristic histopathologic features of Sweet syndrome are observed at low (A) and high (B) magnification: papillary dermal edema, swollen endothelial cells, and a diffuse infiltrate of predominantly neutrophils with leukocytoclasia, yet no evidence of vasculitis (hematoxylin and eosin stain). (From Cohen PR et al: Concurrent Sweet’s syndrome and erythema nodosum: A report, world literature review and mechanism of pathogenesis. J Rheumatol 19:814-820, 1992, with permission.)

Sweet syndrome. Abnormal neutrophils (leukemia cutis)—in addition to mature neutrophils—comprise the dermal infiltrate in occasional Sweet syndrome patients with hematologic disorders.1,70,71,93,109,165,205–211 Pathologic findings of Sweet syndrome can also occur in extracutaneous sites. Often, these present as sterile neutrophilic inflammation in the involved organ. These changes have been described in the bones, intestines, liver, aorta, lungs, and muscles of patients with Sweet syndrome.2

OTHER LABORATORY TESTS

368

B

Peripheral leukocytosis with neutrophilia and an elevated erythrocyte sedimentation rate and are the most consistent laboratory findings in Sweet syndrome.23 However, leukocytosis is not always present in patients with biopsy-confirmed Sweet syndrome.26 For example, anemia, neutropenia, and/or abnormal platelet counts may be observed in some of the patients with malignancy-associated Sweet syndrome. Therefore, a complete blood cell count with leukocyte differential and platelet count, evaluation of acute phase reactants (such as the erythrocyte sedimentation rate or C-reactive protein), serum chemistries (evaluating hepatic function and renal function), and a urinalysis should be performed. It is also reasonable to perform a serologic evaluation of thyroid function since there appears

to be a strong association between thyroid disease and Sweet syndrome.1,2

SPECIAL TESTS EVALUATION FOR EXTRACUTANEOUS MANIFESTATIONS. Extracutaneous manifesta-

tions of Sweet syndrome may result in other laboratory abnormalities. Patients with central nervous system involvement may have abnormalities on brain SPECTs (single photon emission computed tomography), computerized axial tomography, electroencephalograms, magnetic resonance imaging, and cerebrospinal fluid analysis. Patients with kidney and liver involvement may demonstrate urinalysis abnormalities (hematuria and proteinuria) and hepatic serum enzyme elevation. And, patients with pulmonary involvement may have pleural effusions and corticosteroid-responsive ­culture-negative infiltrates on their chest roentgenograms.2,343

MALIGNANCY WORKUP. Recommendations for the initial malignancy workup in newly diagnosed Sweet syndrome patients without a prior cancer were proposed by Cohen and Kurzrock in 1993.15 Their recommendations were based upon the age-related recommendations of the American Cancer Society for

early detection of cancer in asymptomatic persons and the neoplasms that had concurrently been present or subsequently developed in previously cancer-free Sweet syndrome patients. The recommended evaluation included the following: 1. A detailed medical history 2. A complete physical examination, including: (a) examination of the thyroid, lymph nodes, oral

cavity, and skin;

(b) digital rectal examination; (c) breast, ovary, and pelvic examination in

women; and

(d) prostate and testicle examination in men.

DIFFERENTIAL DIAGNOSIS

Consider   Acral erythema   Erythema elevatum diutinum   Erythema multiforme   Halogenoderma   Lymphoma   Neutrophilic eccrine hidradenitis   Periarteritis nodosa   Urticaria   Viral exanthem Always Rule Out   Bacterial sepsis   Behcet’s disease   Bowel bypass syndrome   Dermatomyositis   Familial Mediterranean fever   Granuloma faciale   Leprosy   Lupus erythematosus   Lymphangitis   Metastatic tumor   Rheumatoid neutrophilic dermatitis   Rosacea fulminans   Schnitzler’s syndrome   Syphilis   Systemic mycosis   Thrombophlebitis   Tuberculosis Adapted from Cohen PR, Kurzrock R: Sweet’s syndrome and cancer. Clin Dermatol 11:149-157, 1993.

Acute Febrile Neutrophilic Dermatosis (Sweet Syndrome)

Since the initial appearance of dermatosis-related skin lesions had been reported to precede the diagnosis of a Sweet syndrome-associated hematologic malignancy by as long as 11 years, they also suggested that it was reasonable to check a complete blood cell count with leukocyte differential and platelet count every 6–12 months.2,15

Most Likely   Drug eruptions   Cellulitis   Chloroma   Erysipelas   Erythema nodosum   Leukemia cutis   Leukocytoclastic vasculitis   Panniculitis   Pyoderma gangrenosum

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(b) complete blood cell count with leukocyte differential and platelet count; (c) pap test in women; (d) serum chemistries; (e) stool guaiac slide test; (f) urinalysis; and (g) urine culture. 4. Other screening tests: (a) chest roentgenograms; (b) endometrial tissue sampling in either menopausal women or women with a history of abnormal uterine bleeding, estrogen therapy, failure to ovulate, infertility, or obesity; and (c) sigmoidoscopy in patients over 50 years of age.

Clinical Differential Diagnosis of Sweet Syndrome

Chapter 32

3. Laboratory evaluation: (a) carcinoembryonic antigen level;

TABLE 32-3

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CLINICAL DIFFERENTIAL DIAGNOSIS Sweet syndrome skin and mucosal lesions mimic those of other conditions (Table 32-3.)2,15,23,148,165,202,220,344,345,409, 421,448,498 Therefore, infectious and inflammatory disorders, neoplastic conditions, reactive erythemas, vasculitis, other cutaneous conditions, and other systemic diseases are included in the clinical differential diagnosis of Sweet syndrome.

HISTOLOGIC DIFFERENTIAL DIAGNOSIS The histologic differential diagnosis of Sweet syndrome includes conditions microscopically characterized by either neutrophilic dermatosis or neutrophilic panniculitis (eTable 32-3.1 in online edition).2–4,6,12,193,346–353,432,451

The pathologic changes associated with Sweet syndrome are similar to those observed in an abscess or cellulitis; therefore, culture of lesional tissue for bacteria, fungi, and mycobacteria should be considered to rule out infection.23 Leukemia cutis not only mimics the dermal changes of Sweet syndrome, but can potentially occur within the same skin lesion as Sweet syndrome; however, in contrast to the mature polymorphonuclear neutrophils found in Sweet syndrome, the dermal infiltrate in leukemia cutis consists of malignant immature leukocytes.354 The pathologic changes in the adipose tissue of subcutaneous Sweet syndrome lesions can be found in either the lobules, the septae, or both; therefore, conditions characterized by a neutrophilic lobular panniculitis also need to always be considered and ruled out.2,4

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COMPLICATIONS Complications in patients with Sweet syndrome can be directly related to the mucocutaneous lesions or indirectly related to the Sweet syndrome-associated conditions. Skin lesions may become secondarily infected and antimicrobial therapy may be necessary. In patients with malignancy-associated Sweet syndrome, reappearance of the dermatosis may herald the unsuspected discovery that the cancer has recurred. Systemic manifestations of Sweet syndrome-related conditions—such as inflammatory bowel disease, sarcoidosis and thyroid diseases—may warrant diseasespecific treatment.

PROGNOSIS AND CLINICAL COURSE The symptoms and lesions of Sweet syndrome eventually resolved without any therapeutic intervention in some patients with classical Sweet syndrome. However, the lesions may persist for weeks to months.10,23,254,355 In patients with malignancy-associated Sweet syndrome, successful management of the cancer occasionally results in clearing of the related dermatosis.13,15,23 Similarly, discontinuation of the associated medication in patients with drug-induced Sweet syndrome is typically followed by spontaneous improvement and subsequent resolution of the syndrome.13,15,23 Surgical intervention has also resulted in the resolution of Sweet syndrome in some of the patients who had associated tonsillitis, solid tumors, or renal failure.1,2,19,315,356,357,507 Sweet syndrome may recur following either spontaneous remission or therapy-induced clinical resolution.10 The duration of remission between recurrent episodes of the dermatosis is variable. Sweet syndrome recurrences are more common in cancer patients; in this patient population, the reappearance of dermatosis-associated symptoms and lesions may represent a paraneoplastic syndrome that is signaling the return of the previously treated malignancy.1,2,15,135

Potassium iodide and colchicine are also first-line systemic treatments for Sweet syndrome (eTable 32-3.2 in online edition).10,12,17,20,23,30,49,70,143,184,198,203,221,223,231, 240,245,250,259,261,281,284,294,296,329,359–363,368–384,468,496 Vasculitis and hypothyroidism are potential drug-induced side effects of potassium iodide.385 Gastrointestinal symptoms such as diarrhea, abdominal pain, nausea, and vomiting are potential adverse effects from colchicine which may improve after lowering the daily dose of the drug.2 Second-line systemic agents for Sweet syndrome include indomethacin,259,261,284,378,490 clofazimine,12,296,379 cyclosporine,12,30,231,294,380,381 and dapsone17,20,30,203,221,245,284, 372,382–384,459,460,486 (eTable 32-3.2 in online edition). They have all been used as monotherapy either in the initial management of the patient or after first-line therapies has failed. In addition, cyclosporine and dapsone have been used in combination therapy either as a corticosteroid-sparing agent or with other drugs.1,2,7,303 There are certain patients whose Sweet syndrome lesions have improved after receiving systemic antibiotics7,412: individuals with Staphylococcus aureus secondarily impetiginized lesions treated with an antimicrobial agent to which their bacterial strain is susceptible,23 patients with inflammatory bowel disease treated with metronidazole,267,387 and persons with dermatosis-related Yersinia125,126 or Chlamydia306,307 infection treated with either doxycycline,125,389 minocycline,30,126 or tetracycline.306,307,388 In addition, effective treatment of Sweet syndrome has also been described, predominantly in case reports, with other drugs: cytotoxic chemotherapies and antimetabolites (chlorambucil and cyclophosphamide),30,39,148,200,251,360,390 danazol,9 etretinate,361 hepatitis therapy,9 immunoglobulin,303 interferon α,202,366 and tumor necrosis factor antagonists444 (adalimumab,501 etanercept,392,404 infliximab,264,265,278,266,501 and thalidomide5,393). Anakinra (an interleukin-1 receptor antagonist), in combination with oral prednisone, was promptly effective in resolving the symptoms—and subsequently the clinical lesions—of Sweet syndrome in a patient with long-standing disease that was refractory to other therapies.399 Pentoxifylline was hypothesized to be beneficial for treating Sweet syndrome394,395; however, when used as monotherapy, it was not found to be efficacious.1,2,7,295,362

KEY REFERENCES

TREATMENT

Full reference list available at www.DIGM8.com

Systemic corticosteroids are the therapeutic mainstay for Sweet syndrome (eTable 32-3.2 in online edition).7,8–10,12,16,17,19,20,23,36,49,50,70,184,223,233,240,250,284,358–361  Initiation of therapy promptly results in improvement of the symptoms and resolution of the mucocutaneous lesions. Daily pulse methylprednisolone administered intravenously may be necessary in patients with refractory disease. Topical (such as 0.05% clobetasol propionate)13,19–21,30,234,362–365 or intralesional (such as triamcinolone acetonide at a dose between 3.0 and 10.0 mg/cc)362,366,367 corticosteroids may be effective for treating localized Sweet syndrome lesions.1,2,7,9

1. Cohen PR, Kurzrock R: Sweet’s syndrome revisited: A review of disease concepts. Int J Dermatol 42:761-778, 2003 2. Cohen PR: Sweet’s syndrome—A comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis 2:34, 2007 (26 July (2007). http://www.ojrd.com/ contents/2/1/34 3. Cohen PR: Skin lesions of Sweet syndrome and its dorsal hand variant contain vasculitis: An oxymoron or an epiphenomenon? Arch Dermatol 138:400-403, 2002 4. Cohen PR: Subcutaneous Sweet’s syndrome: A variant of acute febrile neutrophilic dermatosis that is included in the histologic differential diagnosis of neutrophilic panniculitis. J Am Acad Dermatol 52:927-928, 2005

DVD contains references and additional content

5. Cohen PR: Sweet’s syndrome and relapsing polychondritis: Is their appearance in the same patient a coincidental occurrence or a bonified association of these conditions? Int J Dermatol 43:772-777, 2004 6. Cohen PR: Neutrophilic dermatoses occurring in oncology patients. Int J Dermatol 46:106-111, 2007 7. Cohen PR, Kurzrock R: Sweet’s syndrome: A review of current treatment options. Am J Clin Dermatol 3:117-131, 2002 8. Cohen PR: Iotaderma #120 (Gomm-Button disease: Sweet’s syndrome). J Am Acad Dermatol 50:100, 274, 2004 9. Cohen PR: Neutrophilic dermatoses: A review of current treatment options. Am J Clin Dermatol 10:301-312, 2009

10. Cohen PR, Almeida L, Kurzrock R: Acute febrile neutrophilic dermatosis. Am Fam Physician 39(3):199-204, 1989 14. Cohen PR, Kurzrock R: Diagnosing the Sweet syndrome. Ann Intern Med 110:573-574, 1989 15. Cohen PR, Kurzrock R: Sweet’s syndrome and cancer. Clin Dermatol 11:149-157, 1993 22. Cohen PR, Kurzrock R: The pathogenesis of Sweet’s syndrome [letter]. J Am Acad Dermatol 25:734, 1991 23. Cohen PR, Kurzrock R: Sweet’s syndrome: A neutrophilic dermatosis classically associated with acute onset and fever. Clin Dermatol 18:265-282, 2000 26. Cohen PR, Talpaz M, Kurzrock R: Malignancy-associated Sweet’s syndrome: Review of the world literature. J Clin Oncol 6:1887-1897, 1988

PG is more frequent in female patients and occurs at any age, but usually between 40 and 60 years. The majority of patients with PG have other systemic diseases (such as arthritis, inflammatory bowel disease, hematological dyscrasias, malignant disease, etc.), but PG occurs independently of these disorders. PG may present as ulcerative, bullous, pustular, or vegetative variants. Clinical features of different variants sometimes overlap in individual patients but usually one variant dominates the clinical picture.

EPIDEMIOLOGY The prevalence of pyoderma gangrenosum (PG) is unknown. Estimates have suggested that approximately three cases of PG per million of the population occur per year, with most large referral centers seeing one to two cases per year.1 It has been reported in all age groups but mainly affects adults between

There is no laboratory test or investigation that establishes the diagnosis of PG with certainty. The histopathological findings are not diagnostic but can be supportive of the diagnosis of PG in the appropriate clinical setting and are essential to rule out alternative diagnoses.

Pyoderma Gangrenosum

Pyoderma gangrenosum (PG) is a rare inflammatory disease of unknown etiology characterized by sterile neutrophilic infiltration of the skin. Similar neutrophilic infiltrations may occur in other organs. It is considered to be one of the groups of neutrophilic dermatoses and clinical and histological overlap with some of these may occur.

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PYODERMA GANGRENOSUM AT A GLANCE

Chapter 33

Chapter 33 :: Pyoderma Gangrenosum :: Frank C. Powell, Bridget C. Hackett, & Daniel Wallach

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Specified criteria (see below) suggest the diagnosis of PG, but other conditions (particularly infection, vascular disease, and malignancy) must be excluded. The mainstays of management are systemic immunosuppressive agents together with appropriate local and topical therapy. Ulcerative PG is a chronic disease. Remission usually requires months of treatment; maintenance therapy is necessary in many and relapses are common. Significant morbidity and mortality are experienced by patients with ulcerative and bullous PG.

the ages of 40 and 60 years.2 Most reported series of patients with PG indicate a moderate preponderance of females. PG often occurs in patients who have other diseases (arthritis, inflammatory bowel disease, hematologic dyscrasias, etc.), but is not a manifestation or complication of these diseases and its clinical course is usually unrelated to their severity or activity.3

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Approach to the patient with pyoderma gangrenosum

General examination Detailed history (includes drugs, trauma, systems review)

Detailed lesions: location, type, size, outline, depth

Clinical impression of pyoderma gangrenosum

Investigations

Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

Routine tests: Full blood count + differential Erythrocyte sedimentation rate Renal/liver/bone profiles Serum iron Autoantibody screen Antineutrophilic cytoplasmic antibody (pANCA, cANCA) Anti-phospholipid antibody screen Rheumatoid factor Serum protein electrophoresis Thyroid function tests Chest x-ray, electrocardiogram Swab for culture

Skin biopsies: In formalin for histology (hematoxylin and eosin, periodic acid-Schiff, Giemsa, Fite, Gram stain, and other stains) Fresh tissue for culture (bacterial, mycobacterial, atypical mycobacterial, fungal)

Rule out differentials: Vascular disease, infections, malignancy, other neutrophilic dermatoses, facticial disorder

Classify to subgroup

Ulcerative

Bullous

Pustular

Other tests as indicated: α1-antitrypsin level Serum bromide/iodide Blood cultures Coagulation screen Cryoglobulins, cryofibrinogens Cold agglutinins Serum B12/folate Antistreptolysin 0 titer Hepatitis/human immunodeficiency virus screening Syphilis serology screen Midstream specimen of urine Bence-Jones protein Computed tomography scan (if deep accesses are likely) Vascular studies Endoscopy (upper and/or lower) Bone marrow aspirate

Vegitative

Consider associated diseases

– Frequent Arthritis, inflammatory bowel disease, monoclonal gammopathy, malignancy

– Frequent Hematologic dyscrasias/malignancy

– Frequent Inflammatory bowel disease

– Uncommon Chronic renal impairment

Figure 33-1  Approach to the patient with pyoderma gangrenosum.

ETIOLOGY AND PATHOGENESIS

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The etiology of PG is unknown, and its pathogenesis poorly understood. Based on the presence of a lymphocytic infiltrate at the active advancing border of PG lesions, it has been postulated that lymphocytic antigen activation occurs with cytokine release and neutrophil recruitment. This may take place not only in the skin but also in other tissues such as the lung, intestine, and joints. The predominance of the neutrophilic infiltrate in established lesions of PG have led to its classification as one of the neutrophilic dermato-

ses.4 Clinical (and to an extent histologic) overlap occurs with the other dermatoses in this category, especially atypical or bullous forms of Sweet syndrome (see Chapter 32). Several of the neutrophilic dermatoses (Sweet syndrome, erythema elevatum diutinum, subcorneal pustular dermatosis, and PG) share an association with immunoglobulin A monoclonal gammopathy, and diseases such as inflammatory bowel disease and hematologic disorders occur more frequently than expected in these patients. The recent description of the PAPA (Pyogenic Arthritis, Pyoderma gangrenosum-Acne) syndrome,5 a disease considered to be one of the “autoinflammatory”

­ iseases, raises the possibility that PG may lie within d this spectrum.

CLINICAL FINDINGS

Figure 33-2  Several pathergic pyoderma gangrenosum lesions occurring along a thoracotomy scar site. Note central ulceration, violaceous borders, and peripheral rim of erythema.

PG is protean in its clinical expression with variable presentation according to the variant and the stage of disease. Lesions can be classified morphologically as being (1) ulcerative (the commonest and originally described variant), (2) bullous, (3) pustular, or (4) vegetative. Although some patients may show more than one variant (e.g., isolated pustular lesions frequently occur in patients with ulcerative PG), usually one variant of PG dominates the clinical picture and the patient should be classified accordingly. The most common initial clinical lesion in a patient with ulcerative PG is an inflammatory pustule or nodular furuncle (these lesions are usually single but may be multiple). They erupt on apparently normal skin (the most common site being the leg), or sometimes at the site of trauma or surgery (Fig. 33-2). The enlarging initial lesion develops a surrounding areola or zone of erythema that extends into the surrounding skin (Fig. 33-3). As it enlarges, the center degenerates, crusts, and erodes, converting it into an eroding ulcer the development of which is accompanied by an alarming increase in the severity of the pain. The ulcer often has a bluish/ violaceous edge (due to undermining by the necrotizing inflammatory process) and the base is covered with purulent material. Ulcerative PG may erode deeply with exposure of muscle or tendon in some cases. Bullous PG (sometimes called atypical PG) presents as a painful, rapidly expanding superficial inflammatory blister that quickly erodes. In the early acute stage, the bullous nature of the lesion is evident, but because the roof of the blister necroses rapidly, close inspection of the border of established lesions is necessary to reveal its bullous nature (Fig. 33-4). Bullous PG is commonly associated with hematologic disease and most

Figure 33-3  Established lesion of ulcerative pyoderma gangrenosum showing well-defined ulceration with surrounding zone of erythema.

Pyoderma Gangrenosum

A patient with PG usually complains of severe pain that is out of proportion to the clinical appearance of the lesion. Approximately 25% of patients note the onset of PG at sites of cutaneous trauma (needle stick, inoculation site, insect bites, or surgical procedures). This is called the pathergic phenomenon (Fig. 33-2). Lesions progress rapidly (with the exception of vegetative PG) and cutaneous destruction evolves over days rather than weeks. Special inquiry regarding drug intake (especially iodides/bromides, hydroxyurea); exposure to and symptoms of infectious diseases (Box 33-1); symptoms relating to the musculoskeletal system (joint pains, swelling, etc.), the gastrointestinal tract (abdominal pain, diarrhea, constipation, etc.), hematologic disease (tiredness, anemia, bruising, blood clotting disorders, etc.), ­respiratory disease, and nonspecific but potential

CUTANEOUS LESIONS: CLINICAL VARIANTS OF PG

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HISTORY

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Chapter 33

The approach to an individual suspected of having PG is outlined in the patient algorithm (Fig. 33-1). The clinical presentation of PG may be diverse and there is neither a diagnostic laboratory test nor pathognomonic histopathologic findings. Therefore, it is important to avoid misdiagnosing other diseases as PG.6 The most important considerations are the exclusion of infection (bacterial, viral, and deep fungal), vascular disease (stasis, occlusion, and vasculitis), and malignancy in every patient. Close follow-up and reevaluation (with repeated skin biopsies, tissue and swab cultures, and other tests as clinically indicated) is an important part of the ongoing evaluation of patients with suspected PG, particularly those who show a poor response to therapy.

malignancy-related symptoms, such as weight loss and fatigue, should be made.

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BOX 33-1  Differential Diagnosis of Pyoderma Gangrenosum (PG)

Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

VARIANT SPECIFIC Ulcerative PG

SITE SPECIFICa Parastomal

  Most Likely   Vascular    Venous stasis ulceration    Occlusive disease/Arteritis    Vasculitis    Antiphospholipid–antibody syndrome   Malignancy    Primary or secondary   Infection    Bacterial    Mycobacterial/Atypical mycobacterial    Viral (herpes simplex)   Deep fungal infection (Sporotrichosis, Aspergillus, Cryptococcus)   Other   Drugs (halogenoderma/hydroxyurea, etc.)   Consider   Infection    Necrotizing fasciitis    Syphilis/Amebiasis/Mucormycosis    Histoplasmosis/Rhizopus   Other    Dermatitis artefacta    Calciphylaxis/Insect bite (spider)

  Most Likely   Dermatoses (extraintestinal Crohn’s)    Irritant/Allergic contact dermatitis    Other (e.g., psoriasis)   Infection   Bacterial (Staphylococcus/Streptococcus)/Cellulitis    Fungal (Candida)   Other    Extraintestinal inflammatory    Bowel disease    Malignancy

Bullous PG   Most Likely   Infection    Bacterial (cellulitis/impetigo)    Viral (in immunocompromised)    Fungal (mucormycosis in diabetics)   Other    Sweet syndrome/Behçet disease   Consider   Bullous dermatoses   Erythema multiforme/Bullous pemphigoid   Other    Insect/Arthropod bite/Malignancy Pustular PG   Most Likely   Infection    Bacterial/Viral/Fungal   Vasculitis    Pustular vasculitis   Consider   Other    Pustular psoriasis    Sneddon–Wilkinson disease    Pustular drug eruption    Bowel bypass syndrome    Pyostomatitis vegetans

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In Wounds   Most Likely   Infection    Bacterial/Cellulitis    Fungal (e.g., mucormycosis)   Breakdown    Suture allergy    Mechanical   Consider    Malignancy Genital   Most Likely   Infection   Bacterial/Viral infection (herpes simplex virus, Epstein–Barr virus, cytomegalovirus)    Tuberculosis/Tuberculide    Fournier gangrene   Malignancy    Squamous cell/Extramammary    Paget disease   Consider   Infection    Syphilis/Lymphogranuloma    Venereum/Histoplasmosis    Leishmaniasis/Granuloma inguinale   Other    Dermatitis artefacta    Behçet disease Head and Neck   Most Likely   Infection    Bacterial/Viral/Fungal    Dissecting cellulitis of the scalp   Malignancy    Squamous cell carcinoma    Basal cell carcinoma   Consider   Vasculitis    Granulomatosis with polyangiitis (Wegener’s)    Malignant pyoderma (continued)

BOX 33-1  Differential Diagnosis of Pyoderma Gangrenosum (PG) (Continued)

a

SITE SPECIFICa   Other    Dermatitis artefacta

The differential diagnosis of lower limb PG is essentially that delineated for variant-specific ulcerative PG.

RELATED PHYSICAL FINDINGS The clinician should be aware that sterile neutrophilic abscesses of internal organs (lung, bone joints, CNS, CVS, intra-abdominal viscera, eye) can occur in association with or even precede the onset of cutaneous PG.7 In the patient without cutaneous lesions surgical procedures may be undertaken to establish the

Figure 33-5  Pustular pyoderma gangrenosum lesions of the penis in a patient who also had ulcerative pyoderma gangrenosum.

Pyoderma Gangrenosum

Figure 33-4  Bullous pyoderma gangrenosum lesion showing collapsed roof of blister and superficial erosive quality of the subsequent ulceration.

recently been reported as an autosomal dominant condition classified as being one of the group of “autoinflammatory” diseases.

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often appears on the upper limbs.2 This variant of PG may show clinical and histological overlap with Sweet Syndrome (one of the neutrophilic dermatoses which is itself often associated with hematologic disease). Pustular PG (also called the pustular eruption of inflammatory bowel disease) is a generalized eruption that occurs almost exclusively in the setting of an exacerbation of acute inflammatory bowel disease (usually ulcerative colitis). Its onset is dramatic, with the rapid development of multiple, large, circular-to-oval, painful pustules on the trunk and, to a lesser extent, the face and limbs (Fig. 33-5). Control of this eruption is difficult without controlling the bowel disease, which in some cases requires extensive resective surgery. Vegetative PG (or superficial granulomatous pyoderma) usually presents as a single furunculoid nodule, abscess, plaque, or superficial ulcer, typically on the trunk (Fig. 33-6). In contrast to other variants, it is gradual in its onset, mild in the discomfort it generates, and not usually associated with the presence of systemic disease. This form of PG is usually more responsive to localized or mild forms of systemic therapy than the other variants.7 Postoperative and Peristomal PG are considered to be examples of ulcerative PG demonstrating the pathergic phenomenon, while the PAPA syndrome has

Chapter 33

VARIANT SPECIFIC Vegetative PG   Most Likely   Infection    Bacterial/Viral/Fungal    Mycobacterial/Atypical mycobacterial    Leishmaniasis   Consider   Blastomycosis-like pyoderma   Dermatitis artefacta/Malignancy   Pyoderma vegetans

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Figure 33-7  Chest X-ray showing neutrophilic abscess in the right upper lung with clear fluid level visible. Figure 33-6  Vegetative pyoderma gangrenosum—an indolent area of chronic inflammation and ulceration that was present for months. ­ iagnosis of the internal neutrophilic infiltration, the d wounds of which may subsequently break down and present as postoperative PG. Because many patients with PG also have diseases of other systems (more than 70% of cases), a thorough physical examination is mandatory with particular search for clinical and ­biological markers of inflammatory bowel disease, arthritis, vasculitis (leukocytoclastic/granulomatous/ cryoglobulinemic/Takayasu arteritis), hematologic disease (monoclonal gammopathy and other dyscrasias), and internal malignancy.

LABORATORY TESTS ROUTINE INVESTIGATIONS (See Fig. 33-1) All patients with PG should have the following tests carried out: full blood cell count with differential white cell count and erythrocyte sedimentation rate liver, and bone profiles; autoantibody screen (including antiRo/La antibodies, antineutrophilic cytoplasmic antibodies, antiphospholipid antibodies, rheumatoid factor); serum protein electrophoresis; thyroid function studies; chest X-ray (Fig. 33-7), electrocardiogram, and midstream specimen of urine; and swabs from lesions sent for bacterial, fungal, and viral cultures. An incisional, wedge skin biopsy should be taken from the edge of the lesion sampling a portion of normal skin progressing through the border into the area of active inflammation to allow the various histological patterns to be discerned. The excised tissue should then be divided with one section (fresh tissue) sent for bacterial, mycobacterial, and fungal culture, and another portion sent in formalin for histological evaluation requesting hematoxylin and eosin and periodic acidSchiff, Giemsa, Fite, Gram, and other stains considered relevant. Although immunofluorescent studies may show positive vascular staining in perilesional skin, this is not essential for diagnostic purposes and can be

omitted unless vasculitis is suspected in the differential diagnosis.

HISTOPATHOLOGY The histopathological changes in the skin are not diagnostic but can be highly suggestive of PG and require experience to interpret. The inflammatory changes that are seen depend on (1) the clinical variant of PG (ulcerative, bullous, pustular, or vegetative), (2) the timing of the biopsy (early lesions show less marked changes than established lesions), and (3) the site of the biopsy relative to the inflammatory process.8 The site of the biopsy is particularly important because biopsies taken from the center of established ulcerative, bullous, or pustular PG lesions usually show marked neutrophilic infiltration with abscess formation in the mid and deep dermis extending to the panniculus, whereas those taken from peripheral areas (the ulcer edge or inflammatory zone of erythema) show a mixed or predominantly lymphocytic inflammatory infiltrate. A marked perivascular lymphocytic infiltration is seen in biopsies taken from the “zone” or area of erythema which surrounds active lesions of ulcerative PG. Lymphocytes may be seen to infiltrate vessel walls with intramural and intravascular fibrin deposition indicative of vascular damage (sometimes called lymphocytic vasculitis).9 Abscess formation with intense dermal neutrophilic infiltration extending to the panniculus and areas of tissue necrosis dominates the histological findings in biopsies taken from central areas of ulcerative PG lesions. Leukocytoclasis is not a prominent finding and although occasionally evidence of leukocytoclastic vasculitis is seen close to the abscess center, this is a minor feature and considered secondary to the intense inflammatory changes rather than the primary event. Histological examination of lesional skin from a patient with bullous PG shows a subepidermal or intraepidermal bulla with overlying epidermal necrosis and marked upper dermal edema with prominence of neutrophils. Biopsy of pustular PG shows a dense dermal neutrophilic infiltration (often centered about a follicle) with subepidermal edema and infiltration of neutrophils into the epidermis with

subcorneal aggregations. Vegetative PG is characterized histologically by the presence of pseudoepitheliomatous hyperplasia, sinus tract formation, and the presence of palisading granulomas in the setting of focal dermal neutrophilic abscesses.

SPECIAL INVESTIGATIONS

DIFFERENTIAL DIAGNOSIS

morphologic descriptions outlined above (ulcerative, bullous, pustular, or vegetative) in a (usually middle-aged) apyrexial patient without significant toxemia or relevant drug intake (b) Histological evidence of marked tissue neutrophilia in the absence of significant leukocytoclastic vasculitis and histopathological exclusion of malignancy and of infective organisms by special studies and negative tissue culture (c) Exclusion of vascular stasis/occlusion/ vasculitis by appropriate studies 2. Minor criteria that are supportive of the diagnosis are as follows: (a) Localization of lesions at characteristic sites (ulcerative PG on the legs, vegetative on the trunk, bullous PG on the upper limb, pustular PG on the trunk or face) or at a site of cutaneous trauma (postoperative ulcerative PG or peristomal PG). (b) Rapid progression of the inflammatory lesion with escalating pain severity (except vegetative PG). (c) Occurrence in an individual with systemic disease, such as arthritis, inflammatory bowel disease, or hematological dyscrasias (except vegetative PG). (d) Rapid reduction of pain and inflammation on initiation of systemic steroid therapy.

PROGNOSIS AND CLINICAL COURSE The prognosis depends on the PG variant; the age and sex of the patient; presence of other systemic disease; and the type, dosage, and duration of therapy required to bring the disease under control. Patients with vegetative PG generally have a good prognosis and the skin lesions often heal within 6 months of the initiation of relatively mild forms of treatment.7 Peristomal PG similarly has a good prognosis often responding to topical or intralesional therapy. Patients with pustular PG often have complete remission of their cutaneous lesions if the severe inflammatory bowel disease that usually accompanies this variant is controlled. Ulcerative PG is a chronic recurrent disease with a significant morbidity and mortality.2,10 Patients with this variant older than 65 years of age and male patients seem to have a worse prognosis. Patients with bullous PG who have an associated hematological disorder also have a poor prognosis. The onset of bullous PG in a patient with stable polycythemia rubra vera appears to herald the onset of leukemic change in some patients.11

Pyoderma Gangrenosum

1. Major criteria are as follows: (a) Sudden onset of a painful lesion fitting the

Active or poorly controlled cutaneous PG causes significant morbidity (loss of mobility, pain, exposure to secondary infection, anemia of chronic disease, etc.). Lack of recognition of the neutrophilic infiltration of internal organs in PG may lead to unnecessary surgical procedures. Many of the treatments for PG must be administered for many months and may have significant side effects. Frequent monitoring and follow-up of patients are necessary. Elective surgery should be undertaken with caution because of the possibility of inducing new PG lesions.

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The differential diagnosis to be considered in a patient with PG is extensive.6 Different variants of PG (ulcerative, bullous, vegetative, pustular) suggest alternative diagnoses and the occurrence of PG at certain cutaneous sites raises further diagnostic issues for the clinician, as shown in Box 33-1. Because there is no confirmatory diagnostic test for PG, the following major criteria are proposed which make the diagnosis of PG likely:

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Chapter 33

In some patients the following additional tests may be warranted: endoscopy (upper and/or lower gastrointestinal); vascular studies; bone marrow aspirate examination; ultrasound of abdomen (including liver/ spleen/aorta); computed tomography of the thorax, abdomen, or brain; and other directed investigations as outlined in Fig. 33-1.

COMPLICATIONS

TREATMENT GENERAL MEASURES The age, mobility, social support networks, pain threshold, extent and severity of disease, and ability to comply with therapeutic measures should be evaluated for each patient and the treatment adapted accordingly. The patient should be given realistic expectations of the speed of recovery likely in this disease. Thus, although lesions develop and evolve within days, the healing process usually takes weeks or even months. Adequate bed rest, efficient pain relief, correction of anemia, and appropriate therapy of any associated disease are pivotal in the overall management strategy of a patient with PG.12 If other systemic illnesses are present, cooperation with an internal medicine specialist is important, and if surgery is anticipated appropriate measures (such as the use of subcuticular sutures and systemic steroid cover) should be adopted to avoid precipitating new postoperative PG lesions.

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The location, morphology, size, and outline of each lesion should be recorded (by photography and by using a calibrated transparent plastic sheet placed over lesions on which the outline is traced) on presentation and subsequent review.

WOUND CARE

Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

The cutaneous lesions of PG are usually extremely tender so cleansing should be carried out daily with tepid sterile saline or a mild antiseptic solution. Potassium permanganate solution diluted 1:2,000 is helpful if there is marked exudation. Silver sulphadiazine 1% cream is usually soothing when applied to the ulcerated lesions of PG and may facilitate granulation tissue formation as well as inhibiting bacterial growth. A nonadhesive dressing should be applied over the lesion and held in place with a crêpe elasticized bandage wound firmly, but not tightly, over it. Some patients, particularly those with superficial lesions, obtain significant relief with the use of hydrocolloid dressings, which can be left on for 2–3 days and “melt” into the lesion. Careful instruction to the patient and nurse is important to ensure compliance and to avoid the use of irritants such as chemical desloughing agents, caustics (such as silver nitrate), or dressings (such as gauze impregnated with soft paraffin and/or antibacterial agents which may adhere to the ulcer base) or pressure dressings as are sometimes prescribed for patients with ulcers due to venous insufficiency. A variety of bacteria may be cultured from the wound surface, but these usually represent contaminants and directed antibiotic therapy is not required unless there are clinical signs of incipient cellulitis around the wound.

TOPICAL TREATMENTS Topical treatments are important adjuncts to the systemic treatment needed for the management of most PG patients, and may be sufficient to bring the condition under control in those who have vegetative or mild ulcerative PG. Potent topical corticosteroids applied to the periphery of an active PG lesion can reduce inflammation and may be sufficient to heal vegetative or peristomal ulcerative PG.13 Although topical disodium cromoglycate (with or without occlusion), benzoyl peroxide, nicotine cream or patches, hyperbaric oxygen, and radiotherapy have all been reported as being helpful in individual patients with PG, their effectiveness has not been established. Clinical impression suggests that topical tacrolimus (with or without occlusion) is particularly effective for isolated pustular lesions and for the superficial ulcerations of peristomal PG.

INTRALESIONAL TREATMENTS

378

Intralesional triamcinolone acetonide (5–10 mg/mL) injected twice weekly into the border of a vegetative or peristomal PG lesion may lead to healing and can also

be useful in a patient with ulcerative PG if one section of the ulcer is proving recalcitrant to other therapies. Intralesional cyclosporine and tacrolimus have also been reported to be effective in some PG patients.

SYSTEMIC TREATMENTS Because PG is a rare disease, most systemic treatment recommendations are based on experience gained from small series of patients studied.14 The main systemic treatments used for PG with their suggested dosages are listed in Box 33-2. As experience with newer agents is gained, it is likely these recommendations will change.15 The initiation of systemic therapy is based on the variant of PG (ulcerative and bullous PG usually require systemic therapy), the rapidity of its evolution, the extent of cutaneous involvement, and the general medical status of the patient. Systemic corticosteroid treatment is probably the initial treatment of choice for most patients with PG. It is important to initiate systemic steroids at a sufficiently high dose to control the disease. Rapid diminution of pain is often recorded by the patient after initiation of therapy and steroids should be continued at this dosage until lesions show evidence of healing, after which gradual tapering of the dose can be undertaken. A steroid-sparing agent should be added as soon as possible, as well as bone protective measures to diminish the risk of osteoporosis because prolonged therapy can be anticipated in most patients. Intravenous corticosteroids in pulsed doses have been used to induce PG remission, but serious potential adverse effects limit their use to exceptional circumstances. Dapsone has been traditionally used in the treatment of PG and remains a useful drug, particularly when used in conjunction with systemic corticosteroids. Dapsone is generally well tolerated, but hematological complications (including agranulocytosis, hemolysis, hemolytic anemia, and methemoglobulinemia) as well as other potentially serious side effects may occur. Other antimicrobial agents reported as successful in

BOX 33-2  Systemic Treatments for Pyoderma Gangrenosum MEDICATION

DOSAGE

Prednisone Methylprednisolone (pulsed dose) Dapsone Clofazimine Minocycline Cyclosporine Tacrolimus Mycophenolate mofetil Infliximab

0.5–1.5 mg/kg/day PO 500 mg–1 g IV 50–200 mg/day PO 200–400 mg/day PO 50–100 mg twice daily PO 3 to 5 mgs/kg/day PO 0.1–0.3 mg/kg PO 500 mg–1 g bid PO 5 mg/kg IV

donor sites, but cultured tissue allografts/autografts and the use of bovine collagen matrix have been reported to be useful in patients in whom the disease is controlled but reepithelialization incomplete.23 The unpredictable nature of PG and its variable aggressiveness in individual patients mean that a flexible approach to treatment is required and the use of therapeutic agents have to be adapted to the patient’s physiologic state (childhood, pregnancy, old age). By whichever modality control of PG is achieved, maintenance therapy should be continued until there is complete wound healing. In addition, patients with ulcerative PG have a significant risk of relapse, so longterm follow-up is required.

PREVENTION

:: Pyoderma Gangrenosum

A patient who has had a history of PG should be advised to avoid trauma to the skin as there is the possibility of precipitating a new lesion (the pathergic phenomenon). If such patients have to undergo surgery, they should have close supervision by a dermatologist of their postoperative course. Patients with a history of aggressive PG may warrant a course of systemic steroids during and for a period (2 weeks or longer) postoperatively to prevent the development of new PG lesions and subcuticular sutures should be used where possible. Patients with a history of PG and Crohn’s disease who are to have an ileostomy should be warned about the possible development of peristomal PG lesions.

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Chapter 33

the treatment of PG patients include rifampicin, tetracyclines, vancomycin, mezlocillin, clofazimine, and minocycline. These have usually been prescribed in combination with other systemic therapies and seem to work in PG patients by mechanisms other than their antibacterial properties. Most experience has been with clofazimine and minocycline (100–200 mg daily). The latter agent is well tolerated and often allows for a reduction in systemic corticosteroid dosage and appears to prolong remission in some patients. Cyclosporine is an alternative first-line therapy of PG16 or may be used in combination with systemic corticosteroids to achieve rapid control of disease. Doses of 3 to 5 mgs/kg/day have shown efficacy and continued treatment is usually required for 3–4 months. Less risk of serious side effects (such as impairment of renal function and hypertension) is seen at these low doses, but careful monitoring of patients is required and attention should paid to the possibility of other drugs interacting with this medication. Tacrolimus (FK-506) and mycophenolate mofetil have also been used successfully in the treatment of PG either as monotherapies or in combination with systemic corticosteroids or cyclosporine.17 Both drugs cause significant immunosuppression with resultant susceptibility of the patient to infection and malignant disease and can have other potentially serious side effects. Infliximab, an antitumor necrosis factor antibody, has been used successfully to treat patients with inflammatory bowel disease and has been reported to be effective in some patients with PG.18 Other similar drugs that have been reported to be efficacious in the treatment of patients with PG include etanercept and adalimumab. The role of these agents in the management of PG has yet to be fully defined and susceptibility to reactivation of tuberculosis infection and other significant side effects remain a concern. Anakinra, an IL-1 receptor antagonist has been reported to be effective in treating PG of the PAPA syndrome and suggests another possible treatment for this condition.5 The use of thalidomide in the treatment of PG has probably been superseded by the development of these other agents. Other drugs which have been reported to be helpful in the treatment of PG include azathioprine (thiopurine methyl transferase levels should be checked pretreatment), colchicine,19 cyclophosphamide, chlorambucil, and melphalan. These agents can have toxic effects and evidence of their efficacy is ­limited. Other modalities which have been reported to be useful in the management of individual patients or small series of patients with PG include human intravenous immunoglobulin,20 interferon-α, nicotine,21 potassium iodide, leukocytapheresis,22 and plasma exchange. Skin grafting should be avoided if possible because of the risk of inducing new PG lesions at the

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Powell FC, Su WP, Perry HO: Pyoderma gangrenosum: Classification and management. J Am Acad Dermatol 34:395, 1996 2. Bennett ML et al: Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions. Medicine (Baltimore) 79:37, 2000 3. Powell FC et al: Pyoderma gangrenosum: A review of 86 patients. Q J Med 55:173, 1985 4. Wallach D, Vignon-Pennamen MD: From acute febrile neutrophilic dermatoses to neutrophilic disease: Forty years of clinical research. J Am Acad Dermatol 55:1066-1071, 2006 5. Brenner M et al: Treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol 161:1199-1201, 2009 6. Weenig RH et al: Skin ulcers misdiagnosed as pyoderma gangrenosum. N Engl J Med 347:1412, 2002

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Chapter 34 :: Granuloma Faciale :: David A. Mehregan & Darius R. Mehregan GRANULOMA FACIALE AT A GLANCE Granuloma faciale is an uncommon inflammatory dermatosis characterized clinically by reddish brown papules and plaques primarily involving the face.

Section 5

The pathology shows changes of a chronic leukocytoclastic vasculitis with a mixed infiltrate containing eosinophils, extensive perivascular fibrin deposition, and dermal fibrosis.

::

Etiology is unknown.

CLINICAL FINDINGS

Inflammatory Diseases Based on Neutrophils and Eosinophils

Granuloma faciale is characterized by solitary papules, plaques, or nodules. The lesions are typically asymptomatic red, brown, or violaceous plaques that are soft, smooth, and well circumscribed, often showing follicular accentuation and telangiectasia (Figs. 34-1 and 34-2). Ulceration is rare. Lesions are most common on the face. Sites of predilection include the nose, preauricular area, cheeks, forehead, eyelids, and ears.4,12 Rarely, patients may present with multiple lesions or lesions on the trunk or extremities. Extrafacial lesions have been reported both as isolated findings and in conjunction with facial lesions. Lesions may be present for weeks or months and tend to follow a chronic course. Lesions are typically asymptomatic; however, patients may complain of tenderness, burning, or pruritus.4 Photoexacerbation of lesions has been reported.13

EPIDEMIOLOGY

LABORATORY FINDINGS

Early cases of granuloma faciale were reported as “eosinophilic granuloma” of the skin. Weidman was the first to separate three cases that had been previously reported in the literature as variants of erythema elevatum diutinum.1 Lever and Leeper helped to differentiate the lesions from other eosinophil-rich diseases.2 Cobane, Straith, and Pinkus later stressed the histologic resemblance to erythema elevatum diutinum (EED) and termed the lesions “facial granulomas with eosinophilia” and later granuloma faciale.3 Granuloma faciale occurs predominantly in adult men and women. There is a slight male predominance, and mean age at presentation is 52 years.4,5 Granuloma faciale can occur in individuals of any race; however, it is more common in Caucasians. The disease presents most commonly with a single lesion on the face, but extrafacial lesions have been described.6 Patients with multiple lesions have also been reported.7 A rare mucosal variant has been described as eosinophilic angiocentric fibrosis, which typically involves the upper respiratory tract.8

An extensive laboratory evaluation is not required. Peripheral blood eosinophilia is occasionally detected. The diagnosis may be established by a combination of clinical findings and confirmatory tissue biopsy results. A punch biopsy that includes the full thickness of the dermis is recommended. Histologic examination shows a normal-appearing epidermis, which may be separated from the underlying inflammatory infiltrate by a narrow grenz zone (Fig. 34-3). Within the dermis is a dense and diffuse infiltrate of lymphocytes, plasma cells, eosinophils, and neutrophils with evidence of leukocytoclasis (Fig. 34-4). The inflammatory infiltrate surrounds the blood vessels, which show evidence of fibrin deposition. In later stages, the perivascular fibrin

ETIOLOGY AND PATHOGENESIS

380

The etiology of granuloma faciale is unknown. The disease can be considered a localized chronic fibrosing vasculitis.9 Immunofluorescence studies have revealed deposition of immunoglobulins and complement factors in the vessel walls consistent with a type III immunologic response, marked by deposition of circulating immune complexes surrounding superficial and deep blood vessels.10,11 However, other authors have described negative results with immunofluorescence.12

Figure 34-1  Granuloma faciale. Raised edematous plaques on cheek showing prominent follicular ostia.

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Chapter 34

Figure 34-2  Granuloma faciale. Single plaque on the temple showing prominent follicular ostia and central dell.

The clinical differential diagnosis for granuloma faciale includes discoid lupus erythematosus, polymorphous

Figure 34-4  Granuloma faciale. This histologic section shows perivascular deposition of fibrin and a mixed infiltrate of lymphocytes, neutrophils, and eosinophils. light eruption, fixed drug eruption, benign lymphocytic infiltrate of Jessner, lymphoma cutis, pseudolymphoma, sarcoidosis, granuloma annulare, tinea faciei, insect bite reaction, xanthogranuloma, mastocytoma, basal cell

Granuloma Faciale

DIFFERENTIAL DIAGNOSIS

::

deposition becomes extensive and dominates the histologic picture. Deposition of hemosiderin may contribute to the brown color seen clinically. Electron microscopic studies confirm the presence of an extensive eosinophilic infiltrate with Charcot–Leyden crystals and numerous histiocytes filled with lysosomal vesicles; however, cases with few eosinophils in the infiltrate have also been described.14 Immunoglobulins, fibrin, and complement can be found deposited along the dermal–epidermal junction in a granular pattern and around blood vessels by direct immunofluorescence.10

BOX 34-1  Differential Diagnosis of Granuloma Faciale Most Likely Face Sarcoidosis Benign lymphocytic infiltrate of Jessner Rosacea Extrafacial Erythema elevatum diutinum Consider Face Discoid lupus erythematosus Lymphoma cutis Angiolymphoid hyperplasia with eosinophilia Tinea faciei Basal cell carcinoma Xanthogranuloma Mastocytoma Extrafacial Granuloma annulare Benign lymphocytic infiltrate of Jessner Fixed drug eruption

Figure 34-3  Granuloma faciale. This low-power histologic section shows a mixed infiltrate of lymphocytes, histiocytes, neutrophils, plasma cells, and eosinophils. There is sparing of a narrow grenz zone between the inflammatory infiltrate and the overlying epidermis.

Always Rule Out Face Discoid lupus erythematosus Trunk Erythema elevatum diutinum

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BOX 34-2  Treatments for Granuloma Faciale First-line therapy

TOPICAL Topical corticosteroids

PHYSICAL Cryotherapy Intralesional steroids Pulsed dye laser

Second-line therapy

Topical tacrolimus ointment

Surgical excision

Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

carcinoma, Langerhans cell histiocytosis, and rosacea (Box 34-1). The diagnosis can be reliably made by histologic examination. Absence of serologic evidence of lupus erythematosus helps to differentiate these lesions from the lesions of discoid lupus erythematosus. The primary histologic differential diagnosis is EED. Both diseases represent chronic forms of fibrosing small vessel vasculitis and may be related. However, there are several clinical and histologic differences. EED is characterized by multiple lesions, primarily located on extensor surfaces of the extremities in a symmetric acral distribution. The trunk and face are typically spared in EED. Histologically, both show a chronic fibrosing vasculitis.15 However, a grenz zone of normal collagen beneath the epidermis is not typical of EED. Eosinophils and plasma cells are more prominent in granuloma faciale while neutrophils are more frequently found in EED. EED may be associated with systemic conditions, primarily monoclonal gammopathies, and shows an excellent response to dapsone.16,17 The histologic and clinical differential may also include angiolymphoid hyperplasia with eosinophilia. However, the lesions of angiolymphoid hyperplasia with eosinophilia contain blood vessels with prominent “hobnail” endothelial cells that protrude into the vascular lumina rather than perivascular fibrin deposition. One case of tinea faciei caused by Trichophyton rubrum has been described with clinical and histologic changes consistent with granuloma faciale.18

COMPLICATIONS Granuloma faciale is rarely associated with systemic disease.19

PROGNOSIS AND CLINICAL COURSE Lesions tend to be chronic and resistant to treatment.

TREATMENT

382

A variety of medical and surgical therapies have been used in the treatment of granuloma faciale (Box 34-2). Because of the small number of patients involved, randomized trials to evaluate these treatments are lacking. Resistance to therapy and cosmetic complications should be discussed with the patient before initiation of therapy.

SYSTEMIC Dapsone, 50–100 mg/day

Topical and intralesional steroids have been administered with modest improvement.4,20 Cryosurgery has been applied with effective results.21,22 Because the disease is known to be a variant of chronic leukocytoclastic vasculitis, dapsone 25 to 100 mg/day has been used with benefit in a number of patients.23,24 Topical tacrolimus ointment 0.1% also has been used with success.25 Surgical excision may be an option for small lesions. Lesions of granuloma faciale have been treated with a variety of medical lasers. In multiple studies utilizing pulsed dye lasers at 585–595 nm, clinical improvement has been demonstrated.26–30 A carbon dioxide laser has also been applied with varying success.31 The use of an argon laser resulted in total resolution of the granuloma faciale with subsequent scarring. The lesions in two patients were reported to respond to the potassium-titanyl-phosphate 532-nm laser in combination with tacrolimus ointment 0.1%.32 Case studies have suggested a beneficial effect of tacrolimus ointment,33,34 as well as pimecrolimus cream 1%.34

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 3. Cobane JH, Straith CL, Pinkus H: Facial granulomas with eosinophilia: Their relation to other eosinophilic granulomas of the skin and to reticulogranuloma. Arch Derm Syphilol 61:442, 1950 4. Radin DA, Mehregan DR: Granuloma faciale: Distribution of the lesions and review of the literature. Cutis 72:213, 2003 5. Marcoval J, Moreno A, Peyr J: Granuloma faciale: A clinicopathological study of 11 cases. J Am Acad Dermatol 51:269, 2004 9. Carlson JA, LeBoit PE: Localized chronic fibrosing vasculitis of the skin: An inflammatory reaction that occurs in settings other than erythema elevatum diutinum and granuloma faciale. Am J Surg Pathol 21:698, 1997 10. Nieboer C, Kalsbeek GL: Immunofluorescence studies in granuloma eosinophilicum faciale. J Cutan Pathol 5:68, 1978 11. Barnadas MA, Curell R, Alomar A: Direct immunofluorescence in granuloma faciale: A case report and review of literature. J Cutan Pathol 33:508-511, 2006 12. Ortonne N et al: Granuloma faciale: A clinicopathologic study of 66 patients. J Am Acad Dermatol 53:1002, 2005 17. Crowson AN, Mihm MC Jr, Magro CM: Cutaneous vasculitis: A review. J Cutan Pathol 30:161, 2003 19. Dowlati B, Firooz A, Dowlati Y: Granuloma faciale: Successful treatment of nine cases with a combination of cryotherapy and intralesional corticosteroid injection. Int J Dermatol 36:548, 1997 31. Ludwig E et al: New treatment modalities for granuloma faciale. Br J Dermatol 149:634, 2003

Chapter 35 :: S  ubcorneal Pustular Dermatosis (Sneddon–Wilkinson Disease) :: Franz Trautinger & Herbert Hönigsmann SUBCORNEAL PUSTULAR DERMATOSIS AT A GLANCE A rare condition with worldwide occurrence.

Pathology: subcorneal pustules filled with polymorphonuclear leukocytes.

Subcorneal pustular dermatosis (SPD) is a rare, chronic, recurrent, pustular eruption characterized histopathologically by subcorneal pustules that contain abundant neutrophils. The condition was originally described in 1956 by Sneddon and Wilkinson,1 who separated SPD from other previously unclassified pustular eruptions. Until 1966, when the first comprehensive review appeared, more than 130 cases had been reported, but not all fulfilled the clinical and histopathologic criteria required for this diagnosis.2 A considerable number of additional cases have since appeared in the literature, and a subtype with intraepidermal deposits of immunoglobulin (Ig) A directed against desmocollin 1 has been recognized.3 Today, these cases are usually classified as SPD-type IgA pemphigus and it is a matter of debate whether the finding of epidermal IgA deposits define a subset of SPD or a new pemphigus variant that is otherwise indistinguishable from “classic” SPD.

EPIDEMIOLOGY There is no racial predilection. Most of the reported cases have been in whites, but the disease has also been observed in Africans, Japanese, and Chinese. The condition is more common in women and in persons older than 40 years of age, but SPD may occur at any age.2 A pustular eruption that is clinically and histologically similar to the human disease, which also responds to dapsone treatment, has been observed in dogs.4

Subcorneal Pustular Dermatosis (Sneddon–Wilkinson Disease)

Usually distributed symmetrically in the axillae, groins, submammary, the flexor aspects of the limbs, and on the abdomen.

The cause of SPD is unknown. Cultures of the pustules consistently do not reveal bacterial growth. The role of trigger mechanisms such as preceding or concomitant infections, though repeatedly discussed, has remained speculative. Immunologic mechanisms have been implicated in the pathogenesis and in a subset of patients, whose disease clinically resembled SPD, intraepidermal IgA deposits have been detected. Some of these patients also had circulating IgA antibodies against the same sites within the epidermis. Desmocollin 1 and in a single case also desmocollins 2 and 3 have been described as autoantigens in these cases and the disease has been classified as a rare pemphigus variant (SPD-type IgA pemphigus).3,5–7 The pathogenetic role of these antibodies is still to be demonstrated.8 The occasional association of SPD with certain other diseases may represent more than a mere coincidence. Increased serum IgA has been detected in a number of patients, and the disease has been reported to occur in cases of IgA-paraproteinemia and IgA multiple myeloma.9–12 In addition, SPD is associated with pyoderma gangrenosum,13,14 ulcerative colitis,15 and Crohn disease.16 On the other hand, pyoderma gangrenosum is not uncommon in patients with inflammatory bowel disease, paraproteinemia, and myeloma (see Chapter 33). Whether or not the coexistence of these conditions reflects common pathogenetic mechanisms remains to be clarified, but an additional common denominator linking these disorders is their response to sulfone and sulfonamide therapy. Further associations reported to date include IgG paraproteinemia,17,18 CD30+ anaplastic large-cell lymphoma,19 marginal zone lymphoma,20 nonsmall cell lung cancer,21 apudoma,22 rheumatoid arthritis,23,24 systemic lupus erythematodes,25 hyperthyroidism26 and mycoplasma pneumoniae infection.27

::

Crops of flaccid, coalescing pustules; often in annular or serpiginous patterns.

ETIOLOGY AND PATHOGENESIS

Chapter 35

A chronic recurrent disorder with a benign course frequently associated with various forms of immune dysfunction [most commonly immunoglobulin (Ig) A monoclonal gammopathy]. Occurrence of intraepidermal deposits of IgA indicates a relationship with IgA pemphigus.

5

CLINICAL FINDINGS The primary lesions are small, discrete, flaccid pustules, or vesicles that rapidly turn pustular and usually arise in crops within a few hours on clinically normal or slightly erythematous skin (Fig. 35-1). In dependent regions, pus characteristically accumulates in the lower half of the pustule (see Fig. 35-1B); as the pustules usually have the tendency to coalesce, they often, but not always, form annular, circinate, or bizarre serpiginous patterns. After a few days, the pustules rupture and dry up to form thin, superficial scales and crusts, closely resembling impetigo. Peripheral spreading and central healing leave polycyclic, erythematous areas in which new pustules arise as others disappear (see Fig. 35-1A).

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A

B

Figure 35-1  Subcorneal pustular dermatosis. A. Typical distribution. Note accentuated involvement of groin and abdomen. Hyperpigmented macules mark previously affected areas. B. Close-up showing coalescence of pustules, which form annular and circinate patterns. Lesions of different developmental stages are seen side by side. At the lower right, newly formed pustule with characteristic hypopyon formation. There is no atrophy or scarring, but an occasional brownish hyperpigmentation may mark previously affected sites. Variable intervals of quiescence, lasting from a few days to several weeks, may be followed by the sudden development of new lesions. The eruptions tend to occur symmetrically, affecting mainly the axillae, groin, abdomen, submammary areas, and the flexor aspects of the limbs. In rare cases, the face,28 palms, and soles29 may be involved. Scalp and mucous membranes invariably remain free of lesions. Episodic itching and burning represent subjective symptoms in a small

number of patients, but there are no systemic symptoms or abnormalities in routine laboratory parameters.

HISTOPATHOLOGY The hallmark of the disease is a strictly subcorneal pustule filled with polymorphonuclear leukocytes,1 with only an occasional eosinophils.2 Acantholysis is not involved in pustule formation, but a few acantholytic cells may be found in older lesions (secondary acantholysis). Surprisingly, the epidermal layers underlying the pustule exhibit little pathology, and, apart from a variable number of migrating leukocytes, there is little evidence of spongiosis or cytolytic damage to the epidermal cells. The dermis contains a perivascular infiltrate composed of neutrophils and rarely mononuclear cells and eosinophils (Fig. 35-2).

BOX 35-1  Differential Diagnosis of Subcorneal Pustular Dermatosis

384

Figure 35-2  Subcorneal pustular dermatosis. Strictly subcorneal pustule filled with polymorphonuclear leukocytes, with the underlying epidermal layers exhibiting only slight edema and some migrating leukocytes. There is a mild inflammatory infiltrate around dermal blood vessels.



Bacterial impetigo Dermatitis herpetiformis Pemphigus foliaceus IgA pemphigus/intraepidermal IgA pustulosis Pustular psoriasis Necrolytic migratory erythema Acute generalized exanthematous pustulosis

BOX 35-2  Treatments for Subcorneal Pustular Dermatosis First line

Dapsone Corticosteroids

Second line (anecdotally reported beneficial responses)

Retinoids, photochemotherapy, ultraviolet B, colchicine, cyclosporine, infliximab, etanercept

PROGNOSIS AND CLINICAL COURSE SPD is a benign condition. Without treatment, attacks recur over many years and remissions are variable, lasting from a few days to several weeks. Despite the protracted course the general health of the patient is

TREATMENT The drug of choice is dapsone (Box 35-2) in a dose of 50 to 150 mg daily. The response is slower and less dramatic than in dermatitis herpetiformis, but complete remission is most often obtained. In some patients, the treatment may be withdrawn after several months, although in others it may have to be continued for years; the minimal effective dose to suppress disease should be determined in these patients. Systemic corticosteroids are less effective, although they can suppress generalized flares when given in high doses. Responses to retinoids, photochemotherapy, ultraviolet B, colchicine, cyclosporine, and topical tacalcitol (1α-24R-dihydroxyvitamin D3) have been anecdotally reported.31–34 More recently antitumor necrosis factor α therapy has been successfully used in single cases. Infliximab was described to induce rapid responses in three recalcitrant cases, with one patient relapsing despite continuing treatment.25,35,36 In two patients etanercept was able to induce almost complete continuing remissions for 22 and 7 months, in one case combined with acitretin.37

KEY REFERENCES

Subcorneal Pustular Dermatosis (Sneddon–Wilkinson Disease)

(Box 35-1) An early localized eruption of SPD may be clinically and histologically indistinguishable from impetigo, but the distribution pattern of the lesions, the absence of bacteria in the pustules, and the ineffectiveness of antibiotic therapy suggest the correct diagnosis. Dermatitis herpetiformis is highly pruritic, affects primarily the extensor surfaces, and has subepidermal vesicles with granular IgA deposits in the dermal papillary tips. Pemphigus foliaceus has acantholysis and a typical immunofluorescence pattern. Generalized pustular psoriasis (von Zumbusch’s type) presents with systemic symptoms (fever, malaise, leukocytosis), and spongiform pustules within the epidermis. The necrolytic migratory eruption of glucagonoma syndrome can be differentiated by its distribution, lack of actual pustule formation, erosions of the lips and oral mucosa, and, histologically, necrobiosis of the upper epidermis. Biochemically, hyperglycemia and excess levels of glucagon are diagnostic. Acute generalized exanthematous pustulosis (AGEP) is widespread with an acute febrile onset and histologically exhibits spongiform subcorneal and intraepidermal pustules sometimes with leukocytoclastic vasculitis.

usually not impaired. However, one of our own cases who had SPD, pyoderma gangrenosum, and IgA paraproteinemia of more than 20 years’ duration died of septicemia with staphylococcal abscesses in the lungs, liver, and spleen.

::

DIFFERENTIAL DIAGNOSIS

50–150 mg/day As required

Chapter 35

In a subset of patients, direct immunofluorescence reveals intraepidermal IgA deposits.17 In these cases, IgA is usually present in a pemphigus-like intercellular pattern, either in the entire epidermis or confined to its upper layers. By indirect immunofluorescence, circulating IgA antibodies directed against the intercellular substance of the epidermis were detected in single cases. Today these cases are usually diagnosed as SPD-type IgA pemphigus (see Chapter 54). Ultrastructural examination of paralesional skin has shown cytolysis of keratinocytes confined to the granular layer30; the formation of pustules has been regarded as a secondary event caused by invasion and subcorneal accumulation of leukocytes.

5

Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Sneddon IB, Wilkinson DS: Subcorneal pustular dermatosis. Br J Dermatol 68:385, 1956 3. Robinson ND et al: The new pemphigus variants. J Am Acad Dermatol 40:649, 1999 6. Ishii N et al: Immunolocalization of target autoantigens in IgA pemphigus. Clin Exp Dermatol 29:62, 2004 8. Reed J, Wilkinson J: Subcorneal pustular dermatosis. Clin Dermatol 18:301, 2000 36. Bonifati C et al: Early but not lasting improvement of recalcitrant subcorneal pustular dermatosis (SneddonWilkinson disease) after infliximab therapy: Relationships with variations in cytokine levels in suction blister fluids. Clin Exp Dermatol 30:662, 2005 37. Berk DR: Sneddon-Wilkinson disease treated with etanercept: Report of two cases. Clin Exp Dermatol 34:347, 2009

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Chapter 36 :: Eosinophils in Cutaneous Diseases :: Kristin M. Leiferman & Margot S. Peters EOSINOPHILS IN CUTANEOUS DISEASES AT A GLANCE Eosinophils may be seen in skin biopsy specimens from a broad range of cutaneous diseases but are not pathognomonic for any dermatosis.

Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

386

Eosinophils are an important component of the characteristic histologic pattern in a limited number of diseases, including the following: Angiolymphoid hyperplasia with eosinophilia Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy Eosinophilic pustular folliculitis Erythema toxicum neonatorum Eosinophilic ulcer of the oral mucosa Eosinophilic vasculitis

Hypereosinophilic syndromes Incontinentia pigmenti Kimura disease Pachydermatous eosinophilic dermatitis Wells syndrome (eosinophilic cellulitis) Clinical reaction patterns with eosinophil involvement include diseases in which eosinophils probably play a pathogenic role and are a component of the histological pattern, but are not essential for diagnosis. Evidence for involvement of eosinophils in cutaneous diseases is provided by observation of intact eosinophils in lesional tissue sections and/or by immunostains for their toxic granule proteins, which are deposited in tissues.

Granuloma faciale

Eosinophils have myriad phlogistic activities that implicate them in disease.1–3 (See Chapter 31.) Peripheral blood eosinophilia and/or tissue infiltration by eosinophils occur in a variety of common and unusual diseases, including those of infectious, immunologic, and neoplastic etiologies. Organ-specific eosinophil disorders occur in the skin, lung, and gastrointestinal tract.4–6 Eosinophils are conspicuous in tissue sections stained with hematoxylin and eosin because of their intense avidity for eosin dye. Common dermatoses associated with eosinophils in lesional tissues include arthropod bites and drug eruptions. Parasitic infections, especially those due to ectoparasites and helminthes, typically have a marked host response with eosinophilia.7,8 Autoimmune blistering diseases, such as bullous pemphigoid and the various forms of pemphigus, often have prominent eosinophil infiltration, including histologic presentation as eosinophilic spongiosis.9,10 Infiltration of eosinophils in the subcutaneous tissues, so-called eosinophilic panniculitis, is not a specific diagnosis but rather is seen to a variable degree in diverse entities.11,12 Eosinophils may be found in Langerhans cell histiocytosis,13 cutaneous epithelial neoplasms,14 and lymphoproliferative

­disorders.15 Although eosinophils constitute one of the histologic features in numerous cutaneous diseases, eosinophil infiltration represents a criterion for histologic diagnosis in relatively few entities (Table 36-1). The absence, presence or number of eosinophils in skin biopsy specimens is often of limited value in reliably choosing among differential diagnoses with different and potentially important implications for clinical management, such as drug reaction versus acute graft-versus-host disease.16,17 Eosinophils play a role in certain categories of clinical reactions, particularly those characterized by edema.18 The degree of tissue eosinophil granule protein deposition in such diseases, that exhibit relatively few or no intact eosinophils, suggests that the pathogenic influence of eosinophils may be unrelated to their numbers in tissues. The degree of cutaneous eosinophil infiltration should be taken in the context of other clinical features, other histological features, and knowledge that its diagnostic power has limitations.19 However, eosinophils do have potent biological activities, particularly imparted by their distinctive granules, and eosinophils may play a pathogenic role in the absence of identifiable cells in tissues.

5

TABLE 36-1

Eosinophils in Cutaneous Diseases

Eosinophils in Cutaneous Diseases

HYPEREOSINOPHILIC SYNDROMES

::

  Parasitic diseases/infestations   Urticaria and angioedema   Vasculitis   Churg-Strauss syndrome   Eosinophilic vasculitis   Histological patterns defined by eosinophils   Eosinophilic spongiosis   Acute dermatitis   Allergic contact dermatitis   Arthropod bite   Immunobullous diseases   Pemphigoid   Pemphigus   Incontinentia pigmenti   Eosinophilic panniculitis   Arthropod bite   Erythema nodosum   Gnathostomiasis   Injection granuloma   Vasculitis   Wells syndrome  Eosinophils of doubtful, limited or no value in histological diagnosis   Drug reaction versus graft-versus-host disease   Granuloma annulare   Interstitial granulomatous dermatitis   Neoplasms   Lymphoproliferative disorders (except HES types)   Keratoacanthoma

Chapter 36

  Diseases characterized by tissue eosinophils   Angiolymphoid hyperplasia with eosinophilia  Eosinophilic, polymorphic, and pruritic eruption associated with radiotherapy   Eosinophilic pustular folliculitis   Classical (Ofugi disease)   Infantile/neonatal   Human immunodeficiency virus-associated   Erythema toxicum neonatorum   Eosinophilic ulcer of oral mucosa   Granuloma faciale   Hypereosinophilic syndromes   Kimura disease   Pachydermatous eosinophilic dermatitis   Wells syndrome (eosinophilic cellulitis)   Diseases typically associated with tissue eosinophils   Arthropod bites and sting reactions   Bullous dermatoses   Pemphigoid   Pemphigus   Incontinentia pigmenti   Dermatoses of pregnancy   Drug reactions  DRESS (drug rash with eosinophilia and systemic symptoms)/drug hypersensitivity syndrome   Interstitial granulomatous drug reaction   Histiocytic diseases   Langerhans cell histiocytosis   Juvenile xanthogranuloma

HYPEREOSINOPHILIC SYNDROMES AT A GLANCE Spectrum of entities defined by criteria (Table 36-2). Cutaneous lesions are common and may be the presenting sign. Two major hypereosinophilic syndromes (HES) subtypes and several variants. Lymphocytic HES characterized by T-cell clones that produce interleukin 5. Variant HES subtypes may evolve into lymphocytic HES. Organ-restricted. Associated with specific disorders such as Churg–Strauss syndrome. Undefined with benign, complex, and episodic presentations. Myeloproliferative HES associated with a deletion on chromosome 4 that

produces a tyrosine kinase fusion gene Fip1-like 1/platelet-derived growth factor receptor-α or other mutation associated with eosinophil clonality. Responsive to imatinib. Severely debilitating mucosal ulcers portend a grim prognosis unless HES is treated. Overlap with mastocytosis. Familial HES variant, family history of documented persistent eosinophilia of unknown cause. Associated embolic events constitute a medical emergency. Eosinophilic endomyocardial disease occurs in HES and in patients with prolonged peripheral blood eosinophilia from any cause.

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388

EPIDEMIOLOGY The hypereosinophilic syndromes (HES) consist of a spectrum of disorders that occur worldwide and span all age groups. Over 90% of patients with myeloproliferative HES and the mutant gene are men, but lymphocytic HES shows equal gender distribution. The relative frequencies of these subtypes are unknown, although up to 25% of HES patients may have lymphocytic HES. Rare familial cases have been reported. A miniepidemic of eosinophilic esophagitis, a subtype of overlap HES with organ-restricted disease, emerged over the last decade with prevalence estimates as high as 1:2,500 among children and 1:4,000 among adults.31,32

ETIOLOGY Eosinophils are implicated as the cause of most endorgan damage in all HES subtypes.2,33 Clinical improvement usually parallels a decrease in eosinophil count. Patients with lymphocytic HES have abnormal T-cell clones with unusual surface phenotypes, including CD3+CD4−CD8− and CD3−CD4+. These T cells display activation markers, such as CD25, and secrete T helper 2 cytokines, including high levels of interleukin 5 (IL-5).23,34 An 800-kilobase deletion on chromosome band 4q12 that codes for a tyrosine kinase has been found in myeloproliferative HES.26 Patients with this FIP1L1-PDGFRA gene mutation form a distinct subset of HES, with cardiomyopathy and endomyocardial fibrosis, that responds to imatinib. Patients in this HES subset have elevated serum tryptase levels and increased atypical spindleshaped mast cells in bone marrow.27,28,35 Although they do not have clinical manifestations of systemic mastocytosis or exhibit all its immunological markers, these patients satisfy criteria for mastocytosis.36 The FIP1L1PDGFRA gene is detected in mast cells,37 eosinophils, neutrophils, and mononuclear cells. Many HES patients also have marked neutrophilia, likely due to the aberrant gene in the neutrophil lineage. Thus, alteration of several cell lines probably contributes to the pathogenesis of myeloproliferative HES.38,39 Multiple other chromosomal abnormalities have been identified in myeloproliferative HES, including translocations, partial and complete chromosomal deletions, and trisomies 8, 15, and 21. Myeloproliferative HES with documented mutations also is known as chronic eosinophilic leukemia. The World Health Organization has an updated 2008 classification scheme for myeloid disorders and eosinophilia.40,41 The etiology of the other HES variants is not well understood, although patients in several HES subtypes, including with episodic angioedema and eosinophilia [Gleich syndrome42; see section “Episodic Angioedema Associated with Eosinophilia (Gleich Syndrome)”] and the nodules, eosinophilia, rheumatism, dermatitis, and swelling (NERDS) syndrome,43 have developed T-cell clones.30

TABLE 36-2

Revised Diagnostic Criteria for Hypereosinophilic Syndromes30 1. Blood eosinophilia greater than 1500 eosinophils/mm3 on at least two separate determinations or evidence of prominent tissue eosinophilia associated with symptoms and marked blood eosinophilia 2. Exclusion of secondary causes of eosinophilia, such as parasitic or viral infections, allergic diseases, drug- or chemical-induced eosinophilia, hypoandrenalism, and neoplasms Original Criteria21  Peripheral blood eosinophilia of at least 1,500 eosinophils/ mm3   Longer than 6 months; or   Less than 6 months with evidence of organ damage.   Signs and symptoms of multiorgan involvement.  No evidence of parasitic or allergic disease or other known causes of peripheral blood eosinophilia.

CLINICAL FINDINGS AND COURSE Patients satisfying HES diagnostic criteria (Table 36-2) present with signs and symptoms related to the organ systems infiltrated by eosinophils.44–46 HES often present with skin lesions47,48 that may be the only manifestations of HES.49–51 Pruritic erythematous macules, papules, plaques, wheals, or nodules are present in over 50% of patients.52 Lesions may involve the head, trunk, and extremities. Urticaria and angioedema occur in all HES subtypes and are characteristic of certain variant subtypes. Erythema annulare centrifugum,53–55 bullous pemphigoid,56 lymphomatoid papulosis,57 livedo reticularis, purpura and/or other signs of vasculitis,58–61 Wells syndrome (eosinophilic cellulitis),62,63 and multiple other mucocutaneous manifestations48 may be found in patients with HES (Table 36-3). In myeloproliferative HES, the usual presenting complex includes fever, weight loss, fatigue, malaise, skin lesions, and hepatosplenomegaly.29,46,64,65 Mucosal ulcers of the oropharynx or anogenital region (Fig. 36-1) portend an aggressive clinical course; death is likely within 2 years of presentation if the disorder is untreated.64,66 Cardiac disease occurs frequently.67 Eosinophils adhere to endocardium and release granule proteins onto endothelial cells, thrombus formation follows, and, finally, subendocardial fibrosis with restrictive cardiomyopathy occurs. Mitral or tricuspid valvular insufficiency results from tethering of chordae tendineae.67 Cardiac abnormalities that are essentially identical to those of HES but are confined to the intramural regions can occur without appreciable peripheral blood eosinophilia.68,69 Splinter hemorrhages and/or nail fold infarcts may herald the onset of thromboembolic disease. The central and peripheral nervous system, lungs, and, rarely, kidneys may be affected.46 Patients with myeloproliferative HES frequently present with clinical features resembling those of chronic myelogenous leukemia and, depending on

TABLE 36-3

Mucocutaneous Manifestations in Hypereosinophilic Syndromes

(Modified from Leiferman KM, Gleich GJ, Peters MS: Dermatologic manifestations of the hypereosinophilic syndromes. Immunol Allergy Clin North Am 27(3):415-441, 2007 and Stetson CL., Leiferman, KM: Chapter 26, Eosinophilic dermatoses. In: Dermatology, 2nd edition, edited by JL Bolognia, J Jorizzo, RP Rapini, TD Horn, AJ Mancini, JM Mascaro, SJ Salasche, J-H Saurat, G Stingl. Mosby, St. Louis 2008. pp. 369-378).

the classification, are regarded as having chronic eosinophilic leukemia. Although chromosomal abnormalities characterize this subtype and the disease may evolve into definite leukemia, the relatively mature nature of the eosinophils and lack of evidence for clonal expansion may preclude such classification. Lymphocytic HES commonly is associated with severe pruritus, eczema, erythroderma, urticaria, and

A

B

A key criterion for diagnosis is marked peripheral blood eosinophilia (see Table 36-2).44,70–72 Other causes of eosinophilia, including allergic and parasitic diseases, should be excluded. Tests to detect organ involvement, particularly measurement of liver enzyme levels, are important. Because eosinophilic endomyocardial disease can develop in any patient with prolonged peripheral blood eosinophilia, patients should undergo periodic echocardiography along with close observation for signs of thromboembolism. Increased serum levels of immunoglobulin E (IgE) are often present in lymphocytic HES, and levels of vitamin B12 and tryptase may be increased in myeloproliferative HES. The Chic2 fluorescent in situ hybridization assay detects the deletion that produces the FIP1L1PDGFRA gene product and should be performed, because patients with this mutation respond to treatment with imatinib.35,37 Alternatively, the mutant gene can be detected by a polymerase chain reaction assay. Both tests are available commercially. In patients who lack the fusion gene, testing for other clonal

Eosinophils in Cutaneous Diseases

LABORATORY TESTS

::

Angioedema Bullae (bullous pemphigoid) Dermographism Digital gangrene Eczema Eosinophilic cellulitis (Wells syndrome) Erosions Erythema Erythema annulare centrifuge Erythroderma Excoriations Livedo reticularis Lymphomatoid papulosis Macules Mucosal ulcers (oral and genital) Nail fold infarctions Necrosis Nodules Papules Patches Pruritus Purpura Raynaud phenomenon Splinter hemorrhages Ulcers Urticaria Vasculitis

5

Chapter 36

angioedema, as well as lymphadenopathy and, rarely, endomyocardial fibrosis.34 In contrast to myeloproliferative HES, lymphocytic HES generally follows a benign course, and T-cell clones can remain stable for years. Patients should be observed closely and regarded as having premalignant or malignant T-cell proliferation, because the disease may evolve into lymphoma. Churg–Strauss syndrome (see Chapter 164) is a variant HES subtype. Other variant HES subtypes include Gleich syndrome42 [see section “Episodic Angioedema Associated with Eosinophilia (Gleich Syndrome)”], in which eosinophil counts fluctuate with extreme angioedema. During the decade or more after diagnosis, HES may evolve into acute leukemia and, less commonly, has been associated with B-cell lymphomas. The overall 5-year survival rate for HES patients is 80%; congestive heart failure from the restrictive cardiomyopathy of eosinophilic endomyocardial disease is a major cause of death, followed by sepsis.

C

Figure 36-1  Hypereosinophilic syndrome. Mucosal erosions and ulcers of the mouth (A) and glans penis (B); conjunctival irritation (C).

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cytogenetic abnormalities or abnormal clonal T-cell populations is warranted.27 Cytoflow of peripheral blood lymphocytes and immunophenotyping of tissue lymphocytes should be performed for the diagnosis of lymphocytic HES and repeated periodically to detect transformation from a variant HES type to lymphocytic HES or to T-cell lymphoma.34 An HES evaluation assessment scheme for patients with eosinophilia is presented in Table 36-4. The cutaneous histopathological features of HES vary with the type of lesion. Skin biopsy specimens from urticarial lesions resemble idiopathic urticaria, with generally mild, nonspecific perivascular and interstitial infiltration of lymphocytes, eosinophils, and, occasionally, neutrophils. Immunostaining reveals extensive deposition of eosinophil granule proteins, in the absence of intact eosinophils, in episodic angioedema with eosinophilia,42 HES with mucosal ulcers,73 and in synovial tissues in NERDS.43 Other than in Churg–Strauss syndrome, vasculitis only rarely has been associated with HES.58–60

DIFFERENTIAL DIAGNOSIS (Box 36-1) Clinically, parasitic infections and infestations may closely resemble HES.74 A history of travel to endemic areas or certain dietary exposure implicates helminthiasis. Along with eosinophilia, total serum IgE levels higher than 500 IU/mL commonly are found in helminthic infections. Examination of stool samples for ova and parasites and serologic testing for Strongyloides antibodies should be performed. In patients with isolated urticarial plaques with or without angioedema, the differential diagnosis includes common and persistent urticaria,75,76 but demonstration of multiorgan involvement supports HES. HES with episodic angioedema may resemble hereditary angioedema clinically, although patients with hereditary angioedema often have a family history of the disease rarely have the markedly elevated eosinophil counts that characterize HES, and may be distinguished by complement abnormalities. Pruritic eczematoid lesions of lymphocytic HES may resemble those of atopic dermatitis, contact dermatitis, drug reaction, fungal infection, and T-cell lymphoma. There are multiple diseases in the differential diagnosis of patients with orogenital ulcers,64 including those associated with thrombosis, such as Behçet syndrome, Crohn disease, ulcerative colitis, and Reiter syndrome. Others considerations are recurrent aphthous stomatitis, immunobullous diseases, erythema multiforme, lichen planus, herpes simplex infection, and syphilis.

TREATMENT 390

The goal of treatment is to relieve symptoms and improve organ function while keeping peripheral blood eosinophils at 1,000 to 2,000/mm3 and

TABLE 36-4

Evaluation of Patients with Eosinophilia   History  Attention to travel (parasite exposure)  Ingestants (drugs, health foods, food supplements, and food allergy)   Close contacts with itch (ectoparasites)   Physical examination   Cutaneous features (see Table 36-3)   Cardiovascular signs   Murmur of mitral insufficiency   Nails for splinter hemorrhage (medical emergency)   Hepatosplenomegaly   Lymphadenopathy   Laboratory studies   Repeated complete blood counts with differentials   Cytogenetics for chromosomal abnormalities to include   FIP1L1-PDGFRA (CHIC2 gene) deletional mutation  T cell subsets for clonality by cytoflow/T cell receptor gene rearrangement   B cell clonality analyses   Inflammatory and immunological markers   Erythrocyte sedimentation rate   C-reactive protein   Rheumatoid factor  Antiproteinase 3 and antimyeloperoxidase (c-ANCA and p-ANCA)   IgE level   Strongyloides IgG antibody   Interleukin-5 serum level   Metabolic parameters  Liver function tests to include aspartate aminotransferase and alanine aminotransferase  Renal function tests to include creatinine, blood urea nitrogen and urinanalysis for protein and sediment  Muscle enzymes to include creatine phosphokinase and aldolase   B12 serum level   Mast cell/basophil tryptase (protryptase) level   Coagulation factors   Troponin (before initiation of imatinib treatment)   Serum protein analyses   Serum protein electrophoresis   Quantitative immunoglobulins   Immunofixation electrophoresis for monoclonal proteins   Imaging tests   Echocardiography  Computerized axiotomography of chest, abdomen, and pelvis   Gastrointestinal endoscopy, as indicated   Pulmonary function tests, as indicated  Bone marrow aspirate and biopsy with staining for tryptase and reticulum (myelofibrosis)  Tissue biopsy of skin and/or other accessible affected organs   Histological examination   Direct immunofluorescence for immunobullous disease   Immunostaining for eosinophil granule proteins Modified from Gleich GJ, Leiferman KM: The hypereosinophilic syndromes: Current concepts and treatments. Br J Haematol 145(3):271-285, 2009.

Box 36-1  Differential Diagnosis HYPEREOSINOPHILIC SYNDROMES Behçet syndrome Crohn disease Ulcerative colitis Reiter syndrome Recurrent apthous stomatitis Erythema multiforme Lichen planus Immunobullous disease Herpes simplex infection Syphilis

WELLS SYNDROME WELLS SYNDROME (EOSINOPHILIC CELLULITIS) AT A GLANCE Single or multiple lesions commonly located on the extremities or trunk. Lesions may be painful or pruritic. Associated with general malaise but uncommonly with fever.

Blisters may be a prominent feature. Individual lesions persist for weeks and gradually change from red to blue–gray or greenish gray, resembling morphea. Multiple recurrences. Peripheral blood eosinophilia common. Histological pattern characterized by dermal infiltration with eosinophils, and flame figures surrounded by histiocytes.

Eosinophils in Cutaneous Diseases

Edematous and erythematous lesions evolve into plaques with violaceous borders.

::

­ inimizing treatment side effects (Fig. 36-2). Recent m reviews have delineated evaluation and management of HES.29,70–72,77 Myeloproliferative HES is responsive to imatinib.78 In patients with the mutant gene FIP1L1PDGFRA, administration of imatinib mesylate is indicated and usually induces hematologic remission, but endomyocardial disease may worsen during the first several days of treatment. Troponin levels should be monitored before and during imatinib therapy.79,80 To improve cardiac function, glucocorticoids should be given before and with initiation of imatinib therapy. Imatinib resistance can develop.81–83 In the absence of the gene mutation, after Strongyloides infection has been excluded,84 first-line therapy is prednisone. Approximately 70% of patients will respond, with peripheral eosinophil counts returning to normal. Patients for whom glucocorticoid monotherapy fails have a worse prognosis generally; in such cases or when long-term side effects become problematic, other treatments should be used. Effective treatment of HES in imatinib-responsive patients results in improvement of associated conditions including cardiac involvement with endocarditis85 and myelofibrosis86 and skin disease with bullous pemphigoid.56 Patients who have features of myeloproliferative HES but who lack FIP1L1-PDGFRA still may respond to imatinib.25 Interferon (IFN)-α has been beneficial in treating myeloid and lymphocytic HES.87,88 In one patient, loss of the FIP1L1-PDGFRA mutation after several years of IFN-α therapy was associated with complete remission.89 Extracorporeal photopheresis alone or in combination with IFN-α or other therapies represent additional therapeutic options. Other treatments for HES with reported benefit include hydroxyurea, dapsone, vincristine sulfate, cyclophosphamide, methotrexate, 6-thioguanine, 2-chlorodeoxyadenosine and cytarabine combination therapy, pulsed chlorambucil, etoposide, cyclosporine, intravenous immunoglobulin, and psoralen plus ultraviolet A (UVA) phototherapy.90 Refractory disease may respond to infliximab (antitumor necrosis factor-α)91 or alemtuzumab (antiCD52),92–94 as well as to bone marrow and peripheral blood stem cell allogeneic transplantation.95,96 Two monoclonal antibodies against human IL-5 have been

5

Chapter 36

Parasitic infection Ectoparasitic infestation Urticaria Hereditary angioedema Atopic dermatitis Contact dermatitis Drug reaction Fungal infection Mycosis fungoides Sézary syndrome

associated with clinical improvement and reductions in peripheral blood and dermal eosinophils, particularly in patients with lymphocytic HES.97–101 Treatments targeting IL-5 have provided new insights into understanding eosinophil-associated disease.33

Systemic glucocorticoids usually therapeutic.

CLINICAL FINDINGS AND COURSE Cutaneous edema was the common clinical thread in the first four cases reported by Wells.102 After prodromal burning or itching, lesions begin with erythema and edema (Fig. 36-3A), sometimes in the form of annular or arcuate plaques or nodules. Over a period of days, they evolve into large edematous plaques with violaceous borders. Bullae may develop.108,109,120,139 Individual lesions gradually change from bright red to brown–red and then to blue–gray or greenish gray, resembling morphea (Fig. 36-3B). Less common clinical presentations include papules, vesicles (Fig. 36-4), and hemorrhagic bullae. The cutaneous lesions may be single or multiple and may be located at any site, but typically involve the extremities and, less often, the trunk.137 The most frequent systemic complaint in patients with Wells syndrome is malaise; fever occurs in a minority of cases. Lesions resolve without scarring, usually within weeks to months, but multiple recurrences are common.

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Hypereosinophilic syndromes (HES): classification and treatment

FIP1L1-PDGFRA gene mutation Myeloproliferative forms

Familial Family members with persistent eosinophilia of unknown cause

Negative

Lymphocytic forms

Positive

Chronic eosinophilic leukemia Clonal eosinophils or Cytogenic abnormalities and/or blasts

Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

392

Myeloproliferative HES Etiology undetected 4 or more of: Dyplastic eosinophils High serum B12 High serum tryptase Anemia Thrombocytopenia Hepatosplenomegaly Marrow hypercellularity Spindle-shaped mast cells and/or myelofibrosis

Imatinib alone (dose sufficient to eradicate FIP1L1-PDGFRA, 100-400 mg/d) or with glucocorticoids if cardiac involvement

Undefined

Benign, no organ involvement

Overlap Associated with other organ-restricted eosinophilic disorders

Complex, organ dysfunction but not myeloproliferative or lymphocytic variant

Interferon alpha

Episodic, cyclical angioedema and eosinophilia

Treat specific disease

Monitor for development of T-cell clone (or FIP1L1-PDGFRA)

Systemic glucocorticoids 0.5-1 mg/kg/d

Other tyrosine kinase inhibitors, new agents in development

Associated with Churg-Strauss, inflammatory bowel disease, sarcoidosis, HIV and other diseases

Monitor for cardiac disease

Consider trial of imatinib therapy (up to 50% of responsive patients do not have FIP1L1-PDGFRA mutation)

One or combinations of the following agents: Hydroxyurea Extracorporeal photopheresis PUVA Dapsone Methotrexate Vincristine sulfate Cyclophosphamide 6-thioguanine 2-chlorodeoxydenosine and cytarabine Pulsed chlorambucil Etoposide Cyclosporine Intravenous immunoglobulin Alemtuzumab IL-5 monoclonal antibody (currently only in clinical trials) Bone marrow transplantation (only after failure of above)

Figure 36-2  Hypereosinophilic syndromes (HES): classification and treatment. Provisional classification consists of myeloproliferative, lymphocytic and familial forms of HES. Chronic eosinophilic leukemia with clonal eosinophilia and myeloproliferative HES with features of the disease but without proof of clonality are included in the myeloproliferative forms of HES; HES with eosinophil hematopoietin-producing T-cells with or without a documented T-cell clone constitute the lymphocytic forms of HES. Further HES classification refinement expected in near future from a multidisciplinary consensus compendium in preparation. FIP1L1-PDGFRA, Fip1-like 1/platelet-derived growth factor receptor-α; HIV, human immunodeficiency virus; IL-5, interleukin 5; PUVA, psoralen plus ultraviolet A phototherapy. Further classification revisions likely in near future. (Information from Roufosse F, Weller PF: Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol 126(1):39-44, 2010; Klion AD: Approach to the therapy of hypereosinophilic syndromes. Immunol Allergy Clin North Am 27(3):551-560, 2007; and Stetson CL, Leiferman KM: Chapter 26: Eosinophilic dermatoses. In: Dermatology, 2nd edition, edited by JL Bolognia, J Jorizzo, RP Rapini, TD Horn, AJ Mancini, JM Mascaro, SJ Salasche, J-H Saurat, G Stingl. Mosby, St. Louis, 2008. pp. 369-378.)

5

B

Peripheral blood eosinophilia is observed in approximately 50% of patients. Skin lesions histologically are characterized by diffuse dermal infiltration with eosinophils, histiocytes, and foci of amorphous and/ or granular material associated with connective tissue fibers, which Wells termed flame figures.102 In the early stages, there also is dermal edema. Later, histiocytes palisade around flame figures. In addition to eight patients with the syndrome, the 1979 report of Wells and Smith includes nine patients with the typical histologic features of eosinophilic cellulitis but in association with a variety of clinical diagnoses, including pemphigoid, eczema, and tinea.103 This and subsequent reports of flame figures in lesions from patients with a wide spectrum of diseases (see Table 36-5 and

Figure 36-4  Familial Wells syndrome. Plaques with erythema, edema, vesicles, and bullae resembling acute dermatitis or pemphigoid. (From Davis MD et al: Familial eosinophilic cellulitis, dysmorphic habitus, and mental retardation. J Am Acad Dermatol 38:919, 1998, with permission.)

referenced above) indicate that the flame figure is characteristic for, but not diagnostic of, Wells syndrome.105 When examined for eosinophil granule major basic protein by immunofluorescence, flame figures show bright extracellular staining (Fig. 36-5), indicating that extensive eosinophil degranulation has occurred.113

TABLE 36-5

Eosinophils in Cutaneous Diseases

LABORATORY TESTS AND HISTOPATHOLOGY

::

Figure 36-3  Wells syndrome. A. Early lesion with erythema and edema. B. Late lesion resembling morphea.

Chapter 36

A

Conditions Associated with Wells Syndrome and/or Flame Figures Arthropod bite Ascariasis Bronchogenic carcinoma Churg–Strauss syndrome Colonic adenocarcinoma Dental abscess Dermographism Drug reaction Eczema Eosinophilic fasciitis Eosinophilic pustular folliculitis Herpes gestationis Herpes simplex infection Human immunodeficiency virus Hymenoptera sting Hypereosinophilic syndromes Immunobullous diseases Mastocytoma Molluscum contagiosum Myeloproliferative diseases Onchocerciasis Vaccinations Tinea Toxocariasis Urticaria Ulcerative colitis Varicella

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A

B

Section 5

Figure 36-5  Flame figure in familial Wells syndrome. A. Hematoxylin- and eosin-stained section. B. Eosinophil granule major basic protein immunostain (of serial section to A) shows extensive granule protein deposition localized to the flame figure. (Original magnification ×400.)

:: Inflammatory Diseases Based on Neutrophils and Eosinophils

DIFFERENTIAL DIAGNOSIS (Box 36-2) Urticaria, erysipelas, and acute cellulitis should be considered in the differential diagnosis of the early stages of Wells syndrome (see Fig. 36-3A). Later, plaques may resemble morphea (see Fig. 36-3B). The presence of blisters may suggest pemphigoid (see Fig. 36-4). Flame figures are the hallmark of Wells syndrome, but, because they have been identified in biopsy specimens from other dermatoses (Table 36-5), they are not alone sufficient for the diagnosis. However, a diagnosis of Wells syndrome in the absence of flame figures should be met with skepticism, even in the presence of dermal infiltration with eosinophils and histiocytes.105

EPIDEMIOLOGY Angiolymphoid hyperplasia with eosinophilia (ALHE) occurs in both males and females, but there is a slight female predominance. Patients are generally in the third to fifth decade of life. In contrast to Kimura disease (KD), which develops mainly in patients from Asia, ALHE has no racial predilection.

ETIOLOGY TREATMENT Wells syndrome usually improves dramatically after administration of systemic glucocorticoids, and tapering of steroid dose over 1 month is well tolerated in most patients. Recurrences may be treated with additional courses of systemic glucocorticoids. For patients who fail to respond, or who experience relapse often enough to raise concerns about the long-term side effects of systemic glucocorticoid therapy, other options such as minocycline, dapsone, griseofulvin, and antihistamines may be beneficial. Cyclosporine and IFN-α also have been used with success. For treatment of mild disease, topical glucocorticoids may be sufficient.

Box 36-2  Differential Diagnosis WELLS SYNDROME

394

ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA (EPITHELIOID HEMANGIOMA)

Urticaria Erysipelas Acute cellulitis Pemphigoid Morphea

The pathogenesis of ALHE is unknown, but it has been considered a vascular proliferation arising in response to or in association with underlying vascular malformation. There is a history of trauma in some cases. ALHE has been reported to occur in pregnancy, which implies that sex hormones may be a factor in its development.145 ALHE also has developed in patients with T-cell clonality, which suggests that it may be an early or low-grade T-cell lymphoma and further highlights a relationship between T-cells and eosinophils, particularly T-cells with the TH2 phenotype.146,147

CLINICAL FINDINGS AND COURSE ALHE shows a predilection for the head and neck area, including the ears,148 and is characterized by solitary, few, or multiple, sometimes grouped, erythematous, violaceous or brown papules, plaques, or nodules of the dermis and/or subcutaneous tissues (see Chapter 146). Lesions may be associated with pruritus or pain, or may pulsate. Although they are confined to the skin in most patients, mucosal involvement may occur.149 ALHE tends to be chronic and nonremitting over months to years.

5

ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA (EPITHELIOID HEMANGIOMA) AND KIMURA DISEASE AT A GLANCE Kimura disease (KD) occurs mainly in Asian males; angiolymphoid hyperplasia with eosinophilia (ALHE) occurs in all races, with a female predominance. KD is found in a younger age group than ALHE.

Chapter 36

Characterized by recurrent dermal and/or subcutaneous lesions, primarily of the head and neck area. A

:: Eosinophils in Cutaneous Diseases

ALHE lesions tend to be smaller, more superficial, and more numerous than those of KD. KD tends to involve subcutaneous tissues, regional lymph nodes, and salivary glands. ALHE may be painful, pruritic, or pulsatile, whereas KD is generally asymptomatic. Peripheral blood eosinophilia present in both diseases. Increased immunoglobulin E levels are found only in KD. Renal disease is associated only with KD (reported incidence of 10% to 20%). Histopathological features: Dominant feature of KD is lymphoid proliferation, often with germinal centers, whereas ALHE is characterized by vascular proliferation with numerous large epithelioid or histiocytoid endothelial cells. Fibrosis is characteristic of KD and is limited or absent in ALHE. Inconspicuous to numerous eosinophils in ALHE. Eosinophil abscesses may occur in KD.

LABORATORY TESTS AND HISTOPATHOLOGY Approximately 20% of patients have peripheral blood eosinophilia; IgE levels are unremarkable. There is no association with renal disease. The dominant histological feature is a well-defined area, in the

B

Figure 36-6  Angiolymphoid hyperplasia with eosinophilia. A. Forehead nodule. B. Recurrence of lesions in skin graft and adjacent sites 6 years after surgical removal of lesion in A.

dermis and/or subcutis, of prominent vascular proliferation with large epithelioid or histiocytoid endothelial cells that contain abundant eosinophilic cytoplasm, often with cytoplasmic vacuoles (see Chapter 147). There are variable numbers of eosinophils and lymphocytes,150 with an occasional finding of lymphoid nodules. In their report of 116 patients with ALHE, Olsen and Helwig found 53 cases in which “an arterial structure” appeared to be associated with venules or “was the area of endothelial proliferation,” which provided evidence that these lesions may represent a form of arteriovenous shunt.151 The stroma typically is myxoid, and fibrosis is minimal or absent. Mast cells may be a component of the histologic picture.

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5

Box 36-3  Differential Diagnosis ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA Kimura disease Pyogenic granuloma Epithelioid hemangioendothelioma Epithelioid angiosarcoma Kaposi sarcoma

DIFFERENTIAL DIAGNOSIS Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

396

(Box 36-3) Lesions of ALHE generally are smaller, more superficial, and more numerous than those of KD, and often are symptomatic. Although lymphoid follicles may occur in ALHE, they represent the dominant characteristic of KD (Table 36-6), and although KD may exhibit some vascularity, it lacks the large epithelioid endothelial cells that are a key feature of ALHE (see Table 36-6). ALHE should be distinguished from a variety of benign and malignant vascular proliferations, including pyogenic granuloma, epithelioid hemangioendothelioma, and Kaposi sarcoma—all of which lack a noticeable eosinophil infiltrate.

TREATMENT Intervention is dictated in part by the number, location, size of lesions, and the patient’s general health.152 Patients with solitary or a few small lesions may benefit from excision or Mohs surgery, 153 but there may be recurrence at the surgical site (see Fig. 36-6). A variety of other treatment modalities have been used with success, including systemic and intralesional glucocorti-

Box 36-4  Differential Diagnosis KIMURA DISEASE Angiolymphoid hyperplasia with eosinophilia Lymphoma coid administration, INF-α therapy,154 cryotherapy,155 laser therapy,156 and topical application of tacrolimus.157

KIMURA DISEASE (Box 36-4)

TREATMENT Surgical excision is the treatment of choice when feasible in patients with a single or a limited number of nodules, but lesions may recur.167,168 Other therapeutic options include systemic glucocorticoids, cyclosporine, and radiation therapy.169,170 The presence of renal disease may influence or dictate the therapeutic regimen. The finding of platelet-derived growth factor-α and c-kit in tissues from KD patients suggests that imatinib or another tyrosine kinase inhibitor may be effective in the disease.171

EOSINOPHILIC PUSTULAR FOLLICULITIS CLINICAL FINDINGS AND COURSE Classical EPF presents as recurrent crops or clusters of follicular papules and pustules, which may form an

TABLE 36-6

Comparison of Angiolymphoid Hyperplasia with Eosinophilia (ALHE) and Kimura Disease (KD) ALHE

KD

Gender

Typically middle-aged females

Predominantly young adult males

Symptoms

Pruritus, pain, pulsation

Asymptomatic

Lesion type and location

Small and superficial, with overlying erythema; head and neck region

Large, mainly subcutaneous; overlying skin normal; head and neck region; may involve regional lymph nodes and salivary glands

Lymphoid follicles

Uncommon

Prominent lymphoid follicles with germinal centers

Vascular proliferation

Prominent vascular proliferation with large epithelioid/histiocytoid endothelial cells; evidence of underlying vascular malformation may be evident

Some stromal vascularity with unremarkable endothelial cells

Fibrosis

Absent or limited

Prominent

Serum immunoglobulin E level

Normal

Increased

Nephropathy

Absent

Present in up to 20% of patients

EOSINOPHILIC PUSTULAR FOLLICULITIS AT A GLANCE Three clinical types, characterized by follicular papules and pustules that may involve the head, trunk, and extremities Classic eosinophilic pustular folliculitis (Ofuji disease)

Eosinophilic pustular folliculitis associated with immunosuppression

Follicular pustules of the scalp Tendency for recurrences and chronicity (except eosinophilic pustular folliculitis of infancy) Characterized by follicular and perifollicular eosinophil infiltration Associated with peripheral blood eosinophilia

annular pattern and usually resolve in 7 to 10 days. Lesions predominantly involve the face and trunk but also may affect the extremities, with involvement of the palms and soles in approximately 20% of patients.177 In EPF of infancy, lesions typically are located on the scalp but also may be found on the face and extremities. In some neonates who have pustular eruptions that clinically resemble EPF and typically have peripheral blood eosinophilia, the disorder may be classified more appropriately under the term eosinophilic pustulosis because the cutaneous infiltrates are not folliculocentric (see Chapter 107).202 In contrast, HIV-associated EPF tends to manifest as extremely pruritic discrete follicular papules, typically involving the head and neck and often the proximal extremities (see Fig. 198-3, Chapter 198). Rosenthal et al emphasized the urticarial quality of such lesions.178 EPF of infancy has a good prognosis, whereas classical and HIV-associated EPF are characterized by recurrences. Postinflammatory pigmentation may be seen as lesions resolve, but scarring does not occur.

(Box 36-5) Folliculitis secondary to bacterial or fungal infection must be kept in mind, particularly in immunosuppressed patients. Based on the distribution of lesions, seborrheic dermatitis should be considered, when there is head and neck involvement, and palmar– plantar pustular psoriasis may also be included in the differential diagnosis when there is hand and foot involvement. Acneiform eruptions may resemble EPF. Erythema toxicum neonatorum, acropustulosis, and acne neonatorum also should be considered in infants. Follicular mucinosis usually is clinically and histologically distinguishable from EPF.

Eosinophils in Cutaneous Diseases

Eosinophilic pustular folliculitis of infancy/neonatal period

DIFFERENTIAL DIAGNOSIS

::

Most often occurs in patients with human immunodeficiency virus infection, who have severely pruritic papules of the face and upper trunk

Patients suspected of having EPF should be evaluated for underlying immune deficiency, particularly HIV infection. Peripheral blood eosinophilia is a component of all three types of EPF. Although patients with classical EPF usually have eosinophilia with leukocytosis, HIV-positive patients often exhibit eosinophilia with lymphopenia. Low CD4 cell counts and high IgE levels are typical of HIV-associated EPF.178 Histologically, the most striking feature is the infiltration of eosinophils into hair follicles and perifollicular areas (see eFig. 36-6.2 in online edition), sometimes with follicular damage. The infiltrates also may contain lymphocytes and neutrophils, and may be perivascular as well as follicular.203 Follicular mucinosis (see Chapter 145) has been noted in association with EPF204; however, T-cell clonality is not observed in EPF-associated follicular mucinosis.205

5

Chapter 36

Typically occurs in Japanese patients, who have chronic, recurrent follicular pustules, with a tendency to form circinate plaques, in a seborrheic distribution

LABORATORY TESTS AND HISTOPATHOLOGY

TREATMENT Topical glucocorticoids and topical calcineurin inhibitors generally are the first approach to the treatment of all types of EPF. Topical tacrolimus is helpful for facial lesions.206 Nonsteroidal anti-inflammatory drugs, particularly indomethacin, also are recommended as firstline therapy; clinical improvement may be observed within 2 weeks and is associated with a decrease in peripheral blood eosinophil counts.207–209 A mechanism

Box 36-5  Differential Diagnosis EOSINOPHILIC PUSTULAR FOLLICULITIS Folliculitis, bacterial or fungal Seborrheic dermatitis Palmar–plantar pustular psoriasis Acne, including acne neonatorum Erythema toxicum neonatorum Acropustulosis Follicular mucinosis

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5

for this has been proposed based on the observation that indomethacin, not only inhibits cyclooxygenases and subsequent prostaglandin D2 synthesis, but also is associated with reduction in the prostaglandin D2 receptor (chemoattractant receptor homologous molecule expressed on TH2 cells, CRTH2) on eosinophils and lymphocytes.210 UV light therapy (UVB or psoralen and UVA) may be beneficial. Topical permethrin, systemic retinoids, systemic glucocorticoids, cyclosporine, itraconazole, metronidazole, cetirizine, minocycline, dapsone, and IFNs have been tried with success.207,208 Antiretroviral treatment that results in increased CD4 cell counts often is associated with improvement in HIV-associated EPF.

Section 5 ::

CLINICAL REACTION PATTERNS WITH EOSINOPHIL INVOLVEMENT

Inflammatory Diseases Based on Neutrophils and Eosinophils

There are a variety of diseases in which eosinophils may be present in cutaneous lesions, with or without associated peripheral blood eosinophilia, but either the histologic pattern is unremarkable or eosinophils are not critical for the histological diagnosis of the given entity (see Table 36-1). In many of these dermatoses, the eosinophil loses its morphologic integrity after disruption through cytolysis and is not identifiable histologically.216 However, toxic granule proteins and other phlogistic eosinophil products are deposited in skin, persist for extended periods of time, and cause tissue effects.73,217

EDEMA Prominent among the eosinophil-associated skin reactions are those manifesting edema, including urticarias.218–221 In addition to the presence of distinctive, toxic eosinophil cationic granule proteins in lesions, the ability of eosinophils to elaborate vasoactive mediators, induce histamine release from mast cells and basophils, and elicit a cutaneous wheal-and-flare reac-

A

398

tion supports a role for the eosinophil as a primary participant in the edema associated with certain cutaneous diseases (see Chapter 31).2,18

EPISODIC ANGIOEDEMA ASSOCIATED WITH EOSINOPHILIA (GLEICH SYNDROME).

Episodic angioedema associated with eosinophilia is characterized by recurrent angioedema (with up to 30% increase in body weight), urticaria, fever, increased serum IgM levels, and leukocytosis as high as 100,000 cells/mm3 with up to 90% eosinophils; disease activity fluctuates with the peripheral eosinophil count.42,222 Skin biopsy specimens from this disorder42 and its localized variant, recurrent facial edema with eosinophilia,223 show few eosinophils, but immunofluorescence staining reveals extracellular deposition of eosinophil granule proteins around collagen bundles and blood vessels. The syndrome is associated with a number of immunologic abnormalities, including increased activated T cells224,225 and increased serum IL-5 levels.226,227 Capillary leak syndromes, due to administration of IL-2228 and granulocyte-macrophage colony-stimulating factor,229 also are associated with peripheral blood eosinophilia, increased serum IL-5 levels, and eosinophil degranulation.

CHRONIC DERMATITIS/PRURITUS Although infestations typically are associated with eosinophils, the histologic pattern is nondiagnostic unless a specific organism is identified in tissue sections.8,230 Infection with Onchocerca volvulus causes a pruritic dermatitis with lichenification, associated with slight cutaneous eosinophil infiltration but extensive deposition of eosinophil granule proteins throughout the dermis231; after treatment, extracellular deposition of eosinophil granule proteins is located around degenerating microfilaria.230,232 Although eosinophils are rarely a prominent histological feature of atopic dermatitis, extensive dermal deposition of eosinophil granule proteins is seen in lesions (Fig. 36-7) but not in normal-appearing skin.231,233 A link between

B

Figure 36-7  Involved skin from a patient with atopic dermatitis. A. Eosinophil granule major basic protein immunostain shows extensive extracellular granule protein deposition in the presence of only three intact eosinophils (brightly fluorescent ovals). B. Hematoxylin and eosin counterstain of A shows minimal nonspecific chronic inflammation. (A and B ×400, original magnification) (From Leiferman KM et al: Dermal deposition of eosinophil-granule major basic protein in atopic dermatitis. Comparison with onchocerciasis. N Engl J Med 313:282, 1985, with permission).

5

Figure 36-8  Eosinophilic spongiosis. There are eosinophils and intercellular edema within the epidermis. (Hematoxylin and eosin ×400, original magnification)

BLISTERS Autoimmune blistering diseases (see Chapters 54 and 56) often are associated with prominent infiltration of eosinophils, including presentation as eosinophilic spongiosis (Fig 36-8), and extracellular deposition of eosinophil granule proteins. IL-5 and eotaxin are present in pemphigoid blister fluid, and eosinophil-derived matrix metalloproteinase 9 that likely cleaves basement membrane zone.247,248, 249 In addition to pemphigoid gestationis (which may exhibit eosinophilic spongiosis),250 other pruritic dermatoses of pregnancy (see Chapter 108) may demonstrate tissue eosinophilia.251–253

EOSINOPHILIC FASCIITIS. Eosinophilic fasciitis usually presents with pain, erythema, edema, and induration of the extremities, as well as peripheral blood eosinophilia and hypergammaglobulinemia.256 Contractures and rippling of the skin may develop (Fig. 36-9). There is infiltration of lymphocytes, plasma cells, mast cells, and eosinophils, as well as increased thickness of the fascia. EOSINOPHILIA–MYALGIA

SYNDROME.

Eosinophilia–myalgia syndrome (EMS), historically related to ingestion of certain lots of l-tryptophan,257 is characterized by marked peripheral eosinophilia, disabling generalized myalgias, pneumonitis, myocarditis, neuropathy, encephalopathy, and fibrosis,258 a constellation of features that are similar to but distinguishable from eosinophilic fasciitis.259,260 Cutaneous abnormalities of EMS include edema, pruritus, a faint erythematous rash, hair loss, and peau d’orange or morphea-like skin lesions.261 Lungs, heart, and nervous system may be affected.262 There

Eosinophils in Cutaneous Diseases

Eosinophils are found in all types of drug reactions. There is evidence that, when eosinophils are part of the histologic pattern in leukocytoclastic vasculitis, the eruption is probably drug-induced243 (see Chapter 41). The drug reaction with eosinophilia and systemic symptoms syndrome, so-called DRESS and also known as drug hypersensitivity syndrome, is a serious multiorgan disorder. Many drugs induce DRESS, and a spectrum of skin lesions may present with DRESS. Eosinophils and other inflammatory cells infiltrate skin, lymph nodes, and organs, including the liver. Fulminant hepatitis is associated with a mortality rate of 10%, and transplanted livers may also be affected. Eosinophil infiltration with and without granulomas with hepatocyte necrosis and cholestasis are prominent in liver failure that occurs with DRESS.244–246

::

DRUG REACTIONS

Chapter 36

­ eratinocytes and eosinophils in atopic dermatitis was k reported through activity of a novel TH2 cytokine, IL-31.234 Prurigo nodularis235 and pachydermatous eosinophilic dermatitis236 exhibit a pattern of dermal extracellular eosinophil granule protein deposition similar to that seen in atopic dermatitis and onchocercal dermatitis. In both atopic dermatitis and prurigo nodularis, eosinophil granule products are deposited around cutaneous nerves,235,237 and there is evidence that eosinophils play a role in itch provocation.238–242 A particularly difficult clinical presentation is the patient with intractable itching and peripheral blood eosinophilia. Such patients may satisfy criteria for the hypereosinophilic syndromes, but their itch is refractory to most therapies. Understanding the eosinophil’s role in the pathogenesis of this disorder may help with identifying effective therapies.

FIBROSIS Eosinophils are found in association with fibrotic reactions, including those resulting from parasitic infections, pulmonary and hepatic drug sensitivity reactions, and HES.254 Eosinophils elaborate mediators (see Chapter 31) that degrade collagen and stimulate dermal fibroblast DNA synthesis and matrix production.255

Figure 36-9  Eosinophilic fasciitis. Puckered skin of the thighs.

399

5

is a prominent inflammatory infiltrate in the perimysium and fascia, and striking evidence of eosinophil granule protein deposition in skin and around muscle bundles.257

Section 5 :: Inflammatory Diseases Based on Neutrophils and Eosinophils

TOXIC OIL SYNDROME. Toxic oil syndrome (TOS), which resembles EMS, was linked to consumption of adulterated rapeseed oil distributed in the industrial belt around Madrid.263 Patients experienced acute respiratory symptoms followed by intense myalgias, thromboembolism, weight loss, and sicca syndrome, followed by a chronic phase characterized by eosinophilic fasciitis-like lesions, peripheral neuropathy, muscle atrophy, and pulmonary hypertension. The cutaneous manifestations of TOS were nonspecific pruritic, erythematous skin lesions that persisted up to 4 weeks, followed over the next 2 months by subcutaneous edema, mainly of the extremities, accompanied by myalgias, arthralgias, contractures, and peripheral blood eosinophilia. Over many years, patients developed indurated plaques of the pretibial areas, and, occasionally, the forearms and abdomen,263 with marked fibrosis extending into subcutaneous fat. Eosinophil infiltration and degranulation were especially prominent in the acute phase of TOS, and serum eosinophil granule protein levels were elevated during all phases.264 Potential pathogenic links between TOS and EMS and also eosinophilic fasciitis have been identified.265,266 VASCULITIS In 1951, Churg and Strauss described the complex of systemic vasculitis, asthma, and eosinophilia as allergic granulomatosis.267 Cutaneous lesions develop in approximately two-thirds of cases and are variable consisting of nodules, urticaria, livedo reticularis, purpura, digital gangrene, and blisters. Histologically, the lesions are characterized by eosinophil infiltration, necrotizing vasculitis, and extravascular granulomas with prominent extracellular eosinophil granule protein deposition268–270 (see Chapter 164). Granuloma faciale is characterized clinically by brown–red infiltrative plaques of the face and represents a localized type of necrotizing vasculitis that contains infiltration of eosinophils as well as neutrophils, lymphocytes, and histiocytes (see Chapter 34). Eosinophilic vasculitis (EV) is associated with peripheral blood eosinophilia and is characterized by chronic, recurrent, widespread pruritic, erythematous, purpuric papules as well as angioedema of face and hands; skin biopsies show necrotizing small vessel vasculitis with prominent infiltration of eosinophils.271,272 EV may be idiopathic or associated with connective tissue disease,273 Raynaud phenomenon, or HES.58

MALIGNANCY 400

Eosinophils may be observed in a variety of cutaneous and extracutaneous neoplasms. Their presence in tumors appears to be independent of immune surveil-

lance and likely is part of an early inflammatory reaction at the site of tumorigenesis.274 Various types of peripheral T-cell lymphomas are eosinophil-rich, including follicular mycosis fungoides and cutaneous anaplastic large cell lymphoma275–277; the prognostic significance of tissue eosinophilia in such lesions is not established. Underlying malignancy may prompt lesions associated with eosinophil infiltration, such as the exaggerated arthropod-bite reactions seen in patients with chronic lymphocytic leukemia.278 Eosinophilic, polymorphic and pruritic eruption associated with radiotherapy (EPPER) is an uncommon idiopathic disorder that appears in patients undergoing radiation treatment for malignancy. Women are affected more often than men. Onset of the eruption is typically during radiation treatment, but delays up to 7 months are reported.279,280 Cutaneous findings are not localized to irradiated areas and may include local and generalized pruritus, erythematous papules, wheals, and vesicles and bullae. Eosinophils are prominent in affected skin, but not characteristically in the tumors.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content    1. Leiferman KM: A current perspective on the role of eosinophils in dermatologic diseases. J Am Acad Dermatol 24(6 Pt 2):1101-1112, 1991    4. Simon D, Wardlaw A, Rothenberg ME: Organ-specific eosinophilic disorders of the skin, lung, and gastrointestinal tract. J Allergy Clin Immunol 2010   44. Roufosse F, Weller PF: Practical approach to the patient with hypereosinophilia. J Allergy Clin Immunol 2010   45. Ogbogu PU et al: Hypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 124(6):1319-1325, e3, 2009 137. Moossavi M, Mehregan DR: Wells’ syndrome: A clinical and histopathologic review of seven cases. Int J Dermatol 42(1):62-67, 2003 138. Espana A et al: Wells’ syndrome (eosinophilic cellulitis): Correlation between clinical activity, eosinophil levels, eosinophil cation protein and interleukin-5. Br J Dermatol 140(1):127-130, 1999 150. Helander SD et al: Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: New observations from immunohistochemical studies of lymphocyte markers, endothelial antigens, and granulocyte proteins. J Cutan Pathol 22(4):319-326, 1995 151. Olsen TG, Helwig EB: Angiolymphoid hyperplasia with eosinophilia. A clinicopathologic study of 116 patients. J Am Acad Dermatol 12(5 Pt 1):781-796, 1985 160. Kung IT, Gibson JB, Bannatyne PM: Kimura’s disease: A clinico-pathological study of 21 cases and its distinction from angiolymphoid hyperplasia with eosinophilia. Pathology 16(1):39-44, 1984 166. Chong WS, Thomas A, Goh CL: Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: Two disease entities in the same patient: case report and review of the literature. Int J Dermatol 45(2):139-145, 2006 176. Nervi SJ, Schwartz RA, Dmochowski M: Eosinophilic pustular folliculitis: A 40 year retrospect. J Am Acad Dermatol 55(2):285-289, 2006 208. Fukamachi S et al: Therapeutic effectiveness of various treatments for eosinophilic pustular folliculitis. Acta Derm Venereol 89(2):155-159, 2009

Inflammatory Diseases Based on Abnormal Humoral Reactivity and Other Inflammatory Diseases

Chapter 37 :: Humoral Immunity and Complement :: Lela A. Lee HUMORAL IMMUNITY AND ANTIBODY STRUCTURE AT A GLANCE Humoral immunity, mediated by antibodies produced by B lymphocytes, is a form of specific immunity directed primarily toward extracellular antigens. Antibody molecules consist of two identical light chains covalently linked to two identical heavy chains. The variable region of the antibody molecule is responsible for antibody binding, and the constant region mediates most effector functions. The five antibody classes serve distinct functions. Immunoglobulin (Ig) M is involved in primary antibody responses, IgD is an antigen receptor on naive B cells, IgA is critical for mucosal immunity, IgG is the major Ig in the circulation and is important in secondary antibody responses, and IgE mediates immunity to parasites. An individual is capable of generating millions of distinct antibodies in millions of distinct B-cell clones through the processes of gene rearrangement and junctional diversity.

B LYMPHOCYTES During evolution, jawed vertebrates developed the capacity to respond with exquisite specificity to foreign organisms.1 Specific immunity is characterized by an enormous diversity of possible responses and by refinement in the immune response with successive exposures to the organism.2 The cells that can discriminate with fine specificity through their vast repertoire of receptors are lymphocytes. Specific immunity, also called adaptive immunity because it develops as an adaptation to infection, can be segregated into humoral immunity, mediated by antibodies produced by B lymphocytes, and cellular immunity, mediated by T lymphocytes. These two forms of specific immunity

developed to serve different functions. Humoral immunity is directed primarily toward extracellular antigens such as circulating bacteria and toxins. Cellular immunity is directed primarily toward antigens that infect or inhabit cells (see Chapter 10). To combat extracellular pathogens, the defending agent needs to be abundant and widely distributed in the body, particularly at its interfaces with the environment. Antibodies fulfill these characteristics by being capable of being secreted in great quantity from the cells that produce them and by being distributed in blood, mucosa, and interstitial fluid. In addition, antibodies can attach through Fc receptors (FcRs) to the surface of certain other cells of the immune system, such as mast cells, conferring antigen specificity to cells that do not have their own endogenously produced antigen-specific receptors. In addition to their major function in humoral immunity as antibody producers, B lymphocytes have a role in antigen presentation, regulation of T-cell subsets and dendritic cells, organization of lymphoid tissues, and cytokine and chemokine production.3,4

ANTIBODY STRUCTURE Antibodies, or immunoglobulins (Ig), are a family of glycoproteins that share a common structure.2,5,6 The antibody molecule has a symmetric Y-shape consisting of two identical light chains, each about 24 kDa, that are covalently linked to two identical heavy chains, each about 55 or 70 kDa, that are covalently linked to one another (Fig. 37-1). Within the light and heavy chains are variable and constant regions. The major function of the variable region is to recognize antigen, whereas the constant region mediates effector functions. The light and heavy chains contain a series of repeating, homologous units of about 110 amino acids that assume a globular structure and are called Ig domains. The Ig domain motif is found not only in antibody molecules but also in a variety of other molecules of the Ig “superfamily,” including the T-cell receptor, the major histocompatibility complex (MHC), CD4, CD8, intercellular adhesion molecule 1, among other molecules. The light chain has two major domains, (1) a variable (VL) and (2) a constant (CL) domain. The heavy chains have four or five domains, a variable (VH) and three (in IgA, IgD, and IgG) or four (in IgM and IgE) constant (CH1–4) domains. In IgA, IgD, and IgG, there is a hinge region

6

Immunoglobulin G (IgG) molecule

VL

S

S

CL

S

CL S

S

S

S

S

CH1

S

S S S

Section 6

Complement and Fc receptor binding sites

S

Antigen binding region

VH

S

S

S

VH

S

S

S

S

S

S

VL

S S

CH1

Hinge region

CH2

S S

S S

CH2

CH3

S S

S S

CH3

:: Inflammatory Diseases Based on Abnormal Humoral Reactivity

402

ANTIBODY CLASSES

KEY Ig domain Light chain Heavy chain S

tively. The different heavy chain classes have significantly different functions, as discussed in Section “Antibody Classes”. The IgA and IgG classes contain closely related subclasses, consisting of IgA1 and IgA2, and IgG1, IgG2, IgG3, and IgG4 (Table 37-1). Enzymatic digestion of IgG molecules by papain results in three cleavage products, two identical Fab fragments consisting of a light chain bound to the V– CH1 region of the heavy chain and an Fc portion consisting of two CH2–CH3 heavy chains bound to each other. Fab was so named for its property of antigen binding, and Fc was so named for its property of crystallizing. When IgG is digested by pepsin, the C-terminal region is digested into small fragments. The remaining product consists of the Fab region along with the hinge region. Fab fragments containing the hinge region are termed Fab′. When the two Fab′ fragments in an antibody molecule remain associated, the fragment is called F(ab′)2.

S

Disulfide bond

Carbohydrate Papain cleavage site Pepsin cleavage site

Figure 37-1  Schematic representation of an immunoglobulin G (IgG) molecule. between CH1 and CH2 that confers additional flexibility to the molecule. The variable domains are at the N-terminus. At the C-terminus are the constant domains and, in the heavy chains of membrane-bound antibodies, the transmembrane and cytoplasmic domains. Within the variable regions of the light and heavy chains are three areas of intense variability called hypervariable regions. These three regions, which are in proximity to one another in the three-dimensional structure of the antibody, are the areas most responsible for binding antigen. Because the hypervariable regions form a shape complementary to that of the antigen, the hypervariable regions are also called the complementaritydetermining regions. The unique areas formed by the hypervariable regions are present in too low an amount in the individual to generate self-tolerance. Thus, the immune system may not distinguish the unique portion of the antibody as self and may produce antibodies to that region of the antibody. The area of the antibody capable of generating an immune response is called an idiotope, and antibody responses to idiotopes result in a network of idiotypic–anti-idiotypic interactions that may help regulate the humoral immune response.7 There are two types of light chains, κ and λ, each encoded on different chromosomes. Each antibody molecule has either two κ or two λ chains, never one of each. The functional differences, if any, between κ and λ are not known. There are five types of heavy chains, (1) α, (2) δ, (3) ε, (4) γ, and (5) μ, corresponding to the antibody classes IgA, IgD, IgE, IgG, and IgM, respec-

(See Table 37-1)

IMMUNOGLOBULIN M IgM is evolutionarily the most ancient antibody class and is the first Ig molecule to be expressed during B-cell development.1 Its secretory form exists mainly as a pentamer consisting of five IgM molecules joined at their C-termini by tail pieces and stabilized by a molecule called a joining (J) chain. The engagement of membranebound IgM by antigen results in the activation of naive B cells. Secreted IgM recognizes antigen, usually through low-affinity interactions, and it can activate complement. IgM is the major effector of the primary antibody response. Although IgM interactions are typically low affinity, IgM can be very effective in responding to a polyvalent antigen (such as a polysaccharide with repeating epitopes) because its pentameric structure allows for multiple low-affinity interactions, resulting in a high-avidity interaction. (Avidity refers to the overall strength of attachment, whereas affinity refers to the strength of attachment at a single antigen-binding site.)

IMMUNOGLOBULIN D The IgD molecule exists primarily in a membranebound form and is the second antibody class to be expressed during B-cell development. Its function is not completely understood, but in its membrane-bound form it can serve as an antigen receptor for naive B cells.8 Secreted IgD has been found on the surface of basophils, where it induces production of antimicrobial, opsonizing, inflammatory, and B-cell–stimulating factors.9

IMMUNOGLOBULIN A IgA is the most abundant Ig in the body, being present in large quantity at mucosal sites. It is responsible

6

TABLE 37-1

Immunoglobulin Classes and Their Functions

Secreted Form

Approximate Molecular Weight of Secreted Form (kDa)

Serum Serum Concentration Half-Life (mg/mL) (Days)

IgM

None

Pentamer, hexamer

970

1.5

5

Primary antibody response; antigen receptor on naive B cells; complement activation

IgD

None

Monomer

180

Trace

3

Antigen receptor on naive B cells

IgA

IgA1

Monomer, polymer (usually dimer) Monomer, polymer (usually dimer)

160 (monomer), 390 (secretory IgA)

3

6

Mucosal immunity; neonatal immunity

160 (monomer), 390 (secretory IgA)

0.5

6

IgA2

Functions

::

Subtypes

IgG1 IgG2 IgG3 IgG4

Monomer Monomer Monomer Monomer

150 150 170 150

9 3 1 0.5

23 23 7 23

Neonatal immunity; opsonization; complement activation (except IgG4); phagocytosis; antibodydependent cell-mediated cytotoxicity; feedback inhibition of B cells

IgE

None

Monomer

190

0.05

2

Immediate hypersensitivity; defense against parasites

Ig = immunoglobulin.

IMMUNOGLOBULIN G IgG is the most abundant Ig in the circulation. Its secreted form is a monomer. IgG plays an important role in secondary antibody responses, and its interactions with antigen tend to be high affinity, particularly as the immune response matures. A number of cells have FcRs for IgG, including monocytes, neutrophils, eosinophils, natural killer (NK) cells, and B cells. IgG opsonizes (coats) antigen, allowing phagocytosis of the antigen, and activates complement. An exception is IgG4, which does not activate complement. IgG is important in neonatal immunity, as it is the only Ig class

Humoral Immunity and Complement

IgG

for mucosal immunity and is secreted in breast milk, thus contributing to neonatal immunity. In its secreted form, it exists as a monomer, dimer, or trimer, with the multimers being formed by interactions between tail pieces and stabilized by the J chain. For transport across epithelial surfaces, IgA dimers attach to a type of FcR called the polymeric Ig receptor.10 Once the transport process is complete, the IgA dimers remain attached to the extracellular portion of the receptor, called the secretory component, which protects the IgA from proteolysis. Cells of the immune system that have receptors for IgA include neutrophils, eosinophils, and monocytes.

Chapter 37

A

to cross the placenta, and it is secreted in breast milk. The interaction of IgG with the MHC class I-related receptor FcRn is involved in the delivery of IgG across the placenta as well as in prolonging its level in the circulation.11 The serum half-life of IgG is 23 days, considerably longer than that of the other Ig classes.

IMMUNOGLOBULIN E IgE is found in very small amounts in the circulation. High-affinity receptors for the Fc portion of IgE are present on mast cells, basophils, and eosinophils, and low-affinity receptors are present on B cells and Langerhans cells. In mast cells and basophils, IgE engagement with antigen activates the cells. IgE mediates immediate hypersensitivity, but its principal protective role may be to combat parasites.

MECHANISMS FOR THE GENERATION OF ANTIBODY DIVERSITY The information encoded by an individual’s DNA is limited by the need for the DNA to fit into a package of

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Section 6 :: Inflammatory Diseases Based on Abnormal Humoral Reactivity

the size of a cell. This space is far too small for sufficient DNA to encode billions of different lymphocyte receptors if the genes were encoded separately. Lymphocytes have adapted to this limitation by special mechanisms that increase by orders of magnitude the number of different possible antigen receptors.12 Each clone of B cells produces identical antigen receptors (i.e., antibodies) with unique specificity. It is estimated that an individual has approximately 107 different B-cell clones, resulting in 107 distinct antibodies. A major mechanism for generating this enormous diversity is gene rearrangement, whereby segments of DNA within a lymphocyte undergo somatic recombinations.13 Light chain genes contain three regions, (1) V (variable), (2) J (joining), and (3) C (constant), and heavy chain genes contain four regions, (1) V, (2) D (diversity), (3) J, and (4) C. Within each region are many gene segments from which to select for the final antibody product, which is comprised of one gene segment randomly selected from each region. The initial event in antibody formation is the joining of one D and one J segment from a heavy chain gene, with subsequent deletion of the DNA between the two segments. Next, a V segment is selected to join to the DJ segment, and any remaining D segments are deleted. The VDJ complex has attached 3′ to it any remaining J segments plus the C region. The unused J segments are removed during RNA processing. A similar process occurs in light chain loci; because there are no D segments in light chain loci, a VJ rather than a VDJ complex is formed. (Particularly in the k locus, VJ recombination may occur through a somewhat different mechanism involving inversion of the DNA without deletion of intervening sequences, but the functional result is the same.) The ability to select one segment each from the many segments available in the V, D, and J regions leads to a vast increase in the repertoire of possible antibodies. Additional diversity is generated by the juxtaposition of a rearranged light chain to a rearranged heavy chain; by the addition, deletion, or transposition of nucleotides at the junctions between V and D, D and J, and V and J segments, a phenomenon called junctional diversity; and by somatic hypermutation after antigen stimulation (see below).

B-CELL MATURATION

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Cells destined to become mature B cells undergo an orderly progression of events during development, resulting in the formation sequentially of heavy chains, light chains, and whole antibody molecules, with checkpoints to select against cells making unproductive gene rearrangements or autoreactive antibodies, and survival signals to select for cells making potentially useful antibodies. The process of B-cell development occurs in distinct stages, characterized by specific events and identifiable by specific cell surface markers and Ig gene expression. Bone marrow and fetal liver stem cells that give rise to B cells are initially pluripotent.2,14 Stem cells developing in the lymphocytic pathway initially become common lymphoid progenitors, which can give rise to B,

B-CELL MATURATION AT A GLANCE The pro-B cell expresses enzymes needed for gene rearrangement and junctional diversity, but neither heavy nor light chains are expressed. The pre-B cell expresses μ heavy chains in the cytoplasm. On the cell surface, the heavy chains associate with surrogate light chains to form pre-B cell receptors. The immature B cell produces light chains and can therefore express antibody molecules on the cell surface. If antigen exposure occurs at this stage, negative selection may take place. During the transitional stage, B cells gradually lose sensitivity to negative selection and acquire immune competence. The mature B cell expresses both IgM and IgD and is competent to respond to antigen.

T, or NK cells. B cells originating from fetal liver are mainly B1 cells (see Section “B-Cell Activation and Antibody Function”), whereas B cells originating in the bone marrow are primarily follicular B cells. Cells and extracellular molecules in the stromal microenvironment provide signals required for differentiation of lymphocytes. Induction of the transcriptional regulators EBF, E2A, and Pax-5 leads to the expression of proteins critical to B-cell development. Posttranscriptional regulation of mRNA by RNA-binding proteins and microRNAs provides further control over the process of B-cell differentiation.15 The earliest cell committed to the B-cell lineage is called a pro-B cell. At the pro-B cell stage, the cell expresses recombination activating gene (RAG) and terminal deoxyribonucleotidyl transferase (TdT) proteins, which will be needed subsequently for somatic recombination and nucleoside transfers involved in junctional diversity, respectively. At the pro-B-cell stage, limited somatic recombination has taken place, and Ig is not yet expressed. The next stage of B-cell maturation is represented by the pre-B cell and is marked by the synthesis of a cytoplasmic μ heavy chain. Because light chains are not yet expressed at this stage, surface Ig is not present. Some of the μ heavy chains associate with invariant molecules called surrogate light chains and with the signal transducing proteins Ig α and Ig β to form complexes called pre-B cell receptors. Cells that have synthesized heavy chains that are capable of forming part of a pre-B cell receptor are selected for at this stage, as pre-B cell receptors provide important signals for survival, proliferation, and maturation. The formation of light chains marks the next stage in B-cell maturation, the immature B-cell stage. When

B-CELL ACTIVATION AND ANTIBODY FUNCTION AT A GLANCE When the B-cell receptor (surface antibody) binds antigen, a second signal provided by C3d engagement with complement receptor 2 significantly augments B-cell activation.

Humoral Immunity and Complement

B cells recognize a variety of macromolecules, including proteins, lipids, carbohydrates, and nucleic acids. The portion of the molecule recognized by the antibody is called an epitope or determinant. B cells recognize both linear epitopes (epitopes formed by several adjacent amino acids) and, quite commonly, conformational epitopes (epitopes present as a result of folding of the macromolecule).21 In contrast to B cells, T-cell responses are almost entirely restricted to linear epitopes of peptides. Macromolecules, particularly large proteins, may contain several different epitopes, and a humoral response

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ANTIGENS BOUND BY B CELLS

to a macromolecule typically is comprised of multiple different antibodies. Although each different antibody is specific for a given epitopic configuration, similarities in epitopes may exist such that an antibody to a given epitope on a given macromolecule also may be able to bind a different epitope on a different macromolecule. This phenomenon is called cross-reactivity, and may be important in the genesis of autoimmune antibody responses. Macromolecules that have multiple identical epitopes are classified as being polyvalent or multivalent. Antibodies to these macromolecules or aggregates of macromolecules may form complexes called immune complexes with the antigen. At a particular concentration of antibody and antigen, called the zone of equivalence, a large network of linked antigens and antibodies forms. At lower or higher concentrations of antibody or antigen, the complexes are much smaller. Immune complexes, formed in the circulation or in tissue, may be responsible for disease through the initiation of an inflammatory response.

Chapter 37

light chains join with the μ heavy chains, an IgM molecule results and can be expressed on the cell surface in association with Ig α and Ig β. Although the presence of a B-cell receptor complex confers the ability to recognize specific antigens, at this stage such recognition does not result in proliferation or differentiation. Rather, the cells may undergo negative selection when antigen is encountered. Immature B cells recognizing self-antigen may be negatively selected through deletion,16 anergy, or receptor editing, a process of secondary gene rearrangement by which a new, nonself specificity is acquired.17 The exit of immature B cells from the bone marrow to the spleen marks the beginning of the next stage, the transitional B-cell stage.18 Transitional cells gradually acquire surface IgD, CD21, and CD23 expression and become more immune competent. Alternative splicing of RNA allows the simultaneous expression of IgM and IgD. At the beginning of the stage, cross-linking of the B-cell receptor leads to negative selection. With further maturation, transitional cells become responsive to T-cell help and lose sensitivity to negative selection. The mature B cell expresses IgM and IgD and is competent to respond to antigen. The cell is considered naive because it has not been activated by antigen. The majority of mature B cells circulate through peripheral lymphoid tissues (spleen, lymph nodes, mucosal lymphoid tissue) and are called follicular B cells, or recirculating B cells. B cells are recruited to the follicle by the chemokine CXCL13, secreted by follicular dendritic cells, and survive in the follicle with the assistance of a cytokine called BAFF (B-cell activating factor), also known as BLyS (B lymphocyte stimulator). A small percentage of mature B cells home to the marginal zone of the spleen and remain resident there. The encounter of antigen by mature naive B cells leads to B-cell activation, proliferation, and differentiation (see Section “B Cell Activation and Antibody Function”). A subset of B cells become memory B cells, which can persist for long periods apparently without stimulation by antigen, and which respond rapidly if the antigen is encountered subsequently.19 Another subset of B cells differentiates into cells that make progressively less membrane-bound Ig and more secreted Ig. The terminally differentiated B cells committed to the production of secreted Ig are plasma cells and have abundant rough endoplasmic reticulum, consistent with the function of the cells as antibody factories.20

B-cell responses to protein antigens typically involve T-cell help, with resultant antibody class switching and affinity maturation. Activated B cells may become short-lived plasma cells, memory B cells, or longlived plasma cells. Long-lived plasma cells migrate to the bone marrow, where they may persist indefinitely and are a major source of antigen-specific antibodies in the circulation. Effector functions of antibodies include neutralization of antigen, complement activation, cell activation, phagocytosis, and antibody-dependent, cell-mediated cytotoxicity. Most of these are mediated through the binding of Ig to Fc receptors containing an immunoreceptor tyrosinebased activation motif. Negative signaling to B cells is provided by binding of IgG to a B-cell Fc receptor that contains an immunoreceptor tyrosine-based inhibition motif. The availability of excess IgG to bind this receptor is an indication that antigen is being successfully eliminated and the immune response is no longer required.

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On cross-linking of the mature B-cell receptor by antigen, clustering of receptors initiates signaling transduced by Igα and Igβ. The complex signaling cascade involving the phosphorylation of tyrosine kinases, including Lyn, Fyn, Btk, and Syk, eventuates in the expression of genes involved in B-cell activation.22 B-cell activation is facilitated by second signals, one of which is provided by the complement protein C3d.23 Complement fragment C3d is formed as a result of complement activation through any of the complement activation pathways (see Section “Complement”). The B-cell surface contains a coreceptor complex consisting of complement receptor 2 (CR2), CD19, and CD81 (also called TAPA-1, or target for antiproliferative antigen-1). Simultaneous binding of antigen by antibody on the B-cell surface and of C3d by CR2 leads to markedly increased B-cell activation. B-cell activation may also occur through Toll-like receptors that recognize specific microbial products.24 The subsequent response to an antigen often involves a complex interaction between B cells and T cells, leading to a fine-tuning of the immune response.25 Recognition of antigen by both B cells and T cells leads to increased expression of cell surface proteins and cytokines that render these cells increasingly capable of migrating toward and productively interacting with each other. T cells recognizing peptide-class II MHC complexes on dendritic cells receive a primary signal from the complex and a secondary signal from costimulatory interactions involving the binding of B7–1 and B7–2 on dendritic cells to CD28 on T cells.26 These activated T cells express CXCR5, the ligand for CXCL13, which results in T-cell migration toward the follicle and therefore increasingly toward B cells. In response to a protein antigen, B cells take up the antigen, process it, and present processed antigen on the cell surface in complex with class II MHC. Activated B cells express less CXCR5, which allows them to migrate from the follicle toward the T-cell zone. At the boundary between follicles and T-cell zones, activated T cells interact with B cells and provide signals to the B cells through the binding of CD40 on B cells to CD40 ligand (CD154) on T cells and through the action of cytokines, notably interleukin 2 (IL-2), IL-4, IL-21, BAFF, and APRIL (a proliferation-inducing ligand).2 These signals will be necessary for subsequent class (heavy chain isotype) switching, affinity maturation, and memory B-cell generation. The overall effects on B cells are stimulation of proliferation and differentiation. At this phase, some of the activated B cells become short-lived plasma cells, which provide a prompt initial response to an antigen, while others migrate back from the periphery of the follicle to proliferate rapidly and form germinal centers. It is primarily in the germinal centers that class switching, affinity maturation, and generation of memory B cells occur. Class switching from IgM to IgA, IgE, or IgG occurs as a result of T cell–B cell interactions.27,28 The determination of the antibody class selected is based on the site where the antigen is encountered and the cytokine milieu. For example, B-cell responses to antigens encountered on mucosal surfaces characteristically result in class switching to IgA, and transforming growth factor-β is

an important contributing cytokine. IL-4 is an important signal for class switching to IgE. T-cell interaction with B cells also results in affinity maturation, whereby the affinity of antibodies for the antigen progressively increases. During affinity maturation, somatic hypermutations in antibody genes result in antibodies with both greater and lesser affinity for the antigen.29,30 Those antibodies with greater affinity confer a survival advantage on the B cells that produce them. Progressively, the population of B cells evolves in favor of those producing higher affinity antibodies for the antigen. Both class switching and affinity maturation require the expression of an enzyme called activation-induced cytosine deaminase (AID).31 The culmination of germinal center activity is the formation of memory B cells and long-lived plasma cells.32 A number of transcriptional regulators are involved in late B-cell development, including BLIMP1 (B-lymphocyte maturation protein 1), IRF4 (interferonregulatory factor 4), and XBP1 (X-box-binding protein 1). Plasma cells may arise from and be replenished by memory B cells or may arise from an intermediate cell, the plasmablast. Long-lived plasma cells migrate to and have a survival niche in the bone marrow, where they can persist indefinitely. These bone marrow longlived plasma cells are the major source of antigenspecific antibody in the circulation. As noted in Section “Antigens Bound by B Cells,” T-cell responses are limited almost entirely to peptides. Thus, B-cell responses to nonprotein antigens may not result in T-cell help through the mechanisms described earlier.33 In selected cases, T-cell independent nonprotein antigens can induce class switching, but in general, T-cell independent responses are characterized by IgM antibodies of lower affinity. One type of T-cellindependent B-cell response produces so-called natural antibodies—IgM antibodies that are largely anticarbohydrate antibodies produced without apparent antigen exposure.34 These natural antibodies are characterized by a limited repertoire and are produced primarily by B1 peritoneal cells either spontaneously or in response to bacteria that colonize the gut. Marginal zone B cells, located near the marginal sinus in the spleen, may also produce natural antibodies. Antigen occupation of antibody-binding sites on B cells leads to functional results, called effector functions. With the exception of direct neutralization of antigen by antibody binding, effector functions are typically mediated through the binding of Ig to FcRs.35,36 FcRs can be categorized as those that trigger cell activation and those that do not. Those that can trigger activation contain one or more motifs called immunoreceptor ­tyrosine-based activation motifs. Of those that do not trigger activation, some can inhibit cell activation and contain a motif called immunoreceptor tyrosine-based inhibition motif. FcRs that neither activate nor inhibit cell activation are involved in the transport of Ig through epithelia and the prolongation of the half-life of IgG. The effector functions of antibodies serve to eliminate the antigen that initiated the immune response and also to downregulate the immune response when activation is not required. Effector functions of

a­ ntibodies include neutralization of antigen, complement activation, cell activation (of monocytes, neutrophils, eosinophils, and B cells), phagocytosis (by monocytes and neutrophils), and antibody-dependent cell-mediated cytotoxicity (mediated by NK cells and eosinophils). In addition, engagement of IgG by antigen provides a negative signal to B cells, mediated through the binding of the antigen-antibody complex to an immunoreceptor tyrosine-based inhibition motifcontaining Fcγ receptor, FcγIIB, on the B cell.37

The complement system was discovered through its ability to contribute to, or “complement,” bacterial cell lysis by antibodies.46,47 At physiologic temperatures, serum containing antibacterial antibodies lysed bacteria effectively, whereas serum heated to 56°C (133°F) lost its ability to lyse bacteria. Because antibodies are quite stable at 56°C (133°F), it was postulated that the

The early steps in complement activation are triggered enzyme cascades in which cleavage of an inactive protein into fragments results in cleavage of subsequent proteins in the cascade. The alternative and lectin pathways are primarily pathways of innate immunity; the classical pathway is a pathway characteristically initiated by humoral immunity. The complement pathways converge at the cleavage of C3 and subsequent cleavage of C5. The final steps of activation consist of the addition of C6–8 to C5b, and polymerization of C9 to form the membrane attack complex.

loss of lytic ability was due to the degradation of heatlabile nonantibody molecules. Although the complement system was first identified through its role in humoral immunity, a primitive complement system emerged more than 1.3 billion years ago as a component of innate immunity (see Chapter 10).48 The complement system is constituted in part by a set of plasma proteins that are normally inactive or minimally active. The initial steps of activation involve the cleavage of an inactive protein into a smaller and a larger fragment. The larger fragment, then, is itself able to cleave other proteins in the cascade. Because an activated molecule in one step is capable of generating many activated molecules in the following step, the sequential cleavage and activation of complement proteins result in amplification of the cascade.

Humoral Immunity and Complement

COMPLEMENT

The three pathways of complement activation are the alternative, classical, and lectin pathways.

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Disorders of B cells or antibodies cause or contribute to many diseases of dermatologic relevance. Immunodeficiency diseases may result from abnormalities of B-cell development or activation, or from abnormalities in effector function pathways.38 B-cell lymphomas may result from failure to regulate proliferation, differentiation, or programed cell death.39 Ectopic lymphoid aggregates can arise as a result of aberrant chemokinemediated lymphocyte homing.40 Antibodies may initiate an inflammatory response that results in injury, as in IgE-mediated allergic reactions or immune-complex diseases.41,42 In some cases, the antigen may not be obviously harmful, but the response to the antigen is. In other cases, the antigen may be pathogenic, but the character or magnitude of the immune response is inappropriate or inadequately controlled. The regulatory systems that protect an organism from attack by its own immune system occasionally go awry.43,44 Failure to eliminate autoreactive cells may be a major underlying abnormality in many patients with autoimmunity. In some cases, autoimmunity may be initiated as a result of an immune response to a pathogen.45 The pathogen may act as a nonspecific activator of the immune system, or may activate the immune response specifically (e.g., by containing an epitope or epitopes that are cross-reactive with an autoepitope). These responses may be particularly difficult to control because the major stimulus for the immune response, the antigen, is a normal component of “self” and cannot be eliminated. As mentioned earlier, B cells have important roles beyond antibody production. Abnormalities or imbalance of immune regulatory functions by B cells may lead to autoimmunity. Thus, through many mechanisms, the normal protective B-cell response, which developed as an elegant means to discriminate very finely among various potential pathogens, can be subverted to result in harm to the organism.

The complement system functions to kill microbes via lysis or phagocytosis, to clear immune complexes and apoptotic debris from the circulation, to promote inflammation, and to stimulate humoral immunity.

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B CELLS AND ANTIBODIES IN DISEASE

COMPLEMENT SYSTEM AND ACTIVATION PATHWAYS AT A GLANCE

6

PATHWAYS OF COMPLEMENT ACTIVATION The early stages of the activation of complement ultimately result in cleavage of the complement protein C3. This is followed by the cleavage of C5 and initiation of the final steps of complement activation. There are three distinct pathways that lead to the cleavage of C3, the classical, the alternative, and the lectin pathways. Although the classical pathway was the first to be described, the alternative pathway is evolutionarily older.49

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ALTERNATIVE PATHWAY

Section 6

(Fig. 37-2) The first step in the activation of the alternative pathway is the binding of C3b to a cell surface such as a bacterial cell surface. Intact C3 is an inactive molecule, but there is a low-level spontaneous cleavage of C3, called tickover, which results in the continuous availability of the C3b fragment. C3b can bind stably to a cell surface through an interaction between a thioester group of C3b and a hydroxyl group of the cell surface. In intact C3, the thioester domain is covered by hydrophobic residues that prevent hydrolysis of the thioester bond. The anaphylatoxin (ANA) domain of C3 stabilizes this inactive conformation. When the ANA domain is cleaved to release C3a, the thioester group is exposed, and conformational change results in its abil-

:: Inflammatory Diseases Based on Abnormal Humoral Reactivity

Alternative pathway of compliment activation Tickover

C3

C3b

C3b

Microbial cell surface

C3a

Factor B

Factor D

Properidin C3 convertase

C3bBb Ba

C3

C3b

C5 convertase C3bBbC3b

C3a

C3b

Amplification of pathway

C5

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C5b

C5a

Figure 37-2  The alternative pathway of complement activation. Shown are the steps from the initial attachment of C3b to a microbial cell surface through the cleavage of C5 into C5a and C5b. The final steps of complement activation are shown in Fig. 37-4. See Section “Alternative Pathway” for details.

ity to bond to the cell surface.50,51 If this chemical bonding does not occur, the thioester group is hydrolyzed and C3b is inactivated. Once stable attachment of C3b to the cell surface takes place, a plasma protein called Factor B binds to C3b. Factor B is in turn cleaved by factor D, generating Bb and Ba. The complex of C3b and Bb, stabilized by the plasma protein properidin, is the alternative pathway C3 convertase (i.e., it cleaves C3 into C3a and C3b). The result of the activity of the C3 convertase is an amplification of the pathway by two or three orders of magnitude. The addition of further C3b to the complex results in C3bBbC3b, which constitutes the alternative pathway to C5 convertase. The late steps of complement activation, after the cleavage of C5, are common to the three pathways and are described in Final Steps of Complement Activation. Thus, the low level of C3b in the plasma acts as a sentinel for microbes. Once C3b is bound to the cell surface, subsequent molecular interactions result in a substantial amplification of the alternative pathway and cleavage of C5. The requirement for binding of C3b to a structural element serves to limit the effect of complement activation to the area where complement activation is needed. The alternative pathway of complement activation does not require finely specific recognition of antigen and so is considered a component of innate immunity. It follows that if specific recognition is not required, C3b can bind to human cells as well as microbes. However, activation on human cells is generally prevented by the intervention of regulatory proteins present on the surface of human cells, protecting these cells from inappropriate and harmful attack.52

CLASSICAL PATHWAY (Fig. 37-3) The initial step in the activation of the classical pathway is characteristically the binding of the portion of the C1 complex called C1q to IgG or IgM antibodies.46 The C1q molecule consists of six identical arms attached to a central trunk. The globular ends of the arms attach to the complement-binding regions of the heavy chains of certain Ig classes. In order for C1q to be activated, it must bind simultaneously to at least two Ig heavy chains. This means, in effect, that the Ig must have bound antigen. In the case of IgG, binding of multiple epitopes by antibodies results in close proximity of the antibodies and thus the proper configuration for C1q activation. (As mentioned in Section “Immunoglobulin G,” IgG4 is an exception, in that it does not bind C1q or activate complement.) Because IgM exists as a pentamer, theoretically IgM without bound antigen could activate complement. However, when IgM is not bound by antigen, the C1q binding site is not accessible. When antigen is bound, a conformational change results in exposure of the C1q binding site. The complement component C1 is a complex of C1q, C1r, and C1s. Binding of two or more of the globular heads of C1q results in activation of C1r. Activated C1r is a protease that cleaves and activates C1s, and activated C1s, in turn, cleaves C4 into C4a and C4b.

Classical pathway of compliment activation

C1q

C1r2s2

C1 complex

Microbial cell surface with antibodies

C3 convertase

C2a

C4bC2b

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C4a C4b

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C4

(The numbering of the complement proteins differs from their positions in the activation sequence, as components were discovered before the elucidation of their positions in the pathway.) C4b, like C3b, contains a thioester group that can form stable bonds with hydroxyl groups on a particular structure. Bound C4b is then bound by C2, which is cleaved into C2a and C2b. The C4bC2b complex is the classical pathway C3 convertase. (Note: Typically, suffix “a” denotes the smaller and “b” the larger complement fragment. Historically, the exception was C2, where C2a represented the larger and C2b the smaller fragment. Some recent textbooks now identify the smaller fragment as C2a and the larger as C2b, to maintain consistency with the nomenclature of the other complement proteins. However, many recent publications continue to adhere to the historic nomenclature.) The cleavage of C3 results in C3a and C3b. The C3b fragment may then go on to activate complement by the alternative pathway, or act in concert with C4bC2b to form C4bC2bC3b, the classical pathway C5 convertase. The major characteristics of the classical pathway are much the same as those of the alternative pathway. Activation of the pathway requires attachment of a complement protein to a structure such as a cell surface or immune complex, so that the effects of complement activation are spatially limited. Initial activation steps result in the formation of a C3 convertase that cleaves C3. Cleavage of C3 leads to the formation of a C5 convertase that cleaves C5 into C5a and C5b. A major difference is the initiation of the classical pathway by specific recognition of antigen by antibodies, in contrast to the less specific binding that occurs to initiate the alternative pathway.

LECTIN PATHWAY

C3

C3b

C3a

C5 convertase C4bC2bC3b

C3b

Amplification of pathway

C5

C5b

C5a

Figure 37-3  The classical pathway of complement activation. Shown are the steps from the initial binding of C1q to antibody–antigen complex through the cleavage of C5 into C5a and C5b. The final steps of complement activation are shown in Fig. 37-4. See Section “Classical Pathway” for details.

The lectin pathway is very similar to the classical pathway, with the exception of the initiating steps. The first step is the binding of a plasma lectin, mannosebinding protein (MBP), to polysaccharides on microbial cell surfaces.53 MBP, a member of the collectin (collagenous lectin) family, is structurally similar to C1q and can associate with C1r and C1s. MBP attachment to a microbe can begin the cascade through the activation of C1r and C1s. MBP also interacts with MBP-associated serine proteases (MASPs), which are analogous to C1r and C1s. Binding of MBP to microbial cell surfaces results in cleavage of MBP-associated serine protease and thence cleavage of C4.54 In either event, the effect is the formation of C4b and its stable binding to a cell surface. As is the case for the alternative pathway, the lectin pathway is a component of innate immunity.

FINAL STEPS OF COMPLEMENT ACTIVATION (Fig. 37-4) The alternative, classical, and lectin pathways converge at the cleavage of C5. The C5b fragment remains

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Formation of the membrane attack complex

C5b C5 convertase

C5b6

C5b67

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410

C5b678

C5b678 + unpolymerized C9

C5b678 + polymerized C9

Figure 37-4  Formation of the membrane attack complex. The alternative, classical, and lectin pathways converge at the formation of C5b and its sequential attachment to C6, C7, C8, and C9. The polymerization of C9 results in tubular structures on the cell membrane.

surface bound. The next steps do not involve enzymatic cleavage, but rather the sequential binding of C6, C7, and C8 to C5b. The C5b-8 complex stably bound to a cell membrane becomes an active membrane attack complex (MAC) through the addition of C9. C9 polymerizes around the complex and forms pores in cell membranes. These pores may result in cell death through osmotic rupture, particularly in nonnucleated erythrocytes. Nucleated cells are more resistant to lysis, but may still exhibit effects attributable to MAC binding.55 It is quite possible that the nonlytic changes induced by MAC are of more functional and pathologic significance overall than is MAC-induced cell lysis.56 These nonlytic effects may differ depending on cell type and milieu, and similar effects may lead to different outcomes. For example, MAC insertion into phagocyte cell membranes can lead to the production of inflammatory mediators such as reactive oxygen species and prostaglandins, resulting in phagocyte activation.57

Glomerular epithelial cells may also exhibit inflammatory mediator production, but, in that setting, the inflammatory mediators may lead to tissue injury.58 MAC has also been reported to cause proliferation of certain cells, and MAC has been reported to have both apoptotic and antiapoptotic properties.55

ADDITIONAL INITIATORS OF COMPLEMENT ACTIVATION In addition to the characteristic initiators of the three pathways, certain additional structures can trigger complement activation.59 These include, among others, the following: in the alternative pathway, IgA immune complexes and endotoxin; in the classical pathway, C-reactive protein, apoptotic bodies, and serum amyloid P; and in the lectin pathway, serum ficolins (lectins which bind N-acetylglucosamine).53,60

FUNCTIONS OF COMPLEMENT PROTEINS As mentioned earlier, the earliest function of the complement system to be discovered was the lysis of bacteria. Killing of microbes through direct lysis is mediated by the MAC, C5b-9. Microbes may also be destroyed through coating, or opsonization, by complement and phagocytosis of the opsonized particles by phagocytic cells. The processes of opsonization and phagocytosis are also mechanisms for another important function of complement—the clearance of immune complexes and apoptotic debris from the circulation. An ancillary function of complement activation is the induction of inflammation. Inflammation, characterized by vascular changes and ingress and activation of leukocytes and inflammatory proteins, serves to augment the localized immune response in tissue. Three mediators of inflammation initiated by complement activation are the complement fragments C3a, C4a, and C5a. These are called anaphylatoxins because of their ability to induce degranulation of mast cells.61 The most potent of these ANAs is C5a. Receptors for C5a are expressed on endothelial cells, mast cells, eosinophils, basophils, monocytes, neutrophils, smooth muscle cells, and epithelial cells. Binding of C5a to endothelial cells results in increased vascular permeability and expression of P-selectin, both of which promote leukocyte accumulation in tissue. Binding to neutrophils results in increased neutrophil motility, adhesion to endothelial cells, and production of reactive oxygen species. The overall result is the accumulation of inflammatory cells at local sites in tissue where they can phagocytose and efficiently kill microbes. The activation of complement also results in stimulation of the humoral immune system through the generation of C3d. B cells whose cell surface antibodies recognize complement-bound antigen are upregulated by the concurrent binding of C3d to CR2 on the B-cell surface. Opsonization by complement also facilitates antigen presentation to B cells by follicular dendritic cells.

COMPLEMENT RECEPTORS COMPLEMENT RECEPTORS AND REGULATORY PROTEINS AT A GLANCE

There are several proteins that interact with complement and serve to mediate or regulate its functions. The C5a receptor, which is a member of the seven-transmembrane a-helical G-protein-coupled receptor family, was mentioned in the previous section. Some of the best described of the complement receptors are CR1–CR4. The type 1 complement receptor, CR1 (CD35), is a member of a family of proteins called regulators of complement activation (RCA), which share a common structure consisting of multiple short consensus repeats, also known as complement control protein repeats.52 CR1 binds C3b or C4b and is expressed on peripheral blood cells, including monocytes, B and T lymphocytes, neutrophils, eosinophils, and erythrocytes; on follicular dendritic cells; and on keratinocytes.62 On phagocytic cells, binding of CR1 to C3b or C4b results in phagocytosis of particles opsonized by complement fragments, as well as activation of microbicidal mechanisms in the phagocytic cells. On erythrocytes, binding of CR1 to C3b- or C4b-coated immune complexes results in transport of the complexes to the spleen and liver, where they are cleared from the circulation by phagocytes. Thus, CR1 serves as an important mediator of complement function. It can also serve as a downregulator of complement activation, as it is involved in the dissociation of C3 convertase complexes. The type 2 complement receptor, CR2 (CD21), is also a member of the RCA family.59 CR2 binds C3 fragments iC3b (“i” stands for inactive), C3dg, and C3d, as well as Epstein–Barr virus, interferon-α, and the immuno-

REGULATION OF COMPLEMENT ACTIVATION Molecules involved in the regulation of complement activation serve to downregulate the immune response once an immune response is no longer needed and to limit the immune response to the sites required, specifically protecting self from complement attack. The C1 inhibitor (C1 INH) is a protease inhibitor that inhibits certain plasma serine proteases, including C1, kallikrein, and factor XII.46 C1 exists as a complex of C1q and a tetramer of two C1r and two C1s fragments. When C1q binds antibody, C1 INH can act to limit complement activation by binding to the C1rC1s tetramer, dissociating it from C1q and preventing downstream activation of the pathway. Another major point of interaction of regulatory proteins is with bound C3b or C4b.52 As mentioned earlier, the thioester group of unbound C3b or C4b is rapidly hydrolyzed, rendering these molecules inactive. For surface-bound C3b or C4b, inactivation occurs through the displacement of components of the alternative or classical pathway C3 convertase from C3b or C4b or through proteolysis of C3b or C4b. In the alternative pathway, inactivation of the C3 convertase complex, C3bBb, can take place through the displacement of Bb from C3b by the plasma protein factor H or the cell surface proteins decay accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46), and CR1. These three cell surface proteins, all members of the RCA family, are expressed on human cells but not

Humoral Immunity and Complement

Some of the regulatory proteins downregulate complement activation by displacing components of the early steps of the cascade. These include C1 inhibitor, factor H, C4 binding inhibitor, decay accelerating factor, membrane cofactor protein, and CR1.

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Regulation of complement activation is provided by certain serum and cell surface proteins. Many of the regulatory cell surface proteins are expressed on human cells but not microbes, thus protecting human cells from complement damage.

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Some of the important effects of complement are mediated through binding of complement proteins to complement receptors. CR1 functions in phagocytosis, immune complex clearance, and downregulation. CR2 is important in stimulation of humoral immunity. CR3 and -4 promote phagocytosis.

regulatory protein CD23. CR2 is expressed on subsets of B and T lymphocytes, basophils, mast cells, follicular dendritic cells, and some epithelial cells, including keratinocytes. On B cells, CR2 serves as a coreceptor for B-cell activation. When CR2 is bound by C3d, the level of B-cell activation is increased by orders of magnitude.63 On dendritic cells, CR2 engagement results in a trapping of immune complexes in germinal centers. CR2 also appears to play a role in antigen presentation to T cells. The type 3 complement receptor, CR3 (CD11b/CD18, Mac-1), is an integrin cell surface molecule expressed on monocytes, neutrophils, NK cells, and mast cells.64 It functions to promote phagocytosis of microbes through binding to iC3b and through direct binding to microbes. It interacts with intercellular adhesion molecule 1 expressed endogenously on endothelial cells to stabilize the adhesion of leukocytes to endothelium, facilitating the recruitment of leukocytes from the circulation into tissue. The type 4 complement receptor, CR4 (CD11c/CD18), is also an integrin cell surface molecule. It is expressed on monocytes, neutrophils, NK cells, and dendritic cells, and probably functions similarly to CR3. Among the recently described complement receptors are SIGN-R1,65 which binds C1q and is expressed on splenic marginal zone macrophages, and CRIg (complement receptor of the immunoglobulin family),66 which binds C3b and iC3b and is expressed on a subset of tissue-resident macrophages.

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microbes, thereby allowing complement activation to proceed on microbes while protecting human cells from injury. Factor H preferentially binds cell surfaces with high levels of sialic acid, and the relative abundance of sialic acid on human cells but not microbes further focuses the downregulation of complement activation on human cells. In the classical and lectin pathways, the C3 convertase is C4bC2b. DAF, MCP, and CR1 can displace C2b from C4b, as can the plasma protein C4binding protein (C4BP). Thus, the cell surface proteins DAF, MCP, and CR1 can dissociate the C3 convertases of both the alternative and the classical/lectin pathways, whereas the plasma proteins factor H and C4BP are specific for alternative or classical/lectin, respectively. Proteolysis of C3b or C4b is mediated by factor I, a plasma protein that requires cofactors for its activity. MCP, CR1, factor H, and C4BP can all serve as cofactors for factor I. Regulation of complement at the late steps is mediated in part by CD59, a cell surface protein expressed on human cells but not microbes. It binds the C5b-8 complex and inhibits addition of C9, blocking formation of the MAC. Plasma S protein binds the C5b-7 complex and blocks its insertion into the cell membrane and also inhibits C9 polymerization.67 Intact MACs may be removed from cells through shedding on membrane vesicles or by internalization and degradation.55 Carboxypeptidase N can remove the terminal arginine of C3a, C4a, and C5a and has been referred to as ANA inactivator.68 Carboxypeptidase R has also been shown to remove the terminal arginine of C3a and C5a.69

COMPLEMENT AND DISEASE GENETIC ABNORMALITIES OF THE COMPLEMENT SYSTEM Deficiencies of complement cascade proteins, complement receptors, or complement regulatory proteins can lead to a variety of diseases.70 Genetic deficiencies of complement have been associated primarily with increased risk for infection or autoimmunity. As examples, deficiencies of many complement components, particularly the early complement components C1–C4, have been associated with early-onset systemic lupus erythematosus (SLE), C3 deficiency has been associated with life-threatening pyogenic infections, and C5–C9 deficiencies have been associated with Neisserial infections (reviewed in Chapter 143). Genetic deficiency of mannose-binding lectin is relatively common, with significantly low levels occurring in about 10% of Caucasians, and is associated with increased risk for infection and autoimmunity, including SLE.71,72 Altered expression of CR3 (CD11b/CD18) and CR4 (CD11c/CD18) occurs in leukocyte adhesion deficiency-1, a congenital disorder resulting from mutations in the gene encoding CD18. Mutation in CD18 also affects expression of CD11a/CD18 (leukocyte function-associated antigen-1). Patients with leukocyte adhesion deficiency-1 exhibit significant abnormalities of leukocyte adhesion and have recurrent infections (see Chapter 143).

COMPLEMENT AND DISEASE AT A GLANCE Genetic deficiencies of complement components have been associated primarily with susceptibility to infection or autoimmunity. Genetic deficiencies of regulatory complement proteins may result in inappropriately prolonged complement activation, such as occurs with C1 inhibitor deficiency. Complement is associated with systemic lupus erythematosus through several possible mechanisms. These include increased risk of autoimmunity conferred by certain complement deficiencies, tissue damage resulting from autoantibody-induced complement activation, ineffective clearance of autoimmunity-promoting apoptotic debris, and failure to eliminate self-reactive B cells. Complement activation has been implicated in the pathogenesis of atherosclerosis, reperfusion injury after myocardial ischemia, diabetic microvascular disease, and cerebral infarct in ischemic stroke. Certain infectious agents have evolved mechanisms for evasion of destruction by complement, and some use complement receptors or regulatory proteins to gain entry into the cell.

Deficiency of the complement regulatory protein C1 INH causes angioneurotic edema as a result both of poorly regulated classical pathway activation and of excess bradykinin due to the actions of kallikrein and factor XII. Angioedema may also occur if one has markedly reduced levels of the ANA inactivator, carboxypeptidase N73 (see Chapter 38). Deficiency of a protein required for the proper expression of DAF and CD59 on the cell surface is associated with paroxysmal nocturnal hemoglobinuria, a disease characterized by complement-mediated erythrocyte lysis.74 Hemolytic-uremic syndrome has been associated with mutations in MCP, factor H, and factor I.75 Factor H deficiency has also been associated with membranoproliferative glomerulonephritis. The risk for developing age-related macular degeneration is affected significantly by the presence of certain polymorphisms in genes of the complement system, particularly complement factor H but also factor B and C2.76

COMPLEMENT, SYSTEMIC LUPUS ERYTHEMATOSUS, AND AUTOANTIBODIES Complement has been closely associated with SLE (see also Chapter 155), albeit in seemingly paradoxical

EVASION OR SUBVERSION OF COMPLEMENT BY MICROBES The observation that individuals with deficiencies of components of the late stages of complement activation

Full reference list available at www.DIGM8.com

Humoral Immunity and Complement

Complement activation has been implicated in the pathogenesis of atherosclerosis, reperfusion injury after myocardial ischemia, and cerebral infarct in ischemic stroke.82,83 In the microvascular proliferative disease associated with diabetes, glycation, and thereby inactivation of CD59, may result in cellular proliferation due to nonlytic proliferative effects of MAC.84 Complement activation has also been implicated in hyperacute rejection of xenotransplants due to the presence of natural antibodies to components of the endothelial cells of the transplanted organ, with resultant complement activation, endothelial cell injury, and intravascular coagulation.

KEY REFERENCES

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are at increased risk for only a limited set of infections illustrates that infectious agents have evolved means of evading destruction by complement.85 Gram-positive bacteria have thick cell walls that are difficult to penetrate by MAC.46 Group A streptococcus M protein binds factor H, which downregulates complement activation, and many pathogens have evolved mechanisms to attract factor H through the expression of sialic acids on their surfaces. Staphylococcus aureus expresses several proteins that inhibit C3 activation. A protein of vaccinia virus (VCP-1, vaccinia virus complement control protein-1) acts as a cofactor for factor I, leading to proteolysis of C3b and C4b. In human immunodeficiency virus (HIV) infection, the inclusion of downregulatory molecules of the complement system into the viral or host cell membrane allows HIV to evade complementmediated destruction.86 DAF and CD59 can be subsumed into the HIV virus membrane upon budding from infected human cells, and factor H can bind to HIV surface glycoproteins on infected human cells. The complement system has been subverted by certain infectious agents for entry into the cell. Epstein– Barr virus penetrates B cells via binding to CR2 on the B-cell surface.46 Measles virus binds to cells via MCP. Mycobacteria make C4-like molecules that bind C2b and then cleave C3. The deposition of C3b on the mycobacterial cell membrane leads to its uptake into macrophages, where it exists as an intracellular parasite. Knowledge of these evasive and subversive strategies of pathogens may be useful in designing vaccines and targeted therapies.85

Chapter 37

ways.77,78 Genetic deficiencies of complement components are associated with SLE, but some of the tissue injury seen in SLE appears to be mediated in part by complement activation. Thus, complement seems to be simultaneously protective and deleterious. These observations underscore the protean roles of complement in the immune system. Complement activation has the potential for causing tissue injury, but complement components may be important in clearance of immune complexes and apoptotic debris. Apoptotic bodies that are not cleared effectively may be able to trigger autoimmunity through presentation of normally sequestered autoantigens to the immune system. It has also been suggested that complement participates in eliminating self-reactive immature B cells, a further mechanism for a protective effect of complement in SLE.78 Altered expression of both CR1 and CR2 has been observed in patients with SLE.79 In murine models of lupus, knockout mice lacking expression of CR1 and CR2 (located on the same gene in mice and produced through alternative splicing) have accelerated autoimmunity if the mice otherwise have the optimal genetic background. These findings indicate that the interaction of CR2 and C3d, important in B-cell response to antigen, is another factor that determines susceptibility to SLE. Autoantibodies to complement components can result in or exacerbate disease.80 Autoantibodies to C1q are relatively common in SLE and have been associated with more severe renal disease, possibly through an adverse affect on the clearance of immune complexes or apoptotic bodies.81 C3 nephritic factor is an autoantibody to the C3 convertase, C3bBb, which acts to stabilize the complex. Its clinical significance is its association with membranoproliferative glomerulonephritis type II and partial lipodystrophy.

DVD contains references and additional content 1. Flajnik MF, Kasahara M: Origin and evolution of the adaptive immune system: Genetic events and selective pressures. Nat Rev Genet 11(1):47-59, 2010 2. Abbas AK, Lichtman AH, Pillai S: Cellular and Molecular Immunology, 6th edition. Philadelphia, Elsevier Saunders, 2010 3. LeBien TW, Tedder TF: B lymphocytes: How they develop and function. Blood 112(5):1570-1580, 2008 13. Jung D et al: Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 24:541-570, 2006 20. Fairfax KA et al: Plasma cell development: From B-cell subsets to long-term survival niches. Semin Immunol 20(1):49-58, 2008 46. Walport MJ: Complement. First of two parts. N Engl J Med 344(14):1058-1066, 2001 48. Nonaka M, Kimura A: Genomic view of the evolution of the complement system. Immunogenetics 58(9):701-713, 2006 50. Janssen BJ et al: Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437(7058):505-511, 2005 52. Kim DD, Song WC: Membrane complement regulatory proteins. Clin Immunol 118(2–3):127-136, 2006 55. Cole DS, Morgan BP: Beyond lysis: How complement influences cell fate. Clin Sci (Lond) 104(5):455-466, 2003

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Chapter 38 :: Urticaria and Angioedema :: Allen P. Kaplan URTICARIA AND ANGIOEDEMA AT A GLANCE Occurs acutely at some time in 20% of the population; incidence of chronic urticaria/ angioedema is approximately 0.5%.

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Acute urticaria/angioedema is caused by drugs, foods, occasionally infection in association with immunoglobulin E-dependent mechanisms (allergy), or metabolic factors. Chronic urticaria/angioedema is an autoimmune disorder in 45% of patients. In the absence of urticaria, angioedema can be due to overproduction or impaired breakdown of bradykinin. Treatment of acute urticaria/angioedema relies on antihistamines and short courses of corticosteroids, and identification and elimination of endogenous and exogenous causes. Treatment of C1 inhibitor deficiency includes androgenic agents, antifibrinolytic agents, and C1 inhibitor (C1 INH) concentrates, a kallikrein inhibitor, and bradykinin receptor antagonist. Treatment of physical urticaria/angioedema includes high-dose antihistamine prophylaxis, except for delayed pressure urticaria. Treatment of chronic idiopathic or autoimmune urticaria/angioedema includes antihistamines (nonsedating preparations primarily), low-dose daily or alternate day corticosteroids, or cyclosporine.

Urticaria is defined as a skin lesion consisting of a wheal-and-flare reaction in which localized intracutaneous edema (wheal) is surrounded by an area of redness (erythema) that is typically pruritic. Individual hives can last as briefly as 30 minutes to as long as 36 hours. They can be as small as a millimeter or 6–8 inches in diameter (giant urticaria). They blanch with pressure as the dilated blood vessels are compressed, which also accounts for the central pallor of the wheal. The dilated blood vessels and increased permeability that characterize urticaria are present in the superficial dermis and involves the venular plexus in that location. Angioedema can be caused by the same pathogenic mechanisms as urticaria but the pathology is in

the deep dermis and subcutaneous tissue and swelling is the major manifestation. The overlying skin may be erythematous or normal. There is less pruritus (fewer type C nerve endings at the deeper cutaneous levels) but there may be pain or burning.

EPIDEMIOLOGY Urticaria and angioedema are common. Age, race, sex, occupation, geographic location, and season of the year may be implicated in urticaria and angioedema only insofar as they may contribute to exposure to an eliciting agent. Of a group of college students, 15%–20% reported having experienced urticaria, while 1%–3% of the patients referred to hospital dermatology clinics in the United Kingdom noted urticaria and angioedema. In the National Ambulatory Medical Care Survey data from 1990 to 1997 in the United States, women accounted for 69% of patient visits. There was a bimodal age distribution in patients aged birth to 9 years and 30–40 years.1 Urticaria/angioedema is considered to be acute if it lasts less than 6 weeks. Most acute episodes are due to adverse reactions to medications or foods and in children, to viral illnesses. Episodes of urticaria/angioedema persisting beyond 6 weeks are considered chronic and are divided into two major subgroups: (1) chronic autoimmune urticaria (45%) and (2) chronic idiopathic urticaria (55%) with a combined incidence in the general population of 0.5%.2 Physically induced urticaria/angioedema is not included in the definition. Various types of physical urticaria/angioedema may last for years, but the individual lesions last fewer than 2 hours (except delayed pressure urticaria) and are intermittent. Whereas 85% of children experience urticaria in the absence of angioedema, 40% of adult patients with urticaria also experience angioedema. Approximately 50% of patients with chronic urticaria (with or without angioedema) are free of lesions within 1 year, 65% within 3 years, and 85% within 5 years; fewer than 5% have lesions that last for more than 10 years. Angioedema alters the natural history, and only 25% of patients experience resolution of lesions within 1 year. There are no data regarding the remission rate in patients with only angioedema. The hereditary group is considered to be life long once the diagnosis becomes clinically manifest.

PATHOGENESIS MAST CELL AND HISTAMINE RELEASE The mast cell is the major effector cell in most forms of urticaria and angioedema, although other cell types undoubtedly contribute. Cutaneous mast cells adhere

sure urticaria is a variant of a late-phase reaction while mast cell degranulation in most other physical urticarias has no associated late phase. These include typical acquired cold urticaria, cholinergic urticaria, dermatographism, and type I solar urticaria.

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The first suggestion that patients with chronic urticaria and angioedema might have an autoimmune diathesis was the observation that there is an increased incidence of antithyroid antibodies in such patients relative to the incidence in the population at large.9 These include antimicrosomal (perioxidase) and antithyroglobulin antibodies, as seen in patients with Hashimoto’s thyroiditis.10 Patients may have clinical hypothyroidism, but a small number might be hyperthyroid if inflammation is at an early stage when thyroid hormone is released into the circulation. This atypical presentation should be distinguished from the occasional patient with Grave’s disease. Nevertheless, most patients are euthyroid. The incidence of antithyroid antibodies in chronic urticaria, as reported in the literature, varies between 15% and 24%,11,12 but the most recent data are closer to the latter figure12 and demonstrate segregation of antithyroid antibodies with chronic autoimmune urticaria rather than chronic idiopathic urticaria. However, the association is not absolute. The incidence in the autoimmune subgroup was 27%, in the chronic idiopathic urticaria subgroup 11%, while in the population at large it is 7%–8%. Gruber et al (1988)13 considered the possibility that patients might have circulating and anti-IgE antibodies that are functional and did indeed find these in about 5%–10% of patients. Gratten et al14,15 sought antibodies reactive with skin mast cells by performing an autologous skin test and found a 30% incidence of positive reactions in patients with chronic urticaria. There were only rare positive reactions in healthy control subjects or patients with other forms of urticaria. Subsequently, this level of positivity was shown by Hide et al16 to be due to an IgG antibody reactive with the α subunit of the IgE receptor; in addition a 5%–10% incidence of functional anti-IgE antibodies was confirmed (eFig. 38-1.1 in online edition).17

Chapter 38

to fibronectin and laminin through the very late activation (VLA) β1 integrins VLA-3, VLA-4, and VLA-5 and to vitronectin through the αvβ3 integrin. Cutaneous mast cells, but not those from other sites, release histamine in response to compound 48/80, C5a, morphine, and codeine. The neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), and somatostatin, (but not neurotensin, neurokinins A and B, bradykinin, or calcitonin gene-related peptide), activate mast cells for histamine secretion. Dermal microdialysis studies of the application of SP on skin indicate that it induces histamine release only at 10−6 M, which suggests that after physiologic nociceptor activation, SP does not contribute significantly to histamine release.3 Yet it is a major contributor to the flare reaction induced by histamine stimulation of afferent type C fibers (mediating pruritus) with release of SP from adjacent nerve endings by antidromic conduction. Histamine is found associated with the wheal.4 Recently, the spinal cord afferent fibers mediating pruritis have, for the first time, been distinguished from pain fibers in the lateral spinothalamic tracts.5 Not all potential biologic products are produced when cutaneous mast cells are stimulated. For example, SP releases histamine from cutaneous mast cells above 10−6 M but does not generate prostaglandin D2 (PGD2). Vascular permeability in skin is produced predominantly by H1 histamine receptors (85%); H2 histamine receptors account for the remaining 15%. The current hypothesis regarding cellular infiltration that follows mast cell degranulation suggests that the release of mast cell products (histamine, leucotrienes, cytokines, chemokines) leads to alterations in vasopermeability, upregulation of adhesion molecules on endothelial cells, and rolling and attachment of blood leukocytes, followed by chemotaxis and transendothelial cell migration. Various forms of physical urticaria/angioedema have provided experimental models for the study of urticaria/angioedema by allowing the observation of the elicited clinical response, examination of lesional and normal skin biopsy specimens, assay of chemical mediators released into the blood or tissues, and characterization of peripheral leukocyte responses.6,7 The intracutaneous injection of specific antigen in sensitized individuals has provided an experimental model for analysis of the role of immunoglobulin (Ig) E and its interaction with the mast cell. In many subjects, the challenged cutaneous sites demonstrate a biphasic response, with a transient, pruritic, erythematous wheal-and-flare reaction followed by a tender, deep, erythematous, poorly demarcated area of swelling that persists for up to 24 hours. This is the late-phase response with recruitment of variable numbers of neutrophils, prominent eosinophils, monocytes, small numbers of basophils, and CD4+ T-lymphocytes of the TH2 subclass.8 Chemokines (chemotactic cytokines) strongly associated with Th2 lymphocyte predominance include those reactive with chemokine receptors CCR3, CCR4, and CCR8 on T lymphocytes. Characteristic cytokines produced by Th2 lymphocytes include interleukins (ILs) 4, 5, 9, 13, 25, 31 and 33. The cellular infiltrate seen in biopsy specimens of delayed pres-

CELLULAR INFILTRATE Mast cell degranulation certainly initiates the inflammatory process in autoimmune chronic urticaria and is assumed to also do so in idiopathic chronic urticaria. Evidence for an increased number of mast cells in chronic urticaria has been presented,36,37 but there are also publications indicating no significant differences from normal;38 these studies did not discriminate the autoimmune from the idiopathic groups. However, no alternative mechanisms for mast cell degranulation in the idiopathic groups have been suggested to date. Yet the histology of the two groups differs only in minor ways. Common to all biopsy specimens is a perivascular

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studied. The presence of increased plasma IL-4 levels25 in patients with chronic urticaria provides indirect evidence of lymphocyte activation, basophil activation, or both, and isolated CD4+ lymphocytes of patients were shown to secrete greater amounts of both IL-4 and IFN-γ compared with that seen in healthy control subjects on stimulation with phorbol myristate acetate. A direct comparison between cutaneous latephase reactions and the histology of chronic urticaria revealed that infiltrating cells had characteristics of both TH1 and TH2 cells, with production of IFN-γ by the former cells and IL-4 and IL-5 by the latter.46 Alternatively, this might represent activated TH0 cells (i.e., activated CD4+ lymphocytes that are not differentiated to TH1 or TH2 cells). When the histology of autoimmune and idiopathic chronic urticarias was compared,41 the autoimmune subgroup had greater prominence of granulocytes within the infiltrate, whereas other infiltrating cells were quite similar, with a small increment in cytokine levels in the autoimmune group and greater tryptase positivity (? less degranulation) in the autoantibody-negative group. The patients with autoimmune chronic urticaria generally had more severe symptoms than those with idiopathic chronic urticaria.47

BASOPHIL RELEASIBILITY (Figs. 38-1 and 38-2) The basophils of patients with chronic urticaria have been shown to be hyporesponsive to anti-IgE, an observation made by Kern and Lichtenstein48 long before there were any clues to the pathogenesis of this ­disorder. These findings were confirmed49 and

Basophil histamine release 100

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Inflammatory Diseases Based on Abnormal Humoral Reactivity

infiltrate that surrounds small venules within the superficial and deep venular plexus, with a prominence of CD4+ T lymphocytes and monocytes and virtually no B cells.36,39 Granulocytes are quite variable but are plentiful if the lesion undergoes biopsy early in its development. Neutrophils and eosinophils are both present,40,41 although the degree of eosinophils accumulation varies greatly.39 Even when eosinophils are not evident, major basic protein can be identified within lesions (in at least two-thirds of patients), which most likely represents evidence of prior eosinophil degranulation.42 The presence of basophils has also been recently demonstrated by using an antibody (BB1) that is specific for this cell type.41 Thus, the infiltrate resembles that of an allergic late-phase reaction, as suggested previously,43 although the percentage of each cell types differs, with neutrophils and monocytes being relatively more prominent in urticaria. Endothelial cell activation is suggested by the presence of intercellular adhesion molecule 1 and E-selectin in biopsy specimens of urticarial lesions.44 Sources of chemokines include the mast cell and the activated endothelial cell; the latter cells are stimulated not only by cytokines or monokines, such as IL-4, IL-1, and tumor necrosis factor-α (TNF-α), but also by the vasoactive factors, for example, histamine and leukotrienes released from activated mast cells.45 Complement activation and the release of C5a results not only in augmented mast cell (and basophil) histamine release, but C5a is also chemotactic for neutrophils, eosinophils, and monocytes. The presence of C5a is one of the factors that would distinguish this lesion from a typical allergen-induced cutaneous late-phase reaction. The particular chemokines released in chronic urticaria have not been

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Figure 38-1  Basophil histamine release comparing normal sera (N = 35) with sera from patients with chronic urticaria (N = 104). Those designated as having chronic autoimmune urticaria are shown on the right.

Activation of cutaneous mast cells by IgG antireceptor C3 C4b2a

C4 + C2 C1

C3b

Activated C1 Antigen-antibody (IgG) complex

C4b2a3b C5

C5b C5a

C5a receptor

Figure 38-2  Schematic diagram of the activation of cutaneous mast cells by IgG antireceptor antibody, followed by activation of complement, release of C5a, and augmentation of mast cell release.

appeared to be associated with basopenia50 and to segregate with the autoimmune subgroup. One obvious interpretation is that there is in vivo desensitization of basophils in the presence of circulating anti-IgE receptor. Vonakis et al have demonstrated that patients’ basophil hyporesponsiveness to anti-IgE is due to augmented levels of SHIP phosphatase51 that limits phosphorylation reactions critical for histamine secretion. Although manifest in about half the patients with chronic urticaria (and not segregated with either the autoimmune or idiopathic subgroups), the abnormality appears to reverse when patients remit. Thus, it may be a marker of disease activity. We have found a paradoxical result when the isolated basophils of patients with chronic urticaria were activated and compared with the basophils of healthy control subjects. Although the basophils of the patients with urticaria were clearly less responsive to anti-IgE, they demonstrated augmented histamine release when incubated with serum and it did not matter whether the sera were taken from normal subjects, other patients with chronic urticaria, or was their own.52

ROLE OF THE EXTRINSIC COAGULATION CASCADE Studies of the plasma of patient with chronic urticaria demonstrate the presence of d-dimer and prothrombin 1 and 2 fragments indicating activation of prothrombin to thrombin as well as digestion of fibrinogen by thrombin.53 The reaction is not specific for chronic

BRADYKININ: ROLE IN ANGIOEDEMA Kinins are low-molecular-weight peptides that participate in inflammatory processes by virtue of their ability to activate endothelial cells and, as a consequence, lead to vasodilatation, increased vascular permeability, production of nitric oxide, and mobilization of arachidonic acid. Kinins also stimulate sensory nerve endings to cause a burning dysesthesia. Thus, the classical parameters of inflammation (i.e., redness, heat, swelling, and pain) can all result from kinin formation. Bradykinin is the best characterized of this group of vasoactive substances. There are two general pathways by which bradykinin is generated. The simpler of the two has only two components: (1) an enzyme tissue kallikrein57 and (2) a plasma substrate, low-molecular-weight kininogen.58,59 Tissue kallikrein is secreted by many cells throughout the body; however, certain tissues produce particularly large quantities. These include glandular tissues (salivary and sweat glands and pancreatic exocrine gland) and the lung, kidney, intestine, and brain. The second pathway for bradykinin formation is far more complex and is part of the initiating mechanism by which the intrinsic coagulation pathway is activated (eFig. 38-1.2 in online edition).60 Factor XII is the initiating protein that binds to certain negatively charged macromolecular surfaces and autoactivates (autodigests) to form factor XIIa.61,62 This is synonymous with Hageman factor as designated in the figure. There are two plasma substrates of factor XIIa, namely (1) prekallikrein63 and (2) factor XI,64,65 and each of these circulates as a complex with high-molecular-weight kininogen (HK).66,67 These complexes also attach to initiating surfaces, and the major attachment sites are on two of the domains of HK, which thereby places both prekallikrein and factor XI in optimal conformation for cleavage to kallikrein (plasma kallikrein) and factor XIa, respectively. It is important to note that plasma kallikrein and tissue ­kallikrein are

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urticaria as similar observations have been noted in multiple nonsteroidal hypersensitivity syndrome.54 Nevertheless, the data are of considerable interest and activation of the coagulation cascade is dependent on tissue factor rather than factor XII, i.e., the extrinsic coagulation cascade. Although activated endothelial cells are a well-known source of the tissue factor, histologic studies suggest that eosinophils are a prominent source.55 The relationship of these observations to histamine release by basophils or mast cells is not clear. Whereas thrombin activation of mast cells has been reported, the amounts required are large and the observations thus far are confined to rodent mast cells. One publication relating to eosinophil to histamine release found IgG antibody to FceRII in the serum of patients with chronic urticaria which activates eosinophils to release cationic proteins.56 They propose basophil activation by these eosinophil cationic proteins but do not demonstrate it; however, they offer an additional mechanism for basophil and possibly mast cell histamine release.

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separate gene products and have little amino acid sequence homology, although they have related functions (i.e., cleavage of kininogens). Tissue kallikrein prefers low-molecular-weight kininogen but is capable of cleaving HK, whereas plasma kallikrein cleaves HK exclusively. The two kininogens have an identical amino acid sequence starting at the N-terminus and continuing to 12 amino acids beyond the bradykinin moiety59 but differ in C-terminal domains because of alternative splicing at the transcription level.68,69 Both factor XII and HK bind to endothelial cells (which may function as the “natural” surface in the presence of physiologic zinc ion), thus activation may occur at the cell surface.70,71 A scheme for both production and degradation of kinins is shown in eFig. 38-1.2 in online edition. The enzymes that destroy bradykinin consist of kininases I and II. Kininase I is also known as plasma carboxypeptidase N,72 which removes the C-terminal arg from bradykinin or kallidin to yield des-arg73 bradykinin or des-arg74 kallidin, respectively.75 It is the same enzyme that cleaves the C-terminal arg from the complement anaphylatoxins C3a and C5a. Kininase II is identical to angiotensin-converting enzyme (ACE).76 Kininase II is a dipeptidase that cleaves the C-terminal phearg from bradykinin to yield a heptapeptide, which is cleaved once again to remove ser-pro and to leave the pentapeptide arg-pro-pro-gly-phe.75 If the C-terminal arg of bradykinin is first removed with kininase I, then ACE functions as a tripeptidase to remove ser-pro-phe and to leave the above pentapeptide.77 Bradykinin and kallidin stimulate constitutively produced B2 receptors,78 whereas des-arg73-BK or des-arg74 lys-BK both stimulate B1 receptors,79 which are induced as a result of inflammation. Stimuli for B1 receptor transcription include IL-1 and TNF-α.80,81

CLINICAL FINDINGS Circumscribed, raised, erythematous, usually pruritic, evanescent areas of edema that involve the superficial portion of the dermis are known as urticaria (Fig. 38-3); when the edematous process extends into the deep dermis and/or subcutaneous and submucosal layers, it is known as angioedema. Urticaria and angioedema may occur in any location together or individually. Angioedema commonly affects the face or a portion of an extremity, may be painful but not pruritic, and may last several days. Involvement of the lips, cheeks, and periorbital areas is common, but angioedema also may affect the tongue, pharynx, or larynx. The individual lesions of urticaria arise suddenly, rarely persist longer than 24–36 hours, and may continue to recur for indefinite periods. They are highly pruritic.

IMMUNOLOGIC: IMMUNOGLOBULIN E- AND IMMUNOGLOBULIN E RECEPTOR-DEPENDENT URTICARIA/ ANGIOEDEMA 418

ATOPIC DIATHESIS. Episodes of acute urticaria/ angioedema that occur in individuals with a personal

Figure 38-3  Urticaria and angioedema. This patient has urticaria occurring on the face, neck, and upper trunk with angioedema about the eyes. or family history of asthma, rhinitis, or eczema are presumed to be IgE dependent. However, in clinical practice, urticaria/angioedema infrequently accompanies an exacerbation of asthma, rhinitis, or eczema. The prevalence of chronic urticaria/angioedema is not increased in atopic individuals.

SPECIFIC ANTIGEN SENSITIVITY. Common examples of specific antigens that provoke urticaria/ angioedema include foods such as shellfish, nuts, and chocolate; drugs and therapeutic agents notably penicillin; aeroallergens; and Hymenoptera venom (see Fig. 38-3). Urticaria in patients with helminthic infestations has been attributed to IgE-dependent processes; however, proof of this relationship is often lacking. Specific allergens and nonspecific stimuli may activate local reactions termed recall urticaria at sites previously injected with allergen immunotherapy. PHYSICAL URTICARIA/ ANGIOEDEMA5,6 DERMOGRAPHISM. Dermographism is the most common form of physical urticaria and is the one most likely to be confused with chronic urticaria. A lesion appears as a linear wheal with a flare at a site in which the skin is briskly stroked with a firm object (Fig. 38-4). A transient wheal appears rapidly and usually fades within 30 minutes; however, the patient’s normal skin is typically pruritic so that an itch–scratch sequence may appear. The prevalence of dermographism in the general population was reported as 1.5% and 4.2%, respectively, in two studies, and its prevalence in patients with chronic urticaria is 22%. It is not associated with atopy. The peak prevalence occurs in the second and third decades. In one study, the duration of dermographism was greater than 5 years in 22% of individuals and greater than 10 years in 10%.

pressure urticaria and no spontaneously occurring hives. An IgE-mediated mechanism has not been demonstrated; however, histamine and IL-6 have been detected in lesional experimental suction-blister aspirates and in fluid from skin chambers, respectively.87–89

PRESSURE URTICARIA. Delayed pressure urticaria appears as erythematous, deep, local swellings, often painful, that arise from 3 to 6 hours after sustained pressure has been applied to the skin.85,86 Spontaneous episodes are elicited on areas of contact after sitting on a hard chair, under shoulder straps and belts, on the feet after running, and on the hands after manual labor. The peak prevalence occurs in the third decade. Delayed pressure urticaria may occasionally be associated with fever, chills, arthralgias, and myalgias, as well as with an elevated erythrocyte sedimentation rate and leukocytosis. In one study, it accompanied chronic urticaria in 37% of patients. This is far more commonly seen than patients with

Figure 38-5  Positive ice cube test in a patient with cold urticaria.

Urticaria and Angioedema

Elevations in blood histamine levels have been documented in some patients after experimental scratching, and increased levels of histamine,82 tryptase, SP, and VIP, but not calcitonin gene-related peptide, have been detected in experimental suction-blister aspirates. The dermographic response has been passively transferred to the skin of normal subjects with serum or IgE.83 In delayed dermographism, lesions develop 3–6 hours after stimulation, either with or without an immediate reaction, and last 24–48 hours. The eruption is composed of linear red indurated wheals. This condition may be associated with delayed pressure urticaria and these two may, in fact, represent the same entity. Cold-dependent dermographism is a condition characterized by marked augmentation of the dermatographic response when the skin is chilled.84

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Figure 38-4  Topical dermatographic response to scratching the skin.

COLD URTICARIA. There are both acquired and inherited forms of cold urticaria/angioedema; however, the familial form is rare. Idiopathic or primary acquired cold urticaria may be associated with headache, hypotension, syncope, wheezing, shortness of breath, palpitations, nausea, vomiting, and diarrhea. Attacks occur within minutes after exposures that include changes in ambient temperature and direct contact with cold objects. The elicitation of a wheal after the application of ice has been called a diagnostic cold contact test (Fig. 38-5). This can be performed with thermoelectric elements with graded temperatures so that the temperature threshold for producing a wheal can be determined and a dose-response (sensitivity) in terms of stimulus duration can be readily obtained.92 If the entire body is cooled (as in swimming), hypotension and syncope, which are potentially lethal events (by drowning), may occur. In rare instances, acquired cold urticaria has been associated with circulating cryoglobulins, cryofibrinogens, cold agglutinins, and cold hemolysins, especially in children with infectious mononucleosis.93–95 Passive transfer of cold urticaria by intracutaneous injection of serum or IgE to the skin of normal recipients has been documented.96,97 Histamine, chemotactic

Chapter 38

VIBRATORY ANGIOEDEMA. Vibratory angioedema may occur as an acquired idiopathic disorder, in association with cholinergic urticaria, or after several years of occupational exposure to vibration.90 It has been described in families with an autosomal dominant pattern of inheritance.91 The heritable form often is accompanied by facial flushing. An increase in the level of plasma histamine was detected during an experimental attack in patients with the hereditary form and in patients with acquired disease.91,92 A typical symptom is hives across the back when toweling off after a shower (in the absence of dermatographism).

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factors for eosinophils and neutrophils, PGD2, cysteinyl leukotrienes, platelet-activating factor, and TNF-α have been released into the circulation after experimental challenge.98–104 Histamine, SP, and VIP, but not calcitonin gene-related peptide, have been detected in experimental suction-blister aspirates. Histamine has been released in vitro from chilled skin biopsy specimens that have been rewarmed.105 Neutrophils harvested from the blood of an experimentally coldchallenged arm manifested an impaired chemotactic response suggesting in vivo desensitization. Whereas complement has no role in primary acquired cold urticaria, cold challenge of patients with cold urticaria who have circulating immune complexes (such as cryoglobulins) can provoke a cutaneous necrotizing venulitis with complement activation.106–109 Rare forms of acquired cold urticaria have been described mainly in case reports include systemic cold urticaria,84 localized cold urticaria,110 cold-induced cholinergic urticaria, cold-dependent dermographism,84 and localized cold reflex urticaria.111,112 Three forms of dominantly inherited cold urticaria have been described. Familial cold urticaria which has been termed familial cold autoinflammatory syndrome and is considered a type of periodic fever.113 It is a disorder showing an autosomal dominant pattern of inheritance with a genetic linkage to chromosomes 1q44. The responsible gene has been identified as CIASI, which codes for a protein involved in regulation of inflammation and apoptosis.114 The eruption occurs as erythematous macules and infrequent wheals and is associated with burning or pruritus. Fever, headaches, conjunctivitis, arthralgias, and a neutrophilic leukocytosis are features of attacks. The delay between cold exposure and onset of symptoms is 2.5 hours, and the average duration of an episode is 12 hours. Renal disease with amyloidosis occurs infrequently. Skin biopsy specimens show mast cell degranulation and an infiltrate of neutrophils. Results of the cold contact test and passive transfer with serum have been negative. Serum levels of IL-6 and granulocyte colony stimulating factor were elevated in one patient. Other studies suggest a pathogenic role for IL-1. Delayed cold urticaria occurs as erythematous, edematous, deep swellings that appear 9–18 hours after cold challenge. Lesional biopsy specimens show edema with minimal numbers of mononuclear cells; mast cells are not degranulated; and neither complement proteins nor immunoglobulins are detected. Cold immersion does not release histamine, and the condition cannot be passively transferred. Recently, a new form of familial cold urticaria with dominant inheritance has been reported with pruritus, erythema, and urticaria with cold exposure that can progress to syncope. The ice cube test is negative and it lacks the fever, and flu-like symptoms associated with familial cold autoinflammatory syndrome.115

CHOLINERGIC URTICARIA. Cholinergic urticaria develops after an increase in core body temperature, such as during a warm bath, prolonged exercise, or episodes of fever.116 The highest prevalence

Figure 38-6  Lesions of cholinergic urticaria observed in a patient after 15 minutes of exercise in a warm room.

is observed in individuals aged 23–28 years. The eruption appears as distinctive, pruritic, small, 1- to 2-mm wheals that are surrounded by large areas of erythema (Fig. 38-6). Occasionally, the lesions may become confluent, or angioedema may develop. Systemic features include dizziness, headache, syncope, flushing, wheezing, shortness of breath, nausea, vomiting, and diarrhea. An increased prevalence of atopy has been reported. The intracutaneous injection of cholinergic agents, such as methacholine chloride, produces a wheal with satellite lesions in approximately one-third of patients.117,118 Alterations in pulmonary function have been documented during experimental exercise challenge119 or after the inhalation of acetylcholine, but most are asymptomatic. A major subpopulation of patients with cholinergic urticaria have a positive skin test result and in vitro histamine release in response to autologous sweat.120 It is not clear whether this is IgE mediated and any antigen present in sweat is unidentified. This is the same subpopulation with a positive methacholine skin test with satellite lesions and a nonfollicular distribution of the wheals. The remaining patients had negative results on autologous sweat skin tests or in vitro histamine release. Results of the methacholine skin test are negative for satellite lesions and the hives tend to be follicular in distribution. Familial cases have been reported only in men in four families.121 This observation suggests an autosomal dominant pattern of inheritance. One of these individuals had coexisting dermographism and aquagenic urticaria. After exercise challenge, histamine and factors chemotactic for eosinophils and neutrophils have been released into the circulation.99,119 Tryptase has been detected in lesional suction-blister aspirates. The urticarial response has been passively transferred on one occasion; however, most other attempts to do so have been unsuccessful. Cold urticaria and cholinergic urticaria are not uncommonly seen together122,123 and cold-induced cholinergic urticaria represents an unusual ­variant

in which typical “cholinergic” appearing lesions occur with exercise, but only if the person is chilled, for example, with exercise outside on a winter’s day. The ice cube test and methacholine skin test are both negative.124

AQUAGENIC URTICARIA AND AQUAGENIC PRURITIS. Contact of the skin with water

Urticaria and Angioedema

EXERCISE-INDUCED ANAPHYLAXIS. Exercise-induced anaphylaxis is a clinical symptom complex consisting of pruritus, urticaria, angioedema respiratory distress, and syncope that is distinct from cholinergic urticaria.134–137 In most patients, the wheals are not punctate and resemble the hives seen in acute or chronic urticaria. The symptom complex is not readily reproduced by exercise challenges as is cholinergic urticaria. There is a high prevalence of an atopic diathesis. Some cases are food dependent, i.e., exercise will lead to an anaphylaxis-like episode only

ADRENERGIC URTICARIA. Adrenergic urticaria occurs as wheals surrounded by a white halo that develop during emotional stress. The lesions can be elicited by the intracutaneous injection of norepinephrine.

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SOLAR URTICARIA. Solar urticaria occurs as pruritus, erythema, wheals, and occasionally angioedema that develop within minutes after exposure to sun or artificial light sources. Headache, syncope, dizziness, wheezing, and nausea are systemic features. Most commonly, solar urticaria appears during the third decade.126 In one study, 48% of patients had a history of atopy. Although solar urticaria may be associated with systemic lupus erythematosus and polymorphous light eruption, it is usually idiopathic. The development of skin lesions under experimental conditions in response to specific wavelengths has allowed classification into six subtypes; however, individuals may respond to more than one portion of the light spectrum. In type I, elicited by wavelengths of 285–320 nm, and in type IV, elicited by wavelengths of 400–500 nm, the responses have been passively transferred with serum, suggesting a role for IgE antibody. In type I, the wavelengths are blocked by window glass.127,128 Type VI, which is identical to erythropoietic protoporphyria, is due to ferrochelatase (hemesynthetase) deficiency (see Chapter 132).74 There is evidence that an antigen on skin may become evident once irradiated with the appropriate wave length of light followed by complement activation and release of C5a.129–131 Histamine and chemotactic factors for eosinophils and neutrophils have been identified in blood after exposure of the individuals to ultraviolet A, ultraviolet B, and visible light.132,133 In some individuals, uncharacterized serum factors with molecular weights ranging from 25 to 1,000 kDa, which elicit cutaneous wheal-and-erythema reactions after intracutaneous injection, have been implicated in the development of lesions.

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LOCAL HEAT URTICARIA. Local heat urticaria is a rare form of urticaria in which wheals develop within minutes after exposure to locally applied heat. An increased incidence of atopy has been reported. Passive transfer has been negative. Histamine, neutrophil chemotactic activity, and PGD2 have been detected in the circulation after experimental challenge.125 A familial delayed form of local heat urticaria in which the urticaria occurred in 1–2 hours after challenge and lasted up to 10 hours has been described.

if food was ingested within 5 hours of the exercise. The food dependency is subdivided into two groups: in the first the nature of the food eaten is not relevant, whereas in the second a specific food to which there is IgE-mediated hypersensitivity must be eaten for hives to appear.138–141 Yet in these cases, eating the food without exercise does not result in urticaria. The food-dependent group is easier to treat because avoidance of food (or a specific food) for 5–6 hours before exercise prevents episodes. Cases not related to food require therapy for acute episodes and attempts to prevent episodes with high-dose antihistaminics or avoidance of exercise. Results of a questionnaire study of individuals who had had exercise-induced anaphylaxis for more than a decade142 disclosed that the frequency of attacks had decreased in 47% and had stabilized in 46%. Forty-one percent had been free of attacks for 1 year. Rare familial forms have been described. In exercise-induced anaphylaxis, baseline pulmonary function tests are normal. Biopsy specimens show mast cell degranulation, and histamine and tryptase are released into the circulation when symptoms appear.

of any temperature may result in pruritus alone or, more rarely, urticaria. The eruption consists of small wheals that are reminiscent of cholinergic urticaria. Aquagenic urticaria has been reported in more than one member in five families.143 Aquagenic pruritus without urticaria is usually idiopathic but also occurs in elderly persons with dry skin and in patients with polycythemia vera, Hodgkin’s disease, the myelodysplastic syndrome, and the hypereosinophilic syndrome. Patients with aquagenic pruritus should be evaluated for the emergence of a hematologic disorder. After experimental challenge, blood histamine levels were elevated in subjects with aquagenic pruritus and with aquagenic urticaria. Mast cell degranulation was present in lesional tissues. Passive transfer was negative.

CONTACT URTICARIA Urticaria may occur after direct contact with a variety of substances. It may be IgE mediated or nonimmunologic. The transient eruption appears within minutes, and when it is IgE mediated, it may be associated with systemic manifestations. Passive transfer has been documented in some instances. Proteins from latex products are a prominent cause of IgE-mediated contact urticaria.144 Latex proteins also may become airborne allergens, as demonstrated by allergen-loaded airborne glove powder used in inhalation challenge tests. These patients may manifest cross-reactivity to fruits, such

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as bananas, avocado, and kiwi.145 Associated manifestations include rhinitis, conjunctivitis, dyspnea, and shock. The risk group is dominated by biomedical workers and individuals with frequent contact with latex, such as children with spina bifida. Agents such as stinging nettles, arthropod hairs, and chemicals may release histamine directly from mast cells.

PAPULAR URTICARIA

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Papular urticari occurs as episodic, symmetrically distributed, pruritic, 3- to 10-mm urticarial papules that result from a hypersensitivity reaction to the bites of insects such as mosquitoes, fleas, and bedbugs. This condition appears mainly in children. The lesions tend to appear in groups on exposed areas such as the extensor aspects of the extremities.146

URTICARIA/ANGIOEDEMA MEDIATED BY BRADYKININ, THE COMPLEMENT SYSTEM OR OTHER EFFECTOR MECHANISMS KININS AND C1 INHIBITOR DEFICIENCY.

C1 inhibitor (C1 INH) is the sole plasma inhibitor of factor XIIa and factor XIIf,147,148 and it is one of the major inhibitors of kallikrein149 as well as factor XIa.150 Thus, in the absence of C1 INH, stimuli that activate the kinin-forming pathway will do so in a markedly augmented fashion; the amount of active enzyme and the duration of action of the enzymes are prolonged. C1 INH deficiency can be familial, in which there is a mutant C1 INH gene, or it can be acquired. Both the hereditary and acquired disorders have two subtypes. For the hereditary disorder, type I hereditary angioedema (HAE) (85%) is an autosomal dominant disorder with a mutant gene (often with duplication, deletions, or frame shifts) leading to markedly suppressed C1 INH protein levels as a result of abnormal secretion or intracellular degradation.151 Type 2 HAE (15%) is also a dominantly inherited disorder, typically with a point (missense) mutation leading to synthesis of a dysfunctional protein.152 The C1 INH protein level may be normal or even elevated, and a functional assay is needed to assess activity. The acquired disorder has been portrayed as having two forms, but they clearly overlap and have in common B cell activation that is often clonal. One group is associated with B-cell lymphoma153–155 or connective tissue disease,156 in which there is consumption of C1 INH. Examples are systemic lupus erythematosus and cryoglobulinemia, in which complement activation is prominent, and B-cell lymphomas, in which immune complexes are formed by anti-idiotypic antibodies to monoclonal immunoglobulin expressed by the transformed B lymphocytes.157 A second group has a prominence of a circulating IgG antibody to INH itself,158–160 but this may be seen with lymphoma or systemic lupus erythematosus as well. Acquired types have depressed C1q levels, whereas hereditary types do not, and depressed C4 levels characterize all forms of C1 INH deficiency.

The acquired autoimmune subgroup has a circulating 95-kDa cleavage product of C1 INH because the antibody depresses C1 INH function yet allows cleavage by enzymes with which it usually interacts.159–162 It is now clear that depletion of C4 and C2 during episodes of swelling163,164 is a marker of complement activation but does not lead to release of a vasoactive peptide responsible for the swelling. Bradykinin is, in fact, the mediator of the swelling165–167and the evidence in support of this conclusion is summarized below. Patients with HAE are hyperresponsive to cutaneous injection of kallikrein.168 They have elevated bradykinin levels, and low prekallikrein and HK levels during attacks of swelling.169–171 The augmentation in complement activation seen at those times may be due to activation of C1r and C1s by factor XIIf.172 The presence of kallikreinlike activity in induced blisters of patients with HAE also supports this notion,173 as does the progressive generation of bradykinin on incubation of HAE plasma in plastic (noncontact-activated) tubes165,166 as well as the presence of activated factor XII and cleaved HK levels seen during attacks.174 One unique family has been described in which there is a point mutation in the C1 INH (A1a 443 → Val) leading to an inability to inhibit complement but normal inhibition of factor XIIa and kallikrein.175,176 No family member of this type 2 mutation has had angioedema,175 although complement activation is present. In recent studies plasma bradykinin levels have been shown to be elevated during attacks of swelling in both hereditary and acquired C1 inhibitor deficiency,169 and local bradykinin generation has been documented at the sites of swelling.177 It is not known whether bradykinin generation is predominantly seen in the fluid phase, occurs along cell (endothelial) surfaces, or both. A rodent model of HAE demonstrated that angioedema can be prevented by “knockout” of the B-2 receptor.178 Figure 38-7 depicts a patient with facial swelling due to HAE. Figure 38-8 is a diagram depicting the steps in the bradykinin-forming cascade that are inhibitable by C1 INH. An estrogen-dependent form of hereditary angioedema has been recognized that is now designated type 3 HAE. One of the first reports involved a single family with seven affected individuals in three generations, which suggests a hereditary (autosomal dominant) pattern.73 Clinical features include angioedema without urticaria, laryngeal edema, and abdominal pain with vomiting. Attacks occur during pregnancy and with the administration of exogenous estrogen. Numerous subsequent reports support these observations.179 In one subgroup, there is a mutation in factor XII such that the activated form (factor XIIa) is more potent than normal.180 These patients all have normal C4 and normal C1 INH protein and function. Bradykinin is the likely mediator; for those with a factor XII mutation, the active enzyme may be less readily inhibited. Although uncommon, a male with the disorder has been described181 and a bradykinin receptor antagonist (Icatibanit) has provided effective therapy for acute episodes.

ANGIOTENSIN-CONVERTING ENZYME IN­HIBI­ TORS. Angioedema has been associated with the

administration of ACE inhibitors.182 The frequency of

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Chapter 38 ::

B

Figure 38-7  Hereditary angioedema. Extensive involvement (A) is to be contrasted with the patient’s normal facies (B).

angioedema occurring after ACE inhibitor therapy is 0.1%–0.7%. There is a predilection to ACE inhibitor reactions in the African-American population that may relate to polymorphisms in the genes encoding other enzymes that catabolize bradykinin such as aminopeptidase P or neutral endopeptidase. Low levels of these would predispose to bradykinin accumulation. Angioedema develops during the first week of

therapy in up to 72% of affected individuals and usually involves the head and neck, including the mouth, tongue, pharynx, and larynx. Urticaria occurs only rarely. Cough and angioedema of the gastrointestinal tract are associated features. It has been suggested that therapy with ACE inhibitors is contraindicated in patients with a prior history of idiopathic angioedema, HAE, and acquired C1 INH deficiency.183 It

Urticaria and Angioedema

A

Pathways for formation of bradykinin

Trace HFa or trace activity in native HF

HF

HFa

Prekallikrein surface HMW-kininogen

HMW-kininogen Kallikrein HMW-kininogen

Bradykinin

Inhibited by C1 INH

HF

surface

HFa

HFf

Autodigestion kallikrein

C1

C1

C4 and C2 digestion

Figure 38-8  Pathways for formation of bradykinin, indicating all steps inhibitable by C1 inhibitor as well as complement activation by means of factor XIIf.

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appears that this swelling is also a consequence of elevated levels of bradykinin;169 however, the accumulation of bradykinin is due to a defect in degradation rather than an excessive production. ACE, being identical to kininase II, is the major enzyme responsible for bradykinin degradation (See eFig. 38-1.2 in online edition) and although it is present in plasma, the vascular endothelium of the lung appears to be its major site of action.184 The action of ACE always leads to the formation of degradation products with no activity, whereas kininase I alone yields the desarg products, which are capable of stimulating B1 receptors. The excessive accumulation of bradykinin implies that production is ongoing, with activation of the plasma cascade or release of tissue kallikrein faulty inactivation of bradykinin then leads to swelling. ­Continuous turnover of the plasma cascade is implied by data demonstrating activation along the surface of cells and cellular expression or secretion of a prekallikrein activator other than factor XIIa.185,186

URTICARIAL VENULITIS Chronic urticaria and angioedema may be manifestations of cutaneous necrotizing venulitis, which is known as urticarial venulitis (See Chapter 163).187,188 Associated features include fever, malaise, arthralgia, abdominal pain, and less commonly conjunctivitis, uveitis, diffuse glomerulonephritis, obstructive and restrictive pulmonary disease, and benign intracranial hypertension. The term hypocomplementemic urticarial vasculitis syndrome is used in patients with more severe clinical manifestations of urticarial venulitis with hypocomplementemia and a low-molecularweight C1q-precipitin that has been identified as an IgG autoantibody directed against the collagen-like region of C1q.

SERUM SICKNESS Serum sickness, which was defined originally as an adverse reaction that resulted from the administration of heterologous serum to humans, but may similarly occur after the administration of drugs. Serum sickness occurs 7–21 days after the administration of the offending agent and is manifested by fever, urticaria, lymphadenopathy, myalgia, arthralgia, and arthritis. Symptoms are usually self-limited and last 4–5 days. More than 70% of patients with serum sickness experience urticaria that may be pruritic or painful. The initial manifestation of urticaria may appear at the site of injection.189–197

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Urticaria/angioedema may develop after the administration of blood products. It usually is the result of immune complex formation and complement activa-

tion that leads to direct vascular and smooth muscle alterations and indirectly, via anaphylatoxins, to mast cell mediator release. Aggregated IgG may also be responsible for human reactions to immunoglobulins as evidenced by the fact that the administration of IgG from which aggregates have been removed is not associated with urticaria or anaphylaxis. An uncommon mechanism for the development of urticaria after the administration of blood products is the transfusion of IgE of donor origin directed toward an antigen to which the recipient is subsequently exposed. Another mechanism may be the transfusion of a soluble antigen present in the donor preparation into a previously sensitized recipient.

INFECTIONS Episodes of acute urticaria can be associated with upper respiratory tract viral infections, most commonly in children.198 The acute urticaria resolves within 3 weeks. Hepatitis B virus infection has been associated with episodes of urticaria lasting up to 1 week that are accompanied by fever and arthralgias as part of the prodrome. The mechanism is analogous to that seen in serum sickness-like reactions with virus– antibody immune complexes. The mechanism for urticaria occasionally associated with infectious monomucleosis may be analogous.

URTICARIA/ANGIOEDEMA AFTER DIRECT MAST CELL DEGRANULATION Various therapeutic and diagnostic agents have been associated with urticaria/angioedema. Up to 8% of patients receiving radiographic contrast media experience such reactions, which occur most commonly after intravenous administration. Decreased serum alternative pathway complement protein levels and increased serum histamine levels have been detected in patients receiving radiocontrast media. Opiate analgesics, polymyxin B, curare, and d-tubocurarine induce release of histamine from mast cells and ­basophils.

URTICARIA/ANGIOEDEMA RELATING TO ABNORMALITIES OF ARACHIDONIC ACID METABOLISM Intolerance to aspirin manifested as urticaria/angioedema occurs in otherwise normal individuals or in patients with allergic rhinitis and/or bronchial asthma. Urticaria/angioedema in response to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) occurred in approximately 10%–20% of individuals referred to a hospital dermatology clinic in the United Kingdom. Patients intolerant of aspirin also may react to indomethacin and to other NSAIDs. Reactions to aspirin are shared with other NSAIDs because they reflect inhibition of prostaglandin endoperoxide synthase 1 (PGHS-1, cyclooxygenase I)199 as

MISCELLANEOUS Muckle–Wells syndrome consists of urticaria, amyloidosis, and nerve deafness and is due to the same gene defect as is seen in familial cold urticaria.114 Schnitzler syndrome is a chronic urticaria with histology resembling an urticarial vasculitis associated with fever, joint pain, an IgM monoclonal protein, and osteosclerosis. An antibody to IL-1α has been shown to be present.212

APPROACH TO THE PATIENT The evaluation of patients with urticaria/angioedema (Fig. 38-9) begins with a comprehensive history, with particular emphasis on the recognized causes, and a physical examination. Some varieties of urticaria may be identified by their characteristic appearance, such as the small wheals with a large erythematous flare of cholinergic urticaria, the linear wheals in dermographism, and the localization of lesions to exposed areas in light- or cold-induced urticaria. If suggested by the history, the physical examination in all patients with urticaria should include tests for physical urticaria, such as a brisk stroke to elicit dermographism, the use of a weight to elicit delayed pressure urticaria, and application of a cold or warm stimulus for cold-induced urticaria and localized heat urticaria, respectively. Exercise, such as running in place, may elicit cholinergic urticaria and, in some instances, exercise-induced anaphylaxis. Phototests to elicit solar urticaria usually are performed in referral centers, as are challenges for exercise-induced anaphylaxis. When urticaria has been present for days or weeks at a time (but less than 6 weeks) or occurs recurrently for similar intervals, the main considerations are allergic reactions (IgE mediated) to food or drugs. A careful history regarding possibilities is essential. Skin testing can corroborate IgE-mediated hypersensitivity to foods or can provide suspects when the history is unrevealing. Double-blind placebo-controlled food challenge can demonstrate clinical relevance in cases in which the role of a food is uncertain. Non-IgEmediated causes of urticaria include adverse reactions to NSAIDs and opiates. Any of these can be associated with concomitant angioedema or, less commonly, present as angioedema in the absence of urticaria. Children may have acute urticaria in association with viral illnesses; it is unclear whether infection with bacteria such as Streptococcus can induce urticaria as well, but neither form occurs in adults with the exception of urticaria in association with infectious mononucleosis (Epstein–Barr virus) or as a prodrome to hepatitis B

Urticaria and Angioedema

Because the clinical entities of chronic idiopathic urticaria (with or without angioedema) and idiopathic angioedema are frequently encountered, have a capricious course, and are recognized easily, they are frequently associated with concomitant events. Such attributions must be interpreted with caution. Although infections, food allergies, adverse reactions to food additives, metabolic and hormonal abnormalities, malignant conditions, and emotional factors have been claimed as causes, proof of their etiologic relationship often is lacking. Among the recent considerations is chronic urticaria as a consequence of infection with Helicobacter pylori. Articles both supporting203–205 and denying206–209 a relationship are numerous and a definite answer is not available. However, the H. pylori infection rate in the population at large is far greater than the incidence of chronic urticaria and in the opinion of this author, the association is spurious. The controversy has been put in perspective by M. Greaves.210 Idiopathic angioedema is diagnosed when angioedema is recurrent, when urticaria is absent, and when no exogenous agent or underlying abnormality is identifiable. An extensive review of angioedema has been recently published.184 Cyclic episodic angioedema has been associated with fever, weight gain, absence of internal organ damage, a benign course, and peripheral blood eosinophilia.211 Biopsy specimens of tissues show eosinophils, eosinophil granule proteins, and CD4 lymphocytes exhibiting HLA-OR. Blood levels of IL-1, soluble IL-2 receptor, and IL-5 are elevated. Idiopathic angioedema is characterized by recurrent episodes of angioedema in the absence of any urticaria, which may include the face (lips, tongue, periorbital region, pharynx), extremities, and genitalia, but is not associated with laryngeal edema or massive tongue/ pharyngeal swelling that yield airway obstruction. It may not be a continuum with chronic urticaria with or without concomitant angioedema, as is often considered, because the incidence in men and women is about

6

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CHRONIC IDIOPATHIC URTICARIA AND IDIOPATHIC ANGIOEDEMA

the same and the presence of antithyroid antibodies or anti-IgE receptor antibodies is far less. Extreme cases, particularly if associated with laryngeal edema, could represent type 3 HAE in a patient with a new mutation (i.e., no family history) or a variant of idiopathic anaphylaxis.

Chapter 38

well as inhibition of the inducible PGHS-2 (cyclooxygenase 2). Sodium salicylate and choline salicylate generally are well tolerated because of their weak activity against PGHS-1. PGHS-2 inhibitors are generally well tolerated in those with NSAID-induced urticaria.200,201 Reactions to NSAIDs increase the levels of cysteinyl leukotrienes,202 which may relate to the appearance of urticaria, although their role in NSAID-induced asthma is better characterized. Prick skin tests are of no diagnostic value, passive transfer reactions are negative, and neither IgG nor IgE antibodies have been associated with clinical disease. The clinical manifestations elicited by aspirin challenge of aspirin-intolerant patients are blocked when such patients are protected with a cysteinyl leucotriene receptor blocker or biosynthetic inhibitor; this finding confirms a pathobiologic role for the cysteinyl leukotrienes.

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Approach to patient with urticaria/angioedema History: Recurrent transient hives or swelling

30 min. to 2 hrs.

Section 6

History physical stimulus Physical challenge

:: Inflammatory Diseases Based on Abnormal Humoral Reactivity

426

Physical urticaria

Clinical Appearance: wheals, angioedema

Wheals + angioedema

Angioedema only

Duration of individual hive

Drugs, ACE inhibitor, other family history

4 hrs. to 36 hrs.

Course < 6 weeks

Course > 6 weeks

Consider drugs, foods, food skin testing, infection (particularly in children), other identifiable stimulus

Thyroid function tests, anti microsomal antibody, anti thyroglobulin antibody, autologous skin test, in vitro – anti IgE receptor

Acute urticaria/ angioedema

24-48 hrs with either bruising, severe arthralgia, fever, _ C4

Chronic autoimmune urticaria

C4 level C1 inhibitor by protein and function

Skin biopsy Idiopathic angioedema

Normal C1Q

Chronic idiopathic urticaria

Urticarial vasculitis

Hereditary angioedema C1 INH protein and function abnormal – Type I C1 INH protein normal or elevated, function abnormal – Type II Acquired C1 INH deficiency , depressed C1Q level

Search for lymphoma, connective tissue disease, Type I

Anti C1 INH, Type II

Overlap situation

Figure 38-9  Approach to the patient with urticaria/angioedema. ACE = angiotensin-converting enzyme; IgE, immunoglobulin E; INH = inhibitor; ↓ = decreased.

infection. In each of these circumstances, individual lesions last anywhere from 4 hours to 24 hours and fade without associated purpura. If hives last less than 2 hours, the cause is usually physical urticaria, the most common being dermatographism, cholinergic urticaria, and cold urticaria. The main exception is delayed pressure urticaria, in which lesions typically last 12–36 hours and first appear 3–6 hours after the initiating stimuli. Once urticaria continues for longer than 6 weeks (particularly if present for many months or years) chronic urticaria is present. The term chronic spontaneous urticaria has been employed recently to eliminate confusion with physical urticarias. Chronic urticaria is now divided into chronic idiopathic urticaria for which a cause has not yet been found and chronic autoimmune urticaria. Angioedema accompanies chronic urticaria in 40% of cases and is more problematic in the autoimmune subgroup. Swelling in association with chronic urticaria can affect hands,

feet, eyes, cheeks, lips, tongue, and pharynx, but not the larynx. When angioedema is present in the absence of an identifiable antigen or exogenous stimulus, the main entities to consider are C1 INH deficiency (hereditary or acquired) and idiopathic angioedema. Approximately 0.5% of patients have an urticarial vasculitis with palpable purpura or other stigmata of a possible vasculitis, such as fever, elevated sedimentation rate, petechiae or purpura, elevated white blood cell count, or lesions of unusual duration (36–72 hours). The differential diagnosis of acute, chronic, and physical urticaria/angioedema is summarized in Box 38-1.

LABORATORY FINDINGS In most patients with chronic urticaria/angioedema, no underlying disorders or causes can be discerned.

Box 38-1  Differential Diagnosis of Urticaria/Angioedema ACUTE (6 WEEK)

indicated, unavailable, or unrevealing despite a highly suspected history. A finding of the release of histamine from peripheral basophilic leukocytes has supported the diagnosis of anaphylactic sensitivity to a variety of antigens, which include pollens and insect venom.

Urticaria and Angioedema

Diagnostic studies should be based on findings elicited by the history and physical examination. Evaluation of chronic urticaria/angioedema should include thyroid function tests, assays for antimicrosomal and antithyroglobulin antibodies, and the autologous skin test can be done, even in an office setting.213 Routine screening laboratory tests are of little value. The histamine release assay for anti-IgE receptor or anti-IgE antibodies are now available in specialized laboratories. Serum hypocomplementemia is not present in chronic idiopathic urticaria or chronic autoimmune urticaria and mean levels of serum IgE in these patients are not different from the general population in which the incidence of atopy is 20%. Cryoproteins should be sought in patients with acquired cold urticaria. An antinuclear antibody test should be obtained in patients with solar urticaria. Assessment of serum complement proteins may be helpful in identifying patients with urticarial venulitis or serum sickness (C4-, C3-, C1q-binding assay for circulatory immune complexes), as well as those with hereditary and acquired forms of C1 INH deficiency (C4, C1 INH by protein and function, C1q level). Skin biopsy of chronic urticarial lesions should be undertaken to identify urticarial venulitis or to assess rashes where the urticarial nature is not clear. There is little role for routine prick skin testing or the radioallergosorbent test in the diagnosis of specific IgE-mediated antigen sensitivity in chronic urticaria/ angioedema. Inhalant materials are uncommon causes of urticaria/angioedema, and food skin tests may be difficult to interpret. The tests for drugs are limited to penicillin but cannot be performed in patients with dermographism. The radioallergosorbent test should be reserved for those in whom skin testing is contra-

Autoimmune, often with antithyroid antibodies Idiopathic Urticarial vasculitis Idiopathic—skin only Associated with other connective tissue disease Familial febrile syndromes with urticaria-like rash Schnitzler’s syndrome

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Individual lesions last 2 hours Delayed pressure urticaria Vibratory angioedema Familial cold-induced syndromes, usually with fever

Chapter 38

Drug reaction Immunoglobulin E (IgE) mediated Metabolic—idiosyncratic Cellular immunity Food reactions IgE mediated Non-IgE mediated (e.g., scombroid poisoning) Intravenous administration Blood products Contrast agents Intravenous γ globulin Infection Viral in children Infectious mononucleosis or hepatitis B prodrome ? Bacterial in children

PHYSICAL

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HISTOPATHOLOGY Edema involving the superficial portion of the dermis is characteristic of urticaria, whereas angioedema involves the deeper dermis and subcutaneous tissue. Both disorders are associated with dilatation of the venules. In chronic urticaria, the dermal infiltrating inflammatory cells may be sparse or dense and include more CD4 than CD8 T lymphocytes, neutrophils, eosinophils, and basophils46,214 without B lymphocytes or natural killer (NK) cells. NKT cells have not been assessed. Increased expression of TNF-α and IL-3 on endothelial cells and perivascular cells was detected in the upper dermis of patients with acute urticaria, chronic idiopathic urticaria, and delayed-pressure urticaria and in one patient with cold urticaria.215 TNF-α also was detected on epidermal keratinocytes in lesional and nonlesional biopsy specimens. In chronic idiopathic urticaria, CD11b and CD18 cells were detected about the blood vessels in the superficial and deep dermis. Direct immunofluorescence tests for immunoglobulins and complement proteins were negative. Major basic protein and eosinophil cationic protein, which are derived from the eosinophils granule, are present around blood vessels and are dispersed in the dermis in lesions of acute urticaria, chronic

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idiopathic urticaria, delayed-pressure urticaria, cholinergic urticaria, and solar urticaria. In chronic idiopathic urticaria, free eosinophil granules in the dermis were increased in wheals of greater than 24 hours’ duration as compared with wheals lasting fewer than 24 hours. The secreted form of eosinophil cationic protein and eosinophil-derived neurotoxin were detected on cells in greater amounts in biopsy specimens from patients with chronic urticaria without autoantibodies than in those with autoantibodies. P-selectin, E-selectin, intercellular adhesion molecules 1, and vascular cellular adhesion molecule 1 have been demonstrated on the vascular endothelium of patients with chronic idiopathic urticaria and dermographism. Major histocompatability complex class II antigen also is upregulated on the endothelial cells of patients with chronic urticaria, and the peripheral blood lymphocytes have increased CD40 ligand expression and higher Bcl-2 expression; these observations suggest an augmentation of autoimmune phenomena.216 In papular urticaria, the epidermis is thick with intercellular edema and lymphocytes. In the dermis, there is edema with an infiltrate containing T lymphocytes, macrophages, eosinophils, and neutrophils without B lymphocytes or the deposition of immunoglobulins, fibrin and C3.

TREATMENT Therapy of acute urticaria uses antihistamines as described in Fig. 38-10; however, the rash can be severe and generalized, and angioedema may be present as well. Thus, if relief provided by nonsedating antihistamines appears insufficient, one can try hydroxyzine or diphenhydramine at 25–50 mg qid.217 Alternatively nonsedating antihistamines can be tried employing up to 4–6 tablets/ day as has been reported for treatment of cold urticaria.92 A course of corticosteroid can be used, for example, 40–60 mg/day for 3 days and taper by 5–10 mg/day. Epinephrine can relieve severe symptoms of urticaria or angioedema (generalized urticaria, severe pruritus, accelerating angioedema) and is indicated if laryngeal edema is present. Edema of the posterior tongue and/or pharyngeal edema can be confused with it. The ideal treatment for urticaria/angioedema is identification and removal of its cause. Many patients with acute urticaria and angioedema probably are not treated by physicians because the cause is identified by the individual or the course is limited. Treatment of chronic urticaria focuses on measures that provide symptomatic relief. The physician should provide not only medications but also support and reassurance. In a questionnaire study, patients with chronic idiopathic urticaria considered the worst aspects to be pruritus and the unpredictable nature of the attacks. The presence of facial angioedema can be particularly disconcerting and tongue and/or pharyngeal edema is often considered life threatening. This is not the case and is confused with the potential for laryngeal edema seen with anaphylaxis, or anaphy-

lactic-like reactions, C1 INH deficiency, or reactivity to ACE inhibitors. Affected individuals reported sleep disturbances, diminished energy, social isolation, and altered emotional reactions as well as difficulties in relation to work, home activities, social life, and sex life.218,219 Another study showed a correlation between the severity of chronic idiopathic urticaria and depression. In a questionnaire study, individuals with delayed pressure urticaria and cholinergic urticaria had the most quality-of-life impairment.220 Those with cholinergic urticaria suffered in relation to their sporting activities and sexual relationships. Although urticaria/angioedema may be a source of frustration to both physicians and patients, most individuals can achieve acceptable symptomatic control of their disease without identification of the cause. In some individuals, it is important to avoid aspirin and other NSAIDs. Antipruritic lotions, cool compresses, and ice packs may provide temporary relief. H1-type antihistaminic drugs are the mainstays in the management of urticaria/angioedema. The older H1-type antihistaminics are known as classic, traditional, or first generation H1-type antihistamines. Newer, low-sedating, or second- and third-generation H1-type antihistamines with reduced sedative and anticholinergic side effects have become the initial therapeutic agents of choice. The drug should be taken on a regular basis and not as needed. If the initial drug chosen is ineffective, an agent from a different pharmacological class should be used and nonsedating antihistaminics can be combined or the dose of any one of them increased. When this is ineffective, doses of hydroxyzine or diphenhydramine in the 25–50 mg qid may be tried. The same is true for the treatment of dermatographism when it is particularly severe. It should be noted that if the molar release of histamine in the skin exceeds that of the delivered antihistamine (as can be seen with dermatographism), the histamine will keep the receptors to which it is bound in the active conformation, and therapeutic efficacy with the antihistamine will be achieved only when its molar concentration is much greater than that of histamine. Diphenhydramine is an alternative to hydroxyzine or cetirizine for dermatographism but not for cholinergic urticaria.221,222 Cold urticaria can be treated with most antihistaminics but cyproheptadine at 4–8 mg tid or qid seems to be particularly effective.223–226 Excellent results have been recently reported with desloratadine at four times/day.92 Local heat urticaria is treated with antihistaminics; no regimen is particularly favored. Although anecdotal reports suggest that delayed pressure urticaria will respond to NSAIDs, dapsone, cetirizine, or sulfasalazine, most require corticosteroids (used as in chronic urticaria) to control symptoms and cyclosporine can be a particularly effective alternative. Familial cold autoinflammatory syndrome (urticaria) responds to parenteral IL-1 receptor antagonist (anakinra) as does some cases of Schnitzler syndrome. Treatment choices for chronic urticaria (idiopathic or autoimmune) have been reviewed227 and are

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Chapter 38 :: Urticaria and Angioedema

Figure 38-10  Treatment of chronic idiopathic or autoimmune urticaria/angioedema. Note that the following agents are expected to be effective rarely, if ever: hydroxychloroquine, colchicine, dapsone, sulfasalazine, mycophenolate mofetil. Hydroxychloroquine is, however, the drug of choice for the hypocomplementemic urticarial vasculitis syndrome. Urticarial vasculitis may respond to dapsone or colchicine. Omalizumab (IgG anti IgE monoclonal antibody), not yet approved for treatment of chronic spontaneously occurring urticaria and angioedema is as effective as cyclosporine with far less toxicity and when available, will be a major therapeutic advance.

summarized in Fig. 38-10. It is important to use first-generation antihistamines at a maximal dose if nonsedating antihistamines have not been helpful before resorting to corticosteroids or cyclosporine. H2-receptor antagonists may yield some additional histamine receptor blockade, although their contribution is usually modest. The efficacy of leucotriene antagonists is controversial, with equal numbers of pro and con articles. If steroids are used, this author recommends not exceeding 25 mg q.o.d. or 10 mg daily. With either approach, attempts to slowly taper the dose should be made every 2–3 weeks. One mg prednisone tablets can be very helpful when the daily dose is less than 10 mg. Double-blind placebocontrolled studies of cyclosporine indicate that it is a good alternative to corticosteroid,228,229 and can be safer when used appropriately. Measurement of blood pres-

sure, blood urea nitrogen level, and creatinine level, and a urinalysis should be done every 6–8 weeks. The starting adult dose is 100 mg bid; it can be slowly advanced to 100 mg tid, but not higher. The response rate is 75% in the autoimmune groups and 50% in the idiopathic group. No comparable studies (or clinical effects) have been obtained with dapsone, hydroxychloroquine, colchicine, sulfasalazine, or methotrexate and only small numbers cases have been treated successfully with intravenous γ globulin or plasmapheresis.230,231 Successful treatment of chronic autoimmune urticaria has been reported with Omalizumab232 with results comparable to that seen with cyclosporine. The rate of response can be very striking, for example, remission with a single dose. Additional articles have appeared,233,234 although uncontrolled.

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Urticarial vasculitis is treated with antihistamines and if severe, with low-dose corticosteroid. Here dapsone or hydroxychloroquine may be steroid sparing. When urticarial vasculitis is part of a systemic disease, the treatment will focus on what is needed for the underlying disorders. The drug of choice for the hypocomplementemic urticarial vasculitis syndrome (with circulating immune complexes due to IgG anti-C1q)195 is hydroxychloroquine.235 Angioedema caused by ACE inhibitors can be an acute emergency with laryngeal edema or tongue or pharyngeal edema that is so extensive the patient cannot manage secretions and intubation is necessary. Supportive therapy, epinephrine, and time are needed; there is no response to antihistamines or corticosteroids. Other antihypertensive agents can be substituted, including those that block angiotensin II receptors. Acute attacks of HAE are unresponsive to antihistaminics or corticosteroid. Epinephrine may be given but a positive response is actually uncommon. Intubation or tracheostomy may be needed when severe laryngeal edema is encountered. Recently, a preparation of C1 INH (Berinert) has been approved in the United States for intravenous infusion to treat acute attacks of HAE. It is effective and has been available and employed in Europe and Brazil for over two decades. Icatibant,236 a bradykinin B-2 receptor antagonist, has been approved for acute treatment in Europe but not in the United States. It is given by subcutaneous injection. Kalbitor, a plasma kallikrein inhibitor (ecallantide), has been approved for the treatment of acute attacks of HAE in the United States. It too is administered by subcutaneous injection.237 In the past, fresh frozen plasma was an option. It has been used with excellent success for years, but occasional dramatic worsening of symptoms has been reported because all the plasma factors needed for bradykinin generation are also being infused. A second C1 INH nanofiltered preparation (Cinryze) has been approved in the United States for prophylactic treatment of AHE types I and II. It is administered by intravenous injection up to twice weekly. Prophylaxis with androgens such as Danazol (200 mg tablets) or Stanazolol (2 mg tablets)238,239 or antifibrinolytics such as E-aminocaprioc acid or tranexamic acid240 have been employed (used) successfully for many years.241,242 The androgens are more commonly used—one watches for hirsutisum, irregular menses, and abnormal liver chemistries, as potential side effects. In the long term, hepatic adenomas may appear. Increased dosages may be used when a patient undergoes elective surgical procedures (e.g., 3 tablets/day for 2–3 days before the procedure, the day of the procedure, and 1 day after).

Fresh frozen plasma is a safe alternative given a few hours prior to the procedure and clearly C1 INH concentrate can be used. Acquired C1 INH deficiency can be treated with low-dose androgens in addition to therapy for the underlying condition. C1 INH concentrate may be helpful but the presence of anti-C1 INH will limit responsiveness to reasonable doses. Plasmapheresis and/or cytotoxic agents may be used.

ACKNOWLEDGMENT I wish to thank Dr Nicholas Soter who reviewed this manuscript, made many helpful suggestions, and contributed two of the photos.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 6. Gorevic P, Kaplan A: The physical urticarias. Int J Dermatol 19:417, 1980 13. Gruber B et al: Prevalence and functional role of anti-IgE autoantibodies in urticarial syndromes. J Invest Dermatol 90:213, 1988 15. Grattan C et al: A serological mediator in chronic idiopathic urticaria–A clinical, immunological and histological evaluation. Br J Dermatol 114:583, 1986 35. Kikuchi Y, Kaplan A: A role for C5a in augmenting IgGdependent histamine release from basophils in chronic urticaria. J Allergy Clin Immunol 109:114, 2002 41. Sabroe R et al: Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: Comparison of patients with and without anti-FcepsilonRI or anti-IgE autoantibodies. J Allergy Clin Immunol 103:484, 1999 60. Kaplan AP, Joseph K, Silverberg M: Pathways for bradykinin formation and inflammatory disease. J Allergy Clin Immunol 109:195, 2002 166. Fields T, Ghebrehiwet B, Kaplan AP: Kinin formation in hereditary angioedema plasma: Evidence against kinin derivation from C2 and in support of “spontaneous” formation of bradykinin. J Allergy Clin Immunol 72:54, 1983 183. Kaplan A, Greaves M: Angioedema. J Am Acad Dermatol 53:373, 2005 210. Greaves M: Chronic idiopathic urticaria and Helicobacter pylori–Not directly causative but could there be a link. Allergy Clin Immunol Int 13:23, 2001 213. Sabroe R et al: The autologous serum skin test: A screening test for autoantibodies in chronic idiopathic urticaria. Br J Dermatol 140:446, 1999 222. Zuberbier T et al: Double-blind crossover study of highdose cetirizine in cholinergic urticaria. Dermatology 193:324, 1996 227. Kaplan A: Clinical practice. Chronic urticaria and angioedema. N Engl J Med 346:175, 2002 232. Kaplan A et al: Treatment of chronic autoimmune urticaria with omalizumab. J Allergy Clin Immunol 122:569, 2008

Chapter 39 :: Erythema Multiforme :: Jean-Claude Roujeau ERYTHEMA MULTIFORME AT A GLANCE Rare cutaneous and/or mucocutaneous eruption characterized by target lesions. Benign course but frequent recurrences.

Erythema Multiforme

Erythema multiforme (EM) is an acute self-limited, usually mild, and often relapsing mucocutaneous syndrome. The disease is usually related to an acute infection, most often a recurrent herpes simplex virus (HSV) infection. EM is defined only by its clinical characteristics: target-shaped plaques with or without central blisters, predominant on the face and extremities. The absence of specific pathology, unique cause, and biologic markers has contributed to a confusing nosology. Recent medical literature still contains an overwhelming number of figurate erythema reported as EM, and the International Classification of Diseases (ICD9) still classifies Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) under the heading of EM. The definition of EM in this chapter is based on the classification proposed by Bastuji-Garin et al.1 The principle of this classification is to consider SJS and TEN as severity variants of the same process, i.e., epidermal necrolysis (EN), and to separate them from EM (see Chapter 40). The validity of this classification has been challenged by some reports, especially for cases in children and cases related to Mycoplasma pneumoniae. It has been confirmed by several others studies however, especially the prospective international Severe Cutaneous Adverse Reactions study.2 That study demonstrated that, compared with SJS and TEN, EM cases had different demographic features, clinical presentation, severity, and causes. The original name proposed by von Hebra was erythema exudativum multiforme. The term erythema multiforme has now been universally accepted (Box 39-1). EM is usually called minor when mucous membranes are spared or minimally affected, for example, lips, and majus (or major) when at least two mucosal sites are involved.

EM is considered relatively common, but its true incidence is unknown because largely cases severe enough to require hospitalization have been reported. Such cases are in the range of 1 to 6 per million per year. Even though the minor form of EM is frequent than the major form, many other eruptions (including annular urticaria and serum sickness-like eruption) are erroneously called EM.3 EM occurs in patients of all ages, but mostly in adolescents and young adults. There is a slight male preponderance (male–female sex ratio of approximately 3:2). EM is recurrent in at least 30% of patients. No established underlying disease increases the risk of EM. Infection with human immunodeficiency virus and collagen vascular disorders do not increase the risk of EM, in contrast to their increasing the risk of epidermal necrolysis. Cases may occur in clusters, which suggests a role for infectious agents. There is no indication that the incidence may vary with ethnicity or geographic location. Predisposing genes have been reported, with 66% of EM patients having HLA-DQB1*0301 allele, compared with 31% of controls.4 The association is even stronger in patients with herpes-associated EM. Nevertheless, the association is relatively weak, and familial cases remain rare.

::

Frequent recurrences can be prevented by long-term use of anti-HSV medications. Thalidomide is usually effective in recalcitrant recurrent cases.

EPIDEMIOLOGY

Chapter 39

Most cases related to herpes simplex virus (HSV) infection. Medications are not frequent causes.

6

ETIOLOGY Most cases of EM are related to infections. Herpes virus is definitely the most common cause, principally in recurrent cases. Proof of causality of herpes is firmly established from clinical experience, epidemiology,2 detection of HSV DNA in the lesions of EM,5,6 and prevention of EM by suppression of HSV recurrences.7 Clinically, a link with herpes can be established in about one-half of cases. In addition 10% to 40% of cases without clinical suspicion of herpes have also been shown to be herpes related, because HSV DNA was detected

BOX 39-1  Erythema Multiforme Subtypes Erythema multiforme minor: Skin lesions without involvement of mucous membranes Erythema multiforme major: Skin lesions with involvement of mucous membranes Herpes-associated erythema multiforme Mucosal erythema multiforme (Fuchs syndrome, ectodermosis pluriorificialis): Mucous membrane lesions without cutaneous involvement

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in the EM lesions by polymerase chain reaction (PCR) testing.6 EM eruptions begin on average 7 days after a recurrence of herpes. The delay can be substantially shorter. Not all symptomatic herpes recurrences are followed by EM, and asymptomatic ones can induce EM. Therefore, this causality link can be overlooked by both patients and physicians. HSV-1 is usually the cause, but HSV-2 can also induce EM. The proportion probably reflects the prevalence of infection by HSV subtypes in the population. M. pneumoniae is the second major cause of EM and may even be the first one in pediatric cases.8–10 In cases related to M. pneumoniae, the clinical presentation is often less typical and more severe than in cases associated with HSV. The relationship to M. pneumoniae is often difficult to establish. Clinical and radiologic signs of atypical pneumonia can be mild, and M. pneumoniae is usually not directly detected. PCR testing of throat swabs is the most sensitive technique. Serologic results are considered diagnostic in the presence of immunoglobulin (Ig) M antibodies or a more than twofold increase in IgG antibodies to M. pneumoniae in samples obtained after 2 or 3 weeks. M. pneumoniae-related EM can recur.11 Many other infections have been reported to be causes of EM in individual cases or small series, but the evidence for causality of these other agents is only circumstantial. Published reports have implicated infection with orf virus, varicella zoster virus, parvovirus B19, and hepatitis B and C viruses, as well as infectious mononucleosis and a variety of other bacterial or viral infections. Immunization has been also implicated as a cause in children. Drugs are a rare cause of EM with mucous membrane lesions. Most literature reports of “drug-associated EM” actually deal with imitators, for example, annular urticaria12 or maculopapular eruption with some lesions resembling targets. “EM-like” dermatitis may result from contact sensitization. These eruptions should be viewed as imitators of EM, despite some clinical and histopathologic similarities. Idiopathic cases are those in which neither HSV infection nor any other cause can be identified. Such cases are fairly common under routine circumstances. However, HSV has been found in situ by PCR in up to 40% of “idiopathic” recurrent cases.9 Some such cases respond to prophylactic antiviral treatment and are thus likely to have been triggered by asymptomatic HSV infection; others are resistant.

