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Aung Kyaw Oo



McKee’s

Pathology of the Skin

Commissioning Editor: William R. Schmitt Development Editors: Louise Cook & Rachael Harrison Editorial Assistant: Kirsten Lowson Project Manager: Nancy Arnott Design: Kirsteen Wright Illustration Manager: Merlyn Harvey Marketing Manager (USA): Tracie Pasker



Fourth Edition

McKee’s

Pathology of the Skin with Clinical Correlations Volume 1

Eduardo Calonje MD, DipRCPath Director of Dermatopathology Department of Dermatopathology St John's Institute of Dermatology St Thomas' Hospital London, UK

Thomas Brenn MD, PhD, FRCPath

Consultant Dermatopathologist and Honorary Senior Lecturer Department of Pathology Western General Hospital and The University of Edinburgh Edinburgh, UK

Alexander Lazar MD, PhD

Associate Professor Departments of Pathology and Dermatology Sections of Dermatopathology and Sarcoma Pathology Faculty, Sarcoma Research Center and Graduate School of Biomedical Science The University of Texas M.D. Anderson Cancer Center Houston, Texas, USA

Editor-in-Chief Phillip H McKee MD, FRCPath

Formerly Associate Professor of Pathology and Director, Division of Dermatopathology Department of Surgical Pathology Brigham and Women's Hospital and Harvard Medical School Boston, MA, USA

For additional online references and video content visit expertconsult.com

SAUNDERS an imprint of Elsevier Limited © 2012, Elsevier Limited All rights reserved. First edition 1989 Second edition 1996 Third edition 2005 Fourth edition 2012 The right of Eduardo Calonje, Thomas Brenn, Alexander Lazar and Phillip H McKee to be identified as author of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher's permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. British Library Cataloguing in Publication Data McKee's Pathology of the Skin. – 4th ed. 1. Skin–Diseases. 2. Skin–Histopathology. I. Pathology of the skin II. Calonje, Eduardo. III. McKee, Phillip H. Pathology of the skin. 616.5'07-dc22 ISBN-13: 978 1 4160 5649 2

Printed in China Last digit is the print number: 9  8  7  6  5  4  3  2  1

Contents List of Contributors vii Preface to the fourth edition  x Acknowledgements xi Dedications xii Glossary xiii

Volume 1   1 The structure and function of skin  1 John A. McGrath

11 Diseases of the oral mucosa  362 Sook-Bin Woo

  2 Specialized techniques in dermatopathology  32 Pratistadevi A. Ramdial, Boris C. Bastian, John Goodlad, John K. McGrath and Alexander Lazar

12 Diseases of the anogenital skin  437 Eduardo Calonje, Sallie Neill, Chris Bunker, Nick Francis, Alcides Chaux and Antonio C Cubilla

  3 Disorders of keratinization  46 Dieter Metze

13 Degenerative and metabolic diseases  520 Nooshin Brinster and Eduardo Calonje

  4 Inherited and autoimmune subepidermal blistering diseases  99

14 Cutaneous adverse reactions to drugs  590 Nooshin Brinster

  5 Acantholytic disorders  151   6 Spongiotic, psoriasiform and pustular dermatoses  180   7 Lichenoid and interface dermatitis  219 Wei-Lien Wang and Alexander Lazar   8 Superficial and deep perivascular inflammatory dermatoses  259   9 Granulomatous, necrobiotic and perforating dermatoses  281

15 Neutrophilic and eosinophilic dermatoses  631 16 Vascular diseases  658 17 Idiopathic connective tissue disorders  711 Bostjan Luzar and Eduardo Calonje 18 Infectious diseases of the skin  760 Wayne Grayson

10 Inflammatory diseases of the subcutaneous fat  326 Bostjan Luzar and Eduardo Calonje

Volume 2 19 Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)-associated cutaneous diseases  896 Pratistadevi K. Ramdial and Wayne Grayson

22 Diseases of the hair  967 Rodrigo Restrepo and Eduardo Calonje 23 Diseases of the nails  1051 Josette Andre, Ursula Sass and Anne Theunis

20 Disorders of pigmentation  912

24 Tumors of the surface epithelium  1076

21 Diseases of collagen and elastic tissue  935 Wei-Lien Wang and Alexander Lazar

25 Melanocytic nevi  1150 Bostjan Luzar, Boris C. Bastian and Eduardo Calonje

vi

Contents

26 Melanoma  1221 Boris C. Bastian and Alexander Lazar 27 Tumors of the conjunctiva  1268 Jacob Péer and Shahar Frenkel 28 Sentinel lymph node biopsies  1296 Alistair J. Cochran 29 Cutaneous lymphoproliferative diseases and related disorders  1311 John Goodlad and Eduardo Calonje

Index  I1

30 Cutaneous metastases and Paget's disease of the skin  1421 Doina Ivan, Alexander Lazar and Eduardo Calonje 31 Tumors of the hair follicle  1445 32 Tumors and related lesions of the sebaceous glands  1488 33 Tumors of the sweat glands  1508 34 Cutaneous cysts  1571 35 Connective tissue tumors  1588

Chapter

List of Contributors Josette André, MD

Alistair J. Cochran, MD

Head of the Dermatology and Dermatopathology Department. CHU Saint-Pierre - CHU Brugmann Hôpital Universitaire des Enfants Reine Fabiola Université Libre de Bruxelles Brussels, Belgium Ch 23: Diseases of the nails with Ursula Sass and Anne Theunis

Distinguished Professor of Pathology and Laboratory Medicine and Surgery Department of Pathology and Laboratory Medicine David Geffen School of Medicine at UCLA Los Angeles, CA, USA Ch 28: Sentinel node biopsies

Boris C. Bastian, MD Chairman, Department of Pathology The James Ewing Alumni Chair Member, Human Oncology and Pathogenesis Program Memorial Sloan-Kettering Cancer Center Professor of Pathology Weill Cornell Medical College New York, NY, USA Ch 2: Specialized techniques in dermatopathology with Pratistadevi K Ramdial, John Goodlad, John A. McGrath and Alexander Lazar Ch 25: Melanocytic nevi with Eduardo Calonje Ch 26: Melanoma with Alexander Lazar

Nooshin K. Brinster, MD Assistant Professor Department of Pathology and Dermatology Director of Dermatopathology VCU Medical Center Richmond, VA, USA Ch 13: Degenerative and metabolic diseases Ch 14: Cutaneous adverse reactions to drugs

Chris Bunker, MA, MD, FRCP Consultant Dermatologist University College and Chelsea and Westminster Hospitals London; Professor of Dermatology University College London London, UK Ch 12: Diseases of the anogenital skin with Eduardo Calonje, Sallie Neill, Nick Francis, Alcides Chaux, Antonio C Cubilla