PATHOGENESIS

432

The underlying mechanisms have been extensively investigated for herpes-associated EM.13 It is unknown whether similar mechanisms apply to EM due to other causes. Complete infective HSV has never been isolated from lesions of herpes-associated EM. The presence of HSV DNA in EM lesions has been reported in numerous studies using the PCR assay. These studies have demonstrated that keratinocytes do not contain complete viral DNA, but only fragments that always include the viral polymerase (Pol) gene. HSV Pol DNA

is located in basal keratinocytes and in lower spinous cell layers, and viral Pol protein is synthesized. HSVspecific T cells, including cytotoxic cells, are recruited, and the virus-specific response is followed by a nonspecific inflammatory amplification by autoreactive T cells. The cytokines produced in these cells induce the delayed hypersensitivity-like appearance in histopathologic evaluation of biopsy sections of EM lesions. HSV is present in the blood for a few days during an overt recurrence of herpes. If keratinocytes are infected from circulation virus, one would expect disseminated herpes, rather than EM. In fact, HSV DNA is transported to the epidermis by immune cells that engulf the virus and fragment the DNA. These cells are monocytes, macrophages, and especially CD34+ Langerhans cell precursors harboring the skin-homing receptor cutaneous lymphocyte-associated (CLA) marker. Upregulation of adhesion molecules greatly increases binding of HSV-containing mononuclear cells to endothelial cells and contribute to the dermal inflammatory response. When reaching the epidermis the cells transmit the viral Pol gene to keratinocytes. Viral genes may persist for a few months, but the synthesis and expression of the Pol protein will last for only a few days. This may explain the transient character of clinical lesions that are likely induced by a specific immune response to Pol protein and amplified by autoreactive cells. To the best of current knowledge, the mechanisms and regulation of this immune response are different from drug reactivity leading to SJS or TEN.14,15 Incomplete fragmentation of viral DNA, increased number of circulating CD34+ cells, and/or increased immune response to Pol protein may explain why only a small proportion of individuals with recurrent herpes infections develop EM.

CLINICAL FINDINGS The first step is to suspect EM, based on clinical features. A skin biopsy and laboratory investigations are useful mainly if the diagnosis is not definite clinically. The second step is to determine whether hospitalization is needed when EM major (EMM) occurs with oral lesions severe enough to impair feeding, when a diagnosis of SJS is suspected, or when severe constitutional symptoms are present. The third step is to establish the cause of EM by identifying a history of recurrent herpes, performing chest radiography, or documenting M. pneumoniae infection (Fig. 39-1).

HISTORY Prodromal symptoms are absent in most cases. If present, they are usually mild, suggesting an upper respiratory infection (e.g., cough, rhinitis, low-grade fever). In EMM, fever higher than 38.5°C (101.3°F) is present in one-third of cases.2 A history of prior attack(s) is found in at least one-third of patients and thus helps with the diagnosis. The events of the preceding 3 weeks should be reviewed for clinical evidence of any precipitating agent, with a special focus on recurrent herpes.

6

Approach to the patient with erythema multiforme (EM)

Pro: Typical papules with target features Acral distribution Mucous membrane erosions Previous episodes

Is it EM?

YES

Is hospitalization needed?

Biopsy Direct IF Serum antibodies

NO

NO

Urticaria ADR with some EM-like features Autoimmune blisters SJS

::

What is the cause?

Cough, URT infection

Other patient infection, e.g., orf

HAEM

MP-related EM

Post-infection EM

Positive

No clue

Herpes serology

Negative

Frequent recurrences Acyclovir prophylaxis

Erythema Multiforme

History of recurrent herpes

Possible HAEM

Chapter 39

YES

MAYBE

Con: Transient lesions Widespread erythema Macules and blisters, flat targets Subacute evolution

Idiopathic EM Frequent recurrences Azathioprine thalidomide

Figure 39-1  Approach to the patient with erythema multiforme (EM). ADR = adverse drug reaction; HAEM = herpesassociated erythema multiforme; IF = immunofluorescence; MP = Mycoplasma pneumoniae; SJS = Stevens–Johnson syndrome; URT = upper respiratory tract.

CUTANEOUS LESIONS The skin eruption arises abruptly. In most patients, all lesions appear within 3 days, but in some, several crops follow each other during a single episode of EM. Often there are a limited number of lesions, but up to hundreds may form. Most occur in a symmetric, acral distribution on the extensor surfaces of the extremities (hands and feet, elbows, and knees), face, and neck, and less frequently on the thighs, buttocks, and trunk. Lesions often first appear acrally and then spread in a centripetal manner. Mechanical factors (Koebner phenomenon) and actinic factors (predilection of sunexposed sites) appear to influence the distribution of lesions. Although patients occasionally report burning and itching, the eruption is usually asymptomatic. The diversity in clinical pattern implied by the name multiforme is mainly due to the findings in each

single lesion; most lesions are usually rather similar in a given patient at a given time. The typical lesion is a highly regular, circular, wheal-like erythematous papule or plaque that persists for 1 week or longer (Fig. 39-2). It measures from a few millimeters to approximately 3 cm and may expand slightly over 24 to 48 hours. Although the periphery remains erythematous and edematous, the center becomes violaceous and dark; inflammatory activity may regress or relapse in the center, which gives rise to concentric rings of color (see Fig. 39-2). Often, the center turns purpuric and/or necrotic or transforms into a tense vesicle or bulla. The result is the classic target or iris lesion. According to the proposed classification, typical target lesions consist of at least three concentric components: (1) a dusky central disk, or blister; (2) more peripherally, an infiltrated pale ring; and (3) an

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434

Figure 39-2  Mixture of typical targets and papules in a case of EM minor erythematous halo. Not all lesions of EM are typical; some display two rings only (“raised atypical targets”). However, all are papular, in contrast with macules, which are the typical lesions in epidermal necrolysis (SJS–TEN). In some patients with EM, most lesions are livid vesicles overlying a just slightly darker central portion, encircled by an erythematous margin (Figs. 39-3–39-5, Fig. 39-8). Larger lesions may have a central bulla and a marginal ring of vesicles (herpes iris of Bateman) (Figs. 39-6 and 39-7). Unusual presentations include cases in which recurrent EM in the same patient produces typical target lesions in one instance but plaques in a subsequent event. Mucous membranes can be severely involved in some episodes and spared in others (see section “Mucous Membrane Lesions”).

Figure 39-3  Typical target lesions on the palm.

Figure 39-4  Late lesions of EM with nonspecific blisters and erosions but target shapes still visible. In most cases, EM affects well under 10% of the body surface area. In 88 hospital cases of EMM prospectively included in the Severe Cutaneous Adverse Reactions study, the median involvement was 1% of the body surface area.2 Very rare instances of extensive skin lesions with “giant” targets and prominent involvement of several mucous sites may be difficult to distinguish from SJS. The duration of an individual lesion is shorter than 2 weeks, but residual discoloration may remain for months. There is no scarring.

MUCOUS MEMBRANE LESIONS Mucosal lesions are present in up to 70% of patients, most often limited to the oral cavity.

Figure 39-5  Typical targets around the knee.

6

Chapter 39 ::

Figure 39-8  Unusual location of EM.

Erythema Multiforme

Figure 39-6  Giant targets in a case of recurrent EMM associated to recurrent Mycoplasma pneumoniae infection.

Predilection sites for mucosal lesions are the lips (eFig. 39-7.1 in online edition), on both cutaneous and mucosal sides, nonattached gingivae, and the ventral side of the tongue. The hard palate is usually spared, as are the attached gingivae. On the cutaneous part of the lips, identifiable target lesions may be discernible (see Fig. 39-9). On the mucosa proper there are erosions with fibrinous deposits, and occasionally intact vesicles and bullae can be seen (Fig. 39-10). The process may rarely extend to the throat, larynx, and even the trachea and bronchi. Eye involvement begins with pain and bilateral conjunctivitis in which vesicles and erosions can occur (Fig. 39-11). The nasal, urethral, and anal mucosae also may be inflamed and eroded.

Figure 39-7  Multiple concentric vesicular rings (herpes iris of Bateman). This pattern may be more frequent in Mycoplasma pneumoniae-related cases of erythema multiforme major.

Figure 39-9  Erythema multiforme major. Involvement of the lips with a target pattern.

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6

tions. EM usually follows recurrent herpes but may also occur after primary HSV infection. The average interval is 7 days (range, 2 to 17 days); the duration of the lag period appears to be specific for individual patients. In a small number of patients, HSV recrudescence and EM may occur simultaneously. Not all episodes of EM are preceded by clinically evident HSV infection, and not all HSV episodes are followed by EM. Episodes of recurrent HSV infection may precede the development of HSV-related EM by many years.

RELATED PHYSICAL FINDINGS Section 6

Figure 39-10  Erythema multiforme major (EMM). Mouth lesions of EMM usually manifest as erosions.

:: Inflammatory Diseases Based on Abnormal Humoral Reactivity

Ectodermosis pluriorificialis (synonym Fuchs syndrome) is a rare occurrence characterized by severe involvement of two or three mucosal sites in the absence of skin lesions. Its often relapsing nature suggests that it is HSV related. Moreover, typical target lesions may arise on the skin with new attacks.

RELATIONSHIP TO RECURRENT HERPES In more than 70% of patients with recurrent EM, an episode of recurrent HSV infection precedes the rash; the association with herpes labialis predominates over that with genital herpes or herpes in other loca-

Fever and other constitutional symptoms are usually absent in EM minor, and the physical examination is normal. Fever higher than 38.5°C (101.3°F) is present in 32% of cases of EMM. Mouth erosions may be very painful and may impair alimentation. The patient may be unable to close the mouth and may constantly drool bloodstained saliva. Cervical lymphadenopathy is usually present in these patients. The pain of genital erosions may lead to reflex urinary retention. Cough, polypnea, and hypoxia may occur in M. pneumoniae-related cases.

LABORATORY FINDINGS HISTOPATHOLOGIC ANALYSIS Early lesions of EM exhibit lymphocyte accumulation at the dermal–epidermal interface, with exocytosis into the epidermis, lymphocytes attached to scattered necrotic keratinocytes (satellite cell necrosis), spongiosis, vacuolar degeneration of the basal cell layer, and focal junctional and subepidermal cleft formation (eFig. 39-11.1 in online edition). The papillary dermis may be edematous but principally contains a dense mononuclear cell infiltrate, which is more abundant in older lesions. The vessels are ectatic with swollen endothelial cells; there may be extravasated erythrocytes and eosinophils. Immunofluorescence findings are negative or nonspecific. In advanced lesions subepidermal blister formation may occur, but necrosis rarely involves the entire epidermis (see eFig. 39-11.2 in online edition). In late lesions, melanophages may be prominent. The histopathologic appearance of EM lesions is different from that of SJS–TEN lesions, in which dermal inflammation is moderate to absent and epidermal necrosis much more pronounced (see Chapter 40). Still, the histopathologic appearances are somewhat overlapping and do not allow the distinction of EM from SJS–TEN in all instances. The main reason for performing a biopsy in EM is to rule out other diagnoses, for example, autoimmune blistering diseases, Sweet syndrome, and vasculitis.

OTHER LABORATORY TESTS 436

Figure 39-11  Erythema multiforme major. Eye lesions. Conjunctivitis with erosions.

There are no specific laboratory tests for EM. In more severe cases, an elevated erythrocyte sedimentation rate, moderate leukocytosis, increased levels of

COURSE AND COMPLICATIONS

Erythema Multiforme

(Table 39-1) In a retrospective analysis of 66 pediatric cases discharged from hospital with a diagnosis of EM 24 (36%) were clearly not EM.8 Diseases that had been frequently erroneously called EM were urticaria (eFig. 39-11.3 in online edition) and maculopapular drug eruption (Fig. 39-12).8,15 The designation of Rowell syndrome16,17 is used for a variety of cutaneous lupus erythematosus with often erosive circinate lesions resembling those of EM. Subacute evolution, a positive result on direct fluorescence testing, and the presence of antinuclear antibodies exclude EM.

6

::

DIFFERENTIAL DIAGNOSIS

Sweet syndrome can mimic EM minor; biopsy easily distinguishes the two. Paraneoplastic pemphigus and more rarely other autoimmune blistering diseases occasionally present with target-like lesions that can be confused with those of EM (Figs. 39-13 and eFig. 39-14 in online edition). Original cases were reported as EMM with antidesmoplakin antibodies.18 Clinical features resemble EMM in their acute and recurrent course, but the presence of acantholysis, deposits of IgG around basal cells, and serum antibodies against desmoplakin distinguish such cases from EM. Better considered a separate disease, SJS should be recognized promptly for three reasons: (1) the possibility of life-threatening complications, (2) the risk of progression to TEN, and (3) the need for urgent withdrawal of suspected causative drug(s) (see Chapter 40). Pain, constitutional symptoms, severe erosions of mucosae, rapid progression, and dusky or violaceous skin lesions are alerting features. In rare cases of EM affecting only mucous membranes, the diagnosis is especially difficult and often made when further bouts include a few skin lesions. In such cases, pemphigus, cicatricial pemphigoid, allergic or toxic contact stomatitis, toxic erosive stomatitis, aphthous lesions, and lichen planus should be considered.

Chapter 39

acute-phase proteins, and mildly elevated liver aminotransferase levels may occur. In the presence of respiratory symptoms a chest radiograph is needed, and documentation of M. pneumoniae infection by PCR assay of a throat swab and serologic testing (a pair at a 2- or 3-week interval) should be sought. Investigations to document causality are important in cases with frequent recurrences when prevention with long-term antiviral treatment is considered and when there is no clinical evidence of association with herpes. HSV can rarely still be isolated from the initial lesion of labial herpes. Amplification of HSV Pol gene from biopsy samples of EM lesions is not done routinely. A negative result on serologic testing for HSV may be helpful to exclude the possibility of herpes-associated EM. The positive predictive value of the presence of HLADQB1*0301 is too low to have any clinical value.

EM runs a mild course in most cases, and each individual attack subsides within 1 to 4 weeks. Recovery is

TABLE 39-1

Differential Diagnosis of Erythema Multiforme (EM) Mucous Membrane Lesions

Clinical Pattern

Pathologic Findings

Urticaria

No

Circinate, transient

Edema

Maculopapular drug eruption

Rare (lips)

Widespread polymorphous target-like lesions, macules, papules, plaques

Most often nonspecific

Lupus (Rowell syndrome)

Possible (mouth)

Face and thorax Large target-like lesions, annular plaques

Interface dermatitis Positive result on DIF (“lupus band”)

Antinuclear antibodies present

Subacute

Paraneoplastic pemphigus

Constant; always early and severe

EM-like lesion plus lichenoid papules Positive Nikolsky sign

Acantholysis Positive result on DIF

Antibodies present

Chronic

Cicatricial pemphigoid

Constant

Circinate erythematous patches

Subepidermal blister, Positive result on DIF

Antibodies present

Chronic

Antidesmoplakin “EM major”

Constant

EM-like lesions

Basal acantholysis Positive result on DIF

Antibodies present

Acute relapsing

Stevens–Johnson syndrome

Constant

Widespread small blisters Atypical targets Constitutional symptoms

Interface dermatitis Epidermal necrosis

DIF = direct immunofluorescence testing.

Laboratory Testing

Course More acute than EM

Acute

437

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Section 6

Figure 39-13  Figurate blisters, in a case of linear IgA blistering disease.

:: Inflammatory Diseases Based on Abnormal Humoral Reactivity

Figure 39-12  Figurate erythema in a cases of “drug eruption” to amoxicillin. Commonly and erroneously reported as drug-induced EM. complete, and there are usually no sequelae, except for transient discoloration in some cases. In rare instances the ocular erosions of EMM may cause severe residual scarring of the eye. M. pneumoniae-related EMM may be associated with severe erosive bronchitis that may rarely lead to sequelae. Recurrences are common and may characterize the majority of cases. In reports of large series of patients with recurrent EM, the mean number of attacks was 6 per year (range, 2 to 36), and the mean total duration of disease was 6 to 9 years. In 33%, the condition persisted for more than 10 years.19,20 Up to 50 recurrences have been described in a single patient. The severity of episodes in patients with recurrent EM is highly variable and unpredictable. The frequency of episodes and cumulative duration of disease are not correlated with the severity of attacks. The frequency and severity of recurrent EM tend to decrease spontaneously over time (after 2 years or longer), parallel with the improvement of recurring HSV infection when it is the cause. In a substantial proportion of recurrent cases a cause cannot be determined.20 A small fraction of patients experience a prolonged series of overlapping attacks of EM; this has been labeled continuous EM or persistent EM.19

TREATMENT 438

The aims of treatment are to reduce the duration of fever, eruption, and hospitalization. Based on retrospective series or small controlled trials, the use of

systemic corticosteroids seems to shorten the duration of fever and eruption, but may increase the length of hospitalization because of complications. However, the methodology of most studies was poor, with small series often mixing the various forms of idiopathic and virus-associated EM and druginduced SJS. The use of systemic corticosteroids cannot be recommended.21 Several series indicate that administering anti-HSV drugs for the treatment of established episodes of postherpetic EM is useless. When symptomatic, M. pneumoniae infection should be treated with antibiotics (macrolides in children, macrolides or quinolone in adults). There is no evidence indicating whether it improves the evolution of the associated EM. Therefore, when asymptomatic infection is suggested by serologic testing, treatment is not mandatory. Liquid antacids, topical glucocorticoids, and local anesthetics relieve symptoms of painful mouth erosions.

PREVENTION Continuous therapy with oral anti-HSV drugs (see Chapter 231) is effective to prevent recurrences of herpes-associated EM with or without clinical evidence that herpes is the precipitating factor.7 Topical acyclovir therapy used in a prophylactic manner does not prevent recurrent herpetic EM. In a series of 65 patients with recurrent EM, 11 were treated with azathioprine when all other treatments had failed. Azathioprine was beneficial in all 11 patients.19 Mycophenolate mofetil can be also useful.20 Retrospective uncontrolled analyses of thalidomide therapy have indicated that it is moderately effective for the treatment of EM.22 However, thalidomide is probably the most effective treatment of recurrent/persistent cases when resistant to antiHSV drugs. In one randomized controlled trial, levamisole appeared useful. Because agranulocytosis is a severe and not exceptional adverse effect, levamisole use is permitted in only a few countries. The benefit–risk ratio is probably too low to support its use in the treatment of EM.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Bastuji-Garin S et al: A clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme. Arch Dermatol 129:92, 1993 2. Auquier-Dunant A et al: Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson Syndrome and toxic epidermal necrolysis. Arch Dermatol 138:1019, 2002 5. Weston WL: Herpes-associated erythema multiforme. J Invest Dermatol 124:xv, 2005

7. Tatnall FM, Schofield JK, Leigh IM: A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 132:267, 1995 13. Aurelian L, Ono F, Burnett J: Herpes simplex virus (HSV)associated erythema multiforme (HAEM): A viral disease with an autoimmune component. Dermatol Online J 9:1, 2003 20. Wetter DA, Davis MD: Recurrent erythema multiforme: Clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol 62:45, 2010 21. Riley M, Jenner R: Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. Bet 2. Steroids in children with erythema multiforme. Emerg Med J 25:594, 2008

Widespread apoptosis of keratinocytes provoked by the activation of a cellmediated cytotoxic reaction and amplified by cytokines, mainly granulysin. Confluent purpuric and erythematous macules evolving to flaccid blisters and epidermal detachment predominating on the trunk and upper limbs and associated with mucous membrane involvement. Pathologic analysis shows full-thickness necrosis of epidermis associated with mild mononuclear cell infiltrate. A dozen “high-risk” drugs account for one half of cases. Up to 20% of cases remain idiopathic. Early identification and withdrawal of suspect drugs are essential for good patient outcome. Treatment is mainly symptomatic. Sequelae are nearly constant, needing systematic follow-up examinations.

Epidermal Necrolysis

Rare and life-threatening reaction, mainly drug induced.

Toxic epidermal necrolysis (TEN) and Stevens– Johnson syndrome (SJS) are acute life-threatening mucocutaneous reactions characterized by extensive necrosis and detachment of the epidermis. Stevens and Johnson first reported two cases of disseminated cutaneous eruptions associated with an erosive stomatitis and severe ocular involvement.1 In 1956, Lyell described patients with epidermal loss secondary to necrosis and introduced the term toxic epidermal necrolysis.2 Both SJS and TEN are characterized by skin and mucous membrane involvement. Because of the similarities in clinical and histopathologic findings, risk factors, drug causality, and mechanisms, these two conditions are now considered severity variants of an identical process that differs only in the final extent of body surface involved.3–5 Therefore, it is better to use the designation epidermal necrolysis for both, as proposed by Ruiz-Maldonado (acute disseminated epidermal necrosis)6 and Lyell (exanthematic necrolysis).7

::

EPIDERMAL NECROLYSIS AT A GLANCE

Chapter 40

Chapter 40 :: E  pidermal Necrolysis (Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis) :: L. Valeyrie-Allanore & Jean-Claude Roujeau

6

EPIDEMIOLOGY Epidermal necrolysis (EN) is rare. The overall incidence of SJS and TEN was estimated at 1 to 6 cases per million person-years and 0.4 to 1.2 cases per million person-years, respectively.8,9 EN can occur at any age, with the risk increasing with age after the fourth decade, and more frequently affects women, showing a sex ratio of 0.6. Patients infected with human immunodeficiency virus and to a lesser degree patients with collagen vascular disease and cancer are at increased risk.10–12 The overall mortality associated with EN is 20% to 25%, varying from 5% to 12% for SJS to more than 30% for TEN. Increasing age, significant comorbidity, and greater extent of skin involvement correlate with poor prognosis. In the United States, evaluation

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TABLE 40-1

SCORTEN: A Prognostic Scoring System for Patients with Epidermal Necrolysis SCORTEN Prognostic Factors

Points

Age >40 years Heart rate >120 beats/minute Cancer or hematologic malignancy Body surface area involved >10% Serum urea level >10 mM Serum bicarbonate level >20 mM Serum glucose level >14 mM

1 1 1 1 1 1 1

Section 6 :: Inflammatory Diseases Based on Abnormal Humoral Reactivity

SCORTEN

Mortality Rate (%)

0–1 2 3 4 5

3.2 12.1 35.8 58.3 90

Data from Bastuji-Garin S et al: SCORTEN: A severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 115:149, 2000.

of death certificates suggested a seven time higher risk of dying from EN among blacks than whites.13 A prognosis score (SCORTEN) has been constructed for EN,14 and its usefulness has been confirmed by several teams.15–18 (See Table 40-1.)

ETIOLOGY The pathophysiology of EN is still unclear; however, drugs are the most important etiologic factors. More than 100 different drugs have been implicated,19–21 but fewer than a dozen “high-risk” medications account for about one half of cases in Europe (Table 40-2), as evidenced by two multinational case–control studies.12,22–25 These high-risk drugs are antibacterial sulfon-

amides, aromatic anticonvulsants, allopurinol, oxicam nonsteroidal anti-inflammatory drugs, lamotrigine, and nevirapine.26–27 The risk seems confined to the first 8 weeks of treatment. Slow dose escalation decreases the rate of rash with lamotrigine and nevirapine,28,29 but there is no evidence that it decreases the risk of EN.26 Oxcarbazepine, a 10-keto derivative of carbamazepine, which was considered to carry a lower risk, seems to significantly cross-react with carbamazepine.30 Many nonsteroidal anti-inflammatory drugs (primarily oxicam derivatives and diclofenac) were suspected to be associated with EN.12,31,32 A significant but much lower risk has also been reported for non-sulfonamide antibiotics such as aminopenicillins, quinolones, cephalosporins, and tetracyclines.22Corticosteroids were significantly associated with a high relative risk, but confounding was not excluded.22 The role of infectious agents in the development of EN is much less prominent than for erythema multiforme. However, cases of EN associated with Mycoplasma pneumoniae infection, viral disease, and immunization have been reported, particularly in children.33,34 These rare observations underscore the fact that medications are not the only cause of EN, but there is still little evidence that infections can explain more than a very small percentage of cases. Cases of EN have been reported after bone marrow transplantation. Some are an extreme form of acute graft-versus-host disease (see Chapter 28); others could be drug induced. The relationship between EN and graft-versus-host disease is difficult to assess because clinical and histological skin features are nearly indistinguishable.35 Lupus erythematosus (systemic LE or subacute cutaneous LE) is associated with an increased risk of EN.12,22 In such cases, drug causality is often doubtful and necrolysis might be an extreme phenotype of cutaneous lupus.36 Finally, radiotherapy in addition to treatment with antiepileptic drugs, such as phenytoin, phenobarbital, or carbamazepine, can trigger EN with lesions localized predominantly at sites of radiation treatment.37,38 In

TABLE 40-2

Medications and the Risk of Epidermal Necrolysis

440

High Risk

Lower Risk

Doubtful Risk

No Evidence of Risk

Allopurinol Sulfamethoxazole Sulfadiazine Sulfapyridine Sulfadoxine Sulfasalazine Carbamazepine Lamotrigine Phenobarbital Phenytoin Phenylbutazone Nevirapine Oxicam NSAIDs Thiacetazone

Acetic acid NSAIDs (e.g., diclofenac) Aminopenicillins Cephalosporins Quinolones Cyclins Macrolides

Paracetamol (acetaminophen) Pyrazolone analgesics Corticosteroids Other NSAIDs (except aspirin) Sertraline

Aspirin Sulfonylurea Thiazide diuretics Furosemide Aldactone Calcium channel blockers β Blockers Angiotensin-converting enzyme inhibitors Angiotensin II receptor antagonists Statins Hormones Vitamins

NSAIDs = nonsteroidal anti-inflammatory drugs.

clinical practice, the causality of a medication can be clearly established in approximately 60% of cases and suspected in 20%. Other causes (infection, GVH, LE) are rarely apparent, about 20% of cases as idiopathic.39

PATHOGENESIS

:: Epidermal Necrolysis

CLINICAL FINDINGS

6

Chapter 40

Even if the precise sequence of molecular and cellular events is incompletely understood, several studies provided important clues to the pathogenesis of EN. The immunologic pattern of early lesions suggests a cell-mediated cytotoxic reaction against keratinocytes leading to massive apoptosis.39–41 Immunopathologic studies have demonstrated the presence within early lesions of cytotoxic cells including natural killer T cells (NKT) and drug-specific CD8+ T lymphocytes; monocytes/macrophages and granulocytes are also recruited.42–44 However, it is generally accepted that specific and nonspecific cytotoxic cells are too few within the lesions to explain the death of cells on the full thickness and large areas of the epidermis and mucous membranes. Amplification by cytokines has been suspected for years, especially for factors activating “death receptors” on cell membranes, especially antitumor necrosis factor (TNF) α and soluble Fas ligand (Fas-L).42,45 In the past decade it had been widely accepted that Fas-L was inducing the apoptosis of keratinocytes in EN,45,46 despite partial evidence and discordant findings.47–49 An important recent study has challenged this dogma by demonstrating the key role in EN of granulysin.50 Granulysin was present in the blister fluid of EN at concentrations much higher than those of perforin, granzyme B, or Fas-L. At such concentrations, only granulysin, and to a much lesser degree perforin, were able to kill human keratinocytes in vitro; Fas-L was not. Furthermore injection of granulysin in the dermis of normal mice resulted in clinical and histological lesions of EN.50 When combined, the above results strongly suggest that the effector mechanisms of EN have been deciphered. Cytotoxic T-cells develop and are usually specifically directed against the native form of the drug rather than against a reactive metabolite, contrarily to what has been postulated for 20 years. These cells kill keratinocytes directly and indirectly through the recruitment of other cells that release soluble death mediators, the principal being granulysin.50,51 These advances on understanding the final steps of the reaction point to inhibition of release and/or blockade of granulysin as major aims of therapeutic interventions. Little is known on what are the initial and intermediate steps. We still do not understand why very few individuals develop a violent immune response to medications and why effector cells are especially directed to the skin and other epithelia. Actually, most drugs associated with a “high risk” for EN can also induce a variety of milder and more frequent reactions. Drug-specific CD8 cytotoxic T-lymphocytes were also often found in skin reactions with more benign phenotype.52 Hence, it is tempting to speculate on an abnormal regulation of immune response. Regulatory CD4+

CD25+ T cells have been demonstrated to be potentially important in the prevention of severe epidermal damage induced by reactive cytotoxic T lymphocytes in a mouse model of EN.53 Similar regulatory cells may play a role in drug eruptions in humans.54 Altered regulation of the immune response to medications in patients with EN could result from comorbidities that are frequent, for example, cancer, HIV infection, collagen vascular disease; from comedications, for example, corticosteroids; or from genetic background. Genetic susceptibility plays an important role in the development of EN to a few “high-risk” medications. A strong association was observed in Han Chinese from Taiwan between the human leukocyte antigen HLA-B*1502 and EN induced by carbamazepine, and between HLA-B*5801 and EN induced by allopurinol.55,56 B*1502 association with carbamazepine-related cases was confirmed in several Asian countries,57,58 with the remarkable exceptions of Japan and Korea.59,60 The association between carbamazepine-induced EN and HLA-B*1502 was not present in European patients who do not have Asian ancestry.61 On the other hand, HLA-B*5801 was confirmed to be associated with allopurinol-related EN in Japan59 and Europe,62 but the strength of association was lower than in Taiwan.

Even in cases requiring immediate referral to specialized wards, the dermatologist will have a specific role in the management of patients with EN (Fig. 40-1). Decision tree for referral of a patient with EN Diagnosis of epidermal necrosis

Involved BSA < 10%

Slow progression No severity marker

Stable

Progression

Involved BSA > 10%

Serum bicarbonate < 20 mM Serum urea level > 10 mM Serum glucose level > 14 mM Respiratory rate > 20 pO2 < 80 mm Hg or rapid progression

Transfer to specialized center

Usual medical wards

Systemic follow-up High risk of serious sequelae (skin, eyes, genitalia, mouth, psychic...)

Figure 40-1  Decisional tree for referral of a patient with EN. (Adapted from Ellis MW: A case report and a proposed algorithm for the transfer of patients with StevensJohnson syndrome and toxic epidermal necrolysis to a burn center. Mil Med 167:701, 2002)

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HISTORY

Section 6 ::

EN clinically begins within 8 weeks (usually 4 to 30 days) after the onset of drug exposure for the first time. Only in very rare cases with prior reaction and inadvertent rechallenge with the same drug does it appear more rapidly, within a few hours. Nonspecific symptoms such as fever, headache, rhinitis, cough, or malaise may precede the mucocutaneous lesions by 1 to 3 days. Pain on swallowing and burning or stinging of the eyes progressively develop, heralding mucous membrane involvement. About one-third of cases begin with nonspecific symptoms, one-third with symptoms of mucous membrane involvement, and one-third with an exanthema. Whatever the initial symptoms are, their rapid progression, the addition of new signs, severe pain, and constitutional symptoms should alert one to the onset of a severe disease.

Inflammatory Diseases Based on Abnormal Humoral Reactivity

CUTANEOUS LESIONS The eruption is initially symmetrically distributed on the face, the upper trunk, and the proximal part of limbs.63 The distal portions of the arms as well as the legs are relatively spared, but the rash can rapidly extend to the rest of the body within a few days and even within a few hours. The initial skin lesions are characterized by erythematous, dusky red, purpuric macules, irregularly shaped, which progressively coalesce. Atypical target lesions with dark centers are often observed (Fig. 40-2A). Confluence of necrotic lesions leads to extensive and diffuse erythema. Nikolsky’s sign, or dislodgement of the epidermis by lateral pressure, is positive on erythematous zones (Fig. 40-3 and eFig. 40-3.1 in online edition). At this stage, the lesions evolve to flaccid blisters, which spread with pressure and break easily (see Fig. 40-2B). The necrotic epidermis is easily detached at pressure points or by frictional trauma, revealing large areas of exposed, red, sometimes oozing dermis (see Figs. 40-2C and 40-2D). In other areas, epidermis may remain. Patients are classified into one of three groups according to the total area in which the epidermis is detached or “detachable” (positive Nikolsky): (1) SJS, less than 10% of body surface area (BSA); (2) SJS/TEN overlap, between 10% and 30%; (3) TEN, more than 30% of BSA (eFig. 40-3.2 in online edition). Correct evaluation of the extent of lesions is difficult, especially in zones with spotty lesions. It is helpful to remember that the surface of one hand (palm and fingers) represents a little less than 1% of the BSA.

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Mucous membrane involvement (nearly always on at least two sites) is observed in approximately 90% of cases and can precede or follow the skin eruption. It begins with erythema followed by painful erosions of the oral, ocular, and genital mucosa. This usually leads to impaired alimentation, photophobia, con-

junctivitis, and painful micturition. The oral cavity and the vermilion border of the lips are almost invariably affected and feature painful hemorrhagic erosions coated by grayish white pseudomembranes and crusts of the lips (Fig. 40-4). Approximately 80% of patients have conjunctival lesions,64,65 mainly manifested by pain, photophobia, lacrimation, redness, and discharge. Severe forms may lead to epithelial defect corneal ulceration, anterior uveitis, and purulent conjunctivitis. Synechiae between eyelids and conjunctiva often occur. There may be shedding of eyelashes (see Fig. 40-4B). Genital erosions are frequent, often overlooked in women, and may lead to synechiae.66 Shedding of nails occurs in severe forms.

EXTRACUTANEOUS SYMPTOMS EN is associated with high fever, pain, and weakness. Visceral involvement is also possible, particularly with pulmonary and digestive complications. Early pulmonary complications occur in approximately 25% of patients and are essentially manifested by elevated respiratory rate and cough, which should prompt strict surveillance.67,68 Bronchial involvement in EN is not correlated with the extent of skin lesions or with the offending agent. In most cases chest radiographs are normal on admission but can rapidly reveal interstitial lesions that can progress to acute respiratory distress syndrome (ARDS). In all reported cases, when acute respiratory failure developed rapidly after the onset of skin involvement, it was associated with poor prognosis. In the case of respiratory abnormalities, fiberoptic bronchoscopy may be useful to distinguish a specific epithelial detachment in the bronchi from an infectious pneumonitis, which has a much better prognosis. Gastrointestinal tract involvement is less commonly observed, with epithelial necrosis of the esophagus, small bowel, or colon manifesting as profuse diarrhea with malabsorption, melena, and even colonic perforation.69,70 Renal involvement has been reported. Proteinuria, microalbuminuria, hematuria, and azotemia are not rare. Proximal tubule damage can result from necrosis of tubule cells by the same process that destroys epidermal cells.71 Glomerulonephritis is rare.72

LABORATORY TESTS LABORATORY VALUES There is no laboratory test to support the diagnosis of EN. Laboratory examinations are essential to evaluation of severity and daily management as for all lifethreatening conditions in intensive care units. Evaluation of respiratory rate and blood oxygenation are among the first steps to take in the emergency room. Any alteration should be checked through measurement of arterial blood gas levels. Serum bicarbonate levels below 20 mM indicate a poor prognosis.14

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C

B

Epidermal Necrolysis

A

D

Figure 40-2  A. Early eruption. Erythematous dusky red macules (flat atypical target lesions) that progressively coalesce and show epidermal detachment. B. Early presentation with vesicles and blisters, note the dusky color of blister roofs, strongly suggesting necrosis of the epidermis. C. Advanced eruption. Blisters and epidermal detachment have led to large confluent erosions. D. Full-blown epidermal necrolysis characterized by large erosive areas reminiscent of scalding.

They usually result from respiratory alkalosis related to the specific involvement of bronchi and more rarely from metabolic acidosis. Massive transdermal fluid loss is responsible for electrolyte imbalances, hypoalbuminemia, and hypoproteinemia, and mild and transient renal insufficiency and prerenal azotemia are common. Raised blood urea nitrogen level is one marker of severity. Anemia is usual, and mild leukocytosis as well as thrombocytopenia may occur. Neutropenia is often considered to be

an unfavorable prognostic factor but is too rare to have a significant impact on SCORTEN. Transient peripheral CD4+ lymphopenia is nearly always seen and is associated with decreased T-cell function. Mild elevation in levels of hepatic enzymes and amylase (most probably of salivary origin) are frequent but without impact on prognosis. A hypercatabolic state is responsible for inhibition of insulin secretion or insulin resistance, which results in hyperglycemia and occasionally overt diabetes. A blood glucose level above 14 mM is

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full-thickness necrosis and subepidermal detachment (Fig. 40-5). Apoptosis of epithelial cells may involve sweat glands and hair follicles. A moderately dense mononuclear cell infiltrate of the papillary dermis is observed, mainly represented by lymphocytes, often CD8+ and macrophages.73,74 Eosinophils seems to be less common in patients with the most severe form of EN. Results of direct immunofluorescence study are negative. Histopathology of involved mucous membranes, rarely performed, would show similar alterations.75

DIFFERENTIAL DIAGNOSIS Section 6 :: Inflammatory Diseases Based on Abnormal Humoral Reactivity

Figure 40-3  Early exanthematous phase with Nikolsky’s sign. one marker of severity.14 Other abnormalities in laboratory values may occur, indicating involvement of other organs and complications such as sepsis.

HISTOPATHOLOGY Skin biopsy for routine histologic and possibly immunofluorescence studies should be strongly considered, especially if there are alternative diagnoses to consider. In the early stages, epidermal involvement is characterized by sparse apoptotic keratinocytes in the suprabasal layers, which rapidly evolves to a

A

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(Box 40-1) Milder presentations of EN must be distinguished from erythema multiforme minor (EMM) (see Chapter 39). Early EN cases are often initially diagnosed as varicella. The rapid progression of skin lesions and the severity of mucous membrane involvement should raise the probability of EN. The absence of mucous membrane involvement or its restriction to a single site must always raise the suspicion of an alternative diagnosis: staphylococcal scalded skin syndrome in infants; purpura fulminans in children and young adults; acute generalized exanthematous pustulosis, phototoxicity, or pressure blisters in adults. Thermal burns or scalding are occasionally an issue when a transient loss of consciousness occurs. Linear immunoglobulin (Ig) A bullous disease and paraneoplastic pemphigus present with a less acute progression. Pathologic findings and a positive result on direct immunofluorescence testing are important for these diagnoses. In all aspects, including pathology, generalized bullous fixed drug eruption (GBFDE) resembles EN. It

B

Figure 40-4  A. Extensive erosions and necroses of the lower lip and oral mucosa. B. Massive erosions covered by crusts on the lips. Note also shedding of eyelashes.

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B

Figure 40-5  Histologic appearance of toxic epidermal necrolysis. A. Eosinophilic necrosis of the epidermis in the peak stage, with little inflammatory response in the dermis. Note cleavage in the junction zone. B. The completely necrotic epidermis has detached from the dermis and folded like a sheet.

BOX 40-1  Differential Diagnosis of Epidermal Necrolysis (EN) Most Likely Limited EN (Stevens–Johnson syndrome) Erythema multiforme major Varicella Widespread EN Acute generalized exanthematous pustulosis Generalized bullous fixed drug eruption Consider Paraneoplastic pemphigus Linear immunoglobulin A bullous disease Pressure blisters after coma Phototoxic reaction Graft-versus-host disease Always Rule Out Staphylococcal scalded skin syndrome Thermal burns Skin necrosis from disseminated intravascular coagulation or purpura fulminans Chemical toxicity (e.g., colchicine intoxication, methotrexate overdose)

Epidermal Necrolysis

A

may have a similar drug-related mechanism. However, the distinction is worthwhile because GBFDE has a reputation for much better prognosis, probably because of the mild involvement of mucous membranes and the absence of visceral complications. Prior attacks, rapid onset after drug intake, and very large, well-demarcated blisters are the hallmarks of GBFDE. Toxic destruction of epithelia, whether through contact (fumigants) or ingestion (colchicine poisoning, methotrexate overdose), may result in clinical features of EN, but with skin erosions often predominating in the folds. In these rare cases, causality is generally obvious. Overreporting of SJS is common. It usually arises from confusion between desquamation and detachment of epidermis, and also between mucous membranes and periorificial skin. Because of such confusion, patients with a desquamative rash and scaly lips are not rarely diagnosed with and reported as having SJS.

COMPLICATIONS AND SEQUELAE During the acute phase, the most common complication of EN is sepsis. The epithelial loss predisposes these patients to infections, which are the main causes of mortality.4,63 Staphylococcus aureus and Pseudomonas are the most frequent pathogens, but about one-third of positive blood cultures contain enterobacteriae not present on the skin, a finding that suggests bacterial translocation from gut lesions.76 Multisystem organ failure and pulmonary

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complications are observed in more than 30% and 15% of cases, respectively.77 A very important advance in EN is the recent understanding that sequelae are more frequent and more severe than previously thought.78 After the well-known risks of the acute stage, EN behaves as a chronic disease. More medical attention should be directed to that phase to better understand the frequency, mechanisms, and evolution of sequelae. Adequate management and prevention of sequelae are as important as saving the life during the acute phase. A large European cohort has found that 90% of patients who survived EN suffered from sequelae at 1 year, with a mean of three different problems per patient and an important negative impact on the quality of life for about half of them (RegiSCAR group, unpublished data). Symptoms suggesting posttraumatic stress disorder are not rare. Psychiatric consultation and/or psychological support are probably necessary in a majority of cases. Late ophthalmic complications are reported in 20% to 75% of patients with EN, with a credible figure of about 50% (Fig. 40-6).64,65,78 The relationship between the initial severity of ocular involvement and the development of late complications seems now to be well established. Late ophthalmic complications are mainly due to functional alteration of the conjunctival epithelium with dryness and abnormal lacrimal film. This leads to chronic inflammation, fibrosis, entropion, trichiasis, and symblepharon. Long-term irritation and deficiency of stem cells in the limbus may result in metaplasia of corneal epithelium with painful ulcerations, scarring, and altered vision. Such severe eye lesions occasionally develop in patients who had no patent ocular signs during the acute phase of EN.64 Hypopigmentation and/or hyperpigmentation are most frequent; residual hypertrophic or atrophic scars rarely occur. Nail changes, including change in pigmentation of the nail bed, ridging, dystrophic nails, and permanent anonychia, occur in more than 30% of cases (Fig. 40-7). Mouth sequelae are present in about

Figure 40-7  Abnormal regrowth of nails after SJS. one-third of patients who complain of dryness, altered taste, and late alterations of teeth.79 Vulvar and vaginal complications of EN are reported by about 25% of patients.66 Dyspareunia is not rare and is related to vaginal dryness, itching, pain, and bleeding. Genital adhesions may lead to the requirement for surgical treatment. Esophageal, intestinal, urethral, and anal strictures may also develop in rare cases. Chronic lung disease can be observed after EN, often attributed to bronchiolitis obliterans, and occasionally requires lung transplantation.68,80 Because these late complications and sequelae may develop insidiously, it is strongly suggested that all patients surviving EN have a clinical follow-up a few weeks after discharge and 1 year later, including examination by an ophthalmologist and by other organ specialist(s) as indicated by abnormal signs and symptoms.

PROGNOSIS AND CLINICAL COURSE The epidermal detachment progresses for 5 to 7 days. Then, patients enter a plateau phase, which corresponds to progressive reepithelialization. This can take a few days to a few weeks, depending on the severity of the disease and the prior general condition of the patient. During this period, life-threatening complications such as sepsis or systemic organ failure may occur. The overall hospital mortality rate of EN is 22–25%, varying from 5% to 12% for SJS to more than 30% for TEN. The prognosis is not affected by the type or dose of the responsible drug or the presence of human immunodeficiency virus infection (see Table 40-1).12,14,63,77 Prospective follow-up has shown an additional abnormally increased mortality in the 3-month period following hospital discharge, which seems to result from the negative impact of EN on prior severe chronic conditions, for example, malignancies (RegiSCAR, unpublished data).

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Figure 40-6  Late ocular complications of SJS. Note opaque corneal epithelium, neovessels, and irritating eyelashes on lower eyelids. (Photograph provided by Julie Gueudry MD and Marc Muraine MD, PhD, Hôpital Charles Nicolle, Rouen, France.)

EN is a life-threatening disease that requires optimal management: early recognition and withdrawal of the offending drug(s) and supportive care in an appropriate hospital setting.

Prompt withdrawal of offending agent(s) is associated with an increased rate of survival in patients with EN induced by drugs with short elimination halflives.81 On the other hand, it is preferable to continue every important and nonsuspected medication. That will avoid reluctance on the part of the patient’s physicians to prescribe them in the future. In case of doubt, all nonlife-sustaining drugs should be stopped, and particularly those administered within the previous 8 weeks.

SYMPTOMATIC TREATMENT

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SPECIFIC TREATMENT IN ACUTE STAGE Because of the importance of immunologic and cytotoxic mechanisms, a large number of immunosuppressive and/or anti-inflammatory therapies have been tried to halt the progression of the disease. None has clearly proved its efficacy. The low prevalence of the disease makes randomized clinical trials hard to perform.

Epidermal Necrolysis

INTRAVENOUS IMMUNOGLOBULIN. The proposal to use high-dose intravenous Ig was based on the hypothesis that Fas-mediated cell death can be abrogated by the anti-Fas activity present in commercial batches of normal human Ig .45 Benefits have been claimed by several studies and case reports,45,88–90 but refuted by several others.16,87,91,92 Thus, intravenous Ig cannot be considered the standard of care,5 especially after recent findings that the Fas-L/Fas pathway was not, or only marginally, involved in the mechanisms of EN.50 If used, a minimal precaution is to avoid preparations that are potentially nephrotoxic.

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CORTICOSTEROIDS. The use of systemic corticosteroids is still controversial. Some studies found that such therapy could prevent the extension of the disease when administered during the early phase, especially as intravenous pulses for a few days.86 Other studies concluded that steroids did not stop the progression of the disease and were even associated with increased mortality and adverse effects, particularly sepsis. Thus, systemic corticosteroids cannot be recommended as the mainstay treatment of EN,5 but a large cohort study has suggested a possible benefit that should be explored by a prospective study.87

Chapter 40

Only patients with limited skin involvement, a SCORTEN score of 0 or 1, and a disease that is not rapidly progressing can be treated in nonspecialized wards. Others should be transferred to intensive care units or burn centers.82 There is no “specific” treatment of demonstrated efficacy and supportive measures are the most important.5 Supportive care consists of maintaining hemodynamic equilibrium and preventing lifethreatening complications. The aims are basically the same as for extensive burns. EN is associated with significant fluid loss from erosions, which results in hypovolemia and electrolyte imbalance. Fluid replacement must be started as soon as possible and adjusted daily. Volumes of infusions are usually less than for burns of similar extent, because interstitial edema is absent. Peripheral venous lines are preferred when possible, because the sites of insertion of central lines are often involved in detachment of epidermis and prone to infection. The environmental temperature should be raised to 28°C to 30°C (82.4°F to 86°F). The use of an air-fluidized bed improves patient comfort. Early nutritional support is preferentially provided by nasogastric tube to promote healing and to decrease the risk of bacterial translocation from the gastrointestinal tract. To reduce the risk of infection, aseptic and careful handing is required. Skin, blood, and urine specimens should be cultured for bacteria and fungi at frequent intervals. Prophylactic antibiotics are not indicated. Patients should receive antibiotics when clinical infection is suspected. Prophylactic anticoagulation is provided during hospitalization. We do not recommend extensive and aggressive debridement of necrotic epidermis in EN because the superficial necrosis is not an obstacle to reepithelialization, and might even accelerate the proliferation of stem cells due to the inflammatory cytokines. This is the single noticeable divergence between authors of this chapter and the recommendations of US Burn centers.5 A few recent series suggest that debridement is necessary neither in superficial burns81 nor in EN. 84,85 There is no standard policy on wound dressings and the use of antiseptics. It is a matter of experience for each center. Skillfulness on the part of specialized nurses, careful manipulation, and an aggressive protocol of prevention and treatment of pain are essential. Eyes should be examined daily by an ophthalmologist. Preservative-free emollients, antibiotic or antiseptic eye drops, and vitamin A are often used every 2 hours in the acute phase, and mechanical disruption of early synechiae is indicated. Early graft of cryo-

preserved amniotic membrane has been proposed as capable to decrease the rate of severe eye sequelae.64 The mouth should be rinsed several times a day with antiseptic or antifungal solution.

CYCLOSPORINE A. Cyclosporine is a powerful immunosuppressive agent associated with biologic effects that may theoretically be useful in treatment of EN: activation of T helper 2 cytokines, inhibition of CD8+ cytotoxic mechanisms, and antiapoptotic effect through inhibition of Fas-L, nuclear factor-κB, and TNF-α. Several case reports and series suggested some efficacy of cyclosporine A in halting the progression of EN without worrisome side effects when administered early.93,94 PLASMAPHERESIS OR HEMODIALYSIS. The rationale for using plasmapheresis or hemodialysis is to prompt the removal of the offending medication, its metabolites, or inflammatory mediators such as cytokines. A small series reported their efficacy and safety in treating EN.95–98 However, considering the absence of evidence and the risks associated with intravascular catheters, these treatments cannot be recommended. ANTITUMOR NECROSIS FACTOR AGENTS.

Anti-TNF monoclonal antibodies have been successfully used to treat a few patients. Because a prior

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randomized controlled trial of thalidomide, an antiTNF agent, had to be interrupted due to significantly increased mortality,99 extreme caution is suggested in the use of anti-TNF agents to treat EN.

TREATMENT OF SEQUELAE

Section 6

Very promising treatments have now been developed for the ocular sequelae of EN, including gas permeable scleral lenses100,101 and grafting of autologous stem cells from contralateral limbus or mouth mucosa.102,103 With the exception of ocular sequelae, the literature contains only case reports related to treating sequelae. Photoprotection and cosmetic lasers may help resolve the pigmentation changes on the skin.

PREVENTION

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Primary prevention is only feasible in populations where a strong association has been established between a simple genetic maker and the risk of EN. That is the case for HLAB*1502 and EN induced by carbamazepine. The FDA has issued the recommendation to test patients from “Asian ancestry” for HLAB*1502 before prescribing carbamazepine. This recommendation should be refined to exclude persons of Japanese or Korean origin. In individuals of Han Chinese origin, alternative antiepileptic drugs can be carefully prescribed, although there may be an association of EN with phenytoin and HLAB*1502 as well.57 The present status of research on the pharmacogenetics of EN (RegiSCAR unpublished data) makes unlikely the finding of other genetic markers useful for primary prevention. Secondary prevention is important for patients who experienced EN and are reluctant to take any medication. The most important issue is to evaluate drug causality. In vitro tests or patch tests to medications occasionally can be useful in the exploration of drug allergy. When used in EN patients, their sensitivity is low.104,105 Careful inquiry into all exposures to medications in the few weeks preceding the onset of the reaction leads to the identification of a probable culprit drug in approximately 70% of cases. The most useful clinical criteria are duration of treatment before onset (typically 4 to 30 days), absence of prior intake, and use of a drug known for being associated with a high risk.39 The few published cases of recurrent SJS or TEN were always due to inadvertent readministration of the same or a very closely related medication. Epidemiology and in vitro studies suggest that the list of possible cross-reactive medications is rather narrow, based on close chemical similarities. As an example, there is no evidence that patients who experienced SJS or TEN in reaction to an anti-infectious sulfonamide are at increased risk for reaction to sulfonamiderelated diuretics or antidiabetic medications. Only anti-infectious sulfonamides should be contraindicated in this situation.

A list of the suspected medication(s) and molecules of the same biochemical structure must be given to the patient on a personal “allergy card.” It is also very useful to provide a list of drugs of common use that cannot be suspected. Because of recent indications of genetic susceptibilities to the development of EN, prescription of the offending agent to family members should also be avoided.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 3. Bastuji-Garin S et al: Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129:92, 1993 5. Endorf FW et al: Toxic epidermal necrolysis clinical guidelines. J Burn Care Res 29:706, 2008 22. Mockenhaupt M et al: Stevens-Johnson syndrome and toxic epidermal necrolysis: Assessment of medication risks with emphasis on recently marketed drugs. The EuroSCARstudy. J Invest Dermatol 128:35, 2008 23. Auquier-Dunant A et al: Correlation between clinical patterns and causes of erythema multiforme major, Stevens Johnson and toxic epidermal necrolysis. Arch Dermatol 138:1019, 2002 25. Halevy S et al: Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel. J Am Acad Dermatol 58:25, 2008 36. Ting W et al: Toxic epidermal necrolysis-like acute cutaneous lupus erythematosus and the spectrum of the acute syndrome of apoptotic pan-epidermolysis (ASAP): A case report, concept review and proposal for new classification of lupus erythematosus vesiculobullous skin lesions. Lupus 13:941, 2004 44. Nassif A et al: Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 118:728, 2002 50. Chung WH et al: Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 14:1343, 2008 54. Takahashi R et al: Defective regulatory T cells in patients with severe drug eruptions: Timing of the dysfunction is associated with the pathological phenotype and outcome. J Immunol 182:8071, 2009 55. Chung WH et al: Medical genetics: A marker for Stevens Johnson syndrome. Nature 428:486, 2004 56. Hung SI et al: HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 102:4134, 2005 62. Lonjou C et al: A European study of HLA-B in StevensJohnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics 18:99, 2008 64. Shay E et al: Amniotic membrane transplantation as a new therapy for the acute ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis. Surv Ophthalmol 54:686, 2009 87. Schneck J et al: Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 58:33, 2008 101. Tougeron-Brousseau B et al: Vision-related function after scleral lens fitting in ocular complications of StevensJohnson syndrome and toxic epidermal necrolysis. Am J Ophthalmol 148:852, 2009

Chapter 41 :: Cutaneous Reactions to Drugs :: Neil H. Shear & Sandra R. Knowles CUTANEOUS ADVERSE DRUG ERUPTIONS AT A GLANCE Drug-induced cutaneous eruptions are common. They range from common nuisance rashes to rare life-threatening diseases.

Drug reactions may be limited solely to skin or may be part of a severe systemic reaction, such as drug hypersensitivity syndrome or toxic epidermal necrolysis.

Complications of drug therapy are a major cause of patient morbidity and account for a significant number of patient deaths.1 Drug eruptions range from common nuisance eruptions to rare or life-threatening drug-induced diseases. Drug reactions may be solely limited to the skin, or they may be part of a systemic reaction, such as drug hypersensitivity syndrome or toxic epidermal necrolysis (TEN) (see Chapter 40). Drug eruptions are often distinct disease entities and must be approached systematically, as any other cutaneous disease. A precise diagnosis of the reaction pattern can help narrow possible causes, because different drugs are more commonly associated with different types of reactions.

EPIDEMIOLOGY A systematic review of the medical literature, encompassing nine studies, concluded that cutaneous reaction rates varied from 0% to 8% and were highest for antibiotics.2 Outpatient studies of cutaneous adverse drug reactions (ADRs) estimate that 2.5% of children who are treated with a drug, and up to 12% of children treated with an antibiotic, will experience a cutaneous reaction.3

PATHOGENESIS OF DRUG ERUPTIONS Constitutional factors influencing the risk of cutaneous eruption include pharmacogenetic variation in drug-metabolizing enzymes and human leukocyte antigen (HLA) associations. Acetylator phenotype alters the risk of developing drug-induced lupus due to hydralazine, procainamide, and isoniazid. HLADR4 is significantly more common in individuals with hydralazine-related drug-induced lupus than in those with idiopathic systemic lupus erythematosus.4 HLA factors may also influence the risk of reactions to nevirapine, abacavir, carbamazepine, and allopurinol.5–7 Many drugs associated with severe idiosyncratic drug reactions are metabolized by the body to form reactive, or toxic, drug products.8 These reactive products comprise only a small proportion of a drug’s metabolites and are usually rapidly detoxified. However, patients with drug hypersensitivity syndrome, TEN, and Stevens–Johnson syndrome (SJS) resulting from treatment with sulfonamide antibiotics and the aromatic anticonvulsants (e.g., carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine) show greater sensitivity in in vitro assessments to the oxidative, reactive metabolites of these drugs than do control subjects.9 Acquired factors also alter an individual’s risk of drug eruption. Active viral infection and concurrent use of other medications have been shown to alter the frequency of drug-associated eruptions. Reactivation of latent viral infection with human herpes virus 6 also appears common in drug hypersensitivity syndrome and may be partially responsible for some of the clinical features and/or course of the disease.10,11 Viral infections may act as, or generate the production of, danger signals that lead to damaging immune responses to drugs, rather than immune tolerance. Drug–drug interactions may also alter the risk of cutaneous eruption. Valproic acid increases the risk of severe cutaneous adverse reactions to lamotrigine, another anticonvulsant.12 The basis of these

Cutaneous Reactions to Drugs

Fixed drug eruptions are usually solitary dusky macules that recur at the same site.

In the evaluation of a patient with a history of a suspected ADR, it is important to obtain a detailed medication history, including use of over-the-counter preparations and herbal and naturopathic remedies. New drugs started within the preceding 3 months, especially those within 6 weeks, are potential causative agents for most cutaneous eruptions (exceptions include drug-induced lupus, drug-induced pemphigus, and drug-induced cutaneous pseudolymphoma), as are drugs that have been used intermittently.

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These reactions may mimic other cutaneous diseases such as acne, porphyria, lichen planus, and lupus.

ETIOLOGY

Chapter 41

The spectrum of clinical manifestations includes exanthematous, urticarial, pustular, and bullous eruptions.

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interactions and reactions is unknown, but they may represent a combination of factors, including alterations in drug metabolism, drug detoxification, antioxidant defenses, and immune reactivity. The course and outcome of drug-induced disease are also influenced by host factors. Older age may delay the onset of drug eruptions and has been associated with a higher mortality rate in some severe reactions. A higher mortality rate is also observed in patients with severe reactions who have underlying malignancy.13 The pathogenesis of most drug eruptions is not understood, although the clinical features of most drug reactions are consistent with immune-mediated disease. The immune system may target the native drug, its metabolic products, altered self, or a combination of these factors.14

MORPHOLOGIC APPROACH TO DRUG ERUPTIONS Although there are many presentations of cutaneous drug eruptions, the morphology of many cutaneous eruptions may be exanthematous, urticarial, blistering, or pustular. The extent of the reaction is variable. For example, once the morphology of the reaction has been documented, a specific diagnosis [e.g., fixed drug eruption (FDE) or acute generalized exanthematous pustulosis (AGEP)] can be made. The reaction may also present as a systemic syndrome [e.g., serum sickness-like reaction or hypersensitivity syndrome reaction (HSR)]. Fever is generally associated with such systemic cutaneous ADRs.

EXANTHEMATOUS ERUPTIONS Exanthematous eruptions, sometimes referred to as morbilliform or maculopapular, are the most common form of drug eruptions, accounting for approximately 95% of skin reactions2 (Fig. 41-1). Simple exanthems are erythematous changes in the skin without evidence of blistering or pustulation. The eruption typically starts on the trunk and spreads peripherally in a symmetric fashion. Pruritus is almost always present. These eruptions usually occur within 1 week of initiation of therapy and may appear 1 or 2 days after drug therapy has been discontinued.15 Resolution, usually with 7–14 days, occurs with a change in color from bright red to a brownish red, which may be followed by desquamation. The differential diagnosis in these patients includes an infectious exanthem (e.g., viral, bacterial, or rickettsial), collagen vascular disease, and infections. Exanthematous eruptions can be caused by many drugs, including β-lactams (“the penicillins”), sulfonamide antimicrobials, nonnucleoside reverse transcriptase inhibitors (e.g., nevirapine), and antiepileptic medications. Studies have shown that drug-specific T cells play a major role in exanthematous, bullous, and pustular drug reactions.16 In patients who have concomitant infectious mononucleosis, the risk of devel-

Figure 41-1  Exanthematous drug eruption: ampicillin. Symmetrically arranged, brightly erythematous macules and papules, which are discrete in some areas and confluent in others on the trunk and discrete on the extremities.

oping an exanthematous eruption while being treated with an aminopenicillin (e.g., ampicillin) increases from 3%–7% to 60%-100%.17 A similar drug–viral interaction has been observed in 50% of patients infected with human immunodeficiency virus (HIV) who are exposed to sulfonamide antibiotics.14 An exanthematous eruption in conjunction with fever and internal organ inflammation (e.g., liver, kidney, central nervous system) signifies a more serious reaction, known as the hypersensitivity syndrome reaction, drug-induced hypersensitivity reaction (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS) (Table 41-1). It occurs in approximately 1 in 3,000 exposures to agents such as aromatic anticonvulsants, lamotrigine, sulfonamide antimicrobials, dapsone, nitrofurantoin, nevirapine, minocycline, metronidazole, and allopurinol (Fig. 41-2). HSR occurs most frequently on first exposure to the drug, with initial symptoms starting 1–6 weeks after exposure. Fever and malaise are often the presenting symptoms. Atypical lymphocytosis with subsequent eosinophilia may occur during the initial phases of the reaction in some patients. Although most patients have an exanthematous eruption, more serious cutaneous manifestations may be evident (Fig. 41-3). Internal organ involvement can be asymptomatic.11 Some patients may become hypothyroid due to an autoimmune thyroiditis approximately 2 months after the first symptoms appear.18 The formation of toxic metabolites of the aromatic anticonvulsants may play a pivotal role in the development of HSR.9 In most individuals, the chemically reactive metabolites that are produced are detoxified by epoxide hydroxylases. However, if detoxification is defective, one of the metabolites may act as a ­hapten and initiate an immune response, stimulate apoptosis,

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TABLE 41-1

Clinical Features of Selected Cutaneous Reactions to Drugs

Present

Present

Absent

Present

Aromatic anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine), sulfonamide antibiotics, dapsone, minocycline, allopurinol, lamotrigine

Serum sicknesslike reaction

Urticaria, exanthem

Present

Absent

Present

Present

Cefaclor, cefprozil, bupropion, minocycline, infliximab, rituximab

Drug-induced lupus

Usually absent

Present/ absent

Present/absent

Present

Absent

Procainamide, hydralazine, isoniazid, minocycline, acebutolol

Drug-induced subacute cutaneous lupus erythematosus

Papulosquamous or annular cutaneous lesion (often photosensitive)

Absent

Absent

Absent

Absent

Thiazide diuretics, calcium channel blockers, ACE inhibitors

Acute generalized exanthematous pustulosis

Nonfollicular pustules on an edematous erythematous base

Present

Absent

Absent

Absent

β Blockers, macrolide antibiotics, calcium channel blockers

ACE = angiotensin-converting enzyme; SJS = Stevens–Johnson syndrome; TEN = toxic epidermal necrolysis.

or cause cell necrosis directly. Approximately 70%– 75% of patients who develop anticonvulsant HSR in response to one aromatic anticonvulsant show crossreactivity to the other aromatic anticonvulsants. In addition, in vitro testing shows that there is a pattern of inheritance of HSR induced by anticonvulsants. Thus, counseling of family members and disclosure of risk are essential.

Sulfonamide antimicrobials are both sulfonamides (contain SO2-NH2) and aromatic amines (contain a benzene ring-NH2). Aromatic amines can be metabolized to toxic metabolites, namely, hydroxylamines and nitroso compounds.19 In most people, the metabolite is detoxified. However, HSRs may occur in patients who either form excess oxidative metabolites or are unable to detoxify such metabolite. Because siblings and other

Figure 41-2  Drug hypersensitivity syndrome: phenytoin. Symmetric, bright red, exanthematous eruption, confluent in some sites; the patient had associated lymphadenopathy.

Figure 41-3  Hypersensitivity syndrome reaction, characterized by fever, a pustular eruption, and hepatitis, in a 23-year-old man after 18 days of treatment with minocycline.

Cutaneous Reactions to Drugs

Exanthem, exfoliative dermatitis, pustular eruptions, SJS/ TEN

Hypersensitivity syndrome reaction

::

Lymphadenopathy Implicated Drugs

Drug Eruption

Chapter 41

Fever

Internal Organ Involvement Arthralgia

Clinical Presentation

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Section 6 :: Inflammatory Diseases Based on Abnormal Humoral Reactivity

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first-degree relatives may be at an increased risk (perhaps as high as 1 in 4) of developing a similar adverse reaction, counseling of family members is essential. Other aromatic amine-containing drugs, such as procainamide, dapsone, and acebutolol, may also be metabolized to chemically reactive compounds. It is recommended that patients who develop symptoms compatible with a sulfonamide-induced HSR avoid these aromatic amines, because the potential exists for crossreactivity. However, cross-reactivity is much less likely to occur between sulfonamides antimicrobials and drugs that are not aromatic amines (e.g., sulfonylureas, thiazide diuretics, furosemide, celecoxib, and acetazolamide).20 Allopurinol is associated with the development of serious drug reactions, including HSR. Active infection or reactivation of HHV-6 has been observed in patients who develop allopurinol HSR.21 Allopurinol-induced severe adverse reactions, specifically HSR and SJS/ TEN spectrum, have been strongly associated with a genetic predisposition in Han Chinese and Thai populations; presence of the HLA-B*5801 allele was found to be an important genetic risk factor.6,22

URTICARIAL ERUPTIONS Urticaria is characterized by pruritic red wheals of various sizes. Individual lesions generally last for less than 24 hours, although new lesions can commonly develop. When deep dermal and subcutaneous tissues are also swollen, the reaction is known as angioedema. Angioedema is frequently unilateral and nonpruritic and lasts for 1–2 hours, although it may persist for 2–5 days.21 Urticaria and angioedema, when associated with drug use, are usually indicative of an immunoglobulin (Ig) E-mediated immediate hypersensitivity reaction. This mechanism is typified by immediate reactions to penicillin and other antibiotics (see Chapter 38). Signs and symptoms of IgE-mediated allergic reactions typically include pruritus, urticaria, cutaneous flushing, angioedema, nausea, vomiting, diarrhea, abdominal pain, nasal congestion, rhinorrhea, laryngeal edema, and bronchospasm or hypotension. Urticaria and angioedema can also be caused by non-IgE-mediated reactions that result in direct and nonspecific liberation of histamine or other mediators of inflammation.15 Drug-induced non-IgE-mediated urticaria and angioedema are usually related to nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin converting enzyme (ACE)-inhibitors and opioids. Serum sickness-like reactions (see Table 41-1) are defined by the presence of fever, rash (usually urticarial), and arthralgias 1–3 weeks after initiation of drug therapy. Lymphadenopathy and eosinophilia may also be present; however, in contrast to true serum sickness, immune complexes, hypocomplementemia, vasculitis, and renal lesions are absent. Cefaclor is associated with an increased relative risk of serum sickness-like reactions. The overall incidence of cefaclor-induced serum sickness-like reactions has been estimated to be 0.024%–0.2% per course of cefaclor prescribed. In genetically susceptible hosts, a reactive metabolite is generated during the metabolism of

cefaclor that may bind with tissue proteins and elicit an inflammatory response manifesting as a serum sickness-like reaction.23 Other drugs that have been implicated in serum sickness-like reactions are cefprozil, bupropion, minocycline, and rituximab24 as well as infliximab.25 The incidence of serum sickness-like reactions caused by these drugs is unknown.

PUSTULAR ERUPTIONS Acneiform eruptions are associated with the use of iodides, bromides, adrenocorticotropic hormone, glucocorticoids, isoniazid, androgens, lithium, actinomycin D, and phenytoin. Drug-induced acne may appear in atypical areas, such as on the arms and legs, and is most often monomorphous. Comedones are usually absent. The fact that acneiform eruptions do not affect prepubertal children indicates that previous hormonal priming is a necessary prerequisite. In cases in which the offending agent cannot be discontinued, topical tretinoin may be useful.26 An acneiform eruption often occurs during treatment with epidermal growth factor receptor inhibitors (e.g., gefitinib, erlotinib, cetuximab). The acneiform rash is often accompanied by paronychia, dry skin, and skin fissures. The eruption is dose dependent, with respect to both incidence and severity.27 In a systemic review and meta-analysis encompassing over 1,000 patients receiving cetuximab as a single-agent, the incidence of an acneiform eruption was 81.6%.28 AGEP is an acute febrile eruption that is often associated with leukocytosis (Fig. 41-4 and Table 41-1). After initiation of the implicated drug, 1–3 weeks

Figure 41-4  Acute generalized exanthematous pustulosis in a 48-year-old man who developed nonfollicular ­pustules and fever after 7 days of treatment with diltiazem.

PSEUDOPORPHYRIA. Pseudoporphyria is a cutaneous phototoxic disorder that can resemble either porphyria cutanea tarda in adults or erythropoietic protoporphyria in children (see Chapter 132). Pseudoporphyria of the porphyria cutanea tarda variety is characterized by skin fragility, blister formation, and scarring in photodistribution; it occurs in the presence of normal porphyrin levels. The other clinical pattern mimics erythropoietic protoporphyria and manifests

Cutaneous Reactions to Drugs

(Table 41-2)

DRUG-INDUCED LINEAR IgA DISEASE. Both idiopathic and drug-induced linear IgA diseases (see Chapter 58) are heterogeneous in clinical presentation. Cases of the drug-induced type have morphologies resembling erythema multiforme, bullous pemphigoid, and dermatitis herpetiformis. The drug-induced disease may differ from the idiopathic entity in that mucosal or conjunctival lesions are less common, spontaneous remission occurs once the offending agent is withdrawn, and immune deposits disappear from the skin once the lesions resolve. Biopsy specimens are necessary for diagnosis. Histologically, the two entities are similar. A study suggests that, as in the idiopathic variety, the target antigen is not unique in the drug-induced disease. Although 13%–30% of patients with sporadic linear IgA have circulating basement membrane zone antibodies, these antibodies have not been reported in drug-induced cases.34 In patients with linear IgA bullous disease

6

::

BULLOUS ERUPTIONS

as cutaneous burning, erythema, vesiculation, angular chicken pox-like scars, and waxy thickening of the skin. The eruption may begin within 1 day of initiation of therapy or may be delayed in onset for as long as 1 year. The course is prolonged in some patients, but most reports describe symptoms that disappear several weeks to several months after the offending agent is withdrawn. Because of the risk of permanent facial scarring, the implicated drug should be discontinued if skin fragility, blistering, or scarring occurs.31 In addition, the use of broad-spectrum sunscreen and protective clothing should be recommended. Drugs that have been associated with pseudoporphyria include naproxen and other NSAIDs, and voriconazole.32,33

Chapter 41

may elapse before skin lesions appear. The lesions often start on the face or major skin creases. Generalized desquamation occurs approximately 2 weeks later. The estimated incidence of AGEP is approximately 1–5 cases per million per year. AGEP is most commonly associated with β-lactam and macrolide antibiotics, anticonvulsants, and calcium channel blockers.29 Differential diagnosis includes pustular psoriasis, HSR with pustulation, subcorneal pustular dermatosis (Sneddon–Wilkinson disease), pustular vasculitis, or in severe cases of AGEP, TEN. The typical histopathologic analysis of AGEP lesions shows spongiform subcorneal and/or intraepidermal pustules, an often marked edema of the papillary dermis, and perivascular infiltrates with neutrophils and exocytosis of some eosinophils. Discontinuance of therapy is usually the extent of treatment necessary in most patients, although some patients may require the use of corticosteroids. Patch tests have been used in the diagnosis of AGEP.30

TABLE 41-2

Drug Eruptions Mimicry Clinical Presentation

Pattern and Distribution of Skin Lesions

Mucous Membrane Involvement

Stevens–Johnson syndrome

Atypical targets, widespread

Toxic epidermal necrolysis

Implicated Drugs

Treatment

Present

Aromatic anticonvulsants,a lamotrigine, sulfonamide antibiotics, allopurinol, piroxicam, dapsone

IVIg, cyclosporine, supportive care

Epidermal necrosis with skin detachment

Present

As above

IVIg, cyclosporine, supportive care

Pseudoporphyria

Skin fragility, blister formation in photodistribution

Absent

Tetracycline, furosemide, naproxen

Supportive care

Linear IgA disease

Bullous dermatosis

Present/absent

Vancomycin, lithium, diclofenac, piroxicam, amiodarone

Supportive care

Pemphigus

Flaccid bullae, chest

Present/absent

Penicillamine, captopril, piroxicam, penicillin, rifampin, propranolol

Supportive care

Bullous pemphigoid

Tense bullae, widespread

Present/absent

Furosemide, penicillamine, penicillins, sulfasalazine, captopril

Supportive care

IVIg = intravenous immunoglobulin. a Aromatic anticonvulsants = phenytoin, carbamazepine, phenobarbital, oxcarbazepine, primidone.

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6

proven by direct immunofluorescence, the index of suspicion of drug induction should be higher in cases with only IgA and no IgG in the basement membrane zone. Several drugs can induce linear IgA bullous dermatosis, the most frequently reported being vancomycin.35

Section 6 :: Inflammatory Diseases Based on Abnormal Humoral Reactivity

DRUG-INDUCED PEMPHIGUS. Pemphigus may be considered as drug-induced or drug-triggered (i.e., a latent disease that is unmasked by the drug exposure; see Chapter 54). Drug-induced pemphigus caused by penicillamine and other thiol-containing drugs (e.g., piroxicam, captopril) tends to remit spontaneously in 35%–50% of cases, presents as pemphigus foliaceus, has an average interval to onset of 1 year, and is associated with the presence of antinuclear antibodies in 25% of patients. Most patients with nonthiol drug-induced pemphigus manifest clinical, histologic, immunologic, and evolutionary aspects similar to those of idiopathic pemphigus vulgaris with mucosal involvement and show a 15% rate of spontaneous recovery after drug withdrawal. Treatment of drug-induced pemphigus begins with drug cessation. Systemic glucocorticoids and other immunosuppressive drugs are often required until all symptoms of active disease disappear. Vigilant follow-up is required after remission to monitor the patient and the serum for autoantibodies to detect an early relapse.36 DRUG-INDUCED BULLOUS PEMPHIGOID.

Drug-induced bullous pemphigoid (see Chapter 56) can encompass a wide variety of presentations, ranging from the classic features of large, tense bullae arising from an erythematous, urticarial base with moderate involvement of the oral cavity, through mild forms with few bullous lesions, to scarring plaques and nodules with bullae. Medications that have been reported to cause bullous pemphigoid include furosemide, amoxicillin, and spironolactone. In contrast to patients with the idiopathic form, patients with druginduced bullous pemphigoid are generally younger. In addition, the histopathologic findings are of a perivascular infiltration of lymphocytes with few eosinophils and neutrophils, intraepidermal vesicles with foci of necrotic keratinocytes, thrombi in dermal vessels, and a possible lack of tissue-bound and circulating antibasal membrane zone IgG.37 In the acute, self-limited condition, resolution occurs after the withdrawal of the culprit agent, with or without glucocorticoid therapy. However, in some patients the drug may actually trigger the idiopathic form of the disease.

determinants may influence the likelihood of a reaction and variability in innate and adaptive immunity may influence the clinical presentation.38 In addition, the detection of drug-specific T-cell proliferation provides evidence that T cells are involved in severe skin rashes.39 Treatment of SJS/TEN includes discontinuance of the suspected drug(s) and supportive measures such as careful wound care, hydration, and nutritional support. The use of corticosteroids in the treatment of SJS and TEN is controversial.40,41 Intravenous Ig (IVIg, up to 3–4 g over 3 days) has been shown in some reports to halt progression of TEN, especially when IVIg is started early. However, some studies have not found an improved outcome in patients with TEN who are treated with IVIg.38 A recent study concluded that neither corticosteroids nor intravenous Ig had any significant effect on mortality in comparison to supportive care only.42 Other treatment modalities include cyclosporine,43 cyclophosphamide, and plasmapharesis. Patients who have developed a severe cutaneous ADR should not be rechallenged with the drug. Desensitization therapy with the medication may also be a risk.

FIXED DRUG ERUPTIONS FDEs usually appear as solitary, erythematous, bright red or dusky red macules that may evolve into an edematous plaque; bullous-type lesions may be present, widespread lesions may be difficult to differentiate from TEN. FDEs are commonly found on the genitalia and in the perianal area, although they can occur anywhere on the skin surface (Fig. 41-5). Some

STEVENS–JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS. SJS and TEN

454

or the SJS/TEN spectra represent variants of the same disease process. Differentiation between the two patterns depends on the nature of the skin lesions and the extent of body surface area involvement (see Chapters 39 and 40). Recently, the understanding of the pathogenesis of severe cutaneous ADRs has expanded greatly. Various factors including pharmacogenetic and immunogentic

Figure 41-5  Fixed drug eruption: tetracycline. A welldefined plaque on the knee, merging with three satellite lesions. The large plaque exhibits epidermal wrinkling, a sign of incipient blister formation. This was the second such episode after ingestion of a tetracycline. No other lesions were present.

DRUG-INDUCED LICHENOID ERUPTIONS Drug-induced lichen planus produces lesions that are clinically and histologically indistinguishable from those of idiopathic lichen planus (see Chapter 26); however, lichenoid drug eruptions often appear initially as eczematous with a purple hue and involve large areas of the trunk. Usually, the mucous membranes and nails are not involved. Histologically, focal parakeratosis, cytoid bodies in the cornified and granular layers, the presence of eosinophils and plasma cells in the inflammatory infiltrate, and an infiltrate around the deep vessels favor a diagnosis of lichenoid drug eruption. Many drugs, including β-blockers, penicillamine, and ACE-inhibitors, especially captopril, reportedly produce this reaction. Lichen planus-like eruptions have also been reported with tumor necrosis factor-α (TNF) antagonists, such as infliximab, etanercept, and adalimumab.48,49 The mean latent period is between 2 months and 3 years for penicillamine, approximately 1 year for β-adrenergic blocking agents, and 3–6 months for ACE-inhibitors. For anti-TNF treatments, the time to reaction is similar with onset occurring between 3 weeks and 62 weeks. The latent period may be shortened if the patient has been previously exposed to the drug. Resolution usually occurs with 2–4 months. Rechallenge with the culprit drug has been attempted in a few patients, with reactivation of symptoms within 4–15 days.50

Cutaneous Reactions to Drugs

Anticoagulant-induced skin necrosis begins 3–5 days after initiation of treatment. The majority of cases of anticoagulant-induced skin necrosis have been attributed to coumarin congeners (bishydroxycoumarin, phenprocoumon, acenocoumarol, and warfarin) (Fig. 41-6). Early red, painful plaques develop in adiposerich sites such as breasts, buttocks, and hips. These plaques may blister, ulcerate, or develop into necrotic areas. It is estimated that 1 in 10,000 persons who receive the drug is at risk of this adverse event. The incidence is four times higher in women, especially in obese women, with a peak incidence in the sixth and seventh decades of life. Affected patients often have been given a large initial loading dose of war-

6

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ANTICOAGULANT-INDUCED SKIN NECROSIS

farin in the absence of concomitant heparin therapy. An accompanying infection such as pneumonia, viral infection, or erysipelas may be seen in up to 25% of patients. An association with protein C and protein S deficiencies exists, but pretreatment screening is not warranted. An association with heterozygosity for factor V Leiden mutation has been reported. The pathogenesis of this adverse event is the paradoxical development of occlusive thrombi in cutaneous and subcutaneous venules due to a transient hypercoagulable state. This results from the suppression of the natural anticoagulant protein C at a greater rate than the suppression of natural procoagulant factors. Treatment involves the discontinuation of warfarin, administration of vitamin K, and infusion of heparin at therapeutic dosages. Fresh frozen plasma and purified protein C concentrates have been used. Supportive measures for the skin are a mainstay of therapy. The morbidity rate is high; 60% of affected individuals require plastic surgery for remediation of fullthickness skin necrosis by skin grafting. These patients may be treated with warfarin in the future, but small dosages (2–5 mg daily) are recommended, with initial treatment under heparin coverage.46,47

Chapter 41

patients may complain of burning or stinging, and others may have fever, malaise, and abdominal symptoms. FDE can develop from 30 minutes to 8–16 hours after ingestion of the medication. After the initial acute phase lasting days to weeks, residual grayish or slatecolored hyperpigmentation develops. On rechallenge, not only do the lesions recur in the same location, but also new lesions often appear. More than 100 drugs have been implicated in causing FDEs, including ibuprofen, sulfonamides, naproxen, and tetracyclines. A haplotype linkage in trimethoprim–sulfamethoxazole-induced FDE has been documented. A challenge or provocation test with the suspected drug may be useful in establishing the diagnosis. Patch testing at the site of a previous lesion yields a positive response in up to 43% of patients. Results of prick and intradermal skin tests may be positive in 24% and 67% of patients, respectively.44,45 Food-initiated fixed eruptions also exist and are important to consider when assessing causation.

DRUG-INDUCED CUTANEOUS PSEUDOLYMPHOMA Figure 41-6  Skin necrosis in a patient after 4 days of warfarin therapy.

Pseudolymphoma is a process that simulates lymphoma but has a benign behavior and does not meet

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6

the criteria for malignant lymphoma. Drugs are a wellknown cause of cutaneous pseudolymphomas (see Chapter 146), but the condition may also be induced by foreign agents such as insect bites, infections (e.g., HIV), and idiopathic causes.51 Anticonvulsant-induced pseudolymphoma generally occurs after 1 week to 2 years of exposure to the drug. Within 7–14 days of drug discontinuation, the symptoms usually resolve. The eruption often manifests as single lesions but can also be widespread erythematous papules, plaques, or nodules. Most patients also have fever, marked lymphadenopathy and hepatosplenomegaly, and eosinophilia. Mycosis fungoideslike lesions are also associated with these drugs.52

Section 6

DRUG-INDUCED VASCULITIS

:: Inflammatory Diseases Based on Abnormal Humoral Reactivity

Drug-induced vasculitis represents approximately 10% of the acute cutaneous vasculitides and usually involves small vessels (see Chapter 163). Drugs that are associated with vasculitis include propylthiouracil, hydralazine, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, allopurinol, cefaclor, minocycline, penicillamine, phenytoin, isotretinoin, and anti-TNF agents, including etanercept, infliximab, and adalimumab.49 The average interval from initiation of drug therapy to onset of drug-induced vasculitis is 7–21 days; in the case of rechallenge, lesions can occur in less than 3 days.15 The clinical hallmark of cutaneous vasculitis is palpable purpura, classically found on the lower extremities. Urticaria can be a manifestation of small vessel vasculitis, with individual lesions remaining fixed in the same location for more than 1 day. Other features include hemorrhagic bullae, ulcers, nodules, Raynaud disease, and digital necrosis. The same vasculitic process may also affect internal organs such as the liver, kidney, gut, and central nervous system and can be potentially life threatening.53 Drug-induced vasculitis can be difficult to diagnose and is often a diagnosis of exclusion. In some cases, serologic testing has revealed the presence of perinuclear-staining antineutrophil cytoplasmic autoantibodies against myeloperoxidase. Alternative causes for cutaneous vasculitis such as infection or autoimmune disease must be eliminated. Tissue eosinophilia may be an indicator of drug induction in cutaneous small vessel vasculitis. Treatment consists of drug withdrawal. Systemic glucocorticoids may be of benefit.

DRUG-INDUCED LUPUS

456

(See Chapter 155) Drug-induced lupus is characterized by frequent musculoskeletal complaints, fever, weight loss, pleuropulmonary involvement in more than half of patients, and in rare cases renal, neurologic, or vasculitic involvement (see Table 41-1). Many patients have no cutaneous findings of lupus erythematosus. The most common serologic abnormality is positivity for antinuclear antibodies with a homogenous pattern. Although

antihistone antibodies are seen in up to 95% of druginduced lupus, they are not specific for the syndrome and are found in 50%–80% of patients with idiopathic lupus erythematosus. Unlike in idiopathic lupus erythematosus, antibodies against double-stranded DNA are typically absent, whereas antisingle-stranded DNA antibodies are often present.54 Genetic factors may also play a role in the development of drug-induced lupus. HLA-DR4 is present in 73% of the patients with hydralazine-induced lupus and in 70% of patients with minocycline-induced lupus.55 Evidence now suggests that abnormalities during T-cell selection in the thymus initiate lupus-like autoantibody induction.56 In contrast, drug-induced subacute cutaneous lupus erythematosus is characterized by a papulosquamous or annular cutaneous lesion, which is often photosensitive, and absent or mild systemic involvement. Circulating anti-Ro (Sjögren syndrome A) antibodies have also been identified in many patients. Many drugs have been implicated in causing druginduced lupus syndromes, especially hydralazine, procainamide, isoniazid, methyldopa, and minocycline.57 Drugs that have been associated with subacute cutaneous lupus erythematosus include thiazide diuretics, calcium channel blockers, and ACE inhibitors. The number of patients who develop subacute cutaneous lupus erythematosus during treatment with these medications is very low, and these drugs are thought to have a low risk for causing or exacerbating cutaneous lupus.58 Other drugs that have been associated with drug-induced lupus include terbinafine, proton pump inhibitors, and anti-TNF treatments.58 The identification of minocycline as a cause of druginduced lupus makes it important for dermatologists to recognize this syndrome. Minocycline-induced lupus typically occurs after 2 years of therapy. The patient presents with a symmetric polyarthritis. Hepatitis is often detected on laboratory evaluation. Cutaneous findings include livedo reticularis, painful nodules on the legs, and nondescript eruptions. Antihistone antibodies are seldom present. A study of HLA class II alleles revealed the presence of HLA-DR4 or HLA-DR2 in many of the patients.55

DIAGNOSIS AND MANAGEMENT The iatrogenic disorders described here are distinct disease entities, although they may closely mimic many infective or idiopathic diseases. A drug cause should be considered in the differential diagnosis of a wide spectrum of dermatologic diseases, particularly when the presentation or course is atypical. The diagnosis of a cutaneous drug eruption involves the precise characterization of reaction type. A wide variety of cutaneous drug-associated eruptions may also warn of associated internal toxicity (Table 41-3). Even the most minor cutaneous eruption should trigger a clinical review of systems, because the severity of systemic involvement does not necessarily mirror that of the skin manifestations. Hepatic, renal, joint, respiratory, hematologic, and neurologic changes should be sought, and any systemic symptoms or signs investi-

TABLE 41-3

Clinical Features That Warn of a Potentially Severe Drug Reaction Systemic Fever and/or other symptoms of internal organ involvement such as pharyngitis, malaise, arthralgia, cough, and meningismus Lymphadenopathy

Cutaneous reactions to drugs are largely idiosyncratic and unexpected; serious reactions are rare. However, once a reaction has occurred, it is important to prevent future similar reactions in the patient with the same drug or a cross-reacting medication. For patients with severe reactions, wearing a bracelet (e.g., MedicAlert) detailing the nature of the reaction is advisable, and patient records should be appropriately labeled. Host factors appear important in many reactions. Some of these can be inherited, which places firstdegree relatives at a greater risk than the general population for a similar reaction to the same or a metabolically cross-reacting drug. This finding appears to be important in SJS, TEN, and drug hypersensitivity syndrome. Reporting reactions to the manufacturer or regulatory authorities is important. Postmarketing voluntary reporting of rare, severe, or unusual reactions remains crucial to enhance the safe use of pharmaceutical agents.

Cutaneous Reactions to Drugs

PREVENTION

::

gated. Fever, malaise, pharyngitis, and other systemic symptoms or signs should be investigated. A usual screen would include a full blood count, liver and renal function tests, and a urine analysis. Skin biopsy should be considered for all patients with potentially severe reactions, such as those with systemic symptoms, erythroderma, blistering, skin tenderness, purpura, or pustulation, as well as in cases in which the diagnosis is uncertain. Some cutaneous reactions, such as FDE, are almost always due to drug therapy, and approximately 40%–50% of SJS/ TEN cases are also drug related.59 Other more common eruptions, including exanthematous or urticarial eruptions, have many nondrug causes. There is no gold standard investigation for confirmation of a drug cause. Instead, diagnosis and assessment of cause involve analysis of a constellation of features such as timing of drug exposure and reaction onset, course of reaction with drug withdrawal or continuation, timing, and nature of a recurrent eruption on rechallenge, a history of a similar response to a crossreacting medication, and previous reports of similar reactions to the same medication. Investigations to exclude nondrug causes are similarly helpful. Several in vitro investigations can help to confirm causation in individual cases, but their exact sensitivity and specificity remain unclear. Investigations include the lymphocyte toxicity and lymphocyte transformation assays.60 The basophil activation test has been reported to be useful to evaluate patients with possible drug allergies to β-lactam antibiotics, NSAIDs, and muscle relaxants.14 Penicillin skin testing with major and minor determinants is useful for confirmation of an IgE-mediated immediate hypersensitivity reaction to penicillin.14 Patch testing has been used in patients with ampicillin-induced exanthematous eruptions, AGEP reactions,61 abacavir-induced hypersensitivity,62 and in the ancillary diagnosis of FDEs. Patch testing has greater sensitivity if performed over a previously involved area of skin. Cutaneous drug eruptions do not usually vary in severity with dose. Less severe reactions may abate with continued drug therapy (e.g., transient exan-

6

Chapter 41

Cutaneous Evolution to erythroderma Prominent facial involvement ± edema or swelling Mucous membrane involvement (particularly if erosive or involving conjunctiva) Skin tenderness, blistering, or shedding Purpura

thematous eruptions associated with commencement of a new HIV antiretroviral regimen). However, a reaction suggestive of a potentially life-threatening situation should prompt immediate discontinuation of the drug, along with discontinuation of any interacting drugs that may slow the elimination of the suspected causative agent. Although the role of corticosteroids in the treatment of serious cutaneous reactions is controversial, most clinicians choose to start prednisone at a dosage of 1–2 mg/kg/day when symptoms are severe. Antihistamines, topical corticosteroids, or both can be used to alleviate symptoms.63 Resolution of the reaction over a reasonable time frame after the drug is discontinued is consistent with a drug cause but also occurs for many infective and other causes of transient cutaneous eruptions. Drug desensitization, also known as induction of drug tolerance, has been used primarily for IgE-mediated reactions caused by drugs such as penicillin or more recently, monoclonal antibodies such as rituximab and infliximab.14,64 Patients should not be rechallenged or desensitized if they have suffered a potentially serious reaction.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 11. Eshki M et al: Twelve-year analysis of severe cases of drug reaction with eosinophilia and systemic symptoms. Arch Dermatol 145:67-72, 2009 14. Khan D, Solensky R: Drug allergy. J Allergy Clin Immunol 125:S126-S137, 2010 39. Mockenhaupt M: Severe drug-induced skin reactions: Clinical pattern, diagnostics and therapy. J Dtsch Dermatol Ges 7:142-160, 2009 53. Justiniano H, Berlingeri-Ramos A, Sanchez J: Pattery analysis of drug-induced skin diseases. Am J Dermatopathol 30:352-369, 2008

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Chapter 42 :: Pityriasis Rosea :: Andrew Blauvelt PITYRIASIS ROSEA AT A GLANCE Common acute papulosquamous eruption normally lasting 4–10 weeks.

Section 6

Most often begins as a single 2- to 4-cm thin oval plaque with a fine collarette of scale located inside the periphery of the plaque (“herald patch”).

:: Inflammatory Diseases Based on Abnormal Humoral Reactivity

Similar-appearing, but smaller, lesions appear several days to weeks later, typically distributed along the lines of cleavage on the trunk (“Christmas tree” pattern). Usually asymptomatic, sometimes pruritic with mild flu-like symptoms. Occurs most commonly in teenagers and young adults. Probably a viral exanthem associated with reactivation of human herpes virus (HHV)-7 and sometimes HHV-6. Treatment is usually supportive, although midpotency topical corticosteroids can reduce pruritus; high-dose acyclovir for 1 week may hasten recovery.

The term pityriasis rosea (PR) was first used by Gibert in 1860 and means pink (rosea) scales (pityriasis).1 PR is a common acute, self-limited skin eruption that typically begins as a single thin oval scaly plaque on the trunk (“herald patch”) and is typically asymptomatic. The initial lesion is followed several days to weeks later by the appearance of numerous similar-appearing smaller lesions located along the lines of cleavage of the trunk (a so-called Christmas tree pattern). PR most commonly occurs in teenagers and young adults, and is most likely a viral exanthem associated with reactivation of human herpes virus 7 (HHV-7) and sometimes HHV-6,2–5 the viruses responsible for rubeola (see Chapter 192). Possible treatment may focus on associated pruritus. One study suggests that administration of high-dose acyclovir for 1 week, if initiated early in the disease course, hastens recovery from PR.6

EPIDEMIOLOGY

458

PR is reported in all races throughout the world, irrespective of climate.7–9 The average annual incidence at one center was reported to be 0.16% (158.9 cases per 100,000 person-years).9 Although PR is usually

considered to be more common in the spring and fall months in temperate zones, seasonal variation has not been borne out in studies performed in other parts of the world. Clustering of cases can occur and has been used to support an infectious etiology for PR, although this is not a consistent feature observed in all communities.8 Most studies have shown a slight female preponderance of approximately 1.5:1.7,9 PR most commonly occurs between the ages of 10 and 35 years.9 It is rare before age 2 years and after age 65 years. Recurrences of PR are rare, which suggests lasting immunity after an initial episode of PR.

ETIOLOGY AND PATHOGENESIS Historically, PR has been considered to be caused by an infectious agent, given (1) the resemblance of the rash to known viral exanthems; (2) rare recurrences of PR that suggest lifelong immunity after one episode; (3) occurrence of seasonal variation in some studies; (4) clustering in some communities; and (5) the appearance of flu-like symptoms in a subset of patients. Numerous studies over the past 50 years have explored various pathogens as possible causes of PR. These pathogens have included bacteria, fungi, and, most notably, viruses. Beginning with a study by Drago and colleagues in 1997,2 most recent PR etiologic and pathogenic studies have been focused on two ubiquitous viruses: (1) HHV-7 and (2) HHV-6. Critical evaluation of the medical and scientific literature on PR reveals neither credible nor reproducible evidence that PR is associated with any pathogen other than HHV-7 and HHV-6.10 Indeed, the best scientific evidence suggesting that PR is a viral exanthem associated with reactivation of either HHV-7 or HHV-6 (and sometimes with both viruses) is strong.2–5,11–13 The most definitive and compelling study on HHVs and PR was by Broccolo and colleagues in 2005.4 Using sensitive and quantitative techniques, investigators have collectively shown that (1) HHV-7 DNA, and less commonly HHV-6 DNA, can be readily detected in cell-free plasma or serum samples from many patients with PR, but not in serum or plasma from healthy individuals or patients with other inflammatory skin diseases; (2) HHV-7 messenger RNA and protein, and less commonly HHV-6 messenger RNA and protein, can be detected in scattered leukocytes found in perivascular and perifollicular regions within PR lesions, but not in normal skin or skin from patients with other inflammatory skin diseases; (3) HHV-7- and HHV-6-specific immunoglobulin (Ig) M antibody elevations in the absence of virus-specific IgG antibodies do not occur in PR patients, whereas in primary viral infections elevation of IgM antibodies alone is typical; and (4) HHV-7 and HHV-6 DNA are present in saliva of individuals with PR, which is not observed in those with a primary infection with these viruses. Taken together, these data strongly suggest that PR is

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Chapter 42 ::

Figure 42-1  A typical primary plaque (herald patch) of pityriasis rosea, demonstrating an oval shape and fine scale inside the periphery of the plaque. later by the onset of numerous smaller lesions on the trunk. Pruritus is severe in 25% of patients with uncomplicated PR, slight to moderate in 50%, and absent in 25%. In a minority of patients, flu-like symptoms have been reported, including general malaise, headache, nausea, loss of appetite, fever, and arthralgias.

Pityriasis Rosea

a viral exanthem associated with systemic reactivation of HHV-7 and, to a lesser extent, HHV-6. Patients are viremic, which may explain associated flu-like symptoms in some patients, and they generally do not have infected epithelial cells or large viral loads within skin lesions, which explains the difficulty in detecting these viruses by electron microscopy and by nonnested polymerase chain reaction testing. Despite these findings, there is still controversy over the role of HHV-7 and HHV-6 in the etiology of PR, because a number of studies with “negative” results have failed to support a causative role for HHV-7 and HHV-6 in this disease.14–16 Whereas the studies with positive results have used the most sensitive, specific, and calibrated techniques for virologic studies and reports have been published in high-quality journals, the studies with negative results either used laboratory methods that were not particularly sensitive, calibrated, or quantifiable, or focused on peripheral blood mononuclear cells rather than cell-free plasma or serum. Correct interpretation of the recent viral literature on PR also requires proper understanding of the biology of HHV-7 and HHV-6. HHV-7 and HHV-6 are closely related β-herpes viruses, and the clinical diseases and biology associated with this group of HHVs are not as well studied as those of the α-herpes viruses (herpes simplex virus 1 and 2, varicella-zoster virus) and the γ-herpes viruses (Epstein–Barr virus and Kaposi sarcoma-associated herpes virus). HHV-6 and HHV-7 are ubiquitous, with 90% of the US population infected with HHV-6 by the age of 3 years17 and 90% of the US population infected with HHV-7 by the age of 5 years.18 Unlike the α-herpes viruses, HHV-7 and HHV-6 do not infect keratinocytes, but instead infect CD4+ T cells within blood and are retained within these cells in a latent form in most individuals.10,17–19 These cells are the likely source of cell-free viral DNA found in plasma or serum samples of patients with PR. They are also the likely source of the scattered perivascular and perifollicular virus-positive cells observed within some lesions of PR.3,4 It is important to note that the concept that PR represents a reactive viral exanthem containing few infected cells within skin lesions and viral reactivation within circulating blood CD4+ T cells is perfectly analogous to that of the disease roseola, which is well accepted to be caused by primary infection with either HHV-6 or HHV-720,21 (see Chapter 192). Children with roseola are viremic and skin lesions generally do not contain infected cells.22 Complete understanding of the role of HHV-7 and HHV-6 in the pathogenesis of PR is lacking at this time. For example, the mechanisms by which HHV-7 and HHV-6 are reactivated are unknown. As well, the characteristic distribution of lesions and differences in lesional and nonlesional skin are unexplained.

CUTANEOUS LESIONS The primary plaque of PR, or herald patch (Figs. 42-1– 42-3 and see eFigs. 42-3.1 and 42-3.2 in online edition), is seen in 50%–90% of cases. It is normally well demarcated; 2–4 cm in diameter; oval or round; salmon

CLINICAL FINDINGS HISTORY In classic PR, patients usually describe the onset of a single truncal skin lesion followed several days to weeks

Figure 42-2  A nonscaly purpuric primary plaque (herald patch) of pityriasis rosea.

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Primary and secondary plaques

Herald patch

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Figure 42-4  Schematic diagram of the primary plaque (herald patch) and the typical distribution of secondary plaques along the lines of cleavage on the trunk in a Christmas tree pattern. Figure 42-3  A double herald patch of pityriasis rosea.

c­ olored, erythematous, or hyperpigmented (especially in individuals with darker skin); and demonstrates a fine collarette of scale just inside the periphery of the plaque. When the plaque is irritated, it may have an eczematous papulovesicular appearance (eFig. 42-3.3 in online edition). The primary plaque is usually located on the trunk in areas covered by clothes, but sometimes it is on the neck or proximal extremities. Localization on the face or penis is rare. The site of the primary lesion does not differ between males and females. The interval between the appearance of the primary plaque and the secondary eruption can range from 2 days to 2 months, but the secondary eruption typically occurs within 2 weeks of the appearance of the primary plaque. At times, the primary and secondary lesions may appear at the same time. The secondary eruption occurs in crops at intervals of a few days and reaches its maximum in approximately 10 days. Occasionally, new lesions continue to develop for several weeks. The symmetric eruption is localized mainly to the trunk and adjacent regions of the neck and proximal extremities (Fig. 42-4). The most pronounced lesions extend over the abdomen and anterior surface of the chest as well as over the back (Figs. 42-5–42-7 and eFigs. 42-7.1 and 42-7.2 in online edition). Lesions distal to the elbows and knees can occur. Two main types of secondary lesions occur: (1) small plaques resembling the primary plaque in miniature, aligned with their long axes along lines of cleavage and distributed in a Christmas tree pattern, and (2) small, red, usually nonscaly papules that gradually increase in number and spread peripherally. The two types of lesions may coexist.

In approximately 20% of patients, the clinical picture diverges from the classic one described above. The primary plaque may be missing or present as double or multiple lesions (Fig. 42-3 and see eFig. 42-3.1 in online edition), often close together. The primary plaque may be the sole manifestation of the disease or only one of the two lesions (eFig. 42-3.2 in online edition). The distribution of the secondary eruption may be exclusively peripheral. Facial and scalp involvement occurs more commonly in black children. Localized forms of disease may involve

Figure 42-5  Typical distribution of secondary plaques along the lines of cleavage on the back in a Christmas tree pattern.

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Chapter 42

Figure 42-8  Typical nonspecific histologic features of pityriasis rosea, including patchy parakeratosis, absence of a granular cell layer, slight acanthosis, spongiosis, and a lymphohistiocytic infiltrate in the superficial dermis.

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certain body regions such as the palms, soles, axillae, vulva, and groin (eFigs. 42-3.3 and 42-7.1 in online edition) and also may be localized to one side of the body. The morphology of the secondary lesions may also be atypical, and in these cases, the diagnosis of PR can be more challenging. Macules lacking scales may occur, papules may be follicular, and typical plaques may be absent or resemble psoriasis (eFig. 42-7.3 in online edition). The palms and soles are involved at times, and the clinical picture in these patients may simulate a widespread eczematous eruption. A vesicular type of

PR (eFig. 42-3.3 in online edition) uncommonly affects children and young adults. Urticarial, pustular, purpuric (Fig. 42-2 and eFig. 42-7.4 in online edition), and erythema multiforme-like variants of PR also exist. Many patients will have classic PR plaques admixed with the atypical vesicles, follicular papules, and purpura.

Pityriasis Rosea

Figure 42-6  Typical distribution of secondary plaques along the lines of cleavage on the chest of a black individual.

RELATED PHYSICAL FINDINGS In rare cases enanthema may occur with hemorrhagic macules and patches, bullae on the tongue and cheeks, or lesions that resemble aphthous ulcers. Nail dystrophy after PR has also been reported. Lymphadenopathy may occur in patients with PR, especially early in the course of the disease and in association with ­f­lu-like symptoms. In cases of classic PR, most patients do not require skin biopsies because the diagnosis is straightforward on clinical grounds and the histologic findings are nonspecific. Typical histopathologic features include focal parakeratosis, a reduced or absent granular cell layer, mild acanthosis, mild spongiosis, papillary dermal edema, a perivascular and superficial dermal interstitial infiltrate of lymphocytes and histiocytes, and focal extravasation of erythrocytes (Fig. 42-8).23,24 Similar histologic findings are observed in both primary and secondary plaques. The histologic picture is indistinguishable from that of superficial gyrate erythema. In older lesions, the perivascular infiltrate is often both superficial and deep, with less spongiosis and more pronounced acanthosis. These late lesions may be difficult to distinguish from psoriasis and lichen planus.

LABORATORY TESTS

Figure 42-7  Vesicular pityriasis rosea, showing typical primary plaque and secondary papulovesicles. Note Christmas tree distribution.

Routine blood studies usually give normal results and are not recommended. However, leukocytosis, neutrophilia, basophilia, lymphocytosis, and slight increases in erythrocyte sedimentation rate and levels of total protein, α1- and α2-globulins, and albumin have been reported.

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DIFFERENTIAL DIAGNOSIS (Box 42-1) Secondary syphilis may present with slightly scaly lesions and can mimic papular PR with no primary plaque. Mucosal lesions and lymphadenopathy may occur in both PR and syphilis, but as with involvement of the palms and soles, these findings are much more common in the latter. Serologic tests for syphilis will differentiate the two. Tinea corporis may resemble PR, especially when PR occurs as only a primary plaque or when it is localized to the groin area. Scaling will be at the periphery of the plaques in tinea corporis as opposed to inside the periphery of plaques in PR. Mycologic investigation is often necessary to rule out dermatophyte infection. The lesions of nummular dermatitis are usually round, not oval, and pinpoint papules and vesicles are more prominent than in PR. Guttate psoriasis may be difficult to distinguish from PR when only a few lesions are present, when lesions follow lines of cleavage, and when the disease course is chronic. Histologic examination may be useful in these cases. Pityriasis lichenoides chronica may present with a Christmas tree pattern on the trunk, but as a rule, typical lesions will be found on the extremities. Many drugs have been reported to cause PR-like rashes. Thus, it is always important to obtain a drug history to investigate this possibility. These include arsenic, barbiturates, bismuth, captopril, clonidine,

BOX 42-1  Differential Diagnosis of Pityriasis Rosea (PR) Secondary syphilis: history of primary chancre, no herald patch is present, lesions typically involve palms and soles, condyloma lata may be present, usually more systemic complaints and lymphadenopathy, presence of plasma cells on histology, positive serologic test for syphilis [e.g., a Venereal Disease Research Laboratory (VDRL) test]. Tinea corporis: scale is usually at periphery of plaques, plaques usually not oval and distributed along lines of cleavage, positive KOH examination. Nummular dermatitis: plaques usually circular and not oval, no collarettes of scale, tiny vesicles common. When in doubt, perform a biopsy. Guttate psoriasis: plaques usually smaller than PR plaques and do not follow lines of cleavage, scales are thick and not fine. When in doubt, perform a biopsy. Pityriasis lichenoides chronica: longer disease course, smaller lesions, thicker scale, no herald patch, more common on extremities. When in doubt, perform a biopsy. PR-like drug eruption: see text for extensive list. When in doubt, obtain a drug history.

gold, interferon-α, isotretinoin, ketotifen, labetalol, organic mercurials, methoxypromazine, metronidazole, omeprazole, d-penicillamine, salvarsan, sulfasalazine, terbinafine, lithium, and tripelene amine hydrochloride. Of note, more recent additions to this list include imatinib,25 a drug used in the treatment of chronic myeloid leukemia, and tumor necrosis factor (TNF)-α blockers used to treat psoriasis.26,27 Druginduced PR may closely resemble classic PR, but it often shows atypical features, a protracted course, large lesions, subsequent marked hyperpigmentation, and transformation to lichenoid dermatitis.

COMPLICATIONS Patients may experience flu-like symptoms, but these are relatively mild if they occur. About one-third of patients with PR experience significant levels of anxiety and depression, mostly centered around uncertainty over the cause of the disease and the length of disease recovery.28 Reassurance is important for these individuals. No serious complications occur in otherwise healthy PR patients. However, PR during pregnancy is of concern. In one series of 38 pregnant women with PR, Drago and colleagues reported nine premature deliveries, although all babies born to women who had PR during their pregnancy showed no birth defects.29 Five women had miscarriages, which was most common in the first trimester. Thus, pregnant women who develop PR should warrant careful evaluation and follow-up.

PROGNOSIS AND CLINICAL COURSE All patients with PR have complete spontaneous resolution of their disease. The disease duration normally varies between 4 and 10 weeks, with the first few weeks associated with the most new inflammatory skin lesions and the greatest likelihood of flu-like symptoms. Both postinflammatory hypopigmentation and hyperpigmentation can follow PR. As with other skin diseases, this occurs more commonly in individuals with darker skin color, with hyperpigmentation predominating.30 Treatment with ultraviolet light phototherapy may also worsen postinflammatory hyperpigmentation and should be used with caution. Otherwise, patients have no residual effects secondary to the occurrence of PR. Recurrent disease is possible, but it is rare.

TREATMENT Because PR is self-limited, there is no need to treat uncomplicated cases.31 Patient education and reassurance is warranted in all cases. Midpotency topical corticosteroids may be used for symptomatic relief of pruritus. Interestingly, Drago and colleagues have

BOX 42-2  Treatment of Pityriasis Rosea

PREVENTION There are no data on how PR can be prevented.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

Chapter 43 :: E  rythema Annulare Centrifugum and Other Figurate Erythemas :: Walter H.C. Burgdorf ERYTHEMA ANNULARE CENTRIFUGUM AT A GLANCE Clinical pattern of annular expanding erythematous rings, which enlarge rapidly, fade, and then disappear, as new lesions appear. Diagnosis of erythema annulare centrifugum is one of the exclusions. Superficial and deep variants can be separated clinically and histologically. Deep form is usually lupus tumidus or erythema migrans.

Erythema Annulare Centrifugum and Other Figurate Erythemas

2. Drago F et al: Human herpesvirus 7 in pityriasis rosea. Lancet 349:1367, 1997 3. Watanabe T et al: Pityriasis rosea is associated with systemic active infection with both human herpesvirus-7 and human herpesvirus-6. J Invest Dermatol 119:793, 2002 4. Broccolo F et al: Additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and -7. J Invest Dermatol 124:1234, 2005 6. Drago F, Vecchio F, Rebora A: Use of high-dose acyclovir in pityriasis rosea. J Am Acad Dermatol 54:82, 2006 10. Drago F, Broccolo F, Rebora A: Pityriasis rosea: an update with a critical appraisal of its possible herpesviral etiology. J Am Acad Dermatol 61:303, 2009 29. Drago F et al: Pregnancy outcome in patients with pityriasis rosea. J Am Acad Dermatol 58:S78, 2008

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reported that patients given high-dose acyclovir (i.e., 800 mg five times daily for 1 week) experienced more rapid resolution of PR than patients treated with placebo for 1 week.6 Specifically, 79% of 42 patients had complete resolution of PR within 2 weeks of starting acyclovir therapy, whereas 4% of 45 patients treated with placebo experienced resolution of their disease at 2 weeks. Although patients were blinded to the type of treatment they received, the trial was limited in that the investigators were not blinded and the patients were not randomly assigned to one of the two treatment groups. Given that acyclovir and its derivatives are relatively inexpensive and well-tolerated drugs, this form of therapy should be considered in PR patients presenting early in their disease course who demonstrate

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For all patients, education about the disease process and reassurance. For patients with associated pruritus, topical corticosteroids. For patients early in the disease course who demonstrate associated flu-like symptoms and/or extensive skin disease, oral acyclovir 800 mg five times daily for 1 week (or equivalent acyclovir derivative) may hasten recovery from disease. For selected patients, phototherapy may be useful.

associated flu-like symptoms and/or extensive skin disease. Erythromycin was reported to be of benefit to patients with PR,32 but clinical experience and more recent reports have not confirmed this initial result.33–35 Some patients with PR may benefit from phototherapy,36 although this should be used with caution given that it can increase the risk of postinflammatory hyperpigmentation after disease resolution (Box 42-2).

The figurate erythemas include a variety of eruptions characterized by annular and polycyclic lesions. Classification of this group has always been controversial; the literature abounds with contradictions, uncertainties, and a bewildering array of synonyms. Darier in 1916 was the first to use the term erythema annulare centrifugum1 (EAC), although similar lesions had been described previously under other names. Table 43-1 lists the figurate erythemas and the differential diagnoses to consider.

EPIDEMIOLOGY EAC is an uncommon disorder. No epidemiologic data are available. There are only three large series in the literature: (1) 66 cases identified clinically,2 (2) 73 first

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TABLE 43-1

Migratory Erythemas

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Disorder

Key Features

Erythema annulare centrifugum (EAC)

Slowly migrating lesions; often idiopathic.

This chapter

Erythema gyratum repens

Rapidly moving; usually cancer marker.

153

Erythema chronicum migrans

Annular lesions originating from tick bite; skin sign of Lyme borreliosis.

187

Lupus erythematosus

Most deep EAC is lupus tumidus. Annular lesions common in neonatal and subacute cutaneous LE; Ro/La antibodies should be sought; overlaps with Sjögren syndrome (especially in Asians).

155

Urticaria

Giant urticaria is often annular and migratory; patients have ordinary urticaria elsewhere and more pruritus.

38

Pityriasis rosea

Individual lesions closely resemble superficial EAC but pattern and course different

42

Bullous pemphigoid

Early lesions often urticarial and may be annular.

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Erythema multiforme

Target lesions, usually acral, often mucosal disease; some lesions annular.

39

Dermatophyte infections and tinea versicolor

Many fungal infections are annular (ringworm); the scale contains hyphae or spores.

188

Psoriasis

Pustular and occasionally ordinary psoriasis may have annular lesions.

18

Erythema marginatum

Transient, rapidly spreading annular erythema; specific for rheumatic fever.

160

Necrolytic migratory erythema

Marker for glucagonoma; erosive perioral and acral lesions, but truncal lesions may be polycyclic.

153

Carrier state chronic granulomatous disease

Female carriers may have annular lupus erythematosus-like rash.

143

Hereditary lactate dehydrogenase M-subunit deficiency

Rare genodermatosis with annular erythematous and scaly lesions.

This chapter

Familial annular erythema

Extremely rare.

This chapter

Annular erythema of infancy

Many different disorders; must rule out neonatal lupus erythematosus.

This chapter

diagnosed histologically,3 and (3) 90 carrying either a clinical or histological diagnosis.4 EAC appears to have no predilection for either sex or for any age group.

and often returning as the tumor recurs.14–16 This paraneoplastic marker must be distinguished from metastatic tumors with an annular pattern.17,18

ETIOLOGY AND PATHOGENESIS

CLINICAL FINDINGS

Both the annularity and the peripheral spread of EAC have attracted speculation as to a possible mechanism. Most hypotheses have centered on interactions among inflammatory cells, their mediators, and ground substance as foreign antigens diffuse through the skin.5,6 While many possible triggers have been suggested, all are common problems and EAC is very rare, so a direct causality is impossible to prove. It is better to view EAC as idiopathic. In one series, 24 patients were closely evaluated, and in none of the cases was any definite cause found.7 Suspected triggers include bacterial8 and candidal9 infections, autoimmune diseases,10 menses,11 pregnancy,12 and even stress.13 Although medications are often identified as causing EAC in case reports, none regularly induces such lesions. EAC may be coupled with malignant neoplasms, with the eruption disappearing after treatment of the tumor

HISTORY The history is most important in exploring the differential diagnostic considerations. In general, the lesions are asymptomatic but may be cosmetically disturbing.

CUTANEOUS LESIONS EAC presents as one or more lesions that begin as erythematous macules or urticarial papules and enlarge by peripheral extension to form ringed, arcuate, or polycyclic figures. They are usually asymptomatic. EAC has traditionally been divided into superficial and deep forms. In the superficial form, the bands have fine scales, which are more prominent on the inner aspect rather than the advancing edge. The lesions spread

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Figure 43-3  Superficial erythema annulare centrifugum showing perivascular lymphocytic infiltrates in papillary dermis. (Used with permission from Heinz Kutzner, ­Friedrichshafen, Germany.)

Superficial EAC has epidermal changes of parakeratosis and spongiosis, with a superficial perivascular infiltrate (eFig. 43-2.1 in online edition, Figs. 43-3 and Fig. 43-4). There is minimal papillary dermal edema and no spongiosis. Thus, there are histological similarities to pityriasis rosea. The deep form has superficial and deep perivascular infiltrates (Fig. 43-5). Histopathology is important in excluding common differential diagnostic considerations; interface change or mucin helps identify lupus erythematosus; a plasma cell infiltrate suggests erythema chronicum migrans; and eosinophils are a possible clue to drug reactions.

Figure 43-4  Higher view of superficial erythema ­annulare centrifugum with parakeratosis and focal spongiosis. (Used with permission from Heinz Kutzner, Friedrichshafen, Germany.)

Erythema Annulare Centrifugum and Other Figurate Erythemas

Figure 43-2  Superficial erythema annulare centrifugum. Multiple lesions, once again demonstrating scale. (Used with permission from Wilfried Neuse and Thomas Ruzicka, Düsseldorf, Germany.)

HISTOPATHOLOGY

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Figure 43-1  Superficial erythema annulare centrifugum. A large annular plaque with trailing scale behind the ­advancing erythematous edge.

Chapter 43

gradually to form large rings with central clearing, with the edges of the lesions often advancing several millimeters a day (Fig. 43-1 and Fig. 43-2). After a variable period of time, the lesions disappear, often to be replaced by new ones. In some cases annual recurrence has been described. In the deep form of EAC, there is no scale and the rings are infiltrated (eFig. 43-2.1 and eFig. 43-2.2 in online edition); almost all these cases represent either lupus erythematosus or erythema migrans caused by infection with Borrelia burgdorferi.4 A few may be drug-induced.

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Box 43-1  Differential Diagnosis of Erythema Annulare Centrifugum (EAC) Most Likely Dermatophyte infections Tinea versicolor Erythema migrans Annular urticaria Lupus erythematosus Annular psoriasis

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Figure 43-5  Deep erythema annulare centrifugum with normal epidermis and lymphocytic infiltrates about vessels of superficial and deep dermis. Many such lesions are lupus tumidus, so a careful search for mucin is mandatory. None is seen here. (Used with permission from Heinz Kutzner, Friedrichshafen, Germany.)

OTHER LABORATORY TESTS There are no other laboratory tests diagnostic for EAC.

DIFFERENTIAL DIAGNOSIS (Box 43-1) The differential diagnostic challenge in EAC is multiple. First, one must exclude lupus erythematosus and erythema migrans. We view superficial EAC as a specific entity; the annular variants of diseases such as dermatophyte infections, psoriasis, urticaria, bullous diseases, leukocytoclastic vasculitis, secondary syphilis, and sarcoidosis are not EAC. While a relationship to chronic pityriasis rosea has been suggested,4 there are so many clinical differences that we prefer not to make this association. There also are a number of rare figurate erythemas that cause problems. Erythema gyratum repens, which is generally more rapidly moving, usually reflects an underlying malignancy (see Chapter 153). Annular erythemas are seen in the carrier state of chronic granulomatous disease or a lactate dehydrogenase Msubunit deficiency. Annular lichenoid dermatitis of youth is clinically similar. Familial EAC, originally described as erythema gyratum perstans, is rare. Finally, there is the broad spectrum of annular erythemas of infancy,19 including neonatal lupus erythematosus, Malassezia furfur infections, and the idiopathic variants which themselves may show eosinophilic or neutrophilic infiltrates, as well as atrophy.

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EAC tends to be a chronic disease, which waxes and wanes.

Consider Erythema multiforme Pityriasis rosea Granulomatous diseases (granuloma annulare, actinic granuloma, sarcoidosis) Bullous pemphigoid (urticarial phase) Leukocytoclastic vasculitis (especially in children) Erythema marginatum Erythema gyratum repens Necrolytic migratory erythema Hypereosinophilic syndrome Carrier state chronic granulomatous disease Hereditary lactase dehydrogenase M-subunit deficiency Familial annular erythema Annular erythemas of infancy Always Rule Out Lupus erythematosus Lyme borreliosis Underlying tumor or annular metastasis

TREATMENT Only symptomatic relief is available. Systemic glucocorticoids usually suppress EAC, but recurrence is common when these drugs are stopped. Systemic therapy with antipruritics may help. Topical vitamin D analogs, perhaps combined with ultraviolet irradiation, are another option.20,21 Empiric use of antibiotic, antifungal, or anticandidal agents has sometimes been useful. Biologics may represent yet another option.22

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 2. Kim KJ et al: Clinicopathologic analysis of 66 cases of erythema annulare centrifugum. J Dermatol 29:61, 2002 3. Weyers W, Diaz-Cascajo C, Weyers I: Erythema annulare centrifugum: Results of a clinicopathologic study of 73 ­patients. Am J Dermatopathol 25:451, 2003

4. Ziemer M, Eisendle K, Zelger B: New concepts on erythema annulare centrifugum: A clinical reaction pattern that does not represent a specific clinicopathological entity. Br J Dermatol 160:119, 2009 7. Mahood JM: Erythema annulare centrifugum: A review of 24 cases with special reference to its association with underlying disease. Clin Exp Dermatol 8:383, 1983

10. Watkins S, Magill JM Jr, Ramos-Caro FA. Annular eruption preceding relapsing polychondritis: Case report and review of the literature. Int J Dermatol 48:356, 2009 18. Patrizi A et al: Neutrophilic figurate erythema of infancy. Pediatr Dermatol 25:255, 2008

GRANULOMA ANNULARE AT A GLANCE

The cause is unknown, and the pathogenesis is poorly understood. Pathologic features consist of granulomatous inflammation in a palisaded or interstitial pattern associated with varying degrees of connective tissue degeneration and mucin deposition. Most cases resolve spontaneously within 2 years.

Granuloma annulare is a benign self-limited disease, first described by Colcott-Fox1 in 1895 and RadcliffeCrocker2 in 1902.

EPIDEMIOLOGY Granuloma annulare is a relatively common disorder.3 It occurs in all age groups, but is rare in infancy.3–5 The localized annular and subcutaneous forms occur more frequently in children and young adults. The generalized variant is more common in adults. Many studies report a female preponderance,3 but some have found a higher frequency in males.6 Granuloma annulare does not favor a particular race or geographic area, with the possible exception of the perforating type, which may be more common in Hawaii.7 Most cases of granuloma annulare are sporadic. Occasional familial cases are described with occur-

The etiology of granuloma annulare is unknown, and the pathogenesis is poorly understood. Most cases occur in otherwise healthy children. A variety of predisposing events and associated systemic diseases is reported, but their significance is unclear. It is possible that granuloma annulare represents a phenotypic reaction pattern with many different initiating factors.12

Granuloma Annulare

A localized ring of beaded papules on the extremities is typical; generalized, subcutaneous, perforating, and patch subtypes also occur.

ETIOLOGY AND PATHOGENESIS

::

Relatively common disorder; exact prevalence is unknown; favors children and young adults.

rence in twins, siblings, and members of successive generations.3,8,9 Attempts to identify an associated HLA subtype have yielded disparate results in different population groups.10,11

Chapter 44

Chapter 44 :: Granuloma Annulare :: Julie S. Prendiville

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PREDISPOSING EVENTS Nonspecific mild trauma is considered a possible triggering factor because of the frequent location of lesions on the distal extremities of children. An early study of subcutaneous granuloma annulare found a history of trauma in 25% of children,3 but this observation has not been replicated. Trauma is also a suspected factor in auricular lesions.13 Granuloma annulare has occurred after a bee sting,14 a cat bite,15 and an octopus bite,16 and insect bite reactions have also been implicated.3 There is a report of perforating granuloma annulare in long-standing tattoos.17 Widespread lesions have developed after waxing-induced pseudofolliculitis18 and erythema multiforme minor,19 and in association with systemic sarcoidosis.3,20 Severe uveitis without other evidence of sarcoidosis has occurred in a few patients with granuloma annulare.21,22,23

INFECTIONS AND IMMUNIZATIONS. There are several reports of the development of granuloma annulare within herpes zoster scars, sometimes many years after the active infection.24 It is also described after chickenpox.25 Generalized, localized, and perforating forms of granuloma annulare may occur in association with human immunodeficiency virus (HIV) infection (see eFig. 44-0.1 in online edition).26–31 Adenovirus was isolated from a lesion in one HIVpositive patient.32 Epstein–Barr virus was excluded as a causative agent in these cases.26,27 However, in other

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instances generalized granuloma annulare has been linked to viral infections, including Epstein–Barr virus infection,33 chronic hepatitis B,34 and hepatitis C.35 Vaccinations for tetanus,36 diphtheria toxoid,37 and hepatitis B vaccination38 have been implicated as triggering factors, although vaccination sites were spared in one case of generalized granuloma annulare.39 Lesions compatible with granuloma annulare may occur in patients with active tuberculosis.12 There are also reports of granuloma annulare after tuberculin skin tests3 and Bacille Calmette-Guérin immunization.40 Evidence of Borrelia burgdorferi infection was detected in two reports,41,42 but this association was not confirmed in a serologic study.43 A case in which chronic relapsing granuloma annulare flared during scabies infestation was attributed to the Koebner phenomenon.44

SUN EXPOSURE. Granuloma annulare with a pre-

dilection for sun-exposed areas45–48 and seasonal recurrence45 has been described. Photosensitive granuloma annulare has been observed in patients with HIV infection.49 One patient developed generalized disease after psoralen plus ultraviolet A (UVA) light therapy,50 but it is of note that phototherapy and psoralen/UVA phototherapy have also been used to treat generalized granuloma annulare.51–54 Actinic granuloma, also known as annular elastolytic giant cell granuloma, develops on photodamaged skin and is believed to represent a granulomatous reaction to actinic elastosis.55 Its relationship to granuloma annulare is debated.

DRUGS. Granuloma annulare-like drug reactions are reported for gold therapy and treatment with allopurinol, diclofenac, quinidine, intranasal calcitonin, and amlodipine.56 An interstitial granulomatous drug reaction linked to the use of angiotensin-converting enzyme inhibitors, calcium channel blockers, and other medications is considered a distinct entity but may mimic granuloma annulare.57–59 DIABETES MELLITUS AND THYROID DISEASE. Development of granuloma annulare in

patients with diabetes mellitus is extensively documented. Whether this is a true relationship has long been debated. The link is primarily with type 1 insulindependent diabetes,60 but cases are also reported with type 2 noninsulin-dependent disease.61–63 Localized60 and generalized46,63,64 as well as subcutaneous nodular61,65,66 and perforating5,7 forms of granuloma annulare have been observed. Granuloma annulare rarely predates the onset of diabetes.60,66 The histopathologic similarity between granuloma annulare and necrobiosis lipoidica diabeticorum and the coexistence of both conditions in occasional diabetic patients62 suggest a true association. However, most patients with granuloma annulare do not have diabetes mellitus. Studies attempting to establish a causal correlation have yielded conflicting results.60,67,68 Granuloma annulare has also occurred in a number of patients with thyroiditis, hypothyroidism, and thyroid adenoma.64,69–72

MALIGNANCY. An association between granuloma annulare and malignancy in adult patients is reported primarily with Hodgkin and non-Hodgkin lymphoma, including mycosis fungoides, Lennert lymphoma, B-cell disease,73–76 T-cell leukemia/lymphoma,77,78 and angioblastic T-cell lymphoma.79 It is reported less commonly with myeloid leukemias80 and with solid tumors, particularly of the breast.46,73 The skin lesions of cutaneous lymphoma and other hematologic malignancies can mimic granuloma annulare both clinically and histopathologically.81,82 It may be difficult to distinguish whether they represent true granuloma annulare with atypical lymphocytes, or cutaneous lymphoma obscured by a granulomatous infiltrate.75,76 PATHOGENETIC MECHANISMS The pathogenetic mechanisms that result in foci of altered connective tissue surrounded by a granulomatous inflammatory infiltrate are not understood. ­Proposed mechanisms include (1) a primary degenerative process of connective tissue initiating granulomatous inflammation,83 (2) a lymphocyte-mediated immune reaction resulting in macrophage activation and cytokine-mediated degradation of connective ­tissue,30,84–88 and (3) a subtle vasculitis or other microangiopathy leading to tissue injury.84

CLINICAL FINDINGS HISTORY The typical history is of one or more papules with centrifugal enlargement and central clearing. These annular lesions are often misdiagnosed as tinea corporis and treated unsuccessfully with topical antifungal agents. Subcutaneous nodules may raise suspicion about malignancy or rheumatoid disease.89 Granuloma annulare is usually asymptomatic. Mild pruritus may be present, but painful lesions are rare.90,91 Nodular lesions on the feet may cause discomfort from footwear.92 Cosmesis is often a concern for adolescent and adult patients, particularly with generalized disease.

CUTANEOUS LESIONS Clinical variants of granuloma annulare include the localized, generalized, subcutaneous, perforating, and patch types. Linear granuloma annulare,93,94 a follicular pustular form,95 and papular umbilicated lesions in children96 have also been described. There is overlap between the different variants, and more than one morphologic type may coexist in the same patient.

LOCALIZED TYPE. The most common form of granuloma annulare is an annular or arcuate lesion. It may be skin colored, erythematous, or violaceous. It usually measures 1–5 cm in diameter.3 The annular margin is firm to palpation and may be continuous or

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SUBCUTANEOUS TYPE. The subcutaneous form of granuloma annulare occurs predominantly in children,89,99,100 but is also described in adult patients.101–103 It is characterized by firm to hard, usually asymptomatic nodules located in the deep dermis and subcutaneous tissues. They may extend to underlying muscle, and nodules on the scalp and orbit are often adherent to the underlying periosteum. Individual lesions measure from 6 mm to 3.5 cm in diameter.100,104 They are distributed most often on the anterior lower legs in a pretibial location.99 Other sites of predilection are the ankles, dorsal feet, buttocks, and hands.103,105 Nodules on the scalp,104,106 eyelids,107–109 and orbital rim65,110,111 may present a diagnostic challenge. Subcutaneous granuloma annulare may also be found on the penis.112–114

Granuloma Annulare

GENERALIZED TYPE. The generalized form of granuloma annulare is said to comprise 8%–15% of cases.3,46 The majority of patients are adults, but it may also be seen in childhood.46,98 Unlike in localized disease, the trunk is frequently involved, in addition to the neck and extremities. The face, scalp, palms, and soles may also be affected.46 Generalized granuloma annulare presents as widespread papules (Fig. 44-3A), some of which coalesce

to form small annular plaques or larger discolored patches with raised arcuate and serpiginous margins (see Fig. 44-3B). Lesions may be skin colored, pink, violaceous, tan, or yellow. An annular or nonannular morphology may predominate.46 A generalized form of perforating granuloma annulare has also been described.5,7

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consist of discrete or coalescent papules in a complete or partial circle (Fig. 44-1). The epidermis is usually normal, but surface markings may be attenuated over individual papules. Within the annular ring, the skin may have a violaceous or pigmented appearance. Solitary firm papules or nodules may also be present. Papular lesions on the fingers may appear umbilicated. The dorsal hands and feet, ankles, lower limbs, and wrists are the sites of predilection (see Figs. 44-1 and 44-2). Less commonly, lesions occur at other sites, including the eyelids.97 The palms and soles are occasionally involved.90,91 Localized annular lesions may coexist with the subcutaneous or patch forms.

Chapter 44

Figure 44-1  A. Typical annular lesion of granuloma annulare on a finger. B. A larger annular lesion of granuloma annulare on the dorsum of the hand.

PERFORATING TYPE. The perforating type of granuloma annulare is a rare variant characterized by transepidermal elimination of the necrobiotic collagen. It may be localized, usually to the dorsal hands and fingers (see eFig. 44-3.1 in online edition), or generalized over the trunk and extremities.5,7 It has been described on the ears,115 on the scrotum,116 and within herpes zoster scars and tattoos.16 Superficial small papules develop central umbilication or crusting, and there may be discharge of a creamy fluid. Lesions heal with atrophic or hyperpigmented scars. In one series, 24% of patients complained of pruritus and 21% of pain.117 Papular umbilicated granuloma annulare on the hands of children96 and a generalized follicular pustular type of granuloma annulare95 may be clinical variants.

Figure 44-2  Localized granuloma annulare with nodule on the hand of a child.

PATCH TYPE. Macular lesions that present as erythematous, red–brown, or violaceous patches without an annular rim are reported in adult women.88,118 An arcuate dermal erythema is also observed. General-

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ized confluent erythema has been described in an HIVpositive patient.30

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Figure 44-3  A. Generalized granuloma annulare. Small papular lesions that are too small to exhibit annular configuration. B. Multiple annular lesions on the lower arm.

RELATED PHYSICAL FINDINGS Most patients with granuloma annulare are healthy and have no other abnormal physical findings. Arthralgia is reported in association with painful lesions on the hands.91 Granuloma annulare-like skin lesions and joint disease characterize a multisystem disorder described as interstitial granulomatous dermatitis with arthritis.119 Oral involvement was observed in one patient with HIV-associated disease.27

LABORATORY TESTS A diagnosis of localized granuloma annulare is made on clinical examination, and further evaluation is rarely indicated. Biopsy to obtain a specimen for histopathologic examination is necessary when the presentation is atypical, when lesions are symptomatic, and when the diagnosis is otherwise in doubt. Histopathologic analysis may be required to confirm a diagnosis of generalized granuloma annulare or subcutaneous nodular disease on the head and orbital region.

tiocytes (Fig. 44-4). The necrobiotic centers are usually oval, slightly basophilic, devoid of nuclei, and marked by a loss of definition of the collagen bundles and diminished or absent elastic tissue fibers. Stains for mucin and lipid often give positive results. An interstitial, nonpalisaded pattern of inflammation with histiocytes infiltrating among fragmented collagen bundles may be predominant, particularly in the generalized form. This interstitial pattern is also observed in the absence of apparent connective tissue change. Stains for mucin may be helpful in detecting connective tissue alteration within the infiltrate. Lymphocytes are admixed with histiocytes in the granuloma and in a perivascular distribution. Multinucleated giant cells may be present but are not as numerous as in actinic granuloma.123 Neutrophils and eosinophils are occasionally seen, but plasma cells are rare. Evidence of vascular reactivity includes variable endothelial cell swelling, red cell extravasation, fibrin, leukocytoclasis, and neutrophilic infiltration in blood vessel walls.124 When leukocytoclastic vasculitis or nuclear debris is a prominent finding, a diagnosis of palisaded neutrophilic and granulomatous dermatitis of immune complex disease should be considered.124

HISTOPATHOLOGIC FINDINGS

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The diagnosis is best made at low magnification. Changes are usually observed in the upper and middle dermis, although any part of the dermis or subcutis can be involved. The characteristic histopathologic finding is a lymphohistiocytic granuloma associated with varying degrees of connective tissue degeneration and mucin deposition. The inflammatory infiltrate may have a palisaded or interstitial pattern, or a mixture of both patterns.120–122 Occasionally, a sarcoid-like pattern with large epithelioid histiocytes is seen.120 The typical appearance is of single or multiple foci of inflammation with a central core of altered collagen (necrobiosis) surrounded by a wall of palisaded his-

Figure 44-4  Palisading granulomatous inflammation surrounding degenerating collagen within the dermis. (Hematoxylin and eosin stain, ×200.) (Used with permission from Dr. Richard Crawford.)

tural changes in the connective tissue and capillaries have been described.83

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SPECIAL TESTS A diagnosis of granuloma annulare is made clinically or by skin biopsy. Special investigations are usually not necessary. Further evaluation to rule out systemic disease such as infection, sarcoidosis, or malignancy may be required in atypical cases of granuloma annulare.12,77,81,82,118 Investigation for endocrine disease is indicated if the patient has signs or symptoms of diabetes or thyroid dysfunction. Imaging studies may be performed in subcutaneous granuloma annulare when the clinical features are not recognized or when the presentation is atypical with rapid enlargement or pain.126 Radiographs show a nonspecific soft tissue mass without calcification

Chapter 44

In subcutaneous granuloma annulare the foci of necrobiosis are larger and lie within the deep dermis and subcutaneous fat. They may be distinguished from rheumatoid nodules by the presence of mucin in the necrobiotic zone.107 Central ulceration and communication between the area of necrobiosis and the surface are characteristic of perforating granuloma annulare. Examination of serial sections may be necessary to demonstrate the necrobiotic plug. An interstitial pattern of inflammation with diffuse necrobiosis is reported in the patch type of granuloma annulare.119 Palisaded granulomas have also been observed in macular lesions.88 Immunofluorescence testing may show deposition of fibrin, immunoglobulin (Ig) M, and C3 as a variable finding around vessel walls or at the basement membrane zone; IgM cytoid bodies are also reported.119 Immunohistochemistry may be useful to confirm the histiocytic nature of equivocal disease.125 Ultrastruc-

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ANNULAR TYPE Consider Tinea corporis Subacute cutaneous lupus erythematosus Neonatal lupus erythematosus Annular lichen planus Acute febrile neutrophilic dermatosis Erythema chronicum migrans Actinic granuloma/annular elastolytic giant cell granuloma Necrobiosis lipoidica diabeticorum Rule Out Infections (e.g., tuberculosis, atypical mycobacteria, syphilis) Interstitial granulomatous dermatitis with arthritis Interstitial granulomatous drug reaction Annular sarcoidosis Lymphoma GENERALIZED TYPE Consider Lichen planus Lichen nitidus Molluscum contagiosum Rule Out Lichenoid and granulomatous dermatitis of acquired immunodeficiency syndrome Infections (e.g., tuberculosis, atypical mycobacteria, syphilis) Sarcoidosis Blau syndrome (familial granulomatous arthritis, skin eruption, and uveitis) Interstitial granulomatous drug reaction Lymphoma

SUBCUTANEOUS TYPE Consider Erythema nodosum Dermoid cyst Rheumatoid nodules

Granuloma Annulare

Box 44-1  Differential Diagnosis of Granuloma Annulare

Rule Out Epithelioid sarcoma Benign or other malignant tumors Deep infections PERFORATING TYPE Consider Molluscum contagiosum Insect bites Pityriasis lichenoides Perforating collagenosis and other perforating disorders Foreign body granuloma Papulonecrotic tuberculid Palisaded neutrophilic and granulomatous dermatitis of immune complex disease PATCH TYPE Consider Morphea Erythema annulare centrifugum Parapsoriasis Rule Out Lymphoma

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Box 44-2  Treatment Options for Granuloma Annulare Await spontaneous resolution Apply topical corticosteroid with or without occlusion Administer intralesional triamcinolone 2.5 mg/mL129

Section 6 :: Inflammatory Diseases Based on Abnormal Humoral Reactivity

ANECDOTAL REPORTS OF BENEFIT Topical Tacrolimus 0.1% ointment130 Pimecrolimus cream131 Imiquimod 5% cream132,133a Intralesional Interferon-γ135 Interferon-β135 Sterile water or saline129 Systemic Antimalarials98 Retinoids136–140 Antibiotics141,142 Corticosteroids92,108 Cyclosporine77,143 Zileuton with vitamin E144 Fumaric acid esters145,146 Hydroxyurea,147 chlorambucil, niacinamide, potassium iodide, dapsone3,46,92 Etanercept148b Infliximab150b Efalizumab151b Adalimumab152–154 Other Phototherapy51–54 Photodynamic therapy155,156 Skin biopsy157 Cryotherapy158 Pulsed dye, Nd:YAG or CO2 laser159–162 a

Application of 5% imiquimod cream has been reported to worsen granuloma annulare in a child.134 b Development of granuloma annulare has been reported during therapy with etanercept, infliximab, and adalimumab.149

or bone involvement. Ultrasonographic examination reveals a hypoechoic area in the subcutaneous tissues.126,127 Magnetic resonance imaging shows a mass with indistinct margins, isointense or slightly hyperintense to muscle with T1-weighted images and with a heterogeneous but predominantly high signal intensity on T2-weighted images.126,128

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DIFFERENTIAL DIAGNOSIS See Box 44-1.

TREATMENT The usual treatment options include awaiting spontaneous resolution, topical steroids and intralesional steroids. These and more anecdotal reports are summarized in Box 44-2.

CLINICAL COURSE AND PROGNOSIS Most cases of localized granuloma annulare resolve spontaneously without sequelae. Lesions may clear within a few weeks or persist for several years. The majority disappear within 2 years.92 Recurrent lesions may develop months or even years later, frequently at the same site. Generalized granuloma annulare often runs a more protracted course.46 Perforating granuloma annulare results in scarring.117 There are a number of reports of anetoderma or middermal elastolysis following generalized granuloma annulare and annular elastolytic giant cell granuloma.47,163–166 One case of generalized granuloma annulare in a photosensitive distribution healed with scarring and milia formation.167

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 3. Muhlbauer JE: Granuloma annulare. J Am Acad Dermatol 3:217, 1980 43. Halkier-Sorensen L, Kragballe K, Hansen K: Antibodies to the Borrelia burgdorferi flagellum in patients with scleroderma, granuloma annulare and porphyria cutanea tarda. Acta Derm Venereol 69:116, 1989 83. Hanna WM, Moreno-Merlo F, Andrighetti L: Granuloma annulare: an elastic tissue disease? Case report and literature review. Ultrastructural Pathol 23:33, 1999 84. Dahl MV: Speculations on the pathogenesis of granuloma annulare. Australas J Dermatol 26:49, 1985 85. Mempel M et al: T-cell receptor repertoire and cytokine pattern in granuloma annulare: defining a particular type of cutaneous granulomatous inflammation. J Invest Dermatol 118:957, 2002 86. Fayyazi A et al: Expression of IFNγ, coexpression of TNFα and matrix metalloproteinases and apoptosis of T lymphocytes and macrophages in granuloma annulare. Arch Dermatol Res 292:384, 2000 100. Felner EI, Steinberg JB, Weinberg AG: Subcutaneous granuloma annulare: a review of 47 cases. Pediatrics 100:965, 1997

Disorders of Epidermal Differentiation and Keratinization

Chapter 45 :: Epidermal Stem Cells :: Rebecca J. Morris EPIDERMAL STEM CELLS AT A GLANCE The epidermis is a continually renewing tissue the function of which is maintained by a hierarchy of stem cells, transit amplifying cells, and terminally differentiating cells. In the proliferative hierarchy, stem cells have the highest proliferative potential. Epidermal stem cells may be identified by their functional characteristics, by distinctive cell cycle patterns, or by characteristic proteins. Epidermal stem cells usually exist in characteristic proliferative units with little lateral migration. The regulation of epidermal stem cells comprises complex pathways many of which are shared by embryonic, morphogenetic, and homeostatic processes. Epidermal diseases are associated with or may arise from proliferative dysfunction in the stem cell or transit amplifying cell compartments. Epidermal stem cells are attractive targets for cell and gene therapies.

The cutaneous epithelium is a continually renewing tissue maintained in a dynamic equilibrium of proliferation in the basal layer and loss through terminal differentiation from the suprabasal layers. This process is orchestrated with great elegance by a hierarchy of stem cells, transient amplifying cells, and terminally differentiating cells. These populations of cells work together to maintain lifelong tissue function and to bring about tissue repair. This chapter focuses on the role of stem cells and their identification in the ­epidermis.

CONCEPT OF STEM CELLS IN RENEWING TISSUES Proliferation in the cutaneous epithelium begins with the stem cells.1,2 Stem cells in this regard lack many characteristics of terminal differentiation, and have an intrinsically high proliferative potential relative to the other proliferating cells, but are generally capable of lifelong proliferation.3 Upon division, a stem cell produces off one daughter that remains a stem cell, and one daughter that goes on to produce a series of transit amplifying cells that serve to magnify or amplify the stem cell’s division resulting in the production of many differentiated cells with minimal input from the stem cell. This hierarchical system that usually involves decreasing proliferative potential is illustrated in Fig. 45-1. Stem cells typically interact with their surroundings in a supportive, protective niche.1

GENERAL METHODS FOR STEM CELL IDENTIFICATION AND ISOLATION Stem cells may be studied by the presence or absence of proteins on their surface that distinguish them from other proliferative cells.2 Such proteins may be internal, or more desirably, proteins on the cell surface that render the cells selective by various methods such as by magnetic bead separation or by fluorescence activated cell sorting (FACS).2 Stem cells may also be studied by cellular kinetic characteristics such as in slowly cycling label-retaining4 cells or through their patterns of mitotic activity.5 Stem cells can sometimes be identified and isolated according to their special physical properties such as cell size or buoyant density,6 or in conjunction with other properties such as in the socalled “side population” cells7 that have active Abcg2 transporters. Candidate stem cells identified or isolated by any of these methods may then be characterized by functional tools such as in vitro colony forming assays,8–10 or in an in vitro or in vivo skin reconstitution assay.2

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However, lateral migration is common during wound healing where a tongue of proliferating epithelium migrates over denuded dermis and reestablishes an epithelium complete with vertical proliferative units and terminal differentiation.18 In addition, Brash and colleagues have suggested that following irradiation of skin with ultraviolet light, clonal patches, each with its own p53 mutation, might reflect epidermal cell proliferation and differentiation beyond the confines of single proliferative units.19

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:: Disorders of Epidermal Differentiation and Keratinization

Stem cells

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Figure 45-1  The proliferative hierarchy in epithelia: the stem cell concept. The ultimate progenitor cells are termed stem cells. They are slow cycling, long-lived, phenotypically undifferentiated, reside in specialized microenvironments, and constitute only a small percentage of the total epithelial cell population. Stem cell division produces transit amplifying or committed progenitor cells, which cycle rapidly and produce a clonal expansion of the offspring arising from an initial stem cell division. These cells eventually become the mature, terminally differentiated cells that constitute the bulk of a given epithelial population. Numbers indicate generation.

ASYMMETRIC DIVISION The hierarchical model for cell proliferation in the cutaneous epithelium implies some degree of cellular, genetic, or population asymmetry.3,11 The model of the stem cell hierarchy suggests a level of asymmetry that could be due to infrequent cell division or to chromosomal segregation.3 As the stem cell mechanism is thought to provide protection for the tissue as well as the cellular DNA, Cairns12,13 hypothesized that perhaps stem cells have a special mechanism for segregating their DNA and retaining an “immortal strand” at each division. Although there is some fairly convincing evidence that stem cells of the breast14 and intestinal epithelium15 may reserve an immortal DNA strand, recent investigation of the multipotential stem cells of the mouse hair follicles suggest that chromosome segregation does not occur.16,17 Moreover, the Tumbar laboratory developed a method to trace the proliferation history of hair follicle bulge keratinocytes and thus provided direct evidence in support of the infrequent division model for these particular stem cells.16

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IDENTIFICATION OF STEM CELLS IN THE CUTANEOUS EPITHELIUM

Cellular proliferation and terminal differentiation in the epidermis are usually thought to occur in columns.

Slowly cycling epidermal stem cells were first identified by of their cell kinetic behavior in the context of the epidermal proliferative units. Hence, Mackenzie identified mitotic basal keratinocytes beneath the edges of the hexagonal squames.20 In vertical cross sections of skin, Christophers21 had found that some basal cells in the shape of a hand mirror stained with a fluorescent dye characteristic of suprabasal cells. These studies were quantified by Potten in 197422 who called these units of structure epidermal proliferative units (EPUs). He focused on the central basal cells, noting that they were rarely mitotic and also rarely incorporated [3H]thymidine administered as a single pulse, and conjectured that the quiescent central cells might have stem cell activity whereas the peripheral cells may have transit amplifying cell activity. The next major advance in understanding the function of the EPU came with the identification of slowly cycling label-retaining cells in the center of the EPUs. Bickenbach4 and later Bickenbach and Mackenzie,23 Morris,24 and Potten25 found that administration of [3H]thymidine continuously for 3 days followed by a 4–8 week chase, could identify these central cells in light microscopic autoradiographs. Further characterization of the central stem cells and peripheral transit amplifying cells has been performed by a variety of in vivo and in vitro techniques.2 The presence of EPUs in some areas of thin human skin has also been noted, and may be as large as 2 millimeters in diameter.20 The EPU concept in skin is illustrated in Fig. 45-2. The distribution of stem cells within the epidermis has been a subject of debate. Hence, Lavker and Sun26 found that mitotic cells and cells that were rarely mitotic (putative stem cells) were located respectively in the upper and lower aspects of the rete ridges. These investigators postulated that the deeper cells were physically more protected than the superficial cells. In contrast, further studies have demonstrated that cells with stem cell characteristics in human epidermis can vary depending upon the site.27 Ghazizadeh and Taichman28 used retrovirally marked human epidermal keratinocytes followed by grafting onto athymic nude mice to visualize proliferative units in human skin. These studies found presumptive stem cells to be distributed throughout the epithelium.

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Compared with the plethora of markers and selectable determinants for various hair follicle stem cells, few such markers have been identified in the epidermis. Notable exceptions are β-1 integrin,10 CD71 (the transferrin receptor),29 and LRIG1 (Fig. 45-3).30 β-1 integrin is a cell adhesion molecule and can be used as a ­selectable determinant to enrich for keratinocytes that have a high proliferative potential in vitro and that can

Epidermal Stem Cells

MARKERS AND SELECTABLE DETERMINANTS

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Figure 45-2  Functional organization of interfollicular epidermis: the epidermal proliferative unit (EPU) concept. Interfollicular epidermis of the skin of certain body sites is histologically organized into columns termed EPUs; each consists of approximately ten basal cells, including a single putative stem cell (yellow), its immediate transitamplifying cell progeny (blue), and early-differentiating cells (purple). More differentiated keratinocytes (green) and then mature enucleated squames lie directly above them, in an ordered stack rising above the basal layer. EPUs represent functionally independent packets of selfrenewing interfollicular epidermis that are ultimately dependent on a single putative stem cell for lifelong cell production. Constant self-renewal within the basal layer of skin compensates for the continual loss of differentiated squames from its surface. (Redrawn from Kaur P: Interfollicular epidermal stem cells: Identification, challenges, potential. J Invest Dermatol 126:1452, 2006.)

Chapter 45

Figure 45-3  A confocal microscopic image of human scalp tissue stained for the EGFR (red) and LRIG1 (green). Immunostaining such as this has provided valuable information on the role and function of stem cells in the epidermis. The significance of these two markers is reported in Jensen KB, Watt FM: Single cell expression profiling of human epidermal stem and transit amplifying cells. LRIG1 is a regulator of stem cell quiescence. Proc Natl Acad Sci USA 103:11958-11963, 2006 and Jensen KB et al: LRIG1 expression defines a distinct multipotent stem ell population in mammalian epidermis. Cell Stem Cell 4:427-439, 2009. (Used with permission from Drs Kim Jensen and Fiona Watt.)

reconstitute a graft. Cells staining brightly with a ­fluorescently labeled antibody to β-1 integrin keratinocytes are found in human epidermis situated at the bottom of the rete ridges or atop the dermal papillae depending on the location of the skin. CD71 is expressed on all proliferating cells and can be used in conjunction with α-6 integrin (the external component of the hemidesmosomes present on epidermal basal cells) to enrich for a population that reacts with a fluorescently labeled antibody to α-6 integrin, but does not bind to fluorescently labeled CD71. This is enriched for epidermal keratinocytes that have in vitro and in vivo properties of stem cells. In the mouse, cells with this phenotype are located in the hair follicle bulge. LRIG1 is a marker of human interfollicular stem cells and helps to maintain stem cell quiescence.30 In the mouse, LRIG1 immunoreactive cells are found in the hair follicle junctional zone between the sebaceous glands and the infundibulum.31

ALTERNATIVE MECHANISMS FOR REGULATING EPIDERMAL PROLIFERATION The stem cell concepts presented above have not gone unchallenged. Clayton et al have studied clonal expansion in the mouse tail epidermis together with mathematical modeling.32 These investigators conclude that the presence of stem cell/transit amplifying cell model in the tails is incompatible with a long-lived stem cell

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population and a short-lived transit amplifying cell population. Moreover, this group infers that clones of two basal cells in the tail can adopt any of the three fates: (1) both cells can remain proliferative, (2) both can differentiate and exit the cycle, or (3) that one cell can remain proliferative and the other differentiates. Thus, epidermis from different sites may have different mechanisms for proliferation and terminal differentiation. At the present time, there are no reports of this model being applied to mouse dorsum or human epidermis from any site.

Section 7

RELATIONSHIPS AMONG VARIOUS EPITHELIAL STEM CELL COMPARTMENTS

:: Disorders of Epidermal Differentiation and Keratinization

Cellular kinetic and labeling data suggest that there are multiple stem and progenitor compartments within the cutaneous epithelium. Under homeostatic conditions, these compartments are stable over intervals with essentially no interactions.33 Hence, there are multiple proliferative units within the hair follicles: the infundibulum of the follicle, the bulge, the upper isthmus, and the sebaceous gland. The progeny of these follicular and sebaceous proliferative units all appear to be able to contribute to the repair of wounded epidermis.

REGULATION OF EPIDERMAL STEM AND TRANSIT AMPLIFYING CELLS Identification and functional characterization of molecules regulating epidermal stem cells and transit amplifying cells is currently a subject of intense investigation.34–37 Mediators under study comprise complex pathways often shared by embryonic, morphogenetic, and adult homeostatic and repair processes. Regula-

tory “switches”34 include (1) stimuli that direct progenitor cells toward a particular type of terminal differentiation, (2) molecules and pathways characteristic of the niche and stem cell homeostasis, (3) molecules that differentially alter stem cell and transit amplifying cell proliferation, and (4) positive and negative regulators involved in commitment to terminal differentiation. Examples of such regulatory molecules are given in Table 45-1.

SKIN DISEASES ARISING FROM PROLIFERATIVE DYSFUNCTION Skin cancer is thought to arise from aberrant proliferation of keratinocyte stem cells.3,38 In this regard, a stem cell is a candidate for a tumor-initiating cell because of its long-term persistence in the tissue and because of its inherently high proliferative potential. The relationship between the epidermal stem cell and the so-called cancer stem cell is not known at the present time; however, current thinking is that the tissue stem cells, when corrupted, may become cancer stem cells that retain such stem cell properties as long-term self renewal, an ability to cast off transit amplifying cells, and production of terminally differentiated cells. Although stem cells are well protected against carcinogen-induced damage by virtue of being a rare and well-protected population, unlike the relatively short-lived transit amplifying cells, stem cells persist to endure the multiple mutations that lead to malignancy. Psoriasis is thought to be an example of hyperproliferation of transit amplifying cells, which among inflammatory and dermal changes, is characterized by increased numbers of β-1 integrin dim cells in the suprabasal layers.39 Additionally, markers of proliferation such as Ki67 and C-myc are upregulated.

TABLE 45-1

Examples of “Molecular Switches” that Direct Epidermal Stem Cell Behavior Stimuli that Direct Progenitor Cells toward a Particular Type of Terminal Differentiation   Epithelial to hair follicle: Wnt/β-catenin; Negatively regulated by Dikk1 and Lef1/Tcf   Hair follicle stem cells to sebaceous cells: BLIMP1 Molecules and Pathways Characteristic of the Niche and Stem Cell Homeostasis   Maintenance of stem cell quiescence in hair follicles: NFATc1, Bmp6   Maintenance of stem cell quiescence in the epidermis: Lrig1 Molecules that Differentially Alter Stem Cell and Transit Amplifying Cell Proliferation   Stem cell to transit amplifying cell and stem cell renewal: Myc, p63, miR203 microRNA, histone modification Positive and Negative Regulators involved in Commitment to Terminal Differentiation   Basal to spinous transition and barrier function: turn off K5/K14 and turn on K1/K10   Pathways: Notch, MAPK, NFκ-B, p63, AP2 family, EGF receptor signaling   Negative regulators of terminal differentiation: extracellular matrix repression, PcG repression

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Please see Blanpain C, Fuchs E: Epidermal homeostasis: A balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 10:207-217, 2009; Fuchs E: Finding one’s niche in the skin. Cell Stem Cell 4:499-502, 2009; and Watt FM, Jensen KB: Epidermal stem cell diversity and quiescence. EMBO Mol Med 1:260-267, 2009 for more information and additional examples.

OUTLOOK

EPIDERMAL STEM CELLS AND GENE THERAPY The accessibility of skin makes it an attractive target for gene therapy.42 Here, one goal is to correct mutant genes in the stem cells ex vivo and transplant resulting normalized epithelium to patients.42 Another goal is to correct defective expression of certain secreted proteins in skin stem cells and to apply the corrected epithelium to patients.43 Although the use of epidermal cells including stem cells was proposed more than a decade ago, these applications still have not been developed for clinical practice. It is possible that the predilection of epidermis to develop into vertical proliferative units rather than to expand laterally precludes these applications. However, the field of gene therapy is still considered to be in its infancy, and identification and targeting of multipotential skin stem cells, as well identification of factors resulting in the lateral migration of epithelium ­during wound healing will increase therapeutic

In this chapter, I have discussed general properties of epidermal stem cells and some of the techniques for studying them. In this regard, keratinocyte stem cells together with transit amplifying cells and terminally differentiating cells play a role in the normal turnover and repair of the epidermis. Additional studies, perhaps with novel approaches are needed for better identification of epithelial stem and transit amplifying cells. Especially, more investigation is needed for an understanding of the molecular “switches” that regulate stem cell and transit amplifying cell homeostases, fate determination, and repair mechanisms. Moreover, there is a great need for understanding stem cell targeting as well as the lateral migration in wound healing, as these are key questions in making cell and gene therapy a reality. Finally, it must be understood that there will never be a “pure” population of stem cells. Rather, each new marker or selectable determinant discovered, and each new functional assay developed is essential for ultimately designing new treatments for skin diseases and skin cancer.

Epidermal Stem Cells

Epidermal stem cells can be cultivated and expanded in tissue culture.8,40 This has led to an application of epidermal cells in cell therapy of burn victims. Hence, from a small biopsy from nonaffected skin, skin cells including stem cells can be expanded ex vivo and then reapplied to affected skin. The transplanted tissue “takes” to debrided skin regions and ultimately forms a new epithelium with the capacity to persist for many years. This application is now standard therapy in many burn units.40 In the transplanted epithelium, it is noteworthy that epithelial appendages such as hair follicles, sebaceous glands, or eccrine glands are absent because techniques for in vitro morphogenesis of these tissues have not yet been developed. The lack of skin appendages in the grafted epidermis results in fragility as well as dryness due to lack of sebaceous glands, and poor thermoregulation due to lack of eccrine glands in the transplanted epithelium. These problems highlight the urgent need to develop in vitro methods to recapitulate embryonic morphogenesis of the cutaneous appendages. Ex vivo expanded epidermal keratinocytes are also used for treating ulcers and other chronic wounds.41

7

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applications. Additionally, other related means of manipulating the keratinocytes such as siRNA show great promise.44

Chapter 45

EPIDERMAL STEM CELLS AND CELL THERAPY

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Blanpain C, Fuchs E: Epidermal homeostasis: A balancing act of stem cells in the skin. Nat Rev Mol Cell Biol 10:207217, 2009 2. Kaur P: Interfollicular Epidermal stem cells: Identification, challenges, potential. J Invest Dermatol 126:1450-1458, 2006 3. Lajtha L: Stem cell concepts. Differentiation 14:23-34, 1979 13. Cairns J: Cancer and the immortal strand hypothesis. Genetics 174:1069-1072, 2006 25. Potten CS: Cell cycles in cell hierarchies. Int J Radiat Biol 49:257-258, 1986 34. Fuchs E: Finding one’s niche in the skin. Cell Stem Cell 4:499-502, 2009 35. Watt FM, Jensen KB: Epidermal stem cell diversity and quiescence. EMBO Mol Med 1:260-267, 2009 38. Watt FM, Driskell RR: The therapeutic potential of stem cells. Philos Trans R Soc London B Biol Sci 365:155-163, 2010 40. Green H: The birth of therapy with cultured cells. BioEssays 30:897-903, 2008

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Chapter 46 :: Epidermal Growth and Differentiation :: Pierre A. Coulombe, Stanley J. Miller, & Tung-Tien Sun EPIDERMAL GROWTH AND DIFFERENTIATION AT A GLANCE The interfollicular epidermis is maintained by a population of stem cells.

Section 7

Slow-cycling stem cells give rise to transit amplifying cells, which yield terminally differentiated cells.

::

Abnormalities in epidermal stem cells may be involved in pathogenesis of skin cancers and other proliferative epidermal diseases.

Disorders of Epidermal Differentiation and Keratinization

INTRODUCTION Although thin, human skin is a marvelously resilient and multifunctional organ. It performs immunomodulatory and thermoregulatory functions, is involved in social, cultural, and reproductive behaviors, and provides broad protection against water loss and environmental insults such as trauma, infection, and exposure to radiation or chemicals. The outermost layer of skin, termed the epidermis, consists of a stratified squamous epithelium and its appendages, including hair follicles, sebaceous, apocrine, and eccrine glands. This chapter discusses epidermal differentiation, with the primary focus placed on keratin filaments that are formed as major structural elements within the epidermis. Defects in epidermal keratins are known to play key roles in a number of important blistering epidermal diseases. Additional major epidermal differentiation markers, including keratohyalin granules and the cornified envelope, are also discussed.

KERATINS AND EPIDERMAL DIFFERENTIATION KERATINS AND THEIR CLASSIFICATION

478

Keratins (also known as cytokeratins) are structural proteins that belong to the superfamily of intermediate filament (IF) proteins. They are heterogeneous in size (40–70 kDa) and charge (pI 4.7–8.4), and notoriously insoluble. Sequencing the human genome revealed the presence of 54 functional keratin genes that are nearly perfectly conserved in other mammals.1 The tremendous diversity of keratin genes had not been fully appreciated until the advent of database mining and genomics, and could not be accom-

Epidermal differentiation is accompanied by orchestrated expression of keratins and subunits of cornified envelope. Keratins contribute to the mechanical stability and pliability of the epidermis. Mutations in major epidermal differentiation products are underlying causes of important skin diseases.

modated in the original nomenclature system aptly devised by Roland Moll, Werner Franke and colleagues in 1982.2 In 2006, an international effort culminated in a revised nomenclature (Table 46-1) that accommodates the newly discovered keratins, adheres to the guidelines of the Human and Mouse Gene Organization Gene Nomenclature Committee, and maintains the original designation of keratins devised by Moll and colleagues.1 Sequence homology and gene substructure (number and position of introns) reveal two distinct groups of keratins of roughly equal size, designated type I and II IF genes1,3 (Fig. 46-1A). In Homo sapiens, functional type I and type II keratin genes are clustered on the long arms of chromosomes 17 (Fig. 46-1B) and 12 (Fig. 46-1C), respectively.1,4 Keratin genes are highly conserved across mammals, at the level of their organization, structure, sequence, and regulation.5 Mature filaments contain type I and II keratins in a 1:1 molar ratio.3,6 This requirement underlies the coordinated transcription of type I and II keratin genes. Remarkably, most type I and II keratin genes are regulated in a pairwise, tissue type-related, and differentiationrelated fashion.7–9 This is illustrated particularly well in stratified epithelia such as epidermis (Fig. 46-2). Given their large number, differential regulation, and ease of detection (owing to abundance), keratin mRNAs and proteins represent unparalleled markers for staging the fate and differentiation of epithelial cells, under healthy and diseased conditions.

KERATIN PROTEINS FORM THE INTERMEDIATE FILAMENT NETWORK OF EPITHELIAL CELLS Despite sequence differences, all keratins display the tripartite domain structure that is typical of IF-forming

7

Table 46-1

Human Keratins and Their Distributiona Type I Keratins Old Name

New Name

Main Site(s) of Expression

K9

K9

Epidermis (suprabasal)

K1

K1

Epidermis (suprabasal)

K10

K10

Epidermis (suprabasal)

K2e

K2

Epidermis (suprabasal)

K12

K12

Cornea

K3

K3

Cornea (suprabasal)

K13

K13

Oral mucosa

K4

K4

Oral mucosa (suprabasal)

K14

K14

Complex epithelia

K5

K5

Complex epithelia (basal layer)

K15

K15

Complex epithelia

K6a

K6a

Epithelial appendages

K16

K16

Epithelial appendages

K6b

K6b

Epithelial appendages

K17

K17

Epithelial appendages

K6e/h

K6c

Skin (needs confirm.)

K18

K18

Simple epithelia

K7

K7

Simple epithelia

K19

K19

Broad distribution

K8

K8

Simple epithelia

K6irs1–4

K71–K74

Inner root sheath (hair follicles)

K6hf

K75

Companion layer (hair follicles)

K2p

K76

Oral mucosa

K1b

K77

Sweat gland ducts

K5b

K78

Tongue

K6l

K79

Skin

Kb20

K80

Tongue

Hb1–Hb6

K81–K86

Hair shaft (hair follicles)

K20

K20

Gut epithelium

K23

K23

Pancreas (needs confirm.)

K24

K24

unknown

K25irs-4

K25–K28

Inner root sheath (hair follicles)

Ha1–Ha8

K31–K38

Hair shaft (Hair follicle)

K39

K39

Hair shaft (Hair follicle)

K40

K40

Hair shaft (Hair follicle)

Epidermal Growth and Differentiation

Main Site(s) of Expression

::

Old Name New Name

Chapter 46

a

Type II Keratins

Note: A revised keratin nomenclature has been published: see Schweitzer et al., J Cell Biol (2006).

proteins (Fig. 46-1D). The central domain consists of an extended α helix featuring long-range heptad repeats that mediate coiled-coil dimerization. This “rod” domain is ∼310 amino acids long and is flanked by highly variable sequences at the N- terminal head and C-terminal tail domains (Fig. 46-1D).3 Neither terminal domain exhibits known functional motifs other than the glycine loops seen in epidermal keratins.10 The head and tail domains are readily protease-accessible at the surface of the filament, where they can foster interactions with neighboring filaments, other proteins, or serve as substrates for posttranslational modifications involved in their regulation.11 Given their heterogeneity of size and primary structure, the head and tail domains are expected to make key contribu-

tions to the differential function and regulation of keratin proteins in vivo.12 The central rod domain of keratins is the main determinant of self-assembly, with important contributions from the head domain as well.13 Assembly begins with the formation of heterodimers in which the α-helical central rod domains of type I and II keratins are aligned in parallel and perfect register. Heterodimers interact along their lateral surfaces and in an end-to-end fashion to give rise to the 10–12-nm wide filaments (Fig. 46-2A) which, depending on IF protein type and assembly conditions, may contain a variable number of subunits in cross section.13 Mature IFs lack a structural polarity, a direct consequence of the antiparallel orientation of their constituent coiled–coiled dimers.

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7

The human keratin gene family

A K84

K82

B

K85 K83 K81, 86 K7

K20

K18

K14 K17 K15 K13 K19

K8 K75 K5

K16

K6a-c K4 K1

K28

Section 7 :: Disorders of Epidermal Differentiation and Keratinization

480

K3

0.1

K25

K2p

K72

K10

K36 K33a K31 K33b

K12 K9

K34

K37

K23

K32

K38 K37

D Head

K2e

C Human chromosome 12q13.13 Cen ... KRT80 KRT7 pseudo pseudo KRT81 KRT86 KRT83 pseudo KRT85 KRT84 KRT82 pseudo KRT75 KRT6b KRT6c KRT6a KRT5 KRT71 KRT74 KRT72 KRT73 pseudo ... KRT2 KRT1 KRT77 pseudo pseudo pseudo KRT76 KRT3 KRT4 KRT79 KRT78 KRT8 ... KRT18

K73 K71 K74

K27 K26

Human chromosome 17q21.2 Cen ... pseudo KRT24 pseudo KRT25 KRT26 KRT27 KRT28 KRT10 KRT12 KRT20 KRT23 KRT39 KRT40 *several KAP genes* KRT33a KRT34 KRT31 pseudo KRT37 KRT38 pseudo KRT32 KRT35 KRT36 KRT13 KRT15 KRT19 KRT9 KRT14 KRT16 KRT17 pseudo ... Tel

α-helical rod 1A 1B

2A

2B

Tail

Figure 46-1  The human keratin gene family. A. Comparison of the primary structure of human keratins using the publicly available ClustalW and TreeView software. Sequence relatedness is inversely correlated with the length of the lines connecting the various sequences, and to the number and position of branch points. This comparison makes use of the sequences from the head and central rod domain for each keratin. A few keratins were left out for clarity purposes. Two major branches are seen in this tree display, corresponding to type I and type II sequences. Beyond this dichotomy, each subtype is further segregated into major subgroupings (denoted by different colors). B. Organization of functional type I keratin genes, all which are clustered on human chromosome 17, with the only exception being K18 (see “*” in C), which is located at the telomeric (Tel) boundary of the type II gene cluster. (Cen = centromere.) A large number of genes encoding keratin-associated proteins (KAP) interrupts the type I gene cluster, between KRT40 and KRT33A. [Pseudo = pseudogene (nonfunctional).] C. Organization of functional type II keratin genes, which are clustered on human chromosome 12. The K8 and K18 genes are separated by 450,000 bp. D. Schematic representation of the tripartite domain structure shared by all keratin and other IF proteins. A central α-helical “rod” domain acts as the major determinant of self-assembly. This rod domain is partitioned into subdomains 1A, 1B, 2A, and 2B, and flanked by nonhelical “head” and “tail” domains at the Nand C-termini, respectively. Both ends of the rod domain contain 15–20 amino acid regions (red) that are highly conserved among all IF proteins.

The extraordinary stability of keratin subunits reflects the tightness of interactions between type I and type II keratins.14 Most of the intracellular pool of keratin proteins (>95%) is polymerized.4 There is evidence that keratin IF assembly is initiated at the cell periphery, near the cortical F-actin cytoskeleton, in cultured epithelial cells.15 Keratins form the major IF network in all epithelial cells.2,3,9 The abundance and organization of keratin IFs in vivo differ among epithelia. Keratin proteins are highly abundant (10%–80% of total cellular proteins) in surface-exposed stratified squamous epithelia (e.g., epidermis, oral mucosa, corneal epithelium, etc.).7 In epithelial cells of such tissues, keratin IFs are organized in a pancytoplasmic network extending from the surface of the nucleus to the cytoplasmic periphery, where they are membrane-anchored at sites of cell–

matrix and cell–cell adhesion (hemidesmosomes, desmosomes) (Fig. 46-2B). In simple epithelia (e.g., liver, gut, pancreas, etc.), keratins are less abundant. In such tissues, polarized epithelial cells often feature asymmetrically organized keratin IFs concentrated mostly at the cytoplasmic periphery and, particularly, the apical pole.4 Several associated proteins contribute to the organization and regulation of keratin IFs in these various settings.16 Some of these proteins promote the bundling of keratin IFs (e.g., filaggrin, trichohyalin), their association with microtubules and actin microfilaments (e.g., plectin, BPAG isoforms) and/or with ­desmosomes or hemidesmosomes (desmoplakin, ­plakophilin, BPAG isoforms, etc.) (Fig. 46-2). Other partners, for example, TRADD, 14–3-3, Akt, reflect the newly discovered participation of keratin IFs in ­signaling roles.17

7 A

C

E

F

Skin provides a beautiful example of the tight relationship that has evolved between keratin gene regulation and epithelial differentiation. More than half of all known keratin genes are expressed in mature mammalian skin tissue alone. The architectural complexity of adult skin epithelia is achieved through a temporally and spatially regulated expression of keratin genes and a number of other epithelial differentiation-related genes.7,18 In the clinical setting, keratin typing is often exploited in diagnosing cancer type, its differentiation status (and therefore prognosis), as well as the origin of the cells forming metastatic foci. This strategy is also applied for diseases other than cancer (see below).4 In “thin” interfollicular epidermis (e.g., trunk; Fig. 46-2), mitotically active cells of the basal layer act as progenitors, and consistently express K5 and K14 as their main keratin pair, along with low levels of K15. Onset of differentiation coincides with the appearance of the K1/K10 pair through a robust transcriptional induction that occurs at the expense of the K5/K14 genes, which are downregulated.7,18 Accordingly, K1/K10 keratins are readily detectable in the lowermost suprabasal layer of epidermis (Fig. 46-2D). The appearance of K1 and K10 correlates with a sudden

and dramatic shift in the organization of keratin IFs, which now exhibit significant bundling.19 Another type II gene, K2e, is expressed at a later stage of differentiation, i.e., the granular layer.20 The epidermis of palm and sole skin is specialized for resisting a high degree of mechanical stress, and thus is markedly thicker. This function is reflected in its architecture of alternating stripes of primary and secondary ridges,21 and again, in keratin expression. In the thick, stress-bearing, primary ridges, the major differentiation-specific (type I) K9 is presumed to foster a more resilient cytoskeleton. In the thinner secondary ridges, postmitotic keratinocytes preferentially express the (type II) K6a and (type I) K16 and K17.22 Relative to K1, K9, and K10, the properties of K6a, K16, and K17 likely foster greater cellular pliability, thereby providing flexible “hinge” regions between the more rigid, K1/K9-rich primary ridges.22 While this attractive model remains to be supported by direct experimentation, it is consistent with the dramatic upregulation of K6a, K6b, K16, and K17 that occurs in keratinocytes recruited from wound margins to participate in the restoration of the epidermal barrier following injury.23,24 Epidermal disease states are often accompanied by a deviation from normal terminal differentiation and, not surprisingly, they are almost always accompanied by altered keratin gene expression. For instance, K6a, K6b, K16, and/or K17, normally restricted to wound repair in trunk epidermis, are ectopically induced in

Epidermal Growth and Differentiation

KERATIN GENE EXPRESSION MIRRORS EPITHELIAL DIFFERENTIATION: THE CASE OF EPIDERMIS

::

Figure 46-2  Keratin filaments and interfollicular epidermis. A. Visualization of filaments, reconstituted in vitro from purified human K5 and K14, by negative staining and electron microscopy. (Bar = 150 nm.) B. Double-labeling for keratin (red chromophore) and desmoplakin, a desmosome component (green chromophore), by indirect immunofluorescence of human epidermal cells in culture. Keratin IFs are organized in a network that spans the entire cytoplasm and are attached at desmosomal cell–cell contacts (arrowheads) between cells. (n = nucleus; bar = ∼50 μm.) [Micrograph used with permission from Dr Kathleen Green (Northwestern University).] C. Histological cross section of resin-embedded human trunk epidermis, revealing the basal (B), spinous (S), granular (G), and cornified (C) cell layers. (Bar = ∼50 μm; n = nucleus.) D and E. Differential distribution of keratin epitopes on human skin tissue cross sections as visualized by an antibody-based detection method. D. K10 is primarily concentrated in the differentiating, suprabasal layers of epidermis. E. K14 occurs in the basal layer, where the epidermal progenitor cells reside. Dashed line indicates the basal lamina. (Bar = ∼50 μm.) F. Ultrastructure of the boundary between the basal and suprabasal cells in mouse trunk epidermis, as seen by routine transmission electron microscopy. The sample, from which this micrograph was taken, is oriented in the same manner as frame C. Organization of keratin filaments as loose bundles correlates with the expression of K5–K14 in basal cells (brackets), whereas the formation of denser, electron-dense filament bundles reflects the onset of K1–K10 expression in early differentiating cells (arrowheads). Arrows point to desmosomes connecting the two cells. (Bar = 2 μm; n = nucleus.)

Chapter 46

B

D

481

7

Section 7 :: Disorders of Epidermal Differentiation and Keratinization

482

psoriasis and related hyperproliferative disorders, nonmelanoma skin cancers, viral infections, and other conditions accompanied by inflammation.23,25,26 Similar “replacement” of the K1 and K10 keratin pair by K6, K16, and K17 occurs when normal human keratinocytes are placed in culture.23,25,27 During early progression toward malignancy, cutaneous squamous cell carcinoma progressively shifts from being K6/K16positive while maintaining some degree of K1/K10 expression, thus reflecting a differentiated state, to being entirely negative for K1/K10 and positive for the simple epithelial keratins K8/K18, indicative of a less differentiated and more aggressive state.28 These variations in keratin gene expression likely impact the biological properties of keratinocyte in a significant way.

FUNCTION OF KERATIN IN THE EPIDERMIS AND OTHER SKIN EPITHELIA A major function fulfilled by keratins and all other IF proteins is to enhance the cell’s ability to withstand trauma. This structural support function3,4 is made possible by the unique mechanical properties exhibited by IF networks.24 This function is enhanced by attachment of IFs to adhesion complexes (desmosomes, hemidesmosomes), and to F-actin and microtubules.3,4,16 Partial or complete loss of this function, for example, through inherited mutations, underlies a wide variety of rare diseases that render cells fragile and unable to sustain mechanical stress (Table 46-2). In vivo, the mechanical properties of IF networks likely need to be modulated, in a dynamic fashion, to meet the demands placed on cells by changing physiological circumstances. To a degree, varying needs along a continuum of viscoelastic properties likely account, at least in part, for the dynamic regulation of keratin IF genes and their proteins in vivo.17,24 The recent discovery of nonmechanical functions for keratin proteins has placed the field on an exciting new path.17 In hair follicles, K17 promotes the anagen (growth) phase by attenuating TNF-α-induced apoptosis in matrix keratinocytes.29 In the epidermis, the suprabasally expressed K10 regulate proliferation in the basal layer of epidermis and in sebaceous glands, likely through a noncell-autonomous mechanism,30,31 while K17 cell autonomously regulates protein synthesis and cell size in wound-proximal keratinocytes.32 Keratins influence the melanin pigment distribution and, thus, skin pigmentation.33–35 In polarized epithelia, keratin IFs impact the distribution of organelles, routing of specific outer membrane proteins, and response to stress.36 These newly defined keratin functions, which are just beginning to be understood, involve regulated interactions between keratin proteins and noncytoskeletal proteins, many exerting key roles in specific signaling pathways.16,17,24,36 Interference with these functions could play a role in the pathogenesis of disorders linked to IF gene mutations.4 The discovery of these novel keratin functions provides an opportunity to better understand the diversity and context-dependent regulation of IF genes and their proteins.

MUTATIONS IN EPIDERMAL KERATINS UNDERLIE SEVERAL INHERITED SKIN BLISTERING DISEASES In the 1980s, ultrastructural studies showed that ­epidermal basal keratinocytes of patients with the Dowling-Meara form of epidermolysis bullosa simplex (EBS) contained dense cytoplasmic aggregates,37,38 later shown to contain mispolymerized keratin.39,40 In parallel, reverse genetic studies showed that expression of dominant-negative keratin mutations cause keratin IF aggregation in cultured cells, and epithelial fragility in vivo.41,42 In the early 1990s, the first mutations in keratins K5 and K14 were linked to EBS.39,43,44 In EBS, K5/K14-expressing basal layer keratinocytes literally rupture in response to mild mechanical trauma to the skin. Fragility is occasionally seen in other sites of K5/K14 expression, such as the cornea and oral mucosa.45 Similarly, dominant mutations in the suprabasally expressed K1, K10, and K2e were found to cause epidermolytic hyperkeratosis (EHK),46,47 ichthyosis bullosa of Siemens,48 and related diseases (Table 46-2). Such efforts established that compromising keratin function engenders structural failure and fragility. In specific instances, depending on the disorder, this primary defect is accompanied by enhanced proliferation and hyperkeratosis,4,30 or aberrations in skin pigmentation.33–35 Since then, a broad range of additional diseases affecting either epidermal appendages (e.g., hair, nail) or nonskin epithelia (e.g., oral mucosa, cornea) have been linked to keratin mutations.4,49 The following general principles can be drawn from the large body of data accumulated to date while studying keratin-based disorders. The majority of cases involve single missense mutations acting in a dominantnegative fashion. Small insertions and deletions are also seen with some frequency.49 In this setting, dominance implies that disease-causing mutant keratin proteins do not markedly alter the early stages of assembly (dimer, tetramer formation) up to the step(s) involving subunit incorporation in a growing IF polymer.4 Depending on their nature and location within the keratin protein backbone, these mutations exert a wide range of effects on the assembly or organization of IFs in keratinocytes, with a corresponding impact on the severity of clinical presentation. This concept can be readily illustrated for EBS.50 Mutations altering residues that are highly conserved within the central rod domain tend to dramatically alter the structure of keratin IFs, foster the formation of aberrantly polymerized keratin aggregates, and cause severe disease (as seen in the Dowling-Meara form of EBS). Conversely, mutant proteins that elicit a clinically milder version of the disease (e.g., Weber-Cockayne EBS) affect keratin assembly more subtly, and do not cause keratin aggregation.50 The extent to which a given keratin mutant compromises the function of the entire IF network is also a function of the number and abundance of potentially redundant IF proteins occurring in a given cell, or its ability to overexpress an alternate IF protein.4 While it is assumed that these mutations elicit a cell fragility phenotype in part through their ability to alter cellular mechanics,51–53 there is evidence that they alter

7

Table 46-2

Keratin-based, Inherited Skin Bullous Disease Affecting Primarily the Epidermisa Disease

Relevant OMIM Catalog Number(s)a

Target Genes

Affected Cell Type

Comments

Basal keratinocyte

K, WC, and DM correspond to different degrees of severity; the position/nature of the mutation in K5 0r K14 is a key determinant Rare mutations in the same genes result in recessive inheritance (OMIM #60100)

Epidermolysis Bullosa Simplex with mottled pigmentation

131960

K5

Basal keratinocyte

A single dominant allele, K5P28L, has been found in multiple pedigrees. Typified by hyperpigmentation of healed skin blisters

Epidermolysis Bullosa Simplex with limb girdle muscular dystrophy

226670 (also,131950)

Plectin

Basal keratinocyte

Plectin is a cytolinker protein attaching IFs to adhesive complexes and F-actin/microtubules in keratinocytes and myocytes

Dowling-Degos disease

179850

K5 (null)

Basal keratinocyte

Inherited recessively; Features multiple aberrations in skin pigmentation

Epidermolytic Hyperkeratosis

113800

K1 or K10

Spinous keratinocyte

Same as Bullous congenital ichthyosiform erythroderma. As for EBS, there is wide variation in severity of clinical presentation, correlating with position and nature of the mutation affecting either K1 or K10

Ichtyosis hystrix (Curth-Macklin)

146490; 146600

K1 or K10

Spinous keratinocyte

Characteristic ridges or spikes present at the skin surface. Ultrastructurally, presence of large bundles of densely packed IFs around nucleus

Ichtyosis Bullosa of Siemens Palmoplantar keratodermas:

146800

K2e

Granular keratinocyte

  Epidermolytic

144200

K9

  Non-epidermolytic

139350 (diffuse) 600962 (focal)

K1 K1 or K16

Spinous keratinocyte Spinous keratinocyte

  Striate

607654

DP, Dsg1 or K1

Affects primarily flexural areas; Blistering confined to the upper suprabasal layers; Can be confused with mild EHK/BCIE Confined to the epidermis of palms and soles Reflects the unique distribution of this large type I keratin This is one of the rare conditions for which the pathogenesis is not indicative of cell fragility; May reflect a non-mechanical role for keratins Desmoplakin (DP) and desmoglein 1 (Dsg1) are structural components of desmosomes, to which keratin IFs are attached in epidermis

Spinous keratinocyte

Epidermal Growth and Differentiation

K5 or K14

::

131800 (Koebner subtype) 131800 (Weber-Cockayne) 131760 (Dowling-Meara)

Chapter 46

Epidermolysis Bullosa Simplex

a

Note: See the Intermediate Filament Database (www.interfil.org) and Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim/) ­websites for further information.

483

7

keratin regulation, for example, via posttranslational modifications,11 and elicit a cellular stress response.4,54 Treatment options for EBS are currently limited, and are primarily palliative in nature.50 They consist of supportive care for skin, management of skin blisters as they heal so as to prevent infection, and preventive avoidance of mechanical trauma.

CORNIFIED ENVELOPE

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484

Alongside the substantial build up in keratin IFs inside differentiating keratinocytes, two specializations allow the epidermis to build a remarkably effective and mechanically resilient barrier: (1) the cornified envelope (CE), a covalently cross-linked protein polymer that forms underneath the plasma membrane, and (2) an extracellular hydrophobic phase that is made up of specialized lipids synthesized by terminally differentiating keratinocytes.55 Epidermal lipids are discussed in detail in Chapter 47, and will not be discussed further here. The CE represents a complex assembly of covalently cross-linked proteins that forms underneath, and eventually replaces, the outer keratinocyte membrane in the granular layer of epidermis, as part of the final push to complete terminal differentiation. This 20-nm thick sheath, which is so insoluble and stable it resists extended boiling in the presence of strong denaturants, encases the cell’s interior, and significantly contributes to the physicochemical properties of the stratum corneum compartment.56 The extraordinary stability of the CE results in large part from the large number of ε-(-γglutamyl)-lysine isopeptide bonds between its primary constituents (see below), which are further reinforced by disulfide bridges. These isopeptide bonds are catalyzed by transglutaminases, a family of calcium-dependent enzymes.57 The outer aspect of the CE is covalently linked to ceramides and other specialized lipids that are produced by, and secreted from, differentiated granular keratinocytes, whereas large bundles of tightly packed keratin IFs are cross-linked to its inner aspect. The major protein constituents of the CE are loricrin, involucrin, filaggrin, elafin, cystatin A, cornifelin, several small proline-rich (SPR) proteins and calciumbinding S100 proteins, and “late-envelope proteins” (LEPs). In addition to these proteins, key components of desmosomes (e.g., desmoplakin, envoplakin, and periplakin) and several type II keratins (K1, K2, K5) are also cross-linked into the CE56–58 (Table 46-3). CE proteins have several interesting features in common. First, many CE proteins are encoded by genes clustered as part of the epidermal differentiation complex (EDC) locus on human chromosome 1q21. In addition to obvious evolutionary implications, this genomic clustering brings up the distinct possibility of coordinated regulation through cis-acting determinants.55,58 Second, many of these proteins are made as precursors that are activated by proteolytic cleavage, calcium binding, or other modifications at the time of CE formation. Third, many CE proteins are made of repeated units that lack an intrinsically defined three-dimensional structure. Fourth, virtually all CE proteins are transglutaminase substrates.55,57

Involucrin, loricrin, and filaggrin, in particular, are well-characterized components of the CE.56,57 Involucrin biosynthesis is initiated in the spinous compartment, soon after the onset of K1/K10 keratin expression, in differentiating epidermal keratinocytes. It is the first major component to be activated and cross-linked into the emerging CE, possibly reflecting a scaffolding role, and is concentrated in the outermost aspect of the mature CE. Profilaggrin and loricrin are synthesized in precursor forms and stored in keratohyalin granules. Loricrin is the major structural component of the CE (∼80% by weight)—this largely unstructured but highly flexible protein features glycine loops as described for type II keratins. Once activated via dephosphorylation and proteolytic cleavage, filaggrin participates in the bundling of keratin IFs in the late granular compartment of epidermis (hence accounting for its incorporation into the CE) and also is degraded to free amino acids that contribute to the cornified cell’s ability to retain water. Basic information about other CE components is provided in Table 46-3.56,57 The protein composition and fine structure of the epidermal CE differs to a degree from those of the other stratified squamous epithelia; the underlying significance of this CE heterogeneity is unclear.56,57 The important contribution of the CE toward proper barrier function in epidermis is reflected in the clinical symptoms associated with mutations altering their primary constituents in the context of human diseases55 (Table 46-3). This is particularly well illustrated by the recently documented role of filaggrin mutations in ichtyosis vulgaris, atopic dermatitis (AD), and ADassociated hay fever or asthma (the so-called atopic march; see Chapter 14).59–61 The partial or complete loss of filaggrin protein engendered by frameshift mutations in the corresponding gene compromises the epidermal barrier function and allows for the entry of irritants and allergens into the skin,62 thereby eliciting local (and even systemic) inflammation accompanied by itching, erythema, and flaking reflecting improper cornification (for further information see Chapter 14). Barrier status in the epidermis thus sets our degree of exposure to external elements and contributes to define the relationship that we have with our environment.

CONCLUDING REMARKS In this chapter, we have discussed epidermal differentiation viewed through the prism of keratin gene regulation and CE formation. While it is well established that specific type I and type II keratins are coexpressed as pairs associated with various stages of normal and pathological epidermal differentiation, and that mutations of major epidermal keratins cause various forms of skin blistering diseases, the functional implications of these different keratins, not only in terms of structural roles, but also in terms of their novel involvements in signal transduction and organelle transport, are just beginning to be understood. Additional studies are needed to better understand the roles of regulatory molecules in epidermal proliferation, homeostasis, and disease; and how the

7

Table 46-3

Protein Composition of the Cornified Envelope (CE)a Protein

Mol. Weight (kDa) (Precursor Form)

Chromos Location

CE Percent Contribution

Loricrin

26

1q21

80

Rich in Gly, Ser, Cys residues; Contains glycine loops; Flexible; Stored in keratohyalin granules; Mutated in Vohwinkel syndrome, a mutilating keratoderma with ichtyosis, and in progressive symmetric erythrokeratodermia, a related condition.

Involucrin

65

1q21

5

Made up of repeated units; Highly α-helical; Gly-, Asp-rich; Early TG substrate; May act as a scaffold during CE assembly

SPR

6–18

1q21

3–5

SPR: small proline-rich proteins; encoded by 15 genes that are differentially regulated in various stratified epithelia; Great transglutaminases substrates; Influence CE’s mechanical properties

Cystatin A

12

3cen-q21

2–5

Cysteine protease inhibitor; Also stored in keratohyalin granules; Mutations in cystatin M/E cause Harlequin ichtyosis

LCEs

9–12

1q21

unknown

LCE: late cornified envelope proteins; Encoded by 18 genes; Synthesized and incorporated at a late stage of CE formation

Profilaggrin/ Filaggrin

>400 36

1q21

2 cm in size Sometimes facial Any age, but some predilection for young adults Often recur after incomplete excision Rare potential for metastasis

a

Some authors consider 15 to be a cutoff.

edges of the lesion are poorly defined with individual cells hugging collagen bundles (“collagen entrapment”). Mitotic figures may be present, but atypical forms are not a feature. Dermatofibromas are generally factor XIIIa-positive36 and CD34−.37 There are many histologic variants of dermatofibroma, most without clinical significance. Exceptions are in Box 66-4.

A

C

Histologic Features Background of dermatofibroma/fibrous histiocytoma Variable areas of atypical cells, high cellularity May extend deeply into subcutaneous, sometimes in a honeycomb pattern May stain with CD34 a

Occasionally overlaps with aneurysmal variant.

B

Figure 66-2  A. Dermatofibroma on the right thigh of a young man. B and C. Haphazardly arranged spindle cells in the dermis. The lesion edge is poorly defined with spindle cells infiltrating between thickened collagen fibers [(hematoxylin and eosin 100× magnification (B); 200× magnification (C)].

9

Chapter 66 :: Dermal Hypertrophies and Benign Fibroblastic/Myofibroblastic Tumors

Box 66-3  Conditions Associated with Multiple (At Least 8a) Dermatofibromas

a

711

9

pink or slightly hyperpigmented), firm, and dome shaped. It must be differentiated from an early, nodular, basal cell carcinoma, and biopsy may be necessary. Unlike a basal cell carcinoma, it rarely bleeds and stays relatively stable in its smaller size. Histologically, the dermis shows fibrosis with stellate fibroblasts and dilated vessels. Identical histology is seen in pearly penile papules and periungual fibromas (Koenen’s tumors) (see Chapter 140). No treatment is necessary, and a simple shave or punch excision is usually curative.

Section 9

FIBROFOLLICULOMA/ TRICHODISCOMA

::

Figure 66-3  Soft fibromas or skin tags on the neck overlying acanthosis nigricans.

Disorders of the Dermal Connective Tissue

No treatment is necessary unless symptomatic. A common reason for removal is repeated trauma to the dermatofibroma, often secondary to shaving the lower legs. Cryosurgery may be helpful in flattening out the dermatofibroma but usually is not curative. Lesions termed “atypical,” “cellular,” “deep,” and/or “indeterminate” are generally best treated with complete excision, particularly if clinical size is >2 cm (see Box 66-4).38–44

ACROCHORDON (FIBROEPITHELIAL POLYP, SKIN TAG, SOFT FIBROMA) Acrochordons are pedunculated papules or tumors that are most commonly located on the eyelids, neck, axillae, and groin. There is a familial disposition, and acrochordons are more commonly seen in obese individuals, sometimes overlying acanthosis nigricans (Fig. 66-3). Acrochordon-like clinical lesions may be a feature of a genetic syndrome, although histologically there are differences (see Table 66-4).45,46 Histologically, an acrochordon is a polypoid lesion with a central collagenous core. Adnexal structures are generally absent. Although usually asymptomatic, lesions can become irritated or necrotic. Patients often request removal for cosmetic reasons.

Fibrofolliculomas/trichodiscomas are 2- to 4-mm, dome-shaped, yellowish to skin-colored papules located on the head, neck, and upper trunk; multiple lesions may be associated with Birt–Hogg–Dubé syndrome (see Table 66-4).45

CONNECTIVE TISSUE NEVUS/ COLLAGENOMA/ELASTOMA These hamartomas can be divided into familial, those associated with genetic disease (see Table 66-4),47,50,53–57 and other isolated variants. Connective tissue nevi present as asymptomatic, flesh-colored to yellow– brown papules or plaques that may be solitary or grouped, linear, or irregular in distribution (Fig. 66-4).58 The overlying epidermis is usually smooth. Histologically, connective tissue nevi show a normal epidermis overlying collagen in the lower dermis. The collagen may be subtly increased, thickened, or oriented vertically to the epidermis, and muscin may be increased. Elastic fibers may also be increased (elastoma). Familial cutaneous collagenoma is an autosomal dominantly inherited condition of multiple, often papular connective tissue nevi usually appearing postpuberty on the trunk and upper extremities.59,60 There

FIBROUS PAPULE (ANGIOFIBROMA)

712

A fibrous papule is a common papule on the lower portion of the nose or the central face. It usually presents in adulthood. Multiple lesions are a feature of certain genetic syndromes (see Table 66-4),47–51 but occasionally may be seen in patients with no other stigmata of a genetic disorder.52 The fibrous papule is small (2–5 mm), nontender, flesh colored (sometimes

Figure 66-4  Cutaneous collagenoma, a connective tissue nevus involving almost the entire back.

may be associated systemic abnormalities such as progressive cardiomyopathy.

DESMOID TUMOR (AGGRESSIVE FIBROMATOSIS)

Infantile fibromatosis presents as a rapidly growing nodule on the head and neck, shoulder/upper arm, or thigh; generally before age 2. The lipofibromatosis variant has a predilection for the hands and feet.69 Histologically, the tumor may have an immature mesenchymal pattern, variable amounts of adipose tissue,69 or a desmoid tumor-like pattern. Local recurrence is common, but surgery is the treatment of choice.70,71

INFANTILE MYOFIBROMATOSIS Infantile myofibromatosis generally presents before age 2, with many cases being congenital.72,73 Multiple nodules involving the skin and other organs (gastrointestinal, kidney, lung, heart) are seen, with mortality approaching 75%.73 Prognosis is generally excellent if only a solitary nodule (then termed myofibroma, see below) or multiple nodules limited to the skin are seen. For multiorgan involvement, treatment with surgical resection, chemotherapy and radiotherapy have been described. Histologic diagnosis relies on the identification of two separate components—a fascicular myofibroblastic pattern at the periphery with a hemangiopericytoma-like pattern in the center. In the past, many cases were considered to be infantile or childhood hemangiopericytomas. Mitotic figures, vascular invasion, and tumor necrosis can be found, but do not predict malignant transformation.74 Biopsy of these lesions, especially in infants and young children, is important to ensure that the lesions do not represent congenital infantile fibrosarcoma. Histopathologic examination as well as cytogenetic and molecular pathology studies will distinguish myofibromas (chromosome 8 abnormalities) from congenital infantile fibrosarcomas (translocation between chromosomes 12 and 15—ETV6 and NTRK3 genes).75

FIBROUS HAMARTOMA OF INFANCY

Figure 66-5  Desmoid tumors involving upper chest and epigastric region. These represent recurrences after multiple surgical interventions. This patient also had intraabdominal desmoid tumors.

9

Fibrous hamartoma of infancy is a rare benign tumor that presents before age 2 (up to 25% congenital)76,77 as a solitary, painless, rapidly growing, flesh-colored, illdefined, subcutaneous nodule, or plaque. There is a male predominance. The most common locations are the axillary region, upper arm, upper trunk, inguinal region, and external genital region.76,77 These lesions rarely present with overlying skin changes such as hypertrichosis, alteration in pigmentation, and eccrine gland hyperplasia.77 Histologic features are characteristic, with an organoid pattern of fibrous trabeculae, myxoid areas with spindle cells, and adipose tissue.76,78 The treatment of choice is complete excision.73 An aggressive approach should be avoided because the overall prognosis is excellent.79

Chapter 66 :: Dermal Hypertrophies and Benign Fibroblastic/Myofibroblastic Tumors

Desmoid tumors, also known as deep or aggressive fibromatoses, are a type of fibromatosis. All types (extra-abdominal, abdominal wall, intra-abdominal) may be induced by trauma (Fig. 66-5). Mutations have been found in the adenomatous polyposis coli (APC) gene (5q21).61 Hormonal influences (e.g., pregnancy) are implicated in abdominal wall tumors.62 Tumors associated with Gardner/Familial adenomatous polyposis (FAP) (see Table 66-4)63 are often intraabdominal,64 may be more aggressive and surgically unresectable, and are associated with a 10% mortality.65 Extra-abdominal tumors are deep-seated, often located in the area of the shoulder and pelvic girdle, chest wall, or head and neck.66 Although surgery is widely accepted as first-line treatment,67 complete surgical excision is difficult to achieve, and recurrences are common. Intra-abdominal tumors, particularly those associated with Gardner/FAP, may be best treated, if symptomatic, with radiation or chemotherapy.68

INFANTILE FIBROMATOSIS (LIPOFIBROMATOSIS, PEDIATRIC DESMOID TUMOR)

713

9

Section 9

A

B

Figure 66-6  A. Well-defined pink nodules of infantile digital fibromatosis in a 9-month-old patient. B. The patient at age 2.5 years, with spontaneous resolution of the nodules. (Used with permission from Richard J. Antaya, MD.)

:: Disorders of the Dermal Connective Tissue

FIBROMATOSIS COLLI (STERNOCLEIDOMASTOID TUMOR OF INFANCY) Fibromatosis colli is an often self-limiting, rapidly growing tumor, presenting in the first few weeks of life. It is characterized by a benign proliferation of fibroblasts in the lower one-third of the sternocleidomastoid muscle, rarely bilateral, and occasionally associated with torticollis or facial asymmetry.80 The tumor often resolves within the first year of life.80 Fine-needle aspiration is the preferred technique for diagnosis.81,82

INFANTILE DIGITAL FIBROMATOSIS Infantile digital fibromatosis is a rare form of superficial juvenile fibromatosis presenting as (an) asymptomatic, flesh-colored, firm nodule(s) on the fingers and toes (tending to spare the thumb or hallux) (Fig. 66-6A), primarily in infants and less commonly in children. One-third of cases are congenital.83 Histologically, poorly circumscribed, interlacing bundles of myofibroblasts are observed. The pathognomonic finding is eosinophilic, perinuclear inclusion bodies composed of actin filaments, which stain red with Masson trichrome stain and purple with phosphotungstic acid-hematoxylin.84 Multiple clinically similar tumors, but without inclusion bodies on histopathologic examination, are associated with brachydactyly and facial dyspigmentation.85 Despite the observation of spontaneous regression over years (Fig. 66-6B) and a high recurrence rate after excision, surgical intervention is common because deformities of the digit and contractures can occur with larger lesions.83

CALCIFYING APONEUROTIC FIBROMA 714

Calcifying aponeurotic fibroma is an uncommon, benign fibrous tumor. It is most commonly found on

the palms and soles of male children and young adults (peak incidence between the ages of 8 and 14).86,87 However, it can present in any area that is closely related to aponeuroses.86 It is a very slow growing, deep-seated firm proliferation that presents as an asymptomatic infiltrative soft tissue mass, usually measuring less than 3 cm in diameter.86 If symptomatic, surgical excision may be performed, although there is a 50% local recurrence rate. Local recurrence is more common in children younger than 5 years of age.86 On histopathologic examination, it is an ill-defined, poorly circumscribed tumor composed of spindled fibroblasts surrounding central calcified foci. The lesion typically is organized into nodules, with central hyalinization and incipient calcification surrounded by a palisade of chondrocyte-like cells. Less cellular areas contain spindled fibroblastic cells between coalescing calcified nodules. Osteoclastic giant cells may border the calcific deposits. These lesions may demonstrate actin and CD99 and S100 proteins with immunostaining.

JUVENILE HYALINE FIBROMATOSIS/INFANTILE SYSTEMIC HYALINOSIS Juvenile hyaline fibromatosis (JHF) is a rare, autosomal recessive condition secondary to a defect on chromosome 4q21 associated with the locus of the capillary morphogenesis gene-2 (CMG2).88 From infancy, subcutaneous, pearly papules and firm, large nodules that progressively enlarge and may ulcerate appear on the nose, chin, ears, scalp, hands (Fig. 66-7), back, and knees.89 Histologically, cells with perinuclear vacuoles are seen in a hyalinized and chondroid stroma. Patients tend to have gingival hypertrophy, which can result in periodontal disease and caries. Progressive joint contractures, osteolysis, and muscular weakness can result in severe debilitation. Preliminary genotype–phenotype analyses suggest that abrogation of binding by von Willebrand’s factor type A domain of CMG2 results in severe disease

Ledderhose disease is characterized by plantar fibrosis especially over nonweight-bearing areas of the sole and has similar features to Dupuytren disease histologically.93,96 Contractures are uncommon.96,98 Typically adults are affected, but children can manifest disease.93 These lesions may be treated with surgical excision.

9

PEYRONIE DISEASE (PENILE FIBROMATOSIS)

typical of infantile systemic hyalinosis (ISH), whereas in-frame mutations affecting the highly conserved cytoplasmic domain result in a milder phenotype.90 Although the fibrous skin lesions, joint contractures, gingival hypertrophy, and osteolysis are shared with JHF, the manifestations of ISH are present within the first months of life and often at birth.91 Patients may also show diffusely thickened skin, hyperpigmented plaques on bony prominences, visceral involvement, frequent infections, and persistent diarrhea with failure to thrive, leading to death during infancy. The histologic and ultrastructural appearance of biopsied lesional skin resembles that of JHF. Currently, no widely accepted effective treatment exists for JHF or ISH. Surgical excision is often not feasible due to the number and size of the tumors, and anesthesia can be complicated because of the oral and dental issues.

PALMOPLANTAR FIBROMATOSES Dupuytren contracture (palmar fibromatosis) is characterized by progressive fibrosis of the palmar fascia, most commonly presenting as one or more nodules over the fourth and fifth metacarpal head. Nodules become cords, and joint contractures and flexion deformities of the fingers may follow.92 Significant risk factors for development of Dupuytren contracture include old age, male sex, white northern European ancestry, family history, seizures, alcohol-induced liver disease, trauma, smoking, and diabetes mellitus.93–95 This condition rarely occurs before age 30 and is very rare in children.93 Concurrent plantar disease, knuckle pads, and/or keloids may be seen.93,96 Histologically, there are uniform, spindled fibroblasts separated by collagen.93 Surgical correction may be the treatment of choice of progressive disease.92 Recurrence is more common in patients with greater initial deformity, but less common if good surgical correction is achieved and postoperative rehabilitation provided.97

KNUCKLE PADS Knuckle pads are circumscribed, thickened plaques over the dorsal aspects of the interphalangeal joints. Many patients have coexisting palmar, plantar, or penile fibromatosis.93 Histologically, these lesions are very similar to Dupuytren disease. False knuckle pads are due to repetitive mechanical trauma.

PACHYDERMODACTYLY Pachydermodactyly is a rare form of benign digital fibromatosis consisting of symmetric, painless, circumscribed swelling of the proximal interphalangeal joints of the fingers, often sparing the thumb.104 It primarily affects adolescent males. Some consider this a variant of knuckle pads. It may be associated with tuberous sclerosis, atrophia maculosa varioliformis cutis (noninflammatory pitted scarring, usually on the face) and carpal tunnel syndrome. Histologically there is hyperkeratosis, acanthosis, and increased dermal fibrosis.

Chapter 66 :: Dermal Hypertrophies and Benign Fibroblastic/Myofibroblastic Tumors

Figure 66-7  Juvenile hyaline fibromatosis. Tumors involving the hand. Both hands were affected.

Fibrosis of the dorso-lateral penis, resulting in curvature of the penis and erectile dysfunction, is termed Peyronie disease. Risk factors include genetic predisposition, trauma to the penis, smoking, alcohol consumption, and history of diabetes or hypercholesterolemia.99,100 Over several years, patients may have stabilization and rarely spontaneous regression of the disorder.101 Conservative management is often recommended.102 Surgery is reserved for those with compromised sexual function or disabling deformity.101,103

NODULAR FASCIITIS Nodular fasciitis is a benign, self-limiting proliferation of fibroblasts of uncertain etiology that often follows trauma, observed most frequently on the upper extremity.105 Although it is seen most commonly in young adults, it can occur at any age, without racial or sex predilection. It presents as a rapidly growing, painful mass (generally less than 2 cm) in the subcutis, fascia, or muscle. Cranial fasciitis is the most common variant in children and involves the head and neck. Histologically, nodular fasciitis presents as a poorly demarcated nodule in the subcutis, fascia, or dermis that is composed of spindled “tissue-culture”-like

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9

fibroblasts and myofibroblasts in a loose, myxoid, highly vascular stroma that resembles granulation tissue. These lesions often have associated hemorrhage. Mitotic figures are present, but atypia and nuclear polymorphism are not seen. Despite the possibility of spontaneous involution, excision is the treatment of choice, with recurrences being rare.

ELASTOFIBROMA (ELASTOFIBROMA DORSI) Section 9 :: Disorders of the Dermal Connective Tissue

Elastofibroma is a rarely diagnosed, benign, fibroproliferative, soft-tissue tumor that occurs predominantly in the periscapular region of middle-aged to elderly women.106 Many patients have bilateral involvement. Although the exact etiology is unknown, it is suspected that chronic subclinical microtrauma may lead to reactive hyperplasia of elastic fibers, with consequently increased production of fibrous tissue. Clinically, this tumor presents as a poorly circumscribed, firm, mobile mass; typically, the lesions are concealed with retraction and protuberant with protraction of the shoulders. More than 50% of patients are asymptomatic and present with a painless swelling. Magnetic resonance imaging often shows a characteristic layering of fibrous tissue and adipose tissue.107 Typical histologic findings are thickened collagen and chenille-like elastic fibers admixed with adipose tissue.

ACQUIRED DIGITAL FIBROKERATOMA (ACRAL FIBROKERATOMA) This lesion is a keratotic papule acquired in adulthood, often on the digits or occasionally the palms/ soles (Fig. 66-8).108 Histologically, there is overlying hyperkeratosis with abundant dermal collagen that is perpendicular to the epidermis in the papillary dermis.

DERMATOMYOFIBROMA This is a 1–2 cm, ill-defined, indurated plaque, most commonly seen in young women on the shoulder or upper arm.109,110 Histologically, in the deep dermis, there are fascicles of slender spindle cells parallel to the epidermis, with sparing of adnexal structures.

PLEOMORPHIC FIBROMA Pleomorphic fibromas are usually solitary and appear in middle-aged to older individuals. They are generally nondescript, slow-growing, dome-shaped, or polypoid lesions with a predilection for the extremities.111 Clinical behavior is benign; histologically, a polypoid lesion with a collagenous core has multinucleated cells and scattered large cells with atypical nuclei. Even with incomplete removal, recurrence is uncommon.

COLLAGENOUS FIBROMA (DESMOPLASTIC FIBROBLASTOMA) Collagenous fibroma usually presents in the fifth to sixth decades with a 5:1 male–female ratio.112 It is a benign tumor that appears as a slow-growing, painless, mobile mass (1–20 cm) located in the subcutaneous tissue or just deep to skeletal muscle. This tumor has a predilection for the upper arm and shoulder; but may also occur on the posterior neck, upper back, lower extremities, hand, abdominal wall, and hip joint. Histologically, the tumor has an infiltrative appearance into fascia or skeletal muscle and is composed of bland stellate and spindle-shaped fibroblasts and myofibroblasts in a collagenous matrix.

MYOFIBROMA All ages may be affected by myofibroma. This is a tumor that some consider of vascular origin113 that is similar histologically to the tumors of infantile myofibromatosis.72,73 When solitary or multiple in the skin, the prognosis is excellent, with spontaneous regression in some cases.72 These tumors have a wide distribution, but are often on the extremities in adults (Fig. 66-9), and are painless.73 Histologic findings are diagnostic, commonly with multiple nodules or poorly circumscribed fascicles of spindle cells that express smooth muscle actin intermixed with thick collagen, sometimes with peripheral cells having a pericytic appearance.

SOLITARY FIBROUS TUMOR 716

Figure 66-8  Acquired digital fibrokeratoma. A hyperkeratotic papule with a collarette on the palm, a slightly unusual location.

Solitary fibrous tumor is a tumor once thought to only involve the pleural cavity but now known to be a rare

Box 66-5  Conditions Associated with Cutis Verticis Gyrata

PACHYDERMOPERIOSTITIS

Figure 66-9  Myofibroma. A somewhat ill-defined, focally firm and focally spongy, pink to flesh-colored tumor (with smaller nodules within it) on the ankle. This asymptomatic lesion had been present since at least age 9 and had been growing slowly over the last 15 years.

soft tissue tumor.114 It usually behaves nonaggressively. Histologically, there are dilated vessels, sometimes staghorn (some consider solitary fibrous tumor and hemangiopericytoma to be part of a spectrum), with interspersed spindle cells that are arranged in a “patternless” pattern. Cells are CD34+. Malignant tumors have been described and should be ruled out when there is increased cellularity, pleomorphism, or mitoses.

Pachydermoperiostosis (primary hypertrophic osteoarthropathy) is a rare genetic syndrome with most cases having autosomal dominant transmission.118 At puberty, there is progressive enlargement of the joints due to pachydermia, periostosis, and clubbing. Other features include thickened skin on the face and scalp (resembling cutis verticis gyrata), palmoplantar hyperhidrosis, and acro-osteolysis. Arthralgias can be quite debilitating. Disease progresses for 5–20 years before stabilizing. Primary hypertrophic osteoarthropathy should be distinguished from secondary hypertrophic osteoarthropathy, which is generally secondary to pulmonary or cardiac disease.

CEREBRIFORM FIBROUS PROLIFERATION In patients with Proteus syndrome, the soles (and sometimes the palms) have cerebriform overgrowth with gigantism. There is increased dermal fibrosis.

KEY REFERENCES Full reference list available at www.DIGM8.com

CUTIS VERTICIS GYRATA This rare condition presents on the scalp, often at puberty, and when primary, affects males more commonly. The scalp appears folded, with furrows running anteriorly to posteriorly. Primary disease is idiopathic or associated with neuropsychiatric disorders.115–117 Histologically, the areas of folded scalp appear normal. Cutis verticis gyrata may also be seen secondarily in association with a variety of inflammatory or neoplastic diseases (see Table 66-4 and Box 66-5).115 Clues for secondary involvement include early onset of disease (sometimes congenital), asymmetric disease, and disordered furrows that are not oriented anterior to posterior.115 If the face and acral sites are involved, pachydermoperiostitis should be considered.

DVD contains references and additional content 13. Seifert O, Mrowietz U: Keloid scarring: Bench and bedside. Arch Dermatol Res 301:259, 2009 31. Wolfram D et al: Hypertrophic scars and keloids—A review of their pathophysiology, risk factors, and therapeutic management. Dermatol Surg 35:171, 2009 41. Horenstein MG et al: Indeterminate fibrohistiocytic lesions of the skin: Is there a spectrum between dermatofibroma and dermatofibrosarcoma protuberans? Am J Surg Pathol 24:996, 2000 43. Guillou L et al: Metastasizing fibrous histiocytoma of the skin: A clinicopathologic and immunohistochemical analysis of three cases. Mod Pathol 13:654, 2000 93. Fetsch JF, Laskin WB, Miettinen M: Palmar-plantar fibromatosis in children and preadolescents: A clincopathologic study of 56 cases with newly recognized demographics and extended follow-up information. Am J Surg Pathol 29:1095, 2005 116. Polan S, Butterworth T: Cutis verticis gyrata: A review with report of seven new cases. Am J Ment Defic 57:613, 1953

Chapter 66 :: Dermal Hypertrophies and Benign Fibroblastic/Myofibroblastic Tumors

Neuropsychiatric (e.g., schizophrenia, mental retardation, seizures) Genetic syndromes (see Table 66-4) Inflammatory (e.g., eczema, psoriasis, folliculitis, impetigo, erysipelas) Local neoplasms (e.g., congenital melanocytic nevus, neurofibroma, fibroma, hamartoma) Systemic illness (e.g., myxedema, acromegaly, amyloidosis, syphilis, leukemia, acanthosis nigricans, insulin resistance syndrome)

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Chapter 67 :: A  netoderma and Other Atrophic Disorders of the Skin :: Catherine Maari & Julie Powell ANETODERMA AT A GLANCE Circumscribed 1- to 2-cm areas of flaccid skin that may be elevated, macular, or depressed. Often circumscribed sac-like protrusions.

Section 9

Primary or secondary to a preceding dermatosis in the same location.

::

Association with antiphospholipid syndrome.

Disorders of the Dermal Connective Tissue

Pathology consists of loss of elastic tissue in the dermis.

ANETODERMA EPIDEMIOLOGY The lesions in anetoderma usually occur in young adults between the ages of 15 and 30 years and more frequently in women than men. Anetoderma is rare, but the incidence is unknown. Several hundred cases have been reported.1–4

PATHOGENESIS The pathogenesis of anetoderma is unknown. The key defect is damage to the dermal elastic fibers. Anetoderma may be considered to be unusual scars, because scars also have decreased elastic tissue. The loss of dermal elastin could be the result of an impaired turnover of elastin caused by either increased destruction or decreased synthesis of elastic fibers.

CLINICAL FINDINGS

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All types of anetoderma are characterized by a circumscribed loss of normal skin elasticity. The characteristic lesions are flaccid circumscribed areas of slack skin with the impression of loss of dermal substance forming depressions, wrinkling, or sac-like protrusions (Fig. 67-1). These atrophic, skin-colored, or blue–white lesions are 5–30 mm in diameter. The number varies from a few to hundreds. The skin surface can be wrinkled, thinned, and often depigmented, and a central depression may be seen. Coalescence of smaller lesions can give rise to larger herniations. The examining finger sinks without resistance into a distinct pit with

sharp borders as if into a hernia ring (buttonhole sign). The protrusion reappears as soon as the pressure from the finger is removed.4 The most common sites for these asymptomatic lesions are the chest, back, neck, and upper extremities. They usually develop in young adults, and new lesions often continue to form for many years as the older lesions fail to resolve. Primary anetoderma occurs when there is no underlying associated skin disease (i.e., it arises on clinically normal skin). It is historically subdivided into two types: (1) those with preceding inflammatory lesions, mainly erythema (the Jadassohn–Pellizzari type), and (2) those without preceding inflammatory lesions (the Schweninger–Buzzi type). This classification is only of historical interest, because the two types of lesions can coexist in the same patient; the prognosis and the histopathology are also the same.4 True secondary anetoderma implies that the characteristic atrophic lesion has appeared in the exact same site as a previous specific pathology; the most common causes are probably acne and varicella. Numerous and heterogeneous dermatoses have been associated with secondary anetoderma, namely syphilis, Lyme disease, molluscum contagiosum, pilomatricomas, juvenile xanthogranuloma, xanthomas, granuloma annulare, leprosy, discoid lupus, sarcoidosis, and lichen planus, to mention only a few. Anetoderma has also been described in premature infants and, in some cases, it may have been related to the use of cutaneous monitoring leads or adhesives.5 Both types may be associated with an underlying disease, mainly antiphospholipid syndrome6 and human immunodeficiency virus. Although most cases are sporadic, rare cases of familial anetoderma have been recently described and are usually not associated with preexisting lesions.7

PATHOLOGY In routinely stained sections, the collagen fibers within the dermis of affected skin appear normal. Perivascular lymphocytes are often present in all types of anetoderma and do not correlate with clinical inflammatory findings.8 The predominant defect as revealed by elastic tissue stains is a focal partial or complete loss of elastic tissue in the papillary and/or midreticular dermis. There are usually some residual abnormal, irregular, and fragmented elastic fibers (Fig. 67-2).9 Presumably, the weakening of the elastic network leads to flaccidity and herniation. Direct immunofluorescence sometimes shows linear or granular deposits of immunoglobulins and complement along the dermal–epidermal junction or around the dermal blood vessels in affected skin.10

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A

B

Electron microscopy demonstrates that the elastic fibers are fragmented and irregular in appearance and occasionally can be engulfed by macrophages.

DIFFERENTIAL DIAGNOSIS Anetoderma must be differentiated from other disorders of elastic tissue as well as atrophies of the connective tissue (Box 67-1).

Keloids form nodules that are much firmer on palpation. A history of trauma is often elicited, and the pathology is very distinct. Glucocorticoid-induced atrophy occurs most commonly over the triceps or buttocks at sites where injections are usually given. Clinically, the lesions resemble atrophoderma. History is obviously most helpful in making the diagnosis. On histopathology, polarization may show the steroid crystals in the dermis. Nevus lipomatosus superficialis of Hoffman and Zurhelle presents as a clustered group of soft, skincolored to yellow nodules usually on the lower trunk and buttocks and present since birth. Histology shows ectopic mature lipocytes located in the dermis. Papular elastorrhexis is an acquired disorder characterized by white, firm nonfollicular papules measuring 1–3 mm, evenly scattered on the chest, abdomen, and back. It usually appears in adolescence or early adulthood. The pathology demonstrates focal degeneration of elastic fibers and normal collagen. There are no associated extracutaneous abnormalities. This is believed by some authors to be a variant of connective tissue nevi11 or an abortive form of the Buschke–Ollendorff

Anetoderma and Other Atrophic Disorders of the Skin

Figure 67-1  Anetoderma. Primary anetoderma. A. Multiple, sharply defined, depressed lesions that look punched out in the supraclavicular region. B. Soft, sac-like protrusions on the back. When depressed, there is the buttonhole phenomenon. This is the same patient as in A.

Box 67-1  Differential Diagnosis of Primary Anetoderma

Figure 67-2  Anetoderma. Pathology shows decrease of elastic fibers in the papillary and reticular dermis (Weigert’s stain). (Used with permission from Victor Kokta, MD.)

ELEVATED

DEPRESSED

Secondary anetoderma Acne scars Keloids Nevus lipomatosus superficialis Papular elastorrhexis Connective tissue nevi

Secondary anetoderma Glucocorticoid-induced atrophy Acne scars

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syndrome,12 whereas others think that these represent papular acne scars.13 They are differentiated from anetoderma by being firm noncompressible lesions. Middermal elastolysis (MDE) usually consists of larger areas with diffuse wrinkling without herniation and with elastolysis limited to the middermis (See below).

TREATMENT

Section 9 :: Disorders of the Dermal Connective Tissue

There is no regularly effective treatment. In secondary anetoderma, appropriate treatment of the inflammatory underlying condition might prevent new lesions. In patients with limited lesions that are cosmetically objectionable, surgical excision may be useful. Various therapeutic modalities have been tried but with no improvement of existing atrophic lesions, including intralesional injections of triamcinolone and systemic administration of aspirin, dapsone, phenytoin, penicillin G (benzylpenicillin), and vitamin E. Some authors have reported improvement with hydroxychloroquine.

OTHER ATROPHIC DISORDERS OF THE SKIN MIDDERMAL ELASTOLYSIS MDE is a rare acquired disorder of elastic tissue. It is characterized by patches and plaques of diffuse, fine, wrinkled skin, most often located on the trunk, neck, and arms. In 1977, Shelley and Wood reported the first case of “wrinkles due to idiopathic loss of middermal elastic tissue.”14 Since then, fewer than 100 cases have been reported. The vast majority of patients are Caucasian women between the ages of 30 and 50 years.15,16

A

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PATHOGENESIS. The pathogenesis of this acquired elastic tissue degeneration is still unknown. Ultraviolet (UV) exposure has been postulated to be a major contributing factor in the degeneration of elastic fibers,17 including narrowband UVB.18 Other possible mechanisms include defects in the synthesis of elastic fibers, autoimmunity against elastic fibers, and damage to elastic fibers through the release of elastase by inflammatory cells or fibroblasts. More recent data suggest that inflammatory processes and an altered balance between matrix metalloproteinase and tissue inhibitor of metalloproteinases are possibly involved in the pathogenesis of MDE.19 CLINICAL FEATURES. MDE is characterized by asymptomatic, well-demarcated, or diffuse areas of fine wrinkling (Fig. 67-3A). Rarely, erythematous patches, telangiectasias, or a reticular variant can be seen. Discrete perifollicular papules can be seen in some cases, leaving the hair follicle itself as an indented center. Lesions are typically found on the trunk, neck, and upper extremities. They are chronic and give the skin a prematurely aged appearance. There is usually no history of a preceding inflammatory dermatosis, but some patients report mild-to-moderate erythema. There is no associated systemic involvement. HISTOPATHOLOGY. The pathology shows a normal epidermis and, occasionally, a mild perivascular infiltrate in the dermis. The characteristic histology is seen on elastic tissue stains and reveals a selective band-like loss of elastic fibers in the middermis (see Fig. 67-3B). There is preservation of normal elastic tissue in the superficial papillary dermis above, in the reticular dermis below, and along adjacent hair follicles. Electron microscopy studies have shown phagocytosis of normal as well as degenerated elastic fiber tissue by macrophages.20

B

Figure 67-3  Middermal elastolysis. A. Well-circumscribed area of fine wrinkling on the neck of a middle-aged woman. (Used with permission from Richard Dubuc, MD.) B. Histology of middermal elastolysis. Note selective loss of elastic fibers in the middermis. Normal elastic tissue is preserved in the superficial papillary dermis and in the reticular dermis (Weigert’s stain). (Used with permission from Danielle Bouffard, MD.)

DIFFERENTIAL DIAGNOSIS. MDE must be dif-

STRIAE (See Chapters 108 and 151) Striae are very common and usually develop between the ages of 5 and 50 years. They occur about twice as frequently in women as in men. They commonly develop during puberty, with an overall incidence of 25%–35%,23,24 or during pregnancy, with an incidence of 77%.25 The factors leading to the development of striae have not been fully elucidated. Striae distensae are the results of breaks in the connective tissue, resulting in dermal atrophy. Many factors, including hormones (particularly corticosteroids), mechanical stress, and genetic predisposition, appear to play a role. During puberty, striae appear in areas where there is a rapid increase in size. In girls, the most common sites are the breasts, thighs, hips, and buttocks, whereas in boys, they are seen on the shoulders, lumbosacral region, and thighs. Other less common sites include the abdomen, upper arms, neck, and axillae. Striae distensae are a common finding on the abdomen, and less so on the breasts and thighs, of pregnant women, especially during the last trimester. They are more common in younger primigravidas than in older pregnant women and are associated with larger weight gain and with babies of higher birth weight. Striae gravidarum can be associated with a higher risk of lacerations during vaginal delivery.26

HISTOPATHOLOGY. Histologic findings show a decrease in dermal thickness and in collagen in the upper dermis. The collagen bundles are thinned and lie parallel to the epidermis, but they are also arranged transversely to the direction of the striae. Alterations in elastic fibers are variable, but dermal elastin can be fragmented, and specific elastin staining can demonstrate a marked reduction in visible elastin content compared with adjacent normal dermis.27 There is absence of both hair follicles and other appendages. DIFFERENTIAL DIAGNOSIS. The diagnosis of striae distensae is usually simple, but the differential diagnosis does include linear focal elastosis (elastotic striae) that was first described by Burket et al in 1989.28 Linear focal elastosis is characterized by rows of yellow palpable striae-like bands on the lower back. Unlike striae, the lesions are raised and yellow rather than depressed and white. Elderly men are most commonly affected, although cases in teenagers have been described. Linear focal elastosis is probably not an uncommon condition. Histologically, there is a focal increase in the number of elongated or fragmented elastic fibers and a thickened dermis. It is postulated that linear focal elastosis may represent an excessive regenerative process of elastic fibers and could be thought of as a keloidal repair of striae distensae.29 TREATMENT. Striae distensae have no medical consequences, but they are frequently distressing to those affected. As stretch marks tend to regress spontaneously to some degree over time, the usefulness of treatments that have been tried without case controls is difficult to assess. Topical treatments that have shown some improvement of early stage striae are: tretinoin 0.1% cream,30 a combination of 0.05% tretinoin/20% glycolic acid, or 10% l-ascorbic acid/20% glycolic acid.31 Several lasers have been used in treating striae: the 585-nm pulsed-dye laser has been demonstrated to be of some efficacy in improving the appearance of striae rubra but has no effect on stria alba32; improvement in the leukoderma of the striae alba was noted with 308-nm excimer laser but maintenance treatment is required to sustain the cosmetic benefit.33 The long-term future of treatment strategies is encouraging with the advance in laser technologies.

Anetoderma and Other Atrophic Disorders of the Skin

There is no known effective treatment for MDE. Sunscreens, colchicine, and topical retinoic acid have been tried without good success.15,16

symmetric, well-defined linear atrophic lesions that follow the lines of cleavage. Initially, striae appear as red-to-violaceous elevated lines (striae rubra) (see Fig. 107-3). Over time, the color gradually fades, and the lesions become atrophic, with the skin surface exhibiting a fine, white, wrinkled appearance (striae alba).24 The striae can measure several centimeters in length and a few millimeters to a few centimeters in width. The striae associated with systemic corticosteroid therapy and Cushing syndrome can be larger and more widely distributed.

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ferentiated from the other common disorders of elastic tissue. Solar elastosis differs by its onset in an older age group, location in only sun-exposed areas, yellowish color, and coarser wrinkling, as well as by hyperplasia and abnormalities of elastic fibers and basophilic degeneration of the collagen in the papillary dermis. Anetoderma is characterized clinically by smaller soft macules and papules instead of diffuse wrinkling, and histologically by elastolysis that can occur in any layer of the dermis. Perifollicular elastolysis differs by a selective and almost complete loss of elastic fibers surrounding hair follicles compared with preservation of elastic fibers around follicles in MDE. Elastase-producing Staphylococcus epidermidis was found in the hair follicles and is the presumed etiology of this condition.21 Postinflammatory elastolysis and cutis laxa were originally described in young girls of African descent. An inflammatory phase, consisting of indurated plaques or urticaria, malaise, and fever, preceded the diffuse wrinkling, atrophy, and severe disfigurement. Insect bites may be the trigger for the initial inflammatory lesions.22

CLINICAL FINDINGS. Striae are usually multiple,

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IDIOPATHIC ATROPHODERMA OF PASINI AND PIERINI

Section 9 :: Disorders of the Dermal Connective Tissue

EPIDEMIOLOGY AND PATHOGENESIS. Idiopathic atrophoderma of Pasini and Pierini is a form of dermal atrophy that presents as one or several sharply demarcated depressed patches with no outpouching, usually on the back of adolescents or young adults.34 Whether atrophoderma is a nonsclerotic, primarily atrophic variant of morphea or a separate distinct entity is still debated.35–39 Its relationship to morphea is favored by its striking clinical and histologic similarities to the atrophy seen at sites of regressing plaques of morphea. Antibodies to Borrelia burgdorferi have been reported.37 Typical lesions of morphea, lichen sclerosus, and atrophoderma have been observed to occur simultaneously in the same patient but in different areas, supporting the view that these conditions are related. In a series of 139 patients, 17% had white induration in the central portions of their atrophic lesions, and 22% had superficial plaques of morphea coexisting in areas outside of their atrophic foci.35 However, to some, the different course and outcome of atrophoderma of Pierini and Pasini as compared with morphea justifies preservation of a distinct name. This disorder is more frequently encountered in women than in men, with a ratio of 6:1. It usually starts insidiously in young individuals in the second or third decades of life. A congenital case was recently reported.40 The lesions usually occur on the trunk, especially on the back and lumbosacral region, followed in frequency by the chest, arms, and abdomen.37 The distribution is often symmetric and bilateral. The lesions are single or multiple and usually round or ovoid, ranging in size from a few centimeters to patches covering large areas of the trunk (Fig. 67-4). They are usually asymptomatic and lack inflamma-

tion. When lesions coalesce, they can form large, irregular, brown patches but can be hypopigmented.41 The surface of the skin is normal in appearance, and there is no skin induration or sclerosis. The borders or edges of these lesions are sharply defined, and they are usually described as abrupt, “cliff drop” borders ranging from 1 to 8 mm in depth, although they can have a gradual slant.34 These depressed patches are characteristic and give the impression of inverted plateaus, or, if multiple lesions are present, they can have the appearance of Swiss cheese. They are even more apparent when present on the back because the dermis is thicker in this area. The skin surrounding the patches is normal in appearance, and there is no erythema or lilac ring as in morphea.

COURSE. The course of this benign disease is progressive, and lesions can continue to appear for decades before reaching a standstill. Transformation to generalized morphea has not been observed. HISTOPATHOLOGY. The histologic picture is generally not diagnostic. The epidermis is usually normal or slightly atrophic. Collagen bundles in the mid- and reticular dermis show varying degrees of homogenization and clumping. Dermal thickness is eventually reduced when compared with adjacent normal skin.38 Some irregular clumping and loss of elastic fibers were described in earlier case reports,34 but in most series, no abnormality was seen with elastic tissue stains35,37; therefore, this is not of diagnostic value. The appendages are usually preserved. If sclerodermatous changes appear in preexisting patches, the histology reveals varying degrees of collagen sclerosis resembling morphea. DIFFERENTIAL DIAGNOSIS. The differential diagnosis is to be made with active lesions of morphea that usually present as indurated, often hyperpigmented plaques with a characteristic peripheral lilac rim. THERAPY. No treatment has been proved effective. Dramatic response to oral hydroxychloroquine was recently reported in one patient.42 FOLLICULAR ATROPHODERMA Follicular atrophoderma refers to dimple-like depressions at the follicular orifices. It can occur as an isolated defect of limited extent, in association with a variety of disorders in which hair follicles are plugged with keratin, or with rare genodermatoses.43,44 Distinctive ice-pick depressions around hair follicles can be seen most commonly on the back of the hands or feet and on the cheeks. These pitted scars can present at birth or early in life. A family history may be present. Follicular atrophoderma occurs in the conditions described in the following sections.

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Figure 67-4  Atrophoderma of Pasini and Pierini. Brownish depressed lesions on the lower back.

ATROPHODERMA VERMICULATUM. Atrophoderma vermiculatum is a term that applies when the lesions are found exclusively on the cheeks. It is a

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Figure 67-6  Ulerythema ophryogenes. Erythematous follicular papules and scarring alopecia of the eyebrow.

condition that can either occur sporadically, be inherited as an autosomal dominant disorder, be part of a group of related diseases including keratosis pilaris atrophicans, or be associated with various syndromes. Multiple inflammatory symmetric papules on the cheeks, presumably centered around hair follicles, may precede the atrophic lesions. These papules then go on to develop pitted, atrophic, and depressed scars in a reticulated or honeycomb pattern (Fig. 67-5). These lesions can extend to the forehead and preauricular regions. This condition usually has its onset in childhood or, less often, around puberty. Men and women seem to be affected equally.45 It usually has a slow progressive course.

ated with plugging, inflammation, and sclerosis of dermal collagen.

Keratosis Pilaris Atrophicans. Keratosis pilaris atrophicans46 can include atrophoderma vermiculatum but also a group of closely related disorders that includes keratosis follicularis spinulosa decalvans and ulerythema ophryogenes. These conditions are characterized by keratotic follicular papules, variable degrees of inflammation, and secondary atrophic scarring. Keratosis follicularis spinulosa decalvans begins in infancy with keratotic follicular papules over the malar area and progresses to involve the eyebrows, scalp, and extremities, with scarring alopecia. This condition is inherited in an X-linked recessive fashion in some patients. Ulerythema ophryogenes (or keratosis pilaris atrophicans faciei) differs from atrophoderma vermiculatum by affecting primarily the lateral portion of the eyebrows (ophryogenes) with erythema, follicular papules, and alopecia (Fig. 67-6). The underlying pathologic defect in these disorders appears to be abnormal follicular hyperkeratinization of the upper third of the hair shaft leading to obstruction of the growing hair and production of chronic inflammation. The end result of this process is scarring below that level. Histopathology is usually not very helpful and shows dilated follicles, sometimes associ-

Associated Syndromes. The various syndromes

that include atrophoderma vermiculatum are the Rombo syndrome (milia, telangiectasias, basal cell carcinomas, hypotrichosis, acral cyanosis, and, rarely, trichoepitheliomas), Nicolau–Balus syndrome (syringomas and milia), Tuzun syndrome (scrotal tongue), and finally the Braun–Falco–Marghescu syndrome (palmoplantar hyperkeratosis and keratosis pilaris).

Therapy. These disorders are mainly a cosmetic but

vexing problem. Various topical treatments, including emollients, corticosteroids, tretinoin, and keratolytics, have shown no consistent benefit. Systemic isotretinoin has been shown to stop progression and to induce remission in some cases.46 Dermabrasion as well as carbon dioxide and 585-nm pulsed-dye lasers are other options to improve the appearance of the atrophic scars.47

Anetoderma and Other Atrophic Disorders of the Skin

Figure 67-5  Atrophoderma vermiculatum. Multiple, small, pitted scars on the cheek of a young girl.

BAZEX–DUPRÉ–CHRISTOL SYNDROME (OMIM #301845). Bazex–Dupré–Christol syn-

drome is characterized by follicular atrophoderma, milia, multiple basal cell carcinomas, hypotrichosis, and localized hypohidrosis.48–50 The follicular atrophoderma described as multiple ice-pick marks or patulous follicles can be found most commonly on the dorsa of the hands. It is inherited in an X-linked dominant fashion, and the gene has been linked to Xq24– q27.48 Subsequently reported findings include facial hyperpigmentation, hair shaft dystrophy, and multiple genital trichoepitheliomas.

CONRADI–HÜNERMANN–HAPPLE SYNDROME (X-LINKED DOMINANT CHONDRODYSPLASIA PUNCTATA, CDPX2, OMIM #302960)). Conradi–Hünermann syndrome is an

X-linked dominant disorder that occurs only in girls

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because it is usually lethal in hemizygous males. The underlying molecular defect consists of mutations in the emopamil-binding protein gene at Xp11.23p11.22.50 The clinical manifestations include an ichthyosiform scaling erythroderma patterned along the lines of Blaschko that usually resolves during the first year of life and is replaced by bands of follicular atrophoderma.43 Hyperpigmentation, cataracts, scarring alopecia, saddle-nose deformity, asymmetric limb reduction defects, and stippled calcifications of the epiphyses can be seen. Ichthyosis with keratotic follicular plugs containing dystrophic calcification in newborns are distinctive histopathologic features.51

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Many systemic conditions [scleroderma (see Chapter 157), lupus erythematosus (see Chapter 155), dermatomyositis (see Chapter 156)], and genodermatoses (poikiloderma congenitale, dyskeratosis congenita, Cockayne syndrome, Hallermann–Streiff syndrome) have skin atrophy as an associated finding and are described in other chapters.

Disorders of the Dermal Connective Tissue

Section 9

OTHER ATROPHIES OF THE CONNECTIVE TISSUE

Full reference list available at www.DIGM8.com DVD contains references and additional content 4. Venencie PY, Winkelmann RK, Moore BA: Anetoderma: Clinical findings, associations, and long-term follow-up evaluations. Arch Dermatol 120:1032, 1984 7. Thomas JE et al: Familial anetoderma. Int J Dermatol 42:75, 2003 9. Venecie PY, Winkelmann RK: Histopathologic findings in anetoderma. Arch Dermatol 120:1040, 1984 16. Gambichler T: Mid-dermal elastolysis revisited. Arch Dermatol Res 302:85-93, 2010. 24. Ammar NM et al: Adolescent striae. Cutis 65:69, 2000 35. Kencka D, Blaszczyk M, Jablonska S: Atrophoderma Pasini–Pierini is a primary atrophic abortive morphea. Dermatology 190:203, 1995 41. Saleh Z et al: Atrophoderma of Pierini and Pasisni: A clinical and histopathological study. J Cutan Pathol 35: 11081114, 2008 45. Frosch P et al: Atrophoderma vermiculatum: Case reports and review. J Am Acad Dermatol 18:538, 1988 46. Callaway SR, Lesher JL: Keratosis pilaris atrophicans: Case series and review. Pediatr Dermatol 21:14, 2004 48. Vabres P et al: The gene for Bazex–Dupré–Christol syndrome maps to chromosome Xq. J Invest Dermatol 105:87, 1995 49. Torrelo A et al: What syndrome is this? Basex-DupréChristol syndrome. Pediatr Dermatol 23:286-290, 2006

Chapter 68 :: Ainhum and Pseudoainhum :: Robert T. Brodell & Stephen E. Helms Ainhum and pseudoainhum are syndromes related to external constricting bands Constricting bands are classified as ainhum and pseudoainhum. Ainhum is defined by a constricting band around a digit and is most common in tropic and subtropic latitudes occurring around the fifth toe or toes of people accustomed to walking barefoot. Pseudoainhum constrictions clinically mimic ainhum and are much more common in the developed world. It may be caused by (1) amniotic bands; (2) constrictions associated with keratotic disorders or those associated with infections or trauma; and (3) constriction by external forces such as hairs and threads. Autoamputation can result from ainhum and pseudoainhum.

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Treatment can simply be the removal of foreign strands wrapped around a digit or limb or surgical intervention in more advanced cases (Z-plasty or amputation).

AINHUM AND PSEUDOAINHUM Constricting bands are classified as ainhum and pseudoainhum. Ainhum describes the development of constricting bands around toes in underdeveloped countries of Africa and may ultimately result in autoamputation. In the African Yorub language, ainhum means “to saw” or “file” and in the Brazilian patois, it means “fissure.” In the remainder of the world, constricting bands that mimic ainhum are termed pseudoainhum.

EPIDEMIOLOGY Ainhum (dactylolysis spontanea) is traditionally a disease of middle-aged African males accustomed to going barefoot.1 In the tropic and subtropic climates, its incidence has been reported as between 0.015% and 2% of the population.2 This same condition is rarely seen throughout the rest of the world. Occasional isolated cases were reported in the United Kingdom and North America.1,3 Pseudoainhum of all types is very rare.

ETIOLOGY AND PATHOGENESIS The pathogenesis of ainhum has not been clearly elucidated. Chronic trauma, infection, hyperkeratosis,

Figure 68-1  Congenital constricting bands about two digits. No etiology was identified.

of the toes or even the hands (Fig. 68-3; eFig. 68-3.1 in online edition). In children, when chronic dermatophyte infection is identified and appropriately treated, complete reversal of the constriction may occur. Severe hyperkeratosis as occurs with Vohwinkel syndrome (keratoderma hereditarium mutilans)6,16 may show constricting bands due to palmar and plantar hyperkeratoses as well as starfish-like and linear keratoses.

Figure 68-2  Pseudoainhum (congenital constricting band) of the leg in an infant. (Used with permission from Ilona Frieden, MD.)

Ainhum and Pseudoainhum

Ainhum usually affects the fifth toe; it may be unilateral, but 75% of the cases are bilateral. One or more digits can be involved. All toes can be involved, even the great toe.11 In early lesions, a groove or sulcus appears at the plantar junction of the toe and the sole. As this sulcus deepens, edema develops distally and roentgenographic examination shows resorption of the underlying bone and ultimately autoamputation.12 Congenital constricting bands (Streeter bands) usually involve more than one part of the body (Fig. 68-1) and frequently encircle large structures such as limbs or even the trunk. They persist throughout life and interfere with normal growth of the involved segment unless surgically treated13 (Fig. 68-2). Autoamputation can occur. More than 50% of cases are associated with other congenital anomalies usually syndactyly or clubfoot when constricting bands are found on the feet.14 Factitious pseudoainhum may prove to be a most challenging diagnosis. Strands of hair, fibers, or threads are intentionally wrapped around digits or other body parts such as a nipple or penis. This phenomenon is most commonly encountered in children, but can occur in mentally ill adults.15 Because of soft-tissue swelling, the ligating band may not be visible and the true cause of the condition may not be immediately recognized.15 Acquired constricting bands are associated with a variety of medical and dermatological conditions. In general, pseudoainhum is more likely to involve any

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decreased vascular supply, and impaired sensation may produce excessive fibroplasia in a susceptible host.4 Dent et al described impaired blood supply to the foot proximal to the groove at the plantar digital junction. Poor perfusion was the result of attenuation of the posterior tibial artery and absence of the plantar arterial arch leading to abnormal healing following mechanical trauma. Ainhum has also been blamed on rotational stress applied to the bare, mechanically unstable foot.5 There are three pathophysiological categories of pseudoainhum: (1) congenital constricting bands are caused by the umbilical cord; (2) constriction by external forces, such as hairs or threads, which are generally factitial; and (3) constricting bands secondary to other diseases. These may be hereditary or nonhereditary. Hereditary causes include pachyonychia congenita, Mal de Meleda, mutilating keratoderma,6 lamellar ichthyosis,7 and psoriasis.8–10 Nonhereditary diseases include vascular anomalies as seen in Raynaud disease, diabetes mellitus, linear scleroderma, systemic sclerosis. Sensory changes associated with leprosy, tertiary syphilis, syringomyelia, and spinal cord tumors as well as trauma resulting in scar formation from burns, frostbite, and physical trauma can also cause constricting bands to form. When associated with chronic trauma and infection of the extremities, the pathophysiology may be identical to true ainhum.

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TREATMENT

Section 9

Figure 68-3  Pseudoainhum of hand with autoamputation due to amniotic bands. (Used with permission from Ilona Frieden, MD.)

:: Disorders of the Dermal Connective Tissue

The pathology of ainhum and pseudoainhum are similar with fibrotic bands resembling scar tissue.4,12 The bands in ainhum usually extend deep into the subcutaneous layers and may impinge upon underlying skeletal and vascular structures. Additionally, moderate inflammation and epidermal or verrucous hyperplasia may be present. In pseudoainhum the bands tend to be more superficial. Also, in pseudoainhum there may be histologic clues to the associated disorder, such as dermatophytosis, foreign bodies, or distinct patterns of keratinization.

COMPLICATIONS The constricting bands of both ainhum and pseudoainhum ultimately produce a dangling, twisted digit, which can become gangrenous or infected. When this tenuous connection produces necrosis, autoamputation occurs.

PROGNOSIS AND CLINICAL COURSE Diseases caused by constricting bands proceed slowly and often painfully over many years eventuating in autoamputation in severe cases.

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Surgery is the mainstay of therapy and early intervention is important. In most cases of ainhum, prompt amputation may allow the patient to escape pain and infection. Early cases of ainhum or pseudoainhum may respond to conservative plastic repair with a Z-plasty or similar relaxing closure by avoiding further disease progression and damage to underlying structures.12 Impending amputation i n Vohwinkel syndrome can sometimes be aborted by therapy with oral etretinate.16 When chronic fungal or bacterial infections or psoriasis are diagnosed in the early phase of band formation, treatment may reverse the threat to the digit (eFig. 68-3.2 in online edition). Other predisposing causes of underlying diseases should be treated aggressively in the hope of forestalling progression. For example, a case of infantile psoriasis with pseudoainhum was successfully treated with narrowband UVB phototherapy and pimecrolimus.17

PREVENTION Ainhum is rarely seen in people who are protected by wearing shoes. Congenital pseudoainhum cannot be prevented. Psychological counseling may prevent recurrences of pseudoainhum in patients with factitial disease. Control of the underlying disease process may delay progression or prevent recurrence in pseudoainhum of the acquired type.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Cole GJ: Ainhum: An account of fifty-four patients with special reference to etiology and treatment. J Bone Joint Surg Br 47:43, 1965 2. Carvalho N et al: Ainhum (Dactylolysis Spontanea): A case report. Foot Ankle 6:189-192, 2000 4. Kerhisnik W: The surgical pathology of ainhum (dactylolysis spontanea). J Foot Surg 25:95, 1986 5. Dent DM et al: Ainhum and angiodysplasia. Lancet 2:396, 1981 9. Almond SL et al: Case Report: Pseudoainhum in chronic psoriasis. Br J Dermatol 149:1064-1066, 2003 12. Pickus EJ et al: Digital constriction bands in pseudoainhum: Morphological, radiographic, and histological analysis. Ann Plast Surg 47:194, 2001

Chapter 69 :: Acquired Perforating Disorders :: Julia S. Minocha & Bethanee J. Schlosser ACQUIRED PERFORATING DISORDERS AT A GLANCE Acquired perforating disorders represent a group of separately identified cutaneous disorders that occur most often in the setting of chronic renal disease or diabetes mellitus.

Treatment is challenging with no universally effective therapy, and patients often exhibit a chronic course.

INTRODUCTION Acquired perforating disorders represent a group of separately identified cutaneous disorders that occur in adult patients, most often in the setting of chronic kidney disease (CKD) or diabetes mellitus (DM).1 Kyrle’s disease (KD), acquired elastosis perforans serpiginosa (AEPS), acquired reactive perforating collagenosis (ARPC), and perforating folliculitis (PF) were previously considered distinct disorders.2–5 Given their shared clinical and histopathological characteristics, these four disorders are now classified under the umbrella term of acquired perforating dermatosis (APD).1 APD is characterized clinically by the presence of umbilicated papules and/or nodules with a central keratotic plug or crust and histologically by the transepidermal extrusion of dermal components (collagen, elastin, and/or fibrin).6 Although some cases may exhibit clinical and histological characteristics that typify one of the four classically recognized disorders, use of the comprehensive term APD is encouraged.

Acquired Perforating Disorders

Histopathological examination of lesional skin demonstrates invagination of the epidermis with extrusion of dermal material (collagen, elastin, and/or fibrin) through the cup-shaped epidermal depression.

Kyrle, in 1916, first described KD in a young diabetic woman and termed it hyperkeratosis follicularis et parafollicularis in cutem penetrans.5 In 1953, Lutz published the initial description of elastosis perforans serpiginosa (EPS) as keratosis follicularis serpiginosa.7 The first case of AEPS associated with CKD was identified in 1986 by Schamroth, Kellen, and Grieve.2 Mehregan, Schwartz, and Livingood reported the earliest description of reactive perforating collagenosis (RPC) in 1967, and the first case associated with DM was recognized by Poliak et al in 1982.3,8 PF was originally described by Mehregan and Coskey in 1968.4 In 1989, Rapini, Heber, and Drucker recognized the common clinical and histopathologic characteristics of these disorders and introduced the term acquired perforating dermatosis.1 Various terminology has been used in the literature to refer to APD (Table 69-1). APD occurs worldwide without gender predilection.17 The most common systemic diseases associated with APD are CKD and DM. APD has been documented in 4.5%–10% of hemodialysis patients in North America and in 11% of a dialysis population (both hemodialysis and peritoneal dialysis) in Great Britain.17,18 APD has also occurred in patients with CKD who are not undergoing dialysis as well as those who have received renal transplants. The most common cause of CKD among APD patients is diabetic nephropathy.18 Table 69-2 lists less commonly reported associated conditions. APD has rarely been associated with the use of certain therapeutics, including tumor necrosis factor-α inhibitors, indinavir, and sorafenib.44–46 A predominance of blacks among hemodialysis patients with APD has been reported in one study, but not confirmed in others.11 AEPS is well recognized as a potential adverse effect of prolonged d-penicillamine therapy.47 AEPS has also been reported in patients with CKD in the absence of penicillamine exposure or other associations.2

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Lesions present as umbilicated papules and/ or nodules with a central keratotic plug or crust distributed preferentially on extensor surfaces of the extremities.

EPIDEMIOLOGY

Chapter 69

The previously recognized Kyrle’s disease (KD), acquired elastosis perforans serpiginosa (AEPS), acquired reactive perforating collagenosis (ARPC), and perforating folliculitis (PF) are now classified under the umbrella term of acquired perforating dermatosis.

9

ETIOLOGY AND PATHOGENESIS The precise etiology and pathogenesis of APD are unknown. APD pathology likely involves a complex interaction between the epithelium, connective tissue, and inflammatory mediators. Superficial trauma to the epidermis may be the primary inciting factor in susceptible patients.8 Predisposing conditions include vasculopathy/angiopathy (related to DM), microdeposition of exogenous materials within the dermis (including calcium salts and silicon, pertinent to the increased frequency of APD in dialysis patients), and epidermal or dermal change related to metabolic derangements including vitamin A deficiency.13,18,43,48,49

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TABLE 69-1

Synonyms for Acquired Perforating Dermatosis

Section 9 :: Disorders of the Dermal Connective Tissue

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Acquired reactive perforating collagenosis9 Hyperkeratosis follicularis et parafollicularis in cutem penetrans5 Hyperkeratosis penetrans10 Keratosis follicularis serpiginosa7 Kyrle’s disease11 Kyrle-like lesions12 Perforating disorder13 Perforating folliculitis8 Perforating folliculitis of hemodialysis14 Reactive perforating collagenosis of diabetes mellitus (DM) and renal failure15 Uremic follicular hyperkeratosis16

Given APD’s common association with CKD, scratching due to chronic pruritus has been thought to lead to microtrauma and subsequent transepidermal elimination of dermal components. Koebnerization, predominant localization to trauma-prone areas, and resolution of APD lesions with discontinuation of manipulation/trauma support this mechanism.6 Diabetic vasculopathy has been proposed as an additional predisposing factor for APD in DM patients by creating a relatively hypoxic environment in which trauma from scratching causes dermal necrosis. The finding of

TABLE 69-2

Conditions Associated with Acquired Perforating Dermatosis Common Associations Chronic kidney disease Diabetes mellitus (insulin-dependent and noninsulindependent) Scabies19,20 Rare Associations Acquired immunodeficiency syndrome (AIDS)21,22 Arthropod bites23,24 Atopic dermatitis25 Cutaneous cytomegalovirus infection26 Hyperparathyroidism9 Liver diseases (hepatitis C, hepatitis B, steatohepatitis, primary biliary cirrhosis)6,27 Lupus vulgaris28 Myelodysplastic syndrome29 Malignancy (Hodgkin lymphoma, mixed histiocytic– lymphocytic lymphoma, hepatocellular carcinoma, pancreatic carcinoma, prostate carcinoma, papillary thyroid carcinoma)30–37 Mikulicz’s disease38 Neurodermatitis9 Poland syndrome39 Primary sclerosing cholangitis40 Pulmonary aspergillosis41 Pulmonary fibrosis25 Salt water application13 Thyroid disease (hypothyroidism, sick euthyroid syndrome, Hashimoto thyroiditis)9,27,42 Vitamin A deficiency43

PAS-positive thickening of vessel walls in the upper dermis of diabetic patients with APD48,50 supports this hypothesis, but has not been noted in all studies.6,51 Imbalances in fibronectin, transforming growth factor-β3 (TGF-β3), and matrix metalloproteinases in APD lesions have also been demonstrated; these molecules are essential to normal epithelial differentiation and wound healing, and their aberration may predispose to the development of APD lesions.48,51,52 In AEPS, it is hypothesized that penicillamine alters dermal elastic fibers in affected patients.53 Elastic fiber abnormalities, including “bramble bush-appearing” fibers of variable thickness and increased numbers of fibers in the papillary and reticular dermis, have been described in patients with penicillamine-induced AEPS.54

CLINICAL FINDINGS HISTORY Most patients report lesional pruritus, ranging from mild-to-severe and intractable, of skin lesions. Lesions may also be painful.6

CUTANEOUS LESIONS APD characteristically manifests as round, umbilicated, skin-colored, erythematous or hyperpigmented papules and nodules with a central crust or keratotic plug, predominantly involving the extensor surfaces of the extremities and the trunk (Fig. 69-1). Lesions less commonly involve the face or scalp. In rare cases, purple annular plaques or pustules mixed with papules have been observed. Some lesions may be follicular (PF) (Fig. 69-2). AEPS lesions exhibit papules in a serpiginous configuration, often with central atrophy, and typically occurring on the neck, trunk, and extremities (Fig. 69-3). Scratching can lead to koebnerization with linear umbilicated papules arising in excoriated skin.

Figure 69-1  Acquired perforating dermatosis. Multiple, round, hyperpigmented papules, each with a central keratotic plug, distributed on the extensor aspects of the hand and wrist in a patient with chronic kidney disease.

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Figure 69-4  Reactive perforating collagenosis. Collagen bundles can be seen crossing from the reticular dermis through the epidermis into an epidermal depression containing necrotic debris. (Hematoxylin and eosin stain.)

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HISTOPATHOLOGY The diagnosis of APD is based on clinical and histopathologic findings. Folliculitis and prurigo nodularis may occur concomitantly, especially in patients with CKD; multiple biopsies should be taken if lesions show different clinical morphologies. APD is characterized histologically by transepidermal elimination of dermal material through an epidermal invagination, which may be follicular or perifollicular. Lesions typically demonstrate a central keratotic plug with crusting or hyperkeratosis; parakeratosis is variable. Within the

dermis surrounding the perforation, there is often a focal inflammatory infiltrate with neutrophils predominating in early lesions and lymphocytes, macrophages, or multinucleated giant cells present in older lesions. The four initially identified acquired perforating disorders [(1) RPC, (2) AEPS, (3) KD, and (4) PF] were classically differentiated histopathologically on the basis of the nature of the eliminated dermal material. In RPC, collagen bundles are detected within the plug (Fig. 69-4); in AEPS, elastic fibers are instead noted (Fig. 69-5). In KD, amorphous dermal material and/or keratin comprise the extruded material. PF is characterized by perforation of the follicular epithelium by degenerating collagen and extracellular matrix (Fig. 69-6). Clear identification of the eliminated material may be impossible and, in addition, multiple substances (i.e., collagen and elastic fibers) may be simultaneously detected, reinforcing the clinical and histopathologic overlap within APD.

Acquired Perforating Disorders

RELATED PHYSICAL FINDINGS Although most common in patients receiving hemodialysis, especially for diabetic nephropathy,18 APD has also been seen in CKD patients without hemodialysis or who have undergone renal transplantation. Table 69-2 lists medical conditions that are less often associated with APD.

Chapter 69

Figure 69-2  Perforating folliculitis. Multiple follicular, erythematous, firm papules with variable central crusting.

LABORATORY TESTS Laboratory evaluation for comorbidities should include fasting blood glucose, glucose tolerance test, serum creatinine, glomerular filtration rate or creatinine clearance, serum uric acid, liver function tests, and thyroid function tests. A comprehensive past medical history and review of systems should be obtained. Additional diagnostic testing for associated conditions (Table 69-2) should be performed as indicated.

DIFFERENTIAL DIAGNOSIS

Figure 69-3  Acquired elastosis perforans serpiginosa in a patient taking penicillamine for Wilson’s disease. Annular plaque with variably crusted erythematous papules at the periphery and central cribriform scarring.

(Box 69-1) The differential diagnosis of APD is broad and includes both infectious and inflammatory disorders, including those that koebnerize (Box 69-1). APD can be especially difficult to differentiate from prurigo nodularis. Perforating pseudoxanthoma elasticum should be distinguished from AEPS.

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A

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Figure 69-5  Acquired elastosis perforans serpiginosa. A. Dilated follicular structure with transepidermal elimination of densely eosinophilic elongated bundles. (Hematoxylin and eosin stain.) B. Transepidermally eliminated elongated bundles are elastin fibers (elastin stain).

Disorders of the Dermal Connective Tissue

COMPLICATIONS Most complications that occur in patients with APD arise from underlying systemic illnesses. However, patients should be monitored for secondary infection (bacterial, fungal, and viral) as well as parasitic infestation. In an attempt to relieve the associated pruritus, patients may apply products to their skin that may result in irritant or allergic contact dermatitis. In darker skinned patients with more excoriations, postinflammatory pigmentary alteration and scarring can be significant.

TREATMENT Treatment of APD is difficult. Table 69-3 details the therapeutic options that have been described in the literature to date. There have not been any well-designed clinical trials of APD, and current treatment strategies are based largely on anecdotal reports. In patients with CKD, improvement in APD lesions has been reported after changing the type of dialysis tubing or modification of the dialysis procedure.18 In a few cases, APD has resolved following renal transplantation.17,14,80 The most commonly employed treatments for APD include topical and oral retinoids, topical and intradermal

PROGNOSIS The prognosis of APD is heavily linked to the presence of underlying diseases. Some studies have shown that APD may improve with successful treatment of the underlying illness.25 Most cases of APD continue for years unless treated.

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B

Figure 69-6  Perforating folliculitis. Dilated follicular unit exhibits necrosis and disruption of the epithelium.

Box 69-1  Differential Diagnosis of Acquired Perforating Dermatosis Actinic granuloma (annular elastolytic giant cell granuloma) Arthropod bites Discoid lupus erythematous Flegel disease (hyperkeratosis follicularis perstans) Folliculitis (bacterial, yeast) Keratosis follicularis (Darier disease) Keratosis pilaris Lichen planus Multiple keratoacanthomas (Ferguson–Smith familial keratoacanthomas, Grzybowski eruptive keratoacanthomas) Perforating granuloma annulare Perforating periumbilical calcific elastosis Perforating pseudoxanthoma elasticum Porokeratosis Prurigo nodularis Psoriasis Sarcoidosis Scabies

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Table 69-3

Treatment of Acquired Perforating Dermatosis

Topical Therapies Retinoic acida Tretinoina Tazarotenea Beclomethasonea Triamcinolone acetonidea Imiquimod Phenol Capsaicin

Retinoid Retinoid Retinoid Corticosteroid Corticosteroid Immune response modifier Antipruritic Capsaicinoid

0.025% gel55 0.1% cream one to three times daily56,57 0.1% gel daily58 0.1% cream17 10 mg/mL intralesional injection17 Daily for 6 weeks then three times per week for 4 weeks59 0.5% phenol with 10% glycerin in sorbolene cream60 0.025%–0.075% ointment

Systemic Therapies Isotretinoinb Acitretinb Prednisolone Allopurinolb Doxycycline Metronidazole Clindamycin Hydroxychloroquine

Retinoid Retinoid Corticosteroid Xanthine oxidase inhibitor Antibiotic Antibiotic Antibiotic Antimalarial

Isotretinoin 0.5 mg/kg/day61,62 25–30 mg/day 60,63 30 mg daily64 100 mg daily65,66 100 mg daily20,67,68 500 mg twice daily69 300 mg three times daily70 200 mg daily71

Physical Modalities UVBa

Phototherapy

NUVBa

Phototherapy

PUVAb74 Liquid nitrogen

Phototherapy Cryotherapy

Carbon dioxide laser

Laser

TENS Surgical debridement70,79

Other

MED for 2 minutes every other day with increments of 30 seconds for 2–4 weeks72 Three times a week for 2–3 months60 400 mJ/cm2 increased to 1,500 mJ/cm2, two to three times per week, 10–15 exposures73 Four times per week for total of 326 J/cm275 10 seconds, on five occasions over 4 months, one occasion 3 months later76 Five lesional passes at 300 J (pattern 5, size 7, density 7), followed by three resurfacing passes at 300 J (pattern 2, size 8, density 5), power of 80 W77 1 hour daily for 3 weeks78

Acquired Perforating Disorders

Dosing

::

Action

Chapter 69

Treatment

UVB = ultraviolet B; NUVB = narrowband ultraviolet B; PUVA = psoralen and ultraviolet A; TENS = transcutaneous electrical nerve stimulation. a First-line therapy. b Second-line therapy.

corticosteroids, and UVB phototherapy. Phototherapy has been shown to be effective for uremic pruritus and therefore may be particularly beneficial for patients with CKD by reducing koebnerization.73 Several authors have reported improvement in APD following treatment with allopurinol in cases of elevated or normal uric acid levels.73 Currently available therapeutic options may not provide complete resolution of APD lesions or associated symptoms.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Rapini RP, Herbert AA, Drucker CR: Acquired perforating dermatosis. Evidence for combined transepidermal elimi-

nation of both collagen and elastic fibers. Arch Dermatol 125(8):1074-1078, 1989 3. Poliak SC et al: Reactive perforating collagenosis associated with diabetes mellitus. N Engl J Med 306(2):81-84, 1982 4. Mehregan AH, Coskey RJ: Perforating folliculitis. Arch Dermatol 97(4):394-399, 1968 5. Kyrle J: Uber einen ungewohnlichen fall von universeller follicularer und parafollikularer hyperkeratose (hyperkeratosis follicularis et parafollicularis in cutem penetrans). Arch Dermatol Syph 123, 1916 8. Mehregan AH, Schwartz OD, Livingood CS: Reactive perforating collagenosis. Arch Dermatol 96(3):277-282, 1967 47. Pass F et al: Elastosis perforans serpiginosa during penicillamine therapy for Wilson disease. Arch Dermatol 108(5):713-715, 1973 51. Gambichler T et al: Up-regulation of transforming growth factor-beta3 and extracellular matrix proteins in acquired reactive perforating collagenosis. J Am Acad Dermatol 60(3):463-469, 2009

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Disorders of Subcutaneous Tissue

Chapter 70 :: Panniculitis :: Iris K. Aronson, Patricia M. Fishman, & Sophie M. Worobec INTRODUCTION Inflammation in subcutaneous fat often poses a diagnostic problem for clinician and pathologist alike, since the clinical and histopathological findings in the various inflammatory disorders of adipose tissue (AT) have overlapping features. Specificity in diagnosis is potentially difficult since similar clinical presentations are sometimes associated with disparate histopathological features. Diagnostic problems may also relate to the corollary observation that a range of clinical presentations may have similar histopathologic findings. There is no universally accepted classification of panniculitis, but from the point of view of many pathologists, a useful classification begins by dividing panniculitis into septal and lobular forms, “septal” signifying inflammation confined predominantly to the septa, and “lobular” indicating inflammation predominantly involving the fat lobule itself. The septal form has been most classically associated with erythema nodosum (EN) and the lobular form with all or most other types of panniculitides. But even this beginning point has not been proven adequate since lobular granulomatous panniculitis may be seen in clinically classic EN,1 and lobular panniculitides may have mixed lobular and septal inflammation.2 This classification has been expanded by making note of the presence or absence of vasculitis in the septa or lobules,3 by the composition of the inflammatory infiltrate, and by additional specific features when present (Fig. 70-1). Since diverse clinical conditions may be expressed by similar histopathologic features, and the spectrum of histopathologic features in EN and other panniculitides may be variable,4 it may not be possible to make a specific diagnosis of panniculitis based on histopathology alone. This necessitates correlation with clinical features, including location of lesions, systemic symptoms, laboratory findings, and etiological factors. A significant aid to success in the diagnosis of inflammation in AT is obtaining a tissue sample that will adequately represent the histopathologic changes in the lesion. This can only be done with large excisional biopsies, as small punch biopsies are unlikely to obtain

adequate AT, and the inflammatory infiltrate can be missed. An additional consideration is that inflammation in AT is not a static process, and as samples taken at different stages of an evolving lesion will present with different histopathologic features, more than one biopsy may be necessary to come to a conclusive diagnosis. Under the best of circumstances, with optimal histopathologic sampling and clinical correlation, there may be no specific etiology for many inflammatory reactions in AT. But even with a specific diagnosis or etiology, underlying questions remain. Why were the inflammatory cells accumulating in the AT? What were they doing there?

ADIPOSE TISSUE REGIONAL DIFFERENCES One of the characteristics of certain types of panniculitides is the preferential localization, such as the pretibial areas for EN, the calf for erythema induratum (EI), and the upper arms, shoulders, and face for lupus panniculitis. Location of panniculitis is a helpful adjunct for differential diagnosis of inflammation in AT and the question of why that occurs may be traced to the origin of the adipocyte regions from different areas of the mesoderm and the varying gene expression in different fat depots.25 The differences in gene expression between fat depots are large, up to 1,000fold, and appear to be intrinsic, autonomous, and independent of the tissue microenvironment.25 Different AT depots may also contain variable percentage of adipocytes of different developmental origins,25 including brown AT (BAT) that has been observed to be present in white AT depots.25,26 The role of AT in innate immunity, inflammation, adaptive immunity, and energy homeostasis places the adipocyte itself centrally in the inflammatory disorders that affect it. The presence of adipocyte transmembrane PRRs, TLRs, and cytosolic PRRs, NLRs, and RLRs and receptors for interaction with macrophages and lymphocytes, as well as production and secretion of multiple cytokines and adipokines reflect the role of

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One approach to clinical classification Sclerosis of the septa

Postirradiation panniculitis Crystal storing histiocytosis

Histiocytes

Gout panniculitis Crystals

Poststeroid panniculitis Fat necrosis of the newborn Lipoatrophy

No crystals

Traumatic panniculitis Subcutaneous sarcoidosis

Without vasculitis

Neutrophils

Lymphocytes

Facticial panniculitis

Bacteria, fungi, protazoa

Infectious panniculitis

Neutrophils between collagen bundles

α1-antitrypsin deficiency

Saponification of adipocytes

Pancreatic panniculitis

Lymphoid follicles and plasma cells

Lupus panniculitis

Superficial & deep perivascular infiltrate

Cold panniculitis

Needle shaped crystals in adipocytes

Sclerema neonatorum

No inflammatory cells

Vascular calcification Necrosis at the center of fat lobule

Panniculitis

Oxalosis

Panniculitis

With vasculitis

Foreign bodies

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Mostly lobular

Cytophagic panniculitis

Chapter 70

Cytophagocytosis

Calciphylaxis Sclerosing panniculitis Neutrophilic lobular panniculitis

Small vessels: venules

Lucio phenomenon Erythema nodosum leprosum Erythemainduratum of Bazin/Nodular vasculitis

Large vessels: arteries & veins Radial granulomas in septa

Erythema nodosum

Cholesterol clefts

Necrobiotic xanthogranuloma

Fibrin

Rheumatoid nodule

Mucin

Subcutaneous granuloma annulare

Histiocytes Without vasculitis Mostly septal With vasculitis

Lymphocytes and plasma cells

No granulomatous infiltrate

Deep morphea

Granulomatous infiltrate

Necrobiosis lipoidica

Arteries

Cutaneous polyarteritis nodosa

Veins

Superficial thrombophebitis

Venules

Leukocytoclastic vasculitis

Large vessels Small vessels

Figure 70-1  Approach to the patient with panniculitis.

the adipocyte in protecting the host from infectious disease and other environmental dangers. The complex interweaving of the adipocyte’s role in such numerous and varied spheres may lead to complications should there be a genetic or acquired functional abnormality and/or molecular perturbations, and this may in some instances result in the inflammatory process known as panniculitis.

NODULAR LESIONS OF THE LEGS Nodular lesions of the legs may represent EN, EI, nodular vasculitis (NV), cutaneous polyarteritis nodosa, or nodules related to vascular disorders. Diagnosis of these disorders often presents difficulties because their clinical manifestations as well as histopathological findings

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may overlap. In order to diagnose lesions of the leg, one needs information on the typical as well as unusual manifestations of each disorder, the associated diseases and conditions, and the histopathological presentation.

ERYTHEMA NODOSUM ERYTHEMA NODOSUM AT A GLANCE

Section 10

Clinical Symmetric, tender, erythematous, warm nodules, and plaques on the anterior aspects of the lower extremities. May become confluent. Acute onset; no ulceration or scarring; more common in women.

:: Disorders of Subcutaneous Tissue

Fever, fatigue, arthralgias, arthritis, headache common. Lasts from 3–6 weeks, with new lesions appearing for up to 6 weeks. Histopathology Mostly septal panniculitis without vasculitis. Thickened septa with inflammatory cells. Neutrophils in early lesions and histiocytes and Miescher granulomas in late-stage lesions. Treatment Treatment of the associated disorder. Bed rest, aspirin, nonsteroidal antiinflammatory drugs. Systemic corticosteroids are rarely indicated.

EPIDEMIOLOGY. EN may occur in both genders, at any age from childhood to 70 years of age, but is more common in young women in the second to fourth decades of life.27 There is no gender difference in childhood cases. Prevalence varies from 2.4 per ten thousand population to 52 per million population, and in patient population from 0.38% to 0.5% of patients seen in clinics in Spain and England, respectively.28,29

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ETIOLOGY AND PATHOGENESIS. EN is a panniculitis that has been reported in association with infections (bacteria, viruses, fungi, and protozoa), medications (antibiotics, oral contraceptives, halides), malignancies (most often leukemias or lymphomas), autoimmune diseases, and other inflammatory disorders, especially sarcoidosis and inflammatory bowel disease (see eTables 70-0.1 and 70-0.2 in online edition). Geographical variations in infectious etiology occur, but streptococcal upper respiratory infections are the most common infectious etiologic factors and the most

common causes in childhood.30 Tuberculosis was a common etiology in the past, and though less frequent now, must always be excluded. Half of all EN cases are idiopathic, without specific etiology, even though in many a viral cause may be suspected.30 EN is considered to be a hypersensitivity reaction to the various etiologic factors, but the pathophysiological mechanism of the disorder is not yet understood. Early studies have shown the presence of IFNγ and IL-2, activation of leukocytes, 31 and upregulation of various adhesion molecules,32,33 and genetic polymorphism in TNF-α promoter, MIF (macrophage migration inhibitory factor), or RANTES (regulated upon activation, normal T-cell expressed, and secreted).34–36 More recent information identifies AT as an immune organ and adipocytes as cells of the innate immune system, with primary responsibilities and capabilities of activating inflammatory systems and the adaptive immune system to destroy pathogens37 (see Section “Introduction”). Historically, the primary function of the adipocyte was thought to be protective. However, excessive adipocyte production and secretion of multiple proinflammatory adipokines and adipocytokines is associated with obesity, cardiovascular disease, hypertension, and diabetes.37 In contrast, the inflammatory reaction of EN is associated with a more limited coccidiomycosis infection38 and with a less severe and shorter duration of sarcoidosis,38 especially in those carrying the HLA-DRB1*03-positive leukocyte antigen,39 which belongs to the “8.1 ancestral haplotype” genes associated with a wide range of immunopathologic diseases.40 Therefore, it is possible that, especially in AT, certain genetic mutations associated with enhanced inflammatory reactions may confer resistance to certain pathogens, and this may explain the observation that EN, whether in association with coccidiomycosis or sarcoidosis, may be protective against disease dissemination.38,39

CLINICAL FEATURES. EN most commonly presents with an acute onset of tender, painful, erythematous, warm nodules and plaques on the anterior and at times the lateral aspect of both lower legs and ankles (Fig. 70-2). Other sites may also be involved, including forearms, thighs, and rarely the trunk or even the face, especially in children.41,42 The nodules may persist a few days or weeks, may become confluent, and evolve from an erythematous or purple-like hue to a bruiselike pigmentation called erythema contusiforme if hemorrhage is present in the AT. The eruption usually lasts from 3 to 6 weeks, with new lesions appearing for up to 6 weeks, but it may persist longer and may recur.42 The lesions do not ulcerate, and they resolve without atrophy or scarring. Systemic symptoms such as fever, fatigue, malaise, arthralgia, arthritis, and headache are common. Abdominal pain, vomiting, diarrhea, and cough are less frequent.30,42 Ocular manifestations may accompany the cutaneous lesions.42 Tonsillitis/pharyngitis/ upper respiratory infection (URI) preceded the onset in 20%–30% in two series29,30 and prodromal symptoms may appear 1–3 weeks prior to lesional onset, at which time symptoms may become exacerbated.43

A

Panniculitis

HISTOPATHOLOGY. Histopathologically, EN is considered the prototype of septal panniculitis, although lobular inflammation may additionally be present. The composition of the inflammatory infiltrate varies according to lesional age, with the earliest lesions demonstrating septal edema, extravasated red

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Laboratory abnormalities may include a high ESR, positive throat culture, or high ASO titer in those with a streptococcal etiology and leukocytosis. A positive PPD must be evaluated in the context of prevalence of tuberculosis in the geographical area. Chest X-ray will rule out pulmonary infectious or noninfectious disease (sarcoidosis), and serology or culture for various infectious diseases as well as other testing may be warranted in the appropriate setting (see eTables 70-0.1 and 70-0.2 in online edition).

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Chapter 70

Figure 70-2  Erythema nodosum. Erythematous nodules located mainly on the anterior of the legs.

blood cells, and scattered neutrophils. More fully developed lesions of EN show widening of the septa and early fibrosis, along with a septal infiltrate that includes lymphocytes, histiocytes, neutrophils, and eosinophils.27,42,44 There may be extension of the infiltrate into adjacent fat lobules, but centrilobular necrosis of adipocytes is not seen.27,41,42 Late-stage lesions show widened and fibrotic septa, often containing granulomas (Fig. 70-3A). The fibrosis and inflammation may encroach upon and partially efface fat lobules. Occasionally, predominantly polymorphonuclear cells may be present in typical EN,45 but this is considered to be part of the early phase of inflammation.27,41,42 Miescher’s granuloma, a discrete micronodular aggregate of small histiocytes around a central stellate cleft27,42 (Fig. 70-3B), is considered characteristic of early EN by some, but is not universally found in EN,41,44 and has been described in other types of panniculitis.41 The picture of Miescher’s granuloma also evolves, as in later-stage lesions, some aggregates of larger histiocytes and multinucleated giant cells retain a central cleft. An overlying superficial and deep perivascular dermal infiltrate is frequently present in EN.41 Lipomembranous changes have been described in late stages of EN.27,42 Although by definition, vasculitis is characteristically absent in EN, thrombophlebitis has been emphasized by some as a feature in early EN,1 and medium vessel arteritis may rarely occur.4

DIFFERENTIAL DIAGNOSIS. Differential diagnosis includes cellulitis, infection-induced panniculitis, acute lipodermatosclerosis (LDS), EI/NV, which tends to appear on the calves and ulcerate, other vasculitides which must be differentiated histopathologically, and pancreatic panniculitis, which may occur anywhere on the leg, ulcerate and drain, and which is accompanied by an increase in serum lipase and amylase. TREATMENT. Treatment of EN primarily focuses on treatment or removal of the etiologic factor. Suspected medications should be discontinued, underlying infections sought and treated if possible, and associated

B

Figure 70-3  Erythema nodosum. A. Widened septa with inflammatory infiltrate including multinucleated giant cells. B. High magnification of a Miescher’s granulomas shows a discrete micronodular aggregate of small histiocytes around a central stellate cleft.

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Section 10

inflammatory disorders or malignancies sought and appropriately treated. The disorder may persist for months before remission, and recurrence is possible, especially if the etiology is unknown.46 Additional management options include bed rest and leg elevation, aspirin, nonsteroidal anti-inflammatory agents (avoided with IBD). Supersaturated potassium iodide solution (SSKI), 2–10 drops (1 drops = 0.03 mL = 30 mg) three times per day in water or orange juice has been useful, but individuals with thyroid disorders and on certain medications may be at risk for hypothyroidism and goiter as well as toxicity reactions of high potassium involving the heart and lungs.47 SSKI is contraindicated in pregnancy. Other medications that have been used to treat EN include colchicine (especially for Behcet’s disease),48 corticosteroids (rarely used, especially since an underlying infection must be ruled out), etanercept,49 and infliximab for IBD-associated EN.50

:: Disorders of Subcutaneous Tissue

ERYTHEMA INDURATUM AND NODULAR VASCULITIS EPIDEMIOLOGY AND CLINICAL FINDINGS.

EI is an inflammatory panniculitis, most commonly presenting with ulcerated nodules on the calves, and frequently associated with MTB infection. A similar disorder, without ulceration appearing in calves and other lower extremity sites was subsequently described without MTB association and was called NV. However, with patients presenting with different features in either the same flare or in preceding or subsequent flares, multiple studies have concluded that the clinical and pathological features of the two nodular leg syndromes are so similar that it is impossible to separate them.51–54 Therefore, at this time the terms are most often used interchangeably. But some still prefer to use EI to denote the MTB-associated panniculitis, and NV for those without MTB association despite the otherwise identical features, to emphasize the need for antituberculosis therapy in the former cases.55 EI/NV is seen most commonly in young to middleaged women, presenting as recurrent erythematous to violaceous nodules and deep plaques on the lower legs that may be tender, or only tender to pressure52 (Fig. 70-4). Some lesions may heal without scarring, but often ulceration leads to scarring.52 Surface changes include crusting of the ulcers and a surrounding collarette of scale (Fig. 70-5). The histology is shown in Fig. 70-6. The posterior leg calf region is the most frequent location, but lesions may also appear in the anterolateral areas of the legs, the feet, thighs, and rarely the arms and face.51 EI lesions develop more frequently during winter, and EI is commonly associated with obesity and venous insufficiency of varying degree and manifestation.52

COURSE. EI/NV can have a protracted course with

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recurrent episodes over years.52,53 Patients with EI/NV are for the most part in fairly good health, except for

ERYTHEMA INDURATUM OF BAZIN/ NODULAR VASCULITIS AT A GLANCE Clinical Erythematous subcutaneous nodules and plaques of lower legs; common on calves, but also on anterolateral legs, feet, and thighs; rarely elsewhere. Commonly associated with venous insufficiency; more frequent in middle-aged women. Often, ulceration and scarring, especially on the calves. Chronic course. Infectious etiology including bacterial [especially Mycobacterium tuberculosis (MTB)], fungal, protozoal, and viral should be sought. Histopathology Mostly lobular or mixed lobular and septal panniculitis with vasculitis in 90%. Extensive necrosis of the adipocytes in the center of the fat lobule. Variable inflammatory infiltrate in the fat lobule: neutrophils in early lesions and epithelioid histiocytes and multinucleated giant cells in fully developed lesions. Vasculitis of the small veins and venules of the fat lobule. Treatment With positive MTB microbiological, serological or Mantoux tests, or when MTB DNA is demonstrated: a full course of antituberculosis triple-agent therapy. If other infection proven or suspect: treat specific infection. In other cases: potassium iodide, other antiinflammatory drugs, supporting bandages, support hose, leg elevation, bed rest.

the associated diseases, without the symptoms usually associated with EN. There has been one case report of membranous glomerulonephritis associated with EI/ NV72 and one case of painful peripheral neuropathy in an initially MTB skin test negative patient who was later found to have MTB-positive culture of cervical lymph node.73

TREATMENT. In patients with positive MTB cultures, positive skin test or Quantiferon gold test for MTB, treatment with triple agent antituberculosis therapy is indicated. Patients with hepatitis B or C should

rated potassium iodide (SSKI), nonsteroidal anti-inflammatory agents (NSAIDS), colchicine, antimalarials, corticosteroids,55 gold74 as well as bed rest or leg elevation, and treatment of venous insufficiency with compression and pentoxifylline. Other treatments that have been used include tetracycline and mycophenolate mofetil.75 If immunosuppressive agents are used, continued monitoring for possible infectious etiology is recommended.

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receive appropriate intervention for that disorder. Other infectious etiologies including fungi, parasites, and viruses should be sought and treated, if present. Medications that may have incited EI should be discontinued. Anti-inflammatory treatments that have been used in EI/NV not associated with MBT include super satu-

A

LDS is the most common form of panniculitis, seen by clinicians far more frequently than EN, which has the next highest incidence. LDS occurs in association with venous insufficiency, mostly in overweight women over the age of 40.76,77 In a review of 97 patients with LDS, 87% were female with a mean age at diagnosis of 62 years; 85% of patients were overweight (BMI >30); and 66% were obese (BMI >34).78 Comorbidities included hypertension (41% of patients), thyroid disease (29%), diabetes mellitus (21%), prior history of lower extremity cellulitis (23%), deep vein thrombosis

Panniculitis

Figure 70-4  Erythema induratum. Erythematous to brown and bluish nodules with ulceration on calves.

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EPIDEMIOLOGY

Chapter 70

LDS (synonyms: sclerosing panniculitis, hypodermitis sclerodermiformis, chronic panniculitis with lipomembranous changes, sclerotic atrophic cellulitis, venous stasis panniculitis) is a form of sclerosing panniculitis involving the lower legs.

B

Figure 70-5  A. and B. Erythema induratum with surrounding collarette of scale.

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ignation by various medical names (see list of synonyms for LDS above), precise data for prevalence of LDS are not available. With increasing rates of obesity in the United States and the aging of the baby boomer generation, a corresponding increase in incidence and prevalence of LDS will likely follow.

LIPODERMATOSCLEROSIS AT A GLANCE Clinical Indurated plaques of wood-like consistency on the lower legs, acute and chronic changes, pain frequent.

ETIOLOGY AND PATHOGENESIS

Chronic venous insufficiency, higher than normal BMI, female gender, arterial hypertension, arterial ischemia, episodes of thrombophlebitis.

Most patients with LDS are female and also have in common venous hypertension and a higher than normal BMI. Additional associated features that have been sought as pathogenetic factors in LDS include the following: elevated hydrostatic pressure-induced increased vascular permeability secondary to downregulation of tight junctions79,80 with extravascular diffusion of fibrin78; microthrombi81; abnormalities in protein S and protein C82; hypoxia83; damage to endothelial cells by inflammatory cells84; upregulation of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), leukocyte ­function-associated antigen 1 (LFA-1), platelet- and endothelial-derived factors85; and inflammation with wound healing and local collagen stimulation leading to fibrosis and further vascular and lymphatic damage.78 The fibrosis is accompanied by increased transforming growth factor-β 1 (TGF-β1) gene and protein expression86 as well as an increase in procollagen type 1 gene expression.87 Hypoxia in AT induces chronic inflammation with macrophage infiltration and inflammatory cytokine expression.88 The adipocyte plays a significant role in extracellular tissue remodeling. For this task, the adipocyte produces multiple matrix metalloproteinases (MMPs) as well as tissue inhibitors of metalloproteinases (TIMPs) and other tissue proteases needed during tissue remodeling,89 all of which may significantly contribute to the tissue remodeling seen in LDS. Recent studies have linked expansion of AT (as seen in obesity) to resultant hypoxia, causing an increase in hypoxia-inducible factor 1α (HIF1α) expression.90 This stimulates multiple extracellular factors, including

Section 10

Pulmonary hypertension in patients with systemic sclerosis and sclerosing panniculitis.

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Histopathology Background of stasis changes; mostly lobular panniculitis without vasculitis.

Disorders of Subcutaneous Tissue

Ischemic necrosis at the center of fat lobule. Thickened and fibrotic septa and atrophy of the subcutaneous fat, with marked fibrosis and sclerosis in late-stage severe cases. Frequent membranocystic changes. Treatment Compression stockings, ultrasound therapy, pentoxifylline. Successful response to anabolic steroids in some cases.

(19%), psychiatric illness (13%), peripheral neuropathy (8%), and atherosclerosis obliterans (5%).78 Due in part to its placement in the ICD9 classification under “Venous insufficiency with inflammation,” and its des-

A

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B

Figure 70-6  Erythema induratum-nodular vasculitis. A. Histopathology: scanning power shows a mostly lobular panniculitis. B. Higher magnification: extensive adipocyte necrosis and vascular damage-necrotizing vasculitis of small venules in the fat lobule.

A

Panniculitis

LDS has an acute inflammatory stage and a chronic fibrotic stage with a spectrum of intermediate77 and overlapping presentations. In patients presenting with the acute form (Fig. 70-7A), very painful, poorly demarcated, cellulitis-like erythematous plaques to purple somewhat edematous indurated plaques or nodules are seen on the lower legs, most commonly on

10

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CLINICAL FINDING’S

the lower anteromedial calf area.77,93 Scaling may be present in some. The pain can be so intense that patients may not even tolerate a sheet while in bed. In this stage, patients are frequently diagnosed as having EN, cellulitis, or thrombophlebitis,77,93 and compression may not be tolerated. The acute form may last a few months or even a year.93 Although patients in this acute phase may present without obvious signs of venous disease,77 vascular studies show venous insufficiency in the majority.93 In the remaining group of LDS patients with normal venous studies, most have a high BMI, and given that obesity is usually associated with inactivity, these patients may not exert enough calf muscle contraction to maintain normal venous pressure in the lower extremities78; also, obesity is frequently associated with arterial hypertension. The chronic form of LDS may or may not be preceded by a clinically obvious acute form.77 Chronic LDS features indurated to sclerotic, depressed, hyperpigmented skin (Fig. 70-7B). These findings occur on the lower portion of the lower leg, predominantly but not limited to the medial aspect, or in a stocking distribution. This is described as having an “inverted champagne bottle” or a “bowling pin” appearance.76,77,93 Although some patients may not describe associated pain or tenderness,93 pain is the most frequent symptom reported by others.78 Most of the patients are obese or overweight and have hypertension and evidence of venous abnormalities, but only rarely obstruction.78 Unilateral involvement is seen in 55%, localized plaque in 51%, and ulceration in 13% of cases78 (Fig. 70-8). Dermatosclerosis in patients with systemic sclerosis has

Chapter 70

collagen I and III, as well as other components involved in remodeling the extracellular matrix, leading to fibrosis as the end result.91 A theory regarding an infectious pathogenesis of LDS was advocated by Cantwell and colleagues, who reported the presence of unusual acid-fast bacteria that could not be grown in culture in biopsies of several patients with LDS.92 This 1979 article dealt with the controversial issue of pleomorphic, nonrodshaped, acid-fast bacteria being responsible for disease. It is widely accepted that other infections associated with repeated episodes of cellulitis cause lymphatic damage and subsequent changes in the AT.77 Particularly in the light of more recent discoveries that adipocytes are cells of the innate immune system and possible reservoirs of infectious organisms of all types, the role of infection as a contributing factor to LDS should be reconsidered and explored, perhaps in an analogous manner to that of the process leading to evidence of MTB DNA and dormant MTB in AT of the legs in EI.58,67

B

Figure 70-7  Chronic lipodermatosclerosis (LDS). A. Sclerotic hyperpigmented skin on medial lower leg. B. Superimposed acute on chronic lipodermatosclerosis with ulceration.

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Figure 70-8  Chronic lipodermatosclerosis with champagne bottle/bowling pin deformity.

Section 10 :: Disorders of Subcutaneous Tissue

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been associated with pulmonary infarction and hypertension secondary to leg thrombi.94 Diagnostic tests to evaluate peripheral vascular disease should include ankle brachial index for arterial evaluation. Also indicated are venous tests: Dopplers to detect thrombi as well as color duplex sonography to detect direction of flow and presence of venous reflux.93 If the clinical findings are characteristic, biopsy of LDS is usually discouraged, due to the high incidence of subsequent development of ulcers at the biopsy site.77 But if necessary for diagnosis, a thin elliptical excision from the margin of an erythematous and indurated area, closed primarily with sutures, is recommended.77

DERMATOPATHOLOGY Histopathologic findings reflect the evolution of the disease. Dermal stasis changes are present at any stage, and these include a variable degree of proliferation of capillaries and venules, small thick-walled blood vessels, extravasated erythrocytes, hemosiderin-laden macrophages, lymphohistiocytic inflammation, and fibrosis.53,95 In the subcutis, early lesions of LDS show a sparse infiltrate of lymphocytes in the septa, accompanied by central lobular ischemic fat necrosis; the latter is recognized by the presence of pale-staining, small anucleate adipocytes. Capillary congestion is also observed within fat lobules; this may be accompanied by endothelial cell necrosis, thrombosis, red cell extravasation, and hemosiderin deposition.53,95 Septal fibrosis and small foci of lipomembranous fat necrosis and fat microcysts have also been described to occur in acute lesions.95 In lipomembranous or membranocystic change, small pseudocystic spaces are formed within necrotic fat. The spaces are lined by a hyaline eosinophilic material believed to be the residue of disintegrated adipocytes and their interaction with macrophages.96 This distinctive membranous lining is highlighted by periodic acid-Schiff (PAS) staining and may present an arabesque pattern, with intricate undulating papillary and crenulated projections into the cystic spaces. However, membranocystic changes are not exclusive to LDS and may be found in any type of panniculitis.53,97 With progression of LDS, the spectrum of histopathologic changes encompasses increasing degrees of membranocystic fat necrosis, septal fibrosis, and thick-

ening; an inflammatory infiltrate comprising lymphocytes, histiocytes, and foamy macrophages; and partial to extensive atrophy of fat lobules.53,77,95 Advanced lesions show septal sclerosis most prominently, with marked atrophy of fat lobules secondary to lipophagic fat necrosis, accompanied by microcystic and lipomembranous change and a marked reduction in inflammation.53,95 The most severe LDS shows marked fibrosis and sclerosis in the AT layer with little inflammation.77 In late stages, with fibrous thickening of the lower dermis and replacement of the subcutis by sclerosis, a punch biopsy of involved skin may not produce any subcutaneous fat.98

TREATMENT Compression therapy is the major universally recommended treatment for LDS.77,78 Higher compression gradient (30–40 mm Hg) may be more effective, but lower class compression (15–20 mm Hg or 20–30 mm Hg) may be associated with higher rate of compliance, especially in the elderly, and has been shown to be effective in decreasing edema.99 One mechanism by which compression improves venous return and decreases edema is via tightening of vascular tight junctions, significantly elevating expression of tight junction proteins and inhibiting permeability of fluid into the perivascular tissue, thereby preventing progression of venous insufficiency.79,80 Stockings must be worn all day and not removed until bedtime, since even a few days without compression may lead to recurrence of the edema and inflammation.99 Stanazolol has been shown to be effective in LDS, with decrease in pain, erythema, and induration.77,100 Patients tolerated the treatment well, but potential side effects of this treatment include hepatotoxicity, and this may preclude its widespread use. In the United States, this drug is no longer distributed. Other anabolic steroids such as oxandrolone and danazol have also been used.101,102 Pentoxifylline has been successfully used in LDS cases with and without associated ulceration. A Cochrane Database System review of 12 trials involving 864 patients in 2007 concluded the drug was a useful adjunct to compression for treating venous ulcers and may be effective in the absence of compression.103 Other treatments for chronic venous insufficiency include horse chestnut seed extract,104,105 oxerutin,106,107 and flavonoid fraction.108 Ultrasound therapy was reported in two studies as being successful in reducing and even resolving hardness, tenderness, and erythema.109,110 Readily available through physical therapy departments, it is a simple and safe treatment of a painful and refractory condition and may be used along with Grade-2 compression therapy.109,110

PREVENTION Since being overweight and obese are common conditions among affected patients, efforts to reduce weight are prudent.

INFECTION-INDUCED PANNICULITIS INFECTIOUS PANNICULITIS AT A GLANCE Clinical Caused by wide variety of infectious agents, including bacteria, fungi, parasites, and viruses.

Due to primary inoculation or hematogenous spead; patients may be immunosuppressed.

In primary cutaneous infections, epicenter of inflammation is superficial dermis; in secondary infections, epicenter is deep reticular dermis and subcutaneous fat. Special stains, cultures, and serologic studies necessary for detection of microorganisms. Treatment Appropriate antimicrobial therapy selected according to susceptibility tests.

EPIDEMIOLOGY Infection-induced panniculitis (Infectious panniculitis, infective panniculitis) is panniculitis directly caused by an infectious agent.62 AT infection can be due to bacteria, mycobacteria, fungi, protozoa, and viruses.53,62,111 Primary infections produced by direct inoculation at a wound site (injury, surgical procedure, catheter, injection, acupuncture) usually result in a single lesion which may enlarge and spread locally.53,62,111 Secondary infections caused by sepsis and hematogenous spread may manifest as single or multiple lesions.53,62,111 In immunosuppressed patients, microorganisms may be numerous and identified on routine histopathology or special stains. In immunocompetent patients, microorganisms may be sparse and not seen on either routine histopathology or special stains, requiring positive cultures or serological studies for identification.53,62,111 Recent reports of infectious etiologies in association with various autoimmune disorders include Staphylococcus aureus panniculitis with juvenile dermatomyositis (DM),112

The clinical appearance of infectious panniculitis varies from fluctuant- or abscess-type lesions with purulent discharge and ulcerations to nonspecific erythematous firm nonfluctuant subcutaneous plaques and nodules, purpuric plaques, and EN-type lesions.62,111,129 Deep nodules or plaques may not always appear fluctuant, and pustules, fluctuant papules, and ulcers can be superimposed on top of the nodules.111 The most common sites of infection are the legs and feet, but upper extremities, trunk, and face may also be involved.62,111 Immunosuppression of varying etiology is the most frequent, but not universal, association.53,62,111 Immunosuppression is associated with more widespread abscess-type lesions containing nontuberculous mycobacteria, whereas in immunocompetent patients, granulomas are more commonly seen.111,130 Fungal infections occur in the following clinical settings: (1) localized environmentally injected panniculitis of mycetoma, chromoblastomycosis, and sprorotrichosis; or (2) panniculitis associated with systemic disseminated fungal infection that may be seen in individuals with normal immune functions, or with opportunistic fungal infection seen in immune compromised individuals.111,129 Clinical features vary with the setting, the infective organism and the underlying state of the individual’s immunocompetence or immunosuppression.111,129

Panniculitis

Histopathology Suppurative granulomas within fat lobule.

CLINICAL FINDINGS

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Erythematous plaques, nodules, abscesses, ulcers with purulent discharge.

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AT may serve as reservoir for various infections.

Mycobacterium- and Histoplasma-associated panniculitis with rheumatoid arthritis,113,114 and diffuse fusariosis with acute lymphobastic leukemia (ALL).115

HISTOPATHOLOGY Evaluation of panniculitis for infections should include histopathologic studies with special stains for all types of organisms as well as culture and sensitivity testing of biopsy material. In the immunosuppressed patient, microorganisms may be numerous and more readily identified, but in immunocompetent patients, microorganisms may not be seen on either routine histopathology or special stains, requiring positive cultures or serological studies for identification.53,62,111 The antiBacille Calmette-Guérin (BCG) polyclonal antibody immunostain cross-reacts with many bacteria, mycobacteria, and fungi with minimal background staining and is advocated as a good screening tool for detection of microorganisms in paraffin-embedded tissue specimens when conventional stains are negative.53,111,131 Molecular PCR techniques have been utilized with mycobacterium infections.56–58,122 Histopathologic features may vary with the organism and its virulence, the host immune status, and the duration of the lesion at time of biopsy.62 Classified by some as a mostly lobular panniculitis,53 infection-induced panniculitis often presents a mixed septal and lobular pattern, and a predominantly septal, EN-like neutrophilic panniculitis has also been reported to occur in cases of bacterial as well as fungal etiology.62 The superficial dermis is the

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epicenter of inflammation in infections acquired by direct inoculation or by an indwelling catheter, in contrast to more deeply seated infections secondary to hematogenous spread involving the deep reticular dermis and subcutaneous fat.53 Generally, in a typical case, the subcutaneous fat contains a dense infiltrate of neutrophils and some admixed lymphocytes and macrophages, often with extension into the overlying dermis and with abscess formation a common finding.62,111 Patterson et al additionally noted distinctive subcutaneous features in the majority of 15 reported cases of infectioninduced panniculitis of bacterial, atypical mycobacterial and fungal origin, independent of the particular causative microorganism. These features included hemorrhage, vascular proliferation, foci of basophilic necrosis, and sweat gland necrosis. Overlying changes such as parakeratosis, acanthosis, and spongiosis were seen in all cases in which the epidermis was available for examination. All 15 cases also had dermal findings, most commonly upper dermal edema, a diffuse and perivascular inflammatory infiltrate, often with prominent neutrophils, proliferation of thick-walled vessels, and focal or diffuse hemorrhage.62 With observation of any of these enumerated features, special stains for bacteria, mycobacteria, and fungi are imperative, and additional immunohistochemistry or PCR amplification techniques may be necessary. Other histopathologic changes may point toward a more particular etiology. Suppurative granulomas formed by epithelioid histiocytes surrounding aggregated neutrophils may occur in panniculitis caused by atypical mycobacteria.53 Caseating granulomas, though rarely seen, raise suspicion for tuberculous panniculitis.111 A case of panniculitis secondary to CMV has been reported as a mostly septal panniculitis with many CMV inclusions contained within endothelial cells.132

DIFFERENTIAL DIAGNOSIS Differential diagnosis includes α1-antitrypsin (α1AT) panniculitis, pancreatic panniculitis, traumatic, and factitial panniculitis. It is important to recall that presence of one of the above diagnostic types of panniculitis does not exclude infection, as in the case of α1AT panniculitis associated with lymph node histoplasmosis.133

TREATMENT

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Treatment will vary and depend on the suspected or known organisms and their cultures and sensitivities. In cases involving bacteria such as MTB and parasites such as T. cruzi, their known capability to remain dormant in AT necessitates the use, for adequate treatment durations, of appropriate antibiotics, selected for their abilities to affect nonreplicating organisms.67,121

a1-ANTITRYPSIN PANNICULITIS a1-ANTITRYPSIN-DEFICIENCY PANNICULITIS AT A GLANCE Clinical ZZ-, MZ-, MS-, and SS-phenotypeassociated panniculitis rare, with higher percentage (>60%) in ZZ cases; low levels of α1-antitrypsin are associated with emphysema, hepatitis, cirrhosis, vasculitis, and angioedema. Subcutaneous nodules mostly located on the lower abdomen, buttocks, and proximal extremities. Frequent ulceration and isomorphic phenomenon. Histopathology Mostly lobular panniculitis without vasculitis. Necrosis of fat lobules with a dense inflammatory infiltrate of neutrophils. Splaying of neutrophils between collagen bundles of deep reticular dermis. Large areas of normal fat adjacent to necrotic adipocytes. Treatment Dapsone, doxycycline. Homozygous ZZ patients with severe forms of the disease: supplemental intravenous infusion of exogenous α1-proteinase inhibitor concentrate or α1-antitrypsin produced by genetic engineering; liver transplantation.

ETIOLOGY AND PATHOGENESIS α1AT is a glycoprotein that accounts for 90% of the total serum serine protease inhibitor capacity in humans.134 It is produced and secreted mainly by hepatocytes, but also in small amounts by monocytes/macrophages and neutrophils,135–137 and is known to inhibit trypsin, chymotrypsin, leukocyte elastase, kallikrein, collagenase, plasmin, and thrombin among other proteases.134 α1AT may also help regulate protease stimulated activation of lymphocytes, phagocytosis by macrophages and neutrophils, and complement activation.138–141 It is an acute phase reactant, increased in times of stress. α1AT deficiency is inherited as a codominant disorder, and more than 100 alleles have been identified.142,143 The α1AT phenotypes are classified according to gel

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Chapter 70 ::

B

Figure 70-9  α1-Antitrypsin deficiency associated panniculitis. A. Fluctuant abscess type appearance. B. Discharge of oily material.

electrophoresis migration/mobility as F (fast), M (medium), S (slow), and Z (very slow), but null variants that do not produce any α1AT and patients may have dysfunctional α1AT with normal levels.144 Homozygous MM, the most common phenotype, is associated with normal levels of α1AT, whereas those homozygous for ZZ have low levels at 10%–15% of normal, and those heterozygous for S or Z allele have levels in between. MS heterozygous individuals may have low normal serum levels.145 Due to the complex nature of these proteins, combination protein levels, or phenotyping and genotyping, have been recommended.144 Estimated prevalence of α1AT deficiency in Caucasians is 1 per 3,000–5,000 in the United States, with incidence in Caucasian newborns similar to that of cystic fibrosis.144

Panniculitis

A

seen between ages 30 and 60.146,148 Patients present with painful erythematous nodules and plaques, but early lesions may have a cellulitic or fluctuant abscesstype appearance (Fig. 70-9A). Lesions may ulcerate and discharge an oily material or serosanguineous discharge9 (Fig. 70-9B) and resolve with atrophic scars.53 The lesions appear most commonly on the lower trunk (buttocks) (Fig. 70-10) and proximal extremities, but lower legs and other sites may be affected.53,146,150 As trauma or excessive activity may precede the onset of lesions in a third of patients,53,146 debridement is discouraged.53 α1AT panniculitis has occurred in patients with such conditions as hypothyroidism, mixed connective tissue disease, lymphoproliferative disorders, and infections, including a focus of histoplasmosis in a lymph node.133,149 Therefore, the presence of α1AT ­deficiency in association with panniculitis should not

CLINICAL FINDINGS α1AT deficiency is most commonly associated with pulmonary and hepatic disease, leading to chronic obstructive pulmonary disease (COPD), hepatic cirrhosis, or hepatocellular carcinoma144; the ZZ genotype is at highest risk. There is no association of the null variant with hepatic disease, as it is the accumulation of polymerized α1AT in the liver that induces damage, and accumulation does not occur in this variant.144 The exact mechanism of injury is still controversial.144 Panniculitis uncommonly occurs in α1AT deficiency. Less than 50 cases have been reported146,147 in ZZ, MZ, MS, and SS phenotypes, with higher percentage (>60%) of ZZ cases as well as higher incidence in women (65%).146 Presenting in an age range from childhood (infancy) to the elderly, panniculitis is most frequently

Figure 70-10  α1-Antitrypsin deficiency associated panniculitis. Nodular lesion on the buttock.

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DIFFERENTIAL DIAGNOSIS

:: Disorders of Subcutaneous Tissue

Differential diagnosis of α1AT panniculitis includes other panniculitides that may ulcerate and drain such as the spectrum of infections, factitial disease, EI, and pancreatic panniculitis. Subcutaneous Sweet syndrome, rheumatoid arthritis, and myelodysplasia-associated neutrophilic panniculitis do not usually drain and ulcerate.160,161

PATHOLOGY TREATMENT

Histopathologic findings vary with the age and type of lesion biopsied. Early in their development, nodular lesions may reveal edema and degeneration of adipocytes, with ruptured and collapsed cell membranes and a perivascular mononuclear infiltrate.153 Also reported at this stage is a mild infiltrate of neutrophils and macrophages in septa and lobules, with foci of early necrosis of subcutaneous fat. This may be accompanied by splaying of neutrophils between collagen bundles throughout the overlying reticular dermis, considered an early and distinctive diagnostic clue.156 More advanced lesions have masses of neutrophils and histiocytes associated with necrosis and replacement of fat lobules (Figs. 70-11A and 70-11B). A focal pattern of involvement is another distinguishing feature that may be appreciated, manifested by large

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744

areas of normal fat in immediate proximity to necrotic septa and fat lobules.157 Liquefactive necrosis and dissolution of dermal collagen may be accompanied by ulceration, and degeneration of elastic tissue may lead to septal destruction and the appearance of “floating” necrotic fat lobules.149,158 A rare occurrence is an exclusively septal pattern of mixed inflammatory infiltrate with a predominance of neutrophils.146,158 Neutrophils and necrotic adipocytes are less prevalent in late stage lesions, with replacement by lymphocytes, foamy histiocytes, and variable amount of fibrosis within fat lobules.149,159

preclude a search for infection or other underlying medical problems such as autoimmune disorders, malignancies, or infections, since they may coexist. Cutaneous and subcutaneous necrosis can develop rapidly. Extensive involvement with α1AT panniculitis can be life threatening, and fatal cases have been reported.148,151,152 Erythrophagocytosis was noted in the biopsy of one of the patients with fatal panniculitis.153 Possible mechanisms leading to the development of α1AT panniculitis include lack of interference with the various proteases that lead to activation of lymphocytes, macrophages, complement, and lysis and destruction of connective tissue at sites of inflammation. Trauma to adipocytes may result in their activation, with release of the various adipokines and cytokines that are chemotactic to inflammatory cells, whose released proteases are unopposed due to absence of the α1AT, leading to severe damage in involved tissue.154,155 Animal models of soft tissue injury show elevated levels of IL-6 and MCP-1 and increased systemic inflammatory mediators.154

Many medications have been used in the treatment of α1AT deficiency panniculitis including colchicine, antimalarials, steroids, immunosuppressive agents, cytotoxic agents, dapsone, doxycyline, plasma infusion and plasma exchange, intravenous α1AT replacement therapy, and liver transplantation.148,150,162–167 Steroids, immunosuppressives, and cytotoxic agents were the least successful treatment options. Doxycycline and especially dapsone were very helpful in mild to moderate cases, but severe panniculitis required A1P replacement therapy.148,149,159,167 Panniculitis resolved with liver transplantation,168 and panniculitis acquired after liver transplantation was successfully treated with retransplantation.169

B

Figure 70-11  α1-Antitrypsin panniculitis. A. Scanning power shows a mostly lobular panniculitis. B. Dense inflammatory infiltrate of neutrophils in the fat lobule.

PANCREATIC PANNICULITIS PANCREATIC PANNICULITIS AT A GLANCE Clinical Erythematous subcutaneous nodules that often ulcerate spontaneously. Lower extremities (around ankles and knees) are most frequent sites of involvement.

Ghost adipocytes with finely granular and basophilic intracytoplasmic material. Treatment Treatment of the underlying pancreatic disease, ocreotide, plasmapheresis.

EPIDEMIOLOGY Panniculitis in association with pancreatic disease is a rare occurrence, developing in 2%–3% of all patients with pancreatic disorders and appearing in the setting of acute or chronic pancreatitis, pancreatic carcinoma, or pancreatic pseudocysts.170–172 Although pancreatitis is most commonly due to alcohol abuse, cholelithiasis, or pancreatic calculi, medications and viral infections are also known etiologic factors.173,174 The cutaneous panniculitis may precede the diagnosis of the associated pancreatic disease by weeks to months in up to 45% of patients.170,173 Mono- or oligoarticular arthritis secondary to periarticular fat necrosis may be present in over half of patients.170 This triad of pancreatic disease, panniculitis, and polyarthritis may occur with either pancreatitis or pancreatic carcinoma.175 and is seen in less than 1% of pancreatitis patients172; joint disease may precede the diagnosis of pancreatic disorder.175 Abdominal symptoms may be mild or absent.175 Pancreatic panniculitis may also be seen in association with pancreatitis following renal or pancreas renal transplant,176,177 with SLE,178 and with hemophagocytic syndrome (HPS).179 Panniculitis associated with pancreatic disease may be fatal,170,172,180 with a mortality rate of up to 24% in one series175 and mortality rates of 100% in those with pancreatic carcinoma and 42% of 19 patients with pancreatitis in another series.181

CLINICAL FINDINGS The cutaneous lesions appear most frequently on the lower legs, especially the periarticular areas,170 but are also found on the arms, thighs, and trunk.170 Lesions often appear in crops, although single nodule pancreatic panniculitis also occurs.185 The lesions are illdefined erythematous to red–brown edematous tender nodules, which in mild cases may involute and resolve with atrophic hyperpigmented scars,170 may have central “softer” areas or may become fluctuant, abscesslike, and drain oily material similar to lesions of α1AT deficiency panniculitis (Fig. 70-12A).170 Extracutaneous manifestations include periarticular fat necrosis with concomitant arthritis,170 painful medullary fat necrosis in bone,172 and pleural effusions and serositis.172,181 The presence of pleural effusions, alone or with arthritis, is associated with a high mortality rate.181 Eosinophilia may be seen in both pancreatitisand pancreatic malignancy-associated pannicultis,181 and a pancreatic tumor in association with panniculitis, polyarthritis, and eosinophilia (Schmid’s triad) imparts a poor prognosis.186

Panniculitis

Intense necrosis of adipocytes at center of fat lobule.

::

Histopathology Mostly lobular panniculitis without vasculitis.

Pancreatic panniculitis has generally been attributed to release of pancreatic enzymes such as lipase, amylase, and trypsin into the circulation, promoting vascular permeability, leading to release of fatty acids from adipocytes and subsequent fat necrosis.172,182 However, there are reports of normal serum levels of pancreatic enzymes in association with typical pancreatic pannicultis.170 Additionally, incubation of normal AT with amylase and lipase and with pancreatitis patient serum high in those enzymes failed to induce fat necrosis in vitro,183 leading to suggestions that other mechanisms may be involved in the development of pancreatic panniculitis. Since many of the lesions appear on lower legs, these mechanisms may include venous hypertension, but likely also involve adipocyte generated cytokines and adipokines related to effects of high levels of free fatty acids170; resistin and leptin have been shown to be potential markers of extrapancreatic fat necrosis.184

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Regression of pancreatitis-associated cutaneous lesions, but those associated with pancreatic carcinoma tend to persist; may be fatal.

ETIOLOGY AND PATHOGENESIS

HISTOPATHOLOGY Fully developed lesions of pancreatic panniculitis demonstrate lobular fat necrosis with distinctive qualities (Fig. 70-12B). Adipocytes lose their nuclei but maintain peripheral outlines, forming characteristic “ghost cells” (Fig. 70-12C). With saponification, calcification occurs, producing fine granular basophilic deposits within and around individual necrotic adipocytes. The ghost cells are frequently aggregated in small clusters at the center of fat lobules, with a peripheral inflammatory infiltrate of neutrophils.53 In older lesions, necrosis and ghost cells are less evident, replaced by foamy histiocytes, multinucleated giant cells, lymphocytes, and eventually, fibrosis.53,98 Of note,

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pancreatic panniculitis has been reported to originate as a septal inflammatory process similar to EN in its earliest manifestation,187 and findings mimicking pancreatic panniculitis have been documented at the site of subcutaneous interferon β injections in the course of treatment of multiple sclerosis.188 Treatment is supportive and directed at the underlying pancreatic disorder. Since patients may not have abdominal symptoms, pancreatic panniculitis should be considered in the differential diagnosis of any panniculitis. Resolution of the lesions occurs with specific surgical treatment appropriate to the underlying disorder.173,175,189 Ocreotide, a somatostatin analog, and plasmapheresis have also been associated with resolution of pancreatic panniculitis.190,191

B

Figure 70-12  Pancreatic panniculitis A. Clinical features: erythematous subcutaneous nodules that ulcerate and exude an oily material. B. Scanning power shows a mostly lobular panniculitis with adipocyte necrosis at the center of the fat lobule. C. Higher magnification shows ghost adipocytes, necrotic adipocytes without nuclei and with cytoplasmic fine granular basophilic material due to calcification.

LUPUS PANNICULITIS [Lupus Erythematosus Panniculitis (LEP), Lupus Profundus, Subcutaneous Lupus Erythematosus] EPIDEMIOLOGY Lupus erythematosus panniculitis (LEP) is a rare variant of lupus erythematosus (LE), which primarily affects the subcutaneous AT.192,193 LEP may appear as the sole manifestation of LE or may occur prior to or

LUPUS PANNICULITIS AT A GLANCE Clinical Erythematous nodules on face, shoulders, upper arms, scalp, chest, buttocks; rarely on lower extremities. Persistent areas of lipoatrophy in regressed lesions.

Lobular lymphocytic infiltrate, with plasma cells in many cases, eosinophils sometimes.

Hyaline necrosis and atrophy of entire fat lobule in late-stage lesions. Interface changes of discoid lupus erythematosus in 20%–30% of cases (changes at the dermal–epidermal interface may also rarely accompany subcutaneous panniculitis-like T-cell lymphoma). Treatment Antimalarials, thalidomide. If active and severely inflamed, short oral courses of corticosteroids. Dapsone, cyclosporine, methotrexate, intravenous immunoglobulin, and rituximab.

after the onset of discoid lupus erythematosus (DLE) or systemic lupus erythematosus (SLE).194,195 The incidence of SLE in patients with LEP has been reported to range from 10% to 41%, with the highest incidence seen in a Japanese series of 44 cases193,195,196; LEP occurs in only 1%–5% of patients with SLE.192,193 Although rare, LEP occurs worldwide, more frequently among women than men, with a female to male ratio of about 4:1.193,195,197 LEP is most common between the ages of 30 and 60, but may rarely be seen in childhood or even as neonatal lupus.53,193,194,198 When present in association with SLE, LEP tends to occur in SLE cases of lesser severity.195,197 There are a few case reports of LEP in more than one family member, or of family members with SLE unaccompanied by LEP.192,193 Patients with LEP may also have other autoimmune disorders such as Sjögren’s syndrome and rheumatoid arthritis.192,193

Panniculitis

Sclerotic collagen bundles within septa.

::

Lymphoid follicles with germinal centers often.

While a complete understanding of why LEP develops is still lacking, the innate immune system has been recently recognized to play a significant role in the development of SLE. Adipocytes are important cells of the innate immune system and function in pathogen recognition, activation of adaptive immunity, and as a reservoir for various microbes. All TLRs are expressed in AT. Adipocytes themselves express TLR1, 2, 3, 4, and 6, whereas TLR5, 7, 8, 9, and 10 are expressed on the nonadipocyte stromovascular fraction of AT.199 The reasons for “lupus panniculitis” may vary from genetic polymorphism of TLRs leading to inappropriate activation of innate immune systems (especially of the type 1 interferon system),200 to inappropriate interactions of adipocytes with inflammatory cells, to immune responsiveness against microbial and nonmicrobial antigens within AT. The localization of LEP to specific fat depots may be a clue to the functions of those adipocytes, or to a specific genetic aberration, or to the type of lymphocytes that are attracted to those AT depots. In SLE, TLR7 and TLR9 recognize RNA and DNA patterns, respectively, and appear to provide a mechanism for recognition of self-DNA or self-RNA, with subsequent activation of the adaptive immune system and production of autoantibodies to nucleic acids and proteins bound to nucleic acids.201–205 Inhibitors of TLR7 and TLR9 can prevent disease in mouse models of autoimmunity,203 although deletion of TLR9 may enhance disease in some experimental models.206 Both receptors have been suggested as therapeutic targets.203,205,206 Genetic variations in TLR9 receptor has been shown to predispose to SLE in a Japanese series207 and regression of SLE was seen in a patient who developed an acquired TLR7 and TLR9 defect and antibody deficiency.208 SLE occurs much more commonly in women, and both TLR7 and TLR8 are encoded on the X chromosome, adding another layer of disease association.209 In addition, hydroxychloroquine, the most common treatment for all variants of SLE and LEP, has been shown to block intracellular TLRs in vitro.210

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Chapter 70

Histopathology Mostly lobular panniculitis without vasculitis (lymphocytic vasculitis occasionally).

ETIOLOGY AND PATHOGENESIS

CLINICAL FINDINGS LEP lesions may be tender and painful and usually appear on the upper arms (lateral aspect), shoulders, face, scalp, hips, buttocks, breasts, and rarely on the lower extremities (Fig. 70-13).193–195 Orbital/ocular involvement may present with periorbital edema.211,212 The lesions are deep subcutaneous nodules without any surface changes, or with surface changes including erythema and DLE features such as atrophy, hyperkeratosis, hyper- or hypopigmentation, telangiectasia, follicular plugging, and focal ulceration and necrosis.193,194 The shoulder and arm sites are frequently associated with surface DLE lesions.193 Incidence of ulceration varies from 500 mg/L; increased soluble CD25, CD163 levels. Low or absent NK cell activity, fibrinogen levels. Rapidly fatal disease course; intermittent remissions and exacerbations prior to death; or nonfatal acute or intermittent course. Histopathological findings Mostly lobular panniculitis without vasculitis. Histiocytes and mature lymphocytes within fat lobules. “Bean-bag” cells: macrophages that contain intact or fragmented erythrocytes, leukocytes or platelets within their cytoplasm; may be focal, hard to find. Necrosis of adipocytes. Treatment Immunosuppressive therapy: glucocorticosteroids, in combination with cyclosporine or etoposide, combined chemotherapeutic medications, anakinra; supportive care; search for associated malignancies and infections.

SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN EPIDEMIOLOGY Subcutaneous fat necrosis of the newborn (SCFN) is a rare panniculitis that occurs in the first few weeks of

SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN AT A GLANCE Clinical Circumscribed, red to violaceous, subcutaneous nodules, or plaques with predilection for buttocks, shoulders, cheeks, and thighs. Hypercalcemia in some cases, even presenting much later than acute episode; rarely, hypertriglyceridemia, hypoglycemia, thrombocytopenia, anemia.

Treatment Nodules and plaques usually resolve spontaneously. Monitor for hypercalcemia for 6 months following onset, treat if hypercalcemia develops.

life. It presents in full-term newborns with a preceding history of perinatal problems, including meconium aspiration, asphyxia, hypothermia (e.g., for cardiac surgery or ice pack application for supraventricular tachycardia), hypoxemia, seizures, sepsis, preeclampsia, factors requiring cesarean section, forceps delivery, severe neonatal anemia, maternal cocaine use, and/or failure to thrive.279–287 SCFN may be complicated by hypercalcemia, and rarely, by hypertriglyceridemia, hypoglycemia, thrombocytopenia, and anemia.282–284

ETIOLOGY AND PATHOGENESIS The cause in not known, but hypothermia or hypoxia is presumed to be involved. Possible explanations have included a biochemical defect in the composition or metabolism of neonatal fat, leading to crystallization, fat necrosis, and subsequent inflammation after cold stress.283,288 The hypercalcemia may be related to increased levels of 25-hydroxyvitamin D3–1α hydroxylase within the granulomatous infiltrate of lesions.289 Another explanation takes into account the presence of BAT in neonates along with its main function, which is to rapidly convert fat stores to heat under conditions of

Panniculitis

Needle-shaped clefts, often in radial array, within cytoplasm of histiocytes and multinucleated giant cells.

Lesions are sharply demarcated, erythematous to violaceous, firm, indurated nodules, or plaques located on the back, shoulders, arms, buttocks, thighs, or face, but usually not on the anterior trunk279,283 (Fig. 70-15A). In one case, MRI findings consistent with fat necrosis were seen in the abdominal wall as well as in the fat surrounding the liver, spleen, and a kidney.293 The subcutaneous nodules range in size from several millimeters to up to 11 cm in greatest dimension,280,294 may be single or multiple, and may be of irregular shape, although usually well defined.280 Rarely, fluctuant nodules may drain an oily or chalky white material.294 Lesions are not warm to touch280 and may vary from entirely painless280 to those requiring morphine for control of pain.284

::

Dense inflammatory infiltrate of lymphocytes, histiocytes, lipophages, and multinucleated giant cells.

CLINICAL FINDINGS

10

Chapter 70

Histopathology Mostly lobular panniculitis without vasculitis.

cold stress.290 BAT is widely distributed in the early years of life. At its maximal size relative to body weight at birth, when nonshivering heat generation is most needed, the presence and function of BAT relates to the immaturity of the heat regulating mechanism, providing the young with a “thermogenic jacket.”25,290 The BAT cells leak hydrogen ions across the inner ­membrane of the mitochondria to generate heat instead of creating ATP for other metabolic processes.291 The mechanism is complex, and uses uncoupling protein isoform 1 (UCP1), found specifically in BAT, cytosolic fatty acids, and Ca2+ ions.292

HISTOPATHOLOGY Characteristically, SCFN is a mostly lobular panniculitis (Fig. 70-15B), with focal necrosis of the fat lobule and a dense inflammatory infiltrate of lymphocytes, histiocytes, and foreign body giant cells; a few eosinophils may insinuate between the fat cells. Many adipocytes retain their cellular outlines, but contain fine eosinophilic strands and granules as well as needleshaped clefts in radial array53,98,283,295 (Fig. 70-15C). On frozen section, these clefts are occupied by doubly refractile crystals, representing triglycerides. Similar clefts and crystals may also be seen within the cytoplasm of the multinucleated giant cells.53,98,282,295 Late stage lesions may demonstrate fibrosis and calcified areas within fat lobules; the latter may also be seen radiographically.53,280

DIFFERENTIAL DIAGNOSIS Differential diagnoses include cellulitis, erysipelas, and cold panniculitis (if cold-induced).285,286 In contrast to SCFN, the histopathology of cold panniculitis does not feature the presence of needle-shaped clefts within the subcutaneous AT.286 Other childhood panniculitides with the histologic finding of needle-shaped clefts in subcutaneous fat include sclerema neonatorum, which manifests with diffuse skin hardening in stressed infants,296 and poststeroid

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B

Figure 70-14  Cytophagic histiocytic panniculitis. A. Multiple erythematous plaques and nodules on lower extremity. B. Lowpower histologic image shows lobular panniculitis. C. Diagnostic cytophagocytic “bean bag” cells in the adipose tissue.

panniculitis.297–299 Only one infant with the clinical findings of both the diffuse hardening of the skin of sclerema and the violaceous nodules of SCFN has been described.300 Poststeroid panniculitis occurs in children, usually within 10 days (range, 1–40 days) after rapid cessation of high-dose systemic corticosteroid therapy.297,298

CLINICAL COURSE

752

SCFN is usually a benign process with an uncomplicated course and excellent prognosis. Lesions regress in a few weeks to 6 months, with some eventuating in atrophy.283,284,293 However, there are several metabolic

complications that may occur during and even after resolution of the panniculitis.283 These include hypercalcemia,280,282,284,293,294 thrombocytopenia,282,283 hypertriglyceridemia, which appears to be related to the fat necrosis283,284 and anemia.283 Hypercalcemia may be asymptomatic and uncomplicated,281,284 or may become symptomatic, with failure to thrive, irritability, fever, vomiting, hypotonia, seizures, polyuria and polydypsia, and even death.280,294 Soft tissue calcification may occur and resolve without evidence of hypercalcemia,280 or calcium may deposit in the kidneys and cardiovascular system.282–284 The hypercalcemia may have a delayed onset up to 6 months after appearance of the skin lesions; therefore, serial monitoring of serum calcium levels is necessary.283,284

10

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B

:: Panniculitis

A

C

Figure 70-15  Subcutaneous fat necrosis of the newborn. A. Circumscribed indurated subcutaneous nodules on the back. B. Scanning power shows mostly lobular pannicultis. C. Higher magnification shows narrow needle-shaped clefts of adipocytes, histiocytes, and multinucleated giant cells.

TREATMENT SCFN nodules resolve spontaneously, and treatment should be conservative in most cases, except for fluctuant lesions that may benefit from aspiration to prevent rupture, infections, necrosis, and scarring.282,283 Serum calcium should be monitored with serial calcium determinations. If hypercalcemia is present, management by a pediatric endocrinologist will include hydration, use of the calcium wasting diuretic furosemide, and a low calcium and vitamin D diet.283,294 The diuretics that increase calcium excretion may also induce dehydration, requiring careful monitoring. If these measures are insufficient to control hypercalcemia, systemic glucocorticoids are used, as they interfere with vitamin D metabolism and inhibit active vitamin D production by the macrophages in the inflamed AT279,283,294; however, nephrocalcinosis may still develop in spite of response to systemic steroids.301 First and second generation bisphosphonates, including etidronate,302,303 clodronate,304 and pamidronate,305 have been used to treat hypercalcemia in SCFN. However, nephrocalcinosis may develop, despite a rapid response to pamidronate.306 The degree and duration of hypercalcemia and hypercalciuria may be the important factor in development of nephrocalcinosis; this calls for close early monitoring and recognition of hypercalcemia, since rapid therapeutic intervention to lower serum and urine calcium may be the best treatment modality for prevention of dystrophic calcification.306

COLD PANNICULITIS COLD PANNICULITIS AT A GLANCE Clinical Circumscribed, red to violaceous, subcutaneous nodules or plaques on the face and thighs, and rarely of the scrotal fat in prepubertal boys. Follows exposure to cold weather, popsicles, ice packs, and swimming in cold ocean water. Histopathology Mostly lobular panniculitis (lymphohistiocytic or mixed infiltrate) without vasculitis. Perivascular lymphohistiocytic infiltrate involving blood vessels at dermosubcutaneous junction and within overlying dermis. Findings similar to those seen in perniosis. Treatment Avoid direct ice placement on skin, mucous membranes. Spontaneous resolution within 3 months.

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10

FACTITIAL PANNICULITIS FACTITIAL PANNICULITIS AT A GLANCE Clinical Erythematous nodules with disparate location or appearance in patients with personality aberrations.

Section 10

Subcutaneous implantation range from medications, cosmetic fillers, oils, food to human waste. Histopathology Mostly lobular panniculitis without vasculitis.

:: Disorders of Subcutaneous Tissue

Suppurative granuloma involving the fat lobule; requires cultures for various organisms. Polarization of the slide may identify the refractile foreign material. Panniculitis morphology, such as histiocyte characteristic inclusions, or cystic spaces with foreign substances may vary with type of injected material. Treatment Psychiatric treatment for self-inflicted factitial panniculitis. Supportive care and interference with injection of responsible agents. In panniculitis induced by cosmetic fillers, intralesional steroids, and often the implanted material must be surgically excised.

754

Factitial panniculitis is a reaction in AT induced by external factors, usually injection of foreign materials. This may be iatrogenic due to injection of medications or cosmetic fillers, or secondary to cupping and acupuncture,320 or other means of trauma (accidental or deliberate). Factitial panniculitis is also associated with self-induced injections of various substances due to psychiatric disorder. History obtained from patients of injections of therapeutic agents or cosmetic fillers aids the diagnosis. Self-inflicted factitial panniculitis due to substances that may not necessarily leave a recognizable clinical or histopathologic footprint may be difficult to diagnose and requires a high index of suspicion.53,320–322 Factitial lesions present a spectrum of clinical findings, from papules and nodules to erosions or ulcerations with perfect round or angulated appearance322 (Fig. 70-16). Lesions due to blunt trauma will

Figure 70-16  Factitial panniculitis. Self-induced round and angulated ulceration on the leg at sites of injections and trauma. often be ecchymotic, show organized hematomas and hemosiderin deposits.322 Injections of various oily substances will lead to foreign body reactions with foamy histiocytes and pseudocystic spaces.53,322 Injection of medication and various other substances such as acids, milk, mustard, acids, alkalis, infected/contaminated materials, urine, and feces have been reported.53,322 Early lesional histopathology is usually predominantly neutrophilic, and later may show a granulomatous infiltrate.53,234 Due to the presence of macrophages and lymphocytes in AT, as well as the adipocyte’s role as an innate immune cell producing multiple cytokines, materials injected into AT are treated as a foreign agent, with an inflammatory immune response with or without associated fat necrosis.53,234 Patients with selfinduced factitial panniculitis suffer from mental illness and require psychiatric care.53,234 If iatrogenic, the causative action must cease. Surgical excision of the injected materials may be necessary.320,322

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 5. Fantuzzi G: Adipose tissue, adipokines and inflammation. J Allergy Clin Immunol 115:911, 2005 27. Requena L, Sanchez Yus E: Panniculitis. Part I. Mostly septal panniculitis. J Am Acad Dematol 45:163, 2001 52. Segura S et al: Vasculitis in erythema induratum of Bazin: A histopathologic study of 101 biopsy specimens from 86 patients. J Am Acad Dermatol 59:839, 2008

53. Requena L, Sanchez Yus E: Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol 45:325, 2001 78. Bruce AJ et al: Lipodermatosclerosis: Review of cases evaluated at Mayo Clinic. J Am Acad Dermatol 46:187, 2002 129. Morrison LK et al: Infections and panniculitis. Dermatol Ther 23(4):328-340, 2010

193. Winkelmann RK: Panniculitis in connective tissue diseases. Arch Dermatol 119:336, 1983 223. Hansen C, Callen J: Connective tissue panniculitis. Dermatol Ther 23(4):341-349, 2010 251. Crotty CP, Winkelmann RK: Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure and terminal hemorrhagic diathesis. J Am Acad Dermatol 4:181, 1981

LIPODYSTROPHY AT A GLANCE

Four loci have been identified for autosomal dominant familial partial lipodystrophy (FPL), namely, (1) LMNA, (2) PPARG, (3) AKT2, and (4) PLIN1. CIDEC is the locus for autosomal recessive FPL, and LMNA and ZMPSTE24 are loci for autosomal recessive mandibuloacral dysplasia-associated lipodystrophy. Molecular basis of many rare forms of genetic lipodystrophies remains to be elucidated. The most prevalent variety of lipodystrophy develops after prolonged duration of protease inhibitor containing highly active antiretroviral therapy in HIV-infected patients. The acquired generalized lipodystrophy and acquired partial lipodystrophy are mainly autoimmune in origin. Localized lipodystrophies occur due to drug or vaccine injections, pressure, panniculitis, and other unknown reasons.

The current management includes cosmetic surgery and early identification and treatment of metabolic and other complications.

Lipodystrophy

Four loci have been identified for the autosomal recessive congenital generalized lipodystrophy (CGL), namely, (1) AGPAT2, (2) BSCL2, (3) CAV1, and (4) PTRF.

::

Lipodystrophies are genetic or acquired disorders characterized by selective loss of body fat. The extent of fat loss determines the severity of associated metabolic complications such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, and acanthosis nigricans.

Lipodystrophies are a heterogeneous group of disorders characterized by selective loss of adipose tissue.1 The extent of fat loss varies, with some patients losing fat from small areas (localized lipodystrophy), whereas others may have more extensive fat loss, for example, involving the extremities (partial lipodystrophy) or the entire body (generalized lipodystrophy). Depending upon the extent of fat loss, patients may be predisposed to develop complications associated with insulin resistance such as, diabetes mellitus, dyslipidemia, hepatic steatosis, acanthosis nigricans, polycystic ovarian disease, and coronary heart disease.2,3 There are two main types of lipodystrophies: (1) genetic and (2) acquired. A detailed classification of various types of lipodystrophies is given in Table 71-1.

Chapter 71

Chapter 71 :: Lipodystrophy :: Abhimanyu Garg

10

GENETIC LIPODYSTROPHIES In the last decade or so, considerable progress has been made in elucidation of the molecular basis of many types of genetic lipodystrophies. In general, mutations in genes involved in adipocyte differentiation, triglyceride synthesis, lipid droplet formation, and adipocyte survival have been reported to cause lipodystrophies.

EPIDEMIOLOGY Although the genetic lipodystrophies are rare, recent advances such as improved definition of the phenotypes and elucidation of the molecular defects, have led to increased recognition of these syndromes. Overall, based on literature reports of less than 1,000 patients, the estimated prevalence of genetic lipodystrophies may be less than 1 in a million. The autosomal recessive, congenital generalized lipodystrophy (CGL) has been reported in fewer than 300 patients, with clustering of patients reported from Lebanon and ­Brazil where there is increased prevalence of consanguinity. The autosomal dominant, familial partial lipodystrophy (FPL) of the Dunnigan variety due to LMNA mutations is the most common with ∼500 patients being reported; autosomal dominant, FPL due to PPARG mutations with ∼30 patients; autosomal

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TABLE 71-1

Classification of Lipodystrophies

Section 10 :: Disorders of Subcutaneous Tissue

756

A.  Genetic Lipodystrophies 1. Autosomal recessive, congenital generalized lipodystrophy (CGL) a.  Type 1: AGPAT2 mutations b.  Type 2: BSCL2 mutations c.  Type 3: CAV1 mutation d.  Type 4: PTRF mutations e.  Others 2. Autosomal dominant, familial partial lipodystrophy (FPL) a.  Dunnigan variety: LMNA mutations b.  PPARG mutations c.  AKT2 mutation d.  PLIN1 mutations e.  Others 3.  Autosomal recessive, familial partial lipodystrophy a.  CIDEC mutation 4. Autosomal recessive, mandibuloacral dysplasia (MAD)associated lipodystrophy a.  LMNA mutations b.  ZMPSTE24 mutations c.  Others 5.  Other lipodystrophies associated with LMNA mutations a.  Atypical progeroid syndrome b.  Hutchinson–Gilford progeria syndrome 6.  SHORT syndrome a.  Autosomal recessive b.  Autosomal dominant 7. Neonatal progeroid (Weidemann–Rautenstrauch) syndrome 8. Mandibular hypoplasia, deafness, progeroid (MDP) syndrome 9. Joint contractures, microcytic anemia, panniculitisassociated (JMP) lipodystrophy syndrome spectrum a.  PSMB8 mutations 9a. Chronic atypical neutrophilic dermatosis with ipodystrophy and elevated temperature (CANDLE) syndrome B.  Acquired Lipodystrophies 1. Highly active antiretroviral therapy-induced lipodystrophy in HIV-infected patients 2.  Acquired generalized lipodystrophy a.  Panniculitis-induced b.  Autoimmune diseases-associated c.  Idiopathic 3.  Acquired partial (Barraquer–Simons) lipodystrophy a.  Autoimmune diseases-associated b. Membranoproliferative glomerulonephritisassociated c.  Idiopathic 4.  Localized lipodystrophies a.  Panniculitis-induced b.  Pressure-induced c.  Drug-induced d.  Centrifugal e.  Idiopathic

recessive, mandibuloacral dysplasia (MAD) due to LMNA mutations in ∼30 patients and due to ZMPSTE24 mutations in eight patients. Affected females are recognized easily and thus are reported more often than males.

CONGENITAL GENERALIZED LIPODYSTROPHY (CGL, BERARDINELLI–SEIP SYNDROME) ETIOLOGY AND PATHOGENESIS. This autosomal recessive disorder can be recognized at birth or soon thereafter due to near total lack of body fat. Genome-wide linkage analysis with positional cloning strategy and candidate gene approach have led to the identification of four genetic loci for CGL: (1) 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) gene on chromosome 9q34,4,5 (2) Berardinelli–Seip congenital lipodystrophy 2 (BSCL2) gene on chromosome 11q13,6 (3) caveolin 1 (CAV1) gene on chromosome 7q31,7 and (4) polymerase I and transcript release factor (PTRF) on chromosome 17q21.8 AGPAT2 is a critical enzyme involved in the biosynthesis of triglycerides and phospholipids from glycerol-3-phosphate and is expressed highly in the adipose tissue.9 The BSCL2encoded protein, seipin, plays a role in lipid droplet formation and may also be involved in adipocyte differentiation.10–12 Caveolin 1 is an integral component of caveolae, specialized microdomains seen in abundance on adipocyte membranes. Caveolin 1 binds fatty acids and translocates them to lipid droplets. PTRF is involved in biogenesis of caveolae and regulates expression of caveolins 1 and 3.8 CLINICAL FINDINGS. Patients with CGL present with near total loss of body fat, marked muscularity, prominent subcutaneous veins, acromegaloid features, acanthosis nigricans, hepatomegaly, and umbilical prominence or hernia (Fig. 71-1A, Table 71-2). During childhood, they have a voracious appetite, and accelerated linear growth. Females usually have hirsutism, clitoromegaly, oligoamenorrhea, and polycystic ovaries. Only a few women have had successful pregnancies. Fertility is normal in men. Some of them develop hypertrophic cardiomyopathy, mild mental retardation, and focal lytic lesions in the appendicular bones after puberty.13–15 Metabolic abnormalities related to insulin resistance, such as diabetes mellitus, hyperlipidemia, and hepatic steatosis, may manifest at a young age and are often difficult to control. Patients with BSCL2 mutations lack mechanical fat located in the retro-orbital region, palm, sole, and in periarticular regions as well as metabolically active adipose tissue located in the subcutaneous (sc), intraabdominal, intrathoracic, and other areas as compared to those with AGPAT2, CAV1, and PTRF mutations where mechanical fat is preserved.7,16 The only reported patient with CAV1 mutation also had short stature and presumed vitamin D resistance.7 Only 21 patients with PTRF mutations have been reported and they have congenital myopathy, increased creatine kinase levels, percussioninduced myoedema, pyloric stenosis, cardiac rhythm disturbances including prolonged QT interval, exerciseinduced ventricular tachycardia, and atlantoaxial instability.8,17,18 Patients of Lebanese origin harbor homozygous c.659delGTATC mutation in BSCL2, whereas those of African origin nearly always have either homozygous or compound heterozygous c.IVS4–2A>G mutation in AGPAT2 gene.5,6,13

10

Chapter 71 ::

B

C

D

E

Figure 71-1  Clinical features of patients with various types of lipodystrophies. A. Anterior view of a 33-year-old Hispanic female with congenital generalized lipodystrophy (also known as Berardinelli–Seip congenital lipodystrophy), type 1 due to homozygous c.IVS4–2A>G mutation in AGPAT2 gene. The patient had generalized loss of sc fat with acanthosis nigricans in the axillae and neck. She has umbilical prominence and acromegaloid features (enlarged mandible, hands, and feet). B. Anterior view of a 27-year-old Native American Hispanic female with familial partial lipodystrophy of the Dunnigan variety due to heterozygous p.Arg482Trp mutation in LMNA gene. She had marked loss of sc fat from the limbs and anterior truncal region. The breasts were atrophic. She had increased sc fat deposits in the face, anterior neck, and vulvar regions. C. Anterior view of an 8-year-old German boy with acquired generalized lipodystrophy. He had severe generalized loss of sc fat with marked acanthosis nigricans in the neck, axillae, and groin. D. Anterior view of a 39-year-old Caucasian female with acquired partial lipodystrophy (Barraquer–Simons syndrome). She had marked loss of sc fat from the face, neck, upper extremities, and chest, but had lipodystrophy on localized regions on anterior thighs. She had increased sc fat deposition in the lower extremities. E. Lateral view of a 53-year-old Caucasian male infected with human immunodeficiency (HIV) virus with highly active antiretroviral therapy-induced lipodystrophy. He had marked loss of sc fat from the face and limbs, but had increased sc fat deposition in the neck region anteriorly and posteriorly showing buffalo hump. Abdomen was protuberant due to excess intra-abdominal fat. He had been on protease inhibitor-containing antiretroviral therapy for more than 8 years.

FAMILIAL PARTIAL LIPODYSTROPHY (FPL) ETIOLOGY AND PATHOGENESIS. FPL is an autosomal dominant disorder characterized by fat loss from the limbs with variable fat loss from the trunk and increased sc fat deposition in nonlipodystrophic regions (Fig. 71-1B). It results from heterozygous missense mutations in one of the four genes: (1) lamin A/C (LMNA) on chromosome 1q21–22,19–22 an integral component of nuclear lamina; (2) peroxisome proliferator-activated receptor γ (PPARG) on chromosome 3p25,23–25 a key transcription factor involved in adipocyte differentiation; (3) v-AKT murine thymoma oncogene homolog 2 (AKT2) on chromosome 19q13,26 involved in downstream insulin signaling; and (4) perilipin 1 (PLIN1) on chromosome 15q26, a key component of lipid droplets.27 Adipocyte loss in patients with

Lipodystrophy

A

LMNA mutations may be due to disruption of nuclear envelope function and integrity resulting in premature cell death.

CLINICAL FINDINGS. Patients with FPL have normal body fat distribution during early childhood, but around the time of puberty, sc fat from the extremities and trunk is progressively lost (Fig. 71-1B). The face, neck, and intra-abdominal region are spared, and often excess fat accumulates there.28,29 Affected men are often more difficult to diagnose clinically, as many normal men are also quite muscular. Women are more severely affected metabolically.30 Some patients with mutations in amino-terminal region of lamin A/C also develop myopathy, cardiomyopathy, and conduction system abnormalities indicative of a multisystem dystrophy.31 On the other hand, others with mutations in the extreme C-terminal region of lamin A may have mild lipodystrophy.32

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TABLE 71-2

Clinical Features of Various Types of Congenital Generalized Lipodystrophy (CGL) Subtype of CGL

Section 10 :: Disorders of Subcutaneous Tissue

Characteristic

CGL1

CGL2

CGL3

CGL4

Gene

AGPAT2

BSCL2

CAV1

PTRF

Loss of metabolically active adipose tissue

+++

+++

++

++

Loss of mechanical adipose tissue

–

+

–

–

Bone marrow fat

–

–

+

+

Lytic bone lesions

++

+

–

–

Mild mental retardation

–

+

–

–

Cardiomyopathy

–

+

–

+

Echocardiogram

Normal

Abnormal

Normal

Normal

Catecholaminergic polymorphic ventricular tachycardia (CPVT)

–

–

–

+

Prolonged QT interval

–

–

–

+

Sudden death

–

–

–

+

Congenital pyloric stenosis

–

–

–

+

Atlantoaxial instability

–

–

–

+

Acanthosis nigricans

+++

+++

++

+/–

Hepatomegaly

+

+

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Nearly 30 patients with FPL due to heterozygous mutations in PPARG gene have been reported so far. They have more marked fat loss from the extremities, especially from distal regions, but the fat from the face, neck, and truncal area is spared. There is increased prevalence of hypertension among the affected subjects. Four subjects from a single family with diabetes and insulin resistance were reported to harbor a heterozygous mutation in AKT2 gene. The female proband had lipodystrophy of the limbs although detailed studies of body fat distribution were not performed. Recently, five FPL patients were reported to harbor PLIN1 mutations.27

MANDIBULOACRAL DYSPLASIA (MAD) ASSOCIATED LIPODYSTROPHY ETIOLOGY AND PATHOGENESIS. Mutations in

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LMNA and zinc metalloproteinase (ZMPSTE24) on chromosome 1p34 also result in autosomal recessive, MAD-associated lipodystrophies.33,34 ZMPSTE24 is involved in posttranslational proteolytic processing of

prelamin A to mature lamin A and its deficiency can result in accumulation of prelamin A in cells which is supposed to cause toxicity.

CLINICAL FINDINGS. Patients with MAD have characteristic skeletal abnormalities including hypoplasia of the mandible and clavicles, acroosteolysis, cutaneous atrophy, progeroid features such as thin beaked nose, hair loss, thin skin with prominent superficial vasculature and mottled hyperpigmentation, delayed dentition and closure of cranial sutures, joint stiffness, and lipodystrophy.35,36 Those with ZMPSTE24 mutations develop clinical manifestations earlier in life, are premature at birth, and can develop focal segmental glomerulosclerosis and calcified skin nodules.37,38 OTHER TYPES ETIOLOGY AND PATHOGENESIS. Recently, a single patient with autosomal recessive, FPL phenotype was found to harbor a homozygous missense mutation in cell death-inducing DNA fragmentation

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Despite recognition of acquired lipodystrophies for more than a century, progress in understanding underlying pathogenetic mechanisms has been slow.

EPIDEMIOLOGY

ACQUIRED PARTIAL LIPODYSTROPHY (APL, BARRAQUER–SIMONS SYNDROME)

Lipodystrophy

Acquired partial lipodystrophy was recognized approximately 125 years ago and only ∼250 cases of various ethnicities with male-to-female ratio of 1:4 have been reported.51 Acquired generalized lipodystrophy has been reported in less than 100 cases, mostly Caucasians with a male-to-female ratio of 1:3.52 The most common type at present is highly active antiretroviral therapy [containing protease inhibitors (PIs)]induced lipodystrophy in human immunodeficiency virus (HIV)-infected patients, which is estimated to be affecting more than 100,000 patients in the United States and many more in other countries.53

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CLINICAL FINDINGS. We recently reported a novel autosomal recessive syndrome with mandibular hypoplasia, deafness, progeroid features (MDP)associated lipodystrophy.45 All males with MDP had undescended testes and were hypogonadal. One adult female showed lack of breast development. The molecular basis of this syndrome remains unclear. PSMB8 mutations present as a spectrum of clinical manifestations ranging from onset during the first months of life46 to later during childhood.47 Early features are recurrent fevers, annular violaceous plaques, poor weight and height gain, persistent violaceous eyelid swelling, hepatomegaly, arthralgias variable muscle atrophy, and progressive lipodystrophy.46 Histopathologic examination of lesional skin shows atypical mononuclear infiltrates of myeloid lineage and mature neutrophils, and laboratory abnormalities include chronic anemia, elevated acute-phase reactants, and raised liver enzymes with a cytokine profile showing high levels of IP-1, MCP-1, IL-6, and IL-1Ra, consistent with an IFN signaling signature.43 This presentation has been called CANDLE syndrome (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperature).46 Older individuals with PSMB8 mutations show joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced (JMP) childhood-onset lipodystrophy.47 Other features of JMP syndrome include hypergammaglobulinemia, elevated erythrocyte sedimentation rate, hepatosplenomegaly, and calcification of basal ganglia.42,44a,44b,47 Other rare syndromes of lipodystrophy include SHORT syndrome, which is characterized by the constellation of Short stature, Hyperextensibility or inguinal hernia, Ocular depression, Rieger anomaly, and Teething delay.48,49 This syndrome is reported to have autosomal recessive as well as dominant inheritance patterns and fat loss is usually confined to the face, upper extremities, and trunk, and sometimes the buttocks.48,49 The autosomal recessive, neonatal progeroid (Weidemann–Rautenstrauch) syndrome presents with generalized loss of body fat and muscle mass and progeroid appearance at birth.50

ACQUIRED LIPODYSTROPHIES

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factor a-like effector c (CIDEC) gene on chromosome 3p25, involved in lipid droplet formation.39 The histopathology of the sc adipose tissue of the patient revealed multilocular, small lipid droplets in adipocytes. Heterozygous LMNA mutations can also cause variable amount of fat loss in patients with atypical progeroid syndrome40 and generalized loss of sc fat in Hutchinson–Gilford progeria syndrome.41 Another distinct autosomal recessive autoinflammatory lipodystrophy syndrome with a spectrum of disease manifestations (see JMP and CANDLE syndromes below) results from mutations in proteasome subunit, beta-type, 8 (PSMB8).42,43,44a,44b PSMB8 encodes the b5i subunit of the immunoproteasome involved in proteolytic cleavage of immunogenic epitopes presented by major histocompatibility complex, class I molecules.44c The molecular genetic basis of many other genetic lipodystrophy syndromes remains unclear (Table 71-1).

ETIOLOGY AND PATHOGENESIS. The exact pathogenesis of sc fat loss remains unclear but there is strong evidence of autoimmune-mediated adipocyte loss as more than 80% of the patients have low levels of complement 3 (C3) and presence of a circulating immunoglobulin (Ig) G, C3-nephritic factor that blocks degradation of the enzyme C3 convertase.51 Loss of fat could be due to C3-nephritic factor-induced lysis of adipocytes expressing factor D.54 CLINICAL FINDINGS. Acquired partial lipodystrophy develops in most patients before age 15. Patients lose sc fat gradually in a symmetric fashion starting with the face and then spreading downwards. Most of them present with fat loss from the face, neck, upper extremities, and trunk with sparing of sc abdominal fat and lower extremities (Fig. 71-1C). Approximately, 20% of the patients develop mesangiocapillary (membranoproliferative) glomerulonephritis, and some develop drusen.51 Usually, patients do not develop metabolic complications. ACQUIRED GENERALIZED LIPODYSTROPHY (AGL, LAWRENCE SYNDROME) ETIOLOGY AND PATHOGENESIS. The exact mechanisms of fat loss are not known. In approximately 25% of patients, sc fat loss occurs following development of sc inflammatory nodules that on biopsy reveal panniculitis.52 These lesions initially result in localized fat loss followed by generalized loss of fat. Another 25% of the patients have associated autoimmune diseases such as juvenile dermatomyositis.52 In the

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remaining patients with the idiopathic variety, multiple unknown mechanisms are likely involved.52 Patients with the panniculitis-associated variety have less severe fat loss and metabolic complications than seen in other types.

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CLINICAL FINDINGS. Acquired generalized lipodystrophies present with variable amount of sc fat loss usually during childhood. Although many patients have generalized loss of fat, some areas are spared in some of them (Fig. 71-1D). Usually, intra-abdominal or bone marrow fat is spared.52 However, patients develop extremely severe hepatic steatosis and fibrosis, diabetes, and hypertriglyceridemia, which are difficult to manage.

:: Disorders of Subcutaneous Tissue

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART)-INDUCED LIPODYSTROPHY IN HIV-INFECTED PATIENTS ETIOLOGY AND PATHOGENESIS. Drugs such as HIV-1 PIs and nucleoside analogs are implicated in causing lipodystrophy in HIV-infected patients. Many, but not all, PIs may induce lipodystrophy by inhibiting ZMPSTE24, resulting in accumulation of prelamin A.55 Other mechanisms may include PI-induced alteration of expression of key transcription factors involved in lipogenesis and adipocyte differentiation, such as, sterol regulatory element-binding protein 1c, and PPARG.56 PIs also reduce glucose transporter 4 expression, which may be a mechanism for inducing insulin resistance.57 Nucleoside analogs, especially zidovudine and stavudine, may induce fat loss by inhibiting polymerase-γ, a mitochondrial enzyme involved in replication of mitochondrial DNA.58 Since most patients receive multiple antiretroviral drugs together, the individual effects of PIs or nucleoside reverse transcriptase inhibitors (NRTIs) on the phenotype are not clear. CLINICAL FINDINGS. Patients infected with HIV usually lose sc fat from the face, trunk, and extremities 2 years or more after receiving PI-containing HAART (Fig. 71-1E; Figs. 71-2A and 71-2B). Fat loss from the face can be so severe as to result in an emaciated appearance. Some of them develop buffalo hump, double chin, and also gain intra-abdominal fat. The fat loss progressively gets worse with ongoing HAART therapy and does not reverse on discontinuation of PIs. Some cases develop diabetes mellitus and many develop combined hyperlipidemia that can predispose the patients to coronary heart disease.59 LOCALIZED LIPODYSTROPHY ETIOLOGY AND PATHOGENESIS. This can occur due to sc injection of various drugs, panniculitis, pressure, and other mechanisms.2

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CLINICAL FINDINGS. Localized lipodystrophies present with sc fat loss from a focal region resulting in

a dimple or a crater with overlying skin usually unaffected. In some patients, large contiguous or anatomically distinct areas on any region of the body may be involved.2

APPROACH TO PATIENT ALGORITHM Lipodystrophies should be strongly suspected in “lean or nonobese” patients who present with premature onset of diabetes, hypertriglyceridemia, hepatic steatosis, acanthosis nigricans, and polycystic ovarian syndrome. These patients should be examined carefully for evidence of loss of sc fat especially from the hips and thighs, as well as excess sc fat deposition in various anatomic regions. For those presenting with generalized lipodystrophy during childhood, pictures at birth should be evaluated for evidence of fat loss. If lipodystrophy phenotype is discovered at or shortly after birth, CGL should be considered; otherwise, the patient may have acquired lipodystrophy.

HISTORY Patients should be asked about the age of onset and progression of lipodystrophy and other associated manifestations. Taking a detailed family history, including the history of consanguinity, is very important to understand the mode of inheritance of genetic lipodystrophies. Associated autoimmune diseases, especially juvenile dermatomyositis, should be considered in patients with acquired lipodystrophies. Those with localized lipodystrophies should be asked about local injections, trauma, pressure, or other insults. A detailed history of duration and type of antiretroviral therapy should be obtained from HIV-infected patients with lipodystrophy.

CUTANEOUS LESIONS The most common cutaneous lesion seen in patients with lipodystrophies is acanthosis nigricans in the axillae, groins, neck, and sometimes even on the knuckles, Achilles tendons, and trunk (Figs. 71-3A and 71-3B). Many patients develop clitoromegaly and hirsutism due to associated polycystic ovarian syndrome. Freckles have been noted in a patient with atypical progeroid syndrome (Fig. 71-3C). Thin beaked nose with loss of the scalp, eyebrow, and axillary hair with cutaneous atrophy and mottled hyperpigmentation can be seen in patients with progeroid syndromes and MAD (Fig. 71-3D) along with acroosteolysis (Fig. 71-3E).35,40,41 Rare patients with MAD develop shiny, taut, atrophic skin with a tendency to breakdown. Eruptive, tuberous, and planar xanthomas are also commonly seen in patients with extreme hypertriglyceridemia (Figs. 71-3F and 71-3G). Loss of sc fat from the soles can result in plantar calluses. Subcutaneous nodules with overlying erythema may be seen in patients with panniculitis.

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Figure 71-2  A. Highly active antiretroviral therapy-induced lipodystrophy in a patient with human immunodeficiency virus (HIV) infection-associated lipodystrophy in a patient receiving highly active antiretroviral therapy. Loss of buccal fat results in prominence of the zygomatic arch B. Highly active antiretroviral therapy-induced lipodystrophy with loss of subcutaneous fat from the lateral buttock and deposit in the trunk, causing an increased waist–hip ratio.

LABORATORY TESTS Laboratory testing depends upon the type of lipodystrophy. Except for patients with localized lipodystrophies, a serum chemistry profile for glucose, lipids, liver enzymes, and uric acid should be obtained. Measurement of fasting and postprandial serum glucose and insulin during an oral glucose tolerance test can provide some estimate of insulin resistance. Serum leptin measurements are not diagnostic, but can help guide treatment decisions as far as investigational human recombinant leptin replacement therapy is concerned. Serum leptin and adiponectin levels are very low in patients with generalized lipodystrophies.60 Patients with acquired partial lipodystrophy should be tested for serum C3 and C3-nephritic factor and annually checked for proteinuria. Radiographs can show presence of lytic lesions in appendicular bones in patients with CGL and skeletal defects in those with MAD. Skin biopsy is useful for patients with localized lipodystrophy or panniculitis-associated varieties.

SPECIAL TESTS (INCLUDING IMAGING STUDIES) Distinction between various types of lipodystrophies can be made by physical examination and supported by anthropometry, including measurement of skinfold

thickness with calipers at various sites. For in-depth phenotyping of body fat distribution, dual energy X-ray absorptiometry, and a whole body T-1 weighted magnetic resonance imaging can be conducted. For those genetic lipodystrophies whose molecular basis is known, various commercial and research laboratories offer genetic testing. Prenatal genetic testing is also feasible. FPL patients and CGL, type 4 patients who are predisposed to cardiomyopathy should undergo electrocardiography and Holter monitoring to detect arrhythmias and echocardiography to assess cardiac function.

DIFFERENTIAL DIAGNOSIS The most important differential diagnosis of generalized lipodystrophies is with conditions presenting with severe weight loss, such as, malnutrition, famine, starvation, anorexia nervosa, uncontrolled diabetes mellitus, thyrotoxicosis, adrenocortical insufficiency, cancer cachexia, HIV-associated wasting, diencephalic syndrome and chronic infections. For partial lipodystrophies, distinction should be made with Cushing syndrome, generalized and truncal obesity, and multiple symmetric lipomatosis (Madelung disease). Patients with MAD and progeroid ­syndromes-associated lipodystrophies should be differentiated from those with Werner syndrome and ­leprechaunism (Donahue syndrome).

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Figure 71-3  Dermatologic manifestations seen in patients with lipodystrophies. A. Acanthosis nigricans (brownish discoloration with thickening of the skin) in the axilla and anterior neck in an 8-year-old Caucasian boy with acquired generalized lipodystrophy. B. Acanthosis nigricans in the perineum and medial parts of the proximal thighs in a 37-year-old female with familial partial lipodystrophy (FPL). Multiple, small skin tags accompany increased pigmentation and thick skin. C. Multiple, slightly hyperpigmented flat plaques (freckles) in a 7-year-old boy with atypical progeroid syndrome due to heterozygous p.Cys588Arg mutation in LMNA gene. D. Loss of hair from the posterior scalp region in a 5-year-old girl with severe mandibuloacral dysplasia (MAD) due to homozygous p.Arg527Cys mutation in LMNA gene. She had narrow shoulders due to clavicular hypoplasia. E. Acroosteolysis in a 20-year-old Hispanic woman with MAD due to homozygous p.Arg527His mutation in LMNA gene. The terminal digits appear short and bulbous due to resorption of the terminal phalanges. The skin on the dorsum of the hand is atrophic, especially over the proximal interphalangeal and metacarpophalangeal joints. F. Tuberous xanthomas over the middle finger of a 45-year-old Caucasian patient with severe hyperlipidemia associated with FPL of the Dunnigan variety due to heterozygous p.Arg482Gln mutation in LMNA gene. G. Planar xanthomas on the sole of the patient described in F. (Panel C reproduced with permission from Garg A et al: Atypical progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab 94:4971-4983, 2009. Copyright 2009, The Endocrine Society. Panel G reproduced with permission from Simha V, Garg A: Lipodystrophy: lessons in lipid and energy metabolism. Current Opin Lipidol 17:162-169, 2006. Wolters Kluwer/Lippincott Williams & Wilkins.)

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Some patients develop extreme hypertriglyceridemia and chylomicronemia, which result in acute pancreatitis and even death. Long-term complications of diabetes such as nephropathy, neuropathy, and retinopathy are frequently seen. Many patients develop coronary heart disease and other atherosclerotic vascular complications.30,61 Hepatic steatosis can lead to cirrhosis, necessitating liver transplantation. Sudden death has been reported during childhood in CGL, type 4, likely due to arrhythmias.17 Some patients with APL and membranoproliferative glomerulonephritis may require kidney transplantation.51 Patients with Hutchinson–Gilford progeria syndrome die of acute myocardial infarction or

cerebrovascular accidents during teenage years.62 Some patients with atypical progeroid syndrome and FPL, Dunnigan develop cardiomyopathy with valvular dysfunction, congestive heart failure, and arrhythmias requiring pacemaker implantation.31,40 Two adult patients with MAD due to ZMPSTE24 mutations have died of renal failure due to focal segmental glomerulosclerosis.37

PROGNOSIS/CLINICAL COURSE The prognosis is dependent upon the type of lipodystrophy. Most of the published cases of CGL have been children and thus there is lack of data about their prog-

With the discovery of the molecular genetic basis of many types of inherited lipodystrophies, prenatal diagnosis can be offered for those families with an affected child. Premarital genetic counseling can be provided to those with high prevalence of consanguinity and CGL such as those from Lebanon and certain regions of Brazil. If the newer HAART regimen (not including PIs) are proven not to be associated with lipodystrophy and are deemed to be efficacious and safe, we may be able to prevent development of lipodystrophy in HIV-infected patients.

Lipodystrophy

Treatment of various types of lipodystrophies is quite challenging. There is no specific treatment available to reverse the loss of body fat. The mainstay of treatment includes cosmetic surgery and management of complications. Patients with partial lipodystrophies can undergo autologous adipose tissue transplantation or implantation of dermal fillers such as hyaluronic acid, calcium hydroxylapatite, silicone, polyacrylamide gels, or poly-L-lactic acid.64 Unwanted excess adipose tissue can be surgically excised or removed by liposuction. Those with CGL can undergo reconstructive facial surgery including fascial grafts from thighs, free flaps from anterolateral thigh, anterior abdomen, or temporalis muscle.1 Support of the parents is critical for preventing unwanted stress and psychological sequelae in children affected with lipodystrophies. All patients are advised to consume low-fat diets. These diets can improve chylomicronemia in patients with extreme hypertriglyceridemia. However, high carbohydrate intake may also raise very low-density lipoprotein triglyceride concentrations. Increased physical activity should be encouraged to mitigate insulin resistance and its complications except in those with FPL who have cardiomyopathy. Lytic bone lesions in appendicular bones in patients with CGL usually do not pose an increased risk of fractures. There are no well-controlled trials available to guide treatment decisions about how to manage metabolic complications. For severe hypertriglyceridemia, an extremely low-fat diet along with fibrates and n-3 polyunsaturated fatty acids should be used. Statins can be added if required. Any form of estrogen therapy should be avoided, as it can pose the risk of severe hypertriglyceridemia-induced acute pancreatitis. Diabetes should be managed initially with metformin. Thiazolidinediones should be used with caution in patients with partial lipodystrophies as they can potentially increase unwanted fat deposition in nonlipodystrophic regions.65 Although thiazolidinediones can be useful in FPL patients with PPARG mutations, the data on their efficacy are equivocal.66 If hyperglycemia persists despite using various combinations of oral anti-

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diabetic drugs, insulin therapy should be initiated. For those with extreme insulin resistance, U-500 insulin should be used. No specific therapy is available at this time for hepatic steatosis. Although, subcutaneous metreleptin replacement therapy has been shown to improve diabetes control, hepatic steatosis, and hypertriglyceridemia in markedly hypoleptinemic patients with generalized lipodystrophies,67,68 its effects in patients with FPL so far have been equivocal.69 Metreleptin therapy is investigational and not approved by the Food and Drug Administration of US. Switching PIs and NRTIs strongly associated with lipodystrophy to other regimen may improve dyslipidemia and insulin resistance in HIV-infected patients with lipodystrophy; however, loss of sc fat may not improve.70

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nosis. In our experience, some have died of complications of acute pancreatitis, cirrhosis, or developed end-stage renal disease, requiring renal transplantation, and blindness due to diabetic retinopathy. Patients with FPL are also predisposed to metabolic complications and die of atherosclerotic vascular and coronary heart disease or cardiomyopathy and rhythm disturbances. Some patients with MAD have reportedly died during childhood and some died later in the 3rd and 4th decades of complications of renal failure.37,63 Patients with AGL suffer severe metabolic complications. Patients with APL and membranoproliferative glomerulonephritis develop renal failure, but others have normal life span as do those with localized lipodystrophy. HIV-infected patients with lipodystrophy are predisposed to developing coronary heart disease.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Garg A: Acquired and inherited lipodystrophies. N Engl J Med 350:1220-1234, 2004 2. Garg A: Lipodystrophies. Am J Med 108:143-152, 2000 5. Agarwal AK et al: AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31:21-23, 2002 6. Magre J et al: Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365-370, 2001 7. Kim CA et al: Association of a homozygous nonsense ­caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab 93:1129-1134, 2008 8. Hayashi YK et al: Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J Clin Invest 119:2623-2633, 2009 19. Cao H, Hegele RA: Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 9:109-112, 2000 23. Agarwal AK, Garg A: A novel heterozygous mutation in peroxisome proliferator-activated receptor-g gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab 87:408-411, 2002 33. Novelli G et al: Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 71:426-431, 2002 34. Agarwal AK et al: Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 12:1995-2001, 2003

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51. Misra A, Peethambaram A, Garg A: Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: Report of 35 cases and review of the literature. Medicine (Baltimore) 83:18-34, 2004 52. Misra A, Garg A: Clinical features and metabolic derangements in acquired generalized lipodystrophy: Case reports and review of the literature. Medicine 82:129-146, 2003

53. Chen D, Misra A, Garg A: Lipodystrophy in human immunodeficiency virus-infected patients. J Clin Endocrinol Metab 87:4845-4856, 2002 59. Grinspoon S, Carr A: Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 352:4862, 2005 67. Oral EA et al: Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570-578, 2002

Disorders of Melanocytes

Chapter 72 :: Biology of Melanocytes :: Hee-Young Park & Mina Yaar BIOLOGY OF MELANOCYTES AT A GLANCE Melanoblasts derive from the neural crest. Their migration/survival in the epidermis is influenced by numerous factors. Melanocytes populate the epidermis, hair follicle, eye, cochlea, and meninges. synthesize melanin, an indole derivative of 3,4 di-hydroxy-phenylalanine (DOPA) that is stored in melanosomes. are influenced by endocrine, paracrine, and autocrine factors and by ultraviolet (UV) irradiation. Melanosomes display four maturation stages. contain structural matrix proteins, melanogenic enzymes, pH-maintaining proteins, and free-radical scavengers. are transported to melanocyte dendrite tips and transferred to epidermal keratinocytes. in skin, absorb UV radiation and protect against photodamage.

EMBRYONIC DEVELOPMENT Melanocytes are pigment-producing cells that originate from the dorsal portions of the closing neural tube in vertebrate embryos1 (eFig. 72-0.1 in online edition). They

derive from pluripotent neural crest cells that differentiate into numerous cell lineages including neurons, glia, smooth muscle, craniofacial bone, cartiledge, and melanocytes.2,3 Progenitor melanoblasts migrate dorsolaterally between the mesodermal and ectodermal layers to reach their final destinations in the hair follicles and the skin as well as inner ear cochlea, choroids, ciliary body, and iris.2,4 Pigment-producing cells can be found in fetal epidermis as early as the 50th day of gestation. Melanoblast migration and differentiation into melanocytes are influenced by a number of signaling molecules produced by neighboring cells. These include Wnt, endothelin (ET)-3, bone morphogenetic proteins (BMPs), steel factor (SF) (stem cell factor, c-Kit ligand), and hepatocyte growth factor (HGF/scatter factor).5–10 By interacting with their specific cell surface receptors, these molecules induce intracellular and intranuclear signaling to influence gene transcription and protein synthesis. Genetic defects in some of these molecules are associated with human genetic diseases: ETs (Waardenburg syndrome and Hirschsprung disease) and c-Kit and stell factor with piebaldism. Detailed discussion of each signaling molecule is available online.

SITE-SPECIFIC MELANOCYTES MELANOCYTE STEM CELLS Generally, stem cells are defined by their undifferentiated state and their capacity to develop into several differentiated cell types. They are quiescent, slowcycling cells that frequently are found in niches where they are surrounded by differentiated cells that affect their behavior through the secretion of cytokines and growth factors.29,30 Melanocyte stem cells reside in the hair follicle bulge (Fig. 72-1). They express TRP-2 as well as the neural crest stem cell intermediate filament nestin in addition to other neural crest stem cell markers including the transcription factors Sox10 and Pax5 that participate in the regulation of microphthalmia-associated transcription factor (MITF) and TRP-2. Melanocyte stem cells can leave the bulge region and migrate/differentiate in the epidermis or the hair follicle.

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Figure 72-1  Melanocyte stem cells in the hair follicle bulge. A stem cell melanocyte is shown in the hair follicle bulge, indicated by an arrow in the high-power insert. These cells stain positive for TRP-2 (green fluorescence), an early marker of commitment to the melanocyte lineage, but are negative for the proliferation marker Ki-67 (red fluorescence) that characterizes melanocytes migrating down the follicle to the dermal papilla during the anagen phase of the hair cycle. (From Botchkareva NV et al: SCF/ckit signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB J 15:645, 2001, with permission.)

CUTANEOUS MELANOCYTES The largest number of melanocytes are present in the skin and hair follicles. While in most furred mammals melanocytes are found only in the hair follicle, in humans, melanocytes are also present in interfollicular epidermis, specifically in the basal layer.28 There is approximately one melanocyte per five or six basal keratinocytes. Melanocytes synthesize melanin, a pigmented polymer that is stored in cytosolic organelles called melanosomes that are transferred to keratinocytes through melanocyte dendritic processes (Fig. 72-2). As keratinocytes are continuously being desquamated, there is a constant need for synthesis and transfer of melanosomes from melanocytes to keratinocytes in order to maintain cutaneous pigmentation. The term “epidermal melanin unit” describes a single epidermal melanocyte surrounded by several epidermal keratinocytes31 (Fig. 72-3). Interestingly, signals from keratinocytes substantially regulate epidermal melanocyte survival, dendricity, melanogenesis and the expression of cell surface receptors32 (see below). Most keratinocyte-derived signals are induced by ultraviolet (UV) irradiation. Melanocyte density/mm2 ranges from approximately 550 to >1,200 with the highest concentrations found in the genitalia and face.33,34 Melanocyte density is the same in individuals of different racial backgrounds,34 and thus cutaneous pigmentation does not depend on melanocyte number, but rather upon melanogenic activity within the melanocyte, the proportion of mature melanosomes, and/or their transfer and distribution within the keratinocytes.35 Indeed, in lightskinned individuals, melanosomes are smaller and are

Figure 72-2  Melanosomes are organized into supranuclear “caps” within keratinocytes. Note melanized dendritic melanocytes and adjacent keratinocytes with the supranuclear “caps.” Melanin silver-stained (Fontana-Masson) section of a heavily melanized human epidermis. (Bar = 50 μm.) (From Byers HR et al: Role of cytoplasmic dynein in perinuclear aggregation of phagocytosed melanosomes and supranuclear melanin cap formation in human keratinocytes. J Invest Dermatol 121:813, 2003, with permission.)

present in clusters within the keratinocytes, while in ethnic groups with darker complexion, melanosomes are larger, darker, and are individually dispersed within the keratinocytes.36

HAIR FOLLICLE MELANOCYTES In contrast with interfollicular epidermal melanocytes, the follicular melanin unit undergoes cyclic modifications in coordination with the hair cycle (Fig. 72-4). Melanocytes are located in the proximal hair bulb during anagen and there is a ratio of 1:5 between melanocytes and keratinocytes and 1:1 between melanocytes and basal layer keratinocytes.37 Melanocytes proliferate, migrate, and undergo maturation during early to mid anagen. Melanogenesis and melanin transfer to keratinocytes occurs throughout anagen. Melanocytes eventually apoptose during late catagen. In mice, melanocyte proliferation and differentiation during anagen depends on c-Kit expression by melanocytes and SF synthesis by keratinocytes.38 Similar to their role in the epidermis, in hair, melanocytes transfer melanin to differentiated keratinocytes that ultimately form the hair shaft. They thus determine hair color by the amount of melanin transferred, as well as by the ratio of eumelanin (black–brown) to pheomelanin (red–yellow) (see below).39 In hair, melanin does not appear to have a protective effect, since UV irradiation does not reach the hair follicle. Still, in furry animals hair color plays an important role in camouflage, mimicry, and social communication.40 It is also speculated that melanocytes restrain keratinocyte proliferation, affect calcium homeostasis, and protect against reactive oxygen species (ROS) during the rapid proliferation and differentiation of the hair follicle.37

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Figure 72-3  The epidermal melanin unit. A. Representation showing the relationship between basal melanocytes, keratinocytes, and Langerhans cells, shown at the upper layer of the epidermis. (From Quevedo WC Jr.: The control of color in mammals. Am Zoology 9:531, 1969, with permission.) B. Electron micrograph of the dermal–epidermal junction of human skin showing a dendritic melanocyte (M) among the basal keratinocytes (K). k′ represents a basal keratinocyte undergoing mitosis with condensed chromatin (arrows). (Bar = 10.0 μm.) (Illustration used with permission from Raymond E. Boissy, Department of Dermatology, University of Cincinnati, Cincinnati, Ohio.) C. Human epidermis immunostained for fibroblast growth factor-2 (FGF2). The figure shows basal keratinocytes with peroxidase reaction indicating the presence of immunore-active FGF2. Arrows point to melanocytes. (Used with permission from Glynis Scott, MD, Department of Dermatology, University of Rochester School of Medicine and Dentistry, Rochester, NY.) D and E. Distribution of melanosomes within keratinocytes in lightly pigmented Caucasian and darkly pigmented African-American skin. Melanosomes in lightly pigmented Caucasian skin (D) are distributed in membrane-bound clusters. In contrast, in darkly pigmented AfricanAmerican skin (E) the melanosomes are individually distributed throughout the cytoplasm of epidermal keratinocytes. Melanosomes in both skin types are frequently concentrated over the apical pole of the nucleus (arrows). L = Langerhans cell. (Bar = 3.0 μm.) (Used with permission from Minwalla L et al: Keratinocytes play a role in regulating distribution patterns of recipient melanosomes in vitro. J Invest Dermatol 117:341, 2001.)

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Figure 72-4  Melanocytes in the hair. A. Pigmented human scalp hair follicle in full anagen with high levels of hair bulb melanogenesis. Mature melanin granules are transferred into cortical keratinocyte. B. Scalp hair bulb. Representation of early catagen hair follicle showing loss of some bulbar melanotic melanocytes via apoptosis. Arrows point at melanocytes located in epidermal, infundibular, and outer root sheath regions. C. Transmission electron micrograph of section of an early catagen hair bulb showing apoptosis of melanotic melanocytes. Inset, high-power view of premelanosomes. D. Primary culture of human scalp hair follicle melanocytes. Mature, fully differentiated (Diff; large arrow), and less differentiated (small arrows) are indicated. DP = dermal papilla. (From Tobin DJ, Paus R: Graying: Gerontobiology of the hair follicle pigmentary unit. Exp Gerontol 36:29, 2001, with permission.)

MELANIZATION The major differentiated function of melanocytes is to synthesize melanin in specialized organelles within the melanocytes, the melanosomes, and to transfer melanosomes to neighboring keratinocytes in order to provide protection from UV irradiation (Fig. 72-5). Melanogenesis, the synthesis and distribution of melanin in the epidermis, involves several steps: transcription of proteins required for melanogenesis; melanosome biogenesis; sorting of melanogenic proteins into the melanosomes; transport of melanosomes to the tips of melanocyte dendrites and transfer of melanosomes to keratinocytes. Disruption in any of these events results in hypopigmentation.

MELANOSOMES MELANOSOME BIOGENESIS 768

The melanosome is a unique membrane-bound organelle in which melanin biosynthesis takes place. Because melanosomes contain enzymes and other proteins also

Figure 72-5  Melanocytes cultured on keratinocytes. Light micrograph showing dendritic melanocytes from a black donor loaded with melanin and adjacent pigmented keratinocytes due to transfer of melanosomes.

11 E A

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Biology of Melanocytes

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Figure 72-6  Melanosome biogenesis. Electron microscopy of eumelanosome (A–F) and of pheomelanosome (G–J) development. I, II, III, and IV in A–J represent the different maturation stages of melanosomes. [Scale bars are as follows (in μm): a = 0.20; b = 0.23; c = 0.24; d = 0.22; e = 0.20; f = 0.35; h = 0.26; i = 0.26; j = 0.30; k = 0.5.] (From Slominski A et al: Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84:1155, 2004, with permission from the American Physiological Society.) present in lysosomes, they are thought to represent a modified version of the latter. Proteins common to both organelles include the lysosome-associated membrane proteins (LAMPs) that participate in autophagy and regulation of intravesicular pH,56 as well as acid phophatase, a marker enzyme for lysosomes.56 Also like lysosomes, melanosomes can endocytose receptors that are targeted for degradation.56 Depending on the type of melanin synthesized, melanosomes can be divided into eumelanosomes and pheomelanosomes (Fig. 72-6). Eumelanosomes are large (∼0.9 × 0.3 mm), elliptical in shape and contain a highly structured fibrillar glycoprotein matrix required for eumelanin synthesis.40 Pheomelanosomes are smaller (∼0.7 mm in diameter), spherical in shape and their glycoprotein matrix appears disorganized and loose40 Although both eumelanosomes and pheomelanosomes may be present within a single melanocyte,57 once committed, they do not change.58 Melanosomes display four maturation stages (Fig. 72-6). Stage I melanosomes or premelanosomes likely develop from the endoplasmic reticulum (ER).40 They have an amorphous matrix and display internal vesicles that form as a result of membrane invagination. Premelanosomes already contain the glycoprotein Pmel17 (gp100) but it requires further processing to

become a component of the final fibrillar matrix.59 Stage II eumelanosomes have organized structured fibrillar matrix, but no active melanin synthesis, whereas in stage II pheomelanosomes melanin synthesis already takes place. Although no active melanogenesis takes place in stage II eumelanosomes, they already contain the enzyme tyrosinase. Deposition of melanin on the fibrillar matrix is found in stage III eumelanosomes, while stage IV eumelanosomes are fully melanized and their internal matrix is masked by melanin deposits.60,61

MELANOGENIC PROTEINS The timely and organized sorting of melanogenic enzymes and structural proteins to melanosomes is an integral part of melanosomal maturation. Melanosome proteins express sorting signals at their amino-­terminus and these direct them into the ER and eventually into the melanosomes.40,60,61

Enzymes Tyrosinase. Tyrosinase is present in plants, insects,

amphibians, and mammals. It was initially identified in the early 1900s in mushroom extracts and was subsequently isolated and purified in 1949 from murine

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Sorting of melanosomal proteins into melanosomes

Plasma membrane

Stage II

Endosome Stage III AP-3 Tyrosinase/ Tyrosine/ TRP-1 TRP-1

Stage II

Stage I TRP-2

PMEL17/ MART-1

Trans-Golgi network

Section 11

Golgi ER

:: Disorders of Melanocytes

770

Tyrosinase/ TRP-1

TRP-2

Figure 72-7  Sorting of melanosomal proteins into melanosomes. Tyrosinase and tyrosinase-related protein-1 (TRP-1) are initially synthesized in the endoplasmic reticulum (ER) and, after additional maturation steps (*) in the Golgi and trans-Golgi network, are packaged in endosomes as a complex. TRP-2 follows similar maturation steps. Melanosomes originate in the ER as stage I already containing the melanosomal proteins PMEL17 and MART-1. They then mature to stage II melanosomes and fuse with tyrosinase/TRP-1 in a process directed by the adaptor protein 3 (AP-3). Melanosomes become progressively darker as melanin biosynthesis takes place.

melanoma cells.62 Mouse and human tyrosinase genes are 60–70 kb, and 50 kb long, respectively. The murine tyrosinase gene maps to chromosome 7, whereas human tyrosinase gene maps to chromosome 11. The human tyrosinase gene is composed of five exons and four introns,63 and tyrosinase mRNA is approximately 2 kb long (genebank access number NM_000372). Tyrosinase is synthesized in the ER as a precursor protein whose nascent chain is processed in the Golgi complex where sialic acid and neutral sugars are added to the peptide via N- and O-glycosidic linkages through a process called glycosylation64 (Fig. 72-7). At least four forms of tyrosinase, all differing with regards to their degree of glycosylation, have been identified. The glycolsylation steps have been shown to be important for proper association of tyrosinase with melanosomes, as well as for its activity.64 Following the glycosylation steps, mature tyrosinase is folded in the ER, a step required for appropriate trafficking/ sorting of tyrosinase into the Golgi apparatus and ultimately into endosomes and finally into melanosomes. A strict control mechanism guarantees the elimination of defective tyrosinase. Within the melanosome, tyrosinase spans melanosomal outer membrane (eFig. 72-7.1 in online edition). It has three domains: (1) an inner melanosomal domain, (2) a melanosomal transmembrane domain, (3) and a

cytoplasmic domain. The inner domain that contains the catalytic region is approximately 90% of the protein. It is followed by a short transmembrane domain, and a cytoplasmic domain composed of approximately 30 amino acids.65 Histidine residues present in the inner (catalytic) portion of tyrosinase bind copper (Cu) ions and the latter are required for tyrosinase activity. The biological function of the tyrosinase cytoplasmic domain was not known for a long time. In a mouse model where the entire cytoplasmic domain is missing, tyrosinase protein is inserted into the cellular plasma membrane instead of into the melanosomal membrane, suggesting that tyrosinase cytoplasmic domain is required for proper trafficking of tyrosinase into melanosomes. Indeed, it was found that the motif EXXQPLL (glutamic acid-X-X-glutamine-proline-­leucine-leucine, where “X” stands for any amino acid) in the cytoplasmic domain is responsible for tyrosinase trafficking into the melanosomes.66 In addition, protein kinase C-β (PKC-β) (see below) must phosphorylate two serine residues on this cytoplasmic domain to activate tyrosinase,65 and in the absence of those phosphorylation events pigmentation does not occur. Tyrosinase mutations including missense, nonsense frameshift, and deletion mutations that lead to inactivation of the enzyme are found in oculocutaneous albinism type I (see Chapter 73 and Albinism database: http://albinism-db.med.unm.edu/). Such mutations may affect tyrosinase glycosylation interfering with enzyme maturation, or may involve Cu-binding sites disrupting tyrosinase activity or premature termination of tyrosinase protein that causes truncation of cytoplasmic domain.64

Tyrosinase-Related Proteins. Two tyrosinaserelated proteins, (1) TRP-1 and (2) TRP-2, play important roles in melanogenesis.67–69 They are structurally related to tyrosinase and share ∼40% amino acid homology. Also, similar to tyrosinase, TRP-1 and TRP-2 are glycoproteins located within the melanosomes and span the melanosomal membrane.70 The conserved nucleotide and amino acid sequences among these three melanogenic enzymes suggest that they originated from a common ancestral gene.71,72 Mutations of TRP-1 and TRP-2 in mice after coat color (“brown” and “slaty” mice, respectively) and polymorphisms of these gene products are implicated in lighter hair and skin color in European population studies. Their functions are incompletely understood, but the proteins complex with tyrosinase and may stablilize it. Protein Kinase C-β.

PKC constitutes a family of at least 12 isoforms86 among that PKC-β has been shown to be involved in regulating tyrosinase activity.87 The mechanisms through which PKC mediates a wide range of membrane generated signals and their relevance to melanocyte biology are further discussed below (see Section “Signaling Pathways Regulating Melanocyte Functions”). PKC-β phosphorylates serine residues on the cytoplasmic domain of tyrosinase, thus activating tyrosinase.88 Still, the means by which PKCβ-mediated phosphorylation of tyrosinase leads to the enzyme activation is not well elucidated. It has been suggested that phosphorylation of tyrosinase causes a

However, there are no known hypopigmentary disorders in humans linked to mutations of Pmel17.

Activation of tyrosinase by protein kinase

Plasma membrane

MART-1/Melan A. MART-1, also known as Melan

A, is a membrane-associated protein98 that is present in stage I and stage II melanosomes and forms a complex with Pmel17 (Fig. 72-7). MART-1 affects the expression, stability, trafficking, and processing of Pmel17 within the melanosomes.98 To date, no hypopigmented phenotypes associated with nonfunctional MART-1 have been identified.

PKC-β

P

PKC-β

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Active

Pmel17. Pmel17, also known as gp100 and the silver locus product, is a glycoprotein recognized by the antibodies HMB45, HMB50, and NKI-β.94 It plays a critical role in fibril matrix formation within eumelanosomes.59,95 Pmel17 transcription is induced by α-MSH through MITF and it is synthesized as a precursor protein in the ER and the protein undergoes glycosylation and eventual cleavage (Fig. 72-7). After its synthesis, Pmel17 is transported to stage I melanosomes to form a fibrillar structure that is the backbone of eumelanosome matrix,94 contributes to melanosome ellipsoid shape and promotes melanin polymerization.94 Melanosomes lacking Pmel17 cannot transit to stage II and have no active melanogenesis.96 It has been suggested that loss of functional Pmel17 results in melanin cytotoxicity, perhaps through leakage of melanin intermediates from abnormal melanosomes into the cytosol.94,97

Biology of Melanocytes

STRUCTURAL PROTEINS. Fibrillar matrix proteins within the melanosomes are required for proper deposition of melanin. Pmel17 and MART-1 are two such melanosomal structural matrix proteins.

::

complex to form between tyrosinase and TRP-1,89 an event known to stabilize tyrosinase and increase its enzymatic activity.79 In melanocytes, activated PKC-β is associated with melanosomes and the enzyme is found in close proximity to the melanosomal membrane.88 While structural differences among PKC isoforms may contribute to their associations with particular subcellular fractions, receptors for activated C-kinase (RACK), unique for each PKC isoform, primarily determine the translocation of specific PKC isoforms to specific cellular compartments to activate its target on the membrane90–92 (Fig. 72-8). RACK-I is the PKC-β partner,90 and in human melanocytes, the activated PKC-β/RACK-I complex translocates to the melanosome membrane to allow tyrosinase phosphorylation (Fig. 72-8)93

including tyrosinase, TRP-1, TRP-2, and Pmel17 and directing them to the appropriate cytosolic organelles is facilitated by heterodimeric adapter protein complexes (APs).99,100 AP-3 and possibly also AP-1 facilitate tyrosinase transport from endosomes to melanosomes101 (Fig. 72-7). Patients with Hermansky–Pudlak syndrome—an autosomal recessive disorder of oculocutaneous albinism, platelet dysfunction, and pulmonary disease (see Chapter 73)—have defects in specific subunits of the AP-3 adaptor protein complex and as a result display several anomalies associated with cellular transport of molecules.102 Studies suggest that a molecule of the kinesin family, microtubule-associated motor proteins, is involved in endosomal sorting and positioning of melanosomal proteins via interaction with AP-1.103,104

Chapter 72

Figure 72-8  Activation of tyrosinase by protein kinase C-β (PKC-β). Under baseline conditions, there is no activation of PKC-β, and tyrosinase (TYR) is not phosphorylated. Activated PKC-β binds receptors for activated C-kinase-I (RACK-I), the complex translocates to the melanosome, and phosphorylates serine residues on the cytoplasmic tail of tyrosinase. Tyrosinase phosphorylation activates the enzyme to catalyze melanin biosynthesis.

TRANSPORT PROTEINS Heterotetrameric Adaptor Protein Complexes. Sorting of membrane-associated proteins

P-Protein. The P-protein (pink-eyed dilution) is a transmembrane protein with 12 membrane-spanning domains whose sequence is homologous to that of other transmembrane transport proteins, including anion transporters97,105,106 thought to function as a transport protein.107 Studies have identified the protein as an ATP-associated proton pump responsible for maintaining acidic environment within the melanosomes.108 Other proposed functions of P-protein include stabilizing the tyrosinase/TRP-1/TRP-2 complex and/or transporting tyrosine into the melanosomes.105 Individuals lacking functional P-protein display occulocutaneous albinism type 2, largely due to improper melanosomal pH.108–110 Also, Angelman and Prader–Willi syndromes display deletion mutations that include the P-locus on chromosome 15. SLC24A5. SLC24A5 is a melanosomal protein whose structure and homology to cation exchange proteins suggests that it is a melanosome-associated cation exchanger.111 Mutations in slc24a5 in zebrafish lead to hypopigmentation of the organism.111 The ancestral human homolog is expressed by darker complexioned individuals including Africans and Asians, while lighter complexioned Europeans tend to express a variant allele.111 SCAVENGER PROTEIN Lysosome-Associated Membrane Proteins.

LAMPs are linked to melanosome membranes and/ or matrix. They are thought to protect melanosomal integrity by acting as scavengers of free radicals that

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are produced during melanin biosynthesis.112 Because LAMPs are also present in lysosomes, it is thought that melanosomes and lysosomes share a common ancestral origin.112

Regulatory proteins Microphthalmia-Associated Transcription Factor

Section 11 :: Disorders of Melanocytes

Gene and Protein. MITF, a basic-helix-loop-helix (bHLH) and leucine zipper transcription factor, has been termed the master gene for melanocyte survival and is a key factor regulating the transcription of the major melanogenic proteins, tyrosinase, TRP-1, TRP-2,12 PKC-β113 and MART-1.114 In melanocytes, it is the MITF-M isoform that stimulates transcription of tyrosinase and PKC-b.114 MITF binds to conserved consensus elements in gene promoters, specifically the M(AGTCATGTGCT) and E- (CATGTG) boxes.115 It can bind as a homodimer or a heterodimer with another related family member.116 MITF appears to be a key regulator determining cell fate, as transfection of human MITF cDNA into mouse fibroblasts converts these cells into dendritic cells expressing melanocyte-specific genes.117 MITF comprises a family of nine isoforms: (1) MITFM, (2) -A, (3) -B, (4) -H, (5) -C, (6) -D, (7) -E, (8) -J, and (9) -Mc.118,119 MITF-M expression is highly specific for melanocytic cells.120 Melanocytes express in addition other MITF isoforms specifically, MITF-A, -B, and, -E114The biologic role of other MITF isoforms in normal melanocytes is not known.

MITF Role in Melanocyte Proliferation and Survival. MITF promotes melanoycte survival by upregulating the expression of a major antiapoptotic protein BCl2.127 It is frequently overexpressed or amplified in melanomas, contributing to their increased survival.128–131 Mutations in MITF are found in the pigmentary disorder Waardenburg syndrome type 2132(see Chapter 73). A role for MITF in melanocyte proliferation has also been proposed, as under certain conditions, MITF induces the expression of the cell cycle-associated kinase Cdk2 that is involved in the progression of cells from G1 into S phase of the cell cycle.133 MITF also suppresses the expression of p21, a protein that inhibits Cdk2 activation.133,134 Conversely, under

The melanocortin receptor and ligands ACTH H2N-SYSMEHFRWGKPVGKKRRPV KVYPNGAEDESAEAFPLEF-OH 138-176

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β-endorphin YGGFMTSEKSQTPLV TLFKNAIIKNAYKKGE 237-267

217-234

H2N-YVMGHFRWDRFG-OH H2N-DEGPYRMEHFRWGSPPKD-OH γ-MSH β-MSH 138-152 Ac-SYSMEHFRWGKPVGK-NH2 α-MSH

B

Extracellular D84E

772

Regulation of MITF Activity and Expression. The activity and stability of MITF are modulated by phosphorylation of the protein. MITF activity is increased upon its phosphorylation by the mitogen-activated protein kinase-2 (MAP kinase-2), whose activity is in turn induced by binding of SF/kit/stem cell factor to c-Kit receptor121 (Fig. 72-8). Phosphorylated MITF binds to another protein, p300/CBP, which belongs to a coactivator family of proteins and acts to enhance MITF transcriptional activity.121,122 Another kinase that is activated by SF/c-Kit interaction is p90RSK that also phosphorylates MITF but at a different site from that phosphorylated by MAP kinase-2.123 These phosphorylation events both activate MITF and at the same time decrease the stability of the protein, as phosphorylated MITF is targeted for degradation by proteosomes (eFig. 72-8.1A in online edition).123,124 The expression of MITF is under the control of several transcription factors, including Sox10 (mutated in Waardenburg’s syndrome type 4, see Chapter 73) and Pax3. MITF expression is also controlled by the cAMPresponse element binding protein (CREB) and Lef1 transcription factor that participates in Wnt-­signaling. These transcription factors bind to specific sites within MITF promoter regions to induce MITF transcription.116 The promoter region of the MITF gene contains a cAMPresponse element (CRE) that interacts with CREB when the cAMP-dependent pathway is activated.125,126 Therefore, cAMP-elevating agents like α-MSH induce the expression of MITF (eFig. 72-8.1B in online edition).

D294H

V6OL

TM R160W R151C

R160W

Intracellular

Loss of function mutants associated with red hair and melanoma Common in red head or blond light skin

Figure 72-9  The melanocortin receptor (MCR) and its ligands. A. Structure of the proopiomelanocortin precursor. Standard abbreviations for amino acids are used. The synthetic superactive α-melanocyte-stimulating hormone (α-MSH) analogue [Nle4 D-Phe7]-α-MSH is modified by the exchange of methionine (M) with norleucine and Lphenylalanine (F) with D-phenylalanine. In red are critical amino acids required for binding to the MCR. B. Schematic representation of the human MC1R receptor. Each of the 318 amino acid residues in the polypeptide chain of the receptor is represented by an empty circle. Branched structures represent N-linked glycosylation sites. Reduced function mutants (red circles), variants common in red- or blond-haired and fair skinned individuals (orange circles), and the conserved C-terminal cysteine (green circle), the possible site for fatty acid acylation and anchoring to the plasma membrane, are indicated. Ac = acetylated; ACTH = adrenocorticotropic hormone; NH2 = amidated; TM = transmembrane domain.

Eumelanin

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Pheomelanin

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­ ifferent conditions, MITF can induce p21 expression d and it can also stimulate the expression of p16INK4a, a protein that inhibits the activation of kinases required for progression through the cell cycle, thus promoting cell cycle arrest.135,136 Because MITF cooperates with other transcription factors to induce its effects, it is to be expected that these transcription factors would influence MITF activity, resulting in either stimulation or inhibition of melanocyte proliferation. Mice bearing null mutations of MITF display loss of melanocytes, deafness and failure of differentiation of retinal pigment epithelium.12

Melanocortin 1 Receptor. Melanocortin recep-

tors (MCRs) comprise a family of five related receptors (MC1R, MC2R, MC3R, MC4R, and MC5R). Each has seven transmembrane domains and they belong to the G-protein-coupled receptor superfamily.137 MC3R and MC4R are mainly found in the central nervous system, are absent in melanocytes,138 and are thought to control energy intake. MC2R is expressed in the adrenal cortex and MC5R is expressed in peripheral adipocytes.139 MC1R is expressed in a number of cells such as endothelial cells, fibroblasts,140 and keratinocytes,140 but the highest expression is found in melanocytes.140 α-MSH and adrenocorticotropic hormone (ACTH), a 39 amino acid proopiomelanocortin-derived peptide that contains the α-MSH sequence (Fig. 72-9A),141–143 activate MC1R (Fig. 72-9B) Receptor– ligand interaction leads to G-protein-dependent activation of the enzyme adenylate cyclase followed by increased intracellular cAMP level141 inducing MITF transcription and upregulating the level of melanogenic proteins including tyrosinase40 promoting the synthesis of brown/black eumelanin.141 Agouti, a

protein expressed in both humans and mice, whose expression in mice leads to yellow coat color, antagonizes α-MSH by competitive binding to MC1R. It thus blocks adenylate cyclase activation144–146 and favors pheomelanin over eumelanin synthesis (Fig. 72-10). However, the role of agouti in human pigmentation is poorly documented. Polymorphisms within the MC1R gene are largely responsible for the different skin/hair color among different racial groups.147 At least 30 MC1R variants have been identified and nine of them display loss of function148,149 (Fig. 72-9B), not being able to induce intracellular cAMP production in response to α-MSH despite adequate receptor/ligand binding. Other MC1R variants have reduced affinity for α-MSH.148,149 Three MC1R variants, each with only a single amino acid substitution, have been associated with red/yellow hair and fair skin150 of Northern Europeans and Australians.151–156 Mice expressing a loss-of-function MC1R variant receptor also fail to respond to UV irradiation with increased pigmentation despite an increased level of epidermal α-MSH,157 but do tan if provided forskolin, a chemical enhancer of pigmentation that bypasses the receptor to directly increase cAMP, demonstrating that the intracellular melanogenic pathway is functional in such individuals.155

Biology of Melanocytes

Figure 72-10  Eumelanin and pheomelanin presentation in mice. A. Two mice with different coat colors are shown. The one on the left displays brown/black coat color due to eumelanin, and the one on the right displays red/yellow coat color due to pheomelanin. B. Representative hair shafts of these mice. (From Sharov et al: Bone morphogenic protein (BMP) signaling controls hair pigmentation by means of cross-talk with the melanocortin receptor 1 pathway. PNAS 102:93, 2004, with permission.)

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MELANIN BIOSYNTHESIS Two types of melanins are synthesized within melanosomes: (1) eumelanin and (2) pheomelanin.158 Eumelanin is dark, brown–black, and insoluble, whereas pheomelanin is light, red–yellow sulfur-containing, and soluble.158 Melanins are indole derivatives of 3,4 di-hydroxy-phenylalanine (DOPA) and they are

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Melanin biosynthesis

Tyrosine Tyrosinase DOPA Tyrosinase DOPAquinone

Section 11

DHI Tyrosinase Indole 5,6-quinone

CysteinylDOPA

TRIP-2 Indole 5,6-quinone carboxylic acid

Alanyl-hydroxybenzothiazine

Tyrosinase or TRIP-2

:: Disorders of Melanocytes

774

DOPAchrome

DHI melanin black insoluble high MW

DHICA melanin brown poorly soluble intermediate MW

Pheomelanin red/yellow soluble low MW

Figure 72-11  Melanin biosynthesis. Melanin biosynthesis begins with the amino acid tyrosine that is converted to DOPA (3,4-dihydroxyphenylalanine) in the rate-limiting step of melanin biosynthesis catalyzed by tyrosinase. DOPA is subsequently converted to DOPAquinone by the same enzyme. DHI (5,6-dihydroxyindole) and DHICA (5,6-dihydroxyindole-2-carboxylic acid) are then formed to produce either black or brown eumelanin. Alternatively, through incorporation of glutathione or cysteine, DOPAquinone can form pheomelanin. MW = molecular weight; TRP = tyrosinase-related protein.

formed in melanosomes through a series of oxidative steps159 (Fig. 72-11). Melanosomal pH affects the activity of the melanogenic enzymes and influences melanin polymerization. The synthesis of both types of melanin involves the rate-limiting catalytic step in which the amino acid tyrosine is oxidized by the enzyme tyrosinase (also called tyrosine oxidase, DOPA oxidase, monophenol, DOPA: oxygen oxidoreductase) to DOPA, a first step in a reaction known as the Raper–Mason pathway160 (Fig. 72-11). Conversion of tyrosine to DOPA is thought to be the critical rate-limiting step in melanogenesis, as inhibition of this reaction blocks melanin synthesis.161 In both reactions, DOPA acts as a cofactor and also as a substrate for tyrosinase. Although the exact interaction between tyrosinase and its substrates is not completely understood, in vitro kinetic studies suggest that distinct sites mediate tyrosinase binding to tyrosine and to DOPA, and that binding to DOPA causes a conformational change in tyrosinase, resulting in increased affinity for both tyrosine and DOPA.

DOPA is oxidized into DOPAquinone,162 DOPAquinone is further converted to DOPAchrome and DOPAchrome can be converted to 5,6-dihydroxyindole (DHI) or to 5,6-dihydroxyindole-2-carboxylic acid (DHICA). The latter reaction is catalyzed by the enzyme DOPAchrome tautomeras or TRP-2. The level of brown versus black eumelanin appears to correlate with DHI/ DHICA ratio, with a higher ratio leading to the formation of black eumelanin and a lower ratio to brown eumelanin.163 DOPAquinone can also combine with glutathione or cyteine to form cysteinylDOPA, which then becomes the yellow/red, soluble, low-molecularweight pheomelanin.163 Interestingly, tyrosinase also catalyzes a more distant step in melanin biosynthesis, namely DHI conversion to indole-5,6-quinone. In mice, the enzyme TRP-1 (also called DHICA oxidase) converts DHICA to indole-5,6-quinone carboxylic acid. However, the TRP-1 role in human melanin biosynthesis is not well established. The main function of melanin is to provide protection against UV-induced DNA damage by absorbing and scattering UV radiation (280–400 nm). Accordingly, energy absorption by melanin is maximal in this portion of the electromagnetic spectrum, and decreases gradually across the visible light spectrum. UV absorbed by melanin is converted into heat, a less toxic form of energy.164 Still, in vitro studies conducted by several investigators suggest that melanin’s capacity to act as a sunscreen is limited and that melanin, when incorporated into a cream and spread over the skin, absorbs only 50%–75% of incident sunlight. Naturally, it is possible that in vivo, by virtue of localizing above the nucleus, melanin in melanosomes achieves a higher level of protection. Melanin intermediates as well as melanin itself can also be harmful to the cell because, depending on their molecular weight and polymerization state, they can promote UVA (320–400 nm)-induced DNA damage, most likely through the generation of ROS.165 It has been suggested that the increased incidence of UV-induced melanomas in lightskinned, red-hair individuals is not only due to decreased ability of pheomelanin to protect against UV-induced DNA damage, but may also be due to mutagenic capacity of pheomelanin and possibly other melanin intermediates as a result of their prooxidant capacity.166

MELANOCYTE DENDRITES Melanocyte dendrites are branching protoplasmic processes that interact with keratinocytes. Actin is a major structural component of melanocyte dendrites, and actin filament disruption leads to dendrite loss.167 Cocultures of keratinocytes and melanocytes demonstrate that keratinocyte-derived factors play a role in melanocyte dendricity.168 These factors include ET-1, nerve growth factor (NGF), α-MSH, ACTH, prostaglandins (PGs) E2 and F2α168 and β-endorphin.169 Integrins, receptors that mediate actin-extracellular matrix contact are likely to play a role in dendrite formation as well.170

Another group of proteins, the Rho family, also plays a role in melanocyte dendrite formation. Rho proteins become active when they bind GTP and inactive when binding GDP.171,172 It appears that when Rho is activated, dendrites retract; while when its family member Rac is activated, dendrites form.172 Indeed, it is currently assumed that by increasing cAMP levels, α-MSH inhibits Rho, enhancing melanocyte dendricity. Thus, the equilibrium between Rho and Rac appears to be an important factor influencing melanocyte dendricity.

MELANOSOME TRANSPORT

Melanocyte dendrite tip

Melanosomes

Rab27 MIph

Dynein

Kinesin

MyoVa Actin

Figure 72-12  Schematic diagram of melanosome transport across melanocyte dendrites. Melanosomes move bidirectionally along melanocyte dendrites. They are attached to microtubules through the motor proteins kinesin (anterograde) and dynein (retrograde). At the tip of the dendrite, melanosomes are captured in the actinrich periphery. Myosin-Va (MyoVa) mediates melanosome binding to actin through the linker proteins Rab27a and melanophilin (Mlph).

Transfer of melanosomes from melanocytes to neighboring keratinocytes is a critical step in normal pigmentation. Studies suggest several ways for melanosomal transfer, including exocytosis, cytophagocytosis, fusion of plasma membranes, and transfer by membrane vesicles.187 The exocytosis pathway of melanosomal transfer involves fusion of the melanosomal membrane with the melanocyte plasma membrane, melanosome release into the intercellular space and phagocytosis by surrounding keratinocytes. Cytophagocytosis is a term indicating the phagocytosis of a live cell or a portion of it. With regard to keratinocytes, they cytophagocytose the tip of a melanocyte dendrite, which then fuses with lysosomes inside the keratinocyte, is transported to a supranuclear location where the phagolysosome membranes break up releasing the melanosomes. Fusion of keratinocyte and melanocyte plasma membranes creates a space through which melanosomes are transferred from the melanocyte to the keratinocyte. Indeed, high-resolution photography shows the presence of filopodia—slender, filliform, pointed cytoplasmic projections at the tip of melanocyte dendrites.188 These filopodia adhere and fuse with keratinocyte plasma membrane prior to melanosome transfer. Another way of melanosomal transfer involves shedding of melanosome-filled vesicles followed by phagocytosis of these vesicles by keratinocytes, or their fusion with keratinocyte plasma membrane. The molecular and cellular mechanisms involved in melanosome phagocytosis have been partially elucidated. It appears that keratinocytes express a

Biology of Melanocytes

Melanosome transport across melanocyte dendrites

TO KERATINOCYTES

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Melanosomes are transferred from their site of origin in melanocyte perikaryon to the tips of melanocyte dendrites. Melanosome transport takes place on microtubules that are arranged parallel to the long axis of the dendrite and is controlled by two classes of microtubule-associated motor proteins: (1) kinesins173–175 and (2) cytoplasmic dyneins176–180 (Fig. 72-12). Both motor proteins act as short cross-bridge structures connecting the organelle to the microtubules. Centrifugal, anterograde organelle movement is mediated primarily by kinesin, whereas centripetal movement is controlled by cytoplasmic dynein. Studies examining melanosomal transport suggest that their microtubule-dependent movement is bidirec-

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Chapter 72

WITHIN MELANOCYTES

tional,181 consistent with a cooperative forward and backward pull of kinesin173 and dynein,176 respectively. For melanosomes with net centrifugal movement, the bidirectional movement appears to terminate with myosin-Va (encoded by dilute locus)-dependent melanosomal capture in the actin-rich periphery of the dendrite (Fig. 72-12).181 Additional proteins that participate in melanosome transport include Rab27a (encoded by ashen locus) that mediates myosin-Va binding to melanosomes through another linker protein-melanophilin (encoded by leaden locus) (Fig. 72-12).182 In the absence of myosinVa, melanosomes do not collect in dendrite tips. Mutations in any of the above gene products results in decreased cutaneous pigmentation. Griscelli syndrome, a rare autosomal recessive disorder in which individuals display dilute skin and hair color, is the result of mutations of myosin-Va, Rab27a, or melanophilin182 (see Chapter 73). Myosin-Va and Rab27a are closely located on chromosome 15.183–186 Because myosin-Va is also expressed in the brain, mutations of this gene may also cause neurological abnormalities. Rab27a also plays a role in immuno-regulation and individuals with mutations of this gene display abnormalities of the immune system. Mutations of melanophilin result only in the distinctive hypopigmentation that characterizes the syndrome.186

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Section 11

seven-transmembrane G-protein coupled receptor called protease activated receptor-2 (PAR-2). PAR-2 is activated when serine proteases cleave the extracellular portion of the receptor, exposing a new segment that acts as a tethered (attached) ligand.189,190 Activation of PAR-2 increases keratinocyte phagocytic activity.189,190 Interestingly, and consistent with its role in melanosome phagocytosis, UV induces the activity and expression of PAR-2.191 UV effect on PAR-2 activity and expression is more pronounced in individuals with skin phototypes II and III than in those with skin phototype I.191 Keratinocyte growth factor receptor has also been implicated in enhancing phagocytosis of melanosmes by keratinocytes.192

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REGULATION OF MELANOCYTE FUNCTION

Disorders of Melanocytes

Melanocyte behavior in skin is largely influenced by signals from neighboring keratinocytes as well as autocrine signals and environmental factors such as UV irradiation (also see Section “UV Irradiation and Melanocytes”). The synthesis and secretion of most keratinocyte-derived factors is increased by UV irradiation, but it is also evident that UV can directly stimulate melanocyte dendricity and melanin production.171,193 Melanocytes receive both positive and negative paracrine signals that modulate their proliferation and differentiated function.

MELANOGENIC STIMULATORS PROOPIOMELANOCORTIN AND DERIVED PEPTIDES. It is well documented that MSH and

776

ACTH are potent stimulators of melanogenesis. They belong to a family of peptides derived from the precursor proopiomelanocortin (POMC) that is synthesized, in addition to the pituitary gland, also by epidermal keratinocytes. Interestingly, POMC expression in keratinocytes is induced by UV, phorbol esters, and interleukins.194,195 In rodents, α-MSH stimulates melanogenesis and favors eumelanin over pheomelanin production, but systemic administration of α-MSH, β-MSH, and ACTH to people increases skin pigmentation predominantly in sunexposed areas.196,197 However, in certain disease conditions characterized by abnormally high levels of ACTH, such as Addison disease198 or Nelson’s syndrome199 (ACTH secreting pituitary adenoma), more generalized hyperpigmentation of the skin has been observed.200 Aside from its effect on melanogenic proteins and eumelanin synthesis, α-MSH was also reported to enhance the repair of UV-induced DNA damage in melanocytes, specifically the repair of pyrimidine dimers, and also to reduce the level of UV-induced hydrogen peroxide in the cell.201 In addition, α-MSH was shown to regulate melanosomal pH.202 These data suggest a role for POMC-derived peptides beyond merely stimulating melanogenesis.

ENDOTHELIN-1. ET-1 appears to play a role in mature melanocytes, inducing melanogenesis by activating tyrosinase and increasing TRP-1 levels.203,204 ET-1 also leads to melanocyte proliferation203,204 and promotes dendrite formation.205 Cultured keratinocytes synthesize and secrete ET-1,204–206 and UV irradiation stimulates ET-1 production by keratinocytes.204,205 ET-1 can also cooperate synergistically with other growth factors/cytokines to further influence melanocyte function. ET-1 upregulates MC1R level and increases MC1R affinity for α-MSH.207,208 Similar to α-MSH, ET-1 displays photoprotective effects on melanocytes, enhancing thymine dimer repair, decreasing the level of UV-induced hydrogen peroxide, and inducing the level of antiapoptotic proteins.201,209 STEEL FACTOR (SF). Like other keratinocytederived factors, SF is induced by UV-irradiation, and in guinea pigs, anti-Kit antibodies block UV-induced tanning. SF can also act synergistically with other cytokines such as IL-3, IL-6, IL-7, IL-9, and granulocyte-macrophage-colony stimulating factor to regulate UV-induced melanogenesis and melanocyte survival.210,211 INFLAMMATORY MEDIATORS. Several inflammatory mediators can affect skin pigmentation. PGs—arachidonic acid-derived metabolites, and ­leukotrienes—lipid compounds related to PGs, both mediators of inflammatory responses, affect melanocyte function. Their level is elevated in sunburned skin212 and in a variety of inflammatory dermatoses, including atopic dermatitis213 (see Chapter 14) and psoriasis214 (see Chapter 18). Human melanocytes express several PG receptors including the receptors for PGE2 and PGF2α.215,216 Indeed, PGF2α stimulates melanocyte dendrite formation and activates tyrosinase,215,216 and UV irradiation upregulates the level of PG receptors on melanocytes.215,216 Similarly, leukotrienes B4 and C4 increase melanin synthesis and stimulate melanocyte proliferation and motility.217 Interestingly, melanocytes also contribute to cutaneous inflammatory responses, as they synthesize and release IL-8 when stimulated by the proinflammatory cytokines IL-1 and TNF-α.218 Melanocytes also respond to histamine released by mast cells during cutaneous inflammation. Histamine binds H1 and H2 receptors to induce melanocyte dendricity and upregulate tyrosinase level.219,220 These effects are decreased when melanocytes are pretreated with the H2 receptor antagonist famotidine.220 NEUROTROPHINS. Neurotrophins (NTs) are a family of molecules that enhance neuronal survival in the central and peripheral nervous systems. They include NGF,221 NT-3,222–224 NT-4,225 and brain-derived neurotrophic factor.226,227 Melanocytes express the low-affinity receptor common to all NTs, p75NTR,228 as well as the high-affinity receptors for NGF (TrkA) and NT3 (TrkC).229 Keratinocytederived NGF, whose expression is upregulated by UV irradiation, is chemotactic for melanocytes and

induces their dendricity.230 Both NGF and NT-3, the latter expressed by dermal fibroblasts, increase melanocyte survival. Specifically, after UV irradiation, NGF supplementation increases the level of the antiapoptotic Bcl-2 protein, reducing melanocyte apoptotic cell death.231,232 Thus, in addition to other keratinocyte-derived cytokines, NGF may help preserve the population of cutaneous melanocytes that would otherwise be depleted by UV damage.

MELANOGENIC INHIBITORS Numerous reports have suggested the existence of endogenous melanogenic inhibitors,245,246 but only few specific molecules have been identified. One group of inhibitors includes sphingolipids, a class of ­membrane-associated lipids247 that act as signal transducers. Sphingolipids were shown to decrease melanogenesis, at least in part by enhancing MITF degradation via ubiquitin-meditated pathways.248,249 Another melanogenic inhibitor, BMP-4, downregulates tyrosinase expression in melanocytes,250 also in part via its effects on MITF.251 Interestingly, physiologic doses of UV irradiation, a potent melanogenic stimulator, decrease the expression of BMP receptors on melanocytes,250 presumably eliminating its inhibition during UV-induced tanning. Mice that transgenically overexpress the physiologic BMP antagonist noggin have a darker coat color than wild-type mice and their hairs have a higher eumelanin to pheomelanin ratio.252

cAMP/PKA-DEPENDENT PATHWAY cAMP, one of the first identified intracellular second messengers, plays a key role in diverse biological functions such as cellular metabolism, growth, and differentiation.253,254 It also mediates α-MSH effect255 and was one of the first recognized regulators of mammalian pigmentation256 The intracellular level of cAMP is upregulated by a membrane-associate enzyme called adenylate cyclase that is activated upon receptor–ligand interaction in receptors that are coupled to GTP-binding proteins like MC1R257 (eFigs. 72-8.1 and 72-12.1 in online edition). cAMP is also elevated by reagents such as choleragen or isobutylmethylxanthine. Providing melanocytes with dibutyryl cAMP, a cAMP analog, increases the intracellular level of cAMP and induces signaling that leads to melanogenesis.258 cAMP-dependent protein kinase (PKA) mediates most of the biologic actions of cAMP.257 PKA is a ­serine/ threonine kinase consisting of two regulatory subunits and two catalytic subunits.257 It exists in the cytosol in an inactive form and binding of cAMP to its regulatory subunits releases the catalytic subunits, activating the enzyme.257 PKA phosphorylates the cAMP responsive element-binding protein (CREB) that binds its DNA consensus sequence CRE in the MITF promoter to induce MITF transcription (eFig. 72-8.1 in online edition). cAMP elevation also affects other target genes by increasing or decreasing their transcription259 (eFig. 72-12.1 in online edition). In vitro, PKA effect can be antagonized by the inhibitor PKI that acts as a pseudosubstrate for the catalytic subunit of PKA and thus prevents it from phosphorylating its endogenous substrates.260

Biology of Melanocytes

CATECHOLAMINES. Catecholamines are a group of signaling molecules, primarily functioning as neurotransmitters and as endocrine hormones.243 Catecholamines bind either α1-adrenergic receptors (AR) or β2-AR and can induce melanogenesis through PKC-β or cAMP-dependent pathways.169,244

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NITRIC OXIDE. Nitric oxide (NO) is a diffusible free radical displaying pleiotropic bioregulatory effects in diverse cells and tissues.236,237 Melanocytes and keratinocytes produce NO in response to inflammatory cytokines,238–241 and NO production in keratinocytes is induced by UV irradiation.242 NO increases tyrosinase activity and melanogenesis242 and is thus an autocrine as well as paracrine molecule that affects melanocyte behavior in skin.

Growth factors, cytokines, hormones, and other ligands for receptors expressed on melanocytes exert their biologic effect by interacting with their specific cell surface receptors, generating a signaling cascade involving activation or inhibition of protein kinases and leading to distinct patterns of protein phosphorylation. Two types of kinases participate in cellular signaling: (1) serine/threonine kinases and (2) tyrosine kinases that by definition phosphorylate serine and/or threonine residues and tyrosine residues, respectively, on their specific target proteins. This section reviews the major signaling pathways that affect melanocyte behavior in skin.

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Chapter 72

BASIC FIBROBLAST GROWTH FACTOR. Basic fibroblast growth factor (bFGF), named for its ability to stimulate the growth of fibroblasts, was one of the first identified melanocyte mitogens.233,234 It is produced by keratinocytes, but lacks a secretory signal and hence is presumed to affect melanocytes through cell–cell contact. It binds tyrosine kinase transmembrane receptors to induce its mitogenic effect in the presence of cAMP elevating factors. Like other keratinocyte-derived cytokines, it is upregulated in response to UV irradiation.234,235 Keratinocyte growth factor, another member of the FGF family of proteins, has been shown to promote melanosome transfer from melanocytes to keratinocytes.192

SIGNALING PATHWAYS REGULATING MELANOCYTE FUNCTION

PKC-DEPENDENT PATHWAY PKC is a serine/threonine kinase involved in diverse cellular functions, including growth, transformation, and differentiation.261 PKC resides as an inactive enzyme in the cytoplasm, and it is activated by diacylglycerol (DAG), a component cleaved from the plasma membrane when cell surface receptors interact with

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Section 11 :: Disorders of Melanocytes

their ligands. DAG can also be released from the membrane by UV irradiation (eFig. 72-12.1 in online edition). DAG induces PKC translocation to membranes where the latter is activated261 to induce phosphorylation of serine/theonine residues on target proteins like tyrosinase. Phorbol esters mimic DAG action and initially activate PKC.261 However, within 24 hours the entire cellular reserves of PKC are depleted, and when melanocytes are treated with phorbol esters they can no longer signal through PKC.87 The critical role of PKC in melanogenesis was first suggested by the observation that addition of DAG, the endogenous activator of PKC, to cultured human melanocytes rapidly increased total melanin content,262 and this increase was blocked by a PKC inhibitor.262 Moreover, topical application of DAG to guinea pig skin increased epidermal melanin content.263 The expression of the 12 PKC isoforms varies among different tissues.86 Each isoform is thought to carry out a distinct biological function. Human melanocytes express PKC-α, -β, -ε, -δ, and -ς264,265 and the PKC-β isoform is specifically involved in regulating tyrosinase activity (see above). ET-1 and histamine also utilize the PKC-dependent pathway (in addition to cAMPdependent pathway) to exert their regulatory effects on melanocyte function.266,267

RECEPTOR TYROSINE KINASES Melanocytes express several distinct tyrosine kinase receptors that bind BMP, bFGF, HGF, and c-Kit ligand. Receptor–ligand interaction activates an intracellular tyrosine kinase domain on the receptor, phosphorylating the receptor and subsequently activating a series of kinases called mitogen-activated protein (MAP) kinases, or other intracellular signaling molecules (eFig. 72-12.1 in online edition). Through a chain reaction involving phosphorylation of proteins like MITF, the signals are transferred to the nucleus to activate or suppress the transcription of genes that participate in melanocyte proliferation, melanogenesis, and/or survival.

b2- AND α1-ADRENERGIC RECEPTORS

778

Studies suggest that pathways that increase intracellular cAMP are also involved in regulation of melanogenesis. POMC-deficient mice (POMC -/−) that lack melanocortin ligands still display normal black coat color.269 Histological and electron paramagnetic resonance spectrometry of the hair follicles showed normal structure and eumelanin pigmentation.269 This study suggests that either MC1R has adequate basal activity to induce pigmentation or that pathways that do not involve melanocortin can also induce melanogenesis. Indeed, melanocytes express both β2-AR and α1-AR, respectively.270,244 a1-AR interacts with melanocyte derived-norepinephrine and increases the level of DAG169,244 inducing melanogenesis in a PKCβ-dependent pathway. Also, keratinocytes produce epinephrine, which then binds to β2-AR expressed on melanocytes and increases the level of cAMP, leading

to melanin synthesis.244 Therefore, numerous pathways may act in tandem to regulate melanogenesis.

UV IRRADIATION AND MELANOCYTES TANNING RESPONSE Melanocyte survival, proliferation, and differentiated function are influenced by environmental factors, the most important of which is UV irradiation. UV irradiation induces tanning, the so-called facultative skin color, an increase above baseline or constitutive skin pigmentation that provides protection against future UV irradiation.271 Tanning is divided into immediate tanning and delayed tanning.

IMMEDIATE TANNING. Immediate tanning or immediate pigment darkening occurs within 5–10 minutes of exposure and fades within minutes to days depending on the UV dose and the complexion of the individual (Fig. 72-13B). As summarized in Table 72-1, immediate tanning does not provide photoprotection and does not increase epidermal melanin level.272 It is primarily produced by UVA irradiation, although visible light can also induce immediate tanning.273 Immediate tanning is only visible in darker individuals, and it is thought to represent melanosomal relocation from the perikaryon to melanocyte dendrites.274 DELAYED TANNING. Delayed tanning, summarized in Table 72-1 and shown in Figure 72-13A, occurs within 3–4 days after UV exposure.271,272 UV is arbitrarily divided into UVC (100–280 nm), UVB (280–320 nm), and UVA (320–400 nm). The UVC portion of the spectrum is generally not present in terrestrial sunlight because it is absorbed by the atmospheric ozone layer. Delayed tanning is affected by both UVB and UVA. The action spectrum that produces delayed tanning is the same as for UV-induced erythema (sunburn), with UVB wavelengths far more effective than UVA.264 Especially in darker skinned individuals, suberythemogemic UV doses may be effective as well. Delayed tanning peaks between 10 days and 3–4 weeks depending on the absorbed UV dose and the individual’s skin type, then fades gradually over a few weeks. Histologically, there are increased epidermal melanocytes, melanocyte dendriticity, and melanosome transfer to keratinocytes with greater melanization of individual melanosomes.272,274 Overall, total epidermal melanin is increased, providing additional photoprotection from UV irradiation. DIRECT AND INDIRECT EFFECTS OF UV IRRADIATION UV irradiation affects melanization, melanocyte proliferation and survival both directly and indirectly through its effect on keratinocytes, inducing the synthesis and secretion of paracrine keratinocyte factors.

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Chapter 72 ::

B

Figure 72-13  A. Delayed tanning. Four template test sites in a phototype III individual were exposed to repeated erythemogenic doses of ultraviolet B (UVB) (+UVA) delivered in 24-hour intervals, and the photograph was taken 10 days after the last exposure. The tan in the more heavily pigmented test sites persisted for 2 months. B. Immediate tanning in a phototype III individual. Four template test sites were exposed to various doses of UVA, and the photograph was taken 2 hours after the end of exposure. After 48 hours, the tan had almost completely faded.

DIRECT EFFECTS. UV irradiation triggers several biological reactions through its interaction with cellular chromophores that absorb photons. Photochemical reactions affect proliferation, survival, and the differentiated function of melanocytes. Most UVA effects are

Biology of Melanocytes

A

assumed to be the result of oxidative damage mediated through UVA absorption by cellular chromophores like melanin precursors that act as photosensitizers leading to the generation of ROS and free radicals.275 UVB irradiation is directly absorbed by cellular DNA, leading

TABLE 72-1

Immediate Tanning versus Delayed Tanning Immediate

Delayed

Onset

Minutes

3–4 days

Peak intensity

Minutes to few hours

10–28 days

Fading

Within 24 hours

Weeks

Mechanism

Redistribution of melanosomes

↑Keratinocyte-derived melanogenic cytokines ↑Tyrosinase level and activity ↑Melanin synthesis ↑Melanocyte dendriticity ↑Melanosome number ↑Melanosome transfer ↑Melanocyte proliferation

Photoprotection

Unchanged

Increased

Change in skin color

Undetectable in fair skin Subtle in darker skin

Obvious in most light-skinned and all dark-skinned individuals

From Dillman AM: Photobiology of skin pigmentation. In: Pigmentation and Pigmentary Disorders, edited by N Levine. Boca Raton, CRC Press, 1993, pp. 61-94; Gilchrest BA et al: Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 63(1):1-10, 1996; Ortonne JP: The effects of ultraviolet exposure on skin melanin pigmentation. J Int Med Res 18(Suppl. 3):8C-17C, 1990; and Sturm RA: Human pigmentation genes and their response to solar UV radiation. Mutat Res 422(1):69-76, 1998.

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to the formation of DNA lesions, mainly cyclobutane dimers and pyrimidine (6–4) pyrimidone photoproducts.276 DNA damage repair systems are activated, at least in part through the tumor suppressor p53 protein. It has been shown that plasma membrane lipids are also affected by UV irradiation to release DAG,277 which then activates PKC-β to stimulate melanogenesis by activating tyrosinase (see above).

Section 11

INDIRECT EFFECTS. Key keratinocyte paracrine factors induced by UV irradiation and their effects on melanocytes are summarized in eTable 72-1.1 in online edition. These factors can act alone and/or synergistically to modulate melanocyte function. Interestingly, UV irradiation also induces the level of TNF-α and IL-1, cytokines that inhibit melanogenesis, suggesting a fine-tuned epidermal equilibrium between melanogenic stimulators and inhibitors after UV irradiation, with the final outcome of increased melanogenesis and melanocyte proliferation.

:: Disorders of Melanocytes

THE ROLE OF DNA DAMAGE IN MELANOGENESIS Interestingly, the action spectrum for tanning is virtually the same as that for the formation of thymine dimers,278,279 and UV-induced melanogenesis can be augmented in pigment cells by treatment with T4 endonuclease V,276 an enzyme that acts exclusively to enhance the repair of UV-induced DNA damage. Moreover, treatment of melanocytes with agents that act exclusively by damaging DNA, unlike UV that has multiple cellular targets, also stimulates melanogenesis.280 A central role for DNA damage and/or its repair in stimulating melanogenesis is further suggested by the fact that p53, a tumor-suppressor protein and transcription factor termed the Guardian of the Genome, when activated, upregulates the level of tyrosinase mRNA and protein, enhancing melanogenesis.281–284 Thus, tanning may be viewed as part of a p53-mediated DNA damage adaptive response that protects the skin during subsequent exposure to UV irradiation.

p53 IN UV-INDUCED MELANOGENESIS.

780

A central role for DNA damage and/or its repair in stimulating melanogenesis is further supported by the fact that the tumor-suppressor protein p53, when activated, upregulates the level of tyrosinase mRNA and protein, enhancing melanogenesis.281–285 In p53 knockout mice, it was observed that UV irradiation of the ears (that contain interfollicular melanocytes) minimally stimulates melanogenesis, compared to the far greater “tanning” response in p53 wild-type mice.282 These findings were expanded by Cui et al,286 who found a p53 consensus sequence in the POMC gene promoter, thus establishing a continuous signaling pathway from UVinduced DNA damage to the final tanning response. It was shown in mice keratinocytes that following UV irradiation p53 activation stimulates POMC transcription, thereby increasing the release of POMC-derived α-MSH, a key physiologic inducer of melanogenesis. Keratinocyte-derived α-MSH then stimulates MC1R

on melanocytes, resulting in increased production of eumelanin.286 It has also been shown that p53 transcriptionally upregulates the hepatocyte nuclear factor-1α (HNF1α) that is a transcription factor for tyrosinase.287 Thus, even in keratinocyte absence, UV directly activates p53 and HNF-1α in melanocytes to increase tyrosinase transcription. Furthermore, UV is known to increase H2O2 that activates p53.288 Thus, tanning may be viewed as part of a p53-mediated DNA damage adaptive response aimed at protecting the skin from subsequent UV irradiation.282,283,289

MELANOCYTE AGING AND PHOTOAGING Epidermal melanocyte aging is affected by both genetic and environmental factors. With aging, there is a decrease in the density of epidermal melanocytes (number per unit area of skin surface), approximately 10% per decade.290 However, the number of DOPApositive melanocytes is greater in chronically sunexposed skin than in sun-protected skin,290 possibly due to melanocyte proliferation after sun exposure and/or UV-induced keratinocyte-derived paracrine factors. Melanocyte loss is especially notable in hair follicles with age, with total loss of melanocytes in approximately half of all scalp follicles by middle age.37 Hair graying (depigmentation) occurs over the entire body but is usually first noted on the scalp, perhaps because of the long anagen (growth) cycle and resulting requirement for melanocyte proliferation and sustained high level of melanogenesis. In vitro melanocytes derived from older individuals show decreased proliferative capacity compared to those derived from younger individuals. Also, with aging in vitro, there is a general increase in the levels of total melanin as well as in the level differentiation-associated proteins such as MITF, TRP-1, and TRP-2291,292 and decrease in the level of proliferation-associated proteins such as cyclin D1 and E.291,292

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 3. Westerhof W: The discovery of the human melanocyte. Pigment Cell Res 19(3):183-193, 2006 23. Mizoguchi M: Melanocyte development: With a message of encouragement to young women scientists. Pigment Cell Res 17(5):533-544, 2004 39. Ito S: Biochemistry and physiology of melanin. In: Pigmentation and Pigmentary Disorders, edited by N Levine. Boca Raton, FL, CRC Press, 1993, pp. 34-59 40. Slominski A et al: Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 84(4):11551228, 2004 65. Park HY, Gilchrest BA: Signaling pathways mediating melanogenesis. Cell Mol Biol 45(7):919-930, 1999 171. Scott G. Rac and rho: The story behind melanocyte dendrite formation. Pigment Cell Res 15(5):322-330, 2002

182. Matesic LA, Copeland, NG, Jenkins, NA: A genetic approach to the study of vesicle transport in the mouse. In: Mechanisms of Suntanning, edited by JP Ortonne, R Ballotti. Nice, Martin Dunitz, 2002:199-208 187. Van Den Bossche K, Naeyaert JM, Lambert J: The quest for the mechanism of melanin transfer. Traffic 7(7):769778, 2006

256. Lerner AB: My 60 years in pigmentation. Pigment Cell Res 12(2):131-144, 1999 271. Gilchrest BA et al: The photobiology of the tanning response. In: The Pigmentary System: Physiology and Pathophysiology, edited by JJ Nordlund, RE Boissy, VJ Hearing, RA King, JP Ortonne. New York, Oxford University Press, 1998, pp. 359-372

Albinism is usually inherited as a recessive trait, but other congenital disorders of pigmentation are usually inherited as dominant traits. There can be marked differences in penetrance. Clinical features of albinism may include lightly pigmented or nonpigmented skin and silvery-white or light hair color. Ocular nystagmus and reduced visual acuity are important features of albinism that distinguish albinism from other congenital disorders of pigmentation. Clinical features of congenital disorders of pigmentation include patches of white hair (poliosis), variations in iris color, and depigmented patches of white skin. The presence of ocular nystagmus is useful for distinguishing albinism from congenital disorders of pigmentation. Albino skin contains melanocytes with reduced or absent DOPA-positivity. Depigmented patches in congenital disorders of pigmentation lack melanocytes.

EPIDEMIOLOGY EPIDEMIOLOGY OF ALBINISM Oculocutaneous albinism (OCA) is the most common inherited disorder of generalized hypopigmen-

Albinism and Other Genetic Disorders of Pigmentation

Worldwide occurrence

tation, with an estimated frequency of 1 in 20,000 in most populations. Four different types of OCA have been described. OCA1 and OCA2 are the most frequent types and account for approximately 40% and 50%, respectively, of OCA worldwide. OCA2 occurs in approximately 1 in 30,000 to 1 in 36,000 Caucasians and 1 in 10,000 to 1 in 17,000 blacks in the United States,1–3 but is reported at higher frequencies ranging from 1 in 1,400 to 1 in 7,000 in Sub-Saharan Africa4,5 and even as high as 1 in 170 individuals in the Kuna population of the Panama coast.6 OCA3 and OCA4 are far less frequent, although the rufous OCA phenotype, described later, associated with OCA3 in South African blacks has been reported at an incidence of approximately 1/8,500,7 while OCA4 accounts for 27% of all cases of OCA in Japan.8 Hermansky–Pudlak syndrome (HPS) is rare except in the Caribbean island of Puerto Rico, particularly in the northwestern region where the majority of patients are found, with an incidence of 1 in 1,800.9 Chediak– Higashi syndrome is also quite rare.

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ALBINISM AND CONGENITAL DISORDERS OF PIGMENTATION AT A GLANCE

Chapter 73

Chapter 73 :: A  lbinism and Other Genetic Disorders of Pigmentation :: Thomas J. Hornyak

11

Box 73-1  Differential Diagnosis of Albinism OCA types 1–4 Hermansky–Pudlak syndrome Griscelli syndrome Chediak–Higashi syndrome Ocular albinism Currently unclassified types of albinism Tietz syndrome Vitiligo (extensive) Ziprkowski–Margolis syndrome (X-linked albinism– deafness syndrome) Cross (Cross–McCusick–Breen) syndrome (oculocerebral syndrome with hypopigmentation)

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TABLE 73-1

Characteristics of Albinism

Section 11

Chromosome

Gene Locus

Oculocutaneous albinism type 1

11q21

TYR

Tyrosinase/TYR

Type 1A—no pigment Type 1B—some pigment

Oculocutaneous albinism type 2

15q11.2-q12

P

Pink protein/P

Some pigmentation apparent; nevi and freckles possible

Oculocutaneous albinism type 3

9p23

TYRP1

Tyrosinase-related protein-1/ TYRP1

Similar to OCA2 phenotype. Includes rufous (red) albinism phenotype.

Oculocutaneous albinism type 4

5p

MATP

Membrane-associated transporter protein/MATP

Similar to OCA2 phenotype. Most common in individuals with Asian biogeographic ancestry.

Type 1

10q24

HPS1

HPS1 (BLOC-3)

Pulmonary fibrosis associated; absent platelet dense granules is a hallmark of all types of HPS

Type 2

15q15

AP3B1

β-3 subunit of adaptor protein 3 complex/AP3B1

Type 3

3q24

HPS3

HPS3 (BLOC-2)

Type 4

22q11.2-q12.2

HPS4

HPS4; distant homology with yeast CCZ1 (BLOC-3)

Type 5

11p14

HPS5

HPS5 (BLOC-2)

Type 6

10q24.32

HPS6

HPS6 (BLOC-2)

Type 7

6p22.3

DTNBP1

Dysbindin (BLOC-1)

Type 8

?

BLOC1S3

BLOC1S3 (BLOC-1)

Chediak–Higashi syndrome

1q43

LYST

Lysosome trafficking/LYST

::

Disease

Protein [Biogenesis of Lysosome-Related Organelles Complex (BLOC)]

Disorders of Melanocytes

Hermansky–Pudlak syndromes

EPIDEMIOLOGY OF CONGENITAL DISORDERS OF PIGMENTATION Waardenburg syndrome (WS) is probably less frequent than OCA. The highest reported incidence is 1/20,000 in Kenya, although most estimates of its incidence in the Netherlands where it was originally reported are in the range of 1/40,000. The incidence of WS with deafness is lower, ranging between 1/50,000 and 1/212,000. WS has been described occurring in a range of frequencies in the congenitally deaf, ranging from 0.9%–2.8% to 2%–5% in different reports. The incidence of piebaldism is estimated to be less than 1/20,000.10,11

ETIOLOGY, PATHOGENESIS, AND CLINICAL FEATURES 782

Distinguishing Signs

Awareness of the biologic basis of the distinction between congenital disorders of pigmentation, which

Pulmonary fibrosis associated

Giant peroxidase-positive lysosomal granules in neutrophils

are disorders of melanocyte development, and the varieties of albinism, which are disorders of melanocyte differentiation, is important for fully understanding their clinical manifestations. Albinism results from the dysfunction of a normal complement of pigment cells, which results in complete or partial loss of cutaneous pigmentation. The forms of albinism, including the subtypes of OCA as well as albinism syndromes with systemic manifestations, result either from enzymatic defects in the biosynthesis of melanin, from melanosomal defects that interfere with melanin formation, or from problems in the intracellular transport and localization of proteins essential for melanin biosynthesis (Table 73-1; see Chapter 72). Congenital disorders of pigmentation usually result from mutations in genes critical for melanocyte development during embryogenesis. These disorders can also be associated with other systemic problems because of the requirement for these gene products in the development of cell types other than melanocytes. More accurate descriptors of these disorders could be congenital (or genetic)

11

Melanocyte life cycle

Differentiated adult skin-Disorders of melanin biosynthesis

Melanocyte embryonic development-Congenital disorders of pigmentation

PAX3

Melanosome formation, transport, and transferDisorders of vesicle formation and trafficking

KIT

MITF

Chapter 73

SOX10

SLUG/SNA12 EDN3 EDNRB

Enzymatic defects (OCA1, OCA3) Melanosome function (OCA2-4)

Figure 73-1  Schematic diagram illustrating the steps of the melanocyte life cycle, from development through differentiation, where key genes, altered in the indicated genetic diseases, act to control the function of the melanocyte. disorders of melanocyte differentiation and congenital (or genetic) disorders of melanocyte development, to reflecting the fact that both categories of conditions, albinism and developmental pigmentary syndromes, are generally inherited but result from different mechanisms of disease (Fig. 73-1).

ETIOLOGY, PATHOGENESIS, AND CLINICAL FEATURES OF ALBINISM Although the pigmentary abnormalities associated with types of albinism can vary widely, common to all types of albinism is reduced visual acuity and ocular nystagmus, a result of misrouting of the optic nerve at the optic chiasm and foveal hypoplasia. This has been described not only in humans12 but also in other albino mammals.13 Experiments using the tyrosinase promoter to express both tyrosinase and tyrosine hydroxylase in albino transgenic mice suggest that the tyrosine hydroxylase activity of tyrosinase is ­particularly important for ensuring the proper routing of retinal projections at the optic chiasm during development.14,15 The ocular manifestations of albinism can vary greatly, ranging from severe (20/400) to nearly undetectable, but is often close to 20/80.16 They also include a reduction in iris pigment, a reduction in retinal pigment, and alternating strabismus.

OCULOCUTANEOUS ALBINISM 1. OCA1 [Online Mendelian Inheritance

TYPE

in Man (OMIM) #203100] is caused by loss of function of the

melanocytic enzyme tyrosinase resulting from mutations of the TYR gene.17–19 Null mutations are associated with a total loss of function and no pigment formation (OCA1A), whereas “leaky” mutations result in an enzyme that retains some function and is associated with some pigment formation (OCA1B). OCA1 appears to be the most common type of albinism in non-Hispanic Caucasian patients.20 Analyses of DNA from individuals with OCA1A have shown a large number of different mutations in the TYR gene. These mutations include missense, nonsense, frameshift, splice site, and deletion mutations. Most individuals with OCA1 are compound heterozygotes with different mutant maternal and paternal alleles.7 Missense mutations in the TYR gene are distributed among distinct regions of the coding sequence, which suggests that the encoded protein has multiple functional domains. Two of the clusters are in the copper-binding regions, with a third near the amino-­terminus of the mature protein, in the extramelanosomal domain of tyrosinase shown to require phosphorylation for enzyme activation.21,22 Clustering of mutations in discrete regions of the coding sequence is consistent with these regions’ importance either for the melanogenic activity of tyrosinase or for functions related to its maturation or processing.7,22 Missense mutations at the signal peptide cleavage site23,24 implicate this cleavage event as an important step in the development of tyrosinase activity. Frameshift mutations near the C-terminus of the coding region25,26 indicate that the cytoplasmic domain of tyrosinase is also important for full activity, possibly because of the presence of protein kinase C-β-dependent

Albinism and Other Genetic Disorders of Pigmentation

TYR TYRP1 P MATP

::

WS1-4 Tietz syndrome Piebaldism

AP3B-HPS2 DTNBP1-HPS7 BLOC1S3-HPS8 other HPS gene products LYST- Chédiak-Higashi MY05A, MLPH, RAB27AGriscelli syndrome (See Chap. 75)

783

11

Section 11 :: Disorders of Melanocytes

784

Figure 73-3  OCA1B with golden blond scalp hair and tan. Figure 73-2  OCA1A with no hair or skin pigment, demonstrating iris translucency.

phosphorylation sites that have been identified at its extreme C-terminus.22 All nonsense and frameshift mutations are associated with a complete loss of tyrosinase activity, presumably because of the subsequent production of a truncated protein. With missense mutations the picture is more complicated. A set of missense mutations that were associated with OCA1 patients accumulating pigment with age in either OCA1B or temperaturesensitive OCA (OCA1TS) patients27 were shown to have residual enzymatic activity. Hence, it is likely that a subset of TYR missense mutations are responsible for the OCA1B and OCA1TS phenotypes because of the reduced, rather than absent, tyrosinase activity in their melanocytes.7 However, other missense mutations resulting in the OCA1A and OCA1TS phenotypes result in defective intracellular processing of tyrosinase and retention of the mutant tyrosinase proteins in the endoplasmic reticulum, which suggests that some molecular variants of OCA1 represent an endoplasmic reticulum retention disease.28–30 Thus, the residual enzymatic activity of a missense tyrosinase mutant cannot fully predict its phenotype, because other, presumably conformational, determinants of nascent mutant proteins may lead to their retention in the endoplasmic reticulum, block transport to the melanosome, and cause a more severe pigmentary phenotype. In OCA1A, or the classic tyrosinase-negative OCA, there is a complete inability to synthesize melanin in skin, hair, and eyes, resulting in the characteristic “albino” phenotype. Affected individuals are born with white hair and skin and blue eyes, and there are no changes as they mature. The phenotype is the same in all ethnic groups and at all ages (Fig. 73-2). The hair may develop a slight yellow tint due to denaturing of the hair protein due to sun exposure and/or shampoo use. The irides are translucent, appear pink early in

life, and often turn a gray–blue color with time. No pigmented lesions develop in the skin, although amelanotic nevi can be present. The architecture of skin and hair bulb melanocytes is normal. The melanosomes show a normal melanosomal membrane, and normal internal matrix formation is observed in stage 1 and 2 melanosomes. The phenotype of OCA1B can range from minimal hair pigment to skin and hair pigmentation approaching the normal pigmentary phenotype for the individual’s genetic composition and continental ancestry. Most individuals with OCA1B have very little or no pigment at birth and develop varying amounts of melanin in the hair and skin in the first or second decade of life (Fig. 73-3). In some cases the melanin develops within the first year. The hair color changes to light yellow, light blond, or golden blond first, as a result of residual pheomelanin synthesis, and eventually can turn dark blond or brown in adolescents and adults. The irides can develop light-tan or brown pigment, sometimes limited to the inner third of the iris, and iris pigment can be present on globe transillumination. However, some degree of iris translucency, as demonstrated by slit lamp examination, is usually present. Many individuals with OCA1B will tan with sun exposure, although it is more common to burn without tanning. Pigmented lesions (nevi, freckles, lentigines) develop in the skin of individuals who have developed pigmented hair and skin. In some patients, the moderate amount of residual tyrosinase activity can lead to near-normal cutaneous pigmentation, so that the clinician may overlook subtle cutaneous pigmentary abnormalities and render instead the mistaken diagnosis of ocular albinism (OA). One variation of OCA1B is the temperature-sensitive phenotype. In this variation, scalp and axillary hair remain white or slightly yellow, but arm and leg hair pigments. The skin remains white and does not tan. The retention of melanin synthesis in the cooler areas of the body, such as the arms and legs, but not

11

the warmer areas, such as the trunk and the scalp, is associated with a temperature-sensitive mutation in tyrosinase, which loses activity above 35°C.27 Similar tyrosinase mutations have been described in the Himalayan mouse31 and in the Siamese cat with dark “points” at the tips of the ears and on the paws.32

OCULOCUTANEOUS ALBINISM TYPE 2.

Chapter 73 ::

Figure 73-4  OCA2 with yellow hair, white skin, and freckles in an African individual (classic tyrosinase-positive OCA phenotype). the Navajo population.48 On the other hand, OCA2 in the Kuna population is caused by a splice site mutation in intron 17 of OCA2.49 Unlike the mutations in TYR, the missense mutations described to date in OCA2 do not seem to cluster in any specific region. Regarding OCA2 gene product function, it has been shown that melanosomes from P protein-deficient melanocytes have an abnormal pH. Melanosomes in cultured melanocytes derived from wild-type mice are typically acidic, whereas melanosomes from P ­protein-deficient mice are nonacidic.50 Hence, it is likely that the P protein regulates the pH of melanosomes, perhaps by functioning as an anion cotransporter in conjunction with a distinct proton pump on the melanosomal membrane. An alternate possibility is that the acidic conditions mediated by the P protein favor the normal biogenesis of melanosomes, including the correct targeting of other melanosomal proteins such as tyrosinase.51 Single nucleotide polymorphisms in the first intron of OCA2 are the major determinant of brown versus blue iris color,52 and a germ line polymorphism of the OCA2 gene is associated with favorable survival of estrogen receptor-negative breast cancer.53 Conceivably this finding may be related to the previously reported enhanced sensitivity of cells overexpressing P protein to cytotoxic agents.54 In African and African-American individuals, there is a distinct OCA2 phenotype (Fig. 73-4). Hair is yellow at birth and remains so throughout life, although the color may turn darker. Hair color can turn lighter in older individuals, and this probably represents the normal graying with age. The skin is creamy white at birth and changes little with time. No generalized skin pigment is present, and no tan develops with sun exposure, but pigmented nevi, lentigines, and freckles often develop, since the cutaneous melanocytes in these individuals both remain susceptible to ultraviolet (UV)induced changes early in life and retain some ability

Albinism and Other Genetic Disorders of Pigmentation

Mutations of the OCA2 (P) gene, which maps to chromosome arm 15q, are responsible for OCA2 (OMIM #203200).33 OCA2 occurs worldwide, though somewhat more frequently in the African, AfricanAmerican, and certain Native American populations. Historically, affected individuals have benefited from limiting their sun exposure, especially in desert and equatorial climates. Interesting anthropological studies have described how various societies have differed in their treatment of members with OCA2. For example, the Cuna Indians of Panama actively forbade marriage between female and male albinos, and infanticide against albino infants was common in the early twentieth century. In contrast, no marriage discrimination was practiced in Hopi tribes, whose albinos were not expected to participate in farming activities requiring substantial exposure to sunlight.34 From the standpoint of melanin synthesis, the defect in OCA2 appears to involve a reduction in eumelanin synthesis primarily, with less effect on pheomelanin synthesis. The predicted structure of the OCA2 gene, a melanosomal protein, includes 12 transmembrane domains.35,36 As expected, a number of mutations of the human OCA2 gene are associated with human OCA2.37,38 In Sub-Saharan Africa, a single 2.7-kb deletion allele accounts for 60%–90% of mutant OCA2 alleles and is associated with a common haplotype, suggesting a common founder.5,38–40 It has been estimated that this single mutation is associated with 25%–50% of all mutant OCA2 alleles in African-Americans.5,38–44 However, other diverse mutant alleles have been described in this population and in Africans. The Brandywine, Maryland, isolate affects an inbred American population, originally located in a rural area east of Washington, DC, that has been studied extensively for its prevalence of albinism, dentinogenesis imperfecta, and other inherited recessive and dominant conditions, with mixed Caucasian, African, and possibly Native American ancestry.45 In this population, 1 in 85 individuals has OCA245,46 and is homozygous for the 2.7kb deletion allele of OCA2.38 Thus, it is likely that this 2.7-kb deletion allele accounts for the distinct OCA2 phenotype in Africans and African-Americans.47 OCA2 also has been reported at relatively high frequencies ranging from 1 in 28 to 1 in 6,500 in specific Native American groups, including those populations in the southwest United States (Hopi population), southern Mexico, eastern Panama (Kuna population), and southwest Brazil.34 In the Navajo population, a homozygous 122.5-kb deletion has been described in members with OCA2. This mutations results in the loss of exons 10 to 20 of OCA2, corresponding to a region containing seven of the transmembrane domains, and appears to be specific for OCA2 within

785

11

Section 11 :: Disorders of Melanocytes

to synthesize melanin later. The irides are blue–gray or light tan or brown. The development of lentigines or ephelides, well-demarcated pigmented patches usually on sun-exposed areas of the skin, may be evidence of a separate genetic susceptibility because these lesions only develop in some OCA2 families and not in others. The presence versus absence of ephelides is associated with a lower risk of skin cancer in South African albinos,55 probably because the ability to produce ephelides by albinos in that environment also signifies a greater ability to produce pigment and thus demonstrate increased protection from UV radiation. In Caucasian individuals with OCA2, the amount of hair pigment present at birth or developing with time varies from minimal in northern Europeans (particularly Scandinavians) to moderate in southern European or Mediterranean individuals. The hair can be very lightly pigmented at birth, having a light yellow or blond color, or more pigmented with a definite blond, golden blond, or even red color. The skin is creamy white and does not tan. The iris color is blue–gray or lightly pigmented, and the amount of translucency correlates with the development of iris pigment. With time, pigmented nevi and lentigines may develop, and freckles are seen in areas with repeated sun exposure. The hair in Caucasian individuals may slowly turn darker through the first two or more decades of life. The normal delayed maturation of the pigment system and sparse hair early in life can make it difficult to recognize albinism early in northern European individuals. For all types of OCA in northern European families, the cutaneous hypopigmentation at birth or early in life is often similar to that of the parents and relatives, and the first concern is raised when it appears that the child is not tracking well or has developed nystagmus.

PRADER–WILLI AND ANGELMAN SYNDROMES. Prader–Willi and Angelman syndromes

often are associated with hypopigmentation.57,58 The intragenic deletion encompassing one P allele in these patients59,60 suggests that the observed pigmentary phenotype is related to OCA2 and the P gene, even if the details of this association are not fully understood.47

Prader–Willi and Angelman syndromes OCULOCUTANEOUS ALBINISM TYPE 3.

786

Mutations in the TYRP1 gene result in OCA3 (OMIM #203290). The first described mutation was in an African-American newborn twin initially classified clinically as brown OCA. Mutation analysis revealed a single-base deletion at codon 368 producing a frameshift and premature stop codon in exon 6 and a slightly truncated TYRP1 molecule.63 This mutation is shared by a substantial proportion of the rufous (“red”) OCA population in southern Africa.64 Rufous OCA is a distinct OCA phenotype in which the skin color is a mahogany brown with a slight reddish hue, and the hair color varies from deep mahogany to sandy

red.2,64 Additional OCA3-associated TYRP1 mutations include a single-base substitution at codon 166, resulting in the alteration of a serine to a premature stop codon in exon 3 and a truncated TYRP1 molecule,64 also identified in the rufous OCA population; and, in a Pakistani kindred, individuals homozygous for a distinct premature termination mutation.65 A Caucasian male was compound heterozygous for a missense mutation in TYRP1 located in the second copper-binding domain, inherited from the patient’s mother, and a stop codon, which apparently occurred spontaneously.66 Interestingly, the p.S166X mutation in TYRP1 previously associated with rufous OCA64 was found to modify an OCA2 phenotype to a red-haired variant.67 OCA3 has presented with both the brown OCA and the rufous OCA phenotypes in the African and AfricanAmerican populations. In the two cases of individuals with OCA3 mutations only, not of African descent, the phenotype has been that of a tyrosinase-positive albinism, such as OCA1B or OCA2. As additional examples of OCA3 are characterized, genotype–phenotype correlation should become clearer.

PATHOGENESIS OF OCA3 HERMANSKY–PUDLAK SYNDROME. Mutations in eight different genes to date have been associated with types of HPS.70 Currently, our understanding about the function of their gene products varies greatly. However, a common theme is their functional involvement in trafficking cell type-specific products in cells containing lysosome-related organelles (LROs), including melanosomes in melanocytes. HPS patients have OCA, with variable hypopigmentation of the skin, hair, and irides, and ocular abnormalities (see Fig. 73-5 and eFigs. 73-4.1, 73-5.1–73-5.3 in online edition). In addition, they lack platelet dense bodies and demonstrate a prolonged bleeding time, mucous membrane bleeding, a predisposition to epistaxis, easy bruising, and metromenorrhagia.75 Whole-mount electron microscopy is used to provide a definitive determination of the absence of platelet dense bodies.76 The greatest clinical experience exists with patients with HPS1 (OMIM #604982), HPS3 (OMIM #606118), and HPS4 (OMIM #606118). Pulmonary fibrosis is a common and severe manifestation of HPS1 and HPS4, generally causing death between the fourth and sixth decades of life.70,77 However, pulmonary fibrosis appears not to be associated with HPS3, which also features less severe pigmentary abnormalities.78–80 Among HPS1 and HPS4 patients, a granulomatous colitis is associated, occurring in approximately 15%.81,77 Ceroid lipofuscin, a complex lipid-protein material, has been reported to accumulate in the cells of HPS patients, predominantly those with HPS1.75 Mutations in distinct genes, rather than clinical phenotypes, define the various types of HPS. For example, more than two dozen distinct mutations have been found in HPS1 that cause disease.76–78 The most common, found in over 400 Puerto Rican individuals, is a 16-base pair (bp) frameshift duplication in exon 15.79,80 Although the precise function of HPS1

protein is not yet known, HPS1 associates with HPS4 in the 200 kDa BLOC-3 (biogenesis of LROs complex-3) complex81 and has also been found in association with HPS4 in a larger, 500-kDa complex in melanoma cells and fibroblasts.82–84 In melanocytes cultured from the skin of HPS1 patients, the melanogenic enzymes TYR, TYRP1, and DCT/TYRP2 are found in large vesicular structures in the cell body and dendrites, instead of in the granular pattern typically associated with melanosomal localization,85,86 suggesting a role in the control of protein trafficking to the melanosome. Mutations in HPS4 have been described in 15 patients,76 although its exact cellular role is not yet known. Functionally, the ATP-dependent pump MRP4 (ABCC4), normally localized to platelet granules and the plasma membrane, was found to be greatly reduced in HPS4 platelets.87 Mutations or deficiencies in the AP3B1 gene, encoding the β3A subunit of adaptor complex 3 (AP-3), one of the four known APs, cause HPS2 disease.88 AP-3 interacts with tyrosinase, which is not targeted properly to melanosomes in AP3B1-deficient melanocytes. Hence, AP-3 protein is required for the trafficking of tyrosinase, and possibly other melanosomal proteins, from an intracellular site to melanosomes. Interestingly, the subcellular distribution of TYRP1 is unchanged in HPS2 melanocytes, suggesting that TYRP1 transport, in contrast to tyrosinase, is not entirely dependent upon the AP-3 mechanism.89 The respiratory infections associated with HPS2 may be due to the abnormal movement of lytic granules in cytotoxic T lymphocytes (CTLs) to the immunologic synapse, leading to impairment of microbial killing.90

CHEDIAK–HIGASHI SYNDROME CHS (OMIM #214500). CHS is a rare autosomal reces-

sive disorder characterized by severe immunologic defects, hypopigmentation, bleeding tendency due to absent or reduced platelet dense bodies,94 progressive neurologic dysfunction, and the presence of giant peroxidase-positive lysosomal granules in peripheral blood granulocytes.95,96 Mutations in the LYST (lysosomal regulator trafficking) gene have been associated with Chediak–Higashi syndrome.97 Although the precise role of the LYST product is not known, structural comparisons and inferences from the cell biology of LYST mutant cells suggest it may be important for membrane fusion during vesicular transport from the trans-Golgi network to late endosomes and multivesicular structures.96,97 Most patients with CHS have a severe form of the disease, childhood CHS,98 with early onset of the socalled accelerated phase, characterized by fever, anemia, and neutropenia, including a lymphoproliferative syndrome with hemophagocytosis and benign infiltration of most tissues by activated T lymphocytes. This form of the disease is uniformly fatal unless patients undergo allogenic bone marrow transplantation. However, this treatment does not prevent future neurologic complications.69 Ten percent to 15% of patients exhibit a much milder clinical disease, adult CHS,98 surviving to adulthood but developing progressive and often fatal neurologic dysfunction in middle age. Very rare patients exhibit the intermediate adolescent CHS phenotype,98 which presents with severe infections in early childhood but has a milder course by adolescence and no accelerated phase. Interestingly, mutation analysis of patients with the childhood, adolescent, and adult forms of CHS showed that patients with severe childhood CHS had only functionally null mutant LYST alleles, whereas patients with the adolescent and adult forms of CHS tended to exhibit missense mutant

Albinism and Other Genetic Disorders of Pigmentation

Figure 73-5  Puerto Rican HPS1 patient. The patient died of pulmonary fibrosis.

Griscelli syndrome is

::

GRISCELLI SYNDROME.

discussed in Chapter 75.

11

Chapter 73

The most commonly described mutation in HPS3 is a 3904-bp deletion mutation that includes the entire first exon, found in a Puerto Rican population, which is distinct from the HPS1 Puerto Rican mutation.72 In addition, a splice site mutation has been described in Ashkenazi Jews with HPS3 who are either homozygous for this mutation or compound heterozygous for this mutation and other, nonconserved mutations.73 The HPS3 protein associates with the HPS5 and HPS6 proteins in the 340-kDa BLOC-2 complex.91,92 Melanocytes from HPS3 patients exhibit defective localization of tyrosinase and TYRP1 in later stage melanosomes, whereas proteins normally incorporated into earlystage melanosomes, such as silver/Pmel17/gp100 and melan-a/MART1, are unaffected.85,93 These melanocytes exhibited lower levels of melanin than control melanocytes, suggesting that the trafficking defect in tyrosinase, and perhaps also TYRP1, is responsible for the pigmentary dilution that can be observed in these patients.

787

11

Section 11 :: Disorders of Melanocytes

alleles that likely encode LYST polypeptides with partial function. Furthermore, some patients with the CHS phenotype do not have LYST mutations detectable with established techniques.98 The hypopigmentation phenotype of CHS is variable and can be quite mild. Hair color is light brown to blond, and commonly has a silvery or metallic sheen.96 Iris pigment is present, and nystagmus and photophobia may be present or absent. Histologic studies of the eye in CHS have shown reduced iris pigment, a marked reduction in retinal pigment granules, and infiltration of the choroid with reticuloendothelial cells.99 Cutaneous hypopigmentation is probably a consequence of both the giant, hypopigmented melanosomes clustered around the nucleus within CHS melanocytes, and their inefficient transfer to keratinocytes.100 Pigment granules in the hair shaft are large and have an irregular shape.101 The giant, peroxidase-positive lysosomal granules in neutrophils are a hallmark of the disease. These granules appear to inhibit neutrophil function, which along with neutropenia commonly observed is a likely determinant of the recurrent bacterial infections.96 CHS natural killer (NK) cells have defective lytic granule secretion,102 and defective cytotoxic T  ­lymphocyte-associated antigen 4 function has been proposed as a potential mechanism for the accelerated, lymphoproliferative stage of the disease.103 A reduced number of irregular platelet dense granules in CHS is responsible for the bleeding diathesis component.69,96

ETIOLOGY, PATHOGENESIS, AND CLINICAL FEATURES OF CONGENITAL DISORDERS OF PIGMENTATION WAARDENBURG SYNDROME. WS, described by the Dutch physician Petrus Waardenburg in 1951,104 is the prototypic congenital disorder of pigmentation. Although it was originally described as a syndrome combining pigmentary defects of the hair (poliosis or white forelock) and iris, congenital deafness, and developmental craniofacial abnormalities, it was subsequently realized that additional phenotypic

Box 73-2  Differential Diagnosis of Congenital Disorders of Pigmentation Waardenburg syndromes types 1–4 Tietz syndrome Piebaldism Woolf’s syndrome Generalized vitiligo Segmental vitiligo Vogt–Koyanagi–Harada syndrome Chemical leukoderma Tuberous sclerosis (hypopigmented macules and patches) Ziprkowski–Margolis syndrome (X-linked albinism– deafness syndrome)

manifestations could be part of the same syndrome. Four types of WS, WS1 through WS4, have been described.105–110 The discovery of molecular mutations accounting for the different types of WS has helped to explain its wide variety of manifestations as well as to illuminate the importance of specific genes for the development of different tissues and organs (Table 73-2). While practically all cases of WS1 and WS3 show mutated PAX3,105,105,109,110 WS4 individuals either have homozygous mutations in EDN3 (the endothelin-3 gene)111–113 or EDNRB (the endothelin-B receptor gene)114 or heterozygous mutations in SOX10.115 On the other hand, WS2 appears to arise more heterogeneously, as a mutation in MITF has been shown in only a small fraction of WS2 patients.107,108

Waardenburg Syndrome Type 1. Individuals with WS1 (OMIM #193500) are usually heterozygous for mutations in PAX3; hence, WS1 is autosomal dominant in inheritance. Although many different mutations in PAX3 have been associated with WS1, these mutations are thought either to be functionally

TABLE 73-2

Waardenburg and Tietz Syndrome Characteristics

788

Disorder

Clinical Signs

Mutated Gene(s)

Waardenburg syndrome (WS) type I

Hypopigmented patches, heterochromia irides, dystopia canthorum, sensorineural deafness (∼75%)

PAX3

WS type II

Same as type I, but no dystopia canthorum

MITF SNAI2/SLUG (homozygous)

WS type III

Same as type I with limb abnormalities

PAX3

WS type IV

Same as type I with Hirschsprung’s disease (congenital aganglionosis of the colon)

EDN3 EDNRB SOX10

Tietz syndrome

Generalized hypopigmentation and sensorineural deafness

MITF

Linkage analysis of families with WS2 (OMIM #193510, 608890,

Albinism and Other Genetic Disorders of Pigmentation

Waardenburg Syndrome Type 2.

::

null alleles or to abrogate the interactions of PAX3 with DNA.116 Individuals with WS1 have pigmentation abnormalities associated with craniofacial abnormalities (see Fig. 73-6). Dystopia canthorum, which is lateral displacement of the medial canthi of the eyes, is the hallmark craniofacial defect found in virtually all cases of WS1. A broadening of the nasal root, the presence of hypoplastic alae nasi, and synophrys are other craniofacial abnormalities associated with WS1. Poliosis, such as the presence of a white forelock, is the most common pigmentation abnormality associated with WS1. Depigmented white spots on the skin occur less commonly, but are often located at the ventral midline reflecting the compromised migration of dysfunctional melanocyte precursors from their origin in the dorsal neural crest. Pigmentary abnormalities of the iris, including complete heterochromia irides (differently colored irises), partial heterochromia irides (variations of color within an iris), or hypoplastic blue irides, can also be associated with WS1. Premature graying may also be observed in WS1. Congenital deafness is present in 57% of cases.117 The importance of PAX3 for the expression of MITF,118,119 with consequent effects upon melanocyte survival during development, is likely to account for the pigmentary defects of WS1. A role for PAX3 in governing the development of neural crest derivatives that contribute to bony and cartilaginous structures of the face,120 particularly those contributing to the formation of the frontal bone, explain the craniofacial anomalies observed in WS1. Sensorineural deafness, observed with incomplete penetrance in WS1, results from the variable failure of melanoblasts to migrate to or to survive in the stria vascularis in the lateral wall of the cochlea.121,122

11

Chapter 73

Figure 73-6  Waardenburg syndrome type 1. Note poliosis (white forelock) and dystopia canthorum (lateral displacement of the medial canthi of the eyes).

600193, 606662) identifed the MITF locus as a candidate locus for the disease gene. At least nine different of mutations have been found in the coding region of the MITF gene in WS2 families.107,123 However, MITF mutations account for only a minor portion (15%) of WS2 cases. A mutation in the transcription factor gene SLUG/SNAI2 has also been associated with WS2,124 as have heterozygous deletion mutations in SOX10,125 but mutations in other, as yet undefined genes are likely to be implicated in the future. WS2 is inherited in an autosomal dominant pattern. Since most of the known MITF mutations in WS2 compromise the HLHZip region, thereby interfering with dimerization of mutant MITF with wild-type MITF,126 the pigmentary developmental pathology in most cases of WS2 probably occurs through haploinsufficiency (reduced gene dosage, expression, or protein activity) rather than through dominant-negative effects.123 Tietz syndrome, described later, is likely to result from dominant-­ negative effects of mutant MITF. That mutations in MITF cause a subtype of WS is mechanistically attractive because of the crucial importance of MITF in melanocyte survival during development. An epistatic relationship exists between PAX3 and SOX10 and MITF in melanocyte development during embryogenesis. PAX3 and SOX10, as transcription factors, synergically transactivate MITF.33,34 Since mutations of PAX3 and SOX10 also cause auditory-pigmentary symptoms in other types of WS, it is likely that failure of MITF transactivation is the main determinant of pigment cell developmental dysfunction in these other subtypes as well. SLUG/SNAI2, as a transcriptional target of MITF,35 may act in the same pathway as an important downstream MITF effector in melanocytes whose activity is inhibited in SLUGassociated WS2. Although all types of WS have skin, hair, and iris pigmentation anomalies and the possibility of hearing loss, WS2 is notable for featuring only these auditorypigmentary symptoms. Diagnostic criteria for WS2 have previously been defined.116 Individuals fulfilling two of the following four criteria, in the absence of dystopia canthorum, limb deformity, or Hirschsprung disease, should be counted as affected: 1. Congenital sensorineural hearing loss 2. Pigmentary disturbance of iris a. Complete heterochromia irides (two eyes of

different color)

b. Partial or segmental heterochromia (segments of

blue or brown pigmentation in one or both eyes)

c. Hypoplastic blue irides (characteristic brilliant

blue, with thin iris stroma, in both eyes)

3. Pigmentary disturbance of the hair a. White forelock from birth or in teens b. Premature graying before age 30 years 4. A first- or second-degree relative with two or

more of criteria 1–3

A survey of 124 cases of WS2 and 270 cases of WS1 revealed differences of phenotypic penetrance between WS2 and WS1: congenital sensorineural hearing loss occurred in 77% and 57%, respectively; heterochromia irides in 48% and 27%, respectively; hypoplastic blue

789

11

eye in 9% and 17%, respectively; white forelock in 9% and 17%, respectively; early graying in 23% and 26%, respectively; and white skin patches in 6% and 31%, respectively. The higher incidence of hearing loss in WS2 may be due to the difficulty of diagnosing WS2 in individuals without hearing loss. The hearing loss is congenital, sensorineural, and nonprogressive, showing marked variation between and within families. Among 81 WS2 cases in one series, 84% of patients reported bilateral hearing loss; 40% of patients noted profound loss, whether unilateral or bilateral.117

Section 11 :: Disorders of Melanocytes

Waardenburg Syndrome Type 3. WS3 (OMIM #148820), also known as Klein–Waardenburg syndrome, is regarded as a variant of WS1. Most affected persons are heterozygous for a mutation in PAX3, although a few severely affected homozygotes have been described.109 No specific mutations in PAX3, with the possible exception of a missense mutation at Asp47, have been correlated with the WS3 phenotype rather than the WS1 phenotype, although individuals with either homozygous or compound heterozygous mutations in PAX3 may tend to exhibit a severe WS3 phenotype instead of WS1.127 In addition to the features of WS1, WS3 patients have musculoskeletal abnormalities, manifested as limb contractures and hypoplasia of the limb musculature. The WS3 phenotype is consistent with the previously described role of PAX3 in the activation of transcription factors that govern muscle and limb development,128 distinct from its role regulating development of neural crest derivatives. Waardenburg Syndrome Type 4. WS4 (OMIM #277580), also known as Shah–Waardenburg syndrome, is caused by heterozygous mutations in the transcription factor gene SOX10, or by homozygous mutations in the gene encoding the peptide ligand endothelin-3, EDN3, or its receptor, EDNRB.129 In addition to governing aspects of melanocyte development, these genes are important determinants of the development of the distal aspect of enteric nervous system cells, also neural crest derived, that innervate the distal part of the colon, which explains the association with Hirschsprung’s disease or congenital aganglionosis of the colon. WS4 is the combination of the WS1 phenotype with Hirschsprung’s disease. TIETZ SYNDROME. Tietz syndrome130 (OMIM #103500) is a hypopigmentation–deafness syndrome resulting, like WS2, from mutations in MITF. Tietz syndrome has been described in three families to date. In each case, the mutation is found in the region of the MITF gene encoding the DNA-binding domain. In two cases,131,132 an in-frame deletion mutation (DelR217) has been described, which affects the DNA-binding basic domain of MITF, leaving the dimerization HLHZip domain intact and functional. In these heterozygous Tietz syndrome individuals, it is likely that DelR217MITF binds with wild-type MITF and interferes with the ability of the dimer to bind to DNA, a dominantnegative effect. Indeed, the identical mutation in

790

mice133 causing a semidominant phenotype, a phenotype that is incomplete in the heterozygous state, in vivo with a mild heterozygous spotting phenotype, but a prominent homozygous phenotype with early embryonic loss of all melanocyte precursors,134 was shown to have a dominant-negative effect in vitro.126 In addition, another mutation described in the family originally reported with the syndrome is predicted to exhibit an Asn210Lys substitution in the basic region.135 The localization of this mutation to the DNA-binding region also suggests that it has dominant-negative effects. Although sometimes regarded as a variant of WS2A (MITF-associated WS2),136 Tietz syndrome individuals exhibit generalized cutaneous hypopigmentation similar to that found in OCA2, rather than distinct depigmented patches. Reduced melanosomes in keratinocytes found in one affected individual132 may account for the generalized hypopigmentation that is observed. Affected individuals invariably exhibit profound hearing loss. Interestingly, a child with a deletion on chromosome arm 3p encompassing the entire MITF locus not only exhibits generalized hypopigmentation reminiscent of Tietz syndrome but also mild craniofacial anomalies and retention of some hearing function, as can be seen in types of WS.137

PIEBALDISM. Piebaldism (OMIM #17280) is caused by mutations in the KIT proto-oncogene.138 Stimulation of the KIT receptor tyrosine kinase by its ligand, stem cell factor (SCF)/KIT ligand, results in the phosphorylation of MITF and potentiation of MITF activity.139 This relationship between the KIT receptor and MITF, as a final common effector of melanocyte survival during development, is likely to explain the developmental patchy loss of melanocytes occurring in human piebaldism when KIT receptor function is compromised. Patients with piebaldism generally have depigmented patches on the ventral or lateral trunk and/ or the mid-extremities, sparing the hands and feet. Poliosis is a common feature. The depigmented patches tend to be larger than those observed in WS. Typically, piebaldism is not associated with deafness, although piebaldism with deafness, otherwise referred to as Woolf syndrome, has been molecularly confirmed.140 DYSCHROMATOSIS SYMMETRICA HEREDI­ TARIA. Dyschromatosis symmetrica hereditaria

(DSH; OMIM #127400), an autosomal dominant condition, was recently shown to be caused by mutations in ADAR1, formerly known as DSRAD, encoding adenosine deaminase acting on RNA 1, an RNA-editing enzyme.141,142 It is not known how reduced activity of this enzyme results in pigmentary loss at acral sites. Patients exhibit speckled hypopigmentation, which is limited to the dorsa of the hands and feet.

COMPLICATIONS OF ALBINISM AND CONGENITAL DISORDERS OF PIGMENTATION

MANAGEMENT OF ALBINISM AND CONGENITAL DISORDERS OF PIGMENTATION All individuals with albinism should be under the care of an ophthalmologist and should have annual examinations until adult life. Most are hyperopic or myopic, and many have significant astigmatism; refractive correction aids in their visual attentiveness and performance. Proper dermatologic care and protection from UV radiation of the sun and care by a dermatologist are strongly advised for individuals with OCA. Precautions

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 9. Wei ML: Hermansky-Pudlak syndrome: A disease of protein trafficking and organelle function. Pigment Cell Res 19:19-42, 2006. doi:10.1111/j.1600-0749.2005.00289.x 18. Spritz RA et al: Detection of mutations in the tyrosinase gene in a patient with type IA oculocutaneous albinism. N Engl J Med 322:1724-1728, 1990 27. King RA et al: Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism. J Clin Invest 87:1046-1053, 1991 47. Brilliant MH: The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH. Pigment Cell Res 14:86-93, 2001 96. Introne W, Boissy RE, Gahl WA: Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab 68:283-303, 1999 117. Liu XZ, Newton VE, Read AP: Waardenburg syndrome type II: Phenotypic findings and diagnostic criteria. Am J Med Genet 55:95-100, 1995 123. Tassabehji M et al: The mutational spectrum in Waardenburg syndrome. Hum Mol Genet 4:2131-2137, 1995 136. Steingrimsson E, Copeland NG, Jenkins NA: Melanocytes and the microphthalmia transcription factor network. Annu Rev Genet 38:365-411, 2004 141. Miyamura Y et al: Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet 73:693-699, 2003

Albinism and Other Genetic Disorders of Pigmentation

With the exception of individuals with OCA1A, patients with OCA can realize gradual pigmentation of the skin and hair over the course of their lives, and develop melanocytic nevi. As long as the life-threatening aganglionic megacolon of WS4 is recognized at birth and corrected surgically, the prognosis of congenital disorders of pigmentation is favorable, with minor long-term health consequences. Spontaneous repigmentation of both the white forelock and white spots has been reported, as has contraction of the white spots.

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PROGNOSIS/CLINICAL COURSE OF ALBINISM AND CONGENITAL DISORDERS OF PIGMENTATION

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The complications of albinism revolve around the impact of the reduced visual acuity and hypopigmentation upon the affected individual. The primary medical complications are the early appearance of skin tumors in individuals with inadequate sun protection in equatorial climates. Delayed recognition and management of squamous cell carcinoma and melanoma in this setting can lead to metastasis and early death. The complications of congenital disorders of pigmentation are more likely to relate to their associated manifestations, such as deafness or aganglionic megacolon, than the pigmentary loss.

include the use of sunscreens, hats, and long sleeves, as well as sun avoidance. For HPS patients, topical control of bleeding can be achieved with thrombin and Gelfoam. In advance of dental procedures or biopsies, intravenous infusion of 1-desamino-8-d-arginine vasopressin can be used prophylactically.69 The accelerated phase of CHS is managed initially with multimodal immunomodulatory therapy and maintenance cyclosporine followed by allogeneic hematopoietic cell transplantation.143 No treatment has been reported for the pigmentary loss associated with congenital disorders of pigmentation. However, melanocyte grafting, either with epidermal grafts or epidermal cell suspensions as used for the treatment of stable vitiligo,144–146 might be an option to consider. Cochlear implants in the pediatric population with WS have led to positive outcomes.147 It is important to recognize the hearing defect early so that proper management, including proper social and mental development and schooling, can be implemented. Genetic counseling can help affected individuals assess their chances of transmitting the disorder to their progeny.

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Chapter 74 :: Vitiligo :: Stanca A. Birlea, Richard A. Spritz, & David A. Norris VITILIGO AT A GLANCE The most frequent depigmenting disorder, affecting 0.3%–0.5% of the population worldwide

Section 11

An acquired disease involving multiple genes and nongenetic environmental factors

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Characterized by progressive autoimmunemediated destruction of epidermal melanocytes

Disorders of Melanocytes

Typical presentation: patches of white skin and hair Cause of physiological and social stigma among affected individuals Increased risk for other autoimmune diseases, unpredictable evolution and unsatisfactory therapeutic outcomes

EPIDEMIOLOGY The prevalence of vitiligo is reasonably consistent among different populations: ∼0.38% in Caucasians,1 0.34% in Afro-Caribbeans,2 0.46% in Indians,3 though perhaps somewhat less frequent in Han Chinese, 0.093%.4 Vitiligo appears to affect both genders equally, though women are overrepresented among patients seeking clinical care. Vitiligo can develop at any age,5 with a mean age-of-onset in Caucasian patients of about 24 years.6 The most common subtype, generalized vitiligo (GV), is an autoimmune disease that is associated with other autoimmune diseases in about 20%–30% of patients, most frequently autoimmune thyroid disease (Hashimoto’s thyroiditis or Grave’s disease), rheumatoid arthritis, psoriasis, type 1 diabetes (usually adult-onset), pernicious anemia, systemic lupus erythematosus, and Addison’s disease.7

ETIOLOGY AND PATHOGENESIS

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Vitiligo is a multifactorial, polygenic disorder, with a complex pathogenesis that is not yet well understood.8 Of various theories of disease pathogenesis, the most accepted is that genetic and nongenetic factors interact to influence melanocyte function and survival, eventually leading to autoimmune destruction of melano-

cytes.7 Other suggested explanations have included defects of melanocyte adhesion,9 neurogenic damage,10 biochemical damage,11 autocytotoxicity,12 and others.

GENETICS OF VITILIGO Large-scale epidemiological surveys have shown that most cases of vitiligo occur sporadically, although about 15%–20% of patients have one or more affected first-degree relatives. Typically, familial aggregation of cases exhibits a non-Mendelian pattern suggestive of polygenic, multifactorial inheritance.8 Concordance in monozygotic twins is 23%,6 indicating that both genetic and nongenetic (presumably environmental) factors play major roles in disease pathogenesis. Almost all studies of vitiligo genetics have focused on GV. Several genes involved in immune function, including loci in the MHC, CTLA4, PTPN22, IL10, MBL2, and NALP1 (NLRP1), have been implicated in susceptibility to GV on the basis of genetic linkage or association studies.7 A recent, very large genomewide association (GWA) study of European Caucasian GV patients and families identified at least ten different loci that contribute to GV risk.13 Seven of these GV susceptibility loci have also been associated with other autoimmune diseases [(1) HLA class I, (2) HLA class II, (3) PTPN22, (4) LPP, (5) IL2RA, (6) UBASH3A, and (7) C1QTNF6], two loci encode proteins involved in immune function [(1) RERE and (2) GZMB], and another locus, TYR, encodes tyrosinase, a key enzyme of melanin biosynthesis and the major GV autoantigen. Segmental vitiligo (SV) appears to be genetically distinct from GV. Its generally sporadic occurrence and unilateral distribution have led to the suggestion that it might result from somatic mosaicism for de novo mutations,14,15 perhaps in genes that are critical for melanoblast/melanocyte development or survival, although this hypothesis remains to be confirmed.

AUTOIMMUNE HYPOTHESIS There is compelling biological evidence supporting an autoimmune basis for GV.16 GV is epidemiologically associated with a number of other autoimmune diseases,6,17 both in patients and in their close relatives, indicative of a heritable autoimmune diathesis. Humoral immunity was first implicated by the finding in some cases of circulating antimelanocyte autoantibodies18 that target various melanocyte antigens, including tyrosinase, tyrosinase-related protein-1, dopachrome tautomerase, and others, and that have the capability to kill melanocytes in vitro19 and in vivo.20 Currently, these autoantibodies are thought to reflect secondary humoral responses to melanocyte

Vitiligo

There is some evidence that vitiligo is a disease of the entire epidermis, possibly involving biochemical abnormalities of both melanocytes and keratinocytes.11 The specific morphological and functional abnormalities observed in vitiligo melanocytes and keratinocytes are thought to have a genetic background.11 Ultrastructural abnormalities of keratinocytes from perilesional vitiligo skin have been related to impaired mitochondrial activity,26 and are thought to affect the production of specific melanocyte growth factors and cytokines that regulate melanocyte survival.11 An essential biochemical finding is elevated levels of H2O2 in affected regions of epidermis,27 that may be caused in part by reduced enzymatic antioxidant capacity of keratinocytes and melanocytes.11,19 A defective antioxidant defense may confer melanocytes an increased susceptibility both to immunologic cytotoxicity and to cytotoxicity induced by reactive oxygen species.19

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BIOCHEMICAL HYPOTHESIS

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Chapter 74

destruction rather than a primary cause of GV.18 A greater role is attributed to the inflammatory infiltrate sometimes seen at the margins of active GV lesions, composed mainly of cytotoxic T lymphocytes. As these T cells express a type-1 cytokine profile and colocalize with epidermal melanocytes, it has been hypothesized that these cells are actively cytolytic toward remaining melanocytes, via the granzyme/perforin pathway.21 An immune mechanism has also been suggested to underlie chemical leukoderma.22 The so-called “occupational vitiligo” may occur in individuals who encounter large doses of phenolic compounds, usually 4-tertiary butyl phenol (4-TBP) and other phenolic compounds that may be contained in cleaning solutions. Occupational vitiligo usually initially involves the hands and forearms (the site of contact with the inciting agent). At present, it is unclear whether these agents are directly toxic to melanocytes, or whether some individuals might be genetically susceptible to melanocyte injury from aliphatic phenolic derivatives, ultimately resulting in melanocyte death, release of antigenic intracellular proteins, loss of tolerance, and autoimmunity. An immune mechanism has also been proposed for the vitiligo-like depigmentation, which can appear in the course of IL-2 immunotherapy-based treatments for cutaneous melanoma, possibly via the stimulatory effect of IL-2 on T cell growth and activation.23–25 Some melanoma-associated antigens (e.g., MART-1, gp100, and tyrosinase) are expressed on normal melanocytes, suggesting that the occurrence of treatmentrelated vitiligo-like depigmentation in melanoma may involve cross-reaction of some antimelanoma immune responses with normal melanocytes.

Figure 74-1  Vitiligo vulgaris in an adult. ­ orders. On the basis of the polymorphic distribution, b extension, and number of white patches, vitiligo is classified into generalized (vulgaris, acrofacial, mixed), universalis, and localized (focal, segmental, and mucosal) types.28 Vitiligo is also classified as segmental and nonsegmental types, on the basis of distinctive clinical features and natural histories.29 According to this classification, non-SV includes all cases not classified as segmental, including localized, generalized, and acrofacial.



Vitiligo vulgaris—multiple scattered lesions distributed in a more or less symmetrical pattern; the most common presentation of GV (Fig. 74-1). Acrofacial vitiligo—affects the distal end of fingers and facial orifices in a circumferential pattern; a subtype of GV (Fig. 74-2).

CLINICAL FEATURES The principal clinical manifestation of vitiligo is the appearance of acquired milk-white macules with fairly homogeneous depigmentation and well-defined

Figure 74-2  Acrofacial vitiligo.

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Figure 74-3  Vitiligo universalis.





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Mixed vitiligo—combination of acrofacial and vulgaris, or segmental and acrofacial types. Vitiligo universalis—complete or nearly complete depigmentation of the whole body (Fig. 74-3); the most severe form of GV. Focal vitiligo—characterized by the presence of one/few macule(s) in one area but not distributed in a segmental pattern (Fig. 74-4); considered a precursor form of GV. Mucosal vitiligo—a term reserved for depigmentation of mucous membrane alone. SV—characterized by macules having unilateral dermatomal distribution that do not cross the mid-

Figure 74-4  Focal vitiligo—unique macule of focal vitiligo.

Figure 74-5  Segmental vitiligo of the face and neck. line (Fig. 74-5). It generally affects young children and typically remains localized, the depigmented lesions persisting unchanged for many years.30 The occurrence of concomitant other autoimmune diseases is uncommon, compared with GV.29,31,32 Vitiligo often demonstrates a predilection for sunexposed regions, body folds, and periorificial areas, although any part of the body can be affected. Various precipitating factors have been suggested, including physical trauma to the skin, sunburn, psychological stress, inflammation, pregnancy, contraceptives, vitamin deficiency, and many others. However, at this time no specific environmental triggers have been proven. Vitiligo may appear at sites of skin trauma (Koebner’s phenomenon) (Fig. 74-6).

Figure 74-6  Koebnerization under brassiere.











Trichrome vitiligo is characterized by the presence of patches of intermediate hue (hypopigmentation) between the normal skin and the completely depigmented skin. Quadrichrome vitiligo is characterized by the presence of a fourth color (dark brown) at sites of perifollicular repigmentation. It is more often encountered in patients with darker skin phototypes. Pentachrome vitiligo—the occurrence of five shades of color: (1) white, (2) tan, (3) medium brown, (4) dark brown, and (5) black. Confetti vitiligo or vitiligo ponctué —tiny punctatelike depigmented macules on a hyperpigmented macule or on normal skin. Red vitiligo—the depigmented lesions have a raised erythematous border. Blue vitiligo—a blue–gray appearance of the skin, which corresponds histologically with the absence of epidermal melanocytes and presence of numerous dermal melanophages.

RELATED PHYSICAL FINDINGS COMORBID ASSOCIATIONS GV has been often associated with a variety of other conditions, principally autoimmune diseases.33 The

Vitiligo

SPECIFIC RARE CLINICAL PHENOTYPES

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Leukotrichia (depigmentation of hair within vitiligo macules (Fig. 74-7), can be quite variable (10%–60%), and is considered to indicate destruction of the melanocyte reservoir within the hair follicle, therefore, predicting a poor therapeutic response.28 Premature graying of the hair has been described in up to 37% of patients with vitiligo,28 although poor definition and quantitation of this feature makes this supposed clinical association uncertain.

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Figure 74-7  Leukotrichia. (Reprinted with permission from Falabella R: Vitiligo and the malanocyte reservoir. Indian J Dermatol 54(4):313-318, 2009.)

most prevalent associated autoimmune disease is autoimmune thyroid dysfunction, either hypothyroidism (Hashimoto’s thyroiditis) or hyperthyroidism (Grave’s disease). Other autoimmune diseases such as rheumatoid arthritis, psoriasis, type 1 diabetes mellitus (usually adult-onset), pernicious anemia, systemic lupus erythematosus, and Addison’s disease also occur with increased frequency in patients with GV.6,17 Most of these disorders, including GV, can occur in various combinations and constitute components of the APECED (APS1) and Schmidt (APS2) multiple autoimmune disease syndromes. Vitiligo can also be part of the Vogt–Koyanagi– Harada (VKH) syndrome, a multiorgan disorder that affects pigmented structures, such as the eye, inner ear, meninges, and skin.34 Several clinical and experimental studies have pointed to a role of cell-mediated immunity in VKH, particularly involving CD4+ T cells and Th1 cytokines.35,36 Another very rare multiorgan disorder, Alezzandrini syndrome, associates facial skin depigmentation, poliosis, deafness, and unilateral tapetoretinal degeneration of the eye.37 However, many investigators now believe that VKH and Alezzandrini’s syndrome are merely different clinical expressions of the same fundamental disease.38

DEPIGMENTATION OTHER THAN VITILIGO Skin depigmentation may occur in melanoma patients in three different clinical contexts39: partial depigmentation (“regression”) of the tumor, leukoderma acquisitum centrifugum around the tumor, and vitiligo-like depigmentation, occurring at distant sites. Vitiligolike depigmentation is thought to be a marker of the patient developing immunity against melanoma cells and to be an indicator of favorable prognosis, especially in advanced stages.25 The most common form of leukoderma acquisitum centrifugum appears around pigmented nevi (called halo nevi), and often progress to spontaneous disappearance of the nevus,39 presumably via lymphocytemediated destruction of nevus cells.

DIAGNOSIS The diagnosis of vitiligo is established principally on clinical grounds, which may include distribution and extent of lesions, and natural history of disease.40

LABORATORY. Given the association between vitiligo and other autoimmune diseases, several screening laboratory tests are helpful, including T4 and thyroid-stimulating hormone levels, antinuclear antibodies, and complete blood count. Clinicians should also consider testing for serum antithyroglobulin and antithyroid peroxidase antibodies, particularly when patients have signs and symptoms suggestive of ­thyroid disease.

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HISTOLOGY. A skin biopsy is rarely necessary to confirm the diagnosis of vitiligo. Generally, histology shows an epidermis devoid of melanocytes in lesional areas,41 and sometimes sparse dermal, perivascular, and perifollicular lymphocytic infiltrates at the margins of early vitiligo lesions and active lesions, consistent with cell-mediated immune processes destroying melanocytes in situ.42 Some reports42 have suggested

that melanocytes may never be completely absent from the depigmented epidermis and that residual melanocytes maintain the capability of recovering functionality. Further studies are needed to clarify this highly debated issue with obvious therapeutic implications. Differential diagnosis for vitiligo is presented in Box 74-1 and Box 74-2.43,44

Box 74-1  Differential Diagnoses for GENERALIZED VITILIGO Section 11 :: Disorders of Melanocytes

Condition

Distinguishing Features

Inherited hypomelanoses Piebaldism Waardenburg’s syndrome Tuberous sclerosis Ito’s hypomelanosis

Stable and circumscribed white patches (with absence of melanocytes) affecting anterior body and limbs; white forelock; autosomal dominant. White forelock, white skin macules, hypertelorism, deafness, ±Hirschsprung disease; multiple genes-autosomal dominant or recessive. Ash leaf hypopigmented macules, facial/periungual angiofibromas, shagreen patches; autosomal dominant. Linear distribution, unilateral or bilateral pattern of hypopigmented macules; sporadic; chromosomal or genetic mosaicism.

Infectious disorders Tinea versicolor Secondary syphilis Leprosy (tuberculoid/borderline forms)

Hypopigmented lesions, beginning as reddish macules with fine scales upon scraping and seborrheic distribution. At mycologic examination: hyphae and spores. Depigmented round/oval patches (postinflammatory depigmentation) around the neck (necklace of Venus), trunk, limbs, or depigmented patches with peripheral reticular hyperpigmentation (primary lesion). Serological tests for treponemal infection are positive. Depigmented patches with polymorphic presentation, usually accompanied by localized anesthesia; histology: compact skin granulomas.

Postinflammatory hypopigmentation Discoid lupus erythematosus, scleroderma, lichen sclerosis et atrophicus, psoriasis

Patients have history of preexisting dermatosis.

Paramalignant hypomelanoses Mycosis fungoides Cutaneous melanoma Autoimmune reactions to advanced melanoma

Hypomelanotic macules or diffuse depigmentation especially in darker skin phototypes. Flat skin patch, plaque, and tumors. Histology: epidermal infiltrates with mononuclear cells. Halo depigmentation around or within the tumor. Depigmentation at a distance from the tumor; the presence of tumor excludes typical vitiligo.

Idiopathic disorders Idiopathic guttate hypomelanosis Postinflammatory pigment loss

Hypopigmented well circumscribed macules, sharply defined and small in size. They are slow progressive and nonconfluent. Histology indicates epidermal atrophy and reduction in melanin content. Postburn hypopigmentary lesions, shaped in the form of the burn. Hypopigmenting inflammatory reactions leave ill-defined, poorly circumscribed lesions. The history of preceding eruption/injury excludes vitiligo.

Toxin-induced depigmentation Drug-induced depigmentation

Vitiligo-like depigmentation generally caused by topical occupational exposure to phenolic–catecholic derivatives, often affecting the hands and forearms. Caused by use of systemic drugs (chloroquine, fluphenazine, physostigmine, imatinib, or topical imiquimod).

From Taïeb A, Picardo M: Clinical practice. Vitiligo. N Engl J Med 360:160, 2009.

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Box 74-2  Differential Diagnoses for Localized Vitiligo NEVUS DEPIGMENTOSUS

NEVUS ANEMICUS

TREATMENT FUNDAMENTS OF VITILIGO THERAPY: MELANOCYTE REPOPULATION The key principle of vitiligo therapy is facilitating repopulation of depigmented patches of the interfollicular epidermis with active melanocytes that are able to migrate, survive to repopulate the depigmented skin, and carry out melanin biosynthesis.45 Repigmentation may occur spontaneously and may also be therapyinduced. Spontaneous repigmentation is unpredictable, often clinically insignificant, and tends to be cosmetically unacceptable.46,47 It occurs in fewer than 50% of patients, most commonly in younger patients and in sun-exposed areas, where natural sunlight may act as an inducing agent.48 In clinical practice, the most frequently encountered pattern of repigmentation is perifollicular (Fig. 74-8), though other patterns, such as marginal, diffuse, or combined also may occur. The principal source of melanocytes involved in repopulation of vitiligo skin is most likely melanocyte precursors derived from the outer root sheath (ORS) or bulge area of the hair follicle.49–51 A secondary potential reservoir may be located near lesional borders.

Vitiligo

The clinical course of any given case of GV is unpredictable, but is typically gradually progressive and difficult to control with therapy. Sometimes lesions spread over time, whereas in other cases disease activity stops, persisting in stable status for a long period. Some clinical parameters such as a long duration of the disease, occurrence of Koebner’s phenomenon, leukotrichia, and mucosal involvement have been suggested as indicators of relatively poor prognosis.28

The middle and lower parts of the ORS are populated by l-3,4-dihydroxyphenylalanine (DOPA)-negative, amelanotic melanocytes,49,50 which may be recruited from the ORS of the hair follicle in response to ultraviolet (UV), corticosteroids, or other stimuli. As a result, the number of melanocytes in the ORS of hair follicles increases significantly and some become active, suggesting that melanocyte precursors proliferate and at least some undergo maturation.50 Activated ORS melanocytes acquire all of the structural and enzymatic proteins required for melanogenesis, proliferation and maturation as they migrate up the hair follicle into the nearby epidermis, where they spread centrifugally and form perifollicular pigment islands. They then become larger cells, with intense DOPA oxidase activity. Vitiligo repigmentation is assessed in terms of the proportion of treated subjects in whom a specified degree of repigmentation is achieved; depending on the study, more than 50% or more than 75% repigmentation may be considered a good response.52 Wood’s lamp (UVA) examination is useful to monitor response to therapy. In the absence of epidermal melanin that otherwise absorbs most of the UVA light, more photons reach the dermis, where they are absorbed by collagen that then fluoresces and emits bright visible light. In contrast, visible wavelengths of ambient room light are less well absorbed by melanin in the normally pigmented epidermis than UVA wavelengths and do not produce fluorescence in the dermis. Hence, under Wood’s light the vitiligo area appears brighter and the normal skin appears darker than when illuminated with ambient room light (Fig. 74-9).

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CLINICAL COURSE AND PROGNOSIS

Figure 74-8  Follicular repigmentation in vitiligo after psoralen and ultraviolet A light therapy.

Chapter 74

Solitary hypopigmented macule well circumscribed with irregular borders, stable in size, solitary, most often present at birth. Hypochromic pale lesion with well-defined borders and irregular margins; often solitary, located on the trunk. Histology and electron microscopic examination reveal no abnormality in melanocytes or melanization.

THERAPEUTIC APPROACHES Different treatment strategies (Box 74-3) have been designed to inhibit the immune response in vitiligo, thereby reducing melanocyte destruction, and also enhancing epidermal repopulation by melanocytes, both by stimulating recovery of damaged melanocytes in situ and by reactivating residual melanocytes or stimulating melanocyte in-migration from neighboring skin or hair follicles. However, at present it is not clearly understood to what extent treatments must suppress the autoimmune process versus stimulate

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A

B

Figure 74-9  Wood’s lamp examination. Wood’s lamp provides bright reflection of white patches and enhanced details on intermediate pigment tones (A), as compared with white light (B). (Reprinted with permission from Taieb A, Picardo M: Vitiligo. NEJM 260:160-169, 2009.)

melanocyte repopulation of the epidermis to provide maximum efficacy. UV radiation therapy includes phototherapy with narrowband UVB (NB-UVB—311 nm) or broadband UVB (BB-UVB—290–320 nm), and photochemotherapy. UV therapy is thought to act as a skin immunomodulator, regulating the activity of inflammatory cytokines, depleting of Langerhans cells, modulating the activity of regulatory T cells, and polarizing the immune response toward the Th2 profile, thereby reducing or stabilizing the depigmentation process in vitiligo.45 In addition, UV radiation coordinates several of the pathways via which melanogenic cytokines stimulate melanogenesis.45 Furthermore, UV may also induce the release of epidermal factors that stimulate melanocyte proliferation and migration,

although this speculation has not been substantiated in repigmenting vitiligo lesions. The release of several paracrine factors produced by UV-exposed keratinocytes53 that regulate melanocyte functions is thought to be under p53 regulation,54 although further studies are needed.