Alcides Chaux, MD GU Research Fellow, Department of Pathology Johns Hopkins University School of Medicine Baltimore, MD, USA Ch 12: Diseases of the anogenital skin with Eduardo Calonje, Sallie Neill, Chris Bunker, Nick Francis, and Antonio C Cubilla

Antonio C. Cubilla, MD Instituto de Patología e Investigación Asuncion, Paraguay Ch 12: Diseases of the anogenital skin with Eduardo Calonje, Sallie Neill, Chris Bunker, Nick Francis and Alcides Chaux

Nick Francis, FRCPath Consultant Histopathologist Imperial College Healthcare NHS trust Honorary Senior Lecturer Imperial College Faculty of Medicine London, UK Ch 12: Diseases of the anogenital skin with Eduardo Calonje, Sallie Neill, Chris Bunker, Alcides Chaux, Antonio C Cubilla

Shahar Frenkel, MD, PhD Ocular Oncologist and Ophthalmic Pathologist Specialized Ocular Oncology Service Ophthalmic Pathology Laboratory Jerusalem, Israel Lecturer in Ophthalmology Department of Ophthalmology Hadassah – Hebrew University Medical Center Jerusalem, Israel Ch 27: Tumors of the conjunctiva with Jacob Pe'er

John Goodlad, MD, FRCPath Consultant Haematopathologist and Honorary Senior Lecturer Department of Pathology Western General Hospital and University of Edinburgh Edinburgh, UK Ch 2: Specialized techniques in dermatopathology with Pratistadevi K Ramdial, Boris C. Bastian, John A. McGrath and Alexander Lazar Ch 29 Cutaneous lymphoproliferative diseases and related disorders with Eduardo Calonje

viii

List of Contributors

Wayne Grayson, MBChB, PhD, FCPath(SA)

Sallie Neill, MB ChB, FRCP

Consultant Anatomical Pathologist and Dermatopathologist AMPATH National Laboratories; Honorary Associate Professor School of Pathology University of the Witwatersrand, Johannesburg Johannesburg, South Africa Ch 18: Infectious diseases of the skin Ch 19: Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)-associated cutaneous diseases with Pratistadevi K Ramdial

Consultant Dermatologist Guys and St Thomas' NHS Trust London, UK Ch 12: Diseases of the anogenital skin with Eduardo Calonje, Chris Bunker, Nick Francis, Alcides Chaux, Antonio C Cubilla

Doina Ivan, MD Assistant Professor Departments of Pathology and Dermatology Section of Dermatopathology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA Ch 30: Cutaneous metastases and Paget's disease of the skin with Alexander Lazar and Eduardo Calonje

Boštjan Luzar, MD, PhD Professor of Pathology Consultant Pathologist Institute of Pathology Medical Faculty University of Ljubljana Ljubljana, Slovenia Ch 10: Inflammatory diseases of the subcutaneous fat with Eduardo Calonje Ch 17: Idiopathic connective tissue disorders with Eduardo Calonje

John A. McGrath, MD, FRCP Professor of Molecular Pathology St John's Institute of Dermatology King's College London Guy's Hospital London, UK Ch 1: The structure and function of skin Ch 2: Specialized techniques in dermatopathology with Pratistadevi K Ramdial, Boris C. Bastian, John Goodlad and Alexander Lazar

Dieter Metze, MD Professor of Dermatology Director, Dermatopathology Unit Department of Dermatology University Hospital Münster Münster, Germany Ch 3: Disorders of keratinization

Jacob Pe'er, MD Professor and Chairman Department of Ophthalmology Jonas Friedenwald Professor of Ophthalmic Research Hadassah – Hebrew University Medical Center Jerusalem, Israel Ch 27: Tumors of the conjunctiva with Shahar Frenkel

Pratistadevi K. Ramdial, MBChB, FCPath(SA) Professor and Head Department of Anatomical Pathology Nelson R. Mandela School of Medicine University of Kwazulu-Natal and the National Health Laboratory Service Durban, South Africa Ch 2: Specialized techniques in dermatopathology with Boris C. Bastian, John Goodlad, John A. McGrath and Alexander Lazar Ch 19: Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)-associated cutaneous diseases with Wayne Grayson

Rodrigo Restrepo, MD Director, Dermatopathology Fellowship Program Universidad CES; Professor of Dermatopathology Universidad Pontificia Bolivariana; Director, Laboratory of Pathology Clinica Medellin Medellin, Colombia Ch 22: Diseases of the hair with Eduardo Calonje

Ursula Sass, MD Assistant Professor Dermatology and Dermatopathology Department CHU Saint-Pierre Université Libre de Bruxelles Brussels, Belgium Ch 23: Diseases of the nails with Josette André and Anne Theunis

List of Contributors

Anne Theunis, MD

Sook-Bin Woo, DMD, MMSc

Assistant Professor Dermatopathology and Pathology Department CHU Saint-Pierre and Institut Bordet Université Libre de Bruxelles Brussels, Belgium Ch 23: Diseases of the nails with Josette André and Ursula Sass

Associate Professor Department of Oral Medicine, Infection and Immunity Harvard School of Dental Medicine, Boston, MA, USA; Attending Dentist and Consultant Pathologist Brigham and Women's Hospital Boston, MA, USA Co-Director Center for Oral Pathology Strata Pathology Services Inc. Lexington, MA, USA Ch 11: Diseases of the oral mucosa

Wei-Lien Wang, MD Assistant Professor Department of Pathology Sections of Dermatopathology and Sarcoma Pathology The University of Texas M.D. Anderson Cancer Center Houston, TX, USA Ch 7: Lichenoid and interface dermatoses with Alexander Lazar Ch 21: Diseases of collagen and elastic tissue with Alexander Lazar

ix

Preface to the fourth edition It is hard to believe that sometime in 1988, when I was just starting my training in dermatopathology, I met Phillip McKee at a course on soft tissue tumors organized in London by an unforgettable teacher, Dr Chris Fletcher. When Phillip heard about my interest in dermatopathology he said to me “I am writing a textbook in dermatopathology and you must buy it”. So I did, little suspecting that I was going to become heavily involved in the third edition and the main editor to the fourth edition with the invaluable help of Thomas Brenn and Alex Lazar. During the 1980s immunohistochemistry was a relatively new diagnostic technique becoming in this age an invaluable ancillary tool that has been instrumental in research and in diagnostic pathology. During the same period molecular biology was being developed as a powerful research mechanism in pathology, becoming an additional and crucial aid in diagnosis in the fields of hematopathology and soft tissue tumors in the 1990s. Furthermore, some of these developments in the latter fields have allowed an understanding of many aspects of the pathogenesis of neoplasia, and this has led to the ever expanding use of targeted therapy in the 21st century. These advances have had an important impact in dermatopathology, and more exciting developments have followed in research, diagnosis and understanding of the pathogenesis of neoplastic processes that are of particular importance in the skin, particularly melanocytic neoplasms. This is ongoing work with many questions still unanswered and although with great limitations particularly in the field of diagnosis, it has nonetheless allowed immense understanding of pathogenesis and the development of some targeted therapies for melanoma some with very promising although limited results. In this edition we have invited a number of experts to contribute in their areas of expertise realizing that it is very difficult if not impossible for a handful of people to cover such an extensive area as dermatopathology. We have tried to include as much material as possible encompassing most of what is new in the literature but realize that inevitably this cannot be achieved to complete satisfaction. The third edition of this book was received with great enthusiasm by many people all over the world and we hope to have fulfilled the task and answered their criticisms in this new edition. Eduardo Calonje The fourth edition has been a huge undertaking and taken an immense amount of time and energy. I would first like to congratulate Eduardo Calonje for doing a wonderful job against a background of a heavy daily workload and lecture commitment. I decided that having left hospital practice and been in charge of the book for three editions, that it was high time for new blood to take over control of the new edition while I became overall editor-in-chief. I have known Eduardo since the early 1980's during which time he has become more than just a close friend; both Gracie and I regard him as one of the family. He is a superb dermatopathologist (without question Europe's leading light) and I had every confidence that he would produce a wonderful new edition of Pathology of the Skin. Needless to say he has gone beyond my greatest expectation and produced a truly magnificent fourth edition. Words cannot express my gratitude.

Thomas Brenn and Alex Lazar are also both very close friends and also regarded by me as members of the family. They both took on much greater responsibilities in the fourth edition than in the third edition and have done a wonderful job. I am deeply indebted to them. Similar to Eduardo this was accomplished in a background of both a heavy routine workload and research commitment. When planning a new edition, it has been my practice to try to make the new edition as different as possible from the preceding one to ensure that people who buy the book get true value for money. To this end, a number of new chapters have been added including, specialized techniques in dermatopathology, sentinel lymph node biopsy pathology, the pathology of HIV/AIDS and tumors of the conjunctiva. The oral pathology chapter has been expanded to include tumors of the salivary glands. We have taken on a large number of very experienced excellent new authors to bring personal experience to many of the more difficult topics and this has certainly paid dividends. Much progress has been achieved in our understanding of the pathogenesis of disease and this is reflected in the new text with up-todate scientific data. I am deeply indebted to all of our new contributors. The Fourth edition is certainly a very different book than the first edition which I wrote for fun almost single handedly as an atlas with integrated text. In order to increase valuable space for the increased figures, enlarged text and new chapters, it was decided to make the references an online only component of the book. This has allowed us to considerably expand the text and increase the number of figures in the book, a large proportion of which are new. I am also heavily indebted to my two friends in the publishing world Louise Cook and Bill Schmitt. I have been associated with Louise for more years than I choose to remember and she has always proven to be a pillar of support particularly during the numerous episodes of stress that are inevitable in a task of this magnitude. I thank her for always being there when help was necessary. I met Bill when I moved to the United States and he has also become a great friend in addition to being the senior Elsevier representative overseeing the progress of the book. Similar to Louise he has had to put up with much from me and has always steered the project with a steady hand during all of its crises which have been innumerable. Producing the Fourth edition would have been an even harder task without their input. More recently I have worked with Nancy Arnott in Edinburgh. She has been the senior editor of the project and most certainly done a wonderful job. The editors and contributors owe her an awful lot. Lastly and most importantly, I owe so much as always to Gracie. She has had to put up with me for the past 4 years while working on the new edition. This has been no mean feat. She has let my ill temper and moods of depression and anxiety wash over her and in her own thoughtful quiet way made the seemingly impossible possible. I would never have been able to complete this task without her loyalty, support and love. Phillip H. McKee

Acknowledgements Working for so many years on a book of this proportion, especially when the task is something that has to be done as a “hobby” after formal work hours, represents a daunting task. I often wondered in times of despair whether the job was ever going to be finished. It has finally been completed and I would not have been able to achieve this without the invaluable help of many people. They not only gave me emotional support but often went out of their way to help me with the many details necessary to finalize the numerous tasks that this job entailed. My wife Claudia has always given me her unwavering support no matter how trying the challenge ahead. My children Mateo and Isabella have given me their patience and understanding. Numerous colleagues, many of them visiting fellows from many different countries, have made my life easy in millions of ways and I cannot thank them enough for their patience, hard work and mainly for being wonderful human beings supporting me in what for many reasons were the darkest days of my life. I especially want to show my appreciation to Drs Maiko Tanaka, Anoud Zidan, Vicki Howard, Viky Damaskou, Thomas Brenn, Bostjan Luzar, Ravi Ratnavel, Rathi Ramakrishnan and Gregory Spiegel (who sadly died last year). EC The path of life is often determined by the people we encounter. There are many ways in which certain individuals touch our hearts, steer us in the right direction and help us achieve goals which would have been unattainable otherwise. Words aren't ever enough to really show one's true appreciation for the generosity, support and motivation received over the years. My wonderful, loving parents, Sonja and Walter, have always been there for me and supported my every move. My wife and daughter, Anne and Yaëlle, have had a terrible time dealing with my tempers throughout the writing of this book. They have always stood by my side and saved a smile for me for which I am ever so grateful. My professional life could have gone very wrong indeed had it not been for the kindness and gracious support from these truly unique mentors and teachers Uta Francke, Heinz Furthmayr, Ramzi Cotran and Christopher Fletcher. Finally, there is so much I owe to these two wonderful individuals who have become very close friends, Phillip McKee and Eduardo Calonje. TB

Academic life is a complex web of mentors, colleagues and students. I have been lucky to have worked with a number of fine mentors and colleagues who strongly influenced my thinking in pathology in general and/or in dermatopathology specifically: Chris Fletcher, Scott Granter, George Murphy, Ramzi Cotran (deceased), Chris Crum, Bill Welch, Rob Odze, Jon Aster, Felix Brown (deceased), Jason Hornick, John Iafrate, Marcus Bosenberg, Jonathan Fletcher, Marty Mihm, Lyn Duncan, Steve Tahan, Steve Lyle, Victor Prieto, Harry Evans, Sharon Weiss, Bogdan Czerniak, Frasier Symmans, Ken Aldape, Russell Broaddus, Greg Fuller, Mike Davies, Jon Reed, John Goldblum, David Berman, Vinay Kumar, Marc Ladanyi, Matt van de Rijn, Brian Rubin, Jesse McKenney, Steve Billings, Howard Gerber, Ron Rapini, Julia Bridge, Paula dal Cin, Andre Oliveira, Pancras Hogendoorn, Paulo Dei Tos, Andrew Folpe, Judith Bovee, Lola Lopez-Terrada, Cristina Antonescu, along with numerous others I have encountered either directly or through their writing and lecturing. This extended list testifies not only to my good fortune in meeting so many wonderful people, but also the generosity of academic pathologists as a group. I have many other friends in pathology and medicine who shall have to remain nameless due to space constraints, but this line hails that brilliant group. The other authors and editors of this present work have been a joy to work with and I have benefited much from these interactions. The Dermatopathology Section at my institution has a delightful combination of great people and fascinating diagnostic material. My former Chairman of Pathology, Janet Bruner, was enthusiastic and supportive of this project from our first conversation regarding it. Another group of colleagues including Ralph Pollock, Dina Lev and the entire Sarcoma Research Center have done more than their share to help me balance the demands of clinical work, research, grants, papers and this book. The talented staff at Elsevier provided invaluable support throughout this project. Last, but certainly not least, I am indebted to my trainees. On a daily basis, they remind me of the marvels of what we do, ask difficult and challenging questions, prompt re-examination of assumptions, expose biases, and force clarity and reproducibility in diagnostic criteria; may we all retain these characteristics of motivated students throughout our career. For all of this, I am humbled and grateful. AL