ULTRAVIOLET B NARROWBAND Narrowband UV (NB-UVB) light, with peak emission at 311 nm, is considered the most effective and safest current therapy for vitiligo, and thus is currently the treatment of choice for patients with moderateto-severe GV. Recent studies evaluating psoralen and UVA (PUVA) versus NB-UVB indicate that NB-UVB

Box 74-3  Treatments for Vitiligo Topical

Physical

First line

Corticosteroids Calcineurin inhibitors

Ultraviolet B (narrowband) Systemic psoralen and ultraviolet A light (PUVA)

Second line

Calcipotriol

Topical PUVA Excimer laser

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Systemic

Surgical

Corticosteroids (pulse therapy)

Grafting Melanocyte transplant

CORTICOSTEROIDS TOPICAL CORTICOSTEROIDS Topical corticosteroids represent the first-line therapy for localized vitiligo, and are highly recommended for facial or small lesions and for use in children. Advantages include ease of application, high compliance rate, and low cost. Compared with PUVA, which promotes a predominantly perifollicular pattern of repigmentation, topical corticosteroids result in more diffuse repigmentation, which occurs more quickly

Vitiligo

Until recently, PUVA was considered the mainstay of therapy for patients with widespread vitiligo. PUVA consists of a combination of topical or oral 8-methoxypsoralen with UVA (320–400 nm) irradiation. The psoralen of choice, methoxsalen, is given in an oral dose of 0.4-mg/kg body weight, 1–2 hours prior to UVA exposure. For topical PUVA therapy, methoxsalen 0.1% is applied to areas of vitiligo 30–60 minutes before exposure to UV radiation. Topical PUVA is indicated in patients whose vitiligo involves less than 20% of the body surface area, and painful burns (phototoxicity reactions) are unfortunately difficult to avoid. Oral psoralens can be used for patients with more extensive involvement or in patients who do not respond to topical PUVA (see Chapter 237). After oral treatment, patients must wear UVA-blocking glasses, and it is also recommended they use broad-spectrum sunscreens and wear protective clothing. Patients with darker complexions tend to respond best to PUVA, possibly because they tolerate higher PUVA exposures.61 Potential side effects of PUVA therapy are discussed in Chapter 237. PUVA is not recommended for use in children under the age of 12 years owing to the long-term delayed risks of cataract formation and skin cancer.

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PHOTOCHEMOTHERAPY (PUVA)

but is less stable.62 Light and electron microscopy of skin biopsies from control and steroid-treated areas showed marked repopulation by functional melanocytes in the repigmented vitiliginous skin. In steroid repigmented areas melanocytes appeared dendritic and DOPA-positive, and unlike melanocytes in the pigment margins of untreated areas of vitiligo, contain many melanosomes of normal size and shape.63 The current trend, based on the results of a large meta-analysis that included randomized controlled trials of 29 patient series, is that class 3 and 4 corticosteroids are the most effective for treatment for localized vitiligo.52 Thus, localized lesions can be treated with a high-potency fluorinated corticosteroid (e.g., clobetasol propionate ointment, 0.05%) for 1–2 months. Treatment can be gradually tapered to a lower potency corticosteroid (e.g., hydrocortisone butyrate cream, 0.1%). Caution is necessary when using topical steroids on and around the eyelids, as their use can increase intraocular pressure and exacerbate glaucoma. Vitiligo recurrence after cessation of treatment and corticosteroid-induced side effects (i.e., skin atrophy, telangiectases, striae, and, rarely, contact dermatitis) are the limiting factors. Combination therapy (corticosteroids + UVB, corticosteroids + calcineurin inhibitors, corticosteroids + vitamin D analogs) may be beneficial in some cases, as two agents together may act synergistically on pigment restoration and on immune suppression, at lower individual doses, thus, potentially minimizing overall side effects.

Chapter 74

produces higher repigmentation rates and better color matching).55 NB-UVB has fewer short-term adverse reactions such as painful erythema and appears to have fewer long-term side effects such as epidermal thickening, atrophy, and photocarcinogenesis than PUVA.56 Several clinical studies have reported high rates (≥75%) of repigmentation in at least 40% of patients treated with NB-UVB.57–60 The most commonly used NB-UVB protocol43 involves twice-weekly administration of a fixed starting dose of 0.21 J/cm2, increasing the dose by 20% at each session until the minimal erythema dose (the lowest dose that results in visible erythema on depigmented skin at 24 hours) has been reached. Approximately 9 months of therapy are required to achieve maximal repigmentation; at least 3 months of treatment are warranted before the condition can be classified as nonresponsive. The most responsive sites are face, trunk, and limbs, and the least responsive sites are the hands and feet.

SYSTEMIC CORTICOSTEROIDS Systemic corticosteroids have been used in pulse therapy and for short periods to halt rapid spread of depigmentation in some cases of GV.61

CALCINEURIN INHIBITORS Calcineurin inhibitors can be effective in vitiligo therapy because of their capacity to restore the altered cytokine network. Tacrolimus has been shown to inhibit T cell activation by downregulating transcription of genes encoding proinflammatory cytokines IL-2, IL-3, IL-4, IL-5, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and granulocytemacrophage colony-stimulating factor (GM-CSF) in T cells.64 In addition, a direct effect of tacrolimus on melanocyte growth and migration during repigmentation has been reported.65 Topical calcineurin inhibitors (e.g., tacrolimus ointment 0.03%–0.1%, pimecrolimus ointment 1%) are generally preferred for treating localized vitiligo lesions of the face and neck,43 and seem to be more effective in combination with UV radiation delivered by high-fluency UVB devices.43 Although several reports have emphasized the advantages of calcineurin inhibitors (selective mode of action, absence of skin atrophy, and systemic absorption), additional studies of their effectiveness are needed, as well as more

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i­ nformation about possible risks of cutaneous and extracutaneous cancers.

TOPICAL VITAMIN D DERIVATIVES

Section 11 :: Disorders of Melanocytes

Vitamin D analogs—calcipotriol ointment (0.005%) and tacalcitol ointment (20 μg/g)—restore pigmentation in vitiligo by inducing skin immunosuppression, which halts the local autoimmune process, and via direct activation of melanocytic precursors and melanogenic pathways.66 Some studies report more efficient repigmentation when vitamin D analogs are used in combination therapy, probably because of more complex stimulation of the repopulation process, targeting both melanocyte growth (with corticotherapy or UV) and differentiation (with a vitamin D analog). Vitamin D derivatives are indicated for use in localized disease; benefits include lack of skin atrophy and their easy application. However, their role in vitiligo treatment remains controversial; whereas some studies have reported substantial benefit, others found vitamin D analogs ineffective.45

PSEUDOCATALASE Pseudocatalase has been used to reconstitute deficient activity of catalase in vitiligo epidermis, degrading excessive H2O2 and allowing recovery of enzyme activities in vitiligo skin.67 Pseudocatalase monotherapy or combination with NB-UVB has shown apparent efficacy in repigmentation and prevention of disease progression in uncontrolled trials,68,69 while in other studies showed no substantial benefit.70–72 Therefore, its effect in vitiligo needs further validation.

LASER THERAPY UV B narrowband excimer laser (XeCl) and monochromatic excimer light (MEL) are currently used for treatment of localized vitiligo. These are similar to classical NB-UVB treatments, with the advantage of fewer side effects because only one lesion is treated at a time. These treatments produce optimal aesthetic results, with minor contrast between normal and affected skin.56 The XeCl has laser-coherent emission of monochromatic rays, whereas the MEL device can generate and selectively deliver 308-nm UVB light. No data for cancer risk and other longterm side effects are available; therefore, caution is currently advised.73

SURGICAL TREATMENT

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Autologous skin grafts are an option for repigmentation only in patients with stable vitiligo that is refractory or only partially responsive to medical treatment, and in general limited in extent (less than 3% of body-surface area).43 The most frequent side effects

are infection, postinflammatory hyperpigmentation, unaesthetic repigmentation, cobblestoning, and scarring.55 UV-light therapy generally hastens and improves repigmentation when combined with surgical methods. Autologous skin graft approaches can be categorized into five principal groups.55 Of note, in the United States any procedure in which cells are manipulated (e.g., cultured) must be performed in a good manufacturing practices (GMP) facility.

NONCULTURED EPIDERMAL SUSPENSIONS This technique is performed by grafting noncultured suspensions containing both keratinocytes and melanocytes74,75 (eFigs. 74-9.1A and 74-9.1B in online edition); suspensions are obtained by 0.25% trypsin digestion of a thin piece of donor skin and are injected into blisters raised by liquid nitrogen freezing or seeded on recipient sites denuded by superficial dermabrasion. An advantage of this method is lack of scarring if recipient and donor sites are carefully manipulated.

THIN DERMAL–EPIDERMAL GRAFTS Grafts are harvested at a depth of 0.1–0.3 mm, placed directly on recipient abraded areas next to each other, and are secured with surgical dressings under mild pressure for 1 week. Repigmentation occurs during the following weeks. Good results have been reported on dorsal hands and fingers.76,77

MINIGRAFTING Minigrafting represents the most commonly used current surgical method for vitiligo repigmentation (eFigs. 74-9.2A and 74-9.2B in online edition). Multiple perforations are made on recipient sites using 1.0–1.2-mm punches 3–4 mm apart from each other. Next, minigrafts are harvested from the donor site using a similar punch and are transferred to recipient sites with fine forceps or a hypodermic needle.78 Repigmentation occurs around each minigraft up to 2–5 mm by coalescence of spreading pigment. Good results are achieved in patients with refractory lip leukoderma, although the risk of cobblestoning seems to be high.76,79 An advantage of this method is its simplicity.

EPIDERMAL GRAFTING Grafts are harvested at negative pressure using different custom-made suction devices, 55 the preferred donor sites being the inner aspect of the thigh and the flexor aspect of the forearm. 80 Recipient sites are prepared by removing the epidermis using liquid nitrogen freezing or superficial dermabrasion 81 or laser ablation. 55 Epidermal grafts have been successfully used for lip vitiligo. 82 The

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Chapter 74 :: Vitiligo

A

C

B

D

Figure 74-10  Treatment with MBEH. Response of disfiguring facial vitiligo to treatment with MBEH (A) before, (B) after 4 months, (C) after 6 months and (D) after 8 months.

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main advantage is the absence of scarring in donor and recipient sites.

IN VITRO-CULTURED EPIDERMIS WITH MELANOCYTES AND MELANOCYTE SUSPENSIONS55

Section 11

EPIDERMIS WITH MELANOCYTES. An epidermal suspension collected from a small donor skin sample is prepared by 0.25% trypsin digestion and seeded in culture flasks. After 3 weeks, epidermal sheets are harvested from the culture vessel and transplanted onto depigmented recipient sites previously denuded by liquid nitrogen freezing, superficial dermabrasion, lasers, or diatermo surgery. A hyaluronic artificial matrix for growing keratinocytes and melanocytes has also been used with ­success.83

:: Disorders of Melanocytes

MELANOCYTE

SUSPENSIONS.

In vitrocultured melanocyte suspensions are obtained in a similar manner using specific and defined cultured media such as Ham’s F12. During subculturing, pigment cells increase in number and may be transplanted onto denuded areas at a density of up to 100,000 melanocytes/cm2. The suspension spreads onto recipient areas and is covered for a week, providing a good cellular take.74,84 The large population of cells obtained from a small donor site represents a great advantage for treating extensive vitiligo areas in a single session.

MICROPIGMENTATION Micropigmentation is useful for vitiligo lesions on mucous and mucocutaneous areas. It is accomplished by tattooing inert pigment granules into the dermis within collagen bundles and extracellularly at a depth of 1–2 mm, delivered by multiple electrically driven needles. Combinations of white, yellow, black, red, and brown pigments are used.55

DEPIGMENTATION

802

Some adult patients with extensive vitiligo may elect to undergo depigmentation of residual pigmented patches on facial and exposed areas. Depigmentation is achieved using 20% monobenzyl ether of hydroquinone (MBEH; monobenzone), which induces melanocyte loss via necrotic death without activating the caspase cascade or DNA fragmentation.85 MBEH is first applied as a patch test for 48 hours to detect hypersensitivity. Subsequently, twice-daily applications for at least a year are followed by irreversible depigmentation86 (Figs. 74-10A–D). Sunlight protection of depigmented skin is essential to prevent nonmelanoma skin cancers.55 We propose a treatment algorithm for vitiligo, considering the therapeutic approaches presented above (Fig. 74-11).

Determine extent of involvement of vitiligo

If 50%

If no response Skin grafting or melanocyte transplantation

Depigmentation

Figure 74-11  Treatment algorithm for vitiligo.

CAMOUFLAGE, SUN PROTECTION, AND PSYCHOLOGICAL SUPPORT Use of cosmetic camouflage, on the face and other exposed areas, and clothing to conceal affected areas can improve the quality of life for patients with vitiligo. Modern camouflage dyes and creams are waterproof, and the wide range of color and shades available can enable patients to choose the most suitable ones for their own skin color (Figs. 74-12A and 74-12B). Tanning should be avoided since it enhances the contrast of vitiligo lesions with normally pigmented skin. Moreover, sunscreens are needed to prevent sunburn of depigmented unprotected skin. However, this is somewhat problematic, as moderate sun exposure (heliotherapy) in many cases can induce epidermal repopulation with melanocytes. As well, it has been suggested that skin friction due to repeated application of sunscreen might exacerbate the disease,43 although there is no evidence to support this hypothesis. Depigmented skin in vitiligo tends to show increased tolerance to UVB light over time (photoadaptation), with the extent of tolerance based in part on skin phototype, supposedly due to both pigmentary and nonpigmentary influences,87 although the specific mechanism remains unknown. Psychological support may be beneficial to some patients. Listening to patients’ complaints and concerns and providing reassurance with advice about possible treatments and capacity for improvement is usually helpful for patients. Consider psychiatric evaluation for patients with marked low self-esteem and depression.

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Chapter 74

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NONTRADITIONAL TREATMENTS A wide range of nontraditional treatments have been suggested for vitiligo, and some may be considered as alternative approaches for patients who either failed or are unsuitable for the above therapies. The most commonly used include vitamin and nutritional supplements, immunomodulators, human placental extracts, khellin, and topical and systemic phenylalanine, among many others. There is no convincing evidence that any of these nontraditional treatments is effective.

PREVENTION Patients, patient support groups, and purveyors of alternative medicines have developed extensive and diverse hypotheses regarding vitiligo causation and approaches to its prevention. At present, there is no compelling evidence that any approach to vitiligo prevention is effective. Moreover, there is currently no useful approach to identify individuals at high risk for developing vitiligo.

Vitiligo

Figure 74-12  Cosmetic camouflage. Focal vitiligo of chin before (A) and after (B) application of cosmetic camouflage.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 7. Spritz RA: The genetics of generalized vitiligo. Curr Dir Autoimmun 10:244, 2008 13. Jin Y et al: Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo. New Engl J Med 362(18):16861697, 2010 16. Ongenae K, Van Geel N, Naeyaert JM: Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res 16:90, 2003 21. Oyarbide-Valencia K et al: Therapeutic implications of autoimmune vitiligo T cells. Autoimmune Rev 5:486, 2006 28. Hann S-K, Nordlund JJ: Clinical features of generalized vitiligo. In: Vitiligo, edited by S-K Hann, JJ Nordlund. London, Blackwell Science, 2000, p. 35 43. Taïeb A, Picardo M: Clinical practice. Vitiligo. N Engl J Med 360:160, 2009 45. Birlea SA, Costin GE, Norris DA: New insights on therapy with vitamin D analogs targeting the intracellular pathways that control repigmentation in human vitiligo. Med Res Rev 29:514, 2009 55. Falabella R, Barona MI: Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res 22:42, 2009

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Chapter 75 :: Hypomelanoses and Hypermelanoses :: Hilde Lapeere, Barbara Boone, Sofie De Schepper, Evelien Verhaeghe, Mireille Van Gele, Katia Ongenae, Nanja Van Geel, Jo Lambert, & Lieve Brochez

Section 11

HYPOMELANOSES AND HYPERMELANOSES AT A GLANCE

:: Disorders of Melanocytes

Pigmentation disorders confront the clinician with a sometimes complex differential diagnosis, but can be approached logically as follows: Congenital or acquired Isolated or part of a syndrome Diffuse or circumscribed Epidermal or dermal With or without inflammation Altered skin pigmentation may be caused by the following factors: Increased or decreased melanin Abnormal melanin distribution Decreased hemoglobin Deposition of exogenous pigments

AN ALGORITHMIC APPROACH TO PIGMENTATION DISORDERS Pigmentation disorders of the skin can either be hypomelanotic, hypermelanotic, or may present with a pattern of mixed hypo- and hypermelanosis. The diagnosis of these disorders can be quite challenging. An algorithmic approach based on clinical features and history of pigmentary disorders is used throughout this chapter and serves as a guide for the clinician’ diagnosis and treatment (eFigs. 75-0.1 and 75-0.2 in online edition) (Table 75-1, eTable 75-1.1 in online edition).

804

HYPOMELANOSIS Generalized hypopigmentation, including the various defects, classified as “albinism” has been discussed in Chapters 73 and 74. Localized forms of hypomelanosis can be related to defects in melanocyte precursor migration and disordered pigment transfer between melanocytes and keratinocytes, and as a result of postinflammatory changes.

CONGENITAL HYPOMELANOSIS Some genetic disorders with reduced skin and hair pigmentation are caused by impaired melanocyte migration/differentiation or melanosome abnormalities.1 Piebaldism, Waardenburg syndrome, and Tietze syndrome, characterized by a localized absence of melanocytes resulting in “white-patch” patterns, belong to the first group whereas oculocutaneous albinism (OCA), Griscelli syndrome (GS), Elejalde syndrome (ES), Chédiak–Higashi syndrome (CHS), and Hermansky–Pudlak syndrome (HPS) belong to the second group. OCA, CHS, and HPS are discussed in Chapter 73; GS and ES are discussed here. They are rare autosomal recessive disorders with abnormal biogenesis or transport of “lysosome-related organelles” (a group of specialized cytoplasmic organelles including melanosomes, platelet dense bodies, and lymphocyte lytic granules).2 GS, ES, and CHS are termed “silvery hair syndromes” because hair of these patients has a particular silver–gray hue.3

GRISCELLI SYNDROME. Three types of GS [GS types I–III (GS1–3)] are known. The phenotype of the patients is characterized by various degrees of skin hypopigmentation and hair with a silvery shine (Fig. 75-1), usually lighter than in unaffected family members. Furthermore, neurological signs and symptoms and/or immunologic impairment with “accelerated phases” of uncontrolled lymphocyte and macrophage activation with lymphohistiocytic infiltration of the central nervous system (CNS) are associated.4 This lymphoproliferative syndrome is similar to that observed in, for example, virus-associated hemophagocytic syndrome.5 Briefly, patients with GS type I (GS1) are characterized by primary and severe neurological symptoms

11

TABLE 75-1

Differential Diagnosis and Management of Dermal Melanocytosis

Nevus of Ota

Nevus of Ito

Mongolian Spot

Nevus of Hori

Dermal Melanocyte Hamartoma

Congenital Often familial Asian, African, and Hispanic population with slight male predominance

Acquired Familial or sporadic Asian and female predominance

Congenital

Clinical presentation

B  lue to slate-gray mottled macular hyperpigmentation

B  lue to slate-gray mottled macular hyperpigmentation

U  niform blue to slate-gray macular hyperpigmentation

B  rown–blue progressing to slate-gray mottled macular hyperpigmentation

M  ottled hyperpigmentation with small blue–gray macules in a diffuse pigmented patch

Distribution

Trigeminal nerve

A  cromioclavicular nerve

L ower back and sacrum

E specially malar region of the cheek (also forehead, upper eyelids, temple)

D  ermatomal distribution

Histology

S pindle-shaped melanocytes diffusely throughout the dermal layers. Sometimes more band-like melanocytic proliferation and stromal fibrotic reaction.

S pindle-shaped melanocytes diffusely throughout the dermal layers. Sometimes more band-like melanocytic proliferation and stromal fibrotic reaction

S pindle-shaped melanocytes diffusely throughout the dermal layers

D  ermal melanocytes in the upper and middermis

D  ermal melanocytes in the upper two-thirds of the dermis (including subpapillary layer)

Therapy

Q-switched laser Cryotherapy Surgery

Q-switched laser Cryotherapy Surgery

U  sually spontaneous regression during childhood

Q  -switched laser in combination with bleaching cream and chemical peels

None

Associated features

R  are malignant transformation

N  o associated features of medical concern

P  ossible association with inborn errors of metabolism

N  o associated features of medical concern

None

occurring early in life or even at birth without signs of an accelerated phase. These symptoms can include seizures, spasticity, psychomotor retardation, peripheral facial palsy, hemiparesis, encephalopathy, and hypotonia. CNS disorder is pertinent and never regresses with time. Immunological and hematological manifestations are only observed in GS type II (GS2) and include: anemia, neutropenia, and lack of natural killer cell function, with development of an accelerated phase of the disease with fever, jaundice, hepatosplenomegaly, lymphadenopathy, pancytopenia, and generalized lymphohistiocytic infiltrates of various organs, including the CNS. Onset of the accelerated phase seems to be associated with viral or bacterial infections. When a remission occurs, recurrent accelerated phases with increasing severity will be observed. Neurological problems may also occur in GS2 patients and are related to lymphocyte infiltration of the CNS. Associated symptoms are, for example,

hyperreflexia, seizures, signs of intracranial hypertension (e.g., vomiting), hypertonia, nystagmus, and ataxia. Psychomotor development is normal at onset, and regression of CNS signs, at least in part, can be observed during remission, although some sequelae may be irreversible. Skin hypopigmentation and silvery-grey hair in Griscelli patients are not caused by deficient melanosome biogenesis but by impaired intramelanocytic melanosome transport. Murine models with autosomal recessive mutations on the dilute (d), ashen (ash), and leaden (ln) locus present a phenotype close to that of their human GS counterparts.6 These loci respectively encode three molecules, myosin Va, Rab27a, and melanophilin (Mlph) that act as a tripartite complex linking the melanosome to subcortical actin. When MYO5A (GS1), RAB27A (GS2), or MLPH (GS3) is mutated in human melanocytes, the tripartite complex fails to form and melanosomes can no longer be tethered near the plasma membrane for transfer to keratinocytes, leading to a pigmentary defect.7

Hypomelanoses and Hypermelanoses

Mostly congenital Sporadic (rare familial cases) Asian and female predominance

::

Mostly congenital Sporadic (rare familial cases) Asian and female predominance

Chapter 75

Epidemiology

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drome or immunological impairment associated with GS2.23,24 Certain patients with ES have clinical and histologic features suggestive of GS1, indicating that these are other cases of MYO5A mutations.25,26 Further work will be required to define the molecular basis of ES and to group all patients with these rare disorders correctly.

ACQUIRED LOCALIZED HYPOMELANOSIS

Section 11

Figure 75-1  A Griscelli patient with silvery gray eyebrows/ eyelashes.

:: Disorders of Melanocytes

The prognosis for patients with GS is generally bad. They usually die in the first or second decade of their life if accelerated phases are not treated adequately. As for GS2 therapy, allogeneic bone marrow transplantation has appeared to be successful in some cases, especially when carried out at an early age.8–11 Palliative therapy consists of suppressing the accelerated phases with immunosuppressive therapy (high-dose corticosteroids, cyclosporine) and chemotherapeutic agents (methotrexate, etoposide, cytosine arabinoside). For GS1 there is no therapy. Palliation consists of treating infections with antibiotics.12 The hematologic, immunologic, and neurologic findings in GS1–3 presumably relate to organelle transport difficulties in the respective organ systems.

ELEJALDE SYNDROME (OMIM #256710).

ES, also referred to as neuroectodermal melanolysosomal disease, is another autosomal recessive pigment mutation with silvery hair, pigment abnormalities, and severe CNS dysfunction21,22 similar to those of GS1. ES patients do not manifest the hemophagocytic syn-

A

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PITYRIASIS VERSICOLOR. (See Chapter 189). Pityriasis versicolor is characterized by slightly scaling macules that can either be hypopigmented, pink or salmon-colored, or hyperpigmented (Fig. 75-2); variants with red and black macules have also been described. The prevalence of pityriasis versicolor is very high in hot and humid climates. This superficial mycosis is caused by Malassezia species of which M. globosa, M. sympodialis, and M. Furfur are most frequently identified in lesional scales. M. Furfur cultures produce a wide range of fluorochromes and pigments that appear to lead to depigmentation, high resistance to ultraviolet (UV)-induced tanning, and lack of inflammation observed in pityriasis versicolor.27 In approximately one out of three patients, a yellow–green fluorescence is visible using Wood’s light. It should be differentiated from the nonscaling depigmented lesions of vitiligo that frequently affect hands and feet, whereas pityriasis versicolor is mainly located on the trunk. The slightly scaling patches of pityriasis alba (PA) usually occur on the face and limbs and are nonfluorescent. Many local and systemic antifungal preparations are effective but relapses often occur.28,29 PIGMENTARY DEMARCATION LINES. Originally described in Japanese patients as a line present on  upper and lower extremities corresponding to a ­border of transition between the more deeply pigmented skin of the outer (dorsal) surfaces and the lighter inner (ventral) surfaces, the concept of

B

Figure 75-2  Pityriasis versicolor. A. Typical macules are round, very well circumscribed, have fine scale, and are off-white to tan colored. Typical distribution involves the upper back and upper chest. Involvement of the lower arms and legs and of the face is unusual. B. Confluent macules create scalloped borders. This is a characteristic pattern of macules of pityriasis versicolor.

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territorial control by different homeobox genes during development.32

Hypomelanoses and Hypermelanoses

­ igmentary ­demarcation lines was expanded to p include five specific patterns, labeled A–E, with A: upper anterolateral arms, across pectoral area (Fig. 75-3), B: posteromedial portion of lower limb, C: vertical hypopigmented line in pre- and parasternal area, D: posteromedial area of spine, and E: bilateral aspect of chest, marking from midthird of clavicle to periareolar skin. In a population survey of black and white patients it was determined that these lines appeared in early childhood. They are present in the majority of female black adults, with types A and B being most prevalent. Seventy-five percent of black adult males had at least one type of pigmentary demarcation line, with type C the most prevalent. Fifteen percent of white female adults had at least one line, and 14% of black women saw type B lines appearing during pregnancy.30 The lines of pigmentation are often called Futcher’s lines in the United States. The pathogenesis of pigmentary demarcation lines is uncertain. Some authors believe that these lines coincide with lines of Blaschko and are secondary to a form of pigmentary mosaicism. Others suggest that there is no true genetic difference but hypothesize that the difference between cells on the dark, posterior side versus the light, anterior side are due to the normal function of genes, such as the agouti locus.31 According to some reports, pigmentary demarcation lines do not follow lines of Blaschko but have a pattern similar to lines of Voigt, which separate dermatomes arising from nonconsecutive dorsal roots. The difference in melanogenesis would be explained by a strict

::

Figure 75-3  Pigmentary demarcation line (Futcher line). These lines are often barely perceptible but common in darker skinned phototypes.

PITYRIASIS ALBA. PA is a common benign condition mainly affecting the head and neck region of preadolescent children. Although the disease is more noticed in darker skin types, there is no predilection for either sex or skin type. The etiology and pathogenesis remain poorly understood. PA is widely understood to represent mild atopic dermatitis. Unprotected sun exposure, frequent bathing, and hot baths are strongly related to the development of PA. Lower serum levels of copper, a cofactor for tyrosinase, could also play a role in the pathogenesis of this condition. PA may present as a pink patch with an elevated border, fading after several weeks into a paler spot covered with powdery white scale (Fig. 75-4). The lesions progress to nonscaly hypopigmented macules persisting for months or years. The three stages may occur simultaneously. Histologically, there is markedly reduced pigment in the epidermis of lesional skin, but no significant difference in melanocyte count was found between lesional and normal skin. Ultrastructurally, degenerative changes in melanocytes and a reduced number of melanosmes within keratinocytes were seen.33 Extensive PA often also involves the inferior torso in a symmetric pattern. The lack of a preceding inflammatory phase and spongiosis differentiate extensive PA from the classic form. This particular form of PA may overlap with progressive macular hypomelanosis (PMH), a condition mainly described in young female adults, characterized by relapsing hypopigmented, nonscaling patches involving the back, particularly after summer.34 Pigmenting PA is a variant associating classic PA with a superficial dermatophyte infection, almost always affecting the face. It is clinically characterized by a bluish hyperpigmentation, attributed to melanin deposits in the dermis surrounded by a hypopigmented scaly area. One-third of patients have concurrent classic PA. Differential diagnosis includes any localized form of hypopigmentation, especially inflammatory skin conditions associated with postinflammatory hypopigmentation, such as psoriasis, but also with fungal infection, nevus depigmentosus, nevus anemicus, tuberous sclerosis, mycosis fungoides (MF), or vitiligo.

Chapter 75

Figure 75-4  Pityriasis alba.

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The disease is self-limited and treatment is often not completely successful. Topical steroids and emollients are helpful. Topical tretinoin has also been used with success, but may be irritating. Extensive PA and pigmenting PA have also responded to UV therapy and oral antifungals, respectively. Supportive measures such as decreasing sun exposure, use of sunscreens, and reducing frequency and temperature of baths should be recommended. The pathogenesis of pigment loss is unclear.34–38

Section 11 :: Disorders of Melanocytes

SARCOIDOSIS. (See Chapter 152). Hypopigmentation is a rare manifestation of sarcoidosis. Hypopigmented macular lesions scattered over the trunk and extremities but also papular or nodular lesions may be present. The presence of noncaseating dermal granulomas, usually most evident in biopsies of indurated lesions, reinforce the diagnosis. A reduction in melanin content of the epidermis with preservation of melanocytes has been demonstrated. The pathogenesis of pigment loss is unclear.39–41 SCLERODERMA. (See Chapter 157). Hypopigmentation has been described as a pigmentary change in morphea (localized scleroderma) (Fig. 75-5) and scleroderma (progressive systemic sclerosis). Localized hypopigmentation and/or hyperpigmentation are seen in areas of localized sclerosis. Focal depigmentation with perifollicular hyperpigmentation (“salt and pepper pigmentation”) especially on upper trunk and extremities, mimicking vitiligo, is reported in up to 30% of patients with scleroderma. The coexistence of scleroderma/morphea and vitiligo has also been reported.42–44 LUPUS ERYTHEMATOSUS. (See Chapter 155). Pigment alterations are frequently seen in discoid lupus erythematosus. Hypopigmented patches result from interface dermatitis with destruction of

808

Figure 75-5  Morphea. Note the discrete hyperpigmentation in the area of localized sclerosis.

the ­epidermal basal layer containing melanocytes. “Burned out” lesions are atrophic and depigmented and may be surrounded by hyperpigmentation. Cutaneous depigmentation is also reported in systemic lupus erythematosus, usually localized to inflammatory skin lesions. Biopsy specimens in depigmented skin feature degeneration of the basal layer with epidermal atrophy, a variable number of melanocytes, and pigmentary incontinence in the superficial dermis. The mechanism of hypopigmentation in lupus is not known but could be postinflammatory or cicatricial. Vitiligo has also been reported in association with lupus erythematosus.45 A shared genetic predisposition may explain the association of these two autoimmune disorders.46

MYCOSIS FUNGOIDES. (See Chapter 146). MF, the most common type of cutaneous T-cell lymphoma, is clinically characterized by three cutaneous phases: (1) the patch phase, (2) the plaque phase, and (3) the tumor phase. Several pigmentary changes have been described in MF. In poikiloderma vasculare atrophicans, a variant of the patch stage, mottled pigmentation, atrophy and telangiectasia of the involved skin are observed. A mix of hyper- and hypopigmentation may remain after regression of the skin lesions following treatment. Hypopigmented MF is an uncommon variant of this lymphoma. It mainly develops before the fourth decade, predominantly in juvenile-onset cases and in dark-skinned individuals, without sex predilection. Irregular hypopigmented patches with variably distinct borders are preferentially located on trunk and extremities. Erythema, scaling, and infiltration may be present. A central area of normal pigmentation may be observed. These lesions may also be associated with the more typical lesions of the three cutaneous phases. The hypopigmentation develops without preceding skin changes and occasionally complete depigmentation is observed. Histopathologically, hypopigmented MF is characterized by minimal dermal involvement, lack of epidermal atrophy, and moderate to marked exocytosis. Pigment incontinence and decrease or absence of melanin may be observed. Infiltrating lymphocytes often have a T-suppressor cell CD8+ phenotype, but a CD4+ phenotype has also been reported. Electron microscopy may disclose degenerative changes in melanocytes. Melanocytes may be incompletely melanized or occasionally reduced in number. The number of melanosomes within keratinocytes is normal or decreased and melanin-containing macrophages can be observed in the papillary dermis. T-cell receptor gene rearrangement analysis may help to confirm the diagnosis but is often negative, as in early stage MF. The pathogenesis of hypopigmented MF is not clear. At least in cases showing a CD8+ phenotype, hypopigmentation could be due to the melanocytotoxic effect of nonneoplastic CD8+ lymphocytes, as hypothesized in vitiligo. Hypopigmented MF responds well to treatment, particularly psoralen and UVA light (PUVA) or

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­ arrowband UVB therapy. It has a relatively benign n course, although recurrences are common. Hypopigmented MF should be distinguished from other causes of diffuse hypopigmentation, especially vitiligo, tinea versicolor, PA, or postinflammatory hypopigmentation.47–51

INFECTIONS Treponematoses.

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Figure 75-6  Pinta. The hypomelanosis in pinta is a vitiligolike hypomelanosis that occurs later in the disease and is associated with deep blue to slate-gray areas of hyperpigmentation. depressed, hairless lesions occur that appear hypopigmented in black patients and erythematous in white patients.56

Hypomelanoses and Hypermelanoses

Onchocerciasis. (See Chapter 207). Several different skin manifestations can become apparent during the course of onchocerciasis. Onchocercal depigmentation or “leopard skin” is rarely associated with itch and is one of the most common skin manifestations of onchocerciasis. Hypopigmented patches with perifollicular spots of normally pigmented skin, typically occur symmetrically on the pretibial area of older people in endemic areas.53 (Fig. 75-7).

Chapter 75

(See Chapters 200 and 201). Nonvenereal treponematoses are currently endemic in parts of Central and South America, Africa, Asia, and the Pacific Islands and can be severely disfiguring. Depigmentation is seen in several stages of yaws, bejel, and pinta. When the primary lesion of yaws disappears, a typical depigmented and pitted scar remains. In the tertiary stage of bejel, gummatous nodules develop in the skin and in other organs. Most skin lesions regress, leaving depigmented, noncontracted scars. Pinta is the only treponematosis that only affects the skin and causes pigmentary abnormalities in the first, second, and third stages of the disease. The sentinel lesion of pinta may heal at the end of the primary stage, leaving a macular dyschromia. The secondary stage is characterized by the appearance of the so-called pintids, which are initially red but often turn brown, slate-blue, gray, or black. This stage can last several years, leading to a mix of depigmentation and hyperpigmented lesions. Generalized pigmentary abnormalities develop during the tertiary stage. A symmetrical pattern of vitiligo-like lesions and brown, gray or blue and black lesions is seen over bony prominences (Fig. 75-6).52

CHEMICAL AND PHARMACOLOGIC AGENTS.

The potential for chemicals to induce hypopigmentation was discovered in the first half of the twentieth century. Leukoderma was noticed in rubber workers exposed to

Post-kala-Azar Dermal Leishmaniasis (PKDL). (See Chapter 206). Post-kala-azar dermal

leishmaniasis develops in insufficiently treated kalaazar or visceral leishmaniasis, which is caused by Leishmani. donovani. Skin manifestations of PKDL are nodules and plaques, facial erythema, and hypopigmented macules. Nodules and plaques typically develop around the mouth and spread to the face, arms and chest, but the macules may occur more generalized over the whole body. Mild disease can resolve spontaneously, but severe forms require systemic treatment.54,55

Leprosy. (See Chapter 186). The presence of a hypopigmented lesion with reduced sensation is the hallmark of leprosy and is one of the diagnostic criteria (Fig. 75-8). Indeterminate leprosy, frequently the first manifestation of leprosy, is characterized by the presence of a few such lesions. Tuberculoid leprosy usually manifests as a limited number of well-defined,

Figure 75-7  Onchocerciasis.

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Section 11

scavengers. Finally, some agents act after melanin synthesis because they are responsible for tyrosinase degradation, inhibition of melanosome transfer, or acceleration of skin turnover, leading to depigmentation.59 MBEH was used as a lightening agent until its ability to cause total permanent and often confettilike depigmentation became apparent. It should be used only to produce total depigmentation in patients with diffuse vitiligo. A formulation with 20% MBEH is usually prescribed for that purpose. Hydroquinone is one of the most popular depigmenting substances and is frequently used for the treatment of melasma in concentrations between 2% and 5%. Concentrations higher than 5% incur a risk of permanent depigmentation. Adverse effects are irritation, postinflammatory pigmentation, and exogenous ochronosis.57,59–61

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PHYSICAL AGENTS. Heat, freezing, X-ray, ionizing radiation, UV irradiation, and laser light can cause hypopigmentation or permanent depigmentation by damaging melanocytes, leading to destruction or impaired function.62

Disorders of Melanocytes

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Figure 75-8  Leprosy. A characteristic off-white hypomelanotic and anesthetic macule.

the monobenzylether of hydroquinone (MBEH), a frequently used antioxidant in the rubber industry. Since then, depigmenting properties have been attributed to many chemicals and new therapeutic depigmenting agents have been developed.57 Occupational exposure to chemicals that have a destructive effect on melanocytes can result in chemical leukoderma. Agents such as para-tertiary butylphenol, para-tertiary butyl catechol, MBEH, and hydroquinone can cause permanent depigmentation. The depigmentation caused by chemicals is difficult to distinguish from idiopathic vitiligo. The former usually starts at the hands and forearms, presumptive sites of contact, but depigmentation at a distance is also possible (Fig. 75-9). Chemical leukoderma spreads by coalescence of small macules, whereas the sudden appearance of large patches with perifollicular sparing is more suggestive of vitiligo. Chemical leukoderma is very likely if several exposed workers develop depigmentation. However, not all exposed individuals develop leukoderma and it is hypothesized that the individual susceptibility is variable.57,58 Chemicals are also employed therapeutically or cosmetically to lighten skin color. There are three main mechanisms of action for bleaching agents. Some act before melanin is synthesized by inhibiting tyrosinase transcription and glycosylation. Other agents act during melanin synthesis by inhibiting enzymes such as tyrosinase or peroxidase or act as reducing agents or radical oxygen species

LICHEN SCLEROSUS. (See Chapter 65). Lichen sclerosus typically presents as a pruritic erythematous patch in the early stage, evolving to a depigmented atrophic plaque with porcelain white appearance. Mechanisms believed to play a role in this idiopathic leukoderma include decreased melanin production, blocked transfer of melanosomes to keratinocytes, and loss of melanocytes. MELANOMA-ASSOCIATED LEUKODERMA.

(See Chapter 124). Regression in a primary melanoma lesion typically causes a depigmented scar-like area within the lesion. Melanoma-associated hypo- or depigmentation, also known as leukoderma acquisitum centrifugum, can occur around the primary melanoma or metastases or at distant sites. The latter is often called vitiligo, although the resemblance is limited. Whereas vitiligo depigmentation is usually symmetric and spreads centripetally to the trunk, melanoma-associated hypo- or depigmentation tends to be extensive, patchy, and asymmetric. The lesions may be mottled (hypomelanotic) or milk white (amelanotic). In most cases, leukoderma appears simultaneously with the finding of metastases. Histologic examination of lesions shows a decrease or complete absence of melanocytes. Macromelanocytes with stubby dendrites can also be observed. Melanoma with associated leukoderma may be associated with a better survival rate than comparably advanced lesions without epidermal pigment loss. Strong evidence suggests that melanoma-associated leukoderma results from host immune reaction against the malignancy, involving humoral and cellular mechanisms. Both passive and active immunotherapeutic strategies used in the treatment of melanoma have been associated with leukoderma (Fig. 75-10).63,64

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Hypomelanoses and Hypermelanoses

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Figure 75-9  Chemical leukoderma. A. O-Syl (a phenolic disinfectant)-induced chemical leukoderma that mimics vitiligo clinically. Repeated exposure is required to depigment, but antecedent clinical inflammation is not observed. B. Reversible hypomelanosis of the face in a South African woman after several weeks’ application of topical hydroquinone. Note color contrast of face to that of (untreated) hand. C. African-American factory worker depigmented from repeated exposure to monobenzyl ether of hydroquinone.

B

Figure 75-10  Melanoma-associated leukoderma. A. This hypomelanosis may resemble vitiligo clinically and be characterized by an absence of melanocytes. It may be associated with a favorable prognosis. B. These macules in a different patient developed after the patient developed metastases to the skin. They surround the individual metastases.

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ACQUIRED DIFFUSE HYPOPIGMENTATION Nutritional disorders and endocrinopathies mainly cause hyperpigmentation. Diseases such as copper deficiency, vitamin B12 deficiency, kwashiorkor, Addison disease, hyperthyroidism, and diabetes can also be associated with hypopigmentation, but are discussed under Section “Hypermelanosis” because hyperpigmentation is their main feature.

Section 11 ::

HYPOTHYROIDISM. (See Chapter 151). Hypothyroidism is frequently associated with cutaneous alterations. The skin is pale due to anemia and vasoconstriction. Yellowish discoloration of the palms, soles, and nasolabial folds is caused by an accumulation of carotene in the stratum corneum. The associated hypercarotinemia results from reduced capacity of the liver to convert β-carotene to vitamin A. Vitiligo has been associated with autoimmune hypothyroidism.65–67

Disorders of Melanocytes

HYPOPITUITARISM. Panhypopituitarism results from a variety of conditions that compromise the anterior pituitary. As a consequence, release of pituitary-derived factors including melanocyte-stimulating hormone (MSH), thyroid-stimulation hormone, adrenocorticotrophic hormone, luteinizing hormone, follicle-stimulating hormone, growth hormone, and vasopressin is decreased. Due to the reduction of circulatory pituitary hormones, production of cortisol, thyroxine, estrogens, and testosterone in target organs is lowered. Patients suffering from panhypopituitarism look pale due to anemia and decreased cutaneous blood flow. As well, generalized hypopigmentation results from decreased adrenocorticotrophic and MSH that stimulate epidermal melanogenesis.66 HYPOGONADISM. Castrated human males are characteristically pale and their genital skin is not hyperpigmented as in normal men. An impaired tanning response to UV radiation has been described. Administration of testosterone makes the skin turn darker and restores the tanning response.68 SELENIUM DEFICIENCY. Loss of hair and skin pigmentation due to selenium deficiency has been described in children receiving long-term total parenteral nutrition. After selenium supplementation, skin and hair darken.69 COPPER DEFICIENCY. Acquired copper deficiency occurs in severely malnourished infants. Hypopigmentation of the hair is attributed to copper deficiency, presumably because tyrosinase is a copper-dependent enzyme, but as multiple nutritional deficiencies tend to coexist pathogenesis is difficult to confirm.70 IDIOPATHIC GUTTATE HYPOMELANOSIS.

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Idiopathic guttate hypomelanosis (IGH) is an acquired leukoderma, characterized by discrete, round, or oval porcelain-white macules of approximately 2–5-mm diameter, which increase in number with aging

Figure 75-11  Idiopathic guttate hypomelanosis. Lesions on the leg of an African-American individual. (Fig. 75-11). Any associated hairs often remain pigmented. Lesions are found in a photodistribution and tend to occur in chronically sun-damaged skin. They are often seen pretibially and on the forearms, although they may also arise on other sun-exposed areas, including the face, neck, and shoulders. IGH has been hypothesized to be UV-induced, although controversy exists. Some suggest that IGH may reflect the normal aging process.71 Histologically, IGH lesions are characterized by slight basket-weave hyperkeratosis with epidermal atrophy and flattening of the rete pegs. Lesions show a decrease in melanocytes and melanin content of the affected epidermis and pigment granules are irregularly distributed. A variety of therapies with variable success are described, including cryotherapy, superficial dermabrasion, topical steroids, and topical retinoids.72,73

LEUKODERMA PUNCTATA. Leukoderma punctata was first described by the development of multiple punctiform hypopigmented and achromic spots after several months of PUVA treatment.74 Later, similar cases were described after UVB therapy for psoriasis and after topical PUVA in one case of segmental vitiligo.75 Lesions are predominantly present on the extremities, upper back and chest. They are round or oval, sharply demarcated, and small (0.5–1.5 mm), without follicular distribution. Spontaneous reduction of the leukodermic lesions has been observed.74

It has been suggested that phototoxicity damage to keratinocytes and melanocytes is the etiologic factor. Leukoderma punctatum is suggested to be distinct from IGH on the basis of the clinical and histologic features. In IGH, lesions are larger and spontaneous resolution is not reported. Ultrastructurally, leukoderma punctata demonstrates slight-to-severe damage of keratinocytes and melanocytes not reported in IGH.

CANITIES.

PROGRESSIVE MACULAR HYPOMELANOSIS. PMH is an entity that affects the trunk with num-

mular, hypopigmented nonscaly macules. It affects young adults, mainly women. Although described in people of mixed racial ancestry (known as Creole dyschromia),80 it is seen in all races. It can be mistaken for PA and pityriasis versicolor. Topical and systemic antifungal treatment and topical steroids are ineffective, but the disorder may resolve, sometimes temporarily, after sun exposure or phototherapy.

ACQUIRED DIFFUSE HYPOPIGMENTATION WITH VASCULAR CAUSES ANEMIA. The color of the skin is determined by several chromophores, usually predominantly melanin pigment, but the hemoglobin content of the skin also contributes to the skin color. The pale skin color observed in anemia is due to decreased levels of circulating oxyhemoglobin and is proportional to the severity of the anemia.

WORONOFF’S RING. (See Chapter 18). Woronoff’s ring represents a blanched halo surrounding a psoriatic lesion. It is observed after UV treatment or topical steroid treatment, but may also occur in untreated psoriasis. The pathogenesis is not clear. A decreased melanin content has been found in both psoriatic and halo epidermis suggesting a true hypomelanosis. A local decreased prostaglandin synthesis with decreased vasodilatation or a diffusion of anti-inflammatory mediators from the psoriatic lesion to the halo is also postulated. CUTANEOUS EDEMA. Cutaneous edema produces an appearance of leukoderma that is not true hypomelanosis. Decreased absorption of light, reduced capillary blood flow, and increased dermal thickness may contribute to the pale appearance of the skin.

HYPERMELANOSIS CONGENITAL DIFFUSE HYPERMELANOSIS CONGENITAL DIFFUSE LINEAR HYPERMELANOSIS Linear and Whorled Nevoid Hypermelanosis. Linear and whorled nevoid hypermelano-

sis (LWNH) is characterized by hyperpigmented macules in streaky configuration along the lines of Blaschko without preceding inflammation or atrophy.89 Similar cases have been described under different descriptive names (zosteriform hyperpigmentation, zosteriform lentiginous nevus, zebra-like hyperpigmentation). Lesions are typically located on the trunk and limbs and do not cross the midline. Face, palms, soles, eyes, and mucous membranes are spared. ­Kalter et al described LWNH as having onset within a few weeks of age and progression during the initial years of life.89 The pigmentation can fade gradually with increasing age. Several cases have been reported with both hyper- and hypopigmentations. Pigmentary mosaicism is a useful term to encompass all these different phenotypes.90 The presence of mosaicism has been confirmed in a few cases (mosaic trisomy 7, 14, 18, 20, and X-chromosomal mosaicism) by chromosomal analysis on lymphatic cultures or dermal fibroblasts.91 LWNH may be differentiated from incontinentia pigmenti (IP) and epidermal nevus.89 Extracutaneous abnormalities have been observed in a number of LWNH cases, including developmental and growth retardation, facial and body asymmetry, ventricular septal defect, and pseudohermaphroditism.

Hypomelanoses and Hypermelanoses

Chronic hemodialysis patients frequently show disorders of skin pigmentation, primarily involving hyperpigmentation of sun-exposed body areas. Hypopigmentation of skin and hair is rather exceptional but occurs, possibly due to a disturbance of phenylalanine metabolism.

ently hypopigmented areas, usually on arms and legs in young adults, resulting in a reticulated appearance. The surrounding skin is erythematous and blanches with pressure causing the “hypopigmented” macules to disappear. The condition is a vascular anomaly with vasoconstriction in the pale areas and venodilatation in erythematous skin.81,82

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HEMODIALYSIS.

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Chapter 75

Hair graying or canities is a process of chronological aging and occurs regardless of gender or race.76 The age of onset, which appears to be hereditary, is usually in the fourth decade. The average age for whites is mid-30s, for Asians late 30s, and for Africans mid-40s. Premature canities (before 20s or 30s) can be associated with pernicious anemia, hyper/hypothyroidism, osteopenia, and several rare syndromes like progeria and pangeria (Werner syndrome). Graying usually appears at the temples first, then the vertex, and, finally, the occiput. Beard and body hair are affected later. Gray hairs seem to be thicker and longer than normally pigmented hairs. The perception of “gray hair” derives in large part from the admixture of pigmented and white hair, but individual hair follicles can indeed exhibit pigment dilution or suboptimal melanocyte–cortical keratinocyte interactions during the graying process.77–79 An acute episode of alopecia areata may result in a very sudden “overnight” graying (so-called canities subita) that is caused by the preferential loss of pigmented hair in this immunemediated disorder.

BIER SPOTS. Bier spots are small, irregular appar-

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Histologic examination reveals increased pigmentation of the basal layer and prominence or vacuolization of melanocytes. Pigment incontinence is usually but not always absent.92

Incontinentia Pigmenti.

Section 11 :: Disorders of Melanocytes

IP, also known as Bloch–Sulzberger syndrome, was first described by Garrod et al in 1906. It is an X-linked, dominantly inherited disorder, reported primarily in females, and believed to be embryonic lethal in the majority of males. In most cases, IP is due to a mutation in the gene NEMO [nuclear factor κB (NF-κB) essential modulator] on the X chromosome at Xq28.93–96 In IP females, inactivation of one of the two X chromosomes through a process termed lyonization occurs during embryogenesis. Epidermal cells expressing the defective NEMO gene give rise to typical skin lesions along the lines of Blaschko, reflecting the embryonic migration path of the affected keratinocytes. Lesions usually proceed through four cutaneous stages, sometimes with some overlap: (1) vesicular stage (from birth or shortly thereafter), (2) verrucous stage (between 2 and 8 weeks of age), (3) hyperpigmented stage (several months of age into adulthood), followed by (4) hypopigmentation stage (from infancy through adulthood) (Fig. 75-12). A significant percentage of IP patients have ocular, dental, skeletal, and CNS anomalies.97 The cutaneous lesions in the first stage represent the population of NEMO-deficient cells that fail to activate NF-κB, leading to apoptosis, as NF-κB normally protects against tumor necrosis factor-induced apoptosis.

A

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The number of NEMO-deficient cells decreases secondary to apoptosis and is replaced by cells expressing the normal allele. Subsequently, the inflammatory and vesicular stage ends. The hyperproliferation in the second stage is likely due to compensatory proliferation of normal NEMO keratinocytes. Hyperpigmentation in the third stage results from incontinence of melanin pigment from the destroyed epidermis into the dermis. The hyperpigmentation appears in streaks and whorls along the lines of Blaschko and is usually most pronounced on the trunk, but can also appear on the extremities. The degree of hyperpigmentation varies among individuals. Histologically, the areas of pigmentation show many melanin-laden melanophages, extensive deposits of melanin in the basal cell layer and dermis. There is vacuolization and degeneration in the epidermal basal cell layer. Usually, the hyperpigmentation fades gradually after several years and the skin can become hypopigmented (stage 4), which represents postinflammatory dermal scarring. The hypopigmentation stage is characterized by linear, atrophic, hairless scars following the Blaschko’s lines. Histologically, the number of melanocytes seems to be normal, although a reduced number of melanocytes also has been reported. The epidermis is thinner and there is an absence or reduction of skin appendages in the dermis that may contribute to the impression of hypopigmentation.98 A beneficial effect of topical steroids and topical tacrolimus in the vesicular stage has been described.99,100

B

Figure 75-12  Incontinentia pigmenti in a mother and her baby. A. Verrucous lesions in a 2-week-old baby. B. Hypopigmented atrophic lesions following the Blaschko’s lines.

CONGENITAL DIFFUSE RETICULAR HYPERMELANOSIS Dyskeratosis Congenita. Dyskeratosis

melanocytic proliferations are characterized by the

ophthalmomaxillaris) was first described by Ota in 1939.112 It is characterized by blue–black or gray–brown dermal melanocytic pigmentation and typically occurs in areas innervated by the first and second branches of the trigeminal nerve. Mucosal pigmentation may occur involving conjunctiva, sclera, and tympanic membrane (oculodermal melanocytosis), (Fig. 75-13) or other sites. It is most frequently seen in the Asian population, has a female predominance, and is usually congenital, although appearance in early childhood or at puberty has been described. Nevus of Ota is now subclassified as mild (type 1), moderate (type 2), intensive (type 3), and bilateral (type 4). Bilateral cases should be differentiated from Hori nevus, which is acquired, does not manifest mucosal involvement and is less pigmented (see Table 75-1).113 Malignant melanoma may rarely develop in a nevus of Ota. This necessitates careful follow-up of the lesion, especially if it occurs in Caucasian patients, in whom malignant degeneration seems to be more frequent. Malignant melanocytic tumors in association with nevus of Ota have been shown to arise in the chorioidea, brain, orbit, iris, ciliary body, and optic nerve.114,115 In addition, association with ipsilateral glaucoma and intracranial melanocytosis has been described.116

Nevus of Ito. Nevus of Ito is a congenital dermal melanocytosis first described by Ito in 1954 as nevus fuscocaeruleus acromiodeltoideus.117 It can be considered as a variant of nevus of Ota but with involvement of the acromioclavicular and deltoideal region. Clinical, demographical, and histological characteristics are similar to nevus of Ota and both lesions can occur simultaneously (see Table 75-1).

Hypomelanoses and Hypermelanoses

CONGENITAL CIRCUMSCRIBED HYPERMELANOSIS WITH DERMAL MELANOCYTOSIS. Dermal melanocytoses or dermal dendritic

Nevus of Ota. Ota’s nevus (nevus fuscocaeruleus

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CONGENITAL CIRCUMSCRIBED HYPERMELANOSIS

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Chapter 75

congenital (DKC) or Zinnser–Engmann–Cole syndrome is characterized by reticulate skin pigmentation, nail atrophy, leukoplakia, and bone marrow failure. Bone marrow failure and malignancy develop in the second and third decades. In all characterized cases of DKC, the causative mutations are present in components of the telomerase complex. Rapidly dividing somatic cells express low but detectable levels of telomerase activity that slows the otherwise progressive telomere shortening that occurs with each cycle of DNA replication and eventually leads to cellular senescence (permanent loss of proliferative capacity). It is now thought that DKC is due to defective telomere maintenance, limiting the proliferative capacity of hematopoietic and epithelial cells. Increased melanin synthesis is now recognized to occur in senescent melanocytes, likely accounting for the pigmentary phenotype of DKC; and critically short telomeres may force cells into “replicative crisis,” at which time activation of an alternative “ALT” mechanism for lengthening telomeres in the absence of telomerase may lead to development of malignancies. The finding of shortened telomeres in DKC was indeed the first evidence of the role of telomeres in cell biology (cellular aging).101 X-linked DKC is caused by mutations in the DKC1 gene located at Xq28, encoding for dyskerin. Females carrying one mutated allele are protected by expression of normal telomerase on the unaffected allele. In autosomal dominant DKC the majority of cases are due to mutations in TERC, the RNA component of the telomerase complex. TERT (telomerase reverse transcriptase) is affected much less often in autosomal dominant DKC. The autosomal dominant form has the better prognosis, presumably because some telomerase activity is preserved, due to the presence of an unaffected allele. In the autosomal recessive form of DKC, mutations in telomerase-associated proteins such as NOP10, NHP2, and TINF2 are involved.102–104 Skin biopsy of hyperpigmented skin shows nonspecific changes, including epidermal atrophy, a chronic inflammatory infiltrate with numerous melanophages in the upper dermis. DKC may be confused with Fanconi’s syndrome, characterized by short stature, hypoplastic or aplastic thumbs, and a reduced number of carpal bones. Here, there is a patchy hyperpigmentation of the trunk, neck, groin, and axillary region that manifests itself earlier than in DKC, i.e., in the first few years of life. For a discussion of Naegeli–Franceschetti–Jadassohn syndrome, dermatopathia pigmentosa reticularis, Dowling–Degos disease, Galli–Galli disease, Kitamura reticular acropigmentation, Haber’s syndrome, and Partington syndrome, see online edition.

presence of melanin-producing dendritic melanocytes in the dermis. They include the nevus of Ito, nevus of Ota, and Mongolian spot and dermal melanocyte hamartoma (Table 75-1). Associated vascular malformation has been described in phakomatosis pigmentovascularis (Port-wine stain type, Klippel–Trenaunay or Sturge–Weber syndrome).111

Mongolian Spots. Mongolian spots are congenital,

benign hyperpigmentations preferentially occurring in the African, Asian, and Hispanic population and only rarely seen in Caucasians.118 They occur in both sexes but with a slight male predominance,119 usually in the sacral area. (Fig. 75-14) They can also be found in the gluteal and lumbar region and on the thorax, abdomen, arms, legs, and shoulders. In most cases Mongolian spots spontaneously regress during childhood, but persistence into adulthood has been described.120 Histologically, these macules consist of spindle-shaped melanocytes in the lower dermis that have failed to migrate to the dermal–epidermal junction during fetal life. Several cases are described with extensive Mongolian spots involving large areas of the trunk and extremities, associated with inborn errors of metabolism such as GM1 gangliosidosis and mucopolysaccharidosis.121,122 Laser treatment in childhood or adolescence can give favorable results with sacral Mongolians spots being more laser-resistant than extrasacral ones.

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:: Disorders of Melanocytes

Figure 75-13  Nevus of Ota in a 20-year-old woman. A. Hyperpigmentation around the orbita. B. The hyperpigmentation extends into the sclera.

Dermal Melanocyte Hamartoma.

Dermal melanocyte hamartoma is a distinctive form of congenital dermal melanocytosis first described by Burkhart et al in 1981.123 Gray–blue pigmentation, caused by melanocytes residing in the dermis, occurs in a dermatomal pattern.

CONGENITAL CIRCUMSCRIBED HYPERMELANOSIS WITH LENTIGINOSIS Familial Lentiginosis Syndromes. Familial

lentiginosis syndromes are characterized by the presence of lentigine-circumscribed brown macules (usually 90% of darkskinned individuals mainly because the whiteness of the lesion shows up more clearly on pigmented mucosa.54,64 834

Clinical Findings. Lesions are usually bilateral on the buccal mucosa or ventral tongue and consist of painless, fine grayish white, opalescent reticulations. They

are not well demarcated, but diffuse. Stretching the mucosa completely eliminates these fine lines since this is not a keratotic lesion, but rather caused by intracellular edema of damaged superficial keratinocytes.21 Differential Diagnosis and Laboratory Findings. Reticular LP may look similar but they are more densely white and do not disappear on stretching the mucosa. A biopsy shows typical findings of keratinocyte edema or hydropic degeneration. Management and Prognosis. No treatment is necessary since these lesions are benign although advice on smoking cessation may be warranted.

Contact Desquamation. This is a common oral condition, where the injury to the tissue is slightly more severe than in leukoedema causing actual degeneration and detachment of the superficial keratinocytes. The offending agents are mouthwashes and toothpastes that are caustic [in particular Listerine (Pfizer Pharmaceutical, NY) mouthwash that contains 27% alcohol as well as eucalyptol and menthol]. Clinical Findings. This is generally a condition of adults. Patients will often report that their mouth is “peeling.” Lesions present as painless sloughs of desquamated tissue that lie in thin ribbons on the mucosa and can be removed without pain or discomfort to the patient, with normal-appearing, pink underlying tissue.65 Since the keratinized tissues are somewhat protected from the adverse effects of such topical agents, it is generally the nonkeratinized tissues that are involved. A helpful sign is a background of leukoedema with faint reticulations. Differential Diagnosis and Laboratory Studies. While some bullosing disorders may form such sloughs, those lesions are almost always painful or sensitive, and may bleed. Lack of symptoms is key to the diagnosis of this condition coupled with the typical history. A biopsy shows desquamating strips of surface keratinocytes. Management and Prognosis. Patients should discontinue the use of the offending dentrifrice, or change to a less caustic agent.

Morsicatio Mucosae Oris (Pathominia Mucosae Oris, Chronic Bite Injury). This

is a yet more intense local factitial injury to the oral mucosa, caused by a chewing habit, leading to reactive keratosis and benign epithelial hyperplasia. It occurs in 3% of the population.66 Any other factitial injury either from an unusual habit, or the rough edge of an appliance may lead to a similar lesion.

Clinical Findings. MMO appears as white papules and plaques on either side of the linea alba on the buccal mucosa, lower labial mucosa, or the lateral tongue, usually caused by raking of the teeth over the mucosa67 Patients may or may not be aware of this habit (especially if this is a nighttime habit). Lesions have a shaggy, rough surface, are poorly demarcated, and

A biopsy shows typical features of lichen simplex chronicus. BARK is closely related to MMO (described above), another frictional keratosis. It is possible that BARK being located on the keratinized mucosa that is closer in histology to the skin, takes on the more typical histologic characteristics of lichen simplex chronicus (LSC).

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Management and Prognosis. No treatment is necessary once the histopathologic diagnosis has been established. If a denture is the source of frictional irritation, this should be adjusted accordingly.

Management and Prognosis. No further management is necessary. These lesions are benign and have no malignant potential. The use of night guards or appliances to break the habit has not been shown to be ­helpful.

Benign Alveolar Ridge Keratosis (BARK, Oral Lichen Simplex Chronicus). BARK is

a very common condition that was recently defined histologically. It occurs primarily on the keratinized mucosa of the gingiva and hard palate as a reaction to frictional trauma. It is the oral equivalent of lichen simplex chronicus. Clinical Findings. BARK presents as poorly demarcated, painless white papules and plaques, often with a rough surface, usually less than 1 cm in greatest dimension (eFig. 76-5.4 in online edition). The most common location is the retromolar pad (at the site of previously extracted wisdom teeth) and other areas where teeth have been extracted.68,69 It is not necessary for the opposing teeth to contact the mucosa, since crushing of food against the alveolar ridge that had been previously protected by a tooth is sufficient. Differential Diagnosis and Laboratory Studies. Leukoplakia, especially verrucous leukoplakia is a very important differential diagnosis and a biopsy should always be performed if the lesion shows signs of sharp demarcation or is extensive. More worrisome, verrucous leukoplakia, a dysplastic lesion, also has a rough surface and is usually greater than 1 cm.

Differential Diagnosis and Laboratory Studies. Leukoplakia and candidiasis of the palate

may both mimic nicotine stomatitis. A biopsy shows hyperkeratosis with benign epithelial changes and importantly, inflammation of excretory salivary ducts that exhibit squamous metaplasia. This diagnosis is difficult if the ducts are not included in the biopsy specimen.

Biology and Pathology of the Oral Cavity

Differential Diagnosis and Laboratory Studies. Candidiasis, some lesions of LP, hairy leukoplakia, and some leukoplakias and erythroleukoplakias may look similar but a biopsy will provide a definitive diagnosis. Such factitial injury may be superimposed upon an underlying condition such as dysplasia or LP, making the diagnosis even more challenging. A biopsy shows varying degrees of parakeratosis with impetiginization and benign epithelial hyperplasia.

Clinical Findings. The palate of adult patients is the site most often affected. It is diffusely white with red, punctuate areas representing the openings of salivary ducts. It is usually not a painful lesion although severe cases may be sensitive to hot and spicy foods, and lesions are usually symmetric and diffuse.21,54

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occasionally may show evidence of erythema and/or ulceration where the “chewing” has been more intense (eFig. 76-5.3A and 76-5.3B in online edition).

Chapter 76

Figure 76-5  Primary herpes simplex virus (HSV) gingivostomatitis with involvement of gingiva and left upper labial mucosa.

Nicotinic Stomatitis. Nicotinic stomatitis is not caused by nicotine as its name suggests but rather by heat, usually from pipe smoking. A similar condition may be seen in patients who reverse smoke, that is, hold the lighted end of the cigarette in the mouth, as is the habit in some South Indian and Southeast Asian populations. It has also been noted in patients who habitually drink very hot beverages.

Management and Prognosis. Lesions may resolve if the habit is discontinued. The risk for malignant transformation has not been well documented. However, the development of raised, indurated areas should raise suspicion for malignant transformation.

Smokeless Tobacco Keratosis. This is a lesion

that results from a combination of direct contact toxicity of the smokeless tobacco on the mucosa (early lesions), and from effects of carcinogens within the snuff, namely tobacco-associated nitrosamines (late lesions that represent true leukoplakias). Not all smokeless tobaccos are alike. Snuff may be moist or dry and in general moist Swedish snuff (“snus”) is lower in nitrosamines than moist and dry snuff from the United States.70 Toombak, snuff from Ethiopia, has the highest levels of nitrosamines of all.71 In many Asian countries, snuff and smokeless tobacco is mixed with other substances such as spices and importantly areca nut, which contains another potent carcinogen, the alkaloid arecoline.72 Over the last 10–15 years, there has been increased interest in using smokeless tobacco as a risk reduction measure in subjects who have difficulty discontinuing cigarette smoking because the risk of developing cancer (oral and other cancers) is reduced.73,74

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Section 12 :: Disorders of the Oral and Genital Integument

836

Clinical Findings. The lesions are located where the snuff is placed, usually the mandibular sulcus/vestibule, between the teeth and the buccal mucosa. The area looks grayish white, opalescent, and wrinkled, often with fissures.21,54 Lesions are generally painless and poorly demarcated (eFig. 76-5.5 in online edition). Differential Diagnosis and Laboratory Studies. The diagnosis includes leukoplakia, candidiasis, and BARK. Aspirin is much more caustic and causes necrosis and ulceration, rather than this delicate white lesion. Biopsy reveals thin parakeratosis, intracellular edema, and devitalization of superficial keratinocytes. Any other agent that is locally irritating and slightly caustic may cause this clinical appearance. Management and Prognosis. Most early lesions are primarily caused by contact injury and are reversible if the habit is discontinued. However, the development of a dense white plaque or erythema may signal transformation to malignancy and these areas should be biopsied. The rate of malignant transformation is only 1%–2% compared with cigarette smoking.

INFECTIOUS LESIONS Candidiasis. Fungal infections are extremely com-

mon in the oral cavity and the most common causative agent is Candida albicans. Approximately 20%–30% of the population are carriers. In immumnocompromised

hosts, other species such as C. tropicalis, C. dubliniensis, C. glabrata, and C. kruseii should also be considered, as some of these may be resistant to conventional therapy. Predisposing factors include hyposalivation (see Section “Xerostomia” and “Hyposalivation” in online edition), immunocompromise, topical steroid therapy (for treatment of oral lesions or as inhalers), and antibiotic therapy. Clinical Findings. Oral candidiasis may present in various forms (Table 76-4) (Figs. 76-6A–76-6E).1,21 Lesions are almost always painful and dentures act as fomites.75 Although C. albicans is the most common pathogen in denture-associated candidiasis, C. glabrata is found in 30% of cases.76 Differential Diagnosis and Laboratory Studies. An important differential diagnosis is hairy or coated tongue. This is not a candidal infection, although cultures may grow Candida in carriers. These lesions are almost always painless and do not involve mucosa other than tongue dorsum, unusual for candidiasis. It is caused by hyperplasia and hypertrophy of the filiform papillae of the tongue, with retention of keratinaceous debris as a result of hyposalivation and poor oral intake. Patients therefore are often ill, dehydrated, and on antibiotic therapy, further adding to the suspicion that the lesions represent candidiasis. Culture is not particularly useful for diagnostic purposes since many individuals are carriers. However, culture is important if speciation or sensitivity is required,

TABLE 76-4

Presentation and Management of Oral Candidiasis

a

Type

Clinical

Treatment

Thrush/Pseudomembranous candidiasis

Curdy yellowish-white papules or plaques; may or may not scrape off Often synchronously on dorsum or tongue and palate so-called “kissing lesions”

Nystatin 1:100,000 iu/mL; swish and spit out 5 mL tid or qid Clortrimazole trochea 10 mg; suck on 1 troche tid or qid Ketoconazole 200 mg qd × 7-14 days Fluconazole 100 mg; take one tablet once a day × 3–10 days

Erythematous/Atrophic candidiasis

1. Erythematous areas under a denture 2. Linear gingival erythema in HIV/AIDS

1. Mycostatin and triamcinolone cream on worn denture (“under occlusion”); treat denture with dilute bleach (1:10), sodium benzoate or other antimicrobial soaks 2. See Thrush above

Hyperplastic candidiasis

Primarily white papules and plaques with minimal erythema; associated with mucocutaneous disease or hairy leukoplakia

See Thrush above

Angular cheilitis

Fissured, weepy lesions at the corners of the mouth; often associated with Staphylococcus aureus

Mycostatin and triamcinolone cream; may need topical erythromycin

Median rhomboid glossitis

Rhomboidal area in posterior midline of tongue, anterior to circumvallate papillae; maybe slightly depressed and erythematous, or raised

See Thrush above

Troches do not dissolve well in patients with hyposalivation.

12

B

Figure 76-6  A. Erythematous candidiasis. B. Angular cheilitis.

Hairy Leukoplakia. Epstein–Barr virus (EBV) infections in the oral cavity may present as a primary infection (infectious mononucleosis). Hairy leukoplakia is an unusual presentation of recrudescent EBV in the oral cavity, where this normally lymphotropic virus is present within the epithelium. Clinical Findings. This manifests as a painless, white plaque usually located on the lateral border of the tongue in immunocompromised patients, and in particular, those with HIV/AIDS and after organ transplantation.77,78 Typically, these present as white linear lesions running perpendicular to the long axis of the tongue but when more advanced, may extend onto the dorsum and present as a plaque (Fig. 76-7). Lesions are usually asymptomatic and usually superinfected with Candida. Infrequently, hairy leukoplakia has been reported in healthy individuals.79

ORAL LICHEN PLANUS Oral LP is an immune-mediated disorder and an interface stomatitis characterized by T-cell destruction of the basal cells of the epithelium, possibly as a result of altered antigen presentation on these cells, mediated by TH1 cytokines. Interferon-α production is thought to mediate lesions involving the oral cavity only while TNF-α may mediate systemic disease.80 Whether this is a disease in and of itself or whether it represents a “final common pathway” of mucosal reaction is unclear at this time. Many local and systemic conditions predispose to the development of such “lichenoid lesions” in the oral cavity. The term “lichenoid” used here to describe reticulated, often erythematous and/or ulcerated lesions, usually bilateral and symmetric. Unfortunately, many erythroleukoplakias that are by definition red and white lesions but usually without significant reticulation are also clinically described as “lichenoid”

Biology and Pathology of the Oral Cavity

Management and Prognosis. Patients who have dry mouths from polypharmacy or substantial damage to salivary glands (such as from radiation) are prone to develop recurrent candidiasis and are particularly difficult to manage. Nystatin rinses and clotrimazole troches contain caries-inducing sugars and should be used long-term only with careful monitoring by the dentist. The use of cholinergic agents such as pilocarpine or cevimeline helps to restore some secretory function of salivary glands and may reduce the frequency of candidiasis.

AIDS, hairy leukoplakia is usually associated with a low CD4 count and high viral load.77 Treatment with an antifungal medication (see Section “Candidiasis”) will resolve the associated candidiasis and treatment with antiretroviral therapy results in resolution.

::

or to identify carriers prior to the start of long-term steroid therapy. A potassium hydroxide preparation using scrapings from oral lesions is a good way to identify infection. Biopsies show typical candidal organisms.

Chapter 76

A

Differential Diagnosis and Laboratory Studies. Lesions of MMO and candidiasis often occur on the lateral tongue and may appear similar. Both cytologic smears and biopsies show characteristic findings and the presence of EBV can be confirmed by in situ hybridization. Management and Prognosis. The presence of hairy leukoplakia may be the first indication that a patient is infected with HIV. In patients with established HIV/

Figure 76-7  Early hairy leukoplakia (Used with permission from Dr. Mark Lerman, Harvard School of Dental Medicine).

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Section 12 :: Disorders of the Oral and Genital Integument

838

by some investigators, causing confusion and leading to the concept of LP as a premalignant lesion. Local lichenoid reactions may develop as a result of contact injury to amalgam restorations or cinnamic aldehyde from chewing gum. Medications implicated in the development of oral LP include antihypertensive agents (especially hydrochlorthiazide), some hypoglycemic agents, allopurinol, sulfasalazine, carbamazepine, and the new biological agents.80–82 It is often impossible to differentiate either clinically or histologically, between lesions of idiopathic LP and lichenoid hypersensitivity reactions.83 Other conditions associated with oral lichenoid lesions include hepatitis C in Mediterranean races and this is associated with HLA-DR684,85; chronic graftversus-host disease, and lupus erythematosus.86,87

CLINICAL FINDINGS. Oral LP occurs in 1%–2% of the population in the United States and affects females more than males, usually those in the fifth decade of life and older. Three clinical forms are noted—(1) keratotic/reticular, (2) erythematous/erosive, and (3) ulcerative—and these often occur in combination.21,54 The most recognizable is the keratotic/reticular form (Wickham striae) that is usually not painful. This is symmetric in distribution and reticulations almost always occur on the buccal mucosa and tongue although any oral mucosal site may be affected (Figs. 76-8A and 76-8B). Lesions on the dorsum of tongue

tend to be subtle and more papular with atrophy of filiform papillae giving the tongue a white cast and smooth appearance (Fig. 76-8C). The erythematous or erosive form is usually painful and this is particularly common as a primary presentation on the gingiva (clinically desquamative gingivitis).88 LP on the gingiva is also noted in the gingival–genital syndrome.89 Ulcerative LP usually occurs in association with the other two forms. The finding of intact blisters (bullous LP) is rare in the oral cavity because it is a trauma-intense environment. Concomitant skin involvement is noted only in 10%–15% of patients. A controversial entity is the so-called “plaque-type LP.” If this lesion occurs as a unilateral plaque without reticulations, it should be considered a leukoplakia. If it occurs within an established, typical symmetric oral LP, it should be considered “leukoplakia developing within LP.” In either case, biopsy is indicated to exclude dysplasia or malignancy. Several scoring systems have been developed for evaluating the severity of disease but none are universally accepted.90–92

DIFFERENTIAL DIAGNOSIS AND LABORATORY STUDIES. Many conditions may result in the

development of LP and lichenoid reactions. However, the most important is erythroleukoplakia. It can be differentiated from oral LP in that it is not usually definitively reticulated (although it may have subtle linear areas), is

A

B

C

D

Figure 76-8  A. Reticular lichen planus (LP) of right buccal mucosa. B. Reticular, erythematous and ulcerative LP of left buccal mucosa in same patient as 76-8A. C. LP of dorsum of tongue; D. LP of gingiva.

Biology and Pathology of the Oral Cavity

CLINICAL FINDINGS. Leukoplakia is more common in adult males. It presents as a painless, white plaque that may be homogenous or nonhomogenous.97 It may occur anywhere in the oral cavity and generally shows areas that are sharply demarcated from the surrounding mucosa (Fig. 76-9). Homogenous leukoplakia may show areas of fissuring. Nonhomogenous leukoplakia have areas of erythema (erythroleukoplakia), rough, warty areas (verrucous leukoplakia), or nodular areas; they have a higher association with dysplasia and carcinoma, as do lesions on the floor of mouth, ventral tongue, and soft palate.101,102 Proliferative verrucous leukoplakia (PVL)103,104 tends to occur in middle-aged females and, as its name suggests, tends to spread or proliferate over the mucosa over time, and is usually multifocal (eFigs. 76-9.1A–76-9.1C in online edition). It is associated with smoking in less than 30% of cases. Patients are usually diagnosed with this condition one to two decades after the first appearance of the white lesion. Areas of it may become verrucous, although not invariably, and other areas may appear red, in which case the term proliferative erythroleukoplakia may be appropriate. Approximately 70%–100% of cases develop SCC over time.103,105 These lesions are particularly difficult to diagnose because patients often have had multiple biopsies over many years, and each time, the diagnosis is one of “hyperkeratosis” only without evidence of dysplasia. Oral erythroplakia, although a red lesion, will be discussed here because of its high associated dysplasia. It is an uncommon lesion and in its pure form

12

::

MANAGEMENT AND PROGNOSIS. Management of oral LP and lichenoid lesions involves pain control and treatment with topical steroids and other anti-inflammatory agents (Table 76-1).95 Gingival lesions are effectively treated with topical steroids held in a stent. Systemic therapy with prednisone (at 1 mg/ kg for 1 week with a fairly rapid taper) or hydroxychloroquine should be instituted in severe cases and topical therapy started concomitantly. Localized, unliateral lesions may respond to removal of dental restorations and a short course of topical steroids. Disease remission occurs in 8,000 ng/mL could have an adrenal tumor and should be referred to an endocrinologist for fur-

ther evaluation. An ovarian source of excess androgens can be suspected in cases where the serum total testosterone is >150 ng/dL. Serum total testosterone in the range of 150–200 ng/dL or an increased LH/ FSH ratio (>2.0) can be found in cases of polycystic ovary disease. Greater elevations in serum testosterone may indicate an ovarian tumor, and appropriate referral should be made. There is a significant amount of variability in individual serum androgen levels. In cases in which abnormal results are obtained, it may be wise to repeat the test before proceeding with therapy or additional testing. Many patients report that their acne flares during periods of stress. Although objective data are limited, stress is known to increase the output of adrenal steroids, which may affect the sebaceous gland.46 It has been shown that patients with acne have a greater increase in urinary glucocorticoid levels after corticotropin administration.47

Acne Vulgaris and Acneiform Eruptions

B

DIFFERENTIAL DIAGNOSIS Although one type of lesion may predominate, acne vulgaris is diagnosed by a variety of acne lesions (comedones, pustules, papules, and nodules) on the face, back, or chest (see Box 80-1). Diagnosis is usually easy, but inflammatory acne may be confused with folliculitis, rosacea, or perioral dermatitis. Patients with

903

13

Box 80-1  Differential Diagnosis of Acne

Section 13

Most Likely Closed comedonal acne Milia Sebaceous hyperplasia Open comedonal acne Dilated pore of Winer Favre–Racouchot syndrome Inflammatory acne Rosacea Perioral dermatitis Neonatal acne Miliaria rubra

:: Disorders of the Sebaceous Glands

Consider Closed comedonal acne Osteoma cutis Trichoepitheliomas Trichodiscomas Fibrofolliculomas Eruptive vellus hair cysts, steatocystoma multiplex Colloid milia Flat warts Open comedonal acne Trichostasis spinulosa Nevus comedonicus Inflammatory acne Pseudofolliculitis barbae, acne keloidalis nuchae Keratosis pilaris Neurotic excoriations/factitial Lupus miliaris disseminatus faciei Neonatal acne Sebaceous hyperplasia Milia Always Rule Out Closed comedonal acne Acne due to systemic agents (e.g., corticosteroids) Contact acne (e.g., occupational acne) Chloracne Open comedonal acne Acne due to systemic agents Contact acne Chloracne Inflammatory acne Acne due to systemic agents Staphylococcal folliculitis Gram-negative folliculitis Eosinophilic folliculitis Furuncle/carbuncle Angiofibromas of tuberous sclerosis Neonatal acne Candidal infections Benign neonatal cephalic pustulosis

904

tuberous sclerosis and facial angiofibromas have been misdiagnosed as having recalcitrant midfacial acne. Facial flat warts or milia are occasionally confused with closed comedones. Acne can be seen in association with endocrinologic abnormalities. Patients with hyperandrogenism may have acne plus other stigmata of increased androgen levels (i.e., hirsutism, deepened voice, irregular menses). Endocrinologic disorders such as polycystic ovarian syndrome (including HAIR-AN syndrome), congenital adrenal hyperplasia, and adrenal and ovarian neoplasms often have accompanying acne. Variants of acne must also be differentiated from typical acne vulgaris in order to guide treatment. These types of acne include: neonatal acne, infantile acne, acne fulminans, acne conglobata, acne with solid facial edema, and acne excoriée des jeunes filles. These variants are discussed in detail later in the chapter. There are several less common acneiform eruptions that can be confused with acne vulgaris. These mimickers include: medication-induced acne, halogen acne, chloracne, acne mechanica, tropical acne, radiation acne, and other various miscellaneous acneiform disorders that are discussed subsequently.

COMPLICATIONS All types of acne lesions have the potential to resolve with sequelae. Almost all acne lesions leave a transient macular erythema after resolution. In darker skin types, postinflammatory hyperpigmentation may persist months after resolution of acne lesions. In some individuals, acne lesions may result in permanent ­scarring. Acne vulgaris may also take a psychological toll on many patients. It is estimated that 30%–50% of adolescents experience psychiatric disturbances due to acne.48 Studies have shown that patients with acne have similar levels of social, psychological, and emotional impairment as those with asthma and epilepsy.49 Additional studies have also shown that unemployment rates are higher among adults with acne than those without.50 When appropriate, patients should be referred for psychiatric counseling.

PROGNOSIS AND CLINICAL COURSE The age of onset of acne varies considerably. It may start as early as 6–8 years of age or it may not appear until the age of 20 or later. The course is one of several years’ duration followed by spontaneous remission in the majority of cases. While most patients will clear by their early twenties, some have acne extending well into the third or fourth decades. The extent of involvement varies, and spontaneous fluctuations in the degree of involvement are the rule rather than the exception. In women there is often a fluctuation in association with menses, with a flare just before the onset of menstruation. This flare is not due to a change in sebaceous gland activity as there is no increase in sebum production in the luteal phase of the menstrual

cycle. It has been shown that prepubescent females with comedonal acne and those females with high DHEAS levels are predictors of severe or long-standing nodulocystic acne.51

for acne can be categorized in the following categories as they relate to the pathophysiology:

13

1. Correct the altered pattern of follicular

keratinization.

2. Decrease sebaceous gland activity. 3. Decrease the follicular bacterial population,

TREATMENT

particularly P. acnes.

4. Exert an anti-inflammatory effect.

LOCAL THERAPY Cleansing. The importance

of cleansing in the treatment of acne is generally intuitive. Twice daily washing with a gentle cleanser followed by the application of acne treatments may encourage a routine and therefore better compliance. Overcleansing or using harsh alkaline soaps are likely to increase the

Chapter 80

Tailoring a patient’s acne regimen with the knowledge of the pathogenesis of acne and the mechanism of action of the available acne treatments will ensure maximum therapeutic response. Treatment regimens should be initiated early and be sufficiently aggressive to prevent permanent sequelae. Often multiple treatments are used in combination so as to combat many factors in the pathogenesis of acne (Table 80-1). The mechanism of action of the most common treatments

::

Treatment Algorithm for Acne Vulgaris Mild

Moderate

Severe

Comedonal

Papular/ Pustular

Papular/Pustular

Nodular

Conglobata/ Fulminans

First

Topical retinoid or combinationa

Topical retinoid + topical antimicrobial or combinationa

Oral antibiotic + topical retinoid ± BPO or combinationa

Oral antibiotic + topical retinoid ± BPO

Oral isotretinoin ± oral corticosteroids

Second

Topical dapsone or azelaic acid or salicylic acid

Topical dapsone or azelaic acid or salicylic acid

Oral antibiotic + topical retinoid ± BPO or combinationa

Oral isotretinoin or oral antibiotic + topical retinoid ± BPO/azelaic acid or combinationa

High-dose oral antibiotic + topical retinoid + BPO or combinationa

Female

—

—

+ Oral contraceptive/ antiandrogen

+ Oral contraceptive/ antiandrogen

+ Oral contraceptive/ antiandrogen

Additional options

Comedone extraction

Laser/light therapy, photodynamic therapy

Comedone extraction, laser/light therapy, photodynamic therapy

Comedone extraction; intralesional corticosteroid, laser/light therapy, photodynamic therapy

Intralesional corticosteroid, laser/light therapy, photodynamic therapy

Refractory to treatment

Check compliance

Check compliance Exclude Gramnegative folliculitis Females: Exclude polycystic ovary syndrome, adrenal or ovarian tumors, congenital adrenal hyperplasia Males: Exclude congenital adrenal hyperplasia

Maintenance

Topical retinoid ± BPO, or combinationa

Topical retinoid ± BPO, or combinationa

Topical retinoid ± BPO, or combinationa

Topical retinoid ± BPO, or combinationa

BPO = benzoyl peroxide. a Manufactured combination products include BPO/erythromycin, BPO/clindamycin, adapalene/BPO, tretinoin/clindamycin. Adapted from Gollnick H et al: Management of acne: A report from a Global Alliance to improve outcomes in acne. J Am Acad Dermatol 49:1, 2003.

Acne Vulgaris and Acneiform Eruptions

TABLE 80-1

905

13

skin’s pH, disrupt the cutaneous lipid barrier, and compound the irritancy potential of many topical acne treatments. Use of a syndet (synthetic detergent) will allow cleansing without disruption of the skin’s normal pH. Antibacterial soaps, containing agents such as triclosan, inhibit Gram-positive cocci but may increase Gram-negative rods; their overall affect on acne is unclear. Medicated cleansers, containing benzoyl peroxide or salicylic acid, offer convenience as a wash and are excellent for hard to reach areas like the back.

Topical Agents. (See Table 80-2) Section 13 :: Disorders of the Sebaceous Glands

Sulfur/Sodium Sulfacetamide/Resorcinol. Products containing sulfur, sodium sulfacetamide, and resorcinol, once favored treatments for acne, are still found in several over-the-counter and prescription niche formulations. Sulfonamides are thought to have antibacterial properties through their inhibition of para-aminobenzoic acid (PABA), an essential substance for P. acnes growth.52 Sulfur also inhibits the formation of free fatty acids and has presumptive keratolytic properties. It is often combined with sodium sulfacetamide to enhance its cosmetic tolerability due to sulfur’s distinctive odor. Resorcinol is also indicated for use in acne for its antimicrobial properties. It is generally found in 2% concentration in combination with 5% sulfur. Salicylic Acid. Salicylic acid is a ubiquitous ingredient found in over-the-counter acne preparations in concentrations ranging from 0.5% to 2%. This lipid soluble β-hydroxy acid has comedolytic properties, though somewhat weaker than those of a retinoid. Salicylic acid also causes exfoliation of the stratum corneum though decreased cohesion of the keratinocytes. Mild irritant reactions may result. Azelaic Acid. Azelaic acid is available by prescription in a 20% cream or 15% gel. This dicarboxcylic acid has both antimicrobial and comedolytic properties.53 It is also a competitive inhibitor of tyrosinase and thus may decrease postinflammatory hyperpigmentation.54 It is generally well tolerated, though transient burning can occur, and is safe in pregnancy. Benzoyl Peroxide. Benzoyl peroxide preparations are among the most common topical medications prescribed by dermatologists and are also readily available over-the-counter. Benzoyl peroxide is a powerful antimicrobial agent through decreasing both the bacterial population and the hydrolysis of triglycerides. Benzoyl peroxide preparations are available in creams, lotion, gels, washes, and pledgets. Products that are left on the skin, such as a gel, are generally considered more effective. Benzoyl peroxide can produce significant dryness and irritation. Allergic contact dermatitis has been uncommonly reported. Of significance, bacteria are unable to develop resistance to benzoyl peroxide, making it the ideal agent for combination therapy.55

906

Topical Antibiotics. (See Chapter 218). Erythromycin and clindamycin are the most commonly used topical

antibiotics for the treatment of acne. These two agents have also been used in combination preparations with benzoyl peroxide. Increased levels of P. acnes resistance have been reported in patients who are being treated with antibiotics. However, the development of resistance is less likely in patients who are treated with a combination of benzoyl peroxide/erythromycin or clindamycin.56 Therefore, the combination of these two products is preferable over monotherapy with topical antibiotics. Topical dapsone is the most recently approved topical antibiotic for acne. With twice daily application topical dapsone has shown better efficacy in controlling inflammatory lesions (58%) versus noninflammatory lesions (19%).57,58 Unlike oral dapsone, topical dapsone is safe for use even in patients with a G6PD deficiency.59 It is generally well tolerated but should not be applied concomitantly with benzoyl peroxide or it may impart an orange color on the skin.60 Retinoids. (See Chapter 217). Retinoids are defined by their ability to bind to and activate retinoic acid receptors (RAR) and in turn activate specific gene transcription resulting in a biologic response. Some have chemical structures similar to tretinoin (all-trans-retinoic acid), but they may be entirely dissimilar, such as adapalene or tazarotene, and still potentiate a retinoid effect. In general, the binding of these agents to nuclear RAR affects the expression of genes involved in cell proliferation, differentiation, melanogenesis, and inflammation.61,62 The result is modification of corneocyte accumulation and cohesion, and inflammation. Thus, retinoids have both comedolytic and antiinflammatory properties.62 Tretinoin is commercially available in several strengths and formulations. Having both potent comedolytic and anti-inflammatory properties, it is widely used. In general, all retinoids can be contact irritants, with alcohol-based gels and solutions having the greatest irritancy potential. Some newer formulations utilize a microsphere delayed-delivery technology (Retin A Micro® 0.04% or 0.1% gel) or are incorporated within a polyolprepolymer (PP-2) (Avita® cream) to decrease the irritancy potential of tretinoin while allowing greater concentration of medication. Advising patients to apply tretinoin on alternate nights during the first few weeks of treatment can help ensure greater tolerability. Patients must also be cautioned about sun exposure due to thinning of the stratum corneum, especially those with any irritant reaction. Regular use of a sunscreen should be advised. The comedolytic and anti-inflammatory properties of topical retinoids make them ideal for maintenance therapy of acne. Generic tretinoin is inactivated by concomitant use of benzoyl peroxide and is photolabile. Therefore, patients should be counseled to apply tretinoin at bedtime. Adapalene is a synthetic retinoid widely marketed for its greater tolerability. It specifically targets the RARγ receptor. It is both photostable and can be used in conjunction with benzoyl peroxide without degradation. Adapalene 0.1% gel has been shown in clinical trials to have greater or equal efficacy to tretinoin 0.025% gel with greater tolerability.63,64 It is available at a 0.1% concentration in both a nonalcohol gel and

13

TABLE 80-2

Commonly Available Prescription Acne Preparations—Topical Generic

Trade

Vehicle

Concentration

Size

Retin-A

Cream Gel Liquid Gel with microsponge

0.025%, 0.05%, 0.1% 0.01%, 0.025% 0.05% 0.04%, 0.1%

Cream Gel Cream Cream Gel Cream Gel Cream Gel Lotion Gel Cream Gel

0.025% 0.025% 0.05% 0.025%, 0.05%, 0.1% 0.025%, 0.1% 0.025%, 0.05%, 0.1% 0.025%, 0.1% 0.1% 0.1%, 0.3% 0.1% 0.1% 0.1% 0.1%

20 g, 45 g 15 g, 45 g (0.025% only) 28 mL 20 g, 45 g 50-g pump 20 g, 45 g 20 g, 45 g 40 g 35 g (kit with cleanser) 35 g (kit with cleanser) 20 g, 45 g 15 g, 45 g 15 g, 45 g 15 g, 45 g 2 oz 45 g 30 g, 60 g 30 g, 60 g

Ziana Epiduo

Gel Gel

0.025%/1.2% 2.5%/0.1%

30 g, 60 g 45 g

Benzac AC

Gel Wash Gel Wash Cream Gel Wash Gel Creamy wash Gel Gel Gel Cleanser Pads Foaming cloths Cleanser Pads Hydrating wash Gel Wash Gel Ointment Solution Pledget Gel Lotion Solution Pledget Foam Gel Gel Lotion Pledget Gel Lotion Solution Gel Gel

2.5%, 5%, 10% 2.5%, 5%, 10% 2.5%, 5%, 10% 5%, 10% 5%, 10% 5.25% 5.25% 4%, 8% 4%, 8% 7% 2.5%, 5%, 10% 3%, 6%, 9% 3%, 6%, 9% 3%, 6%, 9% 3%, 6%, 9% 4.5%. 6.5%, 8.5% 4.5%. 6.5%, 8.5% 5.75% 5%, 10% 2.5%, 5%, 10% 2% 2% 2% 2% 1% 1% 1% 1% 1% 1% 1% 1% 1% 1% 1% 1% 5% 5%/3%

60 g 240 mL (2.5%), 226 mL 60 g 226 mL 113.4 g 50 g 175 g 42.5 g 170 g (kit with cleanser) 45 g 42.5 g 42.5 g 6 oz, 12 oz 1 g (30 or 60/box) 3.2 g (30 or 60/box) 400 mL 6 mL (30/box) 400 mL 45 g, 60 g, 90 g 142 g, 227 g 30 g, 60 g 25 g 60 mL (60/box) 30 g, 60 g 60 mL 30 mL, 60 mL (60/box) 50 g, 100 g 40 mL, 75 mL 30 g, 60 g 60 mL 60 s 30 g, 60 g 30 g, 60 g 30 g 30 g 46.6 g, 60/box

Gel Gel

5%/3% 5%/1%

Duac Acanya Generic Vanoxide HC

Gel Gel Gel Lotion

5%/1% 2.5%/1.2% 5%/1% 5%–0.5%

23.2 g, 46.6 g 25 g, 50 g 50-g pump 45 g 50 g 50 g 25 mL

Sodium sulfacetamide Sodium sulfacetamide/sulfur

Klaron Sulfacet-R Rosula

Azeleic acid

Azelex

Lotion Lotion Gel Cleanser

10% 10–5% 10%–5% in 10% urea 10%–5% in 10% urea

4 oz 25 g 45 mL 355 mL

Retinoids—Topical Tretinoin

Retin-A micro Avita Refissa Tretin-X

Differin

Tazarotene

Generic Tazorac

::

Retinoid Combinations—Topical

Antimicrobials—Topical Benzoyl peroxide

Benzac W Benzashave Benziq LS Brevoxyl Clinac Desquam E Triaz

Zoderm Generic Erythromycin

Generic

Clindamycin

Cleocin T

Evoclin Clindagel ClindaMax Clindets Generic Dapsone Benzoyl peroxide/ erythromycin Benzoyl peroxide/clindamycin

Benzoyl peroxide/ hydrocortisone

Aczone Benzamycin Benzamycin Gel Pak Generic Benzaclin

Acne Vulgaris and Acneiform Eruptions

Tretinoin/clindamycin Adapalene/benzoyl peroxide

Chapter 80

Generic Adapalene

Miscellaneous

Cream

20%

30 g, 50 g

907

13

Section 13 :: Disorders of the Sebaceous Glands

908

cream and as a 0.3% gel. The 0.3% adapalene gel has been shown to have similar efficacy to tazarotene 0.1% gel with increased tolerability.65 A combination topical agent containing 0.1% adapalene and 2.5% benzoyl peroxide is also available.66,67 Tazarotene, also a synthetic retinoid, exerts is action through its metabolite, tazarotenic acid, which in turn inhibits the RARγ receptor. It is a potent comedolytic agent and has been show to be more effective than tretinoin 0.025% gel and tretinoin 0.1% microsphere gel.68,69 Both the 0.1% cream and gel formulations are approved for the treatment of acne. The irritant properties of tazarotene can be minimized by the use of short-term contact therapy. In this regimen, the medication is applied for 5 minutes then washed off with a gentle cleanser. Tazarotene has been given a pregnancy category X rating and female patients of childbearing age should be adequately counseled. An overview of topical agents for acne treatment is outlined in Table 80-2.

SYSTEMIC THERAPY Antibiotics and Antibacterial Agents. Chapter 230).

(See

Tetracyclines. Broad-spectrum antibiotics are widely used in the treatment of inflammatory acne. The tetracyclines are the most commonly used antibiotics in the treatment of acne. Although the oral administration of tetracyclines does not alter sebum production, it does decrease the concentration of free fatty acids while the esterified fatty acid content increases. Decreases in free fatty acid formation also have been reported with erythromycin, demethylchlortetracycline, clindamycin, and minocycline. The free fatty acids are probably not the major irritants in sebum, but their level is an indication of the metabolic activity of the P. acnes bacteria and its secretion of other proinflammatory products. The decrease in free fatty acids may take several weeks to become evident. This, in turn, is reflected in the clinical course of the disease during antibiotic therapy, as several weeks are often required for ­maximal clinical benefit. The effect, then, is one of prevention; the individual lesions require their usual time to undergo resolution. However, the fact that a decrease in free fatty acids does occur strengthens the rationale for the use of tetracycline. Tetracycline may also act through direct suppression of the number of P. acnes, but part of its action may be due to its antiinflammatory activity. In clinical practice, tetracycline is usually given initially in dosages of 500–1,000 mg/ day. Higher doses of up to 3,500 mg/day have been used in severe cases, but prudent monitoring of liver functions is warranted. Tetracycline should be taken on an empty stomach, 1 hour before or 2 hours after meals, to promote absorption; thus, compliance by adolescents with its administration can be challenging. Gastrointestinal (GI) upset is the most common side effect, with esophagitis and pancreatitis possible. Uncommon side effects include hepatotoxicity, hypersensitivity reactions, leukocytosis, thrombocytopenic purpura, and pseudotumor cerebri. Tetracyclines should be used with caution in patients with renal

­ isease as they may increase uremia. Tetracyclines d have an affinity for rapidly mineralizing tissues and are deposited in developing teeth, where they may cause irreversible yellow–brown staining; also, tetracyclines have been reported to inhibit skeletal growth in the fetus. Therefore, they should not be administered to pregnant women, especially after the fourth month of gestation and are not recommend for use in children younger than 9 years of age in the treatment of acne. The tetracycline derivatives, doxycycline and minocycline, are also commonly used in the treatment of acne. They have the distinct advantage of being able to be taken with food without impaired absorption. Doxycycline is administered in dosages of 50–100 mg twice daily. Its major disadvantage is the potential risk of photosensitivity reactions, including photo-onycholysis, and patients may need to be switched to another antibiotic during summer months. Minocycline is given in divided dosages at a level of 100–200 mg/day. Patients on minocycline should be monitored carefully, as the drug can cause blue–black pigmentation, especially in the acne scars, as well as the hard palate, alveolar ridge, and anterior shins. Vertigo has occasionally been described. Minocycline-induced autoimmune hepatitis and a systemic lupus erythematosus-like syndrome have been reported during minocycline therapy, but these side effects are very rare.70,71 Of note, patients who develop lupus-like reactions can be safely switched to an alternative tetracycline. Serum sickness-like reactions and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have also been reported with minocycline use. Macrolides. Due to the prevalence of erythromycinresistant strains of P. acnes, the use of oral erythromycin is generally limited to pregnant women or children. Azithromycin has been used more often for acne, typically at dosages of 250–500 mg orally three times weekly.72 Azithromycin undergoes hepatic metabolism with GI upset and diarrhea as the most common side effects. Trimethoprim–Sulfamethoxazole. Trimethoprim–sulfamethoxazole combinations are also effective in acne. In general, because the potential for side effects is greater with their use, they should be used only in patients with severe acne who do not respond to other antibiotics. GI upset and cutaneous hypersensitivity reactions are common. Serious adverse reactions, including the Stevens–Johnson syndrome-toxic epidermal necrolysis spectrum (see Chapter 40) and aplastic anemia, have been described. If trimethoprim– sulfamethoxazole is used, the patient must be ­monitored for potential hematologic suppression approximately monthly. Cephalexin. Cephalexin, a first generation cephalosporin, has been shown in vitro to kill P. acnes. However, because it is hydrophilic and not lipophilic it penetrates poorly into the pilosebaceous unit. Success with oral cephalexin73 is most likely due to its anti-inflammatory rather than antimicrobial properties. Due to the risk of promoting the development of bacterial resistance,

particularly to Staphylococcus, the authors discourage the use of cephalexin for acne.

Oral Contraceptives. Oral contraceptives can improve acne by four main mechanisms. Firstly, they decrease the amount of gonadal androgen production by suppressing LH production. Secondly, they decrease the amount of free testosterone by increasing the production of sex hormone binding globulin. Thirdly, they inhibit the activity of 5-α reductase activity, so as to prevent the conversion of testosterone to the more potent DHT. Lastly, progestins that have an antiandrogenic effect can block the androgen receptors on keratinocytes and sebocytes. The third-generation progestins—gestodene (not available in the United States), desogestrel, and norgestimate, have the lowest intrinsic androgenic activity.76 Two progestins have demonstrated antiandrogenic properties: (1) cyproterone acetate (not available in the United States) and (2) drospirenone. There are three oral con-

Acne Vulgaris and Acneiform Eruptions

HORMONAL THERAPY OF ACNE. The goal of hormonal therapy is to counteract the effects of androgens on the sebaceous gland. This can be accomplished with the antiandrogens, or agents designed to decrease the endogenous production of androgens by the ovary or adrenal gland, including oral contraceptives, glucocorticoids, or gonadotropin-releasing hormone (GnRH) agonists.

Glucocorticoids. Because of their anti-inflammatory activity, high-dose systemic glucocorticoids may be of benefit in the treatment of acne. In practice, their use is usually restricted to the severely involved patient, often overlapping with isotretinoin to limit any potential flaring from at the start of treatment. Furthermore, because of the potential side effects, these drugs are ordinarily used for limited periods of time, and recurrences after treatment are common. Prolonged use may result in the appearance of steroid acne. Glucocorticoids in low dosages are also indicated in those female patients who have an elevation in serum DHEAS associated with an 11- or 21-hydroxylase deficiency or in other individuals with demonstrated androgen excess. Low-dose prednisone (2.5 mg or 5 mg) or dexamethasone can be given orally at bedtime to suppress adrenal androgen production.44 The combined use of glucocorticoids and estrogens has been used in recalcitrant acne in women, based upon the inhibition of sebum production by this combination.80 The mechanism of action is probably related to a greater reduction of plasma androgen levels by combined therapy than is produced by either drug alone.

::

Antibiotics and Bacterial Resistance. Antibiotic resistance is a growing concern worldwide and should be suspected in patients unresponsive to appropriate antibiotic therapy after 6 weeks of treatment. Increasing propionobacterium resistance has been documented to all macrolides and tetracyclines commonly used in the treatment of acne. A prevalence rate of 65% was documented in one study performed in the United Kingdom.74 Overall, resistance is highest with erythromycin and lowest with the lipophilic tetracyclines, doxycycline, and minocycline.75 The least resistance is noted with minocycline. To prevent resistance, prescribers should avoid antibiotic monotherapy, limit long-term use of antibiotics and combine usage with benzoyl peroxide whenever possible.55

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Chapter 80

Clindamycin and Dapsone. Less commonly used antibiotics include clindamycin and dapsone. Oral clindamycin had been used more readily in the past, but because of the risk of pseudomembranous colitis, it is now rarely used systemically for acne. It is still commonly used topically, however, often in combination with benzozyl peroxide. Dapsone (see Chapter 225), a sulfone often used for cutaneous neutrophilic disorders, may be beneficial in severe markedly inflammatory acne and select cases of resistant acne. It is used at doses of 50–100 mg daily for 3 months. G6PD levels should be examined prior to initiation of therapy and regular monitoring for hemolysis and liver function abnormalities is warranted. While not as reliably effective as isotretinoin, it is relatively low cost and should be considered in severe cases where isotretinoin is not an option.

traceptives currently Food and Drug Administration (FDA) approved for the treatment of acne: (1) Ortho Tri-Cyclen, (2) Estrostep, and (3) Yaz. Ortho Tri-Cyclen is a triphasic oral contraceptive comprised of a norgestimate (180, 215, 250 mg)–ethinyl estradiol (35 μg) combination.77 In an effort to reduce the estrogenic side effects of oral contraceptives, preparations with lower doses of estrogen (20 μg) have been developed for the treatment of acne. Estrostep contains a graduated dose of ethinyl estradiol (20–35 μg) in combination with norethindrone acetate (1 mg).78 Yaz contains ethinyl estradiol (20 ug) and the antiandrogen drospirenone (3 mg). Drospirenone is a 17 α-spironolactone derivative that has both antimineralocorticoid and antiandrogenic properties, which may improve estrogen-related weight gain and bloating.78 An oral contraceptive containing a low dose of estrogen (20 μg) in combination with levonorgestrel (Alesse) has also demonstrated efficacy in acne.79 Side effects from oral contraceptives include nausea, vomiting, abnormal menses, weight gain, and breast tenderness. Rare but more serious complications include thrombophlebitis, pulmonary embolism, and hypertension. With the use of estrogen–progestin-containing oral contraceptives rather than estrogen alone, side effects such as delayed menses, menorrhagia, and premenstrual cramps are uncommon. However, other side effects such as nausea, weight gain, spotting, breast tenderness, amenorrhea, and melasma can occur.

Gonadotropin-Releasing Hormone Agonists. GnRH agonists, such as leuprolide (Lupron),

act on the pituitary gland to disrupt its cyclic release of gonadotropins. The net effect is suppression of ovarian steroidogenesis in women. These agents are used in the treatment of ovarian hyperandrogenism. GnRH agonists have demonstrated efficacy in the treatment of acne and hirsutism in females both with and without endocrine disturbance.81 However, their use is limited

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by their side effect profile, which includes menopausal symptoms and bone loss.

Section 13 :: Disorders of the Sebaceous Glands

Antiandrogens. Spironolactone is an aldosterone antagonist and functions in acne as both an androgenreceptor blocker and inhibitor of 5-α reductase. In doses of 50–100 mg twice a day, it has been shown to reduce sebum production and to improve acne.82 Side effects include: diuresis, potential hyperkalemia, irregular menstrual periods, breast tenderness, headache, and fatigue. Combining spironolactone treatment with an oral contraceptive can alleviate the symptoms of irregular menstrual bleeding. Although hyperkalemia is a risk of spironolactone, this risk has shown to be minimal, even when spironolactone is administered with other aldosterone antagonists (such as drospirenone containing oral contraceptives).83 As an antiandrogen, there is a risk of feminization of a male fetus if a pregnant female takes this medication. Long-term studies in rats receiving high doses of spironolactone demonstrated an increased incidence of adenomas on endocrine organs and the liver. These findings recently led to a black box warning by the FDA.84 Cyproterone acetate is a progestational antiandrogen that blocks the androgen receptor. It is combined with ethinyl estradiol in an oral contraceptive formulation that is widely used in Europe for the treatment of acne. Cyproterone acetate is not available in the United States. Flutamide, an androgen receptor blocker, has been used at doses of 250 mg twice a day in combination with oral contraceptives for treatment of acne or hirsutism in females.85 Liver function tests should be monitored, as cases of fatal hepatitis have been reported.86 Pregnancy should be avoided. Use of flutamide in the treatment of acne may be limited by its side effect profile. Isotretinoin. (See Chapter 228). The use of the oral

910

retinoid, isotretinoin, has revolutionized the management of treatment-resistant acne.87 It is approved for use in patients with severe recalcitrant nodular acne. However, it is commonly used in many other acne scenarios, including any significant acne that is unresponsive to treatment with oral antibiotics and acne that results in significant physical or emotional scarring. Isotretinoin is also effective in the treatment of Gramnegative folliculitis, pyoderma faciale, and acne fulminans.88 The remarkable aspects of isotretinoin therapy are the complete remission in almost all cases and the longevity of the remission, which lasts for months to years in the great majority of patients. However, due to its teratogenicity its use has become highly regulated in the United States with the initiation of the iPledge program in March 2006 to insure that pregnancy-prevention procedures are followed. The mechanism of action of isotretinoin is not completely known. The drug produces profound inhibition of sebaceous gland activity, and this undoubtedly is of great importance in the initial clearing.89,90 In some patients, sebaceous gland inhibition continues for at least a year, but in the majority of patients, sebum production returns to normal after 2–4 months.89

Thus, this action of the drug cannot be used to explain the long-term remissions. The P. acnes population is also decreased during isotretinoin therapy, but this decrease is generally transient.90,91 Isotretinoin has no inhibitory effect on P. acnes in vitro. Therefore, the effect on the bacterial population is probably indirect, resulting from the decrease in intrafollicular lipids necessary for organism growth. Isotretinoin also has anti-inflammatory activity and probably has an effect on the pattern of follicular keratinization. These effects also are temporary, and the explanation for long-term remissions remains obscure. Given the ubiquitous distribution of RAR, isotretinoin almost always causes side effects, mimicking those seen in the chronic hypervitaminosis A syndrome.92 In general, the severity of side effects tends to be dose dependent. The most common side effects are related to the skin and mucous membranes. Cheilitis of varying degrees is found in virtually all cases. Other side effects that are likely to be seen in over 50% of patients are dryness of the mucous membranes and skin. An eczematous dermatitis is occasionally seen, particularly in cold, dry weather. Thinning of hair and granulomatous paronychial lesions are less common. Ophthalmologic findings include xerophthalmia, night blindness, conjunctivitis, keratitis, and optic neuritis. Corneal opacities and hearing loss (both transient and persistent) have also been reported with isotretinoin use. Pseudotumor cerebri, also known as benign intracranial hypertension, is evidenced by severe headache, nausea, and visual changes. The risk of pseudotumor cerebri may be increased with concomitant use of tetracyclines and isotretinoin; therefore, these two medications should not be used together without careful prior consideration. If symptoms suggest benign intracranial hypertension, prompt neurological evaluation for evidence of papilledema is required. Vague complaints of headache, fatigue, and lethargy are also not infrequent. The relationship between isotretinoin use and psychiatric effects is currently being examined. Risk of depression, suicide, psychosis, and aggressive and/or violent behavior are all listed as possible side effects. While no clear mechanism of action has been established, some evidence for biologic plausibility does exist. Psychiatric adverse events are described with high-dose vitamin A and etretinate. Also, retinoids have the demonstrated ability to enter the central nervous system (CNS) of rats and mice. And finally, there are documented case reports and studies linking isotretinoin use to depression in certain individuals.93 A meta-analysis of nine studies looking at the possible link between isotretinoin and depression found that the incidence of depression in patients on isotretinoin ranged from 1%–11%.94 The authors importantly pointed out that this range is similar to control group patients on oral antibiotics. Another author examining case-control studies on isotretinoin and depression found the relative risk to range from 0.9 to 2.7 with wide confidence intervals.95 Some studies demonstrate that those on isotretinoin have an overall improvement in mood.96 Retinoids have not been shown to activate genes to induce behavioral/psychiatric changes. Nor

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:: Acne Vulgaris and Acneiform Eruptions

organogenesis. Therefore, the production of retinoic embryopathy occurs very early in pregnancy, with a peak near the third week of gestation.102,103 A significant number of fetal abnormalities have been reported after the use of isotretinoin. For this reason, it should be emphasized that isotretinoin should be given only to patients who have not responded to other therapy. Furthermore, women who are of childbearing age must be fully informed of the risk of pregnancy. The patient must employ two highly effective contraception techniques such as the use of an oral contraceptive and condoms with a spermicidal jelly. Contraception must be started at least 1 month before isotretinoin therapy. Female patients must be thoroughly counseled and demonstrate an understanding of contraception techniques before starting isotretinoin. Two forms of contraception should be used throughout the course of isotretinoin and for 1 month after stopping treatment. No more than 1 month’s supply of isotretinoin should be given to a female patient so that she can be counseled on a monthly basis on the hazards of pregnancy during isotretinoin therapy. A pregnancy test must be repeated monthly. Abstinence as a form of birth control should only be allowed in special instances. Because the drug is not mutagenic, there is no risk to a fetus conceived by a male who is taking isotretinoin. Although it may seem obvious, it is important to remind men who are taking isotretinoin not to give any of their medication to female companions under any circumstances. The recommended daily dosage of isotretinoin is in the range of 0.5–1 mg/kg/day. A cumulative weight-based dosing formula may also be used with a total dose of 120–150 mg/kg of isotretinoin during a course of therapy.104 This dosing regimen is of particular use in patients who have variable dosages or interrupted periods of treatment as achieving the total dose will ensure the greatest chance of longterm remission. Because back and chest lesions show less of a response than facial lesions, dosages as high as 2 mg/kg/day may be necessary in those patients who have very severe truncal involvement. Patients with severe acne, particularly those with granulomatous lesions, will often develop marked flares of their disease when isotretinoin is started. Therefore, the initial dosing should be low, even below 0.5 mg/ kg/day. These patients often need pretreatment for 1–2 weeks with prednisone (40–60 mg/day), which may have to be continued for the first 2 weeks of therapy. A typical course of isotretinoin is 20 weeks, but the length of the course of treatment is not absolute; in patients who have not shown an adequate response, therapy can be extended. Additional improvement may be seen for 1–2 months after discontinuation, so that complete clearance may not be a necessary endpoint for determining when to discontinue therapy. Low-dose regimens, 0.1–0.4 mg/ kg/day, have shown efficacy. However, with such dosages, the incidence of relapses after therapy is greater. Approximately 10% of patients treated with isotretinoin require a second course of the drug. The likelihood for repeat therapy is increased in patients younger than 16–17 years of age. It is standard

Chapter 80

is there evidence demonstrating functionality of retinoid signaling pathways in the mature CNS. Large population-based studies have not supported causality. As dermatologists are often on the front line seeing adolescents at risk for depression, careful screening of adolescents is particularly needed, since the risk of depression in this population is 10%–20%.97 GI symptoms are generally uncommon, but nausea, esophagitis, gastritis, and colitis can occur. Acute hepatitis is rare but liver function studies should be regularly monitored, as elevation in liver enzymes can occur in 15% of patients, sometimes necessitating dose adjustments. Elevated levels of serum triglycerides occur in approximately 25% of patients on isotretinoin. This elevation, which is dose-related, typically occurs within the first 4 weeks of treatment and is often accompanied by an overall increase in cholesterol with a decrease in the high-density lipoprotein levels. The effect of this transient alteration on overall coronary artery health is unclear. Acute pancreatitis is a rare complication that may or may not be related to triglyceride levels. There are case reports documenting a potential link between isotretinoin and new-onset or flared inflammatory bowel disease. However, a study that critically examined these case reports found no grounds for a causal relationship between isotretinoin use and inflammatory bowel disease.98 A recent population-based case-control study found that patients with inflammatory bowel disease were no more likely to have used isotretinoin than those without inflammatory bowel disease.99 Patients with a family history of inflammatory bowel disease, or those with a preexisting inflammatory bowel disease, should be counseled regarding the possibility of isotretinoin-induced inflammatory bowel disease. Isotretinoin has effects on bone mineralization as well. A single course of isotretinoin was not shown to have a significant effect on bone density.100 However, chronic or repeated courses may result in significant osteopenia. Osteoporosis, bone fractures, and delayed healing of bone fractures have also been reported. The significance of reported hyperostosis is unclear, but the development of bony hyperostoses after isotretinoin therapy is more likely in patients who receive the drug for longer periods of time and in higher dosages, such as for disorders of keratinization.101 Serial bone densitometry should be done in any patient on long-term isotretinoin. Myalgias are the most common musculoskeletal complain, seen in 15% of patients. In severe cases, creatine phosphokinase levels should be evaluated for possible rhabdomyolysis. Other laboratory abnormalities that have been reported with isotretinoin use are an elevated erythrocyte sedimentation rate and platelet count. Alterations in the red blood cell parameters with decreased white cell counts can occur. White blood cells in the urine have rarely been linked to isotretinoin use. Most laboratory changes are mild and spontaneously resolve upon discontinuation of medication use. The greatest concern during isotretinoin therapy is the risk of the drug being administered during pregnancy and thereby inducing teratogenic effects in the fetus.102,103 The drug is not mutagenic; its effect is on

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practice to allow at least 2–3 months between courses of isotretinoin. Furthermore, laboratory monitoring is indicated. It is appropriate to obtain a baseline complete blood count and liver function tests, but the greatest attention should be paid to following serum triglyceride levels. Baseline values for serum triglycerides should be obtained and repeated at 3–4 weeks and 6–8 weeks of therapy. If the values are normal at 6–8 weeks, there is no need to repeat the test during the remaining course of therapy unless there are risk factors. If serum triglycerides increase above 500 mg/dL, the levels should be monitored frequently. Levels above 700 to 800 mg/dL are a reason for interrupting therapy or treating the patient with a lipid-lowering drug. Eruptive exanthemas or pancreatitis can occur at higher serum triglyceride levels.

DIET. Several articles suggesting a role for diet in acne exist.105,106 A recent review of these studies concluded that there may be some link between milk and acne as well as between high-glycemic index foods and acne.107 Yet, overall the implications of these studies is not clear and the role of chocolate, sweets, milk, highglycemic index foods, and fatty foods in patients with acne requires further study. There is no evidence to support the value of elimination of these foods. However, restricting a food firmly thought by the patient to be a trigger is not harmful, as long as the patient’s nutritional well-being is not compromised. ACNE SURGERY. Acne surgery, a mainstay of therapy in the past used for the removal of comedones and superficial pustules, aids in bringing about involution of individual acne lesions. However, with the advent of comedolytic agents, such as topical retinoids, its use is primarily restricted to those patients who do not respond to comedolytic agents. Even in those patients, the comedones are removed with greater ease and less trauma if the patient is pretreated with a topical retinoid for 3–4 weeks. Acne surgery should not be performed at home, as inaccurate placement of the comedo extractor may rupture the follicle and incite an inflammatory reaction. The Unna type of comedo extractor, which has a broad flat plate and no narrow sharp edges, is preferable. The removal of open comedones is desirable for cosmetic purposes, but does not significantly influence the course of the disease. In contrast, closed comedones should be removed to prevent their rupture. Unfortunately, the orifice of closed comedones is often very small, and usually the material contained within the comedo can be removed only after the orifice is gently enlarged with a no. 25 needle or other suitable sharply pointed instrument. INTRALESIONAL GLUCOCORTICOIDS. Intralesional injection of glucocorticoids can dramatically decrease the size of deep nodular lesions. The injection of 0.05–0.25 mL per lesion of a triamcinolone acetate suspension (2.5–10 mg/mL) is recommended as the anti-inflammatory agent. This is a very useful form of therapy in the patient with nodular acne, but it often has to be repeated every few weeks. A major advan-

tage is that it can be done without incising or draining the lesions, thus avoiding the possibility of scar formation. Hypopigmentation, particularly in darker skinned patients, and atrophy are risks.

PHOTOTHERAPY AND LASERS. Various forms of phototherapy are under investigation for their use in treating acne vulgaris. Ultraviolet (UV) light has long been thought to be beneficial in the treatment of acne. Up to 70% of patients report that sun exposure improves their acne.108 This reported benefit may be due to camouflage by UV radiation induced erythema and pigmentation, although it is likely that the sunlight has a biologic effect on the pilosebaceous unit and P. acnes. Although ultraviolet B (UVB) can also kill P. acnes in vitro, UVB penetrates poorly to the dermal follicle and only high doses causing sunburn have be shown to improve acne.109,110 UV radiation may have anti-inflammatory effects by inhibiting cytokine action.111 Twice-weekly phototherapy sessions are needed for any clinical improvement. The therapeutic utility of UV radiation in acne is superseded by its carcinogenic potential.112–116 Other types of phototherapy for acne treatment utilize porphyrins. Treatment of acne with phototherapy works either by activating the endogenous porphyrins of P. acnes or by applying exogenous porphyrins. Coproporphyrin III is the major endogenous porphyrin of P. acnes. Coproporphyrin III can absorb light at the near-UV and blue light spectrum of 415 nm.117 Irradiation of P. acnes with blue light leads to photoexcitation of endogenous bacterial porphyrins, singlet oxygen production, and subsequent bacterial destruction.118 A visible light source, either blue or red, or both may be used to excite the endogenous porphyrins. The high intensity, enhanced, narrowband (407–420 nm) blue light known as ClearLight (Lumenis) is currently FDA approved for the treatment of moderate inflammatory acne.116 Red light too may be beneficial, as it penetrates deeper into the dermis and has greater anti-inflammatory properties, but causes less photoactivation of the porphyrins. Therefore, the combination of blue and red light may prove the most beneficial. Treatments should be given twice weekly for 15-minute sessions for the face alone, and 45 minutes for the face, chest, and back. A multicenter study has shown that 80% of patients treated with the ClearLight for 4 weeks had a 60% reduction in acne lesions. There was a gradual return of lesions over 3–6 months.119 The most consistent improvement in acne after light treatment has been demonstrated with photodynamic therapy.120 Photodynamic therapy involves the topical application of aminolevulinic acid (ALA) 1 hour prior to exposure to a low-power light source. These sources include the pulsed dye laser, intense pulsed light, or a broadband red light source. The topical ALA is taken up by the pilosebaceous unit and metabolized to protoporphyrin IX.121 The protoporphyrin IX is targeted by the light and produces singlet oxygen species, which then damage the sebaceous glands.122 Several studies utilizing ALA-PDT maintained clinical improvement for up to 20 weeks.123,124

Neonatal acne can occur in up to 20% of healthy newborns. Lesions usually appear around 2 weeks of age and resolve spontaneously within 3 months. Typically, small, inflamed papules affect the nasal bridge and the cheeks. Because comedone formation is absent, many consider neonatal acne a variant of neonatal cephalic pustulosis. However, it has been shown that sebum excretion rates in newborns are transiently elevated in the perinatal period.134 Additionally, Malassezia sympodialis, a normal commensal on human skin, may also play a role. Some reports have demonstrated positive cultures of the pustules with Malassezia and improve-

INFANTILE ACNE Infantile acne presents at 3–6 months of age and typically shows comedones. Papules, pustules, and nodules can also present on the face and scarring may occur even with relatively mild disease. Infantile acne is caused in part by the transient elevation of DHEA produced by the immature adrenal gland. Additionally, during the first 6–12 months of life boys may also have an increased level of LH that stimulates testosterone production. Around 1 year of age, these hormone levels begin to stabilize until they surge again during adrenarche. As a result, infantile acne usually resolves around 1–2 years of age. Treatment generally consists of topical retinoids and benzoyl peroxide. Oral therapy with erythromycin, trimethoprim, or isotretinoin can be used in severe or refractory cases.136

ACNE CONGLOBATA This severe form of nodular acne is most common in teenage males, but can occur in either sex and into adulthood. Acne conglobata (conglobate means shaped in a rounded mass or ball) is a mixture of comedones, papules, pustules, nodules, abscesses, and scars. It can be on the back, buttocks, chest, and, to a lesser extent, on the abdomen, shoulders, neck, face, upper arms, and thighs (Fig. 80-6). The comedones often have multiple openings. The inflammatory lesions are large, tender, and dusky-colored. The draining lesions discharge a foul-smelling serous, purulent, or mucoid material. Subcutaneous dissection with the formation of multichanneled sinus tracts is common. Healing results in an admixture of depressed and keloidal scars. The management of these patients is very difficult and the effect of treatment is often temporary. Several medications have been used, including intensive high-dose therapy with antibiotics, intralesional glucocorticoids, systemic glucocorticoids, surgical debridement, surgical incision, and surgical excision. The use of isotretinoin has produced dramatic results in some of these patients. In severe cases, dosages as high as 2 mg/kg/ day for a 20-week course may be necessary. However, because severe flares may occur when isotretinoin is started, the initial dose should be 0.5 mg/kg/day or less, and systemic glucocorticoids are often required either before initiating isotretinoin therapy or as concomitant therapy.

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NEONATAL ACNE

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ACNE VARIANTS

ment with ketoconazole cream.135 While there appears to be a strong association between Malassezia and neonatal acne, definite causality has not yet been proven.136

Chapter 80

Although lasers are beginning to find a role in the treatment of acne, the authors consider them inferior to the traditional medical treatments. They work by emitting minimally divergent, coherent light that can be focused over a small area of tissue. The pulsed KTP laser (532 nm) has demonstrated a 35.9% decrease in acne lesions when used twice weekly for 2 weeks. Although there was no significant decrease in P. acnes, there was significantly lower sebum production even at 1 month.125 The pulsed dye laser (585 nm) can also be used at lower fluences to treat acne. Instead of ablating blood vessels and causing purpura, a lower fluence can stimulate procollagen production by heating dermal perivascular tissue.122 The beneficial effects of a single treatment can last 12 weeks.126 Some of the nonablative infrared lasers, such as the 1,450 nm and 1,320 nm laser, have shown to be helpful in improving acne.127,128 These lasers work by causing thermal damage to the sebaceous glands. The concurrent use of a cryogen spray device protects the epidermis while the laser causes necrosis of the sebaceous gland.129 In a pilot study, 14 out of 15 patients treated with the 1,450 nm laser had a significant reduction in inflammatory lesions that persisted for 6 months. The 1,320 nm Nd:Yag and the 1,540 erbium glass lasers have also been demonstrated to improve acne.130,131 Multiple treatments are needed with either of these lasers to lessen acne lesions. These treatments tend to be painful and show a gradual modest improvement, limiting their utility. One of the newer uses of light for treating acne is with a photopneumatic device (Isolaz, Solta Medical). This photopneumatic device has a handpiece that applies negative pressure (i.e., suction) to the skin and then delivers a broadband-pulsed light (400–1,200 nm). The suction is employed to unplug the infundibulum of the pilsebaceous unit and the light is delivered to activate the P. acnes porphyrins, thus releasing singlet oxygen species. Patients treated with this device may experience some posttreatment erythema or purpura. Results are modest and temporary and the device is best for inflammatory lesions.132,133 Although the lightbased treatments are beneficial in that they avoid some of the side effects of the oral medications, the cost of these light and laser treatments tends to be prohibitive.

ACNE FULMINANS Acne fulminans (also known as acute febrile ulcerative acne) is the most severe form of nodular acne and is accompanied by systemic symptoms. The sudden appearance of massive, inflammatory, tender, oozing, friable plaques with hemorrhagic crusts characterize acne fulminans. The lesions predominate on the chest

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A

B

Figure 80-8  Acne fulminans. An eruptive form of acne with extensive inflammatory papules and nodules on the chest (A) and back (B). Systemic symptoms may accompany this extreme form of acne and scarring is usually quite extensive.

:: Disorders of the Sebaceous Glands

and back (Figs. 80-8A and 80-8B) and rapidly become ulcerative and heal with scarring. The disease is reported to occur primarily in teenage boys. The face is often uninvolved. The patients are febrile, have a leukocytosis of 10,000–30,000/mm3 white blood cells, and usually have polyarthralgia, myalgia, hepatosplenomegaly, and anemia. Bone pain is common, especially at the clavicle and sternum. Radiologic examination may demonstrate lytic bone lesions. Occasionally there is accompanying erythema nodosum. Although this disease is often classified with acne conglobata, there are basic differences. The onset of acne fulminans is more explosive; nodules and polymorphous comedones are less common; the face is not involved as frequently and the neck is usually spared; ulcerative and crusted lesions are unique; and systemic symptoms are more common. Systemic glucocorticoid therapy, along with oral antibiotics and intralesional glucocorticoids, is the treatment regimen required for these patients. Isotretinoin is also of benefit in these patients, but in order to prevent explosive flares, systemic glucocorticoids must be started before isotretinoin and continued during the first few weeks of isotretinoin therapy. The initial dosing of isotretinoin must also be lowered accordingly in the initial weeks of therapy until the inflammation is controlled. The daily dose of glucocorticoids should be slowly decreased as tolerated. Dapsone in conjunction with isotretinoin has been reportedly beneficial in the treatment of acne fulminans associated with erythema nodosum.

SAPHO SYNDROME

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SAPHO syndrome is manifested by synovitis, acne, pustulosis, hyperostosis, and osteitis. It is predominantly associated with hyperostosis of the anterior chest, palmoplantar pustulosis, hidradenitis suppurativa, and acne fulminans. Its etiology is unknown. Reported successful treatments for SAPHO syndrome are NSAIDS, sulfasalazine, and infliximab.137 The bisphosphonates are beneficial for treating the associated bone pain.138

PAPA SYNDROME PAPA syndrome, another acne variant with systemic symptoms, is marked by sterile pyogenic arthritis, pyoderma gangrenosum, and acne. Patients with PAPA syndrome may also give a history of sterile cutaneous abscesses, inflammatory bowel disease, and pancytopenia following administration of sulfacontaining medications.139 It is an autoinflammatoy disorder inherited in an autosomal dominant manner. Due to mutations in the CD2 binding protein-1 gene (also known as the protein serine–threonine phosphatase interacting protein), there is an increase in IL-1β production.140 There have been reports of successful treatment with infliximab and anakinra.139,140

ACNE EXCORIÉE DES JEUNES FILLES Acne excoriée des jeunes filles, as the name suggests, occurs primarily in young women who are picking at their skin. Mild acne may be present and is accompanied by extensive excoriations. Comedones and papules are systematically and neurotically excoriated leaving crusted erosions that may scar. Often the lesions that are excoriated are minute. This condition may suggest underlying depression, anxiety, obsessive–compulsive disorder, or a personality disorder. Antidepressants and psychotherapy can be helpful in treating these patients.

ACNE MECHANICA Acneiform eruptions have been observed after repetitive physical trauma to the skin such as rubbing. This can occur from clothing (belts and straps) or sports equipment (football helmets and shoulder pads). Occluding the skin with adhesive tape can also produce acne mechanica. Obstruction of the pilosebaceous gland results in comedo formation. It presents as a well-defined, lichenified, hyperpigmented plaque interspersed with comedones. A classic example of

acne mechanica is fiddler’s neck, produced where the violin pad repetitively rubs against the player’s lateral neck.

ACNE WITH SOLID FACIAL EDEMA

POLYCYSTIC OVARY SYNDROME. Polycystic ovary syndrome (PCOS) occurs in roughly 3%–6% of the general population. Patients with PCOS, also called Stein–Leventhal syndrome, ovulate infrequently or not at all, have multiple cysts on their ovaries, and often have irregular menses, obesity, androgenic alopecia, hirsutism, and acne. There is an increased risk of diabetes mellitus and endometrial carcinoma in patients with PCOS.143 Serum total testosterone in the range of 150–200 ng/dL or an increased LH/FSH ratio (greater than 2.0) can be found in cases of PCOS. Patients with signs of hyperandrogenism should also be asked about insulin resistance, since acne can occur with the HAIR-AN syndrome, a subset of PCOS. Hyperandrogenism, acne, insulin resistance, and acanthosis nigricans are markers of this syndrome. It is important to identify these patients because they are at increased risk for accelerated cardiovascular disease and diabetes mellitus. CONGENITAL

ADRENAL

HYPERPLASIA.

Congenital adrenal hyperplasia, usually caused by defects in the adrenal enzyme 21β-hydroxylase, occurs as both a classic severe type and as a nonclassic mild type. Neonates are screened at birth for the classic type and typically present with ambiguous genitalia and salt-wasting. The nonclassic type is not identified at

Following administration of systemic glucocorticoids or corticotropin, folliculitis may appear. This is very uncommon in children but may occur in any adult as early as 2 weeks after steroids are started. Similar lesions may follow the prolonged application of topical glucocorticoids to the face. For this reason, topical glucocorticoids have no place in the treatment of acne, and their use on the face, in general, should be limited. The pathology of steroid acne is that of a focal folliculitis with a neutrophilic infiltrate in and around the follicle. This type of acne clearly differs from acne vulgaris in its distribution and in the type of lesions observed. The lesions, which are usually all in the same stage of development, consist of small pustules and red papules. In contrast to acne vulgaris, they appear mainly on the trunk, shoulders, and upper arms, with lesser involvement of the face. Postinflammatory hyperpigmentation may occur, but comedones, cysts, and scarring are unusual. Treatment consists primarily of stopping any corticosteroid use. Typical acne treatments such as topical retinoids and antibiotics may also be helpful.

Acne Vulgaris and Acneiform Eruptions

Although the majority of cases of acne vulgaris occur in patients without endocrinologic disturbances, there is a certain population whose acne is driven or worsened by endocrine abnormalities. As mentioned previously, it is important to screen patients for such abnormalities by taking a thorough history. In addition to the presence of acne, endocrinologic disturbances may be marked by irregular menstrual cycles, deepened voice, increased libido, and hirsutism. Laboratory work can help define an endocrinologic problem causing acne.

STEROID FOLLICULITIS

::

ACNE WITH ASSOCIATED ENDOCRINOLOGY ABNORMALITIES

ACNEIFORM ERUPTIONS

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Chapter 80

A rare and disfiguring variant of acne vulgaris is acne with solid facial edema, also known as Morbihan’s disease. There is a woody edema of the midthird face with accompanying erythema and acne. Similar changes have been reported with rosacea, Melkerson– Rosenthal syndrome, and rosacea. There may be fluctuations in the severity of the edema, but spontaneous resolution does not occur. Oral antibiotic treatment is ineffective. Treatment with low dose isotretinoin (0.2–0.5 mg/kg/day) alone or in combination with oral glucocorticoids, ketotifen (1–2 mg/ day), or clofazimine for 4–5 months has been reported to be beneficial.141,142

birth and can present throughout childhood and adolescence. The prevalence of the nonclassic type in the white population is 1 in 1,000. Patients with this type of congenital adrenal hyperplasia have normal cortisol levels but increased androgens. Female patients present with precocious puberty, irregular menses, polycystic ovaries, hirsutism, and acne.144 Values of DHEAS in the range of 4,000–8,000 ng/mL are suggestive of congenital adrenal hyperplasia. Findings of CAH in males are often subtle, as acne may be the only sign, but CAH should be considered in patients who do not respond to treatment.145 Treatment of congenital adrenal hyperplasia consists of low dose replacement of glucocorticoids, as well as oral contraceptives, spironolactone, or flutamide in females.

DRUG-INDUCED ACNE In addition to glucocorticoids, other medicines can also cause a monomorphic, diffuse popular eruption that mimics steroid folliculitis. Such drugs include: phenytoin, lithium, isoniazid, high doses of vitamin B complexes, halogenated compounds, and certain chemotherapy medications (see Box 80-2). Halogenated compounds containing either bromides or iodides are often found in cold and asthma remedies, sedatives, radioopaque contrast material, kelp (in many fad diet pills), and other vitamin–mineral combinations. With iodides, in particular, inflammation may be marked.146,147 The iodine content of iodized salt is low and, therefore, it is extremely unlikely that enough iodized salt could be ingested to cause this type of acne.

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Box 80-2  Drug-Induced Acneiform Eruptions

Glucocorticoids Phenytoin Lithium Isoniazid High-dose vitamin B complex Halogenated compounds Epidermal growth factor receptor inhibitors

Section 13

EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITOR ASSOCIATED ERUPTION

:: Disorders of the Sebaceous Glands

A newer class of chemotherapy medicine, known as the EGFR inhibitors, may also cause a follicular-based eruption. EGFR inhibitors are primarily used to treat nonsmall-cell lung cancer, colorectal cancer, and breast cancer. Some of the EGFR inhibitors include: gefitinib (Iressa), cetuximab (Erbitux), erlotinib (Tarceva), and trastuzumab (Herceptin). In treatment responsive patients, the EGFR inhibitors are indefinitely administered for their long-term ability to inhibit tumor growth, progression, cell proliferation, and angiogenesis. A frequent side effect of the EGFR inhibitors is a perifollicular, papulopustular eruption distributed on the face and upper torso. The eruption occurs in up to 86% of patients treated with EGFR inhibitors. An associated lateral paronychia may also occur. Histopathological sections of lesional skin show a noninfectious perifolliculitis.148 The etiology of the acneiform eruption is not clear, but it may occur because EGFR is highly expressed in the basal cell layer of the epidermis, follicular keratinocytes, and the sebaceous epithelium. The presence and severity of the eruption correlates with a positive treatment response. If the eruption is absent, dosing may be inadequate or the patient’s tumor may be unresponsive to EGFR inhibitor therapy.149

OCCUPATIONAL ACNE AND CHLORACNE

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Several different groups of industrial compounds encountered in the workplace may cause acne. These include coal tar derivatives, insoluble cutting oils, and chlorinated hydrocarbons (chloronaphthalene, chlorobiphenyls, and chlorodiphenyloxide). Chloracne is the term that is used to describe occupational acne caused from chlorinated hydrocarbons. Occupational acne tends to be quite inflammatory and, in addition to large comedones, is characterized by papules, pustules, large nodules, and true cysts. Tar acne is often accompanied by hyperpigmentation. The lesions of occupational acne are not restricted to the face and, in fact, are more common on covered areas with intimate contact

to clothing saturated with the offending compound. Because the cutting oils are so widely used, they are the most common cause of industrial acne. However, the chlorinated hydrocarbons, which cause chloracne, have posed a more difficult problem because of the severity of the disease induced with these compounds. Exposure can cause comedones, cysts, and pigmentary changes of the skin but can also affect the ophthalmic, nervous and hepatic systems.150 Many cases have occurred as the result of massive exposure in industrial accidents.151 Chlorinated hydrocarbons are found in fungicides, insecticides, and wood preservatives. Chloracne classically affects the malar, retroauricular, and mandibular regions of the head and neck, as well as the axillae and scrotum (see eFig. 80-7.1 in online edition), Pathology demonstrates multiple tiny infundibular cysts.152 In 2,004, Ukrainian President Viktor Yushchenko was poisoned with dioxin, causing severe chloracne. Most chloracne lesions clear up within 2 years, providing exposure to the chemical has stopped. Treatment with topical or oral retinoids and oral antibiotics may be beneficial.

GRAM-NEGATIVE FOLLICULITIS Gram-negative folliculitis may occur in patients with preexisting acne vulgaris treated with long-term oral antibiotics, especially the tetracyclines. Patients usually give a history of initial success with oral tetracyclines followed by a worsening of their acne. Gram-negative folliculitis may appear as either papulopustules concentrated around the nose or as deepseated nodules. Culture of these lesions may reveal Enterobacter, Klebsiella, or Escherichia in the papulopustules or Proteus in the nodules. An appropriate antimicrobial agent with adequate Gram-negative coverage should be used. In recalcitrant cases, Gram-negative folliculitis improves with oral isotretinoin for 4–5 months. Gram-negative bacteria require a moist environment for survival and the drying action of isotretinoin will kill the bacteria.

RADIATION ACNE Different types of radiation such as ionizing radiation and UV radiation may induce acneiform eruptions. Previous sites of therapeutic ionizing radiation (e.g., external beam) can develop comedo-like papules. These lesions begin to appear as the acute phase of radiation dermatitis is resolving. The ionizing rays induce epithelial metaplasia within the follicle, creating adherent hyperkeratotic plugs in the pilosebaceous unit. These keratotic plugs are resistant to extraction. Excessive exposure to UV radiation may produce a yellow, atrophic plaque studded with large open comedones. This condition is known as Favre– Racouchot, but has also been called solar comedones, senile comedones, nodular cutaneous elastosis with cysts and comedones, and nodular elastoidosis with cysts and comedones. It has been estimated to occur in 6% of persons above age 50.153 The lesions are usually

13

symmetrically distributed on the temporal and periorbital areas. The exact pathogenesis of Favre–Racouchot is unknown, but it is suggested that extensive UV exposure as well as exposure to harsh climates and smoking may be risk factors. It can be treated with oral or topical retinoids as well as extraction.154

TROPICAL ACNE

PSEUDOACNE OF THE NASAL CREASE The transverse nasal crease is an anatomic variant that appears as a transverse linear groove across the middle of the nose. Preadolescent patients have been described to develop acneiform red papules within the nasal crease along with milia (Fig. 80-9). Histologic examination of the papules reveals keratin granulomas that may be derived from ruptured, inflamed milia. Due to its similarity in clinical appearance to acne, but deviation from acne histologically, it has been termed “pseudoacne of the nasal crease.”155

Apert syndrome, also known as acrocephalosyndactyly, is an autosomal dominant disorder marked by synostoses of the cranium, vertebral bodies and hands and feet. It is caused by a mutation in the gene encoding FGFR-2. These patients have a diffuse acneiform eruption that often involves the arms, buttocks, and thighs. It is typically very resistant to treatment but excellent responses to isotretinoin have been reported. Patients with Apert syndrome may also present with severe seborrhea, nail dystrophy, and cutaneous and ocular hypopigmentation.

KEY REFERENCES Full reference list available at www.DIGM8.com

Acne Vulgaris and Acneiform Eruptions

This monomorphous eruption consists of multiple, uniform, red, papular lesions seen after sun exposure. It is referred to as Mallorca acne because it occurred in many Scandinavians after they had been on a sunny vacation in Mallorca in southern Europe after a long, dark winter. Almost all cases have occurred in women, mainly 20–30 years old. The lesions are common on the shoulders, arms, neck, and chest. Histologically, the lesions resemble steroid acne in that they show a focal follicular destruction with neutrophilic infiltrate. Comedones are not part of the clinical or histologic picture. The eruption is due to the effects of UV radiation, primarily ultraviolet A (UVA). Rarely, a similar clinical picture can be observed after starting psoralen and UVA (PUVA) treatment. The eruption will subside if the patient is protected from UV light for several months. Oral antibiotics are ineffective in speeding up the resolution, but topical retinoids and benzoyl peroxide may be helpful. Like polymorphous light eruption, patients with acne aestivalis will flare on reexposure to UV light.147

APERT SYNDROME

::

ACNE AESTIVALIS

Figure 80-9  Pseudoacne of the nasal crease. Open and closed comedones and small papules line up along the transverse nasal crease.

Chapter 80

In extreme heat, a severe acneiform folliculitis may develop. This can be seen in tropical climates or in scorching occupational environments, as in furnace workers. This acneiform eruption is a major cause of dermatologic disability in military troops serving in tropical climates. Tropical acne occurs mainly on the trunk and buttocks. It has many deep, large, inflammatory nodules with multiple draining areas, resembling acne conglobata. The pathogenesis of this type of acne is unknown, although secondary infection with coagulase-positive Staphylococci almost always ensues. Systemic antibiotics must be given, but often more important is removing the patient to a cooler environment.

DVD contains references and additional content 3. Bataille V et al: The influence of genetics and environmental factors in the pathogenesis of acne: A twin study of acne in women. J Invest Dermatol 119:1317-1322, 2002 12. Munro CS, Wilkie AO: Epidermal mosaicism producing localised acne: Somatic mutation in FGFR2. Lancet 352:704-705, 1998 26. Jeremy A et al: Inflammatory events are involved in acne lesion initiation. J Invest Dermatol 121:20-27, 2003 35. Kim J et al: Activation of toll-like receptor 2 in acne triggers inflammatory cytokine responses. J Immunol 169:1535-1541, 2002 49. Mallon E et al: The quality of life in acne: A comparison with general medical conditions using generic questionnaires. Br J Dermatol 140(4):672-676, 1999 53. Gollnick H, Schramm M: Topical therapy in acne. J Eur Acad Dermatol Venereol 11(1), 1998 75. Ross JI et al: Antibiotic-resistant acne: Lessons from Europe [see comment]. Br J Dermatol 148(3):467-478, 2003 94. Marqueling AL et al: Depression and suicidal behavior in acne patients treated with isotretinoin: A systematic review. Semin Cutan Med Surg 26(4):210-220, 2007 99. Bernstein CN et al: Isotretinoin is not associated with inflammatory bowel disease: A population-based casecontrol study. Am J Gastroenterol 104(11):2774-2778, 2009 100. DiGiovanna JJ et al: Effect of a single course of isotretinoin therapy on bone mineral density in adolescent patients with severe, recalcitrant, nodular acne [see comment]. J Am Acad Dermatol 51(5):709-717, 2004

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Chapter 81 :: Rosacea :: Michelle T. Pelle ROSACEA AT A GLANCE Rosacea affects all races, but is most common in fair-skinned individuals.

Section 13

Triggers of rosacea may include hot or cold temperature, sunlight, wind, hot drinks, exercise, spicy food, alcohol, emotions, cosmetics, topical irritants, menopausal flushing, and medications that promote flushing.

:: Disorders of the Sebaceous Glands

There are four rosacea subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. The primary clinical features of rosacea include flushing, inflammatory papules, pustules, and telangiectases. Secondary features of rosacea may include facial burning and stinging, edema, plaques, a dry appearance, phyma, peripheral flushing, and ocular manifestations. Sun protection and trigger avoidance are important for prevention in all types of rosacea. Rosacea therapy may include barrier protection practices, topical antimicrobials, oral antibiotics, retinoids, intense pulsed light, and vascular laser modalities for adequate long-term control of symptoms.

ROSACEA

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Despite universal recognition, rosacea is clinically varied and of uncertain pathophysiology. Practitioners and the public can easily identify the prototypical red face of rosacea; however, confusion arises when photodamage, perioral dermatitis, postadolescent acne, and topical steroid overuse present in a similar guise. Recent theory has shifted conceptually from staged progression of rosacea signs and symptoms to a new classification that defines four subtypes with variable severity and potential overlap. Rosacea is characterized by erythema of the central face that has persisted for months or more. The convex areas of the nose, cheeks, chin, and forehead are the characteristic distribution. Primary features of rosacea, which may be observed but are not required for the diagnosis, include flushing, papules, pustules, and

telangiectases. Secondary features include facial burning or stinging, edema, plaques, a dry appearance, phyma, peripheral flushing, and ocular manifestations. Erythema in peripheral locations (the scalp, ears, lateral face, neck, and chest) can be observed in rosacea, but is also a common feature of physiologic flushing and chronic sun damage, and therefore must be interpreted carefully.1

SUBTYPE CLASSIFICATION The subtypes of rosacea were defined provisionally by the National Rosacea Society (NRS) Expert Committee in 2002 and include erythematotelangiectatic, papulopustular, phymatous, and ocular subtypes.1 These represent the most common groupings of rosacea signs and symptoms. The subtypes coincide with the first rosacea “staging” classification devised by Plewig and Kligman.2 The erythematotelangiectatic subtype is analogous to Plewig–Kligman stage I disease, the papulopustular subtype to Plewig–Kligman stage II, and the phymatous subtype to Plewig–Kligman stage III. In contrast, the NRS classification maintains that progression of rosacea in stages (from one subtype to another) does not occur, but that subtypes may overlap in the same individual. A provisional grading system was also incorporated by the NRS Expert Committee to standardize the clinical assessment of rosacea.3 Rosacea severity assessments must additionally include consideration of the psychological, social, and occupational impacts of this disorder and individual responsiveness to treatment.

EPIDEMIOLOGY Although the prevalence of rosacea is unknown, the vast majority of cases occur in fair-skinned populations and it is common. However, persons of African and Asian descent may also develop rosacea.2,4 The NRS has estimated that rosacea affects 14 million Americans. Rosacea occurs in both men and women, with onset typically after age 30.1,5 However, children, adolescents, and young adults may develop rosacea.6–8

ETIOLOGY AND PATHOGENESIS Because of prominent clinical variation among the rosacea subtypes, it has been hypothesized that etiologic and pathophysiologic differences may exist. Such differences may involve facial vascular reactivity, dermal connective tissue structure or composition, matrix composition, pilosebaceous structure, microbial colonization, or a combination of factors that alter the cutaneous response to rosacea trigger factors.9 Rosacea is unmasked or induced by chronic, repeated trigger exposure, in particular by triggers of flushing that may

13

:: Rosacea

not progress to a rosacea phenotype, and photoprovocation studies in rosacea patients have not demonstrated increased cutaneous sensitivity to acute ultraviolet exposure.9,17,20,21 It has long been debated whether oral and topical antimicrobial agents for rosacea exert their effects by anti-inflammatory or antimicrobial mechanisms. The concept of microbe-induced, follicle-based inflammation in rosacea is controversial. It is unclear whether commensal organisms such as Propionibacterium acnes and Demodex folliculorum, which reside in hair follicles and sebaceous glands, trigger folliculocentric inflammatory papules in rosacea patients.9 Alternatively, a hypersensitivity reaction may be triggered by these microbes or by mite-associated bacteria such as Bacillus oleronius.22 Compelling arguments in favor of a microbe-induced mechanism for papulopustular rosacea (PPR) include the observation that nonsteroidal anti-inflammatory drugs and corticosteroids do not clear rosacea papules and pustules as effectively as oral tetracyclines. Furthermore, benzoyl peroxide is quite effective for papules and pustules in rosacea patients who tolerate this drug.10 It remains unclear whether clinical improvement of PPR requires a quantitative reduction of P. acnes.

Chapter 81

include hot or cold temperature, sunlight, wind, hot drinks, exercise, spicy food, alcohol, emotions, cosmetics, topical irritants, menopausal flushing, and medications that promote flushing.10 Both neural and humoral mechanisms produce flush reactions that are visibly limited to the face. Facial prominence occurs because baseline facial blood flow is increased compared with other body sites,11,12 and the facial cutaneous vasculature is more superficial and comprised of larger and more numerous vessels when compared with other sites.13 New investigations have demonstrated that exacerbation of the innate immune response occurs in rosacea.14,15 Individuals with rosacea express high levels of cathelicidin peptides, and those peptides are processed atypically compared to normal skin. Cathelicidin peptides appear to enable stratum corneum tryptic enzyme (SCTE)-mediated inflammation in the epidermis.14,15 Dermal factors also play a role in rosacea pathogenesis. Matrix degeneration and endothelial damage have been demonstrated histologically in rosacea specimens.16,17 Factors that contribute to matrix degeneration include inherent problems with vessel permeability and/or delayed clearance of inflammatory mediators and waste products. Alternatively, photodamaged connective tissue may alter vascular and lymphatic structure and support within the dermis.18 In either case, chronic and persistent dermal inflammation may occur and ultimately manifest as erythema of the facial convexities in predisposed individuals.19 Sun damage is considered a contributing etiologic factor, and solar elastosis is a common background on which rosacea histologic features are superimposed. However, rosacea prevalence is not increased in outdoor workers, sun damage in nonfacial locations does

CLINICAL FEATURES Erythematotelangiectatic rosacea (ETR) is characterized by persistent facial erythema and flushing along with telangiectases, central face edema, burning and stinging, roughness or scaling, or any combination of these signs and symptoms (Fig. 81-1). Mild, moderate,

B

A

C

Figure 81-1  A. Erythematotelangiectatic subtype, mild. B. Erythematotelangiectatic subtype, severe. C. Close-up detailing the common occurrence of erythematotelangiectatic and papulopustular subtype overlap.

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Section 13 :: Disorders of the Sebaceous Glands

A

Figure 81-2  A. Papulopustular subtype. There is persistent erythema with papules and tiny pustules. Mild subtype. B. Severe form of the papulopustular subtype. and severe subtypes are recognized. In contrast, PPR manifests as persistent, central-face erythema with papules and pustules that predominate in convex areas (Fig. 81-2).9 Again, mild (see Fig. 81-2A), moderate, and severe forms (see Fig. 81-2B) are distinguished. Burning and stinging of the facial skin may occur in PPR, but occurs less commonly compared with ETR. Flushing is often less severe in PPR compared with ETR. In both subtypes, erythema spares the

A

920

B

periorbital areas. Edema can be mild or severe. Severe edema may take on the plaque morphology of solid facial edema.1,23 This occurs most often on the forehead and glabella and it less commonly affects the eyelids and upper cheeks. Phymatous rosacea is characterized by patulous follicular orifices, thickened skin, nodularities, and irregular surface contours in convex areas (Fig. 81-3). Here also, mild, moderate, and severe subtypes are distinguished.

B

Figure 81-3  A. Phymatous subtype. Moderate subtype with patulous follicular orifices, thickened skin, and nodularities on nose and cheeks. B. Severe rhinophyma.

13

Chapter 81

HISTOPATHOLOGY Rosacea is a clinical diagnosis; histology may be helpful when the facial distribution is atypical or when

Figure 81-5  Granulomatous rosacea. There are multiple monomorphic red and yellow brown papules that, on diascopy, show apple-jelly-like color.

Rosacea

Phyma most often occurs on the nose (rhinophyma), but may also develop on the chin (gnathophyma), forehead (metophyma), eyelids (blepharophyma), and ears (otophyma).24 Women with rosacea do not develop phyma, perhaps for hormonal reasons, but they can manifest sebaceous or glandular features characterized by thickened skin and large follicular orifices.9 Ocular rosacea may develop before cutaneous symptoms in up to 20% of affected individuals25 (Fig. 81-4). In half of patients, ocular symptoms develop after skin symptoms. In a minority, skin and eye symptoms present simultaneously.26 Ophthalmic rosacea severity does not coincide with cutaneous rosacea severity. Ocular involvement may manifest as blepharitis, conjunctivitis, iritis, scleritis, hypopyon, and keratitis; mild, moderate, and severe subtypes are recognized (see Fig. 81-4).26 Blepharitis is the most common feature, characterized by eyelid margin erythema, scale, and crust, with the variable presence of chalazia and staphylococcal infections due to underlying meibomian gland dysfunction.25 Photophobia, pain, burning, itching, and foreign body sensation may be part of the ocular symptom complex. In severe cases, rosacea keratitis may lead to vision loss. Granulomatous rosacea is considered the only true rosacea variant.1 Granuloma formation is a histologic feature of the condition; the clinical features of granulomatous rosacea include yellow–brown or red papules or nodules that are monomorphic and located on the cheeks and periorificial facial skin27 (Fig. 81-5). Upon diascopy, these papules reveal apple-jelly-like change in color similar to sarcoidosis or lupus vulgaris. The background facial skin is otherwise normal. Other signs and symptoms of rosacea are not required to make a diagnosis of granulomatous rosacea.

::

Figure 81-4  Ocular subtype, severe. This patient has blepharitis, conjunctivitis, and keratitis.

granuloma formation is suspected. In ETR, a sparse, perivascular lymphohistiocytic infiltrate is accompanied by dermal edema and ectatic venules and lymphatics.16 Severe elastosis may be present. Similar features are found in the papulopustular subtype, but the inflammatory infiltrate also surrounds hair follicles and sebaceous glands. Phymatous rosacea is characterized by prominent elastosis, fibrosis, dermal inflammation, sebaceous hyperplasia, and hypertrophy of sebaceous follicles.16,28 Epithelialized tunnels undermine the hyperplastic tissue and are filled with inflammatory debris. D. folliculorum mites may be found in all types of rosacea within the follicular infundibula and sebaceous ducts.28

DIFFERENTIAL DIAGNOSIS (Fig. 81-6) Systemic diseases that must be differentiated from rosacea include polycythemia vera, connective tissue disorders (lupus erythematosus, dermatomyositis), carcinoid syndrome, mastocytosis, and neurologic causes of flushing. Neurologic causes include brain tumors, spinal cord lesions, orthostatic hypotension, migraine headaches, and Parkinson disease.29 Unilateral auriculotemporal flushing may follow parotid gland injury or surgery.30 Medication-induced flushing has been associated with all vasodilators, calcium channel blockers, nicotinic acid (niacin), morphine, amyl and butyl nitrite, cholinergic drugs, bromocriptine, thyroid releasing hormone, tamoxifen, cyproterone acetate, systemic steroids, and cyclosporine.29,31 The flush associated with nicotinic acid may be blocked with aspirin or indomethacin.32 Disulfiram, chlorpropamide,

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Diagnosis and therapy of the rosacea sub-types

Primary features Flushing Persistent erythema Papules and pustules Telangiectasia

Secondary features Burning/stinging Dry appearance Edema/plaques Peripheral erythema Ocular signs Phyma

Patient assessment Physical Psychological Social Occupational Response to therapy

Triggers Heat/cold Wind Hot drinks Spicy food Exercise Alcohol Emotions Topical irritants Medications Menopausal flushing

Section 13

Physician global sub-type assessment

:: Disorders of the Sebaceous Glands

Erythematotelangiectatic

All patients: Trigger avoidance Stress photoprotection Assess topical sensitivity Gentle cleanser Gentle emollient Therapeutics: Mild topical antimicrobials Low-dose isotretinoin Oral tetracyclines (or oral erythromycins or oral metronidazole) Vascular laser Intense pulsed light Topical retinoid maintenance Tretinoin cream plus emollient

Papulopustular

All patients: Trigger avoidance Photoprotection Assess sensitivity Therapeutics: Topical antimicrobial Oral antimicrobial (see ETR) Low to mild dose isotretinoin Vascular laser or intense pulsed light in some cases Topical retinoid maintenance

Phymatous (and “glandular” features in women)

Ocular

All patients: Trigger avoidance Photoprotection

All patients: Ophthalmology assessment

Therapeutics: Mild to high dose isotretinoin Spironolactone Surgical debulking and contouring techniques Topical and/or oral antimicrobials as needed for inflammatory lesions Topical retinoid maintenance

Therapeutics: Gentle nonmedicated cleanser Gentle S/S cleanser S/S 10% ophthalmic ointment Oral tetracyclines

Sub-type overlap Therapeutic modalities are chosen based on the sub-types and clinical features identified

Figure 81-6  Approach to patient. Diagnosis and therapy of the rosacea subtypes. aRegimen recommendation based on author experience. ETR = erythematotelangiectatic; S/S = sodium sulfacetamide/sulfur.

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metronidazole, phentolamine, and cephalosporins induce flushing when they are combined with alcohol.29 Amiodarone has induced rosacea and multiple chalazia.33 Food additives, including sulfites, sodium nitrite, nitrates, and monosodium glutamate, may also cause flushing.29 Dumping syndrome following gastric surgery is characterized by flushing, sweats, tachycardia, and abdominal pain. Cutaneous conditions that may mimic rosacea include topical steroid-induced acneiform eruption (formerly steroid-induced rosacea), acne vulgaris, perioral dermatitis, inflammatory keratosis pilaris, and chronic photodamage. In particular, acne vulgaris

(see Chapter 80) and rosacea may coexist, although rosacea most often begins and reaches its peak incidence in the decades after acne declines. The primary differentiating feature between acne vulgaris and rosacea is the presence of open and closed comedones in acne alone.2 Rosacea fulminans, also known as pyoderma faciale and rosacea conglobata, occurs mainly in women in their 20s.2,34,35 It is characterized by the sudden onset of confluent papules, pustules, nodules, and draining sinuses on the chin, cheeks, and forehead within a background of diffuse facial erythema. Rosacea fulminans has proved controversial in its classification and

TOPICAL THERAPY The topical agents approved by the US Food and Drug Administration (FDA) for rosacea include 15% azelaic

Rosacea

Before implementing therapy, rosacea trigger factors specific to each individual must be identified (see Fig. 81-6).10 Patient education should stress trigger avoidance. Other key aspects of prevention include the daily application of gentle, broad-spectrum ultraviolet A and ultraviolet B sunscreen, hat use, avoidance of midday sun, and seeking shade. Physical sunscreens (zinc or titanium based) are best tolerated. Chemical sunscreens are better tolerated when barrier protective silicones (dimethicone, cyclomethicone) are included.38 Cosmetic intolerance and facial skin sensitivity are common features of the erythematotelangiectatic and papulopustular subtypes, perhaps due to inherent barrier dysfunction or facial vascular hyperreactivity.39 As many as 75% of these individuals may experience burning, stinging, pruritus, or dryness and scaling in affected areas. Avoidance of harsh products and ingredients, including astringents, toners, menthol, camphor, and sodium lauryl sulfate, is important when sensitivity is present.40 A soapfree cleanser applied with the fingers is best tolerated. A protective, gentle emollient should be applied once or twice daily before application of other products. Light liquid foundation makeup is the best choice for patients with sensitivity. Green-tinted makeup can be applied before foundation to further mask red areas.40

13

::

THERAPY

acid gel, 0.75% and 1% metronidazole (available in cream, gel, and lotion vehicles), and 10% sodium sulfacetamide with 5% sulfur (available in cleanser, cream, suspension, and lotion vehicles). Each has proved effective for clearance of inflammatory papules and pustules and for erythema reduction when applied once daily.41 Twice-daily application or combinations of these agents may be necessary when topical monotherapy is inadequate. Metronidazole and azelaic acid are pregnancy category B, whereas sodium sulfacetamide and sulfur is category C. Azelaic acid may be associated with initial tingling or burning that can disappear with continued use. Sodium sulfacetamide/ sulfur medicated cleansers are better tolerated in sensitive patients compared with “leave-on” topical formulations that may increase burning and stinging.42 Daily use of a barrier repair emollient is important in these patients. Off-label topical formulations used for rosacea include benzoyl peroxide, clindamycin, erythromycin, calcineurin inhibitors, and topical retinoids.10 Benzoyl peroxide is effective for clearance of papules and pustules, but should be avoided in sensitive patients.10 Twice-daily topical clindamycin was more effective than oral tetracycline for the eradication of pustules in one series.43 Tacrolimus ointment and pimecrolimus cream are most beneficial for topical, steroid-induced acneiform eruptions, but they may offer a useful therapeutic alternative in some patients with rosacea. Niacinamide-containing facial emollients may improve stratum corneum barrier function and hydration, and have shown benefit as adjunctive topical therapy in rosacea.44 “Manual” therapy should also be considered adjunctively in rosacea patients. Facial massage is performed in the direction of the lymphatic flow, according to Soybe’s technique, beginning at a central location on the face (the glabella and nose) and pressing the fingers in a sweeping motion toward the inferolateral face (the mandibles and lateral neck).17 This can help to mobilize edema and speeds clearance of dermal inflammation. Tretinoin cream promotes connective tissue remodeling and minimizes dermal inflammation with longterm use.45–47 Topical retinoids have demonstrated benefit for rosacea in small clinical series.48,49 The clinical response to retinoids is delayed in the rosacea setting; generally 4 to 6 months of use is required to see significant effects. Because of their potential for irritation and concerns regarding promotion of angiogenesis, retinoids are often avoided for rosacea. However, their long-term use does not appear to promote the development of telangiectasia. Retinoids inhibit vascular endothelial growth factor production by cultured human skin keratinocytes via their anti-AP1 transcription factor activity.50,51 The use of barrier emollients in conjunction with gradual introduction of topical retinoids allows them to be tolerated early on in treatment when retinoid dermatitis is a problem. Topical retinoids are especially useful for long-term maintenance in rosacea. α-Adrenergic receptor agonist topical therapies (brimonidine, oxymetazoline) require further study

Chapter 81

was not included as a rosacea subtype or variant by the NRS Expert Committee.1,2 Perioral dermatitis (see Chapter 82) differs from rosacea in its facial distribution, signs, symptoms, and patient demographic. It is characterized by perioral, and sometimes periorbital, microvesicles, micropustules, scaling, and peeling. It affects younger women and also occurs in children. Central face erythema and inflammatory papules are not features of perioral dermatitis.9 Therapy includes topical and oral antimicrobials. Perioral dermatitis is exacerbated by topical steroid use. Steroid-induced acneiform eruption (see Chapter 80) can mimic PPR. With prolonged use of topical steroids on the face, monomorphic inflammatory papules may develop.1 The treatment is discontinuation of the topical corticosteroid and initiation of an oral tetracycline, a topical antimicrobial, a topical calcineurin inhibitor, or a combination of these agents.36,37 This regimen is generally continued for 1 to 3 months, and relapse does not tend to occur as long as topical steroids are not reintroduced. In chronic photodamage (see Chapter 90), telangiectases and erythema are prominent features. However, unlike rosacea, actinic damage affects the periphery of the face and neck, the upper chest, and the posterior auricular skin. Hyperpigmentation and hypopigmentation are additional feature of sun damage not observed in rosacea. Chin involvement is both mental and submental in rosacea, while in chronic photodamage there is submental sparing.9

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to characterize their efficacy and safety for ETR; however, their vasoconstrictive properties represent a novel approach for the treatment of telangiectasia and erythema.52,53

ORAL THERAPY

Section 13 :: Disorders of the Sebaceous Glands

Topical management of rosacea is possible and generally preferable, especially when considering issues of antimicrobial resistance and the risks associated with long-term use of oral antibiotics. Furthermore, because rosacea is photoaggravated in many affected individuals, photosensitizing oral agents must be used with caution in this population. Oral antimicrobials in particular are useful short-term tools that can achieve rapid control of symptoms, but long-term topical maintenance should be the eventual therapeutic goal. In 2006, Oracea (doxycycline, USP, 40 mg) became the first oral therapy to be FDA-approved for rosacea. For moderate to severe flushing or erythema, shortterm oral therapy (2 to 4 months) with a tetracycline or isotretinoin may be useful for initial control. Tetracyclines achieve faster reduction of papules, pustules, and erythema when compared with isotretinoin, and since the 1950s, rosacea has been treated and maintained with both antimicrobial and subantimicrobial dosages of the tetracyclines.54,55 Relapses occur in approximately onefourth of patients after 1 month off tetracycline, and in over one-half of patients at 6 months off therapy.55 Therefore, topical maintenance therapy is advised. Oral tetracyclines should be avoided in pregnant women and in those contemplating pregnancy. In one small series, a significant reduction of facial cutaneous blood flow, measured by laser-Doppler, was achieved in isotretinoin-treated patients (30 mg daily for 10 weeks), whereas no significant change in facial blood flow was observed in those treated with 250 mg of tetracycline twice daily for 10 weeks.56 Low-dose isotretinoin (10 to 40 mg daily or less than 0.5 mg/kg/ day) can be effective and is better tolerated in rosacea patients.57–59 Isotretinoin is teratogenic, and its use is strictly monitored in women of child-bearing potential. Other oral agents used for rosacea include macrolides, metronidazole, antiandrogenic agents (oral contraceptives, spironolactone, and cyproterone acetate), β blockers, clonidine, naloxone, and selective serotonin reuptake inhibitors.10,60–66 In patients with a history of acne vulgaris or overlap of acne vulgaris with rosacea, spironolactone in low doses (25 to 50 mg daily) and/ or oral contraceptive pills may prove helpful. When high levels of Demodex exacerbate rosacea, or in cases refractory to tetracyclines, ivermectin may be a useful adjunctive therapy. It can be given as a single 0.2 mg/kg dose repeated once weekly or once monthly as needed for symptom control.67

LASER AND LIGHT THERAPY 924

(See Chapter 239) Vascular lasers and intense pulsed light (IPL) therapy are useful alternatives to oral rosacea therapies;

they may be used adjunctively with topical and oral rosacea regimens for faster and more complete symptom resolution. These nonablative modalities can eliminate telangiectasia, reduce or eliminate erythema, reduce papule and pustule counts, and they appear to extend the duration of remission. Their drawbacks are cost and side effects, which may include transient erythema, edema, purpura, blistering, dyschromia, burns, and, rarely, scarring. Vascular lasers include short and long wavelength devices with a variety of pulse durations. Short wavelength lasers emit light that is selectively absorbed by oxyhemoglobin absorption peaks that occur at 541 nm and 577 nm. This allows for superficial vessel destruction without collateral tissue damage. Short wavelength lasers include the pulsed dye laser (585 nm or 595 nm), long pulsed dye laser (595 nm), the potassium-titanyl-phosphate laser (532 nm), and the diode-pumped frequency-doubled laser (532 nm).68–70 Long wavelength vascular lasers can eradicate deeper and larger vessels by targeting the oxyhemoglobin spectral peaks at 800 nm and above 1,000 nm. These lasers include the long pulsed Alexandrite (755 nm), the diode laser (810 nm), and the neodynium:yttriumaluminum-garnet laser (1,064 nm).10 The success and tolerability of laser therapy for rosacea have been improved by modified pulse duration parameters and by advances in epidermal cooling mechanisms. Longer pulse durations can deliver equivalent energy at a slower rate to heat vessels uniformly and gently, minimizing tissue trauma and purpura. Epidermal cooling gels and sprays prevent epidermal damage and can help to minimize pain, erythema, and edema and help to ensure safe delivery of laser energy. Generally, two to four laser treatments are required to achieve best outcomes for rosacea; purpuric treatment settings may eradicate telangiectasia more quickly. Multiple laser passes and pulse-stacking on larger vessels may improve treatment outcomes when subpurpuric settings are utilized.71 Unlike laser devices that emit a single wavelength, IPL (broadband light) emits a broad wavelength spectrum, ranging from approximately 550-nm visible light to 1,200-nm infrared light. Filters are used to establish the short end of the spectrum, which varies depending on the device. Fluence and pulse width also vary with the system used. IPL may cause transient erythema, transient hyperpigmentation, or hypopigmentation, and, rarely, purpura, burns, and scarring.72 Epidermal cooling mechanisms are necessary to protect the epidermis. IPL effectively reduces facial erythema and telangiectases and is generally well tolerated.72–74 Vascular lasers and IPL may also impact rosacea by inducing fibroblasts to increase dermal collagen production, perhaps achieving some degree of dermal remodeling and rejuvenation.75–77

TREATMENT OF PHYMA Oral isotretinoin monotherapy is beneficial for early to moderate phymatous change.24 Advanced phyma is treated with surgical therapy or the combination

of surgery followed by isotretinoin therapy. Surgical approaches to the reshaping of rhinophyma have included cold scalpel tangential excision, heated scalpel excision, electrocautery, dermabrasion, laser ablation, tangential excision combined with scissor sculpturing, radiofrequency electrosurgery, or a combination of these approaches.24,78–83 Techniques that use partial thickness tangential excision and contouring with preservation of the underlying sebaceous glands allow spontaneous reepithelialization within 2 to 3 weeks, result in minimal scarring, and give an excellent aesthetic result with a low risk of recurrence.83

To effectively treat rosacea, practitioners must recognize the clinical spectrum of rosacea phenotypes and what lies outside that spectrum. Subtyping of rosacea is a useful guide to establish a multimodality approach to therapy. Therapeutic success is achieved

Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Wilkin J et al: Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol 46:584, 2002 2. Plewig G, Kligman A: Acne and Rosacea, 3rd edition, Berlin, Springer-Verlag, 2000, p. 455 3. Wilkin J et al: Standard grading system for rosacea: Report of the National Rosacea Society Expert Committee on the classification and staging of rosacea. J Am Acad Dermatol 50:907, 2004 10. Pelle M, Crawford G, James W: Rosacea: II. Therapy. J Am Acad Dermatol 51:499, 2004 16. Marks R, Harcourt-Webster J: Histopathology of rosacea. Arch Dermatol 100:683, 1969 83. Bogetti P et al: Surgical treatment of rhinophyma: A comparison of techniques. Aesth Plast Surg 26:57, 2002

Perioral Dermatitis

SUMMARY

KEY REFERENCES

::

Ophthalmologic referral should be made for patients with ocular symptoms. For mild blepharitis, careful use of a gentle nonmedicated or sodium sulfacetamide/ sulfur cleanser may be used once to twice daily as initial therapy. Sodium sulfacetamide 10% ophthalmic ointment is also effective for control of blepharitis. When topical management is inadequate, oral tetracyclines are generally effective.7,25,26

13

Chapter 82

TREATMENT OF OCULAR ROSACEA

by inducing remission of signs and symptoms, and by minimizing and controlling relapses. Ultimately, early recognition of this disorder, some key behavioral modifications, and the combination of sunscreen and topical agents can achieve safe, effective, and longterm control of rosacea, while avoiding the risks of oral pharmaceuticals and the financial strain of laser and light therapies.

Recommended Reading Rosacea Symposium, ESDR 2009 and 2010. J. invest. Dermatol Symp Proc 15(1):1-62, 2011

Chapter 82 :: Perioral Dermatitis :: Leslie P. Lawley & Sareeta R.S. Parker PERIORAL DERMATITIS AT A GLANCE Inflammatory skin disorder of young women and children. Small papules, vesicles, and pustules in perioral, periorbital, and/or perinasal distribution. Treatment: stop topical corticosteroid use; initiate 2- to 3-month course of systemic antibiotics (tetracycline family or erythromycin) and/or topical metronidazole.

Perioral dermatitis is characterized by small, discrete papules and pustules in a periorificial distribution, predominantly around the mouth. Because this condition can involve areas other than the perioral region, the term periorificial dermatitis has been proposed for this

disorder.1,2 The classic presentation is an eruption with overlapping features of an eczematous dermatitis and an acneiform eruption. Although initially described in young women of 15–25 years of age, perioral dermatitis is now recognized to occur in children as well.3 A subset of perioral dermatitis shows granulomas when lesional skin is examined histologically. Several names have been used to describe this granulomatous form of perioral dermatitis, including granulomatous perioral dermatitis, facial Afro-Caribbean childhood eruption, and granulomatous periorificial dermatitis.2,4,5

HISTORICAL ASPECTS The first reports describing perioral dermatitis appeared in the 1950s; various names were given to the condition, however, there was a lack of defining ­clinical criteria. In 1957, Frumess and Lewis described a “light sensitive seborrheid” that is generally accepted as the first account of what was later termed perioral dermatitis by Mihan and Ayres in 1964.6,7 Later descriptions

925

13

by Cochran and Thomson8 and Wilkinson, Kirton, and Wilkinson9 further defined this disorder, and more recently the term periorificial dermatitis has been proposed.2 The condition was first described in children in the late 1960s.

EPIDEMIOLOGY

Section 13 :: Disorders of the Sebaceous Glands

926

Adult perioral dermatitis predominantly affects women. Pediatric perioral dermatitis may have a slight female preponderance and is seen equally among those of different races.1,10 The granulomatous form of perioral dermatitis has been reported mostly in children of prepubertal age.5 Perioral dermatitis can occur as early as 6 months.1 An increased prevalence in AfricanAmerican children has been reported, but more recent reviews do not support this finding.2,11

ETIOLOGY AND PATHOGENESIS A relationship of perioral dermatitis to the misuse of topical corticosteroids (fluorinated or nonfluorinated) has been well established.12 Patients often reveal a history of an acute steroid-responsive eruption around the mouth, nose, and/or eyes that worsens when the topical corticosteroid is discontinued. Dependency on the use of the topical corticosteroid may develop as the patient repeatedly treats the recurrent eruption. In other cases, the condition may worsen with the application of topical corticosteroids, especially in the granulomatous variant of perioral dermatitis, which usually occurs in prepubertal children.2 Perioral dermatitis has been reported in patients using inhaled corticosteroids13 and with inadvertent facial exposure to topical corticosteroids.14 However, perioral dermatitis is not always linked to topical corticosteroids.9 The exact cause of perioral dermatitis in these other cases is unclear. Although isolated reports of affected siblings exist,2,15 no clear genetic predisposition has been noted, nor have specific environmental exposures been consistently implicated. Of note, the disease is predominant in young women, yet no link to hormonal causes has been found. The initial reports of photosensitivity by Frumess and Lewis6 were not further substantiated, nor were theories of microbiologic causes such as infection with Candida, fusiform bacteria, or Demodex folliculorum.16 Cases of allergic contact with fluorides or other components in toothpaste and dentifrices have also been reported, however, use of these agents after clearing of the perioral dermatitis without further eruption has also been described. Patch testing in a small series of patients led to few positive results, and these were not considered relevant.9 In the past, authors have considered the relationship of perioral dermatitis to acne rosacea, however, the clinical features are distinct (see Section “Differential Diagnosis”). In perioral dermatitis, the histopathologic findings are variable and are dependent on the form of perioral dermatitis. In a histopathologic review of 26 patients with the nongranulomatous form, follicular spongiosis and eczematous changes were prominent features, suggesting that perioral dermatitis is distinct from rosacea.17 A lymphohistiocytic infiltrate and occasional plasma cells

Figure 82-1  Typical perioral dermatitis. The eruption is confined to the nasolabial folds and the skin of the chin. were noted in a perifollicular and perivascular distribution in this series. In granulomatous perioral dermatitis, histopathology demonstrates follicular hyperkeratosis, edema and vasodilatation in the papillary dermis, perivascular and parafollicular infiltrates of lymphocytes, histiocytes, and polymorphonuclear leukocytes with occasional epithelioid granulomas and giant cells, similar to the histopathologic changes in acne rosacea.5,18

CLINICAL FINDINGS The primary lesions of perioral dermatitis are discrete and grouped erythematous papules, vesicles, and pustules (Figs. 82-1 and 82-2). The lesions are often symmetric but may be unilateral and appear in the perioral, perinasal, and/or periocular regions (Figs. 82-2 and 82-3 and eFigs. 82-3.1 and 82-3.2 in online edition). In a retrospective review of 79 children with perioral

Figure 82-2  Perioral (granulomatous periorificial) dermatitis. This child shows the typical small papules studding the area around the mouth and eyes.

vermilion edge is well described (Fig. 82-2). The granulomatous variant of perioral dermatitis presents with small flesh-colored, erythematous, or yellow–brown papules, some with confluence, and shares the distribution of perioral dermatitis in adults (Fig. 82-3). In addition, lesions have been reported to appear on the ears, neck, scalp, trunk, labia majora, and extremities.1,11 Occasionally, an associated burning sensation or itching is reported, and intolerance to moisturizers and other topical products is described.1,9 In a few cases of granulomatous perioral dermatitis, an associated blepharitis or conjunctivitis has been reported.11 Systemic findings and regional lymphadenopathy are absent.

Box 82-1  Differential Diagnosis of Perioral Dermatitis DISORDER

Perioral Dermatitis

­ ermatitis, isolated perioral involvement was present d in only 39%, and in rare cases nonperioral regions were involved exclusively.1 Background erythema and/or scale may be present. A distinct 5-mm clear zone at the

(Box 82-1) The differential diagnosis of nongranulomatous and granulomatous perioral dermatitis is outlined in Box 82-1.19–24 Both forms of perioral dermatitis lack systemic symptoms and a thorough history and physical examination are generally sufficient to establish the diagnosis. However, in some cases histopathological evaluation of lesional skin, chest radiography, and/or

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Figure 82-3  Perioral dermatitis, granulomatous form: child with densely aggregated periorificial erythematous and edematous papules.

Chapter 82

DIFFERENTIAL DIAGNOSIS

13

DISTINGUISHING CLINICAL FEATURES

Nongranulomatous Perioral Dermatitis Most Likely   Rosacea Involves the nose, facial convexities; persistent erythema, and telangiectasias   Seborrheic dermatitis Accentuated at nasolabial folds; scale   Allergic contact dermatitis Consider musical instruments, toothpaste/dentrifices, latex gloves, dental appliances, and lipstick   Irritant contact dermatitis Common in children (from saliva, foods)   Lip-licking cheilitis Common in children; scale, well demarcated border Consider   Acne vulgaris May involve chest and back; comedones   Gram-negative folliculitis Predominance of pustules   Demodex folliculorum infestation Pustules, pruritus; often immunocompromised host19   Acrodermatitis enteropathica Infants with acral and/or diaper dermatitis; zinc deficiency   Tinea facei KOH positive for hyphal elements   Psoriasis Involvement of other cutaneous sites common   Impetigo Honey-colored crusts   Eosinophilic folliculitis-HIV related Immunocompromised host Granulomatous Perioral Dermatitis Most Likely   Granulomatous rosacea Consider  Familial juvenile systemic granulomatosis (Blau syndrome)   Fungal or mycobacterial infection   Lupus miliaris disseminatus faciei   Benign cephalic histiocytosis   Sarcoidosis   Zirconium dermatitis

Flushing, telangiectases, pustules, and edema; similar histopathologic features Synovial cysts, uveitis, granulomatous arthritis, camptodactyly, papular rash Diffuse distribution on the face Rare in children; reported cases may represent Blau syndrome May involve axillae

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Box 82-2  Treatment for Perioral Dermatitis First line

TOPICAL Metronidazole

DOSE Apply bid

SYSTEMIC Tetracycline Doxycycline Minocycline

ADULT DOSE 250–500 mg p.o. bid 50–100 mg p.o. bid 50–100 mg p.o. bid

Second line

Erythromycin or clindamycin

Apply bid

Erythromycin

400 mg p.o. tid



Or Sulfur preparations Azelaic acid

a

Apply bid Apply bid

Pediatric dose

Section 13 :: Disorders of the Sebaceous Glands

ophthalmologic examination may be necessary, particularly with the granulomatous variant.11 Sarcoidosis in young children is rare and often accompanied by systemic signs and symptoms such as weight loss, fatigue, joint pains, lymphadenopathy, and uveitis.5,25 At least some of the reported cases of sarcoidosis in young children represent Blau syndrome with underlying mutations in CARD15/NOD2 (see Chapter 134).11,26

COMPLICATIONS The majority of cases of perioral dermatitis and granulomatous perioral dermatitis resolve without sequelae or relapse. However, there are rare reports of scarring.5

PROGNOSIS AND CLINICAL COURSE Perioral dermatitis is usually a self-limited disorder that evolves over a few weeks and resolves over months or rarely years. The condition may take on a waxing and waning course, often with a tendency to progress (granulomatous form). If treated with topical corticosteroids alone, recurrent episodes on withdrawal of therapy or with continuing therapy are typical. With appropriate intervention the condition resolves with rare recurrences.

TREATMENT

928

30–50 mg/kg/day p.o. divided tida

(Box 82-2) If topical corticosteroids are being used, they should be discontinued. If fluorinated corticosteroids are being applied, initial substitution with a low-potency hydrocortisone cream may minimize a flare of the dermatitis. Patients should be educated about the link between application of topical corticosteroids and exacerbation of the dermatitis. In most cases, effective therapy is oral tetracycline, doxycycline, or minocycline, for a course of 8 to 10 weeks, with a taper over the last 2 to 4 weeks. In children under 8 years of age, nursing mothers, or

tetracycline-allergic patients, oral erythromycin is recommended. Not uncommonly, patients require continued low-dose systemic antibiotic therapy for months or sometimes years to maintain control. In recalcitrant cases, isotretinoin may be considered.27 Topical antibiotic therapy, most commonly with topical metronidazole, should be initiated concurrently with the systemic antibiotic. For milder cases, topical metronidazole alone may suffice.1,28,29 In a retrospective review of 79 children, best outcomes were associated with the use of topical metronidazole, oral erythromycin, or both.1 Response is generally noted within 2–3 months. Other options include topical clindamycin or erythromycin, topical sulfur-based preparations, and topical azelaic acid.30 Reports of successful use of topical calcineurin inhibitors exist, particularly in adults; however, caution is advised given the occasional reports of granulomatous eruptions after the use of these agents.31–35 Ointment preparations should generally be avoided in the treatment of perioral dermatitis. Photodynamic therapy with topical 5-aminolevulinic acid has shown promise for treating perioral dermatitis in one report.36

PREVENTION The only widely accepted factor that may predispose to the development of perioral dermatitis is the use of topical corticosteroids. Avoiding facial skin exposure to these products may prevent the eruption in some cases.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Nguyen V, Eichenfield LF: Periorificial dermatitis in children and adolescents. J Am Acad Dermatol 55:781, 2006 3. Manders SM, Lucky AW: Perioral dermatitis in childhood. J Am Acad Dermatol 27:688, 1992 5. Frieden IJ et al: Granulomatous perioral dermatitis in children. Arch Dermatol 125:369, 1989 9. Wilkinson DS, Kirton V, Wilkinson JD: Perioral dermatitis: A 12-year review. Br J Dermatol 101:245, 1979 12. Weston WL, Morelli JG: Identical twins with perioral dermatitis. Pediatr Dermatol 15:144, 1998

14 Disorders of the Eccrine and Apocrine Glands

SWEATING AT A GLANCE Humans have 2–24 million sweat glands.

Hypothalamic temperature is the strongest stimulus for sweating. Acetylcholine is the major stimulus secreted by sympathetic nerves. Botulinum toxin inhibits sweating by preventing acetylcholine release. Oxidative metabolism of glucose is a major source of eccrine gland adenosine triphosphate.

ANATOMY AND FUNCTION OF ECCRINE SWEAT GLANDS

Ductal reabsorption conserves NaCl.

Two distinct segments, the secretory coil and the duct, form the eccrine sweat gland. The secretory coil secretes an isotonic sweat, while the duct resorbs Na+ and Cl−, thus producing sweat to cool the body while preserving Na+ and Cl– body stores.

In individuals with cystic fibrosis, mutated chloride channels increase NaCl loss. Bacteria are necessary for apocrine odor. Odiferous precursors secretion is controlled by the MRP8 encoded by ABCC11. Adrenergic stimulation controls apocrine gland secretion.

In humans, sweat glands generally are found as two types, (1) eccrine and (2) apocrine. Eccrine-gland sweat allows the body to control its internal temperature in response to thermal stress. Apocrine gland function is more obscure but likely includes pheromone production.

Biology of Eccrine and Apocrine Glands

The three eccrine cell types are (1) clear (secretory), (2) dark (mucoid), and (3) myoepithelial (contractile).

Humans have approximately 2–4 million sweat glands.1 Sweat glands are found over nearly the entire body surface, and are especially dense on the palms, soles, forehead, and upper limbs.2 Analgen of eccrine sweat glands first appear in the 3.5-month-old fetus on the palms and soles (see Chapter 7), then develop in the axillary skin in the fifth fetal month, and finally develop over the entire body by the sixth fetal month.3 The analog of the eccrine sweat gland, which developed from the epidermal ridge, is double layered, and develops a lumen between the layers between the fourth and eighth fetal months. By the eighth fetal month eccrine secretory cells resemble those of the adult; by the ninth fetal month myoepithelial cells form.

::

Up to 10 L/day of sweat is produced by acclimatized individuals.

DEVELOPMENT OF ECCRINE SWEAT GLANDS

Chapter 83

Chapter 83 :: Biology of Eccrine and Apocrine Glands :: Theodora M. Mauro

SECRETORY COIL The secretory coil contains three distinct cell types: (1) clear (secretory), (2) dark (mucoid), and (3) myoepithelial.4 The clear and dark cells occur in approximately equal numbers but differ in their distribution (Fig. 83-1). While the dark cells border the apical (luminal) surfaces, the clear cells rest either directly on the basement membrane or on the on the myoepithelial cells. The clear cells directly access the lumen by forming intercellular canaliculi (Fig. 83-2). Spindle shaped contractile myoepithelial cells lie on the basement membrane and abut the clear cells. The adult secretory coil is approximately 2–5-mm long, and approximately 30–50 μm in diameter. Heat accumulation results in larger sweat glands and ducts, and their dimensions,

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Ultrastructure of the eccrine duct and secretory coil and the localization of Na+, K+-ATPase Basal cell

Luminal cell

(Lumen)

Duct

Disorders of the Eccrine and Apocrine Glands

in turn, correlate with enhanced sweat output.5 Clear cells contain abundant mitochondria and an autofluorescent body, called the lipofuscin granule, in the cytoplasm. The clear cell plasma membrane forms many villi. The clear cell secretes water and electrolytes. Dark cells have a smooth cell surface and contain abundant dark cell granules.4 The function of dark cells are unknown. Myoepithelial cells contain actin filaments6 and are contractile,7,8 producing pulsatile sweat.

Na+, K+-ATPase Secretory coil

M (Lumen)

Section 14 ::

Figure 83-1  Light photomicrograph of the secretory coil of an acetylcholine-stimulated monkey palm eccrine sweat gland. A 1-m thick section was cut from an Eponembedded specimen and stained with methylene blue. Inset: A higher-power view of the area marked by the square. CC = clear cell; DC = dark cell; ICC = intercellular canaliculi; Lu = lumen; MC = myoepithelial cell.

C IC Mc C

DUCT D

The eccrine sweat duct consists of an outer ring of peripheral or basal cells and an inner ring of luminal

BM

Figure 83-3  Drawing of the ultrastructure of the eccrine duct and secretory coil and the localization of Na+, K+-adenosine triphosphatase (ATPase). The thick lines indicate the localization of Na+, K+-ATPase. BM = basement membrane; C = clear cell; D = dark cells; IC = intercellular canaliculi; M = myoepithelial cell; Mc = mitochondria.

930

Figure 83-2  Electron micrograph of the secretory coil of a human eccrine sweat gland. B with arrow = basal lamina; other symbols are the same as in Fig. 83-1.

or cuticular cells. It seems that the proximal (coiled) duct is functionally more active than the distal straight portion in pumping Na+ for ductal Na+ reabsorption, because Na+, K+-adenosine triphosphatase (ATPase) activity and the number of mitochondria are higher in the proximal portion (Fig. 83-3).4,7,9,10 In contrast, the luminal ductal cells have fewer mitochondria, much less Na+, K+-ATPase activity, and a dense layer of tonofilaments near the luminal membrane, which is often referred to as the cuticular border. The cuticular border provides structural resilience to the ductal lumen, which may dilate whenever ductal flow of sweat is blocked. The entire structural organization of the duct is well designed for the most efficient Na+ absorptive

function. The luminal membrane serves as the absorptive surface by accommodating both Na+ and Cl− channels, and the basal ductal cells serve in Na+ pumping by providing maximally expanded Na+ pump sites and efficient energy metabolism. The lumen and the duct contain β-defensin, an antimicrobial, cysteinerich, low-molecular-weight peptide.11,12 In the epidermis, the duct spirals tightly upon itself.

NEURAL CONTROL OF ECCRINE SWEATING

14

:: Biology of Eccrine and Apocrine Glands

Efferent nerve fibers originating from the hypothalamic preoptic sweat center descend through the ipsilateral brainstem and medulla and synapse in the intermediolateral cell columns of the spinal cord without crossing (although sympathetic vasomotor fibers may partially cross).15 The myelinated axons rising from the intermediolateral horn of the spinal cord (preganglionic fibers) pass out in the anterior roots to reach (through white ramus communicans) the sympathetic chain and synapse. Unmyelinated postganglionic sympathetic class C fibers arising from sympathetic ganglia join the major peripheral nerves and end around the sweat gland. The supply to the skin of the upper limb is commonly from T2 to T8. The face and the eyelids are supplied by T1 to T4, so that resection of T2 for the treatment of palmar hyperhidrosis is likely to cause Horner syndrome. The trunk is supplied by T4 to T12 and the lower limbs by T10 to L2. Unlike the sensory innervation, a significant overlap of innervation occurs in the sympathetic dermatome because a single preganglionic fiber can synapse with several postganglionic fibers. The major neurotransmitter released from the periglandular nerve endings is acetylcholine (Ach), an exception to the general rule of sympathetic innervation, in which noradrenaline is the peripheral neurotransmitter. In addition to ACh, adenosine triphosphate (ATP), catecholamine, vasoactive intestinal peptide, atrial natriuretic peptide, calcitonin generelated peptide, and galanin have been localized in the periglandular nerves. The significance of these peptides or neurotransmitters in relation to sweat gland function is not fully understood. Botulinum toxin interferes with ACh release. Its heavy chain binds the neurotoxin selectively to the cholinergic terminal and the light chain acts within the cells to prevent ACh release. Type A toxin cleaves sensory nerve action potential-25, a 25-kDa synaptosomal-associated protein; the type B light chain cleaves vesicle-associated membrane protein (also called synaptobrevin). Botulinum toxins are used for symptomatic relief of hyperhidrosis.16 A more detailed description can be found in Chapters 84 and 255.

Chapter 83

The preoptic hypothalamic area plays an essential role in regulating body temperature: local heating of the preoptic hypothalamic tissue activates generalized sweating, vasodilatation, and rapid breathing, whereas local cooling of the preoptic area causes generalized vasoconstriction and shivering. The elevation of hypothalamic temperature associated with an increase in body temperature provides the strongest stimulus for thermoregulatory sweating responses, while cutaneous temperature exerts a weaker influence on the rate of sweating.13 On a degree-to-degree basis, an increase in internal temperature is about nine times more efficient than an increase in mean skin temperature in stimulating the sweat center. The local temperature effect is speculated to be due to increased release of periglandular neurotransmitters. The sweating in menopausal “hot flashes” reinforces the concept of a central hypothalamic mechanism for thermal sweating, but also shows that the response of individuals to the same changes in core temperature can vary. Although hormonal factors influence sweating during menopause, excessive sweating does not correlate simply with hormonal levels. Instead, menopausal hot flashes seem to be due to a hypersensitive brain response (particularly the hypothalamus, but perhaps the insula, anterior cingulate, amygdala, and primary somatosensory cortex as well). In asymptomatic menopausal women and premenopausal women, the core temperature can change up to 0.4°C (33°F) without eliciting a response. In symptomatic postmenopausal women, changes as small as 0.1°C (32°F) trigger peripheral vasodilation and sweating. Why the brain is hypersensitive to small changes in core temperature is poorly understood, but increased levels of brain norepinephrine appear to influence the response to small changes in core temperature through their action on α2-adrenergic receptors in the brain; higher levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol have also been found in symptomatic menopausal women than in asymptomatic women. Decreased norepinephrine release is postulated as the mechanism by which clonidine relieves hot flashes in symptomatic women. Decreased core temperature may be the reason that women with decreased body mass index tend to have fewer symptoms, even though their estrogen levels probably are lower than those in women with increased body mass index. Levels of estrogen, luteinizing hormone, and β-endorphins also were originally thought to influence hot flashes, but later studies have suggested no association.14

INNERVATION.

DENERVATION. In humans, the sweating response to intradermal injection of nicotine or ACh disappears within a few weeks after denervation of the postganglionic fibers,17 while the sweating response to heat ceases immediately after resection of the nerves. In contrast, after denervation of preganglionic fibers (due to spinal cord injuries or neuropathies), pharmacologic responsiveness of the sweat glands is maintained from several months to 2 years, even though their thermally induced sweating is no longer present.18 EMOTIONAL SWEATING Sweating induced by emotional stress (emotional sweating) can occur over the whole skin surface in some individuals, but it is usually confined to the palms, soles, axillae, and the forehead. Emotional sweating on the palms and soles ceases during sleep,

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whereas thermal sweating occurs even during sleep if the body temperature rises. Because both types of sweating can be inhibited by atropine, emotional sweating is cholinergically medicated.

PHARMACOLOGY OF THE ECCRINE SWEAT GLAND AND SWEATING RATE

Section 14 :: Disorders of the Eccrine and Apocrine Glands

932

Sweat glands respond to cholinergic agents, α- and β-adrenergic stimulants, and other periglandular neurotransmitters, such as vasoactive intestinal peptide and ATP. Periglandular ACh is the major stimulant of sweat secretion, and its periglandular concentration determines the sweat rate in humans. When dissociated clear cells are stimulated in vitro by cholinergic agents, they lose K+ & Cl−, increase intracellular Ca2+, and shrink, mimicking actions seen in vivo.19 Striking individual differences exist in the degree of sweating in response to a given thermal or physical stress. In general, males perspire more profusely than females.20 The sweat rate in a given area of the skin is determined by the number of active glands and the average sweat rate per gland. The maximal sweat rate per gland varies from 2 to 20 nL/min2. Sweat rate increases during acclimatization, but the morphologic and pharmacologic bases of the individual and regional differences in sweating rate during acclimatization are still poorly understood (Fig. 83-4). In thermally induced sweating, the sweat rate can be mathematically related to the body and skin temperatures in a given subject only in the low sweat rate range. Cholinergic stimulation yields a five to ten times higher sweating rate than does β-adrenergic stimulation. α-Adrenergic stimulation (by phenylephrine) is no more potent than isoproterenol (ISO) (a β-adrenergic agonist) in humans in vivo.21 Whereas cholinergic sweating begins immediately on intradermal injection, β-adrenergic sweating requires a latent period of from 1 to 2 minutes, which suggests that the intracellular mechanism of sweat induction

Figure 83-4  Individual variation in the size of the sweat gland in four male adults, aged 22–28 years. Sweat glands were isolated from skin biopsy specimens obtained from the upper back behind the axilla. Subject 1 is a sedentary man who does not exercise regularly, whereas subject 4 is a well-acclimatized athletic individual.

may be different for methacholine and for ISO. Because the sweat rate in response to adrenergic agents is rather low, it may be reasonable to surmise that adrenergic stimulation in periglandular nerves may be involved in the regulation of sweat gland function but not in the induction of sweat secretion. One consequence of dual cholinergic and adrenergic innervation is to maximize tissue accumulation of cyclic adenosine monophosphate, which may be instrumental in stimulating the synthesis of sweat and glandular hypertrophy of the sweat gland. The possibility that periglandular catecholamine is directly involved in emotional sweating or sweating associated with pheochromocytoma22 may be ruled out, because these sweating responses can be blocked by anticholinergic agents.

PHARMACOLOGY AND FUNCTION OF ECCRINE MYOEPITHELIUM The periodicity of sweat secretion in vivo is caused by the periodicity of central nerve impulse discharges, which occur synchronously with vasomotor tonus waves. Myoepithelial contraction occurs with cholinergic stimulation, but neither α- nor β-adrenergic agents induce tubular contraction.23 While the myoepithelium may contribute to sweat production via pulsatile contractions, it also seems to provide structural support for the secretory epithelium, especially under conditions in which stagnation of sweat flow (due to ductal blockade) results in an increase in luminal hydrostatic pressure.8

ENERGY METABOLISM Sweat secretion is mediated by the energy (i.e., ATP)dependent active transport of ions, so a continuous supply of metabolic energy is mandatory for sustained sweat secretion. Endogenous glycogen stored in the clear cells can sustain sweat secretion for less than 10 minutes; thus the sweat gland must depend almost exclusively on exogenous substrates for its energy metabolism. Mannose, lactate, and pyruvate are used nearly as readily as glucose; other hexoses, fatty acids, ketone bodies, intermediates of the tricarboxylic acid cycle, and amino acids are either very poorly used or not used as substrates. The physiologic significance of lactate or pyruvate utilization by the sweat gland is not yet clear. However, because the plasma level of glucose (5.5 mM) is much higher than that of lactate (1–2 mM) or pyruvate (less than 1 mM), glucose may play a major role in sweat secretion. Oxidative metabolism of glucose is favored as the major route of ATP formation for secretory activity.23

COMPOSITION OF HUMAN ECCRINE SWEAT INORGANIC IONS. Sweat is formed in two steps: (1) secretion of a primary fluid containing nearly isotonic NaCl concentrations by the secretory coil, and

UREA. Urea in sweat is derived mostly from serum

Sweat ingredients vs. sweat rates

urea.26 Sweat urea content is usually expressed as a sweat–plasma ratio (S/P urea). S/P urea is high (2–4) at a low sweat rate range but approaches a plateau at 1.2–1.5 as the sweat rate increases.

Hydration 100 Na+ and Clin CF

60

Na+ Cl-

40

Lactate K+

AMMONIA AND AMINO ACIDS. Ammonia concentration in sweat is 0.5–8 mM,27 which is 20–50 times higher than the plasma ammonia level. The concentration of sweat ammonia is inversely related to the sweat rate and sweat pH. Free amino acids are present in human sweat,27 although it is not clear what proportion of measured amino acids derive from epidermal contamination.

Urea Ammonia

20 0

Pyruvate

1.0

0.1 0 0

1

2

3

4

Sweat rate (mL/min/cm2)

Figure 83-5  Relationship between the concentration of sweat ingredients and the sweat rate in thermally induced human sweat in normal individuals and in persons with cystic fibrosis (CF).

(2) reabsorption of NaCl from the primary fluid by the duct. Although a number of factors affect ductal NaCl absorption, the sweat rate (and thus the transit time of sweat) has the most important influence on final NaCl concentration. Sweat NaCl concentration increases with increasing sweat rate to plateau at around 100 mM (Fig. 83-5). Potassium (K+) concentration in sweat is relatively constant. It ranges from 5 to 10 mM, which is slightly higher than plasma K+ concentration. HCO3− concentration in the primary sweat fluid is approximately 10 mM, but that of final sweat is less than 1 mM, which indicates that HCO3− is reabsorbed by the duct, presumably accompanied by ductal acidification.24 Sweat NaCl concentration is increased in individuals with cystic fibrosis. Aquagenic wrinkling of the palms (whitened, wrinkling, and papillation of the palms after brief water exposure) is seen more frequently in carriers and patients with cystic fibrosis (see Chapter 84).

LACTATE. The concentration of lactate in sweat usually depends on the sweat rate. At low sweat rates, lactate concentration is as high as 30–40 mM, but it rapidly drops to a plateau at around 10–15 mM as the sweat rate increases. Acclimatization is known to lower sweat lactate concentrations, whereas arterial occlusion rapidly raises sweat NaCl and lactate concentrations and reduces the sweat rate.23 Sweat lactate is probably produced by glycolysis of glucose by the secretory cells.25

Biology of Eccrine and Apocrine Glands

Glucose

0.2

::

Total Ca2+ Free Ca2+

0.3

PROTEINS INCLUDING PROTEASES. The concentration of sweat protein in the least contaminated, thermally induced sweat is approximately 20 mg/dL, with the major portion being low-molecular-weight proteins (i.e., MW 50% improvement in four patients.150 In a pilot study, 22 patients with Hurley’s grade I and II were treated with 90 mg/day zinc gluconate; 8 complete remissions (CR) and 14 partial remissions were observed. When CR was obtained, the treatment was progressively decreased; 4 out of 22 patients experienced side effects, mainly gastrointestinal.151 Emerging data on the efficacy of biologics as monotherapy152–154 did not fulfill the expectations initially, since etanercept and efalizumab showed a minor effectiveness in a few open and was ineffective in one controlled study (Box 85-7).155–160 In contrast, infliximab, a chimeric monoclonal antitumor necrosis factor antibody, has demonstrated efficacy in several case reports with severe HS patients in both open and a controlled study, although the results seem transient and

Box 85-7  Treatment of Hidradenitis Suppurativa/Acne Inversa with Biologic Agents (studies with ≥3 patients; patients with Crohn’s disease were excluded) Result

Agent reference 168–171

No. of patients

Adalimumab

12

Efalizumab160

5

Etanercept155–158

34

Infliximab161–167

40

Improvement ≥50% Schema 40 mg/2nd week-40– 80 mg/week 1.0 mg/kg/ week 25 mg sc 2×/ week 5–10 mg/kg 0, 2, 6 week

Duration

no yes 0

3 months

5

12 (100%)

Relapse after A Discontinution or Surgical Treatment Required 5/6 (83%)

0 (0%)

3–10 months 19

15 (44%)

10/14 (71%)

2.5–72 months

19 (48%)

11 (53%)

21

Randomized, prospective, double-blind, placebo-controlled studies Result

Agent reference 159

958

No. of patients

Improvement ≥50% Schema

Relapse After A Discontinution or Surgical Treatment Required

Duration

no yes

No significant difference compared with placebo Yes Significant improvement under infliximab (p < 0.001) (27% >50% improvement under infliximab: 5% under placebo)

Etanercept

20 (crossover) 50 mg sc 2×/ week

3

Infliximab168

33 (crossover) 5 mg/kg 0, 2, 6 week

2.5

14

RADIOTHERAPY. Several authors have reported radiotherapy to be successful in the treatment of HS. Given the often young patient population with HS, long-term side effects must be considered.209,210 BIOMARKERS. Soluble interleukin-2 receptor (sIL2R) and tumor necrosis factor-α serum levels were found increased in HS and especially sIL-2R correlated well with Hurley’s grade.211,212 Both serologic markers may be used as a valuable marker for disease staging and evaluation of treatment in patients with HS.

::

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 12. Heckmann M, Teichmann B, Pause BM: Amelioration of body odor after intracutaneous axillary injection of botulinum toxin A. Arch Dermatol 139:57, 2003 34. Matarasso SL: Treatment of facial chromhidrosis with botulinum toxin type A. J Am Acad Dermatol 52:89, 2005 49. Bormate AB Jr, Leboit PE, McCalmont TH: Perifollicular xanthomatosis as the hallmark of axillary Fox-Fordyce disease: An evaluation of histopathologic features of 7 cases. Arch Dermatol 144:1020, 2008 61. Kurzen H et al: What causes hidradenitis suppurativa? Exp Dermatol 17:455, 2008 62. Revuz JE et al: Prevalence and factors associated with hidradenitis suppurativa: Results from two case-control studies. J Am Acad Dermatol 5:596, 2008 95. Fimmel S, Zouboulis CC: Comorbidities of hidradenitis suppurativa (acne inversa). Dermatoendocrinol 2:9, 2010 113. Alikhan A, Lynch PJ, Eisen DB: Hidradenitis suppurativa: A comprehensive review. J Am Acad Dermatol 60:539, 2009 114. Revuz J: Hidradenitis suppurativa. J Eur Acad Dermatol Venereol 23:985, 2009 125. Sartorius K et al: Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and obesity.Br J Dermatol 161:831, 2009 152. Haslund P, Lee RA, Jemec GB: Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors. Acta Derm Venereol 89:595, 2009 186. Kagan RJ et al: Surgical treatment of hidradenitis suppurativa: A 10-year experience. Surgery 138:734, 2005

Disorders of the Apocrine Sweat Glands

SURGERY. Surgical removal of all involved tissue, beyond clinically involved margins, is an effective treatment modality.186–190 Postoperative recurrences may occur. Some authors have advocated the use of CO2 laser191,192 or the neodymium-doped yttrium aluminum garnet laser193,194 for surgical ablation of tissue. The modality of closure has been a topic of debate. Overall, healing by secondary intent is thought to provide the best outcome. Primary closure, grafting, or flaps have been extensively used, but may be associated with poorer results.195–201 In one series of 106 patients, there was a 70% recurrence rate requiring subsequent operation in the primary closure cohort and no recurrence in the split-thickness graft and flap groups.202 A more limited surgical approach also plays a role in disease management. Deroofing or marsupializing of recurrent troublesome lesions or sinus tracts may aid with local control.203 Lancing an inflammatory lesion is of limited benefit and should be discouraged.195,204,205 A study with 200 patients has shown that

enclosure of gentamicin after primary excision of HS lesions can reduce the number of complications 1 week postoperatively but it was ineffective on the long-term recurrence rate.206 Ultrasonography can identify the true extent of lesions in HS, which may be of use in the preoperative planning.207,208

Chapter 85

are associated with significant toxicity as long-term treatment.161–168 Small case series with adalimumab exhibited even more promising results but controlled studies are still missing.169–171 Case reports or small case series have also shown therapeutic success with other systemic therapies, including systemic corticosteroids, azathioprine, cyclosporine, dapsone, and methotrexate.86,172–176 Local therapies have also been recently examined. A single patient with aggressive perianal HS has responded favorably to wide surgical excision in conjunction with perilesional granulocyte-macrophage colony-stimulating factor injections.177 A small case series demonstrated the efficacy of treatment of persistent painful nodules with cryotherapy. Healing time in these patients was lengthy (18–42 days).178 Finally, the first case of botulinum toxin A successfully treating HS has been reported. In this case, injections into the axillae resulted in a 10-month remission.179 Topical 15% resorcinol peel in 12 women with HS Hurley stage I or II led to a significant decrease in pain and a reduction in mean duration of the painful abscesses.180 Photodynamic therapy (PDT) as treatment for HS has recently been described in three small case series, but is neither established nor has been standardized.181–184 Moreover, pulsed dye laser-mediated photodynamic therapy was not successful in a pilot study with four self-controlled cases.185

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Disorders of the Hair and Nails

Chapter 86 :: Biology of Hair Follicles :: George Cotsarelis & Vladimir Botchkarev BIOLOGY OF HAIR FOLLICLES AT A GLANCE The primary purpose of hair in humans is to influence social interactions. Hair follicle development depends on interactions between epithelial and mesenchymal cells. The genes important for this interaction are slowly being elucidated. Genes important for hair follicle development also play a role in hair follicle cycling. The hair follicle bulge possesses stem cells important for the continual regeneration of the follicle during cycling. Hair pigmentation depends on melanocyte stem cells and differentiated cells in the follicle. Many genes important for melanocyte behavior and hair pigmentation have been defined.

EVOLUTION AND FUNCTION OF HAIR Hair is found only in mammals, where during the course of evolution its primary roles were to serve as insulation and protection from the elements. However, in contemporary humans, hair’s main purpose revolves around its profound role in social interactions. Loss of hair (alopecia) and excessive hair growth in unwanted areas (hirsutism and hypertrichosis) can lead to significant psychological and emotional distress that supports a multibillion-dollar pharmaceutical and cosmetic effort to reverse these conditions. Fundamental understanding of hair growth and its controls is increasing and result in new treatments for alopecia.1,2 These advances resulted from the interest

of developmental biologists and other investigators in the hair follicle as a model for a wide range of biologic processes. As each hair follicle cyclically regenerates, it recapitulates its initial development. Many growth factors and receptors important during hair follicle development also regulate hair follicle cycling.3–10 The hair follicle possesses keratinocyte and melanocyte stem cells (MSCs), nerves, and vasculature that are important in healthy and diseased skin.11–13 To appreciate this emerging information and to properly assess a patient with hair loss or excess hair (see Chapter 88), an understanding of the anatomy and development of the hair follicle is essential.

EMBRYOLOGY Morphologically, hair follicle development has been divided into eight consecutive stages, several of which are illustrated in Fig. 86-1. Each stage is characterized by unique expression patterns for growth factors and their receptors, growth factor antagonists, adhesion molecules, and intracellular signal transduction components.14–16 Promising advances in understanding the molecular mechanisms behind hair follicle development arose through the discovery that mammalian counterparts (homologs) of genes important for normal Drosophila (fruit fly) development also affect hair follicle development. Decapentaplegic [Dpp/bone morphogenetic protein (BMP)], Engrailed (en), Homeobox (hox), hedgehog/patched (hh/ptc), notch, wingless/armadillo (wg/wnt/catenin) genes are all critical for hair follicle and vertebrate development in general.17–19 These genes were all first discovered in Drosophila, thus, most of the names assigned to them describe the peculiar appearance (phenotype) of the flies carrying mutations in these genes.20 Follicle formation begins on the head, and then moves downward to the remainder of the body in utero. The first hairs formed are lanugo hairs, which are nonpigmented, soft, and fine. Lanugo hair is typically shed between the 32nd and 36th weeks, although approximately one-third of newborns still retain their lanugo hair for up to several weeks after birth. Patterning genes, called homeobox genes, which are precisely organized in the genome so that they are

15

Molecular regulation of hair follicle morphogenesis

Stage 1

Stage 2

Hair placode (hair germ)

Hair peg

Wnt10b, β-catenin, Lef-1 EDA, EDAR Lhx2, BMP-2, BMPR-IA TGFβR-II, Msx-2 P-cadherin Loss of E-cadherin

SHH, Ptc1 PDGF-α neurotrophins TGFbR-II N-CAM

Differentiating inner root sheath

TCF3 BMPR-IA

Bulge

CK15, CK19 BMP6, Gremlin

CK1, CK10 Loricrin Involucrin Trichohyalin Transglutaminases EGFR Gata3, Cutl1 Foxn1 Notch, Jagged 1/2

Differentiating Hair shaft Hair keratins Lef-1 Hoxc13 Foxn1, Msx-2 Notch Jagged 1/2

Dermal papilla

Arrector pili muscle Inner root sheath Hairshaft Outer root sheath Melanogenic area

BMP-2, BMP-4 Noggin, BMPR-IA KGF, HGF, SCF Versican Alkaline phosphatase

Biology of Hair Follicles

Wnt-5α, Lef-1 Ptc1, Gli1 PFGF-Ra Noggin Versican p75 kd neurotrophin receptor Alkaline phosphatase

CK5, CK14

Sebaceous gland

::

Mesenchymal condensation

Differentiating outer root sheath

Stage 8

Chapter 86

Mesenchymal condensation BMP-4, Noggin, Activin Versican p75 kd neurotrophi receptor Alkaline phosphatase

Stage 5

Figure 86-1  Molecular regulation of hair follicle morphogenesis. The scheme shows the expression of different growth factors, their receptors, adhesion, and cell matrix molecules, transcriptional regulators in hair follicle epithelium, and mesenchyme during distinct stages of hair follicle development. BMP = bone morphogenetic protein; BMPR-IA = bone morphogenetic protein receptor, type IA; CK = keratin 5; Cutl1 = cut-like 1; E-cadherin = epithelial cadherin; EDA = ectodysplasin; EDAR = ectodysplasin receptor; EGFR = epidermal growth factor receptor; Foxn1 = forkhead box N1; Gata3 = GATA binding protein 3; Gli1 = glioma-associated oncogene homolog 1; HGF = hepatocyte growth factor; Hoxc13 = homeobox C13; KGF = keratinocyte growth factor; Lef-1 = lymphoid enhancer factor 1; Lhx2 = LIM homeobox 2; N-CAM = neural cell adhesion molecule; P-cadherin = placental cadherin; PDGF-α = platelet-derived growth factor α polypeptide; PFGF-Rα = platelet-derived growth factor receptor α; Ptc1 = patched1; SCF = stem cell factor; Shh = sonic hedgehog; TCF3 = transcription factor 3; TGF-βR-II = transforming growth factor-β receptor 2.

expressed in strict temporal sequences and spatial patterns during development, likely are responsible for the nonrandom and symmetric distribution of hair follicles over the body.21,22 In adult mice, homeobox gene expression reappears in hair follicles and serves to maintain normal hair shaft production.6 Engrailed, a type of homeobox gene, is responsible for dorsal– ventral patterning, and mice lacking engrailed develop hair follicles on their footpads.23 Although hair follicles and hairs all share the same basic anatomy, their growth, size, shape, pigmentation, and other characteristics differ widely, based on body location and variation among individuals. Many of these characteristics are established during development but are then profoundly altered by hormonal influences later in life. We are beginning to understand

the genes controlling hair length, curl and distribution because of elegant genetic studies on dogs. These studies reveal that fibroblast growth factor-5 (FGF-5), Keratin 71, and R-spondin 2 influence length, curl and distribution respectively.24 In humans, thicker hair found in Asians is associated with increased activity of ectodysplasin receptor (EDAR),25 the receptor of ectodysplasin (EDA) (see below). The size of many types of follicles changes drastically several times throughout life. For example, lanugo hair follicles, which produce hair shafts several centimeters long, convert to vellus follicles that produce small hairs that protrude only slightly from the skin surface. Later in life, vellus follicles on the male beard enlarge into terminal follicles that generate thick, long hairs. On the scalp of genetically

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predisposed individuals, terminal follicles miniaturize and form effete, microscopic hairs.

EPITHELIAL PLACODE OR PRIMARY HAIR GERM

Section 15 :: Disorders of the Hair and Nails

962

In the human fetus, hair follicles develop from small collections of cells, called epithelial placodes, which correspond to stage 1 of hair follicle development and first appear around 10 weeks’ gestation (see Fig. 86-1). The epithelial placode then expands to form the “primary hair germ” whose progeny eventually generate the entire epithelial portion of the hair follicle.26 The cells of the hair placode and germ express placental cadherin and become oriented vertically, losing their desmosomes, hemidesmosomes, and epithelial cadherin, which decreases their adhesion to their neighbors.27–29 Dermal cells beneath the hair placode form a cluster (or condensate), which later develops into the dermal papilla.30 Hair follicle formation depends on a series of mesenchymal/epithelial interactions.30 An initial signal arises in the mesenchyme (primitive dermis) and instructs the overlying epithelium to form an appendage, indicated by the appearance of regularly spaced placodes (see Fig. 86-1). The second signal arises from the epithelial placode and causes an aggregation of cells in the underlying mesenchyme that will eventually form the dermal papilla. Finally, a signal from this primitive dermal papilla initiates proliferation and differentiation of placode cells, ultimately leading to formation of a mature follicle. These reciprocal signals pass through the intervening basement membrane, which undergoes alterations in its morphology and chemical composition that may alter its ability to sequester growth factors and binding proteins, thus possibly modulating the epithelial/mesenchymal interactions. Many of these regulatory molecules important for the formation of the hair follicle have been defined, but how they interact to generate hair follicles in an otherwise homogeneous epithelium is yet to be determined. In one model, the spacing and size of placodes are regulated by a dermal signal, which varies in character in different body regions. The dermal signal occurs uniformly within each body region and triggers the activation of promoters and repressors of follicle fate in the epithelium that then compete with one another, resulting in the establishment of a regular array of follicles.15,31 Differences in the levels of promoter and repressor activation could account for regional differences in the size and spacing of follicles. Consistent with this model, several positive and negative regulators of hair follicle fate are initially expressed uniformly in the epidermis and subsequently become localized to placodes. One of the earliest molecular pathways that positively regulates hair follicle initiation is the WNT/β-catenin pathway. β-Catenin is the downstream mediator of WNT signaling. WNT proteins bind to receptors on the cell membrane and, through a series of signals, inhibit the degradation of cytoplasmic β-catenin. β-Catenin then translocates to the nucleus, forming a complex

with the LEF/TCF family of transcription factors and resulting in expression of downstream genes.15,31 Activation of this β-catenin pathway appears necessary for establishing epithelial competence—a state in which the epithelial tissue has the potential to form a hair follicle. Normally, the β-catenin pathway is inactive in the adult epidermis, but by artificially activating β-catenin in epidermal basal cells of adult transgenic mice, hair follicles develop de novo.32 This remarkable finding could eventually have therapeutic implications, although constant activation of this pathway in the hair follicle also results in pilomatricomas and trichofolliculomas, two types of relatively rare cutaneous tumors.32,33 EDA, a molecule related to tumor necrosis factor, and its receptor (EDAR) also are part of another major pathway that stimulates early follicle development in both mice and humans.34 EDA gene mutations cause X-linked anhidrotic ectodermal dysplasia, a syndrome associated with decreased numbers of hair follicles, and defects of the teeth and sweat glands (see Chapter 142).35 The EDAR gene is mutated in autosomal recessive and dominant hypohidrotic ectodermal dysplasias, causing identical phenotypes to those resulting from EDA mutations. The mouse Edar gene is expressed ubiquitously in the epithelium before placode formation, and then becomes restricted to placodes, whereas the Eda gene is ubiquitously expressed even after placode formation.36 Mice with mutations in these genes have the same phenotype as humans with similar mutations, and mice overexpressing Eda in the epidermis show formation of the “fused” follicles due to the loss of proper spacing between neighboring hair placodes.37,38 Humans with more active EDAR genes have thicker hair.25 In contrast to EDA and EDAR, which promote hair follicle development, members of the BMP family inhibit follicle formation. Bmp2 is expressed diffusely in the ectoderm, but then localizes to the early placode and underlying mesenchyme, while Bmp4 is expressed in the early dermal condensate.39,40 BMP signaling inhibits placode formation, whereas neutralization of BMP activity by its antagonist Noggin promotes placode fate, at least in part via positive regulation of lymphoid enhancer factor 1 (Lef-1) expression.39,41–43 Mice lacking Noggin have fewer hair follicles than normal and retarded follicular development.43 The Notch pathway also appears to play a role in determining the follicular pattern. The Notch ligand Δ-1 is normally expressed in the mesenchyme underlying the placode44–46 and, when misexpressed in a small part of the epithelium, promotes and accelerates placode formation while suppressing placode formation in surrounding cells.44,47 Another secreted protein present in the follicular placode that plays a major role in epithelial-mesenchymal signaling is sonic hedgehog (Shh).48,49 Skin from mice lacking Shh have extremely effete hair follicles with poorly developed dermal papillae.50–52 Patched1 (Ptc1), the receptor for Shh, is expressed in the germ cells and the underlying dermal papilla, suggesting that Shh may have both autocrine and paracrine inductive properties necessary for hair

germ and dermal papilla formation.53 Patched is the gene deficient in basal cell nevus syndrome (see Chapter 116).19

THE BULBOUS PEG OR HAIR BUD

HAIR TYPES After formation of the lanugo hair that is characteristic of the prenatal period, there are two major types of hair classified according to size (Table 86-1). Terminal hairs are typically greater than 60 μm in diameter, possess a central medulla, and can grow to well over 100 cm in length. The duration of the growing stage (anagen) determines the length of the hair. The hair bulb of terminal hairs in anagen is located in the subcutaneous fat. In contrast, vellus hairs are typically less than 30 μm in diameter, do not possess a medulla, and are less than 2 cm in length. The hair bulb of vellus hairs in anagen is located in the reticular dermis. Terminal hairs are found on the scalp, eyebrows, and eyelashes at birth. Vellus hairs are found elsewhere, and, at puberty, vellus hair follicles in the genitalia, axillae, trunk, and beard area in men transform into terminal hair follicles under the influence of sex hormones. Terminal hair follicles in the scalp convert to vellus-like or miniaturized hair follicles during androgenetic alopecia (see Chapter 88).1,69 The curvature of the hair varies greatly among different individuals and races, and ranges from straight to tightly curled. Curved hair shafts arise from curved hair follicles. The shape of the inner root sheath is thought to determine the shape of the hair. Curled

Biology of Hair Follicles

The central lumen where the hair shaft will emerge is formed by necrosis and cornification of epithelial cells in the infundibulum. As the hair shaft is produced, several signaling pathways are involved in the control of its differentiation. Wnt/β-catenin/Lef-1 signaling plays an important role in hair shaft formation, and ectopic expression of Wnt3 in the hair follicle outer root sheath causes hair shaft fragility.57,58 Hair shaft keratin genes contain binding sites for Lef-1,59 which translocates to the nucleus after activation of the WNT/βcatenin pathway. WNT signaling probably regulates expression of hair shaft keratin genes, because nearly

::

MATURE HAIR FOLLICLE

ANATOMY

15

Chapter 86

In the next stage of development, the bulbous peg or hair bud (or stage 2 of hair follicle development, see Fig. 86-1) is formed by elongation of the hair germ into a cord of epithelial cells. The mesenchymal cells at the sides of the peg will develop into the fibrous sheath of the hair follicle, and those at the tip of the peg will develop into the dermal papilla. The deepest portion of the follicle peg forms a bulbous structure that surrounds the underlying mesenchymal cells destined to become the dermal papilla. These epithelial cells will become the matrix of the hair follicle, which gives rise to the hair shaft and inner root sheath. The outer root sheath forms two bulges on the side of the hair follicle forming an obtuse angle with the surface of the skin. The superficial bulge will develop into the sebaceous gland. The deeper bulge serves as the future site of epithelial stem cells that generate the new lower follicle during hair follicle cycling. The arrector pili muscle usually attaches in the bulge area, and contraction of the muscle causes a more vertical orientation of the hair shaft leading to “goose bumps.” In the axillae, anogenital region, areolae, periumbilical region, eyelids (the specialized glands of Moll), and external ear canals, a third bulge develops superficial to the sebaceous gland bud and gives rise to the apocrine gland. As the hair follicle bulb appears during the bulbous peg stage, at least eight different cell layers constituting all of the components of the mature hair follicle are formed. Understanding which genes determine specific cell lineages within the follicle is an important question. GATA-3 is important in inner root sheath differentiation.54 Notch1, a membrane protein involved in determining cell fate through cell–cell interactions and intracellular signal transduction, and its ligands Serrate1 and Serrate2 are expressed in matrix cells destined to form the inner root sheath and hair shaft.46,55 Notch1 appears to control the phenotype of keratinocytes as they leave the bulb matrix and differentiate into specific cell types.56

all of these genes contain Lef-1 binding sites in their promoter regions.60 BMP signaling is also essential for proper differentiation of the inner root sheath and hair shaft, because conditional deletion of BMP receptor type 1A in keratinocytes results in profound alterations of the inner root sheath and hair shaft formation.61–63 Several other putative transcription factors control hair shaft differentiation, including HOXC13,6 a homeobox protein, and the WHN gene,64–66 which is mutated in nude mice and rarely in humans with hair, nail, and immune defects.67,68 This process of hair follicle formation is repeated in several waves, with the formation of secondary follicles alongside the initial follicle. The follicles are primarily clustered into groups of three and possess an oblique orientation with a similar angle to their neighbors.

TABLE 86-1

Hair Types and Characteristics Type of Hair

Anagen Duration

Size (Diameter, Length)

Lanugo

1–3 months

40 μm, 1–2 cm

Vellus

1–2 weeks

60 μm, 10–>100 cm

Miniaturized

50% involvement

varies from 15–40 mg.109,166–168,171 An initial response is often seen after 4–8 weeks. Some patients experience indentation of the scalp skin in the injection sites due to a nonpermanent atrophy of the subcutaneous fat. Permanent skin atrophy can occur if the same skin area is injected repeatedly over months and years. If no regrowth can be seen after 4 months of treatment, other treatment options should be considered. Intralesional corticosteroids injections are usually used on the scalp, eyebrows and beard area and can be combined with topical treatment.

Systemic Corticosteroids. Systemic corticosteroids are effective in the treatment of alopecia areata. However, the regrown hair frequently falls out again when the treatment is discontinued. The use of systemic corticosteroids is controversial and largely used on a short-term basis with rapidly advancing hair loss. They should not be used as routine treatments because they do not alter the long-term prognosis and can cause side effects such as striae, acne, obesity, cataracts and hypertension. Dosages vary from initial 20–40 mg prednisone daily tapered down to 5 mg daily in a few weeks or different pulse therapies regiments with short-term high doses of oral prednisolone (100–300 mg) or i.v. methylprednisolone (250 mg).109,166–168 Topical Minoxidil. There is some evidence of clini-

cally acceptable hair regrowth using topical minoxidil 5% solution.172,173 Better results can be achieved when minoxidil is used in combination with class II topical

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Section 15 :: Disorders of the Hair and Nails

994

corticosteroids or anthralin.170 Minoxidil shows little efficacy in alopecia totalis and universalis.

Anthralin. Anthralin is an irritant that may have a nonspecific immunomodulating effect and is primarily used in the treatment of psoriasis (Chapter 18).174 Several studies have shown efficacy in the treatment of alopecia areata with cosmetically acceptable improvement varying from 20% to 25% for patchy alopecia areata.175,176 Anthralin is used as a 0.2%–1.0% cream or ointment. It is usually applied daily to the affected scalp areas and left on for 20–30 minutes for the first 2 week, and then 45 minutes daily for 2 week, up to a maximum of 1 hour daily. Some patient may tolerate overnight therapy.109,175 When therapy is effective, new hair growth can usually be seen after 2–3 months of treatment. Because of its good safety profile, anthralin can be used safely in affected children. Side effects of anthralin are irritation, scaling, folliculitis and regional lymphadenopathy. Anthralin is not suitable for the treatment of eyebrows and beard area. Patients should be cautious not to get anthralin in the eyes and to protect the treated skin areas from UV irradiation. Brown discoloration of the treated skin and brown staining of clothes and linen may occur. The patient should be advised to rinse off the anthralin with cool or luke-warm water, since hot water increases the likelihood of brown stains of tiles and bathtub. Topical

Immunotherapy. Although not approved by the FDA, topical immunotherapy seems to be the most effective therapeutic option with the best safety profile in the treatment of chronic severe alopecia areata. The exact mechanism of action is not fully understood. A decrease in the peribulbar CD4+/CD8+ lymphocyte ratio and a shift in the position of T-lymphocytes from the perifollicular area to the interfollicular area and dermis are believed to be responsible for the immunomodulating effect.177–179 The desired effect of the treatment is the creation of a contact dermatitis. Diphenylcyclopropenone (DPCP) and squaric acid dibutyl ester (SADBE) are the most commonly used contact sensitizers. DPCP and SADBE are compounded in an acetone base and stored in opaque bottles to protect the solution from photodegradation. Applying a small amount of a 2% solution to a small scalp or other area (often the arm) one week prior to treatment initiation sensitizes the patient. The DPCP or SADBE solution is then applied weekly to the scalp, starting at a concentration of 0.0001%. The scalp should not be washed for 48h post treatment and should be protected from UV radiation. Every week the concentration is carefully increased until the patient develops a mild erythema and mild itching. The treatment is continued with this concentration; the highest concentration used is 2%. Success rates vary from 17%–75% with the lowest success rates in patients with alopecia totalis and universalis.20 Side effects include lymphadenopathy in 100% of patients, severe contact eczema, discoloration of the skin including vitiliginous patches and hyperpigmentation on the scalp and other arts of the body. Greater caution is indicated in patients with atopic dermatitis and dark skin types.

Photo(chemo)Therapy. Ultraviolet B light has been reported to be useful in some patients with alopecia areata.180 Further therapeutic options include both oral and topical administration of psoralen followed by UVA irradiation (PUVA-therapy). PUVA may affect T cell function and antigen presentation, and possibly inhibits the local immunologic attack against the hair follicle by depleting Langerhans cells.181 Photo(chemo)therapy shows a very high relapse rate especially after tapering the treatment. The major concern about long term UV irradiation of any kind is its promotion of all types of skin cancer, including melanoma. Therefore phototherapy should only be considered in exceptional cases.20 Cyclosporine. Systemic cyclosporine at doses of 4–6

mg/kg/day has been shown to have a beneficial effect in some patients with alopecia areata.20,182 Side effect of oral cyclosporine include elevated serum transaminases and cholesterol levels, as well as headaches, dysesthesia, fatigue, diarrhea, gingival hyperplasia, flushing and myalgias. Cyclosporine can be combined with low dose oral prednisone and may be considered in patients with severe atopic dermatitis and alopecia areata. However, due to its side effect profile and the high recurrence rate observed after discontinuation, cyclosporine seems to be a relatively impractical treatment for alopecia areata.

Camouflage, Wigs, and Hairpieces.

When alopecia is progressive despite treatment and sometimes during treatment for improved cosmesis, extensive alopecia areata of the scalp can be camouflaged with wigs. In women with alopecia areata of the eyebrows, permanent makeup may be considered. The treating physician should provide psychological support. Local and national alopecia areata support groups (National Alopecia Areata Foundation, www. naaf.org) can be very helpful for patients and their relatives.

TEMPORAL TRIANGULAR ALOPECIA Temporal triangular alopecia (TTA) is a nonscarring, noninflammatory alopecia that presents with one or more roughly triangular, oval, or lancet-shaped alopecic patches in the fronto-temporal area.183–185 A few terminal hairs or vellus-like hairs can often be found in the periphery of the affected area and the scalp is normal.186–190 The lesions are usually asymptomatic and the hair elsewhere on the scalp is of normal density. The patches are mostly unilateral (80%) but can occur bitemporally as well (20%)34,185,190 (Fig. 88-14). A strip of hair of normal density can be seen between the affected patch and the forehead. Lesions can be present at birth or first appear before school age. TTA has been reported in Asian and Caucasian patients with no sexual predilection. TTA seems to be unresponsive to medical treatment. Hair transplantation or excision is reasonable therapeutic approaches.191 TTA is often misdiagnosed as alopecia areata.

SYPHILIS

Cicatricial or scarring alopecias comprise a diverse group of scalp disorders that result in permanent hair

CICATRICIAL ALOPECIA AT A GLANCE Scarring alopecia occurs in a heterogeneous group of hair disorders of a wide variety of causes. The inflammatory process leads to permanent destruction of hair follicular stem cell structure and subsequent replacement with fibrous tissue.

Hair Growth Disorders

CICATRICIAL ALOPECIA

PRIMARY CICATRICIAL ALOPECIAS

::

Hair loss is a common symptom of secondary or tertiary syphilis. In its classical form, the hair loss is an irregular, patchy loss of hair scattered throughout the scalp, which has been described as “moth eaten” (Fig. 88-15). Eyebrows may be shed and patchy alopecia may occur in the beard or other hair-bearing areas of the body. Syphilitic alopecia can be very difficult to distinguish from alopecia areata. The presence of plasma cells, lack of peribulbar eosinophils, and abundant lymphocytes in the isthmus are histological features of syphilitic alopecia. Essential syphilitic alopecia occurs in the absence of any other cutaneous sign of secondary syphilis,192 and is characterized by a diffuse shedding, thereby resembling TE.

15

Chapter 88

Figure 88-14  Temporal triangular alopecia.

loss. The destructive process can occur as a primary or secondary cicatricial alopecia. Primary cicatricial alopecia refers to a group of idiopathic inflammatory diseases, characterized by a folliculocentric inflammatory process that ultimately destroys the hair follicle. Secondary cicatricial alopecias can be caused by almost any cutaneous inflammatory process of the scalp skin or by physical trauma, which injures the skin and skin appendages. Regardless of whether a cicatricial alopecia is primary or secondary in nature, all scarring alopecias are characterized clinically by a loss of follicular ostia and pathologically by a replacement of hair follicles with fibrous tissue. Cicatricial alopecias are psychosocially distressing for the affected patient and medico-surgically challenging for the treating physician.

The destructive process can occur as a primary or secondary cicatricial alopecia In each case, the differential diagnosis includes alopecia areata, an alternative form of cicatricial alopecia, temporal triangular alopecia, trichotillomania, and secondary syphilis (alopecia areolaris). Loss of hair ultimately occurs with permanent alopecia. No evidence-based treatment is available.

EPIDEMIOLOGY.

cias are rare.

Figure 88-15  Alopecia secondary to syphilis. (From Wolff K, Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatrick’s Dermatology in General Medicine. 7th ed. Copyright © The McGraw-Hill Companies, Inc. All rights reserved, with permission.)

Inflammatory cicatricial alope-

ETIOLOGY AND PATHOGENESIS. The mechanisms causing the follicle stem cell destruction are not completely understood, and there is no cure to date. Primary cicatricial alopecias are characterized by an inflammatory infiltrate affecting the upper, permanent portion of the follicles referred to as the infundibulum, and below it, the isthmus of the follicle. The isthmus is the home of pluripotent hair stem cells, which are found in the bulge region where the arrector pili muscle attaches to the outer root sheath. Pluripotent hair follicle stem cells are responsible for the renewal of the upper part of the hair follicle and sebaceous glands,

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15

Box 88-5  Forms of Primary Cicatricial Alopecia

Section 15

Lymphocytic Chronic cutaneous lupus erythematosus (discoid lupus erythematosus, DLE) Lichen planopilaris (LPP) Classic LPP Frontal Fibrosing Alopecia Graham–Little syndrome Classic Pseudopelade of Brocq (PPB) Central centrifugal cicatricial alopecia (CCCA) Alopecia mucinosa

:: Disorders of the Hair and Nails

Neutrophilic Keratosis follicularis spinulosa decalvans Folliculitis decalvans Dissecting cellulites/folliculits (perifolliculitis abscedens et suffodiens) Mixed

Folliculitis (acne) keloidalis Folliculitis (acne) necrotica Erosive pustular dermatosis

Source: Olsen EA et al: Summary of North American Hair Research Society (NAHRS)-sponsored Workshop on Cicatricial Alopecia, Duke University Medical Center, February 10 and 11, 2001. J Am Acad Dermatol 48:103-110, 2003.

and for the restoration of the lower cyclical component of the follicles at the onset of a new anagen period.27,193 Damage to the bulge area and the sebaceous gland with the isthmus, affected either stem cells or sebaceous glands, may result in an incomplete hair cycle and can be associated with chronic follicular inflammation and foreign body reaction.194 Scarring hair loss is the consequence.5,195–197 A working classification on the basis of pathology of scalp biopsy was suggested by the North American Hair Research Society in 200127 (Box 88-5).

996

CLINICAL FINDINGS. Primary cicatricial alopecia usually affects the central and parietal scalp before progressing to other sites of the scalp. Isolated alopecic patches showing atrophy and a lack of follicular ostia with inflammatory changes such as diffuse or perifollicular erythema, follicular hyperkeratosis, pigment changes, tufting, and pustules provide hints to the diagnosis.20,198 However, clinically visible inflammatory change might be absent in the affected lesions and may present histologically as inflammatory infiltrates in the deep dermis and subcutaneous tissue. Diagnostic tools such as a tenfold magnifying dermatoscope with and without polarized light can help to identify the presence or absence of follicular ostia, perifollicular erythema and follicular hyperkeratosis in the affected areas.

A thorough examination of the entire scalp, a detailed clinical history, and skin biopsies of an active lesion are crucial in the correct diagnosis of cicatricial alopecia. Patient-reported symptoms such as itching or pain might be used as approximate indicators of disease activity but can also be completely absent. The presence of other indirectly related symptoms, such as sun sensitivity, can also help support a particular diagnosis [e.g., discoid lupus erythematosus (DLE)]. A scalp biopsy is necessary to confirm the diagnosis of scarring alopecia, and should be taken as described in Section “Diagnostic Techniques for Evaluating Hair Growth Disorders” under “Biopsy.”1,27,199,200 Keratoses follicularis spinulosa decalvans is a form of cicatricial alopecia associated with follicular plugging that is more fully described in Chapter 87 as well as online.

LYMPHOCYTIC PRIMARY CICATRICIAL ALOPECIAS CHRONIC CUTANEOUS LUPUS ERYTHEMATOSUS (Discoid Lupus Erythematosus). (See also Chapter 155). Discoid lupus

erythematosus (DLE), together with LPP, is the most common cause of inflammatory cicatricial alopecia.198 Women are more often affected than men and the disease is more common in adults (with first onset typically at the age of 20–40 years) than in children.201–203 Systemic lupus erythematosus (SLE) will develop in 26%–31% of children and approximately 5%–10% of adult patients with DLE.203,204 Patients with DLE are found to have a higher incidence of concurrent alopecia areata. Moreover, DLE has also been associated with verruciform xanthoma and papulonodular dermal mucinosis.205

Clinical Presentation. DLE usually presents with one or more erythematous, atrophic, and alopecic patches on the scalp (Fig. 88-16). Follicular hyperkeratosis, hyperpigmentation, hypopigmentation and telangiectasia can be present.194,206 Hyperpigmentation is frequently found in the center of the lesion. Active lesions can be sensitive or pruritic, and the patient might report a worsening after UV exposure. Pathology.

Characteristic features of early, active DLE lesions are lymphocyte-mediated interface

Figure 88-16  Discoid lupus erythematosus.

15

dermatitis with vacuolar degeneration of the basal cell layer and necrotic keratinocytes, a thickening of the basement membrane and destruction of sebaceous glands. Elastic fibers are frequently destroyed throughout the reticular dermis.1,195 The lymphocytic infiltrate is predominantly found in the upper part of the follicle, but can also be found in deeper parts of the follicle, in the interfollicular epidermis and around the periadnexal vessels.18,207–209 DIF typically shows a linear granular deposition of IgG and C3 at the dermal–epidermal junction. IgM, C1q, and rarely IgA can also be found.

Management and Treatment.

Figure 88-17  Extensive lichen planopilaris. clinical features with those of DLE are frequently seen. Patients complain about itching, burning sensations and sensitivity of the scalp (Fig. 88-17). FFA is characterized by a frontal, band-like, or circumferential scarring alopecia.195 In some cases a few hairs are spared in the original frontal hairline. Follicular hyperkeratosis and perifollicular erythema may be found in a band-like pattern in the frontal hairline. Alopecia of the eyebrows is also frequently seen in FFA (Fig. 88-18). Graham–Little syndrome presents with lesions of classic LPP on the scalp, nonscarring alopecia of axillae, pubic area, and eyebrows as well as keratosis pilaris of the trunk and extremities.

Hair Growth Disorders

Clinical Presentations of LPP. Classic LPP typically starts at the crown and vertex area. In classic LPP, the affected areas usually show perifollicular erythema and follicular hyperkeratosis. The alopecic areas of LPP are often smaller, irregularly shaped and interconnected, which can lead to a reticulated clinical pattern as compared to DLE. However, overlapping

::

LICHEN PLANOPILARIS. LPP is a follicular variant of lichen planus. Together with DLE, this is the most common cause of primary cicatricial alopecia. LPP can be divided in classic LPP, frontal fibrosing alopecia (FFA), and Graham–Little syndrome. The typical age of onset of classic LPP is around the fifth decade, and women are more often affected than men. Extracranial lichen planus may occur in up to 28% of patients.196,213,214 FFA predominantly affects postmenopausal women. Graham–Little–Piccardi–Lassueur Syndrome is a very rare condition that predominantly affects female adults. It is characterized by LPP of the scalp, noncicatricial of the eyebrows, axilla, and groin and keratosis pilaris. Lichenoid drug eruptions can be triggered by many drugs and might present as LPP. Some of the most common drugs, causing lichenoid drug eruption are gold, antimalarials and captopril. Actinic lichenoid drug eruption is confined to sun exposed sites. The most likely drugs to cause this are quinine, and thiazide diuretics.215–217

Chapter 88

Hydroxychloroquine at a dose of 200–400 mg daily in adults or 4–6 mg/kg in children has been shown to be highly effective. A baseline ophthalmologic examination and complete blood count is required before the therapy is started.201,203 Bridge therapy with oral prednisone (1 mg/kg) tapered over the first 8 weeks of treatment might be helpful in adult patients with rapidly progressive disease.20,198 In limited or slowly progressive DLE, intralesional triamcinolone acetonide should be used at a concentration of 10 mg/cc every 4–6 weeks, alone or in addition to oral therapy.198 Intralesional triamcinolone acetonide can be used with or without topical class I or class II corticosteroids. Topical corticosteroids alone have also been shown to be effective in milder forms of DLE,1,18,20,203 and oral acitretin and isotretinoin have shown some efficacy.210,211 Immunosuppressive therapies such as mycophenolate mofetil, methotrexate, or azathioprine should only be considered if the above therapies fail. Multimodal aggressive therapy in rapidly progressive DLE might reverse early alopecic patches and save hair follicles from the destructive process.212

Pathology. The three subgroups of LPP show similar histopathological features. A lymphocytic infiltrate and interface dermatitis are predominantly found in and around the upper permanent part of the hair follicle. Unlike DLE, the vascular plexus is not affected by inflammation and mucin deposits are absent.195 DIF typically shows globular cytoid depositions of IgM, and rarely IgA, IgG or C3, in the dermis around the infundibulum.218

Figure 88-18  Frontal Fibrosing alopecia.

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Section 15

Management and Treatment. First line treatment for moderately active classic LPP lesions is intralesional triamcinolone acetonide at a concentration of 10 mg/cc every 4–6 weeks or in combination with topical class I or class II corticosteroids.198,211 Literature on the efficacy of oral medication is limited. Oral cyclosporine, retinoids, antimalarials and griseofulvin194,206,219–222 have been shown to have a positive effect in patients with rapidly progressive LPP. Oral corticosteroids in the first weeks of treatment as bridge therapy might be considered in very active cases. In FFA, a lower dose of intralesional triamcinolone acetonide (2.5–5 mg/cc), or topical application of minoxidil or tacrolimus can be considered, although no effective treatment has been reported yet. The treatment of Graham–Little syndrome is typically similar to the management of classic LPP.

:: Disorders of the Hair and Nails

CLASSIC PSEUDOPELADE OF BROCQ. PPB is classified as an idiopathic lymphocytic primary cicatricial alopecia that predominantly affects the scalp. It is the second most common cause of primary cicatricial alopecia.196 Women between 30 and 50 years of age are most frequently affected. Clinical Presentation. Pseudopelade of Brocq usu-

ally affects the vertex and occipital area of the scalp. It presents with small flesh-toned alopecic patches with irregular margins. This pattern has been described as “footprints in the snow.”223 PPB can also present as a noninflammatory centrifugally spreading patch of alopecia, which might be seen as a variant of central centrifugal cicatricial alopecia in Caucasians. Follicular hyperkeratosis and perifollicular or diffuse erythema is mostly absent.206 Clinically the features may overlap with LPP.

Pathology. Early PPB lesions typically show a sparse to moderate lymphocytic infiltrate around the follicular infundibulum with a complete destruction of the sebaceous glands.176 In later disease stages, hair follicles are completely replaced by fibrous tracts. Unlike DLE and LPP, interface dermatitis is usually absent and the elastic fibers are preserved and thickened in PPB.224 Management and Treatment. Intralesional tri-

amcinolone acetonide at a concentration of 10 mg/cc every 4–6 weeks in combination with topical corticosteroids is the treatment of first choice. Hydroxychloroquine, oral prednisone, and isotretinoin have shown some effectiveness in treating PPB.196,206,225,226

CENTRAL CENTRIFUGAL CICATRICIAL ALOPECIA. CCCA is classified as a lymphocytic primary

cicatricial alopecia, primarily affecting women of color. It remains unclear which of the following contribute most to its formation: chemical processing, heat, traction or other traumas.1,18 CCCA can rarely be seen in Caucasians (sometimes called “central elliptical pseudopelade”) and African-American men. Due to clinical and histopathological similarities, it has been debated whether CCCA is a variant of PPB.

998

Clinical Presentation. CCCA presents with a skin

colored patch of scarring alopecia on the crown, gradu-

Figure 88-19  Central centrifugal cicatricial alopecia. ally progressing centrifugally to the parietal areas. Perifollicular hyperpigmentation and polytrichia might be present.198 Patients may complain about itching, tenderness and “pins and needle” sensations227 (Fig. 88-19).

Pathology. Limited studies suggest that histopathological features of CCCA seem to be similar to those of PPB.18,194 Management and Treatment. Topical cortico-

steroids and tetracycline have shown to be effective in active progressive cases.18 Since a multifactorial etiology is debated for CCCA, some dermatologists recommend a switch to more natural, less traumatizing, hair care practices.1,206,228 Wigs and hairpieces can help camouflage the alopecia and are frequently used by women with CCCA.

ALOPECIA MUCINOSA. Alopecia mucinosa (AM) can present as indurated, well-demarcated erythematosus or skin colored patches of scarring or nonscarring alopecia that can be accompanied by diffuse hair loss229 and alopecia of the eyebrows.230 Grouped follicular papules, follicular cysts and follicular hyperkeratosis may be present in some cases. Early lesions of AM show mucin deposition in the outer root sheath and replacement of the entire pilo-sebaceous unit by pools of mucin in more advanced lesions.195,230 AM strictly speaking it is not a primary cicatricial alopecia because the hair follicle is not replaced by a true scar.195 AM can occur idiopathically or in the setting of cutaneous T-cell lymphoma or mycosis fungoides.231 Cell atypia and monoclonal populations of T-lymphocytes can be present in the idiopathic form of AM as well as in the latter form.231 Management and Treatment.