Dedications To my wife Claudia who always gives without expecting anything in return. To my children Mateo and Isabella and to the memory of my parents Julio and Alicia both of whom passed away while this edition was in production. EC To Anne, Yaelle, Sanja and Walter. TB I am assured that my two beautiful children, Elliott and Abigail, have no memories that predate me working on this book. I hope that this example of what fascination with a subject, continued application to a task, and working as a disciplined team can accomplish will be a small, but meaningful substitution for the time designated to this endeavor. My wife, Victoria, has been ever supportive in every way despite having an extremely busy and demanding career in law as has been my mother-in-law Sara. My parents, Joe and Glenda, always allowed me the freedom to pursue my own interests and the encouragement and support to accomplish them, a wonderful gift I hope to pass on to my children as well. AL This new edition is dedicated to my wife and best friend Gracie with all my love PHM

Glossary 5-ARD AA ACE

5-a-reductase alopecia areata angiotensin converting enzyme [inhibitor] AgNORS argyrophilic nucleolar organizer regions AHNMD associated clonal hematological non-mast cell lineage disease AIDS acquired immunodeficiency syndrome AILD angioimmunoblastic lymphadenopathy with dysproteinemia ALA aminolevulinic acid ALK anaplastic lymphoma kinase ALK1 activin-like receptor kinase 1 ALM acral lentiginous melanoma AN acanthosis nigricans ANA antinuclear antibodies ANCA antineutrophil cytoplasmic antibodies API2 apoptosis inhibitor-2 ARC AIDS-related complex ATF1 activating transcription factor 1 ATLL adult T-cell leukemia/lymphoma BANS back, arm, neck and scalp [sites] BB mid borderline leprosy BCC basal cell carcinoma BCG bacille Calmette–Guérin B-FGF basic fibroblast growth factor BIDS brittle sulfur-deficient hair, intellectual impairment, decreased fertility and short stature BL borderline lepromatous leprosy BLAISE Blaschko linear acquired inflammatory skin eruption BMP bone morphogenetic protein BP bullous pemphigoid BPA bullous pemphigoid antigen BSAP B-cell-specific activator protein BSLE bullous systemic lupus erythematosus BT borderline tuberculoid leprosy C3NeF C3 nephritic factor CAD chronic actinic dermatitis cAMP cyclic adenosine 3'-5'- monophosphate c-ANCA cytoplasmic-antineutrophil cytoplasmic antibodies CDC Centers for Disease Control and Prevention CEA carcinoembryonic antigen CGRP calcitonin-gene-related polypeptide CHILD congenital hemidysplasia with ichthyosiform nevus and limb defects [syndrome] CK cytokeratin CLA cutaneous lymphocyte antigen CLL chronic lymphocytic leukemia CMG capillary morphogenesis protein CNS central nervous system CP cicatricial pemphigoid (mucous membrane pemphigoid)

CRASP complement regulator-acquiring surface

protein CREST calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasis [syndrome] CTCL cutaneous T-cell lymphoma dcSSc diffuse cutaneous systemic sclerosis DDEB dominant dystrophic epidermolysis bullosa DEB dystrophic epidermolysis bullosa DH dermatitis herpetiformis DIC disseminated intravascular coagulation DIMF direct immunofluorescence DLE discoid lupus erythematosus DNCB dinitrochlorobenzene DSAP disseminated superficial actinic porokeratosis Dsc desmocollin dsDNA double-stranded DNA Dsg desmoglein DSP disseminated superficial porokeratosis EB epidermolysis bullosa EBA epidermolysis bullosa acquisita EBS epidermolysis bullosa simplex EBS-DM epidermolysis bullosa simplex, Dowling–Meara EBS-K epidermolysis bullosa simplex, Koebner EBS-MD epidermolysis bullosa simplex with muscular dystrophy EBS-WC epidermolysis bullosa simplex, Weber–Cockayne EBV Epstein–Barr virus ECE endothelin-converting enzyme ECM extracellular membrane EDS Ehlers–Danlos syndrome EGFR endothelial growth factor receptor ELAM endothelial leukocyte adhesion molecule ELISA enzyme-linked immunosorbent assay EM electron microscopy EMA epithelial membrane antigen ENA extractable nuclear antigen ENL erythema nodosum leprosum EPPER eosinophilic, polymorphic and pruritic eruption associated with radiotherapy EPPK epidermolytic palmoplantar keratoderma EPS extracellular polysaccharide substance ESR erythrocyte sedimentation rate ETA exfoliative toxin A ETB exfoliative toxin B EV epidermodysplasia verruciformis EWSR1 Ewing’s sarcoma [proto-oncogene] FACE facial Afro-Caribbean childhood eruption FADS fetal akinesia deformation sequence

FAMMM familial atypical multiple mole

melanoma [syndrome] familial adenomatous polyposis fever, aphthous stomatitis, pharyngitis, adenitis [syndrome] FHIT fragile histidine triad FIGURE facial idiopathic granulomata with regressive evolution FISH fluorescent in situ hybridization GA granuloma annulare GABEB generalized atrophic benign epidermolysis bullosa GCDFP gross cystic disease fluid protein G-CSF granulocyte-colony stimulating factor GFAP glial fibrillary acidic protein GM-CSF granulocyte–macrophage colony stimulating factor GSE gluten-sensitive enteropathy GVHD graft-versus-host disease HA hyperandrogenism HAART highly active antiretroviral therapy HAIR-AN hyperandrogenism–insulin resistance– acanthosis nigricans [syndrome] HBV hepatitis B virus HDL high density lipoprotein HF hemorrhagic fever HG herpes gestationis HHV human herpesvirus HIT heparin-induced thrombocytopenia [syndrome] HIV human immunodeficiency virus HLA human leukocyte antigen HMFG human milk fat globulin HNPCC hereditary non-polyposis colorectal carcinoma [syndrome] HPF (hpf) high power fields HPL hyperlipoproteinemia HPV human papillomavirus HRF histamine-releasing factor HSP heat shock protein HSV herpes simplex virus HTLV human T-cell lymphotropic virus hTR telomerase RNA HUS hemolytic uremic syndrome IBIDS ichthyosis and BIDS (see BIDS above) ICAM intercellular adhesion molecule ICH indeterminate cell histiocytosis IDL intermediate density lipoproteins IEN intraepidermal neutrophilic [IgA dermatosis variant] IFAP ichthyosis follicularis–alopecia– photophobia [syndrome]; intermediate filament associated protein IFN interferon Ig immunoglobulin IIMF indirect immunofluorescence FAP FAPA