A complete workup is necessary to rule out an underlying malignancy such as mycosis fungoides and Sézary syndrome, its advanced endpoint. Oral corticosteroids, minocycline and isotretinoin have been shown to be

effective. Topical and intralesional corticosteroids, dapsone, indomethacin and light therapy have also been used with variable outcomes.232

NEUTROPHILIC PRIMARY CICATRICIAL ALOPECIA

Hair Growth Disorders

Pathology. Early lesions are characterized by keratin aggregation in the infundibulum with numerous intraluminal neutrophils, as well as an intrafollicular and perifollicular neutrophilic infiltrate.194,195,206 Sebaceous glands are destroyed early. In advanced lesions, the infiltrate may consist of neutrophils, lymphocytes, and plasma cells and extend into the dermis.198,206 Hair shaft granulomas with foreign-body giant cells can frequently be found.194,206 In end-stage lesions, follicular and interstitial dermal fibrosis as well as hypertrophic scarring can be observed.206

DISSECTING FOLLICULITIS. Dissecting folliculitis (DF) (or dissecting cellulites or perifolliculitis capitis abscedens et suffodiens of Hoffman) is related to acne conglobata and hidradenitis suppurativa. These three diseases have been described as follicular occlusion triad. DF predominantly occurs in young men between 18 and 40 years of age.198 African-American men seem to be more commonly affected compared to Caucasian men. The pathogenesis of DF may include follicular occlusion, seborrhea, androgens and secondary bacterial overpopulation as well as an abnormal host response to bacterial antigens.239–246

::

Clinical Presentation. FD frequently starts at the vertex area of the scalp with erythematous alopecic patches, follicular pustules and follicular hyperkeratosis. Tufted folliculitis is typically found in FD, but can also occur in other cicatricial inflammatory alopecias. Tufted folliculitis is characterized by multiple hairs (5–15) emerging from one single, dilated follicular orifice. In older lesions pustules might be absent but progressive scarring may still continue (Fig. 88-20). An overlap with acne keloidalis is possible since some patients with acne keloidalis not only develop cicatricial lesion on the nape of the neck but also develop progressive cicatricial alopecia that resembles FD in other areas of the scalp. Patients frequently complain about pain, itching and/or burning sensations.

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Chapter 88

FOLLICULITIS DECALVANS. Approximately, 11% of all primary cicatricial alopecia cases are diagnosed with folliculitis decalvans (FD).194,196 FD predominantly occurs in young and middle-aged adults with a slight preference of the male gender. A bacterial infection involving S. aureus, in combination with hypersensitivity reaction to “superantigens” and defect in host cell-mediated immunity have all been suspected as possible pathogenetic factors.194,234,235

over many years. Bacterial cultures with the testing of antibiotic sensitivities are recommended. Eradication of Staphylococcus aureus with minocycline, erythromycin, cephalosporines, and sulfamethoxazole-trimethoprim has shown some effectiveness. Relapse can often be observed after the antibiotics are discontinued.20,234,236 If so, the patient might have to stay on low dose antibiotics for many years. Rifampin in combination with clindamycin has shown good response; however, this combination shows a higher incidence of side effects.234,237 Oral fucidic acid alone or in combination with other agents has also shown to be effective in some patients.238 Oral therapy should be combined with topical antibiotics such as mupirocin, 1.5% fusidic acid and 2% erythromycin237,238 and antibacterial cleansers. Intralesional triamcinolone acetonide at a concentration of 10 mg/cc every 4–6 weeks might help to reduce the inflammation and reduces symptoms such as itching, burning, and pain.20,196 Intranasal eradication of S. aureus with topical antibacterial agents have been described to be useful.206

Clinical Presentation. DF typically presents with

Management and Treatment. Treatment of FD

fluctuating nodules, abscesses, and sinuses, which frequently show spontaneous discharge of pus, as well as with erythematous, follicular papules and pustules. Initial lesions are mostly found on the vertex and occipital scalp. Multifocal lesions can form an intercommunicating ridge and sero-purulent exudates can be discharged when pressure is applied to one region of the scalp (Fig. 88-21). The lesions can be pruritic and tender. Chronic and relapsing courses result in cicatricial alopecia, which can show hypertrophic or keloidal scars.246

Figure 88-20  Folliculitis decalvans.

Figure 88-21  Dissecting cellulitis.

in general is difficult and disease activity can be noted

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15

Pathology. The main histological feature is an intra-

follicular and perifollicular neutrophilic infiltrate with follicular occlusion in early lesions.195 In more advanced stages, interconnecting sinus tracts lined by squamous epithelium, follicular perforation, perifollicular and deep dermal abscesses are typical findings.195,206,209

Section 15 :: Disorders of the Hair and Nails

Management and Treatment. Multimodal treatment has been reported with successful results, such as systemic antibiotics (minocycline, tetracycline, cloxacillin, erythromycin, cephalosporin or clindamycin), intralesional corticosteroids, and oral prednisolone.247,248 The benefits of systemic antibiotics are most likely due to their antiinflammatory effects rather than to their antibacterial action. Isotretinoin at a dose of 0.5–1 mg/kg/d has shown prolonged remission.249,250 Incision and drainage of therapy resisted, painful nodules, marsupialization with curettage of the cyst wall, complete scalp extirpation with skin grafting have been reported, but should be an exception for extreme and therapy refractory cases.250–252 MIXED PRIMARY CICATRICIAL ALOPECIAS ACNE KELOIDALIS NUCHAE. Acne keloidalis nuchae (AKN) predominantly occurs in AfricanAmerican men age 14 to 25. This idiopathic primary cicatricial alopecia might be triggered by trauma (shirt collars) or infection (Demodex or bacteria). Clinically AKN presents with skin-colored follicular papules, pustules and plaques as well as keloid-like scarred lesions in the occipital scalp (Fig. 88-22). Histologically, acne keloidalis is characterized by an acute inflammation with neutrophilic or lymphocytic infiltration and chronic granulomatous inflammation around the isthmus and the lower infundibulum. Treatment is usually difficult and protracted. Monthly intralesional triamcinolone acetonide (10–40 mg/mL) alone or combined with topical 2% clindamycin or oral (tetracyclines) antibiotics is the treatment of first choice.1,18,194,253,254 Class I or II topical steroids alone or in combination with topical antibiotics for mild cases of AKN as well as cryotherapy and laser therapy have shown some success. Surgical excision of extensive keloidal lesions

may be considered but should be reserved for therapy refractory, extensive and symptomatic cases.

ACNE NECROTICA (VARIOLIFORMIS). Acne necrotica varioliformis is a very rare, chronic condition, which predominantly occurs in adults. Frontal and parietal scalp as well as seborrheic areas of the face are most commonly affected. Acne necrotica presents with umbilicated, pruritic or painful papules that undergo central necrosis. The condition leaves varioliform, or smallpox-like scars.255,256 Histology shows a suppurative, necrotic, infundibular folliculitis with lymphocytic or mixed inflammatory infiltrate.256 Oral antibiotics, isotretinoin, intralesional or topical corticosteroids have shown success.257 Excision of larger scarred areas can be considered. EROSIVE PUSTULAR DERMATOSIS. Erosive pustular dermatosis is an uncommon disorder predominantly occurring in elderly women.258,259 The characteristic lesion is a suppurative, necrotic, erosive papule or plaque.258,260 Histology of early lesions is nonspecific, but older lesions show an extensive, chronic mixed inflammatory infiltrate the dermis and later dermal fibrosis. Treatment include class I or II topical steroids with or without topical antibiotics, systemic antibiotics, and oral isotretinoin.258,260 DIFFERENTIAL DIAGNOSIS (Box 88-6)

PROGNOSIS AND CLINICAL COURSE Once the hair follicle is destroyed and replaced by fibrous tissue, there is no hope for hair regrowth. Various medical treatment options may fail and the inflammatory process may continue and leave the patient with a disfiguring permanent alopecia.

TREATMENT The main goal in treating primary cicatricial alopecia is to stop the inflammation and therefore further progression of the disease. If hair loss is already extensive and/or medical treatment fails, patients should be advised about camouflage techniques, hairpieces and wigs. Women with extensive LPP lesion on the crown and vertex benefit highly from a well designed hair piece, which can look very natural, particularly if the

Box 88-6  Differential Diagnosis

1000

Figure 88-22  Acne keloidalis nuchae.

Alopecia areata Secondary cicatricial alopecia Temporal triangular alopecia Trichotillomania Secondary Syphilis (alopecia areolaris)

frontal hairline is preserved and is usually more comfortable to wear compared to a full wig. Hair restoration surgery including HT and scalp reduction can be an option for burnt out cicatricial alopecia. No disease activity should occurs on the scalp for at least 1 year without therapy. The patient has to be warned about a possible limited graft survival and disease recurrence, which seems to be higher in neutrophilic primary.

SECONDARY CICATRICIAL ALOPECIA

DIFFERENTIAL DIAGNOSIS. (Box 88-7) PROGNOSIS AND CLINICAL COURSE. Prognosis and clinical course of secondary cicatricial alopecia depend on the underlying disease. Once scar tissue has formed and the adnexal structures are destroyed no hair regrowth can be expected.

Minimal or severe injuries to the scalp can result in alopecia. It usually presents with fine streaks of hair loss in the injured scalp area, but if the wound borders undergo contusion or destruction, this may result in irregular and large patches of hair loss. Traumatic hair loss can occur after scalp surgery, especially after extensive scalp reduction or large donor strip harvesting in hair restoration surgery, if too much tension is applied with wound closure. This type of hair loss is usually reversible but can also be permanent. Traumatic birth induced alopecia is infrequent; causes include mechanical extractor marks, tears or contusions or resulting infections. Aplasia cutis congenita should be considered in the differential diagnosis of cicatricial alopecia at birth.1

TRACTION ALOPECIA Prolonged traction of the hair may lead to transient or if continued over a period of time, may lead to follicular atrophy, resulting in cicatricial alopecia. Chronic traction can be caused by tight ponytails, braids, heavy dead locks, or extensive use of rollers. Due to ethnic differences in hair fragility and cultural differences in hair styling practices, marginal traction alopecia is more commonly seen in African-American women due to hair braiding and weaving procedures1 (Fig. 88-23). Patchy traction alopecia in the frontal hairline or temples is commonly seen in Sikh boys, whose hair is usually tight up in a “topknot.”270 Cicatricial alopecia caused by prolonged traction can be treated with HT, if the patient discontinues the injuring hairstyles and sufficient donor hair supply is available.

Hair Growth Disorders

is crucial in the diagnosis of secondary cicatricial alopecia. Diagnosis in early stages can sometimes be made based on specific clinical and histological features of the underlying disorder. Follicular orifices are lost clinically, and histology shows extensive scarring with fibrosis, loss of elastic fibers and adnexal structures.261

TRAUMATIC INJURIES

::

CLINICAL FINDINGS. A thorough clinical history

15

Chapter 88

ETIOLOGY AND PATHOGENESIS. In secondary cicatricial alopecias, permanent hair loss is caused by various other scalp conditions not related to the hair follicle. In these conditions, the primary event develops outside the FU and this leads to incidental destruction of the follicle. Possible causes are congenital defects, trauma, inflammatory conditions, infections, neoplasms, and rarely drugs (eBox 88-6.1 in online edition). Permanent, chronic traction alopecia and scars from surgery can be considered secondary scarring alopecias as well.261

scalp. Traumatic alopecias are usually of three types: (1) acute trauma, (2) prolonged traction, and (3) pressure.

TREATMENT. Treatment is specific in active conditions, while in localized end-stage lesions, specific medical treatment is no longer efficient and hair restoration surgery techniques become the mainstay of therapy.

TRAUMATIC HAIR LOSS An acute or chronic mechanical insult to the scalp hair may lead to reversible or irreversible alopecia of the

Box 88-7  Differential Diagnosis Box

Primary cicatricial alopecia Alopecia areata Temporal triangular alopecia Trichotillomania Secondary Syphilis (alopecia areolaris)

Figure 88-23  Traction alopecia. (From Wolff K, Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatrick’s Dermatology in General Medicine. 7th ed. Copyright © The McGrawHill Companies, Inc. All rights reserved, with permission.)

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Section 15 :: Disorders of the Hair and Nails

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TRICHOTILLOMANIA Trichotillomania (Greek: tricho = hair, tillo = pull, mania = excessive excitement) is a form of traumatic alopecia caused by an irresistible compulsion to pull out or twist or break of one’s own hair. Trichotillomania is relatively common with an estimated incidence of 1 million Americans.1 Two forms of trichotillomania can be distinguished: (1) infantile trichotillomania or (2) early onset trichotillomania, which starts in early childhood is typically of short duration and may resolve spontaneously or with simple interventions.271,272 Childhood trichotillomania may be seen analogous to other habitual infantile behaviors such as thumb sucking. Boys are more frequently affected. Trichotillomania, which starts around or after puberty, shows a more chronic course and is usually a sign of a more severe underlying psychopathology. It is classified as an impulse control disorder.273–275 Women are far more often affected than men. The clinical presentation is usually quite distinctive with a single or multiple asymmetrical, occasionally geometrically shaped areas of hair loss on the scalp or other areas of the body (Fig. 88-24). The areas are not smoothly devoid of hairs, as seen in alopecia areata but display short or bristly anagen hair. Telogen hair in the involved area is usually plugged out easily; anagen hair may be plucked out, twisted and broken at various lengths. Regrowing anagen hair needs to reach a certain length before it can be plugged out again. Alopecia areata and tinea capitis should be considered as differential diagnosis. Where doubt remains, a scalp biopsy can be diagnostic, showing a characteristic increase in catagen hair, trichomalacia and pigment casts within the follicular canal secondary to traumatic hair removal. Most important in the therapy of trichotillomania is the education of patient and/or parents and in late onset trichotillomania the treatment of the underlying psychopathology. Especially if patients deny the self-inflicting nature of their hair loss, a referral to a psychiatrist or psychologist is usually refused and treatment becomes difficult.

Figure 88-24  Trichotillomania.

PRESSURE ALOPECIA Pressure alopecia can occur after a patient was unconscious and completely immobile for a certain length of time. Hair loss is presumably due to ischemia caused by the pressure of the body weight to a certain scalp area. The ischemic injury may lead to permanent hair loss.

HAIR SHAFT ABNORMALITIES Hair shaft abnormalities are structural defects of the hair shaft. They can be inherited or acquired. Inherited hair shaft abnormalities can be associated with increased hair breakage or can lead to unruliness of the scalp hair.

HAIR SHAFT ABNORMALITIES WITH INCREASED HAIR BREAKAGE TRICHORRHEXIS NODOSA. Trichorrhexis nodosa can be inherited or acquired. Affected hair shafts develop a breach in the cuticle with separation and fraying of the exposed cortical fibers, which leads to a node-like swelling.142 The fibers then fracture and the shaft breaks with the resultant appearance of a splayed paint brush or fan-like array (Fig. 88-25). Congenital trichorrhexis nodosa can be present at birth or may develop in the first months of life. In rare cases, Trichorrhexis nodosa can be associated with teeth and nail defects or hyperkeratosis1 and with metabolic disorders such as argininosuccinic aciduria (see Chapter 131), Menkes syndrome, and trichothiodystrophy. Acquired trichorrhexis nodosa is much more common. Hair breakage may either occur in the proximal or distal hair shaft. Proximal trichorrhexis nodosa is more commonly seen in African-American women usually after repetitive chemical or hot-comb straightening. Distal trichorrhexis nodosa is mostly secondary

Figure 88-25  Trichorrhexis nodosa. (From Wolff K, Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatrick’s Dermatology in General Medicine. 7th ed. Copyright © The McGraw-Hill Companies, Inc. All rights reserved, with permission.)

to excessive brushing, teasing or chemical treatment such as bleaching or permanent waves. Patients with trichorrhexis nodosa should be advised to avoid any harsh chemical or physical hair styling practice. Proximal trichorrhexis nodosa may take month to year to resolve even if the initiating hair care is avoided.

15 A

TRICHOSCHISIS AND TRICHOTHIODYSTROPHY. Trichoschisis is characterized by a clean

In pili torti, the affected hair shafts are flattened and twisted on their axis, usually through an angle of 180°, with a range of 90°–360° (Fig. 88-26). The twisting occurs in multiple irregular intervals along an otherwise straight hair shaft. Pili torti do not signify a particular abnormality but can be seen in many different syndromes and in the presence of other hair shaft disorders.277 The way of inheritance in pili torti is mostly autosomal dominate, but can also be autosomal recessive or sporadic. Clinically, the patients may present with patchy alopecia with coarse stubble or longer broken hairs. Hair fragility usually improves after puberty. Pili torti occurs in combination with trichorrhexis nodosa, trichoclasis, and trichoptilosis in Menkes kinky hair syndrome, also called steely hair syndrome or trichopoliodystrophy. Menkes syndrome is an X-linked recessive multisystem disease, which begins in infancy. It is associated with depigmented hairs, hypopigmentation of the skin, metal retardation, neurologic impairment secondary to degeneration of cerebral, cerebellar, as well as bone and connective

B

Figure 88-26  Pili torti. A. Irregularly spaced 180° twists in hair shaft. (From Whiting DA: Hair shaft defects. In Disorders of Hair Growth: Diagnosis and Treatment, edited by EA Olsen. New York, McGraw-Hill, 2003, with permission.) B. Brittle broken hair typical of congenital pili torti.

Hair Growth Disorders

PILI TORTI AND MENKES SYNDROME

::

TRICHOCLASIS. Trichoclasis is the common “greenstick” fracture of the hair shaft. It is characterized by a transverse fracture of the shaft, which is splinted partly or completely by intact cuticle. Cuticle, cortex and sulfur content are normal. Trichoclasis does not indicate any specific underlying disease. It can occur in normal hair or may be associated with pili torti.1

Chapter 88

transverse fracture of the hair shaft in an area of a focal absence of the cuticle. It is usually, but not specifically, a marker for sulfur-deficient hair in trichothiodystrophy, in which the scalp hair, eyelashes and eyebrows are short and brittle (see Chapter 139). The hair cysteine content is less than one-half normal, primarily from a major reduction and altered composition of the ultrahigh-sulfur matrix proteins.276 Microscopic examination with polarized light characteristically shows a “tiger tail” pattern with altering light and dark bands, secondary to alterations in the sulfur content1 (eFig. 88-25.1 in online edition). Various structural abnormalities can be detected by confocal and scanning electron microscopy. These complex alterations make hair shafts in trichothiodystrophy excessively prone to breakage and weathering.1 Sulfur and amino acid analysis of the hair is diagnostic. Hair shaft abnormalities in trichothiodystrophy identify a group of autosomal recessive disorders that are associated with neuroectodermal abnormalities (eTable 88-1.2 in online edition).

tissue degeneration. The clinical features result from a defective copper transport and an accumulation of intracellular copper, which results in a functional deficiency of copper-dependent enzymes. Most patients die by the age of 3 years. In Menkes’ syndrome, copper uptake is normal, therefore copper supplementation is ineffective, but copper-histidin given immediately postpartum may prevent or ameliorate the severe neurodegeneration. Low serum concentrations and ceruloplasmin levels are diagnostic.1

TRICHORRHEXIS INVAGINATA (“BABOO HAIR”) AND NETHERTON SYNDROME Trichorrhexis invaginata is a diagnostic marker for Netherton syndrome, although it also may occur sporadically and in association with other hair shaft abnormalities. Netherton syndrome is an autosomal recessive inherited disorder, characterized by a triad of atopic diathesis, ichthyosiform skin changes and trichorrhexis invaginata (see Chapter 49). The primary hair defect appears to be abnormal keratinization of the hair shaft in the keratogenous zone, allowing intussusception of the fully keratinized and hard distal shaft into the incompletely keratinized and soft proximal portion of the shaft.278 This leads to the typical “balland-socket” deformity (Fig. 88-27). Once the hair fractures, it shows a typical golf tee-shaped the distal end. Affected short, brittle hairs can be distributes over the scalp, which may result in sampling errors. Retinoids and phototherapy may be considered as therapy,

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Section 15

Figure 88-27  Trichorrhexis invaginata (light micrograph ×400). (From Whiting DA: Hair shaft defects. In: Disorders of Hair Growth: Diagnosis and Treatment, edited by EA Olsen. New York, McGraw-Hill, 2003, with permission.)

:: Disorders of the Hair and Nails

although the condition frequently improves, as the patient gets older.

MONILETHRIX Monilethrix present with extremely short, brittle, fragile, beaded hairs emerging from a hyperkeratotic follicular orifice. Monilethrix hair shafts show elliptical nodes, 0.7–1 mm apart, with intervening, tapered constrictions that are nonmedullated (Fig. 88-28). These internodes are the predetermined breaking points and often present with longitudinal ridges. Most cases of monilethrix are of autosomal dominant inheritance, with variable expression. In rare cases it is autosomal recessive. It is caused by one of the three genes encoding type II hair keratin (KHb1 or KRT81, KHb3 or KRT83, and KHb6 or KRT86). In the case of autosomal recessive inheritance, the underling gene encodes desmoglein 4 (DSG4). In mildest cases monilethrix is localized to the occiput or the nape of the neck. The hair shaft defect may occur alone or in association with keratosis pilaris, nail and teeth abnormalities, syndactyly, cataracts and physical retardation. Retinoids and topical minoxidil may improve the condition, although monilethrix frequently improves spontaneously with age.1,279,280

LOCALIZED AUTOSOMAL RECESSIVE HYPOTRICHOSIS. This rare autosomal recessive

disorder present with localized sparse broken hair involving scalp and eyebrows. The gene defect lies in a

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Figure 88-28  Monilethrix. Typical beaded appearance of hair as seen under light microscopy (×40). (From Wolff K, Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatrick’s Dermatology in General Medicine. 7th ed. Copyright © The McGraw-Hill Companies, Inc. All rights reserved, with permission.)

Figure 88-29  Uncombable hair syndrome. mutation in the gene for desmoglein 4 (DSG4). Unlike Monilethrix, the hair does not present with beading.281

HAIR SHAFT ABNORMALITIES ASSOCIATED WITH UNRULY HAIR Uncombable Hair Syndrome. Uncombable hair

syndrome, also known as spun glass hair or pili trianguli et canaliculi is an inherited autosomal dominant trait or a sporadic structural hair abnormality.282 This unique syndrome is characterized by rigid hair shafts with a triangular or kidney bean-shaped cross section, but irregular forms, such as flattened, heart-shaped and longitudinal grooves may be present. Clinically, the hair is dry, coarse, usually blond to light brown, and with a spangled appearance. The scalp hair is frizzy, unruly, kinky and unmanageable from infancy, grows in multiple directions and cannot be combed flat (Fig. 88-29). Male and female individuals are equally affected. It first occurs more often during early childhood, but it can develop as late as age 12 years. Microscopic analysis of hair samples under polarized light shows a homogeneous band on one edge caused by the shadow thrown as light passes over the pili canaliculi.283 There is no definitive therapy, but uncombable hair syndrome may improve over time without treatment.284

Wooly Hair. Wooly hair is a rare congenital struc-

tural anomaly of scalp hair. It is marked by an extreme kinkiness of the hair in Caucasians. Wooly hair can be present at birth or appear in the first months of life. The curls, which have an average diameter of only 0.5 cm, lie closely together and usually make the hair difficult to comb. In addition, the hairs may be more fragile than usual. Hair growth rate is usually normal but the anagen phase may be truncated, with the result that the hairs do not grow to be long. The hair shaft exhibits an elliptical cross section, an axial rotation and a kinked formation. A circumscribed occurrence of wooly hair in the form of a wooly hair nevus285 is distinguished from the forms that affect the entire scalp. The latter forms are: autosomal dominant wooly hair (hereditary wooly hair) and, the much rarer form, autosomal recessive hereditary wooly hair (familial wooly hair).286 Autosomal recessive hereditary wooly hair can be syndromic and accompanied by palmoplantar hyperkeratosis and heart anomalies (Fig. 88-30). No treatment is currently available. Harsh physical and chemical

HIRSUTISM

15

Hirsutism is defined as excessive growth of terminal hair in a male distribution in women.292 Hirsutism is indicated by a hirsutism score of 8 or more on the Ferriman–Gallwey scale (Fig. 88-31).61 It must be distinguished from hypertrichosis, generalized excessive hair growth that may be hereditary or result from certain medications in men and women. Hypertrichosis is distributed in a generalized, nonsexual pattern and is not caused by excess androgen (although hyperandrogenism may aggravate it).

Defined as terminal body hair growth in women in a male distribution

MARIE–UNNA HYPOTRICHOSIS. Marie–Unna hypotrichosis is of autosomal dominant inheritance and is characterized by sparse or absent hair at birth and variable coarse, wiry hair growth during childhood, affecting scalp and eyebrows. Once the child grows older, scalp hair is lost in a pattern, resembling AGA with scattered thick hair in the balding areas. Body hair is sparse or absent. Male and female individuals are equally affected. Light and electron microscopic examination shows irregular twisting, longitudinal ridging and cuticle peeling. Diffuse follicular hyperkeratosis and facial milia-like lesions may be present. Marie–Unna hypotrichosis results from mutations in the upstream untranslated open reading frame region of the hairless gene,287 which maps to chromosome 8p21.288 There is no known treatment. HAIR SHAFT ABNORMALITIES UNASSOCIATED WITH BREAKAGE OR UNRULINESS Pili Annulati. Pili annulati or ringed hairs occur as

an autosomal dominant or sporadic hair shaft abnormality without increased hair breakage. Pili annulati can be present at birth or develop during infancy. It is characterized by altering light and dark bands, which are secondary to air-filled cavities in the cortex.289 The ringed appearance is clinically only detectable in blond or light brown hair. The gene locus for pili annulati maps to chromosome 12q24.290,291 No treatment is necessary, although hair care practices should be gentle.

Women with mild to moderate hirsutism and regular menstrual cycles are most likely diagnosed with idiopathic hirsutism; hormone testing is not necessary Hormone testing is necessary in women with moderate to severe hirsutism and all women with hirsutism and irregular menstrual cycles or sign of virilization

Hair Growth Disorders

cosmetic treatments should be avoided. Wooly hair is most pronounced during childhood; the manifestation often becomes less severe in adulthood.

Women with a Ferriman–Gallwey score 8 or higher are considered hirsute

::

Figure 88-30  Sporadic recessive wooly hair. (From Wolff K, Goldsmith LA, Katz SI, Gichrest BA, Paller AS: Fitzpatrick’s Dermatology in General Medicine. 7th ed. Copyright © The McGraw-Hill Companies, Inc. All rights reserved, with permission.)

Chapter 88

HIRSUTISM AT A GLANCE

Therapy should always consist of direct hair removal with or without medical therapy

EPIDEMIOLOGY Approximately 5% of women of childbearing age are suffering from mild to severe hirsutism (Ferriman– Gallwey score 8 or higher).

ETIOLOGY AND PATHOGENESIS Prior to puberty, body hair is vellus (small, straight, and fair), and the sebaceous glands are small. In response to the increased levels of androgens at puberty, vellus follicles in specific areas develop into terminal hair follicles (larger, curlier, and darker). The growth of terminal body hair (sexual hair) is entirely dependent on the presence of androgens, especially testosterone.292 Higher androgen levels are required for the growth of beard hair than for pubic and axillary hair. In other areas of the body (for example, the forehead and cheeks), the increased androgen levels dramatically increase the size of the sebaceous glands while the hair remains vellus. Hirsutism results from an interaction between the androgen level and the sensitivity of the hair follicle to androgens. Some women have hirsutism without evidence of androgen excess (“idiopathic hirsutism”).

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15 Upper lip 1

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Section 15

Chest

:: Disorders of the Hair and Nails

Abdomen

Pelvis

Upper arms

Thighs

Upper back

1

Lower back

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Figure 88-31  Ferriman–Gallwey scale.

1006

LABO RATORY TESTS If hirsutism is mild (Ferriman–Gallwey score 8–15) and menses are regular with no evidence of risk factors that would suggest a secondary cause, it is reasonable not to pursue laboratory evaluation, given the very high likelihood of idiopathic hirsutism. If hirsutism is moderate or severe (Ferriman–Gallwey score over 15), or there are features to suggest an underlying disorder (Box 88-8), androgen excess must be ruled out. An onset or progression of hirsutism or evidence of virilization (such as clitoromegaly or increasing muscularity) would raise concern for an androgen-secreting neoplasm.62,297 Since most androgenic drugs are not detected by testosterone assays, the history is particularly important. Medications that cause hirsutism include anabolic or androgenic steroids; thus, whether the patient is an athlete or has endometriosis or sexual dysfunction heightens this risk. Valproic acid is unique in raising plasma testosterone.298 The high frequency of PCOS as a cause of hirsutism warrants attention to evidence for anovulation (such as menstrual irregularity), obesity, metabolic syndrome, or insulin resistance (acanthosis nigricans or a family history of type 2 diabetes mellitus). If risk factors like menstrual irregularity are present, even normal degrees of focal hirsutism are usually associated with androgen excess.299 Other disorders to be considered include various endocrinopathies. Cushing syndrome is suggested by the development of truncal obesity, moon facies, buffalo hump, purple striae, or proximal muscle weakness; virilizing congenital adrenal hyperplasia or PCOS by a

Hughes CL: Hirsutism. In: Disorders of Hair Growth: Diagnosis and Treatment, edited by EA Olsen. New York, McGraw-Hill, 1994, p. 344, Table 14-2.

Hair Growth Disorders

Clinical diagnosis and scoring can be difficult since most women with hirsutism will practice various hair removal techniques. Therefore, it is useful to let the patient rate her degree of hair growth is different skin areas according to the Ferriman–Gallwey score (upper lip, chin and checks, chest, abdomen, pubic area and lower abdomen, arms, legs, upper back and lower back, and buttocks) with the help of images.

Androgen-secreting tumors Adrenal Adenoma Adenocarcinoma (rare) Ectopic adrenocorticotropic hormone-secreting tumor (rare) Ovarian Gonadal stromal tumor Thecoma Lipoid tumor Functional androgen excess Adrenal enzyme deficiencies (congenital adrenal hyperplasia) Early onset 21-hydroxylase deficiency Late-onset 21-hydropxylase deficiency 11β-hydroxylase deficiency 3β-ol dehydrogenase deficiency Cushing syndrome Polycystic ovarian disease With or without adrenal contribution Hyperthecosis “Idiopathic” hirsutism Medication/drug use

::

CLINICAL FINDINGS AND DIAGNOSIS

Box 88-8  Hirsutism

15

Chapter 88

Most women with a twofold or greater elevation of androgen levels have some degree of hirsutism, but in others these levels are associated with a “hirsutism equivalent” (acne vulgaris, seborrhea, pattern alopecia, hidradenitis suppurativa, or hyperhidrosis).292 Androgen excess relates to an increase in bioactive free testosterone plasma levels. Total testosterone includes the albumin bound and SHBG (sex hormone binding globulin) bound testosterone. Hirsute women commonly have a relatively low level of SHBG and therefore more bioactive testosterone.62,293,294 Thus, the free testosterone level may be elevated when the total testosterone level is normal. SHBG levels are suppressed by the hyperinsulinemia of insulin-resistance and by androgen excess itself.62,295 The level of SHBG is also low in persons with hypothyroidism; rarely, it is congenitally absent.296

history of the premature development of pubic hair or acne; hyperprolactinemia by the presence of galactorrhea; and acromegaly by coarsening of the facial features or hand or foot enlargement.292

SPECIAL TESTS Once androgen excess is confirmed, further tests should be considered such as pregnancy test (if the patient has amenorrhea), pelvic ultrasonography (if an ovarian neoplasm or PCOS is suspected) and measurement of dehydroepiandrosterone sulfate and early morning 17-hydroxyprogesterone (if congenital adrenal hyperplasia or adrenal neoplasm is suspected), and a prolactin level. It may include measurement of thyroid function, adrenocortical function, and IGF-I. Further workup typically begins with dexamethasone suppression testing to determine the source of androgen. If androgen excess is not suppressible by dexamethasone, the presence of Cushing’s syndrome, neoplasm, and PCOS must be considered. If androgen excess is dexamethasone-suppressible, an adrenocorticotropic hormone (ACTH) test for congenital adrenal hyperplasia is indicated. If an undetected neoplasm is suggested, further imaging studies may be warranted, such as abdominal computed tomography for adrenal neoplasm.300

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15

PROGNOSIS AND CLINICAL COURSE Hirsutism tends to get more severe as the patient gets older. Underlying disorders associated with hyperandrogenemia as mentioned earlier have to be ruled out.

TREATMENT

Section 15 :: Disorders of the Hair and Nails

The main treatment goals are to remove the existing terminal hair and to prevent further vellus-to-terminal hair transformation. Direct hair removal should be considered for all women with hirsutism. In patients with moderate to severe hirsutism and women with androgen access additional medical therapy is necessary. Direct hair removal can be achieved with nonpermanent techniques such as shaving, depilatories (lasts 12 hours to a few days), waxing, threading and sugaring (lasts up to 4 weeks), or permanent hair removal techniques such as electrolysis (for white and blond hair) and photoepilation (intense pulsed light or laser). Several sessions of photoepilation at intervals of 4–6 weeks are necessary to achieve a satisfying result, since only anagen hair follicles with dark bulb areas can be destroyed by the light source. Topical eflornithine has been shown to slow down the hair cycle and can be used in combination with every hair removal technique. The first line medical therapy is oral contraceptives, eventually in combination with antiandrogens. Glucocorticoids can be considered for women with hirsutism due to nonclassic congenital adrenal hyperplasia who have a suboptimal response to oral contraceptives and/or antiandrogens, cannot tolerate them, or are seeking ovulation induction. GnRH agonists in women with severe forms of hyperandrogenemia, such as ovarian hyperthecosis, who have a suboptimal response to oral contraceptives and antiandrogens.

HYPERTRICHOSIS Hypertrichosis is defined as an androgen-independent generalized, increased growth of hair on the body. The hair can be terminal or lanugo. Hypertrichosis can be acquired or inherited. Congenital hypertrichosis lanuginosa is characterized by a generalized overgrowth of silvery blonde to gray lanugo hair at birth or in early childhood. This rare condtion is thought to be of autosomal dominant inheritance with variable expressivity. Most patients display anomalous dental eruptions. Lanugo hair may persist, increase or decrease with age.301,302 Autosomal dominant Ambras syndrome or

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Hypertrichosis universalis congenita is characterized by much longer thicker hair distributed over the entire body with accentuation over the face ears and shoulders. Ambras syndrome can be associated with facial dysmorphism and dental anomalies.303–305 An X-linked dominant congenital generalized Hypertrichosis has been described in a five-generation family with an accentuation on the face and upper body.302,306 Patients with autosomal dominant or recessive gingival fibromatosis frequently display hypertrichosis, mostly on the face, eyebrows limbs and upper back, which may be associated with seizures and oligophrenia. Hypertrichosis may show a delayed onset until puberty although gingival fibromatosis usually appear with the emergence of the primary teeth1 (eBox 88-8.1 in online edition).

ACKNOWLEDGMENT Thanks to Dr. Elise Olsen, an active investigator of hair diseases, and author of this chapter in three previous editions for her contributions to hair research and to this text.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 27. Olsen EA et al: Summary of North American Hair Research Society (NAHRS)-sponsored Workshop on Cicatricial Alopecia, Duke University Medical Center. J Am Acad Dermatol 48:103-110, 2003 34. Tosti A, Gray J: Assessment of hair and scalp disorders. J Investig Dermatol Symp Proc 12:23-27, 2007 43. Otberg N, Finner AM, Shapiro J: Androgenetic alopecia. Endocrinol Metab Clin North Am 36:379-398, 2007 62. Zouboulis CC et al: Sexual hormones in human skin. Horm Metab Res 39:85-95, 2007 102. Shapiro J, Price VH: Hair regrowth. Therapeutic agents. Dermatol Clin 16:341-356, 1998 109. Price VH: Treatment of hair loss. N Engl J Med 341:964973, 1999 115. Rogers NE, Avram MR: Medical treatments for male and female pattern hair loss. J Am Acad Dermatol 59:547-566, 2008 166. Alkhalifah A et al: Alopecia areata update: Part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol 62:177-188, 2010 167. Alkhalifah A et al: Alopecia areata update: Part II. Treatment. J Am Acad Dermatol 62:191-202, 2010 199. Otberg N et al: Diagnosis and management of primary cicatricial alopecia: Part I. Skinmed 7:19-26, 2008 200. Wu WY et al: Diagnosis and management of primary cicatricial alopecia: Part II. Skinmed 7:78-83, 2008

Chapter 89 :: Biology of Nails and Nail Disorders :: Antonella Tosti & Bianca Maria Piraccini BIOLOGY OF NAILS

Biology of Nails and Nail Disorders

(See Fig. 89-1A) The nail plate is a fully keratinized structure that is continuously produced throughout life (see Fig. 89-1B). It results from maturation and keratinization of the nail matrix epithelium and is firmly attached to the nail bed, which partially contributes to its formation. Proximally and laterally the nail plate is surrounded by the nail folds, which cover its proximal third and lateral margins. At the tip of the digit, the nail plate separates from the underlying tissues at the hyponychium. The nail plate is rectangular, translucent, and transparent. It is curved in both the longitudinal and transverse axes, especially in the toes. The nail plate surface is smooth but frequently shows mild longitudinal ridges that increase with aging (Fig. 89-2). The pattern of these ridges can be used for forensic identification. The bottom of the nail plate shows longitudinal ridges that correspond to the rete ridges of the nail

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NAIL PLATE

Chapter 89

The nail apparatus consists of a horny “dead” product, the nail plate, and four specialized epithelia: (1) the proximal nail fold, (2) the nail matrix, (3) the nail bed, and (4) the hyponychium (Fig. 89-1A). The nail apparatus develops during the 9th embryonic week from the epidermis of the dorsal tip of the digit as a rectangular area, the nail fold that is delineated by a continuous groove.1 The proximal border of the nail fold extends downward and proximally into the dermis to form the nail matrix primordium. By the 15th week the nail matrix is completely developed and starts to produce the nail plate, which will continue to grow until death. The nail apparatus lies immediately above the periosteum of the distal phalanx. The intimate anatomic relationship between the nail and the bone is responsible for the common occurrence of bone alterations in nail disorders and vice versa. The shape of the distal phalangeal bone also determines the shape and the transverse curvature of the nail. Fingernails usually present a longitudinal major axis and toenails a transverse major axis. The ratio between length and width is important for the aesthetic appearance of the nails. The size of the nails varies in the different digits. The biggest nail is that of the first toe, which covers approximately 50% of the dorsum of the digit. Nails have numerous functions. Fingernails not only contribute to the pleasing appearance of the hands, but are very important in protecting the distal phalanges and enhancing tactile discrimination and the capacity to pick up small objects. They are also widely used for scratching and grooming and are an efficient natural weapon. Toenails protect the distal toes and contribute to pedal biomechanics.

bed. The nail plate is homogeneously pink, except for its free edge, which is white. The pink color of the nail plate is due to the nail bed blood vessels. The proximal part of the fingernails, especially of the thumbs, shows a whitish, opaque, half-moonshaped area, the lunula that is the visible portion of the nail matrix. In this area the nail plate attachment to the underlying epithelium is loose. More than 90% of fingernails show a thin distal transverse white band, the onychocorneal band, better defined as the isthmus, which marks the most distal portion of firm attachment of the nail plate to the nail bed.2,3 This area represents an important anatomic barrier against environmental hazards, and its disruption produces nail plate detachment with onycholysis. The onychocorneal band is separated from the nail plate white free edge by a 1.0– 1.5-mm pink band called the onychodermal band. In transverse sections, the nail plate consists of three portions: (1) dorsal nail plate, (2) intermediate nail plate, and (3) ventral nail plate.4 The dorsal and the intermediate portions of the nail plate are produced by the nail matrix, whereas its ventral portion is produced by the nail bed. Above the lunula the nail plate is thinner and consists only of the dorsal and intermediate portions. There is a natural line of cleavage between the dorsal and the intermediate nail plate. The nail plate progressively thickens from its emergence to its distal margin. The mean toenail thickness at the distal margin is 1.65 ± 0.43 mm in men and 1.38 ± 0.20 mm in women. Fingernails are thinner; the mean thickness is 0.6 mm in men and 0.5 mm in women. There is an increase in nail thickness with age, particularly in the first two decades. Nail thickness depends on the length of the nail matrix and nail bed.5 Thinning of the nails is usually a sign of nail matrix disorders, whereas nail thickening is most commonly a consequence of nail bed disorders.

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PROXIMAL NAIL FOLD (See Fig. 89-1A) The proximal nail fold is a skin fold that consists of a dorsal and a ventral portion. The dorsal portion is anatomically similar to the skin of the dorsum of the digit but thinner and devoid of pilosebaceous units. The ventral portion, which cannot be seen from the exterior and proximally continues with the germinative matrix, covers approximately one-fourth of the nail plate. It closely adheres to the nail plate surface and keratinizes with a granular layer. The limit between the proximal nail fold and the nail matrix can be histologically established at the site of disappearance of the granular layer. The horny layer of the proximal nail fold forms the cuticle, which is firmly attached to the superficial nail plate and prevents the separation of the plate from the nail fold. The integrity of the cuticle is essential for maintaining the homeostasis of this region.

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Normal nail

A

Proximal nail fold Nail matrix

Lunula region Cuticle

Nail bed

Nail plate Hyponychium

Section 15

B

:: Disorders of the Hair and Nails

Ventral proximal nail folds: suprabasal K1, K10, K16, K6 basal pattern of LH6

Matrix tip: K7, K8, K17, K18

Nail bed: suprabasal K16, K17

Panepidermal: K6, K14, LH6 C46 antibody to K7/K1

Digit pulp: K6, K16 Basal pattern of LH6 Panepidermal, K14

Suprabasal, K1, K10, Ha-1

Small clusters of cells in some cases

K17 Normal expression of K1, K10, K14, LH6 in digit pulp

Figure 89-1  A. Diagrammatic drawing of a normal nail. B. Keratin gene expression at different locations within the nail. (From De Berker D et al: Keratin expression in the normal nail unit: Markers of regional differentiation. Br J Dermatol 142:89, 2000, with permission.)

The dermis of the proximal nail fold contains numerous capillaries that run parallel to the surface of the skin and may easily be observed in vivo by capillary microscopy. This permits the observation of both the arterial and the venous limbs of the capillaries, which are arranged in parallel rows and appear as fine regular loops with a small space between the afferent and efferent limbs. The morphology of proximal nail fold capillaries is typically altered in connective tissue diseases.6–8

NAIL MATRIX 1010

Figure 89-2  Longitudinal ridging of the nail plate surface. This is commonly observed in the elderly.

(See Fig. 89-1A) The nail matrix is a specialized epithelial structure that lies above the mid portion of the distal phalanx.

erhans cells are more numerous in the proximal than in the distal nail matrix. As in normal epidermis, Langerhans cells are predominantly found in the suprabasal layers. However, they may occasionally be seen within the basal layer of the nail matrix epithelium.

MERKEL CELLS. The presence of Merkel cells in the nail matrix has been demonstrated. Their density is possibly influenced by age, with these cells being more numerous in fetus than in adult nails.18 NAIL BED (See Fig. 89-1A) The nail bed extends from the distal margin of the lunula to the isthmus and is completely visible through the nail plate. The nail bed epithelium is so adherent to the nail plate that it remains attached to the undersurface of the nail when the latter is avulsed. The nail bed epithelium is thin and consists of two to five cell layers. Its rete ridges, which are longitudinally oriented, interdigitate with the underlying dermal ridges in a “tongue-and-groove”-like fashion. The nail bed epithelium is a specialized epithelial structure with a horny layer that interlocks to of the inferior border of the nail plate and is responsible for the strong attachment between the two tissues. Nail bed horny layer forms the ventral nail plate, which corresponds to approximately one-fifth of the terminal nail thickness and mass.19 In pathologic sections, the ventral nail plate is easily distinguishable because of its light eosinophilic appearance. Nail bed keratinization is not associated with the formation of a granular layer. This may appear, however, when the nail bed becomes exposed after nail avulsion.1 The nail isthmus is a thin transverse distal band that represents a transitional zone between the nail bed and the hyponychium and exhibits a unique pattern of keratinization, the onycholemmal keratinization, with pale, nucleated keratinocytes. The cornified layer of the nail isthmus closely adheres to the undulating inferior surface of the nail plate preventing onycholysis; the two grow forward together.3 Keratin expression in the nail bed differs form that of the nail matrix since keratins K6, K16, and K6hf are only expressed in the nail bed.20 The isthmus differs from nail bed because of a strong suprabasal expression of K10. Transition from isthmus to hyponychium is marked by the disappearance of expression of K6hf and K6/16, and return to expression of K5/17.

Biology of Nails and Nail Disorders

MELANOCYTES. (See Chapter 72). Nail matrix melanocytes are usually quiescent and therefore not detectable in pathologic sections. However, they possess the key enzymes that are necessary for melanin production, and may become activated by a large number of physiologic and pathologic conditions.15 Nail matrix melanocyte activation produces diffuse or banded nail pigmentation and is more common in blacks and Japanese than in Caucasians. DOPA-negative (inactive) melanocytes are sparsely present in the nail matrix and in the nail bed.16 DOPA-positive, activable melanocytes are especially seen in the distal nail matrix, where they are frequently arranged in small clusters among the suprabasal layers of the nail matrix epithelium.17

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NAIL MATRIX KERATINOCYTES. (See Fig. 89-1B). The nail matrix cells are able to synthesize both “soft” or skin-type and “hard” or hair-type keratins.10–12 Evaluation of keratin expression in the different constituents of the nail apparatus showed that the nail matrix is the sole site of expression of hard keratin proteins, particularly Ha1 keratin.13 Data indicate that fibroblasts derived from the nail matrix may induce hard keratin expression in nonnail-matrix keratinocytes.14

LANGERHANS CELLS. (See Chapter 10). Lang-

Chapter 89

After elevation of the proximal nail fold, the matrix appears as a distally convex crescent with its lateral horns extending proximally and laterally. In longitudinal sections the matrix has a wedgeshaped appearance and consists of a proximal (dorsal) and a distal (ventral) portion. Nail matrix keratinocytes divide in the basal cell layer and keratinize in the absence of a granular zone. The site of keratinization (keratogenous zone) of nail matrix onychocytes can be clearly distinguished in histological sections as an eosinophilic area where cells show fragmentation of their nuclei and condensation of their cytoplasm.1 In this area, nuclear fragments are destroyed by deoxyribonuclease and ribonuclease enzymes. In some conditions nuclear fragments may persist within the intermediate nail plate, producing leukonychia spots. However, these frequently disappear before reaching the nail-free edge, due to the persistence of active DNA and RNA lytic enzymes within the horny nail plate. Maturation and differentiation of nail matrix keratinocytes do not follow a vertical axis, as in the epidermis, but occur along a diagonal axis that is distally oriented. For this reason, keratinization of the proximal nail matrix cells produces the dorsal nail plate and keratinization of the distal nail matrix cells produces the intermediate nail plate. In some fingers the distal matrix is not completely covered by the proximal nail fold but is visible through the nail plate as a white half-moon-shaped area, the lunula. The white color of the lunula results from two main anatomic factors: (1) the keratogenous zone of the distal matrix contains nuclear fragments that cause light diffraction, (2) nail-matrix capillaries are less visible than nail bed capillaries because of the relative thickness of the nail-matrix epithelium.9

HYPONYCHIUM The hyponychium marks the anatomic area between the nail bed and the distal groove, where the nail plate detaches from the dorsal digit (see Fig. 89-1A). Its ­anatomic structure is similar to that of plantar and volar skin, and keratinization occurs through the formation of a granular layer. The horny layer of the

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hyponychium partially accumulates under the nail plate free margin. The hyponychium is normally covered by the distal nail plate, but it may become visible in nail biters. The architecture of the capillary network of the hyponychium dermis consists in regular capillary loops arranged perpendicularly to the skin, visible as red dots with dermoscopy.

BASEMENT MEMBRANE ZONE

Section 15 :: Disorders of the Hair and Nails

The antigenic structure of the basement membrane zone of the nail is identical to that of the epidermis, and there are no differences in the antigenic composition of the basement membrane zone in the different portions of the nail apparatus.21 This may explain the involvement of the nails in conditions characterized by mutations of basement membrane-associated genes as well as in autoimmune skin diseases involving the basement membrane zone antigens.22

DERMIS (See Fig. 89-1A) The nail apparatus is devoid of subcutaneous tissue, and its dermis does not contain pilosebaceous units. The arrangement of the rete ridges varies in the different portions of the nail apparatus. The dermis beneath the proximal nail matrix consists of condensed connective tissue that forms a tendon-like structure connecting the matrix to the periosteum of the proximal phalangeal bone (posterior ligament). A small amount of subdermal fat tissue is present close to the periosteum of the base of the phalanx.23 The close connection between the lateral horns and the periosteum is possibly responsible for the nail plate’s lateral convexity. The rete ridges of the dermis underneath the nail matrix are characteristically long and root-like in shape. The dermis under the distal matrix consists of a loose network of connective tissue containing numerous blood vessels and rare glomus bodies. The dermis of the nail bed has a unique arrangement with longitudinal grooves and ridges that run from the lunula to the hyponychium.1 The longitudinal orientation of the capillary vessels within the nail bed grooves explains the linear pattern of nail bed hemorrhages (splinter hemorrhages). The nail bed dermis contains abundant connective tissue networks with connective tissue bundles radiating to the phalangeal periosteum. It contains numerous glomus bodies.

BLOOD AND NERVE SUPPLY

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The nail apparatus has an abundant blood supply provided by the lateral digital arteries. These run along the sides of the digits and produce both branches that supply the matrix and the proximal nail fold and arches that supply the matrix and the nail bed. The nail matrix, therefore, has two different sources of blood supply. The nail bed is richly supplied (10–20 cm2) by encapsulated neurovascular structures containing one

to four arteriovenous anastomoses and nerve endings. These glomus bodies are arteriovenous shunts involved in the regulation of the blood supply to the digits related to thermoregulation. The cutaneous sensory nerves, which originate from the dorsal branches of the paired digital nerves, run parallel to the digital vessels.

CHEMICAL PROPERTIES (See Fig. 89-1B) The nail plate, like hair, consists mainly of low-sulfur filamentous proteins (keratins) embedded in an amorphous matrix composed of high-sulfur proteins rich in cysteine. Other nail constituents include water, lipids, and trace elements. Nail keratins consist of 80%–90% hard hair-type keratins and 10%–20% soft skin-type keratins. Hard keratins have been identified as the acidic 44K/46K and basic 56K/60K keratins. Soft keratins have been identified as the 50K/58K and 48K/56K keratin pairs.24 Keratin filaments have a transverse orientation that is parallel to the nail surface. This explains why the nail plate is more susceptible to transverse fractures than to longitudinal fractures. Specific keratins are expressed only in some compartments of the nail unit; for instance, K6a and K6b, K16, and K17 are not expressed in the nail matrix.13,25,26 Mutations of the genes encoding for these keratins are associated with nail thickening due to nail bed hyperproliferation, as is seen in pachyonychia congenita (PC).27,28 Nail keratin content and composition, measured as the quantity of carbon (C), nitrogen (N), and sulfur (S) in the fingernails, vary between sexes and in relation to the aging process. Sulfur content is higher in female than in male nails and the opposite is for nitrogen. Carbon content is equal in the two sexes. The carbon content increases with aging, possibly due to loss of inorganic material, and the nitrogen content decreases, while the sulfur content remains stable.29 Under normal conditions, the water content of the nail plate is 18%, and most of the water is in the intermediate nail plate.30 The average water content of the nail plate is significantly lower in winter than in summer.31) and varies significantly in time, due to the high porosity of the nail plate, which allows it to be rapidly hydrated and dehydrated. Dehydration is faster when the nails are kept long. When the water content decreases below 18%, the nail becomes brittle; when it increases above 30%, it becomes opaque and soft.32 The nail contains less than 5% lipids, mainly cholesterol; the nail plate lipid content is under hormonal control and decreases after menopause.33 The nail plate also contains traces of several inorganic elements, particularly iron, zinc, and calcium. However, these do not contribute to nail hardness.

PHYSICAL PROPERTIES The nail plate is hard, strong, and flexible. The hardness and strength of the nail plate are due to its high content of hard keratins and cysteine-rich high-sulfur

(See Table 89-1)

BEAU’S LINES AND ONYCHOMADESIS (NAIL SHEDDING) Beau’s lines result from a temporary arrest of proximal nail matrix proliferation and appear as transverse grooves, often deeper in the central nail plate, that move distally with nail growth. Onychomadesis also results from a temporary arrest in nail matrix activity,

Biology of Nails and Nail Disorders

The nail plate grows continuously in a proximal to distal manner throughout life. The nail plate is “pushed” out by two factors: (1) matrix keratinocytes proliferation and differentiation which makes a new plate, (2) the nail bed which moves slowly, parallel to the direction of the nail growth, toward the inferior border of the nail plate.3 Fingernails grow two times faster than toenails, with a mean growth rate in adults of 3.5 mm/month for fingernails and 1.5 mm/month for toenails. The 5th fingernail growth rate is significantly slower than other fingernails and the growth rate of the great toenail significantly faster than other toenails.38 Complete replacement of a fingernail requires 100– 180 days (6 months). When the nail plate is extracted, it is approximately 40 days before the new fingernail first emerges from the proximal nail fold. After a further 120 days it will reach the fingertip.39 The total regeneration time for a toenail is 12–18 months. As a consequence of the slow nail growth rate, diseases of the nail matrix only become evident a considerable time after their onset and require a long time to disappear after treatment. Nail growth rate varies among different individuals and among the different digits of the same individual. It depends on the turnover rate of the nail matrix cells and is influenced by several physiologic and pathologic conditions. Nail growth rate is slow at birth, increases slightly during childhood, and usually reaches its maximum between the second and the third decades of life. It sharply decreases after the age of 50 years.39 Conditions that have been associated with a slow growth rate include systemic illness, malnutrition, peripheral vascular or neurologic diseases, and treat-

NAIL SIGNS AS A FUNCTION OF THE SITE OF PATHOLOGY1,32

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NAIL GROWTH

ment with antimitotic drugs. Nails affected by onychomycosis frequently exhibit a slow growth rate. An arrest of nail growth is a typical feature of yellow nail syndrome. Conditions that have been associated with accelerated nail growth include pregnancy, finger trauma, psoriasis, and treatment with oral retinoids or itraconazole. Accelerated nail growth may cause longitudinal ridging of the nail plate (nail beading). Due to their slow growth rate, the nails may provide information on pathologic conditions that have occurred up to several months before the time of observation. Drugs, chemicals, and biologic substances accumulate in nails, where they can be detected and measured. Advantages of analyzing nail samples include the ease and noninvasiveness of their collection, the small sample size required for analysis, and the ease of storage at room temperature. The nail of the big toe is the best site for investigation because of its size (big toenail length of an adult: 20 mm) and slow growth rate (about 2 mm/month) permitting to obtain data on exposure to drugs and chemicals over a period of 10 months.40

Chapter 89

proteins, whereas its flexibility depends on its water content and increases with nail plate hydration.34,35 The double curvature of the nail plate along its longitudinal and transverse axes enhances nail plate resistance to mechanical stress.36 The physical properties of the nail also depend on the arrangement and adhesion of onychocytes in the different portions of the nail plate, as well as on the orientation of the keratin filaments within the nail plate onychocytes.36 At the ultrastructural level, the corneocytes of the dorsal nail plate are flat, with their shorter diameter perpendicular to the nail plate surface. The average sizes of these cells are 34 μm in length, 64 μm in width, and 2.2 μm in height.37 Cell adhesion is strong. This portion of the nail is responsible for nail plate hardness and sharpness. The onychocytes of the intermediate nail plate show multiple interdigitations of their cell membranes. The average dimensions of these cells are 40 μm in length, 53 μm in width, and 5.5 μm in height. Cell adhesion is provided by desmosomes. This part of the nail plate is responsible for nail pliability and elasticity. The ventral nail plate is thin and consists of soft keratins. It provides adhesion to the underlying nail bed.

TABLE 89-1

Relation Between Resultant Clinical Manifestations and Location of Pathologic Change Proximal Matrix

Beau’s Lines Pitting Longitudinal striations Longitudinal fissures Longitudinal grooves Trachyonychia

Distal matrix

True leukonychia

Proximal and distal matrix

Koilonychia Onychomadesis

Nail bed

Longitudinal erythronychia Onycholysis Splinter hemorrhages Apparent leukonychia

Nail bed and hyponychium

Subungual hyperkeratosis

Proximal nail fold

Paronychia Periungual erythema

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Box 89-1  Causes of Beau’s Lines and Onychomadesis

Section 15 :: Disorders of the Hair and Nails

Trauma Manicure Onychotillomania Dermatologic diseases Eczema Erythroderma Paronychia Systemic conditions Use of certain drugs High fever Viral illness (hand-foot-and-mouth disease; measles) Diarrhea Kawasaki syndrome Peripheral ischemia

and the proximal nail plate is detached from the proximal nail fold by a whole-thickness sulcus. Causes of onychomadesis are the same as those for Beau’s lines but are more severe (Box 89-1). Multiple Beau’s lines or onychomadesis in the same nail indicates repetitive insults. Measuring the distance of the groove from the proximal nail fold can date the time of the insult leading to Beau’s lines. Local trauma, such as from manicures or onychotillomania, or related to local cutaneous disease, particularly dermatitis, periungual erythema, and paronychia, are causes of Beau’s lines. Beau’s lines or onychomadesis at the same levels in several nails suggest a systemic cause (Fig. 89-3). Most common among these are drugs (especially chemotherapy), high fever, viral illness,41,42 surgery, and peripheral ischemia. Onychomadesis in children often relates to recent coxsackievirus infection (hand-footmouth disease).41,43

Figure 89-3  Beau’s lines of several nails after systemic illness. Note involvement of all the nails at the same level. and fissures. Onychorrhexis is a sign of severe nail fragility and typical of lichen planus (see Chapter 26).

LONGITUDINAL GROOVES Longitudinal grooves are usually single and appear as a longitudinal depression of the nail plate (1–2 mm large) due to compression of the nail matrix by tumors of the proximal nail fold.

TRACHYONYCHIA Trachyonychia results from multiple foci of defective keratinization of the proximal nail matrix. The nails are rough due to excessive longitudinal ridging.

TRUE LEUKONYCHIA True leukonychia results from defective keratinization of the distal matrix with persistence of parakeratotic

PITTING Pits result from small areas of abnormal keratinization of the proximal nail matrix that produce foci of parakeratotic cells in the superficial nail plate. They appear as small punctate depressions of the superficial nail plate, which progress distally and often become more evident with nail growth. Deep and irregularly distributed pits are seen in psoriasis (Fig. 89-4) and atopic dermatitis; geometric and superficial pits are typical of alopecia areata (see Chapters 14, 18, and 88).

ONYCHORRHEXIS (LONGITUDINAL STRIATIONS AND FISSURING)

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Onychorrhexis results from diffuse defective keratinization of the proximal nail matrix. The nail plate is usually thinned and presents multiple longitudinal ridges

Figure 89-4  Pitting: small punctate depressions of the superficial nail plate. In psoriasis, pits are irregularly distributed and often associated with onycholysis and splinter hemorrhages.

Box 89-2  Causes of Longitudinal Melanonychia

Figure 89-5  Punctate leukonychia due to microtraumas in a child.

MELANONYCHIA44 Melanonychia describes a brown to black color of the nail due to the presence of melanin in the nail plate. It can be caused by activation or proliferation (benign or malignant) of nail matrix melanocytes. The pigmentation may involve the whole nail (total melanonychia) or may be banded, as in transverse melanonychia (rare) or in the most common longitudinal melanonychia (LM). LM may appear as a single band involving one digit, or as multiple bands affecting several digits, which are usually due to melanocyte activation, as is seen in dark-skinned individuals, pregnant women, inflammatory nail disorders, individuals with Laugier–Hunziker syndrome, and those taking certain medications (Box 89-2). LM has also been described in individuals with a variety of systemic disorders, particularly human immunodeficiency virus infection and Addison syndrome. In Laugier–Hunziker syndrome, melanonychia begins during adolescence, affects several digits, and is associated with the presence of lip and/or genital pigmented macules45,46 (see Chapter 78). Melanonychia due to melanocyte activation may in some cases involve a single digit, as in patients with onychotillomania, with frictional melanonychia of the 4th or 5th toenails (Fig. 89-6), with inflammatory nail diseases, such as psoriasis or lichen planus, or with nail tumors, such as Bowen’s disease. A single band of melanonychia deserves a careful evaluation, since it may be a sign of a nail matrix nevus or melanoma (see Chapters 122 and 124). LM of a single nail often deserves biopsy.

Longitudinal erythronychia reflects a nail bed disorder and appears as a pink–red longitudinal band of various width extending from the proximal nail to the distal edge. A single band of longitudinal erythronychia is most commonly caused by an onychopapilloma or by another benign or malignant subungual tumor (Fig. 89-7). Multiple bands of longitudinal erythronychia are seen in lichen planus. In Darier’s disease bands of longitudinal erythronychia alternate with white longitudinal bands and V-shaped indentations of the nailfree margin (see Chapter 51).

ONYCHOLYSIS Onycholysis is detachment of the nail plate from the nail bed and can be caused by traumatic, inflammatory, infectious, or neoplastic nail bed disorders. See Section “Onycholysis under Environmental Nail Disorders.”

Biology of Nails and Nail Disorders

In koilonychia the nail plate is thin and spoon shaped. Koilonychia is physiologic in the toenails of children. In adults it can be a sign of iron deficiency or occupational damage to the nail plate.

LONGITUDINAL ERYTHRONYCHIA47

::

KOILONYCHIA

Race Acquired immunodeficiency syndrome Inflammatory nail disorders Use of certain drugs Addison disease Pregnancy Laugier–Hunziker syndrome Trauma

Chapter 89

cells in the ventral nail plate. The superficial nail plate is structurally normal, but the nail presents opaque white patches or striae, which often disappear before reaching the distal edge of the nail. Punctate leukonychia is due to microtrauma and is typically seen in the fingernails of children (Fig. 89-5). Striate leukonychia of fingernails is a consequence of aggressive manicure. Total or subtotal leukonychia is rare and usually hereditary.



15

SPLINTER HEMORRHAGES Splinter hemorrhages appear as red to black small thin longitudinal lines under the nail plate. They are more commonly located in the distal nail plate and represent

Figure 89-6  Frictional melanonychia of the 4th and 5th toenails.

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SUBUNGUAL HYPERKERATOSIS Subungual hyperkeratosis is due to inflammatory disorders that cause an abnormal keratinization of the distal nail bed and hyponychium with accumulation of scales under the distal nail plate. The most common causes include psoriasis, onychomycosis, trauma, contact and atopic dermatitis (see Chapters 13, 14, and 18).

PARONYCHIA

Section 15

Paronychia is inflammation of the proximal nail fold and presents as painful periungual erythema, sometimes with associated purulence. Acute paronychia is usually caused by infection (see Section “Infectious Nail Disorders”). Chronic paronychia is most commonly due to mechanical or chemical factors. If the periungual area is fluctuant or shows purulence, it should be drained to avoid matrix damage. Topical and/or systemic antibiotics should be administered if bacterial infection is suspected.

:: Disorders of the Hair and Nails

NAIL PIGMENTATION

Figure 89-7  Longitudinal erythronychia. The nail plate shows a narrow longitudinal pale pink band that ends with a dark red steak corresponding to a splinter hemorrhage. This clinical feature is typical of onychopapilloma. rupture of the longitudinally oriented nail bed capillaries (Fig. 89-8). Causes include trauma and inflammatory nail disorders, such as psoriasis.

APPARENT LEUKONYCHIA In apparent leukonychia the nails are pale white due to nail bed discoloration that fades with pressure.

Nail pigmentation is most commonly due to exogenous staining of the nail plate. In this case the proximal margin of the pigmentation follows the shape of the proximal nail fold. Exogenous nail pigmentation is most commonly due to occupational exposures or nail cosmetics. Nail pigmentation due to endogenous causes is rare. The proximal margin of the pigmentation follows the shape of the lunula. Possible causes include drugs, argyria, hemochromatosis, alkaptonuria, and Wilson disease.

HEREDITARY AND CONGENITAL NAIL DISORDERS48 (See Table 89-2)

ECTODERMAL DYSPLASIAS (See Chapter 142) Nail changes may be associated with hypotrichosis, hypodontia, and hypohidrosis. Most commonly the nails are short, thickened, and hypoplastic.

EPIDERMOLYSIS BULLOSA

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Figure 89-8  Multiple distal splinter hemorrhages in a manual worker with mild nail psoriasis.

(See Chapter 62) Nail abnormalities are a common feature in most subtypes of epidermolysis bullosa (EB) and have recently been included among the criteria for scoring EB severity.49 Trauma undoubtedly contributes to the development of nail dystrophy and for this reason the great toenails are more often severely affected. Pachyonychia of the toenails be the first or the only symptom of dominant dystrophic EB (DDEB) in some families (eFig. 89-8.1 in online edition). Junctional and dermolytic EB may produce anonychia.50

15

TABLE 89-2

Hereditary and Congenital Nail Disorders

Partial or total anonychia Pachyonychia Subungual/periungual hemorrhagic blisters Periungual erosions with granulation tissue

Pachyonychia congenita

Onychogryphosis Severe thickening Yellow–brown discoloration

Iso-Kikuchi syndrome

Micronychia/anonychia Hemionychogryphosis

Nail patella syndrome

Hypoplasia/aplasia Triangular lunulae

Congenital malalignment of the hallux

Lateral deviation of the nail plate Lateral/distal embedding of nail Nail thickening Yellow–brown discoloration Transverse ridging

PACHYONYCHIA CONGENITA (See Chapter 50) PC is an autosomal dominant genodermatosis characterized by painful keratoderma, nail thickening, oral leukokeratosis, and epidermal cysts. The severity of PC can vary greatly among patients and the most problematic aspect of PC, the painful palmoplantar keratoderma (PPK), have vary in extent from focal to a severe, diffuse PPK.51 The International Pachyonychia Congenita Research Registry (IPCRR) has compared the PC phenotype with genotype in hundreds of individuals, and have found issues with the classical division into PC1 (Jadassohn-Lewandowski type) and PC2 (JacksonLawler). A new molecular classification has been proposed, in which subtypes of PC refer to the mutated keratin gene.52 Mutations in KRT6A account for almost 50% of known cases, while 24% have mutations are in KRT16, 23% in KRT17, and 3% in KRT6B.53 In contrast to the old classification, in which PC1 was thought to result from mutations in KRT6a or 16, and PC2 from mutations in KRT6b or 17, the clinical features of the former subtypes overlap. For example, cysts (a feature of PC2 and not PC1) most commonly occur in individuals with either a KRT17 mutation or KRT6a mutation. Nail abnormalities are a constant feature and develop dur­ing infancy to early childhood, although a late-onset variety of PC has been described.54 In typical cases the 20 nails are thickened, very difficult to trim, darkened, and with an increased transverse curvature. Nail thickening is a consequence of nail bed hyperkeratosis and is more evident on the distal half of the nails, which have an upward angling. Recent evidence indicates that PC may also present with very

Figure 89-9  Nail patella syndrome: nail hypoplasia of the 1st and 2nd fingers. subtle nail changes and that there is not a good correlation between mutations detected at molecular level and clinical phenotype. Severity may even vary among family members with the same gene mutation.55,56

NAIL PATELLA SYNDROME Nail abnormalities in nail patella syndrome may involve all fingernails or may be limited to the thumbs, which are always the most severely affected digits (Fig. 89-9). Nail hypoplasia is usually more marked in the medial portion of the nail. The shape of the lunula is typically triangular.48

Biology of Nails and Nail Disorders

Epidermolysis bullosa

::

Atrophy/Thickening

Chapter 89

Ectodermal Dysplasias

CONGENITAL MALALIGNMENT OF THE HALLUX Congenital malalignment of the hallux is the most common cause of ingrowing (ingrown) nails and is usually diagnosed when the child starts to walk. The great toenail shows a lateral deviation that produces embedding of the lateral side of the nail plate (Fig. 89-10). The digit is painful and the toenail often shows Beau’s lines and

Figure 89-10  Congenital malalignment of the big toenail associated with mild disto-lateral ingrowing on the medial side.

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TABLE 89-3

Infectious Nail Disorders Bacterial   Staphylococcus aureus   Streptococcus pyogenes Viral   Herpes simplex

  Warts Fungal   Dermatophytes

Section 15

  Nondermatophytes   Candida sp.

Acute paronychia Acute paronychia Acute paronychia Onycholysis Periungual vesicles Periungual/subungual papules DSO PSO WSO PSO + periungual inflammation Deep WSO TO + paronychia

:: Disorders of the Hair and Nails

DSO = distal subungual onychomycosis; PSO = proximal subungual onychomycosis; WSO = white superficial onychomycosis; TO = total onychomycosis.

onycholysis. Congenital malalignment may be unilateral or bilateral. Spontaneous improvement may occur, and most children do not have symptoms by the age of 2 years.57 Inflammation due to lateral ingrowing can be managed by daily massaging of the lateral nail fold with creams containing steroids, antibiotics, and urea. Surgical treatment may be necessary if nail symptoms are severe and do not subside with growth.58,59

INFECTIOUS NAIL DISORDERS (See Table 89-3)

ACUTE PARONYCHIA Acute paronychia is most commonly due to Staphylococcus aureus infection and typically affects a child’s fingernail. Predisposing factors include nail biting or sucking and occupational traumas. The proximal nail fold is painful, erythematous, and swollen. Pus may be discharged after pressure (see Chapter 176). The

differential diagnosis includes herpes simplex virus infection (see Chapter 193) and Hallopeau’s acrodermatitis (see Chapter 21), both of which have a typical relapsing course. Suspicion of Herpes simplex-virus infection should arise when the pain intensity is disproportionate to the clinical symptoms and the disease is recurrent. The treatment of choice depends on the extent of the infection. If diagnosed early, acute paronychia without obvious abscess can be treated nonsurgically, often with topical antibiotics alone. If an abscess has developed, incision and drainage must be performed. Oral antibiotics with Gram-positive coverage against S. aureus, such as cephalexin, amoxicillin with clavulanic acid, and clindamycin, are effective.

GREEN NAILS Bacteria are not capable of attacking a healthy nail plate. The Gram-negative bacterium Pseudomonas aeruginosa may colonize the dorsal or ventral nail plate under propitious conditions, such as chronic paronychia or onycholysis. The presence of Pseudomonas is revealed by characteristic green–black nail pigmentation due to pyocyanin staining. Topical application of a few drops of diluted bleach or chlorhexidine solution two or three times a day clears the pigmentation in a few weeks. Administration of systemic antibiotics is unnecessary.

ONYCHOMYCOSIS60,61 For a detailed description of the onychomycoses, see Chapter 188. Onychomycosis is a common toenail disease, and its prevalence increases with age. Clinical features depend on type of nail invasion (Table 89-4). The possibility of mold onychomycosis should be suspected when proximal subungual onychomycosis (PSO) is associated with periungual inflammation, or when white superficial onychomycosis is severe and involves the entire nail plate (Fig. 89-11). Nondermatophytic onychomycoses are becoming more frequent worldwide and represent a clinical problem, because they usually respond poorly to systemic treatment.

TABLE 89-4

Clinical Presentations of Onychomycosis (See Chapter 188) Distal subungual onychomycosisa

Trichophyton rubrum, Trichophyton interdigitale

Onycholysis associated with subungual hyperkeratosis, patchy or linear yellow discoloration

Proximal subungual onychomycosis

T. rubrumb Fusarium sp. Aspergillus sp. Scopulariopsis sp.

Proximal leukonychia with normal nail plate surface

Trichophyton interdigitalea

Multiple superficial areas of friable opaque leukonychia

White superficial onychomycosis

Fusarium sp. Aspergillus sp. a

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Associated with tinea pedis. Possible marker of human immunodeficiency virus infection.

b

Associated with periungual inflammation and purulent discharge

Involvement more diffuse and deeper

ONYCHOMYCOSIS AT A GLANCE Fifteen percent of the general population and 40% of individuals older than 60 years are affected. Clinical presentation reflects the route of nail invasion. Dermatophytes account for 85% of cases, nondermatophyte fungi for 15%.

Toenails are involved in most cases; tinea pedis is usually associated. The cure rate for toenail onychomycosis is approximately 80% with the use of systemic antifungals, but recurrences are frequent (up to 20%). Mold infections respond poorly to systemic treatment.

ENVIRONMENTAL NAIL DISORDERS NAIL FRAGILITY62 (Box 89-3) With nail fragility, the nails are brittle and show distal lamellar splitting (onychoschizia) (Fig. 89-12). Several fingernails are usually affected. The nail plate margin is irregular due to distal splitting. Idiopathic nail fragility

Figure 89-11  White superficial onychomycosis due to Fusarium sp. Note diffuse and “deep” nail invasion.

usually affects middle-aged women who are exposed to water and chemicals that dehydrate the nail plate. Aging also is associated with increased nail fragility. The risk of nail fragility from trauma is increased by manicures, onychotillomania, and certain occupations, especially those that involve frequent exposure to water and chemicals. Fragile nails can be a feature of several dermatologic disorders, such as lichen planus, alopecia areata, psoriasis, and onychomycosis. In addition, nutritional deficiency, peripheral neuropathies, peripheral vascular disease, and use of certain medications increase the risk of nail fragility. Management includes protection of the hands by the use of cotton gloves under rubber gloves and frequent application of topical moisturizers.61 Oral biotin, 5 mg/day, can be helpful.63

Biology of Nails and Nail Disorders

Candida sp. is the causative agents only in immunosuppressed individuals.

::

Mold fungal infection should be suspected when PSO is associated with acute periungual inflammation or when white superficial onychomycosis involves most of the nail plate.

Idiopathic Aging Exposure to water and chemicals Traumatic Occupational injury Manicure Onychotillomania Dermatologic diseases Lichen planus Alopecia areata Psoriasis Onychomycosis Systemic conditions Use of certain drugs Peripheral vascular diseases Peripheral neuropathies Nutritional deficiencies

Chapter 89

Infection with human immunodeficiency virus should be suspected with proximal subungual onychomycosis (PSO) due to Trichophyton rubrum.

Box 89-3  Causes of Nail Fragility

15

CHRONIC PARONYCHIA64–66 Chronic paronychia is an inflammatory disorder that almost exclusively involves the fingernails of adult women. Mechanical or chemical traumas damage the cuticle and permit penetration of irritant and allergenic environmental substances under the proximal

Figure 89-12  Onychoschizia lamellina: lamellar exfoliation of the distal nail plate.

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CHRONIC PARONYCHIA AT A GLANCE Occurs most commonly in food handlers and housecleaners. Associated with mechanical or chemical cuticle damage. Characterized by eczematous inflammation of the proximal nail fold and matrix. Secondary colonization by bacteria and yeasts usually occurs.

Section 15

First, second, and third digits of the dominant hand are most often affected.

:: Disorders of the Hair and Nails

Management includes protective measures, topical and/or systemic steroids, and topical antimicrobials.

Box 89-4  Onycholysis Primary Idiopathic Fingernails: women (mechanical/chemical damage) Trauma Fingernails: occupational injury Toenails: podiatric abnormalities, improper shoes Secondary Vesiculobullous disorders Contact dermatitis Pompholyx Herpes simplex Nail bed hyperkeratosis Onychomycosis Psoriasis Nail bed tumors Drugs (often hemorrhagic)

Systemic antifungals are not effective.

nail fold, causing an inflammatory reaction of the nail folds and matrix. Secondary colonization with Candida sp. and/or bacteria occurs in most cases, causing self-limited episodes of painful acute inflammation (see Chapter 189). Chronic paronychia most commonly affects the first, second, and third fingers of the dominant hand. Clinically, the proximal and lateral nail folds show mild erythema and swelling, and the cuticle is absent. The nail plate may show superficial abnormalities and green discoloration due to Pseudomonas invasion. Hand protection from the environmental hazards is mandatory for remission of chronic paronychia, which can be considered cured only when the cuticle has regrowth. Systemic antifungals are not effective. Chronic paronychia should be treated as contact dermatitis, with topical steroids or tacrolimus associated with topical antiseptics to prevent secondary microbial colonization.

Idiopathic onycholysis usually affects the fingernails of women and is a consequence of mechanical and chemical damage of the nail bed isthmus (Box 89-4). The detached nail plate is white due to the presence of air and frequently presents areas of green–brown discoloration due to bacterial colonization (Fig. 89-13). The use of sharp tools to clean the nail plate free margin produces roller coaster onycholysis (manicure onycholysis). Traumatic onycholysis of the fingernails is usually occupational and is more commonly observed in butchers, slaughterhouse workers, chicken processing workers, and workers lifting heavy bags. Traumatic onycholysis of the toenails most frequently affects the big toe, often bilaterally. It is usually a consequence of anatomic abnormalities (overlapping of the second toe on the first toe) or poorly fitting shoes. Subungual hematoma is frequently associated. Secondary onycholysis is seen in several dermatologic disorders. When only one nail is affected, it is important

IDIOPATHIC ONYCHOLYSIS65 IDIOPATHIC ONYCHOLYSIS AT A GLANCE Occurs in homemakers and those in certain occupations. Caused by mechanical or chemical damage. Follows asymptomatic and slowly progressive nail plate detachment.

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Management includes taking protective measures, trimming the onycholytic nail plate, and applying topical antiseptics.

Figure 89-13  Idiopathic onycholysis: note areas of green discoloration of the onycholytic space due to Pseudomonas colonization.

to explore the nail bed after cutting the onycholytic nail to rule out a nail tumor. Patients with idiopathic onycholysis should be instructed to keep the nail dry, trim the onycholytic nail plate, and wear cotton gloves under rubber gloves. Application of topical 4% thymol in chloroform solution on the exposed nail bed can accelerate cure.

NAIL TUMORS67

SUBUNGUAL EXOSTOSIS.68 Subungual exosto-

sis appears as a subungual hard nodule that detaches and lifts the nail plate. The toenails of young adults are usually affected, and a history of trauma is not unusual. Radiography confirms the diagnosis.

MYXOID CYST.69 Myxoid cyst appears as a nodule

NAIL MATRIX NEVI.71,72 Nail matrix nevi produce a

band of LM and usually appear in childhood. The color and width of the band are variable, and modification of the pigmentation (fading or darkening) with time is common (eFigs. 89-13.1 and 89-13.2 in online edition). Pigmentation of the periungual tissues (Hutchinson’s sing) is commonly associated with congenital nevi. Clinical management of nail matrix nevi in children is often problematic as lesions frequently show signs (Box 89-5) that are indicative for nail melanoma in adults.73,74 Excision of the lesions that show rapid increase in size is probably the best option, to exclude the possibility of a melanoma, which is rare but can occur.

MALIGNANT TUMORS SQUAMOUS CELL CARCINOMA. (See Chapter 114). In situ squamous cell carcinoma (Bowen’s disease) usually manifests in fingernails, with a lesion that clinically, closely resembles a wart. Associated melanonychia or paronychia may be a diagnostic clue (Fig. 89-14).

Biology of Nails and Nail Disorders

FIBROMA/FIBROKERATOMA. Fibroma/fibrokeratoma appears as a nodular or filiform growth that often has a keratotic surface. Most fibromas originate in the proximal nail fold and extend to the nail plate surface, where the tumor presents as a longitudinal furrow or groove. Subungual lesions are uncommon. Tuberous sclerosis should be considered, especially if multiple lesions are present (see Chapter 140).

Periungual pigmentation Adult age Change in color/width of the band Hyperpigmented lines within the band Proximal portion of the band wider than distal Thumb, index finger, or toe involvement Blurred margins

::

BENIGN TUMORS



Chapter 89

Tumors of the nail usually affect one digit and are associated with symptoms that depend on tumor localization: nail plate furrows or grooves are due to tumors in the proximal nail fold, while onycholysis or subungual nodule are a consequence of nail bed tumor. The nail plate may be altered both in its shape and thickness and in color.

Box 89-5  Clinical Signs That Require Histologic Evaluation of Longitudinal Melanonychia

15

of the proximal nail fold associated with a longitudinal groove in the correspondent nail plate. Because the cyst often drains spontaneously, the shape of the groove is irregular. Myxoid cysts usually affect the fingernails of middle-aged women and are associated with osteoarthritis of the interphalangeal joints.

GLOMUS TUMOR. Glomus tumor may hardly be seen, appearing as a small red patch under the nail plate and usually affecting the hand. The minimal clinical appearance is disproportionate to the intense pain, which is usually accentuated by cold and radiates to the limb. Due to the small size of the tumor, preoperative assessment with MRI or high-variable frequency ultrasound is advisable to improve the out come of surgery. ONYCHOMATRICOMA.70

Onychomatricoma is a rare benign fibroepithelial tumor that originates from the nail matrix and produces typical clinical features: the whole or part of the nail is thickened, overcurved, with a yellow–white discoloration and multiple longitudinal tunnels (hollows) that end in the distal nail producing a beehive appearance of the free margin.

Figure 89-14  Bowen’s disease. Verrucous lesion of the nail bed, associated with onycholysis and melanonychia.

1021

15

Section 15

Figure 89-15  Subungual squamous cell carcinoma: ulcerated subungual nodule.

:: Disorders of the Hair and Nails

Human papillomavirus (HPV) 56 has been detected in tumoral cells of cases of Bowen’s diseases associated with LM, indicating that the virus may be involved in the carcinogenesis of these cases.75 Squamous cell carcinoma presents as a slowly growing subungual nodule that eventually ulcerates (Fig. 89-15) or a warty periungual growth. The underlying bone is commonly involved. It is more common in the fingernails and after the fifth decade of life, and the diagnosis is often delayed, since the tumor simulates other benign nail lesions and is frequently not recognized until it ulcerates.76 Oncogenic HPV may be isolated from fingernail lesions. Surgical excision with Mohs surgery is the best treatment for squamous cell carcinoma without bone involvement.

MELANOMA.77–79 (See Chapter 124) MELANOMA AT A GLANCE Involvement of nails is rare (0.7%–3.5% of melanomas). Thumb or hallux is most often affected. Longitudinal melanonychia and Hutchinson sign are classic. Lesion is amelanotic in 25% of cases. Only 15% of patients survive 5 years or longer.

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Nail melanoma is an uncommon form of acral melanoma that arises within the nail matrix or bed. The incidence for acral melanomas is similar worldwide, but the proportion is higher in dark-skinned individuals. It represents about 2% of cutaneous melanomas in Caucasians, and up to 25% in Africans and 10% in Japanese. Nail melanoma most commonly affects the thumb or great toe of middle-aged or elderly patients and is usually an acral lentiginous melanoma. Melanoma of the nail matrix presents as a band of LM, usually dark in color and with irregular border. Periungual brown–black pigmentation (Hutchinson nail

Figure 89-16  Nail melanoma: note Hutchinson’s sign of the hyponychium. sign) indicates superficial spreading of the tumor and is a diagnostic clue (Fig. 89-16). Although dermoscopy is increasingly utilized in the evaluation of nail pigmentation, the experience in this field is still limited and there are no data showing that dermoscopy is superior to clinical evaluation in early detection of nail melanoma. Recent evidence indicate that dermoscopy should not be considered a substitute for pathology in the differential diagnosis of doubtful cases of LM and an excisional biopsy is recommended in all cases of LM showing suspicious features (Box 89-5).74 Up to 33% of subungual melanomas are amelanotic, and they are often misdiagnosed as pyogenic granuloma or squamous cell carcinoma, because the tumor appears as a nail bed growth that first detaches the nail plate and then destroys the epithelium with erosion and bleeding. The low survival rate of patients with nail melanoma is related mainly to the delay in diagnosis.

NAIL PSORIASIS (See Chapter 18)

NAIL PSORIASIS AT A GLANCE Present in up to 50% of patients with skin psoriasis and up to 83% of those with psoriatic arthritis. Isolated nail psoriasis is not rare. Nail matrix and nail bed are most commonly affected. Most often precipitated or worsened by trauma. Most common signs are onycholysis, salmon patches, subungual hyperkeratosis, and irregular pitting. Fingernails and/or toenails may be affected. Several nails are involved in most cases. Treatment is often unsatisfactory.

typical of nail psoriasis (eFig. 89-18.1 in online edition). The capillary density positively correlates with disease severity and decreases with the response to treatment.83

TREATMENT Treatment of psoriasis affecting only the nails is often unsatisfactory and should be limited to patients who experience functional impairment or severe cosmetic problems. It is important to instruct patients to avoid trauma and to refer the patient to a rheumatologist if digital pain is described. Systemic treatments for skin and joint psoriasis are generally effective for nail psoriasis (methotrexate, cyclosporine A). Since the advent of biologic therapies for severe skin and joint psoriasis, their effects on nails symptoms has been investigated and infliximab 5 mg/kg appears to be the most effective to date. Statistically significant mean percent improvement in the Nail Psoriasis Severity Index (NAPSI) score over placebo was obtained at both week 10 and week 24.84 Phototherapy is not effective. Intralesional steroids (triamcinolone acetonide 2.5– 5.0 mg/mL in saline) are the best treatment for nail

Biology of Nails and Nail Disorders

The differential diagnosis of nail psoriasis is summarized in Box 89-6. Pathology of nail clipping can be helpful for diagnosis and to rule out onychomycosis.82 When typical symptoms are not present, diagnosis of nail psoriasis may rely on videodermoscopy of the hyponychium (magnification 40×), which shows dilated, tortuous, elongated, and irregularly distributed capillaries, a finding

Figure 89-18  Psoriasis of the toenails producing subungual hyperkeratosis and onycholysis.

::

DIFFERENTIAL DIAGNOSIS

15

Chapter 89

Up to 50% of patients with psoriasis have concurrent nail psoriasis, which can occur in the absence of skin lesions. Up to 30% of patients with skin psoriasis also have psoriatic arthritis and of these, approximately 80% have nail disease. It has been recently understood that the close proximity of the nail unit to the distal phalanx and the joint has important functional and pathological consequences.80 The fibers of the extensor tendon of the digit insert to the periosteum and then are directed to the nail matrix, which they envelop and link to the bone. The collateral ligaments of the digit anchor the lateral sides of the nail to the interphalangeal joint. Thus, any acute inflammatory process affecting the interphalangeal joint necessarily affects the nail and vice versa. Psoriasis limited to the nails can be easily diagnosed when it produces typical signs, usually detectable only in the fingernails: psoriatic pitting, onycholysis with erythematous border and salmon patches of the nail bed.81 Psoriatic pits are large, deep, and irregular (see Fig. 89-4), and represent psoriatic involvement of the proximal nail matrix. Onycholysis is actually the most common manifestation of nail psoriasis and may affect both fingernails and toenails. In fingernails the presence of an erythematous border along the onycholytic area is diagnostic for nail psoriasis (Fig. 89-17). In toenails, onycholysis is usually combined with subungual hyperkeratosis and may closely resemble onychomycosis (Fig. 89-18). Salmon patches (oil drop sign) appear as yellow–red areas of discoloration in the center of the nail or bordering an onycholytic area. Rarely, nail psoriasis may produce severe nail plate abnormalities such as trachyonychia or crumbling. Other common but rather aspecific signs include splinter hemorrhages and paronychia.

Box 89-6  Differential Diagnosis of Nail Psoriasis

Figure 89-17  Nail psoriasis: onycholysis surrounded by an erythematous border and salmon patches of the nail bed.

Onycholysis Onychomycosis (usually associated with subungual hyperkeratosis): up to 21% of psoriatic nails have secondary onychomycosis Idiopathic onycholysis (fingernails): usually seen with other nail changes Trauma (toenails): psoriasis usually affects several nails, not just the great toenails Pitting Eczema: often has periungual scaling and Beau’s lines Alopecia areata: different morphology of pits

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15

matrix psoriasis limited to a few fingernails, for which they can be injected in the proximal nail fold every 4–8 weeks. Acitretin at low dosages (0.2–0.3 mg/kg/day) for 4 to 6 months is an effective option in severe nail psoriasis.85 In nail bed psoriasis, topical treatment with calcipotriol, combination of calcipotriol and betamethasone, or tazarotene may be effective after removal of the detached nail plate.86–88

PUSTULAR PSORIASIS

Section 15 :: Disorders of the Hair and Nails

(See Chapters 18 and 21) The diagnosis of Hallopeau’ acrodermatitis is suggested by a clinical history of relapsing periungual and subungual pustules with onycholysis (Fig. 89-19). The patient is most commonly seen when the acute episode has subsided; at this time the affected digit shows onycholysis with nail bed and periungual erythema and scaling. Low-dose acitretin (0.3 mg/kg/day) may be useful.

LICHEN PLANUS81 (See Chapter 26)

NAIL LICHEN PLANUS AT A GLANCE Nail lichen planus is seen in approximately 10% of patients with skin lichen planus. Nail involvement is not associated with oral, skin, or scalp lesions in most cases. Nail matrix lichen planus produces nail thinning, with longitudinal fissuring, dorsal pterygium, and trachyonychia. Nail bed lichen planus is frequent, but clinical signs are not specific (onycholysis and mild subungual hyperkeratosis). Several nails are involved in most cases. Scarring of the nail matrix with dorsal pterygium is a possible sequela.

Figure 89-19  Hallopeau acrodermatitis continua. tion and appears as a V-shaped extension of the skin of the proximal nail fold that adheres to the nail bed. Idiopathic atrophy of the nails is a rare variety of nail matrix lichen planus characterized by acute and progressive painless nail destruction leading to diffuse nail atrophy with and without pterygium. Onycholysis is quite frequent in both fingernails and toenails. Severe toenail involvement causes features that resemble yellow nail syndrome, with thickened, yellow–brown toenails. More rarely, nail lichen planus may present with erosive lesions of the nail bed and periungual tissues. Other possible clinical presentations include trachyonychia and nail plate thickening.

DIFFERENTIAL DIAGNOSIS (Box 89-7) In patients with brittle nails, the nail abnormalities are milder. The nails are thin and ridged, but fissuring at multiple sites is not observed. Onychoschizia is frequently associated. Trauma that produces damage to the matrix in an area wider than 3 mm causes permanent thinning and fissuring. Only one nail is

Diagnosis should be confirmed by nail biopsy, and systemic treatment is necessary to avoid scarring.

1024

Nail lichen planus is not rare, and nail lesions may occur in the absence of cutaneous or mucosal involvement. Nail localization of lichen planus should be taken seriously, because it may destroy the nails. Therefore, it is important to diagnose and treat the disease as soon as possible. Although lichen planus often affects both the nail matrix and the nail bed, clinical suspicion should be aroused by nail matrix signs, particularly nail thinning with longitudinal ridging and fissuring (Fig. 89-20). Dorsal nail pterygium formation is not common. It results from nail matrix destruc-

Figure 89-20  Nail matrix lichen planus: note longitudinal ridging and fissuring of the nail plate.

15

Box 89-7  Differential Diagnosis of Lichen Planus Longitudinal fissuring Brittle nails Trauma (single fissure) Systemic amyloidosis Lichen striatus Graft-versus-host disease Pterygium Trauma Bullous diseases Digital ischemia Dyskeratosis congenita Graft-versus-host disease

Parakeratosis pustulosa is a rather common condition that occurs only in children. The disease is limited to one nail in most cases (usually the thumb or index finger) with a clinical picture that closely resembles that of psoriasis. Characteristics are distal onycholysis, fingertip desquamation, and mild subungual hyperkeratosis. Spontaneous regression usually occurs after puberty.

Biology of Nails and Nail Disorders

Nail matrix lichen planus requires oral or intramuscular treatment with systemic steroids, which induce remission of the disease in 2/3 of the cases (Figs. 89-21 and 89-22). Intralesional (vs. systemic) corticosteroid injections should be considered in patients with involvement of fewer than three digits. Relapses are not uncommon, but usually respond to treatment.

PARAKERATOSIS PUSTULOSA

::

TREATMENT

Dorsal pterygium is not reversible and when it is the sole manifestation, should not be treated. Solitary nail lichen planus presenting as trachyonychia does not lead to nail scarring and therefore does not necessarily require treatment.

Chapter 89

usually affected, and it may show a single fissure. Nail abnormalities may be the first sign of systemic amyloidosis, with nail thinning, ridging, and fissuring closely resembling mild nail matrix lichen planus. In amyloidosis, nail bed hemorrhages are common. Diagnosis depends on nail biopsy. Lichen striatus may manifest as nail thinning and fissuring limited to one or two adjacent digits. Skin changes that course from the affected nail in a linear configuration are typical. Inherited (EB) and acquired (e.g., bullous pemphigoid) bullous diseases can produce pterygium. Skin and mucosal lesions are usually present. Digital ischemia is distinguished in that the digit is cold and shows skin signs of impaired vascular skin supply.

Figure 89-22  Nail matrix lichen planus before and after treatment with systemic steroids.

TRACHYONYCHIA (TWENTY-NAIL DYSTROPHY) TRACHYONYCHIA (TWENTY-NAIL DYSTROPHY) AT A GLANCE Idiopathic but likely reflects alopecia areata, psoriasis, dermatitis, or lichen planus of the nail. More common in children. Characterized by nail roughness due to excessive longitudinal ridging (sandpaper nails). Several nails are involved in most cases; involvement of 20 nails is not necessary for diagnosis. Nail changes often regress spontaneously.

Figure 89-21  Nail matrix lichen planus before and after treatment with systemic steroids.

Treatment is not required.

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YELLOW NAIL SYNDROME YELLOW NAIL SYNDROME AT A GLANCE In the typical syndrome, nail changes are associated with respiratory disorders and lymphedema. Arrested nail growth is diagnostic.

Section 15

Figure 89-23  Trachyonychia.

:: Disorders of the Hair and Nails

Trachyonychia (twenty-nail dystrophy) is a nail sign that can be caused by several inflammatory disorders that produce a mild disturbance of nail matrix keratinization. These include alopecia areata, psoriasis, lichen planus, and eczema. The nail is rough and opaque due to excessive longitudinal ridging (Fig. 89-23). The disease occurs most commonly in children. Trachyonychia does not produce nail scarring, even in cases due to lichen planus.

DARIER DISEASE1 (See Chapter 51) The nail abnormalities noted in Darier disease are diagnostic but are not seen in all patients). Key features are longitudinal erythronychia, longitudinal leukonychia associated with distal nail plate nicking (V shaped), and subungual hyperkeratotic papules.

ALOPECIA AREATA (See Chapter 88) Nail involvement is seen in approximately 20% of adults and 50% of children with alopecia areata and is most common in male patients with severe involvement. Geometric pitting is most typical. Pits are small, superficial, and regularly distributed in a geometric pattern along longitudinal and transverse lines. Trachyonychia is quite common in children affected by alopecia totalis or universalis. Other nail abnormalities include punctate leukonychia, mottled lunulae, and acute onycholysis. Nail abnormalities may improve with systemic steroid treatment or spontaneously; they respond poorly to application of topical medications.

Nails are overcurved and thickened, the cuticle is absent, and nail color varies from pale yellow to green. Onycholysis is often associated. Most or all nails are usually involved.

Yellow nail syndrome may or may not be associated with a systemic disorder and is occasionally familial.88,89 However, it is important to refer patients to a pneumologist to exclude respiratory tract involvement. Other conditions that may be associated with yellownail syndrome include rheumatoid arthritis and internal malignancies. The history is the most important clue to diagnosis, because patients always claim that their nails have stopped growing (Fig. 89-24). The nail changes may benefit from treatment with high oral dosages of vitamin E. Spontaneous improvement is possible. Topical vitamin E and systemic antifungal medications (itraconazole, fluconazole) do not appear to be effective.89–91

NAIL SIGNS OF SYSTEMIC DISEASES (Table 89-5) In systemic diseases, nail manifestations usually involve most or all nails. The diagnosis is suggested by clinical history, morphology, and distribution of

ATOPIC DERMATITIS

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(See Chapter 14) Nail abnormalities associated with atopic dermatitis are nonspecific in most cases. Manifestations are most commonly Beau’s lines, irregular pitting, and chronic paronychia. Onycholysis and subungual hyperkeratosis are seen in severe cases, especially those triggered by occupational exposure.

Figure 89-24  Yellow nail syndrome.

TABLE 89-5

Nail Signs of Systemic Disease See Box 89-1

Koilonychia

Sideropenic anemia

Proximal splinter hemorrhages

Bacterial endocarditis Trichinosis Antiphospholipid syndrome Altitude sickness

Periungual erythema

Collagen disorders Infection with human immunodeficiency virus or hepatitis C virus

Lichenoid nail changes with hemorrhages

Systemic amyloidosis

Clubbing

See Box 89-8

Melanonychia

See Boxes 89-2 and 89-5

the nail abnormalities. Beau’s lines located at the same level in all digits or onychomadesis occurring simultaneously in all digits is strongly diagnostic for nail matrix damage from a systemic cause. Examination and capillaroscopy of the proximal nail fold are very important for the diagnosis of connective tissue diseases. Patients with scleroderma and dermatomyositis show enlarged capillary loops with reduced capillary density and avascular areas. In systemic lupus, erythematous, periungual erythema and telangiectasia are typical; although periungual vessels can be tortuous, the capillary density tends to be normal. Cuticular hyperkeratosis and hemorrhages are seen in systemic lupus erythematous and dermatomyositis. Pterygium inversum unguium is typical of scleroderma; in this condition the nail plate adheres to the fingertip skin, which makes nail trimming very painful. The diagnosis of systemic amyloidosis can be suggested by nail symptoms, which sometimes precedes skin and mucosal changes. The nails are thinned, longitudinally fissured, and show subungual hemorrhages. Mild leukonychia is often seen in normal individuals and therefore does not represent a specific sign of systemic disorders. Clinical patterns include half-and-half nails (leukonychia affects the proximal half of the nail bed), Terry’s nails (leukonychia affects the entire nail bed except for its 2-mm distal margin), and Muehrcke’s lines (narrow paired transverse bands parallel to the lunula). Clubbing may or may not be associated with cyanosis (Box 89-8). In clubbing the angle between the proximal nail fold and nail plate is greater than 180 degrees. The digit has a bulbous appearance, and the nail plate is enlarged and excessively curved. Melanonychia can be associated with a variety of systemic disorders and conditions, particularly human immunodeficiency virus infection, adrenal disease, pregnancy, and certain drugs (Box 89-9).

a

Unilateral. Associated with cyanosis. c Associated with hypertrophic osteopathy. b

DRUG-INDUCED NAIL ABNORMALITIES92 A few nail abnormalities are highly likely to have resulted from administration of medication (see

Box 89-9  Drug-Induced Nail Changes

Biology of Nails and Nail Disorders

Renal disorders Hepatic disorders Systemic chemotherapy Hypoalbuminemia

::

Apparent leukonychia   Half-and-half nails   Terry’s nails   Banded nails (Muehrcke’s lines)

Cardiovascular disorders Aortic aneurysma Congenital/acquired cardiovascular diseaseb Bronchopulmonary conditionsc Intrathoracic neoplasms Chronic intrathoracic suppurative disorders Gastrointestinal disorders Inflammatory bowel disease Gastrointestinal neoplasms Hepatic disorders Multiple polyposis Bacillary dysentery Amoebic dysentery Chronic methemoglobinemia

Chapter 89

Beau’s lines/onychomadesis

Box 89-8  Causes of Clubbing

15

Chemotherapy Beau’s lines Onychomadesis Muehrcke’s lines Hemorrhagic onycholysis Pyogenic granulomas Melanonychia Antiretrovirals Azathioprine Melanonychia Indinavir Pyogenic granuloma β Blockers Digital ischemia Bleomycin Digital ischemia Psoralen plus ultraviolet A phototherapy Photo-onycholysis Melanonychia Retinoids Nail fragility Pyogenic granuloma Paronychia

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Section 15

Figure 89-26  Photo-onycholysis: note the presence of nail bed hemorrhages.

:: Disorders of the Hair and Nails

HABIT TIC DEFORMITY (ONYCHODYSTROPHIA MEDIANA CANALIFORMIS) Figure 89-25  Hemorrhagic onycholysis due to taxanes

Box 89-9). Pyogenic granulomas involving several nails are an occasional side effect of treatment with retinoids, indinavir, and antiepidermal growth factor receptor chemotherapeutic agents, often leading to drug discontinuation. Retinoids have also been associated with nail fragility and paronychia. Taxanes (docetaxel and paclitaxel) frequently induce painful onycholysis with subungual hemorrhage and abscess formation (Fig. 89-25). The nail lesions resemble a subungual infection and are reversible after drug discontinuation. Both β blockers and bleomycin may lead to digital ischemia. Therapy with psoralen plus ultraviolet A light has been associated with photo-onycholysis and melanonychia. Photoonycholysis has recently been seen after photodynamic therapy.93 and can rarely follow the intake of tetracycline derivatives, psoralens, and fluoroquinolones. It may be associated with a photosensitivity reaction in the skin and typically affects the central part of the nail plate of one or more fingernails (Fig. 89-26). Onycholysis is painful and often hemorrhagic.94

In habit tic deformity the thumb shows a central longitudinal furrow with multiple transverse parallel lines (Fig. 89-28). The nail deformity is due to the nervous tic of pushing back the cuticle and the proximal nail fold of the thumb with the index finger.

SUBUNGUAL HEMATOMA Subungual hematoma may be caused by a single acute trauma or by repeated microtraumas (see Chapter 99). Nail hematomas last several months because part of the blood is incorporated into the nail plate. Very dark lesions require differentiation from melanotic pigmentation. Dermoscopy shows rounded red–black globules (eFig. 89-28.1 in online edition).74 Acute hematomas require immediate drainage to avoid matrix compression.

ONYCHOLYSIS Traumatic onycholysis of the great toenails is frequent in athletes, in women wearing high-heeled shoes,

TRAUMATIC NAIL DISORDERS NAIL BITING

1028

Nail biting is common in children and may encourage spreading of subungual warts (Fig. 89-27). When nail biting is associated with picking and chewing of the cuticle and periungual skin, the nail plate often shows superficial abnormalities and melanonychia due to melanocyte activation.

Figure 89-27  Subungual warts in a nail biter.

15

Chapter 89

Figure 89-28  Longitudinal furrow of the nail plate due to habit tic.

Onychogryphosis is common in the elderly and neglected individuals .The nail is thickened, distorted, opaque, and yellow–brown, and tends to have an oyster shell appearance.

PINCER NAILS Pincer nails is a painful abnormality that usually affects the toenails and may be associated with subungual exostosis. The distal nail plate is overcurved and compresses the subungual soft tissues (Fig. 89-29).

INGROWING TOENAILS Ingrowing toenails most commonly affect young adults with congenital malalignment of the great toenails. Improper nail cutting may lead to embedding of a nail edge, causing inflammation and granulation tissue formation. Hyperhidrosis is frequently associated. The aim of treatment for ingrowing toenails is to extract the nail edge that is ingrowing and prevent further penetration of nail fragments into the lateral

Figure 89-30  Retronychia: proximal ingrowing of the nail plate.

folds. To accomplish this, the lateral nail plate can be lifted by using a cotton pack or by inserting a gutter splint along the lateral nail margin.95 The width of the nail plate can also be reduced by surgical or chemical (phenolization) removal of the lateral nail matrix.96,97

RETRONYCHIA

Biology of Nails and Nail Disorders

ONYCHOGRYPHOSIS

::

and in individuals with podiatric abnormalities. Nail detachment is not associated with nail bed hyperkeratosis.

Retronychia describes the ingrowth of the proximal nail plate into the proximal nail fold associated with multiple generations of nail plate misaligned beneath the proximal nail.98 It involves 1 or both the first toenails and starts as an onychomadesis (posttraumatic) not followed by nail shedding. The persistence of the partially detached plate under the proximal nail fold, associated with the growth of new nail plates underneath it, results in inflammation with pain and granulation tissue formation (Fig. 89-30). Nail plate avulsion leads to a slow regrowth of a normal nail.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

Figure 89-29  Pincer nails.

1. Zaias N: The Nail in Health and Disease, 2nd edition. Norwalk, CT, Appleton & Lange, 1990 16. Perrin C et al: Anatomic distribution of melanocytes in normal nail unit: An immunohistochemical investigation. Am J Dermatopathol 19:462, 1997 28. McGowan KM, Coulombe PA: Keratin 17 expression in the hard epithelial context of the hair and nail, and its relevance for the pachyonychia congenita phenotype. J Invest Dermatol 114:1101, 2000 32. Runne U, Orfanos CE: The human nail. Structure, growth and pathological changes. Curr Probl Dermatol 9:102, 1981

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Section 15 :: Disorders of the Hair and Nails

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38. Yaemsiri S et al: Growth rate of human fingernails and toenails in healthy American young adults. J Eur Acad Dermatol Venereol 2009 Sept (epub ahead of print) 40. Daniel CR, Piraccini BM, Tosti A: The nail and hair in forensic science. J Am Acad Dermatol 50:258, 2004 44. Baran R, Kechijian P: Longitudinal melanonychia (melanonychia striata): Diagnosis and management. J Am Acad Dermatol 21:1165, 1989 47. De Berker DA, Perrin C, Baran R: Localized longitudinal erythronychia: Diagnostic significance and physical explanation. Arch Dermatol 140:1253, 2004 48. Fistarol SK, Itin PH: Nail changes in genodermatoses. Eur J Dermatol 12:119, 2002 64. Tosti A, Piraccini BM: Paronychia. In: Contact Urticaria Syndrome, edited by S Amin, A Lahti, HI Maibach. Boca Raton, CRC Press, 1997, p. 267

67. Tosti A, Richert B, Pazzaglia M: Tumors of the nail apparatus. In: Nails: Diagnosis, Therapy, Surgery, 3rd edition, edited by KR Scher, CR Daniel III. Philadelphia, WB Saunders, 2005, p. 195 73. Levit EK et al: The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol 42:269, 2000 74. Tosti A, Piraccini BM, de Farias DC: Dealing with melanonychia. Semin Cutan Med Surg 28:49, 2009 80. McGonagle D, Tan AL, Benjamin M: The nail as a musculoskeletal appendage- implications for an improved understanding of the link between psoriasis and arthritis. Dermatology 218:97, 2009 92. Piraccini BM, Iorizzo M: Drug reactions affecting the nail unit: Diagnosis and management. Dermatol Clin 25:215, 2007

Disorders Due to the Environment

PA RT

Disorders Due to Ultraviolet Radiation

Chapter 90 :: F  undamentals of Cutaneous Photobiology and Photoimmunology :: Irene E. Kochevar, Charles R. Taylor, & Jean Krutmann FUNDAMENTALS OF CUTANEOUS PHOTOBIOLOGY AND PHOTOIMMUNOLOGY AT A GLANCE When radiation enters the skin, it is scattered or absorbed. Only light absorbed by molecules (chromophores) in the skin can cause a photobiologic response. Electromagnetic radiation can be conceptualized either as a wave or as packets of energy called photons. An action spectrum indicates which wavelengths produce a photobiologic response most effectively and is plotted as the reciprocal of the minimum effective fluence versus wavelength. The most erythemogenic wavelengths present in sunlight are in the ultraviolet B (UVB) range. Ultraviolet A (UVA) is roughly 1000-fold less effective than UVB. Prostaglandins and nitric oxide appear to be the major mediators for UVB erythema. When certain drugs and dyes absorb UV/ visible light, inflammation ensues. This is called photosensitization. Photosensitivity responses are usually mediated by reactive oxygen species.

Blocked by sunscreen use, cutaneous vitamin D production is mediated by wavelengths from 295–300 nm. Optimal vitamin D blood levels are essential for good bone health and increasingly associated with a myriad of other potential health benefits. Ultraviolet radiation is immunosuppressive. Local and systemic immunosuppressions are recognized. Pyrimidine dimers, reactive oxygen species and urocanic acid initiate UV-induced immunosuppression. Interleukin-10 (IL-10), tumor necrosis factor (TNF)-α, platelet-activating factor, plateletactivating factor-like lipids and other molecules mediate photoimmunosuppression. The major cellular players in UV immunosuppression are Langerhans cells, keratinocytes, macrophages, and T cells. UV radiation impairs T helper 1-mediated cellular immune response.

4

16

Section 16 :: Disorders Due to Ultraviolet Radiation

Knowledge of the interaction of sunlight with the skin is fundamental to understanding the pathogenesis, diagnosis, and treatment of more than 100 cutaneous disorders. Whenever ultraviolet (UV) or visible radiation is used to diagnose or treat a skin condition, important principles of photophysics involving absorption and emission of light underlie the success of the therapy. Sunscreen recommendations rely on an understanding of solar UV radiation and the ways in which the causative wavelengths can be minimized. Skin cancer is an epidemic clinical problem, whose pathophysiology necessitates comprehension of the photophysical, photochemical, and photobiologic events described in this chapter. Almost every ancient civilization worshipped a god of the sun whose healing powers were believed to be broad reaching. Even today, sun exposure is widely felt to induce a sense of well-being. In addition, sunlight is important for the synthesis of vitamin D3 and the setting of internal clocks. On the negative side, sunlight causes deleterious acute and chronic inflammatory skin reactions, skin cancer, and photoaging, and can elicit adverse reactions to certain drugs (see Chapters 91, 92, 109, 112). Although the sun is a major source of the UV and visible radiation that interacts with human skin, UV and/or visible radiation are also emitted from common sources such as fluorescent lights, incandescent bulbs, photocopy machines, and phototherapy lamps. Tanning salons are another familiar example. Thus, UV

Generalized steps for ultraviolet (UV) and visible radiation hitting skin

UV and visible radiation

Tissue optics

Absorption by chromophores

Excited states

Photoproducts

Biochemical and cellular changes

Acute and chronic skin responses

1032

Figure 90-1  Generalized steps from ultraviolet (UV) and visible radiation hitting the skin to observation of clinical responses.

and visible radiation are a constant part of the human environment and play a role in health, disease, and therapy. Photodermatology is the study of this interaction between human skin and UV and visible radiation. To understand the responses of skin to UV and visible radiation, it is essential to be acquainted with the principles governing the interaction of these wavebands with biomolecules in the skin. When UV and visible light photons reach the skin surface the energy of the radiation is transformed into an observable response as shown schematically in Figure 90-1. First, the radiation must penetrate to the appropriate level in the skin where it is absorbed by molecules in the skin, termed chromophores. Photochemical reactions then convert the chromophores into new molecules, the photoproducts. These photoproduct molecules stimulate cellular signal transduction pathways leading to biochemical changes that culminate in cellular effects, such as the proliferation, secretion of cytokines, and apoptosis that are responsible for the observed acute skin responses.

ULTRAVIOLET AND VISIBLE RADIATION UV radiation and visible light are portions of the electromagnetic (EM) spectrum, which includes a wide range of wavelengths, from high-energy X-rays to low-energy microwaves and radio waves (Table 90-1; Fig. 90-2). The UV waveband is of special interest because dozens of skin disorders are aggravated by these wavelengths and, many popular therapies, such as UVB phototherapy (see Chapter 237) and psoralen and ultraviolet A light (PUVA) photochemotherapy (see Chapter 238), use sources emitting UV radiation. Visible light encompasses those wavelengths perceived as color by the human eye and is also frequently used in therapies, such as blue-light amino levulinic acid– photodynamic therapy (PDT; see Chapter 238), and is emitted by several lasers intended to target cutaneous chromophores (see Chapter 239).

ULTRAVIOLET RADIATION For medical photobiology, the UV range (200–400 nm) is subdivided into UVA, UVB, and UVC (see Table 90-1 and Fig. 90-2). A division was made at 290 nm because wavelengths from the sun shorter than 290 nm are absorbed by ozone in the stratosphere and do not reach the earth’s surface at sea level. Wavelengths in the range of 200 to 290 nm are referred to as UVC or germicidal radiation. These wavelengths are strongly absorbed by DNA and therefore can be lethal to viable cells of the epidermis or to bacteria. UVC lamps emit at 254 nm and are used for air and water purification. Care must be taken to avoid exposure of eyes and skin to UVC radiation because of the danger of UV keratitis and mutation. The range 290 to 320 nm is known as UVB and is often referred to as mid-UV or sunburn spectrum. It includes the biologically most active wavelengths

Table 90-1

Electromagnetic Radiation According to Wavelength

0.1–10

Vacuum ultraviolet

10–200

Ultraviolet C

200–290

Ultraviolet B

290–320

Ultraviolet A (UVA)

320–400

UVA I

340–400

UVA II

320–340

Visible

400–760

Violet

400

Blue

470

Green

530

Yellow

600

Red

700

Near infrared

760–1000

Far infrared

1000–100,000

Microwaves and radio waves

>106

reaching the earth’s surface. The UVB constitutes only approximately 5% of the UV and 0.5% of total radiation reaching the earth’s surface; the exact amount varies markedly with the time of day, season, cloud conditions, and other factors. Ordinary window glass blocks UVB. Most sunscreens efficiently reflect or absorb these wavelengths, and the sun protection factor (SPF) is primarily based on testing against this waveband. However, it is important to note that different wavelengths within these subdivisions can elicit greatly

VISIBLE RADIATION The visible spectrum (400–760 nm) is defined by the wavelengths that are perceived as color by the retina.

Electromagnetic spectrum divided into major wavelength regions Energy Gamma rays

X-rays

Vacuum UV 10

Ultraviolet

UVC 200

Visible

UVB

Infrared

UVA

Fundamentals of Cutaneous Photobiology and Photoimmunology

X-ray

::

Wavelength Range (nm)

16

Chapter 90

Waveband

varying biologic responses. For example, consider the response of skin to two wavelengths in the UVB range, 297 and 313 nm. Radiation at 297 nm is nearly 100 times more erythemogenic than 313-nm radiation1 and more effectively causes DNA damage and photocarcinogenesis.2 An example relevant to phototherapy is the great efficacy of certain UVB wavelengths for treatment of full UVB spectrum.3,4 Narrowband UVB (311 nm) and excimer laser (308 nm) are used to treat psoriasis because these wavelengths are more effective than other portions of the UVB spectrum.3,4 Long-wave UV or UVA (320–400 nm) is sometimes referred to as black light because it is not visible to the human eye but causes certain substances to emit visible fluorescence. Approximately 95% of the UV radiation reaching the earth’s surface is UVA. As described for UVB radiation, the response of skin to UVA is not constant across all wavelengths from 320 to 400 nm.3 In fact, UVA has been divided into UVA I (340–400 nm) and UVA II (320–340 nm) because the latter band is more damaging to unsensitized skin than the longer wavelengths. Although most sunscreens offer their greatest protection against UVB wavelengths, those products said to be “broad-spectrum” indeed have considerable ability to protect against UVA wavelengths, although no widely used formal measure equivalent to the SPF rating yet exists. Generally, the higher the SPF, for example, 45 or greater, the more likely one is going to find some UVA protection in that preparation. Newer sunscreen agents enhance protection against damaging UVA rays (see Chapter 223). Because of its predominance in the UV radiation reaching the earth’s surface, protection against UVA is quite important for minimizing adverse cutaneous effects such as photoaging and carcinogenesis.

Radio waves

Visible

290

760 UVAII 320

UVAI 340

400

Wavelength, nanometers

Figure 90-2  Electromagnetic spectrum divided into major wavelength regions. The lower band emphasizes the ultraviolet (UV) and visible bands that are important for photobiologic responses in human skin.

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16

Specific colors are associated with different wavelengths, as shown in Fig. 90-2. Skin responses to visible light generally require photosensitization. For example, in PDT, dyes absorbing long wavelength visible light (red) are used (see Chapter 92). Because they take advantage of the absorption spectra of endogenous chromophores, intense pulsed visible light sources such as lasers are used to treat vascular, pigmented and other lesions without application of a photosensitizing dye (see Chapter 239).

OTHER WAVEBANDS OF ELECTROMAGNETIC RADIATION Section 16 :: Disorders Due to Ultraviolet Radiation

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X-rays and γ rays occupy the short wavelength (high energy) end of the EM spectrum, and infrared radiation (IR) is found at longer wavelengths (lower energy) than visible radiation (see Table 90-1). X-ray and γ rays ionize molecules (remove electrons) indiscriminately and are known as ionizing radiation, the subject of radiobiology (see Chapter 240). In radiation therapy of tumors, these wavelengths kill tumor cells by ionizing water molecules and producing free radicals that damage DNA. IR has lower energy than visible light. It is subdivided into IR-A (760–1,440 nm), IR-B (1,440–3,000 nm), and IR-C (3,000 nm–1 mm). IR-A penetrates into the dermis and causes skin damage whereas IR-B and IR-C are felt as heat. Recent studies suggest that IR-A wavelengths might also be therapeutic.5

PROPERTIES OF ELECTROMAGNETIC RADIATION Certain principles are better illustrated by conceptualizing EM radiation as waves, whereas others are better understood by thinking of it as packets of energy called photons. These two descriptions are complementary. When considering EM radiation as a wave, it is described as oscillating electric and magnetic fields at right angles to each other and to the direction of propagation. Consequently, it may be described either by its frequency (number of oscillations per second) or by its wavelength (distance traveled per oscillation). Frequency and wavelength have an inverse relationship, which is expressed as: ν = c/λ, where ν = frequency (number of oscillations per second), c = speed of light (3 × 108 m/s), and λ = wavelength in meters. EM radiation also may be described as a stream of discrete packets of energy known as quanta or photons. The amount of energy in a photon (quantum) is directly proportional to the frequency of the radiation and inversely proportional to its wavelength, as expressed by Planck’s law: E = hc/λ, where E = the energy of the photon in joules (J), h = Planck’s constant (6.626 × 10−34 J/s), c = speed of light, and λ = wavelength in meters. This relationship shows that the energy of the photon increases when the wavelength is shorter and decreases when the wavelength is longer. For example, a 300-nm UVB photon has twice the energy of a 600-nm yellow photon.

SOURCES OF ULTRAVIOLET AND VISIBLE RADIATION SUNLIGHT The shortest wavelength of the solar spectrum reaching the earth’s surface at sea level is approximately 290 nm, although slightly shorter wavelengths are detected at high altitudes. Depending on the geographic location and the season, it has been estimated that sunlight produces between 2 and 6 mW/cm2 of UV radiation between 290 and 400 nm. Filtering of wavelengths less than 290 nm by ozone is a very important process because the shorter UVC wavelengths are highly damaging to animals and plants. Because the transmission of solar UVC and UVB through the atmosphere varies exponentially with ozone concentration, small changes in the ozone layer may result in hazardous increases in UV irradiance at the earth’s surface.6 For example, calculations of the effects of ozone depletion predicted a doubling of skin cancer incidence by 2,100 ad even if the Montreal Protocol restrictions on ozone-depleting substances were followed.7 The UV Index developed by the National Weather Service and the US Environmental Protection Agency represents an attempt to quantify the risks attendant with solar radiation at a given time and place. Among other factors, the effects of altitude, latitude, season, and clouds are considered. The scale goes up to 15, and any UV Index greater than 10 is considered a high-risk day for possible overexposure in that locale.

ARTIFICIAL SOURCES OF ULTRAVIOLET AND VISIBLE RADIATION Skin is exposed to UV and visible radiation from a wide variety of sources in daily life and from a different set of light sources for therapy and diagnosis. Specific information should be obtained from the manufacturer before using a new light source.

INCANDESCENT SOURCES. Incandescent light sources include conventional electric light bulbs, flood lamps, and some quartz iodide bulbs. In these lamps, an electric current passing through a metal filament heats the filament, causing it to emit mostly visible and IR. Only the occasional patient with solar urticaria, chronic actinic dermatitis, or some porphyrias is bothered by the output of ordinary incandescent sources. Tungsten-halogen incandescent lamps, often used as flood lamps, emit UVA and visible radiation. Some quartz iodide incandescent lamps produce significant UVA and some UVB emission. ARC SOURCES. Arc sources include xenon lamps, medium- and high-pressure mercury (hot quartz) lamps, fluorescent lamps, and halide lamps. In arc lamps, electrons are driven through a gas by a potential difference between two electrodes. The gaseous

16

Emission spectra of some of the fluorescent lamps used in phototherapy

A

Relative spectral irradiance

100 80 60

Broadband UVB

Broadband UVA

40 20 0 280

300

320

340

360

380

400

380

400

380

400

Wavelength, nm

::

B

Chapter 90

Relative spectral irradiance

100 80

Narrowband UVB

60

Wood’s lamp

40 20 0 280

300

320

340

360

Wavelength, nm

C

Relative spectral irradiance

100 80

UVA-1 lamps

60 40 20 0 280

300

320

340

360

Fundamentals of Cutaneous Photobiology and Photoimmunology

molecules are ionized and subsequently release EM radiation. Radiation is emitted preferentially at specific wavelengths (emission lines) as well as in a continuum, that is, all wavelengths are emitted rather than just specific wavelengths. The wavelengths and relative power at each wavelength depend on the gas used, the arc temperature, the pressure within the lamp, and the lamp wall material. Xenon arc lamps emit both UV and visible radiation and are now the most common sources used in solar simulators. Photoprovocation testing for polymorphic eruption is often done with such sources using filters to limit the wavelengths. Xenon arcs are also used in some phototherapy and photobiologic research applications. In a xenon lamp, xenon gas under 20–40 atmospheres (atm) of pressure produces intense visible and UV radiation. At these pressures, the xenon spectrum becomes a continuum. The wavelengths emitted by mercury arc lamps are strongly influenced by the pressure of the gas within the envelope. Low-pressure mercury germicidal lamps emit 85% of the radiant energy at 254 nm. Because the operating temperature is low, they are also known as cold quartz lamps. With increasing pressure (1 atm), the primary 254nm emission is absorbed by other mercury atoms within the lamp and reemitted at longer wavelengths (297, 302, 313, 334, and 365 nm, and visible wavelengths). With further pressure increases (2–100 atm), these spectral lines broaden and decrease relative to the intensity of the continuous spectral background. In medical practice, medium- and high-pressure mercury (hot quartz) lamps are generally used as sources of UVB, although their spectral power distribution is mainly in the UVA and visible range. The commonly used UVB sunlamps (see Chapter 237) and UVA lamps for PUVA therapy (see Chapter 238) are fluorescent lamps. They are, in essence, modified low-pressure mercury arc lamps. The inner surface of the glass tube is coated with a phosphor, which absorbs the 254-nm radiation and reemits the energy at longer wavelengths. The chemical composition of the phosphor determines which wavelengths are reemitted. In general, fluorescent lamps have a relatively wide, bell-shaped emission spectra, with emission lines of mercury superimposed, and are referred to as broadband light sources. Fluorescent sunlamps (type FS) emit mainly in the UVB range (Fig. 90-3). They are often referred to as UVB lamps, even though they emit a portion of UVA radiation, because the therapeutically significant radiation is in the UVB range (Table 90-2). A fluorescent lamp with a major emission peak at 311 nm (Philips TL01) was developed for use in phototherapy (see Fig. 90-3).8,9 This lamp is an efficient source for psoriasis phototherapy because, compared to a conventional UVB lamp, the energy emitted almost entirely overlaps with the action spectrum for clearance of psoriasis.3 Interestingly, this lamp has also been successfully used for the treatment of vitiligo, atopic dermatitis, and polymorphic light eruption, all of whose action spectra are unknown and may possibly differ from that for psoriasis. High-intensity, UVA-emitting fluorescent lamps are most often used in PUVA therapy of psoriasis, vitiligo,

Wavelength, nm

Figure 90-3  Emission spectra of some of the fluorescent lamps used in phototherapy. A. Broadband ultraviolet B (UVB) fluorescent lamps and UVA (black light) fluorescent lamps. B. Narrowband (Phillips TL01) fluorescent lamp with a maximum at 311 nm and a fluorescent lamp with a Wood’s glass filter. C. UVA I halide lamps (Sellamed 24,000 bed system). Emission spectra were measured with a Luzchem model SPR-4001 spectroradiometer.

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Table 90-2

Approximate Spectral Power Distribution of UVB and UVA Radiation Expressed as Percentage of Total Emission in the UV Waveband in Common Phototherapy Sources % UVB Broadband UVB (Westinghouse Sunlamp)

60

40

80

20

Broadband UVA (Houva Lite; Black Light by Sylvania, Westinghouse, and General Electric; Sylvania Puva Life Line; Dermalight Metal)

2

98

UVA Ib (Dermalight UltrA1, Dr. K. Hönle Medizintechnik GmbH)

0

100

a

Narrowband UVB (Phillips Fluorescent UVB, TL01, 311 nm)

c

Section 16 :: Disorders Due to Ultraviolet Radiation

1036

% UVA

Wood’s light (RA Fisher; Spectronics)

0

100

Halide lampsd (Dermalight Systems, Dr. K. Hönle Medizintechnik GmbH)

0

100

a

Most (∼95% of the UVB emission of the typical narrowband UVB source is centered around 311 nm). This UVA emission is above 340 nm. c The filter used (so-called Wood’s filter) is glass with nickel oxide phosphor. Consequently, UVB is screened. A moderate amount of visible light is produced. d The actual amount depends on the model purchased and the filters used (glass vs. quartz). Some models allow the operator to change the filters readily and thus increase the amount of UVB to >50% of the irradiance. b

and other skin diseases. The most efficient UVA source for PUVA therapy would maximize the emission of 320- to 360-nm radiation for photoactivation of psoralen molecules, while minimizing the UVB emission. Table 90-2 shows the percentage of total emission that is in the 320–360-nm range from several UVA-emitting light sources that are used in phototherapy units. Wood’s lamps are small, low-pressure, UVAemitting fluorescent lamps with a UVA-transmitting, visible-absorbing glass envelope. They are useful in clinical practice because, after UVA absorption, the fluorescent emission from normal and abnormal components of skin, hair, teeth, and urine may be diagnostic (e.g., in porphyria, vitiligo, and fungal infection). Halide lamps emit a high-intensity continuum in the UVB and especially the UVA range. With appropriate filters, this lamp is used increasingly as a UVB, as well as a UVA, source for phototherapy (in particular, UVA I therapy) and photochemotherapy. The metal halide lamp usually consists of a high-pressure mercury lamp with metal halides as additives. The continuous range of wavelengths emitted from halide lamps differentiates them from mediumpressure mercury arc lamps that emit in narrow wavelength ranges. Approximately 20% of the ­emission spectrum can be UVA radiation.

LASERS. (See Chapter 239.) Lasers produce intense beams of monochromatic (single wavelength) radiation. The laser operates by exciting molecules to a metastable excited state from which photon emission is stimulated by a subsequent photon incident on the excited molecule. The emitted photon and the stimulating photon are then each capable of stimulating emission of yet other excited molecules, eventually producing an avalanche of photons of the same wavelength, phase, and direction of propagation. Different lasers emit UV, visible, or infrared wavelengths and may operate as either continuous or pulsed sources.

ULTRAVIOLET AND VISIBLE RADIATION DOSIMETRY To treat patients with the appropriate amount and wavelengths of UV or visible radiation, it is important to become acquainted with how the radiation is quantified and related to the exposure time. The basic unit of EM energy is the joule (J). Power is the rate of energy flow, joules per second (J/s), usually expressed as watts (W). The rate at which the radiant energy is delivered to a surface, such as skin, is expressed as the power delivered per unit area of surface (power/area; W/cm2). This quantity is called irradiance. The total radiant energy delivered per unit area of skin surface over a period of time is called the exposure dose or fluence and is the product of irradiance and time: Irradiance (w/cm2) × time (s) = Exposure dose or fluence (J/cm2) For most responses to UV and visible radiation, it is the fluence at particular wavelengths that determines the magnitude of the response. The irradiance generally does not affect the response using conventional light sources. The irradiance delivered by a source as a function of wavelength is called the spectral irradiance and is expressed as units of irradiance per nanometer [(W/ cm2)/nm]. A spectroradiometer is used to measure the spectral irradiance of a light source. When measuring a light source’s irradiance over a given spectral region, a detector weighted to the wavelengths of interest is most useful. For example, a broadband radiometric measurement of wavelengths less than 315 nm provides a rough indication of the erythemally effective wavelengths emitted by a source of UV radiation. There is, however, no substitute for knowing the full spectral irradiance delivered by a source, as determined by a spectroradiometer. For example, in phototesting, only the wavelengths of interest should be

used. To assess endogenous UVA sensitivity, the UVB portion of a source’s emission, if present, must be filtered out so that the more erythemogenic UVB wavelengths do not lead to a falsely lower determination of erythema threshold in the UVA range.

Approximate penetration of ultraviolet and visible radiation into skin 250 300 350 400

Stratum corneum 10-20 µ

Epidermal reflectance

Dermal reflectance

Epidermal absorption

Epidermis 40-150 µ

Dermis 1000-4000 µ Dermal absorption Scattering

Figure 90-4  The interaction of ultraviolet and visible radiation with skin. The incident radiation is reflected from the surface, scattered (circles), and absorbed (black dots) as it travels through the skin.

Depth, mm

0.4

0.6

0.8 1.0

Figure 90-5  Illustration of the approximate penetration of ultraviolet and visible radiation into skin. λ = wavelength. Scattering includes any process that deflects the path of optical radiation. For example, skin with scales, as in psoriasis, scatters more light than does normal skin. During phototherapy, application of emollients to the psoriatic plaques helps reduce the scattering of UV radiation and allows more of the effective wavelengths to penetrate into the viable tissue. Melanin, which absorbs relatively uniformly over the visible wavelengths and is normally present only in the epidermis, acts largely as a neutral density filter to diminish remittance from the dermis. The greater overall melanin content in darker skin absorbs more visible light and therefore causes the skin to appear darker as there is less light remitted back to the observer. Blood (hemoglobin) within the dermis absorbs the shorter (blue) visible wavelengths, diminishing these spectral regions, and giving a reddish hue to our perception of the total remittance. Abnormal location and quantity of these or other pigments account for the appearance of the skin in pathologic conditions (e.g., melasma with extra pigment in the epidermis and/or dermis, vitiligo with an absence of epidermal melanin).

Fundamentals of Cutaneous Photobiology and Photoimmunology

Direct reflectance

0.2

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Incident radiation

700 λ, nm

Chapter 90

Interaction of ultraviolet and visible radiation with skin

600

0

OPTICAL PROPERTIES OF SKIN When UV and visible radiation strike the skin, part is remitted (reflected and scattered), part is absorbed by chromophores in various layers, and part is transmitted inward to successive layers of cells until the energy of the incident beam has been dissipated (Figs. 90-4 and 90-5). The two major processes limiting the penetration of UV and visible radiation into skin, absorption and scattering, vary with wavelength.10 UV wavelengths less than 320 nm are readily absorbed by proteins, DNA, and other components of epidermal cells. Along with scattering, this absorption accounts for the low penetration of these wavelengths into skin (see Fig. 90-4). For example, approximately 10% of 300-nm radiation and 50% of 350-nm radiation reaches the dermal–epidermal junction in fair skin. Between 5% and 10% of incident light is reflected by the outer surface of the stratum corneum. This surface or so-called specular reflectance is relatively constant for all visible wavelengths and accounts for the surface appearance of skin, which is especially glossy if the surface is smooth, wet, or oily. In contrast, if the surface is irregular, the light is scattered and the skin appears dull or “rough.” Moisturizers applied to the skin reduce this rough appearance by smoothing out the many air–surface interface irregularities and making the skin look shinier.

500

16

ABSORPTION OF ULTRAVIOLET AND VISIBLE RADIATION BY MOLECULES IN SKIN When a photon is taken up by a chromophore, it is said that absorption has occurred. The specific wavelengths absorbed by each molecule (called an absorption spectrum) are characteristic of the structure of the molecule (i.e., the arrangement of the nuclei and electrons). Only radiation that is absorbed by the chromophores can initiate biologic responses. The absorption spectrum of a compound is a plot of the probability of absorption of photons of a specific wavelength on the Y-axis against wavelength on the

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Absorption sprectra of cutaneous chromophores absorbing ultraviolet radiation

EXCITED STATE MOLECULES

Absorption (not to scale)

1.2 1.0 0.8 0.6 0.4 0.2

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0 250

300

350

400

Wavelength, nm

KEY

:: Disorders Due to Ultraviolet Radiation

NADH

Hemoglobin

7-DHC

Urocanic acid

DNA

Protein

Melanin

Figure 90-6  Absorption spectra of cutaneous chromophores absorbing ultraviolet radiation. Note that the relative amounts of ultraviolet radiation absorbed by these chromophores in skin depend on the heights of the absorption peaks as shown in this figure, the amount of each chromophore in skin, and the penetration of each wavelength into skin. 7-DHC = 7-dihydrocholesterol; NADH = reduced nicotinamide adenine dinucleotide.

X-axis (Fig. 90-6). The wavelengths that have the highest probability of absorption are called absorption maxima, λmax, (e.g., DNA, λmax = 260 nm; porphyrins, λmax = 400–410 nm). Many of the biomolecules that absorb in the UVB spectrum actually have absorption maxima at shorter wavelengths in the UVC range (see Fig. 90-6). These include the purine and pyrimidine bases in DNA and RNA (λmax ∼260 nm) and 7-dehydrocholesterol (λmax = 285 nm). Many endogenous cutaneous chromophores absorb UVA or a combination of UVA and visible radiation, including hemoglobin (λmax = 410 nm) and bilirubin (λmax = 450 nm). Melanin absorbs throughout the UV, visible, and near IR spectra without a distinct absorption maximum wavelength. The absorption spectra of few chromophores extend into the IR-A waveband, an exception being cytochrome c oxidase, which is last enzyme in the mitochondrial respiratory electron transport chain.

PHOTOCHEMICAL REACTIONS LEADING TO SKIN RESPONSES

1038

duction processes that lead to the observed responses in skin.

After absorbing the energy of a photon, the chromophore is in an “excited state,” which exists for only a very short time before reacting with nearby molecules. The products of these reactions initiate signal trans-

Normally, molecules are in the so-called ground state and have a certain distribution of electrons in space around the nuclei of their atoms. For each molecule, a series of electronic states with higher energies and different distributions of electrons also exist; these are called excited states. When a molecule in the ground state absorbs the energy of a UV or visible photon, the molecule is promoted to an excited electronic state (Fig. 90-7). According to quantum mechanics, only certain energy gaps are allowed to exist between electronic states. Consequently, a molecule can absorb photons only with certain energies; this results in a unique absorption spectrum for each molecule. A molecule exists in this first excited state formed for a very brief period. It is called a singlet excited state and exists for a few nanoseconds. The molecule may return to the ground state by emitting light (fluorescence) or releasing the energy as heat by a process called internal conversion (see Fig. 90-7). Alternatively, the singlet excited state may undergo a chemical reaction to form a photoproduct, or it may convert into another excited state with lower energy, the triplet excited state, by a process called intersystem crossing (see Fig. 90-7). Singlet and triplet excited states differ in the spins of a pair of electrons in an orbital. The ground state is almost always a singlet state. The triplet excited state may exist for a longer time (i.e., a few microseconds). It may emit light (phosphorescence), undergo a chemical reaction, or return to the singlet ground state by intersystem crossing (see Fig. 90-7). These excited state processes are responsible for the effectiveness of light for diagnosis and therapy. For example, fluorescence occurs every time a Wood’s light is used. UVA emitted from this lamp causes autofluorescence of dermal collagen fibers. To the examining physician, this fluorescence is viewed through

Absorption of ultraviolet and visible radiation Singlet excited state

isc Triplet excited state

ic

Photoproduct Fl hν

isc Ph

Photoproduct

Ground state

Figure 90-7  Absorption of ultraviolet and visible radiation (hν) by molecules and the dissipation of the absorbed energy by fluorescence (Fl), internal conversion (ic), intersystem crossing (isc), phosphorescence (Ph), and photochemistry to form photoproducts.

the overlying epidermis. Thus, any epidermal lesions such as lentigines tend to have their borders accentuated by contrast because the fluorescence is observed most brightly around the lesion. The heat generated by internal conversion is responsible for the effects of pulsed lasers (see Chapter 239).

PHOTOPRODUCTS

PHOTOSENSITIZATION When certain drugs (e.g., tetracyclines, fluoroquinolones, psoralens) and dyes absorb UV and/or visible radiation, delayed erythema or inflammation is observed (see Chapter 92). This phenomenon is called photosensitization, and the dyes and drugs are called photosensitizers. Photosensitization requires the presence of oxygen in most cases and the initial photoproducts are reactive oxygen species (ROS). ROS are small molecules and free radicals including singlet oxygen, hydrogen peroxide, superoxide anion and hydroxyl radical. These ROS oxidize unsaturated lipids in membranes, certain amino acids in proteins (histidine, methionine, tryptophan, cysteine), and guanine in nucleic acids. The oxidized products initiate signal transduction processes leading to inflammatory mediators,

ACUTE RESPONSES TO UV RADIATION Sunburn and tanning are the most obvious responses elicited by exposure of skin to a single dose of UV radiation. Many other responses are less visually apparent, but have important physiologic effects including formation of vitamin D3, altered immune responses, production of antimicrobial peptides and disruption of the epidermal barrier function. In addition, the cumulative effect of repetitive exposures gives rise to chronic skin changes including skin cancer development and photoaging. All of these responses result from a complex burst of UV-induced activity in the epidermis and dermis involving cytokines, neuropeptides, prostaglandins, ROS, and altered expression of at least 600 proteins.11,15–17

Fundamentals of Cutaneous Photobiology and Photoimmunology

Number of photoprroduct molecules formed Number of photons abbsorbed

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Photoproduct quantum yield =

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Chapter 90

During a photochemical reaction, the excited state molecule is transformed into a new, stable molecule called the photoproduct. Photoproducts in DNA are important for UVB-induced responses in skin. The photoproduct molecule may be produced entirely by rearrangement of the bonds in the chromophore, for example, the formation of previtamin D3 from 7-dehydrocholesterol or in DNA of a four-membered ring structure called a cyclobutyl pyrimidine dimer (CPD) from adjacent thymines or cytosines. These DNA photoproducts lead to mutations and development of nonmelanoma skin cancers (see Chapter 112). Alternatively, the chromophore may form covalent bonds with another molecule in the cell, for example, the formation of covalent adducts between psoralen and DNA. The phototherapy of diseases such as psoriasis makes use of this photochemical reaction (see Chapter 238). In addition, many skin responses to UV and visible light are initiated when the excited state chromophore transfers its energy to oxygen to form singlet oxygen or transfers an electron to form superoxide anion. These forms of oxygen react with cellular molecules, which often initiates intracellular signal transduction leading to the inflammation seen in sunburn and drug phototoxicity. Photochemical reactions vary in efficiency. Not every chromophore molecule that absorbs a photon undergoes a photochemical reaction because the excited states may fluoresce or follow other pathways (see Fig. 90-7). The term quantum yield indicates the likelihood that one of these processes occurs. For example, the quantum yield for forming a certain photoproduct is:

for example, prostaglandin E2 (PGE2) and tumor necrosis factor (TNF)-α, that produce the inflammation observed as erythema. A photosensitizer molecule in an excited triplet state can transfer its energy to an oxygen molecule, thereby generating the ROS called singlet oxygen (1O2). Singlet oxygen is relatively long-lived for a singlet state (32 ng ml-1) 25 (OH)D levels at UK latitudes. J Invest Dermatol 130:1411, 2010 107. Bischoff-Ferrari HA et al: Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84:18, 2006 118. Kripke ML et al: Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice. Proc Natl Acad Sci USA 89:7516, 1992 131. Schwarz A et al. Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair. Nat Cell Biol 4:26, 2002

Chapter 91 :: A  bnormal Responses to Ultraviolet Radiation: Idiopathic, Probably Immunologic, and Photoexacerbated :: Travis W. Vandergriff & Paul R. Bergstresser

POLYMORPHIC (POLYMORPHOUS) LIGHT ERUPTION EPIDEMIOLOGY. Polymorphic light eruption (PMLE) is common worldwide, but thought to occur more frequently in temperate latitudes and rarely in equatorial latitudes. However, a large-scale crosssectional study has revealed no latitudinal gradient Box 91-1  Differential Diagnosis of Polymorphic Light Eruption USUAL ACUTE FORM Photoexacerbated dermatoses such as atopic or seborrheic dermatitis or acne Solar urticaria Erythropoietic protoporphyria Xeroderma pigmentosum RARE PERSISTENT FORM Jessner lymphocytic infiltrate

Clinical presentation: a pruritic, erythematous, symmetrically distributed, papulovesicular eruption, usually on exposed areas, within hours of exposure to ultraviolet radiation, most commonly sunlight, with full resolution in days to several weeks. Histopathology: epidermal spongiosis with a superficial and deep dermal, perivascular, mainly mononuclear cell infiltrate and papillary dermal edema. Genetics: most likely a genetically determined delayed-type hypersensitivity reaction against UVR-induced cutaneous antigen(s). Therapy: responds to broad-spectrum sunscreen use, oral or topical steroids, and prophylactic low-dose immunosuppressive phototherapy.

TABLE 91-1

Abnormal Responses to Ultraviolet Irradiation Acquired idiopathic, presumed immunologic photodermatoses Polymorphic light eruption Actinic prurigo Hydroa vacciniforme Chronic actinic dermatitis Solar urticaria DNA repair defect disorders Xeroderma pigmentosum Cockayne syndrome Trichothiodystrophy Bloom syndrome Rothmund–Thomson syndrome (probable) Chemical and drug photosensitivities Exogenous Systemic Topical Endogenous The porphyrias Photoexacerbated dermatoses

Abnormal Responses to Ultraviolet Radiation: Idiopathic

ACQUIRED IDIOPATHIC, PROBABLY IMMUNOLOGIC PHOTODERMATOSES

A common acquired sunlight-induced disorder typically presenting in the spring.

::

Abnormal responses to ultraviolet radiation (UVR) exposure divide into four categories (Table 91-1): (1) acquired idiopathic, presumed immunologic; (2) DNA repair defect disorders; (3) chemical and drug photosensitivity, including the porphyrias; and (4) photoexacerbated dermatoses not caused directly by UVR. The first and last categories and an approach to assessing photosensitivity are covered in this chapter. The other categories are covered in other chapters in this book. Diagnosis of photodistributed eruptions is discussed in Box 91-1 and Figure 91-1, and the entities are discussed in the following sections.

POLYMORPHIC LIGHT ERUPTION AT A GLANCE Chapter 91

ABNORMAL RESPONSES TO ULTRAVIOLET RADIATION: IDIOPATHIC, PRESUMED IMMUNOLOGIC, AND PHOTOEXACERBATED

16

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Polymorphic light eruption

Are lesions present despite rigorous avoidance of sunlight? OR Are lesions present in photoprotected sites?

YES

Consider photoexacerbated primary dermatosis

NO Consider patient’s age

Section 16

Child

Are pock scars present?

:: Disorders Due to Ultraviolet Radiation

Hydroa vacciniforme

Young adult

Elderly

NO Do excoriations, swallow scars, or dyspigmentation predominate?

YES Actinic prurigo

Does the patient have a history of atopic or contact dermatitis? OR Does patient pursue outdoor hobbies?

NO

NO

Does the patient take a photosensitizing medication?

YES

YES Chronic actinic dermatitis

NO

Phototoxic or photoallergic drug eruption

Consider onset and duration of lesions

Onset within hours to days, resolution within days to weeks

Polymorphic light eruption

Onset within minutes, resolution within hours

Solar urticaria

Figure 91-1  Diagnostic algorithm for abnormal responses to ultraviolet radiation.

in Europe.1 This study estimated an overall suspected lifetime prevalence of 18% among Europeans. Previous reports indicate a prevalence of 10%–15% among North Americans2 and southern Britons,3 and 5% among southern Australians.3 Women are affected more than twice as frequently as men.1 Fitzpatrick skin type also influences the risk of developing PMLE, with the highest prevalence in people with skin type I and the lowest prevalence in people with skin type IV or higher.1

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ETIOLOGY AND PATHOGENESIS. A delayedtype hypersensitivity (DTH) response to a sunlightinduced cutaneous photoantigen was first suggested as the cause of PMLE in 1942, based on the delay between UVR exposure and onset of the eruption, as well as on its lesional histologic features.4 In normal skin, UVR is known to induce a transient state of

immunosuppression by depleting epidermal Langerhans cells and by promoting the release of immunosuppressive cytokines, including IL-4 and IL-10. In patients with PMLE, the immunosuppression normally associated with UVR is diminished substantially. It is thought that this creates an environment in which hypersensitivity responses to one or more photoinduced neoantigens is permissible. The notion that PMLE represents a DTH response is supported by histopathologic, molecular, and epidemiologic data. Histopathologic examination of biopsy specimens from lesions of PMLE induced by solar-simulated radiation demonstrates the consistent appearance within hours of a T-cell dominated perivascular infiltrate that peaks by 72 hours. CD4+ T cells are most numerous in early lesions, whereas by 72 hours CD8+ T cells predominate, perhaps abolishing the response.5 Increased

mitting some UVA and all visible light, may even have a PMLE-enhancing effect if exposure times are lengthened. There is most likely genetic predisposition to PMLE,19 but the intensity of initial UVR exposure may also be important in such predisposed individuals.

16

CLINICAL FEATURES History. PMLE usually

Abnormal Responses to Ultraviolet Radiation: Idiopathic

Figure 91-2  Polymorphic light eruption. Papular lesions of exposed sites.

::

has onset within the first three decades of life and affects females two to three times more often than males. It occurs in all skin types and racial groups, but is more common in Caucasians. A positive family history is present in about a fifth of patients.19 The typical PMLE eruption (Fig. 91-2) occurs each spring or on sunny vacations after the first substantial UVR exposure following a prolonged period with little exposure. It can also occur after recreational sunbed use or, very rarely, after exposure to visible light,18 and it often abates with continuing exposure. It is rare in winter except after extended outdoor recreational activities. Sufficient exposure may also occur through window glass. The threshold required to trigger PMLE varies from patient to patient and is usually from 30 minutes to several hours, although it may occur several days into a vacation. Lesions appear in hours to days following exposure, but usually in not less than 30 minutes. Patients may note itching as the first sign of an impending PMLE eruption. Once UVR exposure ceases, all lesions gradually resolve fully without scarring over one to several days, occasionally taking a week or two. In any given patient, PMLE outbreaks always tend to affect the same exposed sites. The distribution is generally symmetric. Only some of the exposed skin is usually affected, particularly skin that is habitually covered, and large areas may be spared. An apparent extreme example of PMLE is juvenile spring eruption,20 which tends to affect boys in the

Chapter 91

numbers of epidermal Langerhans cells and dermal macrophages are also present. Additionally, it has been demonstrated that neutrophil infiltration into the skin following UVB irradiation is deficient, leading to impaired IL-4 and IL-10 release.6 Whereas a Th2 cytokine milieu is favored in normal skin following irradiation, a Th1 cytokine profile is favored in patients with PMLE.7 Molecular studies have revealed increased intercellular adhesion molecule-1 expression on keratinocytes overlying the perivascular infiltrate in PMLE,8 as has been noted in DTH reactions but not in irritant contact dermatitis or after the UVB (290–320 nm) irradiation of normal skin.9 More recently, the induction of allergic contact sensitivity to dinitrochlorobenzene after solar-simulated irradiation of sensitization sites has been shown to occur more easily in PMLE patients than in normal individuals,10,11 which suggests that sensitization to a putative UVR-induced cutaneous antigen may also be easier during disease-inducing exposure. On the other hand, elicitation of allergic contact responses to dinitrochlorobenzene in previously sensitized PMLE patients and normal individuals were equally suppressed by irradiation,12 which explain the frequent development of immunologic tolerance, often called hardening or desensitization, as summer progresses or during prophylactic phototherapy. In fact, normalization in the depletion of epidermal Langerhans cells in response to UVR has been observed in patients with PMLE after undergoing therapeutic hardening.13 Finally, epidemiologic studies also point to hypersensitivity in patients with PMLE. The prevalence of PMLE is much lower in patients with skin cancer, suggesting that UVR-induced immunosuppression that may allow the persistence of malignant cells also inhibits hypersensitivity to photoantigens.14 Also, PMLE is quite uncommon in iatrogenically immunosuppressed transplant recipients, occurring in only 2% of this population.15 The photoinduced neoantigens that initiate PMLE have not been identified, but several molecules may play roles, even in a single patient. The altered molecule(s) itself may hypothetically become antigenic directly by UVR, or secondarily through UVR-induced free radicals that modify nonantigenic peptides in such a way that they become antigenic. Of course, both mechanisms may even take place simultaneously. UVA radiation (320–400 nm) usually seems more effective than UVB (290–320 nm)12,16 at initiating PMLE. In one study, UVA irradiation elicited the eruption successfully in 56% of patients exposed to UVA or UVB daily for 4–8 days, in 17% of those exposed to UVB, and in 27% of those exposed to both.17 However, other reports have suggested that UVB radiation may be implicated in up to 57% of patients. Therefore, it could broadly be said that approximately 50% of PMLE patients seem sensitive to UVB radiation and 75% to UVA, including in each case approximately 25% who are sensitive to both. Even visible light may be responsible on rare occasions.18 As a result, paradoxically, patients may note that the use of sunscreens, which tend preferentially to remove UVB while trans-

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Small papular PMLE, generally sparing the face and occurring after several days of continuing exposure, has been designated benign summer light eruption in Europe.22

LABORATORY TESTS Histology. The histologic features of PMLE are char-

Section 16

Figure 91-3  Polymorphic light eruption. Papulovesicular lesions on the arm.

:: Disorders Due to Ultraviolet Radiation

spring and is characterized by pruritic papules and vesicles on their ear helices, although typical PMLE sometimes coexists. Systemic symptoms in PMLE are rare, but malaise and nausea may occur.

Cutaneous Lesions. PMLE has many morphologic forms, all probably with similar pathogenesis and prognosis. The term “polymorphous” describes the variability in lesion morphology observed among different patients with the eruption. In fact, the lesions are usually quite monomorphous in an individual patient. Papular, papulovesicular (Fig. 91-3), plaque (Fig. 91-4), vesiculobullous, insect bite-like, and erythema multiforme-like forms have been described, and pruritus alone may even occur, albeit rarely.21 The papular form, characterized by large or small separate or confluent erythematous and edematous papules that generally tend to form clusters, is most common. Papulovesicular and plaque variants occur less frequently, and the other forms are rare. An eczematous form has been claimed but probably refers to mild chronic actinic dermatitis or photoexacerbated seborrheic or atopic dermatitis.

acteristic but not pathognomonic,23 and they vary with clinical presentation. There is generally a moderate to dense perivascular infiltrate in the upper and mid dermis in all forms. The infiltrate consists predominantly of T cells, with neutrophils and infrequent eosinophils. Other common features are papillary, dermal and perivascular edema with endothelial cell swelling. Epidermal change, not always present, may include variable spongiosis and occasional dyskeratosis, exocytosis, and basal cell vacuolization.

Blood Tests. Assessment for circulating antinuclear

antibodies (ANA) and extractable nuclear antibodies (ENA) is advisable to exclude subacute cutaneous or other form of cutaneous lupus erythematosus (LE), and, if there is uncertainty, red blood cell protoporphyrins should be assessed to exclude erythropoietic protoporphyria (EPP). Approximately 11% of patients with PMLE have been found to have a positive ANA, with the vast majority having insignificant titers of less than 1:160.24 An even smaller fraction (less than 1%) of patients with PMLE have anti-Ro antibodies.24 Clinical correlation is necessary in these patients to exclude the possibility of cutaneous LE.

Phototesting. Cutaneous phototesting with a monochromator confirms photosensitivity in up to half of cases,25 but usually does not differentiate PMLE from other photodermatoses. However, provocation testing with a solar simulator or other broadband source, sometimes repeated over 2 or 3 successive days, may induce the eruption, allowing a subsequent skin biopsy. This is most appropriate when the history and clinical features are not diagnostic. DIFFERENTIAL DIAGNOSIS. (See Box 91-1) COMPLICATIONS. A very few patients with PMLE may develop LE, as there is a higher than normal prevalence of prior PMLE in patients with LE.26 However, the presence of autoantibodies does not portend development of LE. Patients with PMLE may also experience significant disease-related psychosocial morbidity. The rate of both anxiety and depression in patients with PMLE are twice that of the general population, and these rates are similar to those observed in patients with psoriasis and atopic dermatitis.27 PROGNOSIS AND CLINICAL COURSE. Over 7 years, 57% of 114 patients reported steadily diminishing sun sensitivity, including 11% in whom the condition cleared.28

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Figure 91-4  Polymorphic light eruption. Variably sized itchy plaques on the cheek.

PREVENTION. PMLE may often be avoided by moderating sunlight exposure, wearing protective clothing,

and applying broad-spectrum high-protection-factor sunscreens regularly. Sunscreens with UVA and UVB protection may prevent PMLE eruptions in photoprovocable patients,29 but sunscreens without UVA protection are generally ineffective. Prophylactic phototherapy each spring or before sunny vacations tends to prevent attacks.

TREATMENT. The first goal in treating PMLE is to

A persistent variant of the sometimes coexistent polymorphic light eruption. Similar to the hereditary or familial variant of PMLE that affects native North and South Americans predominantly but which is usually more severe, persisting into adulthood. Prevention through avoidance of sunlight is the first line therapy; thalidomide or other immunosuppressive agents may be required.

PATHOGENESIS. AP appears to be UVR-induced in that it is more severe in spring and summer and often demonstrates abnormal skin phototest responses to UVB and/or UVA radiation.41 UVA is implicated more often than UVB.42 The cytokine TNF-α is overexpressed by keratinocytes in lesions of AP, creating a proinflammatory environment.40 Sunlight exposure and solar simulating irradiation may sometimes induce an eruption resembling PMLE in patients with AP, and many patients have close relatives with PMLE.19 A dermal, perivascular mononuclear cell infiltrate similar to that of PMLE may be seen in early lesions. Therefore, AP may be a slowly evolving, excoriated variant of PMLE, and thus also a DTH reaction. The human leukocyte antigen (HLA) DRB1*0407 (DR4) is found in 60%–70% of patients with AP but in only 4%–8% of normal DR4 positive controls.42 Additionally, HLA DRB1*0401 is found in approximately 20% of affected individuals.42 These immunogenetic features may well be responsible for modulating conventional PMLE into AP. In addition, in some patients, AP appears to transform into PMLE and, in others, PMLE appears to transform into AP,43 all of which suggests a relationship between the two disorders. The cutaneous UVR chromophores responsible for the eruption are not known, but they are likely to be diverse.

Abnormal Responses to Ultraviolet Radiation: Idiopathic

EPIDEMIOLOGY. Actinic prurigo (AP) occurs throughout much of the world. Native North and South Americans are particularly affected. The disease is estimated to occur in 2% of the Canadian Inuit population.39 In Mexico, AP is seen most commonly in the indigenous and Mestizo populations living at altitudes greater than 1,000 m.40 Less commonly, inhabitants of Europe, United States, Australia, and Japan are reported to develop AP.

Beginning in childhood, it may remit at puberty, exacerbate most often in summer, and fade in winter.

::

ACTINIC PRURIGO

A rare, persistent, pruritic and excoriated papular or nodular eruption of sun-exposed and, to a lesser extent, nonexposed skin.

Chapter 91

prevent it. As noted above, one should advise restricting midday sunlight exposure and employing frequent applications of broad-spectrum, high-protection sunscreens. If this is not fully effective, patients who have outbreaks only infrequently, such as on vacations, usually respond well to short courses of oral steroids that are prescribed and taken with them to use in the event of an eruption.30 If PMLE does develop, approximately 20–30 mg prednisone taken at the first sign of pruritus and then each morning until the eruption clears usually provides relief within several days, and recurrences are then uncommon during the same vacation. This treatment, if well tolerated, may be repeated safely every few months. More severely affected individuals who experience repeated attacks of PMLE throughout the summer may require prophylactic courses of low-dose photochemotherapy (psoralen and UVA radiation: PUVA) in the spring. This appears to be more effective than broadband UVB radiation, controlling symptoms in up to 90% compared to approximately 60% of cases.31 Narrowband (311-nm) UVB phototherapy, effective in 70%–80% of cases, is now probably the treatment of choice, because of ease of administration.32 Prophylactic PUVA or UVB irradiation may sometimes trigger the eruption, particularly in severely affected patients, in which case a brief course of oral steroid therapy is indicated. Various other therapies have also been tried but appear largely ineffective. These include hydroxychloroquine,33 which is perhaps occasionally useful; β-carotene,34 which is rarely effective; nicotinamide,35 which is usually ineffective; and ω-3 polyunsaturated fatty acids, which are perhaps of moderate assistance in some patients.36 A small percentage of patients remain who are unsuitable for, unable to tolerate, or not helped by any of these measures. For these patients, when severely affected, oral immunosuppressive therapy, usually intermittent, with azathioprine or cyclosporine can be helpful.37,38

ACTINIC PRURIGO AT A GLANCE

16

CLINICAL FEATURES History. AP occurs more commonly in females, with

a female to male ratio of about 2:1.42 The eruption has its onset in childhood, usually present by age 10 years.41 A positive family history of either AP or PMLE is present in about a fifth of patients.19 The eruption is often present all year round, but it is commonly worse in summer. Very rarely it is worse in winter or both spring and

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Section 16 :: Disorders Due to Ultraviolet Radiation

Figure 91-6  Cheilitis of actinic prurigo seen in a Mexican landscape gardener.

Figure 91-5  Actinic prurigo. Papules and nodules on the legs of a 15-year-old girl.

fall, with immunologic tolerance presumably developing during the summer. Exacerbations tend to begin gradually during sunny weather in general rather than after specific sun exposure, although PMLE-like outbreaks may also occur.

Cutaneous Lesions. The primary lesion of AP is a pruritic papule or nodule that occurs singly or in clusters (Fig. 91-5). Papules and nodules are often excoriated and crusted, and plaques may assume a lichenified or eczematous appearance. Vesicles are not seen unless superinfection is present.42 Sun-exposed areas are most often affected, particularly the forehead, chin, cheeks, ears, and forearms. There is a gradual fading toward habitually covered skin, and the sacral area and buttocks may be mildly affected. Lower lip cheilitis and conjunctivitis are also possible, particularly in Native Americans44 (Figs. 91-6, and 91-7). Healed facial lesions may leave dyspigmentation and sall pitted or linear scars.

Blood Tests. Assessment of ANA and ENA should be undertaken to exclude subacute cutaneous or other forms of cutaneous LE. The finding of HLA type DRB1*0401 (DR4) or DRB1*0407, especially the latter, supports the diagnosis of AP. Phototesting.

Cutaneous phototesting with a monochromator confirms light sensitivity in up to half of cases,41 but, as in PMLE, does not differentiate other photodermatoses. Most patients with positive monochromator testing have reduced minimal erythema doses (MED) in the UVA spectrum or in the combined UVA/UVB spectra.42 Provocation testing with a solar simulator or other broadband sources induces typical lesions of AP in about two-thirds of patients.42

DIFFERENTIAL DIAGNOSIS. (See Box 91-2)

LABORATORY TESTS Histology. Early papular lesions show changes similar

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to those of PMLE, namely, mild acanthosis, exocytosis, and spongiosis in the epidermis and a moderate lymphohistiocytic superficial and middermal perivascular infiltrate.23 A dense dermal lymphoid infiltrate and lymphoid follicles may be seen in lesions from the lip.40 In persistent lesions, however, excoriations, more acanthosis, variable lichenification, and a dense mononuclear cell infiltrate produce a nonspecific appearance.

Figure 91-7  Lip biopsy from a patient with actinic prurigo shows a dense lymphohistiocytic infiltrate as well as a lymphoid follicle in the lamina propria.

Box 91-2  Differential Diagnosis of Actinic Prurigo Most Likely Polymorphic light eruption Atopic eczema Photoexacerbated atopic or seborrheic eczema Insect bites Prurigo nodularis Always Rule Out Scabies

TREATMENT. In less severe cases of AP, sufficient relief may be achieved by restricting sun exposure and by using broad-spectrum, high-protection-factor sunscreens alone.47 Higher potency topical corticosteroids may be used to relieve the inflammation and pruritus associated with the disease. Phototherapy with narrowband UVB or PUVA may occasionally help,48 perhaps more reliably if the skin is cleared first with oral steroids. Topical tacrolimus or pimecrolimus may also help, again if the skin is cleared first. The treatment of choice in more severe or recalcitrant cases is thalidomide, with initial doses of 50–100 mg daily, preferably given intermittently. Responses to thalidomide are evident in most patients within several weeks. The most serious complication associated with thalidomide is teratogenicity, so pregnancy must be rigorously avoided. Other potential adverse effects are typically mild, including drowsiness, headache, constipation, and weight gain. An increased risk of thromboembolism and dose-related peripheral (mostly sensory) neuropathy are other potential adverse effects of thalidomide. In cases where thalidomide is unavailable or otherwise not appropriate, oral immunosuppressive therapy with azathioprine or cyclosporine may also be considered.

A rare, chronic, scarring photodermatosis sometimes associated with Epstein–Barr virus infection Characterized by recurrent sunlight-induced crops of papulovesicles and vesicles, most commonly on the face and dorsa of the hands. Onset commonly in childhood, remitting most often at puberty. May be a scarring variant of polymorphic light eruption. Focal intraepidermal vesiculation, reticular keratinocyte degeneration, epidermal and upper dermal necrosis, and sometimes ulceration are virtually pathognomonic histologic changes. Avoidance of ultraviolet radiation, including the use of broad-spectrum high-protectionfactor sunscreens, is the only established therapy. Prophylactic immunosuppressive phototherapy, administered with great care to avoid induction of new lesions, may help.

EPIDEMIOLOGY. Hydroa vacciniforme (HV) occurs in North America, Europe, Japan, and very likely elsewhere. However, its rarity and lack of universally acknowledged diagnostic criteria may make the diagnosis difficult to establish. ETIOLOGY AND PATHOGENESIS. The pathogenesis of HV is not known. No chromophores have been identified, and although UVB minimal erythemal dose responses are normal in most patients, some have increased UVA sensitivity.49 Blood, urine, and stool porphyrin concentrations are normal, as are all other laboratory tests. Nevertheless, its clear relationship to sunlight exposure, its distribution, and its early clinical appearances are all similar to that of PMLE, which suggests a relationship. On the other hand, fully developed HV eruptions are more severe than those found in PMLE, are associated with permanent scarring, and are unresponsive to treatments ordinarily effective in PMLE, apart perhaps from sunscreens and occasionally prophylactic phototherapy. Reports from Asia and Mexico have linked HV to chronic Epstein– Barr virus (EBV) infection,50,51 although a relationship

Abnormal Responses to Ultraviolet Radiation: Idiopathic

PREVENTION. Prevention begins by restricting midday sunlight exposure and the compulsive use of broad-spectrum sunscreens.46 In addition, topical calcineurin inhibitors tacrolimus and pimecrolimus may be effective in preventing recurrences in patients with previously documented disease. Of course, there is no known way to prevent its initial onset.

HYDROA VACCINIFORME AT A GLANCE

::

PROGNOSIS AND CLINICAL COURSE. AP commonly arises in childhood and often improves or resolves in adolescence, although persistence into adult life is possible. Persistent cases may assume features of PMLE in adulthood. More rarely, the disorder arises in adulthood and persists indefinitely.46

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Chapter 91

COMPLICATIONS. Mild scarring, especially on the face, and hypopigmentation may result from excoriations associated with AP. Additionally, two cases of primary cutaneous B-cell lymphoma arising on the face in patients with AP have been reported.45

HYDROA VACCINIFORME

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between EBV and HV in all populations has not been established. Japanese reports indicate that EBV nucleic acids are found in the cutaneous lesions of HV in 85%–95% of patients but not in lesional skin of control patients.51,52 A recent report from France has now provided substantial evidence that EBV infection persists in adult patients with HV and that it plays an important pathogenic role.53

CLINICAL FINDINGS History. HV commonly develops in early childhood

Section 16 :: Disorders Due to Ultraviolet Radiation

and resolves spontaneously by puberty, although, in some patients, it is lifelong. There is male predominance for severe forms, whereas milder disease is more common in females.49,54 Familial incidence is exceptional. One estimate of the prevalence of HV is 0.34 cases per 100,000 with an approximately equal sex ratio; males had a later onset and longer duration of the disorder than females.54 HV eruptions typically occur in summer,41 often with an intense burning or stinging sensation followed by the appearance of individual or confluent papules and then vesicles, all within hours of sunlight exposure (Fig. 91-8). This is followed by umbilication, crusting, and progression to permanent pock scarring within weeks. The eruption affects the cheeks and, to a lesser extent, other areas of the face as well as the backs of the hands and outer aspects of the arms. The distribution tends to be symmetrical.

Cutaneous Lesions. HV is characterized by initial erythema, sometimes with swelling, followed by symmetrically scattered, usually tender papules within 24 hours; vesiculation, occasionally confluent and hemorrhagic (Fig. 91-9); umbilication; then crusting and detachment of the lesions with permanent, depressed, hypopigmented scars within weeks. These scars are

Figure 91-9  Typical hydroa vacciniforme lesions provoked by repeated ultraviolet A irradiation.

invariably present. Oral ulcers and eye signs also occur rarely.55,56

LABORATORY TESTS Histology. Early histologic changes include intraepi-

dermal vesicle formation with subsequent focal epidermal keratinocyte necrosis and spongiosis. There is a dermal perivascular neutrophil and lymphocyte infiltrate.23 Older lesions show necrosis, ulceration, and scarring. Vasculitic features have been reported.49

Blood Tests. Blood, urine, and stool porphyrin con-

centrations should be assessed to exclude cutaneous porphyria, and an ANA and ENA to exclude the small possibility of cutaneous LE.

Phototesting.

Phototesting may show increased sensitivity to short-wavelength UVA in some patients, but phototesting usually does not discriminate HV from other photodermatoses. Simulated solar irradiation may also induce erythema at reduced doses or occasionally provoke the typical vesiculation of HV (see Fig. 91-7).

Other Tests. Viral studies for herpes infection or other viral disorders should be undertaken if photoexacerbation or photoinduction of these other disorders seems at all possible.

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Figure 91-8  Hydroa vacciniforme. Vesicular, bullous, and crusted facial lesions, which are precursors of vacciniform scars.

DIFFERENTIAL DIAGNOSIS. (See Box 91-3). There are reports of severe HV-like eruptions occurring in patients with chronic EBV infection and other associated disorders such as hypersensitivity to mosquito bites and the hemophagocytic syndrome. HVlike eruptions are distinguished from true HV by the development of lesions in both exposed and sun-protected skin and by the presence of systemic symptoms such as fever, hepatosplenomegaly, and wasting.51,57

Box 91-3  Differential Diagnosis of Hydroa Vacciniforme Photoexacerbated viral dermatoses such as herpes simplex Erythropoietic protoporphyria Polymorphic light eruption Subacute cutaneous lupus Xeroderma pigmentosum

A rare acquired persistent eczematous eruption of exposed skin, sometimes having pseudolymphomatous features. Commonly affects older men, but sometimes young atopic patients and rarely patients with hydroa vacciniforme or human immunodeficiency virus infection. Histologic features are eczematous, but pseudolymphomatous forms may be virtually indistinguishable from cutaneous T-cell lymphoma.

Pock scarring is an inevitable sequela of HV. Cases of severe HV-like eruption may progress to lymphoproliferative disease.

Persistent light reaction, actinic reticuloid, photosensitive eczema, and photosensitivity dermatitis are all considered clinical variants.

PROGNOSIS AND CLINICAL COURSE. HV often resolves in adolescence but may occasionally persist into adult life.

Very likely due to a delayed-type hypersensitivity reaction against an endogenous photoinduced epidermal antigen(s).

PREVENTION. Sun avoidance and sunscreen use, as well as prophylactic phototherapy annually in spring, tend to prevent HV in some patients. TREATMENT. Treatment of HV consists of restricting sunlight exposure and use of high-protection-factor broad-spectrum sunscreens. Occasionally, antimalarials appear to have helped, but their true value has not been established. As with PMLE, prophylactic phototherapy with narrowband UVB or PUVA, particularly the latter, may be helpful but must be administered with care to avoid disease exacerbation.49,53,61 If conservative measures are ineffective, however, as often occurs, topical or intermittent oral steroids, topical calcineurin inhibitors, or even oral immunosuppressive medication may be tried if clinically appropriate, though these agents too are usually ineffective. In patients with chronic EBV infection, antiviral therapy with acyclovir and valacyclovir was reported in a small series of patients to reduce the frequency and severity of eruptions.62 CHRONIC ACTINIC DERMATITIS EPIDEMIOLOGY. Chronic actinic dermatitis (CAD) has regularly been diagnosed in Europe, North America, Africa, Australia, New Zealand, Japan, and India. The disorder therefore appears to have worldwide distribution, affecting all skin types, although it is perhaps more common in temperate regions.

Therapy consists of strict avoidance of ultraviolet radiation, along with topical and intermittent oral steroids, topical calcineurin inhibitors, or prolonged lowdose immunosuppressive phototherapy. Oral immunosuppression with cyclosporine or azathioprine is often required.

ETIOLOGY AND PATHOGENESIS. Studies of the clinical, histologic, and immunohistochemical features of CAD all show it to resemble the DTH reaction of allergic contact dermatitis,73–75 even in its severe pseudolymphomatous form (formerly called actinic reticuloid), in which the clinical and histologic features duplicate those seen in long-standing allergic contact dermatitis.76 It is therefore highly probable that CAD is an allergic reaction. In addition to hypersensitivity to cutaneous photoantigens, patients with CAD often have concomitant allergic contact dermatitis to airborne or other ubiquitous allergens, including plant compounds, fragrances, and medicaments.77 Commonly implicated allergens include sesquiterpene lactone from plants of the Compositae family and sunscreens. A recent study indicates that sesquiterpene lactone remains the most common allergen in patients with CAD, with positive and clinically relevant photopatch testing to this allergen documented in approximately 20% of patients.78

Abnormal Responses to Ultraviolet Radiation: Idiopathic

COMPLICATIONS.

::

Ordinarily induced by small amounts of ultraviolet B radiation, often with ultraviolet A radiation, and sometimes even visible light; in rare cases, induced by UVA radiation or visible light alone.

Chapter 91

The distinction between an HV-like eruption and true HV is important because patients with a severe HVlike eruption may rarely go on to develop potentially fatal hematologic malignancy.56–59 Finally, a recent quality-of-life study indicates that HV causes embarrassment and self-consciousness among children with the disease.60 The negative impact of HV on quality of life exceeds previously reported indices for atopic dermatitis and psoriasis.60

CHRONIC ACTINIC DERMATITIS AT A GLANCE

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TABLE 91-2

Original Criteria for the Eczematous Photosensitivity Disorders

Section 16 :: Disorders Due to Ultraviolet Radiation

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Persistent light reaction62: Eczema of predominantly light-exposed skin sensitive to UVB ± UVA following acute photoallergic contact dermatitis Actinic reticuloid63: Infiltrated papules and plaques of mainly light-exposed skin with lymphoma-like histologic features and sensitivity to UVB + UVA ± visible light; negative results on photopatch testing Photosensitive eczema64: Morphologic and histologic eczema of mainly light-exposed skin with photosensitivity only to UVB; negative results on photopatch tests Photosensitivity dermatitis65: Morphologic and histologic eczema of mainly light-exposed skin with photosensitivity to UVB ± UVA; positive results on photopatch testing in some of the patients Chronic actinic dermatitis66: Syndrome encompassing photosensitive eczema, photosensitivity dermatitis, and actinic reticuloid; persistent light reaction also now included UVA = ultraviolet A radiation; UVB = ultraviolet B radiation.

In addition, cc has emerged as an increasingly common antigen in CAD78 as has balsam of Peru.79 When CAD occurs in the absence of an obvious epicutaneous contact allergen, the relevant novel antigen must be either directly radiation-induced or formed indirectly as a result of secondary oxidative metabolism. Important support for the latter possibility comes from the fact that albumin can become antigenic in vitro through photooxidation of its histidine moieties.80 There is no evidence for a genetic susceptibility to CAD; however, one stimulus for the acquisition of skin reactivity may be concurrent allergic contact dermatitis to recognized exogenous sensitizers or photosensitizers,81,82 often airborne, which may predispose by altering cutaneous immunity, and thus permitting immunological recognition of an endogenous photoantigen. Long-standing endogenous eczema,68,69,83,84 drug-induced photosensitivity,85 human immunodeficiency virus infection,86 and possibly PMLE75 may also play similar roles. On the other hand, in addition or instead, chronic photodamage in frequently sun-exposed elderly outdoor enthusiasts, those who most often develop CAD,75 may impair normal UVR-induced skin immunosuppression sufficiently for endogenous UVR-induced photoantigens to be recognized, as apparently also occurs for genetic reasons in PMLE.19 Clearly, there is much work left to be done to identify the immunologic mechanisms that account for CAD. Determining the action spectrum for CAD should theoretically help identify the postulated antigens, and the action spectra for CAD have been shown to resemble that of sunburn in many patients.87 However, the eruption in CAD is eczematous, and much lower doses of UVR are required to evoke CAD than to produce erythema. In any event, the UVR chromophore for some patients may be the same as that of sunburn, namely DNA,87 with UVR-damaged DNA serving directly as an antigen in CAD. In other patients with

CAD, however, the photoallergen must be different, because these patients react only to UVA radiation,88 and some patients react only to visible light.89 In summary, CAD appears to be an allergic contact dermatitis-like reaction against UVR-altered DNA or similar or associated molecules, perhaps as a result of enhanced immune reactivity due to concomitant airborne contact dermatitis or a reduced immunosuppressive capacity in photodamaged skin. The eruption occurs most often in patients with long-standing exposure to sunlight and airborne contact allergies.

CLINICAL FEATURES History. CAD may arise

de novo in apparently normal skin or in the skin of patients with previous endogenous eczema, photoallergic or allergic contact dermatitis, or rarely PMLE.75,90 Concurrent allergic contact sensitivity to plant allergens, fragrances, or sunscreens is common.82 The condition usually affects middle-aged or elderly men,75 as CAD is rarely seen in patients under 50 years of age, except for those with prior atopic eczema.83,84 The disorder is worse in summer, developing within minutes to hours after sunlight exposure and producing a pruritic confluent erythematous eruption that occasionally remits over several days with scaling, if exposure ceases and if the reaction is mild. However, severely affected patients frequently do not even recognize that exacerbations are related to sunlight exposure, especially when affected all year round.

Cutaneous Lesions. The lesions of CAD are eczematous, patchy or confluent, and acute, subacute, or chronic (Figs. 91-10 and 91-11). In severe cases, lichenification is common. Less commonly, scattered or widespread erythematous, shiny, infiltrated pseudolymphomatous papules or plaques are present on a background of erythematous, eczematous,

Figure 91-10  Chronic actinic dermatitis. Infiltrated eczematous eruption on the face.

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B

Chapter 91 ::

Figure 91-11  Chronic actinic dermatitis. A, B. Severe lightinduced eczema of the face and neck. C, D. Patient in full remission after low-dose psoralen plus ultraviolet A irradiation over weeks, with initial high-dose oral steroid cover to prevent initial exacerbation. or normal skin.75 Habitually exposed areas are most often affected, commonly with sharp cutoff at lines of clothing. There is sparing of deep skin creases, upper eyelids, finger webs, and skin behind the earlobes. In severe disease, eczema of the palms and soles may also be found. Eyebrows, eyelashes, and scalp hair may be stubbly or altogether lost from constant rubbing and scratching. Erythroderma, usually but not always accentuated on exposed sites, supervenes rarely. Variable, sometimes geographic, sparing of exposed areas of the face or elsewhere, as well as irregular hyperpigmentation and hypopigmentation, sometimes vitiligolike,91 may also occasionally be found.

LABORATORY TESTS Histology. Histologic features

include epidermal spongiosis and acanthosis, sometimes with hyperplasia. There is usually a predominantly perivascular lymphocytic cellular infiltrate confined to the upper

C

D

Abnormal Responses to Ultraviolet Radiation: Idiopathic

A

dermis that in milder cases may resemble chronic eczema.23 Severe CAD, however, may mimic cutaneous T-cell lymphoma (CTCL), on occasion being virtually indistinguishable. Features mimicking CTCL include epidermal Pautrier-like microabscesses and deep, dense epidermotropic mononuclear cell infiltration, sometimes with atypia. Typically, there is no marked increase in mitoses. T-cell receptor gene rearrangement studies should be undertaken if there is suspicion of CTCL. However, T-cell receptor clonality may also be observed in benign dermatoses.

Blood Tests. Assessment of the ANA and ENA is

advisable in all patients to exclude the unlikely possibility of cutaneous LE. In severe or erythrodermic CAD, there may be large numbers of circulating CD8+ Sézary cells without other suggestions of malignancy.92,93 Human immunodeficiency virus status should be assessed if there is suspicion that this may be a predisposing factor.86 Serum IgE may be elevated,

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with higher levels of IgE correlating with more severe disease.79

Phototesting. Phototesting is essential, if available,

Section 16

to confirm the diagnosis of CAD. Almost invariably one finds low erythemal thresholds and eczematous or pseudolymphomatous responses after irradiation with UVB, usually with UVA, and rarely with visible wavelengths.75 A small number of patients react only to UVA,88 and fewer still only to visible light,89 in which case, drug photosensitivity must be excluded. Testing should be done on uninvolved skin of the back with no topical or systemic steroid therapy for at least the preceding few days to avoid false-negative results.94 Monochromatic and broad-spectrum sources both induce abnormal responses, with the former determining the action spectrum for disease induction and the latter tending to demonstrate acute eczema.

:: Disorders Due to Ultraviolet Radiation

Patch and Photopatch Testing. Patch and photopatch testing is also essential in suspected CAD, because contact sensitivity to airborne allergens such as Compositae oleoresins, phosphorus sesquisulfide, and colophony alone may resemble CAD or even coexist. In addition, occasional secondary contact or photocontact sensitivity to sunscreens or other topical therapies may complicate the clinical picture further. Positive results with photopatch testing are found in approximately 80% of patients.78,79 DIFFERENTIAL DIAGNOSIS. (See Box 91-4) COMPLICATIONS. A relationship to CTCL seems likely to be coincidental, especially because results of T-cell receptor, immunoglobulin gene rearrangement, and other studies are negative in CAD.92,95,96 In addition, CAD gradually resolves in many patients, there is no higher incidence of malignancies, and life expectancies are thought to be normal.97 However, CTCL itself may present very rarely with severe CAD-like photosensitivity, and careful investigation to exclude CTCL is necessary when the disease suspected.98 PROGNOSIS AND CLINICAL COURSE. Once established, CAD usually persists for years before resolving gradually.98 TREATMENT.

Treatment of CAD is often difficult and not fully effective. Rigorous avoidance of UVR and exacerbating contact allergens is essential, along with regular application of high protection-factor broad-spectrum topical sunscreens of low irritancy

Box 91-4  Differential Diagnosis of Chronic Actinic Dermatitis

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Photoexacerbated atopic or seborrheic eczema Drug or chemical photosensitivity Cutaneous T-cell lymphoma Eczematized actinic prurigo

and allergenic potential. Strong topical steroids such as clobetasol propionate are also often needed and frequently produce marked symptomatic relief without adverse effects, even after long-term use, if confined to affected skin. Occasional oral steroid use is often helpful for disease flares. In more resistant disease, the topical calcineurin inhibitors—tacrolimus and pimecrolimus—sometimes produce good results if tolerated.99,100 For refractory CAD, however, oral immunosuppressive therapy is almost always necessary and generally helpful if tolerated. Azathioprine 1.5–2.5 mg/ kg/day often produces remission in months,101 after which it may be reduced in dosage, or perhaps discontinued in the winter. Cyclosporine 3.5 to 5.0 mg/kg/ day is usually rapidly effective,102 but is more likely to produce adverse effects, which sometimes necessitate withdrawal. Mycophenolate mofetil is less often useful. Finally, long-term low-dose phototherapy with PUVA, usually several times weekly initially followed by maintenance exposures about every 3 weeks may be helpful,103 generally accompanied initially by oral and topical steroid therapy to avoid disease flares.

PREVENTION. The risk of CAD can probably be reduced by moderating outdoor pursuits, especially those associated with plant allergen exposure such as gardening, even more so for individuals who already have a tendency to develop eczematous eruptions in exposed areas. Avoidance of UVR is critical, and patients should be aware that indoor lighting may also be a source of UVA exposure. Compact fluorescent lamps even emit UVR at wavelengths as low as 254 nm, and some patients with CAD appear to be susceptible to disease flares after exposure to such lamps.104 SOLAR URTICARIA EPIDEMIOLOGY. Solar urticaria (SU) has been reported in Asia, Europe, and the United States, and, thus, probably occurs worldwide. Perhaps 3 per 100,000 are affected.105 Ultraviolet and visible radiation are causes of this form of urticaria, but SU accounts for less than 0.1% of all cases of chronic urticaria.106 ETIOLOGY AND PATHOGENESIS. Primary SU is an immediate type I hypersensitivity response against a cutaneous or circulating photoallergen(s) generated from a precursor at the time of irradiation. Both circulating photoallergens and relevant IgE antibodies have been demonstrated. This has been termed primary SU, for which no genetic basis has been identified. Very rarely, SU may occur in association with drug photosensitivity, such as chlorpromazine and coal tar,106 cutaneous porphyria, or LE. This has been termed secondary SU. Two types of primary SU have been proposed, both involving immunoglobulin E-mediated hypersensitivity against a neoantigen that is photoinduced. In type 1, the photoallergen is the chromophore, which is generated only in patients with SU. Type 2 is mediated by circulating antibodies found only in patients and

SOLAR URTICARIA AT A GLANCE An uncommon sunlight-induced whealing disorder that occurs more often in females. Rarely is secondary to phototoxic drug use or with cutaneous porphyria. Onset within 5 to 10 minutes of sunlight exposure. Resolves in an hour or two; may be disabling and, rarely, life threatening.

Clinical and histologic features are those of urticaria.

Sunlight avoidance prevents solar urticaria, and high protection-factor broad-spectrum sunscreens and antihistamines may help. When necessary, phototherapy, plasmapheresis, or oral immunosuppressive drugs may be helpful in management.

directed against a common chromophore-generated antigen.106 The wide range of inducing wavelengths is attributed to the unique action spectra of different photoallergens (chromophores). Patients with type 1 SU appear to have photoallergens of molecular mass 25–34 kilodaltons (kDa) and action spectra within the visible region, whereas type 2 SU has photoallergens of 25–1,000 kDa and variable action spectra.107 The range of eliciting wavelengths can narrow or broaden over months or even years, suggesting that the relevant choromophores may vary over time. Exposure to visible or UVA irradiation before, during, or after the urticaria-inducing irradiation inhibits whealing in some patients, possibly by inactivation of the initial photoproduct or the inhibition of subsequent reactions.108,109

skin with an initial macular erythema, followed by whealing and a surrounding patchy erythematous flare (Fig. 91-12), often with clear demarcation at lines of clothing. Rarely, there is sparing of the face and hands, perhaps as a result of UVR-induced tolerance. In some patients, specific sites may be affected repeatedly.

LABORATORY TESTS Histology. There is dermal

vasodilation, edema, and predominantly perivascular neutrophil and eosinophil infiltration at 5 minutes and at 2 hours, but not 24, hours.23 Endothelial cell swelling occurs early on, with mononuclear cell infiltration later following higher irradiation doses. Extensive eosinophil granule major basic protein deposition is also present in the dermis at 2 and 24 hours, which suggests eosinophil degranulation.113 Histologic features do not distinguish SU from other causes of urticaria.

Abnormal Responses to Ultraviolet Radiation: Idiopathic

Sensitivity may be to ultraviolet B, ultraviolet A, visible light, and/or any combination, but most commonly to ultraviolet A and visible light.

Cutaneous Lesions. SU usually affects all exposed

::

Phototesting may confirm the diagnosis and identify the action spectrum.

16

Chapter 91

An immediate type I hypersensitivity response against a cutaneous or circulating photoallergen(s).

other photosensitive skin disorders more often than expected.110 Typically, 5–10 minutes or, rarely, 20–30 minutes of exposure leads to itching and erythema, followed by patchy or confluent urticarial whealing, with gradual resolution within 2 hours. Rarely, patients report itching alone, and the onset of symptoms may be delayed for up to several hours.111 A rare variant termed “fixed solar urticaria” has been reported and is characterized by urticarial lesions that are induced repeatedly in the same location.112 In patients with mild disease, or in those who quickly recognize their SU onset and avoid further exposure, whealing may not be reported, even if it may be elicited during phototesting. Patients having extensive whealing may also describe headache, nausea, bronchospasm, and syncope, which rarely may be life threatening. Angioedema and anaphylaxis are exceedingly rare but have been reported. Secondary SU should be excluded by ruling out drug photosensitivity, cutaneous porphyria, and LE.

Clinical Features History. Primary SU is

slightly more common in females and may arise at any age, although most patients develop the disease in childhood or young adulthood.106 The first episode typically occurs after prolonged sunlight exposure or occasionally following tanning bed use. It also seems to be associated with

Figure 91-12  Solar urticaria. Pruritic wheals with a surrounding patchy flare occurring within 15 minutes of sun exposure after irradiation of the patient’s back through a template.

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Blood Tests.

Tests for an ANA and ENA should be employed to exclude cutaneous LE, as should the blood, urine, and stool porphyrins to exclude cutaneous porphyria.

Phototesting.

Section 16 ::

Phototesting with a monochromator, broad-spectrum source, or sunlight allows confirmation of the diagnosis of SU and identification of the inducing wavelengths. However, negative phototest results do not exclude the disorder, because the ease of SU induction, particularly when mild, may vary. If no monochromator is available, appropriately filtered broadband sources can be used, and minimal urticarial dose estimation may help in assessing treatment efficacy. Patients with SU may have a biphasic response to phototesting whereby wheals develop in response to one action spectrum but are inhibited by another action spectrum.114 Most commonly, shorter wavelengths induce wheals on phototesting while longer wavelengths may inhibit wheal formation.114

Disorders Due to Ultraviolet Radiation

DIFFERENTIAL DIAGNOSIS. (See Box 91-5) COMPLICATIONS. Severe primary SU may lead to

anaphylactic shock, which is rarely fatal. The rare secondary SU related to drug or chemical photosensitivity, cutaneous porphyria, or cutaneous lupus may be associated with the complications of the primary conditions.

COURSE AND PROGNOSIS. SU often persists indefinitely, sometimes with deterioration but also sometimes with improvement, with the probability of clinical resolution at 5, 10, and 15 years of 12%, 26%, and 46%, respectively.105,106 TREATMENT. Restricting sun exposure and using high protection-factor broad-spectrum sunscreens and appropriate clothing may be helpful in preventing SU. Sunscreens with UVA and UVB protection effectively increase the minimal urticarial dose on phototesting.115 Antihistamines have been demonstrated to suppress wheal and itch formation in patients with SU, and, when combined with sunscreens, the increase in UV tolerance may be remarkable.115 Phototherapy may be helpful in those patients who commonly develop SU tolerance as summer advances and also sometimes Box 91-5  Differential Diagnosis of Solar Urticaria (SU) Polymorphic light eruptiona Subacute cutaneous lupusa,b Photoexacerbated dermatoses such as atopic or seborrheic eczema Erythropoietic protoporphyriab Hepatic porphyriasb Drug or chemical photosensitivityb a

Rarely may coexist with SU. A rare cause of secondary SU.

b

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in those with persistent disease. Unfortunately, phototherapy usually needs to be continued to maintain its effect, and, consequently, carries the usual risks of long-term phototherapy. In addition, phototherapy should be undertaken with caution early on to avoid the risk of anaphylaxis, particularly in severely affected individuals.113 Multiple UVA exposures with increasing doses during the same day (so-called rush hardening) have helped some patients.116 Others with recalcitrant disease have been reported to respond to plasma exchange, or plasmapheresis, particularly if they are found to have circulating SU-associated serum factors; these remissions may be long-lived.117,118 Intravenous immunoglobulin has also been helpful on occasion,119 as has oral cyclosporine. Partial improvement has recently been reported with omalizumab, a monoclonal antibody directed against IgE.120

PHOTOEXACERBATED DERMATOSES Several dermatoses that are not caused by UVR may be worsened by it (Table 91-3). Mechanisms of this phenomenon, termed photoexacerbation, have rarely been studied. The initial condition may be severely worsened even if it was originally only mild or subclinical.121,122 These disorders are relatively common and account for a significant percentage of all photodermatoses. Such conditions, especially the eczemas, psoriasis, and acne, improve with UVR exposure in most patients, perhaps because cutaneous reactivity is reduced, but in a small proportion of individuals, it is instead aggravated. If photoexacerbation does occur, the new eruption generally develops or worsens initially at sites typical of the basic disorder (Fig. 91-13), followed at times by extension to other areas. In photoexacerbated

TABLE 91-3

Selection of Diseases Sometimes Exacerbated by Ultraviolet Irradiation Acne Atopic eczema Carcinoid syndrome Cutaneous T-cell lymphoma Dermatomyositis Disseminated superficial actinic porokeratosis Erythema multiforme Familial benign chronic pemphigus (Hailey–Hailey disease) Keratosis follicularis (Darier disease) Lichen planus Lupus erythematosus Pellagra Pemphigus foliaceus (erythematosus) Pityriasis rubra pilaris Psoriasis Reticulate erythematous mucinosis syndrome Rosacea Seborrheic eczema Transient acantholytic dermatosis (Grover disease) Viral infections

CLINICAL FEATURES Patients with abnormal photosensitivity present in three ways: (1) sporadic or (2) persistent eruptions in sunlight-exposed areas, or, infrequently, (3) erythroderma. When sporadic, the patient usually considers sunlight exposure to be responsible; when persistent, the physician often must identify the association. However, careful history taking is essential, first to confirm that sunlight exposure is responsible and then to make

Abnormal Responses to Ultraviolet Radiation: Idiopathic

APPROACH TO THE PATIENT WITH ABNORMAL SKIN PHOTOSENSITIVITY

::

seborrheic eczema, however, an unpleasant sensation at the exposed sites may be the first or only feature. Treatment consists of minimizing UVR exposure, protection with suitable clothing, application of high protectionfactor broad-spectrum sunscreens, and careful treatment of the underlying disorder. Taking these steps alone, frequently, if perhaps surprisingly, even may abort the photosensitivity.121 If these actions are inadequate, low-dose phototherapy, as for PMLE, can sometimes help, for example, in seborrheic or atopic eczema and psoriasis, but its use is contraindicated in cutaneous LE or dermatomyositis, in which aggravation of the systemic disease is a risk. Photoexacerbated acne commonly requires treatment with oral isotretinoin. Individual diseases for which photoexacerbation may occur are discussed in more detail in the online sections of this chapter include the disorders many of the disorders in Table 91-3.

16

Chapter 91

Figure 91-13  Photo-exacerbated seborrheic dermatitis, affecting the face only at sites of predilection for the seborrheic eruption.

a diagnosis. Information of considerable importance are age at disease onset, gender, family history, previous sunlight sensitivity, occupation, leisure pursuits, and systemic and topical drug (or chemical) use. Additional relevant details include distribution of lesions, effects of season, exposure times required for induction, time between exposure and the appearance of lesions, duration of the eruption after exposure ceases, effects of sunlight received through window glass (implicating UVA and visible light), presence of systemic symptoms, and patient-assessed morphologies (progression of the disease before the clinic visit). In terms of age and sex, young woman are more likely to develop PMLE; women or girls more commonly develop AP; children of either gender may have HV, xeroderma pigmentosum (XP), or EPP; elderly men or younger individuals with a history of eczema most often develop CAD. A family history of sunlight sensitivity may be present in patients with PMLE, AP, XP, and the porphyrias. CAD is more common in outdoor enthusiasts exposed to both sunlight and airborne allergens, although exacerbations of disease, despite sunscreen use, invoke the possibility of sunscreen allergy. On the other hand, exacerbations with sunscreens may even occur in the absence of allergy in PMLE. An eruption appearing in minutes and remitting within 2 hours suggests SU or occasionally photosensitivity to drugs, such as amiodarone. Onset within 20 minutes to several hours, with resolution over days suggests PMLE, HV, EPP, cutaneous LE or other photoexacerbated dermatoses, or other drug photosensitivities, such as to thiazides. Systemic malaise is uncommon in PMLE, HV, and SU. Development of lesions after exposure through window glass suggests an inducing spectrum that includes UVA, although it may occur in virtually all of the photodermatoses. The eruption described by patients with PMLE is generally that of small or large, elevated, pruritic, red or skin-colored, and often clumped spots of blisters, sometimes confluent, that usually involve several, but not all exposed sites. In HV, blistering with scar formation occurs, and in SU, elevated pruritic wheals are often confluent. In EPP and amiodarone drug photosensitivity, a marked burning sensation, without visible change, has been reported. In EPP, relatively lengthy exposure may lead to firm, colorless or pink, diffuse swelling, rarely with scattered blisters. In most drug photosensitivity reactions and in XP, an exaggerated sunburn-like reaction is possible, which is often maximal in XP at 2–3 days. Finally, in photoexacerbated dermatoses, the eruption resembles that of the primary disorder. Photosensitivity eruptions are usually present on some, and occasionally all, of the forehead, nose, upper cheeks, tip of the chin, rims of the pinnae, back and sides of the neck, upper chest, backs of the hands and feet, and extensor aspects of the limbs. Covered areas may also be involved, but to a lesser extent. On the other hand, portions of the face protected by hair or customarily shown in shadow such as upper eyelids, finger webs, skin creases and skin under the nose, lower lip, chin, and earlobes are frequently unaffected, except when there is associated airborne contact dermatitis.

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Excoriated papules suggest AP, whereas eczematous lesions, or very rarely light-associated erythroderma, suggest CAD or photoexacerbated atopic or seborrheic eczema. Finally, skin fragility, bulla formation, and atrophic superficial scarring suggest hepatic porphyria or pseudoporphyria, especially if there has been drug or excessive alcohol intake. Clinical appraisal along with the history usually results in a diagnosis, although for complete certainty, several of the studies listed below may be appropriate.

LABORATORY STUDIES Section 16 :: Disorders Due to Ultraviolet Radiation

If the diagnosis is not certain, appropriate additional studies include an assessment of the ANA and ENA. If present at significant titers, cutaneous LE should be considered. In addition, examination of blood, urine, and stools for porphyrins should be considered. Biopsies may be helpful. Lesional histologic features are characteristic in several photodermatoses, especially PMLE, HV and CAD. However, with the exception of HV, histopathologic changes in photodermatoses are rarely entirely diagnostic. These are reviewed in the preceding disease descriptions. Phototesting of normal back skin with a monochromator in CAD and SU often produces the papules or wheals of the condition itself, frequently at low irradiation doses, and this also may identify the action spectrum. Phototesting also helps to confirm XP through the delayed development of erythema over 2–3 days, with an abnormally low-dose threshold, often eventuating in blister formation (Table 91-4). In eczematous photosensitivity, patch and photopatch testing are also essential to identify relevant allergens. Finally, special techniques such as the assessment of DNA excision repair or of RNA synthesis recovery rate in cultured fibroblasts after UVR exposure are essential for the diagnoses of certain genophotodermatoses.

PHOTOTESTING. Techniques of phototesting vary greatly from country to country and from center to center. Although it is the investigational technique of choice for photodermatoses when the diagnosis is uncertain or when details of the inducting action spectrum are

required, it remains primarily a research tool employed in a limited number of clinical centers. The cost of the equipment and its infrequent use in most clinical practices means that patients should be referred for consultation to such centers whenever indicated. Phototesting falls into two categories: (1) Monochromatic phototesting, usually of the upper back with selected wavelengths and selected doses to identify the action spectrum for the disorder and (2) photoprovocation with a broad-spectrum source to induce the eruption for its clinical appearance and subsequent biopsy if indicated. Table 91-4 lists the disorders for which monochromatic testing may be helpful. For precise characterization of the wavelength dependency of a disorder, monochromatic testing, preferably with a xenon arc irradiation monochromator, should be employed. For photoprovocation, the favored device is a solar simulator, usually a xenon arc-filtered source that produces a spectrum that resembles the terrestrial sunlight spectrum at noon on a midsummer’s day in temperate regions of the world. Keep in mind that the terrestrial spectrum at noon in June varies considerably between Iceland and Kenya, as it also does between high elevations and sea level. Several suitable protocols have also been described for using simple broad-spectrum metal halide or fluorescent light sources with filters if necessary. In some parts of the world, sunlight with filters has also been used, although this method is generally too unpredictable for clinical use.148,149 The mainstay of phototesting is a monochromator. It is composed of a high-pressure xenon arc source that emits radiation along a pathway incorporating a diffraction grating angled to produce the required waveband at the exit slit. Such equipment needs regular calibration of output and wavelength. Because even large centers cannot always afford such equipment, lesser alternatives have been created, for example, metal halide or fluorescent light sources of sufficient output intensity. With such sources, the UVB, UVA, and visible light components of patient photosensitivity can be studied, based on deviation from normal erythemal reactions throughout the UVR spectrum. Monochromatic phototesting is preferably performed on unaffected skin of the upper back, lateral

TABLE 91-4

Usual Monochromatic Phototest Responses in Idiopathic, Probably Immunologic Photodermatoses

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Disease

Action Spectrum

Frequency of Abnormal Findings

Polymorphic light eruption

UVA more often than UVB

Only sometimes

Actinic prurigo

UVA more often than UVB

Only sometimes

Hydroa vacciniforme

More often UVA

Only sometimes

Chronic actinic dermatitis

UVB ± UVA ± visible light

Virtually always

Solar urticaria

UVB, UVA, or visible, or combination

Usual

Xeroderma pigmentosum

UVB

Usual

Photoexacerbated dermatoses

UVB, UVA, or combination

Rare

UVA = ultraviolet A radiation; UVB = ultraviolet B radiation.

16

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

Abnormal Responses to Ultraviolet Radiation: Idiopathic

1. Rhodes LE et al: Polymorphic light eruption occurs in 18% of Europeans and does not show higher prevalence with increasing latitude: Multicenter survey of 6,895 individuals residing from the mediterranean to scandinavia. J Invest Dermatol 130(2):626-628, 2010 [Epub Aug 20, 2009] 6. Wolf P et al: New insights into the mechanisms of polymorphic light eruption: Resistance to ultraviolet radiation-induced immune suppression as an aetiological factor. Exp Dermatol 18:350, 2009 9. van de Pas CB et al: Walker SL: Ultraviolet-radiationinduced erythema and suppression of contact hypersensitivity responses in patients with polymorphic light eruption. J Invest Dermatol 122:295, 2004 10. Palmer RA, Friedmann PS: Ultraviolet radiation causes less immunosuppression in patients with polymorphic light eruption than in controls. J Invest Dermatol 122:291, 2004 19. McGregor JM et al: Genetic modeling of abnormal photosensitivity in families with polymorphic light eruption and actinic prurigo. J Invest Dermatol 115:471, 2000 23. Hawk JLM, Calonje E. The photosensitivity disorders. In: Lever’s Histopathology of the Skin, 9th ed, edited by DE Elder et al. Philadelphia, Lippincott Williams & Wilkins, 2005, p. 345 27. Richards HL et al: Evidence of high levels of anxiety and depression in polymorphic light eruption and their association with clinical and demographic variables. Br J Dermatol 159:439, 2008 41. Hönigsmann H, Hojyo-Tomoka MT. Polymorphic light eruption, hydroa vacciniforme, and actinic prurigo. In: Photodermatology, edited by HW Lim, H Hönigsmann, JLM Hawk. New York, Informa Healthcare, 2007 p. 149 43. Grabczynska SA, McGregor JM, Kondeatis E, Vaughan RW, Hawk JL: Actinic prurigo and polymorphic light eruption: common pathogenesis and the importance of HLA-DR4/DRB1*0407. Br J Dermatol 140:232, 1999 60. Huggins RH et al: Quality of life assessment and disease experience of patient members of a web-based hydroa vacciniforme support group. Photodermatol Photoimmunol Photomed 25:209, 2009 75. Hawk JLM, Lim HW: Chronic actinic dermatitis. In: Photodermatology, edited by HW Lim, H Honigsmann, JLM Hawk. New York, Informa Healthcare, 2007 p. 169 120. Waibel KH et al: Partial improvement of solar urticaria after omalizumab. J Allergy Clin Immunol 125:490, 2010 142. Orteu CH, Sontheimer RD, Dutz JP: The pathophysiology of photosensitivity in lupus erythematosus. Photodermatol Photoimmunol Photomed. 17:95, 2001 148. Neumann NJ, Lehmann P. Photodiagnostic modalities. In: Dermatological Phototherapy and Photodiagnostic Method, edited by J Krutmann et al. Berlin, SpringerVerlag, 2001, p. 329 150. Bruynzeel DP et al: Photopatch testing: A consensus methodology for Europe. J Eur Acad Dermatol Venereol 18:679, 2004

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PHOTOPATCH TESTING. (See Chapter 92.) Photopatch testing is an established investigational tool designed to identify photoallergic contact dermatitis, although it can also be employed to help identify phototoxic agents. It is essentially a more complex version of patch testing, and it is used in patients with exposed-site eczema, whether or not they also have another photodermatoses, to determine whether photoallergy is also present. The methodology of photopatch testing has received less attention than allergen testing or phototesting, as it resides between the two specialty areas of photodermatology and contact dermatology. However, consensus methodology is now available.150 Using this approach, test materials (usually sunscreens, topical nonsteroidal and anti-inflammatory agents, and other possible causative agents) are applied in duplicate for 24–48 hours to normal skin. One set of test sites is then uncovered and irradiated with a broad-spectrum UVA source, usually at 5 J/cm2 from fluorescent PUVA lamps, and the results read 24 and 48 hours later. Strongly positive reactions at sites exposed to both chemical agent and UVA, with no reactions at the covered control sites, confirms a diagnosis of photoallergy. Occasionally, however, contact irritation or contact allergy occurs in both sites, making a diagnosis of photoallergy uncertain. One should also be alert to the possibility that all irradiated sites may become positive, suggesting that underlying widespread UVA photosensitivity is responsible. Furthermore, the identification of potential photoallergens is still primitive, often with separation of phototoxicity from photoal-

lergy uncertain. Once again, testing for photoallergy is best conducted in regional centers or by physicians with appropriate experience. The current authors (Travis W. Vandergriff and Paul R. Bergstresser) are grateful to the authors of this chapter in the previous edition for leaving behind an outstanding framework that we employed as our starting point for this updated edition. Special thanks go to John L. M. Hawk and James Ferguson.

Chapter 91

to the paravertebral groove whereas lesion induction, except when done relatively easily with the monochromator, as in SU and CAD, is best undertaken using broadband sources with output directed over larger areas of skin known to be susceptible to the eruption. PMLE, AP, and HV are conditions in which repeated irradiation with UVA- or UVB-emitting or combined sources is often required to reproduce the disease. It is important that the use of potent topical and systemic steroids be avoided when possible for at least several days before phototesting to prevent false-negative results. It is not certain how much the other oral immunosuppressive agents affect testing, but they should be stopped whenever possible, as well. False-positive results may also occur in patients with widespread disease, and the eruption should first be well controlled whenever possible, if necessary by keeping the patient in a reduced-light environment. However, it is often difficult to fulfill these requirements if the eruption is active, and in such circumstances, testing may need to be undertaken with knowledge of its limitations. All phototesting should be undertaken at carefully standardized sequential doses (often a geometric series) and wavelengths, and the results read at consistent times after exposure in carefully controlled conditions of light and temperature. Furthermore, because testing involves UVR exposure, potentially noxious to both skin and eyes, the patient and the investigator should be protected with appropriate clothing, shielding and goggles.

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Chapter 92 :: A  bnormal Responses to Ultraviolet Radiation: Photosensitivity Induced by Exogenous Agents :: Henry W. Lim ABNORMAL RESPONSES TO ULTRAVIOLET RADIATION AT A GLANCE

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Phototoxicity occurs in anyone exposed to sufficient phototoxic agent and UV radiation and usually manifests as an exaggerated sunburn reaction.

Disorders Due to Ultraviolet Radiation

Section 16

Photosensitivity is broadly divided into phototoxicity and photoallergy, caused by topical or systemic agents that absorb ultraviolet A (UVA) energy.

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Photoallergy is an immune reaction to a UVA-modified chemical, commonly topical sunscreen agents and antimicrobials in the United States and the United Kingdom and topical nonsteroidal anti-inflammatory agents in Europe. It presents as eczematous eruption on sun-exposed areas. History taking is an important part of the evaluation; phototesting and photopatch testing are sometimes helpful.

individuals exposed to adequate doses of the agent and the activating wavelengths of radiation (Table 92-1). In contrast, photoallergy is a type IV delayed hypersensitivity response to a molecule that has been modified by absorption of photons. It has a sensitization phase, occurs only in sensitized individuals, and requires only a minimal concentration of the photoallergen (see Table 92-1).

INCIDENCE Over 350 medications in the United States have been reported to cause photosensitivity.1 Only a small number of them, however, induce reactions frequently or have been well studied (Tables 92-2, 92-3, 92-4, and 92-5). In evaluations performed at photodermatology centers in New York City, Melbourne, Singapore, and Detroit, photosensitivity induced by a systemic drug was documented in 5% to 15% of the referred patients.2–5 In studies performed in the United States, United Kingdom, Europe, and Australia, the percentage of photopatch-tested patients who had clinically relevant reactions leading to a diagnosis of photoallergic contact dermatitis ranged from 1.4% to 12.0%, with the value in most series being around 10%.2,5–11

Differential diagnosis includes contact allergic or contact irritant dermatitis, airborne contact dermatitis, and other photodermatoses.

PHOTOTOXICITY

Management consists of identification and avoidance of the precipitating agent, photoprotection, and symptomatic therapy.

Several pathways eventuate in the development of phototoxic tissue damage, and for many phototoxic agents more than one pathway is responsible.

Photosensitivity may be caused by exogenous or endogenous agents. It occurs when a compound, classically one with unsaturated double bonds in a six-carbon ring, absorbs radiation energy in its action spectrum, usually ultraviolet A (UVA) wavelengths. Exogenous photosensitizers can be agents administered systemically or applied topically. Well-characterized examples of photosensitivity induced by endogenous photosensitizers are the cutaneous porphyrias, which are associated with enzymatic defects in heme biosynthetic pathways that result in elevated levels of porphyrins, known phototoxic agents (see Chapter 132). Photosensitivity induced by exogenous agents can be divided into phototoxicity and photoallergy. Phototoxicity is the result of direct tissue injury caused by the phototoxic agent and radiation. It can occur in all

PATHOPHYSIOLOGY

PHOTODYNAMIC PROCESSES. On absorption of radiation energy by the photosensitizer (P) at its ground state, formation of an excited (usually triplet) state (3P) molecule occurs. The excited state molecule may then participate in oxygen-dependent processes (i.e., photodynamic processes) via two major pathways, type I and type II reactions, both of which result in cytotoxic injury.12 The type I reaction involves transfer of an electron or a hydrogen atom to the excited state photosensitizer (3P), which results in the formation of free radicals [Eq. (92-1)]. These may then participate in an oxidation– reduction reaction that results in peroxide formation and subsequent cell damage [Eqs. (92-2) and (92-3)]. 3

P + RH → PH ⋅+ R ⋅ PH ⋅ + PH ⋅ → P + PH2 PH2 + O2 → P + H2O2

( 92-1) ( 92-2) ( 92-3)

16

Table 92-1

Characteristics of Phototoxicity and Photoallergy Phototoxicity

Photoallergy

Clinical presentation

Exaggerated sunburn reaction: erythema, edema, vesicles, and bullae; burning, stinging; frequently resolves with hyperpigmentation

Eczematous lesions; usually pruritic

Histologic features

Eosinophilic keratinocytes, epidermal necrosis, dermal edema, sparse dermal infiltrate of lymphocytes, macrophages, and neutrophils

Spongiotic dermatitis, dermal lymphohistiocytic infiltrate

Onset after exposure

Minutes to hours

24 to 48 hours

Dose of agent needed for reaction

Large

Small

Cross-reactivity with other agents

None

Common

Diagnosis Topical agent Systemic agent

Clinical Clinical + phototests

Photopatch tests Clinical + phototests; possibly photopatch tests

Alternatively, interaction of 3P with ground state oxygen could result in the formation of superoxide anion (O2−.), which, in turn, can be converted into highly reactive and cytotoxic hydroxyl radicals (OH·). The type II reaction is also known as an energy transfer process. Transfer of energy to ground state oxygen results in the formation of singlet oxygen (1O2), which is highly reactive and has a lifetime of 50 ns [Eq. (92-4)]: 3

P + O2 → P + 1O2

( 92- 4 )

Cytotoxic injury occurs upon singlet oxygeninduced oxidation of amino acids and unsaturated fatty acids; interaction with the latter results in the

TABLE 92-2

Topical Phototoxic and Photosensitizing Agents

a

Agent

Exposure

Fluorescein

Used topically to visualize the anterior surface of the eye

Fluorouracila

Topical treatment of actinic keratoses

Furocoumarins

Occur naturally in plants (especially Compositae species), including fruits and vegetables (lime, lemon, celery, fig, parsley, and parsnip); used in topical photochemotherapy

Retinoidsa

For treatment of acne and photoaging

Rose Bengal

Used in ophthalmologic examinations

Tar

Used as topical therapeutic agent; found in roofing materials

Induces exaggerated UV response due to skin irritancy.

formation of hydroperoxides, which initiate lipid and protein oxidation. Phototoxicities induced by porphyrins,12 quinolones,13 nonsteroidal anti-inflammatory agents, tetracyclines, amitriptyline, imipramine, sulfonylureas, hydrochlorothiazide, furosemide, and chlorpromazine14 are examples of photodynamic phototoxic reactions.

GENERATION OF PHOTOPRODUCTS. Exposure to radiation may result in the generation of stable photoproducts that are responsible for tissue injury. Phototoxic products have been demonstrated on irradiation of phenothiazines, chlorpromazine, tetracyclines, quinolones, and nonsteroidal anti-inflammatory agents.15 BINDING TO SUBSTRATE. Another mechanism of phototoxicity is radiation-mediated binding of the photosensitizer to its biologic substrate. A photoaddition reaction occurs when the excited state molecule covalently binds to a ground state molecule. An example is the covalent binding of 8-methoxypsoralen to pyrimidine bases of the DNA molecules, which results in the formation of a cross-link between the DNA strands.

Abnormal Responses to Ultraviolet Radiation: Exogenous

Type IV delayed hypersensitivity response No

::

Direct tissue injury Yes

Chapter 92

Pathophysiology Occurrence after first exposure

INFLAMMATORY MEDIATORS. Mediators of inflammation and inflammatory cells participate in phototoxic tissue injury. Biologically active products of complement activation, mast cell-derived mediators, eicosanoids, proteases, and polymorphonuclear leukocytes contribute to the development of phototoxicity induced by porphyrins, demeclocycline, and chlorpromazine.16 APOPTOSIS. Photodynamic therapy (PDT) involves the use of a photosensitizer and electromagnetic

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TABLE 92-3

Systemic Phototoxic Agents Class Antifungal

Chloroquine (Aralen) Quinineb

Antimicrobials

Sulfonamides Tetracyclines Demeclocycline (Declomycin)c Doxycycline (Adoxa, Doryx,   Monodox, Periostat, Vibra-Tabs,   Vibramycin)c Minocycline (Arestin, Dynacin,   Minocin) Tetracycline (Helidac, Sumycin) Trimethoprim (Bactrim, Polytrim,   Primsol, Septra) Quinolones Ciprofloxacin (Cipro) Enoxacin (Penetrex)b Gemifloxacin (Factive) Lomefloxacin (Maxaquin)b,c Moxifloxacin (Avelox) Nalidixic acid (NegGram)b,c Norfloxacin (Chibroxin, Noroxin) Ofloxacin (Floxin, Ocuflox) Sparfloxacin (Zagam)c

Section 16 :: Disorders Due to Ultraviolet Radiation

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Griseofulvin (Fulvicin, Grifulvin V,   Gris-PEG)b Voriconazole (Vfend)

Antimalarials

Cardiac drugs

Amiodarone (Cordarone, Pacerone)c Quinidine (Quinaglute, Quinidex)b

Diuretics

Furosemide (Lasix)c Thiazides Bendroflumethiazide (Corzide) Chlorothiazide (Aldoclor, Diuril)c Hydrochlorothiazide (Accuretic,  Aldactazide, Aldoril, Atacand, Avalide, Capozide, Diovan, Dyazide, Hyzaar, Inderide, Lopressor, Lotensin, Maxzide, Micardis, Microzide, Moduretic, Prinzide, Teveten HCT, Uniretic, Vaseretic, Zestoretic, Ziac)c

Dyes

Fluorescein (AK-Fluor, Fluorescite) Methylene blue

Furocoumarins

Psoralens 5-Methoxypsoralenc 8-Methoxypsoralen   (Oxsoralen-Ultra)c

Hypoglycemics

a

Generic Name (Common US Trade Names)a

Sulfonylureas Acetohexamide (Dymelor) Chlorpropamide (Diabinese) Glipizide (Glucotrol, Metaglip) Glyburide (DiaBeta, Glucovance,   Glynase PresTab, Micronase) Tolazamide (Tolinase) Tolbutamide (Orinase)c

Class

Generic Name (Common US Trade Names)a

Immunosuppressant

Azathioprine (Azasan, Imuran)

Nonsteroidal antiinflammatory drugs

Acetic acid derivative Diclofenac (Arthrotec, Cataflam,   Voltaren) Alkanone derivative Nabumetone (Relafen)c Anthranilic acid derivative Mefenamic acid (Ponstel) Cyclooxygenase-2 inhibitor Celecoxib (Celebrex) Enolic acid derivative Piroxicam (Feldene)b,c Propionic acid derivatives Ibuprofen (Advil, Motrin, Nuprin,   Vicoprofen) Ketoprofen (Orudis, Oruvail) Naproxen (Aleve, Naprelan,   Naprosyn)c Oxaprozin (Daypro) Tiaprofenic acid Salicylic acid derivative Diflunisal (Dolobid)

Oncologic drugs

Dacarbazine (DTIC-Dome) Docetaxel (Taxotere) Fluorouracil (Adrucil) Methotrexate (Rheumatrex)d Paclitaxel (Taxol) Vinblastine (Velban)

Photodynamic therapy agents

Porfimer (Photofrin)c Verteporfin (Visudyne)c

Psychotropic drugs

Alprazolam (Xanax) Chlordiazepoxide (Librax, Librium,  Limbitrol) Clozapine (Fazaclo) Phenothiazines Chlorpromazine (Thorazine)c Perphenazine (Triavil, Trilafon) Prochlorperazine (Compazine)c Thioridazine (Mellaril) Trifluoperazine (Stelazine) Tricyclics Amitriptyline (Elavil, Limbitrol,   Triavil) Desipramine (Norpramin) Imipramine (Tofranil)

Other

Dapsone Flutamide (Eulexin) Hypericin (St John’s wort) Pyridoxine (vitamin B6) Ranitidine (Zantac)

Although it is the policy not to use trade names in this book, exceptions are made in cases in which we consider this information highly useful. Also reported as a systemic photoallergen. c Commonly reported. d Induces erythema on previously UV-exposed sites. b

TABLE 92-4

Topical Photoallergens Group Sunscreens (see Chapter 223)

Chemical Name Trade Namea

Anti-infective agents

Surface disinfectants: halogenated salicylanilides Dibromosalicylanilide (dibromsalan, DBS)b Tetrochlorosalicylanilide (Irgasan BS200)b Tribromosalicylanilide (tribromsalan, TBS)b Skin cleansers Chlorhexidine (Hibiclens) Hexachlorophene (pHisoHex) Pesticides Bithionol (thiobis-dichlorophenol)b Dichlorophene (G4, Korium, Teniatol) Dimethylol dimethyl hydantoin Fenticlor (bis-hydroxy-chlorophenyl sulfide)b Personal care products Triclosan (Irgasan DP300, Microban, Lexol 300) Topical antifungals Buclosamide (Jadit, butylchlorosalicylamide) Multifungin (bromochlorosalicylanilide,  BCSA)

Others

Antibiotic for cattle Olaquindoxb Nonsteroidal anti-inflammatory agents (topical) Etofenamate Fepradinol Flufenamic acid Ketoprofenb Phenothiazines Chlorpromazine (Thorazine)b Promethazine (Phenergan)b Miscellaneous Acyclovir cream (Zovirax) Clioquinol (Vioform,   iodochlorhydroxyquin) Cadmium sulfide Cinchocaine (Dibucaine) Thiourea (thiocarbamide, sulfourea)

PABA = para-aminobenzoic acid. Although it is the policy not to use trade names in this book, exceptions are made in cases in which we consider this information highly useful. b Commonly reported to be photoallergens. a

Generic Name (US Trade Namea)

Antifungal

Griseofulvin (Fulvicin, Grifulvin V,   Gris-PEG)

Antimalarial

Quinine

Antimicrobials

Quinolone Enoxacin (Penetrex)

Cardiac medication

Quinidine (Quinaglute, Quinidex)

Nonsteroidal antiinflammatory drugs

Ketoprofen (Orudis, Oruvail) Piroxicam (Feldene)

Vitamin

Pyridoxine hydrochloride   (vitamin B6)

a Although it is the policy not to use trade names in this book, exceptions are made in cases in which we consider this information highly useful.

radiation in the presence of oxygen to treat premalignant and malignant skin conditions. In addition to generating reactive oxygen species, which results in cytotoxicity, PDT also is a potent inducer of apoptosis.12

CLINICAL MANIFESTATIONS ACUTE PHOTOTOXICITY. (See Table 92-1.) Acute phototoxicity occurs within hours of exposure to the phototoxic agent and UV radiation. Symptoms are drug-dose and UV-dose dependent—usually asymptomatic, but at sufficient doses, the patient complains of a burning and stinging sensation on exposed areas, such as forehead, nose, V area of the neck, and dorsa of the hands (Fig. 92-1). Erythema and edema may appear within hours of exposure; in severe cases, vesicles and bullae may develop accompanied by pruritus. Protected areas, such as nasolabial folds, postauricular and submental areas, and areas covered by clothing, are spared. A notable exception to these kinetics is psoralen-induced phototoxicity, in which often the acute response first appears after 24 hours, and peaks at 48–72 hours, which is the rationale for administering psoralen plus UVA (PUVA) photochemotherapy doses 48–72 hours apart. The phototoxic response resolves with a varying degree of hyperpigmentation, which may last for months. At lower drug/UV doses, gradual tanning only, without preceding sunburn-like reaction, can be seen. PHOTO-ONYCHOLYSIS. Separation of the distal nail from the nail bed, usually painful, is a manifestation of acute phototoxicity, with the nail plate serving as a lens to focus UV energy on the nail bed. It has been reported with doxycycline and other tetracyclines, fluoroquinolones, psoralens, benoxaprofen, clorazepate dipotassium, olanzapine, aripiprazole, indapamide, and quinine (Fig. 92-2).17

Abnormal Responses to Ultraviolet Radiation: Exogenous

6-Methylcoumarinb Musk ambretteb Sandalwood oil

Property

::

Fragrances

Systemic Photoallergens

Chapter 92

Benzophenones Benzophenone-3 (oxybenzone)b Benzophenone-4 (sulisobenzone) PABA derivatives Ethylhexyl dimethyl PABA (padimate O)b PABAb Cinnamates Ethylhexyl methoxycinnamate (octinoxate) Cinoxate (cinoxate) Others Butyl methoxydibenzoylmethane   (avobenzone, Parsol 1789)b Octocrylene (octocrylene) Octyl triazone Phenylbenzimidazole sulfonic acid   (ensulizole)

16

TABLE 92-5

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Section 16

Figure 92-3  Minocycline-induced blue–gray pigmentation on cheeks and upper lip.

:: Disorders Due to Ultraviolet Radiation

Figure 92-1  Amiodarone-induced phototoxicity. Note the erythema and slate-gray pigmentation (nose, forehead) on the sun-exposed area.

SLATE-GRAY PIGMENTATION. Asymptomatic blue–gray pigmentation on sun-exposed areas has been associated with exposure to several agents.18,19 One percent to ten percent of patients taking amiodarone develop this side effect (Fig. 92-1). Chlorpromazine and clozapine can induce a similar change. The tricyclic antidepressants imipramine and, less commonly, desipramine have also been reported to cause slate-gray pigmentation. A drug metabolite–melanin complex has been postulated to be the cause of this alteration. Minocycline can induce blue–gray pigmentation on the face (Fig. 92-3), frequently on sites of acne

scars, although similar pigmentation on forearms and shins can also occur. Chronic exposure to diltiazem, a benzothiazepine calcium channel blocker, has resulted in photodistributed, reticulated, slate-gray pigmentation. Slate-gray pigmentation seen in argyria involves the nail lunulae, mucous membranes, and sclerae. A photochemical reaction, in which silver granules are deposited in the dermis, results in these pigmentary alterations.

LICHENOID ERUPTION. Lichenoid eruption has been reported as a form of phototoxicity, but is controversial. PSEUDOPORPHYRIA. The development of porphyria cutanea tarda-like cutaneous changes of skin fragility, vesicles, and subepidermal blisters is associated with several phototoxic agents (Fig. 92-4). Although histologic and immunofluorescence findings are similar to those of porphyria cutanea tarda, the porphyrin profile is normal or in the upper range of normal in these patients. Naproxen is the most commonly reported causative agent. Other drugs incriminated include amiodarone, β-lactam antibiotics, celecoxib, ciprofloxacin, cyclosporine, diflunisal, etretinate, furosemide, imatinib, nabumetone, nalidixic acid, narrowband UVB, oral contraceptives, oxaprozin, ketoprofen, mefenamic acid, the tetracyclines, tiaprofenic acid, torsemide, and voriconazole.20,21 ACCELERATED PHOTO-INDUCED CHANGES.

This has been uniquely described with voriconazole, a broad spectrum antifungal agent. Immunosuppressed patients receiving voriconazole for >12 weeks can develop photosensitivity, pseudoporphyria, photoaging, lentigines, premature dermatoheliosis; in addition, squamous cell carcinoma and melanoma have been described in this group of patients who were on voriconazole for >12 months.21

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Figure 92-2  Distal onycholysis in a patient receiving psoralen plus ultraviolet A therapy.

PHOTODISTRIBUTED TELANGIECTASIA. Telangiectasia on sun-exposed areas has been reported with calcium channel blockers, including nifedipine, amlodipine, felodipine, and diltiazem, with the

16

Chapter 92

Figure 92-4  Pseudoporphyria. Note subtle erosions on dorsum of hand and at the base of the index finger, and crusting on the knuckle.

::

PERSISTENCE OF PHOTOSENSITIVITY AND EVOLUTION TO CHRONIC ACTINIC DERMATITIS. Although phototoxicity usually resolves after

discontinuation of the causative agent, there are reports of persistence of photosensitivity for many years after the cessation of exposure, which results in the development of chronic actinic dermatitis (Fig. 92-5). The condition presents with pruritus and lichenification and excoriation on sun-exposed sites; it has been reported with thiazides, quinidine, quinine, and amiodarone.23

CHRONIC EFFECTS. Cutaneous effects of longterm, repeated phototoxic tissue injury are best exemplified by the manifestations in patients who have received long-term PUVA photochemotherapy, which is known to affect DNA. These effects include premature aging of the skin, lentigines, squamous cell and basal cell carcinomas, and melanoma. These are discussed in greater detail in Chapter 238. PHOTOTOXIC AGENTS TOPICAL AGENTS. Table 92-2 lists the major topical phototoxic and photosensitizing agents. It should be noted that fluorouracil and retinoids induce exaggerated UV response due to their irritant effect on the skin. Therapeutic or occupational exposures to these agents are the common route of contact. Furocoumarins. Topical exposures to furocoumarins may occur in individuals in certain occupations (bartenders, salad chefs, gardeners) and in patients receiving topical photochemotherapy with psoralens. Tar.

Crude coal tar, although no longer commonly used in dermatologic therapy, is well documented to produce a burning and stinging sensation on exposure to UVA (“tar smarts”). In addition to phototoxicity, occupational exposure to tar is associated with increased risk of nonmelanoma skin cancers.

Figure 92-5  Chronic actinic dermatitis. Note the lichenification and hyperpigmentation on sun-exposed areas, and sparing of skin folds.

SYSTEMIC AGENTS. Table 92-3 lists the major systemic phototoxic agents.24–28 They commonly produce an exaggerated sunburn reaction but, like most phototoxins, may also induce an eczematous photoallergic response in a small percentage of users, especially after topical exposure. As a rule, the action spectra are in the UVA range; notable exceptions are the porphyrins, fluorescein, and other dyes, whose action spectra are in the visible light range. HISTOPATHOLOGY Acute phototoxicity is characterized by individual necrotic keratinocytes and, in severe cases, epidermal necrosis (see Table 92-1). There may be epidermal spongiosis, dermal edema, and a mild infiltrate consisting of neutrophils, lymphocytes, and macrophages. Slate-gray pigmentation is associated with increased dermal melanin and dermal deposits of the drug or its metabolite.18,19 Histologic features of lichenoid eruptions are similar to those of idiopathic lichen planus; however, there may be a greater degree of spongiosis and dermal eosinophilic and plasma cell infiltrates, and a larger number of necrotic keratinocytes and cytoid bodies. In pseudoporphyria, as in porphyria cutanea tarda, there is dermal–epidermal separation at the lamina lucida and deposits of immunoglobulins at the dermal–epidermal junction and surrounding blood vessel walls.20,21

Abnormal Responses to Ultraviolet Radiation: Exogenous

antibiotic cefotaxime, and with antidepressant venlafaxine. In some of these patients, provocation with UVA resulted in the development of telangiectasia.22

MANAGEMENT Identification and avoidance of the causative phototoxic agent are the most important steps in management.

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Beyond this or if the agent cannot be removed, sun avoidance is essential. Because the action spectrum for most agents is in the UVA range, high sun protection factor, broad-spectrum sunscreens containing efficient UVA filters should be used (see Chapter 223). Acute phototoxicity can be managed with topical corticosteroids and compresses; systemic corticosteroids should be reserved for only the most severely affected patients. Management of patients with slate-gray pigmentation, lichenoid eruption, pseudoporphyria, and photodistributed telangiectasia is symptomatic only, and patients should be advised that it will take months after the discontinuation of the offending agent for the condition to resolve. Patients with nonsteroidal antiinflammatory drug-induced (NSAID-induced) pseudoporphyria who require NSAIDs should be switched to a different class of agents or to those that are less photosensitizing, such as indomethacin or sulindac.29

:: Disorders Due to Ultraviolet Radiation

PHOTOALLERGY PATHOPHYSIOLOGY Photoallergy is a type IV delayed hypersensitivity response requiring the presence of both photoallergen and the activating wavelengths of radiation, which for most agents are in the UVA range.30 After the absorption of UV energy, a photoallergen may be converted to an excited state molecule, which subsequently reverts to ground state by releasing the energy. In this process, the molecule may conjugate with a carrier protein to form a complete antigen. This is thought to be the mechanism of photoallergy induced by halogenated salicylanilides, chlorpromazine, and para-aminobenzoic acid (PABA). Alternatively, a photoallergen may form a stable photoproduct on exposure to radiation, which in turn may conjugate with a carrier protein to form a complete antigen. Sulfanilamide and chlorpromazine have both been shown to participate in this reaction. Once the complete antigen is formed, the mechanism of photoallergy is identical to that of contact allergy. The antigen is taken up and processed by Langerhans cells, which then migrate to regional lymph nodes to present the antigen to T lymphocytes. Cutaneous lesions develop when the activated T lymphocytes circulate to the exposed site to initiate an inflammatory response.

CLINICAL MANIFESTATIONS

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In sensitized individuals, exposure to the photoallergen and sunlight results in the development of a pruritic, eczematous eruption within 24 to 48 hours after exposure (see Table 92-1). Although the morphology is clinically indistinguishable from that of allergic contact dermatitis, the distribution of the eruption in photoallergy is predominantly confined to sun-exposed areas; however, in severe cases, it may spread to the covered areas, albeit at a lower intensity. Unlike the lesions in phototoxicity in fair-skinned individuals, those in photoallergy usually resolve without signifi-

cant postinflammatory hyperpigmentation. Lichenoid eruption has also been reported. Currently, in the United States, United Kingdom, and France, UV filters in sunscreen products (especially benzophenone-3) and antimicrobial agents are the most common cause of photoallergy, whereas NSAIDs are the leading topical photoallergens in Eur ope.10,11,30–32 Although there have been reports of systemic agents inducing a photoallergic response, the evidence of such response remains unclear.30 As with phototoxicity, persistence of photosensitivity and evolution to chronic actinic dermatitis (see Chapter 91) have been reported after exposure to photoallergens, including chlorpromazine, dioxopromethazine, halogenated salicylanilides, ketoprofen, musk ambrette, olaquindox, and quinidine.33,34 The mechanism is not completely understood. One possible explanation is that UV radiation alters the carrier protein that originally binds the photoallergen; this results in the formation of a neoantigen that stimulates the immune system over the long term. This hypothesis is supported by the observation that the histidine moiety in albumin can undergo oxidation in the presence of salicylanilide, which binds to albumin.

PHOTOALLERGENS TOPICAL AGENTS. Topical exposure is the most common route of sensitization to photoallergens.30,35 Table 92-4 lists the common groups of photoallergens. SYSTEMIC AGENTS. Photoallergy caused by systemic agents is much less frequent, and not as well documented, than that induced by topical agents. All but one of these photoallergenic agents (pyridoxine) are also phototoxic and have been discussed previously in this chapter (see Section “Systemic Agents” under Section “Phototoxic Agents” and Table 92-3). HISTOPATHOLOGY The histologic features of photoallergy are similar to those of allergic contact dermatitis. There is epidermal spongiosis associated with infiltrate of mononuclear cells in the dermis (see Table 92-1).

MANAGEMENT Management is identical to that of phototoxicity: identification and avoidance of the photoallergen, sunprotective measures, and symptomatic therapy.

EVALUATION OF PATIENTS WITH PHOTOTOXICITY AND PHOTOALLERGY The evaluation of patients with phototoxicity and photoallergy is similar to the evaluation of patients

PORPHYRIA CUTANEA TARDA (See Chapter 132) Ingestion of wheat treated with hexachlorobenzene (HCB) as a preservative resulted in an outbreak of a porphyria cutanea tarda-like syndrome in Turkey in the 1950s.36 Inhibition of the enzyme uroporphyrinogen decarboxylase by HCB was thought to be responsible for the clinical manifestations. However, a study of adults highly exposed to HCB in Catalonia, Spain, and of children from the same area, did not show any increase in prevalence of porphyria cutanea tarda or increased urinary concentrations of porphyrins.37

LUPUS ERYTHEMATOSUS (See Chapter 155) Drug-induced systemic lupus erythematosus present with purpura, erythema nodosum, urticarial and necrotizing vasculitis, and/or photosensitivity. It is most commonly associated with exposure to hydralazine, procainamide, isoniazid, and minocycline; antinuclear antibody (ANA) test is positive and antihistone antibodies are characteristically present.38 Drug-induced subacute cutaneous lupus erythematosus (SCLE) presents with similar cutaneous lesions as idiopathic SCLE, although blisters and targetoid lesions may occur, and lower extremities may be involved. Antinuclear antibody and anti-Ro/SSA antibodies are frequently present, while antihistone antibodies are usually absent. Drugs associated with this condition include calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine and tumor necrosis factor(TNF)-α antagonists.38 Drug-induced discoid lupus erythematosus is very rare; it has been reported with exposure to fluorouracil and TNF-α antagonists. Identification and avoidance of the precipitating agent is the treatment of drug-induced lupus erythematosus.

Abnormal Responses to Ultraviolet Radiation: Exogenous

Airborne allergic contact dermatitis is characterized by involvement of skinfolds on exposed areas, such as the nasolabial folds, and the eyelids that receive minimal direct sunlight. It also involves exposed areas that are relatively sun protected, such as the postauricular areas and area under the chin. Allergic contact derma-

OTHER EXOGENOUS AGENTINDUCED PHOTODERMATOSES AND PHOTOEXACERBATED DERMATOSES

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DIFFERENTIAL DIAGNOSIS OF PHOTOTOXICITY AND PHOTOALLERGY

titis and irritant contact dermatitis occur at sites of contact, in both sun-exposed and in sun-protected areas. Other photodermatoses can be differentiated from phototoxicity and photoallergy by their characteristic time course and morphology and lack of a compatible exposure history. Polymorphous light eruption manifests itself within a few hours of sun exposure as pruritic papules, plaques, and, uncommonly, vesicles on sun-exposed sites and resolves in a few days. Chronic actinic dermatitis presents as chronically lichenified plaques on sun-exposed areas. Lesions of solar urticaria appear within minutes of sun exposure as mildly pruritic urticaria and resolve within a few hours.

Chapter 92

with other photosensitivity disorders and is described in greater detail in Chapter. A history of exposure to known photosensitizers is most important. It is also helpful to ascertain whether window glass-filtered sunlight can induce the cutaneous eruption, because UVB is filtered out by window glass. Distribution of the cutaneous eruption is a helpful clue to the type of photosensitizer responsible. Widespread eruption suggests systemic photosensitizers, whereas topical photosensitizers produce lesions only in areas that have been exposed to both sensitizers and radiation. Vesicular and bullous eruptions are most commonly associated with phototoxicity, whereas eczematous eruptions strongly suggest photoallergy; usually, the former is associated with a burning sensation, the latter with pruritus. Skin biopsy findings may also be helpful in differentiating these two conditions: necrotic keratinocytes are commonly seen in phototoxicity, whereas spongiotic dermatitis is associated with photoallergy (see Table 92-1). Phototests and photopatch tests are an integral part of the evaluation of photosensitivity when history and physical examination alone are insufficient to determine the responsible agent. Approximately 10% of patients who undergo photopatch testing have clinically relevant positive results, which leads to the diagnosis of photoallergic contact dermatitis.2,11 The procedures for phototesting and photopatch testing are generally as follows, although there are variations in testing methods.5,10 On day 1, exposure to UVB and UVA to determine minimal erythema dose (MED) is carried out, and duplicate sets of photoallergens are applied symmetrically to another site on the back and covered by an opaque tape. On day 2, the MEDs are determined. One of the duplicate set of photoallergens is exposed to 10 J/cm2 of UVA or 50% of the MED to UVA, whichever is lower. After irradiation, the exposed site is covered again with an opaque tape. On day 3, both irradiated and nonirradiated test sites are uncovered, and the reactions are graded. On day 5 or day 8, the irradiated and nonirradiated sites are evaluated for delayed reactions. Reaction only at an irradiated site indicates photoallergy. Reaction of equal intensity at both irradiated and covered sites indicates allergic contact dermatitis. Reaction at both sites, but with higher intensity at the irradiated site, signifies both photoallergy and allergic contact dermatitis. Well-defined erythema that resolves promptly indicates an irritant dermatitis.

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KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 5. Kerr HA, Lim HW: Photodermatoses in African Americans: A retrospective analysis of 135 patients over a 7-year period. J Am Acad Dermatol Oct;57(4):638-43, 2007 10. Victor FC, Cohen DE, Soter NA: A 20-year analysis of previous and emerging allergens that elicit photoallergic contact dermatitis. J Am Acad DermatolApr 62(4):605-10, 2010

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13. Ferguson J, DeLeo VA: Drug and chemical photosensitivity: Exogenous. In: Photodermatology, edited by HW Lim, H Hönigsmann, JLM Hawk. New York, Informa Healthcare, 2007, p. 199-218 14. Moore DE: Drug-induced cutaneous photosensitivity: Incidence, mechanism, prevention and management. Drug Saf 25:345-72, 2002 30. Kerr A, Ferguson J: Photoallergic contact dermatitis. Photodermatol Photoimmunol Photomed 26(2):56-65, 2010 35. Scheuer E, Warshaw E. Sunscreen allergy: A review of epidemiology, clinical characteristics, and responsible allergens. Dermatitis 17(1):3-11, 2006

Skin Changes Due to Other Physical and Chemical Factors

Chapter 93 :: Thermoregulation :: Dean L. Kellogg, Jr. HUMAN THERMOREGULATION AT A GLANCE Thermoregulatory reflexes involve changes in skin blood flow and sweating that act to preserve thermal balance with an internal temperature of approximately 37°C (98.6°F). Thermal balance is determined by metabolic heat production; evaporative heat loss; heat gain or loss through radiant, convective, and conductive mechanisms; and useful mechanical work done. Dermal papillary loops, arteriovenous anastomoses, and sweat glands are the major skin effectors of thermoregulation. Heat stress evokes large increases in skin blood flow and sweating through cholinergic cotransmitter and nitric oxide-dependent mechanisms to facilitate heat dissipation. Local skin heating causes a local vasodilation through antidromic neurotransmitter release from afferent skin nerves and increased nitric oxide generation. Cold stress evokes reduced skin blood flow through noradrenergic cotransmitter mechanisms to facilitate heat conservation. Local skin cooling causes a local vasoconstriction through noradrenergic and afferent neural mechanisms as well as nonneural mechanisms.

THE ROLE OF SKIN IN HUMAN THERMOREGULATION Human beings are homeotherms: we maintain our internal, or core temperature of the body within a narrow range despite thermal stresses. Thermal stress can

arise from variations in environmental temperature or from the human body itself, as with heat generation by skeletal muscle during dynamic exercise. When thermal stresses arise from the environment, changes in skin temperature occur prior to any change in internal temperature. When thermal stresses arise from the body itself as with exercise, changes in core temperature occur prior to any change in skin temperature. In either case, thermal gradients are established between the skin and the body core. If skin temperature is lower than core temperature, heat will be lost from the body unless skin blood vessels constrict. If skin temperature is greater than core temperature, the body will gain heat, unless skin vessels dilate and sweat glands produce perspiration. The skin is thus a crucial component of human thermoregulation. Human thermoregulation is achieved through an integration of several physiological processes. These integrated processes make up thermoregulatory reflexes that maintain a stable internal temperature at a “set point” of 37°C (98.6°F) despite thermal stresses. The set point is not invariant and may fluctuate as much as 0.5°C–1.0°C (0.9°F–1.8°F) according to circadian rhythms and during the menstrual cycle in females. The thermoregulatory reflexes designed to preserve internal temperature at the set point are coordinated by thermally sensitive neurons in the anterior hypothalamic–preoptic area and spinal cord, which respond to the changes in internal and skin temperatures. For example, cold-sensitive neurons in the anterior hypothalamic–preoptic area and spinal cord integrate afferent sensory inputs and activate heat-conserving mechanisms that include cutaneous vasoconstriction and increased metabolic heat production (shivering). Conversely, the stimulation of heat-sensitive neurons in the anterior hypothalamic–preoptic area and spinal cord integrate afferent sensory inputs and activate heat-dissipating mechanisms that include cutaneous vasodilation and sweat production.

HEAT TRANSFER To maintain thermal balance, heat gained or lost by the body must equal heat dissipated from, or produced

17

by the body. This concept can be mathematically expressed as: ∆S = M − E ± R ± C ± K − W where

Section 17 :: Skin Changes Due to Other Physical and Chemical Factors

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ΔS = change in heat storage by the body M = metabolic heat production and is defined as the rate of transformation of chemical energy into heat and mechanical work E = evaporative heat loss and is defined as the rate of heat loss by evaporation of water from skin and surfaces of the respiratory tract. E is dependant on (1) rate of sweat secretion, (2) water vapor pressure of the environment, and (3) the area of evaporative surface. R = radiant heat gain or loss and is defined as heat exchange by emission and absorption of electromagnetic (infrared) radiation. This component accounts for 50%–60% of the heat loss in a thermally comfortable (thermoneutral) individual, but can easily become a net heat gain as when one is in direct sunlight. C = convective heat gain or loss and is defined as heat exchange due to forced movement of a fluid, either liquid or gas. This component is responsible for the transfer of heat to the skin through skin blood flow and transfer from the skin to the environment by air or water movement. Within the body, the cardiovascular system is the major mediator of convective heat transfer. C is dependent on (1) body surface area, (2) temperature differences, and (3) fluid (or air) movement. K =  conductive heat gain or loss and is defined as heat transfer by flow down a temperature gradient, as between tissues and blood, between blood and skin, and between skin and the environment. This is usually combined with convective heat transfer. W = useful mechanical work The sum of R, C, and K is determined by the temperature gradient between the skin and the environment. If ΔS is zero, the body is in heat balance. This “thermoneutral” condition is characterized as having low skin blood flow of approximately 5% of cardiac output. Sweating does not occur during thermoneutrality. If ΔS < 0, the body is losing heat, core temperature is falling, and thermoregulatory reflexes are evoked to conserve heat. Thermal stability is maintained through reduction of skin blood flow that can approach zero during maximal vasoconstriction. Reduction in skin blood flow increases the thermal insulation between the body and the environment by minimizing losses through conductive (K), convective (C), and radiant (R) mechanisms. If heat loss continues despite low skin blood flow, metabolic generation of heat (M) through the shivering of skeletal muscle is initiated to restore and maintain core temperature. Brown adipose tissue can also be a source of metabolic heat generation through nonshivering thermogenesis.1 Although originally thought to be important only in human neonates where brown adipose tissue is 2%–5% of body weight,

some brown adipocytes persist into adulthood.2 These adipocytes can directly generate heat (M) to maintain core temperature.3 If, despite all these mechanisms, ΔS remains negative, core temperature will fall and lifethreatening hypothermia may result. If ΔS > 0, the body is gaining heat and core temperature is rising. Under this circumstance of heat stress, thermal stability is maintained by increases in skin blood flow to facilitate heat loss through K, C, and even R losses. If heat gain continues despite these mechanisms, sweating is evoked to increase heat loss through evaporation (E) of perspiration. If ΔS remains positive, blood flow is diverted from skeletal muscle and gastrointestinal beds, providing for dramatic increases in skin blood flow. Sweat rate will also increase until maximal levels are achieved. If, despite maximal skin blood flow and maximal stimulation of sweating, ΔS remains positive, core temperature will rise and life-threatening hyperthermia, i.e., heat stroke, will occur.