xiv

Glossary ILVEN

inflammatory linear verrucous epidermal nevus IMF immunofluorescence IP inducible protein; immunoprecipitation IR insulin resistance ISSVD International Society for the Study of Vulvovaginal Disease JEB junctional epidermolysis bullosa JEB-H junctional epidermolysis bullosa, Herlitz JEB-nH junctional epidermolysis bullosa, non-Herlitz JEB-PA junctional epidermolysis bullosa with pyloric atresia KID keratitis–ichthyosis–deafness [syndrome] KOH potassium hydroxide KPAF keratosis pilaris atrophicans facei L&H cells lymphocytic and/or histiocytic Reed–Sternberg cell variants LAD linear IgA disease LATS long-acting thyroid stimulator LCA leukocyte common antigen LCH Langerhans’ cell histiocytosis lcSSc limited cutaneous systemic sclerosis LDL low density lipoprotein LE lupus erythematosus LFA lymphocyte function-associated antigen LH–RH luteinizing hormone–releasing hormone LL lamina lucida; lepromatous leprosy LP lichen planus LPP lichen planus pemphigoides LS lichen sclerosus LYVE lymphatic vessel endothelial [hyaluronan receptor] MAC membrane attack complex MAI M. avium intracellulare MALT mucosa-associated lymphoid tissue MART-1 melanoma antigen recognized by T-cells 1 MBP myelin basic protein MC1R melanocortin-1 receptor MCGN mesangiocapillary glomerulonephritis MCP molecule chemoattractant protein M-CSF macrophage colony stimulating factor MCTD mixed connective tissue disease MDR multidrug resistance gene Mel-CAM melanoma cell adhesion molecule MEN multiple endocrine neoplasia [syndrome] MFH malignant fibrous histiocytoma MGS/ melanoma growth stimulatory GRO activity MHC major histocompatibility complex miH minor histocompatibility complex MITF microphthalmia transcription factor MMP matrix metalloproteinase MMR mismatch repair MSA muscle-specific actin MSI microsatellite instability NADH nicotine adenine dinucleotide, reduced nDNA native [double-stranded] DNA NEMO nuclear factor [NF]-kappaB gene modulator NF necrotizing fasciitis NFI neurofibromatosis type I

NFII neurofibromatosis type II NFP neurofilament protein NIH National Institutes of Health NISH non-isotopic in situ hybridization NK natural killer NL necrobiosis lipoidica NRAMP1 natural resistance-associated

macrophage protein 1 non-steroidal anti-inflammatory drugs neuron-specific enolase osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, immunodeficiency [syndrome] ORF open reading frame PAIN perianal intraepithelial neoplasia p-ANCA perinuclear-antineutrophil cytoplasmic antibodies PAPA pyogenic sterile arthritis, pyoderma gangrenosum and acne [syndrome] PAS periodic acid–Schiff PBG porphobilinogen PCNA proliferating cell nuclear antigen PCR polymerase chain reaction PDGFβ platelet-derived growth factor b PECAM platelet endothelial cell adhesion molecule PEComa perivascular epithelioid cell tumor PGL phenolic glycolipid PGP protein gene product PGWG purely granulomatous Wegener’s granulomatosis PI protease inhibitor PIBIDS photosensitivity and IBIDS (see IBIDS above) PILA papillary intralymphatic angioendothelioma PLEVA pityriasis lichenoides et varioliformis acuta PNET primitive neuroectodermal tumor POEMS polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes [syndrome] PPD purified protein derivative PPDL pure and primitive diffuse leprosy PPK palmoplantar keratoderma pRB retinoblastoma protein PSS progressive systemic sclerosis PTEN phosphatase and tensin homolog PUPPP pruritic urticarial papules and plaques of pregnancy PUVA psoralen plus ultraviolet light of A [long] wavelength r IL-2 recombinant interleukin 2 RBC red blood cell RDEB recessive dystrophic epidermolysis bullosa RDEB-HS recessive dystrophic epidermolysis bullosa, Hallopeau–Siemens RDEB- recessive dystrophic nHS epidermolysis bullosa, non-Hallopeau– Siemens RER rough endoplasmic reticulum RNP ribonucleoprotein RT-PCR reverse transcription polymerase chain reaction SA syphilitic alopecia SA1 slowly adapting type-1 [mechanoreceptor] NSAIDs NSE OL-EDA- ID

SALE summertime actinic lichenoid eruption SALT skin-associated lymphoid tissue SAPHO synovitis, acne, pustulosis, hyperostosis, SCC SCH SCID SCLE scRNP SEA SEB Shh SIBIDS SIL SLE SLL SMA snRNP SPD SPRRs SPTL

osteitis [syndrome] squamous cell carcinoma squamous cell hyperplasia severe combined immunodeficiency subacute cutaneous lupus erythematosus small cytoplasmic ribonuclear protein staphylococcal enterotoxin A staphylococcal enterotoxin B Sonic Hedgehog osteosclerosis and IBIDS (see IBIDS above) squamous intraepithelial lesion systemic lupus erythematosus small lymphocytic lymphoma smooth muscle actin small nuclear ribonuclear protein subcorneal pustular dermatosis small proline rich proteins/cornifins subcutaneous panniculitis-like T-cell lymphoma signal recognition particle single-stranded DNA staphylococcal scalded skin syndrome sexually transmitted disease sub-lamina densa T-cell receptor toxic epidermal necrolysis transcription/DNA repair factor IIH transforming growth factor triethylene thiophosphoramide