THERMOREGULATION AND THE SKIN ANATOMIC CONSIDERATIONS The critical role of the skin in human thermoregulation is well understood: thermoregulation is achieved through variations in blood flow and sweat production so as to maintain thermal stability.4 Without these variations, thermal stability cannot be maintained resulting in risk of hypothermia or hyperthermia (see Chapters 94 and 95). Under normothermic conditions, skin blood flow ranges from 30–40 mL/min/100 g of skin in resting humans. However, the cutaneous vasculature is exceedingly compliant so that skin blood flow can vary from nearly zero during cold stress periods with maximal vasoconstriction to 8 L/min over the body’s surface during maximal vasodilation in heat stress.5 Blood vessels in the skin are arranged in several plexuses in superficial and deep layers parallel to the skin surface. Most vessels are in the superficial layer and consist of high-resistance terminal arterioles, papillary loops, and postcapillary venules. Papillary loops are true capillaries. Blood flow through the loops is controlled by highly innervated arterioles. The loops are located near the dermal–epidermal junction, a region characterized by a maximal thermal gradient because of its proximity to the skin surface. Since the papillary loops also have a large surface area, blood flow through these vessels is a major determinant of heat exchange through vasodilation during heat stress and vasoconstriction during cold stress. While papillary loops are found in both glabrous (palms, plantar aspect of feet, and lips) and nonglabrous skin (most of the body’s surface, including the limbs, head, and trunk), arteriovenous anastomoses (AVAs) are found mainly in glabrous skin. They represent direct connections between arterioles and venules that bypass the high-resistance arterioles and capillaries of the papillary loops. AVAs have thick muscular walls with rich noradrenergic innervation and lie deep

SWEATING Heat dissipation through the secretion and evaporation of eccrine sweat is critical to maintaining thermal stability in hot environments or during heat stress induced by strenuous dynamic exercise. Indeed, when environmental temperature exceeds blood temperature, the evaporation of sweat is the sole mechanism for heat dis-

NEURAL CONTROL MECHANISMS OF THE CUTANEOUS VASCULATURE In glabrous skin, cutaneous arterioles are innervated by sympathetic vasoconstrictor nerves that release norepinephrine and other cotransmitters.7,13–16 All thermoregulatory reflex changes in blood flow in these areas are caused by changes in noradrenergic vasoconstrictor activity and the effects of local temperature on the skin blood vessels themselves (Fig. 93-1).4,7,17 In nonglabrous skin, changes in skin blood flow are mediated by two branches of the sympathetic nervous system: (1) noradrenergic vasoconstrictor nerves as found in glabrous skin and (2) a cholinergic active vasodilator system.4,7,17 These dual sympathetic neural control mechanisms are the major effectors of thermoregulatory responses. Vessels in nonglabrous skin also respond to the effects of local temperature changes (Fig. 93-2).4,7,17 In normothermia, cutaneous arterioles are under little neural tone. During cold stress, reduction of skin temperature and/or internal temperature cause a thermoregulatory reflex-mediated reduction in skin blood flow to conserve body heat. Enhanced noradrenergic vasoconstrictor tone mediates an arteriolar vasoconstriction and, thus, decreases skin blood flow. Conversely, during heat stress, thermoregulatory reflexes that facilitate body cooling are affected. As internal temperature continues to rise over a threshold value of approximately 37°C (98.6°F), a cutaneous vasodilation begins. At this threshold, active vasodilator tone to the cutaneous arterioles is enhanced. At rest, sweating also begins at the same internal temperature threshold. Vasodilator tone increases as internal temperature increases. Enhanced vasodilator activity decreases smooth muscle tone, leading to an arteriolar vasodilation, and, thus, an increase in skin blood flow, especially through the papillary loops. High skin blood flow delivers heat to the body surface where it is dissipated to the environment in conjunction with the evaporation of sweat. Overall, the active vasodilator system is responsible for 80%–95% of the elevation in skin blood flow that accompanies heat stress. A small, but significant portion of the vasodilation is mediated by the direct vasodilator effects of local heat on the cutaneous vessels.18 Dual vasoconstrictor nerves and vasodilator nerves in skin were first suggested in 1931 by Lewis and Pickering19 and confirmed by Grant and Holling.20 They measured skin temperature as an index of blood flow in the human forearm and found that large increases in response to heat stress could be abolished by sympathectomy or nerve blockade. They noted that while sympathectomy or nerve blockade caused only a slight

Thermoregulation

Cutaneous circulation is a major effector of human thermoregulation.4 During heat stress, elevated internal temperature and skin temperature lead to cutaneous vasodilation through neural mechanisms and the local effect of higher temperatures on the skin vessels themselves. During the periods of cold stress, reduced temperatures mediate a cutaneous vasoconstriction through neural as well as local vascular effects. Under normothermic conditions, skin blood flow averages approximately 5% of cardiac output; however, the absolute amount of blood in the skin can vary from nearly zero during periods of maximal vasoconstriction in severe cold stress to as much as 60% of cardiac output in severe heat stress.5

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CUTANEOUS THERMOREGULATORY MECHANISMS

persal. Sweat secretion is controlled primarily by sympathetic cholinergic nerves that release acetylcholine (Ach) to activate muscarinic receptors on the glands. Sweat secretion can be augmented by local production of nitric oxide near sweat glands.12 Stimulated glands produce an isotonic fluid that becomes progressively hypotonic as the Na+ is reabsorbed in the sweat gland duct by active ion transfer (see Chapter 84).

Chapter 93

to papillary loops.6 Because of their deeper location in the dermis and smaller surface area, AVAs are less efficient in heat transfer than papillary loops. While AVAs dilate in response to heat stress and constrict during mild-to-moderate cold stress, their major role is to mediate local vasodilation during prolonged cold exposure. AVA vasodilation delivers warm blood to maintain tissue temperature and thus tissue viability through “cold-induced vasodilation.”7 Sweat glands also play a major role in human thermoregulation (see Chapter 83). The critical thermoregulatory role of the eccrine sweat glands that are found over most of the body surface is well known. Clearly, the main function of eccrine sweat glands is to increase heat loss through the evaporation of sweat. The density of these glands varies from 700 glands per cm2 in planar and plantar skin to 64 glands per cm2 on the back8; these glands may hypertrophy with repeated heat exposure.9 Each gland is made up of a secretory coil found in the dermis with a duct that extends through the dermis and epidermis to the surface of the skin. Sweat is secreted as an isotonic fluid by the coils. NaCl is reabsorbed within the ducts so sweat that is finally delivered to the surface is hypotonic.10 Each liter of sweat evaporated is capable of removing 580 kcal from the body. Although apocrine sweat glands have been dismissed as “atavistic scent glands,” this has recently been questioned.11 Apocrine glands are usually associated with hair follicles and are most developed on the scalp, face, upper back, and chest. It has been proposed that sebum from apocrine glands acts as a surfactant at high temperatures and, thus, facilitates dispersion of eccrine sweat over the skin’s surface. At low temperatures, sebum may function to repel water from the skin and, thus, reduce heat loss.

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Summary of neural controls of thermoregulatory effectors in human skin Neural control mechanisms in non-glabrous skin

Thermoregulatory inputs

Afferent inputs

CNS

Internal temperature

Preoptic-anterior hypothalamus and spinal cord

Skin temperature

Noradrenergic vasoconstrictor nerves Cholinergic submotor nerves

Cutaneous arterioles and arteriovenous anastomoses

Sweat glands

Section 17

Neural control mechanisms in glabrous skin

:: Skin Changes Due to Other Physical and Chemical Factors

Thermoregulatory inputs

Afferent inputs

CNS

Internal temperature

Preoptic-anterior hypothalamus and spinal cord

Skin temperature

Efferent controls Noradrenergic vasoconstrictor nerves Cholinergic vasodilator nerves Cholinergic submotor nerves

Cutaneous arterioles and arteriovenous anastomoses

Sweat glands

Figure 93-1  Summary of neural controls of thermoregulatory effectors in human skin: Thermoregulatory reflexes are mediated by the afferent inputs of internal and skin temperature. These afferent inputs are integrated in the preoptic anterior hypothalamus and spinal cord areas of the central nervous system. Efferent control of blood vessels and sweat glands in glabrous skin is mediated by noradrenergic vasoconstrictor nerves and cholinergic sudomotor nerves, respectively. In nonglabrous skin regions, efferent control of blood vessels is effected through a system of dual sympathetic innervation, noradrenergic active vasoconstrictor nerves and cholinergic active vasodilator nerves. Sweat glands also receive cholinergic sympathetic innervation; however, whether cholinergic active vasodilator nerves and cholinergic sudomotor nerves are one and the same is not known. cutaneous vasodilation during normothermia, heat stress elicited a much greater increase in skin blood flow. In addition, nerve blockade during established heat stress abolished any cutaneous vasodilation. These results suggested that cutaneous vessels in nonglabrous skin are innervated by sympathetic active vasodilator as well as sympathetic vasoconstrictor nerves. In the 1950s, their findings were confirmed by Edholm et al21 and by Roddie et al.22 In addition, it has been shown that bretylium tosylate (a prejunctional noradrenergic neuronal blocking agent) abolishes the cutaneous vasoconstriction induced by cold stress, but does not alter the vasodilator responses induced by heat stress.23 This confirmed that dual efferent neural systems control the cutaneous arterioles: a noradrenergic vasoconstrictor system and a nonadrenergic active vasodilator system.

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Efferent controls

Thermoregulatory responses undergo physiological acclimatization after repeated thermal challenges over a prolonged (2-week) time period. After repeated exposure to a hot environment, sweat glands hypertrophy to produce more sweat and cutaneous active vasodilation begins at lower internal and skin temperatures to

facilitate long-term thermal stability by favoring earlier and greater heat dissipation.87 Humans also acclimate to cold environments after repeated exposure by increasing metabolic heat generation (in part through increased amounts of brown adipose tissue) and habituating to cold. These adaptations are less effective in promoting thermal stability than adaptations to heat.88 Acute and chronic dermatological disorders can impair thermoregulation. For example, sunburn compromises sweat production, thus impairing evaporative cooling and reducing heat tolerance. At the same time, the inflammatory vasodilation that accompanies sunburn can compete against thermoregulatory reflex vasoconstriction during cold exposure. This will compromise the ability to reduce skin blood flow to conserve body heat, thus reducing cold tolerance.87 Other inflammatory skin conditions, of which erythroderma is the most extreme, have the same effect. Medications can alter thermal tolerance, especially during heat exposure. Numerous medications have anticholinergic effects. Since the cutaneous active vasodilator system and sweat glands are both controlled by cholinergic sympathetic nerves, it is not surprising that such agents have deleterious thermoregulatory consequences. Examples of commonly used medications that can compromise heat stress responses include first generation antihistamines, H2-receptor antagonists, and tricyclic antidepressants. These systemic agents

Skin blood flow responses to cold stress and heat stress in non-glabrous skin

20 15

Normal neural tone

10

Increased Normal active neural vasotone constrictor tone

Increased active vasoconstrictor tone

5 0 Normothermia

Cold stress

Normothermia

Heat stress

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

Cold Injuries

4. Kellogg DL, Jr: In vivo mechanisms of cutaneous vasodilation and vasoconstriction in humans. J Appl Physiol 100:1709-1718, 2006 7. Johnson JM, Proppe DW: Cardiovascular adjustments to heat stress. In: Handbook of physiology—environmental physiology, edited by M Fregly, and C Blatteis. New York, Oxford University Press, 1996, p. 215-243 19. Lewis T, Pickering GW: Vasodilation in the limbs in response to warming the body; with evidence for sympathetic vasodilator nerves in man. Heart 16:33-51, 1931 20. Grant RT, Holling HE: Further observations on the vascular responses of the human limb to body warming; evidence for sympathetic vasodilator nerves in the normal subject. Clin Sci 3:273-285, 1938 22. Roddie IC, Shepherd JT, Whelan RF: The vasomotor nerve supply of the human forearm. Clin Sci 16:67-74, 1957 37. Kellogg DL, Jr. et al: Cutaneous active vasodilation in humans is mediated by cholinergic nerve co-transmission. Circ Res 77:1222-1228, 1995

::

Figure 93-2  Skin blood flow responses to cold stress and heat stress in nonglabrous skin: under normothermic conditions, skin blood flow is relatively low (approximately 5% of cardiac output) and skin vessels receive relatively minor neural inputs from active vasoconstrictor and vasodilator nerves. During cold stress, reductions of skin and internal temperatures lead to reflex increases in sympathetic noradrenergic vasoconstrictor nerve activity. Increased vasoconstrictor system tone reduces skin blood flow, thus increasing thermal insulation and conserving body heat. During heat stress, increasing skin and internal temperatures lead to reflex increases in sympathetic cholinergic active vasodilator nerve and cholinergic sudomotor activity. Increased activity of the vasodilator system leads to potentially dramatic increases in skin blood flow that can reach 60% of cardiac output. High skin blood flow delivers heat to the skin surface where it is removed to the environment primarily through evaporation of sweat.

17

Chapter 94

Skin blood flow (mL/100 g/skin/min

25

(and many others) can reduce sweat secretion, attenuate cutaneous active vasodilation, and increase the risk of thermoregulatory failure.17 Aging also modifies thermoregulatory reflexes. Relative to younger subjects, in healthy older persons, noradrenergic mechanisms are more important than cotransmitter mechanisms in vasoconstricting skin during cold stress.89 During heat stress, older subjects show a delay in the onset and reduced magnitude of cutaneous vasodilation.90 These alterations in cutaneous responses to thermoregulatory challenges contribute to increased morbidity and mortality during thermal stresses in older persons.

Chapter 94 :: Cold Injuries :: Gérald E. Piérard, Pascale Quatresooz, & Claudine Piérard-Franchimont COLD INJURIES AT A GLANCE Skin is important for maintaining core body temperature within a narrow physiologic range.

Winter xerosis and acrocyanosis are common consequences of prolonged exposure to cold.

Cold weather, wind, humidity, dampness, and altitude combine to inflict skin damage.

Erythrocyanosis tends to occur over skin areas with thick adipose tissue, whereas chilblain is more frequently seen in lean persons.

Nonfreezing and freezing conditions can both produce cold injuries. Frostbite occurs after exposure to intensely cold air, liquids, or metals. Several degrees of frostbite are recognized.

Cold urticaria is rare and occurs at the sites of localized cooling. Primary erythromelalgia is a rare neuropathic disorder to which there is a genetic predisposition.

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The human capacity for physiologic adaptation to cold is minimal. This deficiency may cause problems, because seasonal changes in the outdoor environment are quite prominent, even in the temperate zones of the world. In this context, skin is important in thermoregulation, and cutaneous blood flow and the resulting skin temperature may vary widely to help preserve the core body temperature.1–3 Physiologic, behavioral, and environmental factors modulate skin responses to cold exposure.

Core body temperature is maintained within a narrow range by thermoregulatory mechanisms that rely largely on control of the cutaneous blood flow. Arteriovenous anastomoses are abundant in acral areas, and they regulate the volume of blood that passes through the skin. When the skin is cooled, there is usually an immediate acute reduction in the amount of blood that flows to the surface. These events alter skin temperature, heat loss, and color. Skin reactivity and the anatomic pattern of blood supply differ in the skin of newborns, adults, and older people. For instance, a reticulate appearance of cooled skin is a common finding in young infants (Fig. 94-1). The parallel arrangement of large arteries and veins in the limbs allows countercurrent exchange of heat. Vasoconstriction due to cold results in shunting of blood from the superficial to the deep venous system, and heat is transferred from arteries to veins. Thus, the blood going to the acral part of the limbs is precooled, and less heat is lost to the environment. With such thermoregulation, the body can maintain a constant core temperature of approximately 37°C (98.6°F) over a range of external temperatures between 15°C and 54°C (59°F and 129.2°F). Normally, the skin is to some extent adapted to a cooler environment than the 37°C (98.6°F) of internal organs. Given the presence of many cold-adapted

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Figure 94-1  Reticulate appearance of cooled skin in the newborn due to the anatomic pattern of the blood supply and factors influencing flow such as arteriolar vasoconstriction and the increased viscosity of cooled blood.

:: Skin Changes Due to Other Physical and Chemical Factors

Section 17

PHYSIOLOGIC RESPONSE TO COLD

enzymes, the skin may even function more effectively when slightly cooled. In the case of adipose tissue, mild long-term exposure to cooling may lead to progressively better insulation. Habitually cold-exposed skin also develops a more efficient system for shunting blood away from the surface. These adaptive mechanisms are most flexible during the first years of life. Tissues in the aged are less able to develop new shunts. The effect of swimming in cold water after extreme heating—for example, after using a sauna4—is somewhat comparable to accidental cold water immersion. Well-being depends substantially on the degree of subcutaneous insulation, so that overweight persons, as well as those who are well clothed, can survive prolonged accidental cold-water exposure.5 Viscosity of fluids generally increases as temperature decreases. However, blood is a non-Newtonian fluid that exhibits thixotropy, i.e., it becomes less viscous with increasing flow velocity, independent of temperature. This effect is strongly influenced by hematocrit and by packing of erythrocytes. Macrophages also can block capillaries when they develop pseudopods as a result of reduced flow. The combination of slow flow and leukocyte conformational changes is, in part, a physiologic process that enables these cells to migrate through the endothelial lining.6 Other factors affecting blood viscosity include increased platelet adhesiveness, changes in concentrations of proteins, and the presence of abnormal proteins. Fibrinogen level is particularly important.

THERMOREGULATION AND HUNTING REACTION Local and systemic thermoregulation is complex. A group of neurons in the hypothalamus responds directly to temperature. When the temperature decreases, the rate of discharges decreases. From this temperaturesensitive area, signals radiate to various other portions of the hypothalamus to control either heat production or heat loss. Stimuli that influence the autonomic nervous system, such as painful stimuli, mental stress, arousal stimuli, and deep breaths, can all produce cutaneous vasoconstriction in warm subjects but vasodilation in cold subjects.7,8 Cold exposure produces an initial massive cutaneous vasoconstriction, which results in a fall in skin temperature. This change serves to maintain core temperature, but at the expense of the skin. Conversely, cold-induced vasodilation represents a protective mechanism to prevent skin necrosis. This physiologic reflex, known as the hunting reaction of Lewis, involves transient cyclic vasodilation caused by the opening of arteriovenous anastomoses.9,10 A chilling effect is produced by applications of dedicated hydrogel pads or cushions previously stored in a refrigerator.11,12 This biothermal procedure is commonly used during laser therapy. It also serves to achieve a sustained removal of heat from the skin and its underlying tissues. It produces discrete skin hemodynamic changes and may relieve pain.

COLD, WIND, HUMIDITY, AND ALTITUDE

:: Cold Injuries

Figure 94-2  Bullous frostbite following contact with a cold steel sheet.

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Chapter 94

Outdoor work and winter sports are common risk situations for cold damages. A cold environment can be a threat to the skin, leading to a subsequent fall in core body temperature. Many physiologic, behavioral, and environmental factors predispose to the global effects of cold injuries. Marked increases in convective, conductive, or radiant heat loss are responsible for the immediate effects of cold exposure. For instance, touching cold metal objects considerably increases conductive cooling (Fig. 94-2). Other predisposing factors increasing heat loss and/or decreasing heat production and insulation from clothing make people especially susceptible to cold.13 There is ample evidence that the effect of low temperature on skin biology is, in part, a function of environmental humidity, wind speed, and altitude. In this respect, the wind chill index is indicative of the convective heat loss. Wind chill affects the gradients of temperature and water content across the stratum corneum, which result in an imbalance in condition between outer and deeper epidermal layers.14 High altitude, which reduces the oxygen supply to tissues, also contributes to increase the skin damage induced by cold.15 Transepidermal water loss (TEWL) plays a prominent role in evaporative thermal loss. The skin temperature and the relative and absolute environmental humidity are key factors affecting cold injuries. The ambient humidity indicates the mass of water vapor present in a unit volume of the atmosphere. An accurate representation of the amount of moisture in the air as a function of temperature is given by the calculation of the dew point,11,16 which is defined as the temperature of the air at which the gaseous moisture begins to condense, that is, the temperature at which relative humidity reaches 100%. Poor clothing insulation is a common reason for cold injuries. The insulation is insufficient when clothing is too light, wet, tight, permeable to wind, or inadequate to cover the cold sensitive body parts. Individual factors predisposing to cold injuries are physical injuries, leanness, low physical fitness level, fatigue, dehydra-

tion, previous cold injuries, sickness, trauma, poor peripheral circulation, the wearing of tight constrictive clothing, and old age.13 Newborns, the elderly, and individuals with impaired mental faculties remain the most vulnerable. Injury is often increased by alcohol, smoking, and psychotropic drug use. Severe cold injuries have historically influenced the outcome of battles and wars.17,18 Peacetime military operations also impose risks.19–22 However, cold injuries are becoming more prevalent among the general population.21 Many cases are associated with alcohol consumption, homelessness in urban centers, and car breakdown. Frostbite also prevails among winter sport enthusiasts such as cross-country skiers and backpackers who get lost or trapped in a snowstorm.2,22–26 Accidental exposure to liquefied gas is another cause of severe cold injuries.27 Adaptation to cold protects one from responding inappropriately, and a moderate degree of exposure to cooling might be health promoting by stimulating a responsive and protective vasculature. In contrast, individuals who have experienced severe cold injury may have a profoundly delayed or abolished hunting reaction in the affected limbs.28 They are rendered more susceptible to recurrent cold injury with pain, hyperesthesia, or paresthesia.29 Some of these individuals also have coldness of the skin, which is very persistent and probably related to a functional imbalance in the sympathetic nervous system that results from increased α-adrenergic receptor density or affinity for norepinephrine.30 In addition, altered vascular structure may reduce vasocompliance after cold exposure. There may also be impairment of normal vascular reflexes to various stimuli, including deep inspiration, venous occlusion, neck cooling, and ipsilateral skin cooling.30

CLASSIFICATION OF SKIN COLD INJURIES Freezing and nonfreezing injuries can be distinguished according to the severity and duration of chilling. However, the damage caused depends on many variables other than the actual temperature. Recognition is generally easy at a clinical level, but awareness of potential uncommon underlying disorders is important. Treatment, both physical and pharmacologic, is aimed at keeping the body warm and maintaining vasodilation. Frostbite is the consequence of extreme and prolonged freezing conditions. In addition, the whole body may cool down so much that life-threatening hypothermia may ensue. This is an important concern for people who enjoy cold weather sports, particularly in mountains and circumpolar regions. Prompt recognition and treatment are of paramount importance, because many hypothermia victims can recover from very low body temperatures. Treatment in an adequate medical facility can make the difference between full recovery and lifelong problems. Even if the victim appears to be dead from exposure to cold, resuscitative efforts should be started and continued until the proper core body temperature is reached.31

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Figure 94-3  Hemorrhagic bulla and necrosis of the skin induced by freezing a wart with liquid nitrogen.

Extreme and often conductive heat loss at a given body site freezes the tissues and results in localized blistering and necrosis (Fig. 94-3). Several cutaneous disorders also occur when the tissue temperature is maintained just above freezing for long periods. These conditions include chilblains, cold urticaria, cold panniculitis, erythrocyanosis, and acrocyanosis, among others. These disorders may be a consequence of impaired blood flow, reduced sensory perception, or a change in the physical properties of the tissues, such as in adipose tissue. Minor but long-term cold exposure combined with environmental desiccation may have profound effects on the biology of the epidermis, leading, for example, to winter xerosis.32,33 Persistent erythema of the face and the hands is not a rare finding (Fig. 94-4).

FROSTBITE Frostbite occurs when tissue freezes after exposure to extremely cold air, liquids, or metals. The clinical effects of accidental injury that leads to the death of tissues are similar to those caused by cryosurgery.34 The components of tissue that may lead to damage when frozen are water, with formation of ice crystals at 0°C (32°F), and lipids such as fat globules or cell membrane constituents. Contrasting with damaging cryoinjuries, cryopreservation is used to preserve or “to freeze” in vitro most of the biomolecules present in tissues.35 Any metabolic activity is blocked in these circumstances. Cryoscopy is a diagnostic procedure applicable in vivo.36 It relies on an acute but short icing of the stratum corneum in order to disclose some structures exhibiting different capacities of thermal conductivity. The rate of freezing determines the site of injury at the cellular level.37 Extracellular formation of ice occurs most commonly with slow freezing, whereas fast

Figure 94-4  Facial redness in a person exposed to cold winters in a temperate climate.

freezing tends to produce intracellular ice. The formation of ice crystals in the extracellular space alters the osmotic properties of the tissues and disturbs the flow of water and electrolytes across the cell membranes. Thawing may be as damaging as the freezing itself, and repeated freeze and thaw cycles, as may occur in accidental injury, compound the damage, making more water available, which rapidly leads to intracellular flooding. The rewarming rate is also important. In slow rewarming, ice crystals become larger and more destructive. Cells are also exposed to a high concentration of electrolytes for a longer period than with rapid rewarming. As the body cools, there is a reflex constriction of the arteries and veins in the extremities.31 This results in increased venous pressure, decreased capillary perfusion, and sludging. Cooling also creates a leftward shift in the oxygen dissociation curve, and hemoglobin gives up its oxygen less readily. These two conditions result in hypoxia and damage to the capillaries and surrounding tissue. Oxygen tension is further decreased by thrombus formation in the microvasculature, which results in arteriovenous shunting. Arterial and arteriolar constriction, mediated by sympathetic outflow, initiates and probably maintains circulatory impairment. In addition, segmental vascular necrosis occurs in areas of erythrostasis, which suggests that ultimate damage may depend more on insufficient clearance of toxic substances than on initial vasoconstriction. Cell types vary in their susceptibility to cold injury. Melanocytes are very sensitive to cold, and irreversible damage may occur at −4°C to −7°C (24.8°F–19.4°F). This sensitivity explains the hypopigmentation that often follows cryotherapy. In addition, it appears that black persons are more susceptible to frostbite than whites. Nerve axons are also easily damaged by cold,

17

TABLE 94-1

Consequences of Cold Injuries Arterial and arteriolar vasoconstriction Excessive venular and capillary vasodilation Increased endothelial leakage Erythrostasis Arteriovenous shunting Segmental vascular necrosis Massive thrombosis

Figure 94-5  Frostnip.

Chapter 94 ::

Frostnip involves only the skin and causes no irreversible damage. There is a sensation of severe cold progressing to numbness followed by pain. Erythema is usually present on the cheeks, ears, nose, fingers, and toes (Fig. 94-5). There is no edema or bleb formation. Frostnip is the only form of frostbite that can be treated safely in the field with first aid measures. Superficial frostbite involves the skin and immediately subcutaneous tissues. It includes the previously described signs but with the pain subsiding to feelings of warmth. This is a sign of severe involvement. The skin has a waxy appearance, but deeper tissues remain soft and resilient. Clear blebs form, accompanied by edema and erythema within 24–36 hours after thawing. Lesions may become eroded (Fig. 94-6). Deep frostbite extends to the deep subcutaneous tissue. The injured skin becomes white or bluish white with a variable degree of anesthesia. Most often the affected skin becomes deceptively pain free, and the discomfort of feeling cold vanishes. The tissue is

Cold Injuries

and nerve injury may occur with axonal degeneration of large myelinated fibers. Autonomic fibers are also affected, and this may account for the abnormal sweating and cold sensitivity that follow nonfreezing cold injury.38,39 Nerve sheaths are quite resistant to cold, as are bone and cartilage.28 Desolidification of lipids in adipose tissue and disruption of endothelial cells lining blood vessels and lymphatics, with secondary disturbances of permeability and blood flow, are other consequences of severe cold. In the overall assessment, there are marked similarities in the pathologic processes to those seen in thermal burns and in ischemiaperfusion injuries. Three stages of cooling are recognized. The first is massive vasoconstriction, which causes a rapid fall in skin temperature. In a second step, the hunting reaction follows with a cyclic rise and fall in skin temperature. If cold exposure continues, the third stage of freezing occurs as the skin temperature falls to approach ambient temperature. The events that ensue in freezing and nonfreezing cold injuries are similar.17,40 Consequences of cold injuries and their classification are presented in Tables 94-1 and 94-2, respectively. Frostbite commonly affects fingers, toes, ears, nose, and cheek.41,42 The clinical presentation of frostbite falls into three categories corresponding to mild frostbite or frostnip, superficial frostbite, and deep frostbite with tissue loss.

Figure 94-6  Superficial frostbite.

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TABLE 94-2

Classification of Nonfreezing Cold Injuries to the Skin Vasoconstriction Hunting reaction Immersion foot Pulling-boat hands Acrocyanosis Chilblains Cold urticaria Cold panniculitis Erythromelalgia Raynaud phenomenon Sclerema neonatorum Subcutaneous fat necrosis of the newborn Livedo reticularis Cryoglobulinemia Cold agglutinins Cryofibrinogenemia

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Figure 94-7  Deep frostbite after rewarming. Large blisters have formed. Note cyanosis of toes as a sign of developing necrosis. This cold injury occurred in a homeless person who was found on the street after heavy alcohol consumption and overnight snowfall. totally numb, indurated with immobility of joints and extremities. Muscles may be paralyzed. Nerves, large blood vessels, and even bone may be damaged. Large blisters form 1 to 2 days after rewarming, and they can be classified according to depth, as in heat-induced burns (Fig. 94-7). Frostbite blister fluid contains high amounts of prostaglandins, including prostaglandin F2α and thromboxane A2. These mediators may contribute to increased vasoconstriction, platelet aggregation, leukocyte adhesiveness, and ultimately progressive tissue injury. The blister fluid begins to be resorbed within 5 to 10 days, which leads to the formation of hard, black gangrene. Weeks later, a line of demarcation occurs, and the tissues distal to the line undergo autoamputation (Fig. 94-8).

PREVENTION Prevention is key to protecting individuals from the effects of cold weather; and frostbite, frostnip, and hypothermia always should be taken seriously. Prognostic factors25,43–46 are listed in Table 94-3. Wearing protective clothing, warm hat, earflaps and scarf together with preventive behavior such as turning bare areas away from the wind are the most important procedures for preventing frostbite. Nonmedicated waterless ointments are traditionally used for protection against facial frostbite, but their benefit is undocumented. The thermal insulation they provide is indeed minimal.41,42 The use of protective emollients seems to cause a false sensation of safety, which leads to an increased risk of frostbite, probably through neglect of other, more efficient protective measures.47,48 In less extreme conditions, however, some specific topical formulations bring beneficial effects.49 The most effective products are those reducing TEWL and perspiration because these biological functions cause emission of body thermal energy and thus cool the skin.

Figure 94-8  Dry gangrene of all fingers in a mountain climber 5 weeks after being caught in a snowstorm.

MANAGEMENT The first consideration in frostbite treatment is to be aware that the victim may be suffering from hypothermia.25,31,50,51 Because of the difficulty in assessing the depth of frostbite injury, conservative waiting after the frostbite episode is often encouraged in an attempt to delineate the extent of tissue loss. Beyond this, the main principles are to avoid trauma, friction, pressure, massaging with snow, and refreezing. Slow rewarming increases tissue damage, and therefore rapid rewarming is the keystone of treatment.20 It should be performed in a

TABLE 94-3

Prognostic Signs of Frostbite Good prognostic signs

Large, clear blebs extending to the tips of the digits Rapid return of sensation Rapid return of normal (warm) temperature to the injured area Rapid capillary filling time after pressure blanching Pink skin after rewarming

Poor prognostic signs

Hard, white, cold, insensitive skin Cold and cyanotic skin without blebs after rewarming Dark hemorrhagic blebs Early evidence of mummification Constitutional signs of tissue necrosis, such as fever and tachycardia Cyanotic or dark red skin persisting after pressure Freeze–thaw–refreeze injury

NONFREEZING COLD INJURY AND DAMPNESS Nonfreezing cold injury occurs when tissues are cooled to temperatures between approximately 15°C (59°F) and their freezing point for prolonged periods. This type of injury, which is exacerbated by dampness, has claimed numerous casualties in warfare. Nonfreezing cold injury may be followed by cold sensitivity and hyperhidrosis, which may persist for years. During World War I, trench foot was identified as a separate entity. Wet conditions at temperatures above freezing and limb dependency due to immobility and constrictive footwear were important pathogenic factors. Three stages were described. Stage I consisted of initial erythema, edema, and tenderness. Stage II followed within 24 hours with paresthesia, marked edema, numbness, and sometimes blisters. Stage III corresponded with progression to a usually superficial gangrene. Immersion foot, similar to trench foot, was described in shipwreck survivors during World War II.

Many individuals present with dryness of the skin, particularly on the lower extremities, during wintertime. The hands, forearms, cheeks, lips, and trunk also may be affected. Itching, a dry appearance, chapping, and cracking of the stratum corneum are more or less prominent. The condition is markedly influenced by cold environments, especially in combination with low humidity.38,39 Predisposing factors include atopic dermatitis, ichthyosis, and increasing age. Excessive washing exacerbates winter xerosis. Indeed, irritant dermatitis of the hands worsens in a cold and dry environment.60 Emollients and improvement in the environmental temperature and humidity are helpful in controlling this condition.

Cold Injuries

Sequelae of frostbite include permanent hypersensitivity to cold and, less often, hyperhidrosis.38 Squamous cell carcinoma is a rare outcome, usually occurring on the heel 20–30 years later.57 Epiphyseal plate damage or premature fusion may occur in children. Premature fusion can result in shortened digits, joint deviation, and dystrophic nails. In addition, frostbite arthritis, resembling osteoarthritis, may occur weeks to years later.

WINTER XEROSIS

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::

SEQUELAE

Tropical immersion foot was described during the Pacific campaign in World War II. Occurring after exposure to the warm, wet conditions of jungle warfare, this condition differed from classic trench foot and immersion foot in that it caused less tissue destruction, numbness, and anesthesia and was followed by more rapid complete recovery. The role of temperature in tropical immersion foot is unclear and may not be important.58 As with trench foot and immersion foot, prevention is most important. Another specific condition known as pulling-boat hands was described, characterized by the presence of erythematous macules and plaques on the dorsum of the hands and fingers of sailors aboard rowboats.59 Small vesicles developed later, accompanied by itching, burning, and tenderness. These individuals were exposed to long periods of high humidity, cool air, and wind, an ideal setting for the development of nonfreezing cold injury. In addition, hours of vigorous rowing daily produced repetitive hand trauma.

Chapter 94

water bath no warmer than 40°C–42°C (104°F to 107.6°F) until the most distal parts of the body are flushed. Large amounts of analgesics may be required. The damaged part should be elevated, and blisters should be left intact. Surgical debridement is often best delayed until 1 to 3 months after demarcation. However, triple-phase bone scans, magnetic resonance imaging, and magnetic resonance angiography can be used to predict ultimate tissue loss and to assess the possibility of earlier surgical intervention.40,52,53 There is no uniformly accepted protocol for other measures allegedly beneficial in the treatment of frostbite injury.51 Intra-arterial reserpine and sympathectomy have been used to reverse vasospasm, which may contribute to tissue loss. Their role is controversial, although some patients have benefited from this therapy. To counteract vasoconstriction caused by local release of inflammatory mediators, the use of topical aloe vera, which inhibits thromboxane synthetase, and systemic ibuprofen, which inhibits cyclooxygenase, have been advocated. Oxpentifylline has been presented as an advanced therapy.54 In addition, several adjunctive therapies, including vasodilators, thrombolysis, and hyperbaric oxygen, are sometimes useful.55 Tetanus toxoid should be given in the case of open wounds. Surgery and amputation remain the ultimate strategies to help the victims.56

ACROCYANOSIS Acrocyanosis is a bilateral dusky mottled discoloration of the hands, feet, and sometimes the face. It is persistent and accentuated by cold exposure. When the temperature is very low, the skin may be bright red. Trophic changes and pain do not occur, and pulses are present. This condition must be distinguished from Raynaud phenomenon (see Chapter 170), which is clearly episodic, often segmental, and painful, as well as from obstructive arterial disease (see Chapter 173). Acrocyanosis is genetically determined and usually starts in adolescence. Chronic vasospasm of small cutaneous arterioles or venules with a secondary dilatation of the capillaries and subpapillary venous plexus has been postulated. Stasis in the papillary loops with aneurysmal dilatation at the tips redistributes blood flow to the subpapillary venous plexus. The blood flow may be compromised by altered erythrocyte flexibility, increased platelet adhesiveness, and other plasma viscosity factors. Cold agglutinins may exacerbate the acrocyanosis manifestations.61,62 The “puffy hand

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syndrome” is defined by the presence of hand edema superposed on acrocyanosis.63 Tissues are less sclerotic in acrocyanosis than in Raynaud phenomenon. They contain twisted collagen fibrils and large pericytes. In cases developing for the first time late in life, an underlying myeloproliferative disorder should be excluded. Remittent necrotizing acrocyanosis is associated with enhanced susceptibility to cooling and pain, as well as ulceration and gangrene of the fingers. Arteriolar occlusion by thrombi or intimal proliferation may occur. Cold pain should be distinguished from cold allodynia and cold hyperalgesia. There is no effective treatment for acrocyanosis. Supportive measures to keep the skin warm are helpful.

A

ERYTHROCYANOSIS Erythrocyanosis is a dusky cyanotic discoloration, worse in winter, which occurs over areas with a thick layer of subcutaneous fat (Fig. 94-9). The condition is seen most often on the lower legs and thighs of adolescent girls and middle-aged women. Nodular lesions similar to chilblains may occur and have been described in women with severe erythrocyanosis and paraplegia. Keratosis pilaris, angiokeratomas, and telangiectasia are commonly associated. Spontaneous improvement often occurs after a few years. However, the disease may persist with long-standing edema and fibrosis. The wearing of warm clothes and weight reduction are important to decrease the insulating effect of the subcutaneous fat, which is responsible for a chronically low skin temperature. The outcome remains unpredictable.

CHILBLAINS Chilblains, also called pernio or perniosis (Fig. 94-10), are localized inflammatory lesions caused by continued exposure to cold above the freezing point.64,65 Dampness and wind that increase thermal conductivity and convection play a part. Absolute temperature is less important than the cooling of nonadapted tissue. The

Figure 94-9  Erythrocyanosis of plump upper arms of a woman.

B

C

Figure 94-10  Chilblains are common at such sites as the hands and feet when they are exposed to both cooling and tight garments. A. Chilblains on the toes. B. Chilblains on the dorsum of the foot. Children and the elderly are most commonly affected, perhaps, because they take less care to protect themselves from cooling. C. Equestrian chilblains from horse riding on a cold morning with inadequate clothing. condition shows a genetic predisposition. It has been described most often in temperate regions, where winters are occasionally cold and damp. Chilblains are seen less often in very cold climates, where wellheated houses and warm clothing are available. Both acrocyanosis and chilblains appear to be more common in children, women, and persons with low body mass index. Spontaneous remission is common when spring arrives, and relapse is frequent during the following winters. However, chilblains do not always occur at the time of maximum cold. Chilblains develop acutely as single or multiple, burning, erythematous, or purplish swellings (see Fig. 94–10A and C). Patients may complain of itching, burning, or pain. In severe cases, blisters (see Fig. 94-10B), pustules, and ulceration may occur. Characteristic locations include the proximal fingers and toes, plantar surfaces of the toes, heels, nose, and ears, but other sites like the calves and thighs can be affected66,67 (see Fig. 94-10C). Lesions usually resolve in 1 to 3 weeks but may become chronic in elderly people with venous stasis. Tight garments such as gloves, stockings, and shoes are especially to be avoided in cases in which there is also peripheral vascular disease. A papular form of chilblains resembles erythema multiforme and occurs at all times of the year, usually in crops on the sides of the fingers,68 often superimposed on a background of acrocyanosis.

edematous papules and plaques, often with headache, fever, arthralgia, and leukocytosis. Swelling of the oral mucosa and esophagus may occur on ingestion of cold liquids. A rather distinctive combination of cold urticaria and dermographism or cholinergic urticaria is not uncommon. Alarming signs resembling those of histamine shock may lead to loss of consciousness. Death while swimming in cold water has been reported. Familial cold urticaria is a rare autosomal dominant condition with onset at an early age.84,85 A mutation in the gene responsible for the cold-induced autoinflammatory syndrome-1 (CIAS1) has been identified.85 Urticaria develops when the patient is exposed to generalized cooling, particularly chilling wind, rather than local cold application. The delayed type of familial cold urticaria is characterized by localized angioedema developing 9 to 18 hours after cold exposure. Cold urticaria may occur in 3%–4% of patients with cryoglobulinemia, and it also may be associated with cold agglutinins, cryofibrinogens, and cold hemolysins. Cold urticaria has been reported in cases of infectious mononucleosis in association with either cryoglobulins or cold agglutinins, but such occurrences are rare. Cold urticaria may also be a sign of the Muckle–Wells syndrome that associates urticaria, deafness and amyloidosis.86 In this rare genetic disorder recurrent bouts of urticaria, fever, chills and malaise may occur from birth and persist throughout life. Helicobacter pylori has been suggested as a causative agent in some cases of acquired cold urticaria.87 Diagnosis of cold urticaria is confirmed by a cold challenge induced by an ice cube wrapped in a plastic bag placed on the skin of the forearm for periods varying from 30 seconds to 10 minutes (see Fig. 94-11). Wheals form on rewarming. Sometimes water at 7°C (44.6°F) is more effective, presumably because it causes less severe vasoconstriction. Peltier effect-based temperature challenge appears to be an improved method for diagnosis.88 The Peltier effect relies on using two different heat-transferring metals to generate a precise skin surface temperature, sufficiently cold, to induce lesions. The temperature is regulated by a microprocessor control unit monitoring the actual temperature at the test site. Cold erythema seems to be a related disorder with erythema and pain but without urticaria. Familial polymorphous cold eruption is a rare autosomal dominant disease characterized by childhood onset of nonpruritic,

Cold Injuries

Acquired cold urticaria is a form of physical urticaria (Fig. 94-11). Lesions occur at sites of localized cooling, usually when the area is rewarmed. The disease is recognized by wheal and flare-type reactions and/or angioedema. The condition may be idiopathic or associated with some serologic abnormality.79–83 It accounts for approximately 2% of cases of urticaria (see Chapter 38). Most cases fall into the group of essential cold urticaria. They can be subdivided into a rare familial type and an acquired form. Immunoglobulin E and, more rarely, immunoglobulin M have been implicated in the pathogenesis. The antigen is likely a normal metabolite produced on exposure to cold. Histamine is one of the most important mediators, but leukotrienes, plateletactivating factor, and others have been incriminated. In this disease, exposure to cold causes prolonged

Figure 94-11  Cold urticaria induced by the application of ice to the skin.

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COLD URTICARIA AND POLYMORPHOUS COLD ERUPTION

17

Chapter 94

A peculiar clinical presentation may occur in young women riding horses for several hours daily during winter.69,70 Indurated red-to-violet tender plaques develop on the lateral calves and thighs (see Fig. 94-10C). The condition is quite similar to the nodular perniotic lesions described in adolescent girls with erythrocyanosis. For prophylaxis, experienced riders usually wear baggy breeches that provide insulation and are not tight enough to compromise the circulation. Perniotic lesions have been described in association with myeloproliferative disorders,71 probably as a consequence of blood flow changes, presence of cold agglutinins, and altered inflammatory response on cooling. Idiopathic perniosis is characterized histologically by edema of the papillary dermis and by the presence of superficial and deep perivascular lymphocytic infiltrates. Necrotic keratinocytes and lymphocytic vasculitis also have been reported. Thickening of blood vessel walls with intimal proliferation may lead to obliteration of the vascular lumen.72–74 Chilblain lupus is a distinct disease and is similar to discoid lupus erythematosus.75,76 Lupus pernio is a variant of sarcoidosis (see Chapter 152) and is unrelated to cold injuries. The unfamiliarity of physicians with chilblains sometimes gives rise to unnecessary hospital admissions with expensive laboratory and radiologic evaluations and, at times, hazardous therapy. The most important point in management is prophylaxis through the use of adequate, loose, insulating clothing and appropriate warm housing and workplace. Maintaining the blood circulation by avoiding immobility is also helpful. A short course of ultraviolet light therapy at the beginning of winter was a recommendation but has been challenged.77 Once chilblains occur, treatment is symptomatic with rest, warmth, and topical antipruritics. Calcium channel-inhibiting drugs may be effective in the treatment of severe recurrent perniosis,78 although they may cause headache and flushing that are troubling to some patients. In cases of crippling severity, thyrocalcitonin and hemodilution may be helpful.

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erythematous patches often accompanied by influenzalike symptoms and leukocytosis after generalized exposure to cold. Results of the ice cube test are negative. The pathogenesis remains unknown. The disease frequently has been referred to as familial cold urticaria, although the skin lesions are not urticarial.89 Avoiding cold wind exposure and swimming in cold water are important preventive measures. Antihistamines reduce clinical signs and symptoms. Desensitization to cold is possible by immersing one arm into water at 15°C (59°F) for 5 minutes daily.

Section 17

COLD PANNICULITIS AND RELATED ENTITIES

:: Skin Changes Due to Other Physical and Chemical Factors

Cold injuries may affect the subcutaneous tissue in different ways. The freezing injury in deep frostbite results in tissue gangrene. Nonfreezing injuries also can alter the hypodermis. Among them, cold panniculitis is more common in children than in adults. It affects the cheeks and legs most commonly. Tender erythematous subcutaneous nodules appear 1 to 3 days after exposure and subside spontaneously within 2 to 3 weeks. Ice cube challenge to the child’s skin for 10 minutes results in the development of an erythematous plaque 12 to 18 hours later. A perivascular mixed infiltrate with neutrophils, lymphocytes, and histiocytes is present at the dermal– subcutaneous junction after 24 hours, followed by a well-developed panniculitis at 48 to 72 hours. Some adipocytes are necrotic and rupture to form cystic spaces. The reaction subsides completely in 2 weeks. Infants have a higher content of saturated fatty acids in adipose tissue than do adults, and this may result in solidification at higher (less cold) temperatures.90,91 Cold panniculitis should be distinguished from other related disorders, including erythrocyanosis with nodules, sclerema neonatorum, and subcutaneous fat necrosis of the newborn.

SCLEREMA NEONATORUM AND SUBCUTANEOUS FAT NECROSIS OF THE NEWBORN

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(See Chapters 70 and 107) Sclerema neonatorum and subcutaneous fat necrosis of the newborn are distinct disorders involving the subcutaneous fat of the newborn. As noted in the prior paragraph, infant fat differs from adult fat in that it has a higher saturated–unsaturated fatty acid ratio, which results in solidification at a higher temperature. Prematurity and immaturity of enzyme systems may result in a relative inability to desaturate fatty acids, which alters the ratio further. Sepsis, dehydration, chilling, infection, and other stresses also may inhibit the enzyme system. Thus, infants in general, and premature or otherwise compromised newborns in particular, are susceptible to such disorders.

Sclerema neonatorum is a rare disorder characterized by diffuse, rapidly spreading hardening of the skin and subcutaneous tissue in infants.92 It starts on the buttocks and trunk, usually in the first week of life. Palms, soles, and scrotum are spared. Fifty percent of affected infants are premature. They have difficulty feeding and are lethargic, and many are otherwise debilitated. Septicemia is frequent, and the prognosis is poor. Cold exposure does not seem to be important in the etiology of sclerema neonatorum; however, similar clinical findings have been seen in cases of primary cold injury.93 Histologically, the subcutaneous layer is greatly thickened by enlarged fat cells and wide, fibrous bands. There is no fat necrosis, and many of the fat cells contain fine needle-like clefts.94 Treatment of sclerema neonatorum involves correcting dehydration and electrolyte imbalance and treating septicemia if present. The value of systemic glucocorticoids is controversial. Successful treatment with exchange transfusions has been reported.95 Subcutaneous fat necrosis of the newborn is characterized by discrete red to violaceous mobile plaques and nodules that usually appear within a few days of birth. The back, thighs, and cheeks are most commonly affected. Fat necrosis and crystallization are the hallmarks of the disease. There may be a granulomatous inflammatory response with foci of calcification. In most cases, the condition is benign and self-limited, although it has been associated with hypercalcemia and death.96 As in sclerema neonatorum, there is no clear etiologic relationship to cold, and the cause is likely multifactorial. It has been postulated that an underlying defect in fat composition, poor nutrition, and various physical stresses such as hypothermia may be important.

ERYTHROMELALGIA Erythromelalgia or erythermalgia is a rare chronic cutaneous disorder characterized by erythema, burning discomfort, and warmth of the extremities.97,98 Primary erythromelalgia is an autosomal dominant neuropathic disorder involving a mutation in a voltage-gated sodium channel subunit.99–106 Vasoconstriction apparently precedes reactive hyperemia, similar to that seen in Raynaud phenomenon. An early-onset type and an adult-onset type have been recognized. When the extremity is lowered or heat is applied, the pain is intensified. The application of cold or elevation of the extremity has the opposite effect of decreasing the pain. Idiopathic erythromelalgia may involve increased thermoregulatory arteriovenous shunt flow. Secondary erythromelalgia is associated commonly with myeloproliferative syndrome-related thrombocythemia and is mostly evident in the adult-onset type. Treatment for adults with erythromelalgia includes a single daily dose of acetylsalicylic acid (aspirin), but children who have no associated underlying disorder obtain little to no relief from the drug. Other drugs including mexiletine107 and venlafaxine108 may also help. Pain may be decreased by topical amitriptyline combined with ketamine.109 Lidocaine in patches110 or

administered intravenously in combination with oral mexiletine111 may also alleviate pain. Sympathectomy in the upper extremities is another option for treating refractory primary erythromelalgia.112

RAYNAUD PHENOMENON (See Chapter 170)

CRYOGLOBULINEMIA

LIVEDO RETICULARIS

Full reference list available at www.DIGM8.com DVD contains references and additional content 22. Long WB 3rd et al: Cold injuries. J Long Term Eff Med Implants 15:67, 2005 32. Middleton JB, Allen BM: The influence of temperature and humidity on stratum corneum and its relation to skin chapping. J Soc Cosmet Chem 24:239, 1974 33. Piérard-Franchimont C, Piérard GE: Beyond a glimpse at seasonal dry skin: A review. Exog Dermatol 1:3, 2002 46. Daanen HA, van der Struijs NR: Resistance index of frostbite as a predictor of cold injury in arctic operations. Aviat Space Environ Med 76:1119, 2005 83. Buss YL, Sticherling M: Cold urticaria; disease course and outcome – An investigation of 85 patients before and after therapy. Br J Dermatol 153:440, 2005 91. Quesada-Cortés A et al: Cold panniculitis. Dermatol Clin 26:485, 2008 98. Davis MD, Rooke T: Erythromelalgia. Curr Treat Options Cardiovasc Med 8:153, 2006

Serious burns require inpatient care, ideally in a verified burn center.

jobs are at modest increased risk. In developed countries, about 70% of pediatric burns are caused by hot liquid. Flame injuries are more common in older children and young working adults. Scalding and flame injuries each account for approximately half of burn injuries in the elderly, with kitchen and bathing accidents being predominant. Approximately 20% of burns in younger children involve abuse or neglect.

Large burns are managed in four general phases:

ETIOLOGY AND PATHOGENESIS

THERMAL INJURIES AT A GLANCE Burns are common; most are small and managed in the outpatient setting.

Initial evaluation and resuscitation. Wound excision and biologic closure. Definitive wound closure. Rehabilitation and reconstruction. Styles of outpatient burn care are variable, but proper patient selection and monitored wound healing are essential. Long-term outcome quality tends to be very good in patients surviving large burns.

EPIDEMIOLOGY The very young and very old are at increased risk of domestic burns.1,2 Active young adults in industrial

The development of an envelope of cornified skin was a crucial component of the adaptation of aquatic sea animals to the land environment. The vapor and fluid barrier created by the epidermal layer facilitates the maintenance of fluid and electrolyte homeostasis within very narrow limits. The dermis provides strength and flexibility, and the reactive dermal vasculature facilitates control of internal body temperature within very narrow limits. The appendages provide lubrication and prevent desiccation. All of these critical functions are lost when substantial areas of the skin are burned. There is both a local and a systemic response to the burn wound.3,4 The local response consists of coagulation of tissue with progressive thrombosis of surrounding vessels in the zone of stasis over the first 12–48 postinjury hours. An ability to truncate this secondary microvascular injury and its associated tissue loss is a major area of ongoing investigation. In larger burns, a systemic response develops that is driven initially by release of mediators from the injured tissue, with a secondary diffuse loss of capillary integrity and accelerated

Thermal Injuries

Chapter 95 :: Thermal Injuries :: Robert L. Sheridan

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(See Chapter 173)

17

Chapter 95

(See Chapter 169)

KEY REFERENCES

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Section 17 :: Skin Changes Due to Other Physical and Chemical Factors

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transeschar fluid losses. This systemic response is subsequently fueled by by-products of bacterial overgrowth within the devitalized eschar. Burn wounds are initially clean but are rapidly colonized by endogenous and exogenous bacteria.5 As bacteria multiply within the eschar over the days following injury, proteases result in eschar liquefaction and separation. This leaves a bed of granulation tissue or healing burn, depending on the depth of the original injury. In patients with large wounds involving 40% or more of the body surface, the infectious challenge generally cannot be localized by the immune system, leading to systemic infection. This explains the rare survival of patients managed in an expectant fashion with burns of this size. The systemic response to injury is characterized clinically by fever, a hyperdynamic circulatory state, increased metabolic rate, and muscle catabolism.6 This stereotypical response to injury has been retained by all mammalian species. It is effected by a complex cascade of mediators, including changes in hypothalamic function resulting in increases in glucagon, cortisol, and catecholamine secretions; deficient gastrointestinal barrier function with translocation of bacteria and their by-products into the systemic circulation; bacterial contamination of the burn wound with systemic release of bacteria and bacterial by-products; and some element of enhanced heat loss via transeschar evaporation. It is likely that this response has significant survival value, but control of some of the adverse aspects of this response, particularly muscle catabolism, is an active area of ongoing investigation.7,8

Box 95-1  Essentials of Burn Management Burn size, extent, depth, and circumferential components influence decisions regarding outpatient care, hospitalization or transfer. Burn extent is best estimated using the Lund– Browder diagram that compensates for the changes in body proportions with age (see eFig. 95-4.1 in online edition). An alternative is a “rule-of-nines” for adults and children (see eFig 95-5.1 in online edition). In the adult rule-of-nines, the head and neck is given 9%, each lower extremity is given 18%, each upper extremity is given 9%, and the anterior and posterior torso are each given 18%. In the pediatric rule-of-nines, the head and neck is given 18%, each lower extremity is given 15%, each upper extremity is given 10%, and the anterior and posterior torso are each given 16%. For scattered or irregular burns, the entire palmar surface of the patient’s hand represents approximately 1% of the body surface over all ages.

CLINICAL FINDINGS (See Box 95-1) Burns are classified by depth:



First degree: Red, dry, and painful and are often deeper than they appear, sloughing the next day (Fig. 95-1A). Second degree: Red, wet, and very painful with enormous variability in their depth, ability to heal, and propensity to hypertrophic scar formation (see Fig. 95-1B).

A

B

C

D

Figure 95-1  Burn depth is classified as first, second, third, or fourth degree. A. First-degree burns are red, dry and painful and are often deeper than they appear, sloughing the next day. B. Second-degree burns are red, wet and very painful. There is an enormous variability in their depth, ability to heal, and propensity to hypertrophic scar formation. C. Third-degree burns are leathery, dry, insensate, and waxy. D. Fourth-degree burns involve underlying bone and/or muscle.



Third degree: Leathery, dry, insensate, and waxy (see Fig. 95-1C). Fourth degree: Involve underlying subcutaneous tissue, tendon, or bone (see Fig. 95-1D).

Circumferential burns require special monitoring and possible surgical decompression. If across the torso, they will interfere with ventilation. If they involve an extremity, limb-threatening ischemia may occur during resuscitation.

LIGHTNING STRIKES

17

Burn Wound Complications Common Outpatient Burn Complications Wound sepsis, usually streptococcal cellulitis Excessive pain and anxiety Underestimation of burn depth

Thermal Injuries

unusual. Serious injury is more often the result of associated blunt trauma or occasional cardiac arrest. In most survivors, lingering symptoms are nonfocal, neurologic in nature, often preceded by an immediate but transient loss of consciousness.9 The most common physical finding in those injured by side flash is an evanescent serpiginous cutaneous erythema, as noted in Figure 95-2.

::

Common Inpatient Burn Complications Wound sepsis, often invasive Septic shock and organ failures Inadequately controlled pain and anxiety Compartment syndromes Ocular exposure Respiratory failure Gut failure Pancreatitis Cholecystitis Urosepsis Donor site infection Soft-tissue contractures

Chapter 95

Although lightning strikes carry large amounts of energy, measured in millions of volts, human injuries are rare, with only about 50 people so injured annually in the United States and a fatality rate of only about 10%. Injury can rarely occur from direct strike, and is usually fatal. More commonly, people are injured by current flow around the skin envelope, or side flash, when a nearby object is struck. Destructive burns are

TABLE 95-1

COMPLICATIONS

A

B

Figure 95-2  (A and B) An evanescent serpiginous cutaneous erythema is characteristic of lightning injury.

In the outpatient setting, patient selection should ensure that major complications are few (Table 95-1). The most common issues that arise are wound sepsis, excessive pain and anxiety, and underestimation of burn depth.10 The most common wound infection in this setting is streptococcal cellulitis, which presents initially with surrounding erythema that progresses to lymphangitis and systemic toxicity (Fig. 95-3). These patients often need admission for antibiotics, observation, and sometimes surgery. In some situations, adequate pain and anxiety management is very difficult in the outpatient setting, especially around dressing changes. This can be addressed with judicious medication and sometimes carefully monitored membrane dressings. Some patients will require admission. It is common for burn depth to be underestimated initially, with areas of fullthickness injury not appreciated for several days. These patients may require admission for surgery. As burns increase in size and depth, the local injury is accompanied by an increasing degree of systemic derangement. Classically, this response has two phases. An initial “ebb” phase of reduced perfusion and metabolic rate, which lasts 24–48 hours, is followed by a “flow” phase of protein catabolism and a hyperdynamic circulation.11 This later phase lasts until well after wound closure. Management of this physiology is an essential part of inpatient burn care. Those with large burns are susceptible to a host of other complications

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Figure 95-3  The most common wound infection in this setting is streptococcal cellulitis, which presents initially with surrounding erythema that progresses to lymphangitis and systemic toxicity. related to sepsis and organ failure. Careful monitoring and early intervention are essential to successful outcomes (Table 95-1).

PROGNOSIS AND CLINICAL COURSE PATIENT EVALUATION AND TREATMENT PLANNING In both outpatient and inpatient settings, a careful evaluation of the patient is essential for treatment planning. Patient evaluation is organized into a primary and a secondary survey, following the guidelines of the American College of Surgeons Committee on Trauma and the Advanced Burn Life Support Course of the American Burn Association. As in trauma, the primary survey begins with an assessment, and control if necessary, of the airway. Deeper burns of the face and neck can result in progressive airway edema. Occasionally, a child will aspirate hot liquids resulting in very severe upper airway edema mandating urgent intubation. A burn-specific survey evaluates the issues uniquely associated with burn injury (eTable 95-1.1 in online edition). This may take just a few seconds if the burn is small, but will be much more time consuming in the more seriously injured.12 In those with small injuries, essentials include a detailed determination of the mechanism of injury, a screen for associated trauma, consideration of the possibility of abuse (Fig. 95-4), and a detailed assessment of the burn wound. Delayed presentation for care, confusing stories, sharply demarcated margins, immersion patterns, and contact injuries are physical findings suggesting for abuse or neglect.13 All such children should be admitted for evaluation. After the patient has been evaluated, the burn wound should be examined for size, extent, depth, and circumferential components.14 Burn extent is best estimated using a chart based on the Lund–Browder diagram that

Figure 95-4  Some burn patterns are very suggestive of possible abuse. Here is illustrated flexor sparing in an immersion injury. compensates for the changes in body proportions with age (eFig. 95-4.1 in online edition). An alternative is a modified “rule-of-nines,” in which the head and neck is given 18% (instead of the adult 9%), each lower extremity is given 15% (instead of the adult 18%), each upper extremity is given 10% (instead of the adult 9%), and the anterior and posterior torso are each given 16% (instead of the adult 18%). For scattered or irregular burns, the entire palmar surface of the patient’s hand represents approximately 1% of the body surface over all ages. Burn depth is classified as first, second, third, or fourth degree (Fig. 95-1A–D). First-degree burns are red, dry and painful and are often deeper than they appear, sloughing the next day. Second-degree burns are red, wet and very painful. There is an enormous variability in their depth, ability to heal, and propensity to hypertrophic scar formation. Third-degree burns are leathery, dry, insensate, and waxy. Fourth-degree burns involve underlying subcutaneous tissue, tendon, or bone. Near or completely circumferential burns should be identified for special monitoring, as they may need to be decompressed in the hours following injury to avoid ischemia (extremities) or failure of ventilation (torso). The majority of burns can be successfully managed in the outpatient setting. However, poorly provided outpatient burn care can be frustrating and painful for patients and providers. The key is careful patient selection (eTable 95-1.2 in online edition) and a detailed care plan, especially an inpatient care plan (eTable 95-1.3 in online edition).

PATIENT OUTCOMES Burn wounds and grafts typically develop some degree of hypertrophic scarring.15 This involves a gradual increase in vascularity and collagen deposition in the months following healing. Some wounds will demonstrate significant contracture formation, with important functional and esthetic consequences (Fig. 95-5). Many patients will have bothersome pruritus and sometimes temporary neuropathic pain if burns are deep. A

17

Chapter 95 ::

B

Figure 95-5  Hypertrophic scarring and contracture formation can become difficult problems after serious burns (A), but are often amenable to surgical improvement (B). long-term follow-up plan, consisting of scar management strategies, rehabilitation, reconstructive surgery, and emotional support will facilitate optimal outcomes. This care is best provided in a multidisciplinary burn clinic, ideally part of a comprehensive burn program. With such supports in place, the long-term outcome for most patients is surprisingly good. When managed in a comprehensive follow-up program, even those who have suffered devastating burns tend to become happy and productive again.16,17

TREATMENT OUTPATIENT BURNS Practice patterns vary widely, but certain characteristics are universal.18 The wound should be kept generally clean and regularly inspected for infection. Desiccated exudates and topical medications should be periodically cleansed. Burns selected for outpatient management tend to be small and superficial with a corresponding low risk of infection, so clean rather than sterile technique is reasonable. If topical agents rather than membrane dressings are used, wounds may be cleansed with lukewarm tap water and a bland soap. Soaking adherent dressings prior to removal will decrease the pain associated with daily wound care. The wound is gently cleansed with a gauze or clean washcloth, inspected for any sign of infection, patted dry with a clean towel and redressed. It is important to instruct each patient to return promptly if they notice

Thermal Injuries

A

erythema, swelling, increased tenderness, lymphangitis, odor, or drainage so that infectious complications can be addressed early. Most small burns are adequately managed with a daily cleansing and dressing change. In some cases, a membrane dressing is applied once it is clear that early surgery is not needed, early infection is unlikely, and wounds are superficial. Pain and anxiety can be an issue for many. Some will benefit from an oral narcotic given 30–60 minutes prior to a planned dressing change. If dressings are occlusive, pain between dressing changes tends to be modest. Increasing pain and anxiety associated with dressing changes; inability to keep scheduled follow-up appointments; delayed healing; signs of infection or a wound, which appears deeper than appreciated at the time of the initial examination, should prompt early return and specialty evaluation. Wounds selected for outpatient management are usually fairly superficial and heal within two weeks, but patients with mid and deep dermal injuries may have a deeper component with resulting scarring that may benefit from specialty evaluation. Finally, wounds of the face, ears, hands, genitals, and feet have functional and cosmetic importance out of proportion to their wound size. In some cases, early specialty evaluation may be prudent, as initial care can have an impact on long-term outcome.19

INPATIENT BURNS A system of burn center verification has evolved to ensure that the patients requiring care of more

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serious injuries receive coordinated efforts by experienced providers. Burn center referral criteria can be found at www.ameriburn.org (eTable 95-1.4 in online edition). Care of severe burns can be divided into phases, each with important objectives (eTable 95-1.3 in online edition).20 Critical care is an important component, especially in the first three phases. Verified burn programs are required to have embedded burn intensive care units.

TOPICAL MEDICATIONS AND MEMBRANES Section 17 :: Skin Changes Due to Other Physical and Chemical Factors

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There is an increasingly confusing array of wound medications and membranes available for burn wounds. Wound medications and membranes provide three benefits: (1) pain control, (2) prevention of wound desiccation, and (3) reduction of wound colonization. Topical wound medications range from aqueous solutions through antibiotic-containing ointments and debriding enzymes. Most topical agents in outpatient use have a viscous carrier that prevents wound desiccation and a more or less broad antibacterial spectrum that reduces wound colonization. A gauze wrap minimizes soiling of clothing and protects the wound from trauma. Silver sulfadiazine is in common use because it is painless on application and has a broad spectrum of antibacterial activity. Superficial burns are commonly treated with a clear, viscous antibacterial ointment containing low concentrations of various antibiotics. Wounds around the eyes can be treated with topical ophthalmic antibiotic ointments. Significant ear burns should be treated with mafenide acetate, as it is the only agent that will penetrate the relatively avascular cartilage. Wound membranes provide transient physiologic wound closure while the underlying wound heals.21 Physiologic closure implies a degree of protection from mechanical trauma, vapor transmission characteristics similar to skin, and a physical barrier to bacteria. The major benefit of wound membranes is that, when successful, they minimize wound manipulations. These membranes help create a moist wound environment with a low bacterial density and are generally intended for use on selected clean superficial wounds and donor sites. Occlusive synthetic membranes must be used

with caution if wounds are not clearly clean and superficial, as submembrane infection can occur, deepening underlying wounds and causing systemic infection and toxicity.

PREVENTION There have been a plethora of burn prevention efforts, which have met with mixed success. They can be based on (1) public education, (2) legislation, or (3) engineering.22 Public education campaigns depend for their success on an educated literate community. The “stop, drop, and roll” campaign in elementary schools is an excellent example. Legislation is often more effective. Examples include safe factory set points for home water-heaters and flammability standards for children’s bedclothes. Engineering solutions are perhaps the most effective. Examples are common in industry, and include physical isolation of high-power lines and “child-proof” cigarette lighters. Often all the three are combined, a current example being the fire-safe cigarette. A self-extinguishing cigarette has been engineered and, in some places, its sale is mandated after public education influenced the legislative process.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Fagenholz PJ et al: National study of Emergency Department visits for burn injuries, 1993 to 2004. J Burn Care Res 28(5):681-690, 2007 10. Sheridan R: Outpatient burn care in the emergency department. Pediatr Emerg Care 21(7):449-656, 2005 12. Sheridan RL: Comprehensive management of burns. Curr Probl Surg 38(9):641-756, 2001 13. Chester DL et al: Non-accidental burns in children—Are we neglecting neglect? Burns 32(2):222-228, 2006 14. Sheridan RL: Evaluating and managing burn wounds. Dermatol Nurs 12(1):17-31, 2000 16. Sheridan RL et al: Longterm outcome of children surviving massive burns. JAMA 283(1):69-73, 2000 20. Sheridan RL: Burn care: Results of technical and organizational progress. JAMA 290(6):719-722, 2003

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Chapter 96 :: Skin Problems in Amputees :: Calum C. Lyon & Michael H. Beck SKIN PROBLEMS OF AMPUTEES AT A GLANCE Skin problems under limb prosthesis result from: Trauma.

Pressure. Occlusion and maceration.

Irritant and allergic contact dermatitis occurs due to materials applied to skin, worn, or used in construction of the prosthesis. Koebner phenomenon may occur in skin under prosthesis. Management: most important are basic hygiene measures. Early medical intervention and collaboration with prosthetist are essential to address problems.

The skin of an amputation stump is not designed to withstand the physical insults it encounters within a prosthetic limb. For example, although some adaptation to friction or pressure occurs, some skin problems are inevitable. If these dermatoses cannot be prevented or rapidly resolved by prosthesis adjustment or medical intervention, they can incapacitate the patient, particularly those who have lower limb, weight-bearing prostheses. As a result, patients may suffer social isolation,

Skin Problems in Amputees

Microclimate under prosthesis promotes bacterial and fungal infections.

DERMATOLOGIC PROBLEMS IN AMPUTEES

::

Physical trauma, disturbances of tissue fluid dynamics may cause other distinctive skin changes.

Chapter 96

Heat.

either a butyl rubber sleeve or corset to hold the appliance firmly onto the thigh (Fig. 96-2). Many patients with above-knee amputations now use a suction socket device that provides sufficient suspension by holding the prosthesis in place through negative pressure without the need for additional belts (see Fig. 96-1). Limb prostheses are the subject of continual technological development particularly in the field of bionics. Myoelectric devices, for example, rely on skin contact with electrodes to detect neuromuscular signals that can be converted to artificial limb movement. Neuroprosthetic devices involve implantation of electrodes into neural tissue usually through the skin, for example, cochlear implants. Such devices are under development for prosthetic limbs. These devices thus have the potential for causing skin problems.

Above-knee prosthesis

TECHNICAL BACKGROUND: LIMB PROSTHESES In most centers, artificial limbs are constructed in a modular fashion.1 The stump is placed in a thermoplastic socket that is then fitted into the main body of the limb. The bulk of the prosthesis comprises a metal frame with articulations and an outer casing of acrylic resin or carbon composite material. Before fitting the limb, many patients place their stump in a liner designed to reduce friction on the skin. This may be an expanded plastic cup, a silicon/mineral oil sleeve, or a cotton or nylon sock. The prosthetic limb, once fitted, is held in position by one of a range of suspension elements. In above-knee (Fig. 96-1) or proximal arm amputations, this is usually a fabric belt arrangement worn around the waist or shoulders, respectively. Below-knee amputees require a different system using

Figure 96-1  Above-knee prosthesis.

prosthesis.

Suction-socket

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Below-knee prosthesis

used, and peripheral vascular disease.4 A more recent questionnaire-based study of 805 lower limb amputees5 suggests that the factors more likely to be associated with skin problems are, smoking, younger age, female sex, washing the stump frequently and the use of antibacterial soaps. Overall one-third of amputees, either upper or lower limb, experiences a skin problem that significantly interferes with the normal use of the artificial limb.6

DERMATOSES RELATED TO THE REASONS FOR AMPUTATION Section 17 :: Skin Changes Due to Other Physical and Chemical Factors

Figure 96-2  Below-knee prosthesis. Patellar tendonbearing cuff suspension. emotional distress, or even financial deprivation if they are unable to work. Skin problems may occur because of allergy or chemical irritation to materials in contact with the skin, as well as from trauma and occlusion. Examples of physical stresses on the skin include shearing and friction from elements in the socket and pressure on load-bearing areas, especially on the tibial tuberosity in below-knee amputations and the ischial tuberosity, adductor region, or groin in above-knee amputations. In all cases, the occlusion results in increased humidity from trapped perspiration, increasing the likelihood of irritation, allergy, and infection. The common skin disorders in amputation stumps can be classified into diseases related to the reasons for the amputation, physical effects of a prosthesis, infection, contact dermatitis, and other cutaneous disorders.

EPIDEMIOLOGY

1096

The great majority of artificial limb wearers are amputees, although a small proportion are people with congenital limb malformations. Lower limb amputees are the most numerous and are also the group at greatest risk of skin problems. Traumatic amputations are possibly more likely to be associated with a dermatosis2 although the commonest problems encountered are the same as for all amputees.3 Modern limb prostheses allow many of today’s amputees to lead an active life with good mobility. Nevertheless, as many as 73% of one cohort of lower limb amputees reported at least one skin disorder.2 In a further group of 745 lower leg amputees, 40.7% had at least one skin problem. Further analysis identified four factors independently associated with dermatologic disorders, namely transtibial amputation, employment status, type of walking aid

Several disorders resulting in the need for amputation can have a significant impact on skin integrity. In general, younger patients require artificial limbs because of traumatic amputations, congenital abnormalities, or malignancy, whereas in the older age group, arterial disease and vascular complications of diabetes mellitus predominate. Amputations after trauma or severe vasculitis may be associated with scarring that makes for a suboptimal prosthesis fit (Fig. 96-3). Stump dermatoses appear to be more likely in patients following traumatic amputations. Koc et al2 found a skin problem in nearly three quarters of amputees most of whom had lost a limb as a consequence of mine explosions. The nature of current conflicts means that, presently, such amputations are unfortunately common amongst both service personnel and civilians. Vasculitis resulting in amputation may be ongoing and cause problems in the skin of amputation stumps (Fig. 96-4). However, it is diabetes mellitus that is particularly associated with protracted skin problems (Chapter 151) as a result of impaired wound healing, susceptibility to infection, abnormal sensory nerve function, and disruption of normal tissue fluid balance.7 Diabetic amputees as a group require more frequent clinical review to prevent complications. Treatment of the diabetic amputee not only requires good control of the blood glucose level but possibly a change of the stump environment through adjustment or redesign of the artificial limb. The diabetic amputee highlights the need for close links with a prosthetics department, which allow rapid referral of patients for assessment.

Figure 96-3  Scarring of the stump after amputation for severe postinfective vasculitis.

17

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A

Skin Problems in Amputees

C

D

E

Figure 96-4  Patient with vasculitis resulting in ischemia (A) that required amputation (B–C). This recurred on the amputation stump (D) but fortunately responded to systemic therapy.

PHYSICAL DERMATOSES The physical effects of wearing a prosthesis are the most common causes of skin problems.6,8 These can be divided into those resulting from repeated direct trauma and those secondary to disturbance of tissue fluid dynamics.

DIRECT PHYSICAL TRAUMA Ulceration. Ulceration and callus

formation are seen where there is chronic pressure or repeated frictional forces on stump skin. Ulceration may also be caused by infection or poor cutaneous nutrition, particularly secondary to diabetes mellitus (Figs. 96-5 and 96-6). Stump ulcers should be treated early as malignancy may develop in long-standing ulceration.9 With

repeated infection and ulceration, an amputation scar on the distal stump skin can erode further. In some cases, the skin may become completely adherent to bone and develop thick, callus-like hyperkeratosis (Fig. 96-7), which may necessitate revision of the distal bony surface. Ulceration or other injuries incurred while putting on artificial limb components may be particularly associated with poor manual dexterity consequent on neurological disorders or arthritic changes.10,11 Incorrect use of some appliance components can also result in injury.12 Patient selection and access to follow-up advice is therefore important in reducing such injuries. Apparently spontaneous ulceration at unexpected sites is occasionally seen (Fig. 96-8). In every instance, the cause of the ulceration must be determined to resolve a chronic process that can become totally disabling. However, a recent study

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Figure 96-5  Chronic ulcer of stump skin. examining 102 patients over 4 years suggests that the majority of patients with delayed wound healing or secondary ulcers will experience healing despite continuing to use their prosthesis, provided they are carefully monitored.13

Figure 96-7  Chronic ulceration resulting in thick hyperkeratosis and scab formation adherent to the underlying bone.

Epidermoid Cysts and Follicular Keratoses.

invagination of keratin around hair follicles, which then results in a foreign-body reaction. Follicular keratoses are therefore the earliest changes.14 These are very common, often multiple, and distributed at sites of weight bearing such as the anterior tibial area, popliteal fossa, and the adductor or inguinal areas of the thigh (Fig. 96-9A). Fortunately, they cause little trouble in many cases, but they can become inflamed and painful particularly if the patient picks at them to extract

Figure 96-6  Ulceration associated with infection in a diabetic man with an amputation for ischemia.

Figure 96-8  Ulceration in a patient receiving nicorandil for angina. The ulcer appeared spontaneously and not at a site of friction. It resolved slowly over 3 months after nicorandil was stopped suggesting the drug may have been involved.

Physical Dermatitis. In some patients, eczema may be caused by a poorly fitted or misaligned prosthesis or by edema and congestion of the terminal portion of the stump; only with alleviation of these problems does the condition clear. Epidermoid cysts and follicular keratoses are two ends of a spectrum of the same disorder. Repeated pressure and friction from the prosthesis appears to cause

17

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B

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the keratin plug or if they become infected. Inflamed follicular keratoses can have an acneiform appearance, leading some to suggest that they represent a form of acne mechanica. When the continued pressure and friction causes the keratin to extend deeper into the dermis, larger cystic lesions, 1–3 cm in diameter, form; these are commonly termed posttraumatic epidermoid cysts. Meulenbelt et al15 described a case of follicular keratoses of a transfemoral amputation stump in a patient who did wear an appliance at all. These lesions recurred after resection and were associated with retention of vellus hairs. This raises the possibility that, in some individuals, mechanisms other than just friction may be involved. Deeper cysts can be very tender when compressed by the prosthesis. Some cysts have an obvious punctum and patients may express keratinous material from them. Large cysts can be so painful that the patient can no longer wear a weight-bearing prosthesis each day (see Fig. 96-9B and 96-9C). Distention of the overlying epidermis can occur, followed by spontaneous rupture. A serous, purulent, or hemorrhagic fluid is then discharged. The resulting sinus is difficult to occlude and the discharge continues as long as the prosthesis is worn. Intercommunicating sinuses

can appear and spontaneous ruptures may occur. In advanced cases, a granulomatous reaction occurs around the cyst with considerable capillary dilation, vascularization, and a heavy inflammatory infiltrate progressing to abscess formation (see Fig. 96-9B). Management of this condition can be difficult. Clearly, prevention is the ideal but is not always possible despite regular prosthetic assessments. The fit of the prosthesis is the single most important method of preventing cyst formation. The problem can sometimes be improved or successfully eliminated by proper fitting and aligning of the prosthesis and continued adjustment by the prosthetist. Rough surfaces in areas of increased contact pressure in the socket, particularly the suction socket, tend to catch the skin, increasing the shearing forces. For this reason, the lining of the socket should be kept smooth. With the idea of inserting a buffer between the skin and the socket, protective devices such as liners and stump socks are used. Various synthetic films and adhesives, such as Teflon, have been found satisfactory as liners. They allow for a smooth, gliding action of the prosthetic socket wall or brim against the skin. Applying a vapor-permeable adhesive membrane to the skin before fitting the appliance can

Skin Problems in Amputees

C

Figure 96-9  Epidermoid cysts in different stages. A. Early follicular keratoses in the popliteal fossa of a man with belowknee amputation. B. Hemorrhagic and inflamed large epidermoid abscess in a man with an above-knee prosthesis. Note the follicular hyperkeratosis. C. Inflamed epidermoid cysts in the groin of a man with an above-knee prosthesis.

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Section 17 ::

also help reduce frictional trauma. Topical glucocorticoids can be used at night to reduce inflammation and provide symptomatic relief. Intralesional injection of glucocorticoids into the cysts and their channels also results in temporary improvement. Surgical intervention is useful in cases with a few lesions that are not infected. Lesions can be surgically incised and drained. In other instances, removal of the prosthesis is sufficient to cause the lesion to involute, provided that the cyst has not become too large. However, spontaneous rupture, incision, and drainage, and even spontaneous resorption of the lesion are of only temporary benefit. When the prosthesis is worn again, these cysts can recur so that surgical excision is not always the treatment of choice, especially in continually rubbed areas. In selected cases, systemic retinoid therapy may be appropriate to minimize hyperkeratosis. One author found oral isotretinoin to be effective in a patient described as having acne mechanica.16

Skin Changes Due to Other Physical and Chemical Factors

DISTURBANCES OF TISSUE FLUID DYNAMICS Edema. Amputation of a lower extremity greatly dis-

turbs the normal pattern of blood and lymph channels, as well as the relationship of pressure both inside the vessels and in the surrounding tissues of the stump. An important feature of care during convalescence after amputation is the reduction of edema and stabilization of new circulatory patterns in the stump. Swelling can be partially prevented by gradual compression of the stump tissues with an elastic bandage or “shrinker” sock before fitting the prosthesis and socket. When an amputee begins to wear a suction-socket prosthesis, the skin must adapt to an entirely new environment. The patient can expect edema, reactive hyperemia for days or weeks, a reddish-brown pigmentation resulting from capillary hemorrhage, and, occasionally, serous exudation and crusting of the skin of the distal portion of the stump. These changes are relatively innocuous, usually short lived, and do not usually require therapy. The extent to which edema may persist or recur in the healed stump depends on many factors.17 Edematous portions of the skin of the distal part of the stump may become pinched and strangulated within the socket (Fig. 96-10). Such areas may ulcerate if they catch in the spring-valve opening and become gangrenous as a result of the impaired blood supply. Therapy includes eliminating all mechanical factors contributing to the edema, such as choking by the socket, poor fitting, and misalignment. Excessive negative pressure in a suction-socket prosthesis also contributes to circulatory congestion and edema. Treatment should be directed toward better support of the distal soft tissues. Occasional use of an oral diuretic sometimes allows the edema to resolve.

Verrucous Hyperplasia. 1100

Verrucous hyperplasia refers to a reactive hyperplastic condition, characterized morphologically by numerous, coalescent warty papules (Fig. 96-11). It occurs when the chronic

Figure 96-10  Dependent edema/early verrucous hyperplasia in a man with multiple amputations after severe peripheral vasculitis and necrosis. pressure effects of a poor prosthetic fit disrupt vascular and lymphatic channels, resulting in chronic tissue edema. The same appearance is seen around longstanding leg ulcers where there is an element of lymphedema (see Chapter 174). Histologic examination can show evidence of pseudoepitheliomatous hyperplasia, although the condition itself is benign and potentially reversible. However, in neglected cases, malignant change can occasionally occur (see Fig. 96-11C). Bacterial infection may play a role in the development of pseudoverrucous hyperplasia, as secondary mixed flora infections are common because of the poor superficial blood flow and the convoluted surface (Fig. 96-12). External compression is the best method of treatment, in combination with topical control of bacterial infection. In below-knee amputees, the distal part of the stump is edematous; the stump dangles freely in the socket or has no distal support or partial end-bearing. When the stump end is supported in the socket by a temporary cushion or platform, compression gradually reduces and slowly clears the verrucous condition. The greater the compression on the distal stump, the more immediate and lasting is the improvement. The use of compression bandaging, shrinker socks and other pads, and partial endbearing all have a definite place in therapy and can be skillfully applied by the prosthetist. Short courses of oral diuretics may be indicated to reduce edema of the stump. The medication can be gradually decreased when the stump and its skin return to normal.

Acroangiodermatitis.   Acroangiodermatitis

occurs when the chronic pressure changes result in vessel proliferation in the upper- and middermis. There is also extravasation of red blood cells and these features combine to give a purplish hue to the papules and plaques that appear on a background of edematous skin. The appearance may mimic Kaposi sarcoma.18 Some authors suggest that acroangiodermatitis occurs in above-knee amputees who use a suction socket prosthesis that exerts negative pressure.19 However, there are reports of acroangiodermatitis in below-knee amputees,20 and the same condition is seen in chronic venous insufficiency and in the patients with arteriovenous

17

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Chapter 96

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shunts (acroangiodermatitis of Mali). Management of this condition is the same as for stump edema and verrucous hyperplasia.

BACTERIAL AND FUNGAL INFECTIONS The bacterial flora of amputation stumps have been examined in small groups of patients,21,22 and the most common species encountered are Staphylococcus epidermidis, S. aureus, and Streptococcus sp. (see Chapter 176). The moist, occluded environment under a prosthesis is ideal for fungal and bacterial growth so that minor skin infections occur fairly frequently. In one study, S. aureus folliculitis or Trichophyton rubrum infection was identified in 3% of the study population.6 Infections are more common during hot weather and in those amputees who pay insufficient attention to stump hygiene, partly because in these situations the skin becomes macerated more readily and follicular infec-

Figure 96-11  Verrucous hyperplasia of the distal stump skin. A. Before compression therapy. B. Total resolution after compression therapy. C. Malignant degeneration into squamous cell carcinoma. tions become more likely. Although folliculitis (Fig. 96-13) and furuncles are more common, superficial infections of the skin itself may also occur (see Chapter 176). Superficial dermatophyte and candidal infection (see Chapters 188 and 189) are also common and may be difficult to eradicate because of the ideal environment for fungal growth within a prosthesis. The diagnosis of infection is usually obvious when the rash extends onto skin not covered by the prosthesis. Underneath the prosthesis, any superficial infection may present as a nonspecific scaling erythema indistinguishable from that caused, for example, by chronic irritation. All stump rashes should be swabbed and scraped for bacterial and fungal culture. In the management of bacterial infections, oral antibacterial therapy should be directed by bacterial culture and sensitivity. Topical antiseptics or antibacterials can be used but some antiseptic preparations can cause irritation and there is also the potential for sensitization.

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Section 17 :: Skin Changes Due to Other Physical and Chemical Factors

1102

Figure 96-12  This man developed postinfectious purpura fulminans after varicella-zoster infection as a child in the 1960s and lost both legs as a consequence. He presented with infected verrucous hyperplasia having lived a reclusive life in a cabin in the woods wearing an old-fashioned unadjusted aluminum prosthesis for many years. The infection was treated with new hygiene measures, and he was fitted with a modern modular prosthesis. The skin rapidly resolved, although some of the verrucous hyperplasia changes persisted. Superficial fungal infections respond to appropriate topical therapy (see Chapters 188 and 189) but can be hard to completely eradicate because of the favorable conditions for fungal growth. In this situation, systemic antifungal therapy is useful.

Figure 96-13  Folliculitis of stump skin showing the typical distribution in the occluded area.

contain allergens such as fragrances or preservatives. Colored stump socks may contain potentially allergenic nylon dyes. Knowledge of the materials used in prosthesis manufacture is also necessary when considering potential sensitizers and irritants. This is best achieved by liaison with the local prosthetist, as different construction techniques may be used in different areas. In general,

CONTACT DERMATITIS (See Chapters 13 and 48) The clinical presentations of irritant and allergic contact dermatitis affecting amputation stumps are indistinguishable (Fig. 96-14), ranging from dry, scaling erythema to weeping dermatitis.6 Indeed, the morphologic features may be the same as nonspecific eczematization where no irritant, allergic, or infectious cause is found, and where there is no history of eczema or atopy. Consequently, a careful history and examination is essential if one is to identify irritant or allergic causes (Table 96-1). This includes accurate timing of the onset of dermatitis in relation to changes in the patient’s appliance routine or the composition of the prosthesis. The distribution of rash typically matches the site of the contactant. To identify a primary irritant or allergen, it is particularly important for the dermatologist to observe the patient removing and refitting their limb, making note of its construction and any medicaments or other agents such as cleansers, talcs, and creams that the patient uses. These products may

Figure 96-14  Allergic contact dermatitis to formaldehyde-releasing biocides in a lubricating “baby oil.” Note the nonspecific, dry, eczematous appearance.

TABLE 96-1

Causes of Dermatitis on Amputation Stump

Skin Problems in Amputees

A

OTHER CUTANEOUS DISORDERS

::

modern modular prostheses are fabricated with sockets, liners, and casings that may contain acrylic resins, carbon composites, and thermoplastics. Epoxy and, occasionally, polyester resins are still used by some manufacturers. Acrylate-based thread sealants are commonly used in socket bolts and metalwork. Butyl or black rubber material may be used to conceal access points to the metal frame. Rubber materials can also be found in some suction socket valves (Fig. 96-15). Accelerators used in the manufacture of natural or synthetic rubbers are potential allergens, for example, dialkyl thiourea used in chloroprene rubber.23 Suspension elements often include chrome-tanned leather and sometimes have metal fastenings, rivets, or screws

17

Chapter 96

Traumatic Irritant Soaps and washing materials Topical applications, including medicaments Solvents in glues and resins used to make prosthesis Allergic Active ingredients, perfume, and excipients of topically applied materials (e.g., deodorizers, cleansers, topical medicaments, and moisturizers) Acrylic, epoxy, polyester, and formaldehyde resins Resin hardeners Other plastic additives (e.g., para-tertiary butylphenol catechol) Nickel Rubber accelerators and antioxidants Chromate (leather) Nylon dyes

containing nickel. Glues containing para-tertiary butylphenol formaldehyde resins are often used. Repairs or adjustments to prostheses can introduce new irritants and allergens. For example, sockets sometimes have additional leather linings cemented to points of friction or pressure. Irritant dermatitis (see eFig. 96-15.1 in online edition) can be due to occluded contact with volatile solvents in glues or resins and from fragrances and detergents in topical medicaments or lubricants. Soaps and other washing materials used to clean appliances can cause irritation if they are not removed by proper washing (see Table 96-1). Burns from a malfunctioning electrode used in a myoelectric prosthesis have been reported.24 Contact allergy should always be considered as a cause of inflammatory and dermatitic disorders affecting the stump, especially if there is secondary spread (see Table 96-1). In addition to standard series patch testing, the authors recommend an extra series of allergens to include components of plastic, including acrylic, epoxy, and polyester resin systems, as well as an azo dye series. It is important to test with pieces of the prostheses and all materials applied to the stump skin including emollients, cleansers, powders, medicaments, and cosmetics. In our experience, the most common relevant allergens are nickel, acrylates, rubber, chromate (in leather), paratertiary butylphenol formaldehyde resin, and components of topical applications.6

Common skin diseases, for example, eczema (see eFig. 96-15.2 in online edition) and psoriasis (see eFig. 96-15.3 in online edition), may affect amputation stumps. Those

B

Figure 96-15  Allergic contact dermatitis to rubber materials in a suction socket from an arm prosthesis. A. The prosthesis fitted. B. The dermatitis is worst around the areas where the pressure is released on removing the limb.

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Section 17 :: Skin Changes Due to Other Physical and Chemical Factors

diseases that exhibit the Koebner phenomenon, especially psoriasis or lichen planus, have been reported on amputation stumps with little involvement of other areas of skin. Treatment should always take into account the implications of an occluded environment. Hyperhidrosis can be a problem in some patients resulting in maceration of the skin increasing the risk of erosions and even ulceration. Standard topical antiperspirants can be irritating under occlusion and one novel approach is to use intradermal botulinum toxin A.25 Benign keratoses, warts, nevi, and a variety of cutaneous papillomas may occur on stump skin and occasionally cause discomfort when a prosthesis is worn. Malignancies have also been described and squamous cell carcinoma (Marjolin’s ulcer)9 may develop in nonhealing chronic stump ulcers or verrucous hyperplasia (see Fig. 96-11). The patients who have amputations for lymphangiomas may develop the Stewart–Treves syndrome and metastatic lymphangiosarcoma (see Chapter 128). There is a risk that such malignancies may not be recognized as an ulcer might be wrongly blamed entirely on trauma from a poorly fitting prosthesis. A biopsy of persistently ulcerated areas should be undertaken. Treatment of these benign and malignant tumors is the same as when they occur elsewhere on the skin. Healing after tumor excision may take weeks, during which time the artificial limb may not be worn.

General Management Considerations Many of the more common skin problems can be prevented or controlled by adherence to an appropriate hygiene and skin-care regimen in conjunction with regular prosthetics reviews, which ensure that the

prosthesis remains appropriate and correctly adjusted. To this end, it is important that good communication exists between the dermatologist and prosthetist, which permits rapid referral of patients before skin disorders become established. As a general routine, the stump skin should be washed at night rather than in the morning because newly washed skin is hydrated and swollen, thereby increasing the likelihood of friction and shearing trauma. Nonperfumed soap should be used to minimize contact with potential sensitizers and fully removed with tepid water and gentle rubbing with a nonabrasive towel. Antibacterial soaps and washes can reduce the possibility of infection in addition to their cleansing action. However, these antiseptic preparations can cause irritation or allergy in a small number of cases and patients should be warned about this. If a stump sock is worn, it should be changed daily and washed and rinsed fully as soon as it is taken off, before perspiration is allowed to dry within it. Silicone liners should be washed every day.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Marks LJ, Michael JW: Science, medicine, and the future: Artificial limbs. BMJ 323(7315):732-735, 2001 4. Dudek NL et al: Dermatologic conditions associated with use of a lower-extremity prosthesis. Arch Phys Med Rehabil 86(4):659-663, 2005 6. Lyon CC et al: Skin disorders in amputees. J Am Acad Dermatol 42(3):501-507, 2000 8. Levy SW: Skin problems of the leg amputee. Prosthet ­Orthot Int 4(1):37-44, 1980

Chapter 97 :: Skin Problems in Ostomates :: Calum C. Lyon & Michael H. Beck SKIN PROBLEMS IN STOMA PATIENTS AT A GLANCE Peristomal skin is chronically occluded and subject to pressure, shearing forces, and fecal/urine soiling. Some skin problems are therefore inevitable. Two-thirds of ostomates develop dermatological problems. Irritant reactions, common skin diseases, and infections are the most common.

1104

The occlusion under a stoma appliance can result in unusual clinical appearances of common dermatoses. All rashes should be swabbed to exclude primary or secondary infection.

Allergic contact dermatitis is relatively uncommon. Nonetheless patients should be advised to minimize exposure to potential allergens especially fragrances and preservatives. Some dermatoses are commoner than expected around stomas, particularly psoriasis, pyoderma gangrenosum, and lichen sclerosus. Liaison with stoma nurses (ET therapists) and surgeons is essential to provide an effective service for patients with peristomal dermatoses.

17

SKIN PROBLEMS IN PATIENTS WITH ABDOMINAL STOMAS (OSTOMATES)

EPIDEMIOLOGY

Skin Problems in Ostomates

Figure 97-1  A typical drainable stoma bag with a convex barrier.

convex appliance that apply less pressure on the skin and collars or sleeves that fit snugly around the stoma before applying the bag thereby reducing the chance of leaks of effluent or intestinal mucus under the barrier. As many as two-thirds of ostomates experience skin problems that interfere with the normal use of their stoma appliance,2,3 and such dermatoses are the commonest reasons for a visit to outpatient stoma services.4,5 The majority of these problems are irritant reactions, usually dermatitis secondary to leaks from the stoma; however, there are also a number of other well-defined irritant reactions. Common coincidental dermatoses, particularly psoriasis and constitutional eczema, account for around 15% of the diseases seen.2,6 An approach to diagnosing peristomal dermatoses is given in eFigure 97-1.1 in online edition.

::

There are estimated to be more than 1.4 million ostomates in the United States and 100,000 in the United Kingdom and Ireland. Some stomas are temporary, with surgical anastomosis delayed, pending resolution of the acute disorder. Temporary stomas are often “loop stomas” where a loop of bowel is brought to the skin surface and part of the wall removed to allow preferential drainage into a stoma pouch in order to relieve a distal problem, for example, perianal ulceration. Such stomas are more frequently associated with skin problems secondary to leaks.1 Many stomas formed for malignant indications can be seen as palliative procedures. A stoma appliance is essentially a device for collecting stoma effluent with a high degree of comfort and security until it can be disposed of. There continues to be promising advances in the design of stoma bags. Essentially, the device is a pouch or bag held in place over the stoma by an adhesive skin barrier made solely or partly from hydrocolloid. Many ileostomists and urostomists use two-piece appliances where the barrier remains on the skin for 2–4 days and is detachable; disposable bags are changed as necessary. Appliances with convexity on the surface next to the skin are available for patients with short or buried stomas (Fig. 97-1). Useful recent innovations include softer

Figure 97-2  Peristomal dermatitis due to fecal irritation. The skin beneath the stoma was chronically exposed to feces because a bag with too large an aperture was used.

Chapter 97

A stoma is a surgically created opening onto the skin of part of the gastrointestinal or urinary tract in order to drain the effluent from that viscus. The most frequently performed stomas are ileostomies, colostomies, and ileal conduits (urostomies or urinary diversion). The commonest indications for stoma surgery are inflammatory bowel disease, malignancy and neurological problems. A patient with a stoma is usually termed an “ostomist” or “ostomate.”

IRRITANT REACTIONS DERMATITIS. Dermatitis most frequently results from the chronic leakage of effluent onto the skin because the patient is using an inappropriately shaped appliance or one with too large a hole for their stoma. The most common cause is the remodeling of the stoma and abdominal wall that occurs in the months after surgery, whereby a stoma usually becomes a little shorter and thinner, resulting in leaks unless a correctly fitting appliance is selected (Figs. 97-2–97-6). Leaks will also occur when patients gain a lot of weight after surgery and the effective length of their stoma diminishes because it becomes buried by subcutaneous fat.7 Irregular scarring after surgery or retraction of the stoma, may also be associated with chronic leakage. Such irregularities can be corrected with topically applied pastes. One effective alternative is to use collagen fillers (Porcine collagen Permacol™)8 to recontour the skin surface. Short stomas (5 drinks on >5 occasions).

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18

Number of emergency department visits associated with various drugs

Section 18 :: Neurocutaneous and Psychocutaneous Skin Disease

LSD GHB Ketamine Antihistamines Antibiotics/antivirals Ecstasy (MDMA) PCP (’Angel dust’) Prozac (Fluoxetine) Aspirin Paxil (Paroxetine) Barbituates Oxycodone Amphetamines NSAIDs All antidepressants Heroin Benzos (Xanax, etc.) Marijuana Cocaine

2,821 3,340 3,474 4,112 5,282 5,542 6,102 6,362 8,499 8,932 9,506 18,409 18,555 22,663 61,012 93,064 103,972 110,512

0

50,000

150,000

200,000

Figure 105-1  Number of emergency department visits associated with various drugs. Cocaine, marijuana and benzodiazepines were the most common drugs associated with emergency department visits in 2001. Data from the United States Substance Abuse and Mental Health Services Administration, 2001, http://thedea.org/statistics.html.158

tolerance. Addictive drugs also inhibit or excite neuronal activity in various areas of the nervous system. To compensate for these alterations, neuroadaptation develops with either formation of new neuroreceptor sites or diminished synthesis and sensitivity of neurotransmitters and neuroreceptor sites. Discontinuation of the drug reverses the neuroadaptation process and results in an exaggerated neural response that produces withdrawal symptoms.

CLINICAL FINDINGS ASSOCIATED WITH COMMONLY USED DRUGS ALCOHOL

1168

100,000

193,043

Ethyl alcohol, or ethanol, is the intoxicating ingredient found in alcoholic beverages. It is a central nervous system depressant that impairs brain function and motor skills and is rapidly absorbed from the stomach and small intestine into the bloodstream. Heavy use can increase the risk of liver disease, stroke and certain cancers. Direct liver toxicity of alcohol can cause hepatomegaly, jaundice, shrunken liver in the setting of cirrhosis, and hypoalbuminemia leading to Muehrcke lines and Terry nails (see Chapter 89). Hyperestrogenemia can lead to gynecomastia, palmar erythema, spider angiomata, and testicular atrophy. Portal hypertension secondary to alcohol-induced liver cirrhosis can lead to an enlarged spleen, ascites, variceal bleeding,

hemorrhoidal bleeding and caput medusae. Dupuytren contractures due to fibroblastic proliferation and disorderly collagen deposition may be seen in 66% of alcohol abusers. Asterixis and confusion are seen in patients with hepatic encephalopathy. Alcohol withdrawal delirium, also known as delirium tremens, is characterized by tachycardia, hypertension, body temperature elevation and delirium. Ataxia, confusion and lateral gaze palsy are indications of Wernicke encephalopathy. Wernicke encephalopathy followed by anterograde and retrograde amnesia along with confabulation characterize Korsakoff syndrome.

CLUB DRUGS Club drugs include γ-hydroxybutyric acid (GHB, date rape drug), flunitrazepam (Rohypnol®, roofies), ketamine, MDMA, and LSD (Table 105-1). These drugs tend to be used by teenagers and young adults in social settings. In 2008, NIDA showed that among 12th graders, 1.3% had abused flunitrazepam, 1.2% had abused GHB and 1.5% had abused ketamine at least once in the year prior to their being surveyed.8 GHB is sedating and can cause coma and seizures. It is being used increasingly by bodybuilders, who believe that it helps to metabolize fat and build muscle. Flunitrazepam is also sedating and can incapacitate users and cause amnesia; when combined with alcohol, this drug can be lethal. Ketamine distorts perception and produces feelings of detachment from the environment and self.

18

TABLE 105-1

Drugs: Street Names and Routes of Administration

Booze Brew Juice

Ingestion

Anabolic steroids

Gym candy Juice Pumpers Stackers

Ingestion Injection

Betel

Bunga (Tagalog) Cau (Vietnamese) Jambe (Javanese) Kunya (Burmese) Paan (Sanskrit) Supadi (Nepali) Shupari (Bengali)

Alcohol

Flunitrazepam

LSD

Acid Blotter Dots

Ingestion

Marijuana

Ganga Grass Mary Jane Pot Reefer Weed 420

Smoke inhalation Ingestion

MDMA

Adam E Ecstasy Love X XTC

Ingestion

Methamphetamine

Chalk Crystal Glass Ice Meth Speed

Ingestion Injection Nasal inhalation Smoke inhalation

Phencyclidine

Angel dust Fuel Ozone PCP Rocket Wack

Ingestion Nasal inhalation Smoke inhalation

Prescription medications: Opioids, CNS depressants, stimulants

Dust, dillies (dilaudid) Emsel, God’s drug (morphine) Oxy, cotton (oxycontin) Rids, vitamin R (Ritalin)

Ingestion

Club Drugs

Chewed

Bogie, cancer stick, cigs (cigarettes) Chaw, snuff, chew (smokeless tobacco)

Chewed Smoke inhalation

Fantasy G Georgia Home Boy Liquid ecstasy Soap

Ingestion

Roofies

Ingestion

Club Drugs

GHB

Route of Administration

Ketamine

Jet Special K Vitamin K

Cocaine

Blow Coke Crack Flake Snow

Heroin

H Junk Ska Smack

Injection Smoke inhalation

Inhalants

Poppers Snappers Whippets

Inhalation

Ingestion Nasal inhalation Injection Transdermal application

Cutaneous Manifestations of Drug Abuse

Tobacco

Street Namesa

Drug

::

Route of Administration

Chapter 105

Street Namesa

Drug

a

More terms at NIDA (National Institute of Drug Abuse) http://www.drugabuse.gov and Office of National Drug Control Policy website http://www.whitehousedrugpolicy.gov.2,159

COCAINE Cocaine (benzoylmethylecgonine) is an alkaloid extracted from the leaves of the coca plant Erythroxylon coca.9–15 It is a powerful sympathomimetic, vasoconstrictor, local anesthetic, and stimulant. Cocaine

hydrochloride is a powder that can be can be nasally inhaled or injected intravenously or subcutaneously, also known as “skin popping” (Fig. 105-2). Crack cocaine or “crack,” the freebase rock crystal form of cocaine hydrochloride, is smoked (Table 105-1). Freebase refers to the pure basic form of an amine, as

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Section 18 :: Neurocutaneous and Psychocutaneous Skin Disease

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Figure 105-2  Skin popping scars. Multiple white angular atrophic scars on the dorsal forearms and hands. opposed to its salt form. The amine is usually a natural alkaloid product. Cocaine can produce intense vasoconstrictive effects by directly stimulating the central nervous system and increasing peripheral catecholamines. The vasospastic action of cocaine is greatest at one hour after use and can be associated with ischemia, infarction and hemorrhagic injuries of most organ systems including the skin.16–18 The ischemic effects of cocaine in the skin can lead to acute multifocal skin necrosis,19 chronic skin ulcers,20 cutaneous fibrosis,21 blackened hyperkeratotic “crack hands”22 and claw-like “parrot beak” curvature of the nails. These changes are commonly found in association with pernio and some atrophy of the distal portions of the digital pulp secondary to ischemia. At skin-popping sites, there may be central pallor surrounded by ecchymosis due to the vasoconstrictive properties of cocaine acting locally at the injection site with hemorrhage occurring in the surrounding tissue. Skin popping is a method of drug administration whereby a substance is injected subcutaneously or intradermally, but not intravenously and not typically intramuscularly. Individuals with vasomotor instability are more susceptible to these types of reactions.23 Inadvertent or deliberate direct intraarterial injection of cocaine can cause severe tissue ischemia and necrosis via direct vasoconstriction. Individuals experience an initial intense burning pain, followed by cyanosis and marked edema. Compartment syndrome may also result. In the most severe cases necrosis leads to amputation.24,25 Skin popping also puts one at risk for developing secondary amyloidosis. Cocaine-induced vasospasm may cause major internal organ injury including acute myocardial ischemia, cerebrovascular accidents, renal infarction26 and splenic infarction.18,27 Vasoconstriction of mesenteric vessels and the direct toxic effect of cocaine on gastro-

intestinal mucosa can result in acute abdominal crises (known as crack belly) secondary to perforations, intestinal ischemia and infarction.28,29 Various vasculitic and vasculopathic processes have been associated with cocaine use including pseudovasculitis,30 urticarial vasculitis,31 Churg–Strauss vasculitis,32 Raynaud phenomenon,33,34 Henoch–Schonlein purpura, necrotizing vasculitis35,36 and Buerger disease (see Chapters 163, 164, and 173).37,38 The local anesthetic properties of cocaine make it difficult for individuals to feel traumatic injury. This leaves users prone to repetitive trauma from the irritant properties of the drug itself and implements of drug delivery, thus exposing them to an increased risk of infection.39 Missing a vein and injecting into the surrounding tissue creates a niche environment in which bacteria can thrive.40 Repeated needlesticks increase the likelihood of cutaneous infection and transmission of blood-borne viruses.41 Mucosal manifestations of ischemia secondary to cocaine inhalation or smoking include dental caries,42 gingival recession,43 oral blisters44 and nasal and palatal perforation.45 Insufflating (snorting) cocaine may lead to recurrent epistaxis, intranasal crusting, rhinitis and chronic sinusitis.42,46 Inhalation utensils themselves can act as vectors for viruses and may induce “snorter’s warts.” Nasal septum perforation reduces nasal support and results in a broad, flat nose or “saddle nose deformity.”46–49 Nasal septum perforation typically occurs prior to development of palatal perforation. Cocaine burns of the upper airway are associated with hoarseness, dysphonia, odynophagia, dysphagia and stridor.23,26,50–53 Crack cocaine smoke has a direct toxic effect on the corneal epithelium of the eye. Repeated exposure to the alkaloid smoke may cause an irritant effect leading to excessive eye rubbing and subsequent infectious complications, and chemical burns.51 Drug reactions including acute generalized exanthematous pustulosis54 and Stevens–Johnson syndrome 55 have also been reported. The stimulant properties of cocaine are associated with increased metabolism and dramatic weight loss.56 Psychiatric conditions, most commonly delusions of parasitosis and subsequent formication are experienced approximately 20% of the time in cocaine users (also known as coke bugs)57 (see Chapter 104). Recent reports have emerged of febrile agranulocytosis and often vasculitis with prominent involvement of the ear lobes secondary to cocaine adulterated with levamisole, an anthelmintic medication used in veterinary medicine to control parasites in livestock.58,59

HEROIN Natural and semisynthetic derivatives of the opium poppy are known as opiates. Biologically natural opiates include morphine and codeine, while semisynthetic opiates such as heroin and hydromorphone are derived from biologically active opiates. Diacetylmorphine, or heroin, crosses the blood–brain barrier and binds opioid receptors in the brain, resulting in its euphoric, analgesic and anxiolytic effects. Heroin

foreign materials in the dermis after “cooking” of the drug and/or flaming of needles (Fig. 105-4).63 Diluting or “cutting” heroin to retail “street strength” is a common practice. Common diluents for white powder heroin include quinine, lactose, lidocaine, caffeine, lemon juice, inositol, dextrose, sucrose, procaine, starch, magnesium silicate and mannitol.64 Diluents may cause lymphatic destruction, foreign body granulomas, cutaneous nodules, ulcerations, panniculitis and dermal sclerosis secondary to irritation and dermal inflammatory processes (Fig. 105-5).65–67 The subsequent vascularized granulation tissue in and around chronic ulcers may be used as a site for drug injection.20 (see eFig. 105-5.1 in online edition) Black tar heroin is a dark, gummy form of heroin that is less refined and cheaper than the white powder variant. It is mixed with a variety of diluents including dextrose, burnt cornstarch, instant coffee and dirt.68 The mixture may

18

Chapter 105

is the most common parenterally injected illicit drug, either by intravenous or subcutaneous (skin popping) administration. Heroin may also be inhaled. With a peak “rush” at 7–8 seconds, it is the fastest-acting and via smoking most potent opiate, accounting for up to 90% of opiate use in the United States. Scarring is the primary cutaneous stigma of injection drug use. The antecubital fossa is the usual starting point of intravenous drug use, followed sequentially by the upper arms, hands, neck, feet, legs, groin and digits.60 Linear cord-like scars along a vascular distribution (track-marks), are formed after repeated injections along a superficial vein, resulting in venous thrombosis and subsequent fibrosis.61 (Fig. 105-3) Skin popping scars are irregular round hypopigmented or hyperpigmented, atrophic or hypertrophic scars or keloids.62 (see Fig. 105-2) Soot tattoos or shooting tattoos result from soot deposition or the introduction of

:: Cutaneous Manifestations of Drug Abuse

A

C

B

Figure 105-3  Track marks formed after repeated intravenous drug injections. (A) Inflammatory tracks of the dorsal hand, (B) inflammatory tracks with associated ulcers, nodules and abscesses on the hands and forearms, and (C) fibrotic tracks on the dorsal forearms.

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Section 18

chondritis has been described in individuals injecting brown heroin diluted with lemon juice.78 Inhaling smoke and then exhaling it into another individual’s mouth (known as shotgunning) is associated with efficient transmission of respiratory pathogens. 79 Opiates induce histamine release that results in subsequent pruritus that starts almost immediately after heroin injection and can last 10 minutes to 24 hours.80 Urticaria, severe angioedema and bronchospasm have also been reported with heroin use.80 Rare morbilliform eruptions, fixed drug eruptions and a case of toxic epidermal necrolysis have also been reported.62,64,81 Adulterants are thought to be responsible for most of these reactions. Secondary systemic amyloidosis is an important cause of renal disease in heroin users. Its pathogenesis is thought to be associated with chronic antigenic stimulation and prolonged inflammation secondary to cutaneous infections. Patients were observed to progress to end stage renal disease over several months to 3 years.82

:: Neurocutaneous and Psychocutaneous Skin Disease

3,4-METHYLENEDIOXYMETHAMPHETAMINE Figure 105-4  “Soot tattoo.” Soot tattoos result from the deposition of soot and other foreign materials in the dermis. Foreign materials may be introduced via adulterated drugs and/or introduction of needles with adherent soot after flaming for sterilization. also contain dust and pathogens introduced during the process of manufacturing or storage.64,66 Irritant substances can also cause sterile chemical cellulites and abscesses. Cutaneous infections are common in injection drug users (Table 105-1). Skin popping and black tar heroin use are associated with cutaneous necrosis and necrotizing ulcers.69–72 An increase in Clostridial infections including wound botulism due to Clostridium botulinum, tetanus due to Clostridium tetani, and rapidly progressive myonecrosis with a fulminant shock syndrome due to Clostridium sordellii have been observed with the use of black tar heroin in California.73–76 Fungi have been cultured from confiscated heroin specimens.77 Systemic candidosis characterized by painful nodules and pustules on the scalp and hairbearing areas, chorioretinitis or uveitis, and costo-

3,4-methylenedioxymethamphetamine (MDMA, ecstasy), along with lysergic acid diethylamide (LSD) and hallucinogenic mushrooms, is one of the most commonly used illicit hallucinogens (Table 105-1). More than 7 million persons have tried MDMA at least once in their lifetime. MDMA is a synthetic stimulant with psychoactive properties that acts both by causing a massive synaptic release of serotonin, and to a lesser extent dopamine and norepinephrine, as well as inhibiting the reuptake transporters within the synapse. Its short-term effects include inducing euphoria, a sense of enhanced intimacy with others, and diminished anxiety and depression. Adverse health effects can include nausea, chills, sweating, teeth clenching, muscle cramping, and blurred vision. MDMA is usually ingested, but may be injected or inhaled with effects lasting for 3–6 hours. It is frequently used in combination with alcohol, cannabis, amphetamine or cocaine, resulting in unpredictable effects.83 MDMA is associated with xerostomia and is therefore often coupled with soft drinks, which may lead to dental caries. The neurotransmitter release associated with MDMA induces bruxism, trismus and teeth grinding that can wear down tooth enamel. Direct application of MDMA to the gums may cause necrotizing gingivitis and widespread perioral and intraoral swelling. MDMA can also interfere with systemic temperature regulation that can, rarely, be lethal.

METHAMPHETAMINE

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Figure 105-5  Foreign body response and cellulitis. Angular ulcerations, firm erythematous nodules, and warm tender induration at the site of subcutaneous and intravenous injection of adulterated heroin.

Methamphetamine is a very addictive synthetic stimulant that affects the brain and central nervous system through the release of dopamine, norepinephrine, and serotonin. By concurrently blocking reuptake of these neurotransmitters, sensations of euphoria, lowered inhibitions, feelings of invincibility, and hyperactivity are produced.84 Metamphetamine a white, odorless,

ANABOLIC STEROIDS Most anabolic steroids are synthetic substances similar to the male sex hormone testosterone. They may be ingested or injected, and are used especially by athletes to build muscle and enhance athletic performance. In 2000, approximately 3.6% of male and 0.9% of female twelfth graders in the United States had used anabolic steroids. Their abuse is most commonly associated with acne vulgaris, striae formation and alterations in hair growth. Anabolic steroids induce sebaceous gland enlargement and the development of comedones through abnormal follicular keratinization.92,93 Steroid-associated acne is characteristically distributed on the face, shoulders, chest and back.93 It can progress to acne conglobata and fulminans secondary to the brisk immune response to Propionibacterium acnes in individuals who have never even had acne.94 Steroid-associated acne does not always respond to routine therapy and may

Through the use of tobacco, nicotine is one of the most heavily used addictive drugs in the United States. Cigarette smoking accounts for 90% of lung cancer cases in the US. Tobacco is an agricultural product processed from the leaves of plants in the genus Nicotiana, which can be smoked or chewed (more precisely, placed between gingival and buccal mucosa) to allow nicotine absorption via oral mucosa. Nicotine in the tobacco leaves is responsible for the vasoconstrictive effects of smoking via increased vasopressin secretion and stimulation of the sympathetic nervous system, thereby causing peripheral vasoconstriction.104–108 Smoking a single cigarette can produce cutaneous vasoconstriction for up to 90 minutes.109 Smoking decreases tissue oxygenation via vasoconstriction and by increasing carboxyhemoglobin, thereby limiting the blood’s oxygen carrying capacity.110 Smoking also increases platelet aggregation111 and blood viscosity,112 and decreases prostacyclin formation.113 This combination of mechanisms also leads to impaired postoperative wound healing in smokers.114,115 The tar in cigarettes increases a smoker’s risk of lung cancer, emphysema, and bronchial disorders. The carbon monoxide in smoke increases the chance of cardiovascular diseases. Although the mechanism is unknown, smoking tobacco has also been linked with premature aging and rhytid formation. Elastin from photoprotecting skin in smokers is thick and fragmented, resembling that of sundamaged skin but involving the reticular rather than the papillary dermis. Chronic dermal ischemia of as well as

Cutaneous Manifestations of Drug Abuse

Sedatives as a class of drugs includes benzodiazepines, hydroxybutyrate, flunitrazepam and cannabis. Cutaneous manifestations and reactions to this group of drugs is quite rare, however drug reactions have been rarely associated with benzodiazepines, including type IV morbilliform drug hypersensitivity eruptions,89 acute generalized exanthematous pustulosis to tetrazepam90 and erythema multiforme to clonazepam.91

TOBACCO

18

::

SEDATIVES

persist for weeks to months following discontinuation of the drugs (see Chapter 80).93,95 Anabolic steroid use is also associated with alterations in hair growth, including hirsutism and androgenic alopecia, both of which are often more noticeable in women and may not be reversible with discontinuation of the drug.93,96,97 Males can develop testicular atrophy, gynecomastia and infertility. Women may experience menstrual changes, male-pattern alopecia, and deepening of the voice. Teenagers risk permanently stunted height and accelerated pubertal changes. Steroid use is associated with striae formation secondary to dramatic hypertrophy of muscle tissue.98 Gingival enlargement has also been observed in those using anabolic steroids for greater than one year. Systemic effects of steroid abuse include hepatic damage, jaundice, hypertension and dyslipidemia. Bacterial abscesses may occur at steroid injection sites secondary to nonsterile injection techniques.93,96 Repeated injection into the same site can result in inflammation and oil-induced granuloma formation.99 Soft tissue pseudotumors100 and rhabdomyolysis101 have also been reported in injectors. In addition to causing de novo conditions, anabolic steroid use is also associated with exacerbation of existing acne and psoriasis.93 Case reports have described exacerbation of angiolipomas102 and latent acute hereditary coproporphyria as well.103

Chapter 105

bitter-tasting powder that can be ingested orally, snorted or injected. It may also be smoked in its rock “crystal” form.85 Short-term effects include feelings of euphoria, decreased fatigue associated with difficult life situations, headache, difficulty concentrating, diminished appetite, abdominal pain, vomiting, diarrhea, disordered sleep, paranoid or aggressive behavior, and psychosis. Long-term use of methamphetamine use is associated with anorexia, neurotoxicity, neurodegeneration, and clinical depression that may lead to homicidal and suicidal ideation and action.85 An increased rate of skin and soft tissue infections have been reported in methamphetamine users, including increased rates of methicillin-resistant Staphylococcus aureus (MRSA) infections in noninjection drug users. Methamphetamine use is associated with formication that can lead to subsequent skin picking, skin breakdown, and portals of infection (see eFig. 105-5.2 in online edition). Use of methamphetamine and other sexually stimulating drugs can also increase direct skin-to-skin sexual contact and transmission of MRSA86 (Table 105-1). Methamphetamine users are at risk for developing meth mouth, or oral decay characterized by poor oral hygiene, xerostomia and rampant caries typically on the smooth surfaces of teeth, and excessive tooth wear.87 Methamphetamine use has also been associated with psychosis and subsequent self-injurious behavior including genital mutilation.88

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ciated with heavy cigarette smoking in young men. Cutaneous manifestations include blanching, cyanosis, burning, tingling, ulceration, necrosis, and gangrene (see Chapter 170). Cigarette smoking has been shown to exacerbate and possibly induce palmoplantar pustulosis.135,136 Both allergic and irritant contact dermatitis characterized by itching and burning, have been documented to nicotine patches.137 Allergic contact dermatitis to the tobacco leaf has also been reported in tobacco harvesters and factory workers.138,139

Section 18

Figure 105-6  The “nicotine sign.” The orange hue of tobacco can lead to yellow–orange discoloration of the fingertips and fingernails in chronic cigarette smokers. Clubbing of the distal digits indicates the presence of chronic lung disease.

:: Neurocutaneous and Psychocutaneous Skin Disease

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the decreased collagen synthesis likely play roles in the damaging elastic fibers.116 Increased plasma neutrophil elastase activity secondary to smoking may contribute to abnormal elastin.117 Smoking also causes a yellow– brown discoloration of the fingers and fingernails of digits habitually holding the cigarette (Fig. 105-6).118 Cigarette smoking and chewing tobacco use are associated with a number of mucosal conditions. Leukokeratosis nicotinica palati (nicotine stomatitis, smoker’s palate) is characterized by uniform keratosis of the hard palate with multiple tiny umbilicated erythematous papules representing the inflamed orifices of minor salivary glands.119 This benign oral lesion is seen exclusively in smokers and is caused by the tars and heat in tobacco smoke. Resolution is usually complete within 2 weeks of smoking cessation. All forms of tobacco use play a significant causative role in the development of leukoplakia.120 Leukokeratosis nicotinica glossae (also known as tongue) is a homogeneous leukoplakia affecting the anterior two-thirds of the dorsal tongue.121 Acute necrotizing ulcerative gingivitis “trench mouth,” Vincent disease is caused by bacteria but is not communicable. Smokers tend to have fewer oral aphthous ulcers than nonsmokers due to decreased mucosal blood flow resulting from the vasoconstrictive effect of nicotine. Yellow discoloration of teeth secondary to tar deposition is also commonly observed. Oral verrucous carcinoma, black hairy tongue, oral melanosis and oral warty dyskeratoma have been linked to tobacco use, but the connection is not as strong as in the aforementioned conditions.122,123 All forms of tobacco are associated with an increased risk of oral cancer.124–127 Cigarette smoke may act as a direct carcinogen or via systemic absorption.128,129 Smokers are also at an increased risk of developing squamous cell carcinomas at sites other than the oral mucosa, likely because of the immunosuppressive effects of smoking.130–132 Immune dysregulation associated with smoking is thought to be the reason that smokers with melanomas present with more advanced lesions and have a poorer disease prognosis.133,134 Thromboangiitis obliterans (Buerger disease) is an obstructive vascular disease that is indisputably asso-

BETEL Betel (Piper betle) belongs to the Piperaceae family; its leaf has an important social and cultural role in South Asia, Southeast Asia and the South Pacific. Betel leaves are chewed with the areca nut (also known as betel nut), calcium hydroxide, Acacia catechu bark, and occasionally tobacco in a wrapped package known as “betel quid.” Betel leaves are used as a stimulant, antiseptic and breath freshener. The areca nut contains the alkaloid and stimulant arecoline which promotes salivation and stains saliva and teeth dark red to rust-colored. Calcium hydroxide keeps the active ingredients alkaline, thereby enabling its sublingual absorption and entry into the bloodstream. Continuous chewing of betel quid maintains constant moisture at the oral commissures which, when coupled with continuous friction of opposing surfaces, causes maceration, erosion and fissures. These lesions can be mistaken for angular cheilitis, candidiasis or vitamin-deficiency associated perleche.140 The mixture is usually kept between the teeth and lip and may thus cause burning and erosions of the buccal mucosa.140 Chewer’s mucosa results from the direct chemical action of the quid and/or traumatic effect of chewing, and is characterized by a brownish–red discoloration of the buccal mucosa with an irregular desquamative epithelial surface. These mucous membrane findings are not thought to be malignant or premalignant.141 Oral lichenoid lesions regress with decrease in frequency, duration or change in site of placement of the quid.142 Oral submucous fibrosis is directly related to betel quid chewing and affects the buccal mucosa, lips, retromolar areas, soft palate and occasionally the pharynx and esophagus.143 It is characterized by prodromal oral dysesthesia aggravated by spicy foods, followed by early blanching mottled mucosal lesions and subsequent late development of palpable vertical fibrous bands in the buccal mucosa and around the mouth opening requiring surgical release for sufficient opening of the mouth.144 Trismus, dysphagia, xerostomia, rhinolalia and tongue stiffening present late in the disease course. Mucosal petechiae, leukoplakia and epithelial dysplasia are also seen.145,146 The most serious complication of oral submucous fibrosis is the development of oral carcinoma, which can be seen in up to 10% of users and is typically localized to the buccal tongue and labial mucosa.147 Of all oral cancers in Taiwan, as many as 86.2% of cases have been reported to be in betel quid chewers.148

18

POLYSUBSTANCE ABUSE

TABLE 105-2

Common Infectious Agents Associated with Drug Abuse and Addiction Class

Infectious Agent

Bacterial

Staphylococcus aureus Streptococcal species Pseudomonas aeruginosa Clostridium botulinum Eikenella corrodens Anaerobes Unusual organisms

Fungal

Dermatophytes Candida Aspergillus Mucor

Viral

herpatic viruses Human T-cell lymphotropic virus Human immunodeficiency virus Hepatitis B virus Hepatitis C virus

Sexually transmitted

Chlamydia trachomatis Neisseria gonorrhoeae Human immunodeficiency virus Human papilloma viruses Molluscum contagiosum Treponema pallidum

Cutaneous Manifestations of Drug Abuse

In addition to the local reactions and systemic effects of specific drugs themselves complications of drug use must also be considered. Injection drug use is associated with inoculation and transmission of infectious agents leading to local skin and soft tissue infections and abscesses, as well as the subsequent hematogenous spread of microbes. Grampositive cocci including Staphylococcus aureus, group A β-hemolytic streptococcus and other streptococci are the most commonly observed microbial agents.149–151 Anaerobes are the second most common group of bacteria to be isolated, while Gram-negative bacteria are less commonly isolated. The source of the pathogens is variable, but most originate from the flora of the skin and oropharynx secondary to needle-licking practices and use of saliva to clean or moisten skin and injection implements.149 Abscesses and cellulitis occur in 22%–65% of drug users152 (Fig. 105-7). Irritant substances including the drug or its diluents may cause sterile chemical cellulitis and abscesses. Systemic infections including bacteremia, endocarditis, osteoarthritis, and systemic candidosis may result. Systemic candidosis is the most common systemic fungal infection in injection drug users (Table 105-2). Direct intra-arterial injection of drugs may cause severe ischemia and necrosis. Early intense burning is noted in the injected area, followed by marked edema, compartment syndrome, cyanosis, and livedoid patches of the affected limb within a few hours. Distal necrosis may occur in the most severe cases, and has been seen with the use of drugs such as cocaine, heroin, pentazocine, diazepam, amphetamine and others25,153,154 The local cytotoxicity of a drug may cause a chemical endarteritis resulting in vasospasm and thrombosis. The behavioral effects of injection drug use has been associated with an increased risk of sexually transmitted diseases as well as blood-borne diseases transmitted through unsterilized needles including hepatitis B virus (HBV), hepatitis C virus (HCV), human immu-

nodeficiency virus (HIV) and human T-lymphotropic virus (HTLV) (Table 105-2). The repeated trauma of venipuncture, local infections and the irritant drugs and adulterants can lead to superficial and deep venous thrombosis. Chronic venous insufficiency can result from vein trauma, necrotic ulcers at sites of past subcutaneous injection, vein thrombosis and blockage of the lymphatic system.155,156 Other noninfectious diseases associated with drug use include psychiatric disease, accidental injury due to altered mental status and trauma due to criminal violence or domestic abuse.

::

COMPLICATIONS

Figure 105-7  Cellulitis at the site of repeated drug injection. Tender warm erythema and induration surrounding a chronic ulceration at the site of routine drug injection. Secondary infections at injection sites can be caused by introduction of pathogens via unsterilized needles, adulterated drugs, and at sites of compromised skin integrity. S. aureus infectious endocarditis occurred following bacteremia from this site.

Chapter 105

Polysubstance abuse, the concurrent use of several drugs with different pharmacologic effects, is becoming increasingly common. The diversity of reported drug use combinations suggests that achieving some perceptible change in state may be the primary motivator driving this practice. One drug may be used to enhance the effects of another, as with the combined use of benzodiazepines and methadone or cocaine and heroin (speedballs). Polysubstance abuse can cause adverse health consequences, such as pulmonary disease, reproductive dysfunction and immunosuppression in chronic cocaine and psychostimulant abuse. It may also exacerbate preexisting conditions such as hypertension and cardiac disease. The concurrent use of some drugs, including cocaine and opiates, is frequently associated with deleterious behavior such as needle sharing by injection drug users.

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TABLE 105-3

Drug Detection in Body Fluids and Hair Substance

Blood/Saliva

Urine

Hair

Alcohol

12–24 hours

6–24 hours

Up to 90 days

Amphetamines (except meth)

12 hours

1–3 days

Up to 90 days

Methamphetamine

1–3 days

3–5 days

Up to 90 days

MDMA (Ecstasy)

25 hours

24 hours

Up to 90 days

Benzodiazepines

6–48 hours

Therapeutic use: 0–7 days Chronic use (>1 year) 4–6 weeks

Up to 90 days

Section 18

Cannabis

2–3 days, up to 2 weeks in heavy users

3–7 days, up to >30 days after heavy use and/ or in users with high body fat

Up to 90 days

Cocaine

2–5 days

2–5 days with exceptions for certain kidney disorders

Up to 90 days

::

Codeine

Neurocutaneous and Psychocutaneous Skin Disease

2–3 days

Cotinine (break-down product of nicotine)

2–4 days

2–4 days

Up to 90 days

Morphine

1–3 days

2–4 days

Up to 90 days

Heroin

1–2 days

3–4 days

Up to 90 days

LSD

0–3 hours

24–72 hours (tests for LSD are very uncommon)

Up to 3 days

Methadone

24 hours

3 days

Up to 90 days

PCP

1–3 days

3–7 days for single use; up to 30 days in chronic users

Up to 90 days

Urine data from Labcorp I. Drugs of Abuse Reference Guide, 2004, https://www.labcorp.com/pdf/doa_reference_guide.pdf. accessed May 1, 2011.

DIAGNOSIS While mucocutaneous findings can be suggestive of drug use drug testing is needed to identify the agents used. Bodily fluids including saliva, blood, urine and hair can be used in drug detection. Urinalysis for qualitative detection of psychoactive substances and their metabolites is often the fastest way to determine ingestion of a substance (Table 105-3). Systemic conditions secondary to the effects of substance abuse should also be part of the evaluation of these patients. Cutaneous infections at sites of trauma, ulcers, or necrosis should be swabbed or biopsied for culture to identify and treat causative organisms. Thorough evaluation and imaging may be required to rule out injury to or involvement of vital organs and bony structures. In injection drug users, thorough cardiac evaluation and examination of mucocutaneous and acral surfaces should be undertaken to access for embolic phenomenon. Evaluation for transmitted infections such as HIV, hepatitis and sexually transmitted diseases may be required.

DIFFERENTIAL DIAGNOSIS 1176

It is imperative to rule out primary infectious causes of ulcers, nodules, skin and subcutaneous infections in

suspected drug users. Inflammatory and vasculopathic processes such as pyoderma gangrenosum, livedoid vasculopathy and medium vessel vasculitides must be considered in the setting of ulcers and nodules. Evidence of distal vascular compromise can be seen in pernio, thromboembolic phenomenon and Raynaud phenomenon. The edematous phase of scleroderma, eosinophilic fasciitis and secondary lymphatic obstruction are rare entities to consider the setting of distal extremity swelling. Infectious and noninfectious granulomatous diseases [including tuberculosis, leishmaniasis, granulomatosis with polyangiitis (Wegener’s) and sarcoidosis] can present with nasopalatal infiltration and perforation. Patients with pruritus and formication may require evaluation for infestation, metabolic or psychiatric etiologies of their symptoms.

TREATMENT A detailed discussion of the treatment of drug abuse and dependence is beyond the scope of this chapter, but it is essential to recognize that these are chronic illnesses that require long-term strategies. Combined medical and behavioral therapy are important elements of a therapeutic process comprising detoxification, treatment and relapse prevention. Amelioration of withdrawal symptoms is key to initiation of therapy. A multidisciplinary approach including addiction

can provide advice on safe injection techniques and instituting strictly supervised heroin, diamorphine or buprenorphine prescription programs for long-term injectors.157 This may help reduce the risk of life-threatening infection from nonsterilized drugs, prevent overdose from drugs of unknown purity, break the link between drug use and criminal activity to acquire drugs and decrease the number of injections in public places.

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KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

:: Skin Signs of Physical Abuse

2. Abuse NIoD: 2010, http://www.drugabuse.gov, accessed Jun 2010 23. Payne-James JJ, Munro MH, Rowland Payne CM: Pseudosclerodermatous triad of perniosis, pulp atrophy and ‘parrot-beaked’ clawing of the nails—A newly recognized syndrome of chronic crack cocaine use. J Forensic Leg Med 14(2):65-71, 2007 58. Zhu NY, Legatt DF, Turner AR: Agranulocytosis after consumption of cocaine adulterated with levamisole. Ann Intern Med 150(4):287-289, 2009 66. Heng MC, Feinberg M, Haberfelde G: Erythematous cutaneous nodules caused by adulterated cocaine. J Am Acad Dermatol 21(3 Pt 1):570-572, 1989 86. Cook HA, et al: Heterosexual transmission of community-associated methicillin-resistant Staphylococcus aureus. Clin Infect Dis 44(3):410-413, 2007 145. Pindborg JJ et al: Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 92(3):224-229, 1984

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counseling, social work support and management of associated infectious, vascular, cardiac and hepatic complications is critical to comprehensive care. Potential therapies for opiate dependence include drug detoxification (office-based, inpatient or ultra rapid under anesthesia), agonist maintenance (injectable diacetylmorphine, methadone, levomethadyl or buprenorphine), antagonist maintenance (naltrexone) and pharmacologic treatment of withdrawal symptoms (clonidine, lofexidine or guanfacine). Treatment options for tobacco addiction include nicotine replacement therapies (patch, spray, gum and lozenges). Bupropion and varenicline have been approved by the Food and Drug Administration for management of nicotine addiction. Behavioral interventions include group and individual therapies, and telephone quitlines. Outpatient and residential treatment centers can provide environments in which individuals can participate in therapeutic communities and benefit from behavioral therapy and peer support. Alternative therapies including acupuncture may also prove useful in combination with medical and behavioral therapeutic interventions. Although relapses are common, successful outcomes are accomplishable, indicating the importance of candid, supportive, nonjudgmental, care-facilitating discussions in patients whose drug use has been revealed through skin examination. The transmission of infectious disease via injection drug use can be addressed by encouraging physicians to prescribe sterile injection equipment, setting up injection rooms staffed by healthcare personnel who

Chapter 106 :: Skin Signs of Physical Abuse :: Howard B. Pride ABUSE AT A GLANCE Child abuse, elder abuse, and domestic violence are common. Abuse is a problem of all socioeconomic classes and races. Bruising on soft padded areas of the body and patterned bruising that are multiple and in different stages of healing are suspicious of abuse. Burns that are bilateral and uniform are suspicious of abuse. Law mandates the reporting of all suspected cases of child abuse and, in some states, elder abuse.

CHILD ABUSE Child abuse is an uncomfortable topic for most practitioners and is a source of anxiety, anger, and confusion among those who care for children. True incidence statistics are difficult to determine, but each year in the United States, of the approximately three million children referred to child protective services, approximately one million are determined to be the victims of abuse and neglect (or about 12 cases per 1,000 children) and approximately 1,500 die from abuse or neglect.1 Clearly, those whose practices involve the dermatologic care of children encounter real or suspected child abuse. Practitioners must have some basic knowledge of abuse and its evaluation to appropriately manage these cases. Because many forms of physical abuse have external manifestations, the skin examination may serve as the first clue that abuse is taking place. Conversely, a broad knowledge of skin diseases provides a unique

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TABLE 106-1

Conditions Mistaken for Abusive Bruising

Section 18 :: Neurocutaneous and Psychocutaneous Skin Disease

True petechiae and purpura Disorders of coagulation Ehlers–Danlos syndrome Infections Rocky Mountain spotted fever Meningococcal infections Group A streptococcal infections Palpable purpura of vasculitis Valsalva petechiae Lichen sclerosus Folk remedies Cao gio: rubbing vigorously with a hard object such as a coin Cupping: suction mark left by the cooling of a warm metal cup Nodular lesions mimicking deep bruises Neuroblastoma Vascular malformations Dermatomyositis-associated nodules Erythema nodosum Discolorations that look like bruises Phytophotodermatitis Maculae coeruleae from lice infestation Mongolian spots Dye from blue jeans Inflammatory conditions that mimic bruising Urticaria/angioedema/urticarial vasculitis Pernio Conditions that mimic whip marks Incontinentia pigmenti Striae Phytophotodermatitis

insight into those diagnoses that may mimic various forms of child abuse (Tables 106-1 and 106-2). The literature is rich in examples in which an astute clinician averted the disastrous results of a false claim of abuse by correctly diagnosing a dermatologic condition. True abuse must be reported and a thorough evaluation conducted. It is essential that practitioners develop

TABLE 106-2

Conditions Mistaken for Nonaccidental Burns

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Phytophotodermatitis Folk remedies (Maquas, or moxibustion): burns delivered near diseased organs or therapeutic sites as in acupuncture Impetigo/ecthyma Epidermolysis bullosa Immunobullous diseases Sunburn/xeroderma pigmentosum Burns from objects heated by sun Electric burn from an enuresis blanket Chemical burn from use of undiluted acetic acid Chemical burn from Icy Hot balm Chemical burn from calcium chloride Diaper dermatitis Pernio Fixed drug eruption

TABLE 106-3

Helpful Agencies for Information on Abuse and Domestic Violence Child Welfare Information Gateway, 1250 Maryland Avenue, SW, Eighth Floor, Washington, DC 20024, Ph: (800) 394-3366, email: [email protected], http://www. childwelfare.gov/ Childhelp National Headquarters, 15757 N. 78th Street, Suite B, Scottsdale, AZ 85260, Ph: (480) 922-8212, http:// www.childhelpusa.org Domestic Violence International Resources, http://www. vachss.com/help_text/domestic_violence_intl.html International Network for the Prevention of Elder Abuse, http://www.inpea.net, e-mail [email protected] International Society for Prevention of Child Abuse and Neglect, 13123 E. 16th Ave, B390, Aurora CO 80045, Ph: (303) 864-5220, Fax: (303) 864-5222, email: ispcan@ispcan. org, http://www.ispcan.org National Adult Protective Services Association, 920 S. Spring Street, Suite 1200, Springfield, IL 62704, Ph: (217) 523-4431, Fax: (217) 522-6650, http://www.apsnetwork.org National Center on Elder Abuse, c/o Center for Community Research and Services, University of Delaware, 297 Graham Hall, Newark, DE 19716, Ph: (302) 831-3525, Fax: (302) 831-42525, e-mail [email protected], http://www. elderabusecenter.org National Committee for the Prevention of Elder Abuse, 1612 K Street, NW, Suite 400, Washington, DC 20006, Ph: (202) 682-4140, Fax: (202) 223-2099, email: ncpea@verizon. net, http://www.preventelderabuse.org National Coalition Against Domestic Violence, 1120 Lincoln Street, Suite 1603, Denver, CO 80203, Ph: (303) 839-1852, Fax: (303) 831-9251, email [email protected], http:// www.ncadv.org National Resource Center on Domestic Violence, 6400 Flank Drive, Suite 1300, Harrisburg, PA 17112, Ph: (800) 537-2238 ext. 5, Fax (717) 545-9456, http://www.nrcdv.org

a relationship with the institution or individual in their area who is best able to manage these difficult cases. Ideally there should be an abuse team consisting of a dermatologist, pediatrician, social worker, medical photographer, and, when needed, pediatric subspecialists such as orthopedists, hematologists, psychologists, and gynecologists. The need for specialization in this field is highlighted by the institution in the United States of pediatric subspecialty board certification in child abuse, beginning in 2010. It is most helpful if one’s relationship is forged with the abuse team before an abuse incident and a set protocol for dealing with alleged or suspected abuse is established in the practitioner’s office. Local emergency phone numbers for reporting abuse can be obtained from the Child Welfare Information Gateway or Childhelp National Headquarters (Table 106-3). Child abuse spans all ages with 32% of abused children being younger that 4 years of age, 24% being 4–7 years of age, and 19% being 8–11 years of age. Typical children who suffer abuse have emotional or behavioral problems, have special medical needs, have several siblings, live in single-parent households, or live at or below the poverty level. Abuse is approximately

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two times more common in Pacific Islanders, American Indians, Native Alaskans, and African American children compared to the average American population. Perpetrators tend to have emotional or psychological problems, have frequently been victims of abuse themselves, abuse drugs or alcohol, are perpetrators of spousal abuse or have a history of marital discord, have marginal parental skills or knowledge, and have poor self-esteem. Parents are the perpetrator 80% of the time.2 Although these profiles are helpful, it is important to remember that any child may be the victim of abuse.

Figure 106-1  Purpura and erosions on the soft, padded areas of the buttock and thighs, representing very obvious abuse. (Used with permission from Paul Bellino, MD.)

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small triangle at the base (Fig. 106-2) representing the interdigital and finger web spaces, occurs after a slap injury. Grab or pinch marks can be recognized by their location on soft padded areas and their unusual patterning. Circumferential purpura or hemosiderin pigmentation (Fig. 106-3) suggests a ligature injury, which would be difficult to explain as accidental. Bite marks (Fig. 106-4) are always inflicted, although they are sometimes from siblings or other children. The shape and size of the marks can identify an adult mouth versus a bite from a child. It is helpful to include a ruled measuring scale in any photographs to help forensic identification at a later date. The head is the most common target of physical abuse (see eFig. 106-4.1 in online edition). Black eyes are common accidental injuries but are more suspicious if they are bilateral or are unaccompanied by evidence of trauma to the nose or superior orbital ridge. Subconjunctival hemorrhages can be seen in 0.5%–13.0% of typical newborns, but a large subconjunctival hemorrhage beyond 1 and 2 weeks of life is suspicious of abuse. Petechiae in the periorbital region

Figure 106-2  Linear purpura representing the interdigital spaces from a hand slap. Note the inferior triangular shape that corresponds to the finger web space. (Used with permission from Paul Bellino, MD.)

Skin Signs of Physical Abuse

Bruising is the result of blunt trauma, delivered either accidentally or intentionally. Active children, particularly toddlers, are prone to multiple bruises, and the identification of abusive injury is fraught with difficulty. The size, shape, color, and feel of a bruise varies on the basis of anatomic site, the degree of force used, the firmness of the object delivering the force, and the underlying health of the injured individual. Great care and attention to detail must be exercised when evaluating these children who likely have been brought to the office for some other complaint. The history should include as much detail as possible and inconsistencies in the parent’s story clearly documented in the medical record (eTable 106-3.1 in online edition).3 It is essential to perform a total body, skin, and mucous membrane examination. It is also important to note the child’s behavior and parent–child interactions. The color of all bruises should be noted and clearly documented. This may aid in determining the age of a bruise and may point out inconsistencies in the caretaker’s history. Multiple bruises of differing colors may indicate ongoing trauma rather than one isolated incident. Caution must be exercised in dogmatically, stating the time of injury based on bruise characteristics because color depends on the intensity, depth, and location of the injury. There is good evidence that a bruise with any yellow color must be older than 18 hours, but a bruise may be red, blue, or purple/black throughout its life span, from beginning to resolution. Bruises of identical age and cause on the same person may not appear as the same color and may not change at the same rate.4 It is most prudent to document color without alluding to a specific age of a bruise in the medical record. Faint bruised might be more easily visualized with the use of a Wood’s lamp. Although there are no absolute differentiating features, certain aspects of an intentionally inflicted bruise may suggest abuse. Because young children tend to explore in a forward direction, accidents are more frequent on the distal arms and legs, knees, elbows, and forehead. Soft, padded, posterior, and protected areas of the body are far less likely to be accidentally injured. Bruises on the abdomen, buttocks (Fig. 106-1), thighs, genitalia, ear lobes, and cheeks are uncommon, so marks in these areas should raise concern. Inflicted bruises often leave patterned imprints of a hand, whip, or hard object. Linear purpura, with a

Chapter 106

THE BATTERED CHILD

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Section 18 :: Neurocutaneous and Psychocutaneous Skin Disease

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Figure 106-3  Linear, circumferential hyperpigmentation at the site of previous ligature. (Used with permission from Paul Bellino, MD.) have been seen in children with abuse related retinal hemorrhages. Accidental bruising or other injuries to the oral mucous membranes are unusual and should be considered as suspect (see eFig. 106-4.2 in online edition). Any bruises in a young infant who is not yet pulling to a stand should raise concerns of abuse or of an unsafe environment (see eFig. 106-4.3 in online edition). A shaken infant may have bruising on the hands because he or she is liable to be flailing during the shaking incident (see eFig. 106-4.4 in online edition). Concern should be raised whenever the history of an accident is inconsistent with the developmental level of the child.

INFLICTED BURNS The most common agent involved in childhood burns, both accidental and inflicted, is hot liquid. Accidents such as inadvertently stepping into a hot tub or pulling

Figure 106-4  Human bite marks. (Used with permission from Paul Bellino, MD.)

a hot liquid off a table counter or stove leave irregular or geographic burn patterns that lack symmetry. By contrast, inflicted scalds tend to be symmetric, with sharply demarcated edges and an absence or paucity of splash marks. In one study, all the children whose bathtub burns were inflicted had associated features of abuse, including bruises, fractures, or evidence of neglect.5 Stocking and glove burns result when the feet or hands are forcibly held under hot water. The uniformity of the burn indicates that the child was not able to reflexively withdraw from the scalding water as would happen with accidental immersion. A common pattern of inflicted immersion burn involves the buttocks, low back, and thighs. The child is flexed at the waist and dipped into the hot water, frequently as a punishment for a toilet training accident. The resultant pattern may give “zebra stripes” on the abdomen due to sparing of the flexural skin that is protected from the scald when bent forward. A “donut hole” pattern of sparing might be seen on the buttock if the child is pushed forcibly to the bottom of the tub that is cooler than the scalding water.6 Inflicted splash burns are much more difficult to differentiate from accidents. A careful history is needed to detect inconsistencies between the proposed injury and the physical examination. When doubt exists, it is mandatory that child protective services be contacted. An inflicted contact burn can be recognized by the pattern that duplicates the object creating the injury (see eFig. 106-4.5 in online edition). Accidental contact burns tend to be smaller, less severe, less patterned, and of irregular depth. When a child is held against a hot object, the depth is more uniform, the pattern is more clearly defined, and the burn is more severe. Irons, curling irons, hot plates, and cigarettes are objects commonly used to inflict burns.7 Some burns may, in fact, be accidental but represent inadequate supervision and neglect. This situation is also harmful to children and needs to be reported to the appropriate agencies.

SEXUAL ABUSE It is estimated that more than 300,000 children suffer from sexual abuse each year in the United States. The lifetime risk of sexual abuse is approximately 25%–40% for girls and approximately 10% for males. Sexual abuse is defined by the American Academy of Pediatrics as the engaging of a child in sexual activities that the child cannot comprehend, for which the child is developmentally unprepared, and cannot give informed consent and violate the social taboos of society.8 This broad definition includes inappropriate touching, genital penetration, fondling, and sexual kissing, but also includes noncontact activities such as exhibitionism, voyeurism, and the involvement of a child in verbal sexual propositions or the making of pornographic pictures or movies. Clearly, many forms of sexual abuse leave no physical examination findings. Girls are more likely than boys to suffer sexual abuse and the risk rises in preadolescence (Fig. 106-5). Most abuse is at the hands of someone known to the child

TABLE 106-4

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Conditions Mistaken for Sexual Abuse

Skin Signs of Physical Abuse

Genital warts pose a particularly difficult problem for practitioners. They certainly can be sexually transmitted to children, and the possibility of sexual abuse needs to be discussed with parents. However, there is much evidence that genital warts can be acquired perinatally from an infected mother, through autoinoculation from warts on other parts of the body or through nonsexual contact with caretakers.11 Children younger than 3 years of age at the onset of warts are least likely to have acquired their warts from sexual contact, whereas children with onset after 5 years of age have a much greater risk of having suffered sexual abuse. The ages in between represent a gray zone. Other signs of abuse will seldom be present to aid in the diagnosis, and human papillomavirus typing is not helpful. History provides the most valuable insight into the correct diagnosis; again, it is imperative that an abuse team be involved. At the author’s institution, all children with perianal or genital warts are referred, in a nonaccusatory and nonjudgmental fashion, to the hospital’s abuse social worker and pediatrician as routine protocol.12

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and only 10% is carried out by strangers. Victims and perpetrators span all racial, religious, and socioeconomic spectrums but risk factors for sexual abuse include the presence of a stepfather, single-parent families, children whose mothers are extensively out of the home, a history of parental violence, parents who have suffered abuse themselves, parental substance abuse, and low household income level. Most victims of sexual abuse have no physical findings.9,10 Pregnancy, positive cultures for sexually transmitted diseases, presence of sperm or acid phosphatase, acute genital or anal injuries without plausible explanation, and marked hymeneal opening enlargement with associated hymeneal disruption are very definitive signs of abuse. However, it is very seldom that such signs are present. The American Academy of Pediatrics Committee on Child Abuse and Neglect recommends that certain findings are consistent with, but not diagnostic of, abuse. These include chafing, abrasions or bruising of the inner thighs and genitalia, scarring, tears or distortion of the hymen, a decreased amount or absent hymeneal tissue, scarring of the fossa navicularis, injury to or scarring of the posterior fourchette, scarring or tears of the labia minora, and enlargement of the hymeneal opening, even without disruption of the hymen.8 The child’s spoken word is the most valuable piece of evidence in establishing sexual abuse. All historical information must be very well documented and preserved with the same care as any piece of forensic evidence. It is immensely important to enlist the help of an experienced abuse team in obtaining the history and completing an appropriately thorough physical examination with the aid of colposcopic observations. The skin examination’s greatest contribution may be in correctly diagnosing those dermatoses that may look similar to sexual abuse but are not. Irritant dermatitis, atopic dermatitis, psoriasis, seborrheic dermatitis, pinworms, candidiasis, scabies, and other common dermatoses tend to cluster in the diaper region and should be easily diagnosed with a critical eye. Other conditions that have been reported as mimickers of sexual abuse are listed in Table 106-4.

Chapter 106

Figure 106-5  Sexual abuse. Perianal wound in a 3-yearold girl after anal penetration. (Used with permission from Dr. Francesca Navratil, Zurich, Switzerland.)

Lichen sclerosus Crohn disease Localized vulvar pemphigoid Langerhans cell histiocytosis Perianal streptococcal dermatitis Hemangiomas Urethral prolapse Entities that look like condylomata acuminata Focal epithelial hyperplasia Darier disease Lymphangioma circumscriptum Pigmented vulvar hamartomas Pseudoverrucous papules Epidermal nevus and inflammatory linear verrucous epidermal nevus Entities that look like herpes simplex Localized varicella/zoster Allergic contact dermatitis

ELDER ABUSE Elder abuse is one of the fastest growing forms of abuse. Although statistics vary, the National Center on Elder Abuse in Washington, DC, estimates that 1 to 2 million Americans 65 years of age or older are victims of various forms of abuse each year. Abuse may affect a range of 2%–10% of the elderly population. Those older than age 80 years are two to three times more likely to suffer abuse, and the American population in this age range continues to increase each year. For every case of reported elder abuse, at least another five cases go undetected.13 All segments of society are affected. Although there is inherent inaccuracy in these statistics, it is readily apparent that elder abuse is common enough for a busy dermatologist to encounter a few abused patients every week.

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TABLE 106-5

Types of Elder Abuse

Neglect: 55% Physical abuse: 15% Financial and material abuse: 12% Emotional or psychological abuse: 8% Sexual abuse: 1% Unspecified forms of abuse: 9%

The US National Academy of Sciences has defined elder abuse as:

Section 18 ::

(a) intentional actions that cause harm or create a serious risk of harm (whether or not harm is intended) to a vulnerable elder by a caregiver or other person who stands in a trust relationship to the elder, or (b) failure by a caregiver to satisfy the elder’s basic needs or to protect the elder from harm.

Neurocutaneous and Psychocutaneous Skin Disease

Acts of commission and omission are thus included in the definition. Types of abuse and their respective incidence rates are listed in Table 106-5. More than one type of abuse can occur simultaneously.14,15 Abuse most often occurs at the hands of caregivers or family members who have frequent close contact with patients and often may live with them. Historically, adult children of the abused patient have been the most common perpetrators, but most recent data show that spouses now account for the majority of abuse cases. Men are more likely to abuse than women. The abuser is often financially dependent on the victim, and they are usually in a shared living situation. However, financial abuse is more common among those who live alone. Risk factors for abuse are listed in Table 106-6. Note that the risk factors have far more to do with the caretaker than the abused patient. In particular, the level of debility or health status of the patient does not predict abuse. Physical abuse is defined as the intentional application of any force that causes bodily injury, pain, or impairment to an elderly individual. It may include acts such as hitting, beating, shaking, kicking, slapping, pushing, pinching, burning, overly aggressive force-feeding, and the improper use of physical or chemical restraints. The signs discussed in Section

TABLE 106-6

Risk Factors for Elder Abuse

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Older age Lack of access to resources Low income Social isolation Minority status Low level of education Functional impairment Substance abuse by elder or caregiver Previous history of family violence History of psychological problems Caregiver stress Cognitive impairment

“Child Abuse” above apply to elder abuse as well and include multiple bruises or fractures in different stages of healing, bruises in normally well-protected areas such as the inner thighs, odd-shaped injuries such as from pinching or slapping, belt marks or patterned bruising (see eFig. 106-5.1 in online edition), unusual welts or puncture wounds, cigarette burns, rope marks that might indicate restraints, bed sores, strangely patterned alopecia, attempts to hide part of the body, and signs of malnutrition or dehydration. Because many of these signs, particularly multiple bruises, can occur normally in elderly individuals, detection of abuse can be very challenging. Unexplained repetitive injuries or explanations by caretakers that do not match the pattern of injury are concerning. Caretakers who act withdrawn, infantilize the patient, or insist on providing the medical history should alert the clinician. It is important to interview by directing questions to the patient rather than the caregiver, and it is prudent to try to arrange a time to confer with and examine the patient alone. Repetitive follow-up visits help develop a rapport with the patient and allow serial observation of past and ongoing injuries. The assurance of confidentiality facilitates garnering sensitive information. Once abuse is suspected, most states mandate that physicians contact the appropriate authorities. Information on a particular state’s laws can be obtained from the National Center on Elder Abuse (see Table 106-3). The nearest medical center’s social service department is well equipped to offer guidance, but the agencies listed in Table 106-3 are also helpful resources. Treatment, support, and counseling may be needed for the perpetrator as well.

DOMESTIC VIOLENCE Domestic violence is a pattern of coercive behaviors that may include repeated battering, psychological abuse, sexual abuse, social isolation, deprivation, and intimidation perpetrated by someone who is or was involved in an intimate relationship with the victim. Conservative estimates say that in the United States approximately 1 million people suffer domestic violence each year, but the actual number likely approaches 4 million. Women comprise approximately 90%–95% of all victims, and men 95% of all perpetrators. Forty percent to 60% of men who abuse their partner or spouse are also abusing their children. In the United States, approximately one in three women suffers a least one physical assault during her life, and 1,500 women are murdered by their husbands or boyfriends each year.16,17 Domestic violence is a devastatingly common problem. The profiles of domestic abuse are similar to child and elder abuse. Women ages 19–29 years are the most common victims, with other risk factors being low income, mental health issues, alcohol or substance abuse by the victim or the perpetrator, pregnancy, large age difference between partners, separated or divorced status, and a family history or personal past history of abuse and violence. Women with educational or occupational levels above that of their partners may be at

suggesting a defensive posture and might include purpura, sprains, dislocations, and fractures to the wrist or forearms, palms, and soles. The social service department at the local medical center is a good resource for information and help on domestic violence. The National Domestic Violence hotline (800–799-7233) is a 24-hour resource for women who need to find a local shelter. Other helpful organizations can be contacted (see Table 106-3).

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KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content

:: Skin Signs of Physical Abuse

1. Legano L, McHugh MT, Palusci VJ: Child abuse and neglect. Curr Probl Pediatr Adolesc Health Care 39:31e1, 2009 6. Kos L, Shwayder T: Cutaneous manifestations of child abuse. Pediatr Dermatol 23:311, 2006 7. Swerdlin A, Berkowitz C, Craft N: Cutaneous signs of child abuse. J Am Acad Dermatol 57:371, 2007 14. Abbey L: Elder abuse and neglect: When home is not safe. Clin Geriatr Med 25:47, 2009 16. Zolotor AJ, Denham AC, Weil A: Intimate partner violence. Prim Care Clin Off Pract 36:167, 2009 17. Toohey JS: Domestic violence and rape. Med Clin N Am 92:1239, 2008

Chapter 106

higher risk. Abusers are typically underachievers with occupational status below their educational level.16,17 Whenever possible, the patient should be interviewed alone, without the partner’s presence. A thorough examination should be done with a nurse chaperone, but not the partner, in the room. Repeat visits may be used to document new or progressing skin findings and to build trust with the patient. Statements such as “Because domestic violence is such a prevalent problem, we have begun to ask about it routinely” may open the door to more discussion regarding difficulties at home. Literature and posters in the clinic setting with information and hotline numbers for abuse victims indicate the common reality of abuse and may facilitate disclosures. For various reasons, a victim may not want to reveal abuse. Implausible explanations for an injury or a delay in seeking medical attention may be clues of abuse. Signs of depression, excessive use of sedatives, chronic pain disorders, or vague stress-related symptoms may be subtle signs of abuse.17 Physical examination findings are the same as outlined for child and elder abuse. The distribution of injuries tends to be central, and the perpetrator may choose to injure hidden areas, such as the breast or genitals, to deter detection. Unlike infants or debilitated adults, blows to a young adult may be to areas

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Skin Changes across the Span of Life

PA RT

From Birth to Old Age

Chapter 107 :: N  eonatal, Pediatric, and Adolescent Dermatology :: Mary Wu Chang NEONATAL, PEDIATRIC, AND ADOLESCENT DERMATOLOGY AT A GLANCE Many dermatologic diseases exhibit different manifestations in newborns, infants, and children. Some dermatoses are encountered only in neonates and infants and therefore require special attention. Obtaining a history and methods of clinical examination in infants and children differ from the approaches chosen for adults. In adolescents, different skills are required to enhance compliance. Many outpatient procedures in pediatric dermatology can be done easily with appropriate planning and age appropriate

Just as dermatology cannot be separated from internal medicine, pediatric dermatology is inseparable from general pediatrics. Since most dermatologists have experience and training in internal medicine but less exposure to pediatrics and neonatology, an introduction to the special issues that can arise in pediatric dermatology is presented herein. As it is impossible to

techniques. Necessary biopsies should not be avoided simply because of a patient’s young age. The infant has increased risk for systemic toxicity from topically applied substances; the risk is even greater in premature infants. Children with disorders of barrier function are at high risk of excess percutaneous absorption and toxicity as well. Drug labeling for pediatric patients is different from that in adults and most therapeutic agents are prescribed off-label.

discuss all of pediatric dermatology in one chapter, the focus is instead on certain methods, diseases, and issues divided by three age divisions: neonates and infants, children, and adolescents. Topics of special importance such as pediatric medication use and biopsy pitfalls are discussed. Methods to enhance success in outpatient procedures in pediatric dermatology are also reviewed.

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TABLE 107-1

Ten Helpful Tips in Pediatric Dermatology

Section 19 :: From Birth to Old Age

  1. The child is the patient, not the parents.   2. Biopsy when indicated, regardless of age. (Refer if necessary)   3. Be aware of the family situation: Does the child live in two homes? Are the parents going through a divorce?   4. Be aware of the parents’ perception of the child: Was there difficulty in conceiving? Prematurity? Significant early illness?   5. A team approach with the pediatrician, neonatologist, or family physician is most efficient. Psychiatrist comanagement may be indicated (e.g., isotretinoin issues or trichotillomania).   6. Chronic illness in one person affects the entire family (e.g., severe atopic dermatitis).   7. Guide parents and patients to appropriate Internet resources, but always review materials for accuracy beforehand.   8. Obtain consent from parents, and assent from children, for procedures and photos.   9. An adolescent’s confidentiality must be maintained unless there is a danger of harm to the patient, or others. Consider interviewing patient alone without parents for a portion of the visit. Consider a chaperone in the office for full skin exams. 10. Remember the aphorism, “To cure sometimes, to relieve often, to comfort always.”

Successful care of the pediatric patient is best achieved via comanagement with the neonatalogist, pediatrician, or primary care physician. In addition, an understanding of the parental or family situation is important. For example, children living in two households (due to divorced parents) may do best with two sets of medications, one in each home, to enhance compliance. Table 107-1 reviews ten helpful tips in practicing pediatric dermatology. As an example, if Internet access exists, patients or parents will likely search online for medical information before or after the office encounter. Parents and patients should be warned that medical information on the Internet is often inaccurate.1 It is wise to direct them to specific Internet Web sites, support groups, or pamphlets, but these resources should be reviewed before recommending them. Lastly, the aphorism, “To cure sometimes, to relieve often, to comfort always,” should always be kept in mind when delivering pediatric care. Parents often have higher expectations, and a heightened level of worry and concern for their children and the office visit cannot be rushed.

NEONATES AND INFANTS

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The neonatal period is defined as the first 30 days of life. Neonatal skin diseases evolve much more rapidly than adult skin diseases, and some conditions that initially appear to be serious turn out to be trivial, whereas in others, the opposite is true. Infancy is defined as beginning after the first 30 days of life.

NEONATAL SKIN After birth, the neonate’s skin undergoes a series of changes in adaptation to the extrauterine environment. In utero, the skin of the fetus is protected by the vernix caseosa and is immersed in amniotic fluid. After birth, the vernix is wiped off, and the skin is exposed and adapts to the dry ambient air. For example, desquamation of the upper layers of the stratum corneum occurs normally in all infants and is believed to be a normal adaptive process. Research regarding the maturation of the neonatal stratum corneum in neonates has produced varying results, and the question of when full barrier function is achieved is not fully answered. Barrier stabilization appears to be a dynamic process, one dependent upon a balance between different biologic and environmental parameters. Postnatal life is believed to accelerate stratum corneum maturation in premature and term infants. Parameters such as skin thickness, skin pH, and stratum corneum hydration indicate that neonatal skin is continuously adjusting to the extrauterine environment, in contrast to the adult skin, which remains in a steady state.2 In vivo studies of human skin show that infant stratum corneum and epidermis is thinner than adult skin and has higher transepidermal water loss (TEWL) rates, but infant stratum corneum has higher water content. Infant corneocytes and granular cells are smaller than adult corneocytes suggesting a more rapid cell turnover than in adults.3 Infants have an increased risk for systemic toxicity from topically applied substances. This is due in large part to the great surface area–body mass ratio in the infant. In addition, the infant’s metabolism, excretion, distribution, and protein binding of substances can be significantly different from those of an adult and add to increased risk of toxicity.4 The postmature infant (>40 weeks’ gestation) typically has dry and cracked or peeling skin noted soon after birth (Fig.  107-1). Shedding of the dry peeling skin of postdates infants occurs spontaneously in the first month of life, leaving normal, healthy skin. Topical care should include moisturizers and avoidance of overbathing. Premature infants, particularly those born before 34 weeks of gestation, have markedly decreased epidermal barrier function and an even greater surface area– body mass ratio than term infants. In addition, the immature organs of the premature infant may affect the metabolism, excretion, distribution, and protein binding of chemical agents. Local or systemic toxicity can occur in the premature infant not only from topical medications, but also soaps, lotions, or other cleansing solutions.4,5 Increased skin fragility is a hallmark of prematurity (gestational age less than 37 weeks). Epidermal and dermal injury may lead to significant cutaneous pain even with routine handling and nursing care. The premature infant is at risk for infection and sepsis from skin-associated organisms entering through breaks in the thin and fragile skin and via iatrogenic portals of entry. Sweating

EXAMINATION TECHNIQUES

Neonatal, Pediatric, and Adolescent Dermatology

in the premature infant is functionally reduced and contributes to poor thermal regulation. Heat regulation is dysfunctional due to a thin subcutaneous fat layer for insulation, poor autonomic control of cutaneous vessels, and a large surface–body ratio. In the nursery, the premature infant is usually placed in a temperature and humidity-controlled isolette until the infant matures and temperature and fluid regulation stabilizes. In the 1990s researchers reported application of petrolatum-based emollient therapy to be beneficial in hospitalized preterm infants, decreasing transepidermal water loss.6 Subsequently, various emollients and regimens have been tested in infants of variable prematurity and birthweight. Improved skin integrity consistently improved in these studies, however, a threefold increase in the incidence of systemic candidiasis was reported after emollient therapy was implemented in extremely low birthweight (≤1,000 g) premature infants in one neonatal intensive care unit.7 Another outbreak of systemic candidiasis occurred in very low birthweight neonates (≤1,500 g) in a different neonatal intensive care unit.8 A 2004 Cochrane review concluded that prophylactic application of topical ointments increased the risk for nosocomial infection and advised against their routine use in preterm infants. In contrast, randomized, controlled studies in impoverished Bangledeshi preterm neonates have demonstrated decreased mortality rates when sunflower seed oil or Aquaphor ointment was applied by massage, compared to premature infants not receiving massage or emollients.9 Until prospective, controlled trials are performed, neonates receiving petrolatum-based emollient therapy should be carefully monitored for infections, particularly those infants with birthweights less than 1,500 g.

::

Figure 107-1  The feet of a postmature newborn. The dry, hyperlinear, and scaly skin is typical of a postdates baby. There are also pustules of transient neonatal pustular melanosis.

A complete history includes gestational and birth history as well as family history. Exposures during pregnancy, including medications, illicit drugs, and infectious diseases such as varicella and sexually transmitted diseases, should be reviewed. Obstetric data, including placental appearance and cultures, can be invaluable. In examining an infant, the most important element is thoroughness. Whether the infant is examined in the lap of the parent or on the examination table, all surfaces, including the creases and valleys of body folds and the diaper region (including the genitalia), deserve close examination. A vascular stain, vasoconstricted macule, or erosion can be the presenting sign of a hemangioma.12 A stray hair may later strangulate an appendage and should be removed. Infants with digital tourniquet (pseudoainhum) and clitoral tourniquet have been described.13,14 Congenital lesions of all classifications (e.g., pigmented, vascular, aplasias) warrant closer inspection to rule out associated findings. Midline lesions on the face, scalp, or spine may have central nervous system (CNS) connections and should not be biopsied without proper evaluation (see Table 107.7). The diaper area has its own unique set of problems and deserves examination at every visit. The infant is vulnerable and completely dependent on the caretakers. The social support system and family structure must be considered when implementing a medical plan. There are times when the parents’ desire for treatment may not be in the best interest of the patient. Medical and surgical decision making for the infant is based primarily on function rather than cosmesis. For example, extraction of a natal tooth is indicated if breast-feeding is impaired; whether or not the tooth is a component of a genetic syndrome is a separate issue.

19

Chapter 107

Once at home, bathing once or twice a week in plain water is sufficient for most infants; if bathing is more frequent, moisturization with unscented, simple emollients is recommended. The face, hands, and diaper area may be cleansed daily using a small amount of a mild, unscented, pH-neutral cleanser. Well-meaning parents often bathe their infants too frequently and use a multitude of products on their infant’s skin. In addition to irritation and asteatosis, these practices may increase the risk of allergic contact dermatitis in infants. It has been estimated that the average newborn is exposed to approximately 10 skin care products in the first month of life, leading to exposure to more than 50 different chemicals ranging from mildly toxic to toxic.10 Parents should be taught that “less is best.”11

DISEASES OF NEONATES AND INFANTS TRANSIENT DERMATOSES OF THE NEONATE. Skin conditions encountered in newborns

that tend to resolve by 30 days of age are considered to be transient. They are very common and many are expected in newborns.

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19

Caput Succedaneum and Cephalohematoma. Caput succedaneum is subcutaneous edema

Section 19

over the presenting part of the head and is a common occurrence in newborns. Cephalohematoma is a subperiosteal collection of blood and is less common. Both lesions are due to shearing forces on the scalp skin and skull during labor. Caput succedaneum is soft to palpation, and borders are ill-defined. Cephalohematoma is bounded by the suture lines of the skull and often feels fluctuant. If purpura is extensive, it can lead to hyperbilirubinemia. Congenital lymphedema or lymphatic malformations (such as in Turner syndrome) can mimic caput succedaneum. Both caput succedaneum and cephalohematoma resolve spontaneously; however, caput usually fades in 7–10 days, whereas cephalohematoma slowly resolves over several weeks.

:: From Birth to Old Age

Milia. Milia are multiple pinpoint- to 1-mm papules representing benign, superficial keratin cysts. They are seen most commonly on the nose of infants and may be present in the oral cavity as well, where they are called Epstein’s pearls. They are expected findings in the newborn and resolve spontaneously within a few weeks of life. Sebaceous Gland Hyperplasia. At

least 50% of normal newborns have sebaceous gland hyperplasia (Fig.  107-2). Tiny (4 month, or if sonographic expertise unavailable   Atypical sacral dimple (deep, farther than 2.5 cm from the anus, size ≥5 mm)   Unclassified hamartoma   Aplasia cutis congenita   Deviation of gluteal crease

Low

Group 3: No imaging needed   Port-wine stain   Hypertrichosis (unless large and/or unusual)   Pigmented nevus   Simple sacral dimple (80 years is significantly associated with MRSA ­carriage.164 Because community-associated MRSA infection most often presents as skin and soft tissue infections, dermatologists should be aware of this possibility when managing infections in the elderly.

Aging of Skin

XEROSIS AND ASTEATOTIC DERMATITIS

INFECTIOUS PROCESSES

19

::

PAPULOSQUAMOUS DISORDERS

humidity, frequent bathing, or application of irritants to the skin. However, in up to 10%–50% of patients in some series, pruritus may have other etiologies. These include metabolic or endocrine disorders, such as diabetes mellitus, renal failure, thyroid disease, or hepatic disease, in particular the obstructive type. Pruritus can be a manifestation of a malignant neoplasm, in particular lymphoma or leukemia, or the result of a hematologic disease such as polycythemia vera. Adverse drug reactions can manifest predominantly or exclusively as pruritus and always should be considered in this segment of the population. Finally, infestations such as scabies lead to intense pruritus, and associated primary skin lesions may be overlooked.

Chapter 109

Merkel cell carcinoma (trabecular carcinoma) (see Chapter 120) is a rare cutaneous tumor thought to arise from a pluripotential cell that displays neuroendocrine differentiation.182,183 It is seen most often in sun-exposed areas of the head, neck, or extremities and presents as a rapidly growing nodule with a poor prognosis. More than 90% of patients diagnosed with this tumor are older than age 50, with the mean age of onset being 68 years. Polyomavirus sequences found integrated within the DNA of tumor cells are likely the etiologic agent for Merkel cell carcinoma,184 and age-associated subtle losses in cellular immunity may well account for the demographics of this malignancy. The most common form of angiosarcoma (see Chapter 128) occurs overwhelmingly on the head and neck of the elderly. Its rapid growth, associated with early metastasis, usually results in death within 2 years of diagnosis.185 Immunohistochemical analysis shows high levels of VEGF and its receptor, VEGF receptor-2, as well as cell cycle-associated proteins in cutaneous angiosarcoma explaining in part the rapid growth of these vascular tumors.186

PARASITIC195 (See Chapter 208.)

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19

Scabies can occur in any age group, but nursing homes provide a fertile ground for rapid spread of the infestation. In the elderly, in part because of their decreased immunity, lesions may be atypical and display less inflammation and pruritus. In addition, the elderly frequently have xerosis, and their pruritus at times may be attributed to this etiology.

DERMATOPHYTES AND YEASTS

BULLOUS PEMPHIGOID

196

Section 19 :: From Birth to Old Age

(See Chapters 188 and 189.) Onychomycosis is present in approximately 40% of patients after age 60 years, and tinea pedis is present in approximately 80% of this patient population. Although usually present for decades, tinea pedis may exacerbate with age. Indeed, in elderly diabetic patients, interdigital tinea pedis may ulcerate and predispose to bacterial cellulitis, a presentation that is relatively rare in the young adult immunocompetent patient. Cutaneous infections due to Candida albicans are common in the elderly. When recurrent or difficult to control, candidiasis may be a sign of poorly controlled diabetes, an endocrinopathy, malnutrition, or malignancy.

VIRAL (VARICELLA-ZOSTER VIRUS)163 (See Chapter 194.) The incidence of herpes zoster peaks at approximately 1,500 cases per 100,000 persons annually at age 75 years. Postherpetic neuralgia, uncommon in patients younger than 40 years old, occurs in more than 40% of patients aged 60–69 years and 50% of patients 70 years of age or older.100 A number of patients older than 60 years also experience paresthesias and muscle weakness. Decreased cellular immunity and impaired wound healing in the elderly may account for slower resolution of the acute eruption, but the pathogenesis of their postherpetic neuralgia is unclear. A new vaccine composed of live, attenuated varicella zoster virus is now available and reported to reduce the incidence of postherpetic neuralgia by 66.5%.197

ULCERS198

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than in younger patients, as the former tend to be less mobile, needing help turning in bed, and have additional aggravating disorders such as dry skin over bony prominences, incontinence, sensory deficiency, and/or poor nutritional state.199,200

Chronic ulcers of all etiologies are more common in the elderly than in younger individuals, presumably due to a combination of impaired wound healing and higher prevalence of underlying diseases. The most common are leg ulcers, usually in the setting of chronic venous insufficiency leading to venous hypertension (see Chapter 174). Exudation of macromolecules such as fibrinogen into the dermis may block the passage of oxygen and nutrients and sequester cytokines and growth factors required for tissue homeostasis, maintenance, and repair. The sclerotic indurated quality of affected skin, termed lipodermatosclerosis, is postulated to further impair healing. In addition, diseases such as diabetes mellitus and atherosclerotic peripheral vascular disease may contribute to ulcer evolution. Decubitus ulcers (see Chapter 100) are proportionately far more common in elderly hospitalized patients

(See Chapter 56.) Bullous pemphigoid is far more common after age 60 years than in younger persons, a predilection that may be explained in part by the age-associated increases in circulating autoantibodies and ease of dermal–epidermal separation,201 although many other autoimmune and blistering dermatoses are not more common in old age. Possibly, age-associated changes in the basement membrane itself render it specifically vulnerable to this disease process. Bullous pemphigoid is a selflimited condition that frequently resolves within 6–12 months, but elderly patients may experience increased morbidity and mortality because of debilitated general health or as a side effect of treatment.

DRUG ERUPTIONS Adverse drug reactions of all kinds increase with age, in part because the elderly consume more medications than younger age groups and in part because of medical conditions, including impaired renal, cardiac, or hepatic function, that compromise drug metabolism or excretion. The most frequently observed adverse cutaneous drug reactions are pruritus, exanthems, and urticaria, but drug-induced autoimmune reactions, including pemphigus, bullous pemphigoid, and lupus erythematosus, also occur in the elderly. A careful history to elicit all prescription medications as well as over-the-counter preparations is critical to diagnosis and optimal patient care.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 6. Campisi J: Replicative senescence: An old lives’ tale? Cell 84:497-500, 1996 29. Weng NP: Aging of the immune system: How much can the adaptive immune system adapt? Immunity 24:495-499, 2006 34. Harman D: Free radical theory of aging: An update: Increasing the functional life span. Ann N Y Acad Sci 1067:10-21, 2006 39. Kosmadaki MG, Gilchrest BA: The role of telomeres in skin aging/photoaging. Micron 35:155-159, 2004 65. Wolpowitz D, Gilchrest BA: The vitamin D questions: How much do you need and how should you get it? J Am Acad Dermatol 54:301-317, 2006 94. Van Neste D, Tobin DJ: Hair cycle and hair pigmentation: Dynamic interactions and changes associated with aging. Micron 35:193-200, 2004 96. Verdier-Sevrain S, Bonte F, Gilchrest B: Biology of estrogens in skin: Implications for skin aging. Exp Dermatol 15:83-94, 2006

Neoplasia

PA RT

Carcinogenesis

Chapter 110 :: G  enome Instability, DNA Repair, and Cancer :: Thomas M. Rünger & Kenneth H. Kraemer GENOME INSTABILITY, DNA REPAIR, AND CANCER AT A GLANCE DNA can be damaged by physical agents (ultraviolet or ionizing radiation) or chemical agents in the environment. DNA damage may lead to mutations (changes in DNA sequence). The ability of cells to repair DNA damage and to maintain genome stability is of utmost importance to prevent malignant transformation.

A number of hereditary disorders are characterized by genome instability due to defects in genes involved in DNA repair or DNA damage signaling. Many different laboratory tests can be used to diagnose genome instability and/or DNA repair defects. Inherited or acquired genome instability is associated with an increased cancer risk.

Different agents induce different types of DNA damage, which in turn require different responses and repair pathways.

INTRODUCTION The integrity of the genome of all living organisms is constantly threatened by exogenous and endogenous DNA-damaging agents. Exogenous DNA-damaging agents include physical agents, such as ultraviolet (UV) or ionizing radiation (IR), and a wide variety

of chemical agents, such as components of cigarette smoke. Endogenous DNA damage arises from regular metabolic processes within the cell, mediated, for example, by reactive oxygen species. Maintaining the stability of the genome is of utmost importance to all living organisms. Therefore, since early evolution, all organisms ranging from prokaryotes to eukaryotes

7

20

TABLE 110-1

Cellular Damage Induced by Physical and Chemical Agents Agent

Damage

Ultraviolet (UV) radiation

Dipyrimidine cyclobutane dimers (TT, TC, CT, or CC), pyrimidinepyrimidone (6–4) photoproducts (mostly TC), DNA-protein crosslinks

X-irradiation

DNA single- and double-strand breaks, oxidative base damage

Section 20

Psoralens plus UVA

DNA-psoralen monoadducts, DNA interstrand cross-links (binds to T at TA sequences)

Mitomycin C

DNA interstrand cross-links

::

Benzo-[a]-pyrene

Bulky adducts

Carcinogenesis

Reactive oxygen species

Oxidative base damage (8-oxo-deoxyguanine, thymine glycol), cyclopurines (A or G) making bulky lesions

have been equipped with mechanisms that react to and repair DNA damage and thereby maintain genomic stability. The types of damage produced include alterations in the structure of nucleotides, DNA strand breaks, DNA cross-links, and DNA adducts. Different types of DNA-damaging agents induce different types of DNA damage (Table 110-1), which in turn require different responses and repair pathways for processing (Table 110-2).1

If DNA damage is not repaired adequately, it may lead to altered cell function, cell death, or the formation of mutations (alterations of the DNA sequence) in the damaged cells. These DNA damage-induced mutations will persist as long as the affected cell survives. At a cellular level, mutations in vital genes can lead to alterations of cell functions or malignant transformation. Accumulation of mutations may lead to organ dysfunction, aging, and cancer. Although most DNA damage is adequately repaired, none of the cellular responses is 100% effective in repairing all DNA damage under all circumstances. A hereditary or acquired impairment in the way cells respond to DNA damage may result in genome instability with an increased rate of mutation formation. Numerous hereditary disorders are characterized by such genome instability (reviewed in Chapter 139). Many, but not all, of those are associated with an increased cancer risk and/or accelerated aging. Exposure of the skin to UV radiation has multiple cellular and clinical effects, including an increase in skin cancer risk. The photocarcinogenesis cascade of events (Fig. 110-1) exemplifies the link between genome instability, DNA repair, and cancer. UV light produces a type of DNA damage involving the generation of photoproducts, which are alterations in the structure of nucleotides. The major DNA photoproducts are cyclobutane pyrimidine dimers (CPDs; Fig. 110-2) and 6,4-pyrimidine–pyrimidone dimers. Unrepaired CPDs or 6,4-pyrimidine–pyrimidone dimers may result in characteristic mutations: C to T single base and CC to

Photocarcinogenesis cascade of events

UV-exposure

TABLE 110-2

Types of DNA Damage and Associated DNA Repair Pathways

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Type of DNA Damage

DNA Repair Pathway

DNA photoproducts (CPDs, 6,4-PP)

Nucleotide excision repair (NER)

Oxidative base modifications (e.g., 8-oxoG)

Base excision repair

Incorrect DNA base pairing

Mismatch repair

DNA double-strand breaks

Nonhomologous end joining, homologous recombination (i.e., recombination repair)

DNA adducts

NER

DNA cross-links (interstrand and intrastrand)

Recombination repair

Persistent DNA lesions

Translesion (bypass) DNA synthesis

CPDs = cyclobutane pyrimidine dimers; 6, 4-PP = 6, 4-pyrimidine– pyrimidone photoproducts; 8-oxoG = 8-oxo-deoxyguanine.

DNA damage DNA photoproducts Mutation incl. C T transitions Skin cancer monoclonal expansion of mutated keratinocytes or melanocytes

Inherent defense mechanisms Pigmentation Skin thickening DNA repair Cell cycle arrest Apoptosis Removal of mutated cells (immune-surveillance)

Figure 110-1  Photocarcinogenesis cascade of events. Exposure to ultraviolet (UV) light induces typical types of DNA damage, namely, cyclobutane pyrimidine and 6,4-pyrimidine–pyrimidone photoproducts. These often generate single and tandem base substitution mutations (C→T and CC→TT) that are typical for UV light exposure and are therefore termed UV-signature mutations. With sufficient numbers of inactivating mutations in crucial genes (tumor suppressor genes), individual cells may undergo malignant transformation, clonally expand, and form skin cancers. Several inherent defense mechanisms counteract this chain of events (see text).

20

Example of UV light-induced generation of DNA damage and subsequent mutation

Formation of DNA damage (photoproduct) T

Repair

G

C

T

T

T

T

C

C

A

G

T

G

T

Normal sequence UV P

P

P

P

P

P

Cyclobutane pyrimidine dimer (CPD)

T

G

C

T

T

T

T

C

T

C

A

T mutation

::

No repair

DNA DAMAGE AND REPAIR More than 100 DNA repair genes have been identified (http://sciencepark.mdanderson.org/labs/wood/ DNA_Repair_Genes.html). The nucleotide excision repair (NER) pathway acts on DNA damaged by UV radiation, repairing CPDs and other photoproducts, as well as on DNA damaged by certain carcinogens (such as benzo-[a]-pyrene) (see Table 110-2). In NER, the damaged nucleotide is removed and replaced with undamaged DNA. A simplified schema of the NER system describing some of the many proteins that act in concert to repair UV-induced DNA damage is shown in Fig. 110-3. Defects in these repair genes can cause human diseases (Table 110-3), including xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD) (for details on these disorders, see Chapter 139). For instance, XP can be caused by a defect in any one of several genes involved in NER. Cells/patients with defects in the same gene are considered to be in the same complementation group, and in different complementation groups if different genes are affected. The term “complementation group” is based on cell fusion experiments, in which cells from different XP patients are fused to investigate if the DNA repair defect in the fused cells is corrected. If DNA repair in the fused cell is increased, each cell

Genome Instability, DNA Repair, and Cancer

Figure 110-2  Example of ultraviolet (UV) light-induced generation of DNA damage and a subsequent mutation. On direct excitation of the DNA molecule by UV light, adjacent pyrimidine bases (cytosine or thymine) may form covalent bonds between them, which lead to creation of pyrimidine dimers. The illustration shows an example in which two covalent bindings generate a tricyclic cyclobutane ring between two pyrimidines. Hence, this type of UV light-induced DNA damage is called a cyclobutane pyrimidine dimer, a common type of DNA photoproduct. The nucleotide excision repair DNA repair system functions to remove this damage, which results in the normal DNA sequence (upper box). If the damage is not repaired, this type of DNA photoproduct can lead to formation of a typical C→T single base substitution mutation (lower box). This is most likely to occur on replication of damaged DNA and misincorporation of adenine opposite the cytosine-containing photoproduct. An example of such a UV-signature mutation is shown on the right.4 Note that the mutation is located within a run of seven pyrimidines, a common location for UV-signature mutations. TT tandem base substitution mutations.2–4 Such mutations are typical for UV light exposures and only rarely are induced by other mutagens. They have therefore been termed UV-signature mutations (see Fig.  110-2). Pleasance et al.5 sequenced all the genes in cells from a melanoma metastasis and reported that they harbor approximately 25,000 such mutations, accounting for about 70% of all mutations found. This clearly links the mutation burden in this cancer to prior UV-exposures. DNA repair is an important cellular defense mechanism that prevents mutation formation at sites of DNA damage after UV exposure. However, it is not the only defense mechanism (see Fig.  110-1). Most mutations are generated during replication of damaged DNA. Therefore, a damage-induced arrest in cell cycling, which allows more time for repair, is another important cellular damage response that prevents mutation formation.6,7 Furthermore, programmed cell death (apoptosis) prevents the survival of cells with overwhelming DNA damage, and through that mechanism the frequency of cells with UV-induced mutations is also reduced.8 Other inherent defense mechanisms against the ultimately carcinogenic properties of UV light include increased melanogenesis and thickening of the epidermis and stratum corneum, which protect from future DNA damage. Other protection includes removal of mutated cells through host immune responses (see Fig. 110-1).

Chapter 110

Two adjacent pyrimidine bases

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20

DNA nucleotide excision repair scheme

A DNA damage recognition Global gene repair XPE

Transcription-coupled repair RNA-polymerase

XPC 5’ 3’

5’ 3’

CSA

B Unwinding of DNA helix TFIIH

XPA

Section 20

XPB

5’ 3’

CSB

XPD

C Incision and release of 24-34 residue oligonucleotide

:: Carcinogenesis

XPF complexed with ERCC1 nuclease

XPG XPB

5’ 3’

XPD

D Gap filling and ligation 5’ 3’

PCNA

DNA polymerase ε/δ

RPA

Figure 110-3  DNA nucleotide excision repair scheme. A. Right: Damaged DNA in actively transcribed genes results in stalling of the RNA polymerase in a process that involves the CSA and CSB proteins. This serves as a signal to initiate transcription-coupled DNA repair. Left: Damaged DNA in the remainder of the genome is bound by the XPE and XPC gene products. This serves as a signal to initiate global genome repair. B. A portion of the DNA, including the damage, is unwound by a complex of proteins including the XPB and XPD gene products. These proteins are also part of the 10subunit basal transcription factor IIH (TFIIH). The XPA protein may stabilize the unwound DNA. C. The XPF and XPG nucleases make single-strand cuts on either side of the damage, releasing a 24- to 34-residue segment of DNA. D. The resulting gap is filled by DNA polymerase in a process that includes the proteins proliferating cell nuclear antigen (PCNA) and replication protein A (RPA). CSA, CSB = Cockayne syndrome complementation groups A and B; ERCC1 = excision repair crosscomplementing gene 1; LIG1 = ligase 1; XPA, XPC, etc. = xeroderma pigmentosum complementation groups A, C, etc.

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provides proteins that the other is lacking and the cells “complement” each other and are in different complementation groups. If DNA repair in the fused cells is not normalized, the cells do not “complement” each other, meaning that both cells harbor mutations in the same DNA repair gene. Seven such complementation groups have been identified (XP-A to XP-G), which correspond with mutations in seven distinct genes that can cause XP. Transcribed genes are repaired faster than the rest of the genome. In the NER pathway, the first steps involving DNA damage recognition are different in nontranscribed (global genome NER) and transcribed genes (transcription-coupled NER). In nontranscribed genes and noncoding areas, which represent most of the genome, the XPE and XPC gene products bind to UVdamaged DNA, marking it for further processing. In contrast, DNA damage in transcribed genes appears to be sensed by a stalled RNA polymerase acting in con-

junction with the CS complementation groups A and B (CSA and CSB) gene products. After the DNA damage recognition steps, global genome NER and transcription-coupled NER follow the same pathway. The XPA gene product functions in conjunction with replication protein A (RPA), the transcription factor IIH (TFIIH), XPF, and excision repair cross-complementing gene 1 (ERCC1). The following steps occur in both nontranscribed and transcribed gene repair:



The XPB and XPD gene products partially unwind the DNA in the region of the damage, thereby exposing the lesion for further processing. These proteins are part of the TFIIH basal transcription factor (see Fig. 110-3B). The XPF gene product, in a complex with ERCC1, makes a single-strand nick at the 5′ side of the lesion, whereas the XPG gene product makes a similar nick on the 3′ side, which results in the

20

TABLE 110-3

DNA Repair and Telomere Maintenance Genes Associated with Human Diseasesa Function

XPA

9q22.3

NER

Binding of damaged DNA

XPB (ERCC3)

2q21

NER

DNA helicase, part of TFIIH

XPC

3p25

NER

Binding of damaged DNA, global genome repair

XPD (ERCC2)

19q13.3

NER

DNA helicase, part of TFIIH

XPE (DDB2)

11p12-p11

NER

Binding of damaged DNA, global genome repair

XPF (ERCC4)

16p13.3-p13.11

NER

DNA endonuclease

XPG (ERCC5)

13q22

NER

DNA endonuclease

TTDA (GTF2H5)

6p25.3

NER

Part of TFIIH

CSA (ERCC8)

5q12

NER

Transcription-coupled repair

CSB (ERCC6)

10q11

NER

Transcription-coupled repair

XPV (polymerase eta)

6p21.1-p12

Bypass

DNA damage bypass polymerase

MSH2

2p22-p21

MMR

Mismatch repair (Muir–Torre syndrome, HNPCC)

MLH1

3p21.3

MMR

Mismatch repair (Muir–Torre syndrome, HNPCC)

PMS1

2q31-q33

MMR

Mismatch repair (HNPCC)

PMS2

7p22

MMR

Mismatch repair (HNPCC)

MSH6

2p16

MMR

Mismatch repair (HNPCC)

MLH3

14q24.3

MMR

Mismatch repair (HNPCC)

DKC1

Xq28

Telomere maintenance

Dyskerin, Posttranscriptional pseudouridylation, forms a ribonucleoprotein complex with NOP10 (gene name NOLA3) and NHP2 (gene name NOLA2)

TERT

5p15.33

Telomere maintenance

Telomerase, extends nucleotide repeats at chromosome ends

TERC

3q21-q28

Telomere maintenance

RNA template for telomerase

TINF2

14q12

Telomere maintenance

Part of protein complex shelterin, regulates telomere length

NOLA2

5q35.3

Telomere maintenance

See dyskerin

NOLA3

15q14-q15

Telomere maintenance

See dyskerin

Genome Instability, DNA Repair, and Cancer

Repair Pathway

::

Chromosome Location

Chapter 110

Geneb

ERCC = human excision repair cross-complementing genes that correct defects in cultured hamster cells; HNPCC = hereditary nonpolyposis colon cancer; NER = nucleotide excision repair; MMR = mismatch repair; TFIIH = transcription factor IIH. a More than 100 DNA repair genes have been identified. An updated list can be found at (http://sciencepark.mdanderson.org/labs/wood/ DNA_Repair_Genes.html). b The genes designated XP are defective in the corresponding xeroderma pigmentosum complementation group, and those designated CS are defective in the corresponding Cockayne syndrome complementation group.



release of a region of approximately 30 nucleotides containing the damage (see Fig. 110-3C). The resulting gap is filled by DNA polymerase using the other (undamaged) strand as a template in a process involving proliferating cell nuclear antigen (PCNA). DNA ligase 1 seals the region, restoring the original undamaged sequence (see Fig. 110-3D).

Other DNA repair pathways include base excision repair, recombination repair, and mismatch repair. Defects in mismatch repair are also associated with

human diseases—Muir–Torre syndrome and human nonpolyposis colon cancer.1,9–11

REGULATION OF CELLULAR RESPONSES TO DNA DAMAGE Several cellular responses to DNA damage contribute to the maintenance of genome integrity, including: cell cycle arrest, apoptosis (programmed cell death), and DNA repair.6,12–19 These responses need to be carefully

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20

Section 20 ::

orchestrated, and there are many proteins involved in the signaling of DNA damage and the regulation of DNA damage responses. Different types of DNA-damaging agents and different types of DNA damage require different DNA damage responses. A simplified version of this complex pathway is presented in Figure 110-4. As with defects in DNA repair genes (see Table 110-3), defects in many of these DNA damage-signaling genes (boxed in Fig. 110-4) are also implicated in hereditary disorders of genome instability (Table 110-4; for further details see Chapter 139). These disorders are characterized by an increased cancer risk, which is due to the genome instability from impaired DNA damage signaling. The tumor suppressor gene p53, termed the guardian of the genome,20 plays a pivotal role in regulating and orchestrating these responses and is mutated in many cancers, including cutaneous squamous cell carcinomas. Upstream regulators of p53 in the cellular DNA damage response pathway are ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and

Rad3-related (ATR) genes. One of p53’s several functions is the regulation of the cell cycle in response to DNA damage. After cell division (mitosis), cells have 23 pairs of chromosomes and are in the G1 phase of the cell cycle. The chromosomes then replicate during DNA synthesis, or S phase, and as a result have twice the number of chromosomes (G2 phase) just before mitosis (M phase). In response to damage, the cell may stop cycling (arrests) in specific cell cycle phases called cell cycle checkpoints. An important downstream effector in preventing cells from entering S phase (G1/S checkpoint) is p21.6,12 p53 also induces NER by transcriptionally inducing XPC, XPE/p48, and GADD45.21,22 This indicates that a cell’s capacity to repair DNA damage can be upregulated in response to DNA damage. If cells enter S phase with unrepaired DNA damage, or if cells are UV exposed during S phase, regular DNA polymerases stall at DNA photoproducts and fall off the DNA strand. For these instances, cells are equipped with several specialized DNA polymerases for translesional

Carcinogenesis

Signaling cascades that regulate apoptosis, DNA repair, translesional DNA synthesis, and activation of cell cycle checkpoints in response to DNA damage DNA damage

Caspase 2 Bax

Chk1

ATM

Chk2

Caspase 9

ATR

Caspase 3 FA/BRCA pathway

p53

Apoptosis p95/Nbs1

Recombination repair

Cdc25A, B, C degradation A, B, C

A

p21

XPC

GG-NER

XPE/DDB2 GADD45

Cell cycle checkpoints:

1232

intra S

G2/M

G1/S

Error-prone translesional DNA synthesis

Figure 110-4  Signaling cascades that regulate apoptosis, DNA repair, translesional DNA synthesis, and activation of cell cycle checkpoints in response to DNA damage. This is a highly simplified diagram that depicts only the most important players in the intricate and interwoven DNA damage-signaling networks. The traditional thinking was that ataxia telangiectasia mutated (ATM) gene is activated (phosphorylated) in response to ionizing radiation (IR) and ATR (ataxia telangiectasia- and Rad3-related gene) is activated in response to ultraviolet (UV) radiation, but newer data indicate that both are activated by IR and UV. ATM/ATR can activate (i.e., phosphorylate) p53 either directly or indirectly through activation (phosphorylation) of Chk2 (an ATM target) or Chk1 (an ATR target). Through transcriptional activation of p21 and subsequent inhibition of cyclin-dependent kinases, which usually drive cells from the G1 into the S phase of the cell cycle, activated p53 activates the G1/S checkpoint (i.e., arrests cells in G1). The G1/S checkpoint is also activated by Chk1/Chk2induced phosphorylation and then degradation of Cdc25A and subsequent failure to activate cyclin-dependent kinases. Phosphorylation and subsequent degradation of Cdc25A, Cdc25B, and Cdc25C also mediate the G2/M arrest, as does p21. Intra-S-phase arrest is mediated through activation (phosphorylation) of p95/Nbs1. p53 also induces global genome nucleotide excision repair (GG-NER) through transcriptional activation of XPC, XPE/p48, and GADD45. Translesional DNA synthesis has been shown to be downregulated by p53 via p21. Recombination repair is mediated through the Fanconi anemia (FA)/BRCA pathway, which in turn is dependent on ATR activation. The mitochondrial pathway of apoptosis is activated through activation of Bax by caspase 2 and p53, the initiator caspase 9, and the effector caspases 3, 6, and 7 (for references, see text). Gene products that are defective in hereditary human diseases are boxed. DDB2 = DNA damage binding protein 2; XPC, XPE = xeroderma pigmentosum complementation groups C and E.

20

TABLE 110-4

DNA Damage-Signaling Genes Associated with Human Diseasesa

ATM

11q22.3

Ataxia telangiectasia

ATR

3q22–24

Seckel syndrome

FANCA

16q24.3

Fanconi anemia

FANCB

Xp22.31

Fanconi anemia

FANCC

9q22.3

Fanconi anemia

FANCD1/BRCA2

13q12.3

Fanconi anemia, familial breast cancer

FANCD2

3p25.3

Fanconi anemia

FANCE

6p21-p22

Fanconi anemia

FANCF

11p15

Fanconi anemia

FANCG

9p13

Fanconi anemia

FANCI

15q25-q26

Fanconi anemia

FANCJ

17q22

Fanconi anemia

FANCL

2p16.1

Fanconi anemia

FANCM

14q21.3

Fanconi anemia

FANCN

16p12.1

Fanconi anemia

BRCA1

17q21

Familial breast cancer

p53

17p13.1

Li–Fraumeni syndrome

22q12.1

Li–Fraumeni syndrome

9p21

Familial malignant melanoma

CDK4

12q14

Familial malignant melanoma

Nbs1 (p95)

8q21

Nijmegen breakage syndrome

Rb

13q14.1–14.2

Bilateral retinoblastoma

Chk2 INK4

CDKN2A (p16

)

a

Please see Fig. 110-4 for the function of these genes in the DNA damage-signaling cascade and Chapter 139 for a clinical descriptions of these disorders.

DNA synthesis.23 DNA polymerase eta is one of these; it is specialized to bypass DNA photoproducts but may introduce mutations while doing so.24 It is mutated in XP variant patients, who are clinically indistinguishable from other XP patients with defects in NER (see Table 110-3, Chapter 139).25,26 This demonstrates the importance of this second line of defense against the mutagenic and carcinogenic consequences of DNA photoproducts. p53 and p21 also downregulate the activity of this translesional DNA synthesis to maintain a low mutagenic activity at the price of reduced damage bypass.27 If this translesional DNA synthesis fails, cells can use recombination repair to resolve stalled replication forks.28 When invoked in response to damage from UV light, this third line of defense is mediated by activation of the Fanconi anemia/BRCA DNA damage response pathway.29 The exact mechanisms that initiate these DNA damage response signaling cascades is under investigation. Telomeres, which are repeats of TTAGGG that cap the ends of chromosomes and whose ends form a loop structure, are suggested to be important players in sensing DNA damage, for example,

Genome Instability, DNA Repair, and Cancer

Hereditary Disorder

::

Chromosome Location

Chapter 110

Gene

through opening of the telomere loop.30 Other sensors may be stalled DNA or RNA polymerases, or proteins that detect bending of the DNA helix at sites of DNA damage. Apoptosis is a regulated physiologic process leading to cell death characterized by cell shrinkage, membrane blebbing, and DNA fragmentation. A group of cysteine proteases called caspases are central regulators of apoptosis. Triggers may be extrinsic or intrinsic to the cell (e.g., DNA damage) and involve separate initiator caspases (e.g., caspase 2 in response to DNA damage) but share the same downstream effector caspases.8

APPROACHES TO DIAGNOSIS OF GENOME INSTABILITY AND/OR DNA REPAIR DEFECTS When a disorder of genome instability is suspected, the clinician is challenged with choosing the appropriate laboratory tests to secure a diagnosis and to provide

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20

TABLE 110-5

TABLE 110-6

Hallmark Clinical Features That May Indicate a Disorder of Genome Instability or DNA Repair and Prompt Clinicians to Initiate Testinga

Section 20

Clinical Features

Xeroderma pigmentosum

Burning or blistering on minimal sun exposure (some patients), childhood freckling, early or multiple skin cancers

Cockayne syndrome

Burning on minimal sun exposure, postnatal growth failure, sensorineural deafness

Trichothiodystrophy

Burning on minimal sun exposure (some patients), brittle hair, ichthyosis

Ataxia-telangiectasia

Telangiectasias, ataxia, leukemias or lymphomas

Bloom syndrome

Photosensitivity, malar erythema, growth retardation, infections, cancers

Fanconi anemia

Aplastic anemia, growth retardation, café-au-lait spots, thumb abnormalities, acute myelogenous leukemia

Dyskeratosis congenita

Triad of reticulated hyperpigmentation, nail dystrophy, and mucosal leukoplakias Sebaceous tumors, keratoacanthomas, personal or family history of colon cancer

::

Disorder

Carcinogenesis

Muir–Torre syndrome a

Refer to Chapter 139 for more information.

guidance for affected patients and families. Table 110-5 lists some hallmark clinical features that may indicate the presence of such disorders and should prompt clinicians to initiate testing. Various laboratory tests for genome stability, DNA repair, and response to physical and chemical agents are listed in Table 110-6.

USE OF CULTURED CELLS

1234

Cells obtained directly from patients and grown in culture medium are termed primary cultures. Dermal fibroblasts generally grow easily in culture and can generally be established from a 2- to 4-mm sterile skin punch biopsy specimen. The inner surface of the upper arm has proven to be a suitable biopsy site because this area heals easily, the resulting scar is not readily visible, the site is shielded from UV radiation, and attempts to establish cultures from specimens are generally successful. The tissue is placed in sterile culture medium (or sterile saline) with antibiotics and transported to a cell culture laboratory at room temperature. Human cell cultures are made available for research by the National Institutes of Health-funded Human Genetic Mutant Cell Repository (401 Haddon Ave, Camden, NJ 08103; telephone: 856–966-7377; http:// ccr.coriell.org).

Diagnostic Tests of Genome Stability, DNA Repair, and Response to Physical or Chemical Agentsa Intact cell function (proliferation or cell death) Cell counts (growth in mass culture) Thymidine incorporation Colony-forming ability Chromosome integrity and breakage Giemsa-stained metaphase karyotype analysis G2 chromosome breakage Sister chromatid exchanges Fluorescent in situ hybridization Microsatellite instability testing Telomere length DNA repair Unscheduled DNA synthesis RNA synthesis inhibition Host cell reactivation Comet assay Immunological analysis of DNA damage and removal (enzyme-linked immunosorbent assay, slot blot) Microsatellite instability testing Characterization and expression of defective genes Real-time polymerase chain reaction Western blotting DNA sequencing a

Agents are listed in Table 110-1.

DIAGNOSTIC TESTS OF GENOME INSTABILITY AND DNA REPAIR Tests to assess genome instability and/or DNA repair capacity may be divided into tests of intact cellular function and tests of chromosome integrity and breakage in response to DNA-damaging agents. Other tests measure the mechanism of impairment of a cell function such as DNA repair or characterize or determine the expression of defective genes (see Table 110-6).

TESTS OF INTACT CELL FUNCTION. Tests of cellular function measure the capacity of the intact cell to recover from DNA damage. These tests do not provide information regarding the specific type of damage resulting in cellular injury or the mechanism of cellular recovery, but they do form the basis for identifying cells as hypersensitive to DNA-damaging agents and are often used as simple screening tests. Cell Counts or Thymidine Incorporation.

One of simplest tests after exposure to UV radiation or X-rays is the assessment of the growth rate in mass culture by using a microscope or an automated cell counter to count the number of cells or by measuring incorporation of radioactive thymidine into newly synthesized DNA (see Tables 110-6 and 110-7).

Colony-Forming Ability. A test of colony-forming ability assesses the capacity of a single cell to proliferate enough to form a visible colony (Fig. 110-5).

20

TABLE 110-7

Suggested Sequence of Diagnostic Testing for Diseases of Genome Instability or DNA Repaira Step 3

Step 4

Testing Availableb

Xeroderma pigmentosum

Post-UV hypersensitivity

Post-UV DNA repair

DNA sequencing

—

CLIA/R

Xeroderma pigmentosum variant

Post-UV hypersensitivity (with caffeine)

Post-UV DNA repair (normal)

DNA sequencing

—

R

Cockayne syndrome

Post-UV hypersensitivity

Post-UV inhibition of RNA synthesis

DNA sequencing

—

CLIA

Trichothiodystrophyc

Post-UV hypersensitivity

Post-UV DNA repair

DNA sequencing

—

CLIA/R

Ataxia telangiectasia

Chromosome breakage

X-ray hypersensitivity

Western blotting for level of protein

DNA sequencing

CLIA/R

Bloom syndrome

Chromosome breakage

Sister chromatid exchange

DNA sequencing

—

CLIA

Fanconi anemia

Chromosome breakage

Hypersensitivity to DNA cross-linking agents

Western blotting for FANCD2

DNA sequencing

CLIA/R

Dyskeratosis congenita

Telomere length

DNA sequencing

Muir–Torre syndrome

Microsatellite instability

Western blotting for level of protein

DNA sequencing

—

CLIA

CLIA = testing available by laboratories certified under the Clinical Laboratory Improvement Act; R = research testing available; UV = ultraviolet radiation. a These are suggestions only and may change based on availability of different assays or new scientific information. In recent years, sequencing has become much easier and cheaper through automated processes. Thus, DNA sequencing may be considered as a first diagnostic test, in particular for diseases with no or few complementation groups. However other tests (e.g., of cell function or protein levels) may be required to exclude a diagnosis if no mutation is identified. b Testing laboratories are listed on the National Institutes of Health-funded Web site http://genetests.org. c Screen by polarizing microscopic examination of hair followed by measurement of sulfur-containing amino acids in the hair (see Chapter 139).

TESTS OF CHROMOSOME INTEGRITY AND BREAKAGE. Chromosome breakage is usually

assessed in primary cultures of mitogen-stimulated peripheral blood leukocytes or in long-term cultures of fibroblasts or lymphoblastoid cell lines. Cell cycle progression is stopped at metaphase by treatment of the cells with an inhibitor of mitosis such as colchicine. In this procedure, the 23 pairs of metaphase chromosomes from a single cell are spread over a discrete area of the slide and stained (usually with Giemsa stain). Preparations may be analyzed for the number of chromosomes per metaphase, the morphology of the individual chromosomes, and the attachments or rearrangements of chromosomes in relation to each other.

Sister Chromatid Exchange. During DNA rep-

lication, chromatids occasionally exchange positions along the arms of a chromosome. This sister chromatid exchange (SCE) may be detected by permitting the cells to grow through two cycles of replication in medium containing the nucleic acid analog bromodeoxyuridine (BrUdR) (Fig. 110-6). SCEs are thought to be related to DNA recombination repair, although their precise significance is not understood.

Genome Instability, DNA Repair, and Cancer

Step 2

::

Step 1

Chapter 110

Disease

Telomere Length. Shortened telomeres characterize cells from patients with dyskeratosis congenita. Several methods can be used to measure telomere length, including terminal restriction fragment (TRF) measurement on Southern blots, fluorescence in situ hybridization (FISH) with immunostaining, quantitative polymerase chain reaction (PCR), single telomere length analysis, and flow-cytometry with FISH (flowFISH).31 Those tests are usually done on freshly isolated white blood cells, not cultured cells. TESTS OF DNA REPAIR Unscheduled DNA Synthesis. One of the most

commonly used tests of NER is unscheduled DNA synthesis. This test has been used to measure DNA repair in intact human skin, in cultured epidermal or dermal cells, and in blood cells, and for prenatal diagnosis using amniotic fluid cells. Unscheduled DNA synthesis testing measures the repair-associated DNA synthesis in G1 or G2 cells (which usually do not synthesize DNA). Cells are treated with UV radiation or another DNA-damaging agent and then incubated in medium containing radioactive thymidine. During the

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20

Colony-forming ability assay of cell sensitivity

Host Cell Reactivation.

100

The host cell reactivation assay relies on the fact that plasmids do not have the ability to repair damage to their DNA but depend on cellular repair systems. Thus, when transfecting plasmids with DNA damage into host cells, the DNA repair enzymes of the host cells need to repair the damage before the plasmids’ genes can be expressed. Therefore, damaged plasmids would be expected to be expressed at a higher level in cells with normal repair capacity. A nonreplicating plasmid that contains the gene for the firefly enzyme luciferase, constructed to permit expression in human cells,32 is widely used; generation of light provides a quantitative endpoint for its repair (Fig. 110-7).

Section 20

Cell survival %

10

96TA HSTA

Comet Assay. The comet assay is a single cell-based

XP12TA

::

1

XP25TA

Carcinogenesis

XPH27TA 35TA

0.1 0

2

4 6 9 UVC dose to cells (J/m2)

10

Figure 110-5  Colony-forming ability assay of cell sensitivity. Xeroderma pigmentosum (XP) fibroblasts from two affected siblings (XP12TA and XP25TA), their father (XPH27TA), and an unaffected brother (35TA) as well as normal fibroblasts (96TA and HSTA) were treated with 254-nm ultraviolet C (UVC) radiation and colony-forming ability was determined. The XP complementation group C (XPC) fibroblast strains from the affected siblings were much more sensitive than the normal strains and showed similar post-UVC hypersensitivity. Cells from the unaffected brother and the clinically normal father, a heterozygous carrier of the XPC defect, had normal post-UVC survival. (Modified from Slor H et al: Clinical, cellular, and molecular features of an Israeli xeroderma pigmentosum family with a frameshift mutation in the XPC Gene: Sun protection prolongs life. J Invest Dermatol 115:974, 2000.)

process of NER, the damage is removed and the radioactive thymidine is incorporated into the repaired region. The cells are treated with fixative, coated with autoradiographic (photographic) emulsion, and kept in the dark for an appropriate interval, and then the emulsion is developed. UV radiation of normal fibroblasts results in a large increase in the number of grains seen over all the nuclei. In marked contrast, irradiation of the XP fibroblasts that cannot repair DNA damage results in very few grains over the nuclei.

RNA Synthesis Inhibition. After exposure to UV 1236

sis is delayed in cells from patients with CS and some forms of XP.

radiation, normal cells temporarily reduce RNA synthesis from active genes. Synthesis resumes when the damage is repaired. This resumption of RNA synthe-

technique that allows detection and quantitation of DNA damage, in particular DNA strand breaks that were either introduced directly by the DNA-damaging agent or by repair endonucleases at sites of other types of DNA damage. For this assay, damaged cells are embedded in agarose, lysed, and exposed to an electric field. In the electrical field, the DNA migrates out of the nucleus forming a “comet” when stained. In presence of DNA strand breaks, DNA migrates out of the nucleus faster and with that generates a longer comet. Thus, the length of the comet is proportional to the fragmentation of the nuclear DNA. This assay can be modified for detection of single-strand or double-strand DNA breaks, UV damage, or oxidative DNA damage. Cells from patients with XP have defective repair in the postUV comet assay.

Microsatellite Instability. Normal DNA has tens of thousands of regions with repeats of the dinucleotide CA or other short motifs up to five nucleotides long. In normal individuals each of these microsatellites (also called simple sequence repeats or short tandem repeats) has a uniform size. However, these sizes are highly variable among different individuals and are often used for DNA “fingerprinting.” The appearance of abnormally longer or shorter simple sequence repeats in different tissues or tumors from a patient is called microsatellite instability. This can be associated with a defect in mismatch repair genes. CHARACTERIZATION AND EXPRESSION OF DEFECTIVE GENES Real-Time Polymerase Chain Reaction. Many

disease-causing mutations, including those responsible for disorders of genome instabilty disrupt the gene product’s function by changing its amino acid sequence. In some genome instability genes, disease-causing mutations create premature stop codons for protein synthesis. These mutations result not only in truncated but also in low levels of messenger RNA (mRNA) for the gene product through a process called nonsense-mediated message decay. The mRNA levels can be accurately measured by the use of quantitative reverse transcriptase real-time polymerase chain reaction. For example, low

20

Sister chromatid exchange (SCE) assay of chromosome integrity

Stage of cell cycle G1 BrUdR S / G1

B

Chapter 110

Uniformly dark stained chromosome

First metaphase

::

BrUdR S / G1

Second metaphase

A

Differential staining No SCE

SCE

C

Figure 110-6  A. Sister chromatid exchange (SCE) assay of chromosome integrity. After the first cycle of replication, the DNA of the newly synthesized strand is labeled with bromodeoxyuridine (BrUdR), whereas the older strand is unlabeled. Such chromosomes appear uniformly dark with Giemsa stain. After a second cycle of replication in BrUdR-containing medium, one arm of a chromosome will contain two labeled chromatids, whereas the other will contain one labeled and one unlabeled chromatid. The doubly substituted arm will stain lightly, whereas the singly substituted arm will stain darkly. If an SCE occurred during replication, a portion of each chromosome arm will be doubly substituted and the remainder singly substituted with BrUdR. B. Undamaged normal cultured peripheral blood lymphocytes have approximately ten SCEs per metaphase. C. Cultured peripheral blood lymphocytes from a patient with Bloom syndrome have a manifold increase in SCEs. (From Chaganti RS, Schonberg S, German J: A manyfold increase in sister chromatid exchanges in Bloom’s syndrome lymphocytes. Proc Natl Acad Sci U S A 71:4508, 1974, with permission.)

XPC mRNA levels have been found in cells from most XP patients with defects in this gene.33

Western Blotting.

Some mutations result in reduced levels or size of encoded proteins, often through creation of premature stop codons.33 Reduced protein levels are most commonly detected by Western blotting. Cells are lysed and the proteins are extracted and separated by gel electrophoresis. The separated proteins are transferred to a membrane and probed with an antibody that is specific for the protein of interest. The intensity of the antibody staining reflects the amount of protein in the cells, and its location on the membrane is an indication of the size of the protein molecules. For example, undetectable or low levels of polymerase eta protein are present in cells from most XP variant patients.34

Genome Instability, DNA Repair, and Cancer

G1

DNA Sequencing. Direct sequencing of defective

genes is the gold standard for determination of the presence of a mutation. The final step in confirmation of a diagnosis may be DNA sequencing to determine the disease-causing mutation. By definition, diseasecausing mutations alter the function of genes. However, not every alteration in the sequence of a gene alters the function of the encoded protein. In the human genome there are millions of single nucleotide polymorphisms, or changes in one nucleotide, that are not associated with disease and may not even change the amino acid composition of the encoded protein. In recessive disorders, each clinically unaffected parent has one normal allele and one potentially disease-causing mutation in the other allele. The affected child receives an allele with a disease-causing mutation from each parent. The

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Plasmid host cell reactivation assay with assignment to xeroderma pigmentosum (XP) complementation group

A Host cell reactivation assay with the plasmid pCMVIuc

B Post UV luciferace expression in complemented XPC cell line

1. Irradiation of plasmid with UV Formation of DNA damage (DNA photoproducts)

Section 20

2. Transfection of host cells DNA repair and expression of luciferase

:: Carcinogenesis

3. Determine luciferase activity in cell extract Luciferase activity reflects repair efficiency of host cells

10

1

pLUC + pXPA HSTA XP12TA

0.1

XP25TA XPH27TA 35TA

0

0

500

0

Dose of UVC to plasmid (J/m2)

Figure 110-7  Plasmid host cell reactivation assay with assignment to xeroderma pigmentosum (XP) complementation group. A. The plasmid is damaged by ultraviolet (UV) radiation and introduced into cultured human cells by a transfection technique. The cells’ DNA repair enzymes repair the damage in a manner similar to the repair of cellular DNA. Repaired DNA will then function to transcribe the plasmid-encoded luciferase gene in the human cell. The amount of luciferase activity within the host cells therefore reflects the efficiency of the cellular DNA repair system. This assay can also be used to determine the complementation group by cotransfecting UV-treated plasmid plus plasmids expressing wild-type XP complementary DNA (cDNA). B. The results of plasmid host cell reactivation experiments and complementation group assignment with DNA excision repair-deficient XP46DC cells. UV-treated plasmid showed low expression in the XP65BE cells that was increased only by cotransfection with a plasmid expressing the wild-type XPC cDNA. This result indicates that XP65BE cells are in XP complementation group C (XPC). rLU = relative light units; pCMVluc and pLUC = plasmids containing gene for luciferase; pXPA–pXPG = plasmids expressing xeroderma pigmentosum complementation groups A–G.

two mutations must be in the same gene, although they need not necessarily be identical to each other.

CONSIDERATIONS IN DIAGNOSTIC TESTING

1238

Host cell reactivation mean relative luciferase activity (rLU; of unirradiated control)

100

Diagnosis of disorders of genome instability or DNA repair is often a multistep process. A suggested sequence of steps is listed in Table 110-7. As new tests are developed and new information is obtained about these disorders, testing procedures may change accordingly. In addition, decisions regarding the extent of testing performed may be made with consideration of how much the tests cost and whether additional information would alter treatment. For example, DNA sequencing is rarely required for establishment of a diagnosis of XP in a child with classical clinical features and cells that are hypersensitive to killing by UV and have defective DNA repair. But if a family has one child affected with XP and is considering having additional children, DNA sequencing might offer them the possibility of prenatal diagnosis through DNA sequencing of a trophoblast biopsy specimen.

Genetic counseling is an important component of patient management for these genetic diseases. This function may be performed by the treating physician or by a trained genetic counselor. In the United States, only laboratories certified in accordance with the Clinical Laboratory Improvement Act (CLIA) are allowed to perform these specialized tests in the context of patient care. Tests performed in research laboratories generally have limited use in clinical practice. However, a research laboratory may identify a disease mutation in cells from a patient that could then be confirmed in a CLIA-certified laboratory and used in clinical practice. A current listing of laboratory testing facilities for these diseases may be found at the Web site http://genetests.org, funded by the National Institutes of Health.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Friedberg EC et al: DNA Repair and Mutagenesis. Washington, DC, ASM Press, 2006

2. Wikondahl NM, Brash DE: Ultraviolet radiation induced signature mutations in photocarcinogenesis. J Invest Dermatol Symp Proc 4:6, 1999 9. Bootsma D et al: Nucleotide excision repair syndromes: Xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. In: The Genetic Basis of Human Cancer, 2nd edition, edited by B Vogelstein, KW Kinzler. New York, McGraw-Hill, 2002, p. 211

22. Hanawalt PC: Subpathways of nucleotide excision repair and their regulation. Oncogene 21:8949, 2002 23. Lehmann AR: Replication of damaged DNA by translesion synthesis in human cells. FEBS Lett 579:873, 2005 33. Khan SG et al: Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients. Carcinogenesis 27:84, 2006

Over 200 chemicals have been linked to human cancer development, according to the National Toxicology Program’s 11th Report on Carcinogens (2005). Chemicals implicated in human skin cancer development include polycyclic aromatic hydrocarbons and arsenic. Studies in mouse skin have defined operational stages of epithelial carcinogenesis: initiation, promotion, and malignant progression. Chemicals linked to human cancer are classified as tumor initiators, promoters, or “complete” carcinogens. Tumor initiation, associated with gene mutations that permanently alter the cell’s biological responsiveness, is irreversible; tumor promotion a nonmutagenic process that provides a selective growth advantage to initiated cells, is reversible at early stages; agents that facilitate malignant progression are generally genotoxic. Most carcinogens must undergo metabolic activation, which involves enzymes involved in xenobiotic metabolism, including cytochrome p450 enzymes and glutathione S-transferase. An individual’s likelihood of developing chemically induced skin cancer is a function of exposure history; presence of additional risk factors (e.g., UV exposure); and genetic background, including gene polymorphisms that influence susceptibility.

According to the American Cancer Society, it is estimated that over 2,000,000 cases of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 46,770 cases of melanoma in situ, and 68,130 cases of invasive melanoma will be diagnosed that in the year 2010.1 The precise number of nonmelanoma skin cancers is unknown since they are not routinely reported to registries, but recent data suggest that previous approximations are likely to have been underestimates.2 Although only a small fraction of patients with nonmelanoma skin cancer will die as a result of their cancer, which is SCC in nearly all cases, the frequency of these cancers nonetheless results in an estimated 1,000 and 2,000 deaths per year. In contrast, although much less common than nonmelanoma skin cancer, melanoma has a continually rising death rate now estimated at 8,700 per year, and it is currently predicted that the lifetime risk in Caucasians of developing melanoma is a staggering 1 in 37 for males and 1 in 56 for females.1 Because they are so common, cutaneous cancers have a major impact on health care costs: in addition to the mortality burden, treatment is associated with considerable morbidity and cosmetic defects. For these reasons, understanding the etiology and pathogenesis of these malignancies is a significant public health goal, and development of rational nondeforming therapies to reduce morbidity and mortality is urgently needed. The high prevalence of skin cancer, the external location of the tumors, and well-defined preneoplastic lesions all provide an excellent opportunity for studying the factors regulating cutaneous cancer induction in humans. Those qualities that facilitate the study of cutaneous neoplasms in human populations have also been useful in establishing relevant animal models. Advances in molecular genetics, keratinocyte cell culture, and development of genetically altered mice and reconstructed human skin models have greatly facilitated the analysis of basic mechanisms of cutaneous carcinogenesis. Our main focus in this chapter will be on nonmelanoma skin cancer: the reader is referred to Chapter 124 for further discussion of melanoma.

Chemical Carcinogenesis

In 1775, Sir Percivall Pott’s report of scrotal cancer in chimney sweeps established a link between environmental exposure and cutaneous malignancy.

CUTANEOUS CANCER AND PUBLIC HEALTH

::

CHEMICAL CARCINOGENESIS AT A GLANCE

Chapter 111

Chapter 111 :: Chemical Carcinogenesis :: Adam B. Glick & Andrzej A. Dlugosz

20

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20

AGENTS ASSOCIATED WITH SKIN CANCER INDUCTION IN HUMANS

Section 20 :: Carcinogenesis

The ultraviolet radiation (UVR) in sunlight is the primary etiologic agent for all skin cancers, and thus UVR is the major carcinogen in the human environment. The powerful carcinogenic activity of UVR is attributable to its ability to damage DNA and cause mutations, its capacity to clonally expand incipient neoplastic cells whose altered signaling pathways provide a survival advantage in the face of ultraviolet-induced cytotoxicity, its ability to induce reactive oxygen species, and its activity as an immune suppressant (see Chapter 112). The association of UVR with skin cancer is so strongly supported by clinical, epidemiologic, and experimental data that it represents the most clear-cut etiologic factor in human malignancy. Also implicated in the development of human skin cancer are various chemicals, as a result of environmental, occupational, or medicinal exposures (Table 111-1). In 1775, Sir Percivall Pott3 attributed the increased incidence of scrotal cancer in chimney sweeps to repeated exposure to soot. This report provided the first link between occupational exposure and the development of cancer as well as the first example of chemical carcinogenesis. According to the National Toxicology Program’s 11th Report on Carcinogens, published in 2005 (http://ntp.niehs.nih.gov/ntp/roc/toc11.html), 246 agents are listed as known or likely human carcin-

ogens, and the great majority of these are chemicals. In the last 35 years, the mechanisms by which chemicals cause cancer have been unraveled, and reveal striking similarities to the properties responsible for UVR carcinogenicity, namely DNA damage, selective cytotoxicity, and immune suppression. The carcinogenic potential of coal and petroleum derivatives is now firmly established as a result of experimental animal studies and epidemiologic reports. Petroleum products, grease as well as insecticides, herbicides, and fungicides are particularly pathogenic for SCC, while fiberglass and dry-cleaning agents increase the incidence of BCC.4 Cigarette and pipe smokers have an overall twofold increased risk for cutaneous SCC, and the risk increases with the intensity of the tobacco use.5 Arsenic exposure is associated with the development of premalignant keratoses, Bowen’s disease, SCC, and BCC, as well as a number of internal malignancies.6 While Fowler’s solution (1% potassium arsenite) is no longer used in medical practice, certain herbal medicines are still a source of arsenic exposure. Occupational exposures to arsenic as a component of agricultural pesticides, sheep and cattle dip, mining and smelting, glass manufacturing, and other industries are well documented. A more insidious source of environmental arsenic exposure is contaminated drinking water or shellfish, and analysis of affected populations shows a dose-dependent increase in skin cancer.7 Mouse models have provided evidence for an interaction of ingested arsenic acting as a cocarcinogen with solar radiation to

TABLE 111-1

Environmental Agents Associated with the Development of Human Skin Cancer

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Agent

Individual at Risk

Route of Exposure

Tumor Types

UV radiation

General population

T

BCC, BD, SCC, M

Cigarette smoke

Smoker

T or S

SCC

Soot

Chimney sweep

T

SCC

Coat tar, pitch

Coker of coal, steel worker

T

SCC

Petroleum oils

Machinist, textile worker

T and S

SCC

Arsenic

Agriculture worker, living in areas of high groundwater and soil contamination

S and/or T

BD, SCC, BCC

4,4′-Bipridyl

Pesticide manufacturer

T

SCC, BD

Polychlorinated biphenyl

Petrochemical worker

T or S

M

Dry cleaning reagents

Dry cleaner

T or S

BCC

Fiberglass

Insulator

T

BCC

Psoralen (PUVA)

Psoriasis patient

T and S

SCC, BCC, M

Nitrogen mustard

CTCL patient

T

SCC

Immunosuppressants

Transplant recipient, etc.

S

SCC, BCC

Ionizing radiation

Cancer therapy patient

T

BCC, SCC

Abbreviations: T = topical; S = systemic; SCC = squamous cell carcinoma; BD = Bowen’s disease; BCC = basal cell carcinoma; PCB = polychlorinated biphenyl; M = melanoma; CTCL = cutaneous T-cell lymphoma. Source: Modified from Dlugosz A, Merlino G, Yuspa SH: Progress in cutaneous cancer research. J Invest Dermatol Symp Proc 7:17, 2002, with permission of Nature Publishing Group, London, UK.

Chemical Carcinogenesis

How can such a diverse group of chemical and physical agents contribute to cutaneous cancer when the great

20

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THE NATURE OF CHEMICAL CARCINOGENS: CHEMISTRY AND METABOLISM

majority of environmental agents to which humans are exposed are not carcinogenic? We now know that carcinogens can be genotoxic, nongenotoxic, or both.26 Genotoxic carcinogens have high chemical reactivity (such as alkylating agents like nitrogen mustard) or can be metabolized to reactive intermediates by the host (such as petroleum products). They form covalent adducts with macromolecules and target DNA in the nucleus and mitochondria.27 Since there is a good correlation between the ability to form covalent DNA adducts and the potency to induce tumors in laboratory animals, DNA is considered the ultimate target for most genotoxic carcinogens. The interaction with DNA is not random, and each class of agents reacts selectively with purine and pyrimidine targets.27 Furthermore, targeting of carcinogens to particular sites in DNA is determined by nucleotide sequence, by host cell, and by selective DNA repair processes making some genetic material at risk over others. As expected from this chemistry, genotoxic carcinogens are potent mutagens, particularly adept at causing base mispairing or small deletions, leading to missense or nonsense mutations. Others may cause macrogenetic damage such as chromosome breaks and large deletions. In all cases, mutations detected in tumors represent a combination of the effect of the mutagenic change on the function of the protein product and the effect of the functional alteration on the behavior of the specific host cell type. A number of chemicals that cause cancers in laboratory rodents and contribute to human skin cancer incidence are not demonstrably genotoxic.28 Synthetic pesticides and herbicides, dry-cleaning reagents, and arsenic may fall within this group. The mechanism of action by nongenotoxic carcinogens is controversial and may be related in some cases to toxic cell death and regenerative hyperplasia. Induction of endogenous mutagenic mechanisms such as DNA oxyradical damage,29 depurination of DNA, and deamination of 5-methylcytosine may contribute to carcinogenicity of these agents. Nongenotoxic carcinogens may interfere with host protective mechanisms as has been suggested for the action of arsenic in suppressing DNA repair or inhibiting the activity of tumor suppressor genes.8 Thus, nongenotoxic carcinogens may serve as modifiers in concert with genotoxic agents such as UVR. While a number of carcinogens can directly interact with DNA, many require bioactivation by cellular metabolic enzymes to form a compound that can react and form adducts with DNA. In general, these reactive intermediates are inadvertent byproducts of xenobiotic detoxification pathways. These pathways are complex and interactive,30 and genetic polymorphisms both in animal models and humans contribute to cancer susceptibility.31 This genetic variation in metabolic enzymes leading to differing rates of biotransformation and detoxification among individuals provides an approach to estimate individual risk profiles for particular chemical exposures. Initial stages in metabolic activation are most often carried out by cytochrome P450s, a class of heme containing monooxygenases, although other enzymes can be involved.32,33 Oxidation

Chapter 111

increase the frequency and size of cutaneous carcinomas and reduce the latency period.8,9 A variety of medications have been associated with the development of skin cancer. Systemic treatment with immunosuppressive agents results in an increased incidence of both benign and malignant skin lesions,10 which is generally attributed to reduced immune-surveillance of nascent tumor cells. However, a more specific mechanism predisposing to skin cancer has been proposed for azathioprine, which may sensitize DNA to ultraviolet A (UVA) radiation via its metabolite 6-thioguanine, leading to the production of mutagenic reactive oxygen species.11 In addition, cyclosporine A inhibits DNA repair and cell death in UVB-irradiated keratinocytes,12 raising the possibility that this compound may also increase photocarcinogenesis. Topical nitrogen mustard also increases the risk of developing skin cancer.13 Despite the clear-cut association between occupational exposure to tars and skin cancer, the use of coal tar in patients with psoriasis or eczema does not appear to increase the risk of developing skin cancer, based on a large study including over 13,000 patients.14 In contrast, the use of ionizing radiation to treat a variety of skin diseases increases the risk of BCC in all treated patients, and SCC in individuals with sun-sensitive skin.15 Systemic administration of 8-methoxypsoralen combined with UVA treatments (PUVA) is associated with a dose-dependent increase in the risk of developing cutaneous SCC that persists following discontinuation of therapy.16 Patients receiving high-level exposures (≥337 PUVA treatments) had over a 100-fold increase in SCC incidence while those receiving BCC; lower DMBA doses may increase BCC incidence Also other skin tumors BCC > SCC, also internal tumors

Mouse, rat Mouse, rat Mouse

  Ultraviolet A

Mouse

DMBA = 7,12-Dimethylbenz[a]anthracene; PAH = polycyclic aromatic hydrocarbons; NA = nitrosamines; AA = aromatic amines.

local damage. Even those rare BCCs exhibiting cellular atypia generally have a benign course,99 suggesting that the full complement of factors driving malignant progression in SCCs and other neoplasms is not operating in these tumors. BCC cells exhibit abnormalities in growth control and terminal differentiation, induce clinically apparent angiogenesis, and invade their immediate surroundings. However, transplantation studies using human BCCs or transgenic mouse skin with BCC-like lesions58 suggest that the tumor cells are critically dependent on adjacent stroma for survival. This property may help explain both the lack of BCC metastases and the difficulty in establishing BCC cell lines. Interestingly, in a recent study in which global gene expression profiling was performed on stromal cells derived from tumors versus normal tissue, the bone morphogenetic protein (BMP) antagonist, GREMLIN 1, was found to be highly expressed in BCC stroma but not normal skin.100 BCCs express BMP 2 and 4, and GREMLIN 1 stimulates growth of cultured BCC cells in vitro, suggesting that GREMLIN 1 may be a stromal factor needed to support BCC proliferation in vivo, by antagonizing growth-inhibitory effects of BMPs. Studies performed using human and rodent BCCs have identified additional candidate molecules that may be important in the biology of these tumors. Upregulation of various matrix metalloproteases (MMPs), both in tumor cells and stroma, is likely to be important in the local invasion of BCC, and may impact on growth control and other cellular functions given the emerging role of MMPs in regulating signaling at multiple levels.101

Chemical Carcinogenesis

  Ultraviolet B

Predominantly papilloma Predominantly SCC p53 mutations, immune suppression, SCC Papillomas and SCC

::

Squamous Cell Tumors   (PAH, NA, AA) + promoter   (PAH, NA, AA) repeated

20

Chapter 111

Agent

Expression of several adhesion molecules is downregulated in BCCs, and this may account for the characteristic appearance of artifactual clefts between tumor cells and stroma in histological sections, but the functional significance of this finding in BCC biology has not been established. The antiapoptotic molecule BCL2 is consistently upregulated in BCCs probably because BCL2 is an Hh target gene,102,103 but this does not appear sufficient to block apoptosis in these tumors as it does in other settings. Indeed, the remarkably slow growth rate of BCCs has been attributed in part to baseline apoptotic cell loss. Expression studies in human BCCs and experimental models suggest the involvement of growth factor signaling pathways such as PDGF104,105 and EGFR.106 Several lines of evidence point to components of the cell cycle machinery as potentially critical targets in mitogenic responses to Hh signaling. Keratinocytes overexpressing Shh have enhanced proliferative potential and fail to undergo growth arrest in response to the cell cycle inhibitor p21107; in the absence of Shh, Ptch1 interacts with and may sequester Cyclin B1, a component of M-phase promoting factor which is required for mitosis and cell cycle progression108; and Shh can drive proliferation of immature cerebellar cells by causing prolonged induction of Cyclins D1, D2, and E.109 In skin, Hhdriven proliferation of hair follicle epithelium is likely to be mediated by Cyclin D2 and N-Myc.110 Oncogenic Hh signaling in skin leads to activation of the Wnt/βcatenin pathway; remarkably, signaling via this additional pathway is required for Hh pathway-driven skin tumor development.111 The discovery of key molecules and other pathways required for Hh-driven tumorigenesis will provide additional targets for therapy.

THE PATHOGENESIS OF SQUAMOUS CELL CARCINOMAS Both mice and rats are sensitive to SCC induction by a variety of chemical and physical agents (Table 111-4), and the induction of SCC in mice by UVR mimics the pathogenesis of SCC in human skin (Chapter 114). Multistage chemical carcinogenesis in mouse skin has been a powerful tool for delineating many of the fundamental concepts underlying epithelial carcinogenesis in other organs. Inbred strains of mice differ in their sensitivity to tumor induction using chemical carcinogens and tumor promoters, and extensive genetic analysis has led to identification of loci that confer sensitivity or resistance to induction of either benign and malignant tumors.112–114 Interestingly, benign tumors that develop in FVB/n mice have a high frequency of conversion to SCC, and this is due to a polymorphism in the FVB/n Ptch allele which enhances Ras-induced SCC development.115 Building on the association of deregulated EGFR signaling in human cancer, mouse models suggest that constitutive EGFR activation is an important component of skin tumor formation. Transgenic epidermal targeting of TGFα, which activates the EGFR, can produce a benign tumor phenotype in the absence of activating Ras mutations.116,117 However, activation of the EGFR by ligand overexpression alone is not an

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Section 20 :: Carcinogenesis

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efficient stimulus for autonomous tumor formation, since many of these tumors regressed. Loss of function studies also point to an important role for EGFR in squamous tumorigenesis in skin. Transformation of Egfr null keratinocytes with oncogenic ras, followed by transplantation onto immune-deficient mice, results in the formation of smaller benign tumors that those arising from ras-expressing control keratinocytes. These data imply point to an important role for EGFR signaling in squamous tumors, but suggests that an alternative, ras-induced pathway for tumor growth exists in the early, premalignant tumor.18 Additional evidence implicating enhanced growth factor signaling in SCC is provided by transgenic studies using a dominant form of SOS, an adapter molecule involved in transducing growth-stimulatory signals from receptor tyrosine kinases like EGFR, which resulted in spontaneous development of papillomas in mouse skin.119 Overexpression of ErbB2, a receptor tyrosine kinase related to and capable of interacting with EGFR, results in spontaneous skin tumor development in transgenic mice.120 Insulin-like growth factor 1 (Igf1), when overexpressed in mouse skin, also triggers development of squamous papillomas, some of which progressed to carcinomas.121 While most of these studies invoke an autocrine mechanism for growth stimulation of tumor cells, factors produced by cells in the tumor stroma may supply mitogenic signals to keratinocytes or angiogenic signals as well.122 Additional studies performed in mice suggest that specific components of the cell cycle machinery, including E2F1,123 Cyclin D1,124 and Cdk4,125 can contribute to SCC development and/or progression. The TGFβ signaling pathway is an additional growth factor pathway that contributes to SCC development but in contrast to the EGFR it functions as a negative regulator of epidermal proliferation and to maintain epidermal homeostasis.126 Reduced levels of intracellular mediators of TGFβ signaling, Smad2 and Smad4, are observed in human SCC,127,128 suggesting that loss or disruption of this growth control pathway is important in tumor development. Interestingly, SCC that develop in organ transplant recipients receiving antirejection drugs exhibit significant activation of the TGFβ pathway. Thus, in this context the TGFβ pathway may enhance tumor susceptibility.128 In addition to deregulated growth control, there is a progressive loss in the capacity for terminal differentiation during SCC progression (Fig. 111-1), culminating in a tumor with a spindle cell morphology that is indistinguishable from malignancies originating in mesenchymal tissues. Although the mechanisms responsible for defective differentiation at different stages of human skin cancer are not known, there is evidence that deregulation of the protein kinase C (PKC) family of enzymes plays a role in aberrant differentiation of mouse skin keratinocytes expressing the Ras oncogene.88 PKCδ, which has been implicated in terminal differentiation of normal epidermal keratinocytes, is rendered inactive as a result of tyrosine-phosphorylation in ras-transformed keratinocytes. Restoring PKCδ to its native, nontyrosine phosphorylated state reversed the block to terminal differentiation in ras-transformed keratinocytes. In addi-

tion, overexpression of PKCδ in the skin of transgenic mice inhibits the development of squamous papillomas and carcinomas.129 In contrast, skin-targeted overexpression of PKC ε resulted in less differentiated SCCs that rapidly metastasized to regional lymph nodes.130 Additional work is needed to better understand the mechanism by which SCC tumor cells evade signals that trigger differentiation of normal keratinocytes. Prostaglandin metabolism is activated by UVR and is constitutively induced in human SCCs, probably due to overexpression of the enzyme cyclooxygenase 2 (COX-2). Although the mechanism by which changes in prostaglandins influence skin cancer is not clear, they appear to operate at the tumor promotion stage. Telomerase activity is detected in a substantial proportion of human skin cancers, suggesting that these tumor cells are capable of evading cellular senescence, and telomerase-deficient mice are resistant to chemical carcinogenesis.131 Additional contributors that are likely to be involved in SCC development and progression include mediators of angiogenesis, MMPs, and integrins, as well as other molecules involved in cellular adhesion and migration. Spontaneous or carcinogen-induced tumor formation in genetically modified mice has revealed genes and pathways that appear to be important in skin cancer induction but would not have been apparent from hereditary cancer syndromes or analysis of human skin cancers. Suprabasal targeting of c-Myc in transgenic mice permits suprabasal cells to cycle and produces the papilloma/actinic keratosis phenotype while basal cell targeting of c-Myc is not oncogenic.132,133 Deletion of the Cyclin/CDK inhibitor p21waf1, a downstream effector of p53, increases the number of benign tumors but not the rate of premalignant progression.134,135 Inactivation of TGFβ signaling enhances premalignant progression while overexpression blocks papilloma outgrowth and promotes invasion and metastasis of established tumors and progression from SCC to a spindle cell phenotype.136–139 Surprisingly, reduction of cutaneous TGFβ1 also suppresses papilloma formation indicating a critical role for physiological levels of this growth factor in supporting tumor outgrowth.140 Two AP-1 transcription factors influence distinct stages of skin tumor development, where c-Jun is essential for papilloma and c-Fos is essential for SCC development.141,142 Inhibition of AP-1 activity in benign papillomas prevents progression to carcinomas, but instead, converts these lesions into benign sebaceous adenomas,143 supporting the concept that squamous tumors are derived from progenitor cells with multilineage potential. Additional molecules now implicated in SCC development are ornithine decarboxylase, p16Ink4a, p15Ink4b, E-cadherin, STAT3, c-Myc, Notch, α−catenin, NF-κB, and Smad3.144–152

CONSTITUTIONAL MODIFIERS OF CARCINOGENESIS Inbred mouse strains differ in susceptibility to particular carcinogenic exposures by several orders of magnitude, and transplantation studies indicate sensitivity resides in the target tissue rather than systemically.

Modifiers of Carcinogenesis Inhibitor Class Inhibitors of Initiation   Antioxidants, scavengers

 Inducers of mixed function of oxidase  Inhibitors of mixed function oxidase   Cytotoxic agent  Suppressor of tumor development Inhibitors of Promotion   Antiproliferative

  Antioxidant

 Natural products and dietary factors

Examples Butylated hydroxyanisole; butylated hydroxytoluene; selenium; vitamin C; vitamin E; ellagic acid Polycyclic aromatic hydrocarbons; TCDD; PCB α-napthoflavone; glucocorticoids; Sulfur mustard Retinoids

Anti-inflammatory steroids: dexamethasone, fluocinolone acetonide; inhibitors of arachidonic acid metabolism: indomethacin, celecoxib; inhibitors of polyamine metabolism: α-difluoromethylornithine Antioxidants: tertbutylhydroxyanisole, selenium; protease inhibitors: leupeptin, tosyl lysine chloromethylketone; superoxide dismutase; copper (II) 3,5-diisopropylsalicyclic acid Retinoic acid; vitamin D; green tea; silymarin; resveratrol; ursolic acid; caffeic acid phenethyl ester; curcumin; 1,25-dihydroxyvitamin D3

Chemical Carcinogenesis

In experimental models, antioxidants and agents that alter microsomal metabolism of carcinogens can reduce or prevent tumor initiation by inhibiting the formation of ultimate carcinogens or accelerating their detoxification (Table 111-5). Similar mechanisms may influence ultraviolet light or ionizing radiation mutagenesis through inhibition of mutagenic oxyradicals produced endogenously following exposure. Scavengers prevent reactive mutagens from reaching critical targets. Cell cycle inhibitors prevent fixation of mutations, allowing for DNA repair while cytotoxic agents kill initiated cells prior to their expansion into a tumor mass. A number of agents are effective in the postinitiation phase of experimental tumor development, and some are being clinically evaluated.163 Inhibitors of COX-2 (celecoxib, indomethacin) and ornithine decarboxylase (difluoromethylornithine) prevent both UVR and chemically induced tumors.164,165 While the mechanism of action of retinoids as modifiers of tumor development is not clear, retinoids are effective inhibitors of benign tumor formation in mouse skin carcinogenesis studies. Low-dose systemic retinoids also reduce SCC development in organ transplant recipients,166 but additional studies are needed to assess whether they will be useful in long-term chemoprevention in certain

TABLE 111-5

::

EXOGENOUS MODIFIERS OF CARCINOGENESIS

20

Chapter 111

Genomic scans of backcrossed mice among sensitive and resistant mouse strains indicate that constitutional determinants are multigenic and distinct for squamous tumor formation or progression.113,153 Similar studies indicate genetic loci determine the survival potential for tumor bearing animals.154 Classical genetic approaches are frequently difficult and complex because multiple interacting loci are typically involved in defining cancer susceptibility.155 However, the study of skin cancer susceptibility may uncover genes of broad relevance to oncology. For example, the identification of a lowpenetrance susceptibility gene for mouse skin cancer, Stk6,156 fueled investigation of the human homologue AURKA which is now implicated in the development of multiple tumor types. More recently, studies examining the susceptibility of different mouse strains to cutaneous SCC uncovered, surprisingly, an alteration in the Ptch1 gene,115 which is strongly implicated in the development of a BCC.45 Thus, alterations in the same gene can promote either SCC or BCC development, and this may in part be determined by influencing a cell’s decision to enter either the squamous or basal cell lineage. Analysis of genetically modified mouse models has also revealed pathways associated with skin tumor susceptibility. Alterations in p53,79 drug metabolizing enzymes,157 T cell function158 and DNA repair74 modify risk for experimental skin cancer induction. Remarkably, polymorphisms in drug metabolizing enzymes and DNA repair pathways,159,160 and variable responses in the p53 tumor suppressor pathway or in T cell immunity after exposure to skin carcinogens161,162 modify the human risk for skin cancer.

TCDD = 2,3,7,8-tetrachlorodibenzo-p-dioxin; PCB = polychlorinated biphenyl.

high-risk populations. Predictable and parallel alterations in retinoid receptors in mouse and human cutaneous SCC indicate that the retinoid pathway must be central to cancer development in epidermis.167,168 Considerable interest has developed in dietary factors that modify skin carcinogenesis. Restricted fat/ energy diets reduce papilloma incidence in mouse models169 and decrease the frequency of actinic keratoses in human populations.170 Diverse dietary or natural factors such as green tea, caffeic acid phenethyl ester from honey bee hives, resveratrol from grapes, silymarin from milk thistle, ginger extract, crocetin, and ursolic acid from the rosemary plant are among natural products shown to be effective inhibitors of skin tumor formation by topical application or systemic exposure.171 Several of these agents are believed to be antioxidants, but the precise mechanism of inhibition and their effectiveness as chemopreventive agents for human skin cancer remain to be established. Finally, immune response modifiers such as imiquimod may

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be effective for treating some types of skin cancer by modulating cytokine expression.172

NOVEL THERAPEUTIC TARGETS BASED ON MECHANISTIC DATA

Section 20 :: Carcinogenesis

1250

The substantial progress in our understanding of factors involved in skin tumor pathogenesis holds the promise of new approaches to treatment and prevention. In addition to the identification of new therapeutic targets, improved strategies are being developed for altering gene and protein function in skin with great selectivity. The abundance and unrivaled accessibility of skin cancers and precancers makes them prime targets for rigorous translational studies and clinical trials. On the basis of the basic research studies outlined above, potential therapeutic targets include p53; COX-2; telomerase; EGFR or other receptor tyrosine kinases, and intracellular signaling elements such as SOS; Ras; ornithine decarboxylase; the DNA repair machinery; MMPs; PKC; molecules involved in cell cycle progression, such as Cyclins D1 and D2, CDK4, p16INK4a, and E2F1; retinoid receptors; and c-Fos. In all cases, the potential efficacy of the proposed treatments would need to be carefully evaluated in animal models or human tissues grown in immune-deficient mice. Although the great majority of cutaneous SCCs are effectively treated using surgery or radiation therapy it is likely that dermatology patients would benefit from agents, which could prevent appearance of premalignant lesions, block neoplastic progression to SCC or cause tumor ablation with minimal invasive methods especially in cosmetically sensitive sites. This is likely to be especially true for genetically predisposed individuals or organ transplant recipients that are prone to multiple aggressive SCC. Along these lines, a double-blind study reported a significant reduction in the development of actinic keratoses and BCCs in XP patients treated topically with the DNA repair enzyme T4 endonuclease V, administered over a 1-year period.173 Pathogenic mutations in BRAF have recently been exploited for the treatment of melanoma, and in a promising phase I trial using a mutated BRAF inhibitor, the majority of individuals with melanomas carrying the V600E BRAF mutation exhibited either a partial or complete response.174 In contrast to the multiple genetic and biochemical changes associated with SCC development, the majority of BCCs have mutations in PTCH1 or SMO and essentially all of these tumors exhibit uncontrolled

activation of the Hh pathway. Since several experimental models suggest that deregulated Hh signaling plays a central role in BCC development and maintenance, this pathway is a prime target for mechanism-based drug development. Cyclopamine is a natural product which blocks Hh signaling by inhibiting the function of SMO,175 a pivotal effector of Hh signaling. Cyclopamine and other Hh pathway inhibitors targeting SMO have been shown to effectively inhibit growth of BCClike cancers and other Hh-activated tumors in preclinical studies.176 In a phase I clinical trial, a systemic Hh pathway antagonist showed promising results in patients with advanced and metastatic BCC,177 raising hopes that these cancers, and multiple other malignancies linked to deregulated Hh signaling, may be amenable to treatment with Hh pathway antagonists.178 BCC is rarely lethal, but its common occurrence on sun-exposed, cosmetically-sensitive sites makes a medical approach to treatment highly desirable, particularly if a topical Hh pathway antagonist is effective in treating tumors or preventing their appearance in high-risk individuals, including those with Nevoid BCC syndrome. Additional trials are currently underway in BCC patients using both systemic and topical Hh pathway antagonists, and if they establish efficacy with an acceptable safety profile, they may change our approach to treating these extremely common cancers. Given the fundamental advances in our understanding of nonmelanoma skin cancer, we can look forward to additional, rationally designed therapeutics to complement and perhaps in some cases replace, surgical management.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 26. Luch A: Nature and nurture—Lessons from chemical carcinogenesis. Nat Rev Cancer 5:113, 2005 37. Somoano B, Niendorf KB, Tsao H: Hereditary cancer syndromes of the skin. Clin Dermatol 23:85, 2005 45. Saran A: Basal cell carcinoma and the carcinogenic role of aberrant Hedgehog signaling. Future Oncol 6:1003, 2010 57. Dlugosz A, Merlino G, Yuspa SH: Progress in cutaneous cancer research. J Investig Dermatol Symp Proc 7:17, 2002 155. Quigley D, Balmain A: Systems genetics analysis of cancer susceptibility: From mouse models to humans. Nat Rev Genet 10:651, 2009 163. Wright TI, Spencer JM, Flowers FP: Chemoprevention of nonmelanoma skin cancer. J Am Acad Dermatol 54:933, 2006

Chapter 112 :: Ultraviolet Radiation Carcinogenesis :: Masaoki Kawasumi & Paul Nghiem ULTRAVIOLET RADIATION CARCINOGENESIS AT A GLANCE Ultraviolet radiation (UVR) from the sun is the most prevalent carcinogen in humans, particularly among Caucasians.