SRP ssDNA SSSS STD sub-LD TCR TEN TFIIH TGF thio- TEPA TIMP tissue inhibitor of metalloproteinase TNF tumor necrosis factor TORCH toxoplasmosis, other infections, rubella,

cytomegalovirus and herpes simplex [syndrome] TRAPS tumor necrosis factor receptorassociated periodic syndrome TSST toxic shock syndrome toxin TT tuberculoid leprosy tTA tetracycline transactivator [transcription factor] TTF-1 thyroid-transcription factor 1 tTG tissue transglutaminase TTP thrombotic thrombocytopenic purpura UPS undifferentiated pleomorphic sarcoma URO uroporphyrinogen URO-D uroporphyrinogen decarboxylase URR upstream regulatory region UV ultraviolet UVA ultraviolet A UVB ultraviolet B UVL ultraviolet light VCAM vascular cell adhesion molecule VEGF vascular endothelial growth factor VEGFR vascular endothelial growth factor receptor VIN vulval intraepithelial neoplasia VIP vasoactive intestinal peptide VLDL very low density lipoprotein VZV varicella-zoster virus wrfr wrinkle free [mouse model] XP xeroderma pigmentosum

See www.expertconsult.com

for references and additional material

The structure and function of skin John A. McGrath

Properties of skin  1

Melanocytes  10

Dermal elastic tissue  24

Normal epidermal histology  1

Merkel cells  12

Ground substance  26

Regional variations in skin anatomy  2

Intercellular junctions  13

Fibroblast biology  26

Skin development  2

Pilosebaceous units  15

Keratinocyte biology  5

Eccrine glands  17

Cutaneous blood vessels and lymphatics  27

Epidermal stem cells  6

Apocrine glands  19

Skin barrier  8

Dermal–epidermal junction  21

Skin immunity  9

Dermal collagen  22

Skin is a double-layered membrane covering the exterior of the body and consists of a stratified cellular epidermis and an underlying dermis of connective tissue. In adults, the skin weighs over 5 kg and covers a surface area approaching 2 m2. The epidermis is mainly composed of keratinocytes and is typically 0.05–0.1 mm in thickness. The dermis contains collagen, elastic tissue and ground substance and is of variable thickness, from 0.5 mm on the eyelid or scrotum to more than 5 mm on the back (Fig. 1.1). The dermis is subdivided into a more superficial component (the papillary dermis) which is bounded inferiorly by the superficial vascular plexus and an underlying much thicker reticular dermis. Below the dermis is a layer of subcutaneous fat which is separated from the rest of the body by a vestigial layer of striated muscle.

Properties of skin A key role of skin is to provide a mechanical barrier against the external environment. The cornified cell envelope and the stratum corneum restrict water loss from the skin while keratinocyte-derived endogenous antibiotics (defensins and cathelicidins) provide an innate immune defense against bacteria, viruses and fungi. The epidermis also contains a network of about 2 × 109 Langerhans cells which serve as sentinel cells whose prime function is to survey the epidermal environment and to initiate immune responses against microbial threats. Melanin, which is mostly found in basal keratinocytes, provides some protection against DNA damage from ultraviolet radiation. An important function of skin is thermoregulation. Vasodilatation or ­vasoconstriction of the blood vessels in the deep or superficial plexuses helps regulate heat loss. Eccrine sweat glands are found at all skin sites and are present in densities of 100–600/cm2; they play a role in heat control and aspects of metabolism. Secretions from apocrine sweat glands contribute to body odor. Skin lubrication and waterproofing is provided by sebum secreted from sebaceous glands. Subcutaneous fat has important roles in cushioning trauma as well as providing insulation and a calorie reserve. Fat also has an endocrine function and contributes to tissue remodeling and phagocytosis. Nails provide protection to the ends of the fingers and toes as well as being important in pinching and prising objects. Hair may have important social and psychological value. Skin also has a key function in synthesizing various metabolic products, such as vitamin D.

Chapter

1

Nervous system of the skin  28 Subcutaneous fat  30

Normal epidermal histology Although the basic structure is relatively constant at various skin sites, there are often clear differences which enable one to determine the site of origin. The epidermis consists of four clearly defined layers or strata: • Basal cell layer (stratum basale) • Prickle cell layer (stratum spinosum) • Granular cell layer (stratum granulosum) • Keratin layer (stratum corneum) An eosinophilic acellular layer known as the stratum lucidum is sometimes seen in skin from the palms and soles (Fig. 1.2). Basal cells are cuboidal or columnar with a large nucleus typically containing a conspicuous nucleolus. Small numbers of mitoses may be evident. Clear cells are also present in the basal layer of the epidermis; these represent melanocytes. Cells with clear cytoplasm seen in the stratum spinosum represent Langerhans cells. Very occasional Merkel cells may also be present but these are not easily identified in hematoxylin and eosin stained sections. Histologically, prickle cells are polygonal in outline, have abundant eosinophilic cytoplasm and oval vesicular nuclei, often with conspicuous nucleoli. Keratohyalin granules typify the granular cell layer (Fig. 1.3). Further maturation leads to loss of nuclei and flattening of the keratinocytes to form the plates of the keratin layer (stratum corneum). Adjacent cells are united at their free borders by intercellular bridges (prickles), which are most clearly identifiable in the prickle cell layer and in disease states of the skin where there is marked intercellular edema (spongiosis) (Fig. 1.4). Toker cells represent an additional clear cell population, which may be found in nipple epidermis of both sexes in up to 10% of the population.1 The cells are large, polygonal or oval and have abundant pale staining or clear cytoplasm with vesicular nuclei often containing prominent, albeit small, nucleoli. The cytoplasm is mucicarmine and PAS negative.1 The cells may be distributed singly but more often they are found as small clusters, not uncommonly forming single layered ductules.1 They are located along the basal layer of the epidermis or suprabasally and are also sometimes seen within the epithelium of the terminal lactiferous duct. Toker cells are of particular importance as they may be mistaken by the unwary as Paget cells. They are thought to be the source of mammary Paget's disease in those exceptional cases where an underlying ductal carcinoma is

2

The structure and function of skin

Fig. 1.1 Skin from forearm: there is a fairly thin epidermis. Compare the thickness of the dermis with that from the back (see Fig. 1.5).

Fig. 1.4 Spongiosis: the intercellular bridges (prickles) are stretched and more visible in this biopsy from a patient with acute eczema.

absent.2 Toker cells express CK7, AE1, CAM 5.2, epithelial membrane antigen (EMA), cerbB2, estrogen and progesterone receptors.3,4 They do not express p53 or CD138. Carcinoembryonic antigen (CEA) may also be present albeit weakly.4 Paget's cells by way of contrast are often negative for estrogen and progesterone receptors and are p53 and CD138 positive.4

Regional variations in skin anatomy

Fig. 1.2 Skin from palm: note the eosinophilic stratum lucidum clearly separating the granular cell layer from the overlying stratum corneum.