The importance of exposure timing, dose rate, and total UVR exposure differ between the types of skin cancer.

Genetic polymorphisms in genes for DNA repair, melanin, and free radical scavenging affect skin cancer risk. Novel, pathway-based approaches to prevent or treat skin cancer are being developed. Educational and behavioral approaches are key to minimizing skin cancer rates in the future.

ULTRAVIOLET RADIATION AS A CARCINOGEN Skin cancer offers a very clear picture of how a carcinogen causes human neoplasia. The basic principles of carcinogen exposure and slow development were discovered when Sir Percivall Pott traced scrotal cancers in adults to childhood employment as a chimney sweep1 and they also apply to sunlight-induced cancers.2,3 The process begins with carcinogen exposure, DNA damage, and failure to repair DNA or failure to apoptotically eliminate a damaged cell.4–7 A mutant gene arises in a single cell which then expands into a mutant clone.8 Rare cells of the clone repeat this carcinogenesis cycle to generate mutations in additional genes. Sunlight acts at each of these steps.

1. A chronic sun damage (CSD) etiology affects the

head and neck and is associated with chronic elastosis—a classic indicator of CSD—as well as gene amplification of the cell cycle genes CDK4 and CCND1.27 The slow-growing lentigo maligna melanoma and its precursor, lentigo maligna occur on habitually exposed body sites of lightskinned individuals.28 2. A non-CSD route involves intermittent sun exposure of sites such as the trunk. Non-CSD melanomas carry mutations in the BRAF or NRAS oncogene—upstream regulators of cell cycle genes—and the patients have variant alleles of the melanocortin 1 receptor.27,29,30 Intermittently exposed body sites are the main locations of melanoma increases in recent decades, melanomas in patients younger than age 50 years, and the additional melanomas seen near the equator.23,25,31 Recreational sunburn may explain these and the twofold higher melanoma incidence in office workers compared to outdoor workers.32,33 Sunlight is also implicated by the susceptible population: both classes of skin cancer are more frequent in light-skinned individuals with blonde or red hair who burn rather than tan.13,34 Compared to dark-skinned individuals, nonmelanoma skin cancer risk rises ∼10fold in Asians and ∼100-fold in Caucasians, with a further 2–12-fold risk for people with blonde or, especially, red hair.13,34–37 The divergence is less for melanoma,

Ultraviolet Radiation Carcinogenesis

DNA repair, apoptosis, and cell signaling pathways are critical to preventing skin cancer, and UVR affects each of these processes.

The lifetime expectation of skin cancer in Australia is ∼60%.9 In the southern United States and Hawaii, nonmelanoma skin cancers exceed all other cancers combined.10–12 Basal and squamous cell carcinomas (BCC and SCC), and an SCC precursor, actinic keratosis (AK), are most frequent on sun-exposed skin, in outdoor workers, and at lower latitudes.13–16 SCCs increase more quickly with dose of sun exposure or nearness to the equator than BCCs, and occur later in life, implying that SCC requires more sun-related steps.16–20 In contrast, one-third of BCCs occur on body sites having only intermittent sun exposure, such as the trunk and legs.16,21 Melanoma also depends on sunlight. The relation to latitude is clear,22–25 yet it is often stated that the predilection for the back and lower legs makes the relation to sunlight uncertain. This predilection likely reflects the large surface area of back and legs. When expressed as lesions per unit area, melanomas are 10–20-fold more frequent on the ears of males and face than on intermittently exposed sites such as the lower legs in women, shoulders, back, or neck.25,26 Melanomas are rare on the buttocks and soles. Melanoma appears to have two distinct origins:

::

Sunlight leaves characteristic mutations that identify key molecular and cellular steps in skin tumor development.

EPIDEMIOLOGIC OBSERVATIONS

Chapter 112

Annual increases continue in the incidence of all types of skin cancer.

20

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Section 20 :: Carcinogenesis

about 1:1:15 (Blacks:Asians:Caucasians).38 In black skin, BCC is rare even in patients with the hereditary nevoid basal cell carcinoma syndrome (NBCCS or Gorlin syndrome).39 Skin tumors in black patients are often scar-related, but these may be associated with sunlight as well.36 Melanin-related effects result from less melanin in light skin,40 less shielding by pheomelanin than eumelanin, and greater production of photosensitized reactive oxygen from pheomelanin.41–43 Molecular epidemiology has provided the most direct evidence for ultraviolet radiation (UVR) as the active component of sunlight: UVB signature mutations are present in human BCC, SCC, AK, and melanoma (see Section “Ultraviolet Radiation-Induced Mutations”). Mutant cells are associated with elastotic dermis, indicating chronic sun exposure.44 UVB’s effectiveness is due to its ability to partially penetrate the ozone layer and stratum corneum and then be absorbed by DNA.45 The ozone layer absorbs all but 1 part per million of UVC (used in germicidal bulbs), which otherwise would be lethal; UVA penetrates well but is poorly absorbed by DNA.45,46 Nevertheless, chronic UVA can induce tumors in mice47 and malignantly transforms predisposed human cells.48 The cumulative dose of sunlight required to cause BCC or SCC in adults is fairly large, approximately 10,000 and 70,000 hours of exposure, respectively.16 Psoriasis patients who received long-term maintenance UVB phototherapy had a threeto eightfold higher risk of nonmelanoma skin cancer than people with an outdoor occupation, although the mean annual UVB dose received by psoriasis patients was 22 J/cm2, lower than the solar UVB dose annually received by individuals with an outdoor occupation (134 J/cm2).49 Some melanomas appear to be independent of sunlight: tumors of the mucosa, palms, soles, and nail beds are equally frequent in whites and blacks and have remained constant over time. In contrast, melanomas of the skin have increased manyfold in recent decades.50 Ocular melanomas are more frequent in whites than blacks,51 but have not increased in the last few decades.52,53 Although the risk of external ocular melanoma (eyelid and conjunctival melanomas) decreases with higher latitude (less sun exposure), the risk of internal ocular melanoma (uveal melanoma), which is not exposed to sunlight, increases with higher latitude, as does the risk of other internal malignancies.53,54

THE SKIN CANCER EPIDEMIC

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The incidence of melanoma and nonmelanoma skin cancers has doubled each decade since the 1960s.10,23,25,55–57 AK, lentigo maligna, and lentigo maligna melanoma— typically lesions of the middle-aged and elderly—are now seen in young adults. The best evidence that recreational sun exposure is responsible for much of the increase in skin cancers is that intermittently sunexposed sites, such as the trunk and limbs, account for most of the increase in skin cancers, with little change in melanomas of the head and neck.10,23,25 Another suspect has been ozone depletion; because of a steep absorption curve in the UVB region, small changes in ozone

concentration greatly affect UVB penetration (UVC is fortunately still blocked). Epidemiological data do not support a close relationship between ozone holes and skin cancer rates. The Antarctic ozone hole caused a 50% ozone reduction over southern Chile and Argentina in the last two decades, with UVB increasing up to 40-fold. Yet skin cancers in these areas are increasing at the same rate as elsewhere.58,59 The Arctic ozone hole has been offset by screening from air pollutants, yet skin cancers in Scandinavia are rising.60 An iatrogenic source of increased skin cancer incidence is psoralen plus ultraviolet A (PUVA) therapy for psoriasis, which increases the risk of SCC eightfold; in some but not all patient cohorts it raises melanoma >14-fold (see Chapter 238).61 Cancer is now increasing as a result of tanning beds. Individuals whose first sunbed exposure occurred as a young adult, or who had long durations or high frequencies of tanning bed exposure, already have a 70% higher risk of melanoma.62

CHARACTERISTICS OF ULTRAVIOLET RADIATIONINDUCED CANCERS AND PRECANCERS In the United States, ∼800,000 BCCs are diagnosed annually, as well as 200,000 SCCs and 70,000 melanomas.11,12 Survival differs strikingly. Fewer than 1 in 10,000 BCCs will metastasize and threaten the patient (see Chapter 115). This number increases to 1 in 40 for SCC, with clinical experience indicating that SCCs on sun-exposed skin are less likely to metastasize than those arising in scars.63 One in seven invasive melanomas is lethal (see Chapter 124). Merkel cell carcinoma (see Chapter 120) is a sun- and polyomavirus-induced cutaneous neuroendocrine cancer that will kill one in three patients diagnosed with it. Its reported incidence has tripled in the past 15 years to approximately 1,500 per year in the United States.64,65 The type of exposure preferentially leading to each malignancy differs. Cumulative lifetime sun exposure is strongly associated with SCC incidence.16,20 BCC and AK instead seem to depend on reaching a certain threshold of UV exposure, often attained in youth, such that sensitive individuals develop BCC at a relatively early age, and the incidence does not increase with further exposure.16,20,66 Case-control studies link melanoma with intense exposure early in life, with one or two blistering sunburns doubling the melanoma risk (see Chapter 124).67 Children are particularly sensitive to sunlight: moving from England to Australia before age 20 years confers the higher Australian incidence of AK, SCC, BCC, and melanoma, but the risk is much less when adults immigrate.68,69 This is not simply due to children spending more time outdoors, as 60 years old) Fair skin, light eyes, red or blonde hair History of significant cumulative UVR exposure High-risk genetic syndromes immunosuppression

Perform a total body skin examination (TBSE)

Chapter 113

Biopsy lesions suspicious for NMSC and MM Isolated number or a handful of AKs

Numerous AKs

::

Second visit Re-evaluate previously-treated AK sites and consider biopsies of recurrent or persistent lesions Review counseling on AKs and skin cancer prevention Lesion-targeted treatment for new AKs or previously-treated AKs with small residual

Regular follow-up with TBSE every 6-12 months

Epithelial Precancerous Lesions

First visit Lesion-targeted treatment -cryosurgery -currettage -shave excision Counsel on -skin self-examination -proper sun-protective measures -increased risk for NMSC and MM Prevention -daily broad spectrum sunscreen -hats, glasses, long-sleeve shirts Encourage life-long follow-up Schedule a follow-up visit in 2-3 -months to re-evaluate treated AK lesions

First visit Lesion-targeted treatment to most prominent AKs -cryosurgery -currettage -shave excision Counsel on -skin self-examination -proper sun-protective measures -increased risk for NMSC and MM -need for life-long follow-up Discuss field therapy treatment Schedule follow-up visit in 2-3 months

Second visit Re-evaluate previously-treated AK sites and either retreat if necessary or biopsy to exclude squamous cell carcinoma (SCC) Re-discuss patient's thoughts and preferences on field therapies Patient able to understand and be compliant with topical field therapies and their side effects

Begin full treatment with 5-FU or imiquimod

Patient compliant and wanting topical field therapy but not willing to tolerate side effects of 5-FU or imiquimod

Begin treatment with diclofenac gel

Patient unable to comply with topical field therapy Patient prefers one time office procedure Patient with more cosmetic concerns Cost not an issue

Laser ablation Chemical peels PDT Dermabrasion Cryopeeling Sun protection measures Regular follow-up and TBSE every 3-6 months

Figure 113-6  Approach to the management of actinic keratoses. 5-FU = 5-fluorouracil; PDT = photodynamic therapy; UVR = ultraviolet radiation.

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and avoids overinterpretation or underinterpretation. Obtaining biopsy samples through curettage produces crushed and fragmented specimens that are difficult to interpret, which can lead to erroneous diagnoses.

Box 113-2  Topical Field Therapies of Actinic Keratoses*

SHAVE EXCISION.

MEDICATION

Section 21 :: Epidermal and Appendageal Tumors

The third lesion-targeted destructive therapy for AKs is shave excision. This technique involves injection of a local anesthetic followed by tangential excision of the lesion with a surgical blade (see Chapter 243). Hemostatic agents must also be used to stop the bleeding. No data exist on the cure rate of this technique, but as with curettage, anecdotal experience says it is effective. Healing time may be 1–2 weeks, and potential complications include infection, scarring, and dyspigmentation. Use of this technique is most often indicated when a clinically apparent AK is suspicious for SCC or BCC and histopathologic examination is needed. Shave excision offers the patient an attempt at curative therapy simultaneous with a diagnostic procedure. Signs and symptoms that should arouse suspicion of SCC include marked erythema, pain, ulceration, bleeding, induration, or failure to respond to prior destructive therapies. Care must be taken to shave deeply enough to avoid transecting the AK at the deep margin, because this precludes unequivocal interpretation due to the proclivity for invasive SCC to develop at the deepest extensions of the atypical keratinocytes in AKs.

FIELD THERAPIES FOR ACTINIC KERATOSIS. Field therapies treat larger areas of photodam-

aged skin that contain both clinical and subclinical AK lesions. Field therapies can be further categorized into topical/medical and procedural field therapies. Such treatments are best used in patients with moderate to severely photodamaged skin and numerous AKs that would be too burdensome and painful to treat with the lesion-targeted therapies. Many patients with AKs, upon close inspection, are found to be extensively affected with early disease in sun-exposed areas, which may make field therapy a more rational approach to this difficult problem.

Topical Field Therapy.

Several topical agents are available and approved by the US Food and Drug Administration (FDA) for the generalized treatment of AKs, including 5-fluorouracil (5-FU), 5% imiquimod cream, and 3% diclofenac gel (Box 113-2). A full discussion of these therapies can be found in the online edition.

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PROCEDURAL FIELD THERAPY. The second category of field therapies for treating diffuse AKs is the procedural field therapies. These include cryopeeling (see Chapter 246), dermabrasion, medium and deep chemical peels (see Chapter 251), laser resurfacing (see Chapter 251), and photodynamic therapy (PDT) (see Chapter 238). Cryopeeling consists of extensive liquid nitrogen cryosurgery to the areas of discrete AKs as well as to the surrounding actinically damaged skin. Dermabrasion is an older technique that is quite effective in the treatment and prophylaxis of AKs but

5-Fluorouracil

Imiquimod

TOPICAL PREPARATION 2% solution 5% solution 1% cream 5% cream 0.5% micronized cream

Twice daily for up to 4 weeks

5% cream

Twice per week for 16 wks daily for 2 wks, then no treatment for 2 wks, then daily for 2 weeks Twice daily for 90 days

3.75% cream

Diclofenac

DOSAGE

2.5% cream 3% gel

Once daily for 4 weeks

*FDA-approved regimens

is now rarely used for this purpose. It causes physical destruction of the AKs with abrasion using either drywall sanding sheets or dermabrasion diamond fraises, which are powered or handheld (see Chapter 251). Medium-depth chemical peels using Jessner’s solution and 35% trichloroacetic acid (TCA) are moderately effective in treating diffuse AKs, especially when a series of such peels are administered over time69,70 (see Chapter 251). A combined peel, in which 35% TCA is used, after applied to obtain uniform frosting after Jessner’s solution degreasing and deepithelialization, has been shown to be equivalent in efficacy to 5-FU therapy.71 Deep chemical peeling using phenol or high concentrations of TCA is more effective in treating thick AKs or those with appendageal epithelial atypia but are rarely used because of the potential cardiac and renal toxicity of phenol, the greater risk of scarring and infection, and the dramatic hypopigmentation that may occur postoperatively. Laser resurfacing for the treatment and prophylaxis of AKs is another procedural field therapy that has been utilized. The carbon dioxide (CO2) laser and the erbium:yttrium-aluminum-garnet (er:YAG) laser are the two laser systems that have primarily been investigated for these purposes (see Chapter 252). Both of these devices ablate the epidermis at varying depths allowing reepithelialization with adnexal keratinocytes that are less actinically damaged. In preliminary small series, both laser resurfacing systems have been reported to be effective in shortterm clearing of multiple facial and scalp AKs72–74 and in the long-term prevention of recurrences75 and possibly the development of NSMC.72 Laser resurfacing is probably best reserved for use by specially trained and experienced physicians and for patients with

In summary, evidence supports the treatment of AKs to prevent the progression to malignancy. There are a number of effective lesion targeted and field treatments available to choose from to decrease the burden of AKs. Consideration of the individual’s needs, the physician’s skills, the mechanisms of action of the various treatments and their side effect profiles, plus the cost of treatment should all be considered when choosing a treatment strategy. To help physicians in choosing a treatment strategy for their patients, the American Academy of Dermatology and the European Dermatology Forum has proposed guidelines for the management of AKs, based upon available evidence at the time of their writings.85,86 In addition, the authors of this chapter have proposed a treatment algorithm (Fig. 113-6).

PREVENTION

:: Epithelial Precancerous Lesions

Given the potential of AKs to progress to malignant lesions, it is important to focus on the prevention of these precancerous lesions. Educational and preventive efforts should be directed toward children, targeted high-risk populations, and all patients. Avoidance of UV radiation is the single most effective means of decreasing the risk of AKs. A strategy designed to limit the amount and intensity of sun exposure, starting in childhood and continuing throughout the person’s life, will likely decrease the number of AKs an individual will develop. Because complete avoidance of the sun is impractical, the next best preventive measures are to avoid exposure to intense midday sun; consistently apply and reapply broad-spectrum sunscreens; wear UV-protective clothing, hats, and sunglasses; install UV-protective windows where indicated; and make sure to take an oral vitamin D supplement if necessary to avoid vitamin D insufficiency or deficiency.90 Numerous randomized studies have shown that the use of sunscreen can decrease the incidence and prevalence of AKs, reduce the number of AK lesions, and increase their rate of regression.29,91–94 There is also evidence that sunscreen use can prevent certain types of skin cancer, mostly SCC.93,94 There is limited evidence that adhering to a diet low in fat may decrease the incidence of AKs95,96 and NMSC.97,98 In older studies, topical retinoids were shown to reduce the number of AKs after long-term consistent use,99,100 and in another study, long-term treatment with topical retinoic acid was shown to reduce keratinocyte and melanocyte atypia in photoaged skin.101 However, the more recent multicenter VATTC trial found that up to twice-daily application of 0.1% tretinoin cream over 1.5–5.5 years in mostly elderly (n = 1,131, mean age = 70 years) males (95%) at very high risk for NMSC was ineffective for preventing BCC and SCC.102 This study was stopped 6 months prematurely because of excess mortality in the treatment group. However, the authors could not establish a cause and effect relationship.103 They also concluded that retinoids may have very different clinical effects when administered topically as opposed to orally.102

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Chapter 113

more cosmetic concerns or with diffuse AKs for which topical field therapies and/or chemical peeling have failed. They are also excellent modalities for patients with severe actinic cheilitis and for those patients with multiple, thicker AKs. PDT is another procedural therapy available for the treatment of multiple and diffuse AKs. The FDA has approved two PDT systems for the treatment of nonHAK lesions on the face and scalp (see Chapter 238). The first to receive approval was the combination of 5-aminolevulinic acid (ALA) with a blue light source in 1998. More recently, the FDA approved a system that has been widely available in Europe, combining a methyl ester of aminolevulinic acid (MAL) with a red light source. The topically applied ALA or MAL accumulates preferentially in the more rapidly dividing atypical cells and is converted sequentially to protoporphyrin IX, a heme precursor and photosensitizer. When the ALA or MAL-treated skin is then exposed to a light source of the appropriate wavelength several hours later, the accumulated protoporphyrin IX generates a phototoxic reaction that destroys the treated cells.76–79 Randomized, placebo-controlled studies have demonstrated the efficacy of both ALA and MAL PDT for the treatment of AKs.79–82 A more recent, randomized, double-blind, prospective study comparing the safety and efficacy of ALA-PDT with MAL-PDT found both forms to have no significant difference in efficacy of decreasing AK lesion burden, but that ALA-PDT was associated with more painful and adverse effects and a longer duration of discomfort compared with MALPDT.82 Patients can expect some discomfort with PDT, including erythema, edema, and burning or stinging during exposure to the light source. In a subgroup of patients with severe sun damage, PDT can create intolerable pain that sometimes results in premature discontinuation of treatment. Allergic reactions to ALA and MAL have also been reported. Severe phototoxic reactions can occur if patients do not follow the protocol and practice strict sun avoidance for the recommended period after ALA and MAL application. Cosmetic outcomes have been good to excellent in those who complete adequate treatment. There is a paucity of comparative effectiveness research amongst these various field therapies for AKs. In general, topical 5-FU, 5% imiquimod cream, diclofenac gel, and PDT are all effective in decreasing the AK lesion burden. From the mostly small comparative studies that have been published, a few additional points can be made. Topical 5-FU and topical 5% imiquimod cream seem to create more inflammation, irritation, and patient discomfort compared with topical diclofenac gel. There is some data to suggest that topical 5% imiquimod cream may have lower, long-term recurrence rates of AKs, in part by creating longer term immune memory and antitumor response.56,83 A pharmacoeconomic study of AK field treatment modalities (5% imiquimod vs. diclofenac gel vs. 5-FU vs. ALA-PDT) in combination with liquid nitrogen cryosurgery found that ALA-PDT was the least costly and that imiquimod was the most expensive.84

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Section 21

Unlike the controversy with topical retinoids, there is strong evidence for the use of systemic retinoids in preventing NMSC and AKs, especially in highrisk populations, such as organ transplant recipients, patients with xeroderma pigmentosum, and other chronically immunosuppressed patients.104–107 Unfortunately, the systemic retinoids are only effective while the patient is taking them and their use is also limited by the frequent occurrence of systemic toxicities, including hypercholesterolemia, hypertriglyceridemia, mucocutaneous xerosis, musculoskeletal abnormalities, and alteration in liver function. Thus, when considering the use of systemic retinoids in such high-risk patients, one must weigh these risks and benefits. Topical imiquimod has also been safely used in the organ transplant population to prevent the development of cutaneous SCC.65,108

:: Epidermal and Appendageal Tumors

ARSENICAL KERATOSES ARSENICAL KERATOSES AT A GLANCE Arsenical keratoses (ArKs) are precancerous lesions associated with chronic arsenicism. ArKs have the potential to become squamous cell carcinomas (SCCs). Chronic arsenicism has resulted from medicinal, occupational, and environmental exposures. Clinical appearance is of punctuate, keratotic, yellow papules overlying pressure points on palms and soles. Chronic arsenicism is associated with ArKs, Bowen disease, basal cell carcinoma, SCC, and internal malignancies, with latency periods of up to 40 years. No standard recommendations for treatment; most lesions are followed clinically or treated symptomatically.

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Arsenical keratoses (ArKs) are precancerous lesions found in association with chronic arsenicism. These lesions have the potential to develop into invasive SCC. Arsenic is a ubiquitous element that has no color, taste, or odor. It has the potential to cause characteristic acute and chronic syndromes in persons exposed to it, and such exposures are typically obscure because medicinal, occupational, and environmental sources still exist. Detection of acute and chronic arsenicism is important, because the acute form can be fatal and the chronic form is associated with a variety of cutaneous and internal malignancies. ArKs are associated with chronic arsenicism.

PROGNOSIS AND CLINICAL COURSE ArKs and arsenical-induced BD tend to persist for many years, and progression to invasive SCC is believed to be relatively rare. However, invasive SCCs that arise in ArKs are more locally aggressive and have a greater chance of metastasis than SCCs arising in AKs.110 In lesions of arsenical-induced BD, locally invasive SCC has been seen histopathologically in up to 20% of cases. Once invasive SCC has occurred in BD, it is said that at least one-third will demonstrate evidence of metastasis unless adequate treatment is provided.122

TREATMENT Management of patients with chronic arsenicism and ArKs should include regularly scheduled total-body skin examinations and general physical examinations, possibly every 6 months.121 The exact incidence of internal malignancies associated with chronic arsenicism is unknown, so there is no standard protocol for the evaluation of potential internal malignancies. Exhaustive evaluations to detect such malignancies have not been recommended. Biannual detailed history taking and physical examination, yearly chest radiography, and selective testing when clinically indicated are probably reasonable recommendations. Treatment of ArKs likewise is not standard and not mandatory, although treatment of these lesions is sometimes initiated to relieve the associated discomfort that some patients experience. Available treatment options include surgical excision, cryosurgery, curettage with or without electrosurgery, CO2 laser treatment, and topical chemotherapy with 5-FU, although 5-FU therapy is less successful in treating ArKs than in treating AKs.110 PDT has also been used to treat these lesions. Limited studies suggest that oral retinoids and keratolytics may be useful in treating ArKs.123,124 One case report of effective treatment of ArKs, BD, and BCC lesions in one patient with chronic arsenicism with topical 5% imiquimod cream has been reported.125

THERMAL KERATOSES THERMAL KERATOSES AT A GLANCE Precancerous lesions that result from longterm exposure to infrared radiation; can progress to squamous cell carcinoma (SCC). Sources of infrared radiation include open fires, railway engines, wood-burning stoves, heating pads and blankets, and laptop computers. Precursor lesion is erythema ab igne; biopsy should be performed on any hyperkeratotic papule or plaque within such a patch. Risk of progression of thermal keratosis to SCC is unknown.

HYDROCARBON KERATOSES

CHRONIC SCAR KERATOSES

HYDROCARBON KERATOSES AT A GLANCE

CHRONIC SCAR KERATOSES AT A GLANCE

Hydrocarbon keratoses (HKs) are also known as pitch keratoses, tar keratoses, and tar warts. They occur in persons who are occupationally exposed to polycyclic aromatic hydrocarbons (PAHs).

Presence of atypical keratoses on the nostril rims, upper lip, and genitalia should prompt a search for occupational exposures to PAHs. Other skin findings include patchy hyperpigmentation, acne, and telangiectases.

CHRONIC RADIATION KERATOSES CHRONIC RADIATION KERATOSES AT A GLANCE Chronic radiation keratoses (CRKs) are precancerous lesions that may arise at irradiated sites years after such exposure and may progress to squamous cell carcinoma (SCC). Ionizing radiation sources include X-rays, grenz rays, and contaminated gold rings. Common sites are the palms, soles, and mucosal surfaces. Clinically present as hyperkeratotic papules or plaques within areas of chronic radiation dermatitis and occasionally on clinically normal skin. Latency for the development of CRKs can be up to 56 years after exposure. Ionizing radiation-induced SCC can be extremely aggressive. Patients with ionizing radiation exposure and CRKs are also at risk for internal malignancies.

Approximately 2% of burn scars will undergo malignant changes. Most burn scar carcinomas are squamous cell carcinomas (SCCs), but basal cell carcinomas (BCCs), melanomas, sarcomas, and malignant fibrous histiocytomas have also been described. Acute Marjolin’s ulcer develops within 1 year of the time of injury; chronic Marjolin’s ulcer develops more than 1 year after an injury, with an average latency period of 36 years. Sites of predilection are the extremities and overlying joints. Any persistent lesion, erosion, or ulceration within a scar requires biopsy.

Epithelial Precancerous Lesions

Latency periods between PAH exposure and development of HK or SCC range from 2.5 years to 45 years.

Marjolin’s ulcer describes malignant changes within a burn scar but can also refer to such changes in chronic ulcers or sinus tracts.

::

HK can progress to squamous cell carcinoma (SCC), but the rate of progression and risk are unknown.

Chronic scar keratoses (CSKs), or cicatrix keratoses, are precancerous lesions that arise in long-standing scars from various causes.

Chapter 113

Occupations at risk include tar distiller, shale extractor, roofer, asphalt worker, road paver, highway maintenance worker, brick mason, diesel engineer, and chimney sweep.

21

Prevention includes excellent wound care, early skin grafting, avoidance of contractures, and early excision of any tissue showing degenerative changes.

VIRAL-ASSOCIATED EPITHELIAL PRECANCEROUS LESIONS Several types of precancerous epithelial lesions have a viral association (Box 113-3), including bowenoid papulosis (BP), epidermodysplasia verruciformis (EV), vulvar intraepithelial neoplasia (VIN), anal and perianal intraepithelial neoplasia (AIN and PaIN), and penile intraepithelial neoplasia (PIN). Extensive research has shown that certain oncogenic or highrisk HPV (hrHPV) types play a significant role in the p s of these precancerous lesions.144 Over 100 types of HPV have been discovered, and the hrHPV subtypes that have been associated with these precancerous epithelial lesions are shown in Box 113-3. The role of the human papillomavirus (HPV) in the etiology and development of these precancerous lesions, as well as other malignant neoplasms, is further discussed in

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VIRAL-ASSOCIATED PRECANCEROUS LESIONS AT A GLANCE Two viral-associated precancerous lesions are bowenoid papulosis (BP) and epidermodysplasia verruciformis (EV). BP is a precancerous condition of the genitalia caused by infection with human papillomavirus (HPV); oncogenic types 16, 18, and 33 are most commonly involved.

Section 21

BP may regress spontaneously, persist, or rarely transform into Bowen disease (BD) or squamous cell carcinoma (SCC).

::

Treatment options include topical imiquimod, curettage, excision, and laser vaporization.

Figure 113-7  Bowenoid papulosis of the penis. (Used with permission from James E. Fitzpatrick, MD.)

Epidermal and Appendageal Tumors

Chapter 196. The premalignant lesions of the lower anogenital tract (VIN, AIN, PaIN, PIN) are discussed later in this chapter.

Sexual partners of patients must be examined and followed closely for development of cervical, vulvar, or penile carcinoma. EV is a rare genodermatosis associated with mutations in the EVER1 and EVER2 genes. Affected individuals show a propensity toward infection with certain strains of HPV5 and HPV-8. Clinical presentation is with widespread flat wart-like papules and plaques in childhood; risk of developing SCC later in life is high. Sun avoidance, sun-protective measures, regular dermatologic follow-up, and screening of family members for the disease are important.

BOWENOID PAPULOSIS BP is characterized clinically by the presence of pigmented verrucous papules and plaques primarily on the genitalia of predisposed, usually younger, individuals, and histopathologically by the presence of SCC in situ-like changes (Fig. 113-7) (see also Chapters 77 and 78). Genital lesions that histopathologically resembled SCC in situ were first described by Lloyd in 1970 as multicentric pigmented BD of the groin.145 In 1977, Kopf and Bart described multiple bowenoid papules of the penis.146 In 1979, Wade et al coined the term bowenoid papulosis of the genitalia.147 Other terms used for this condition include pigmented penile papules with carcinoma in situ changes, genital keratinocytic dysplasia, and penile carcinoma in situ associated with HPV infection.

Box 113-3  Viral Associated Premalignant Neoplasms ASSOCIATED VIRUS PREMALIGNANT LESION

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Bowenoid papulosis (BP) Epidermodysplasia verruciformis (EV) Vulvar intraepithelial neoplasia (VIN) Anal intraepithelial neoplasia (AIN) Perianal intraepithelial neoplasia (PaIN) Penile intraepithelial neoplasia (PIN) Digital or periungual Bowen disease

Most Often Detected

HPV-16,18 HPV-5,8 HPV-16 HPV-16 HPV-16 HPV-16 HPV-16

Less Often Detected

HPV-31–35,39,42,48,51–54 HPV-9,12,14,15,17,19,25,26,38,47,50, etc. HPV-18,31,33 HPV-18,31,33 HPV-18,31,33

SQUAMOUS CELL CARCINOMA IN SITU (BOWEN DISEASE) SQUAMOUS CELL CARCINOMA IN SITU (BOWEN DISEASE) AT A GLANCE Bowen disease (BD) is squamous cell carcinoma (SCC) in situ, with the potential to progress to SCC. Etiologic factors include ultraviolet (UV) radiation exposure, chronic arsenicism, previous therapy with psoralen and UVA radiation, immunosuppression, exposure to ionizing radiation, and infection with human papillomavirus (HPV). Clinical variants are pigmented, intertriginous, periungual, and subungual BD. Histopathologic features include fullthickness epidermal atypia with adnexal involvement.

Epithelial Precancerous Lesions

(See Chapter 196) EV is a rare inherited skin condition that arises when genetically susceptible individuals are infected with certain HPV subtypes, most notably HPV 5 and HPV 8, but also including HPV types 9, 12, 14, 15, 17, 19, 25, 36, 38, 47, and 50. EV individuals present in childhood with numerous thin, pink, flat papules and plaques that resemble verruca plana. They also have widespread scaly, erythematous, or hypopigmented macules and flat papules that appear similar to tinea versicolor. Approximately 30%–60% of persons with EV will develop cutaneous malignancies in these wartlike lesions, most often in the fourth to fifth decades of life and usually on sun-exposed areas of the skin. About 90% of these EV-related SCCs have been associated with HPV subtypes 5 and 8. A susceptibility for EV was localized to chromosome 17q25 in 1999,157 and mutations in two novel genes from this same region (EVER1 and EVER2) were identified and associated with EV more recently.158 In addition to the host genetic background, these EV-HPVs are activated by UV exposure and immunosuppression. EV histopathologically may mimic other skin conditions and therefore a combination of patient history, clinical and histopathologic findings, plus viral and

21

::

EPIDERMODYSPLASIA VERRUCIFORMIS

genetic testing is crucial to making the diagnosis of EV. Lastly, as EV-like lesions have been observed in the setting of immunosuppression (acquired EV), patients suspected of having EV should also be tested for HIV and other etiologies for impaired cell-mediated immunity should be considered.159 No specific or successful treatments exist for EV lesions. Mixed results have been seen with topical 5% imiquimod cream.159

Chapter 113

BP is caused by infection with HPV, and numerous HPV types have been linked to BP, particularly hrHPV subtypes 16 and 18, but also including 31–35, 39, 42, 48, and 51–54 (see Chapter 196). Lesions are pink, reddish brown, or violaceous (see Fig. 113-7). Differential diagnosis includes early condylomata acuminata (see Chapters 77 and 78). Histopathologically, the epidermis is usually hyperplastic with atypia, disordered maturation, scattered mitotic figures, and dyskeratotic keratinocytes. The course of BP is variable, but mostly benign, ranging from spontaneous regression to persistence of lesions to rarely transformation into BD and invasive SCC. It has been estimated that the risk of malignant transformation is quite low, ranging from less than 1%–2.6 %.144,148 BP is highly contagious and patients with BP and their sexual partners should be followed and examined periodically, because of the increased risk of developing SCC, cervical, and vulvar neoplasia.149 Patients with persistent disease should probably undergo testing for altered immune status. Treatment of BP is recommended, and it typically responds well to local therapy, although recurrences are common. Therapeutic options include local destructive measures such as curettage with or without electrosurgery, CO2 laser, neodymium:YAG laser, cryosurgery, and excision. Topical tretinoin, topical 5-FU, and topical cidofovir have been used in anecdotally reported cases with mixed results.150 More recently, topical 5% imiquimod cream has shown promising results in a few case reports and would be the logical choice given its efficacy against HPV.151–156

Lesions progress to invasive carcinoma in 3%–5% of cases. Treatment methods include excision and Mohs micrographic surgery, which permit histopathologic evaluation to exclude invasive SCC. Curettage treatment of BD may miss appendageal involvement. Topical therapy may be used in areas that are difficult to treat with other methods with limited trials supporting their use.

Bowen disease (BD) is SCC in situ, originally described in 1912 by John T. Bowen, a Boston dermatologist.160 It affects both skin and mucous membranes and has the potential to progress to invasive SCC.

EPIDEMIOLOGY BD may occur at any age in adults, but it is rarely seen in individuals younger than 30 years. The

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typical patient with BD is older than 60 years. The disease is said to occur with an equal incidence in men and women, although most studies report a slight preponderance in women.161 BD can be found on any body site, including both sun-exposed and nonsun-exposed regions of the body, although it appears to have a predilection for sun-exposed surfaces such as the head and neck and for the lower legs of women, in particular. The exact incidence of BD in the United States is unknown, but in one population study in Hawaii, the incidence was estimated at 142 per 100,000 persons.162 Lesions of BD are usually solitary but are multiple in up to 10%–20% of individuals.

Section 21

ETIOLOGY AND PATHOGENESIS

:: Epidermal and Appendageal Tumors

A number of different factors have been implicated in the development of BD, including a history of significant sun exposure, arsenic exposure, ionizing radiation, immunosuppression, and certain types of HPV infection. Up to 30% of extragenital BD lesions have been found to harbor HPV DNA.163,164 The

age group and sites of predilection of BD suggest a strong association with sun exposure. BD is also rare in more heavily pigmented individuals, and it has been described with increased frequency in patients undergoing psoralen plus ultraviolet A (PUVA) therapy. The association with arsenic exposure has already been discussed. SCC in situ is seen commonly in organ transplant recipients after years of immunosuppressive drug therapy. Infection with HPV has been implicated in causing certain subtypes of BD. In particular, HPV-16 has been detected in many cases of anogenital BD and in some cases of finger and periungual BD.165

CLINICAL FINDINGS BD typically presents as a discrete, slowly enlarging, pink to erythematous thin plaque with well-demarcated, irregular borders and overlying scale or crust (Fig. 113-8A) resembling a psoriatic plaque. Hyperkeratotic and verrucous surface changes may be seen, and a pigmented variant of BD has been reported in fewer

A B

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C

Figure 113-8  A. Large plaque of Bowen disease (BD) of the leg. B. BD of the nail unit. C. BD showing full-thickness atypia of epithelium.

Clinically, BD is most often mistaken for superficial BCC; patches of dermatitis, psoriasis, or lichen planus; AK; benign lichenoid keratosis (BLK) or lichen planus-like keratosis; irritated seborrheic keratosis; or amelanotic melanoma (Box 113-4). More

Box 113-4  Clinical and Histopathologic Differential Diagnosis of Bowen Disease CLINICAL DIFFERENTIAL DIAGNOSIS OF BOWEN DISEASE Erythematous Bowen disease Superficial basal cell carcinoma Dermatitis, eczema Psoriasis Seborrheic dermatitis Lichen planus Benign lichenoid keratosis Irritated or inflamed seborrheic keratosis Actinic keratosis Squamous cell carcinoma Amelanotic melanoma Hyperkeratotic Bowen disease Verruca vulgaris Seborrheic keratosis Discoid lupus erythematosus Hypertrophic lichen planus Squamous cell carcinoma Pigmented Bowen disease Melanoma Bowenoid papulosis Intertriginous Bowen disease Inverse psoriasis Seborrheic dermatitis Candidiasis Paget disease Hailey–Hailey disease Subungual or periungual Bowen disease Nail dystrophy Onychomycosis Squamous cell carcinoma Amelanotic melanoma HISTOPATHOLOGIC DIFFERENTIAL DIAGNOSIS OF BOWEN DISEASE Paget disease Pagetoid melanoma in situ Intraepidermal eccrine carcinoma Intraepidermal Merkel cell carcinoma Intraepidermal sebaceous carcinoma Bowenoid papulosis Podophyllin-induced changes in a wart

Epithelial Precancerous Lesions

The epidermis displays full-thickness atypia, including in the intraepidermal portions of the adnexal structures (see Fig. 113-8C). Involvement reaches from the stratum corneum down through the basal cell layer, although the basement membrane remains intact. Characteristically, parakeratosis and hyperkeratosis are present, as is acanthosis, with complete disorganization of the epidermal architecture. At times, the hyperkeratosis and parakeratosis are so pronounced that a cutaneous horn is present. Throughout the epidermis are numerous atypical, pleomorphic, hyperchromatic keratinocytes. These cells are sometimes vacuolated and have a prominent pale-staining cytoplasm, reminiscent of the cells in Paget disease. These cells show loss of maturation and polarity, in addition to numerous mitotic figures. Individually, keratinized cells with large, rounded, eosinophilic cytoplasm, and hyperchromatic nuclei can be found in the epidermis, as can multinucleated cells. These atypical cells also are seen throughout the pilosebaceous units, within the acrotrichia, follicular infundibula, and sebaceous glands. The upper dermis is typically infiltrated by numerous chronic inflammatory cells, including lymphocytes, plasma cells, and histiocytes. Several histopathologic subtypes of BD can be seen. Psoriasiform BD displays parakeratosis and marked acanthosis with broad, sometimes fused, epidermal rete ridges. Atrophic BD, like atrophic AK, demonstrates a thinned epidermis, but in addition there is full-thickness atypia and lack of maturation, as well as adnexal involvement. Acantholytic BD shows marked acantholysis in the epidermis. Epidermolytic BD has changes of incidental epidermolytic hyperkeratosis (EHK) present. The phenomenon of intraepidermal epithelioma of Borst-Jadassohn—namely, nesting of the atypical cells within the epidermis, or so-called pagetoid BD—can also be seen.

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HISTOPATHOLOGY

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Chapter 113

than 2% of cases.166 Individual lesions may measure up to several centimeters in diameter, and multiple lesions are not uncommon. As previously mentioned, sites of predilection include sun-exposed areas such as the head and neck and lower legs, although any body site may be affected. A few clinical variants of BD deserve special mention. Intertriginous BD can present as an oozing, erythematous, dermatitic plaque or as a pigmented patch or plaque. BD involving the periungual region may appear as an erythematous, scaly, thin plaque around the cuticular margin, a crusted erosion, nail discoloration, erythronychia, onycholysis, a verrucous plaque, or destruction of the nail plate (Fig. 113-8B). BD of the mucosal surfaces can present as verrucous or polypoid papules and plaques, erythroplakia, or a velvety erythematous plaque. These last two entities are discussed below in the sections on precancerous lesions of the oral cavity and the lower anogenital tract, respectively.

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hyperkeratotic or verrucous lesions of BD may be difficult to distinguish clinically from viral warts, seborrheic keratoses, and SCC, and pigmented BD lesions can be mistaken for melanoma. Superficial BCC can sometimes be distinguished by its raised, subtle, and translucent border. Histopathologically, BD must be differentiated from Paget’s disease; pagetoid melanoma in situ; eccrine, Merkel, and sebaceous carcinomas; BP; and podophyllin-induced changes in a wart (see Box 113-4). Both Paget’s disease and BD may have the findings of vacuolated cells, but in contrast with BD, Paget’s disease shows no dyskeratosis. Also, the material present in Paget’s cells is periodic acid-Schiff (PAS) positive and diastase-resistant, whereas the PAS-positive material sometimes present in BD cells (i.e., clear cell BD) is glycogen and therefore PAS labile. Finally, staining for carcinoembryonic antigen yields positive results in Paget’s disease but negative results in BD. Pagetoid melanoma in situ can be difficult at times to distinguish histopathologically from BD. In BD, the intercellular desmosomal bridges should be identifiable between the atypical keratinocytes, and melanocyte specific immunoperoxidase staining gives positive results in melanoma cells but negative results in BD and Paget’s disease cells. The other rare pagetoid neoplasms are usually recognizable, but erroneous diagnoses can be made by the unwary. BP may lack the full-thickness epidermal atypia present in BD, but the clinical setting is paramount. Podophyllin applied topically to skin lesions causes metaphase arrest with resultant bizarre keratinocyte formation and sometimes a pattern of pseudoepitheliomatous hyperplasia that can be mistaken for BD. These changes typically resolve after a few days to a week.167

Critical analysis and meta-analysis of these past studies do not support the need for routine investigation for internal malignancy in persons with BD. The one exception to this position is in cases of BD related to previous arsenic exposure, in which the possibility of internal malignancy is real, as previously discussed. Also, BD involving the vulvar region in females and the perianal region in males has been associated with an increased risk of uterine, cervical, vaginal, and anal cancer, possibly due to HPV infection, as discussed.122,170

TREATMENT A number of different modalities are available for the treatment of BD. Such treatments can be divided into three main categories: surgical and destructive therapies, topical therapies, and nonsurgical ablative therapies (Box 113-5). Surgical and destructive therapies include excision, Mohs micrographic surgery, curettage with or without electrosurgery, chemoablation with TCA, and cryosurgery. Topical therapies include 5-FU and 5% imiquimod cream (see Chapter 221). Nonsurgical ablative therapies are laser ablation, radiotherapy, and PDT (see Chapter 238). Although some of these modalities have reported cure rates that are better than others, no one treatment is right for all forms of BD. Therapy must be guided by the size and location of the BD, in addition to individual patient characteristics, such as age and healing capability. BD warrants definitive surgical therapy if it has previously failed topical chemotherapy or ablative surgery, due to its propensity to eventually affect large surface areas and to become invasive.

PROGNOSIS AND CLINICAL COURSE The risk that untreated BD will progress to invasive carcinoma has been estimated in one older study at approximately 3%–5%.163 Estimates are that once invasive carcinoma occurs in BD [see thumbnail image in “Squamous Cell Carcinoma In Situ (Bowen Disease) At a Glance” box], approximately 13% of these carcinomas will metastasize, and of these cases, 10% will end in death from widespread dissemination.168 The presence of BD in any given individual is a marker for a high risk of developing a subsequent NMSC.169 In studies addressing the association between the presence of BD and the risk of other NMSCs, approximately 30%–50% of BD patients had either previous or subsequent NMSC. Another study estimated the incidence ratio for subsequent NMSC to be 4.3.169 Previous studies also claimed that the presence of BD is a marker for internal malignancy, although a significant number of other investigations have been unable to substantiate this association.

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Box 113-5  Treatment of Bowen Disease SURGICAL AND DESTRUCTIVE THERAPIES Excision Mohs micrographic surgery Curettage with or without electrosurgery Liquid nitrogen cryosurgery TOPICAL THERAPIES 5-Fluorouracil (5% cream bid for 6–16 weeks) 5% imiquimod (daily for 16 weeks) NONSURGICAL ABLATIVE THERAPIES Laser ablation Radiotherapy Photodynamic therapy

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PRECANCEROUS LESIONS OF THE LOWER ANOGENITAL TRACT ANAL (AIN) AND PERIANAL (PaIN) INTRAEPITHELIAL NEOPLASIA AT A GLANCE Anal intraepithelial neoplasia (AIN) is an human papillomavirus (HPV)-associated precursor lesion of anal squamous cell carcinoma (SCC) and has been previously called anal squamous intraepithelial neoplasia (ASIL) or anal dysplasia; it is embryonically and histopathologically analogous to cervical intraepithelial neoplasia (CIN).

AIN may be asymptomatic or present with pruritus, pain, bleeding, tenesmus, or discharge.

Perianal intraepithelial neoplasia (PaIN) is a precursor lesion of perianal, cutaneous SCC and has also been called genital Bowen disease (GBD), SCC in situ, and sometimes bowenoid papulosis (BP); it is less likely associated with HPV than AIN; and only 5% of such cases may progress to invasive SCC.

Dermatologists play a role in high-risk patients by examining the perianal skin and, if PaIN is diagnosed, initiating treatment for PaIN and then referring such patients to an expert in diagnosing and managing AIN and CIN for further evaluation.

There is a high-risk of recurrence of AIN and an increased association with other anogenital intraepithelial neoplasias (Ins), necessitating referral and ongoing surveillance. HPV vaccination of males for prevention of AIN is undergoing investigation.

AIN is associated with oncogenic hrHPV types 16, 18, 31, and, less so, HPV-33.

Epithelial Precancerous Lesions

The greatest risk factors for AIN are HPV infection, receptive anal intercourse, HIV infection, smoking, and a history of CIN in females.

Treatment options for PaIN include wide local excision, Mohs micrographic surgery, and various topical agents.

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AIN2 and AIN3 are high-grade precursor lesions of anal SCC and histopathologically display moderate and severe dysplasia, respectively.

Histopathology of PaIN is that of cutaneous SCC in situ and that of AIN is analogous to CIN.

Chapter 113

AIN1 is a low-grade lesion and not a direct precursor of anal SCC.

PaIN may present with a variety of clinical patterns, including well-demarcated erythematous, or variably pigmented plaques.

VULVAR INTRAEPITHELIAL NEOPLASIA (VIN) VULVAR INTRAEPITHELIAL NEOPLASIA (VIN) AT A GLANCE Vulvar intraepithelial neoplasia (VIN) is a highgrade precancerous lesion of the vulva that may progress to vulvar squamous cell carcinoma (SCC). It is primarily a disease of younger females (75% of all cases) and its incidence is rising globally. There are three categories of VIN: (1) usual type, (2) differentiated type, and (3) unclassified type. VIN, usual type associated with hrHPV-16, 18, 31; occurs in younger premenopausal females; presents with multifocal and multicentric lesions; has 50% association with cervical intraepithelial neoplasia (CIN).

VIN, differentiated type less common than usual type; usually not associated with HPV; affects postmenopausal females; is associated with lichen sclerosus; unifocal presentation. A diagnosis of VIN mandates referral to gynecologist to look for CIN. VIN has a varied clinical presentation and the differential diagnosis includes lichen sclerosus, lichen planus, condyloma acuminata, and cutaneous melanoma. No consensus on best treatment; consult with gynecologist. HPV vaccine in young females can prevent HPV-related VIN.

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PENILE INTRAEPITHELIAL NEOPLASIA (PIN) PENILE INTRAEPITHELIAL NEOPLASIA (PIN) AT A GLANCE Penile intraepithelial neoplasia (PIN) is a precursor lesion to penile squamous cell carcinoma (SCC); two clinical variants of PIN are the genital Bowen disease (GBD) and the erythroplasia of Queyrat (EQ) variants.

Section 21

PIN and penile cancer are rare in the Western world but increasing in incidence in developing countries.

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PIN and penile SCC are mainly diseases of older, uncircumcised males.

The GBD variant of PIN is less common than the EQ variant; presents as a welldemarcated, erythematous to variably pigmented plaque on the shaft of the penis.

Epidermal and Appendageal Tumors

Risk factors in uncircumcised males include poor hygiene, smegma retention, phimosis, chronic inflammatory and infectious conditions of the penis; and less so coinfection with oncogenic hrHPV (primarily 16, but also 18, 31, and 33), lichen sclerosus, HIV infection, immunosuppression, smoking, PUVA and UVR exposure of the genitalia.

Histopathology of both the GBD and EQ variants of PIN show SCC in situ changes, but EQ has more epithelial hypoplasia and plasma cells in the dermal infiltrate.

About 40%–45% of PIN and penile SCC are associated with HPV.

No definitive treatment guidelines for PIN and treatment options are similar as those for other forms of SCC in situ; must be individualized to preserve anatomy and function as best as possible.

There are two independent pathways in the development of PIN and penile SCC: an HPV-positive pathway and an HPV-negative pathway. The HPV-positive pathway is morphologically associated with the warty and basaloid subtypes of penile SCC and is thought to be more aggressive. The HPV-negative pathway is morphologically associated with the usual or differentiated type of penile SCC, which is the major type (∼49%) of all of the penile SCCs.

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The EQ variant of PIN is the most common type of PIN and is always associated with HPV-8 and most often with concomitant HPV-16 coinfection; presents as a welldemarcated, glistening, erythematous, velvety plaque or plaques on the mucosal surfaces of the penis.

EQ variant of PIN is more likely to progress to invasive SCC (∼30%) vs. the GBD variant (3%–6%).

Prevention is important and can be advocated with neonatal circumcision; in uncircumcised males, must advocate proper hygiene, stopping smoking, treating chronic inflammatory and infectious penile conditions, and avoiding genital PUVA and UVR exposure; HPV vaccine is investigational.

POTENTIALLY MALIGNANT DISORDERS OF THE ORAL CAVITY

doned and that the term potentially malignant disorders be used instead. In this chapter the focus will be on oral leukoplakia (OL) and erythroplakia.

In a World Health Organization (WHO) workshop held in 2005, the terminology, definitions, and classification of oral lesions with a predisposition to malignant transformation were discussed.193 The term potentially malignant was preferred over premalignant or precancerous. In addition, it was recommended that the traditional distinction between potentially malignant lesions and potentially malignant conditions be aban-

LEUKOPLAKIA Leukoplakia is a clinical term that refers to a predominantly white lesion of the oral mucosa that cannot be rubbed off or characterized by any other definable lesion or known disease.194 Leukoplakia is the most common precancerous lesion of the oral mucosa, with

LEUKOPLAKIA AT A GLANCE Leukoplakia is a clinical diagnosis of exclusion for a fixed white lesion in the oral cavity that does not resolve spontaneously. Oral leukoplakia (OL) is the most common precancerous lesion of the oral mucosa, with the potential to become oral squamous cell carcinoma (OSCC). Prevalence is 0.2%–5.0%.

OL and oral erythroplakia (OE) are markers for increased risk for additional oral or upper aerodigestive tract malignancies.

the potential to become oral SCC (OSCC).195 OL is in the same clinical spectrum of disease as oral erythroplakia (OE), but unlike OE it is a much more frequently diagnosed lesion with a much lower rate of malignant transformation.

EPIDEMIOLOGY The reported prevalence of OL varies from 0.2% to 5%, although such rates vary significantly among different geographical areas and demographic groups.196 In a worldwide systematic review of OL that included multiple studies involving more than 1,000 subjects, prevalence rates varied between 0.50% and 3.46%.197 The pooled prevalence estimate of OL in this study was between 1.49% and 4.27%.197 Leukoplakia is six times more common among smokers than among nonsmokers.198 Alcohol is an independent risk factor, regardless of beverage type or drinking pattern.199 There are conflicting results as to the possible role of HPV infection.200–202 In addition to potentially becoming a malignant growth, OL, and for that matter OE, have come to be viewed as risk factors or markers for other epithelial cancers of the oral cavity and upper aerodigestive tract. The concept of field cancerization applied to the oral mucosa implies that its entire surface can be affected by carcinogens. Indeed, approximately 20% of patients with SCC of the head and neck will develop another malignancy or precancerous lesion within 5 years of the first diagnosis.203

Epithelial Precancerous Lesions

No consensus exists on how best to treat OL.

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Risk factors for OL are the use of any tobacco product, concomitant alcohol use, history of previous OSCC or premalignant lesions, and infection with certain human papillomavirus (HPV) subtypes.

Given the current definition of leukoplakia, identification of an etiologic factor for a given white lesion would exclude this diagnosis. Two factors in this setting are tobacco use and candidiasis. Tobacco use is believed to be a strong risk factor for the development of OL. Tobacco-related white lesions of the oral mucosa have been identified and then subsequently found to disappear once the habit of tobacco use has been discontinued. By current definitions and standards, such tobacco-related white lesions are thought to be different entities than true OL, which would not disappear with cessation of tobacco use. Likewise, there has been much debate as to whether or not Candida infection is a cause of leukoplakia or a superimposed infection within a preexisting OL lesion. If one adheres to the strict and accepted definition of leukoplakia, a white lesion that disappears upon treatment of Candida infection is not leukoplakia. Thus, it is probably best to make a preliminary diagnosis of leukoplakia and then treat any underlying candidal infection and have the patient discontinue use of any tobacco products to see if the white lesion resolves. If such a lesion then resolves, it is not true leukoplakia. The development of OL has been associated most strongly with the use of tobacco products, including smoked tobacco (cigarettes, cigars, pipe tobacco), smokeless tobacco (snuff, chewing tobacco), pan masala, and betel nut quid, as well as alternative tobacco products like bidis and kreteks. Also, combined tobacco use and alcohol consumption are thought to be synergistic in the development of OL and OSCC. Persons with a previous malignancy or premalignancy of the upper aerodigestive tract are at increased risk for further such lesions and malignancies, as previously mentioned. Preliminary studies suggest that HPV infection is two to three times more prevalent in oral precancerous mucosa and four to five times more prevalent in OSCC than in normal epithelium.204 In the same meta-analysis, hrHPV (16 and 18) were more frequently associated with OSCC than were low-risk HPV types.204 One study addressed the clinical risk factors for OL in a representative sample of the US population drawn from among the 15,811 participants in the US National Health and Nutrition Examination Survey III.205 In this study, females were less likely than males to have OL. The strongest independent risk factor was tobacco smoking. Three other independent predictors of OL were diabetes, increasing age, and lower socioeconomic status. Alcohol consumption, race and ethnicity, years of education, and body mass index all showed no independent association with OL.205 Investigators strongly urged further studies to confirm these findings (see Chapter 76).

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Chapter 113

Approximately 50% of OSCCs are associated with precancerous lesions.

ETIOLOGY AND PATHOGENESIS

CLINICAL FINDINGS OL is clinically divided into two subtypes: homogeneous OL and nonhomogeneous OL. Homogeneous OL has been defined as a mostly white, flat, uniform lesion

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that may have shallow cracks and a smooth, wrinkled, or corrugated surface that is consistent throughout.206 Nonhomogeneous OL has been defined as a mostly white or white and red lesion (erythroleukoplakia) that may be irregular and flat, nodular (speckled), ulcerative, or verrucous. Nonhomogeneous OL purportedly has a risk of malignant transformation that is four to five times higher than that of homogeneous OL. Another clinical subtype of OL is proliferative verrucous leukoplakia, which is most often found in patients who do not use tobacco products. This subtype has a high rate of transformation to malignancy.207

HISTOPATHOLOGY If the provisional diagnosis of OL is at all in doubt and/ or a waiting period to assess for possible regression or disappearance of a white lesion after eliminating possible causative factors has not resulted in resolution of the lesion, the next advisable step in evaluating the oral white lesion is to obtain a biopsy specimen for histopathologic diagnosis. This is where the concepts of epithelial dysplasia and carcinoma in situ enter the picture. In relation to the oral mucosa, epithelial dysplasia has been defined as a “precancerous lesion of stratified squamous epithelium characterized by cellular atypia and loss of normal maturation and stratification short of carcinoma in situ.”212 Carcinoma in situ of the oral cavity has been described as “a lesion in which the full thickness, or almost the full thickness, of squamous epithelium shows the cellular features of carcinoma without stromal invasion.”212 Criteria have been put forth for diagnosing these changes, and the more prominent and numerous the designated features are, the more severe the grade of dysplasia.195,206 On the basis of these subjective criteria, lesions are usually graded into mild-, moderate-, and severe epithelial dysplasia. A number of studies have shown significant intra- and interexaminer inconsistencies in assessing the presence or absence of oral epithelial dysplasia as well as its grade on histopathologic examination.195 Other studies have shown great variability in the number of lesions that go on to develop into malignancies based on their degrees of dysplasia. Some studies have shown a positive correlation between the degree of dysplasia and the development of malignancy, and others have demonstrated no correlation whatsoever.195 On the basis of these inconsistencies, three major problems have been identified in attaching significance to the degree of epithelial dysplasia in OL lesions as predictors of their malignant potential. First, the diagnosis of epithelial dysplasia is largely subjective. Second, although a definite correlation between degree of dysplasia and malignant potential has been shown, not all dysplastic lesions will progress to malignancy, and some may even regress. Third, OSCC has been shown to develop from nondysplastic oral epithelial lesions.195 As imperfect as this histopathologic grading system is, epithelial dysplasia in its varying degrees is still one

of the few indicators available of an increased risk for OSCC.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS A diagnosis of leukoplakia is made when a fixed white lesion of the oral mucosa is detected and cannot be identified as any other definable lesion or condition. Some suggest distinguishing between a provisional clinical diagnosis of OL and a definitive diagnosis of OL.194 A provisional diagnosis of OL is made at the time of the initial examination when no other diagnosis for the white lesion is obvious. At this point, other possibilities to consider in the differential diagnosis are tobacco-associated lesions, Candida-associated lesions, lichen planus, leukoedema, lupus erythematosus, Epstein–Barr virus-associated oral hairy leukoplakia, oral white sponge nevus, mechanical or frictional irritation, contact lesions, cheek/lip/tongue biting, linea alba, aspirin burn, OSCC, and verrucous carcinoma (Box 113-6). If causative factors for the white lesion

Box 113-6  Clinical Differential Diagnosis of Oral Leukoplakia and Oral Erythroplakia CLINICAL DIFFERENTIAL DIAGNOSIS OF ORAL LEUKOPLAKIA Tobacco-associated lesion Candida-associated lesion Leukoedema Lichen planus Lupus erythematosus Linea alba Habitual cheek biting Frictional lesion Aspirin burn Oral white sponge nevus Oral hairy leukoplakia Verrucous carcinoma Squamous cell carcinoma CLINICAL DIFFERENTIAL DIAGNOSIS OF ORAL ERYTHROPLAKIA Erythematous candidiasis Atrophic lichen planus Lupus erythematosus Pemphigus Cicatricial pemphigoid Kaposi sarcoma Chronic contact or allergic contact dermatitis Chronic mechanical trauma Thermal or mechanical injury Squamous cell carcinoma Amelanotic melanoma

are suspected, it is recommended that these factors be eliminated for a period of 2–6 weeks to observe for regression of the white lesion. If upon reevaluation the white lesion persists, biopsy should be performed. If the lesion is clinically at high-risk for OSCC, biopsy should be performed before such a waiting period.

PROGNOSIS AND CLINICAL COURSE

Box 113-7  Significant Risk Factors for the Conversion of Oral Leukoplakia (OL) into Oral Squamous Cell Carcinomaa Most Important Risk Factor Presence of epithelial dysplasia Other Risk Factors Female gender Long duration of oral leukoplakia (OL) OL in nonsmokers Location on the floor of the mouth or tongue Size >200 mm3 Nonhomogeneous type of OL a

Adapted from van der Waal I: Potentially malignant disorders of the oropharyngeal mucosa: Terminology, classification, and present concepts of management. Oral Oncol 45:317, 2009.

Epithelial Precancerous Lesions

The goal of treatment is to prevent the malignant transformation of OL to OSCC and to relieve patient symptoms, although there is no evidence that treat-

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TREATMENT AND PREVENTION

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Chapter 113

Once a definitive diagnosis of OL has been made, the risk of transformation to OSCC needs to be evaluated. The rate of malignant transformation of OL into OSCC has been found to vary from almost 0% to 20% in 1–30 years.213 A study based on European epidemiologic data investigated the natural limit of malignant transformation of OL to OSCC. This study concluded that the upper limit of the annual malignant transformation rate of OL is unlikely to exceed 1%.196 The commonly recognized variables that statistically carry an increased risk for malignant transformation into an SCC are listed in Box 113-7. Of these variables, the presence of dysplasia is the most important indicator. However, it should be recognized that not all dysplastic lesions progress to malignancy. Some remain clinically unchanged and others may spontaneously regress. Furthermore, malignant transformation may occur in nondysplastic leukoplakia. In spite of great progress in the field of molecular biology, there is not yet one single marker or set of markers that reliably enables prediction of malignant transformation of leukoplakia in an individual with OL.193

ment of OL can prevent the future development of OSCC. There is no consensus on the most appropriate treatment for OL. Some recommend the following approach: if no or mild epithelial dysplasia exists histopathologically, pursue treatment if the OL is in a high-risk location or is large; if moderate or severe dysplasia exists histopathologically, then active treatment to remove the entire lesion is recommended.206 A systematic review of all the randomized, controlled trials of all therapies for OL (n = 7) concluded that there is no known nonsurgical therapy to prevent OL from developing in the first place or to prevent OL from transforming into OSCC.213 The reviewers did find some evidence that treatment with vitamin A, retinoids, and β-carotene may completely resolve the oral lesions and that treatment with retinoic acid may prevent histopathologic worsening, but these findings were based on only a small number of patients.213 Postexcision recurrences are common and occur in 10%–20% of cases, and OSCC develops within excised areas in 3%–9% of instances.210 In addition, surgical excision with histopathologically clear margins did not prevent OSCC or improve survival outcomes in the group of patients with aneuploid dysplastic OL, the most likely form of OL to progress to OSCC, in one study.214 CO2 laser vaporization is another commonly employed treatment modality—again without substantial data to support its use. In one review of 200 patients with 282 OL lesions treated with CO2 laser vaporization between 1976 and 2001, 89% (n = 251) had no recurrence during a mean follow-up time of 52 months; 9.9% (n = 28) had local recurrence between 5 months and 168 months after treatment; and 1.1% (n = 3) developed OSCC within the treated area at 7, 17, and 19 months after the CO2 laser treatment.215 Because the recurrence of OL after treatment is common and the risk of OSCC is present with or without treatment, and because patients with OL are at increased risk for additional head and neck malignancies, these patients need to be followed at regular intervals with thorough examinations and potentially with additional biopsies. Follow-up intervals may vary from every 3 months in high-risk individuals to every 6 months in those at lower risk, for the rest of the patients’ lives. Despite all the controversies and inconsistencies surrounding OL, standard historical, clinical, and histopathologic findings are still the most important factors for predicting the possibility of malignant transformation of precancerous oral lesions. Treatment plans are guided mostly by findings from careful clinical and oral examinations, especially in individuals at high risk, and by histopathologic evaluation for the presence and degree of epithelial dysplasia (Fig. 113-9).

ERYTHROPLAKIA (ERYTHROPLASIA) Erythroplakia, or erythroplasia, is a clinical term used to describe a red macule or patch on a mucosal surface that cannot be categorized as any other known disease

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ERYTHROPLAKIA (ERYTHROPLASIA) AT A GLANCE Erythroplakia is a clinical diagnosis of exclusion for a persistent fixed red patch in the oral cavity.

Risk factors are use of tobacco products and alcohol use. Early and effective treatment is important.

It is the least common of all oral precancerous lesions but has the greatest potential to harbor or become oral squamous cell carcinoma (OSCC).

Treatment for severely dysplastic lesions or in situ carcinoma is complete excision or Mohs micrographic surgery.

Section 21

Approach to the management of leukoplakia

:: Epidermal and Appendageal Tumors

Provisional clinical diagnosis of oral leukoplakia (OL)

Non-homogeneous OL or Erythroleukoplakia

Homogeneous OL with no high-risk features

Homogeneous OL with high-risk features high-risk location large size rapidly growing prior history of oral squamous cell carcinoma (OSCC) significant tobacco and ETOH use

Biopsy of erythematous or most atypical portion of lesion

Elimination of any possible causative factors and then observe for 2–6 weeks

White lesion persists (definitive diagnosis of OL)

Biopsy White lesion resolved (not OL)

OSCC or OSCC in situ

Treatment based on diagnosis

Definitive treatment Complete removal of lesion

OSCC or OSCC in situ

Other histopathologically definable lesion

Life-long follow-up for recurrence or second primary

Definitive treatment Complete removal of lesion

No other histopathologically definable lesion Definitive clinical and histopathological diagnosis of OL

No dysplasia Mild dysplasia

Observation Life-long follow-up every 6 months for progression, growth, change

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Biopsy

Life-long follow-up for recurrence or second primary

Moderate dysplasia Severe dysplasia

Treatment -excision -CO2 laser Life-long follow-up for recurrence or second primary

Definitive treatment Life-long follow-up for recurrence or second primary

Figure 113-9  Approach to the management of oral leukoplakia. ETOH = ethanol.

entity caused by inflammatory, vascular, or traumatic factors. Histopathologically, it almost always displays either findings of SCC in situ or focal areas of invasive SCC, and thus is considered a precancerous lesion at best and always warrants treatment. Erythroplakia can involve any mucosal surface but most commonly occurs on the oral mucosa in more than half of all cases. Of all oral precancerous lesions, it is considered to be the most dangerous and carries the greatest risk of progressing to or harboring invasive carcinoma.

pebbled or stippled surface change and on palpation may have a soft and velvety feel. Induration indicates the presence of invasive carcinoma in many instances. Erythroplakia is commonly seen in association with leukoplakia, a condition termed erythroleukoplakia. It is the red patches of erythroleukoplakia that are most likely to contain or develop into a malignancy.

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KEY REFERENCES Full reference list available at www.DIGM8.com

EPIDEMIOLOGY

Squamous Cell Carcinoma

OE is usually found either intraorally or on the vermillion surface of the lower lip. The most common areas in the oral cavity are the soft palate, the floor of the mouth, and the buccal mucosa. OE usually presents as a solitary, subtle, asymptomatic, erythematous macule or patch. Most often it is less than 1.5 cm in its widest diameter, but lesions up to 4 cm in diameter have been described.217 Characteristically, it is sharply demarcated from the surrounding pink mucosa, and its surface is most often smooth and homogeneous in color. On occasion lesions of erythroplakia demonstrate a

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CLINICAL FINDINGS

14. Salasche SJ: Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 42:S4, 2000 20. Grossman D, Leffell DJ: The molecular basis of nonmelanoma skin cancer. Arch Dermatol 133:1263, 1997 29. Thompson SC et al: Reduction of solar keratoses by regular sunscreen use. N Engl J Med 329:1147, 1993 46. Drake LA et al: Guidelines for the care of actinic keratoses. J Am Acad Dermatol 32:95, 1995 58. Korman N et al: Dosing with 5% imiquimod cream three times per week for the treatment of actinic keratosis: Results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 141:467, 2005 69. Lawrence N et al: A comparison of the efficacy and safety of Jessner’s solution and 35% trichloroacetic acid vs 5% fluorouracil in the treatment of widespread facial actinic keratoses. Arch Dermatol 131:176, 1995 79. Piacquadio DJ et al: Photodynamic therapy with ALA topical solution and visible blue light in the treatment of multiple actinic keratoses of the face and scalp: Investigator-blinded, phase 3, multicenter trials. Arch Dermatol 140:41, 2004 110. Schwartz RA: Arsenic and the skin. Int J Dermatol 36:241, 1997 143. Novick M et al: Burn scar carcinoma: A review and analysis of 46 cases. J Trauma 17:809, 1977 164. Meyer T et al: Importance of human papillomaviruses for the development of skin cancer. Cancer Detect Prev 25:533, 2001 195. Reibel J: Prognosis of oral premalignant lesions: Significance of clinical, histopathological and molecular biological characteristics. Crit Rev Oral Biol Med 14:47, 2003

Chapter 114

Erythroplakia is an uncommon lesion in the oral cavity, and it is said to be one of the least commonly diagnosed lesions among the group of oral lesions that may or may not become malignant.216 The prevalence, based on a small number of worldwide studies, is between 0.02% and 0.83%.217 Both tobacco and alcohol are considered etiologic factors, and it mainly occurs in middle-aged individuals without a gender preference. It has been well described in the chutta smokers (reverse cigar smokers) of India.217

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Chapter 114 :: Squamous Cell Carcinoma :: Douglas Grossman & David J. Leffell SQUAMOUS CELL CARCINOMA AT A GLANCE W  ith basal cell carcinoma, most common human malignancy.

D  iagnosis is by biopsy. Caused by ultraviolet radiation in most cases. P  recursor lesion is actinic keratosis. T  reatment options are excision, Mohs micrographic surgery, and radiation.

Cutaneous squamous cell carcinomas (SCCs) are malignant neoplasms derived from suprabasal epidermal keratinocytes. These and basal cell cancers are the nonmelanoma skin cancers that represent the most common malignancies in humans. Whereas basal cell carcinoma (BCC) (see Chapter 115) is thought to arise de novo, SCC probably evolves in most cases from precursor lesions of actinic keratosis (AK) and Bowen disease (SCC in situ) (see Chapter 113). This chapter focuses on clinical aspects of invasive SCC. Cutaneous SCC represents a broad spectrum of disease ranging from easily managed, superficially invasive cancers to highly infiltrative, metastasizing tumors that can result in death. The clinical presentation can be variable despite the existence of easily identified typical

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lesions. The cellular and molecular aspects of SCC carcinogenesis are discussed elsewhere (see Chapter 113).

HISTORICAL ASPECTS EPIDEMIOLOGY

Section 21 :: Epidermal and Appendageal Tumors

INCIDENCE. The precise incidence of BCC and SCC is unknown, because these cutaneous malignancies are not generally documented by the National Cancer Institute or most state cancer registries. However, it is generally accepted that well over 1 million cases are diagnosed in the United States each year, with approximately 200,000 representing SCC.10 Although less common than BCC, SCC carries a risk of metastasis and thus accounts for the majority of the several thousand deaths attributable to nonmelanoma skin cancer each year. By comparison, cutaneous melanoma accounts for only 60,000 cases, but approximately 9,000 deaths, annually.11 Similar trends for SCC have been noted in Australia12 and the Caribbean.13 SCC is strongly associated with advanced age, and a sharp increase in incidence is seen after age 40 years.14 Today, the lifetime risk of SCC among whites is approximately 15%, almost double that of two decades ago. Increased exposures to ultraviolet (UV) radiation (through greater use of tanning salons, increased time spent outdoors, changes in clothing styles, and ozone depletion) and greater longevity have been suggested as possible causes for the increase in disease. It is likely that this trend will continue as a result of further depletion of the ozone layer and the aging of the US population. The rising incidence of SCC over the past several decades has been paralleled by a 20% decrease in mortality, attributed largely to increased public awareness and aggressive treatment of high-risk lesions.15 After a diagnosis of SCC, patients have a 44%–50% cumulative risk of developing another nonmelanoma skin cancer (18%–30% risk of SCC) in the subsequent 3–5 years.16 In addition, these patients are at increased risk for extracutaneous–cancers.17 DEMOGRAPHICS

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Squamous cell cancer is twice as common in men as in women, probably as a result of greater lifetime UV exposure in men. Similarly, longer hairstyles and use of lipstick may account for the lower frequency of SCC on the ears and lips of women. There is an inverse relationship between skin pigmentation and SCC incidence, largely because of the protective effect of eumelanin. Thus, persons with white skin, blue eyes, fair complexion, red hair, and Celtic ancestry who tan poorly are at greatest risk. Increased pigmentation is associated not only with a lower incidence of SCC, but also with an inversion in the BCC/SCC ratio. In comparison with whites, the incidence of SCC is decreased by 30-fold in American blacks and the BCC/SCC ratio falls to 0.8:1.14 Tanzanian albinos all develop SCC by young adulthood, and the ratio of BCC to SCC is only 0.2:1. Asians and Polynesians, with intermediate skin

pigmentation, have correspondingly intermediate levels of SCC. A gene (MC1R) involved in melanogenesis that encodes the melanocortin 1 receptor is a major determinant of skin pigmentation and hair color. The MC1R gene is highly polymorphic, with more than 20 variants described.18 Several variant MC1R alleles are associated with increased risk of SCC that is independent of skin type and hair color.

ETIOLOGY AND PATHOGENESIS PREDISPOSING FACTORS There are a number of factors, including both acquired and genetic skin conditions that may predispose to SCC (Table 114-1). Patients often demonstrate a multiplicity of factors that together are sufficient to induce SCC development. For example, a given skin site may be exposed to both UV radiation and another environmental carcinogen.

PRECURSOR LESIONS. Most SCCs develop from precursor lesions such as AKs or Bowen disease (see Chapter 113). ULTRAVIOLET RADIATION EXPOSURE. UV radiation is considered the predominant risk factor for SCC. Importantly, there is a linear correlation between the incidence of SCC and exposure to UV radiation. The incidence of SCC has been reported to double with each 8°–10° decline in geographic latitude and is highest at the equator.19 World War II veterans stationed in the Pacific developed much higher rates of SCC than did their colleagues who served in Europe.20 Similarly, SCC is more prevalent in Japanese people who emigrated to Hawaii than in those who remained in Japan.21 Excessive UV radiation appears to be related more to the development of SCC than to the development of BCC. Rates of SCC rise more rapidly than those of BCC with increasing UV exposure,22 and UV radiation-induced skin cancers in mice are almost exclusively SCCs rather than BCCs.23 Moreover, in patients receiving long-term therapy with psoralen plus ultraviolet A (UVA) radiation for treatment of TABLE 114-1

Predisposing Factors for Squamous Cell Carcinoma Precursor lesions (actinic keratosis, Bowen disease) Ultraviolet radiation exposure Ionizing radiation exposure Exposure to environmental carcinogens Immunosuppression Scars Burns or long-term heat exposure Chronic scarring or inflammatory dermatoses Human papillomavirus infection Genodermatoses (albinism, xeroderma pigmentosum, porokeratosis, epidermolysis bullosa)

psoriasis there is an associated 30-fold increase in nonmelanoma skin cancers, most of which are SCCs.24

IONIZING RADIATION. There is a strong association between SCC and exposure to ionizing radiation. In one survey of SCC patients, an association with radiation therapy was observed only in those whose skin was likely to sunburn (see Chapter 113).

THERMAL FACTORS. Long-term heat exposure can lead to SCCs. The role of thermal radiation in the development of skin cancer has long been recognized in many cultures, where common practices include placing hot ashes under the clothes to keep warm in

Squamous Cell Carcinoma

SCARS AND UNDERLYING DISEASES. Historically, SCC was associated with both burn scars and chronic ulcers as noted earlier, but such associations are seldom seen today. Also rare but reported is the development of SCCs in the context of chronic infections, particularly those associated with draining sinuses and scarring, such as perianal pyoderma, osteomyelitis, chromomycosis, hyalohyphomycosis, granuloma inguinale, lupus vulgaris, and leprosy. Chronic inflammatory processes, particularly those associated with scarring, such as venous ulcer, snakebite ulcer, discoid lupus erythematosus, oral lichen planus, morphea, lichen sclerosus, pilonidal cyst, acne conglobata, hidradenitis suppurativa, Hailey–Hailey disease, dissecting folliculitis of the scalp, and necrobiosis lipoidica, all can give rise to SCCs. An exception is vaccination scars, which are associated with BCCs rather than SCCs. SCCs have also been observed in transplanted skin, epidermal cyst, dental cyst, and dermoid cyst.

GENODERMATOSES. A variety of heritable diseases predispose to SCC development. Patients with oculocutaneous albinism develop predominantly SCCs (rather than BCCs) at an early age (see Chapter 73). Xeroderma pigmentosum (see Chapters 110 and 139), a disorder of DNA repair, is also characterized by early development of SCCs. SCCs have been reported to develop in the Mibelli, disseminated superficial actinic, and palmaris et plantaris disseminata forms of porokeratosis (see Chapter 52), and in oral lesions of dyskeratosis congenita. As noted in Section “Viral Infection,” lesions of epidermodysplasia verruciformis can degenerate into SCCs (see Chapter 196). Finally, patients with the dystrophic form of epidermolysis bullosa are at increased risk for SCC (see Chapter 62).

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IMMUNOSUPPRESSION. Chronic immunosuppression may lead to an increase in SCCs, primarily on sun-exposed sites.26 An 18-fold increase in SCC has been reported in renal transplant patients27; these tend to appear 3–7 years after the onset of long-term immunosuppressive therapy, with corticosteroids, azathioprine, and cyclosporine most frequently implicated. With the increase in the total number of organ transplant patients, management of SCCs in this population is becoming more important. In patients with leukemia and lymphoma, SCCs are both increased and more aggressive.28 Although multiple SCCs have been described in patients infected with human immunodeficiency virus, advanced human immunodeficiency virus infection has generally not been associated with an increased incidence of SCC, possibly because many patients do not live long enough to develop them.

VIRAL INFECTION. A role for human papillomavirus (HPV) infection has been well established in some types of SCCs. Verrucous carcinoma appears to be associated with several HPV types, as noted later. Head and neck and periungual SCCs are frequently associated with HPV-16. Patients with epidermodysplasia verruciformis are chronically infected with HPV, most commonly type 5, and one-third of these patients ultimately develop SCCs (see Chapters 113 and 196). Recently, the MCPyV polyoma virus, originally discovered in Merkel cell carcinoma, was identified in approximately 15% of cutaneous SCCs from immunocompetent patients.A An etiological role for MCPyV in SCC remains to be demonstrated.

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Chapter 114

ENVIRONMENTAL CARCINOGENS. Numerous occupational and environmental carcinogens, such as arsenic and aromatic hydrocarbons, predispose to the development of SCCs. With the exception of 3-methylcholanthrene and anthramine, chemical carcinogens generally produce SCCs rather than BCCs.25 Exposures to insecticides and herbicides have also been associated with SCCs. In addition, smoking and alcohol use are strongly associated with SCCs of the oral cavity.

winter or smoking opium while lying on heated beds. The incidence of SCCs is increased in persons who habitually sit in front of heating stoves and at sites of erythema ab igne (see Chapter 113).

MOLECULAR ASPECTS As in most cancers, the development of SCC from normal keratinocytes begins with mutations in the cellular DNA and genomic instability. Alterations in gene expression lead to loss of growth controls, penetration of the basement membrane, and ultimately invasion into surrounding tissue. Along the pathway to SCC, keratinocytes become resistant to apoptosis (programed cell death) and immune attack.

GENETIC ALTERATIONS. Most analyses of genetic alterations in SCCs have been performed in cases of oral or head and neck SCCs. Chromosomal deletions (loss of heterozygosity) commonly involve chromosomes 3, 9, 11, and 17; the regions most commonly identified include 9p21 and 17p13 where the INK4A (p16/Arf) and p53 tumor suppressors, respectively, are located.29 Similar genetic lesions were found in a study of young patients (younger than 40 years of age).30 It is unclear whether these genetic markers will serve as useful prognostic indicators. p53 IN THE DEFENSE AGAINST SKIN CANCER. A role for p53, cyclin D1, human telomerase

reverse transcriptase, p16, and thrombospondin 1 has

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been identified in the multistep process of human skin carcinogenesis.31 Apoptosis of keratinocytes that have sustained UV radiation-induced DNA damage, termed sunburn cells, requires the p53 tumor suppressor and represents a key protective mechanism against skin cancer by removing premalignant cells that have acquired mutations. In keratinocytes, UV radiation upregulates p53,32 which delays cell cycle progression until DNA damage can be repaired or facilitates cell elimination by apoptosis.33 Compromise of p53 function could undermine this apoptosis-based defense mechanism, giving UVdamaged cells a selective advantage to survive additional cycles of UV exposure.34 Further impairment of p53 and other genes through additional UV radiation-induced mutations may then lead to even greater resistance to apoptosis, increased proliferation, and ultimately development of SCC. The increased susceptibility of p53-deficient mice to UV radiation-induced SCC35 highlights this protective role of p53.

Epidermal and Appendageal Tumors

p53 MUTATIONS IN SQUAMOUS CELL CARCINOMA. Consistent with the scenario described

in Section “p53 in the Defense Against Skin Cancer,” mutations in the p53 gene are a common finding in SCC.36 In most cases, these are C→T single base and CC→TT tandem transition mutations at dipyrimidine sequences, i.e., “UVB-signature” mutations.37 Most SCCs exhibit loss of heterozygosity with respect to p53 and isolated mutations on the remaining allele. In one study, the p53-apoptosis pathway was disrupted in 50% of oral SCCs. With respect to SCC precursors, p53 mutations were found in up to 75% of AK and SCC in situ lesions.38 Interestingly, although different p53 mutations were found in separate AKs, all cells within a single precursor lesion had the same mutation.31 Mutations in p53 can also be detected in keratinocytes from clinically normal sun-exposed skin.39 Keratinocytes with p53 mutations occur in clonal patches that are larger and more frequently in sun-exposed skin.40 These findings substantiate a clonal basis for UV radiation-induced SCC and suggest that p53 mutation is an early event in the development of SCC. In addition to undergoing mutation, p53 can be compromised in keratinocytes infected with HPV. The E6 protein encoded by oncogenic HPV types binds p53 and targets it for rapid degradation, which disables the p53-apoptosis pathway. This is a primary mechanism by which HPV infection predisposes to SCC (see Chapter 196).

OTHER APOPTOTIC REGULATORS IN SQUAMOUS CELL CARCINOMA. In addition

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to dysregulation of p53, dysregulation of other apoptotic regulatory proteins has been described in SCC. In a study of vulvar SCC, expression of the apoptotic inhibitor Bcl-2 correlated with metastasis.41 Similarly, in esophageal SCC, expression of the apoptotic inhibitor Bcl-XL correlated with tumor invasion and metastasis.42 In SCC of the tongue, low apoptotic index and decreased expression of the proapoptotic Bcl-2-associated X protein (Bax) correlated significantly with poor prognosis, whereas low Bcl-2 expression was associ-

ated with a favorable clinical outcome.43 Expression of the antiapoptotic Bcl-2-associated athanogene 1 (BAG-1) was associated with nodal metastasis in oral SCC.44 Consistent with these observations, transgenic mice expressing Bcl-2 and Bcl-XL in the skin exhibit increased susceptibility to chemical-induced tumorigenesis. In addition to these Bcl-2 family members, the inhibitor of apoptosis protein survivin is expressed in both SCC and precursor lesions,45 and in one study its expression correlated with aggressive tumor phenotype.46 Interestingly, survivin may be negatively regulated by the binding of p53 to its promoter.47 More recent studies in transgenic mice have yielded paradoxical results, which suggests that apoptosis may be required in the initial phase of UV radiation-induced clonal expansion.48

IMMUNE EVASION. Working with UV radiationinduced SCCs in mice, Kripke and colleagues first demonstrated the importance of immunosuppression in UV radiation-induced SCC in the 1970s (see Chapter 90). They found that although UV radiation-induced SCC was promptly rejected when transplanted into genetically identical recipient mice, the transplanted tumors grew rapidly, and rejection did not occur if recipient mice were first treated with a subcarcinogenic dose of UV radiation. These experiments suggested that UV radiation not only induced SCC but also impaired the ability of host animals to mount protective immune responses against foreign tumor antigens. CLINICAL FINDINGS In white men and women, the majority of SCCs arise on sun-exposed areas such as the head, neck, and dorsal hands. SCC of the legs is more common in women.49 On the other hand, in blacks SCCs tend to be distributed equally on sun-protected and sun-exposed areas.50 SCC typically presents in solitary fashion, arising from precursor lesions as noted earlier. An exception is in immunosuppressed patients, who may manifest eruptive SCCs.

DEVELOPMENT FROM PRECURSOR LESIONS (See Chapter 113) AKs often occur as a multiplicity of lesions, ranging in size from pinpoint to over 2 cm, and the borders are usually ill defined. A dry adherent scale gives them a rough, gritty texture. By contrast, lesions of Bowen disease are usually solitary, sharply demarcated, scaling papules or plaques, often initially mistaken for eczema, psoriasis, or lichen simplex. The latter disorders are often pruritic, whereas Bowen disease is usually not. In sun-protected sites, Bowen disease may have a noneczematous appearance. For example, it may appear verrucous in the anogenital area, nail bed, and eyelid, and as a dark patch or oozing erythematous plaque in intertriginous areas. These precursor lesions

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Chapter 114 ::

are usually asymptomatic, and the development of tenderness, induration, erosion, increased scale, or enlarging diameter may herald evolution into SCC. Typically, a patient with multiple AKs may present with a single lesion that gradually becomes more prominent than the rest (Fig. 114-1), or with a solitary, persistent, nonpruritic, scaling patch that is unresponsive to treatment with topical steroids.

SQUAMOUS CELL CARCINOMA MORPHOLOGIES

There is a male predominance, and the palate and tongue are the most common sites. Oral SCC most commonly evolves from lesions of erythroplakia and is usually asymptomatic (see Chapter 113). Distinct patterns include a persistent rough red patch or granular velvety red plaque that ultimately becomes firm and nodular. Surprisingly, the risk of transformation to SCC does not appear to correlate with the degree of epithelial dysplasia.51 The floor of the mouth, ventrolateral tongue, and soft palate are considered high-risk sites. It may also present as a peritonsillar abscess.

Squamous Cell Carcinoma

Figure 114-1  Papular squamous cell carcinoma (SCC) of the ear. The differential diagnosis includes chondrodermatitis nodularis helicis, which, unlike SCC, is associated with pain.

Figure 114-2  Ulcerative squamous cell carcinoma of the jaw. In this region, extension of the cancer can invade the marginal mandibular nerve.

A firm, flesh-colored or erythematous, keratotic papule or plaque is most common (see Fig. 114-1), but SCCs may also be pigmented. Other presentations include as an ulcer (Fig. 114-2), a smooth nodule (Fig. 114-3), or a thick cutaneous horn. SCC may also be verrucous or present as an abscess, particularly if in a periungual location (see Fig. 113-9 in Chapter 113). The margins may be indistinct. With enlargement, there is usually increased firmness and elevation. Progressive tumor invasion ultimately results in fixation to underlying tissues. Especially in the head and neck region, an enlarged lymph node nearby that is firm and nontender may indicate tumor metastasis (Fig. 114-4).

ORAL SQUAMOUS CELL CARCINOMA SCC of the oral cavity usually occurs in patients with a long history of cigarette smoking, tobacco chewing, or alcohol use, but it has now been documented in younger adults without these traditional risk factors.

Figure 114-3  Nodular squamous cell carcinoma of the forehead. This lesion is recurrent and can be seen arising in the previous surgical scar. It should be considered high risk.

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or ulceration within an area of indurated actinic cheilitis. Symptoms of underlying pain or altered sensation should be investigated as a potential sign of perineural invasion.

GENITAL SQUAMOUS CELL CARCINOMA

Section 21 :: Epidermal and Appendageal Tumors

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Figure 114-4  Preauricular mass resulting from metastasis of cutaneous squamous cell carcinoma (SCC). Involvement of the parotid gland can result from metastasis of SCC in the temple and ear region.

LOWER LIP SQUAMOUS CELL CARCINOMA SCC of the lower lip begins as a roughened papule of actinic cheilitis or scaly leukoplakia, with slow progression to a tumor nodule (Fig. 114-5). Clinical clues associated with evolving SCC include persistent lip chapping with localized scale or crust, red and white blotchy atrophic vermilion zone of the lip, indistinct or “wandering” vermilion border, and small fissuring

Figure 114-5  Squamous cell carcinoma of the lower lip that developed in the setting of habitual sun exposure and actinic cheilitis. There is a large but subtle nodule, better felt than seen, on the lower lip. There are areas of hyperkeratosis and ulceration. Metastasis to draining lymph nodes can occur.

SCC of the vulva most commonly occurs on the anterior labia majora, beginning as a small warty nodule or an erosive erythematosus plaque. These lesions may be asymptomatic but more often are associated with pruritus or bleeding. Lesions of lichen sclerosus are another common precursor of SCC of the vulva. SCC of the cervix is associated with HPV infection, most commonly with type 16. SCC of the scrotum begins as a small pruritic verrucous lesion that becomes friable with increasing size. SCC of the penis usually occurs in uncircumcised males (see eFig. 114-5.1 in online edition) and, although very uncommon in Western countries, may account for 10% of cancers in places where genital hygiene is poor. A distinct precursor of penile SCC is erythroplasia of Queyrat (see Chapter 113), characterized by a velvety red plaque. In addition to lack of circumcision, penile SCC has been associated with a history of condyloma and phimosis and lichen sclerosus et atrophicus (see Chapters 65 and 78). The genitalia were once thought to be a common location for SCC after long-term therapy with psoralen and UVA radiation, but this complication can be avoided by shielding the genitalia during treatment, and such an association is rarely seen today. Perianal SCC may also occur (Fig. 114-6).

Figure 114-6  Perianal squamous cell carcinoma (SCC) in situ. Identification of these lesions requires thorough proctoscopic examination and monitoring for invasive SCC.

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SCAR SQUAMOUS CELL CARCINOMA SCCs arising in scars typically begin decades after injury, with skin breakdown and persistent erosion. Most commonly this occurs on the lower extremities at sites of chronic pyogenic or venous stasis ulcers. Gradually nodularity develops, although detection is often delayed because of concealment by surrounding indurated scar tissue. However, when SCC arises in chronic sinuses nodularity may not be present. The development of increased pain, drainage, or bleeding alone should raise concern and warrants further investigation.

Chapter 114

KERATOACANTHOMA

Verrucous carcinoma is a form of SCC that encompasses several clinical entities, all characterized by slow-growing exophytic tumors with a cauliflower-like appearance that develop at sites of chronic irritation.52 They may be clinically mistaken for giant warts. Four subtypes are recognized based on site of occurrence. Type I consists of oral tumors on the buccal mucosa of elderly male tobacco chewers and has been referred to as oral florid papillomatosis (Fig. 114-7). Representing 2%–12% of all oral cancers, these tumors are most commonly found on the buccal mucosa, tongue, gingiva, and floor of the mouth. Type II is the anogenital type, as described by Buschke and Loewenstein. It occurs on the glans penis of young uncircumcised males, on the scrotum, on the perianal region in both sexes, and, less commonly, on the female genitalia. Type III, also known as epithelioma cuniculatum, is a malodorous tumor often found on the plantar area in elderly men (Fig. 114-8) It usually involves the skin underlying the first metatarsal head and tends to form draining sinuses that are caniculated (like rabbit burrows) in appearance. Finally, type IV occurs at other sites, including the scalp, trunk, and extremities. Detection of sequences from HPV types 6, 11, 16, and 18 in epithelioma cuniculatum and type 11 sequences in oral verrucous carcinoma raises the possibility that these tumors evolve from verruca vulgaris.

Figure 114-7  Verrucous carcinoma presenting as a thick plaque arising on the buccal mucosa. This type of tumor was formerly called oral florid papillomatosis.

METASTATIC SQUAMOUS CELL CARCINOMA Metastatic SCC in the skin can have a variety of presentations. It may be signaled by a palpable lymph node near the site of treatment of a previous SCC. On the other hand, it may present as large keratotic papules or nodules resembling the primary lesion (Fig. 114-9). Metastatic SCC on the skin may be the first sign of internal malignancy, initially presenting in the skin as clusters of firm pink or red papules that may be keratotic centrally.

Figure 114-8  Epithelioma cuniculatum, verrucous carcinoma of the foot.

Squamous Cell Carcinoma

VERRUCOUS CARCINOMA

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(For Full Discussion, See Chapter 117) The hallmark of keratoacanthoma is rapid growth, up to several centimeters in weeks, and then gradual involution over a period of months in most cases (see Chapter 117). The typical presentation is in an elderly patient on a sun-exposed site, particularly an extremity. Morphologically, keratoacanthoma is usually a large, smooth, dome-shaped, verrucous nodule with a central keratotic crater. Although historically viewed as a benign neoplasm because of its tendency toward spontaneous resolution, keratoacanthoma can be locally destructive and aggressive and must be viewed as a clinical subtype of SCC. This tumor may occur in association with sebaceous neoplasms and gastrointestinal malignancies in Muir–Torre syndrome.

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BASIC FEATURES

Section 21

The tumor may appear as single cells, small groups or nests of cells, or a single mass. The inferior border may broadly impose on the dermis or be represented by individual foci of microinvasion. Invasive tumor is usually confined to the dermis and subcutaneous involvement is unusual. There are typically varying proportions of normal-appearing and atypical squamous cells, the latter characterized by increased mitoses, aberrant mitotic figures, nuclear hyperchromasia, and loss of intercellular bridges. Squamous differentiation is seen as foci of keratinization in concentric rings of squamous cells called horn pearls. Loss of differentiation is associated with decreased keratin production.

GRADING

:: Epidermal and Appendageal Tumors

Figure 114-9  Squamous cell carcinoma metastatic to skin.

HISTOPATHOLOGY GENERAL CONSIDERATIONS The hallmark of invasive SCC is the extension of atypical keratinocytes beyond the basement membrane and into the dermis (Fig. 114-10). The absence of a connection between tumor cells and the epidermis should raise concern for metastatic SCC, although this may simply reflect undermining from adjacent tumor. In every case, it is important to note clues that may indicate a precursor lesion or particular etiology. For example, the presence of solar elastosis and keratinocyte atypia at the margins would suggest that the SCC is actinically derived. On the other hand, the presence of scar tissue may indicate recurrent disease or a sinister scar-associated SCC. These considerations have important implications for treatment and prognosis, as discussed in Section “Treatment.”

Histologic grading of SCC is based on the degree of cellular differentiation. Low-grade tumors are comprised of uniform cells, resembling mature keratinocytes, with intracellular bridges and keratin production. By contrast, high-grade SCCs are characterized by atypical cells, loss of intracellular bridges, and minimal or absent keratin production. Another feature of higher grade tumors is a less distinct demarcation between malignant cells and adjacent normal stroma. In 1932, Broders53 introduced a formal grading system based on keratinocyte differentiation that is still used today. Tumors are graded on a scale of 1–4 based on increasing percentages of undifferentiated cells (Table 114-2). In addition to grade, the depth of penetration, tumor thickness, and hair follicle involvement should also be reported.

HISTOLOGIC SUBTYPES There are many histologic subtypes of SCC.54 In the adenoid (or pseudoglandular) SCC, there is a tubular microscopic pattern and keratinocyte acantholysis. In clear cell SCC, the keratinocytes appear clear as a result of hydropic cytoplasmic swelling and accumulation of lipid vacuoles. Spindle cell SCC reveals spindle-shaped atypical cells. Signet-ring cell SCC is

TABLE 114-2

Broders’ Grading System for Squamous Cell Carcinoma

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Figure 114-10  Squamous cell carcinoma demonstrating invasive cancer with atypical keratinocytes and foci of keratinization.

Grade

% Undifferentiated cells

Other features

1

4 mm and Clark level IV or V Tumor involvement of bone, muscle, nerve Location on ear, lip Tumor arising in scar Broders grade 3 or 4 Patient immunosuppression Absence of inflammatory infiltrate

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A

Epidermal and Appendageal Tumors

Figure 114-11  A. Infiltrative squamous cell carcinoma (SCC) demonstrating retraction of underlying tissue of the left cheek, where extension might involve infraorbital nerve. B. SCC of left side of forehead, where extension to bone with invasion or along the supraoptic nerves might lead to death.

whereas close to half of those deeper than 4 mm and at Clark levels IV or V were metastatic in some series. Tumor involvement of bone, nerve, or muscle tissue is strongly associated with metastasis. With respect to anatomic site, SCC of the ear has the highest rate of recurrence (18.7%), whereas lip SCC has the highest rate of metastasis (13.7%), with half of lip metastases present at the time of initial diagnosis. All SCCs arising in scars are high risk, with metastatic rates approaching 40% in some series.60 By contrast, SCCs arising in actinically damaged skin are of considerably lower risk, with an average metastatic rate of 5.2%. Poorly differentiated SCCs (Broders grade 3 or 4) demonstrate a recurrence rate of 28.6% and a metastatic rate of 32.8%, compared with 13.6% and 9.2%, respectively, for well-differentiated tumors. The prognosis is particularly poor for spindle cell SCCs.61 Immune status is another important consideration. One study62 found that 23% of patients with metastatic SCC were immunosuppressed. A heavy inflammatory response appears to be a favorable prognostic sign, because absence of infiltrate has been correlated with higher rates of recurrence and metastasis.

TREATMENT

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B

Box 114-1 summarizes the various modalities available for treatment of SCCs. Treatment selection is directed largely by assessment of tumor risk for recurrence and metastasis, as discussed in the previous section. Ablative techniques such as electrodesiccation and curettage, liquid nitrogen cryotherapy, carbon dioxide laser, intralesional chemotherapy, and photodynamic therapy are superficial, do not allow histologic margin control, and thus are generally inappropriate for

treatment of invasive SCCs. Topical chemo/immuno therapy may be appropriate for SCC in situ, and topical 5-fluorouracil has been used for treatment of conjunctival SCCs.63

SURGICAL EXCISION Conventional surgical excision is viewed by many as the treatment of choice for small primary SCCs. Recommended margins are 4 mm for low-risk lesions or SCCs with a depth of less than 2 mm; for lesions with a depth of more than 6 mm or a diameter larger than 1 cm, Mohs micrographic surgery is recommended.64 Mohs micrographic surgery is also recommended in specific circumstances when the highest cure rate and minimal tissue destruction are desired (Table 114-4). Specifically, tumors involving the periocular or periauricular areas; recurrent or large tumors; lesions with poorly defined clinical margins; tumors at sites where tissue preservation is important (nasal tip, lip, eyelid, ear, genitalia); deeply infiltrative tumors; lesions

Box 114-1  Treatment of Squamous Cell Carcinoma Nonexcisional ablative techniques (in situ disease only, or in special circumstances) Mohs micrographic surgery Conventional surgical excision Topical therapy (in situ disease only) Radiation therapy

TABLE 114-4

Indications for Mohs Micrographic Surgery Infiltrative squamous cell carcinoma (SCC) Poorly defined clinical margins Location on lip, ear, nail bed, nasal tip, eyelid, genitalia History of radiation at site Involvement of nerve, bone, muscle Immunosuppressed patient Recurrence of large SCC Verrucous carcinoma SCC arising from chronic scarring conditions

TOPICAL THERAPY Both topical 5-fluorouracil and imiquimod have been used in patients with SCC in situ Practice varies, but most regimens consist of application either once or twice daily for 2–4 weeks (5-fluorouracil) or three to five times per week for 2–4 months (imiquimod). Recent evidence suggests that efficacy of imiquimod may be due to enhanced interferon-γ production and effector function of T cells infiltrating the tumor.B Topical therapy is not appropriate for invasive disease since there will be minimal penetration of drug into the dermis.

RECURRENCE RATES Many risk factors for recurrence and metastasis have been identified.9 In their review noted in Section “HighRisk Lesions,” Rowe et al58 also assessed responses to treatment. They reported increasing combined rates of recurrence for each of the following treatment modalities (for primary cancers): Mohs micrographic surgery

TREATMENT OF HIGH-RISK LESIONS Management of high-risk lesions is reviewed elsewhere.70 Oral 5-fluorouracil has been used to treat aggressive lesions refractory to conventional therapies. Additional treatments, including β-carotene, interferon, and retinoids, have been employed with variable results. High-risk lesions may require formal staging. Computed tomography or magnetic resonance imaging may be useful in the detection of advanced perineural involvement of head and neck SCC.71 Sentinel lymphadenectomy has been combined with Mohs micrographic surgery.72 Involvement of lymph nodes may warrant radical lymph node dissection and radiation therapy. Elective cervical lymphadenectomy may be indicated for high-risk lesions of the lip.73 When a clinical lymph node examination yields negative results, further intervention may still be indicated if the tumor is considered sufficiently high risk.

Squamous Cell Carcinoma

Radiation can be used to treat superficially invasive to moderate-risk lesions and serves as an important adjuvant to excisional surgery in treating residual microscopic disease and providing prophylaxis against metastatic disease. It has been shown to be particularly useful for SCCs of the external auditory canal,66 although radiation therapy may lead to hearing loss.67 Radiation therapy is not advised for verrucous carcinoma, in which there is an associated low rate of anaplastic transformation. Radiation may also be used as adjuvant therapy in cases in which perineural SCC was identified in surgical pathologic specimens but treatment failures occurred.

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RADIATION

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Chapter 114

at sites that were previously irradiated; tumors with involvement of underlying structures (nerve, bone, muscle); tumors in immunosuppressed patients; and lesions at sites associated with high recurrence rates should strongly be considered for Mohs micrographic surgery.65 Additional indications include verrucous carcinomas and high-risk SCCs such as those arising from chronic scarring conditions.

(3.1%), electrodesiccation and curettage (3.7%), excisional surgery (8.1%), and radiation (10%). A review of the use of Mohs micrographic surgery to treat SCC with 4-year follow-up reported a cure rate of 92%.68 The surprisingly low rate of recurrence for electrodesiccation and curettage likely reflects its judicious use for treatment of low-risk lesions. Similarly, the recurrence rates for both Mohs micrographic surgery and excisional surgery may be somewhat skewed by their use in treating high-risk lesions. A systematic review of studies using topical therapy for SCC in situ (with at least 6 months histologic follow-up) revealed clearance rates of 27%–85% with 5-fluorouracil and 73%–88% with imiquimod.C For lip SCC, the overall recurrence rate was 2.3% with Mohs micrographic surgery compared with 10.5% with other treatment modalities; for ear SCC, the recurrence rates were 5.3% and 18.7%, respectively. For all recurrent tumors, cure rates were 76.7% with excision, compared with 90% with Mohs micrographic surgery. For low-risk SCCs, overall recurrence rates were 1.9% with Mohs micrographic surgery versus 16.5% with all other modalities. Overall 5-year survival rate for patients with metastatic SCCs was 26.8%, with poorer outcomes among patients with lip lesions69 and those treated with surgery alone (and no radiation).

PATIENT FOLLOW-UP After a diagnosis of SCC, all patients should be considered at high risk for developing additional lesions of SCC as well as BCC. They should be seen at regular intervals, ranging from 3 months to 12 months, depending on the degree of risk of prior lesions, status of precursor lesions, and individual patient compliance. A complete skin examination should be performed at each visit, including examination of the oral mucosa. In addition, sites of previous lesions and treatments should be assessed for signs of recurrence. Finally, a lymph node examination is indicated to monitor for metastatic disease.

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PREVENTION Those at risk for SCC—namely, persons with a prior history of nonmelanoma skin cancer or any of the predisposing conditions discussed earlier—should be monitored closely. They should receive complete skin examinations on a regular (annual or semiannual) basis.

SUN PROTECTION

Section 21 :: Epidermal and Appendageal Tumors

The most effective preventive measure is protection from sun exposure. It is likely that adequate sun protection beginning in early childhood could prevent most SCCs.74 This requires establishing patterns of behavior at an early age, such as applying sunscreen repeatedly, wearing hats and protective clothing, and avoiding the sun during the hours of peak intensity. However, the importance of sun exposure prevention in childhood should not be construed to mean that sun protection later in life will be of no benefit. There is evidence that aggressive sun protection throughout life can prevent the development of SCC precursor lesions and cancers themselves.

TREATMENT OF PRECURSOR LESIONS Treatment of precursor lesions is expected to reduce the incidence of SCC. Several options are available for treatment of AK (see Chapter 113). Isolated lesions can often be effectively removed by liquid nitrogen cryotherapy. For patients with many AKs or areas of skin with a multitude or confluence of lesions, topical chemotherapy using 5-fluorouracil or imiquimod is a better option. Topical diclofenac has also been introduced as therapy for widespread AK. Photodynamic therapy using aminolevulinic acid is also an option for areas involving multiple lesions.

OTHER PREVENTIVE MEASURES A number of additional preventive measures can be taken that may reduce the incidence of SCC in indi-

vidual patients. For example, the use of condoms can prevent transmission of HPV and may thereby reduce the risk of genital SCC. Decreased alcohol consumption and smoking cessation is likely to reduce the risk of oral SCC. Several years ago there was great interest in the use of both retinoids and interferons as systemic chemopreventive agents. Low-dose etretinate (10 mg/ day) has been used successfully in renal transplant patients.75 A more recent recommendation is isotretinoin (Accutane; 10 mg every day or every other day) in addition to topically applied tretinoin.76 The introduction of a vaccine for the prevention of infection with HPVs and of precancerous lesions of the cervix may one day translate into the prevention of all HPVinduced precancerous lesions of the skin.78

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 9. Alam M, Ratner D: Cutaneous squamous-cell carcinoma. N Engl J Med 344:975, 2001 14. Miller DL, Weinstock MA: Nonmelanoma skin cancer in the United States: Incidence. J Am Acad Dermatol 30:774, 1994 15. Weinstock MA: Nonmelanoma skin cancer mortality in the United States, 1969 through 1988. Arch Dermatol 129:1286, 1993 19. Johnson TM et al: Squamous cell carcinoma of the skin (excluding lip and oral mucosa). J Am Acad Dermatol 26:467, 1992 31. Burnworth B et al: The multi-step process of human skin carcinogenesis: A role for p53, cyclin D1, hTERT, p16, and TSP-1. Eur J Cell Biol Jan 86(11-12):763-780, 2007 34. Leffell DJ, Brash DE: Sunlight and skin cancer. Sci Am 275:52, 1996 36. Brash DE: Roles of the transcription factor p53 in keratinocyte carcinomas. Br J Dermatol 154(Suppl 1):8, 2006 58. Rowe DE et al: Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 26:976, 1992 64. Brodland DG, Zitelli JA: Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 27:241, 1992 78. Griffiths P: Anticipating full benefits from the new papillomavirus vaccines. Rev Med Virol 17:1, 2007

Chapter 115 :: Basal Cell Carcinoma :: John A. Carucci, David J. Leffell & Julia S. Pettersen BASAL CELL CARCINOMA AT A GLANCE M  ost common cancer in humans.

L  ocally destructive.

Caused by exposure to ultraviolet light; associated

T  reated by surgical excision, electrodesiccation

with PTCH gene mutation in many cases.

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I ncidence increasing in younger populations.

and curettage, Mohs micrographic surgery, and occasionally irradiation.

BCC EPIDEMIOLOGY

Basal Cell Carcinoma

The pathogenesis of BCC involves exposure to UVL, particularly the ultraviolet B spectrum (290–320 nm) that induces mutations in tumor suppressor genes.12,13 UVB radiation damages DNA and affects the immune system resulting in a progressive genetic alterations

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BCC ETIOLOGY AND PATHOGENESIS

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Chapter 115

BCC is the most common cancer in humans. It is estimated that over 1 million new cases occur each year in the United States. The malignancy accounts for approximately 75% of all nonmelanoma skin cancers (NMSC) and almost 25% of all cancers diagnosed in the United States.1 Epidemiological data indicate that the overall incidence is increasing worldwide significantly by 3%–10% per year.2 BCC is more common in elderly individuals but is becoming increasingly frequent in people younger than 50 years of age. Christenson et al noted a disproportionate increase in BCC in women under age 40.3 Men are affected slightly more often than are women. Levi et al reported that the incidence of BCC rose steadily in the Swiss Canton of Vaud between 1976 and 1998 to levels of 75.1 in 100,000 in males and 66.1 in 100,000 in females.4,5 Stang et al in Westphalia, Germany found that the incidence rate of BCC during a 5-year period (1998–2003) was 63.6 in men and 54.0 in women.6 A study of NMSC in Aruba supported these findings.7 In that study, BCC was the most common type of skin cancer diagnosed between 1980 and 1995. Tumors were more frequent in patients older than 60 years of age, and 57% were in men. The highest percentage of lesions occurred on the nose (20.9%), followed by other sites on the face (17.7%).7 Incidence in Europe was examined by the recent study in Croatia. From 2003 to 2005, the crude incidence rate for the Croatian population of 100,000 was 54.9 for men and 53.9 for women. The vast majority of BCCs were located on the head and neck.8 BCC character develops on sun-exposed skin of lighter skinned individuals. Incidence rates of BCC in Asians living in Singapore increased from 1968 to 2006, especially among the older, more fairly complected Chinese patents. Skin cancer trends in Asians from 1968–2006 showed BCC rates increased the most among persons older than 60 years.9 BCC is rare in dark skin because of the inherent photoprotection of melanin and melanosomal dispersion. An estimated 1.8% of BCCs occur in blacks, and BCC is approximately 19 times more common in whites than blacks.10 Risk factors for BCC have been well characterized and include ultraviolet light (UVL) exposure, light hair and eye color, northern European ancestry, and inability to tan.1 An Italian study indicated the important role of sunburns, and therefore intense sun exposure, rather than that of prolonged sun exposure to increase the risk of BCC.11

and neoplasms. UV-induced mutations in the p53 tumor suppressor gene have been found in about 50% of BCC cases.14 Currently, it is thought that the upregulation of the mammalian development signaling pathway, Hedgehog (HH), is the pivotal abnormality in all BCCs, and there is evidence that little more than this upregulation is required for BCC carcinogenesis.15,16 The mutations that activate the aberrant HH signaling pathway are found in PTCH1 and Smoothened (SMO). Approximately 90% of sporadic BCCs have identifiable mutations in at least one allele of PTCH1, and an additional 10% have activating mutations in the downstream SMO protein.17 The most frequently identified mutations in PTCH1 and SMO are of a type consistent with UV-induced damage.18–20 The contribution of high-intensity sunlight exposure to BCC development in the general population is well established.11 A latency period of 20–50 years is typical between the time of UV damage and the clinical onset of BCC. Therefore, in most cases, BCC develops on sun-exposed skin in elderly people, most commonly in the area of head and neck.21 Some studies indicate that intermittent brief holiday exposures may place patients at higher risk than occupational exposure.9,22 An Italian study confirmed the role of intermittent sun exposure as a strong risk factor for BCC.11 Ramani and Bennett reported a significantly higher incidence of BCCs in World War II servicemen stationed in the Pacific theater than in those stationed in Europe. This suggests that several months or years of intense exposure to UVL may have deleterious long-term effects.23 Truncal BCCs can result from acute intense exposures sufficient to cause sunburn on the skin of the trunk among people whose ability to tan makes the skin of their face generally less susceptible to the carcinogenic effects of UV radiation.24 Other factors that appear to be involved in the pathogenesis include mutations in regulatory genes,17,25 exposure to ionizing radiation,26,27 and alterations in immunosurveillance.28–30 The propensity to develop multiple BCCs may be inherited. Included among heritable conditions predisposing to the development of this epithelial cancer are nevoid basal call carcinoma syndrome or basal cell nevus syndrome (BCNS),31 Bazex syndrome,32 and Rombo syndrome.33 Patients with BCNS may develop hundreds of BCCs and may exhibit a broad nasal root, borderline intelligence, jaw cysts, palmar pits, and multiple skeletal abnormalities. BCNS occurs due to mutations in the tumor suppressor PTCH gene.34,35 Bazex syndrome is transmitted in an X-linked dominant fashion.32 Patients have multiple BCCs, follicular atrophoderma, dilated follicular ostia with ice pick scars, hypotrichosis, and hypohidrosis. In contrast, Rombo syndrome is transmitted in an autosomal dominant fashion.33 Patients have vermiculate atrophoderma, milia, hypertrichosis, trichoepitheliomas, BCCs, and peripheral vasodilation. Hypohidrosis is not a feature of Rombo syndrome. The role of the immune system in the pathogenesis of skin cancer is not completely understood. Immunosuppressed patients with lymphoma or leukemia36,37 and

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Section 21 :: Epidermal and Appendageal Tumors

patients who have received an organ transplant have a marked increase in the incidence of squamous cell carcinoma but only a slight increase in the incidence of BCC.28–30,38 Bastiaens et al found that transplant recipients developed more BCCs on the trunk and arms than did nonimmunosuppressed patients.39 Harwood et al found that fewer BCCs occurred on the head and neck of renal transplant recipients, while more BCCs were found on the trunk and arms compared to the immune competent patients.38 Patients with human immunodeficiency virus infection develop BCCs at the same rate as immunocompetent individuals, based on similar risk factors.19,40,41 Immunosuppressed long-term alcoholics tend to develop infiltrative BCCs with increased frequency.20,42 A potential link between UVL and decreased immunity has been suggested by GutierrezSteil et al, who demonstrated that UVL-induced BCCs express Fas ligand (CD95L).43 They further showed that these cells were associated with CD95-bearing T cells undergoing apoptosis.43,44 This represents a potential mechanism by which UVL might help tumor cells avoid being killed by cytotoxic T lymphocytes. Kaporis et al showed that immune suppressive regulatory T cells are surround BCC tumor nests thus providing another potential mechanism for BCC to evade host antitumor immunity.45

CLINICAL MANIFESTATIONS PRESENTATION The presence of any friable, nonhealing lesion should raise the suspicion of skin cancer. Frequently, BCC is diagnosed in patients who state that the lesion bled briefly then healed completely, only to recur. BCC usually develops on sun-exposed areas of the head and neck but can occur anywhere on the body. Features include translucency, ulceration, telangiectasias, and the presence of a rolled border. Characteristics may vary for different clinical subtypes, which include nodular, superficial, morphea-form, and pigmented BCCs and fibroepithelioma of Pinkus (FEP). The anatomic location of BCC may favor the development of a particular subtype.46

Figure 115-1  Basal cell carcinoma (BCC), nodular type. hyperpigmented, translucent papule, which may also be eroded (eFig. 115-2.1 in online edition). The differential diagnosis includes nodular melanoma.

SUPERFICIAL BASAL CELL CARCINOMA.

Superficial BCC occurs most commonly on the trunk and appears as an erythematous patch (often well demarcated) that resembles eczema (Fig. 115-3).47 An isolated patch of “eczema” that does not respond to treatment should raise suspicion for superficial BCC.

MORPHEAFORM (SCLEROSING) BASAL CELL CARCINOMA. Morpheaform BCC is an

aggressive growth variant of BCC with a distinct clinical and histologic appearance. Lesions of morpheaform BCC may have an ivory-white appearance and may resemble a scar or a small lesion of morphea (eFig. 1153.1 in online edition). Thus, the appearance of scar tissue in the absence of trauma or previous surgical procedure

BASAL CELL CARCINOMA SUBTYPES NODULAR BASAL CELL CARCINOMA. Nodular BCC is the most common clinical subtype of BCC (Fig. 115-1).47,48 It occurs most commonly on the sunexposed areas of the head and neck and appears as a translucent papule or nodule depending on duration. There are usually telangiectasias and often a rolled border. Larger lesions with central necrosis are referred to by the historical term rodent ulcer (Fig. 115-2). The differential diagnosis of nodular BCC includes traumatized dermal nevus and amelanotic melanoma.

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PIGMENTED BASAL CELL CARCINOMA. Pigmented BCC is a subtype of nodular BCC that exhibits increased melanization. Pigmented BCC appears as a

Figure 115-2  Basal cell carcinoma, rodent ulcer type.

BIOLOGIC BEHAVIOR LOCAL INVASION The greatest danger of BCC results from local invasion (Fig. 115-4). In general, BCC is a slow-growing tumor that invades locally rather than metastasizes.26,27,53,54

Basal Cell Carcinoma

FIBROEPITHELIOMA OF PINKUS. FEP classically presents as a pink papule, usually on the lower back.25,50 It may be difficult to distinguish from an acrochordon or skin tag. Similar to basal cell carcinomas, fibroepitheliomas of Pinkus express androgen receptors, supporting its classification as a basal cell carcinoma.51 The differential diagnoses of FEP includes acrochordon.52

::

or the appearance of atypical-appearing scar tissue at the site of a previously treated skin lesion should alert the clinician to the possibility of morpheaform BCC and the need for biopsy.

21

Chapter 115

Figure 115-3  Superficial basal cell carcinoma. The welldemarcated plaque with a rolled edge characteristically occurs on the trunk.

The doubling time is estimated to be between 6 months and 1 year. If left untreated, the tumor will progress to invade subcutaneous tissue, muscle, and even bone. Anatomic fusion planes appear to provide a lowresistance path for tumor progression. Tumors along the nasofacial or retroauricular sulcus may be extensive. Metastases are rare and most are said to more closely correlate to the size and depth of tumor invasion and less so to the histologic subtype of the original tumor.1 Although metastases are rare, significant patient morbidity, such as local tissue destruction and disfigurement can occur. In one informative case, a patient documented the progression of his own tumor with photographs over a 27-year period.28,55 The lesion, which encompassed an entire side of the face, including the maxillary sinus, apparently doubled over a 10-year period and grew rapidly in the 2 years before hospital admission. This scenario occurs in the context of physical or psychiatric disability that interferes with judgment or access to health care. In one of the first reports of giant BCC in India, a patient presented with a nonhealing ulcer of the face, which had been present and increasing in size for over 20 years. On examination, the ulcer covered the entire left side of the face involving the preauricular, infraorbital, and bucco mandibular units of the cheek and the orbit and resulted in loss of vision.56 In another case, a 35-cm BCC on the back of a 65-year-old man recurred after wide local excision and X-ray therapy (XRT), resulting in spinal cord compression.57 Lethal extension to the central nervous system from aggressive scalp BCC has been reported.58,59

PERINEURAL INVASION Perineural invasion (PNI) is uncommon in BCC and occurs most often in histologically aggressive or recurrent lesions.54 The presence of PNI has been correlated with recurrent lesions, increased duration and size of lesions, and orbital invasion.60 In one series, Niazi and Lamberty identified PNI in less than 0.2% of cases. In that series, perineural BCC was seen most often with recurrent tumors located in the preauricular and malar areas.61 Brown and Perry found the incidence of PNI to be 3% in aggressive BCC cases. This incidence approaches that reported for cutaneous squamous cell carcinomas.62 Leibovitch et al found an incidence rate of 2.74%.63 Ratner et al found a higher incidence in their study (3.8%); however, this was a smaller study.64 Leibovitch et al reported perineural spread in more than 50% of periocular BCCs eventuating in orbital invasion. These tumors required extensive surgery and in some cases exenteration (Fig. 115-5).65 Perineural spread may manifest as pain, paresthesias, weakness, or paralysis. The presence of focal neurologic symptoms at the site of a previously treated skin cancer should raise concern about nerve involvement.

METASTASIS Figure 115-4  BCC, if untreated, can result in extensive local tissue damage.

Metastasis of BCC occurs only rarely, with rates varying from 0.0028% to 0.55%.34–36,66–68 Involvement of regional lymph nodes and lungs is most

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retraction of stroma from tumor islands is present, creating peritumoral lacunae that are helpful in histopathologic diagnosis.73 The most common form of BCC is nodular, followed by superficial, then morpheaform. Also, nodular and morpheaform are most commonly found on the head and neck, while superficial is most often found on the trunk region.74

NODULAR BASAL CELL CARCINOMA

Section 21

Figure 115-5  BCCs involving the canthus can invade the orbit.

:: Epidermal and Appendageal Tumors

common. Cases of pulmonary metastasis continue to be reported.69 Metastasis to the bone and bone marrow has been reported.70 Aggressive histologic characteristics, including morpheaform features, squamous metaplasia, and PNI, have been identified as risk factors for metastasis.68 Von Domarus et al reported five cases of metastatic BCC in which perineural or intravascular invasion had been noted in three.71 Squamous differentiation was not observed in the primary tumors in the cases they presented but was noted in two of five cases of metastatic cancer. Overall, squamous differentiation was present in 15% of the primary or metastatic tumors from the 170 cases reviewed in that series.

DIAGNOSIS Diagnosis of BCC is accomplished by accurate interpretation of the skin biopsy results. The preferred biopsy methods are shave biopsy, which is often sufficient, and punch biopsy. A sterilized razor blade, which can be precisely manipulated by the operator to adjust the depth of the biopsy specimen, is often superior to a No. 15 scalpel for shave biopsies. A punch biopsy may be useful for flat lesions of morpheaform BCC or for recurrent BCC occurring in a scar. When biopsying a lesion, adequate tissue should be taken. Small, fragmented tissue samples may make diagnosis difficult; potentially compromising the ability to accurately assess BCC subtype and thickness, which can affect treatment choice.72

HISTOPATHOLOGY

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Histopathologic features vary somewhat with subtype, but most BCCs share some common histologic characteristics. The malignant basal cells have large nuclei and relatively little cytoplasm. Although the nuclei are large, they may not appear atypical. Usually, mitotic figures are absent. Frequently, slit-like

Nodular BCCs account for half of all BCCs and are characterized by nodules of large basophilic cells and stromal retraction (Fig. 115-6A). The term micronodular BCC is used to describe tumors with multiple microscopic nodules smaller than 15 μm (see Fig. 115-6B).73 Clinically, this is the type of BCC that most commonly shows a translucent pearly papule or nodule with a rolled border and telangiectasia. The nodular form of BCC is characterized by discrete nests of basaloid cells in either the papillary or reticular dermis accompanied.1

PIGMENTED BASAL CELL CARCINOMA Pigmented BCC shows histologic features similar to those of nodular BCC but with the addition of melanin.38 Approximately 75% of BCCs contain melanocytes, but only 25% contain large amounts of melanin. The melanocytes are interspersed between tumor cells and contain numerous melanin granules in their cytoplasm and dendrites. Although the tumor cells contain little melanin, numerous melanophages populate the stroma surrounding the tumor.73

SUPERFICIAL BASAL CELL CARCINOMA Superficial BCC is characterized microscopically by buds of malignant cells extending into the dermis from the basal layer of the epidermis. 38 The peripheral layer shows palisading cells. There may be epidermal atrophy, and dermal invasion is usually minimal. There may be a chronic inflammatory infiltrate in the upper dermis. This histologic subtype is encountered most often on the trunk and extremities, but may also appear on the head and neck. 73

MORPHEAFORM BASAL CELL CARCINOMA Morpheaform BCC, also called infiltrative or sclerosing BCC, consists of strands of tumor cells embedded within a dense fibrous stroma (see Fig. 115-6C).73 Tumor cells are closely packed columns and, in some cases, only one to two cells thick enmeshed in a densely collagenized fibrous stroma. Strands of

21

B

Chapter 115

A

::

tumor extend deeply into the dermis. The cancer is often larger than the clinical appearance indicates. Recurrent BCC may also demonstrate infiltrating bands and nests of cancer cells embedded within the dense fibrous stroma of scar.

FIBROEPITHELIOMA OF PINKUS In FEP, long strands of interwoven basiloma cells are embedded in fibrous stroma with abundant collagen.38 Histologically, FEP shows features of reticulated seborrheic keratoses and superficial BCC.73

BASOSQUAMOUS CARCINOMA Basosquamous carcinoma is a form of aggressive growth BCC. It can be confused with squamous cell carcinoma and promotes controversy considering its precise histomorphologic classification as it shows both basal cell and squamous cell carcinoma differentiation in a continuous fashion.1 Histologically, basosquamous carcinoma shows infiltrating jagged tongues of tumor cells admixed with other areas that show squamous intercellular bridge formation and cytoplasmic keratinization.

Basal Cell Carcinoma

C

Figure 115-6  A. Nodular BCCs are characterized by nodules of large basophilic cells and stromal retraction. B. Micronodular BCC is characterized by multiple microscopic nodules smaller than 15 μm. C. Morpheaform BCC consists of strands of tumor cells embedded within a dense fibrous stroma.

DIFFERENTIAL DIAGNOSIS The differential diagnosis for BCC is summarized in Box 115-1.

BCC TREATMENT Management of BCC is guided by anatomic location and histological features. Approaches include standard surgical excision, destruction by various modalities, Mohs micrographic surgery (MMS), and topical chemotherapy.73 The best chance to achieve cure is through adequate treatment of primary BCC, because recurrent tumors are more likely to recur and cause further local destruction. An algorithmic approach to management is summarized in Fig. 115-7. While most trials have only evaluated BCCs in low-risk locations, surgery and radiotherapy appear to be the most effective treatments with surgery showing the lowest failure rates. Although cosmetic outcomes appear good with PDT, long-term follow-up data are needed. Other treatments might have some use but few have been compared to surgery. An ongoing study comparing imiquimod to surgery should clarify whether imiquimod is a useful option.75 Overall, removal of the tumor with clear margins remains the gold standard for treating basal cell carcinoma.

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Box 115-1  Differential Diagnosis NODULAR BCC Dermal nevus Squamous cell carcinoma Appendageal tumor Dermatofibroma

Section 21

PIGMENTED BCC Nodular melanoma Superficial spreading melanoma Lentigo maligna melanoma Appendageal tumor Compound nevus Blue nevus

:: Epidermal and Appendageal Tumors

SUPERFICIAL BCC Bowen’s disease Mammary or extramammary Paget’s disease Superficial spreading melanoma Single plaque of psoriasis Single plaque of eczema MORPHEAFORM BCC Scar Morphea Trichoepithelioma FIBROEPITHELIOMA OF PINKUS Skin tag Fibroma Papillomatous dermal nevus

MOHS MICROGRAPHIC SURGERY MMS offers superior histologic analysis of tumor margins while permitting maximal conservation of tissue compared with standard excisional surgery.76,77 Rowe, Carroll, and Day report a recurrence rate of 1% for primary BCCs treated by MMS. This was superior to the rate for other modalities, including standard excision (10%), curettage and desiccation (C&D) (7.7%), XRT (8.7%), and cryotherapy (7.5%).78 Recurrent BCCs treated by MMS reappeared at a rate of 5.6%, which was again superior to the rate for other modalities, including excision (17.6%), XRT (9.8%), and C&D (40%).79 Leibovitch et al found that after 5 years BCC recurrence was diagnosed in 1.4% of primary and in 4% of recurrent tumors. This low 5-year recurrence rate of BCC with MMS emphasizes the importance of margin-controlled excision over other modalities.80 MMS is the treatment of choice for morpheaform, poorly delineated, incompletely removed, and otherwise high-risk primary BCCs. It is the preferred treatment for recurrent BCC and for any BCC that occurs at a site where tissue conservation is desired. MMS is particularly useful in treating BCCs at high-risk anatomic sites, including the embryonic fusion planes represented by the nasofacial junction and retroauricular sulcus. Based on the fact that MMS provides the lowest recurrence rates, it is the treatment of first choice for primary facial BCCs with an aggressive histopathological subtype and for recurrent facial BCCs.81 MMS has shown greater efficacy than surgical excision for the treatment of recurrent facial BCCs.80 Mosterd et al also found that treatment with MMS leads to a significantly lower number of recurrences than treatment with surgical excision in recurrent facial BCCs.77 From a patient perspective, one large prospective cohort study found that MMS was an independent factor for higher longterm patient satisfaction, when compared to standard excision or C&D.82

Management algorithm of basal cell carcinoma

Primary

Non-aggressive growth tumor on trunk or extremities

Excision or ED&C

Aggressive growth tumor on trunk or extremities

Recurrent

Tumor located in canthus, nasolabial fold, periorbital, or postauricular area

Excision or Mohs micrographic surgery

Figure 115-7  Algorithm for the management of basal cell cancer.

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Any size or location

Mohs micrographic surgery

STANDARD EXCISION

Cryosurgery is another destructive modality that has been used in the treatment of BCC. Two freeze-thaw cycles with a tissue temperature of −50°C (−58°F) are required to destroy BCC. In addition, a margin of clinically normal tissue must be destroyed to eradicate subclinical extension.83 A systematic review of recurrence rates published between 1970 and 1997 indicated that cryotherapy in the treatment of primary BCC resulted in a 5-year recurrence rate from 4% to 17%. 98 Cryosurgery lacks the benefit of histologic confirmation of tumor removal. Kuflik and Gage reported 99% cure rates in 628 patients followed for 5 years. Possible complications of cryosurgery include hypertrophic scarring and postinflammatory pigmentary changes. 99 In regards to cosmesis, patient satisfaction was found to be higher with surgical excision than with cryosurgery and should be taken into consideration when choosing a treatment option.100 Another potential serious adverse outcome is the obscuring of tumor recurrence by fibrous scar tissue. Any recent change in a cryosurgery scar after normal healing is completed should raise the suspicion of recurrent BCC.

Basal Cell Carcinoma

C&D is one of the most frequently used treatment modalities for BCC.94 That C&D is operator-dependent was shown by Kopf et al, who identified a significant difference in cure rate between patients treated by private practitioners (94.3%) and those treated by residents (81.2%).95 High 5-year cure rates of up to 98.8% have been obtained after C&D of primary, nonfibrosing BCCs of medium- and high-risk areas of the face when performed by a skilled operator. 96 Spiller and Spiller reported a cure rate of 97% in 233 patients. Cure rate decreased as a function of primary lesion size: for lesions smaller than 1.0 cm, the cure

CRYOSURGERY

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CURETTAGE AND DESICCATION

21

Chapter 115

Compared with nonexcisional techniques, standard surgical excision offers the advantage of histologic evaluation of the removed specimen; however, depending on the sectioning method used (e.g., breadloafing), areas of margin involvement can be missed during routine histologic evaluation.83 The authors of a recent Cochrane review concluded that, based on the available published work, surgery is the standard treatment of choice for BCC.75 Although standard excision is appropriate for many BCCs, cure rates for standard excisional surgery are inferior to those for MMS in cases of primary morpheaform BCCs, recurrent BCCs, and tumors located in high-risk anatomic sites.78,79 One disadvantage of standard surgical excision is the potential for incomplete margin control. The incidence of incomplete excision has varied, with reports ranging from 4.7% to 13.2% of treated patients.84–88 Farhi et al found the pathologically reported incomplete excision rate was over 10% and was significantly associated with the location on the face, particularly on the nose and inner canthus, and with infiltrative and multifocal histologic types.89 Wolf and Zitelli demonstrated that margins of 4 mm were adequate for 95% of nonmorpheaform BCCs smaller than 2 cm in diameter when treated by standard excision.90 Huang and Boyce found that, for a 95% cure rate, BCCs 2 cm in diameter.91 Johnson, Tromovitch, and Swanson reported a 96.7% cure rate when the excision included a 2-mm margin beyond the area defined by curettage. Tumor was present in 64 of 403 curette margins and in 12 of 403 excision margins. The histologic subtype was aggressive in 11 of 12 cases with positive excision margins. Margins of 5 mm are necessary for primary morpheaform BCC or recurrent BCC.92 Preoperative curettage decreases the frequency of positive margins in the management of BCC. Chiller et al found that curettage before excision decreased the surgical failure rate for BCC by 24% (P = .03).93

rate was 98.8%; for lesions between 1.0 cm and 2.0 cm, 95.5%; and for lesions larger than 2.0 cm, 84%. Recurrences were noted most often on the forehead, temple, ears, nose, and shoulders. C&D is not recommended for large primary BCC, morpheaform BCC, or recurrent BCC.97 For appropriately selected lesions and locations, C&D remains an efficacious and cost-effective treatment modality.83

TOPICAL TREATMENT IMIQUIMOD. Imiquimod (5% cream) has been used in the treatment of skin cancers.101 Approved in 2004 by the FDA for the topical treatment of biopsyconfirmed, small (less than 2 cm), primary superficial BCC, imiquimod is a Toll-like receptor 7 agonist believed to induce interferon-α, tumor necrosis factor-α, and other cytokines to boost T helper 1 type immunity. In two double-blind, randomized, vehiclecontrolled trials, clinical and histological clearance rates for dosing five and seven times per week were 75% and 73%, respectively, for superficial BCC.102,103 In another study, 10 of 19 nodular BCCs (approximately 53%) cleared after treatment with imiquimod.104 In general, adverse side effects are limited to local skin reactions; however, researchers have noted the significant correlation between the severity of the local skin reaction (erythema, erosion, and crusting) and the histological clearance rate.102 The safety and effectiveness of imiquimod for other types of BCC have not been established, and with up to 25% of treated patients failing therapy (or with 1301

21

a one in four failure rate), this possible clinical consequence should be discussed and strongly considered when choosing the appropriate treatment. The cost of imiquimod can easily exceed the costs of destructive or surgical modalities as well.105 A case series of 24 patients105 highlights the clinical consequences of imiquimod failure rescued with MMS. The cost of imiquimod can easily exceed the costs of destructive or surgical modalities as well. Imiquimod can be consideration as a monotherapy only for superficial BCCs limited to small tumors in low-risk locations in patients who will not or cannot undergo treatment with other better-established therapies.106

Section 21 :: Epidermal and Appendageal Tumors

5-FLUOROURACIL. 5-Fluorouracil (5-FU), a topically applied chemotherapeutic agent used in the treatment of actinic keratoses, has also been used to treat BCCs. In one series, Epstein showed a 5-year recurrence rate of 21% after 5-FU treatment, which was reduced to 6% when curettage was performed initially.107 Gross et al observed a 90% histologic clearance rate 3 weeks after 5-FU treatment, but with no follow-up. 5-FU was also found to be generally well tolerated with a good cosmetic outcome, with the majority of patients having no pain or scarring and only mild erythema.108 5-FU is metabolized by dihydropyrimidine dehydrogenase (DPD), and its use is contraindicated in patients deficient in that enzyme. A 2-(13)C-uracil breath test can identify DPD-deficient individuals.109–111 The use of 5-FU to treat BCC should be considered carefully and should include an evaluation of the risk of recurrence and treatment failure. Topical therapies may be associated with adverse effects, produces lower clearance rates, may be more difficult to administer, and, in some instances, costs more than other well-established therapies for BCC.106 HEDGEHOG INHIBITORS. With strong evidence of HH activation in BCC, there has been significant recent development of HH inhibitors (HHI) for the treatment of metastatic or locally aggressive BCCs. The well-known HHI compound is the plant alkaloid, cyclopamine, which competitively inhibits SMO protein signaling and therefore the growth of malignant cells driven by HH activation.112,113 In a phase 1 trial, GDC-0449, an orally active small molecule derivative that targets the HH pathway via SMO, appears to have antitumor activity in locally advanced or metastatic BCC (ClinicalTrials.gov number, NCT00607724).114 Further studies are needed to ascertain the full efficacy and adverse-effect profiles. Topical HH pathway inhibitors are also being developed for the treatment of BCC. PHOTODYNAMIC THERAPY Photodynamic therapy (PDT) involves the activation of a photosensitizing drug by visible light to produce activated oxygen species that destroy the constitu-

1302

ent cancer cells. Exogenous δ-aminolevulinic acid increases intracellular production of the endogenous photosensitizer protoporphyrin type IX, which preferentially accumulates in tumor cells.115 Morrison et al reported an 88% initial clearance of 40 large (>2 cm) BCCs after one to three treatments. The time of follow-up was between 12 months and 60 months.116 Basset-Seguin et al reported complete response rates for superficial BCCs from 85% to 93% at 3 months and a response rate on par with cryosurgery at 60 months (75% vs. 74%).117 Marmur et al reviewed PDT for nonmelanoma skin cancer and reported recurrence rates ranging from 0% to 31% for BCC.118 A clinical study comparing methyl-aminolevulinate PDT (MAL-PDT) and surgery in small superficial BCC found that MAL-PDT offers similar high efficacy and a much better cosmetic outcome than standard excision surgery in the treatment of superficial BCC; however, at 12 months, 9.3% lesions recurred with MAL-PDT and none with surgery.119 The longterm cure rates for superficial BCC with PDT remains around 75% and because of the appreciable nonresponse and recurrence rates, patients should be monitored closely during the first 2–3 years after PDT, which is when most lesion recurrences are seen.120 The Cochrane collaboration found that cosmetic outcome for PDT was significantly better than surgery. However, there were also comparatively high failure rates associated with PDT when compared to surgery, radiotherapy and cryotherapy. PDT requires a number of hospital visits and this may not suit all people with BCC.75 Reports of high recurrence rates suggest that this method may be best reserved for select situations in which better established methods are not feasible, particularly in situations where surgery may be problematic or where patients have multiple lesions.

RADIATION THERAPY Radiation therapy (XRT) may be useful in cases of primary BCC or in cases in which postsurgical margins are positive for cancer. Advantages include minimal patient discomfort and avoidance of an invasive procedure for a patient unwilling or unable to undergo surgery. XRT may be a very useful modality as adjunct treatment for BCC when margins are positive after excision or for extensive perineural or large nerve involvement.83 Potential disadvantages include lack of histologic verification of tumor removal, prolonged treatment course, cosmetic result that may worsen over time (cutaneous atrophy and telangiectasia), and predisposition to aggressive and extensive recurrences. Local control rates of 93%–97% have been reported; however, cosmesis has been rated inferior to results achieved surgically.116,121 The Cochrane Collaboration found surgery and radiotherapy to appear the most effective treatments for BCC, while the best overall results being obtained with surgery.75

SPECIAL MANAGEMENT ISSUES INCOMPLETELY EXCISED BASAL CELL CARCINOMA. On the basis of data from the 1960s

METASTATIC BASAL CELL CARCINOMA.

Although it is exceedingly rare, the possibility of metastatic disease exists and may need to be addressed. If nodal disease is suspected on surgical examination, lymph node biopsy and imaging studies, as well as evaluation by medical and surgical oncologists, are indicated.68 Platinum-based chemotherapy has been used with modest results in treatment of metastatic BCC; however, rapid clinical response was reported using a combination of cisplatin and paclitaxel.125 Complete response to carboplatin and paclitaxel has been reported as well.126

Full reference list available at www.DIGM8.com

Basal Cell Carcinoma

PNI by BCC is a rare event (1 μs), or giant pulsed lasers (Q-switched lasers) (1 μs–1 ns) in safety regulations.

glass applicator. The short wavelengths are blocked by an optical edge filter (cut-off filter), which is only transparent for radiation with wavelengths longer than the cut-off wavelength (e.g., 500 nm, 650 nm). The choice of cut-off filter depends on the chromophore and the target in the skin. A 500 nm cut-off is usually employed for vascular lesions, while a 650 nm cut-off is preferred for the melanin chromophores employed in hair removal. This cut-off also reduces the unwanted interaction with oxyhemoglobin in the vessels.

BASIC PARAMETERS OF OPTICAL RADIATION The main parameters of optical radiation are wavelength, optical power, intensity, the exposure time and radiant exposure. In the medical literature the phrase fluence is frequently used instead of radiant exposure. The correlation of these parameters are shown in Table 239-2, where the unit for energy is Joule (J); optical power Watt (W); intensity (W/cm2); radiant exposure (J/cm2); the exposure time second (s); and

RADIANT EXPOSURE. The most frequently modified parameter in laser treatments is the radiant exposure or fluence. It is the product of light intensity and exposure time (Table 239-2). When taking the total range of medical treatments into account, the radiant exposure varies from about 1–400 J/cm2 for pulsed radiation. This range can be exceeded for

Table 239-2

Parameters of Optical Radiation Parameter

Formula

Units

Energy

Energy = power × time

J=W×s

Intensity

Radiant exposure (“fluence”)

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Int ensity =

power area

Radiant exp osure =

W cm2 power × time area

J W×s W = = ×s cm2 cm2 cm2

38

Table 239-3

Typical Parameters for Medical Lasers Radiation

Intensity

IPL

W cm2

Radiant Exposure

1,500

10

15, broadband

fd Nd:YAG laser (e.g., telangiectases)

500

50

25

Pulsed dye laser (e.g., port wine stains)

12,000

0.5

6

Q-switched ruby laser (e.g., tattoos)

25 × 108

0.00002

5

Propagation of optical radiation through normal media such as air or glass can be described in a straightforward fashion, in particular, for monochromatic and collimated laser light. Reflection, refraction and absorption dominate the propagation. However, when optical radiation penetrates turbid media like skin, we also must consider scattering of radiation inside tissue that hampers light propagation in a complex manner. When optical radiation strikes skin, part of the photons is reflected back due to the different refractive index of air and skin. This effect necessitates the wearing of safety goggles during laser therapy. Photons inside the skin do not propagate straight on but frequently and abruptly change their direction due to collision with skin constituents, which is called scattering (Fig. 239-4). The mode and the extent of scattering depend on the size of the scattering objects and the wavelength of the radiation. The size of the scattering objects range from a few nanometers (small cell organelles, cell membranes) to a few microns (large cell organelles, cells, collagen) and to a hundreds of microns (hair follicle, sweat glands). The small objects follow the principle of isotropic Rayleigh scattering, the large objects the non-isotropic scattering. In both processes, the extent of scattering decreases with increasing wavelength. With increasing wavelength, photons are less deflected on their path into skin. Thus, the longer the wavelength, the higher is the penetration depth of radiation in skin. Ultraviolet B radiation (around 300 nm) penetrates skin up to a few tenths of millimeters only, whereas infrared radiation (e.g. Nd:YAG, 1,064 nm) achieves a penetration depth of up to a few millimeters. However, the increase in

Lasers and Flashlamps in ­Dermatology

SKIN OPTICS

penetration depth with increasing wavelength reverses for wavelengths longer than about 1,100 nm because radiation is increasingly absorbed by water in skin. Fortunately, the scattering in skin is mainly forward and many photons penetrate the skin. Unfortunately, the scattering changes the beam geometry in the skin and thereby substantially affects the dosimetry. It is complex to determine the number of photons that reach a target (for example, a vessel) in the skin. The higher the number of photons reaching the target, the more heat can be produced inside the target. The propagation of broadband radiation such as IPL emission is more complex than that of lasers. Photons with different wavelengths in the broadband emission (∼500–950 nm) penetrate skin to different depths. While propagating through the skin, photons can be absorbed by the different chromophores at any time.

::

cw applications. Table 239-3 shows a few examples for different intensities and exposure times that are employed in the treatment of different skin lesions. It is striking that the values of radiant exposures are within a rather narrow range, whereas the respective intensities and pulse durations vary in an inversely proportional manner by orders of magnitude.

J W = ×s cm2 cm2

Chapter 239

Exposure Time ms

Three major process infuence the propagation of radiation in tissue Laser beam Reflection

Stratum corneum 10-20 µ

Epidermis 40-150 µ

Dermis 1000-4000 µ

Scattering Absorption

Figure 239-4  Three major processes influence the propagation of radiation in tissue: reflection, absorption, and scattering.

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INTERACTION OF RADIATION WITH SKIN

Emission spectrum of typical IPL

Section 38 :: Physical Treatments

For monochromatic lasers, photons with single wavelength are absorbed according to the absorption coefficient of the respective chromophores at this single wavelength (Fig. 239-5). The absorption of broadband radiation of IPL is complex (Fig. 239-6). The photons with wavelengths in the range of 500–950 are absorbed to a different extent. This clearly complicates dosimetry of IPL in clinical use. In addition, the different IPL in the market emit radiation with considerable different spectra, even though the same cut-off filters are used. This precludes a comparison of radiation dosimetry for different IPL, which impedes clinical studies. When monochromatic laser radiation or broadband IPL emission is absorbed by the different skin chromophores oxyhemoglobin, melanin, or water, the radiation energy is converted to either heat or chemical reactions. Nd:YAG laser (frequency doubled at 532 nm) and pulsed dye lasers (585–600 nm) preferentially interact with oxyhemoglobin. Radiation of ruby laser (694 nm), alexandrite (755 nm), and diode laser (around 810 nm) is less absorbed by oxyhemoglobin and more suitable for pigmented lesions including hair removal. Radiation of Nd:YAG laser (1,064 nm) is minimally absorbed by all chromophores. Nevertheless, at high radiant exposures (J/cm2), this laser can be used for unspecific coagulation of tissue (cw mode) or vascular lesions (pulsed mode). The latter is also possible for diode and

500 nm cut-off 650 nm cut-off Oxyhemoglobin Melanin

3000

Absorption µa (cm-1)

38

2000

1000

0 400

500

600

700

800

900

1000

Wavelength (nm)

Figure 239-6  The emission spectrum of a typical IPL should match the absorption spectrum of the respective chromophores. 500-nm cut-off filters provide an overlap with the absorption of oxyhemoglobin; 650-nm cut-off filter predominantly with melanin. alexandrite lasers. Infrared lasers such as Er:YAG and CO2 lasers interact solely with water heating up tissue for vaporization or ablation. In contrast to lasers, IPL emission is broadband and may be absorbed by all chromophores simultaneously. Using a 500 cut-off filter, the radiant exposure (J/cm2) is assembled by photons of different wavelengths

The different laser wavelengths match the absorption spectra of different chromophores in skin 10000

ER:YAG laser 2960 nm

fd-Nd:YAG laser 532 nm Dye laser 585 nm

CO2 laser 11600 nm

1000

Absorption µa (cm-1)

Ruby laser 694 nm Alexandrite laser 755 nm Diode laser 810 nm

100

10

Oxyhemoglobin Melanin Water

1

Nd: YAG laser 1064 mn

0,1 400

600

800

1000 1200

1500

2000

3000

4000

5000 6000

8000

10000

Wavelength (nm)

2874

Figure 239-5  The different laser wavelengths match the absorption spectra of different chromophores in skin.

the parameters intensity and pulse duration, the temperature can be adapted to achieve coagulation, vaporization or explosion of a specific target in skin.

38

SELECTIVE PHOTOTHERMOLYSIS

ρc 2 2 D ∼D 16 k

where ρ, c, k are thermal parameters of the target).5 The thermal relaxation time is the time it takes to decrease the temperature in the target to 50% of the maximum value. The thermal relaxation time is roughly proportional to the square of the mean diameter of the target. Many of the calculated times match the pulse durations that are used in clinical practice (Table 239-4). Pigmented lesions containing small melanin or tattoo pigment particles are treated with nanosecond pulses of Q-switched lasers. Besides the short pulse duration, the treatment requires high light intensities to achieve explosion of the pigment particles in the skin. The use of millisecond pulse duration of either IPL or laser is appropriate to coagulate small blood vessels with diameter of 50–150 μm.6–8 Figure 239-7 illustrated coagulation of a blood vessel in the dermis. Pulsed radiation penetrates the skin and the radiant exposure (J/cm2) is reduced from the known value (J/cm2 at skin surface) to a smaller value due to scattering. The reduced value represents the radiant exposure to be absorbed in the blood vessel. Initially, only the temperature in the vessel increases, coagulating

Lasers and Flashlamps in ­Dermatology

tR =

::

It is a major goal to destroy precisely a specific target (such as vessel, pigment) in skin without permanent damage to the adjacent skin structures. This goal can be achieved by applying pulsed radiation and the principle of selective thermolysis.1 To destroy selectively a target by heating, the following issues must be considered. The wavelength of the applied radiation should be preferentially absorbed in the chromophore of the target (Fig. 239-6), which is difficult to accomplish for broadband IPL emission (Fig. 239-7). The energy of the radiation pulse should be high enough to achieve thermal destruction of the entire target. The pulse duration should be comparable to the thermal relaxation time (tR), which mainly depends on the diameter of the target (D)

Chapter 239

(∼500–950 nm), which are diversely absorbed by a skin chromophore like oxyhemoglobin. In addition, these photons reach different depths in skin as explained in skin optics. Thus, the conversion of IPL radiation to heat energy in a target at a certain depth is quite different as compared to laser radiation. While photochemical reactions require only a small intensity, photothermal reactions necessitates a high intensity. After being absorbed in a chromophore of a specific target (e.g., oxyhemoglobin in a blood vessel), the energy of these photons causes an increase of temperature inside the target. At the same time, the elevated temperature provokes a flow of heat energy to outside the target. This counteracts the heat generation and thereby limits the temperature increase to a maximum value. For low intensities and long exposure times (pulse duration), the application of laser or IPL radiation causes moderate temperature increase. The temperature ranges from body temperature to 100°C (coagulation), which is achieved with exposure times from milliseconds to continuous wave (cw). When tissue is heated toward the boiling point, radiation causes vaporization of the skin. The use of short CO2 laser pulses heat up tissue very rapidly leading to a rapid vaporization. This effect precisely causes small holes with minimal thermal damage of the adjacent tissue. The use of sufficient high intensity and pulse duration of microseconds is suitable to perform skin ablation at temperatures higher than 100°C. When using very high intensities (107–109 W/cm2) and very short pulse durations (nanoseconds), the temperature of the target can reach hundreds of degrees celsius. This very short and intense heating may cause explosion of the target. Since the total energy of the laser pulse is limited, ablation and explosion in laser medicine can be restricted to a very small volume. Such high intensities at short pulse durations are accomplished only with lasers and not with IPL. When pulsed radiation is delivered to skin, the radiant exposure (J/cm2) stays in a narrow range of about two orders of magnitude. In contrast to that, the intensity and the pulse duration may vary with 5 orders of magnitude at least (Table 239-3). As a rule of thumb, we can say that the higher the intensity (W/cm2) and the shorter the pulse duration, the higher the maximum temperature inside the targeted volume. By changing

Table 239-4

Thermal Relaxation Times for Common Laser Targets in Skin Target

Mean Diameter

Thermal Relaxation Time

Pigment (melanosome)

∼0,1 μm

5 ns

Small vessel (e.g., port-wine stain)

∼50 μm

1.1 ms

Hair follicle

∼0,2 mm

18 ms

Large vessel (e.g., leg veins)

∼1,5 mm

1,023 ms

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38

Selective photothermolysis

Radiation

ablative or in the nonablative mode. Fractional photothermolysis is a new concept for skin restoration. The MTZs are placed not manually but using computerassisted scanner device to produce a periodic grid of thermal injuries.

SKIN COOLING J/cm2 at skin surface

Epidermis

Section 38

Dermis J/cm2 at vessel surface

:: Physical Treatments

Vessel Radiation absorption in oxyhemoglobin

Figure 239-7  The interaction of pulsed radiation with a vessel in skin demonstrating the concept of selective photothermolysis.

the vessel. Due to the temperature increase inside the vessel, however, heat energy starts to flow to the adjacent dermis. At this point, the radiation pulse should be terminated to achieve selective vessel destruction. Pulse duration longer than the thermal relaxation time results in excessive heat flow to the dermis, which may cause unnecessary adverse reactions. The thermal destruction of hair follicles is achieved by using radiation pulses in the range of 10–50 ms.9–11 The same range of pulse durations is applied for the treatment of large vessels such as leg veins.12 However, the calculated value (Table 239-4) does not match this range. In case of voluminous targets, the selective photothermolysis must be aligned to a new parameter, which is the cooling down of heated target. The larger the target, the slower is the cooling down and hence the higher the probability of effective coagulation.12

FRACTIONAL PHOTOTHERMOLYSIS

2876

Laser radiation is usually applied on the skin surface as a circular spot showing spot sizes in the range of millimeters. The use of fractional photothermolysis leads to spatially distributed zones of microthermal injury within the treatment area, called microscopic treatment zones (MTZs). These are generated in the skin by focused laser irradiation. MTZs consist of sharply confined tissue denaturation with a diameter of about 100 μm that is surrounded by viable tissue, at intervals of about 200 μm.13 MTZs are produced either in the

Laser therapy of skin disorders require high radiant exposure to be delivered to the skin surface. Most of the targets are located at the epidermal-dermal junction or within the dermis. To reach these targets, the photons have to traverse the epidermis, which can partly absorb the incoming radiation. In addition, excess heat, caused by the absorption of radiation in the dermis, may provoke damage of dermal and epidermal structures. To avoid unwanted thermal damage especially to the epidermis, the skin surface is frequently cooled before, during, and after laser impact by a variety of measures. The simplest and cheapest cooling is accomplished by applying ice cubes on the skin surface prior to or even during laser impact.14 An application time of 10 seconds can result in skin surface temperature of about 10°C. About the same results are achieved by applying actively cooled metal or glass to the skin surface15 Instead of contact cooling, some laser systems are equipped with spray cooling. Shortly before laser impact, a burst of cold gas (usually tetrafluoroethane) is applied to skin surface reducing the temperature of the epidermis to about 5°C.10 Cooling is also achieved by exposing the treatment area to cold airflow that is provided by a special air conditioner.

SAFETY It was recognized early that radiation of any wavelength can pose a risk to humans, in particular, to unshielded eyes and skin.16,17 This risk is caused by the absorption of photons leading to photochemical or photothermal alterations of tissue.18,19 These alterations may affect tissue integrity for a short period of time or damage tissue permanently. When lasers or intense pulsed light sources are used to treat skin lesions, a variety of safety measures are required. The use of lasers in medical care is governed by rules and standards that are established in the Safety of Laser Products of the International Electrotechnical Commission (IEC) (http://www.iec.ch/) or American National Standards Institute (ANSI) (http://www. ansi.org/). The safety rules are based on IEC 60825-1 or ANSI Z136.1 for all laser systems, including medical lasers. Lasers have been classified in four groups based on the accessible emission limits (AEL). The rules are applicable to safety of laser products emitting laser radiation in the wavelength range 180 nm to 1 mm. These regulations unfortunately do not cover the use of IPL; there is no existing FDA performance standard for IPL products. We provide some advice regarding IPL safety, based on comparisons with laser systems. IPL systems emit high radiant exposures (J/cm2) that

are comparable to lasers and have therefore the potential to cause substantial damage to the eyes and skin. When using lasers for tissue vaporization, laser plume must be evacuated by using an appropriate device to avoid contact with infectious material.

EYE SAFETY

38

SAFETY OF LASERS AND IPL SYSTEMS

:: Lasers and Flashlamps in ­Dermatology

All laser systems, including the medical lasers, sold in Europe must be certified to EN 60825-1. In the United States, several organizations concern themselves with laser safety including ANSI and the Center for Devices and Radiological Health (CDRH). There are some basic categories of controls useful in laser environments. These are engineering controls, personal protective equipment, administrative and procedural controls, special controls, and correct labeling of the laser products. It is required and mandatory to appoint a laser safety officer (LSO). This person has the authority to monitor and enforce the control of laser hazards and effect the knowledgeable evaluation and control of laser hazards. The LSO administers the overall laser safety program where the duties include items such as confirming the classification of lasers and ensuring that the proper control measures are in place, approving substitute controls and conducting medical surveillance. The LSO should receive detailed training including laser fundamentals, laser bioeffects, exposure limits, classifications, control measures (including area controls, eye wear, barriers, etc.), and medical surveillance requirements. Nearly all medical lasers are assigned to class III or class IV. The class of a laser can be found on the label present on the laser device and in its handbook. Class III means moderate power lasers (cw: 5–500 mW, pulsed: 10 J/cm2 or the diffuse reflection limit, whichever is lower). In general, Class IIIB lasers will not be a fire hazard, nor are they generally capable of producing a hazardous diffuse reflection. Specific controls are recommended. Class IV means high power lasers (cw: >500 mW, pulsed: 10 J/cm2 or the diffuse reflection limit) are hazardous to view under any condition (directly or diffusely scattered) and are a potential fire hazard and a skin hazard. Significant controls are required of Class IV laser facilities (http://www.osha.gov/dts/osta/otm/ otm_iii/otm_iii_6.html). When using medical lasers, it is unavoidable that part of the beam path from a Class IIIB or Class IV laser is not sufficiently enclosed and/or baffled to ensure that radiation exposures will not exceed the MPE. Then a “laser-controlled area” is required. Although recommendations for the safe use of IPL in medical practice are currently not available, many of the items mentioned for lasers can be applied as well for IPL, in particular regarding eye protection.

Chapter 239

The high radiant exposures, high intensities and short pulse durations in laser therapy not only can harm the skin but also can severely damage the eyes even causing complete loss of eyesight. The side effects of radiation to the eyes are comparable to those effects at the treatment site. It is inevitable that radiation partly reaches the eyes due to reflection and scattering at the treatment site. Other reasons are accidental and careless handling of lasers and IPL during treatment. In the spectral range of about 370–1,000 nm, radiation readily penetrates the cornea and the lens reaching the choroid and retina. The radiation of this spectral range is well absorbed by the hemoglobin in the choroid vessels that may lead to thermal damage of the retina. Refraction by the lens and cornea increases the intensity of the incoming radiation by several orders of magnitude. For wavelengths shorter than 370 nm and longer than 1,000 nm, radiation is predominantly absorbed in water (Fig. 239-1) and do not completely traverse lens and cornea. The short wavelengths can cause injury of the cornea (cornea ablation) or cataract formation in the lens. With increasing wavelengths above 1,000 nm, the penetration of radiation decreases leading again to cataract formation (Fig. 239-3). For wavelengths around 3 μm, the water absorption is maximal for causing cornea ablation. At even longer wavelengths, vaporization of the cornea may occur. The eyes try to protect themselves from damage that could be induced by excess radiation energy. The eyelid is closed automatically in case high radiation energy is detected. However, the corresponding time span is about 250 ms, which is longer than most of the pulse durations used for lasers and IPL. Radiation that is invisible for the eyes (UV, IR) will not trigger an eye blink. Users of lasers or IPL should always keep in mind that even small intensities reaching the open pupil can cause severe damage of the retina, which, in most cases, is irreversible and may entail a complete loss of vision. Radiation of lasers or IPL can also damage skin outside the treatment area. For nearly all medical laser systems, even scattered radiation can be dangerous to eyes. To shield the eyes, it is mandatory to wear safety goggles during treatment with lasers or IPL according to EN 207 in Europe or to ANSI Z136 in the United States. To achieve maximal safety for the eyes, it is important to adjust the optical filters of the safety goggles to the radiation source used (laser or IPL). The important parameters of the radiation sources are wavelength, pulse duration, intensity, and radiant exposure. These parameters of a laser or IPL system determine the characteristics of the safety goggles. Each laser or IPL requires spe-

cial safety goggles that are labeled for their use, which are wavelength range of protection, laser mode, and scale number of protection. The manufacturer of lasers or IPL must provide sufficient information about the appropriate safety goggles, which can be found in the handbook of each laser or IPL device.

THERAPEUTICAL APPLICATION Since the introduction of lasers in dermatology by L. Goldman20 and the development of selective photothermolysis in the 1980s,1 laser therapy has become an

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38

indispensable therapeutic modality and more than 80 indications are documented.

PORT-WINE STAINS (PWS)

Section 38 :: Physical Treatments

PWS are asymmetric usually congenital capillary vascular lesions present in up to 2% of newborns. In childhood, they are pale red macules and patches. In adults they tend to become darker (port wine) and develop an irregular surface sometimes with blue-red papules and nodules. PWS are probably secondary to abnormal vascular innervation leading to a reduced vascular tone.21–26 In hypertrophic PWS with nodular surface, besides the vascular abnormalities extensive epithelial, neural, and mesenchymal harmartomatous changes have been observed suggesting a genetically determined multilineage development field defect.27 More recent studies indicate that RASA1 mutations cause capillary and arteriovenous malformations and hereditary capillary malformations and limb enlargement without arteriovenous malformation.28–30 Vascular endothelial growth factor (VEGF) and VEGF-receptor 2 expression is significantly increased in PWS compared to controls, indicating that VEGF and VEGF-R2 may contribute to vessel proliferation and vasodilatation.31 PWS are often associated with other malformations (Sturge-Weber-Krabbe syndrome, Cobb syndrome, KlippelTrenaunay syndrome, Parkes-Weber syndrome). Acquired PWS are rare but may be caused by trauma, hormonal imbalances or medications. The introduction of the pulsed dye laser (PDL) in the 1980s (λ = 585 nm, t = 0,45 ms, Ø = 5 mm) greatly improved the treatment options for PWS. In the past

A

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two decades, important advances include the use of wavelengths of 585–600 nm, longer exposure times and increasing the diameter of the beam. In addition cryogen spray cooling is used to protect the epidermis, allowing a higher fluence to be delivered to the dermis. Standard parameters for treating a PWS are a wavelength between 585 and 600 nm, a fluence of 4–20 J/ cm2, a pulse duration of 1.5–10 ms, a beam diameter between 7 and 10 mm and cryogen cooling of the skin surface, also known as dynamic cooling device (DCD). Larger beam diameters require a lower fluence. In some studies, longer wavelengths produced better results than 585 nm.32–34 The results depend on the age of the patient, the location, the color of the PWS and the number of treatment sessions.35,36 The success rate for children and adolescents is around 65% with the best results obtained when treatment is started in the first year of life (Fig. 239-8). Reyes and Geronemus37 treated 73 children less than 14 years old; 45% got over 75% lightening and 42% obtained 50% improvement. A complete disappearance can be expected in only 15% of patients. In a prospective study by van der Horst et al38 the benefit of early treatment could not be confirmed, although these authors did not employ a laser system with dynamic cooling. The location of a PWS is also a significant factor. PWS on the face and back respond much better than those at other sites. Those on the legs respond worst. Even on the face, there is considerable variation. PWS in the midface and distribution of the second trigeminal branch lighten less than those in the periorbital region, forehead, neck and nape.39–41 The size also affects the response. Small lesions respond better than large ones, and, often in the latter case, uniform lightening is impossible to achieve.42,43 Repeated treatments

B

Figure 239-8  A. PWS in a 6-months-old female baby prior to PDL therapy. B. Result of five PDL therapies at the age of 3 years.

A

Lasers and Flashlamps in ­Dermatology

Hemangiomas are benign proliferative tumors, which occur in about 5% of children. They are more common in premature infants and following amniocentesis. In general, they are not present at birth but appear in the first weeks of live as pale or telangiectatic macules, which then rapidly develop into nodular tumors. After a growth period of 9–10 months, there

38

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HEMANGIOMAS IN INFANCY

is a stable period, followed by a regression phase that can last until 10 years of age. About 50% of patients have residual lesions such as scars, fibrofatty nodules, or telangiectases. Complications of hemangiomas include ulceration, bleeding, and distortion of orifices (nose, eyes, mouth, and anogenital region). We distinguish between superficial, cutaneous-subcutaneous, and deep subcutaneous hemangiomas. They may be circumscribed nodules, plaques in a segmental distribution or multiple. The tumors cells express FCR II (CD32), merosin, and GLUT1, a pattern similar to placental cells. Congenital hemangiomas are much less common; they are divided into noninvoluting congenital hemangiomas (NICH) and rapidly involuting congenital hemangiomas (RICH). The treatment of hemangiomas is controversial, as most of them regress spontaneously.36 Nonetheless, numerous studies have shown that small and initial hemangiomas respond very well to PDL (Fig. 239-9). Growth is arrested in over 60% of treated tumors with just a few PDL sessions: only 15% disappear completely.61–64 Ulcerated hemangiomas also respond well to laser therapy; they become lighter and re-epithelize quicker.65 Deep subcutaneous components of the hemangiomas do not respond.66 In a prospective randomized and controlled study, 121 children with uncomplicated hemangiomas were treated with PDL (585 nm, pulse duration 0.45 ms, spot size 3–5 mm, fluence 6-7.5 J/cm2, no cooling). After a year 30% of the lesions in the treated group had completely disappeared; in the control group, it was only 5%. Residual changes were found in 42% of the treated children and 44% of the control group. Complications were much higher in the treated group with 45% versus 15% in the controls. In the treated group, the hemangiomas had increased in size by 61%; in the control group, 160%.67 In another study, a PDL with a longer pulse duration and surface cooling (595 nm, 7-mm spot size, pulse duration up to 20 ms, 9–15 J/cm2 fluence) was compared to a standard PDL without cooling (585 nm, 7 mm, 0.45 ms, up to 7 J/cm2); treatment with the longer pulse time led to better results with fewer side effects.68

Chapter 239

lead to an improved response, and sometimes more than 10 sessions may be required. The risk of scarring with PDL is quite low, around 1%. It is higher in patients on isotretinoin therapy. The main complications are hypo- or hyperpigmentation and rarely the development of a pyogenic granuloma.44–47 After the treatment is concluded, up to 15% of the patients may develop partial recurrences of their PWS, but not to the same extent and size as prior to treatment.48–50 When PWS are resistant to PDL, there are other laser options. Deeper vessels can be treated with the alexandrite laser (755 nm) and the pulsed Nd:YAG laser (1,064 nm).51–54 McGill et al were able to produce additional improvement in 10 of 18 patients treated with PDL with an alexandrite laser.55 In a study comparing pNd:YAG laser and PDL, both systems produced 50%–75 % improvement. Patients preferred the Nd:YAG laser because it caused less purpura. On the other hand, the risk of scarring was clearly higher with the pNd:YAG laser, which should be used for PWS only by experienced laser therapists. KTP lasers can also produce improvement in PSW but the results are worse than with PDL and the risk of scarring is greater.56 There is also good experience using IPL to treat PWS.3,57,58 In a comparison study in 20 patients, both PDL and IPL produced improvement but the extent of lightening was significantly better with the PDL.59 In contrast, in our own study, IPL was slightly superior to PDL.60 In individual patients with a nodular component to their PWS, vaporization of the individual lesions with the cwCO2 laser has proven helpful.

B

Figure 239-9  A. Childhood hemangioma in a 2-months-old female baby. B. After two PDL treatments, stoppage of growth and induction of regression.

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Section 38

B

C

Figure 239-10  A. Rubeosis faciei (red face) in a 45years-old female patient. B. Improvement in two PDL test spots. C. Result of one complete treatment.

:: Physical Treatments

A

Because of the introduction of propranolol to treat infantile hemangiomas, it is necessary to reexamine the role of lasers in this problem. Cutaneous-­ subcutaneous hemangiomas and rapidly proliferating hemangiomas in complicated locations respond well to systemic propranolol. They are no longer an indication for cwNd:YAG laser or intralesional laser therapy with bare fibers. Propranolol can be combined with PDL.69,70 Residual telangiectases after the regression of hemangiomas can be improved with either PDL or IPL.

TELANGIECTASES

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Telangiectases are permanently dilated small venules, which may be solitary or matted together to form larger flat lesions. Primary or essential telangiectasia is often familial, but no underlying cause has been found. Special forms are progressive, essential disseminated telangiectasia, which increase in numbers on lesions on the extremities, trunk and face, as well as unilateral nevoid telangiectasia syndrome (UNTS). Telangiectases are a good indication for laser and IPL therapy. PDL with large beam size and midrange fluences are employed; the pulses are set to lightly overlap. Many patients consider the resulting purpura after PDL as inacceptable. Pulse stacking has been tried, using a series of impulses all beneath the purpura threshold to reduce problems. The number of sequen-

tial impulses is based on the visible vasoconstriction. Using these techniques, good clinical effects can be obtained without increasing the complication rate.71 In a comparative study, long-pulsed PDL proved more effective than two IPL devices.72 KTP lasers also produce good results for this indication.73,74 Infrared laser such as diode lasers or the pulsed Nd:YAG laser can also be used. In a comparison study, a 940-nm diode laser was more effective than a KTP laser.75 The pulsed Nd:YAG laser is best suited for vessels with a diameter of more than 1 mm; the treatment is relatively painful and the risk of scarring greater than with other lasers.77,78 When telangiectases are grouped together and more diffusely red, IPL can be very effective (Fig. 239-10). A major advantage is that the large rectangular impulses can be very precisely placed next to each other. Poikiloderma of Civatte is also a good indication for PDL and IPL; we prefer the latter.79

STARBURST VEINS AND VARICOSITIES OF THE GREAT SAPHENOUS AND SMALL SAPHENOUS VEINS A phlebology evaluation is required prior to treating these venous problems. Vessels with a diameter of up to 1 mm are a good indication for PDL with a variety

BENIGN TUMORS Xanthelasmas and Syringomas can be coagulated with a KTP laser114 or destroyed with the cw-CO2 laser; there is a certain risk of scarring. Better choices, because

VERRUCOUS EPIDERMAL NEVI. Soft papillomatous epidermal nevi can be treated relatively effectively by coagulation with an argon or KTP laser or ablation with a CO2 or Er:YAG laser. In contrast, the hard or verrucous epidermal nevi often fail to respond to laser therapy and typically recur. A KTP laser can be used to completely coagulate small circumscribed nevi. For more extensive nevi, a chessboard or line-by-line pattern is recommended. About 80% of large but soft epidermal nevi can be successfully treated in this manner.123 Destruction with the CO2 laser (cw, pulsed or with flash scanner) is especially useful for markedly exophytic components of nevi.124,125 (See Fig. 239-11) The Er:YAG laser makes possible a very exact removal of relatively flat lesions on the face without any significant side effects.126,127 A test area should be tried before a complete lesion is treated, especially in problem areas like the neck and face, since hypertrophic scars can develop. After successful removal, the appearance may remain stable for years, but up to onethird of patients eventually develop some degree of ­recurrence.127 For hard verrucous nevi or ILVEN, a CO2 laser ablation is worth trying, although only about 30% of patients get a good response.123 For ILVEN, treatment with PDL (585 nm) can reduce the pruritus and produce partial remissions.128 SEBACEOUS NEVI. The exophytic part of sebaceous nevi can be removed with CO2 lasers (cw,

Lasers and Flashlamps in ­Dermatology

The superficial component of congenital or acquired lymphangioma circumscriptum can be vaporized with the CO2 laser. Although improvement is produced, sometimes for many years, the lesions eventually recur.96–99 Venous lakes respond well to treatment with PDL KTP, diode or Nd:YAG lasers.100 Low-flow venous malformations can be treated with cw Nd:YAG or long-pulsed Nd:YAG lasers or with the intralesional bare fiber technique.101–104 Small angiofibromas in tuberous sclerosis can be treated with the KTP laser. When multiple lesions are being treated, then ablative approaches such as a flash scanned CO2 laser or Er:YAG laser are preferred.105–110 Cherry angiomas respond well to KTP laser and PDL.111 The pulsed Nd:YAG laser can also be used. The ectatic vessels of hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber syndrome) are best treated with the KTP, diode, or long-pulsed Nd:YAG lasers. The pNd:YAG laser can also be used for larger ectatic vessels but the treatment is painful.112 The matted telangiectases in angioma serpiginosum respond well to PDL and IPL therapy, but recurrences are common.113

EPIDERMAL AND ORGANOID NEVI

38

::

OTHER VASCULAR LESIONS

they cause less thermal damage, are pulsed or flash ­scanner-CO2 laser systems. Another reliable approach is the very exact ablation with the Er:YAG laser.115,116 Trichoepitheliomas are usually skin-colored, so that coagulation with a semiselective coagulating laser is not very helpful. Ablation with the CO2 or Er:YAG laser makes it possible to obtain good cosmetic results even when treated multiple aggregated lesions.117–119 Neurofibromas can also be removed with the CO2 laser if they are not too large. Using relatively high power, the dome-shaped neurofibroma is circumferentially incised around its base; then the neural tissue generally herniates up with a little lateral pressure, so it can be vaporized or destroyed at its base. Although large deep defects may result, they heal amazingly well.120 Eruptive vellus hair cysts can be vaporized with the CO2 laser. In patients with steatocystoma multiplex, one can open the cysts with a focused CO2 laser beam, express the contents, and then coagulate the cyst wall with a defocused beam. Cosmetically pleasing results are not always possible.121 Similarly, a digital mucous cyst can be opened with a focused beam of a CO2 laser and then emptied of its gelatinous contents. Then the base and wall of the cyst can be vaporized with the defocused beam. Using this method makes it possible to completely remove digital mucous cysts without a complicated surgical approach.122

Chapter 239

of wavelengths (585, 590, 595, and 600 nm) and a longer pulse duration. For this purpose, oval handpieces with a spot size of 2 × 7 mm are available. Fluences between 12 and 20 J/cm2 are used, and skin cooling is mandatory; despite these measures, sometimes hyperpigmentation cannot be avoided.80,81 The alexandrite laser is well established for treating starburst veins. Using relatively high fluences (60– 80 J/cm2) and pulse durations of 3 ms with surface cooling, 65% of patients experienced an improvement of at least 75% when the vessel diameters were between 0.3 and 2 mm. Hyperpigmentation developed in 35%.82 In a study comparing alexandrite, diode, and pulsed Nd:YAG lasers for starburst veins with a caliber of 0.3 and 3 mm, the Nd:YAG laser was most effective.83 Treatments with a 940-nm diode laser produce greater than 75% improvement in 46% of patients.84,85 For vessels greater than 1 mm in diameter, the pulsed Nd:YAG laser with surface cooling is very effective.77,83,86–88 In direct comparison studies, the pulsed Nd:YAG laser was just as effective as sclerotherapy.89–91 A new use for lasers in phlebology is sealing the great saphenous and small saphenous veins with endoluminal laser therapy. Diode lasers, Nd:YAG lasers, and radio frequency ablation devices have all been employed. In a prospective randomized study, radiofrequency ablation produced just as good results as operative vein stripping.92–95

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Section 38 :: Physical Treatments

A

Figure 239-11  A. Extensive papillomatous epidermal nevus in the groin of a 32-years-old patient. B. Late result 8 months after CO2-laser-vaporization.

pulsed, or flash scanner) as well as with the Er:YAG laser. The intradermal component remains behind, so that the color of lesion is not changed and recurrences are common. Surgical excision is thus preferred if it seems likely to leave a good cosmetic result or if there is concern for malignant degeneration.

INFECTIOUS DISEASES Genital Warts. The vaporization

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B

of genital warts is one of the most common indications for the CO2 laser. Condylomata acuminata are generally vaporized at settings of 10–20 W; very exophytic lesions may require higher settings. By using short pulses and low fluences, it is possible to remove warts in problem areas such as over perianal ectatic veins or on hemorrhoids. Prior to treatment, the entire area should be soaked with 3%–5% acetic acid solution for a few minutes to bring out clinically inapparent lesions, which turn white and can then be seen and treated. Viral DNA is found in the perilesional clinically normal skin around a wart; thus, we recommend superficially ablating a 5- to 10-mm rim of normal skin around each lesion. One should avoid deep destruction because such lesions heal slowly and painfully, and may scar, or even lead to functional impairment.129 Viral DNA is present in the laser plume130; therefore the patient, physician, and nursing personal must all be protected by masks and vacuum exhaust systems. Genital warts can also be vaporized with the Er:YAG laser. One disadvantage is the tendency of the wellvascularized papillomas to bleed, so that this laser is best suited for flat lesions. The Nd:YAG laser can also be used to treat genital warts.131,132 They should be coagulated until they turn

completely white. Postoperatively, the lesions become necrotic and drop off; the exudative wounds may take weeks to heal. Because of both the long and painful recovery period and the risk of scarring, we only use the Nd:YAG laser in patients infected with HIV and hepatitis C virus, as there is no risk of infection through a smoke plume. As far as the recurrence rate is concerned, laser therapy is not superior to other destructive measures such as electrosurgery or argon-plasma coagulation.133,134 No matter what technique is used, the recurrence rate for genital warts is 40%–60%, and even as high as 80% in some series. Patients with bowenoid papulosis (an HPV-induced intraepithelial neoplasm) can often be treated successfully with the CO2 laser, avoiding a mutilating procedure. Recurrences are once again common; because of the greater risk of development of an invasive carcinoma, close clinical control is mandatory.

Common Warts. Common warts, just like genital

warts, can be easily vaporized with the CO2 laser. Filiform warts can be removed with 5–10 W and a diagonal cutting plane. The adjacent normal skin can be protected with moist compresses. The base of the wart is removed exactly down to the skin surface, often using a lower setting. Deeper removal is more likely to cause scarring. Thicker and more keratotic warts should be treated with keratolytic agents prior to laser therapy. The macerated white skin over the wart can be vaporized at relatively high settings (15–20 W) to produce superficial vaporization and charring, but is not completely removed. After a few seconds of treatment, the horn plug can be removed with a forceps from the base of the wart. Sometimes one must reheat the lesion again

Inflammatory Dermatoses Lichen Sclerosus et Atrophicus. The removal

of genital or extragenital lesions of lichen sclerosus et atrophicus with the CO2 laser leads to regression or cure in most patients,144–146 if the standard therapy with topical steroids were ineffective. The vaporization must extend into the normal underlying dermis. Recurrences can be seen both at the border and in the healed areas. They usually appear after 2–3 years, and the patient can be treated once again in the same way.146

Cutaneous Lupus Erythematosus. The selec-

tive destruction of vessels with a flashlamp pumped, pulsed dye laser can produce improvement in lupus erythematosus. Areas of chronic erythema and telangiectases,147 as well as plaques148 may respond. A test site should be treated before larger areas are tackled, as lupus erythematosus can be exacerbated by the laser exposure.149

Chondrodermatitis

Nodularis

Helicis.

Vaporizing the cutaneous nodule and the underlying damaged cartilage with the CO2 laser under local anesthesia is an effective way of treating this troublesome disorder. The defect usually heals without complications and the patient is free of symptoms. With larger lesions, a depressed scar is unavoidable.150,151

Psoriasis Vulgaris. While vaporization of chronic

stationary plaques of psoriasis with the CO2 laser is possible, there is not a great deal of clinical experience. Because of the high infection rate152 and the risk of scarring,153 laser vaporization should only be considered for isolated therapy-resistant plaques.

Hailey-Hailey Disease. Surgical methods such as dermabrasion or excision have long been used in Hailey-Hailey disease. Similarly wide vaporization with the CO2 or Er:YAG laser with local or general anesthesia is also effective.165 The damaged skin must be removed, completed, noted by reaching the chamoiscolored superficial dermis; otherwise, prompt recurrences are the rule. Laser vaporization can provide relief for up to several years, even though recurrences at the edge or within the lesion must be expected. A test patch should be treated prior to embarking on more widespread therapy and evaluated after 6 months in order to exclude patients whose lesions quickly recur and those who develop hypertrophic scars.

Lasers and Flashlamps in ­Dermatology

contagiosa with the PDL appears very effective. After 1 or 2 treatments with fluences of 6 and 8 J/cm2, cure rates between 95% and 100% are described.141,142 The treatment is also well tolerated by children; topical anesthetics or cold aircooling are helpful. Even with far lower fluences of 4 J/cm2, similar results (96%–100%) have been reported.143

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Mollusca Contagiosa. The treatment of mollusca

The treatment with PDL is directed against the abnormal large vessels in the dermal papillae of psoriatic lesions. The success rate is around 50% after repeated treatments at 2- to 3-week intervals; the response is generally short-lived and complete responses are uncommon.153–155 Psoriasis is better treated with excimer lasers or lamps, which deliver high-intensity UV IIA radiation at 308 nm (Table 239-5). Only the psoriatic lesions are treated, so that normal skin is not exposed. In addition, a higher dose of UV can be delivered to the lesions. The higher the individual UV dose, the better the response, although the side effects also become more common including dermatitis, blistering, and hyperpigmentation. High-dose therapy plans are more effective, but less acceptable to the patients because of blistering and crusting. They are also somewhat controversial, because with low and medium dosages, one tries to avoid blistering and crusting, just as with classical UV therapy for psoriasis. The 308-nm phototherapy of psoriasis is unquestionably effective, just like the classic 311-nm UV therapy. When high doses are used, the duration of therapy is shorter and the cumulative dose lower. Long-term effectiveness is comparable to standard measures, with disease-free intervals of 4–6 months,156–162 although some groups have reported responses lasting up to 2 years.163,164 Using the excimer laser is very time-consuming because of the relatively small spot size and the device is very expensive. In summary, the laser therapeutic approaches to psoriasis are mostly experimental and not clinical standard.

Chapter 239

to facilitate this. The well-vascularized and circumscribed base of the wart is then vaporized with a lower setting until the lesion is entirely destroyed, as evidenced by a restored papillary pattern to the dermis. Cure rates of 50%–70% are reported for the vaporization of warts.135–137 Since the treatment brings considerable postoperative pain and can produce painful scars, especially for plantar warts, it should be reserved for warts, which have failed to respond to consequent standard therapy. On weight-bearing surfaces, we view laser vaporization as a last resort. Warts can also be treated with PDL. Here the dilated capillary loops in the wart are destroyed, hastening its demise. Just as with vaporization, the thickened stratum corneum must first be removed with keratolytics, as the laser beam cannot penetrate this tissue. Multiple sessions are always needed; the cure rate is between 60% and 70%138,139 with especially good results for facial warts.140

Acne Vulgaris.

Laser and IPL therapy of acne vulgaris has recently attracted considerable attention. The information on different devices and their effectiveness is incomplete, or even in some instances ­contradictory.166,167 PDL have been employed in two randomized studies with conflicting results. Seaton et al168 compared a treated group (n = 31, 5 mm spot size, 1.5 or 3 J/cm2) to a group treated with simulated or placebo therapy (n = 10). After just one treatment, 12 weeks later, the treated group showed a significant reduction in the Leeds acne score for the total lesions and number of inflammatory lesions. In contrast, Orringer et al169 were unable to show any improvement using a half-face study with one or two treatments (7 mm, 2.5–3 J/cm2).

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Table 239-5

Commonly Used Dermatologic Lasers

Section 38 :: Physical Treatments

Laser (nm)

Target

Effect in Target

Mode (Pulse Duration)

Excimer (XeCl) (308)

DNA, proteins

Photochemical reactions

Pulsed (μs)

Comparable to narrow band UVB (311 nm)

Argon (488/514)

Vascular lesions

Semiselective coagulation

Pulsed (ms)

Tissue

Coagulation

Telangiectases, spider nevi, venous lakes Syringoma, xanthelasma, epidermal nevi

Frequency-doubled Nd:YAG (532)

Vascular lesions

Selective coagulation (“KTP” laser)

Pulsed (ms)

Telangiectases, spider nevi, venous lakes

Frequency-doubled Nd:YAG (532)

Pigmented lesions

Selective and fast heating (explosion)

Pulsed (ns)

Benign melanin-containing lesions, tattoos (red)

Flashlamp pulsed dye (585–600)

Vascular lesions

Selective Coagulation

Pulsed (ms)

PWS, telangiectases, rosacea, spider nevi Scars, keloids, warts, photoaging

Tissue Ruby (694)

Pigmented lesions

Selective and fast heating (explosion)

Pulsed (ns)

Benign melanin-containing lesions, tattoos (black, blue, green)

Alexandrite (755)

Vascular lesions

Selective coagulation

Pulsed (ms)

Selective and fast heating (explosion)

Pulsed (ns)

Large vessels (leg veins, hypertrophic PWS) Hair removal Benign melanin-containing lesions, tattoos (black, blue, green)

Selective coagulation

Pulsed (ms)

Large vessels (leg veins, hypertrophic PWS) Hair removal

Unspecific coagulation Selective coagulation

Continuous wave (cw) Pulsed (ms)

Selective and fast heating (explosion)

Pulsed (ns)

Vascular malformations, tumors Large vessels (leg veins, hypertrophic PWS) Hair removal Benign melanin-containing lesions, tattoos (black, blue, green)

Tissue Pigmented lesions

Diode (810)

Vascular lesions Tissue

Nd:YAG (1,064)

Vascular lesions Vascular lesions Tissue Pigmented lesions

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Applications

Diode (1,450)

Tissue

Selective coagulation (nonablative)

Pulsed (ms)

Skin remodeling, photoaging

Er:YAG (2,960)

Tissue

Selective and fast heating (ablation)

Pulsed (ms)

Skin resurfacing, epidermal ablation

CO2 (10,600)

Tissue

Unspecific coagulation (vaporization) Selective and fast heating (ablation)

cw

Vaporization of tissue

Pulsed (ms)

Skin resurfacing, epidermal ablation

The 1,450-nm diode laser has been approved by the FDA for acne therapy. This device administers 12–14 J/ cm2 to the face and 18 J/cm2 to the back coupled with spray cooling. Even though a single treatment can be effective170; generally, multiple treatments at intervals of several weeks are preferred. In 19 acne patients with facial lesions, one treatment led to a 37% reduction in

lesions; two sessions, 58%; and three sessions, 83%171 Four sessions produced a reduction of at least 50%, which held for 6 months in 13 patients, once again with facial acne.172 After a single treatment (n = 20), Mazer and Fayard170 observed an average improvement of 79% that was almost stable (74%) after 12–18 months. Similar results were obtained on the back; in a half-side

study, 24 weeks after 4 treatments, there was a significant, almost complete improvement on the treated side (n = 15).173

Rosacea. Rosacea appears to respond to PDL. After

two treatments (585 nm, 1.5 ms, 5 mm spot size, 8 J/ cm2), the symptoms of pruritus, burning, flushing, and dryness all improved by about 60%.174 After three treatments (585 nm, 450 μs, 6 J/cm2), the erythema had improved by 50%; the telangiectases, 75%; and the flushing, 55%. The overall severity of the rosacea clearly improved, but not the number of inflammatory lesions.175 The benefits are not very long lasting.176

Scars and Keloids Hypertrophic Scars. Since hypertrophic scars are

well vascularized, they are usually treated with PDL. Even with repeated treatments, the hypertrophic tis-

like hypertrophic scars with the PDL. In addition, the cw-CO2 laser can be used for tumor reduction in large keloids before starting cryotherapy and compression therapy. Otherwise, we do not consider keloids an indication for laser therapy.

Acne Scars, Atrophic Scars and Other Superficial Skin Irregularities. The exact

nature of the scar helps determine what approach is most likely to be helpful. Flat dish-like scars or sharply punched out scars that are less than 1 mm deep respond best to laser therapy. Deep or burrowed scars respond much less well, as all laser approaches are relatively superficial. When confronted with broad scars, flat acne scars on the face, or flat reticular scars, an ablative laser system can be used in a manner similar to dermabrasion.189 When treating older patients, one wants the side effect of “collagen shrinking” to tighten the skin; this is undesirable when treating scars in younger individuals. Thus one should choose laser systems that produce little thermal damage, as this ensures quicker healing and fewer side effects. The usual choice is the Er:YAG laser, but CO2 lasers with flash scanner and a short tissue interaction time also seem promising. Other lasers can also be used; the fluence, number of passes, and overlapping of the pulses (when applicable) should be kept as small as possible to reduce thermal damage and minimize side effects. If the indications are appropriate and the operator skilled, suitable scars can be treated with satisfactory to good results. General clinical improvement of 50%–70% can be obtained; sometimes the 90% level is reached.190–193 Almost all laser and IPL systems that are available for nonablative skin rejuvenation can also be used for acne scars. Most experience exists with the 1,320-nm Nd:YAG with spray cooling and the 1,450-nm diode laser. Unfortunately, the results vary greatly; improvement from as high as 70% down to only 10% have been reported after multiple sessions.194–198 In summary, all of the nonablative treatments are inferior to ablative approaches, but also have few side effects. Good results with ablative fractional laser therapy are also possible in nonacne atrophic scars.199 Fractional laser therapy falls somewhere in between nonablative and ablative approaches. It is capable of producing 26%–50% improvement without side effects.200 The ablative variant of this approach also appears superior to the nonablative, but is once again more aggressive with more side effects.

Lasers and Flashlamps in ­Dermatology

Alopecia Areata. The 308 nm excimer laser has also been tried recently for alopecia areata. Gundogan et al186 treated two patients, each with 12 sessions, and were able to achieve almost complete regrowth. The regrown hairs remained stable for 18 and 5 months, but there were no control areas. Zakaria et al187 treated nine patients but were able to obtain complete regrowth in only two, with >75% improvement in two, >50% in one, and no response in four.

Keloids. Erythematous keloids can be treated such

::

transplantation of the autologous cultured cells. With the Er:YAG laser the necessary de-epithelization can be accomplished quickly and elegantly, analogous to a very fine dermabrasion.177 Treatment with the 308-nm excimer laser is another option. Hadi et al treated 55 vitiligo lesions in 32 patients (2× weekly, starting with 100 mJ/cm2 with careful increase by about 50 mJ/cm2 per treatment depending on side effects). More than 75% repigmentation was achieved in 53% of patients with an average of 23 sessions. About 20% of the lesions completely repigmented.178 Facial lesions responded far better than those on the extremities or trunk. Hong et al179 compared excimer laser irradiation with narrowband UVB therapy in 8 patients with a half-side model. The 308 nm laser therapy produced a quicker and significantly better repigmentation than the UVB. The face once again responded best; the extremities were worst. Other studies show similar results.180–183 Thus, the effectiveness of the 308-nm excimer laser in vitiligo seems well established. One advantage is that the adjacent normal skin s not exposed and does not tan; in conventional UVB therapy, this enhances the contrast between normal and vitiliginous skin. The response rate depends heavily on the location of the lesions (face, neck, trunk better than extremities) and the treatment takes a long time, at least 12 weeks. Adding topical tacrolimus to the excimer laser therapy improves the response. In one study, there was over 75% repigmentation in 70% of the lesions treated with both modalities, as compared to 20% in the group treated just with laser.184,185

38

Chapter 239

Vitiligo. One therapy option for stable vitiligo is the

sue usually regresses but a little, but the pruritus and spontaneous pain may improve more.188 Removal with an ablative laser is generally not advised because of the risk of recurrence.

Striae Distensae.

It is worth trying a PDL for erythematous striae, although the supporting data is unclear. Both improvement, especially in early, still erythematous striae,201,202 as well as lack of effectiveness has been reported.203 Fractional laser therapy with 1,550 nm appears somewhat more effective.204

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Epilation

Section 38 :: Physical Treatments

Principles. The basic principle of photoepilation is the absorption of light by the pigmented structures of the hair follicle with resultant thermal damage. The target chromophore is eumelanin; pheomelanin is found in red and blond hairs and has such different absorption characteristics that these hairs, just like light and white hairs, are hard to remove with photoepilation. Exactly which structures have to be destroyed to ensure long-term epilation is still not certain.205 According to DiBernardo206 both the hair bulb and the bulge region must be destroyed since they contain pluripotential stem cells, which could lead to regeneration of hairs. Tope207 speaks of permanent follicular destruction when just the bulge and its stem cells are destroyed, as this is the region where anagen is initiated and hair production started. Ross et al208,209 indicates that destroying the bulb induces the catagen and telogen phases, so that hairs regrow, but lighter and thinner. On the other hand, when the bulge is destroyed, then miniature or vellus-like hairs result. Photoepilation generally causes a slower regrowth of hairs as well as some degrees of miniaturization, but only rarely produces complete follicle destruction and permanent alopecia. Optimal thermal damage can only be obtained when the follicles (and the hairs) are sufficiently pigmented; in addition, the radiation parameters must make it possible to deliver sufficient energy to the follicle. Longer wavelengths between 700 and 1,000 nm penetrate deep into the dermis reaching the follicle and are well absorbed by melanin. Large spot sizes enhance the depth of penetration further. The optimal impulse duration is not known, but appears to vary depending on system and wavelength, but probably is in the millisecond range (a few ms to 100 ms).205,210,211 Devices for Photoepilation Alexandrite Laser (755 nm). In comparison to

the ruby laser, which did not prove effective for epilation, the alexandrite laser delivers 20% less energy to melanin and proportionally more to oxyhemoglobin; thus, reducing the epidermal damage, especially for dark skin. The epidermis is further protected by cooling during the procedure. The spot size can be varied from 5–12.5 mm and makes possible the rapid treatment of larger areas.

Diode Laser (800/810 nm). At this wavelength,

the energy is well absorbed in the follicle but less absorbed by competing chromophores like oxyhemoglobin or water. In addition, a penetration depth of 3 mm can be reached. The laser light is scarcely absorbed by the epidermis, making the device well suited to dark skin. The long impulse duration (up to 50 ms) and high fluences make epidermal cooling mandatory.

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Pulsed Nd: YAG Laser (1,064 nm). This laser penetrates very deep (5–7 mm), so that even deeplying follicles receive enough energy for epilation.

There is also very little epidermis absorption, making the device well suited for dark skin (FDA approval also for skin types IV–VI)212 Once again surface cooling is essential to reduce pain and side effects. Of the devices used for laser epilation, the Nd:YAG laser has the fewest side effects but is most painful.

High-energy flashlamps (590–1,200 nm).

These sources have a broad emission spectrum extending into the near infrared region, which allows for excellent depth of penetration and have the largest spot sizes (around 5 cm2) of all the photoepilation units, which make rapid treatment possible. In the epilation mode, a cut-off filter at 600 nm is usually employed in order to filter out shorter wavelengths destined to be absorbed in the epidermis. The impulse durations are 0.5–25 ms, while 20 ms is usually chosen. Many different systems are available, and one should follow the manufacturer’s recommendation. A cooling gel is used to improve the coupling of light into the skin, cool the epidermis, and reduce pain. This is a method well suited for all skin types and with few complications.213,214

Side effects. Just after treatment one sees discrete erythema and perifollicular edema. Temporary hypoand hyperpigmentation is common, varying with the system. Occasionally folliculitis, vesicles, crusts and rarely tiny scars may develop. Uncommon complications are a paradoxical hypertrichosis either in or adjacent to the treatment area or leukotrichia.215–217 Melanocytic nevi in the treatment field are best not treated, especially if there is a history of dysplastic nevi or familial melanoma, since there are reports on changes in nevi after photoepilation.218 RESULTS. It is hard to compare the many studies on laser and IPL epilation because of the different devices, treatment parameters, hair colors, treatment areas and intervals. Reductions in the amount of hair are achievable with all the devices (Fig. 239-12). The current status of photoepilation can be summarized as follows211,219–222:



Reduction of hair numbers between 40% and 80% (100%) after multiple treatments. Multiple treatments produce better results. The loss of hairs is generally not permanent; to maintain an epilated condition, the therapy must be repeated at intervals. Dark and thick hairs respond better than light and thin hairs. When hairs regroup after epilation, they are often thinner and lighter. While permanent epilation is possible, it can never be promised or guaranteed.

MELANOTIC AND MELANOCYTIC SKIN LESIONS Lentigines. Lentigines can be treated with the Qs-ruby-, Qs-Nd:YAG at 532 and 1,064 nm and

38

A

B

tigines are employed, but the results are variable and hard to predict. Both incomplete lightening and recurrences are possible.227–231 A test spot should be treated and observed for an adequate period of time to assess both efficacy and likelihood of recurrence.

NEVUS OF OTA, NEVUS OF ITO. The Qs-ruby laser produces good results for nevus of Ota and nevus of Ito. In addition the results are generally stable.232 The time of intervention appears important. When children less than 10 years old are treated, fewer sessions are needed and the complication rate is lower.233 The Qs-alexandrite and the Qs-Nd:YAG laser appear to produce somewhat worse results with more side effects.234 Acquired bilateral Nevus of Ota-like macules (Hori spots) respond very well to laser therapy and can generally be completely removed in just a few sessions.235–237 MELANOCYTIC NEVI. The superficial removal of melanocytic nevi with an ablative laser often leads to recurrences,238 while destruction deep into the dermis invariably causes scarring. In addition, no histological examination is possible. Thus, ablative lasers are not suitable for treating melanocytic nevi. An exception is the early dermablation of congenital melanocytic nevi with the Er:YAG laser analogous to a dermabrasion, as described by Petres and other authors.239 When deep dark congenital nevi are superficially ablated for the first weeks of life, they often become much lighter, even though recurrences are common,240 and the associated hypertrichosis is not influenced. The treatment of melanocytic nevi, whether congenital or acquired, with pigment-selective lasers (Qs-ruby,

Lasers and Flashlamps in ­Dermatology

CAFE-AU-LAIT-MACULES, NEVI SPILI, AND BECKER NEVI. The same laser systems used for len-

Qs-Nd:YAG, Qs-alexandrite lasers) can completely destroy strictly junctional nevi. The dermal component cannot be removed both because of the limited penetration of the lasers and the invariable presence of relatively nonpigmented nests of melanocytes, which are not affected; thus recurrences are very common.241–245 It is unclear if the melanocytes that survive a laser treatment have an increased risk of malignancy; long-term studies are needed.246–248 There are many reasons why we do not consider melanocytic nevi an indication for laser therapy, except in special cases: clearing often requires many sessions and is not impressive, residual nevus cells are always left behind, the long-term effects are unknown and no histological evaluation is possible. Lasers can be tried in giant congenital melanocytic nevi when no other therapy options are open. Using the combination of long pulsed and Qs-ruby lasers over many treatments has produced very good results in some cases.249

::

Qs-alexandrite lasers. Lower fluences than required for tattoos can be employed; for example, the Qsruby laser uses 4–6 J/cm2 at 40 ns. Blisters or crusts are rare; the area is generally healed in a few days. The results are good to outstanding,223–225 while side effects are rare. The Er:YAG and the CO2 laser with flash scanner can be employed to superficially ablate lentigines.226

Chapter 239

Figure 239-12  A. Hypertrichosis of the upper lip in a 35-years-old female patient. B. Reduction of hair growth after five IPL treatments.

MELASMA. Both the pigment-selective lasers and IPL have produced disappointing results in melasma or chloasma; in addition, the risk of reactive hyperpigmentation is great.229,250–253 Somewhat better results seem possible with fractional laser therapy, although the results are highly variable and not always good.200,254 Tattoos and Other Exogenous Pigmentation Decorative tattoos. Procedures often used to remove tattoos like excision, dermabrasion, salabrasion or CO2 laser ablation always cause scarring. The introduction of the Qs laser technology has revolutionized the field, making it possible to remove tattoos almost without scarring.255 The exact mechanisms by which lasers remove tattoos are still poorly understood. Laser therapy leads to changes in the optical qualities of the tattoo pigment, either by destruction or by changes through thermal, photochemical, or photoacoustic reactions.256–259 The

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Section 38 :: Physical Treatments

A

Figure 239-13  A. Professional tattoo at the back of a 34-year-old male patient. B. Result of eight treatments with a Qs Ruby laser.

additional improvement that occurs weeks later probably has a cellular explanation. Histologic studies have demonstrated that macrophages or their lysosomes laden with tattoo pigment rupture and the free but degraded pigment particles can be transported to the lymph nodes. Whatever pigment remains at the site of the tattoo is rephagocytosed and after 4 weeks, is once again intracellular.257,260 This process of

A

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B

damaging pigment, moving it about, and then finally cellular reuptake probably explains the clinical clearing.256,259,260 The usual choices are Qs-ruby (694 nm), Qs-Nd:YAG (1,064 and 532 nm) and Qs-alexandrite lasers (755 nm), all with pulse durations in the ns range. The ruby lasers work best for black, blue-black, and dark blue tattoos (Fig. 239-13). For blue and green tones, the results are

B

Figure 239-14  A. Professional tattoo at the upper arm of a 31-year-old female patient. B. After five treatments with a Qs Ruby laser, lighting of the black color, no change in the red color.

38

Table 239-6

Lasers for Tattoo Removal Tattoo Colours and Suitable Q-Switched Lasers Laser

Wavelength

Pulse Duration

Tattoo Colour

Nd:YAG laser

532 nm

10 ns

Red

Ruby laser

694 nm

30 ns

Black, blue, green

Alexandrite laser

755 nm

50–100 ns

Black, blue, green

Nd:YAG laser

1,064 nm

10 ns

Black, blue

tattoos is unclear, but cannot be completely excluded. The clinical relevance of these products is probably quite low since they are produced in extremely small amounts.

Lasers and Flashlamps in ­Dermatology

PIGMENTATION FROM MEDICATIONS

::

ACCIDENTAL TATTOOS. Without question, the best approach to accidental tattoos (powder burns, explosions, road dirt after falls) is prompt removal. Ideally, the area is pretreated with wet compresses and then cleaned with scrub brushes, as well as fine tweezers or punch excisions for residual pieces. This should be completed within 24 hours of the accident. For residual pigment or when the early treatment was not accomplished, the same Qs lasers used for decorative tattoos can be employed with good benefit. Dirt, soot, coal, and powder usually respond well; harder materials such as metal fragments or stones usually do not. Generally, a test area should be treated to see if a laser treatment is likely to offer benefits.

Chapter 239

highly variable. Red, yellow-orange, and light blue ­tattoos respond poorly to the ruby laser (Table 239-6, Fig. 239-14).230,261,262 With the Qs-Nd:YAG laser, the clinical improvement at 1,064 nm is comparable to the ruby laser.263,264 Using 532 nm makes it possible to destroy some red tattoo pigments.257,261,265 The 755-nm laser produces good results for blueblack tattoos, as well as with green, red, and purple colors.258,259,261,265,266 The treatment can generally be done without anesthesia; the impulses are placed close together without overlapping. Right after the treatment, there is a broadbased swelling with whitening of the skin, while histological examination shows vacuole formation by steam bubbles. The whitening disappears in a few minutes. When higher fluences are used, sometimes there are punctate hemorrhages. Blisters and crusts commonly develop a few days after the treatment. Topical antiseptic agents should be used after the treatment to reduce the risk of infection. The complete destruction of a tattoo requires multiple sessions, no matter which laser system is chosen. The literature suggests that at least 3 and usually 10 or more sessions are needed.265,267 Amateur tattoos generally have less pigment so they respond quicker and better than do professional ones. Blue-black tattoos absorb nearly all the available wavelengths and respond better than do more colorful tattoos.255 Multicolored tattoos are often impossible to remove completely, even when several lasers are employed. Green, purple, and yellow tones are most stubborn.265,267,268 Scarring is rare, but slight atrophic changes in the skin surface are possible. Patients hardly notice them in their elation. The most troublesome side effect is a change in color of a treated tattoo, which does not disappear. Lighter colors (red, pink, white) can become black, gray-black or dark green258,269,270; the same phenomenon can also be seen less often with yellow, green, purple, and violet pigments.261 While the resultant darker pigment may respond to additional laser treatments,270 this is not always the case. Some patients get a permanent aesthetic worsening.269 If there is any doubt about the responsiveness of a color, a test patch is advised. In vitro, it has been shown that when two commonly used red azo dyes are treated with lasers, toxic or carcinogenic degradation products are formed.271,272 Whether this is relevant for the clinical treatment of

Minocycline, amiodarone, and doxorubicin hyperpigmentation generally respond well to treatment with the pigment-selective Qs lasers.273–276 On the other hand, a Qs laser treatment, no matter what the indication is, can cause patchy hyperpigmentation in patients who have taken gold products systemically; this is termed laser-induced chrysiasis.277,278

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 35. Galeckas KJ: Update on lasers and light devices for the treatment of vascular lesions. Semin Cutan Med Surg 27;276-284, 2008 36. Stier MF, Glick SA, Hirsch RJ: Laser treatment of pediatric vascular lesions: Port wine stains and hemangiomas. J Am Acad Dermatol 58:261-285, 2008 49. Huikeshoven M et al: Redarkening of port-wine stains 10 years after pulsed-dye-laser treatment. N Engl J Med 356:1235-1240, 2007 51. Galeckas KJ, Ross EV, Uebelhoer NS. A pulsed dye laser with a 10-mm beam diameter and a pigmented lesion window for purpura-free photorejuvenation. Dermatol Surg 34:308-313, 2008

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58. Bjerring P, Christiansen K, Troilius A: Intense pulsed light source for the treatment of dye laser resistant portwine stains. J Cosmet Laser Ther 5:7-13, 2003 59. Faurschou A et al: Pulsed dye laser vs. intense pulsed light for port-wine stains: A randomized side-by-side trial with blinded response evaluation. Br J Dermatol 160;359-364, 2009

Section 38

Chapter 240 :: Radiotherapy :: Roy H. Decker & Lynn D. Wilson RADIOTHERAPY AT A GLANCE

:: Physical Treatments

Radiotherapy is a collection of versatile treatment modalities including brachytherapy, external beam radiation, and charged particle therapy. The clinical effects of radiotherapy include acute and late skin changes: Acute effects include inflammatory reactions and desquamation. Late effects include fibrotic changes and atrophy of skin adnexa. Radiation-induced malignancy is a rare but serious side effect presenting at a median 10 years after treatment. Radiotherapy is indicated for selected benign, proliferative disease after more conservative measures have failed. Radiotherapy is a valuable option for primary or adjuvant therapy of malignant skin disease.

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75. Tierney E, Hanke CW: Randomized controlled trial: Comparative efficacy for the treatment of facial telangiectasias with 532 nm versus 940 nm diode laser. Lasers Surg Med 41:555-562, 2009 167. Haedersdal M, Togsverd-Bo K, Wulf HC: Evidencebased review of lasers, light sources and photodynamic therapy in the treatment of acne vulgaris. J Eur Acad Dermatol Venereol 22:267-278, 2008

The first documented use of radiation as a therapeutic treatment was for a cutaneous malignancy, in a patient with squamous cell cancer of the nose, in 1900. Over the next century, radiotherapy was widely used in the treatment of both malignant and benign disorders of the skin, in both adults and children. As the long-term consequences of radiotherapy became evident, particularly the risk of radiation-induced malignancy, its use in the treatment of children and benign diseases declined. Radiotherapy continues to have a small but important role in the management of benign proliferative diseases of the skin, but is more commonly used as a valuable adjunct or alternative to surgery for both premalignant and malignant lesions.

Radiation Modalities There are several choices for radiation modalities, some commonly available and others only in specialized centers. The selection is made on the basis of the anatomic location and size of the target, tumor biology, the nature of critical surrounding structures, and availability. In particular, with respect to the cutaneous targets, the depth of the lesion plays a large role in determining the optimal therapy. High-energy photons, in the form of γ- or X-rays, are most commonly produced by a linear accelerator (linac) and are available in a spectrum of energies. Incident radiation deposits its energy as it passes through matter, becoming attenuated as a function of distance and the density of the tissue. Higher energy beams deliver increased dose at depth in tissue, and proportionally less at the surface. Lower energy radiation deposits dose primarily at the target surface, sparing deeper matter. The most commonly available treatment energies are in the megavoltage range, which deposit their dose at a range practical for the treatment of targets in human tissue. Such beams were designed to relatively spare surface structures such as skin, which would otherwise be dose limiting, in the interest of delivering higher dose to deeper target structures. This is in contrast to more superficial radiation energies, which are often more appropriate for cutaneous targets. Depth dose curves demonstrating the absorption of X-rays as a function of their energy are demonstrated in Fig. 240-1A. Most linear accelerators in clinical use provide radiation in the range of 6–18 megavolts (MV).1 Orthovoltage X-rays refer to lower energy photons with maximum energy in the range of 125–400 kilovolts (kV), often used in dermatologic applications because the dose at the skin surface dose is maximized. The dose is then rapidly attenuated as the beam penetrates deeper into soft tissue. Half of the incident energy has been absorbed within the first few centimeters, ideal for treating superficial targets and minimizing dose to deeper normal tissue. Orthovoltage X-rays are produced by specialized treatment units, and are not as commonly available as megavoltage treatment units. Grenz rays are even lower energy X-rays in the range of 5–15 kV, and therefore deposit their dose at more

Depth dose distributions

A

Photons: 10 x 10 cm2

120 18 MV 10 MV 6 MV

100

DD (%)

80 60 40 20

0

5

10

15

20

25

30

Depth (cm)

B

100

DD (%)

80 60 40 20 0

0

5

10

15

20

25

30

Depth (cm)

Figure 240-1  Depth dose distributions. A. The percent of the maximum radiation dose (DD) deposited at depth in tissue (in cm), as a function of the photon (X-ray) energy. As photon energy increases, the percent dose at superficial depth decreases, and the percent dose in deeper tissue increases. B. A similar relationship for electron therapy. In contrast to photons, the percent dose deposited at both superficial and deep tissue increases with electron energy. Note the difference in scale; electron energy is almost completely absorbed at shallower depths, compared to photons.

shallow depths than orthovoltage. These were historically used to treat superficial, benign skin disease. In these cases, the majority of the target processes are occurring within 1 mm of the skin surface. Grenz rays are no longer recommended as first-line therapy for routine treatment of benign cutaneous disease. Charged particle therapy is also commonly used in cancer treatment, including both electrons, which are commonly available, and protons, available at select regional centers. Electrons are the product of the same linear accelerators used to produce megavoltage energy photons. Electron beams are commonly used in dermatologic applications as they are capable of delivering high skin-surface dose, and the deposited dose rapidly falls to negligible values at depth in tissue.

Radiation treatment planning involves a complex set of decisions regarding the appropriate radiation modality, radiation energy, beam orientation, patient positioning, and the use of treatment devices. The latter can help increase the radiation dose to targeted structures, and block or reduce radiation exposure of normal tissue. “Bolus” is tissue-density material commonly used in radiation treatment of superficial skin malignancies. It can be custom designed in varying thicknesses and applied to the patient’s skin during daily treatment. It serves several potential purposes: for higher energy X-rays (e.g., MV energy), or low-energy electrons, the surface dose is low compared to that in deeper tissue. By placing the appropriate thickness of bolus, the skin dose can be raised to therapeutic levels. This is demonstrated in Fig. 240-2. Another function of bolus can be to attenuate the incident beam to lower the dose to deeper structures, for example, during treatment of a skin cancer on the temple, to decrease the dose that penetrates into the underlying brain. Bolus material can also be used to compensate for complex topography, and smooth the dose distribution for treatment of the skin around the nose and ears, as seen in Fig. 240-3. Beams can be shaped by a variety of devices depending on their energy. Megavoltage treatment beams may be shaped by custom-designed, 7-cm thick, lead alloy blocks to conform to the desired shape; most modern linear accelerators have a multileaf collimator (MLC), which contains sliding leaves of tungsten that conform to the desired treatment aperture. Electron beam radiation is normally blocked with custom-made lead or lead alloy blocks. Orthovoltage radiation is blocked using thinner custom lead shielding, typically placed on the patient’s skin. Examples of blocking devices are shown in Fig. 240-4. Traditionally, external beam radiation beams are designed using blocks or static MLCs to conform to a target that is delineated clinically or using CT or other imaging. Multiple beams, beam angles, and energies

Radiotherapy

MODULATION OF EXTERNAL BEAM RADIATION

20 MeV 16 MeV 12 MeV 9 MeV 6 MeV

::

Electrons: 10 x 10 cm2

120

38

Chapter 240

0

Electron-depth dose, like that of photons, is a function of voltage. Higher energy electrons deliver dose to a greater depth, similar to the depth/dose relationship of photon energy. Unlike the skin-sparing properties of higher energy photons, as electron energy increases the skin dose also increases. The depth dose characteristics of electrons are described in Fig. 240-1B. Protons are charged particles that are the product of large and expensive cyclotrons or synchrotrons, available at a small number of specialized centers. Due to their large mass, there is little side scatter during penetration of a proton beam. The dose is largely delivered within a few millimeters of the end of the particle range (the Bragg peak), rather than at shallower or deeper depths. By modulating the energy of the proton beam, radiation absorption can be more precisely delivered to deep tumor targets, with less incidental radiation of surrounding normal tissue.

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Section 38 :: Physical Treatments

Figure 240-2  Bolus to increase the skin dose. A 61-yearold male underwent resection of a deeply invasive squamous cell carcinoma overlying the zygoma, with involvement of parotid lymph nodes and facial nerve. The tumor bed was treated, along with the remaining parotid gland and course of the facial nerve, using megavoltage photons. A tissue-density bolus (white arrow) was placed over the tumor bed to increase the skin dose to 100% in that area.

A

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Figure 240-4  A custom lead shield placed on the patient’s face, with a cutout to allow orthovoltage treatment of a cutaneous malignancy of the left lower eyelid. are chosen to avoid specific normal structures, and the dose is calculated with iterative changes until an acceptable plan was generated. An “inverse planned” method is now increasingly used when the tumor target lies in proximity to a dose-limiting structure. Intensity modulated radiation therapy (IMRT) incorporates individual radiation beams that are not static; the aperture changes during the treatment to finely adjust

B

Figure 240-3  Bolus as a tissue compensator. A deeply invasive basal cell carcinoma was excised from the left nasal ala. A. The patient was immobilized for treatment in a thermoplastic mask. A rectangular, tissue-density, box was constructed overlying the nose to compensate for the irregular tissue contours in this area. B. The patient was treated with right and left lateral megavoltage photon beams, weighted left greater than right. The 100% isodose line (red line) covers the tumor bed (red-shaded area) with full dose at the skin surface and good dose homogeneity.

beam fluence. This requires a dynamic MLC, in which the leaves slide during beam-on time. During the pretreatment-planning phase, the treating physician contours the target volume and those of the normal tissue organs at risk. Dose constraints for each contoured structure are chosen, and the physician, physicist, and dosimetry staff use dedicated treatment planning software algorithms to optimize the treatment plan. This is a time intensive, expensive technique that can generate plans to treat complex shaped tumor targets and spare adjacent critical normal tissue structures.

MECHANISM OF ACTION

:: Radiotherapy

The Systeme International d/Unites (SI) unit of radiation dose is the gray (Gy), which is defined as a joule of energy absorbed per kilogram of tissue. An alternate unit of absorbed dose, largely replaced by the gray, is the rad (an acronym for radiation absorbed dose); one gray is equal to 100 rads. Dose is specified to the target volume as defined by the treating radiation oncologist. Most epithelial malignancies are treated to a total dose in the range of 50–80 Gy, lymphoid malignancies typically respond to doses of 15–40 Gy. Select benign conditions can be treated with lower doses; hypertrophic scars and keloids are commonly prescribed doses in the range of 4–20 Gy. Fractionation refers to the delivery of specified radiation dose in temporally separate treatments, and is recommended to both increase the efficacy of effects on target tissue and to allow normal irradiated tissue to repair radiation damage. Thus, the schedule of radiation fractionation can be used to both increase efficacy of the dose to the target and minimize radiation damage to normal tissue. Common fractionation schemes using conventional radiotherapy deliver treatments at intervals ranging from twice daily to once per week. The effectiveness of radiation treatment is highly dependent upon the treatment schedule; both the total number of days over which the treatment is spread and the fraction size. The common daily fraction size is 1.8–2 Gy per day, treated 5 days per week. Different fractionation schedules can be compared using a mathematical conversion to a biologically effective dose (BED), using a formula that accounts for the number of fractions, fraction size, and the DNA-repair characteristics of the target tissue.

38

Chapter 240

The most common form of radiotherapy used in clinical practice are X-rays, or γ rays. Both represent photon particles or electromagnetic waves that differ only in the method of their generation: γ rays are emitted by nuclear reactions, whereas X-rays are emitted by energy transitions in orbital electrons. Ionizing radiation includes that part of the electromagnetic spectrum of sufficient energy to impart energy to target tissue by the ejection of orbital electrons. This is the primary means of energy absorption in human tissue ­following exposure to therapeutic radiation. Since cells are largely composed of water, it is in water molecules that the majority of the ionization occurs and the result is the generation of short-lived free radicals, such as hydroxyl radicals. The effectiveness of radiation in tissue is therefore dependent upon the availability of oxygen. This is clinically manifest in reduced radiation response in hypoxic tissue, and is the reason that higher radiation doses are used in the postoperative setting when there is diminished microcirculation. The primary mediator of cell death in response to ionizing radiation, in both tumor and normal tissue, is damage to DNA by indirect ionization by radiationinduced free radicals.2 Indirect DNA damage is characteristic of sparsely ionizing radiation including not only X-rays, but also commonly used charged particles such as electron and proton therapy. In contrast, densely ionizing radiation (e.g., neutrons, αparticles) with a higher linear energy transfer (LET) deposit their energy densely along their incident tracks, and therefore more commonly induce double-strand DNA breaks directly, without the intermediate ionization of cellular water. The initial deposition of radiation energy in tissue and the resulting DNA damage occur within thousandths of a second of exposure. The biological response to DNA damage includes modulation of cell death, differentiation, and survival pathways, and activation of DNA repair. These biologic processes occur orders of magnitude more slowly than the initial DNA damage. The ultimate cellular response to radiation can be repair, senescence, differentiation, or cell death. The latter may occur via apoptosis, a relatively rapid process, but more commonly occurs as a mitotic cell death. Misrepair of double-stand DNA breaks generates chromosomal abnormalities, and cells die during failed mitosis, often several generations later.

DOSE AND FRACTIONATION SCHEDULE

CLINICAL AND MOLECULAR ASPECTS OF RADIATION DERMATITIS Skin changes after radiation exposure follow a predictable course dictated by radiation dose, timing, and the biology of the human inflammatory reaction.3 The earliest reaction is erythema that may occur and resolve within hours, and is normally only evident after relatively high-dose exposure. The threshold dose is 2 Gy or greater skin dose, and is not normally noted after daily fractionated treatment of visceral organs with skin-sparing megavoltage radiation. This effect is noted in therapeutic courses aimed at cutaneous targets, where the skin receives full dose, or during treatment regimens that use large fraction sizes. Microscopically, there is a vasodilation and a transiently increased capillary permeability that results in mild erythema and edema at 2–24 hours following exposure. Prior to the adaptation of SI units of radiation dose, skin erythema dose (SED) was used as a crude clinical measure of patient radiation exposure. This

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Section 38 :: Physical Treatments

transient acute ­reaction is no longer commonly noted due to the increased use of high-energy, relatively skinsparing, radiation energies, and the increased use of lower fraction sizes. Acute, transient skin erythema is still reported following interventional diagnostic and therapeutic procedures with prolonged fluoroscopy times. The more sustained, common, and relevant reactions take place over a matter of weeks following initial exposure. Acute radiation dermatitis progresses through characteristic stages of severity based on the accumulation of radiation-induced changes to dermal vasculature, appendageal structures, epidermal stem cells, and the activation of inflammatory pathways. Radiation dermatitis is a distinct adverse event graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). This scale is graded on severity, and primarily describes the acute reaction of skin exposed to therapeutic radiation. Chronic skin changes may occur months to years after exposure, and include a spectrum of changes characterized by fibrosis and atrophy. Common acute and late adverse events attributable to radiation are summarized in Table 240-1. Grade 1 dermatitis first manifests as faint skin erythema within the treatment area. Erythema is seen in two contexts: first, there may be a transient vasodilation in the hours after a single fraction skin exposure of 2 Gy or higher. More commonly, erythema or hyperpigmentation develops over the first 2 to 3 weeks of fractionated radiation with accumulated exposure. Vasodilation and increasing vascular permeability occur early, and the resulting perivascular inflammation results in clinically characteristic erythema and edema. Moderate-to-brisk erythema is grade 2.

With continuing or higher dose radiation exposure, damage to the basal cells in the epidermis may progress until this stem cell population is lost in localized areas, which results in dry desquamation (CTCAE grade 1). Further damage to the basal layer leads to more widespread desquamation, and the production of a fibrinous exudate due to increased arteriole permeability, loss of basement membrane integrity, and edema in the underlying dermis. This is characteristic of moist desquamation. The CTCAE differentiates moist desquamation based on whether it is patchy and localized to areas subject to trauma such as skin folds (grade 2), or confluent and present in a more widespread area (grade 3). Radiation damage to the underlying dermis may lead to ulceration, bleeding, or necrosis (grade 4). Skin adnexal cells are relatively radiosensitive, and may not regenerate following exposure. The process of epilation begins within days of radiation exposure. Sebaceous glands have similar sensitivity, and eccrine sweat glands become dysfunctional shortly afterward in a fractionated radiation treatment course. Histologically, these glandular structures demonstrate apoptosis, necrosis, and loss of normal mitotic activity. Chronically, there can be fibrotic replacement and loss of the supporting microvasculature. This leads to both acute and chronic hypohidrosis or anhidrosis. Regeneration of areas of desquamation occurs through replacement of epidermal basal cells either from islands of intact cells within the epidermis or by the migration of such cells from adjacent, uninvolved areas. Normal healing of the radiation wound becomes clinically evident approximately 2 weeks after exposure, consistent with the basal cell turnover time. Widespread confluent mucositis (grade 3), or more severe toxicity such as necrosis of the epidermis or

TABLE 240-1

Commonly Observed Adverse Events Attributable to Radiation

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Adverse Event

Grade 1

2

3

4

5

Radiation Dermatitis

Faint erythema Dry desquamation

Moderate-to-brisk erythema Patchy moist dequamation (mostly confined to skin folds and creases) Moderate edema

Moist desquamation (other than skin folds and creases) Bleeding induced by minor trauma or abrasion

Skin necrosis Ulceration of full thickness of dermis Spontaneous bleeding

Death

Alopecia Atrophy Dry Skin Hypo or Hyperpigmentation Induration or Fibrosis Telangiectasia

Thinning or patchy Detectable Asymptomatic Slight or Localized Increased Density on Palpation Few

Complete Marked Symptomatic Marked or Generalized Moderate Impairment; marked increase in density; minimal retraction Moderate

— — Interfering with ADLs — Dysfunction Interfering with ADLs; very marked density; retraction or fixation Many and Confluent

— — — — —

— — — — —

ADLs = Activities of Daily Living.

Radiation recall is a phenomenon first described several decades ago, describing a cutaneous reaction in the area of previous radiation exposure, in response to specific systemic agents. The most commonly cited chemotherapeutic agents are anthracyclines, taxanes, and gemcitabine. Other systemic agents implicated in radiation recall reactions include standard chemotherapeutic agents, newer targeted therapeutics, hormonal agents, as well as nononcologic medications; a list of such agents from case reports is compiled in Table 240-2. The clinical manifestations of radiation recall occur with the initial administration of the systemic agent: within minutes to days with intravenous drug, or days to weeks with oral medication. The timing of presentation may be related to the drug dose, and both the severity and timing of the reaction may be related to the prior radiation dose. The duration of the response may range from weeks to months. Interestingly, readministration of the same systemic agent does not consistently lead to recurrence of the ­phenomenon.10 While a recall reaction can occur in any organ, skin is the most common site. It occurs in a well-demarcated area defined by the borders of the previous treatment field, and can occur despite the lack of any clinically significant skin reaction during the previous radiation treatment. The clinical signs and symptoms mimic an acute radiation dermatitis, ranging from erythema to desquamation and necrosis. A localized maculopapular rash, characteristic of a hypersensitivity reaction, has also been described. The pathogenesis of radiation recall is not well understood. An early hypothesis was that tissue stem

Radiotherapy

RADIATION RECALL REACTIONS

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has been correlated with late fibrotic changes. Abrogation of downstream mediator SMAD3, a proinflammatory signaling molecule induced in response to TGF-β, appears to protect tissue from late fibrotic changes after radiation exposure in laboratory models. TGF-β is a complex regulator of inflammation that increases fibroblast proliferation, differentiation, and activation, and thereby increasing secretion of extracellular matrix components. TGF-β promotes its own secretion by fibroblasts in a self-amplifying cascade, and decreases the production of matrix proteinases. Epithelial cell proliferation is diminished, and there is chemotaxis of mast cells and macrophages. The result is increasing production, processing, and deposition of collagen (fibrosis), and loss of epithelial reconstitution of normal tissue structure. The initiating event in TGF-β activation in response to radiation is poorly understood. Latent TGF-β in the extracellular matrix may be activated by proteolytic enzymes that act in the presence of radiation-induced reactive oxygen species. Other potential sources of TGF-β include endothelial cells, fibroblasts, epithelial cells, and tissue macrophages, which may release TGFβ in direct response to radiation, or as a generalized response to tissue damage.

Chapter 240

underlying dermis, may not undergo complete regeneration of the structural and adnexal elements. Instead, there can be prolonged inflammation, fibroblast activation, and collagen deposition. This fibrosis is often termed a consequential late effect, since it is a consequence of the severity of the acute reaction. It is in contrast to the more common late fibrosis, which arises following the regeneration of relatively normalappearing skin and can occur years after treatment. Late radiation toxicity occurs months to years following exposure, following a period during which the skin may not exhibit significant abnormalities. The risk and severity of true late skin changes are a function of the irradiation dose and volume. A landmark study of normal tissue radiation tolerance determined that the risk of grade 4 or greater acute toxicity (i.e., ulceration or necrosis) was 5% when 10 cm2 of skin was treated to 70 Gy, or when 30 cm2 was treated to 60 Gy.4 Comorbid medical disease may exacerbate this risk; clinical risk factors associated with increased symptom severity include advanced patient age, diabetes, peripheral vascular disease, tobacco use.5 The concurrent administration of radiosensitizing drugs significantly increase the severity of acute radiation dermatitis and prolong healing of the radiation wound. Collagen vascular diseases with a fibrotic cutaneous component (e.g., scleroderma and systemic lupus erythematosus) are associated with a pronounced and often debilitating late subcutaneous fibrosis following radiation treatment.6,7 Certain genetic syndromes, particularly inherited defects in DNA damage repair (e.g., ataxia telangiectasia) predispose to a severe, acute, and late radiation response in exposed normal tissue. The late skin toxicity with the most functional consequence is subcutaneous fibrosis. Replacement of the subcutaneous adipose tissue with fibrous tissue leads to loss of normal range of motion, contraction, pain, and poor cosmesis. Even in cases where dermal and subcutaneous fibrosis is not clinically evident, there may be atrophy of the skin adnexa. Hair follicles, sebaceous, and sweat glands may be absent in previously irradiated skin because these are not regenerated during normal radiation wound repair. Loss of glandular elements leads to anhidrosis when extensive skin areas are irradiated, such as in total skin electron therapy. The microvasculature of the dermis and subcutis may exhibit abnormal myointimal proliferation, leading to hypoperfusion. Tortuosity within small vessels, and micro thrombi, results in visible telangiectasia. Irregular regeneration of the basal layer of the epidermis may be evident as dyspigmentation. Paradoxically, there may be a decrease in the population of resident skin fibroblasts in atrophic skin, with loss of the normal collagen structure leading to impaired tissue remodeling, increased skin fragility and poor wound healing. The pathophysiologic mechanism of late changes, particularly fibrosis, in response to radiation is incompletely understood.8,9 Transforming growth factor-beta (TGF-β) is a secreted protein that serves a complex regulatory role in normal tissue inflammation and remodeling by controlling proliferation, differentiation, and secretory function. TGF-β levels are increased within hours of radiation exposure, and this elevation

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Table 240-2

Radiation Recall Reactions Agents implicated in inducing a radiation recall reaction include chemotherapy drugs, targeted and hormonal agents, and nononcologic medications.

Section 38 :: Physical Treatments

Chemotherapy   Arsenic Trioxide   Bleomycin   Capecitabine   Cyclophosphamide   Cytarabine   Dacarbazine   Dactinomycin   Daunorubicin   Docetaxel   Doxorubicin   Epirubicin   Etoposide   Fluorouracil   Gemcitabine   Hydroxyurea   Idarubicin  Lomustine   Melphalan   Methotrexate   Paclitaxel   Vinblastine Targeted anticancer drugs   Bevacizumab   Pemetrexed Hormonal agents   Tamoxifen Nononcologic drugs   Gatifloxacin   Isoniazid  Levofloxacin   Simvastatin

of the rare but serious side effects of radiotherapy.11 This includes not only fibrotic changes in the affected skin, but more significant is the risk of secondary malignancy. It is estimated that the relative risk of malignancy following radiation treatment increases by 10%–50%; the absolute risk remains very low. These malignancies occur at a median of 10 years following treatment. The risk appears to be greater in younger patients, and in those treated to anatomic areas at highest risk for malignancy (i.e., breast or thyroid tissue). For this reason, radiotherapy should be considered in benign disease only after other therapeutic options have been exhausted, should be avoided when possible in children and young adults, and should be delivered with attention to sparing radiation exposure to sensitive normal tissue. Radiotherapy is effective symptomatic treatment of several inflammatory dermatoses, including eczema, psoriasis, and lichen planus at relatively low dose exposure (i.e., less than 10 Gy of fractionated treatment). These conditions are only rarely treated with radiation, given the number of other anti-inflammatory options. Benign lymphoproliferative disorders are sensitive in a similar fashion, and disorders such as lymphomatoid papulosis, lymphoid hyperplasia, and lymphocytoma cutis have an excellent response to radiotherapy. These may be treated with radiation after other options have been exhausted, and are approached using lymphoma regimens. Other benign proliferative processes that can be treated with radiotherapy include keratocanthomas, and hemangiomas. A list of diagnoses for which radiotherapy may be indicated can be found in Table 240-3. A number of large series and one randomized trial have examined the efficacy of localized, low-dose irradiation for the prevention of recurrence of hypertrophic scars or keloids following excision.12–14 This should be undertaken after failure of other therapies.

cells remained depleted long after radiation, making the tissue more sensitive to cytotoxics. This does not explain, however, radiation recall reactions elicited by noncytotoxics or the lack of a reaction to subsequent drug exposure in some cases. The clinicopathologic manifestations are best explained by a localized, acquired hypersensitivity reaction. Prior radiation therapy may alter the normal dermal immunologic response by changing basal and stimulated cytokine production. This is consistent with histologic findings of acute inflammation (vasodilation, infiltration of inflammatory cell mediators) in affected tissue. Radiation recall dermatitis responds to treatment with topical or oral corticosteroids.

TABLE 240-3

Cutaneous Indications for Primary or Adjuvant Radiotherapya

CLINICAL APPLICATIONS OF RADIATION

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Malignant

Eczema Psoriasis Lichen planus Benign lymphoid hyperplasia Keratocanthoma Keloids/hypertrophic scars

Squamous carcinoma Basal cell carcinoma Melanoma Merkel cell carcinoma Eccrine and apocrine carcinoma Cutaneous T- and B-cell lymphoma Kaposi Sarcoma Angiosarcoma

Premalignant Actinic keratoses Lentigo melanoma Bowen disease Erythroplasia of Queyrat Lymphocytoma cutis

BENIGN DISEASE The use of ionizing radiation for benign disease has decreased considerably, due both to improvements in alternative therapy as well as an increasing awareness

Benign

a

Radiotherapy is not recommended as first-line therapy for all the listed indications, particularly the benign disorders.

The most common treatment regimen is to use kilovoltage X-rays or electrons to a total dose of 10–20 Gy delivered over several days. The treatment is usually initiated within 24–48 hours of excision. The recurrence risk after surgery and radiation is approximately 20% or less. The use of radiation without excision on existing keloids is not as effective.

MALIGNANT DISEASE BASAL AND SQUAMOUS CARCINOMA.

Radiotherapy

CUTANEOUS LYMPHOMAS. Cutaneous T-cell lymphomas include numerous subtypes, the most common of which are mycosis fungoides (MF) and anaplastic large cell lymphoma. MF is exquisitely sensitive to radiotherapy and patients may present with localized or disseminated skin disease. Anaplastic large cell lymphoma (CD-30 positive) is also a common CTCL, but has an incidence which is less frequent than MF. The clinical presentation is also somewhat different, and these cells generally demonstrate a CD-4 positive phenotype (which can be seen in MF), and also express cutaneous lymphocyte antigen. As opposed to MF, these cells are typically not epidermotropic and do stain positive for CD-30. Lymphomatoid papulosis is also CD-30 positive and may be associated with anaplastic large cell lymphoma. Anaplastic lymphoma kinase (ALK) is usually not overexpressed in patients suffering specifically from cutaneous lymphoma of the CD-30 positive variety, though it may be expressed in patients with noncutaneous anaplastic large cell lymphoma. There are also a variety of subtypes of cutaneous B-cell lymphoma, but the most commonly encountered are diffuse large B-cell, marginal zone, and follicular center cell. Diffuse large B-cell lymphoma may express CD-20 and CD-79 and lesions involving the lower extremities may express BCL-2, BCL-6, and MUM-1. Marginal zone lymphoma can be identified via expression of CD-20 and CD-79 and often BCL-2, but typically BCL-6 is not noted as a marker in this case. The follicular center cell variant may express CD-20 and CD-79, but expression of BCL-2 and MUM-1 is unusual. Localized radiotherapy fields may be incorporated into the management of patients with limited disease but, in some cases, patients have extensive areas of skin which are involved and a total skin electron beam therapy (TSEBT) technique may be incorporated for adequate disease control. Localized radiotherapy is typically provided utilizing an electron technique and bolus material is applied to the skin in an effort to maintain an ­appropriate

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MELANOMA. The role of radiotherapy in the management of localized melanoma has not been conclusively established. Radiotherapy is frequently used for palliation of unresectable lesions, and there is evidence that selected patients at increased risk of local or regional failure may benefit from adjuvant radiation.18 Risk factors such as tumor thickness greater than 4 mm, ulceration, satellitosis, positive surgical margins, mucosal origin, perineural invasion, and desmoplastic histology are predictive of local relapse after wide excision. Patients with positive lymph nodes at high risk of recurrence after node dissection may benefit from postoperative radiation directed at the nodal basin.19,20 Melanomas are frequently treated with hypofractionated radiation, with fraction sizes of 4–6 Gy (i.e., 30 Gy in five fractions) using megavoltage X-rays. The recurrence risk for melanoma after radiation is significantly higher than that for squamous or basal cell ­carcinoma.

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Chapter 240

Radiation has been used as primary treatment for basal and squamous cell carcinoma, as an alternative to excision, with local control rates of 90% or greater for small lesions.15 There is concern for progressive late skin atrophy and necrosis decades after radiation, and for this reason surgical excision is usually felt to be a better option in younger patients (i.e., those less than 55). The control rate for primary treatment is a function of tumor size and T stage. For small lesions radiation is felt to offer local control that approximates that seen with excision. Radiation is also an effective adjuvant treatment, following excision or Mohs micrographic surgery. The clearest indication for treatment is positive margins; other considerations include tumor depth greater than 4 mm in the case of squamous cell cancer and tumor size greater than 2 cm. Involvement of cartilage or bone is a strong predictor of local recurrence and consensus guidelines recommend adjuvant treatment. Perineural invasion has been correlated with both local and nodal recurrence following excision, and is an indication for treatment.16,17 Involvement of large, named nerves should prompt consideration of extension of the clinical target volume to include the proximal nerve tract. Other relative indications for treatment include poorly differentiated tumors, adenosquamous subtype, and limitations imposed on excision by anatomic location. Patient factors include the presence of neurologic symptoms, implying underlying nerve involvement, and immunosuppressed host status. For squamous cell carcinoma, locally advanced lesions may have a significant risk of nodal metastasis. In patients being treated adjuvantly or definitively for locally advanced primaries with risk factors, draining lymphatics should be electively included. Dose fractionation schemes represent a balance between patient convenience and the relative risk of poor cosmesis. A total of 60–66 Gy in 2 Gy fractions is appropriate for gross disease, with higher doses indicated for lesions greater than 2–4 cm. Published experience with relatively hypofractionated treatment has shown equivalent locoregional control after 45–50 Gy in 2.5 Gy fractions, or radiobiologically equivalent doses in fraction sizes of 3 or 4 Gy. Tumors or postoperative areas that are at superficial depth may be treated with orthovoltage radiation to spare the deeper normal tissue. An alternative is electron therapy, with the appropriate bolus to maximize the surface dose. When the target volume is deeper, then megavoltage X-rays, with appropriate bolus, may be required. Target structures such as lymph node

basins or nerve tracts, in close proximity to critical normal structures, may require IMRT.

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deposition of dose at the skin surface. Typically the 90% isodose curve is utilized to provide homogeneous coverage of the area in question of the skin and margins of 2–3 cm radially are incorporated into the treatment plan. Doses of 30–36 Gy in 2 Gy fractions are used. With this type of regimen for most CBCLs, the complete response (CR) rate is greater than 95% with 5-year local control of approximately 75%.22,23 Some patients may not be able to logistically receive daily therapy over several weeks, but are in need of palliation of lesions which are bleeding, uncomfortable, unsightly, or impairing function. Such patients may be candidates for an abbreviated regimen of 2 Gy × 2 to a total of 4 Gy, which has been found to provide excellent response rates with reasonable durability in selected patients with low grade CBCL.24 TSEBT is significantly more complicated to provide and is typically utilized in patients suffering from extensive MF. It provides excellent response rates for patients with various levels of disease and has also been successful in patients with tumors of the skin, assuming that a supplemental boost be provided to the region involved by tumor. More superficial patches and plaques have an excellent response rate to TSEBT when it is used in the management of patients with MF and the response rate is 100%. The CR rate is variable and decreases with the degree of thickness associated with cutaneous lesions. A typical course of therapy is provided over approximately 8–10 weeks and, based on a Stanford technique, involves 36 fractions to the total skin utilizing six fields with blocking of the eyes, hands, fingernails and feet based on dosimetric parameters resulting from the individualized treatment program.25. The patient is treated in a variety of standing positions. TSEBT is best performed in centers that have a significant amount of experience with the technique given its degree of complexity. An important feature to be considered following

response to TSEBT is a maintenance program, and such maintenance can be provided in a variety of forms. For MF patients with T1 and T2 level disease, effective regimens, which have been documented in the literature, include the use of PUVA and mechlorethamine. Both cutaneous T- and B-cell lymphomas are very sensitive to radiotherapy, and it is generally accepted that all lesions will respond and that localized CBCL lesions have a CR rate approaching 100%. CTCL lesions have CR rates that are also excellent but are more dependent on extent of disease.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Khan FM: The Physics of Radiation Therapy, 4th edition. Philadelphia, Lippincott Williams & Wilkins, 2010, p. 42-43 10. Azria D et al: Radiation recall: a well recognized but neglected phenomenon. Cancer Treat Rev 31(7):555-570, 2005 11. Lahaniatis JE et al: Radiation treatment for benign disease. A survey of current treatment programs. Front Radiat Ther Oncol 35:1-17, 2001 14. Sclafani AP et al: Prevention of earlobe keloid recurrence with postoperative corticosteroid injections versus radiation therapy: A randomized, prospective study and review of the literature. Dermatol Surg 22(6):569-574, 1996 16. McCord MW et al: Skin cancer of the head and neck with clinical perineural invasion. Int J Radiat Oncol Biol Phys 47(1):89-93, 2000 18. Ballo MT, Ang KK: Radiotherapy for cutaneous malignant melanoma: Rationale and indications. Oncology (Williston Park) 18(1):99-107, 2004 21. Decker RH, Wilson LD: Role of radiotherapy in the management of merkel cell carcinoma of the skin. J Natl Compr Canc Netw 4(7):713-718, 2006 24. Neelis KJ et al: Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys 74(1):154-158, 2009

Complementary and Alternative Dermatology

Chapter 241 :: C  omplementary and Alternative Medicine in Dermatology :: Alan Dattner COMPLEMENTARY AND ALTERNATIVE MEDICINE AT A GLANCE Complementary medicine is a holistic approach to diagnosis and treatment. Many dermatologic therapies developed in ways similar to the complementary approach and were subsequently scientifically validated. Attention to the environment and its impact on the patient is a fundamental principle of complementary dermatology. This means our world dermatology organizations have an obligation to speak out about what is harming the skin, health, as it is related. Herbal therapeutics, supplements, diet, and digestive system aid are four of the primary interventions used in holistic dermatology.

Complementary and alternative medicine (CAM) in dermatology encompasses a wide variety of methods of diagnosis and treatment that either supplement or substitute for conventional dermatologic practice. It is also referred to as holistic dermatology because it considers and addresses the entirety of the individual, including the physical, mental, emotional, and spiritual aspects of the individual’s life, as appropriate. Holistic dermatology draws on an expanded knowledge base that includes CAM, conventional practice, and the latest research findings. Its diagnostic and therapeutic choices are made by combining these three knowledge bases, in what might also be termed integrative dermatology. The alternative healthcare systems considered by holistic dermatology may include time-honored practices such as ancient traditional Chinese medicine, Ayurvedic medicine, American folk medicine, homeopathy along with more recently developed techniques from chiropractic, energetic medicine, functional med-

icine, and psychosomatic modalities. Furthermore, holistic dermatology includes any other technique that works or makes sense based on science or observation. Increasingly, patients are using CAM methods in addition to conventional dermatological treatment as cosmeceutical, nutraceutical, and even pharmacological manufacturers more routinely offer these products. CAM practitioners and dermatologists are being called upon to respond to their patients’ expectations, preferences and demands for therapeutic modalities and treatments that avoid or minimize use of prescription drugs, and are safe, natural, and effective. Alternative medicine often embraces treatment that not only presages but also may ultimately be incorporated into conventional practice. Good CAM practice is rooted in basic science, clinical experience and good medicine, but it often lacks the sanctioned level of proof we have come to demand for scientific, allopathic dermatology. Further, CAM practices arise and are developed differently from conventional practices. For example, when a growing body of anecdotal experience is supported by the understanding of underlying mechanisms of pathology, particular CAM approaches to illness are employed, even before the methods are validated in the usual ways. Many of these methods are difficult to study or assess using conventional research methods because they relate to the individual rather than to the disease or condition itself. Many CAM methods and practices have slowly been incorporated into more conventional practice and some have gained widespread acceptance and use. Examples include the increasing use of probiotics, which had its tentative beginnings in the 1980s, to counter Candida overgrowth in the gut, which was later shown to enhance barrier function in the intestines and skin. The CAM use of essential fatty acids (EFA) as anti-inflammatory agents preceded the growing literature on this subject. CAM practice also identified trans-saturated fats as disrupters of cellular functioning, inhibiting the δ-6desaturase and thus the production of anti-inflammatory prostaglandins. This tenet of CAM medicine was set forth by Horrobin and others in the 1980s, decades before products containing transfats were removed from the shelves and castigated as deleterious for health.1,2

39

Similarly, kitchen herbalists and small companies were producing herbal skin applications long before the current popularity of cosmeceuticals. And while historically CAM practices have gradually been adopted by mainstream practitioners, in dermatology, the pace of adoption has quickened in recent years. Perhaps most telling is that much of the herbal pharmacopoeia of CAM dermatology referenced in the last edition of this text is now described in the dermatologic literature or is available in products designed for the skin.

HERBAL MEDICINE Section 39 :: Complementary and Alternative Dermatology

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Eclectic practice and off-label use of pharmaceutical drugs has always been a part of dermatology, perhaps more so than in medicine in general. These practices provide novel and often effective approaches to disorders of uncertain etiology by incorporating methods from other spheres or from observed benefit. Many of the commonly used pharmacological agents used in conventional allopathic medicine are derived from herbal medicine.3 The American “herbal” tradition dates to the Eclectics, a school of physicians who, during the nineteenth and early twentieth century codified the use of Western herbs according to specific indications.4 Today a wide variety of herbs is used, and the methods of selecting specific herb combinations also originate in other traditions. For example, psoralens have been used in China and India for repigmentation of the skin for more than 4,000 years. Other herbs used in treating the skin include mayapple (podophyllin) for condyloma, horse chestnut for leg veins, bloodroot (sanguinaria) for skin tumors, and oatmeal (Avena sativa) to soothe rough, itchy, or inflamed skin.3 In addition to specific herbal remedies, some of the philosophical tenets of herbal medicine have been incorporated as key concepts in dermatology. For example, the principle of using a crude preparation as opposed to a purified single ingredient as tends to be used in a pharmaceutical product, was one of Sulzberger’s observations regarding the use of tar.5 It was the crude tar product from the distillery and not its purified derivative that had activity in treating psoriasis. In fact, variation in batch efficacy was assumed to be an indication of the heterogeneous nature of the preparation. A virtual explosion in the availability of herbs in cosmeceuticals, herbal supplements, and new pharmaceuticals has occurred during the past 15 years. This growth has been accompanied by a substantial increase in peer-reviewed publications seeking to clarify the mechanism of action of herbs and their components and case studies detailing knowledge inferred from their traditional use. Each herb has a number of different activities and actions, which depend on growth conditions, the extent to which they have been challenged to fend off pathogens and predators, method of extraction, and the culture that utilized the herb or herbal preparation. One of the advantages of knowing the traditional uses of herbs and their rich history of folk use is the ability to more fully appreciate their spectrums of action. For example, oats, A. sativa, are well known for

their soothing anti-inflammatory effects on the skin as a topical soak. The milky white sap from green oats is known for its calming properties as a relaxant to the nervous system. In the context of its use as a folk and home remedy, it is easier and intuitively correct to seek out oat extracts for their calming effects on the nervous tissue in the skin, i.e., soothing and anti-pruritic actions as well.