There are two main kinds of human skin: glabrous skin (nonhairy skin) and hair-bearing skin. Glabrous skin is found on the palms and soles. It has a grooved surface with alternating ridges and sulci giving rise to the dermatoglyphics (fingerprints). Glabrous skin has a compact, thick stratum ­corneum, and contains encapsulated sense organs within the dermis but no hair follicles or sebaceous glands. In contrast, hair-bearing skin has both hair follicles and sebaceous glands but lacks encapsulated sense organs. Hair follicle size, structure and density can vary between different body sites. For example, the scalp has large hair follicles that may extend into subcutaneous fat whereas the forehead has only small vellus hair-producing follicles although sebaceous glands are large. The number of hair follicles does not alter until middle life but there is a changing balance between vellus and terminal hairs throughout life. In hair-bearing sites, such as the axilla, there are apocrine glands in addition to the eccrine sweat glands. Sebaceous glands are active in the newborn, and from puberty onwards, and the relative activity modifies the composition of the skin surface lipids. The structure of the dermal–epidermal junction also shows regional variations in the number of hemidesmosomal-anchoring filament complexes (more in the leg than the arm). In the dermis, the arrangement and size of elastic fibers ­varies from very large fibers in perianal skin to almost no fibers in the scrotum. Marked variation in the cutaneous blood supply is found between areas of distensible skin such as the eyelid and more rigid areas such as the fingertips. Regional variation in skin structure is illustrated in Figures 1.5–1.20.

Skin development Fig. 1.3 Skin from palm: there is a conspicuous granular cell layer.

Two major embryological elements juxtapose to form skin. These comprise the prospective epidermis that originates from a surface area of the early ­gastrula, and the prospective mesoderm that comes into contact with the

Skin development

Fig. 1.7 Fig. 1.5 Skin from the lower back: at this site the dermis is very thick and is characterized by broad parallel fascicles of collagen.

Skin from the sole of the foot: this is typified by a thickened stratum corneum and prominent epidermal ridge pattern. The dermis is relatively dense at this site. Similar features are seen on the palms and ventral aspects of the fingers and toes.

Fig. 1.8 Skin from the scalp: there are numerous terminal hair follicles with many of the bulbs in the subcutaneous fat.

Fig. 1.6 Skin of the nose: there are conspicuous sebaceous glands: at this site, they often drain directly onto the skin surface. These appearances should not be confused with that of sebaceous hyperplasia.

inner surface of the epidermis during gastrulation. The mesoderm generates the dermis and is involved in the differentiation of epidermal structures such as hair follicles.1 Melanocytes are derived from the neural crest. After gastrulation, there is a single layer of neuroectoderm on the embryo surface: this layer will go on to form the nervous system or the skin epithelium, depending on the molecular signals (e.g., fibroblast growth factors or bone morphogenic proteins) it receives.2 The embryonic epidermis consists of a single layer of multipotent epithelial cells which is covered by a special layer known as periderm that is unique to mammals. Periderm provides some protection to the newly forming skin as well as exchange of material with the amniotic fluid. The embryonic dermis is at first very cellular and at 6–14 weeks three types of cell are present: stellate cells, phagocytic macrophages and granule­secretory cells, either melanoblasts or mast cells (Fig. 1.21). From weeks

14  to 21, fibroblasts are numerous and active, and perineural cells, pericytes, melanoblasts, Merkel cells and mast cells can be individually identified. Hair follicles and nails are evident at 9 weeks. Sweat glands are also noted at 9 weeks on the palms and the soles.3 Sweat glands at other sites and sebaceous glands appear at 15 weeks. Touch pads become recognizable on the fingers and toes by the sixth week and development is maximal by the 15th week. The earliest development of hair occurs at about 9 weeks in the regions of the eyebrow, upper lip and chin. Sebaceous glands first appear as hemispherical protuberances on the posterior surfaces of the hair pegs and become differentiated at 13–15 weeks. Langerhans cells are derived from the monocyte– macrophage–histiocyte lineage and enter the epidermis at about 12 weeks. Merkel cells appear in the glabrous skin of the fingertips, lip, gingiva and nail bed, and in several other regions, around 16 weeks. Although some cells of the dermis may migrate from the dermatome (venterolateral part of the somite) and take part in the formation of the skin, most of the dermis is formed by ­mesenchymal cells that migrate from other mesodermal areas.4 These ­mesenchymal cells give rise to the whole range of blood and ­connective

3

4

The structure and function of skin

Fig. 1.9

Fig. 1.11

Fig. 1.12

Skin from axilla: apocrine glands as seen at the bottom of the field are typical for this site.

Skin from the outer aspect of the lip: note the keratinizing stratified squamous epithelium and skeletal muscle fibers.

Mucosal aspect of lip: at this site the squamous epithelium does not normally keratinize. Minor salivary glands as shown in this field are not uncommonly present.

Fig. 1.13 Mucosal aspect of lip: close-up view of the salivary gland shown in Figure 1.12.

Fig. 1.10 Skin of areola: there are abundant smooth muscle fibers: lactiferous ducts may also sometimes be present (not shown).

Fig. 1.14 Mucosal aspect of lip: the cytoplasm of the keratinocytes is often rich in glycogen.

Keratinocyte biology

A

Fig. 1.15 Skin from the ear: note the vellus hairs, and a fairly thin dermis overlying the auricular cartilage.

B

Fig. 1.16 (A, B) Vulval vestibule: at this site the stratum corneum is absent and there is no granular cell layer. The suprabasal keratinocytes have clear cytoplasm due to abundant glycogen and revealed by the periodic ­ acid-Schiff reaction.

Fig. 1.17 Variation of skin: sample of skin from the forearm of a 92-year-old female. Note the epidermal thinning and dermal atrophy.

tissue cells, including the fibroblasts and mast cells of the dermis and the fat cells of the subcutis. In the second month, the dermis and subcutis are not discernible as distinct skin layers but collagen fibers are evident in the dermis by the end of the third month. Later, the papillary and reticular layers become established and, at the fifth month, the connective tissue sheaths are formed around the hair follicles. Elastic fibers are first detectable at 22 weeks.

Keratinocyte biology The cytoskeleton of all mammalian cells, including epidermal keratinocytes, comprises actin containing microfilaments ≈7 nm in diameter, tubulin containing microtubules 20–25 nm in diameter, and filaments of intermediate size,

Fig. 1.18 Stasis change: skin from the lower leg. Although abnormal, the presence of stasis change characterized in this example by papillary dermal lobular capillary proliferation is a very common feature at this site.

7–10 nm in diameter, known as intermediate filaments. There are six types of intermediate filaments of which keratins are the filaments in keratinocytes (Figs 1.22, 1.23). The human genome possesses 54 functional keratin genes located in two compact gene clusters, as well as many nonfunctional pseudogenes, scattered around the genome.1 Keratin genes are very specific in their expression patterns. Each one of the many highly specialized epithelial tissues has its own profile of keratins. Hair and nails express modified keratins containing large amounts of cysteine which forms numerous chemical cross-links to further strengthen the cytoskeleton. The genes encoding the keratins fall into two gene families: type I (basic) and type II (acidic) and there is coexpression of particular acidic–basic pairs in a cell- and tissue-­specific manner. Keratin heterodimers are assembled into protofibrils and ­protofilaments by

5

6

The structure and function of skin

Fig. 1.21 A

Fig. 1.19 Stasis change: high-power view.