ANTIOXIDANTS Antioxidants prevent damage from both exogenous and endogenous free radicals. Ultraviolet radiation from the sun is a major source of free radical damage to the skin, but is beneficial for the production of vitamin D. A symphony of antioxidants prevents excessive damage to either the somatic tissues or DNA of the cells. Plants also must develop their own complex of antioxidants in order to withstand excessive damage from the sun. A young sprout or a plant placed prematurely in full sun will wither and die. It is the complex of antioxidants and light absorbing pigments that plants develop which function to protect them from this damage. Therefore, some argue that eating whole plants, with their functional spectrum of antioxidants, is more protective than isolating the most active fraction, such as β-carotene, and administering it alone. Nutritional supplementation can supply external antioxidants, or support the generation of endogenous antioxidants. Carotenoids and polyphenols (bioflavonoid) are two major classes of plant-derived antioxidants. Bioflavonoids are especially protective of the capillaries and blood vessels. Oxidative damage and glycation damage induce metalloprotease activity, which destroys the integrity of collagen and elastic tissue in both the skin and the vasculature, and antioxidant protection may slow this process.

APPROACH TO DISEASE The hallmark of CAM is a search for the elements in the causal chain of functional disturbances that lead to a skin disorder. For inflammatory disorders, an attempt is made to identify exposures, which could stimulate and/or disturb immune responses with secondary targeting of skin structures. CAM focuses on correcting probable underlying causes, often with treatments that are not proven in the traditional scientific method. The patient not only assumes the responsibility of making the necessary lifestyle changes but also the risk of using protocols that are neither conventional nor necessarily well researched. Individual specificity is key to CAM dermatology. Long before knowledge of specific pathogens and genetic polymorphisms, other systems of healing such as Ayurvedic medicine developed classification and treatment paradigms that are still used today, and extend well beyond diagnosis. The long-awaited studies and meta-analyses of CAM in dermatologic disorders such as psoriasis6 will continue to be of very limited usefulness because they persist in classifying

patients solely by disease and fail to choose herbs and supplements for time-tested indications in traditional systems, or based on CAM or individual-specific disease mechanism parameters. Appreciation of these distinctions will lead to the design of research studies that truly indicate how to integrate CAM into dermatology as well as how to accurately evaluate the efficacy of CAM practices.

“FOOD ALLERGY” DETERMINATION AND ELIMINATION. In addition to classic immunoglob-

Complementary and Alternative Medicine in Dermatology

ESSENTIAL FATTY ACIDS. EFAs play an essential role in skin health. EFAs are the precursors of the eicosanoids produced when phospholipase cleaves a lipid fragment, arachidonate, from the cell membrane. Arachidonate, a common pathway byproduct from most foods, leads, via cyclooxygenase, to production of the proinflammatory prostaglandin E2(PGE2), or via lipoxygenase to production of proinflammatory leukotrienes.25 Specific ω-6 unsaturated EFAs such as γ linolenic acid, found in borage oil, evening primrose oil, and human breast milk, lead to formation of the anti-inflammatory PGE1. ω-3 unsaturated fatty acids such as those found in fish oils contain eicosapentae-

Homeopathy pushes the boundaries of the scientific mind because it works by invoking the energy of the substance rather than the substance itself, with greater dilutions having greater potency.32 A key aspect of homeopathy is that substances diluted homeopathically often, but not always, work by counteracting the very symptoms that the undiluted substance produces. For example, Nux vomica is used to counteract nausea, and Coffea, from coffee, is used to induce sleep. Some herbalists also use the information from the provings, the homeopathic repertory, for seeking further insight into the characteristics of herbs.33

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Food Allergy Diagnosis. Diagnosing food allergy is best initiated by a careful history of the specific foods that preceded a reaction; these include foods consumed a few hours or even few days prior to the reaction. A food and reaction diary helps to reinforce memory and document instances of food consumption and reactions. Elimination and challenge is the gold standard for identifying food allergens. Intradermal testing can be helpful, and is far more useful than scratch tests because the latter detect IgE or immediate allergy only.

HOMEOPATHY

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Chapter 241

ulin E-mediated allergic response, the term food allergy also includes other types of allergy such as immune complex, delayed, and Toll-like receptor activation. There is also nonallergic sensitivity. Food allergies develop to the many common foods such as wheat, milk, soy, yeast, and corn. Some believe that a hallmark of food allergy is food craving with repetitive eating of the same food each day.19 A 5-day elimination and rechallenge on the sixth day is an effective way to determine if the food under consideration is the cause of the symptoms of concern. Other symptoms beyond the skin could include digestive upset, nasal stuffiness, fatigue after eating, or even “brain fog.” Brain fog is a popular term for a sense of mental confusion, sluggishness, and slowness that may sometimes include a feeling of unreality or disorientation. Small peptides from casein digestion known as caseomorphins, which can also derive from gluten, rice, bovine albumin, and even spinach, have psychoactive properties.20 Treatment involves elimination, substitution with other foods, and food rotation. Enhancing digestion with digestive enzymes and adding metabolites to enhance the gut permeability barrier (and reduce the impact of leaky gut) helps to prevent sensitization to disease inducing cross-reactive antigens.21,22

noic acid (EPA), which leads to formation of the antiinflammatory and anticlotting PGE3. Flaxseed oil has an ω-3-EFA known as α-linolenic acid, which requires two carbon chain elongation to become EPA, requiring activity of the δ-6-desaturase enzyme. That enzyme has cofactor requirements of zinc, magnesium, vitamins C, B3 and B6, and low insulin levels. ω-3 EFAs also play a role in formation of the barrier lipid in the brick and mortar structure of the stratum corneum barrier. Partially hydrogenated oils not only lead to proinflammatory PGE2 formation, but also inhibit the δ6-desaturase, which is crucial for formation of antiinflammatory γ-linolenic acid. Shifting the balance toward anti-inflammatory EFAs by removing foods with proinflammatory oils and increasing foods and supplements with anti-inflammatory oils (e.g., cod liver oil) is a strategy useful in most conditions involving inflammation and dry skin. It is especially useful in seborrhea and eczema. Rare problems with excessive fish oil include increased bleeding tendency26 and high-birth weight, postmature babies.27 A number of studies have shown the effectiveness of ω-3-EFAs in psoriasis and other inflammatory and autoimmune diseases.28 EFAs also confer powerful protection from UV exposure and have been used to reduce inflammation and promote wound healing in burn victims.29,30

COMPLEMENTARY AND ALTERNATIVE MEDICINE APPROACHES TO SPECIFIC DERMATOLOGIC CONDITIONS Several dermatologic disorders, particularly those that are inflammatory in nature, may benefit from the CAM approach.

SEBORRHEIC DERMATITIS (See Chapter 22) Seborrheic dermatitis34 involves inflammation in sebaceous follicular areas of the scalp, eyebrows, and nasolabial folds. All of these regions harbor the yeast

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Malassezia, which is normal follicular flora. There is evidence that Malassezia is cross-reactive with Candida albicans,35 and it is postulated here that a cross-reactive attack against antigenic epitopes on the Candida and other yeasts and molds becomes directed against the Malassezia organisms in the follicle, causing the inflammation that incites the erythema and desquamative changes characteristic of seborrhea. An altered pattern of EFAs in infantile seborrheic dermatitis implicates impaired function of the δ-6-desaturase.36 Some of the B vitamins previously reported as helpful in seborrhea may function as cofactors for this enzyme.37–39 The tendency toward inflammation is exacerbated by a predominance of arachidonic acid precursors in the cell membranes derived from dietary sources. Treatment by substituting EPA-rich fish oil in the diet and removing partially hydrogenated and saturated oils can reduce this inflammatory state by favoring the generation of anti-inflammatory PGE3.40–42 Flaxseed oil is another ω-3-fatty acid and PGE3 precursor, but the active ω-3EFA in it, α-linolenic acid, requires chain elongation to be converted to EPA, and this process is not uniform among individuals.43

ATOPIC DERMATITIS (See Chapter 14) Atopic dermatitis is an inflammatory disorder of the skin linked to asthma and hay fever. In the past, dermatologists observed cases in which food was considered a trigger, but were generally puzzled that there did not seem to be a specific food that caused the eczema. One challenge was that eczema could be aggravated by one food, and then after diet change, would be exacerbated by the newly substituted food. One theory articulated by practitioners of CAM relates to what is known as leaky gut.44 Disruption of the gut barrier can result from inflammation of the intestinal lining. This inflammation may be caused or precipitated by parasites, Candida overgrowth, food sensitivity, foods containing lectins that punch holes in cell membranes, or pathogenic microorganisms. In addition, nonsteroidal anti-inflammatory drugs are irritating to the gut lining, as are alcohol and aspirin. Any food introduced repeatedly into such an environment can lead to sensitization to that food. In these cases, it is believed that the uncontrolled atopic becomes sensitive to whatever he/she eats repeatedly to avoid that which caused trouble initially. For example, the milk-allergic infant switched to soy protein soon becomes “allergic” to soy. Inflammation in the gut wall stimulated by soy causes allergy to whichever nutrient is next exposed to the gut immune system. This “vicious cycle” could account for the name atopic, which was used to describe the changeable nature of the factors initiating the dermatitis. Treatment consists of removing abnormal microbes and restoring normal flora, removing irritants, eliminating exacerbating foods, enhancing enzymatic breakdown of foods (digestion), coating the gut with

mucilaginous herbs, and providing the nutrients needed to support an intact gut barrier. Proper colonization of the gut with Lactobacillus acidophilus and similar strains has a protective effect against atopy.45 A corollary of this observation is that repeated use of antibiotics favors overgrowth of C. albicans, and simple starches and sugars support Candida growth. It is presumed that consumption of large amounts of yeast, mold, and their byproducts, such as bread, beer, wine, and cheese, could both induce high-dose antigen tolerance to intestinal Candida, and perhaps even sensitize to other antigenic determinants. High-dose tolerance is a lack of immunoreactivity to specific antigenic determinants or substances due to the presence of large quantities of these determinants in the system. Treatment consists of removing the dietary factors that favor Candida and then treating with herbal or other natural remedies to reduce the yeast population. Artemisia annua and short-chain fatty acids such as undecylenic or caprylic acid are a few such treatments. Next, probiotics may be added to prevent Candida from overtaking gut flora. Only when these measures have been taken should pharmaceuticals be used in a progressive fashion. Otherwise, there is the risk of selecting for resistant strains. Nystatin may be considered, followed by ketoconazole and fluconazole. Nystatin should be slowly increased in dosage from 500,000 units/day in divided doses to 6 million units, over 10–12 days. Highly yeast-sensitive individuals absorb cell content material through an already leaky gut wall and are known to develop exacerbation of previous symptoms and sometimes fever, with a Herxheimer-like reaction. All of these drugs have more potential effectiveness when the environment is changed by dietary restrictions on sugars, simple carbohydrates, and foods high in or derived from yeast. Anti-inflammatory EFAs, such as EPA from fish oils, appear to help some atopics.46 Hempseed oil, rich in ω-3- and –6-EFAs, improved the serum fatty acids, and the condition of atopics, in a study conducted in Finland.47 There has been a consistent increase in the number of studies showing that γ-linolenic acid from borage or evening primrose oil48 effectively resolves various aspects of atopic dermatitis, and there is clear indication that it is beneficial for some patients with eczema. The results of a small study performed in Germany showed that GLA supplementation from EPO reduced total IgE in the first year of life, but did not prevent atopic dermatitis. Another study found decreased GLA levels in children with eczema and elevated IgE levels and others with atopy, but not in eczema patients with normal IgE levels.49 Metaanalyses to the contrary50 are likely contaminated by issues discussed under EFAs, above, and should not dissuade physicians or patients from a proper trial of EFAs in atopic patients, once oxidative stress has been calmed down. Furthermore, a balance of antiinflammatory EFAs is likely most effective for allergic individuals. It should be remembered that the industrialization of our food supply over the past halfcentury, including partial hydrogenization of nearly

Complementary and Alternative Medicine in Dermatology

(See Chapter 80) Before the availability of tetracycline, diet change was a mainstay in acne treatment. With the advent of antibiotics for acne, many dermatologists argued that the stress produced by restricting favorite foods was itself acne causing, and consensus evolved to minimize the role of diet in acne. This view was supported by seminal papers that demonstrated that common agents such as chocolate did not cause acne.52 More recent data do reveal a relationship between milk consumption, both full-fat and especially nonfat, and acne in teenage girls53 and boys54,55 Darby and others posit that hormones normally present in milk as well as added to enhance milk production may be responsible for this effect. This includes progesterone-related hormones and 5-α-pregnanedione, which is converted directly into dihyrotestosterone.56 Milk protein allergy causing an inflammatory response that blocks the infundibular apparatus also may contribute.44 It now appears that diet may influence a number of mechanisms related to acne development.57 Bovine milk production by postpartum cows contains placenta-derived progesterone and dihydrotestosterone precursors. Other hormones in addition to steroids in milk also may stimulate acne. The most frequently implicated substance is IGF-1 (insulin-like growth factor), which also increases during the teenage years as a result of growth hormone. IGF-1 is present in organic milk and increased in milk from cows treated with bovine growth hormone. IGF-1 increases lipogenesis in sebocytes.58 It stimulates 5-α-reductase and androgen synthesis. It has also been shown that excess carbohydrate consumption increases insulin,

39

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Acne

which increases IGF-1, which in turn worsens acne.59 IGF-1 and dihydrotestosterone levels in women both correlate with acne.60 Melnik has elegantly suggested the role of deficiency or displacement of nuclear transcription factor Fox01 from suppressing the androgen receptor and the promoter of PPAR-γ as the key initiator of the activation of the genes for sebocyte proliferation, sebum synthesis, and inflammatory cytokines.61 He observes that retinoids increase Fox01, and that all known acneinducing factors work by decreasing it. Milk elimination and reduced carbohydrate ingestion can produce a substantial improvement in some acne patients, as does reduction of proinflammatory fats from fried and partially hydrogenated sources. In women with perimenstrual flaring, reduction of dietary estrogens, and pseudoestrogens may be ­helpful. The holistic perspective posits that the initiator of the inflammatory process that leads to acne is derived from antigens and informational molecules derived from an improper diet and environment, and that the mechanism of inflammation, so elegantly described in the classic and emergent literature, is a key precipitating step in that cascade. Recent evidence indicates that inflammation in the pilosebaceous unit may precede the follicular plugging and Corynebacterium acnes proliferation,62,63 and that the predominant presence of CD+ memory/effector cells suggests a specific antigenic T-cell inflammatory, rather than nonspecific, immune response. Timed immunofluorescent studies reveal a type IV delayed hypersensitivity response, and, therefore, point to a soluble antigen stimulus initiating the acne lesion.64 A primary response to antigen in a structure that concentrates antigenic material from the blood, which ultimately comes predominantly from the digestive tract, makes acne an inflammatory disorder that should respond to the alteration of gut-derived antigens described in this chapter. There is evidence from animal studies that carbon14-radiolabeled α-linolenic acid, dietary ω-3-EFA found in flaxseed, is preferentially found in the coat of guinea pigs, suggesting sebaceous excretion of this dietary lipid.65 There is reason to believe that all of the lipids, and indeed all of the other molecular moieties that are secreted or synthesized into secretions in the pilosebaceous unit, are derived either from diet, body stores, microbial metabolites, or topical absorption. The infundibular apparatus concentrates and excretes both water-soluble wastes in the sweat, and lipid and proteinaceous material in the sebum. Medications, such as ketoconazole, have been found in sebum.66

Chapter 241

all food products that required shelf life, hardening oils for convenience in food, importing southern oils where unsaturated northern oils were local, and farm feeding grains to fish, poultry, and livestock that previously consumed local cold grown plants naturally rich in unsaturated fatty acids, all have served to dramatically reduce the proportion of anti-inflammatory EFAs in our diets and thus cell membranes. Some of the increase in atopy, inflammatory, and autoimmune disorders we are now seeing may be in response to the “hair trigger” this shift is placing on the prostenoid aspect of the immune response. There has been scant attention paid to primary prevention of atopic dermatitis. Although conventional wisdom has held that breastfeeding is associated with reduced incidence of atopic dermatitis in children, recent research questions this, especially when the mother herself is allergic. In fact, it seems likely that dietary allergens present in breast milk of these allergic mothers may actually trigger or contribute to the development of atopic dermatitis in offspring. For this reason, it may be prudent to suggest that mothers of infants at risk for atopic dermatitis avoid dietary allergens. There also is some evidence of benefit from the use of probiotics and supplementation with EFAs.51

HIDRADENITIS SUPPURITIVA Hidradenitis suppuritiva (HS) may respond to treatment that enhances digestive function, gut barrier function, and elimination of reaction to allergenic foods. HS is increasingly being recognized as a ­disorder of immune function, at least in the local ­tissues.

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KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 3. Dattner A: From medical herbalism to phytotherapy in dermatology: Back to the future. Dermatol Ther 16:106, 2003 6. Smith N, et al: Complementary and alternative medicine for psoriasis: a qualitative review of the clinical trial literature. J Am Acad Dermatol 61(5):841-856, 2009

Section 39 :: Complementary and Alternative Dermatology

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7. Untersmayr E, Jensen-Jarolim E: The effect of gastric digestion on food allergy. Curr Opin Allergy Clin Immunol 6(3):214, 2006 14. Walker WA, Isselbacher KJ: Uptake and transport of macromolecules by the intestine: Possible role in clinical disorders. Gastroenterology 67:531, 1974 18. Adebamowo CA et al: High school dietary dairy intake and teenage acne. J Am Acad Dermatol 52:207, 2005 24. Kalliomaki M et al: Probiotics in primary prevention of atopic disease: A randomized placebo-controlled trial. Lancet 357:1076, 2001 36. Tollesson A et al: Essential fatty acids in infantile seborrheic dermatitis. J Am Acad Dermatol 28:957, 1993

Surgery in Dermatology

Chapter 242 :: A  natomy and Approach in ­Dermatologic Surgery :: Sumaira Z. Aasi & Brent E. Pennington INTRODUCTION TO DERMATOLOGIC SURGERY AT A GLANCE Profound knowledge of the anatomy, particularly of the head and neck region, is essential. Preoperative assessment includes a thorough medical, drug, and medication history.

reasons, including communicating precisely with colleagues, performing efficient and safe procedures, obtaining optimal functional and aesthetic reconstruction, understanding the lymphatic drainage, and anticipating the metastatic spread of malignancies. As the majority of cosmetic and surgical procedures are performed on the face, and because of its complexity, this chapter focuses on the superficial cutaneous anatomy of this critical region.

Asepsis and antisepsis are required. The choice of the anesthetic is determined by the nature and duration of the procedure and by patient factors such as allergy or renal or hepatic impairment. Side effects of local anesthetics are pain, a vasovagal reaction, or (uncommon) allergic reactions. Anesthetic toxicity is rare. Infiltrative anesthesia, nerve blocks, and topical anesthesia (for minor procedures) can be performed. Types of suture material and suturing technique depend on the surgical procedure. Postoperative care is essential.

Dermatologic surgery has rapidly become a cornerstone of the practice of dermatology. Factors such as the epidemic of skin cancer, the interest in maintaining a youthful appearance for an aging population that is living longer, and the financial pressures to perform surgery in less expensive outpatient settings have led to an increase in the number of surgical procedures performed in dermatologic practice.

ANATOMY Anatomy is often called the language of surgery.1,2 Knowledge of anatomy is critical for a number of

COSMETIC UNITS AND LANDMARKS Landmarks and cosmetic units help localize areas of the face accurately and precisely for purposes of communication with colleagues and to perform the surgery itself. For instance, it is more helpful to describe a lesion on the face if it is said to be located on the “left nasal sidewall” versus left nose or “right triangular fossa” versus right ear. Cosmetic units are zones of tissue that share cutaneous features such as color, texture, pilosebaceous quality, pore size, and degree of actinic exposure. These cosmetic units are demarcated by junction lines that can be discrete (eyebrows) or subtle (nasofacial sulcus). Cosmetic units can also be further divided into subunits. Because of the tissue similarity, it is often best to reconstruct a surgical defect within a cosmetic unit or subunit or borrow tissue from nearby units. In addition, scar lines can be hidden easily in junction lines between the cosmetic units. The more complex regions of the face that have multiple subunits include the nose, ears, and lips (Figs. 242-1 and 242-2). The subunits of the nose include the glabella (the area between the eyebrows), the root (the deep sulcus below the glabella and uppermost portion of the nose), dorsum or bridge (the area overlying the nasal bone), lateral side walls (the sides of the nose), nasal tip, the nasal ala (the nostril), alar groove and nasolabial crease (the grooves that demarcate the alae superiorly from the lateral nasal sidewall and alae inferiorly from the lip, respectively), and the columella (the mobile linear structure separating the alae inferiorly) (see Fig. 242-1). The lateral surface of the ear is rimmed by the helix, a curved cartilaginous structure that begins at the crus

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Cosmetic units and landmarks of the face

Glabella Root

Nasofacial sulcus

Dorsum Lateral side wall

Columella

Tip

Section 40

Philtral crest Melolabial fold Cupid’s bow

Ala nasi Philtrum Vermilion

Mental crease

:: Surgery in Dermatology

Figure 242-1  Cosmetic units and landmarks of the face. just above the external auditory canal and continues around the ear to end at the fleshy lobule. The central concavity within which the external auditory meatus lies is the concha. The concha is divided by the crus of the helix into a superior portion, the cymba, and an inferior portion, the cavum. The posterior border of the concha is formed by another cartilaginous structure called the antihelix. Superiorly, the antihelix originates from two legs (crus is Latin for leg): (1) the superior crus and (2) inferior crus. The region between the crura is referred to as the triangular fossa. The groove between the helix and antihelix is the scaphoid fossa. The triangulated cartilaginous structure just anterior to the auditory canal is called the tragus, and just posterior to this is the triangulated end of the antihelix, referred to as the antitragus. The inferior region between the tragus and antitragus is the intertragic notch (see Fig. 242-2).

The cutaneous upper lip has a concave depression in the center, called the philtrum, which is bounded by two ridges, the philtral crests. There is a prominent crease, the mental crease, which divides the cutaneous lower lip from the chin. The boundary between the red mucosal surface of the lips and the cutaneous surface is called the vermillion border. The raised contoured area of the inferior portion of the philtrum is a critical aesthetic landmark known as the Cupid’s bow (see Fig. 242-1).

RELAXED SKIN TENSION LINES Relaxed skin tension lines (RSTLs) are another characteristic of the face that help guide surgical reconstruction and allow the structural camouflage of scar lines. RSTLs are creases on the face that form over time due to factors such as loss of elastic tissue tone, lengthening of the collagenous fibrous septae that connect the dermis to the underlying facial muscles, development of excessive skin, gravity, and ultraviolet radiation exposure. Fig. 242-3 illustrates a surgical defect on the upper lip of an elderly woman with prominent RSTL. RSTLs are most obvious on the face because unlike other muscles in the body that connect tendons and bones, facial muscles attach to the overlying skin. These lines can be induced by facial muscle movement in the young but inevitably become more pronounced with age. RSTLs usually run perpendicular to the underlying muscles. In most situations, the long axis of the excision should be placed parallel to the RSTL because they are often in the direction of the least tension for a scar. It is preferable to design flaps such that the majority of the scar lines fall within the RSTL.

DANGER ZONES There are three main danger zones that are critical to understand while performing surgical procedures

Landmarks of the external ear

Triangular fossa Scapha Concha -cymba -cavum Helix Antihelix Antitragus

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Figure 242-2  Landmarks of the external ear.

Crura of antihelix Crus of helix External auditory meatus Tragus Intertragic notch Lobule

Figure 242-3  Relaxed skin tension lines of the face.

on the head and neck. Each of these zones involves a motor nerve and the muscles it innervates. It is important to confirm the proper function of these muscles before performing a procedure in these areas so that it can be readily determined whether an injury occurred during surgery.

TEMPORAL BRANCH OF THE FACIAL NERVE. The temporal branch of the facial nerve is at

SUPERFICIAL MUSCULOAPONEUROTIC SYSTEM. The term fascia refers to connective tissue that

contains both fibrous and fat tissue in various amounts. Superficial fascia is the subcutaneous tissue that is immediately below the dermis. The deep fascia consists of more compact and highly organized collagen fibers. The superficial musculoaponeurotic system (SMAS) is the fascial system that envelops the muscles of the face. It stretches over the cheeks between the temporalis and frontalis muscles above and the platysma muscle below. The SMAS also attaches to the orbicularis oculi muscles anteriorly, the trapezius muscle posteriorly, and includes the fascia of the forehead and galea of the scalp. Most of the superficial muscles of the scalp and face insert into the skin either directly through fibrous bands running in the subcutaneous tissue or indirectly by attachment to the SMAS, which, in turn, is attached to the skin. In the lateral areas of the face, the SMAS is organized and more visible but becomes less discrete medially. Because of its attachment to the skin superficially and muscles deep, the SMAS coordinates a wide range of facial expressions. In addition, the SMAS is an important landmark because most major arteries and nerves run within or deep to it. Thus, dissection above the SMAS allows one to safely avoid injuring branches of the facial nerve.

Anatomy and Approach in ­Dermatologic Surgery

Danger zone for the temporal nerve

UNDERMINING PLANES

::

MARGINAL MANDIBULAR NERVE. Damage to the marginal mandibular nerve results in contralateral and upward pull on the mouth while the affected ipsilateral side of the mouth is fixed in a grimace with a lip droop. As it crosses the angle of the mandible at the inferoanterior border of the masseter, the marginal mandibular nerve is covered only by skin, subcutaneous fat, and fascia, which may be thin in this location, particularly in the elderly.

accessory nerve leads to the paralysis of the trapezius with winging of the scapula, shoulder drop, inability to shrug the shoulder, difficulty with abducting the arm and chronic shoulder pain. Transection of the spinal accessory nerve can occur when operating in the posterior triangle of the neck. This region is delineated by the clavicle inferiorly, the sternocleidomastoid muscle anteriorly, and the trapezius muscle laterally and posteriorly. One can anticipate the location of the spinal accessory nerve by drawing a line connecting the angle of the mandible with the mastoid process. A vertical line is then drawn from the midpoint of this line 6 cm inferiorly. The point at which this line intersects the posterior border of the sternocleidomastoid muscle is Erb’s point. The spinal accessory nerve emerges approximately from this point and lies superficially here, covered only by skin and fascia.

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Chapter 242

greatest risk for injury where it crosses the zygomatic arch. Injury to the temporal branch of the facial nerve leads to an inability to elevate the eyebrows and brow ptosis and paralysis. Asymmetric appearance of the forehead can also occur because there will be a loss of the lines and wrinkles on the affected side. One easy method to delineate the danger area of the temporal nerve is to draw a line from the earlobe to the lateral edge of the eyebrow, and another line from the tragus to just above and behind the highest forehead crease (Fig. 242-4). In the area between these lines, over the zygomatic arch is where the nerve is superficial, and it is critical in this area to undermine just below the dermis in the superficial fat above the fascia.

SPINAL ACCESSORY NERVE. Injury to the spinal

SCALP. The scalp is classically divided into five layers that are often referred to by the mnemonic SCALP. These layers from superficial to deep are: skin, subcutaneous tissue, aponeurosis (galea aponeurotica), loose connective tissue, and periosteum. Because the majority of the nerves and vessels of the scalp are superficial to the subgaleal space, this is an ideal undermining plane. However, it is also known as the danger zone because hematomas and infection can develop here and pass through the emissary veins into the meninges. Figure 242-4  Danger zone for the temporal nerve.

FOREHEAD. The forehead is best undermined immediately above the superficial fascia of the frontalis

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muscle. There may be little subcutaneous fat in this area. The temple should be undermined in the high fat/subdermal region to avoid damaging the temporal branch of the facial nerve.

EYELIDS. The eyelids possess the thinnest skin of the body. The skin of the eyelids lies directly on the orbicularis muscle. Undermining should be performed above the muscle fascia to avoid causing significant bleeding and scars/contractures that can lead to ectropion.

Section 40

CHIN AND LIPS. The large, thick muscles of the lips and chin can make undermining challenging. The chin, in particular, has muscles broadly attached directly to the skin. Sharp undermining performed just above the superficial muscular fascia is appropriate. These areas are at high risk for bleeding, made even more precarious by functions such as talking and chewing.

:: Surgery in Dermatology

NOSE. The nose requires different levels of undermining in different regions. The dorsal nose can be easily undermined above the periosteum, especially when performing reconstruction with flaps. The distal, more sebaceous portion of the nose must be undermined in the subfibrofatty layer to allow the greatest tissue movement. CHEEKS. The cheeks can be safely mobilized in the high or mid subcutaneous fat. Care must be taken when undermining in the hair-bearing regions of the cheek in men, however. Here, undermining should be performed in the deep subcutis to avoid transecting hair follicles. NECK. The neck can be safely undermined while staying above the superficial fascia. One must be careful in the posterior triangle of the neck. This region is delineated by the clavicle inferiorly, the sternocleidomastoid muscle anteriorly, and the trapezius muscle laterally and posteriorly. The spinal accessory nerve lies superficially here, covered only by skin and fascia. SENSORY NERVES

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The trigeminal nerve (cranial nerve V) provides the majority of the sensory innervation of the face (Fig. 242-5). It exits the skull via three foramina located bilaterally in the midpupillary line, the supraorbital, infraorbital, and mental foramina. The first branch, the ophthalmic nerve (V1), has several branches that supply the innervation to the superior portion of the face: the supraorbital, supratrochlear, infratrochlear, external nasal, and lacrimal nerves. The supraorbital (lateral) and supratrochlear (medial) nerves supply the forehead and anterior scalp and are branches of the frontal nerve (the largest branch of the ophthalmic nerve). They exit from two notches along the orbital rim: (1) supraorbital foramen or notch laterally, and (2) supratrochlear notch, medially. The infratrochlear branch (of the nasociliary nerve) supplies the glabella, nasal root, and bridge. The external nasal branch (or the dorsal nasal nerve) is a branch of the anterior eth-

Sensory distribution of the trigeminal nerve

Opthalmic V1

Maxillary V2

Mandibular V3

Figure 242-5  Sensory distribution of the trigeminal nerve.

moidal nerve of the nasociliary branch of V1. The external nasal branch supplies the dorsal nose and provides the anatomical explanation of Hutchinson sign that can occur in some cases of herpes zoster of the ophthalmic nerve. Vesicles on the nasal tip indicate that the eye may be involved because the nasociliary branch of V1 sends branches both to the nasal tip and the cornea. The lacrimal branch supplies sensation to the upper eyelid. The second branch of the trigeminal nerve is the maxillary nerve (V2). The maxillary nerve supplies sensation to the lateral nose, lower eyelid, superior cheek, and anterior temple. The maxillary nerve gives off two main branches that supply the skin of the face. The zygomatic branch of the maxillary nerve gives rise to the zygomaticofacial nerve, which exits the skull through the lateral zygomatic bone and supplies a small area of the lateral canthus. In addition, the zygomatic branch also gives rise to the zygomaticotemporal nerve, which exits the skull through the anterior temporal fossa and supplies skin of the anterior temporal region. The largest branch of the maxillary nerve is the infraorbital nerve that exits the skull through the infraorbital foramen of the maxilla. This supplies sensation to the eyelid and superior cheek. The third branch of the trigeminal nerve is the mandibular nerve (V3). Its branches provide sensory innervation to the lower lip, chin, mandibular and preauricular cheek, anterior ear, and the central temporal scalp. The mandibular nerve gives off three major cutaneous branches: (1) the auriculotemporal, (2) buccal, and (3) mental nerves. The auriculotemporal

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Muscles of facial expression

Epicranial aponeurosis (galea aponeurotica) Frontalis muscle Procerus muscle Corrugator supercilii muscle Orbital portion Palpebral portion

Orbicularis oculi muscle

Levator labii superioris alaeque nasi muscle

Zygomaticus minor muscle Zygomaticus major muscle Levator anguli oris muscle

Orbicularis oris muscle Depressor anguli oris muscle Depressor labii inferioris muscle Mentalis muscle

Figure 242-6  Muscles of facial expression.

nerve innervates most of the temple, the temporoparietal scalp, the anterior ears, parts of the external ear canal, and the tympanic membrane. The buccal nerve lies deep to the parotid gland and supplies the skin over the buccinators, buccal mucosa, and the gingiva. The mental nerve exits through the mental foramen and is a continuation of the inferior alveolar nerve. The mental nerve supplies sensation to the lower lip and chin.

MUSCLES The scalp has two muscles overlying it, the frontalis anteriorly and the occipitalis posteriorly. These muscles are joined by a thick fascia centrally over the scalp, the galea aponeurotica. The frontalis muscle also covers the forehead and elevates the eyebrows. The eyebrows move medially and downward with contraction of the corrugator supercilii muscles. The procerus lies between the supercilii muscles and draws the skin of the forehead inferiorly to create the horizontal creases at the root of the nose. The orbicularis oculi muscle surrounds the eye and consists of an orbital and palpebral portion. The orbicularis oculi muscle serves to close the eyes with the palpebral part with both reflexive and voluntary control and the orbital part with voluntary control. The central sphincter-like muscle around the mouth is the orbicularis oris. This muscle helps purse

the lips to form certain sounds and whistle. The lip depressors are depressor anguli oris, depressor labii inferioris, and the mentalis. The lip elevators are the zygomaticus major, zygomatic minor, levator anguli oris, levator labii superioris, and the levator superioris alaeque nasi. The risorius helps retract the corner of the mouth. The buccinators and masseter muscles help with mastication (Fig. 242-6).

Anatomy and Approach in ­Dermatologic Surgery

Buccinator muscle

::

Risorius

Chapter 242

Levator labii superioris muscle

MOTOR NERVES The facial nerve (cranial nerve VII) provides innervation to all the muscles of facial expression. It exits the skull via the stylomastoid foramen, which lies deep in the infra-auricular sulcus and anterior to the mastoid process. The facial nerve enters the parotid gland at the level of the intertragic notch and usually divides into five branches within the substance of the gland. The well-known mnemonic “to Zanzibar by motor car” can be used to remember the five main branches: (1) temporal, (2) zygomatic, (3) buccal, (4) mandibular, and (5) cervical. For the most part, these nerves enter the muscles they innervate posteriorly and deep. A nice rule of thumb is that if one transects a nerve lateral to the midpupillary line, permanent paralysis can result and if the nerve is cut medial to this demarcation, most nerves will regenerate or have arborizations that will help provide additional innervation.

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Section 40

The temporal branch of the facial nerve exits the superior part of the parotid gland and crosses the zygomatic arch to innervate the frontalis, upper portion of the orbicularis oculi, and corrugator supercilii. Injury to the temporal branch leads to an inability to raise the eyebrows and brow ptosis. The zygomatic branch innervates the orbicularis oculi, nasal muscles, lip elevators, and the buccinators. Damage to the zygomatic nerve results in lower eyelid ptosis and an inability to close the eyes completely. The buccal branch also innervates the buccinators and lip elevators, as well as the orbicularis oris and risorius. Damage to the buccal branch leads to an inability to whistle. The marginal mandibular branch crosses the angle of the mandible at the inferior-anterior border of the masseter. It innervates the depressors of the mouth.

VASCULAR SUPPLY

:: Surgery in Dermatology

The blood supply of the face is almost entirely derived from branches of the external carotid artery (Fig. 242-7). Just posterior and medial to the angle of the mandible, the facial artery branches off the external carotid artery. The facial artery continues anteriorly and superiorly toward the angle of the mouth, giving off the inferior labial artery and superior labial arteries that supply the lips. The continuation of the facial artery in the nasofacial sulcus is called the angular artery. The angular artery continues superiorly to

enter the orbit immediately over the medial canthal tendon where it anastomoses with the ophthalmic artery, a branch of the internal carotid artery. After giving off the facial artery, the external carotid artery then passes deep to the sternocleidomastoid muscle and enters the body of the parotid gland where it gives off the posterior auricular artery that supplies the postauricular scalp, the maxillary artery, and the superficial temporal artery. The terminal branch of the maxillary artery exits the infraorbital foramen with the infraorbital nerve as the infraorbital artery to supply the lower eyelids and infraorbital cheek. The terminal branches of the internal carotid artery are the ophthalmic artery branches, the supraorbital artery, and the supratrochlear artery. The supraorbital artery emerges from the supraorbital foramen, whereas the supratrochlear artery emerges more medially. The internal and external carotid systems join in two places: (1) where the supratrochlear branch and the dorsal nasal artery anastomose with the angular artery and (2) where the forehead branches of the supraorbital and supratrochlear arteries anastomose with branches of the superficial temporal artery. The veins of the face parallel and lie posterior to the arteries. Unlike the veins of the trunk and extremities, facial veins have no valves. This allows blood to flow in either direction. Thus, in the central face where there are anastomoses between branches of the ophthalmic vein and of the angular vein, infection has easy access to travel along the ophthalmic vein to the cavernous

Vascular supply of the face

Supraorbital artery Superficial temporal artery

Supratrocholear artery Dorsal nasal artery

Angular artery Superior labial artery Inferior labial artery

Facial artery External carotid

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Figure 242-7  Vascular supply of the face.

sinus. The angular vein also communicates with the deep facial vein and pterygoid plexus.

LYMPHATICS

ANTIBIOTICS A well-planned and executed surgical procedure can be significantly compromised by an infection. Infections can lead to poor cosmesis, inconvenience, added expense, and patient dissatisfaction. Because every surgical procedure violates the epidermal barrier, no surgical procedure is absolutely sterile. Hence, all surgical wounds are contaminated by bacteria because

Anatomy and Approach in ­Dermatologic Surgery

Preoperative assessment is critical for a successful procedure. It allows one to anticipate and possibly correct factors that predispose to adverse outcomes and minimize complications. A fairly thorough medical, drug, and medication allergy history provides an accurate picture of the patient’s health status. Questioning the possibility of pregnancy in women of childbearing age should not be overlooked, as local anesthetics and antibiotics may be contraindicated. Patients with inherited bleeding disorders can also be identified and, when possible, given clotting factors to correct for these disorders. Uncontrolled hypertension may predispose to increased intraoperative and postoperative bleeding. In addition, poorly controlled diabetes and immunosuppression with use of systemic steroids for medical conditions, such as autoimmune disorders or organ transplantation, may affect healing time. Information from the social history can also have a bearing on the surgery. For instance, healing can be adversely affected if the patient smokes, and this may impact the decision to perform a flap or graft. Alcohol consumption can increase the risk of bleeding because of its qualitative effect on platelets. Finally, knowledge of the patient’s resources and support at home is helpful when providing instructions for postoperative care.

::

PREOPERATIVE ASSESSMENT

40

Chapter 242

The lymphatic vessels of the face generally drain from superficial to deep and medial to lateral and caudad. While the general drainage patterns are described here, variations can occur. The posterior scalp drains to the postauricular and occipital nodes. The lateral and superior face, the forehead, and the lateral eyelids drain to the parotid nodes. The medial and inferior face, including the medial eyelids and lateral lips, drain to the submandibular nodes. The middle twothirds of the lower lip and the chin drain to the submental nodes. These nodes can be optimally palpated by performing a bimanual exam with a gloved hand feeling through the floor of the mouth. The lymph nodes of the head and neck eventually drain into a terminal series of nodes (deep cervical nodes) and finally into the lateral internal jugular chain.

of the inevitable resident flora in humans. However, not all contaminated wounds become infected. Infection depends on a large number of factors: the pathogenicity of the microbe, the quantity of the microbe, the length of surgery/timing of infection, the presence of foreign material (sutures, devitalized tissue), presence of dead space, poor suturing/surgical technique, poorly designed reconstruction, compromised vascular supply, and the host and wound’s resistance to infection. Usually a wound that contains greater than 105 bacteria per gram of tissue is considered infected.3 The American College of Surgeons has defined wounds as: clean (nontraumatic, without break in aseptic technique), clean-contaminated (minor break in aseptic technique, wounds in oral cavity, axillae, perineum), contaminated (acutely inflamed, major break in aseptic technique), and dirty (encountering pus, fecal, or urinary discharge). Antibiotics can be considered for some clean-contaminated, contaminated, and dirty wounds. Most wounds in dermatologic surgery are clean-contaminated wounds and do not require antibiotics. The most common organism is Staphylococcus aureus and a first generation cephalosporin (or clindamycin for the penicillin allergic) is appropriate when necessary. Studies show that to prevent or change the course of infection, antibiotics must be given within 2–3 hours after inoculation and that antibiotics give maximal suppression against infection if given before bacteria colonize tissue. In addition, there is concern that, with increasing time, the wound is sealed off with blood clots and fibrous exudates, and the antibiotic is unable to reach the wound effectively. Routine use of antibiotics postoperatively is discouraged due to the risk of encouraging the development of antibiotic resistance amongst bacteria. Although specific criteria for the use of prophylactic antibiotics to prevent endocarditis do not exist for dermatologic procedures, most dermatologic surgeons follow the revised American Heart Association guidelines. Cardiac conditions for which prophylaxis is reasonable include prosthetic cardiac valve, previous infective endocarditis, congenital heart disease (limited particularly to unrepaired cyanotic congenital heart disease, completely repaired congenital heart defect with prosthetic material during the first 6 months after the procedure, repaired congenital heart disease with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device) and cardiac transplantation recipients who develop cardiac valvulopathy. Appropriate antibiotic regimen for prophylaxis for cutaneous procedures is 2 g of cephalexin (or 600 mg of clindamycin in penicillin-allergic patient) 1 hour before the procedure.4

MEDICATIONS The use of blood anticoagulants, such as warfarin, dipyridamole, clopidogrel, and aspirin, are common in the aging population. In the past, patients were often told to discontinue their blood thinners before surgery. However, recent reports show that discontinuing these medications prior to dermatologic surgery can lead

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Section 40 :: Surgery in Dermatology

to episodes of thrombotic events such as stroke and pulmonary embolism.5 Furthermore, remaining on such medications does not lead to significant adverse events. However, patients who are taking aspirin and other nonsteroidal anti-inflammatory drugs for nonphysician-recommended “preventive” purposes are advised to discontinue these drugs preoperatively. These agents are typically withheld for 7–14 days prior to surgery. Many patients may be taking herbal or over-thecounter drugs that also interfere with clotting. These are not often considered “drugs” by patients, and thus they may not volunteer taking such supplements unless they are specifically asked. Some common preparations in this category include vitamin E, garlic, gingko, ginseng, feverfew, or ginger. Alcohol can also interfere with platelet aggregation, and it is important to instruct patients to avoid drinking a few days before and after the surgery. Most dermatologic surgeons advise patients to avoid alcohol, herbal products, and nutritional supplements several days before surgery. Nonselective β blockers (i.e., propanolol) can occasionally potentiate the effect of epinephrine and lead to complications such as malignant hypertension and bradycardia. Other preoperative considerations include latex allergy or allergy to topical antibiotics or adhesives in tapes. Use of systemic steroids can prolong the wound healing time.

PACEMAKERS AND DEFIBRILLATORS Electrosurgery is widely used in dermatologic surgery to obtain hemostasis. However, electrosurgery can disrupt the function of pacemakers and implantable cardioverter-defibrillators (ICDs) by oversensing, inhibiting firing, device reprogramming, battery depletion, or direct damage to the device.6 Thus, it is important to identify patients with such devices and to use proper precautions. Fortunately, newer pacemakers and ICDs have improved shielding and are more resistant to the electromagnetic interference that can be produced by electrosurgery. ICDs are more sensitive to electromagnetic interference, and this interference can cause the defibrillator to discharge, leading to significant morbidity and possible mortality for the patient. If electrosurgery is necessary, recommendations, such as using short bursts of electricity (less than 5 seconds) and avoiding its use directly around the area of the pacemaker, may minimize risks. In addition, bipolar electrosurgery creates little interference and is safer. Heat cautery does not cause any interference and is the safest but is not as effective for hemostasis with larger or complicated procedures.

SMOKING

2912

Smoking should also be discussed preoperatively with patients. Tobacco use creates vasoconstriction, which impairs wound healing and jeopardizes the reconstruction, especially with more complicated

procedures such as flaps and grafts. Patients should be strongly encouraged to cease tobacco use at least 1 week before surgery and 1 week postoperatively. It is also important to clarify that a nicotine patch is not ideal, and patients must avoid nicotine exposure through patches or gum.

SURGICAL HISTORY A discussion of scars and healing after previous procedures can be informative for the patient and surgeon. The physician can determine if the patient is predisposed to forming hypertrophic scars or keloids and plan reconstruction and postoperative care appropriately. The patient may have a misunderstanding of wound healing and feel that a well-healed visible scar on a high-tension area is a keloid. This can be an opportunity to anticipate patient expectations and educate them on the process of wound healing.

SURGICAL TECHNIQUE SKIN PREPARATION AND ASEPTIC TECHNIQUE The normal skin is colonized by a host of bacteria, primarily aerobic cocci. Staphylococcus aureus is the most common cause of cutaneous wound infections in dermatologic surgery. Other bacteria commonly identified on the skin include Staphylococcus epidermidis, Pseudomonas, Propionibacterium, streptococci, and micrococci. Pseudomonas is frequently the pathogen identified in infections of cartilaginous regions such as the ear. The aim of aseptic solutions is to significantly reduce the amount of normal bacterial flora, as complete sterilization of the skin is not possible due to the presence of bacteria in pilosebaceous units. The ideal antiseptic would be nonirritating, nontoxic, nonsensitizing, be effective against all resident and transient microbes, and long-lasting. In prepping the field, shaving the hair creates multiple superficial microabrasions in which bacteria may reside and is associated with an increased incidence of local wound infections. Hair removal, if needed, has the lowest risk of associated infection if done by clipping or depilatory agents.7 Iodophors, which act through oxidation of cell membranes by free iodine, are common topical antiseptics. The most common form of this antiseptic is povidoneiodine. This antiseptic has broad antimicrobial activity against both Gram-positive and Gram-negative bacteria, as well as fungi, viruses, and mycobacteria. Iodophors have bactericidal activity that persists for several hours after application. On contact with blood or serum, the bactericidal activity is lost, but some bacteriostatic activity is retained. This class offers relatively rapid onset of action with full bactericidal activity being achieved within 1–3 minutes for most bacteria. Side effects of povidone-iodine include allergic contact dermatitis, irritant contact dermatitis, and possible tissue necrosis with prolonged exposure to large amounts in open wounds.

The nature of the procedure determines which local anesthetic is ideal (Table 242-1). The primary variables to consider in choosing between anesthetics are the onset of action and the duration of anesthesia. Patient factors to consider in this selection are a history of allergy to an anesthetic class or renal or hepatic impairment. For simple biopsies and excisions, a rapid-onset anesthetic, like lidocaine, with medium duration of action provides effective anesthesia. For more extensive procedures, an anesthetic with a longer duration of action, such as bupivacaine, may be desired. Some practitioners choose to mix a rapid-onset anesthetic with one of long duration into one injectable solution.

EPINEPHRINE Local anesthetics, with the exception of cocaine, are vasodilators. This vasodilatory effect produces unwanted bleeding at the operative site. Epinephrine with its potent vasoconstrictive effects is often added to local anesthetic preparations to reduce bleeding. Concentrations ranging from 1:100,000–1:500,000 are effective in reducing bleeding at the surgical site. In addition to its hemostatic effect, epinephrine reduces the dispersion of the local anesthetic from the operative site. This prolongs the duration and efficacy of the anesthesia by 100%–150%. It also limits the potential for systemic toxicity, as less anesthetic is allowed to enter the systemic circulation. Epinephrine is a potent agonist of α- and β-adrenergic receptors. Absolute contraindications to its use with local anesthetics are pheochromocytoma and hyperthyroidism. Relative contraindications to the use of epinephrine include severe coronary artery disease, uncontrolled hypertension, peripheral vascular disease, pregnancy, and acute angle glaucoma. In addition, epinephrine should be used with caution in patients on β blockers, monoamine oxidase inhibitors, phenothiazines, and tricyclic antidepressants as these individuals demonstrate greater sensitivity to its effects. Although uncommon, severe hypertension may be encountered in patients on β blockers due to the unopposed α-receptor stimulation of the ­epinephrine. The use of epinephrine-containing local anesthetics on anatomic regions with minimal collateral circulation,

Anatomy and Approach in ­Dermatologic Surgery

Effective anesthesia is critical to the successful performance of dermatologic surgery. The overwhelming majority of cutaneous surgical procedures can be performed with local anesthesia. Local anesthesia provides the benefits of rapid onset of action, ease of use, decreased cost, and minimal associated morbidity and mortality. Nerves transmit stimuli through the opening of sodium channels, which results in an influx of sodium ions into the nerve cell. This influx results in depolarization of the axon generating an action potential. Local anesthetics exert their effect on nerves by blocking the sodium channels on nerve axons. This blockage inhibits depolarization and the formation of an action potential. Local anesthetics affect the smaller unmyelinated C-type nerve fibers, which carry the sensation of pain and heat, more rapidly and effectively than myelinated A-type nerve fibers, which transmit the sensation of pressure and innervate muscle fibers. Thus, adequate anesthesia can be achieved while motor function and pressure sensation are maintained. Local anesthetics structurally are composed of three subunits: (1) a hydrophobic aromatic ring, (2) a hydrophilic amine group, and (3) an intervening group connecting the hydrophobic and hydrophilic units. The

SELECTING THE APPROPRIATE ANESTHETIC

40

::

LOCAL ANESTHESIA

hydrophobic aromatic ring is responsible for the molecule’s ability to diffuse through axonal membranes. The hydrophilic amine maintains the solubility of the compound in aqueous solution and accounts for blockage of the sodium channels of nerve axons. The region connecting the hydrophilic and hyphobic regions may be either an amide group or an ester group. Amide anesthetics, which include lidocaine, prilocaine, bupivacaine and mepivacaine, are metabolized in the liver through dealkylation and hydrolysis by microsomal enzymes. Ester anesthetics, which include procaine, benzocaine, tetracaine, and cocaine, are metabolized by plasma pseudocholinesterase and are excreted renally.

Chapter 242

Chlorhexidine also functions through disruption of cell membranes. It has broad antimicrobial activity with excellent Gram-positive coverage and very good Gram-negative activity. It has some degree of activity against viruses but little effect on mycobacteria or fungi. Chlorhexidine offers a more rapid onset of action than povidone-iodine, providing almost immediate bactericidal activity upon application, which persists for many hours after application. It provides superior decontamination of the skin as compared to iodophors with resulting decreased rates of postoperative infection.8 As a result, chlorhexidine is preferred over povidone-iodine as a surgical antiseptic agent if the surgical site does not limit its usage. The primary side effect of chlorhexidine is the potential for ototoxicity and keratitis. As a result, it should not be used around the eyes or ears. Similar to iodophors, prolonged exposure of chlorhexidine in open wounds has been reported to be toxic to the tissue. Isopropyl alcohol and ethyl alcohol are effective antiseptics for minor skin procedures. They function through the denaturation of microbial proteins. They display good activity against Gram-positive and Gram-negative bacteria, mycobacteria, viruses, and fungi. Alcohols have a rapid onset of activity at the site of application, but there is no persistence of this activity over time. The antimicrobial activity of alcohols is not as extensive as that of chlorhexidine or iodophors. In addition, the flammable nature of alcohols limits their use in procedure requiring electrocautery. Hexachlorophene is rarely used as a skin antiseptic solution. It has excellent Gram-positive activity but limited activity against Gram-negative organisms or fungi. It is also readily absorbed through the skin and has the potential for neurotoxicity, especially in infants.

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TABLE 242-1

Local Anesthetics

Onset

Durationa Plain

Maximum Dose Plain (mg)

Maximumb Dose with Epinephrine (mg)

8

2–10 minutes

3–10 hours

175

250

Topical

—

Rapid

Short

—

—

Etidocaine

Infiltration

6

3–5 minutes

3–10 hours

300

400

Lidocaine

Infiltration/ topical

2

Rapid

1–2 hours

300

500 (3,850 dilute)

Mepivacaine

Infiltration

2

3–20 minutes

2–3 hours

300

400

Prilocaine

Infiltration

2

Rapid

2–4 hours

400

600

Prilocaine/ lidocaine

Topical

—

30–120 minutes

Short

—

—

Benzocaine

Topical

—

Rapid

Short

—

—

Chloroprocaine

Infiltration

1

Rapid

0.5–2.0 hours

600

—

Cocaine

Topical

—

2–10 minutes

1–3 hours

200

—

Procaine

Infiltration

1

Slow

1.0–1.5 hours

500

600

Proparacaine

Topical

—

Rapid

Short

—

—

Tetracaine

Infiltration

8

Slow

2–3 hours

20

—

Tetracaine

Topical

—

Rapid

Short

—

—

b

Generic Name

Primary Use

Relative Potency

Bupivacaine

Infiltration

Dibucaine

Section 40 :: Surgery in Dermatology a

In clinical practice, the duration of anesthesia appears to be less than stated above, especially for head and neck areas, and addition of ­epinephrine prolongs anesthesia by a factor of two. b Maximum doses are for a 70-kg person.

such as the digits, penis, and nasal tip, is a matter of controversy. Reports of local tissue necrosis in these areas with limited perfusion attributed this result to the potent vasoconstrictive effects of the epinephrine. More recent observations indicate this necrosis to actually be the result of excessive volume of anesthetic used, which physically tamponades the vessels. Thus, local anesthetics with epinephrine are now considered safe for use on the digits, penis, and nasal tip, when used judiciously in small volumes. Consideration may be given to using a lower concentration of epinephrine (1:500,000) for those sites with severely limited perfusion. Self-limited, systemic side effects may also be experienced with the administration of epinephrine-containing anesthetics. These include anxiety, fear, palpitations, tachycardia, diaphoresis, tremor, and hypertension. Serious side effects of excessive epinephrine administration include arrhythmias, cardiac arrest, and cerebrovascular hemorrhage. These serious side effects are extremely rare when used at appropriate dosages in individuals without significant contraindication.

SIDE EFFECTS 2914

The most common side effect of local anesthetics is the pain of its administration. Premixed local anesthetic preparations containing epinephrine are manu-

factured as an acidic solution with a pH of between 3 and 5 in order to maintain the stability of epinephrine. Injection of this acidic solution into tissue often produces significant discomfort. To avoid this, the pH of the solution can be adjusted before injection closer to the physiologic pH of 7.4 through the addition of sodium bicarbonate. The standard formula for this is the combination of one part of 8.4% sodium bicarbonate with 10 parts lidocaine. This buffered solution must be used soon after preparation as the epinephrine gradually degrades at a rate of approximately 25% per week. Alternatively, the epinephrine and anesthetic may also be mixed immediately before use, which also provides a neutral solution. In each instance, the neutral or slightly alkaline solution has the added advantages of quicker onset of action and increased anesthetic effect as the pH of the solution is closer to the pKa of the anesthetic, meaning more of the anesthetic is in its active ionized cationic form. Slow injection of the anesthetic through a small gauge needle (27 gauge to 30 gauge) also minimizes the pain of injection. Smaller syringes, such as 1–3 mL, create less pressure at the site of anesthetic administration. Based on the gate theory of pain perception, repeated pinching or vibration of the immediate surrounding area lessens the perception of the stick at site. Verbal distraction of the patient is also useful in lessening the anxiety and discomfort of the anesthetic.

Several local anesthetics are also available as topical preparations. When used properly, these agents provide suitable anesthesia for minor dermatologic procedures, such as shave biopsies or superficial laser treatments. Their efficacy on normal skin is limited by their ability to penetrate the stratum corneum. Thus, most of the preparations require extended application times and/or occlusion for effectiveness. LMX is a topical lidocaine cream in a liposomal vehicle. It is available in 4% and 5% concentrations. Eutectic mixture of local anesthetics (EMLA) cream consists of a combination of 2.5% lidocaine and 2.5% prilocaine. LMX and EMLA have been shown to be more effective than other topical preparations of 4% tetracaine gel and Betacaine-LA (a mixture of prilocaine and lidocaine in a liquid paraffin ointment). LMX typically requires an application time of 30 minutes with or without occlusion, whereas EMLA requires 1 hour with occlusion. Multiple studies have demonstrated the 30-minute application of LMX without occlusion to provide equal anesthesia as 1-hour application of EMLA with occlusion. Caution should be exercised in the use of large amounts of prilocaine-containing topical preparations in infants or those with an impaired skin barrier, as prilocaine has the potential to induce methemoglobinemia. Cryogens, such as ethyl chloride, also provide brief anesthesia at a site for minor procedures or the insertion of a needle. Similarly, an ice cube placed on an injection site often significantly reduces the discomfort of injection in the anxious patient. Mucosal membranes are readily anesthetized using topical preparations due to the ease of penetration in the absence of a stratum corneum. Tetracaine or proparacaine drops rapidly provide effective anesthesia of

Anatomy and Approach in ­Dermatologic Surgery

TOPICAL ANESTHETICS

40

::

epinephrine. The initial presenting signs are circumoral numbness and tingling, tinnitus, lightheadedness, nausea, and numbness of the distal extremities. With additional anesthetic, more extensive central nervous system depression may occur with hallucinations, seizures, and respiratory depression. Cardiovascular toxicity may also occur, but does so at much higher levels of anesthetic than the initial central nervous system toxicity. The manifestations include hypotension, arrhythmias, and cardiac arrest. Both central nervous system and cardiovascular toxicity are directly related to serum levels of the anesthetic. Thus, direct intravenous or intra-arterial injection is to be avoided when anesthetizing an area. This can be done by drawing back on the syringe after needle insertion prior to infiltration of the anesthetic to confirm that the needle is not in a vascular structure. The risk of toxicity can be elevated by other medical problems affecting the metabolism of the anesthetic. In particular, patients with liver disease experience increased serum levels of amide anesthetics due to an impaired ability to metabolize and clear the anesthetic. Thus, a lower dosage of an amide anesthetic or a switch to an ester anesthetic is advisable in these patients.

Chapter 242

Injection of anesthetic into the subcutaneous tissue is less painful than injection into dermal tissue; however, a quicker onset of action and longer duration of anesthesia are observed with dermal injection. If a large area is to be anesthetized, the initial injection should be placed near the origination of sensation and proceed distally. Subsequent injections, if necessary, should be made through previously anesthetized tissue. For large areas, consideration should also be given to the use of nerve blocks to minimize discomfort. One side effect of local anesthetic administration that is not uncommon is the vasovagal reaction. This may be manifested as pallor, weakness, bradycardia, hypotension, diaphoresis, and nausea. Placement of the patient in Trendelenburg position usually results in complete resolution of these symptoms within several minutes. A cool compress on the forehead and fanning the patient are often helpful in comforting the patient during this episode. Patients should be injected in a recumbent or Trendelenburg position to minimize the likelihood of a vasovagal response. These positions also allow providers to be better prepared to deal with the reaction should it occur. Pain and anxiety of anesthetic injection can precipitate a vasovagal reaction; thus, the aforementioned techniques for lessening the discomfort of injection are critical in reducing the likelihood of a vasovagal response. Allergy to a local anesthetic is an uncommon side effect in dermatologic surgery. Amide anesthetics are more likely to be the culprit of allergic reactions whereas allergic reactions to ester anesthetics are exceedingly rare. True allergic reactions are typically immediate type I immunoglobulin E-mediated reactions, which may produce urticaria, angioedema, bronchospasm, tachycardia, hypotension, and, possibly, cardiovascular collapse. For severe reactions, administration of epinephrine and cardiopulmonary support is indicated. Less commonly, type IV-delayed hypersensitivity reactions may be observed. These present similar to an allergic contact dermatitis in the days following the injection of the anesthetic. For those patients in whom an allergy to an anesthetic is unclear, intradermal prick testing to ester anesthetics, amide anesthetics, and any added preservatives, such as sodium metabisulfite and methylparabens may be helpful. Alternatively, for smaller procedures, the intradermal injection of diphenhydramine hydrochloride solution provides temporary anesthesia without risk of an allergic response. Antihistamine side effects, including significant drowsiness, may be encountered with its use. The intradermal injection of normal saline with preservative may also be used for very brief procedures. The temporary ­anesthesia it provides is attributed to a combination of the tamponade effect on nerves and the mild anesthetic effect of the preservative benzoyl alcohol. Anesthetic toxicity is a rare complication given the typical volumes required for dermatologic surgery. Signs of toxicity are usually not observed with dosages less than 5.0 mg/kg of plain lidocaine and 7.0 mg/kg of lidocaine with 1:100,000 epinephrine. For tumescent anesthesia, the maximum safe dose increases to 55.0 mg/kg of 0.05% –0.1% lidocaine with 1:1,000,000

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the conjunctiva and cornea for insertion of eye shields. Benzocaine and lidocaine preparations provide prompt anesthesia for intraoral procedures or before nerve blocks.

NERVE BLOCKS

Section 40 :: Surgery in Dermatology

2916

The use of regional nerve blocks can be of immense value to the dermatologic surgeon. Regional nerve blocks allow large cutaneous areas to be anesthetized with small volumes of anesthetic. They are based on the injection of a local anesthetic into the immediate vicinity of a sensory nerve as it emerges from deeper planes of tissue. This provides effective anesthesia for the patient while minimizing the discomfort of multiple injections. Nerve blocks have the added benefits of limiting the possibility of anesthetic toxicity as well as minimizing tissue distortion. The primary risk of nerve blocks is nerve trauma with resultant neuropraxia. The standard anesthetic used for regional blocks is 1% lidocaine with 1:100,000 epinephrine; however, bupivacaine may be added if more lasting anesthesia is desired. A 1 inch, 30 gauge is suitable for the performance of most nerve blocks. The proper execution of nerve blocks is predicated on a thorough knowledge of the anatomy of the region being anesthetized. The cutaneous sensation of the face is primarily supplied by the trigeminal nerve, with a small fraction of the periphery being supplied by the cervical plexus. As its name implies, the trigeminal nerve consists of three major divisions: (1) the ophthalmic (V1), (2) maxillary (V2), and (3) mandibular (V3) divisions. Each of these divisions has major branches, which are amenable to regional nerve blocks. The ophthalmic division of the facial nerve gives off the supraorbital, supratrochlear, and infratrochlear nerves. The supraorbital nerve exits through the supraorbital foramen, which is a readily palpable bony notch located along the orbital rim just medial to the midpupillary line. The supratrochlear branch exits along the orbital rim approximately 1.5 cm medial to the supraorbital notch. The infratrochlear nerve exits just above the medial canthus. All three of these branches can be anesthetized with a single injection by inserting the needle 2–3 mm lateral to the supraorbital notch and advancing medially through the subcutaneous tissue to the medial canthus. The anesthetic is then injected as the needle is slowly withdrawn in one smooth motion. This single injection provides anesthesia to the ipsilateral forehead, frontal scalp, upper eyelid, medial canthus, and superior nasal sidewall and root. The infraorbital nerve, a branch of the mandibular division, exits through the infraorbital foramen, which is located in the midpupillary line approximately 1 cm below the infraorbital rim. This nerve may be blocked by either an intraoral or a percutaneous approach. The percutaneous method involves insertion of the needle directly over the infraorbital foramen and advancement directly down to the maxillary bone, where the anesthetic is delivered. With the intraoral approach, the sulcus located just above and lateral to the canine tooth is identified by manual palpation. The needle is inserted

in the superior portion of this sulcus and advanced upward approximately 1 cm in the midpupillary line. At this position, the anesthetic is slowly injected. The intraoral approach is less painful than the percutaneous one, and may be further aided by the use of a topical lidocaine or benzocaine gel on the oral mucosa. This block provides anesthesia to the ipsilateral lower eyelid, medial cheek, upper lip, and upper teeth. The mental nerve is a branch of the mandibular division, which exits through the mental foramen just medial to the midpupillary line. This nerve is easily accessed via an intraoral injection. It is located just opposite of the first bicuspid on the mucosa of the lower lip, and is often visible to the naked eye as a thin glistening white strand. It is anesthetized with an injection in the immediate vicinity of its inferior portion. This provides anesthesia to the ipsilateral lower lip and chin. In addition to the above branches, there are other branches of the trigeminal nerve that are also amenable to regional nerve blocks. These include the buccal, auriculotemporal, anterior ethmoidal (external nasal branches), and zygomaticotemporal nerves. A block of the greater auricular nerve off the cervical plexus provides anesthesia to the posterior auricle and angle of the mandible. Nerve blocks can be a valuable tool for nonfacial locations as well. In particular, digital nerve blocks are very useful for procedures involving the digit or nail unit. The cutaneous sensation of a digit is supplied by two nerves coursing down each of the lateral aspects of the digit. For a block, the needle is inserted perpendicularly into the lateral aspect of each side of the digit and advanced until bone is reached. At this position, a small volume of anesthetic is administered. The delivery of a large volume (greater than 1 mL) of anesthetic in the digits can result in tamponade of the digital circulation with subsequent necrosis. This tamponade effect now appears to be more critical factor in cases of digital necrosis than the use of epinephrine.

ELECTROSURGERY AND ELECTROCAUTERY (See Chapter 246)

SUTURE MATERIALS. The proper selection of suture material for any dermatologic procedure is vital to its successful outcome. There are several intrinsic characteristics of each suture material, which will influence this selection process (Table 242-2). Sutures are produced in both absorbable and nonabsorbable forms. An absorbable suture is classified as one, which loses half of its tensile strength within 2 months. Absorbable sutures are primarily used for the approximation of dermal and subcutaneous tissue. As wounds have achieved less than 10% of their final tensile strength at 2 weeks, these sutures maintain the structural support of wounds during the initial healing phase. The time that a suture maintains its tensile strength is dependent on the material of which it is composed.

40

TABLE 242-2

Suture Materials Tensile Strength Half-Life

Twisted Monofilament Braided Monofilament Braided Braided Monofilament Braided/twisted Monofilament/braided/ twisted

Low High Low High Low Low Very high Very low Very high

Very high Low Low Low Low Low Very low High Very low

— — — — — — — — —

Twisted

Very high

High

2 days

Twisted Twisted Braided Braided Monofilament Monofilament Monofilament

Very high Very high Very low Very low Low Low High

High High Low Low Very low Very low Very low

4 days 1 wk 2 wk 2 wk 1 wk 1 mo 1 mo

Data from Melton JL, Hanke WC: Wound closure materials. In: Principles and Techniques of Cutaneous Surgery, edited by GP Lask, RL Moy. New York, McGraw-Hill, 1996, p. 77; and Garrett AB: Wound closure materials. In: Cutaneous Surgery, edited by RG Wheel. Philadelphia, Saunders, 1994, p. 199.

Nonabsorbable sutures are predominantly used for external suturing with subsequent removal in the days after the procedure. In this instance, these sutures are used more for fine epidermal approximation than structural support. On occasion, nonabsorbable sutures are also used for the placement of subcutaneous tissue, muscle, and fascia, when a more permanent placement of the tissue is desired. Sutures are produced as monofilaments (singlestrand) or multifilaments (multiple-braided strands). Monofilaments offer the advantage of increased ease of pull-through tissue, less risk of infection, and decreased tissue reactivity. The disadvantage of monofilaments is the increase in memory, or the tendency for a material to revert to its original shape. This memory results in decreased ease of handling of the suture and decreased knot security for monofilaments. Multifilaments, or braided sutures, offer ease of handling and increased knot security. However, the strands of a multifilament have the capability to trap fluid and bacteria resulting in an increased risk of infection with their use. In general, the smallest suture, which provides adequate tensile strength for a defect, should be utilized. Suture size is measured in multiple of zeros based upon the diameter of the suture material. The higher the number preceding the zero, the smaller the diameter of the suture. Typically, 5-0 and 6-0 sutures are used on regions of low tension, such as the face, eyelids, and ears. Areas of higher tension, such as the trunk, extremities, and scalp, require 3-0 and 4-0 sutures. Areas of intermediate tension, such as the neck, may be closed

with either 4-0 or 5-0 sutures. There are a wide range of needles whose nomenclature varies with manufacturer. In general, most skin surgery procedures are best performed with plastic surgery needles.

SUTURING TECHNIQUE. Meticulous suturing technique is fundamental to obtaining excellent aesthetic and functional results. Properly placed sutures allow for approximation of wound edges, wound-edge eversion, minimization and redistribution of tension, elimination of dead space, maintenance or restoration of natural anatomic contours, and avoiding permanent suture marks on the skin surface. The suturing technique selected for a specific wound closure depends on the anatomic location, tension, thickness of the wound edges, and goals of the surgeon. Interrupted Sutures. The simple interrupted suture is the most basic and versatile suture used by dermatologic surgeons. Absorbable, buried interrupted sutures are used as part of the layered wound closure. These sutures provide support for the wound until tensile strength has increased sufficiently to prevent wound dehiscence and reduce tension on the wound edges. To achieve good eversion of the wound edges, these are best placed in the deep dermis and subcutis in a heart-shaped configuration (Fig. 242-8).9 Wounds in which one skin edge appears higher than the other can be appropriately aligned by taking a larger bite from the lower edge and a smaller, more superficial bite from the higher edge.

Anatomy and Approach in ­Dermatologic Surgery

Tissue Reactivity

::

Absorbable  Catgut, fast absorbing/ mild chromic   Catgut   Catgut, chromic   Polyglactin 910   Polyglycolic acid   Poliglecaprone 25   Polyglyconate   Polydioxanone

Memory

Chapter 242

Nonabsorbable   Cotton   Nylon   Nylon   Polybutester   Polyester, uncoated   Polyester, coated   Polypropylene   Silk   Stainless steel

Type

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“Heart-shaped” subcutaneous buried suture

Section 40 :: Surgery in Dermatology

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Figure 242-8  “Heart-shaped” subcutaneous buried suture.

Epidermal simple interrupted sutures, used to obtain optimal alignment of the epidermal edges of the wound, are more time-consuming to place and remove than continuous running sutures. In settings where wound healing may be impaired because of the patient’s underlying medical condition or in areas of high tension, interrupted sutures may be preferred. This type of suture usually provides greater tensile strength and less potential to cause edema, induration, and impaired microcirculation than running sutures. In addition, in areas of high tension, the risk of wound dehiscence can be assessed by removing alternate sutures. If it seems that dehiscence is likely, the remaining sutures may be left in place for 3–4 additional days. The vertical mattress suture provides wound-edge eversion, reduces dead space, and minimizes tension across the wound (Fig. 242-9). It achieves the same effect as a buried dermal suture and an epidermal suture. Because this suture requires four entry points in the skin, significant crosshatching can be expected if the suture is not removed within 5–7 days. This suture by nature is a tightly placed suture and can be difficult to remove because of its tendency to become embedded in the skin. The horizontal mattress suture has been used to reduce tension across wound closures that are under significant tension (Fig. 242-10). This technique also creates wound eversion. This suture can be placed as an initial tension-reducing or -holding suture and to bring the wound edges closer together, so that subcutaneous sutures can be placed to distribute tension and close the wound. At this point, if the tension has been adequately distributed, the horizontal mattress suture may be removed. If tension across the wound

persists, the horizontal mattress suture may be left in place for a few days while early wound healing proceeds and removed before suture tracks have had a chance to form. The main disadvantage of this suture is the possibility of wound-edge necrosis as this suture can easily strangulate the dermal plexus between its limbs. This problem is minimized by taking large bites with the needle to encompass large amounts of tissue, by using bolsters, by tying the suture only as tight as necessary to accomplish the task of bringing the wound edges together, and by removing the suture as soon as possible. Before contemplating the use of a horizontal mattress suture for tension reduction, the surgeon should consider other means of reducing tension across the wound, including appropriate use of undermining and closure orientation, flaps from areas of tissue excess, preoperative or intraoperative tissue expanders, serial excisions, and subcutaneous sutures. The half-buried horizontal mattress suture is primarily indicated for the positioning of various corners and tips including flap tips, M-plasty tips, and V-Y closure tips. It can also align the edges of tangential flaps and flaps with ischemic wound edges. The buried limb of this suture is placed in the potentially ischemic area in order to minimize interference with the dermal vascular plexus. A superficial simple interrupted suture through a flap tip may also work without resulting in increased risk of flap tip necrosis.

Running Sutures. The simple running suture can be used in situations where the wound edges are of equal thickness without tension, closely approximated, and with an absence of subcutaneous dead space. This suture is most useful for wounds that have already

Vertical mattress suture

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Chapter 242 ::

been closed by buried sutures, for the attachment of full-thickness or split-thickness skin grafts, and in areas of thin skin such as the eyelids, ears, neck, and scrotum. By eliminating all but two knots, there is less suture material resting against the skin, resulting in the development of fewer scars from suture marks. However, fine adjustments along the suture line are difficult to make and the suture has a tendency to pucker when very lax and thin skin, such as eyelid skin, is being sutured. In thin skin, the knots at each end may be tied over small bolsters to prevent them from cutting into the tissue. The running locking suture is a variant of the simple running suture in which, after the placement of each loop, the needle is passed through the previous loop

prior to starting the next loop. It is intended for the closure of well-vascularized wounds under a moderate amount of tension. The wound edges should be stiff and of equal thickness without a tendency for inversion. It is stronger than a simple running suture. However, if it is placed too tightly or if significant postoperative swelling develops, tissue strangulation with wound-edge necrosis may ensue. The running subcuticular suture is a buried running suture that is usually not absorbable. It is ideal for the closure of wounds in areas such as the trunk and extremities where the suture must remain in place for more than 7 days. As the suture is buried, there are no suture marks and the suture may be left in place for several weeks, even months. When

Anatomy and Approach in ­Dermatologic Surgery

Figure 242-9  Vertical mattress suture.

Horizontal mattress suture

Figure 242-10  Horizontal mattress suture.

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absorbable suture material is used, it may be left in place until it is absorbed. As this suture is capable of only modest wound-edge alignment, it should be reserved for wounds in which the tension has been eliminated with deep sutures and the wound edges, of approximately equal thickness, are closely approximated. The running subcuticular suture should be placed with a nonreactive monofilament suture such as polypropylene to facilitate suture removal and prevent suture breakage within the wound. Some surgeons use a permanent suture left in place indefinitely, as this can reduce scar stretching. If nonabsorbable sutures are selected clear, nonreactive suture material should be used.

Section 40 :: Surgery in Dermatology

SUTURE REMOVAL. Timing of suture removal must balance two factors: (1) leaving the sutures in place long enough to allow wound healing and prevent dehiscence and (2) removal before the development of suture track marks along the scar line. These suture track marks occur because reepithelialization occurs around the suture. In general, the less the blood supply to an area and the greater the tension across a wound, the longer the sutures should be left in place. On the face and ears, most skin sutures should be removed within 5–7 days. Eyelid sutures can be removed in 3–5 days. Neck sutures should be removed in 7 days and scalp sutures in 7–10 days. On the trunk and extremities, risk of wound dehiscence takes precedence over suture marks. Sutures on the trunk and upper extremities should be left in place for 7–14 days. Lower extremities may require up to 21 days of suture support, though, with proper deep suture placement, epidermal sutures can generally be removed in 7–10 days. Absorbable sutures are not removed, but some patients develop suture reactions, consisting of sterile suture abscesses and suture extrusion through the wound. If this happens, the suture should be picked up carefully with small forceps and cut out of the wound. Any purulent material should also be drained. STAPLE CLOSURE. Staple closure of wounds is an alternative to suture closure. The staples have the advantage of very quick placement, minimal tissue reaction, and very strong wound closure. Staples are most often used with long wounds, especially on the scalp, where the suture line is hidden by scalp hair. Potentially contaminated wounds that are closed with staples appear to be more resistant to infection than wounds closed with sutures. Staples provide efficient

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wound closure; but when exact wound-edge alignment is required, sutures should be used. Staples are easily removed with a staple remover.

POSTOPERATIVE CARE Most wounds can be cleaned appropriately with tap water and mild soaps. A diluted acetic acid solution can be helpful to prevent Pseudomonas infection in sites predisposed to this. Small amounts of hydrogen peroxide can help debride wounds that have developed significant crusting and exudate. However, in large amounts, hydrogen peroxide can be toxic to the development of new cells and thus inhibit wound healing. Most wounds are also best dressed with petrolatum and a nonadherent dressing. Petrolatum is relatively inert, nontoxic, nonsensitizing, and nonirritating. Although not common knowledge for the layperson, it has been well proven for years that covered or occluded wounds reepithelialize and heal faster than dry wounds.10 There is a significant risk for allergic contact dermatitis with topical antibiotics, and they have not been shown to be superior to petroleum jelly in preventing wound infections. For wounds with significant drainage, dressings such as gauze, foam dressings, or alginates provide absorption.

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Leffell DJ, Brown MD: Manual of Skin Surgery, 2nd edition, PMPH-USA, Shelton, CT, 2011 4. Wilson W et al: Prevention of infective endocarditis: guidelines from the American Heart Association: A guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 116:1736, 2007 5. Alam M, Goldberg LH: Serious adverse vascular events associated with perioperative interruption of platelet and anticoagulant therapy. Dermatol Surg 28:992, 2002 7. Tanner J, Woodings D, Moncaster K: Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev 2:CD004122, 2006 8. Daarouiche RO et al: Chlorhexidine-alcohol versus povidone-iodine for surgical site anti-sepsis. N Engl J Med 362:18, 2010

Chapter 243 :: E  xcisional Surgery and Repair, Flaps, and Grafts :: Jessica M. Sheehan, Melanie Kingsley, & Thomas E. Rohrer Excisional Surgery and Repair, Flaps, and Grafts At a glance

The goal of excisional surgery is to remove the lesion with appropriate margins and obtain the best cosmetic result.

An elliptical or fusiform excision is the fundamental procedure in dermatologic surgery and typically allows for a linear, side-to-side closure. Flap or graft repair may be considered when linear closure is not feasible. Flaps are commonly classified according to their primary movement as advancement, rotation transposition, or interpolation.

RISKS AND PRECAUTIONS It is important that both the patient and practitioner be aware of the risks of dermatologic surgery. In fact, professional standards dictate that these risks be documented for proper patient consent.1 The main risks of excisional surgery include pain and discomfort; bleeding, bruising, and hematoma formation; nerve damage; wound infection; wound dehiscence; and undesirable scar or contracture.

The three basic types of skin grafts are fullthickness, split-thickness, and composite.

The goal of any excisional surgery is to remove the lesion with appropriate margins and leave the least noticeable scar possible. In order to consistently attain aesthetically pleasing results, time must be taken long before the first incision to appropriately plan the procedure. While excisional surgery is as much an art form as it is a science, there are many principles to keep in mind when planning the surgical excision and closure. Wounds should be closed under minimal tension, with scars placed along cosmetic unit junctions or skin tension lines, without distorting critical anatomic structures and landmarks (eyelid, eyebrow, nose, lip,



While the injection of local anesthesia is not without pain, there are several ways to minimize the discomfort. Some of the most effective ways to diminish pain on injection is the addition of sodium bicabonate to the anesthetic agent, using smallgauge needles, inserting the needle into the skin through a pore, and injecting very slowly and into the subcutaneous tissue. In addition, starting at the proximal aspect of the neural innervation and working distally will help minimize discomfort. Postoperative pain is typically minimal and controlled with over-the-counter analgesics such as acetaminophen. Meticulous operative technique will also help minimize postoperative pain. More severe pain may require the prescription of narcotics. Excessive bleeding, subsequent bruising, and possible hematoma formation are also risks. Most dermatologic surgeons now recommend that medically necessary anticoagulation, including aspirin, clopidogrel, heparin, and warfarin, be continued perioperatively.2 Herbal supplements such as ginseng or garlic, vitamin E, aspirin, and nonsteroidal anti-inflammatory agents that are not prescribed by

Excisional Surgery and Repair, Flaps, and Grafts

The closure must preserve sensory and motor nerve function.

::

The planning and execution of dermatologic surgery procedures must balance risk and benefit and consider all options to achieve a particular outcome. Wounds should be closed under minimal tension, with scars placed along cosmetic unit junctions or skin tension lines, without distorting critical anatomic structures and landmarks.

Chapter 243

Excisional surgery is one of the most common surgical procedures in dermatology

hairline, etc.). Biologically, the closure must be such that the mobilized skin and associated adenexal structures are viable, and there is maximal preservation of sensory and motor nerve function. Knowledge of underlying anatomy is critical in both the design and execution of the excision (see Chapter 242). The planning and execution of dermatologic surgery procedures varies from case to case. A skilled surgeon evaluates the risks and benefits of various options in each patient and anticipates potential complications. Key elements of dermatologic surgery procedures include proper patient selection and preparation; comprehension of risks and necessary precautions; obtaining effective local anesthesia; use of sterile or clean technique; informed procedure design and meticulous technique in performing the incision and repair; diligent postoperative wound care and patient education.

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Section 40

a physician should be discontinued 2 weeks prior to surgery if possible.2 The consumption of alcohol should also be restricted immediately before and after the procedure. Meticulous hemostasis with electrocautery or coagulation, ligation of larger arteries, and the application of a compression bandage minimize the risk of bleeding. Risk of infection exists whenever the skin barrier is breached. Wound infection is relatively uncommon3 and occurs more frequently in particular patient populations, such as those who are diabetic, smokers, or immunosuppressed, and at certain surgical sites, such as the ear or lower leg.4 Sterile technique and atraumatic tissue handling minimizes this risk. Prophylactic antibiotics may be administered for high-risk patients, or if the wound base or suture perforates into nonsterile areas, such as the nasal or oral cavities. Guidelines for antibiotic usage are outlined in Table 243-1).





Wound dehiscence occurs in wounds under high tension, or in cases of poor wound healing or infection. This risk is reduced by proper planning of the closure, the use of buried subcutaneous sutures, fascial plication to relieve tension on wound edges where indicated, and minimizing activity and immobilization of the wound edges for 1 to 2 weeks after surgery. Undesirable scars are always a possibility. While many steps can be taken to minimize the appearance of the final scar, it is important for the patient to understand that all excisional surgery will result in the formation of some form of a scar. Many factors must be considered with respect to formation. Free margins must be respected and never distorted. Closures are best hidden when they are placed on along cosmetic unit junctions and contained in as few cosmetic units as possible. The long axis of the excision and/or design of a repair should

:: Surgery in Dermatology

TABLE 243-1

Guidelinesa for Patient Selection for Antibiotic Prophylaxis for the Prevention of Endocarditis and Prosthesis Infections as well as Surgical Site Infections Risk Stratification for Endocarditis and Prosthesis Infection High-Risk Patient

Low-Risk Patient

History of bacterial endocarditis

History of CABG surgery

Prosthetic valve

Pacemaker, defibrillator

Any cardiac valvular dysfunction Hypertrophic cardiomyopathy

No valvular dysfunction (including history of rheumatic fever or Kawasaki disease)

Mitral valve prolapse with regurgitation, all mitral valve prolapse in men >45 years

Mitral valve prolapse without regurgitation Physiologic heart murmur

Cardiac malformation

Atrial septal defect or ostium secundum

CNS shunts

>6 mon since repair of ASD, VSD, PDA

Shunt/fistula near inflamed/infected tissue

Arterial grafts/stents

Orthopedic prosthesis

Nonorthopedic prosthesis (i.e., penile prosthesis, breast implants)

Antibiotic Prophylaxis for the Prevention of Endocarditis and Prosthesis Infection

Risk

Procedure

Skin Condition

Location

Prophylaxis

High

Mohs

Any

Any

Yes No Yes Yes No

a

High

Excision, biopsy, ED&C, ablative laser, cryotherapy

Intact or eroded

Infected/Inflamed

Skin Mucosa Any

Low

Any

Any

Any

Potential Antibiotic Prophylaxis for the Prevention Surgical Site Infection Inflamed or infected skin close to surgical site Flap or graft reconstruction on nose and ear High-tension closures Below-the-knee procedures Hand surgery Multiple simultaneous procedures Mucosal/anogenital sites in immunocompromised patients a

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Unless prosthetic valve. Adapted from: Maragh SL et al: Antibiotic prophylaxis in dermatologic surgery: updated guidelines. Dermatol Surg 2005 Jan;31(1):91-93.

EQUIPMENT



Basic: mechanical table, overhead procedure lights, electrocautery, vital signs monitor, Mayo stand (1 or 2), receptacle for contaminated waste. Optional: depending on the location and scope of the procedure, suction may be needed.

SURGICAL TRAY The specific instruments selected depend on the scope of the procedure and personal preference of the surgeon. It is helpful to set up the basic elements on the tray in the same layout each time. Consistency in placement of sharps prevents inadvertent injury with contaminated instruments to the surgeon or the assistant. A basic excisional surgery tray (eFig. 243-0.1 in online edition) contains:





Instruments: curette, No. 3 or No. 7 Bard-Parker scalpel handle with a No. 15 or No. 10 blade (or a Beaver blade in some cases), small forceps (e.g., Bishop-Harmon) and/or smooth-toothed Adson forceps, delicate standard skin hook or doubleprong skin hook, curved iris scissors, blunt-tipped undermining scissors, hemostat, towel clamps, needle holder, suture scissors. For larger procedures, such as flaps, additional hemostats or hooks may be needed. Special procedures will need other instruments added to this tray (e.g., split-thickness skin grafts require a dermatome). Disposable material: marking pen, gauze sponges, cotton tip applicator sticks, scratch pad for electrocautery tip, electrocautery handpiece and tip, surgical drapes, foam or magnetic pad for discarded needles Suture

PREPARATION Before starting a surgical procedure, it is important to review the patient’s medical history, drug allergies,

ANESTHESIA Most excisions are performed with local anesthesia only.6 The most common agent utilized is 1% or 2% lidocaine, injected in a ring around the involved area. Other anesthetics used include bupivicaine, mepivicaine, or articaine. The addition of epinephrine 1:100,000 causes local vasoconstriction and helps increase the amount of total anesthesia that may be safely administered, increases the duration of anesthetic activity,7 and decreases intraoperative bleeding. Plain lidocaine should be used when the administration of epinephrine is contraindicated, such as in patients with known cardiac arrhythmias, unstable angina, and narrowangle glaucoma. It should be used with care in patients who are hypertensive, pregnant, or with known anxiety disorders. The administration of local anesthetic is painful, particularly on sensitive sites such as the perioral and perinasal areas. There are several ways to decrease this discomfort.8 Lidocaine is slightly acidic, and the addition of sodium bicarbonate 1:10 raises the pH of the solution closer to physiologic levels. Liquid injected at room temperature or warmer is less uncomfortable than that delivered at cooler temperatures. At the

Excisional Surgery and Repair, Flaps, and Grafts



40

::

PROCEDURE ROOM

and current medications, including over-the-counter medications. The entire procedure should be explained in detail, and the patient must sign an informed consent. Vital signs should be taken and recorded. The patient should be positioned in a manner that allows maximum exposure of the surgical site and is comfortable enough that the patient can remain still for the procedure. It is also important to be sure the patient is positioned in an optimally ergonomic way for the surgeon. Patients should be positioned so that the surgeon and assistance are comfortable and not leaning excessively over the table. A back flexion angle of greater than 15° increases the risk of significant back injury. Likewise, the patient should be elevated to a height that is comfortable for the surgeon. While many occupational therapists suggest working at a height that is in line with the elbow, most find bringing the working surface up higher to reduce the angle of the surgeon’s neck to be significantly more comfortable. Operating with a cervical neck angle greater than 15° can lead to serious neck injuries and disabilities (eFig. 243-0.2 in online edition). If hair removal is deemed necessary, it may be trimmed. The operative field is cleansed in a sterile fashion with one of several scrubs, including chlorhexidine (with or without isopropyl alcohol), iodophors, or triclosan.5 The boundaries of the skin prep should be much wider than the planned incision and take into account the path of suture material in the surgical field. For procedures on the face, the patient should be advised to keep the eyes closed and caution should be used not to get any of the prep into the eyes. Sterile towels or a sterile drape should be placed around the edges of the field. In addition, draping the eyes may add additional comfort to the patient by helping avoid the glare of the operative lights.

Chapter 243

be placed in the direction of rhytides or relaxed skin tension lines. It is best to plan an excision with the patient in an upright position, and animation using the underlying muscles of facial expression may also be helpful. On the trunk or extremities, the direction of skin tension may be tested by moving/ pinching the area. The incision should be made perpendicular to the skin surface, and an even depth of resection and undermining across the base of the wound should be maintained. Remove standing cones of redundant tissue. Buried vertical mattress sutures should be placed to attain good wound eversion and minimize the tension on the wound edges as it heals. Wounds heal under the optimal conditions of a clean, occluded environment.

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Section 40 :: Surgery in Dermatology

i­ njection site, the application of ice or vibration may also decrease the sensation of pain. Placement of the needle through an enlarged pore, especially on the nose, may also limit discomfort. Superficial dermal injection induces anesthesia more quickly than that injected into the deep dermal-subcutaneous tissue region, yet since the tissue is less distensible, it is uniformly more painful. Therefore, lidocaine should first be delivered to the deep dermal-subcutaneous tissue and then more superficially as the needle is withdrawn. Anesthesia should be delivered slowly through a small caliber needle. A 30-gauge needle typically is used in these circumstances. The surgical site should also be anesthetized from the proximal to the distal aspect of the local sensory nerve if possible. For example, when injecting around a lesion on the forehead, start the injections at the inferior aspect and move more superiorly with subsequent injections. In this manner, by the time the superior injections are performed, the area may already be numb since the supraorbital nerve had been anesthetized from the inferior injections. For larger procedures, nerve block anesthesia is helpful because a large area can be anesthetized with a limited volume of anesthesia. Tissue distortion is also limited with nerve block anesthesia, and the vascular perfusion of the flap is not impaired.

EXCISIONAL SURGERY ELLIPICAL EXCISION Excisional surgery is one of the most frequently performed dermatologic surgery procedures. Specifically, the elliptical or fusiform excision allows for a linear, side-to-side closure. Mastery of elliptical excision and closure is fundamental to more advanced procedures, including variations on the ellipse itself and planning and executing more complex flaps. An elliptical excision is indicated for the removal of small- to moderatesized benign or malignant neoplasms as well as for excisional biopsy and scar revision.

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PLANNING THE ELLIPSE. In planning the excision, the lesion to be excised should first be identified and confirmed by the patient. Using an appropriate marker a circle is drawn around the lesion with the appropriate margins. The size of the surgical margin is dependent on the nature of the lesion.9,10 Once the margins of the lesion have been marked, the ellipse is planned. When planning a fusiform excision with linear closure, one must consider several factors, including the impact of the procedure on form and function. Free margins are of primary concern. Any distortion of a free margin will be aesthetically unacceptable. Closures should be planned such that tension vectors are perpendicular to free margins so no distortion occurs. For optimal cosmetic results, the long axis of the fusiform excision should be oriented along the relaxed skin tension lines, which are generally perpendicular to the direction of the pull of the underlying muscle (Fig. 243-1). These lines should be identified while the

Relaxed skin tension lines

Figure 243-1  Relaxed skin tension lines. Relaxed skin tension lines generally form perpendicular to underlying muscles of facial expression. Closure lines heal better and with a thinner less noticeable scar when placed in relaxed skin tension lines. patient is sitting upright, and may be highlighted by asking the patient to make certain facial expressions. If the relaxed skin tension lines are not obvious, the direction of laxity may be identified by manipulating tissue manually. Relaxed skin tension lines rarely follow published diagrams, and closures should mimic the subtle arcs in the facial lines of expression. When possible, excisions should be restricted to one of the major cosmetic units (e.g., forehead, nose, periorbital area, lips and perioral area, chin, and cheeks) (Fig. 243-2). Placing the incision line at the junction of the cosmetic units may also minimize the appearance of the resultant scar. An adequate reservoir of surrounding tissue or skin laxity must be present. When the elliptical excision and closure that has been designed cannot include these conditions consideration must be given to other forms of repair such as flaps, grafts, partial purse sting closures, or healing by second intention. The simple ellipse is based on an optimal length to width ratio of 3.5:1 to minimize the formation of ­redundant tissue at the apices, otherwise known as “dog-ears,” “puckers,” or “standing cones skin.” The ratio may be increased to 4:1 or greater in locations with less tissue distensibility or decreased to 3:1 in areas where the tissue is more lax. The apical angle between the two arciform incisions ranges from of 37°–74°, depending on the length to width ratio.11 As

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Chapter 243 ::

the ratio becomes larger, the apical angle decreases; thus, for a ratio of 5:1, which may be needed for scalp surgery, the apical angle approaches 30° (Fig. 243-3). It is important to note that as a wound is closed in a linear fashion, the length of the resultant scar will be longer than the distance between the two distal points drawn out in the preoperative design of the ellipse. The arc of the two sides of the closure that are brought together is necessarily longer than a straight line drawn between the distal points of the ellipse. Mathematically, with the angles used in excisional surgery, the arcs are roughly 20% longer than the straight line drawn down the middle of the ellipse. In most cases this becomes

Figure 243-3  Acute apical angle. Certain areas such as the convex surface of an extremity or the nasal dorsum require a length to width ratio of greater than 3:1.

Figure 243-4  Incision. Incisions should be made 90° (perpendicular) to the skin surface and continued down through the dermis into the subcutaneous tissue. irrelevant as there is contraction along the long axis of a scar and the tissue around the closure distends and absorbs this small difference without any noticeable distortion. In areas such as the upper lip, however, this small difference may be enough to distort the lip margin and be disfiguring. Lengthening the elliptical closure and bringing it around the lip to the wet mucosal margin will often help hide this potential distortion.

TECHNIQUE. After the ellipse is planned and drawn, the field is anesthetized, prepped, draped, and the first incision is made using a scalpel (Fig. 243-4). In most instances, a number 15 blade is used to score the epidermis or to cut through to the fat on the first pass; however, thick back skin may require the use of a No. 10 blade. The surgery begins with the point of the blade at the apex distal from the surgeon’s position. As the incision progresses toward the arc of the ellipse, the belly of the blade is held perpendicular to the skin surface, preventing a beveled incision. As the opposite apex of the incision is approached, the blade rocks back up onto its tip, which allows the surgeon to clearly see the apex of the incision under the advancing hand. This prevents extending the incision beyond the planned apex. To prevent bunching of the tissue ahead of the pressure exerted by the blade, traction on the surrounding skin is held with the nondominant hand; in addition, an assistant may aid with traction. The depth of the excision is, again, dependent on the nature of the neoplasm being excised. When a side-toside closure is planned, the depth of the incision must be full thickness, or into the superficial subcutaneous fat. The proximal apex of the ellipse is grasped gently with a toothed forceps to elevate the tissue. The base of the specimen is dissected in an even plane with a scalpel or scissors. The depth at the apices should be

Excisional Surgery and Repair, Flaps, and Grafts

Figure 243-2  Cosmetic units. The face can be divided into many cosmetic units. The cosmetic units are differentiated from each other by alterations in skin texture, color, or contour. Incisions hide very well when placed in cosmetic unit junctions.

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the same as the depth at the center; there is a tendency to remove the specimen with the depth at the apices more superficially. When the depth of the excision is not uniform, a more noticeable standing cone of tissue may surround the tips as the wound is closed.

Section 40 :: Surgery in Dermatology

CLOSURE. Undermining is performed to increase mobility of the surrounding tissue, aid in wound eversion, decrease tension on the wound edges, and diffuse scar contraction.12 The subcutaneous tissue is undermined at the same level around all edges of the wound, including the apices, utilizing iris or blunt-tipped scissors. The tissue may be snipped or bluntly dissected by inserting the tip of the scissors and spreading. The plane of undermining will vary depending on body site but should be uniform in depth at all edges. Knowledge of anatomy is extremely important and careful attention must be given to surrounding vital structures. Patients receiving anticoagulants or with reduced platelet number or function may benefit by limiting the extent of undermining as the risk of bleeding and hematoma formation is decreased. Electrocoagulation or electrocautery is employed to attain meticulous hemostasis of the bed of the wound. A skin hook is used to elevate the wound edges to expose vessels that were injured during the excision or undermining. Blood that accumulates in the wound must be cleared with gauze or cotton swabs to allow for visualization of pinpoint bleeding and to allow for a relatively dry field. The cautery tip may be applied directly to the vessel until bleeding ceases. Alternatively, indirect coagulation is achieved by using small forceps to grasp the vessel and applying the cautery tip to the forceps. Indirect cautery limits the residual thermal damage surrounding the cauterization and may speed wound healing. Theoretically it could reduce the risk of infection but in facial skin, where much der-

matologic surgery is performed, the excellent blood supply often minimizes the risk of infection. No matter which method is used, care should be taken to stop all significant bleeding while minimizing cautery char. Larger, more high-pressured arteries may require ligation with absorbable suture. Suturing technique (see Chapter 242) reduces and redistributes wound tension, everts the skin edge, eliminates dead space, and maintains or restores natural anatomic contours, while minimizing the formation of permanent suture marks on the skin surface. Most wounds are closed in two layers: (1) absorbable deep sutures and (2) nonabsorbable superficial sutures. Deeper wounds or those with significant dead space may benefit from a third, deep layer in the subcutaneous fat or fascia. Ideally, the wound is closed by first placing the deep sutures using the rule of halves to minimize the formation of dog-ears (Fig. 243-5). The first suture is placed in the center of the wound. Each half of the remaining defect is closed in a similar manner, which is repeated until a suitable numbers of sutures have been placed. A wound gains only 7% of its final strength after 2 weeks.13 As most skin sutures are removed within 1 to 2 weeks of placement, absorbable buried sutures are an important part of a layered wound closure.14 Buried sutures typically dissolve over the course of months and provide support for the wound until epidermal tensile strength has increased sufficiently to prevent wound dehiscence. Buried vertical-mattress sutures aid significantly in wound eversion by reducing or eliminating tension on the wound edge and producing thinner less noticeable scars (Fig. 243-6). This type of buried suture should be used in nearly all closures. Subcutaneous sutures help minimize or eliminate dead space and align deep structures such as skeletal muscle or fascia. They can

Closing wound by rule of halfs

Key suture

2nd suture

3rd suture

A

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B

Figure 243-5  A and B. Closing wound by rule of halves. Sutures are placed at the midpoint of any open area of the defect.

Buried vertical mattress suture

Excisional Surgery and Repair, Flaps, and Grafts

A

::

also be used to anchor overlying tissue to underlying fixed structures, such as periosteum, to prevent distortion of free margins or maintain proper facial contour and function. This is exemplified by anchoring a melolabial flap to the maxillary periosteum. When tying a buried suture, it is important not only to keep both free ends of the suture on the same side of the loop created, but also to tie the suture in such a manner that draws the knot down on the same side so it will tuck up under the loop and not get hung up on it (Fig. 243-7). Buried sutures should align the wound edges such that they are perfectly approximated with good wound eversion before the placement of epidermal sutures.

SUTURE REMOVAL. The risk of crosshatch marks across the suture line can be minimized by removing the sutures within a week of placement, before the formation of epithelial suture tracks develop. On the face and ears, most skin sutures are removed within 5 to 7 days. Neck sutures should be removed in 7 days and scalp sutures in 7 to 10 days. On the trunk and extremities, risk of wound dehiscence mandates that epidermal sutures may be left in place longer, typically 10–14 days, to provide additional support. In repairs under high tension or when dehiscence is likely, sutures may be left in place for 3–4 additional days. However, if sufficient buried sutures have been placed and the wound as well approximated at 7–10 days, epidermal sutures can be removed. The use of a running subcuticular suture for well-approximated wounds will prevent the formation of suture tracks and should be used in most cases that require sutures be left for more than 7 days.

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Chapter 243

Figure 243-6  Buried vertical mattress suture. The buried vertical mattress suture gives excellent eversion to the wound edge and should be used for most if not all subcutaneous sutures.

Epidermal sutures are placed to approximate the margins of the skin edge. They should be evenly spaced and placed at roughly the same distance from the wound as the combined dermal epidermal depth. Therefore, sutures placed on the eyelid will be much closer together than those placed on the thick skin of the back. Most practitioners use a running nonabsorbable minimally-reactive monofilament suture, such as polypropylene, that requires subsequent removal.15 Alternatives include running absorbable fast-acting gut16, absorbable or nonabsorbable running subcuticular sutures17, simple interrupted nonabsorbable sutures, and polymethylmethacrylate tissue glue. Simple interrupted sutures are more time-consuming to place and remove than a running suture. In settings, where wound healing may be impaired due to the patient’s advanced age or underlying disease, interrupted sutures compared with running sutures may be preferred, as interrupted sutures may have, with all other factors being equal, greater tensile strength and less potential to cause edema, induration, and impaired microcirculation.18

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Figure 243-7  A and B. Tying deep sutures. It is important to keep the knot forming from the two free ends on the same side of the loop in the middle so they do not get hung up on the loop. This will allow the knot to cinch up under the loop and draw the wound edges together. The wound should be together with skin edges nicely opposed and everted.

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EXCISION WITHOUT CLOSURE

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There are certain locations and situations where allowing a wound to heal by second intention is the preferred method of closure. Wounds in patients who are poor surgical risks for reconstructive surgery, where there is relatively minimal tissue mobility (scalp, distal lower extremities), and where there is a high risk of infection healing by second intention may be indicated. (eFig. 243-7.1 in online edition). Wounds located in concave areas such as the medial canthus, ear concha, alar crease (if small), temple region, and postauricular sulcus lend themselves well to healing by second intention.19 Wounds allowed to heal by second intention contract significantly and may decrease in size as much as 50% or more.20 Superficial wounds heal with less wound contraction, because there is less deposition of collagen. Therefore, a very superficial wound, even on a convex surface such as the forehead or the nose, can potentially heal well. Because all wounds contract to some degree, it is important that there be no free margin along one side of the wound that can be elevated during wound contracture and cause distortion at the site. This may be encountered along the eyelid margins, ear margins, eyebrow, nasal ala, and lip vermillion border. These areas are almost always better managed with appropriate reconstructive surgery. When a lesion is excised with the intention of allowing the wound to heal by second intention, appropriate margins should be included and the resulting defect will typically be circular in nature. The incision through the skin is beveled inward to provide exposure of the base of the wound. The depth need not reach the subcutaneous fat if the lesion can be removed satisfactorily by transecting the dermis.

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Wounds that are allowed to granulate are more resistant to infection and do not form a hematoma. In addition, the size of the final scar is kept to a minimum by negating the need to remove standing cones. These wounds, however, require more time to heal than those that are closed primarily and exhibit increased contracture. In some cases there is an unpredictable cosmetic result.20 Employing a purse string suture can significantly decrease the size of the wound and abbreviate the healing time considerably.

REVISION OF STANDING CONES OF TISSUE Under certain circumstances, a circular excision may be performed when the orientation of the ellipse is difficult to anticipate. This may occur when the precise direction of relaxed skin tension lines and least tension is difficult to determine, when the length of the ellipse for an optimal outcome is unclear, or when alternative repairs may be considered, such as a local flap. Nonelliptical defects require revision of the cones or dog-ears. First, the wound is closed with a few centrally placed sutures; bilateral standing cones of excess tissue form on either side of the central closure. In addition, tissue redundancies may persist at one or both ends of a planned fusiform excision if the apical angle is too wide, if the sides are of unequal lengths, or on convex surfaces and the techniques for addressing these redundancies are similar under both clinical circumstances 21 Skillful repair of the redundant standing cones extend the incision line by removing an additional triangle of tissue at the tip (Fig. 243-8). The apex of the standing cone is lifted with forceps or

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Figure 243-8  A and B. Standing cones. Redundant tissue may be removed by incising one side, draping the excess skin over the wound, and excising the resultant triangle.

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Figure 243-9  A–C. S-plasty closures are often used to give a wound a curvilinear line and to alter the tension vectors so they do not all pull along the long axis of the wound and cause noticeable contraction. The S-plasty is especially useful on convex surfaces where wound contraction may cause the scar to sink down and appear depressed. a skin hook and manipulated to determine where to place the incision that releases the redundant tissue. The incision is made with a scalpel and the dog-ear is undermined. The free end of the cone is pulled over the incision and the remaining incision is made such that the resultant wound edges lie flat.22 The freed cone is termed a Burow’s triangle. This technique results in a linear extension of the scar. Variations on the revision of tissue cones include a curved extension, an angled extension, and an M-plasty.

pendicular to the long axis of the ellipse. Since wounds contract along their long axis, designing the closure with an S-plasty, displaces the tension over a greater length and a variety of angles (Fig. 243-9) and does not create a contracting in one direction with resulting indentation over a convex surface such as an extremity.

CURVED ELLIPSE. The classic fusiform excision creates a linear scar. At times, it is aesthetically preferable to create a curvilinear scar. The curvilinear repair is useful on the cheek and around the chin. The curved ellipse is created by intentionally designing it with one side longer than the other. The wound is closed by the rule of halves.

M-PLASTY. An M-plasty allows the length of a scar to be shortened. Rather than extending the end of an ellipse or removing a Burow’s triangle, the redundant tissue may be excised inward, forming a M-shaped scar. The long axis of the incision is reduced by the length equivalent to the inverted triangle which makes the center of the M. This technique is useful for confining a scar to a single cosmetic unit, that is, the chin, or when an incision approaches a free margin. The scar may be camouflaged in locations where rhytides bifurcate, such as the crow’s feet in the periorbital area or around the lips. It is important to advance the inverted triangle up into the rest of the ellipse to take full advantage of the scar-shortening effect.

S-PLASTY. An S-shaped repair is useful on convex surfaces such as the extremities where a linear repair may result in persistent standing cones or indentations. The tension vectors of a standard elliptical incision are per-

PARTIAL CLOSURE. Partial closure is used when more extensive repairs are limited by lack of local tissue reservoirs or the patient’s health or coagulation status. The wound is closed from the ends toward the

VARIATIONS OF THE ELLIPSE

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center. When wound tension prevents further closure, the area remains open to heal by second intention. The final scar is usually linear and may resemble a spread scar in the middle. Alternatively, a purse-sting suture is placed around the wound and tissue is drawn together circumferentially. The purse-string suture is closed just to the point of minimal tissue buckling. Additional guiding sutures may then be placed across the partially closed wound to attain better alignment and even further closure.

SERIAL EXCISION. In some cases, the length of an ellipse required to excise a lesion with a 3 or 4:1 ratio is too long for an acceptable cosmetic or functional outcome. In such instances, the lesion may be removed with a series of staged excisions. A partial excision is performed, ideally an ellipse that accommodates the full length of the lesion, with primary linear closure. During the following months, the surrounding tissue stretches and the tension in the area decreases. Additional excisions are performed in a similar manner, removing the remaining lesion as well as the scar or scars created from the first steps of the procedure. This is typically used to minimize the length of the final scar in large circumference neoplasms that are benign or low risk.

FLAPS When simple primary closure cannot be done because a wound is too large, there is excessive tension, or an unacceptable functional or cosmetic result would ensue from a linear scar, a tissue-movement procedure, such as a flap or a graft, should be considered. A local skin flap is a portion of full-thickness skin and subcutaneous tissue transferred from an adjacent donor site into the surgical defect. The flap maintains its blood supply via a vascular pedicle that remains connected to the donor site. Random pattern flaps, the most widely used in dermatologic surgery, are supported by the small arterioles and capillaries of the subdermal vascular plexus found in the mid-to-superficial fat. Therefore, undermining and flap mobilization must be done at or below this level to ensure adequate blood supply. If undermining occurs too superficially, the intradermal vaculature alone will often not be able to support a flap. In certain areas other than the face, the perfusion pressure of even the subdermal vascular plexus is often not sufficient to support a random pattern flap. Fortunately, the blood supply of the face is rich, estimated to be ten times greater than necessary to support the skin’s basic metabolic needs so it can support a wide variety of random pattern flaps. The vascular perfusion pressure, that is the force of blood flow through a vessel, is greatest at the proximal end of a vessel and decreases steadily as it travels more distal into the flap. To ensure flap survival, the perfusion pressure must be great enough to keep the distal capillaries of the flap open. If the pressure falls below a certain critical level, the capillaries close and insufficient blood is supplied to the distal end of the flap.

For years, it was believed that the viable length of a flap was directly proportional to the width of the pedicle. In 1970, Milton discovered that axial flaps in a pig model under the same conditions of blood supply survive only to a finite length regardless of width.23 Daniel and Williams, as well as Stell confirmed Milton’s findings and concluded that there was an upper limit of flap length that cannot be increased by increasing the pedicle width.24,25 The maximal flap length is determined by vascular supply, not simply pedicle width. The greater the perfusion pressure in the flap pedicle, the longer the flap can be without undergoing necrosis.26 In addition, the greater the perfusion pressure in the pedicle, the narrower the pedicle may be. Axial pattern flaps have the highest perfusion pressure at the base and therefore can support very narrow long flaps (generally greater than 4:1 length to width ratio). Musculocutaneous flaps have the next greatest vascular perfusion pressure, followed by fasciocutaneous flaps, and finally random pattern flaps. Stell discovered the greatest length of a viable axial flap was 60% greater than that of a random pattern flap. In general, random pattern flaps on the face should have a maximal length to width ratio of 3:1.27,28 This is however only a rough guideline and individual patient characteristics such as tobacco use, sebaceous nature of skin, prior radiation or surgical procedures, and precise location all affect vascular perfusion. To help ensure flap survival the pedicle length-to-width ratios should not exceed 2:1 on the trunk and extremities. The two movements involved in repairing a defect with a flap are the primary movement, which is the action of placing the flap into the defect and the secondary movement of tissue in the donor area, which closes the secondary defect and facilitates primary flap movement. Both movements are important in terms of distributing tension in the proper direction and over a larger area so as to minimize tension on the flap itself, which might compromise its survival.29 Flaps are commonly classified according to their primary movement—advancement flaps, rotation flaps, transposition flaps, and interpolation flaps. This classification underplays the reality that many flaps have more than one primary movement, e.g., a rotation flap usually has a component of advancement to fill the distal portion of a wound. Therefore, another way to classify flaps is by whether the primary movement is sliding, which displaces tissue redundancy at a site distant from the defect (advancement and rotation) or lifting, where a flap is moved over intact skin, reorienting wound tension (transposition and interpolation). As with elliptical excisions, the flap should be planned paying attention to the concepts discussed above, such as free margins, skin laxity, relaxed skin tension lines, cosmetic units, and attention to function. The flap and possible resultant Burow’s triangles should be drawn out with a marking pen while the patient is in an upright position. It is advisable to plan the flap prior to administering anesthesia, as the injected volume may distort the tissue and alter its movement. Flap incisions should be made perpendicular to the skin and the recipient wound edges should similarly be

squared off. The thickness of the flap should be uniform and should approximate the thickness of the wound edge. The area around the flap should be widely undermined.

ADVANCEMENT FLAPS

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SINGLE ADVANCEMENT. The simplest example of a pure advancement flap is the U-plasty, whereby double, parallel incisions are made tangential to what is most often a round defect. The flap is undermined, advanced into the defect, and secured with sutures, creating a U-shaped scar (eFig. 243-9.1 in online edition). Redundant tissue cones may be sewn out using the rule of halves or removed as Burow’s triangles at the base of the flap. While the U-plasty is occasionally used to make the majority of lines in the repair of a forehead defect run in the horizontal direction with the natural skin tension lines; the fact that it does not alter tension vectors and does not significantly free tissue up limits its usefulness. An L-plasty or O-to-L advancement is a single tangent flap where an incision is made at one end of a defect extending outward for some length, and the tissue mobilized is then advanced into the defect (Fig. 243-10). Tissue redundancy is created on the side

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Chapter 243

The primary movement of an advancement flap is the one-dimensional sliding of tissue directly into a defect. In essence, incisions are made tangentially to the defect to free up neighboring tissue. With the wound edge acting as the free margin of the flap, the tissue is advanced into place, displacing tissue cones. While some adjacent tissue laxity may be tapped into with an advancement flap, the tension vectors of the closure remain the same and therefore the primary advantage of an advancement flap is the displacement of closure lines into more cosmetically acceptable locations.

of the defect opposite the flap incision and must be removed. While this type of advancement flap may tap into some distant laxity, it is generally minimal. Advancement flaps also do not change the tension vectors of the closure. Advancement flaps spread the tension out over a longer distance and offer some of the closure line to be perpendicular to the vector of tension. O-to-L advancement flaps are particularly useful with defects where the limb of the flap may be incorporated into RSTLs or cosmetic unit junctions or where a linear closure may otherwise cross a free margin or cosmetic unit junction, as may be the case on the eyebrow, nose, or upper lip. A larger single advancement flap is the cheek advancement flap, used to repair medium-to-large defects of the medial cheek and/or lateral nose (Fig. 243-11). The incision may be placed in the alar crease or nasolabial fold by removing tissue above and below the defect to allow the cheek to advance into the nasofacial sulcus. It is usually advantageous to tack the leading edge of a cheek advancement flap into periosteum at the nasal sidewall cheek junction, even if the defect is on the nasal sidewall. Tacking the flap to periosteum at the nasal sidewall cheek junction will take pressure off the leading edge and recreate the natural concave surface of the area and prevent unnatural webbing. When a defect involves both the cheek and the ala, a cheek advancement flap may be used to cover the defect on the cheek and a full-thickness skin graft may be used to repair the alar part of the defect (Fig. 243-12). This will keep the cosmetic units separate and place the scar lines along the cosmetic unit junctions. Helical rim advancement flaps may be used to repair defects of the helix, utilizing the tissue laxity of the lobule. Traditionally, this flap was created with a through and through incision inferior to the defect along the scaphoid fossa, terminating in the lobule, and creating a narrow pedicle to be advanced (conceptually similar to the U-plasty). The survivability of this flap is

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Figure 243-10  A–C. A to L advancement flap. Here, one line of the closure is drawn and incised perpendicular to the closure.

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proportional to the length-to-width ratio and could only be performed on inferior helical defects where this ratio will not exceed 3–4:1. A more popular modification of this flap is to use a single tangent incision along the scaphoid fossa, leaving the posterior auricular skin intact30 (conceptually analogous to the L-plasty) (Fig. 243-13). This allows for the maintenance

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Figure 243-11  A–C. Cheek advancement flap. Tissue laxity of the cheek is advanced medially into the defect.

of a more reliable blood supply via the tissue inferiorly and posteriorly and permits the repair of defects more distant from the lobule. It is important to have good eversion when closing this flap at the helical rim as forces of contraction during healing will tend to invert the wound edge and create an aesthetically unpleasant notch.

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BILATERAL ADVANCEMENT. If two sets of parallel incisions are made symmetrically on both edges of the defect, a bilateral advancement flap, termed an H-plasty, has been created. This flap is essentially a bilateral U-plasty and is occasionally used on the forehead and upper lip to hide incision lines along relaxed skin tension lines and cosmetic unit junctions. Another commonly employed bilateral advancement flap is an O-to-T flap, also termed an A-to-T or a T-plasty (eFig. 243-13.1 in online edition), analogous to a bilateral L-plasty. This flap is essentially a bilateral

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O to L flap. The standing cone is removed from one end of the defect, creating a triangle, or transforming on “O” into an “A”. Single incisions extend from the base of this triangular defect, and the two sides of the triangle slide together along this baseline. The T-plasty is best performed with the broad base along a free margin or cosmetic unit junction (e.g., lip, eyebrow).

CRESCENTIC ADVANCEMENT FLAP. The crescentic advancement flap utilizes the removal of small crescent of tissue along an advancement flap to either

Excisional Surgery and Repair, Flaps, and Grafts

Figure 243-12  A–C. Cheek advancement flap with full-thickness skin graft. When the defect involves both the cheek and the ala, it is often best to utilize separate closures for each of the cosmetic units. Here a cheek advancement flap was used to close the part of the defect on the cheek, and a conchal bowl full-thickness skin graft was used to close the alar aspect of the defect.

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Figure 243-13  A–C. Helical rim advancement flap. An incision is made along the anterior helical rim down to the ear lobule. A “dog ear” is taken out on the posterior aspect of the ear. The helix is advanced superiorly to close the defect with everting sutures. This allows for consistent reconstruction of the helical rim.

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better hide the scar line or increase the length of the line to prevent distortion. This flap is particularly useful for the repair of upper lip and perialar defects. The superior standing cone is removed in a crescentic shape around the ala such that the superior scar line is placed in the perinasal sulcus (Fig. 243-14).31 For defects on the upper cutaneous lip, the inferior cone is removed along relaxed skin tension lines and extended through the vermilion border and around to the wet mucosa to prevent a downward distortion of the vermilion. A modification of the crescentic advancement includes the repair of a small, perialar defect of the medial cheek where both cones are removed around the ala, and the entire scar line is placed in the nasal sulcus, similar to the cheek advancement. Another modification includes incorporating a crescent along the vermilion border to an advancement flap closing a defect just superior to the vermilion border. Removing a crescent here increases the length of flap and helps minimize the differences in length between the flap and the total length of the closure (flap + defect). This will take some of the horizontal tension off the flap and minimize distortion of the lip and modeolus (Fig. 243-15).

ISLAND PEDICLE FLAP.

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A subcutaneous island pedicle flap, also referred to as a V-to-Y advancement flap, may be considered as a variation of an

Figure 243-14  A–C. Crescentic advancement flap. A crescent of tissue is removed around the lateral aspect of the ala and the cheek is advanced medially.

advancement flap that has had all of its connections to the epidermis and dermis severed, maintaining its blood supply through a subcutaneous tissue pedicle (eFig. 243-15.1 in online edition).32 The flap is designed Variation on the advancement flap with crescent

Figure 243-15  Variation on the advancement flap with crescent. Removing the crescent of tissue elongates the incision and compensates for the length mismatch of the incision vs. the incision + defect.

ROTATION FLAPS In a rotation flap, skin moves into the defect by rotating around a pivot point (Fig. 243-16). This is classically used to close relatively large defects on the cheek, temple, or scalp. The design of the traditional rotation flap uses a curvilinear incision along an arc adjacent to the primary defect. Adjacent lax tissue is recruited while the closure tension is redirected in multiple directions away from the primary defect. The flap is designed with attention to its length and curvature.33 Rotation flaps often require long incision lines, as a larger arc of the rotation vector allows closure with minimal tension on the flap’s tip while simultaneously decreasing the width of the secondary defect. The ideal arc of a rotation flap extends up to five times the width of the defect and makes up approximately one quarter of the circumference of a circle. As the flap is raised and undermined, the adjacent tissue laxity allows the flap to rotate into the primary defect. The stiffness about the pivot point may hinder the flap’s movement,33 and undermining the area of pivotal restraint improves flap mobility. If restraint of motion keeps the tip from moving into the distal defect, a back cut can increase tissue movement in areas of limited tissue laxity, such as the nose. The back cut cannot extend so far across the base of the flap that it interferes with blood flow into the flap.

DORSAL NASAL ROTATION FLAP. Also known as the Rieger flap, this flap is employed to repair nasal defects involving the distal dorsum or tip.34 The ­tissue

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the defect without upward tension on the nasal tip, the muscular flap is released horizontally at the superior and inferior edge to create a muscular sling that advances with the flap into place. The muscular attachment gives a robust blood supply to the flap and helps ensure its survival.

Chapter 243

within cosmetic units when possible and, as with all repairs, it is optimal for the incision lines to run along cosmetic junctions. The island pedicle flap is frequently used on nasal and perioral closures where free margins are at risk for distortion. The tension vectors of an island pedicle flap are primarily in the same direction as that of a primary closure; however, they are displaced distal to the wound (i.e., superior to the nasal tip, superior or lateral to the vermilion border) and help avoid distortion of the area around the defect. An island pedicle flap is created by extending two nonparallel tangential incisions to meet at an approximate 30° angle, similar to when planning a Burow’s triangle. The difference is that the incision lines stay parallel for a short distance before converging, creating a slightly larger triangle than would be created with a Burow’s triangle. This extra length gives tissue that closely approximates the size of the defect and minimizes local distortion. The triangle may be designed larger or smaller depending on how much tension sharing is desired. The incisions are made just to the superficial subcutaneous tissue. The tip and sides of the flap are undermined widely extending outward from the flap in the subcutaneous plane. The triangular flap is also undermined slightly to help mobilize it. The flap is then advanced into the defect and sutured into place. In order for the flap to fit properly into a circular defect, either the corners of the flap must be trimmed or the defect squared off. The flap must be undermined with attention both to the mobility of the tissue as well as to the maintenance of a subcutaneous vascular pedicle. While the initial design should have a broad pedicle, if mobility is limited the pedicle may be progressively diminished (particularly at the trailing tip of the flap). When closing defects on the nasal dorsum and tip, a muscular flap is often created laterally on one or both sides. For this musculocutaneous island pedicle flap, undermining is performed both above and below the nasalis muscle. If there is not enough laxity to close

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Figure 243-16  A–C. Rotation flap. An arcuate incision is made from one end of the defect and the flap is rotated into the defect. Rotation flaps help spread tension vectors out in multiple directions radiating from the arc.

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Figure 243-17  A–C. Hatchet flap. The hatchet flap is a rotation flap with a cutback. The cutback gives the flap extra length and aides in its movement.

:: Surgery in Dermatology

reservoir of the nasal root and glabella allows for the movement of the dorsal nasal skin superior to the defect. A long, sweeping arc is created that extends into the nasofacial sulcus and terminates in the glabella. A back cut in the glabella improves the rotational mobility of this flap and is termed a hatchet flap (Fig. 243-17). If the arc of this flap is not long enough or there is too much tension on the leading edge of the flap, elevation of the nasal tip will result. Wide undermining at the level of the perichondrium is required.

BILATERAL ROTATION FLAP. At times, the size

of the defect or the tension on the flap mandates a bilateral rotation flap, in which tissue is rotated into

a defect from two opposite sides. The vectors of rotation may be mirror images of each other, recapitulating the premise of the A–T advancement flap. This may be utilized for large defects on the scalp and larger defects on the lower lip (Fig. 243-18). The vectors of movement may also be in opposition, creating an O-to-Z flap.

TRANSPOSITION FLAPS A transposition flap is a random pattern flap, which borrows skin laxity from an adjacent area in order to fill a defect in an area with little or no skin laxity. In its travel from the donor site to the recipient site, the flap

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Figure 243-18  A–C. Bilateral rotation flap of the lip. Incisions are made bilaterally along the vermillion border and a redundant tricone of tissue is removed posteriorly into the wet mucosal lip. Both wings of the flap are rotated together and sutured with braided suture.

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Excisional Surgery and Repair, Flaps, and Grafts

RHOMBIC FLAP. First described by Lindberg in 1963, the classic rhombic flap was designed to create a secondary defect perpendicular to the primary defect.35 When closed, it would not only provide tissue to the primary defect, but also redirect the tension vector by 90°. This allowed the primary defect to be closed under almost no wound edge tension. Subsequent modifications by DuFourmental and Webster provide more tension sharing between the primary and secondary defects. These modifications are useful in situations where some laxity around the primary defect is available.36 The classic Lindberg rhombic flap is designed by conversion of the primary defect into a four-sided parallelogram with each side of equal length and tip angles of 60° and 120°.35 This rhombus forms the recipient site for the flap as well as the template on which to plan the flap incisions. In its classic configuration (Fig. 243-19), the incisions are designed by extending a line (line a-b) outward from one of the obtuse tips for a length equal to that of one side of the rhombus. From the free end of the extended line (point b), a second line (line b-c) is drawn. The tip angle in this configuration is 60°. The flap is lifted and transposed into place. The tension vector is redirected from that of closing the primary defect, to that of closing the new secondary defect created in the design of the flap. This allows the tension vector to be shifted and redirected by 90°. There are four possible flap designs off of the short axis of any rhomboid defect (Fig. 243-20). Which of these four flap configurations is selected depends on

Rhombic transposition flap

Chapter 243

is lifted or “transposed” over a segment of intervening tissue. When the secondary defect is closed, the transposition flap pushes tissue into a defect rather than pulling it, as with the advancement and rotation flaps. While moving to the recipient site, the flap actually follows a rotational path and must be designed so it does not rotate too far and pull too tightly on its pedicle. Transposition flaps have several advantages over other closures. Their primary function is to redistribute and redirect tension. This is useful in the closure of defects, which would otherwise close under high tension or distort a nearby anatomical structure leading to functional or aesthetic impairment. Transposition flaps are usually smaller in size than advancement and rotation flaps. The resulting scars are geometric broken lines that may be less noticeable than longer linear closures in certain areas. This geometric broken line scar, however, may also be thought of as a disadvantage because such a scar is difficult to completely place along a relaxed skin tension line or cosmetic unit junction. One of the major advantages of transposition flaps are that they utilize adjacent skin and provide an excellent color and textural match. The most common transposition flaps in cutaneous surgery include rhombic flaps (and their variations), bilobed flaps, and banner flaps such as the nasolabial flap. Knowledge of the tissue dynamics used in these three basic transposition flaps can be carried over to the planning and execution of the numerous variations of these flaps.

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Figure 243-19  Rhombic transposition flap. Classic rhombic flaps alter the vectors of tension in a closure by 90° and leave a broken geometric scar shape. The tension is taken completely by the closure of the secondary defect as the flap is pushed into the primary defect.

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Rhombic flaps

the shortening of the flap and subsequent tension at the flap tip.



Section 40 :: Surgery in Dermatology

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Figure 243-20  Rhombic flaps may be drawn in any of four directions off of the short axis of any rhomboid shaped defect.

several factors that affect the final outcome. These factors include adjacent anatomic structures, adjacent skin type, and where the scar line will be best hidden. Though the classic rhombic transposition flap can be designed and executed off of the long axis of the rhombus, there are two advantages to designing it off of the short axis of the defect. First, it keeps the flap as small as possible while filling the defect completely. Second, it minimizes the arc through which the flap must rotate to fit into the defect. In designing the flap from the circular defect, the length of the line extended out from the defect should be drawn longer than the diameter of the circular defect. This will account for the fact that the diameter of the circular defect is shorter than the short axis of a rhombus drawn around the defect. A second line of the same length is drawn, keeping the tip angle at 60° to complete the flap. The triangle of tissue redundancy created by the rotation of the transposition flap is removed by trimming a Burow’s triangle at the pivot point. The transposed tissue may be rounded to fit the circular defect, or the defect may be squared off to accommodate the angular flap. This choice can be made based upon which option yields the best aesthetic result. As with any closure, understanding the tension forces is essential to the planning, execution, and outcome of the repair. There are two main tension forces associated with the classic rhombic flap. The first set of tension forces are realized during the approximation and closure of the secondary defect. The second set of tension forces are generated at the tip of the flap when moving it into the primary defect. These forces are due to the resistance to rotation at the flap’s pedicle as well as shortening of the length of the flap during rotation into the recipient site. Dzubow describes these forces as pivotal restraint.33 Securing the flap into the recipient site under high tension is not advised because it may lead to tip ischemia and necrosis. Two modifications in design can be utilized to assist in minimizing

By lengthening both the leading edge and the secondary limb of the flap, the flap can be enlarged and lengthened. This lengthening can compensate for the shortening resulting from pivoting at the base, thus, reducing tension at the tip when secured in the recipient defect. An alternate method to lengthen the flap is by designing the flap with a slightly more obtuse (greater than 120°) flap angle. Widely undermining around the flap also assists in the redistribution of tension vectors as well as redistribution of contractile forces during the healing phase.

THE DUFOURNMENTAL FLAP. The DuFournmental flap modification differs from the classic rhombic transposition flap (Fig. 243-21) in that it utilizes a narrower flap tip angle and a shorter arc of rotation, allowing easier closure of the secondary defect, and some sharing of the tension between the primary and secondary defects. Given that there is generally some tissue laxity at the site of the surgical defect, the DuFourmental modification is utilized by this author more than any of the classic rhombic flap. As with the classic rhombic flap, it is designed by extending the first line from the short axis of the rhomboid defect. However, the angle at which the first line is extended differs from the classic rhombic flap in that it bisects the angle formed by the first line of the classic rhombic flap (which extends straight out from the short axis of the rhombic defect) and the line formed by extending one of the sides of the rhombus from the same corner of the rhombus. The length of the first line is equal to that of a side length of the rhombus. The second line originates from the free end of the first

Dufourmental transposition flap

Angle bisected

Dufourmental flap Classic rhombic flap

Figure 243-21  DuFourmental transposition flap. The flap is designed with a narrower tip angle and a shorter arc of rotation. This allows easier closure of the secondary defect and allows some sharing of tension between the primary and secondary defects. The vectors of tension are altered by 45° not the full 90° seen in a classic rhombic flap.

line, and is drawn parallel to the long axis of the rhombus. This second line’s orientation results in a slightly widened pedicle, a decrease in the tip volume, and a decrease in the degree of rotation necessary to execute the flap. The tissue redundancy at the base of the leading edge of the flap can be removed by taking a slightly larger Burow’s triangle.

Webster 30º flap

Figure 243-22  30° Webster flap. The angle of the rhombic flap is made even more acute and more of the closure tension is shared with the primary defect.

BILOBED FLAP. The bilobed flap used today is a highly evolved transposition flap. The bilobed flap was first described by Esser in 1918. It became a workhorse flap only after the modifications described by Zitelli were published in 1989 (Fig. 243-24). The design of the bilobed flap actually consists of two transposition flaps executed in succession, which follow the same direction of rotation over intervening tissues. The basic premise of this flap is to fill the defect with the primary lobe, while filling the secondary defect with the secondary lobe, leaving a triangle-shaped tertiary defect to be closed primarily. This series of transposition flaps allows the surgeon to further the reach of the flap, and borrow laxity from donor sites at a greater distance from the defect while decreasing the arc of rotation of the pedicle.

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Rhombic flaps

THE BANNER FLAP. Banner type flaps are random pattern finger-shaped cutaneous flaps that, like other transposition flaps, tap into adjacent skin to borrow laxity and fill a defect.37 This flap is most commonly planned as a melolabial transposition to repair defects of the nasal ala or from the pre- or postauricular area to close defects on the ear. For an optimal cosmetic result, the scar is generally placed at the junction of two cosmetic units, providing excellent camouflage (in the nasolabial fold or preauricular sulcus) (Fig. 243-23). The fundamental design of the banner flaps consist of a finger-shaped flap drawn with a width that is equal to the width of the defect and a length equal to the distance from the pivot point to the far edge of the defect. The flap is transposed and rotated in an arc around the pivot point to fill the defect. Since this is a long random pattern flap with a narrow pedicle, the risk of vascular compromise may be high if the entire length of the flap is used and its pedicle originates from an area of minimal vascularity. To minimize risk of vascular compromise, the flap is typically designed to rotate through an angle of 60 to 120° instead of the originally described 180°. Additionally, when designing the backcut and removing the redundancy at the base of the flap, it should be designed in a direction away from the pedicle of the flap to avoid further narrowing of the pedicle thereby maximizing flap viability. Typical locations for use of Banner type flaps include the nasal ala, the superior helix of the ear, and the medial anterior ear.

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THE 30° ANGLE WEBSTER FLAP. The 30° angle Webster modification of the classic rhombic flap utilizes a more acute angle than other rhombic transposition flaps allowing for even greater tension sharing between the primary and secondary defects. A Webster 30° angle flap is planned similarly to the DuFourmental flap; however, its distal tip angle is designed to be 30° (Fig. 243-22). This gives the flap a slimmer design and narrower pedicle. The flap area is only 50% of the area of the primary defect; therefore, it only relieves half of the tension from the primary defect. This modification is used in situations where a fair amount of laxity exists in the horizontal axis of the rhombic

shaped defect. Since this design places more tension on the primary defect, care must be taken not to close with too much lateral tension or distort adjacent anatomic structures. Rhombic transposition flaps are very versatile and may be used to reconstruct a variety of defects. Transposition flaps are generally used when there is insufficient laxity in the immediate surrounding area of closure and/or the tension vectors need to be redirected. This is particularly important when repairing defects near free margins such as the eyelids and the nose. The most common areas they are employed include the nasal dorsum, nasal sidewall, medial and lateral canthus, lateral forehead, temple, cheek, perioral region, inferior chin, and the dorsal hand.

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Figure 243-23  A–C. Banner transposition flap. A finger-shaped flap is incised and draped into the primary defect. These closure lines are generally placed along cosmetic unit junctions such as the preauricular sulcus. The Zitelli modification of the bilobed flap is designed by placing the lobes over a 90° arc from the center of the defect, with the primary lobe rotating from a pivot point that is created by removing a Burow’s triangle at one pole of the defect .38 The width of the primary lobe should be equal to the width of the defect and should be long enough to just extend past the edge of the defect. The secondary lobe must be trimmed to match the secondary defect left by the transposition of the primary lobe. As with the rhombic flap, the bilobed flap redirects the principal tension vector and takes advantage of tissue laxity of the donor site. This flap is predominantly used for small-to-medium sized defects of the lower nose as the tension is redirected to a near vertical vector, preventing distortion of the alar rim (eFig. 243-24.1 in online edition, Fig. 243-25).

Bilobed transposition flap

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Figure 243-24  Bilobed transposition flap. The bilobed flap is designed with two adjacent transposition flaps elevated and rotated into position. The Zitelli modification (shown here) is designed placing the lobes over a 90° arc.

INTERPOLATION FLAPS Interpolation flaps are more complex repairs that import pedicle-based tissue from a site distant to the defect. They are typically utilized on defects that are either too wide or too deep to reconstruct with local flaps or grafts. Many interpolation flaps may be classified as axial flaps if their vascular pedicle is based on a large, named artery. They are also commonly referred to as staged flaps as more than one stage is required to complete the repair. Interpolation flaps require careful planning, substantial time in executing, and significant, albeit temporary, disfigurement of the patient. The first stage of an interpolation flap involves the design and creation of the flap, including repair of the secondary defect. The flap is designed around a substantial artery and therefore is able to support a larger mass of tissue than random flaps. Because the flap is used to repair defects distant from the donor site, the vascular pedicle must temporarily be left in place to ensure adequate blood supply. The distal end of the flap is thinned to match the depth of the defect and sutured in place. The area is bandaged and kept moist. The second stage generally takes place 2- to 3-weeks later, by which time the flap has established a local blood supply from the donor site. The pedicle is then divided from the donor site and the proximal portion of the flap is secured into the original defect. Due to granulation tissue formation, this portion of the flap may need to be thinned out subcutaneously to approximate the depth of the defect. The pedicle is also separated from the donor site which will then require further steps for complete repair.

PARAMEDIAN FOREHEAD FLAP. The paramedian forehead flap is useful to repair large, deep nasal defects that may or may not require cartilage grafts. Tissue is mobilized from the forehead, based on one

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Figure 243-25  A–E. Execution of a medially based bilobed transposition flap. The tertiary defect is closed side to side, the secondary is filled with the second lobe of the flap, and the primary defect is filled with the first lobe of the flap. When used in this location, mobility and flap survival are improved when the flap is undermined below the nasalis muscle.

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of the supratrochlear arteries, and transposed to repair large distal nasal defects with the pedicle remaining attached in the glabellar region (Fig. 243-26). The supratrochlear artery is located at the medial border of the eyebrow, approximately 1.5–2 cm from the midline. The aesthetics of the repair are often improved when the defect is enlarged to include the total cosmetic subunit. The portion of the flap that will fill the defect is the superior portion closest to the hairline; the width here should be equal to the widest portion of the defect, although the pedicle itself need be no

wider than 1–1.5 cm. Its height must be equal to the distance from the base of the flap to the distal edge of the defect. In designing the flap, it is important that the vertical height of the forehead is able to accommodate the necessary length of the flap. The tissue is rotated approximately 180˚ around its pedicle and should be rotated medially as to minimize obscuration of the medial visual field of the ipsilateral eye; therefore, the flap will require less rotation if it is harvested from the forehead supplied by the supratrochlear artery contralateral to the defect.

Section 40 :: Surgery in Dermatology

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Figure 243-26  A–D. Paramedian forehead flap. For deep defects on the nose, a pedicled flap is created on the forehead based on the hearty vasculature of the supratrochlear arterial system and rotated down into place. The pedicle is divided and removed approximately 3 weeks after the inset of the flap (c).

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The donor site is undermined and closed primarily as far superiorly as it will close. The distal aspect of the flap is debulked to the depth of the defect and secured at the distal margin with sutures. The proximal margin, by design, cannot be secured until the pedicle is divided. The donor site is repaired with a side-to-side closure, resulting in a long linear scar. The superior portion of the defect will be the widest, as it is here that the width of the defect must be accommodated, and thus, generally this portion of the wound is too tight to be closed and is left to heal by secondary intention. The pedicle should be circumferentially wrapped with Vaseline or Xeroform gauze or Surgicel to prevent desiccation. The second stage takes place 3 weeks subsequently. The pedicle is separated from the brow, the wound edges are freshened, and the donor defect is closed. After the pedicle is separated from the defect, the tissue is further debulked and trimmed, and the remaining edge is secured.

NASOLABIAL INTERPOLATION FLAP. This flap is utilized to repair complex defects of the ala, particularly in instances when cartilage grafting is also

required to restore the structural integrity of the alar rim. The flap is harvested from the medial cheek and nasolabial fold and is based on branches of the angular artery (Fig. 243-27). The aesthetics of the repair is often improved when the defect is enlarged to include the entire alar lobule. The flap is designed around a pedicle that will be placed at the alar groove, extending as an ellipse that will be easily closed in the nasolabial fold. Throughand-through nasal defects will require the repair of the mucosa, and thus, the width of the flap must take this into account. This myocutaneous flap is dissected from the donor site, rotated downwardly, debulked and trimmed, and secured to the widely undermined defect. As with the paramedian forehead flap, the pedicle may be wrapped with Vaseline or Xeroform gauze or Surgicel. Three weeks later, the pedicle is separated, the wound edges are freshened, and the donor defect is closed. After the pedicle is separated from the defect, the tissue is further debulked and trimmed, and the remaining edge is secured. The reverse nasolabial flap, also known as a Spear’s flap, is employed when the defect involves the alar groove. The motion of this flap is an upward rotation,

Excisional Surgery and Repair, Flaps, and Grafts

Figure 243-27  A–D. Nasolabial interpolation flap. The pedicle is created from excess skin lateral to the nasomelial fold and rotated into the defect. The pedicle is divided and removed approximately 3 weeks after the inset of the flap (c).

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opposite of the traditional nasolabial interpolation flap.

Section 40 :: Surgery in Dermatology

ABBÉ FLAP. The Abbé flap is also known as the lip-switch flap and is reserved for repair of large, deep defects, typically of the upper lip. It is particularly useful for defects that involve up to half of the lip without crossing the midline and those that penetrate into the muscularis. The Abbé flap is harvested from the ipsilateral lower lip and is based on the inferior labial artery. This artery is located deep to or within the orbicularis oris muscle and runs along the mucosal aspect of the vermillion border.39 The vermillion border and flap design must be properly marked out. The defect should be full thickness (including muscularis and oral mucosa) and may be enlarged to encompass the total cosmetic unit, which includes the ipsilateral upper cutaneous lip. The flap, also designed to be full-thickness to fill the enlarged defect, is rotated upon a vascular pedicle that makes up the lateral aspect of the flap. The inferior labial artery will be visualized as it is transected at the mobilized (medial) edge of the flap. The pedicle itself should be about 1 cm thick, containing the robust blood supply. The donor site is undermined and closed first to facilitate the movement of the flap. It should be closed in layers as in the repair of a lip wedge resection: mucosa, muscularis, subcutaneous, then cutaneous. The flap is rotated superiorly and also inset with a layered closure. Careful attention should be given to aligning the vermillion borders at the donor site and defect. The pedicle of the Abbé flap should not be circumferentially wrapped, but kept moist with occlusive ointment. As with other interpolation flaps, the pedicle will remain in place for at least 3 weeks. During this time, the oral aperture will be significantly distorted, and the patient must be counseled. The pedicle is divided and the final repair takes place, again with careful attention to the placement of the vermillion borders. RETROAURICULAR FLAP. The retroauricular flap is a two-staged interpolation flap useful for large defects of the helix. Defects in this location typically involve the perichondrium and are not suitable for grafts. This flap is considered a random flap as it is not based on a large named artery. It is harvested from the richly vascularized skin of the postauricular scalp and is advanced over intervening intact skin to fill the helical defect; the pedicle remains attached to the posterior scalp (Fig. 243-28). The flap should be thinned to match the depth of the defect and carefully sewn into place. The pedicle is circumferentially dressed, and the patient is warned of likely postoperative bleeding and discomfort. The donor site is not repaired until pedicle take-down and often, due to its inconspicuous location, is allowed to heal secondarily.

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Skin grafts are transplanted skin from a donor to recipient site with the goal of closing a surgical defect or

wound. They are typically used in reconstruction after removal of a cutaneous malignancy; however, they are also used in the treatment of chronic skin ulcerations, full-thickness burns, epidermolysis bullosa, and vitiligo. Grafts are completely detached from the donor site and receive all nutrients from the wound bed of the recipient site. The three basic types of skin grafts are full-thickness skin grafts (FTSG), split-thickness skin grafts (STSG), and composite grafts. FTSGs consist of epidermis with full-thickness dermis, while STSGs consist of epidermis with partial-thickness dermis. Composite grafts are full-thickness skin grafts with cartilage attached to the graft. Skin grafts are also categorized by their donor origin. These include autografts (donor = recipient), allografts (human to human), and xenografts (animal to human).

FULL-THICKNESS SKIN GRAFTS FTSGs are useful for defects in which complex linear closures or a flap would not be suitable, where close monitoring of the site is advisable, and in certain areas where they provide optimal aesthetic reconstruction. When possible, FTSGs are chosen over STSGs because of their similarity in thickness and texture to surrounding skin and their relative lack of significant wound contraction. Since STSGs generally result in a depressed, hypopigmented, scar without normal epidermal texture, they are reserved for larger wounds that cannot be covered with FTSGs. When wounds are too deep for even a FTSG to cover without creating a depression (when the depth of the wound exceeds the thickness of a graft), second intension healing may be employed for a period of time to build the base of the wound up to the point where a FTSG would completely fill the defect. FTSGs have essential nutrient requirements and, therefore, should not be placed at a site where the vascular supply is poor. FTSGs will not survive if transplanted directly over bone, cartilage, or tendon.

DETERMINING DONOR SITE. When planning your graft, there are many factors to be taken into consideration. The donor site should be well matched to the skin surrounding the defect in terms of thickness, texture, sun exposure, and adnexal structures.40 Donor sites can be differentiated by thickness, for example, thin (eyelids, postauricular sulcus), medium thickness (preauricular, conchal, cervical), and thick (supraclavicular, clavicular, nasolabial fold, forehead).41 However, examining for tissue similarity, such as adnexal structures and sun exposure, is also pertinent. Common sites for FTSGs for nasal defects include preauricular, postauricular, nasolabial fold, forehead, and conchal bowl skin. Preauricular skin can be used to repair most nasal defects, has similar sun exposure and skin quality and heals with minimal scar visibility.42,43 Conchal bowl grafts are particularly well matched for nasal tip and alar defects due to the similarity in texture and concentration of sebaceous glands

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Figure 243-28  A–D. Retroauricular pedicle flap. A pedicled flap is developed posterior to the ear in a shape similar to the U-Shaped advancement flap. The flap is advanced over the postauricular sulcus and over the auricular cartilage of the helix and sutured into place. The pedicle is divided and set back into place 3 weeks after the inset of the flap (c). The area surrounding the postauricular sulcus is allowed to heal in by second intention.

(Fig. 243-29) as well as the ability to allow the donor site to heal by secondary intention.44 Nasolabial fold and forehead skin offer excellent matches but leave secondary scars in more visible areas.

HARVESTING. Once the donor site has been established, the graft can be harvested. To ascertain the size and shape of the graft needed to fill a given defect, many surgeons will create a template using a nonstick dressing, pressing it against defect. The template

is cut out and then traced with a marking pen onto the donor skin. Although some authors have recommended grafts be designed 3% to 5% larger than the defect to accommodate contraction of the graft skin once it is removed45; oversizing grafts can lead to unsightly pincushoining. For this reason, the authors size their grafts at or just under the size of the defect. If the donor site is to be closed primarily, an ellipse is planned around the designed graft (see Section “Excisional Surgery”).

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Figure 243-29  A–D. Conchal bowl full-thickness skin graft. The graft is harvested from the conchal bowl because, like skin of the nasal tip and ala, the sebaceous density in the conchal bowl is high. The defect in the conchal bowl is allowed to heal by second intention.

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Defatting the graft before securing it to the recipient bed is critical. The subcutaneous tissue is poorly vascularized and, therefore, hinders graft survival. Defatting can be performed with an iris scissors by trimming away the yellow fat to expose the shiny white dermis. If the area being repaired is uneven, thin areas of fat may be left on the graft to more closely approximate the natural contours. Alternatively, at times, it may be necessary to thin the dermis slightly to ensure similar thickness between graft and donor tissue. If this is the case, minimal thinning is recommended to avoid structural damage of adnexae. Once the graft has been prepared, it should be placed in the recipient bed as soon as possible. The recipient bed should have good hemostasis without devitalizing the tissue with overuse of cautery. Grafts generally need to be trimmed at the edges to ensure a perfect match to the donor site. Survival of

the graft is also dependent on the surgical technique during placement. The graft must be manipulated and grasped gently. Small caliber nonabsorbable or fast-absorbing cat gut sutures are commonly utilized for FTSGs on the face. Insertion of sutures should be from graft to recipient tissue to minimize graft movement and best approximate wound edges. It is helpful to place the initial four sutures at intervals of approximately 90° from each other to ensure proper placement and to secure the graft. These are followed by interrupted sutures or, at times, running sutures to complete closure. When grafts are large or placed over concave areas, basting sutures help keep good graft to bed contact. This will stabilize the graft and minimize sheering forces. Several authors recommend the use of bolster dressings. While bolster dressings may assist in prevention of



First 24 hours: plasmatic imbibition or ischemia: the graft affixes to the recipient bed via fibrinous material 48–72 hours: anastomosis and proliferation of vessels 4–7 days: reestablishment of full circulation

Stress on the wound should be avoided to provide the best results. Overstimulation of the patient may lead to increased blood flow to graft site leading to fluid overload and disruption of vascularity. The patient should be advised not to undergo strenuous activity for at least 1–2 weeks.

COMPOSITE GRAFTS Composite grafts consist of one or more adjacent tissues, often involving a typical FTSG with underlying cartilage.47 Small full-thickness defects of the nasal ala and helical rim most commonly require such a graft. Donor sites for composite grafts frequently include the helix and conchal bowl. It is desirable to harvest the graft in a manner that allows the underlying cartilage to extend beyond overlying tissue. This extension allows for the cartilage to insert under the surrounding defect margins. Two small pockets are generally made across from each other at a level below the dermis in the recipient site to accommodate the cartilaginous wings on the composite graft. The cartilage may or may not

FREE CARTILAGE GRAFTS Free cartilage grafts consist of cartilage and perichondrium. This type of graft assists in structural support (e.g., prevent nasal valving) and retention of natural facial contours (e.g., ala and helical rim). Elastic cartilage from the ear, versus hyaline cartilage from the nose, is the best for recontouring. A strip or disc of cartilage is usually harvested through an incision in the postauricular sulcus or conchal bowl. As is done with a composite graft, the strip of cartilage harvested is slightly longer than the size of the defect and the edges are inserted into pockets made under the dermis. The cartilage is sutured lightly into place with absorbable sutures. The site is then typically closed with a flap. Full-thickness skin grafts may be placed over very thin cartilage struts but as the size of the cartilage increases, the vascular supply to the graft becomes increasingly compromised and decreases graft survival. The addition of cartilage helps with structural support such as preventing collapse of the nasal valves which results in disruption of air flow. It also helps retain the patient’s original facial contours and prevents concavity and/or contraction of the repair.

SPLIT THICKNESS SKIN GRAFTS STSGs are composed of epidermis and partial dermis. Because these grafts are much thinner than FTSGs, they have a less rigorous demand for vascular support and have an increased survivability profile. Unfortunately, since they lack the full thickness of dermis and dermal appendageal structures, STSGs appear more like scar tissue than skin; they are depressed, hypopigmented and have a shiny texture. They are used to cover large defects unable to be closed by other methods, to allow better wound bed surveillance, to line tubed pedicle flaps, or to resurface mucosa.49 STSGs are often harvested from the upper inner arm, thigh, or buttock. If small, STSGs may be harvested with a blade by hand. When they are larger STSGs are harvested with a dermatome, which provides a more precise width and depth. Once the graft is obtained, it is placed in sterile saline on the meshing plate. Meshing is beneficial since it expands the donor tissue, allows wound exudate to drain preventing seroma and hematoma formation, and has been found to increase graft survival. Increased wound contraction and decreased cosmesis, however, are associated with meshing. After harvesting is complete, STSGs are placed over the defect and secured similarly to FTSG. For larger defects, surgical staples are often used to secure the graft. STSGs size can vary. They are categorized as thin (0.013–0.033 cm), medium (0.033–0.046 cm), or thick

Excisional Surgery and Repair, Flaps, and Grafts

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BUROW’S/REGIONAL GRAFT. Burow’s or regional grafts essentially use the Burow’s triangle or dog-ear, often from a partial linear closure, to act as an FTSG (eFig. 243-29.1 in online edition). This utilizes removed skin that might otherwise have been thrown away and eliminates the need for removing tissue from a separate donor site. Because these are often local grafts, the tissue match is generally excellent.46 Since a circular defect has a much larger surface area than a standard triangle taken in an elliptical closure, the triangle must be designed more like that of an island pedicle with a wider and longer body.

be sutured, and the remaining FTSG is sutured and secured as described earlier in this section. After being sutured into place, a composite graft with cartilage at its base receives its blood supply from its lateral margins only. Therefore, composite grafts should remain less than 2 cm2, as a larger graft will not receive sufficient nutrients to allow its central portion to survive.48

Chapter 243

hematomas and seromas they also compromise vascularity and can increase the risk of necrosis. For larger defects or those with exposed bone or cartilage at the periphery, a purse-string approach may be introduced. A purse-string suture is placed subdermally along the defect edges, then tightened to advance edges into the defect circumferentially. This technique helps protect exposed tissue as well as reduce the defect size, thereby allowing the surgeon to use a smaller graft. Sutures should be removed in one week for grafts on the face. Healthy grafts are pink in color. Although a purple color indicates relative hypoxia, most grafts with this color will survive. A white color on the surface of a graft generally represents maceration and may do fine when no longer occluded. If the white color is full thickness, it may represent necrosis. Black grafts are necrotic. Gentle wound care without debridement is the best treatment for graft necrosis. The necrotic graft will act as a biologic wound dressing, promote dermal healing, and generally avoid contraction. Antibiotics should also be started to minimize the risk of infection.

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Section 40

(0.046–0.076 cm). The amount of dermis present determines the chance of survival of the graft on a poor vascular bed. Generally, the thinner the graft, the higher the “take rate” but the poorer cosmesis. The donor site re-epithelializes rapidly and relatively painlessly with the use of bio-occlusive dressings. The main advantage of an STSG is that it survives even in locations with poor vascularization, such as over bone or cartilage. It also allows for early detection of tumor recurrence. Cosmetically, the final outcome of this graft is suboptimal with absent appendages, poor color match, and frequent wound contracture under the graft. For this reason, second intention healing and skin substitutes are often employed for defects once covered with STSGs. These methods avoid the wound care and generally unsightly appearance of the STSG harvest site.

:: Surgery in Dermatology

PUNCH AND PINCH GRAFTS. A subset of STSGs includes punch and pinch grafts. These are useful for accelerating the healing phase of a chronic ulcer. Several grafts are harvesting from a donor site and placed in the wound bed. Instruments used are a 4-mm punch for punch grafts or a scalpel (Weck knife) for pinch grafts. The rate of survival of these grafts is good if the site has meticulous postoperative care; however, the cosmetic outcome is suboptimal due to the variable thickness throughout the wound. SKIN SUBSTITUTES Tissue which has been cultured or processed prior to grafting is known as a skin substitute. There are a few different types: autologous epidermal, allogenic dermal, and xenogenic and allogenic bilayered. Epidermal skin substitutes are derived by culturing the patient’s own skin. These are good for covering a wound and stimulating the healing process. Dermal skin substitutes are allografts developed from cadaver skin. They often consist of neonatal foreskin-harvested allogenic fibroblasts with an overlying silicone epidermis. These are helpful in replacing the dermis in a defect and can be covered by a STSG. There are several different types available commercially including Alloderm, Integra, Trancyte, and Dermagraft. Bilayered skin substitutes are made from allogenic neonatal foreskin-derived fibroblasts and keratinocytes and bovine collagen. They are useful for protection of large wounds where donor tissue is insufficient to cover. Commercially available products include Apligraf and Orcel.

POSTOPERATIVE CARE

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Meticulous postoperative wound care is necessary to ensure an optimal outcome. Attention must be made to limit postoperative bleeding of all surgical wounds, particularly flaps and grafts, as hemorrhage or hematoma formation may jeopardize tissue survival and increase the risk of infection. Meticulous intraoperative hemostasis and good postoperative compression dressings are very important in minimizing postopera-

tive bleeding. A pressure dressing should be applied and left intact for 24–48 hours. This dressing includes a layer of ointment applied directly to the wound, a nonstick bandage such as Telfa, gauze for pressure, and surgical tape. Finally, elastic dressing materials, such as Flexinet or Coban, may be helpful for wounds on the scalp or extremities. For the aforementioned procedures, it is important that the wound be kept clean, moist, and covered until suture removal. This will eliminate desiccation and promote re-epithelialization,50 reduce bacterial contamination, and aid in hemostasis. Verbal and written instructions regarding home wound care should be reviewed and then provided in writing to the patient. After removal of the pressure dressing, the wound should be cleaned once or twice daily with attention to gently removing any crust and debris that may form. This is followed by a layer of ointment. A bland, nonmedicated ointment, such as petrolatum or Aquaphor is preferred over topical antibiotics such as Neomycin. The use of these topical antibiotics following cutaneous surgery increases the risk of contact dermatitis51 without imparting a significant reduction in infection rates.52 The patient should be advised to limit activity for 1 to 2 weeks after surgery, particularly, movement that stretches or adds tension to the wound area and may result in wound dehiscence or a widened scar. The signs and symptoms of hemorrhage and wound infection should be reviewed as early intervention can reduce serious complications. To better prepare patients, it is helpful to educate him or her about what to expect during normal wound healing. The patient should be provided with the physician’s contact information and should be encouraged to call with any questions or concerns.

COMPLICATIONS OF DERMATOLOGIC SURGERY Early complications of all forms of cutaneous surgery and closure are bleeding, pain, and infection. Bleeding typically occurs in the first 24 hours after surgery and must be addressed promptly. Low flow ooze may be treated by compression. Patients should be instructed to apply direct pressure for at least 20 minutes without peeking to see if it is working. Frank arterial hemorrhage or large hematoma formation will require partial or complete suture removal, evacuation of clot, and exploration of the wound to allow visualization and closure of the bleeding vessel. Patients should be instructed to call if they see an enlarging mass below or around the wound. Pain is usually manageable with non-narcotic pain relievers such as acetaminophen. Acetaminophen may be administered at the time of surgery and continued for 24 hours to reduce the risk of postoperative discomfort. It is generally easier to get ahead of pain than it is to catch up to it. Patients should be instructed to avoid non-prescribed nonsteroidal antiinflammatory medication for up to 48 hours postoperatively to reduce bruising and bleeding from platelet dysfunction. While more severe pain may require the

to intralesional steroids, flap elevation with flap thinning, and/or dermabrasion. The trapdoor effect may be prevented with wide undermining around the primary defect, proper thinning of the flap, proper size of the flap, and the use of a geometric shape for the flap. Complications of grafting include graft failure in the early postoperative period and results from inadequate nutrient supply to the tissue. This is often due to poor vascular health of the wound bed as encountered in smokers or diabetics, inadvertent shearing forces or trauma to the graft, hematoma formation, or infection. Later complications typically are attributed to the cosmetic appearance of the graft, usually related to mismatch of thickness, color, or texture. Contraction may be considerable, particularly with thinner grafts, which may result in the distortion of free margins.

MONITORING AND FOLLOW-UP

Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Berg JWAP, Lidz CW, Parker LS: The legal requirements for disclosure and consent: history and current status. In: Informed Consent: Legal Theory and Clinical Practice, 2nd edition. New York, Oxford University Press, Inc., 2001, p. 41–74 4. Dixon AJ et al: Prospective study of wound infections in dermatologic surgery in the absence of prophylactic antibiotics. Dermatol Surg 32(6):819-826; discussion 826–817, 2006 6. Grekin RC, Auletta MJ: Local anesthesia in dermatologic surgery. J Am Acad Dermatol 19(4):599-614, 1988 17. Alam M et al: Aesthetic and functional efficacy of subcuticular running epidermal closures of the trunk and extremity: a rater-blinded randomized control trial. Arch Dermatol 142(10):1272-1278, 2006 17. Alam M et al: Aesthetic and functional efficacy of subcuticular running epidermal closures of the trunk and extremity: a rater-blinded randomized control trial. Arch Dermatol 142(10):1272-1278, 2006 22. Book SEAS, Leffell DJ: Ellipse, ellipse variations and dogear repairs. In: Surgery of the Skin: Procedural Dermatology, edited by JK Robinson CH, RD Sengelmann, DM Siegel. Philadelphia, Elsevier Mosby, 2005, p. 265 29. Dzubow LM: Flap dynamics. J Dermatol Surg Oncol 17(2):116-130, 1991 38. Zitelli JA: The bilobed flap for nasal reconstruction. Arch Dermatol 125(7):957-959, 1989 50. Eaglstein WH: Moist wound healing with occlusive dressings: a clinical focus. Dermatol Surg 27(2):175-181, 2001

Excisional Surgery and Repair, Flaps, and Grafts

KEY REFERENCES

::

If nonabsorbable epidermal sutures are placed, the patient should return for suture removal at the appointed time. If the defect has been left to heal secondarily, the wound should be checked in approximately 4 weeks. The surgical site should then again be evaluated 3 to 4 months postoperatively to ensure wound healing is progressing as expected. Patients who have been treated for malignancy should be counseled regarding proper follow-up for full skin examination to monitor for new or recurrent skin ­cancers.

40

Chapter 243

administration of prescription pain medication, it should be investigated to be sure more significant issues such as infection or hematoma are not occurring. Signs of infection usually will occur within the first week after surgery and include increased pain, erythema, and heat around the wound, purulent and sometimes foul-smelling drainage, and fever. When wound infection is suspected, a culture must be obtained for pathogen identification and antibiotic susceptibility, and treatment with a broad-spectrum antibiotic should be initiated. Common pathogens on skin and mucosal surfaces are Gram-positive cocci, notably staphylococci or, less commonly, streptococci. However, Gram-negative aerobes and anaerobic bacteria contaminate skin in the groin/perineal areas. Gram-negative bacilli may also be cultured from ear and lower leg wounds, particularly in diabetic patients. Methicillin resistant Staphylococcus aureus (MRSA) infections are increasing dramatically in frequency and should be vigilantly watched for.53 An expected consequence of surgery is the formation of a scar. While the goal of reconstructive surgery is to minimize the appearance of the resultant scar, at times they may widen, or even become hypertrophic. With time, hypertrophic scars tend to flatten and soften. Their course may be hastened with the administration of intralesional steroids and laser treatment. In areas under tension and or motion, such as the upper back and arms over the deltoids, scars may spread or become atrophic. While scar spread may become less noticeable with time as the initial dark pink color fades, the width generally does not change significantly. Erythema and telangiectasia often form around scars during the healing phase and may persist for extended periods of time. Highly vascular areas (rosacea) and those under high tension are more likely to develop persistent erythema and telangiectasia. This can be effectively treated with lasers, such as the pulsed dye laser, KTP, or intense pulsed light. Spitting sutures or suture granulomas from buried sutures may occur. Placing the buried dermal sutures in the appropriate plane will help minimize the occurrence. If the spitting suture becomes visible it may be trimmed out, but it is unadvisable to aggressively go after these as a scar may result. In the case of a flap repair, additional complications may be encountered. In the early postoperative period, partial or complete flap necrosis may occur. This may be due to inadequate blood supply from the wound bed, which is more commonly encountered in smokers, or when an underlying hematoma is present. Flap design may also lead to vascular compromise and flap necrosis, as when the pedicle is too narrow to support the mass of the flap, when there is too much torque, or when there is too much tension at the flap’s leading edge. Areas of partial necrosis will heal secondarily and may lead to a less appealing scar, which can be revised after wound healing is complete. Later in the postoperative period, a trapdoor deformity may occur in which the center of the flap becomes elevated and the suture line becomes depressed. It may resolve spontaneously over a period of 6–12 months. However, if the trapdoor effect or pin-cushioning persists, it may respond

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Chapter 244 :: Mohs Micrographic Surgery :: Joseph Alcalay & Ronen Alkalay BACKGROUND MOHS MICROGRAPHIC SURGERY AT A GLANCE

Section 40 :: Surgery in Dermatology

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Mohs micrographic surgery (MMS) is a precise method of treating skin cancer that results in the highest cure rate with maximal tissue conservation, cosmesis, and function. MMS is indicated for the treatment or basal cell cancer and squamous cell cancer and certain less common skin cancers. Specific indications for MMS include location in high-risk anatomic sites, aggressive histology, recurrent tumor, and when there is a need for maximal preservation of tissue. Advances in processing and staining techniques and the use of immunostains have increased the speed and accuracy of MMS as a cost-effective means of skin cancer extirpation.

Mohs micrographic surgery (MMS) is a surgical technique developed to excise skin cancer under complete microscopic control. The fresh frozen tissue technique is used, which permits immediate examination of the specimen, and the tissue is oriented in a way to permit evaluation of all surgical margins. This is distinct from the traditional bread loafing technique used to process tissue specimens. A special orientation is combined with a precise mapping technique, which leads to maximal conservation of normal tissue. The technique was developed by Dr. Frederick Mohs approximately 80 years ago using a fixed tissue technique that relied on zinc chloride paste. The original term, chemosurgery refers to the use of the tissue fixative which is no longer used. As a result, the term chemosurgery is considered archaic.1 MMS has been described by various names such as chemosurgery, microscopically controlled excision, and microscopically oriented histographic surgery. The latter is an attempt at creating an acronym to replace the eponymous term Mohs. In the past several decades, the mapping component has been retained but the procedure has been refined using frozen tissue rather than fixed tissue, which has permitted more efficient patient care. The advantages of MMS over conventional excisional surgery include maximum cure rate and optimal preservation of healthy tissue. The latter serves to enhance cosmetic outcome and preserve function where appli-

cable. MMS is now recognized as the standard of care for the treatment of various skin cancers in indicated circumstances. The most common cancers treated by this method are basal cell carcinoma (BCC, 73%) and squamous cell carcinoma (SCC, 23%).2 A defining characteristic of MMS is that the surgeon acts to interpret the histopathologic specimens. Specifically, the MMS procedure requires a single physician to act in two integrated but separate distinct capacities as surgeon and pathologist. MMS is a highly technical procedure that requires meticulous attention to detail and considerable training and experience to achieve the expected high cure rates.

THE PROCEDURE Mohs surgery is performed under local anesthesia in the office setting or in an ambulatory center. In unusual cases, where multiple cancers or complex malignancies are to be removed, sedation may be used.3 Prior to surgery, it is essential to have the patient affirmatively identify the biopsy site as very often the biopsy site may fade due to postbiopsy healing. It has been shown that in 25% of patients, who had prior biopsy, no remnants of tumor were found during MMS. 4 This is consistent with the fact that the inflammatory process may contribute to elimination of residual cancer cells after biopsy. The fundamental elements of MMS are listed in Table 244-1. A complete medical history and list of medications should be documented before surgery is performed. Anticoagulants are not contraindicated and data have shown that they should not be discontinued prior to MMS. 5 Once the patient is properly positioned, it is important to mark the clinical tumor border with a surgical pen. Local anesthesia is then obtained by injection (Fig. 244-1). Marking the clinical borders of the tumor is necessary since the local anesthetic may cause blanching that can obscure the tumor borders. The most commonly used local anesthetic is 1% or

TABLE 244-1

Fundamentals of Mohs Micrographic Surgery Injection of local anesthesia Curettage to determine gross clinical margins Excision of the first layer with the scalpel beveled at 45° (first MMS stage) Color coding and mapping of the tissue Horizontally cut frozen sections Tissue staining Microscopic examination of the tissue by the surgeon Repetition of the tumor excision cycle until cancer is removed Reconstruction

40

Figure 244-4  First stage of Mohs surgery. Nicks are made in the tissue.

Mohs Micrographic Surgery

Figure 244-2  Injection of local anesthetic.

The tissue is then processed by a technician who is specifically trained in the en face method of sectioning. The tissue is frozen and is cut horizontally on a microtome. In contrast to traditional paraffin sections, which are cut vertically (bread-loaf sections) the Mohs sections theoretically allows 100% of the tumor margins (depth and periphery) to be examined. Most Mohs surgeons use hematoxylin-eosin stain (83%) and a minority use toluidine blue as the preferred stain. The latter stain helps distinguish basal cell carcinoma from hair follicles by highlighting mucopolysaccharides in the stroma.7 In between the Mohs stages, the wound is dressed temporarily and the patient waits either in the procedure room or in a dedicated waiting room. Slide preparation takes 20–30 minutes on average. Examination of the slides by the surgeon is then performed in the laboratory. Residual cancer noted microscopically is marked on the Mohs map and the process of excision, mapping,

::

2% lidocaine with 1:100,000–200,000 epinephrine (Fig. 244-2). After the surgical site is gently curetted to determine the clinical extent of the cancer, a specimen is taken using the Mohs technique. (Fig. 244-3). This is considered the first Mohs stage. A thin layer of tissue is excised using a scalpel and incising the skin at a 45° angle. Nicks are made in the surrounding tissue to denote tissue orientation and mapping (Fig. 244-4). In some cases, double nicks can help in the orientation of the tissue.6 Mapping of the tissue is a crucial step in MMS. The topographic map allows the Mohs surgeon to relate the microscopic findings to the excised tissue and the anatomic reference points at the surgical site (Fig. 244-5) The Mohs map is typically created by drawing freehand, using a template or digitally using computerized software (Fig. 244-6). The tissue is brought to the adjacent laboratory (another key element of the Mohs technique is the presence of a contiguous lab under the supervision of the Mohs surgeon). Color coding of specimens is critical. The Mohs technician or the surgeon marks the borders of the tissue with different colors to allow orientation relative to the Mohs map. Usually two dyes are used such as red and black or black and yellow (Fig. 244-7). One of the dyes is represented on the map as a solid line and the other as a dotted line.

Figure 244-3  Debulking stage. Tumor is cut in its visual clinical borders.

Chapter 244

Figure 244-1  Recurrent basal cell carcinoma on the right temple-forehead junction. Marking the clinical borders of the tumor.

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Section 40

Figure 244-5  The Mohs map. Tissue is placed on Telfa in its actual position. A digital image is taken by the Mohs technician.

:: Surgery in Dermatology

and processing is repeated until all margins are free of tumor (Figs. 244-8, 244-9). High quality frozen sections are mandatory for the success of MMS8 Figs. 244-10 and 244-11 illustrate how the Mohs technique ensures complete tumor removal. Once MMS is complete, the wound is evaluated and reconstruction is either performed at that time by the Mohs surgeon or the wound is allowed to heal by second intention. In complex cases, collaboration with other reconstructive surgeons may be indicated. Reconstructive surgery has become an important and integral aspect of the care of the skin cancer patient. The original chemosurgery defects healed by second intention, but the current defects that result from the fresh tissue technique permit primary closures, adjacent tissue transfer, and grafts. As a result, parallel advances in reconstructive surgery have been significant in the evolution of MMS.

MOHS SURGERY FOR BASAL CELL CARCINOMA

Currently, the major indications for MMS are based on the anatomic location of the tumor, tumor size, histology, and patient considerations. Mohs surgery is typically used on the head and neck and for difficult or biologically challenging tumors elsewhere.

BCC accounts for approximately 75%–80% of all cases of non-melanoma skin cancer. This tumor has a predilection for the head and neck as it is related to ultraviolet light exposure. Despite an extremely low metastatic rate (0.0028%), BCC can be locally aggressive and cause significant tissue destruction. Of special importance are high-risk BCCs: those in the midfacial location (the so-called H zone which includes the nose, periocular region, lips, ears), recurrent and incompletely excised tumors, BCC with aggressive histological characteristics (sclerosing, basosquamous, infiltrative, and micronodular), BCC with perineural involvement, and BCC in which tumor size exceeds 2 cm. MMS is also very helpful in treating BCC with indistinct clinical borders. The aggressive tumor subtypes tend to be large, have ill-defined borders, and tend to recur when treated with other modalities. MMS has been shown to result in superior cure rates for high-risk BCCs compared with other approaches. Rowe et al found in their meta-analysis a recurrence rate of 10.1% for primary BCCs treated with simple excision, whereas MMS– treated lesions had only a recurrence rate of 1%.10 Other studies have confirmed that MMS yields the highest cure rate in primary tumors (98.6%–99%) and in recurrent tumors11,12 In the case of recurrent cancers,

Figure 244-6  Digital image of the Mohs map.

Figure 244-8  A Mohs map of the second stage.

INDICATIONS

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Figure 244-7  Color coding of the tissue in the laboratory.

1st excision for diagnosis Stage I (A) layer Stage II (B) layer

Mohs Micrographic Surgery

The iterative nature of MMS

::

the 5-year recurrence rate of recurrent BCCs was 17% with simple excision and only 4.5% with MMS.11,13 A recent study in Europe showed that MMS is preferred over surgical excision for the treatment of recurrent facial BCC on the basis of significantly fewer recurrences after MMS than after surgical excision. However, because there was no significant difference in recurrence of primary BCC between treatment groups,

40

Chapter 244

Figure 244-9  Reconstruction by linear closure.

treatment with surgical excision is probably sufficient in most cases of routine primary BCC.14 BCCs located on the ear, nose, eyelids, and lips have higher recurrence rates when treated by simple excision. The reason is believed to be the tendency of the surgeon to conserve as much tissue as possible, thus risking incomplete excision. Some of the aggressive subtypes of BCC (morpheaform, infiltrative) tend to recur in those locations. These aggressive subtypes may spread along scars, perichondrium, periosteum, perineurium, and fascial planes. The advantage of MMS as a tissue sparing technique was demonstrated for higher-risk BCCs requiring multiple stages of MMS.15 Large BCCs (>2 cm) tend to be more aggressive, and have a higher recurrence rate than smaller cancers. They are usually present for longer duration, allowing the cancer to penetrate the surrounding tissue more extensively. MMS is especially advantageous in this situation. Incompletely excised tumors tend to recur as more aggressive tumors 12%–41% of the time. Recurrent tumors tend to be subtle at first, but when they clinically reappear they can be aggressive, demonstrating extension along deep tissue planes. MMS for recurrent cancer yields the highest cure rates (93%–96%) compared to 80%–83% for other modalities.14

Stage III (C) layer

4

1

3

2

2

1

Stage I

Stage II

No tumor

Stage III Tissue

Microscopic examination

Maps

Figure 244-10  This schematic illustrates how the Mohs technique assures complete tumor removal. Obvious cancer (black) is obtained to determine subtype (upper left). Cancer discovered by microscopic examination is outlined by dots in each layer. In Stage I, a layer was removed and divided into four specimens (as viewed from the bottom); after microscopic examination, residual tumor was found only in the central area of all four specimens. In Stage II, a central layer was excised and bisected; after microscopic examination, residual tumor was found only in the center of specimens 1 and 2. In Stage III, another small block specimen was removed; after microscopic examination no residual tumor was found. In this case, the Mohs procedure consisted of three stages of excision and the microscopic examination of seven specimens. (From Mohs Micrographic Surgery, 2nd ed., edited by SN Snow and GR Mikhail 2004. The university of Wisconsin Press, with permission.)

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MMS technique assures complete tumor removal

Wound management D

Test positive

Section 40

1

First excision

Test negative

A

2

A

Mohs procedure complete

1

:: Surgery in Dermatology

B C

B C

Stage I

Stage II

Figure 244-11  This schematic illustrates the cyclic nature of Mohs surgery. The four main components are the excision of a disc of tissue (a), microscopic examination (b), the appropriate marking of the map when residual cancer is found (c), and wound management (d). In Stage A, the tumor was removed, examined with the microscope. Residual tumor (black) was found throughout specimens 1 and 2. In Stage B, a deeper layer was removed and examined microscopically. In the second layer, no remaining cancer could be found. The defect was then allowed to heal by second intention. (From Mohs Micrographic Surgery, 2nd ed., edited by SN Snow and GR Mikhail 2004. The university of Wisconsin Press, with permission.)

MOHS SURGERY FOR SQUAMOUS CELL CARCINOMA

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Second excision

Squamous cell carcinoma (SCC) is the second most common skin cancer among whites.16 More than 200,000 new tumors are estimated to occur in the United States each year, and there is a significant increase in the incidence of SCC around the world.17 Most cases of primary cutaneous SCC are induced by UV radiation. SCC may also occur on nonexposed skin in the pelvic area including the penis where the cause is usually infection with carcinogenic subtypes of human papilloma virus. Although SCCs and BCCs are treated similarly, they are biologically distinct. SCC metastasizes at a much higher rate and accordingly has a higher mortality rate than BCC even though its metastatic rate remains very low on an absolute basis. Metastases are more common in the setting of chronic scar (37.9%), or certain anatomic locations.18 The indications for MMS are similar to BCC, but additionally involve identifying and reducing the risk for metastasis. MMS permits tracking SCC along nerves or when the histology is highly infiltrative, thus increasing the chance of complete extirpation. As with BCC, histologic pattern is important in determining the potential aggressiveness. Tumors that are poorly differentiated and/or have perineural involvement have a worse

prognosis. Locations such as the ear, penis, lip, and digits, lesions greater than 2 cm, and those occurring in scars carry a higher risk of metastasis and local recurrence. The five-year cure rate for primary SCC of the skin with MMS is 97.4% to 96.9% versus 92% (95%–82%) with simple excision, and 90% for radiation therapy.19 The difference in cure rate increases with the location such as primary SCC of the lip (97.7% vs. 89.5%) and ear (94.7% vs. 81.3%). For recurrent SCC, the cure rate with MMS is 94.1% to 90% versus 76.7% for simple excision and 65%–50% with radiation therapy. (Tables 244-2 and 244-3). The importance of MMS in the treatment of SCC with perineural invasion has also been documented.20,21 MMS has also been proven to be effective for treating Bowen disease with a 5-year recurrence rate of approximately 6%.22 Immunosuppressed patients including organ transplant patients have a disproportionate number of SCCs and also carry a greater risk of more aggressive disease. Recent studies show that SCC is up to 65 times as likely to develop in transplant recipients as in age-matched controls.23 Increased incidence, younger age at onset, higher incidence of multiple tumors, and increased biologic aggressiveness of SCC in these patients is manifested by an increased risk of local recurrence, regional and distant metastasis, and mortality. MMS is an important treatment option in these high-risk patients to minimize recurrence and mortality risks.24

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TABLE 244-2

Five-Year Recurrence Rate After Mohs Micrographic Surgery in Relation to Previous Recurrence of Squamous Cell Carcinoma

Primary SCC (N = 229)

5-year Recurrence

Previously Recurrent SCC (N = 152)

Overall Patients with 5 years Follow-up (N = 381)

Yes

6

9

15

No

223

143

366

%*

2.6

5.9

3.9

MOHS SURGERY FOR DERMATOFIBROSARCOMA PROTUBERANS

Mohs Micrographic Surgery

The role of MMS for management of malignant melanoma is highly controversial. Melanoma in situ (MIS), which typically occurs on sun-damaged skin, can be difficult to interpret on frozen section. A review of MMS for melanoma in situ indicated that the recurrence rates for melanoma in situ post-MMS varied from 0%–3.6%.25 One author claims that MMS for melanoma in situ can maximize the cure rate.26 At some centers, a modified MMS is used in which a 2- to 3-mm margin is excised beyond the final frozen section margin and submitted for permanent paraffin-embedded sections. These sections are processed in the MMS en-face method so that 100% of the peripheral margins are visualized. In addition, a technique of rush permanent sections has been described.27 The introduction of immunohistochemistry (IHC) staining may make MMS more reliable as a treatment for MIS. In one study 100% correlation was found between frozen sections stained with MART-1 and paraffin-embedded sections.28 Many surgeons who do perform Mohs sur-

gery for MIS have begun to use intraoperative IHC to identify melanocytes in frozen sections, and MART-1 is currently the preferred immunostain. S100 and HMB45 have traditionally been used to identify melanocytes but have variable sensitivity and specificity. Although the processing time of MMS frozen sections is less than with paraffin sections, it is still more labor intensive than traditional hematoxylin and eosin-based frozen sections. The need for more accurate diagnosis of MIS in MMS has led to the development of rapid permanent paraffin-embedded sections (R13) and rapid IHC staining.29

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MOHS SURGERY FOR CUTANEOUS MELANOMA

Chapter 244

* p < .001. Reprinted with permission from Leibovitch I, Huilgol SC, Selva D et al: Cutaneous squamous cell carcinoma treated with Mohs surgery in ­Australia. I. Experience over 10 years. J Am Acad Dermatol 53:253, 2005.

Dermatofibrosarcoma protuberans (DFSP) is a rare spindle cell cutaneous tumor with low-grade malignancy. It is a slow growing tumor and, for many years, wide local excision has been the treatment of choice. MMS has become the preferred treatment in most clinical circumstances with recurrence rates as low as 1.3%.30

TABLE 244-3

Comparative Clinical and 5-year Recurrence Data on Mohs Micrographic Surgery for Squamous Cell Carcinoma Mohs18,19

Robin et al20,21

Holmkvist & Roenigk*

Leibovitch et al**

Study years

NA

1965–1980

1986–1989

1993–2002

Tumor location

Head

Head

Lips

Mainly head and neck

Overall number of tumors with 5-y follow-up (1°/2°)

2551 (NA)

414 (1°)

50 (NA)

381 (229/152)

Overall 5-y recurrence (%) (1°/2°)

5.6 (NA)

6.7 (1.8/3.4)

8.0 (NA)

3.9 (2.6/5.9

1° = Primary; 2° = recurrent; NA = not available. *Holmkvist KA, Roenigk RK. Squamous cell carcinoma of the lip treated with Mohs micrographic surgery: outcome at 5 years J. Am Acad Dermatol 1998;38: 960–6. **Reprinted with permission from Leibovitch I, Huilgol SC, Selva D et al: Cutaneous squamous cell carcinoma treated with Mohs surgery in Australia. I. Experience over 10 years. J Am Acad Dermatol 53:253, 2005.

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MOHS SURGERY FOR OTHER CUTANEOUS MALIGNANCIES

Section 40 :: Surgery in Dermatology

MMS has been used to treat a wide range of cutaneous malignancies. The consensus indications outlined by the American Academy of Dermatology31 include verrucous carcinoma, keratoacanthoma, dermatofibrosarcoma protuberans, atypical fibroxanthoma, malignant fibrous histiocytoma, leiomyosarcoma, adenocystic carcinoma of the skin, sebaceous carcinoma, extramammary Paget disease, erythroplasia of Queyrat, oral and central facial paranasal sinus neoplasms, microcystic adnexal carcinoma, apocrine carcinoma of the skin, certain aggressive locally recurrent benign tumors, and Merkel cell carcinoma. All cutaneous malignancies that exhibit a contiguous pattern of radial growth and can be interpreted on frozen section should theoretically be amenable to MMS. However, less than 2% of the tumors treated with MMS are rare cutaneous malignancies. For this reason, it is important to remember that because a lesion can be treated by MMS does not mean that it should be treated in that way. If the Mohs surgeon does not have experience in reading rare tumors and cannot collaborate with a dermatopathologist, the lesion is best treated in another fashion or by a more experienced Mohs surgeon. The introduction of immunostains in MMS in the last decade has created the opportunity to explore its use in treating other cutaneous tumors.32 Microcystic adnexal carcinoma has been shown to have only 5% recurrence rate with MMS.33 Treatment of primary sebaceous carcinoma of the eyelid with MMS has yielded excellent results.34 MMS is more effective and superior to standard surgical excision in the treatment of extramammary Paget disease.35 The effectiveness of MMS in the treatment of dermal spindle cell tumors has also been suggested.36

SAFETY, PATIENT SATISFACTION AND COMPLICATIONS MMS is performed in an office or ambulatory center setting rather than hospital operating rooms. A study performed in almost 4,000 patients that underwent MMS showed that MMS can safely be performed in the office or outpatient hospital setting.37 Patients treated with MMS have well-established long-term satisfaction.38

KEY REFERENCES Full reference list available at www.DIGM8.com DVD contains references and additional content 1. Mohs FE: Chemosurgery: a microscopically controlled surgery for skin cancer—past, present and future. J Dermatol Surg Oncol 4:41, 1978 10. Rowe DE et al: Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: Implications for patient follow-up. J Dermatol Surg Oncol 15:315, 1989 13. Rowe DE et al: Mohs surgery is the treatment of choice for recurrent (previously treated) basal cell carcinoma. J Dermatol Surg Oncol 15:424, 1989 15. Muller FM et al: Randomized comparison of Mohs micrographic surgery and surgical excision for small nodular basal cell carcinoma: Tissue sparing outcome. Dermatol Surg 35:1349, 2009. 16. Garcia-Zuazaga J, Olbricht SM: Cutaneous squamous cell carcinoma. Adv Dermatol. 24:33, 2008. 19. Leibovitch I, et al: Cutaneous squamous cell carcinoma treated with Mohs surgery in Australia. I. Experience over 10 years. J Am Acad Dermatol 53:253, 2005 25. Dawn ME, Dawn AG, Miller SJ: Mohs surgery for the treatment of melanoma in situ. A review. Dermatol Surg 33:395, 2007

Chapter 245 :: Nail Surgery :: Robert Baran The main objectives of nail surgery are to aid diagnosis by biopsy, to treat infection, to alleviate pain, to remove local tumors, and to ensure the best cosmetic results in acquired and/or hereditary and congenital abnormalities.

RISKS AND PRECAUTIONS Factors to be considered include the following:

PATIENT SELECTION

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Providing the patient with an exact illustration of the operation is helpful to give the patient insight into the procedure and its expected outcome. A thorough discussion regarding postoperative morbidity is essential.



History of systemic disease History of allergies Concomitant drug use

Preoperative photographs as well as any taken during surgery may be useful medicolegally. Careful history taking may reveal systemic disease such as diabetes mellitus, blood dyscrasia, vascular disease, vascular collagen disease (scleroderma), allergy, chronic pulmonary disease, or immune impairment. Any of

Sagittal section of the nail unit Proximal nail fold Extensor Eponychium tendon

Nail matrix

Cuticle Lunula

Lateral nail fold Nail plate

Middle phalanx

Flexor tendon

Terminal phalanx

Nail Hyponychium bed

Figure 245-1  Sagittal section of the nail unit.

Nail Surgery

(See Chapter. 89) The nail plate is the permanent product of the nail matrix. Its normal appearance and growth depend on the integrity of the perionychium and the bony phalanx (Fig. 245-1). The nail is a semihard horny plate covering the dorsal aspect of the tip of the digit. The nail is inserted proximally in an invagination that is practically parallel to the upper surface of the skin and laterally in the lateral nail grooves. This pocket-like

40

::

ANATOMY1

invagination has a roof, the proximal nail fold, and a floor, the matrix from which the nail is derived. The matrix extends approximately 6 mm under the proximal nail fold, and its distal portion is only visible as the white semicircular lunula. The general shape of the matrix is a crescent, concave in its posteroinferior portion. The lateral horns of this crescent are more developed in the great toe and are located at the coronal plane of the bone. The ventral aspect of the proximal nail fold encompasses both a lower portion, which continues the matrix, and an upper portion (roughly three-quarters of its length), called the eponychium (see eFig. 245-1.1 in online edition). The germinal matrix forms the bulk of the nail plate. The proximal element forms the superficial third of the nail plate, whereas the distal element provides its inferior two-thirds. The ventral surface of the proximal nail fold adheres closely to the nail for a short distance and forms a gradually desquamating tissue, the cuticle, made of the stratum corneum of both the dorsal and the ventral sides of the proximal nail fold. The cuticle seals and protects the nail cul-de-sac. The nail plate is bordered by the proximal nail fold, which is continuous with the similarly structured lateral nail fold on each side. The nail bed extends from the lunula to the hyponychium. It has parallel, longitudinal rete ridges. In contrast to the matrix, the nail bed has a firm attachment to the nail plate. Colorless but translucent, this highly vascular connective tissue, containing glomus organs, transmits a pink color through the nail. Avulsion of the overlying nail plate denudes the nail bed. Distally, adjacent to the nail bed, lies the hyponychium, an extension of the volar epidermis under the nail plate, which marks the point at which the nail separates from the underlying tissue. The distal nail groove, which is convex anteriorly, separates the hyponychium from the fingertip. The circulation of the nail apparatus is supplied by two digital arteries that course along the digits and give off branches to the distal and proximal arches. The sensory nerves to the distal phalanx of the three middle fingers are derived from fine, oblique, dorsal branches of the volar collateral nerves. Longitudinal branches of the dorsal collateral nerves supply the terminal phalanx of the fifth digit and also the thumb. Among its multiple functions, the nail provides counterpressure to the pulp that is essential to the tactile sensation involving the fingers and to the prevention of hypertrophy of the nail bed.

Chapter 245

these may at times be contraindications to surgery or may call for alteration of the technique to be used. Surgery of the nail is not recommended in patients with high-risk conditions. A history of concurrent use of drugs may be relevant, because these drugs may affect anesthesia (e.g., monoamine oxidase inhibitors or phenothiazines), prolong bleeding (e.g., aspirin and anticoagulants), delay healing (e.g., glucocorticoids), or have toxic effects on the nail apparatus (e.g., retinoids). There may be a history of allergy to lidocaine or mepivacaine or to parabens contained in both as a preservative. A knowledge of previous antitetanus immunization is important, because administration of tetanus toxoid may be advisable in association with surgery involving the toenail or traumatic lesions that come into contact with soil. A magnifying lens may be useful to observe the color, surface, and structure of the periungual tissue and to compare the unaffected contralateral digit. It may be necessary to probe in order to localize pain, to obtain a radiograph to rule out underlying bone involvement, or to ask for ultrasonography and magnetic resonance imaging when a tumor is suspected. The basic requirements for nail surgery include a detailed knowledge of the anatomy and physiology of the nail apparatus on the part of the surgeon. Full aseptic conditions, regional block anesthesia, and local hemostasis are indispensable.

INSTRUMENTS AND DRAPING The instruments used in nail surgery are, in general, the same as those used in cutaneous surgery with the addition of the instruments listed in Box 245-1. Draping is accomplished by means of a sterile glove on the involved hand. The tip of the glove is cut off on the finger that is to undergo surgery. The remaining open finger of the glove is then rolled back down the digit. This exsanguinates the digit and provides a

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Box 245-1  Instruments Required for Nail Surgery

Section 40

Nail elevators Single- or double-pronged skin hooks Double-action nail splitter (bone rongeur) Clippers, splitting scissors, English nail splitter Pointed scissors (Gradle scissors), curved iris ­scissors Small-nosed hemostats Disposable biopsy punches Penrose drains Luer-Lok syringe, 30-gauge needles

Proximal digital block

Dorsal View

Figure 245-2  Proximal digital block.

:: Surgery in Dermatology

tourniquet when it reaches the proximal part of the finger. For toenail surgery, the foot is draped in the usual aseptic manner with sterile towels secured by towel clamps.

ANESTHESIA Local anesthesia should be administered while the patient is reclining or in a supine position. Lidocaine is widely used because the incidence of allergy to this agent is very low. Because the benefit of epinephrine is still debatable, it is preferable to use 2% lidocaine alone. A tourniquet can provide prolonged hemostasis when a bloodless operative field is required. It has been claimed that using tepid lidocaine minimizes the burning sensation associated with its administration. The use of one part 7.5% bicarbonate with nine parts lidocaine for the same purpose has also been advocated. Anesthetics are administered via a 30-gauge needle on a Luer-Lok syringe using either a proximal digital block or a distal digital block (wing block) procedure. Other techniques, such as median distal anesthesia or transthecal block, have not replaced the classic routes of anesthesia. Although emergencies related to minor surgery occur rarely, the ready availability of resuscitative equipment and expertise is essential.

ation is strictly localized to a lateral region, a block limited to the nerves ipsilateral to the lesion suffices, as in the case of a partial distolateral nail avulsion.

DISTAL DIGITAL BLOCK The distal digital block procedure is more painful than the proximal block procedure, but anesthesia occurs immediately. This method is absolutely contraindicated, however, when bacterial infection in the region is being addressed. The latter requires wrist block or general anesthesia. For a distal digital block, the needle is inserted just behind the junction of the proximal nail fold and a lateral nail fold and a few tenths of a milliliter of anesthetic is injected, which whitens the region. The injection is continued by aiming the needle toward the pad. One then returns to the initial area to inject the proximal fold transversely. Finally, at the junction of the proximal fold with the lateral fold on the opposite side, one proceeds as described earlier (Fig. 245-3). The anesthesia is almost immediate, and when the procedure is done correctly, injections rarely have to be extended to the distal area of the finger.

Distal digital block

PROXIMAL DIGITAL BLOCK

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Volar View

The proximal digital block procedure is less painful than the distal block procedure, but the anesthesia takes 5–10 minutes to become established. The hand is laid down flat, with the fingers spread, so that 1–2 mL of anesthetic can be administered by a dorsal injection, with a thin needle inserted and directed tangentially to the sides of the bony phalanx at the base of the involved finger and as far as the lateral side of the flexor tendon (Fig. 245-2). A tourniquet effect may inadvertently be produced by injecting more than 5 mL of anesthetic and should be avoided. The absence of blood reflux in the syringe should be verified before injection if a nondental syringe is used. When the oper-

Figure 245-3  Distal digital block.

TOURNIQUETS

TRANSTHECAL BLOCK The flexor tendon sheath may be used as an avenue for introducing anesthetic to the core of the digit. Through centrifugal anesthetic diffusion all four digital nerves are anesthetized rapidly. This technique involves palmar percutaneous injection of 2 mL of lidocaine into the potential space of the flexor tendon sheath at the level of the palmar flexion crease using a 3-mL syringe and a 25-gauge hypodermic needle.

WRIST BLOCK There are several circumstances under which it is useful to have anesthesia of more than one digit at the same time. A wrist block may be appropriate in the surgical treatment of numerous warts and in the infiltration of more than one finger with triamcinolone in the treatment of nail unit psoriasis. This should be undertaken with the guidance of an experienced clinician.

Nail Surgery

Median distal administration is relatively simple and quick (Fig. 245-4). The needle is introduced at a 30-degree angle into the middle of the proximal nail fold and advanced distally into the underlying matrix. Anesthetic is injected slowly as the needle pierces first the nail plate, then the matrix, and finally the adjacent nail bed. The nail plate is soft and offers little resistance. Blanching confirms the delivery of anesthetic to the nail matrix and bed. Pain is brief and anesthesia nearly instantaneous. This method is suitable for most procedures performed on the proximal half of the nail unit. It is not suitable for matricectomy or complete nail avulsion.

At the end of the operation, either the digit is cleansed with sterile 10% hydrogen peroxide solution and sprayed with a colorless disinfectant, or an antiseptic with hemolytic action is applied. The nail area is then covered with an antiseptic or antibiotic ointment on gauze or pads. Dressing must be done in a way that takes into account oozing, pain, and sensitivity. A bulky dressing provides a cushion against local trauma. Dressings should be changed every other day or daily if there is infection. Several layers of sterile gauze should be kept in place by Micropore (2.5-cm) tape placed first on the dorsal aspect of the finger or toe, then on the ventral aspect, and last on the lateral edges in a U shape (a circular dressing should never be applied in the first week). Finally, use of an X-span tube dressing or Surgitube will give the patient more freedom to use the hand, but care must be taken that dressings do not constrict blood flow. During the first 48 hours the arm must be kept in a sling. Stitches are removed after 7–12 days. When the feet are treated, daily chlorhexidine baths precede the care just described. For all operations involving the toes, the patient should wear an appropriate shoe or sandal after the dressing has been applied. The patient should be recumbent for 24–48 hours, with the foot elevated to 30°.

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Figure 245-4  Median distal block.

DRESSING AND POSTOPERATIVE CARE

Chapter 245

For brief intraoperative hemostasis (e.g., nail avulsion, punch biopsy of the nail bed), squeezing the sides of the digits is effective. If a prolonged bloodless field is required, a Penrose drain may be placed around the base of the digit and secured with a hemostat for use as a tourniquet. It is preferable not to leave it on for more than 15–20 minutes. The tourniquet application can be interrupted for a few minutes during longer procedures. To complement anesthesia and facilitate establishment of a bloodless field, use of an exsanguinating tourniquet is recommended.1 A wide Penrose drain is wound tightly in loops that overlap in a distal to proximal fashion, with an exposed loose end left distally (eFig. 245-4.1 in online edition). This “milks” the blood from the digit. The loose end is then grasped and the drain unwound, again from distal to proximal, until the nail unit is exposed with the final proximal loop.

40

POSTOPERATIVE COMPLICATIONS BLEEDING Bleeding is seen after the tourniquet is removed but can be stopped by compressing the lateral edges of the distal interphalangeal joint. In cases of persistent bleeding, 35% aluminium chloride solution or a cellulose application (Gelfoam) should be applied.

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PAIN

Section 40 :: Surgery in Dermatology

Pain threshold varies from patient to patient. Postoperative pain can be almost nonexistent if, in the absence of infection, the operation is followed by a periungual injection of 0.6 mL of 0.5% bupivacaine with 0.4 mL of 4 mg/mL dexamethasone. While the dressing is being put in place, the patient must be told what precautions to take. Providing a supply of moderately potent oral analgesics will help the patient feel in control of any pain, even if the patient chooses not to take the tablets. Sometimes postoperative pain may be severe, and it is alleviated by elevating the extremity as much as ­possible for 2 days. Pulsating pain beginning after 36–48 hours may indicate an infection, which should be treated according to the results of bacterial culture of the organism. Any bulky dressing that is blood stained after 24 hours should be changed.

INFECTION Prophylactic antibiotic treatment is mandatory for patients with valvular heart disease, including those with a prosthetic valve. Peripheral vascular disease and young age (in childhood, the nail matrix is extremely fragile and behavior is less sanitary) are further indications. If there are ragged surfaces to the nail, which makes thorough preoperative cleaning difficult, antibiotics may prevent wound infection. Postoperative infection may be caused by preoperative colonization or infection. Culture of preoperative swab specimens will indicate the best choice of drug after initial coverage with a broad-spectrum antibiotic. Attention to detail is important. Carelessness may result in serious infectious complications in the soft tissue and occasionally in bone. Routine or preoperative nail cleansing softens the nail plate and keeps contamination to a minimum.

UNPREDICTABLE COMPLICATIONS Implantation epidermoid cysts can occur in operation scars. Reflex sympathetic dystrophy after nail biopsy, although exceptional, has been reported.

NAIL AVULSION The removal of the nail plate can be carried out using distal or proximal approaches. In both techniques, inserting the blunt instrument back and forth between the horny layer of the proximal nail fold and the nail plate loosens the proximal nail fold adherence.

DISTAL APPROACH In the more commonly used distal approach, a Freer septum elevator or a dental spatula is inserted between the nail plate and nail bed (Fig. 245-5A). The nail is separated from its nail-bed attachment using proximal force applied in anterior-posterior movements so as not to injure the longitudinal ridges of the nail bed. The detachment is completed by firmly pushing the instrument into the posterolateral corners of the nail plate. Then, one of the lateral edges is grasped with a sturdy hemostat, and extracted with an upward and circular movement to accomplish the removal of the nail plate.

PROXIMAL APPROACH The proximal approach for nail avulsion is advisable when the subungual distal area adheres strongly to the nail plate and when the hyponychium may be injured by the subungual introduction of the spatula. The proximal nail fold is freed as described in Distal Approach. The spatula is then used to reflect the proximal nail fold, and is delicately inserted under the base of the nail plate where adherence is normally weak (see Fig. 245-5B). The instrument is advanced distally

MISALIGNED NAIL Misaligned nail may result from a lateral longitudinal nail biopsy, especially if the routine 3-mm width is exceeded.

Distal and proximal nail avulsion

A

B

RELAPSE Relapse will depend on the nature of the lesion treated. Warts, ingrown nails, and myxoid cysts can be difficult to eradicate.

RESIDUAL DYSTROPHY 2960

Residual dystrophies are not unusual when surgery involves the proximal area of the matrix.

Figure 245-5  A. Distal nail avulsion. B. Proximal nail ­avulsion.

PARTIAL NAIL AVULSION

TRAP DOOR NAIL AVULSION

40

::

This technique minimises trauma in nail surgery when accessing the nail bed and matrix. Trap door nail plate avulsion entails separation of all periungual attachments except for that between the dorsum of the nail and the ventral aspect of the proximal nail fold. Both are then reflected in bloc in the manner of a trap door, utilising the same oblique incisions normally made for reflection of the PNF alone.

Nail Surgery

The problems that can arise after total nail avulsion may be overcome by partially avulsing the nail. Partial distal avulsion requires only separation of the nail from the distal nail bed. This procedure can be performed under local anesthesia in selected patients, when, for instance, a fungal infection is of limited extent. An affected portion of the nail plate may be removed in one session, even when the disease has reached the deeper regions of the subungual tissue

beneath the proximal nail fold. Commonly, an English anvil nail splitter or a double-action bone rongeur is used for this procedure. Partial surgical section of the lateral and/or medial segment of the nail plate may be sufficient for the treatment of distal lateral subungual onychomycosis. In the toe, this procedure leaves enough normal nail to counteract the upward forces exerted on the distal soft tissue when walking, and this will prevent the appearance of a distal nail wall. In proximal subungual onychomycosis, removal of the nonadjacent base of the nail plate, cut transversely, leaves the distal portion of the nail in place (Fig. 245-6), which decreases discomfort. Similarly, an acute paronychia that does not respond to appropriate antibiotics within 48 hours should be treated surgically by removing the base of the nail plate.

Chapter 245

following the natural cleavage plane, and this operation is repeated on the entire width of the subungual region. After the last attachments are freed, the nail plate is easily pulled out. Total surgical removal should be discouraged, however, because the distal nail bed may shrink and become dislocated dorsally. In addition, the loss of counterpressure produced by the removal of the nail plate allows expansion of the distal soft tissue, and the distal edge of the regrowing nail then embeds itself. In patients at high risk, nonsurgical removal of the nail plate should be considered when necessary. This can be accomplished by applying 40% urea paste directly to the nail after protecting the surrounding skin. Urea acts on the bond between nail keratin and diseased nail plate, sparing only the normal nail tissue.

A

B

Figure 245-6  A and B. Technique of removal of the base of the nail plate.

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SURGICAL APPROACHES TO THE DIFFERENT TISSUES OF THE NAIL APPARATUS NAIL MATRIX

Section 40 :: Surgery in Dermatology

When surgery involves the nail matrix, there are three primary approaches, including (1) a reduction in its width or (2) its length for removal of tumors, for instance, by using a cold steel procedure or (3) a 2-to 3-mm punch biopsy. In contrast to these three procedures, complete matricectomy, that is, ablation of the nail-forming tissue, is rarely performed because the nail is permanently lost (eFig. 245-12.1 in online edition). After reduction of the nail matrix width, one is left with a narrower nail and after reduction of the length, with a diminution in the thickness of the nail. Reduction of the matrix width is a useful and/or necessary procedure in the following major circumstances:

Need for lateral-longitudinal biopsy Lateral nail splitting Benign or malignant tumor in the lateral third of the nail apparatus Longitudinal melanonychia in a lateral location Ingrown nail Racquet nail

Reduction of the matrix length is necessary only in limited cases: to obtain a transverse elliptical biopsy specimen, to treat tumors that are 3 mm wide or larger, and to thin thick nails in patients with dystrophic congenital and/or hereditary disorders.2 3–5

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BIOPSY. Biopsy of the nail matrix is performed to determine the histopathologic features of a lesion or to clarify an uncertain clinical diagnosis. A 3-mm punch biopsy may be performed through the nail plate into the matrix. Three millimeters is the maximum size that does not produce serious dystrophy, although even biopsies of this size can cause such effects if carried out in the most proximal portion of the nail matrix. When a punch biopsy is used to sample longitudinal melanonychia of less than 3 mm in width, the circumferential incision is made around the origin of the band, through the nail plate (Fig. 245-7A). This area may be distal enough to be reached by pushing back the cuticle (Fig. 245-7B), but if it is more proximal, the proximal nail fold may have to be reflected using a posterolateral incision. The next step is to remove the proximal third of the nail plate (see Fig. 245-7B and C), while leaving the cylinder of tissue containing the origin of the longitudinal melanonychia still in place. This technique allows the surgeon to inspect the surrounding nail matrix and bed with a magnifying lens to determine whether pigment extends around the punch incision (see Fig. 245-7C and D) and facilitates the removal of the cylinder of biopsy tissue with a Gradle scissors. For lateral longitudinal biopsy (Fig. 245-8), an elliptical incision may be made on either side of the nail plate and proximal nail fold. For the most part, the incisions

parallel the lateral edge of the nail plate. Beginning in the lateral nail groove, the incisions should include a 3- to 4-mm nail segment reaching to the bone. This ensures that a full-thickness fragment of the matrix with its lateral horn is obtained. Slightly curved iris scissors are useful for separating the tissue from the bone. Starting at the tip of the digit, one proceeds proximally while maintaining contact with the bony phalanx. Lateral longitudinal biopsy is the advised procedure when longitudinal melanonychia3 is located in the lateral part of the nail plate. For transverse biopsy (Fig. 245-9), two small oblique incisions are made on each side of the proximal nail fold. The fold is then reflected to expose the matrix area. The proximal third of the nail plate is avulsed. Then, the lesion is removed by excising an elliptical or crescent-shaped wedge of tissue with the convex portion of the crescent paralleling the anterior border of the lunula. When longitudinal melanonychia lies within the midportion of the nail plate, the potential for postoperative dystrophy is great, and selection of the optimal biopsy method is difficult (eFig. ­245-10.1 in online edition) (Haneke’s releasing flap technique derived from Schernberg’s releasing flat method). It is important to establish the matrix origin (proximal or distal) of longitudinal melanonychia preoperatively, because the more proximal the origin, the greater the risk of nail dystrophy.3 The origin of pigmentation may be determined by microscopic examination of FontanaMasson–stained clippings from the free edge of the nail. Tangential matrix biopsy (Fig. 245-10) for longitudinal melanonychia is a new technique devised by E. Haneke. Cutting, then reclining the proximal portion of the nail plate (1), after reflecting the proximal nail fold (2), the pigmented lesion is exposed. An incision is made around the lesion, followed by its tangential removal. Finally the proximal nail plate is replaced and the oblique incisions of the proximal nail fold are maintained by micropore. This technique is claimed to give the best cosmetic results.

RACQUET NAIL SPLIT-NAIL DEFORMITY.6

The common causes of split-nail deformity include trauma, surgery, lichen planus, and tumors. Split-nail deformity may occur in either the lateral or the medial region. The appropriate surgical technique varies accordingly. If the split is located within the lateral third of either portion of the nail, especially when it is close to the lateral margin, the best method is the technique recommended for lateral longitudinal nail biopsy, that is, the removal of the lateral portion of the nail with the defect. If the split is located in the middle region of the nail and involves its whole length, the proximal nail fold is carefully freed from the underlying nail plate, obliquely incised at both sides, and reflected to expose the whole matrix area (Fig. 245-11). The nail plate bordering the split is cautiously cut as a rectangular block approximately 1 mm wider than the scar that has to be excised. The nail bed and matrix of the defective tissue

40

Chapter 245 :: Nail Surgery

A

B

C

D

Figure 245-7  A. Punch biopsy of longitudinal melanonychia of less 3 mm in width. B–D. Removal of the base of the nail plate (B) to allow easy removal of the biopsied cylinder of matrix tissue (C) and pigment left distally (D).

are dissected from the bone to allow an exact approximation of the remaining bed and matrix, which are sutured with 6-0 monofilament absorbable sutures. To prevent the sutures from tearing the tissue, 3-0 sutures are put through the nail plate. When these threads are knotted firmly, the matrix and nail bed are further approximated, which relaxes the 6-0 sutures. If the scar is too wide to allow primary closure of the defect, relaxing longitudinal incisions along the lateral nail grooves down to the bone usually permit suturing. An alternative approach is the formation of a Schernberg nail bed–matrix flap with an L-shaped

incision of the lateral aspect of the finger (eFig. 24511.1 in online edition).

NAIL ABLATION AND ISOLATED MATRICECTOMY. Nail ablation (eFig. 245-12.1A in online edition)

is the definitive removal of the entire nail organ and matricectomy (eFig. 245-12.1B in online edition), the complete extirpation of the nail matrix, which results in permanent nail loss. The principle of nail ablation is the complete removal of the nail unit with hyponychium, nail bed, matrix, and lateral and proximal nail folds. Except for treatment of malignant tumors of the nail apparatus,

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40

Reflected proximal nail fold

(1) (2)

Section 40

Figure 245-8  Lateral longitudinal biopsy of longitudinal melanonychia located within the lateral third of the nail plate.

:: Surgery in Dermatology

nail ablation is rarely indicated. It may be necessary in the case of an excessively painful nail treated several times without success, but this should be an exception. Scalpel excision is strongly advocated whenever the surgical specimen needs histopathologic examination. If periungual pigmentation is associated with longitudinal melanonychia or if the latter is wider than 6 mm or the full thickness of the nail is pigmented, a large portion of the matrix would necessarily be involved. Under these circumstances, the underlying disease process is unlikely to be benign. The entire portion of the involved nail apparatus has to be excised en bloc. The defect from nail ablation (see Fig. 245-12B) may be covered with a free graft (split-thickness, fullthickness, reversed dermal graft), which usually takes on the bone in this particular location. A cross-finger flap is a very useful alternative to a free graft. The use of the skin from the intermediate phalanx of a neighboring finger is more convenient for the patient than skin from the thenar area of the palm. If only permanent nail matrix removal is necessary, the procedure is less extensive. In cases in which pathologic examination of the removed tissue is unnecessary, phenol cautery, rather than scalpel excision, is the preferred technique for matricectomy. Most patients return to normal ambulation and activity as early as 1 day after the operation.

Figure 245-10  Reflected proximal nail fold and removal of the proximal portion of the nail plate exposing the pigmented lesion. Around the latter is made an incision followed by its tangential removal Haneke’s matrix tangential biopsy technique.

NAIL BED Nail-bed surgery is performed for biopsy, removal of tumors, and treatment of nail dystrophies such as onychogryphosis.

BIOPSY. Biopsy (Fig. 245-13) may be useful in any pathologic condition involving the nail bed. Punch biopsy is done with a 3- or 4-mm diameter punch, which is driven perpendicularly into the nail plate in a circular motion down to the bone. However, it is not always easy to extract the cylinder cut with an area this small. One useful technique is to perforate the nail plate with a 6-mm punch without injuring the underlying tissue (see Fig. 245-13A). The covering nail is then detached by using the tip of the scalpel to remove the disk of nail, and the biopsy is performed easily by using the 4-mm punch to the bone. The tissue can then be released from its tether with fine scissors. It is advisable to replace the 6-mm disk of nail keratin, after cleaning with 10% hydrogen peroxide, to cover the hole. If the Treatment of split nail

Transverse biopsy of the nail matrix

2964

Figure 245-9  Transverse biopsy of the nail matrix.

Figure 245-11  Treatment of split nail in the middle region of the nail plate.

Nail ablation

A Nail matrix

Proximal nail fold

Lateral nail fold Lunula Cuticle

Hyponychium

Nail bed

Defect to heal by secondary intention, grafting, or cross-finger flap

Nail bed biopsy

A 6mm

6mm

4mm

Nail Surgery

nail plate is thick, rotating grinders can be used to thin it down and facilitate the transungual biopsy. If a larger nail bed fragment is needed, fusiform biopsy with a major longitudinal axis can be performed after partial avulsion of the lateral half of the

::

Figure 245-12  Nail ablation. A. Area of excision. B. Remaining defect.

SUBUNGUAL HEMATOMA. In cases of subungual hematoma, acute trauma with severe pain is always remembered by the patient. Depending on the site and intensity of the injury, the hematoma may be visible almost immediately or it may grow out from under the proximal nail fold within a few weeks. When the hematoma is partial (less than 25% of the visible portion of the nail), it should be drained with a pointed scalpel or by hot paperclip cautery over the center of the dark spot (Fig. 245-14). This will produce relief from pain. Sometimes the nail sloughs as the new nail regenerates beneath the old one. Small hematomas may be included in the nail, but they cannot be degraded to hemosiderin and results of the Prussian blue test will be negative. Therefore, to demonstrate the nature of the blackish pigment, scrapings are boiled in a small test tube with Hemostix, which gives a positive benzidine result. A hematoma involving more than 25% of the visible portion of the nail is a sign of significant nail bed injury. A radiograph is mandatory, because the phalanx may be fractured. The nail plate is carefully removed and the hematoma evacuated. Traumatic nail bed laceration or wounds need a surgical approach to avoid delayed complications. Nail bed lacerations can be sutured after thorough cleaning with antiseptics, using 6-0 resorbable monofilament material. The avulsed nail plate should be put back to cover the wound and then kept in place by suturing to the lateral nail folds or the fingertip. Nail bed defects larger than 4 mm can be repaired using a split-thickness graft taken either from the nail bed of the same digit or from the nail bed of a great toe. The torn nail bed should be sutured with 6-0 resorbable thread, and large bites of tissue should be taken

40

Chapter 245

B

Nail plate

nail (see Fig. 245-13B) or after total avulsion if the fragment is central. After excision, the nail bed is undermined to facilitate reapproximation of both sides. The suture needle is used generously on these fragile subungual tissues. The wound is stitched with 6-0 resorbable thread. It is sometimes useful to make relaxing incisions at the most lateral margins of the nail bed.

4mm Treatment of partial hematoma

B

4mm

6mm

Figure 245-13  Nail bed biopsy. A. Punch biopsy. B. Fusiform biopsy.

Figure 245-14  Treatment of partial hematoma.

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so that the suture material does not pull through when it is tied. The nail plate is cleaned, shortened, and slightly narrowed, and then replaced with sutures into the lateral nail folds. The stitches are left in for 2 weeks. Chronic hematomas are usually painless and are caused mainly by repeated microtrauma from either ill-fitting footwear or sporting activities. A notch is made with a scalpel blade at the distal and proximal border of the pigmented spot. Observation over a 3-week period will demonstrate whether the nail grows independently of the pigmentation or with it. However, chronic hematoma may resemble subungual melanoma and pose a distressing problem, and nonmigrating hematoma should be ruled out.

Section 40

PROXIMAL NAIL FOLD

:: Surgery in Dermatology

BIOPSY. A 2- to 3-mm punch may be used for biopsy of a tumor. A blister may be completely removed by shave biopsy using half a razor blade (see eFig. 24514.1 in online edition). Excision of a 3-mm crescentshaped tissue segment in the proximal region of the lateral nail folds may be helpful in the evaluation of collagen disease. RECALCITRANT CHRONIC PARONYCHIA.

Presence of a foreign body (e.g., hair) under the proximal nail fold is the main cause of recalcitrant chronic paronychia. The disorder manifests as a red swelling that is painless except when pressed, with secondary retraction of the paronychial tissue whose cuticle has disappeared and with recurrent episodes of acute paronychial inflammation. For crescentic excision, a Freer septum elevator is inserted under the proximal nail fold to protect the matrix and extensor tendon. A No. 15 Bard-Parker blade is used to excise, en bloc, a crescent-shaped full-thickness skin segment, 4 mm at its greatest width, that extends from one lateral nail fold to the other. Use of a beveled incision prevents accidental damage to the proximal nail matrix and the most proximal portion of the proximal nail fold, which is responsible for the normal shine of the nail plate (see eFig. 245-14.2 in online edition). In patients who experience repeated acute flares associated with chronic paronychia, additional removal of the base of the nail is useful.

TUMORS OF THE PROXIMAL NAIL FOLD.

2966

Different techniques can be used to treat tumors of the proximal nail fold, depending on the nature of the tumor, its location, and the length of its long axis. Crescentic excision is useful for small distal tumors. The crescent should not exceed 4 mm at its greatest width. Tumors of the proximal nail fold that are situated in a median position and have a longitudinal axis longer than 4–5 mm can be excised with a wedge of proximal nail fold whose base is located at the free margin and whose apex points proximally (Fig. 245-15A). Two relaxing lateral incisions are then made in the proximal nail fold to allow suturing of the wedge-shaped defect after the undersurface of the proximal nail fold has been released from the nail plate (see Fig. 245-15B).

A

B

Figure 245-15  A. Tumor of the proximal nail fold situated in a median position. B. Suturing of the defect after relaxing lateral incisions are made and the proximal nail fold has been released from the nail plate. The resulting symmetric narrow defects on both sides heal rapidly by secondary intention. A small tumor on the lateral part of the proximal nail fold may be treated using a wedge-shaped excision (see eFig. 245-15.1 in online edition). Only one lateral relaxing incision is made at the opposite region of the proximal nail fold. To obtain better healing of the secondary defect, which is wider than in the procedure using two relaxing incisions, the surgery may be supplemented by making a relaxing crescent-shaped incision in the proximal nail fold. A dorsal flap can be raised from the proximal nail fold by using two dorsolateral incisions and a horizontal one proximal to the cuticle. This gives complete exposure of subcutaneous tumors.

RECONSTRUCTION OF THE PROXIMAL NAIL FOLD. Reconstruction of the proximal nail

fold may be necessary after any injury (accident, burn, avulsion caused by rapidly rotating belts and sanders, etc.). If the irregular tissue is excised, it is sometimes possible to recreate the distal curve of the proximal nail fold, which may produce a nearly perfect restoration. The proximal nail fold may also be restored by using two long, narrow, V-shaped transposition flaps from the lateral aspects of the terminal phalanx.

LATERAL NAIL FOLD A 2- to 4-mm punch can remove a tumor of the lateral nail fold (see eFig. 245-15.2 in online edition). Benign tumors may be removed by taking an elliptical wedge of tissue from the lateral nail fold and lateral nail wall. Malignant tumors, such as in Bowen disease, are treated by excision of the whole lateral nail fold or by Mohs micrographic surgery followed by healing by second intention.

INGROWN NAILS. Ingrown nail is a condition that occurs mainly in the great toe. It is created by impingement of the nail plate into the dermal tissue distally or

into the distolateral nail groove. Irrespective of the initial cause, the condition finally presents with a nail bed that is too narrow for its nail plate. Logical treatment is therefore aimed at correcting this disparity.

Juvenile or subcutaneous embedded nail is the most common type of ingrown nail. The nail is usually embedded medially, but both sides are often affected. In an effort to relieve the pain, the patient often tries to cut off the offending corner under the inflamed and swollen soft tissue. The remaining portion gives rise to a nail spicule piercing the epithelium of the lateral nail groove, which produces secondary infection and excessive granulation tissue. Treatment at the early stage must be conservative but demands a high degree of patient compliance. The foot is soaked in warm water with povidone-iodine soap; then, under local anesthesia, the nail spicule is removed and a wisp of cotton wool is placed between the nail and the lateral nail groove. It should be moistened repeatedly with a disinfectant. For definitive cure, surgical excision or, better, chemical suppression of the lateral horn of the nail matrix permanently narrows the nail. The lateral fifth of the nail plate is freed with a nail elevator from the proximal nail fold and the subungual tissues. It is then cut longitudinally with an English nail splitter or nail-splitting scissors and extracted using a sturdy hemostat. The lateral matrix horn is cauterized with a freshly made solution of liquefied phenol (88% solution) (see eFig. 245-15.4 in online edition). Above all, a bloodless field is needed, because blood inactivates phenol. Hemostasis is therefore accomplished with a tourniquet, and the blood is carefully cleaned from the space under the proximal nail fold using sterile gauze. The surrounding skin is protected with petroleum jelly. The phenol is rubbed onto the matrix epithelium for 3 minutes with a cotton-tipped swab that is changed two or three times. Postoperative pain is minimal because phenol has a local anesthetic action and is antiseptic. The matrix epithelium is sloughed off, and oozing is usual for 2–6 weeks. Daily warm foot baths with ­povidone-iodine soap accelerate healing.

the great toe alone or all the digits. This condition may be so painful that even contact with a bedsheet becomes unbearable. When the condition is mild, the nail brace technique aims at correcting the inward distortion of the nail by maintaining continuous tension on the nail plate. A stainless steel wire brace is fitted to the nail plate. A series of adjustments adapted to the gradual decrease of curvature is made over a period of 6 months and results in a painless correction of the pincer nail. Because the underlying bone pathology remains untreated, however, relapse is usual. Therefore, the definitive cure—the use of phenol cautery on the lateral matrix horns—is undoubtedly the simplest effective treatment modality.

Hypertrophy of the Lateral Nail Fold. Hyper-

trophic lateral nail folds are usually the result of longstanding ingrown nails. Inflammation may range from the subclinical to the severe. For treatment, approximately one-fifth of the nail digging into the lateral nail fold is removed. Then an elliptical wedge of tissue is taken from the lateral nail wall of the toe, down to the bone (see eFig. 245-15.5 in online edition). Suturing of the defect pulls the lateral nail fold away from the offending lateral nail edge. In severe cases, this procedure may be combined with phenol cautery of the lateral horn of the matrix. In contrast to adult-acquired hypertrophy of the lateral nail fold, congenital lateral hypertrophic lips disappear progressively and spontaneously within 12 months.

Nail Surgery

Juvenile (Subcutaneous) Ingrown Nails.

Pincer Nail.7 Overcurvature of the nails may affect

::

Retronychia. Retronychia represents proximal regrowth of the nail that occurs when the nail embeds backwards into the proximal nail fold. Sonography is a useful tool to diagnose easily this condition. Nail-plate avulsion with supplementary medical management is curative.

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Chapter 245

Distal Toenail Embedding. Surgical avulsion or the loss of the toenail from trauma, such as tennis toe, may initiate the pathology. The distal subungual tissues released from the physiologic counterpressure of the nail plate become hypertrophic, and the newly formed nail plate abuts this distal wall. To treat the condition, a crescentic wedge-shaped excision is made around the distal phalanx (see eFig. 245-15.3 in online edition). The wedge should be 4 mm at its greatest width and must be dissected from the bone. The defect is closed with 5-0 monofilament sutures, which should be removed after 12–14 days.

Besides phenol and sodium hydroxide, 100% trichloracetic acid has been performed for partial matricectomy. The wound almost always heals within 2 weeks without prolonged exsudative discharge. Pain is mild and transient.

Congenital Malalignment of the Great Toenail.8 In congenital malalignment of the nail of the

great toe, typically the nail is malaligned laterally, with transverse furrows on a thick brownish or greenish nail. In 50% of cases, this condition corrects itself without therapy before the age of 10. If the appearance is extreme, surgery diminishes the risk of permanent dystrophy. Treatment requires rotation of a bulky nail unit flap, including the entire nail, nail bed, and matrix (see eFig. 245-15.6 in online edition). This demands creation of an external Burow’s triangle. An eccentric crescentshaped excision is made to undermine the nail unit, with the maximum width located on the internal side of the foot, corresponding to the side to which the nail needs to be redirected. This crescent ends on each side 3–4 mm behind the most proximal part of the proximal nail fold. The nail bed and the matrix are then undermined and lifted until the fibers of the extensor tendon are visible on its bony insertion, and the dorsal expansion of the lateral ligament of the distal interphalangeal joint is cut. Suturing the edges of the excised triangle together reduces the loss of cutaneous substance. The nail unit is rotated inwardly, because the maximum cutaneous resection is mostly distal and medial.

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Chapter 246 :: Cryosurgery and Electrosurgery :: Justin J. Vujevich & Leonard H. Goldberg

Section 40 :: Surgery in Dermatology

CRYOSURGERY, CRYOBIOLOGY, AND CROYGENS

cinations. Cryogen spray cooling is also used to reduce the pain of laser surgery and eliminate overheating of the epidermis.6

Cryosurgery refers to the use of extreme cold to destroy cells of abnormal or diseased tissue. The earliest use of a cold refrigerant in medicine is attributed to White, a New York dermatologist, in 1899.1,2 Using a cottontipped applicator dipped into liquefied air, he successfully treated warts, nevi, and precancerous and cancerous lesions. In 1907, Whitehouse, another New York dermatologist, reported the utilization of the spray method in the cryosurgical treatment of skin cancers.3 Cryobiology refers to the study of the effects of subzero temperature on living systems. Tissue destruction from cryotherapy results from direct cell injury, vascular stasis, and the local inflammatory response. Rapid freezing of cells causes intracellular ice crystal formation with the disruption of electrolytes and pH changes, whereas slow freezing causes extracellular ice formation and less cell damage. Therefore, tissue effects and cell death are most readily achieved when tissue is frozen rapidly.4 During thawing, recrystallization occurs when ice crystals fuse to form large crystals that disrupt cell membranes. As the ice melts further, the extracellular environment becomes hypotonic, causing water to infuse into sells a cell lysis.5 The longer the thawing time, the greater damage to the cells because of increased solute effect and greater recrystallization.5 After freezing, stasis within the vasculature occurs. This loss of circulation and resultant anoxia is a major mechanism of injury from cryosurgery. As the tissue thaws over 0°C (32°F), a brief hyperemic response ensues, with resultant edema and inflammation. Liquid nitrogen is the cryogen of choice in dermatology. It is easy to store and use, environmentally friendly, nonflammable, inexpensive, and at –195.8°C (–320.4°F), has the lowest temperature of all the common cryogens, causing rapid freeze of treated tissue. Other available cryogens include fluorinated hydrocarbons, solid carbon dioxide, and nitrous oxide (Table 246-1). Fluorinated hydrocarbons are used as topical sprays to provide temporary anesthesia before the removal of skin lesions or the administration of vac-

PATIENT SELECTION AND CONSIDERATIONS FOR CRYOSURGERY Cryosurgery is a destructive modality used to treat benign and malignant skin neoplasms. Several factors, including lesion type, size, depth, border, location, and patient skin type, should be considered when cryosurgery is a treatment choice. Absolute contraindications to cryosurgery include lesions that require histopathology for diagnosis and recurrent nonmelanoma skin cancers. Relative contraindications to cryosurgery include patients with cold urticaria, abnormal cold intolerance, cryoglobulinemia or cryofibrinogenemia, or tumors with indistinct borders or darkly pigmented melanotic features.

RISKS AND PRECAUTIONS Precautions should be undertaken when:





PATIENT POSITIONING Patients may be seated or lying on a examination table at a angle but the spray canister should be held upright. Tilting the canister sideways will result in the sudden release of vapor from the canister.

EQUIPMENT

TABLE 246-1

Cryogens Used in Cryosurgery



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Treating lesions overlying nerves, such as the postauricular nerve on the neck or digital nerves on medial and lateral fingers and toes. Damage may result in regional paresthesia or motor dysfunction. Treating sites prone to scarring with retraction, such as the eyelids, mucosa, nasal ala, and auditory canal. Treating patients with darkly pigmented skin, may result in hypopigmentation at treated sites.

Agent

Boiling Point (°C/°F)

Freon

–40.8/–41.4

Solid CO2

–79.0/–110.2

Nitrous oxide

–89.5/–129.1

Liquid nitrogen

–195.8/–320.4



Cryogen storage container Cryogen Cryosurgical spray unit

ANESTHESIA For the majority of patients, anesthesia is not used prior to a cryosurgical procedure. However,

TECHNIQUES FOR CRYOSURGERY

Cryosurgery and Electrosurgery

OUTCOMES ASSESSMENT FOR COMMON BENIGN LESIONS SEBORRHEIC KERATOSIS

TABLE 246-2

Tissue Target Cell Death Temperatures Cell

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Table 246-2 lists targets of cryosurgery with associated cell death temperatures. Melanocytes are the most sensitive to cryosurgery, with cell destruction at –4°C to –7°C (24.8°F–19.4°F).8 Depigmentation may occur, especially in darkly pigmented individuals. Keratinocytes require longer freezing to –20°C to –30°C until cell death and are more resistant to cooling effects. Fibroblasts are the most resistant to freezing and do not undergo cell death until –30°C to –35°C (–22°F to –31°F). A temperature of –50°C to –60°C (–58°F to –76°F) is needed for destruction of malignant lesions, whereas lesser degrees of freezing are needed for benign lesions. There are several cryosurgical techniques that can be used in treating skin lesions. The open spray method is most frequently used. This method uses a handheld cryosurgical unit with fingertip trigger (eFig. 246-0.1 in online edition). Spray tips with varying-sized apertures are attached to the unit, emitting a stream of liquid nitrogen toward the lesion from a distance of 1–2 cm. A new model has been released, which measures the temperature on the skin surface.9 Although freeze times vary for lesion types, an intermittent spray in a solid, circular, or paintbrush pattern is normally used. Longer spray times are required for thicker, keratotic lesions or malignant lesions; shorter times are required for thinner, atrophic, or benign lesions. The intermittent spray helps localize treatment to the lesion with a small freeze halo, thus minimizing collateral normal tissue damage. This is particularly

important when treating lesions around the orbital, nasal, auricular, genital, or periungual regions. As the lesion is treated, a lateral freeze spreads beyond the margins of the lesion. The measurement of the surface radius of the freeze is equal to the central depth of the freeze into the skin.5 Temperature gradients exist within the freeze, with colder temperatures in the middle and warmer temperatures toward the periphery. In general, superficial lesions should have a clinical freeze margin of 2–3 mm, and malignant or deeper lesions should have a clinical freeze margin of 5 mm to ensure successful treatment. The closed technique uses a copper cryoprobe that is attached to the cryosurgical unit. Once the metal probe is pressed against a lesion on the skin, the trigger of the unit is squeezed, and liquid nitrogen leaves the unit through a conduit line that maintains it in a closed system. This technique is useful for treating small, well-circumscribed lesions or lesions found in confined locations. Similarly, a metal, cone-sized chamber can be attached to the cryosurgical unit and held in contact with the lesion. This allows liquid nitrogen spray to enter the cone and rapidly freeze the lesion. Another cone-apparatus option includes holding an otoscope cover tip against the lesion with one hand while freezing with the cryosurgical unit in the other hand. Treatment times using the cone method should be decreased because the final temperature at the orifice of the cone is obtained faster, when compared with an open spray. If a cryospray unit is not available, the dipstick technique can be used. First, a small amount of liquid nitrogen is poured into a polystyrene cup or other insulated container. Cotton-tipped swabs are placed tip-down in the container and cooled. Using firm pressure, the cotton-tips are placed against the lesion until a 2- to 3-mm halo forms around the treated lesion. This method is useful where surrounding tissue must be spared, such as periorbital, mucosal, nail, and genital regions. Alternatively, tissue forceps can be placed in the container and allowed to cool. This method is useful for treating filiform lesions such as verrucae and skin tags. The metal forceps cool rapidly, so gloves should be worn while holding the forceps to prevent freeze injury to the practitioner’s fingers.

Chapter 246

cryosurgery is painful, especially in children. 1% lidocaine with 1:100,000 epinephrine may be locally injected prior to treatment. For longer cryosurgery treatment times, such as treatment of skin neoplasms (up to 30 seconds), local anesthesia is mandatory. Topical anesthesia can be applied approximately 1 hour prior to the procedure to minimize pain. A single-center, double blinded, randomized placebo-controlled, parallel-group trail comparing a lidocaine/prilocaine 5% cream applied 1 hour prior to cryosurgery for warts, however, did not demonstrate a statistically significant difference in pain during the procedure.7 For longer cryosurgery treatment times, such as treatment for skin neoplasms (up to 30 seconds), 1% lidocaine with 1:100,000 epinephrine can be locally injected prior to treatment.

Temperature (°C/°F)

Melanocytes

–4 to –7 (24.8 to 19.4)

Keratinocytes

–20 to –30 (–4 to –22)

Fibroblasts

–30 to –35 (–22 to –31)

The spray technique is an effective modality for treating this common lesion. Although longer freeze times of 10–15 seconds with a 1- to 2-mm halo are required for these raised growths, too aggressive freezing may result in scarring or hyperpigmentation. For cosmetic purposes and to prevent pigmentation changes, a lighter freeze followed by curettage may be preferential. Forewarn patients that a second

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but effective means of treating these recalcitrant lesions. Freeze times of 30 seconds are required over 1-month interval sessions until flattening is achieved. Zouboulis et al reported a prospective study of 93 keloids and hypertrophic scars treated with 30-second freeze times over one to three sessions.12 Improved responses were seen in patients treated with three or more sessions (79%), compared with subjects treated once or twice (33%).

DERMATOFIBROMA Section 40

Figure 246-1  Warts on hand treated with liquid nitrogen.

:: Surgery in Dermatology

treatment may be required, especially for thicker seborrheic keratoses.

VERRUCAE Warts are a common problem, with a high prevalence in the population.10 Although cryosurgery for warts has sustained a common practice in dermatology, varying techniques have been offered with regard to freezing method, number of freeze-thaw cycles, and frequency of treatment sessions. Cryosurgery using the spray technique is probably the most common method due to its quick, convenient use and ease of obtaining a freeze halo around the lesion (Fig. 246-1). The cotton-tip applicator technique is cheaper and may be less frightening to the patient, particularly children. Care must be undertaken not to cross contaminate the liquid nitrogen by reintroducing the cotton-tip applicator into a common flask. Combination therapy with cryosurgery has also been advocated to treat verrucae. Berth-Jones and Huchinson11 demonstrated a 52% cure rate at 3 months with the combination of cryotherapy, keratolytic wart paint, and paring. The authors also noted that paring the wart before cryotherapy improved the cure rates for plantar warts, but not hand warts.

Treatment time may be 60 seconds due to the fibrotic nature of the lesion and the need to treat cells located in the deep dermis. A retrospective study of 393 dermatofibromas treated with cryosurgery reported 65% clearance of a visible and palpable lesion.13

SEBACEOUS HYPERPLASIA These benign lesions may be a cosmetic concern for patients. Freeze times of 5–10 seconds are required, using the cryoprobe technique with the probe applied directly into the central punctum of the lesion. Patients must be advised that retreatment is frequently necessary.

OUTCOMES ASSESSMENT FOR PREMALIGNANT LESIONS ACTINIC KERATOSIS Cryosurgery is an effective modality for the treatment of actinic keratoses (AKs). The open spray technique, using a single freeze-thaw cycle of 8–10 seconds, is the treatment of choice (Fig. 246-2). Hypertrophic AKs

SOLAR LENTIGO As shown in Table 246-2, pigmented cells are highly susceptible to freezing. Therefore, these lesions require a shorter freeze time of 3–5 seconds with minimal halo. For darker-skinned individuals, care must be taken not to induce hypopigmentation at treatment sites. Therefore, a test site in a cosmetically less noticeable region may be performed first before treating multiple lesions on sun-exposed areas. In addition, sunscreen with ultraviolet A and ultraviolet protection should be advocated post-treatment.

KELOIDS AND HYPERTROPHIC SCARS 2970

Treatment of keloids and hypertrophic scars is frequently unsatisfactory. Cryosurgery is a less common

Figure 246-2  Actinic keratosis on forehead treated with liquid nitrogen.

BOWEN DISEASE Ahmed et al17 treated 26 BDs using 3-mm clinical margins and spray technique with two 5- to 10-second freeze-thaw cycles. After 2 years, 50% of the lesions had recurred. The average healing time was 46 days, with lesions on the lower leg taking longer to heal (90 days). Although the cure rate using cryosurgery for BD was low in this study, the authors did use a lower freeze time to minimize side effects postprocedure.

BASAL CELL CARCINOMA Several studies have reported treating basal cell carcinomas (BCCs) with cryosurgery with cure rates ranging between 95% and 99%.18–20 Although excellent cure rates have been claimed, few studies have demonstrated histologically that the BCC is no longer present post-treatment. Furthermore, there are no good studies comparing cryosurgery with other known treatment modalities, such as Mohs micrographic surgery, excision with clinical margins, and electrodesiccation and curettage. Postsurgical cosmetic appearance is a concern to patients. Kokoszka and Scheinfeld21 reported good

SQUAMOUS CELL CARCINOMA Similar cure rates to BCCs are evident when treating squamous cell carcinomas (SCCs) with cryosurgery. In a study of 563 primary SCCs, of which most were between 0.5 and 1.2 cm in diameter, Graham and Clark23 reported a cure rate of 97.3%. Treatment technique with cryosurgery for SCCs is the same as for BCCs.

LENTIGO MALIGNA With proper patient selection, cryosurgery can be an effective treatment option for lentigo maligna (LM) due to the sensitivity of melanocytes to cold. With the aid of a Wood’s lamp, a clinical margin of 5 mm is drawn around the visible borders of the lesion. The lesion is subsequently treated with a double freeze-thaw cycle of 30–60 seconds each cycle. Because atypical melanocytes may extend along the length of the hair follicles, treatment must freeze the tissue to this depth. Stevenson and Ahmed24 reviewed cure rates from more than 200 LMs treated with cryotherapy, with an overall recurrence rate of less than 9%. However, the recurrence rates in these studies ranged from 0%–50%. Advantages of cryotherapy for LM include its efficiency and avoidance of large surgical scars. One major disadvantage of cryosurgery is the inability to assess whether the lesion has been completely destroyed. In addition, because no tissue is obtained for definitive confirmation of cancer removal, the chance exists that recurrent melanoma may develop and that it may be invasive. Overlying scars may conceal the cancer.

Cryosurgery and Electrosurgery

Cryosurgery appears useful in well-defined lesions for situations where surgery is less favorable, either for technical or cosmetic reasons, or when the patient prefers this treatment option. The goal of cryosurgery is to cure the patient by destroying the lesion in a single treatment. The margins of destruction of the lesion cannot be assessed using cryosurgery of malignant tumors.

40

::

MALIGNANT LESIONS

cosmetic results in their review of the literature. Thissen et al,22 however, compared the cosmetic results of surgical excision compared with cryosurgery for BCCs of the head and neck and concluded that cosmetic results after excision are better than after cryosurgery.

Chapter 246

require longer freeze times while atrophic AKs and AKs on thin-skinned regions require shorter freeze times. A 1- to 2-mm freeze margin around the lesion is adequate. For thicker lesions, pretreatment of emollients or curetting may shorten freezing times. Although cryosurgery is widely utilized in dermatology for treatment of AKs, there are few well-designed studies assessing cure rates. Lubritz and Smolewski14 treated 1,018 AKs on 70 patients with cryosurgery with 20–45 seconds thaw times. At 1-year post-treatment, they reported a cure rate of 99%. Another prospective, multicenter study of 421 AKs over 5 mm in diameter on the face and scalp demonstrated a complete response of 39% with a 5-second freeze, 69% for a 5- to 20-second freeze, and 83% for a 20 second freeze.15 Goldberg et al treated a number of AKs with monitoring of the skin surface temperature, and achieved a 100% cure rate after 6 weeks. In patients with diffuse actinic damage, extensive cryosurgery or cryopeeling, may be useful. Chiarello16 reported cryopeeling was twice as effective as 5-fluorouracil in treating AKs, and preventing squamous cell carcinomas at 1–3 years postoperatively.

COMPLICATIONS PAIN In addition to pain during freezing, patients will experience some discomfort several hours posttreatment. Typically, pain is controlled with acetaminophen. Lesions such as periungual warts, digital lesions, or mucous membrane lesions may require stronger analgesics due to intense swelling and throbbing.

BLEEDING Patients on anticoagulant therapy should be warned of bruising due to tissue necrosis. If painful hemorrhagic bullae form, they may be drained with an 18-gauge needle inserted into the lateral blister skin.

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Care should be undertaken not to remove the surface of the bullae, as this tissue acts as a natural wound dressing.

PIGMENTATION CHANGES

Section 40

Hypo- or hyperpigmentation is the most disconcerting complication postcryosurgery. As previously described, pigmented cells are sensitive at temperatures of –4°C to –7°C (24.8°F–19.4°F). Although pigmentation changes are usually transient, prolonged freezing greater than 30 seconds may result in permanent pigment loss. Topical steroids, glycolic acids, retinoids, and hydroquinone may aid in reducing the incidence of hypopigmentation.

NERVE DAMAGE

:: Surgery in Dermatology

Treatment of lesions overlying nerves, such as the postauricular nerve on the neck or digital nerves on medial and lateral fingers and toes, may result in regional paresthesia or motor dysfunction. Digital neuropathy occurring postcryosurgery of digital warts has been reported.25

SCARRING Fibroblasts are the most resistant to freezing and do not undergo cell death until –30°C to –35°C. Therefore, most benign and premalignant lesions treated with cryotherapy heal with little scarring. Scars due to second intention may occur after malignancies treated with cryosurgery.

ALOPECIA Freeze times longer than 20 seconds may result in alopecia. This is especially the case in treating malignant lesions.

MONITORING/FOLLOW-UP Benign and premalignant lesion sites typically heal in 1–2 weeks, with malignant lesion sites requiring 3–4 weeks of healing. Clinically suspicious actinic keratoses not responsive to cryosurgery should be biopsied to rule out invasive Squamous Cell Carcinoma.

PATIENT INSTRUCTIONS

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Patients should be given simple verbal and written wound care instructions post-treatment. Edema, vesicles, bullae, and weeping should be expected from treated areas within 24 hours post-treatment. Treated sites may be rinsed with soap and water and patted dry with a towel daily. If actively weeping, the wound site may be bandaged.

ELECTROSURGERY Electrosurgery is a technique that uses the transmission of electricity to cut tissue, destroy tissue, and cauterize vessels. Variations in current wavelength result in different biologic effects on tissue. For cutaneous procedures, electrosurgery can be categorized into six different treatment modalities: (1) electrofulguration, (2) electrodesiccation, (3) electrocoagulation, (4) electrosection, (5) electrocautery, and (6) electrolysis.

MODALITIES OF ELECTROSURGERY ELECTROFULGURATION Electrofulguration uses a damped sine wave, highvoltage, low-amperage alternating current to generate a spark from a monoterminal electrode to the tissue via the air. There is no contact between the electrode and the tissue. This modality is the least tissue damaging of all of the high-frequency electrosurgery techniques, resulting in rapid tissue healing. Most of the tissue damage is superficial, primarily involving the ­epidermis.

ELECTRODESICCATION Electrodesiccation uses a damped sine wave, highvoltage, low-amperage alternating current to generate a current from direct contact of a monoterminal electrode to the tissue. Superficial tissue damage occurs as heat is transferred to tissue, causing cell death. The extent of tissue damage is directly related to electrode contact time with the skin. Although skin injury is greater with electrodesiccation compared to electrofulguration, most of the tissue damage remains ­superficial.

ELECTROCOAGULATION Electrocoagulation uses a moderately damped sine wave, low-voltage, high-amperage alternating current to generate a current from direct contact of a biterminal electrode to the tissue. Tissue damage is deeper than with electrofulguration and electrodesiccation, providing tissue coagulation through the generation of heat in the tissue. Another distinguishing feature of electrocoagulation is the involvement of the patient within the circuit. This allows the use of a lower voltage and higher amperage to generate more coagulation.

ELECTROSECTION Electrosection uses an undamped or slightly damped sine wave, low-voltage, high-amperage alternating current to cut tissue with minimal peripheral heat

damage. The “Bovie” knife incorporates a blended undamped and damped sine wave that provides both cutting and coagulation at the same time.

ELECTROCAUTERY

PATIENT SELECTION When taking preoperative history for surgery, patients should be asked if they have a cardiac pacemaker or ICD. High-frequency electrosurgery may interfere with their function or damage the pacemaker or defibrillator, resulting in patient morbidity or mortality. Patients commonly present for cutaneous surgery with either a cardiac pacemaker or an ICD. Although technologic advances, such as titanium shielding, have provided safeguards against electromagnetic interference (EMI), electrosurgical devices may cause these cardiac devices to malfunction. Fixed-rate pacemakers are not influenced by EMI from electrosurgery. ICDs deliver an electrical response to an abnormal ventricular rhythm. Some ICDs have a combination of a pacemaker and defibrillator to respond to both bradycardia and tachycardia. EMIs from electrosurgical devices may mimic a cardiac arrhythmia and cause the unit to discharge.

RISKS AND PRECAUTIONS Recommendations have been published for the preoperative and intraoperative management of patients with pacemakers and ICDs during dermatologic





PATIENT POSITIONING Patients should be supine or prone on the examination table. The dispersing electrode (grounding pad) should be placed in a location that directs the current pathway away from the cardiac device (usually the right lower leg). If a pedal is used, it should be placed near the surgeon’s feet.

EQUIPMENT

Cryosurgery and Electrosurgery

Electrolysis uses low-voltage, low-amperage direct current from a negative electrode to the positive electrode. The negative electrode is applied to the target tissue where electrons are released. The electrons interact with the tissue to produce sodium hydroxide and hydrogen gas resulting in tissue liquefaction. Acids are produced at the positive electrode resulting in tissue coagulation. The main use of electrolysis is for hair removal.



Provide continuous electrocardiography monitoring throughout the procedure. Have advance cardiac life support (ACLS) staff and crash-cart equipment available. Place the dispersing electrode in a location that directs the current pathway away from the cardiac device. Use a bipolar forcep device to maintain the electrical circuit between the forcep tips. Use minimal power and short electrosurgical bursts of 5 seconds or less. Consider using a disposable heat cautery device. Do not discharge the electrosurgical electrode on the skin directly over the pacemaker power source.

::

ELECTROLYSIS



40

Chapter 246

Electrocautery uses a heating filament tip connected to a low-voltage, high-amperage direct current, usually a battery. Heat is transferred from the filament to the target tissue, causing protein denaturation and tissue coagulation. There is no electric current transfer to the target tissue, and the patient is not part of the circuit loop. Electrocautery is most used for patients with pacemakers or implantable cardiac defibrillators (ICDs) who are high-risk candidates for receiving electrosurgery. In addition, because patients are not part of the circuit loop, electrocautery is useful for nonconductive tissue areas of the body, such as the cartilage, bone, and nails.

s­ urgery.26–31 Patients should be asked when scheduling surgery if they have one of these devices. If present, a preoperative evaluation by the patient’s cardiologist should be arranged before the surgical procedure. For management of patients with pacemakers or ICDs undergoing surgical procedures, consider the following recommendations:

Electrosurgical equipment uses either direct or alternating current. In direct current, electrons flow in one direction, while in alternating current, electron flow reverses direction. With the exception of electrocautery or electrolysis, electrosurgical units used in dermatologic procedures have high-frequency alternating current. The terms monopolar and bipolar refer to the number of tissue-containing tips at the end of a surgical electrode. Monopolar denotes one tip, and bipolar denotes two tips. Monoterminal refers to the use of a treatment electrode without an indifferent or dispersing electrode. Biterminal refers to the use of both treatment and indifferent electrodes.

ANESTHESIA During electrosurgery, local anesthesia such as lidocaine with epinephrine is required for patient comfort.

TECHNIQUE HEMOSTASIS The most common application of electrosurgery is its use in maintaining hemostasis in the operative field.

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such as seborrheic keratoses, verrucae, dermatosis papulosis nigra, molluscum, or flat warts. First, the area around the lesion is anesthetized with lidocainecontaining epinephrine. Then, the lesion is touched with the low-power electrode until a gray, superficial charred layer involves the entire lesion. The charred tissue is removed from the treated lesion by wiping with a sterile gauze or curetting. The process is repeated until the lesion is removed at the level of the surrounding skin. This method results in minimal bleeding and scarring because just the epidermal components are removed.

Section 40

ELECTRODESICCATION AND CURETTAGE OF MALIGNANT LESIONS Figure 246-3  Electrodesiccation of bleeding vessel during Mohs micrographic surgery.

:: Surgery in Dermatology

Different techniques of electrosurgery can be used based on the type of electrosurgical unit used during surgical procedures. Coagulation can be achieved using electrofulguration electrodesiccation or electrocoagulation by direct application of the electrode to the bleeding vessel. This provides conduction of heat to the vessel, resulting in tissue coagulation (Fig. 246-3). Alternatively, vessels can be grasped by a forcep or hemostat, followed by application of the active electrode. When electrical current is placed against the metal instrument, heat is transferred from the electrode through the metal tip to the vessel. This technique is best used when the surgical field cannot be visualized due to bleeding (Fig. 246-4).

ELECTROSURGERY OF BENIGN LESIONS Electrodesiccation is an effective treatment modality for papular or plaque-like tumors of the epidermis,

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Figure 246-4  Electrocurrent applied to forcep to cauterize bleeding vessel during Mohs micrographic surgery.

Curettage and electrodesiccation (C+D) is a commonly used treatment option for BCCs and SCCs. Certain tumor characteristics, however, should be present to ensure high cure rates and acceptable cosmetic outcome. Tumors should be primary, have distinct clinical borders, be located on sites of low recurrence such as the trunk, extremities, or non-“H”-zone regions of the face (see Chapters 114 and 115), have a superficial or nodular histologic subtype, and have a diameter of