B

(A, B)Development of normal human fetal skin: (A) at 7 week's gestation, the epidermis is only two cell layers thick but the dermis appears very cellular; (B) at 19 weeks gestation the skin has an outer layer specific to mammals known as periderm. This contains surface blebs which are full of glycogen (G). Also present is a hair peg (H). This downgrowth of the epidermis is the first histologic step in generating a hair follicle. Bar = 25 μm.

Fig. 1.20 Variation of normal skin: in dark-skinned races, the presence of intense basal cell melanin pigmentation is a normal histological finding.

Fig. 1.22 an antiparallel stagger of some complexity. Simple epithelia are characterized by the keratin pair K8/K18, and the stratified squamous epithelia by K5/K14. Suprabasally, keratins K1/K10 are characteristic of epidermal differentiation (Fig. 1.24). K15 is expressed in some interfollicular basal keratinocytes as well as keratinocytes within the hair-follicle bulge region at the site of pluripotential stem cells. K9 and K2e expression is site restricted in skin: K9 to palmoplantar epidermis and K2e to superficial interfollicular epidermis. Apart from their structural properties, keratins may also have direct roles in cell signaling, the stress response and apoptosis.2 In epidermal hyperproliferation, as in wound healing and psoriasis, expression of suprabasal keratins K6/K16/K17 is rapidly induced. Currently, 21 of the 54 known keratin genes have been linked to ­monogenic genetic disorders, and some have been implicated in more complex traits, such as idiopathic liver disease or inflammatory bowel disease.3,4 The first

Cytoskeleton of a keratinocyte: the major intermediate filament of a keratinocyte is keratin, highlighted in green.

genetic disorder of keratin to be described was epidermolysis bullosa simplex, which involves mutations in the genes encoding K5 or K14 (Fig. 1.25). About half of the keratin genes are expressed in the hair follicle, and mutations in these genes may underlie cases of monilethrix as well as hair and nail ectodermal dysplasias.5

Epidermal stem cells To maintain, repair and regenerate itself, the skin contains stem cells which reside in the bulge area of hair follicles, the basal layer of interfollicular epidermis and the base of sebaceous glands (Fig. 1.26).1 Stem cells are able to

Epidermal stem cells

Fig. 1.25 Fig. 1.23 Mid-prickle cell layer of normal epidermis: the abundant keratin filaments (tonofibrils) form a distinct interlacing lattice within the cytoplasm of keratinocytes.

Clinicopathological consequences of mutations in the keratin 14 gene: (left) typical appearances of Dowling-Meara epidermolysis bullosa simplex which results from heterozygous missense mutations in the KRT14 gene; (right) ultrastructurally, there is keratin filament disruption and clumping as well as a plane of blistering just above the dermal–epidermal (DE) junction.

Epidermis

Sebocyte stem cells

Epidermal stem cells

Sebaceous gland

Bulge stem cells

Hair shaft

Fig. 1.24 Normal skin: suprabasal keratinocytes preferentially express keratins 1 and 10 as shown in this picture. Anti-Keratin1 antibody courtesy of I.M. Leigh, MD, Royal London Hospital Trust, London, UK.

Outer root sheath

Inner root sheath

self-renew as well as give rise to differentiating cells.2 It is not clear, however, whether every basal keratinocyte or only a proportion of cells is a stem cell.3 Two possible hypotheses have emerged. One theory divides basal keratinocytes into epidermal proliferation units, which comprise one self-renewing stem cell and about 10 tightly packed transient amplifying cells, each of which is capable of dividing several times and then exiting the basal layer to undergo terminal differentiation.4 This unit gives rise to a column of larger and flatter cells that culminates in a single hexagonal surface. The process of division of basal cells in this model is viewed as a symmetrical process in which equal daughter cells are generated with the basal cells progressively reducing their adhesiveness to the underlying epidermal basement membrane, delaminating and committing to terminal differentiation. The alternative theory is that some basal cells (perhaps up to 70% of cells) can undergo asymmetrical cell division, shifting their spindle orientation from lateral to perpendicular.5 Asymmetrical cell divisions provide a means of maintaining one proliferative daughter while the other daughter cell is committed to terminal differentiation. Asymmetrical cell divisions, therefore, can bypass the need for transient amplifying cells.

Dermal papilla

Fig. 1.26 Diagrammatic representation of the location of stem cells in human skin: stem cells are located within the bulge area of hair follicles (where the arrector pili muscle attaches) as well as in the basal keratinocyte layer in the interfollicular epidermis and at the base of sebaceous glands. Stem cells from the bulge area are capable of regenerating all parts of the pilosebaceous unit and interfollicular skin.

Hair follicle stem cells are found in the bulge regions below the sebaceous glands. These stem cells are slow cycling and express the cell surface molecules CD34 and VdR as well as the transcription factors TCF3, Sox9, Lhx2 and NFATc1 (Fig. 1.27). The bulge area stem cells generate cells of the outer root sheath, which drive the highly proliferative matrix cells next to the mesenchymal papillae. After proliferating, matrix cells differentiate to form the hair channel, the inner root sheath and the hair shaft. Hair follicle stem cells

7

8

The structure and function of skin Markers of interfollicular stem cells α6 integrin β1 integrin p63 Markers of hair follicle bulge stem cells DNA label retention CD34 NFATc1 Vitamin D receptor TCF3 Fox9 Lhx2 Markers of sebocyte stem cells Blimp 1

Fig. 1.27 Molecular markers of stem cells in the skin.

can also differentiate into sebocytes and interfollicular epidermis. Despite this multipotency, however, the follicle stem cells only function in pilosebaceous unit homeostasis and do not contribute to interfollicular epidermis unless the skin is wounded.6 Stem cells are also found in the base of sebaceous glands: the progeny of these cells differentiate into lipid-filled sebocytes. Apart from stem cells in the hair follicles, sebaceous glands and interfollicular epidermis, other cells in the dermis and subcutis may have stem cells properties. These include cells that have been termed skin-derived precursors (SKPs), which can differentiate into both neural and mesodermal progeny.7 In addition, a subset of dermal fibroblasts can have adipogenic, osteogenic, chondrogenic, neurogenic and hepatogenic differentiation potential.8

Skin barrier A major function of the epidermis is to form a barrier against the external environment. To achieve this, terminal differentiation of keratinocytes results in formation of the cornified cell envelope. This physical barrier is rendered highly insoluble by the formation of glutamyl-lysyl isodipeptide bonds between envelope proteins, catalyzed by transglutaminases.1 Several different proteins contribute to construction of the cornified cell envelope, including involucrin, and the family of small proline-rich proteins (SPR1) including cornifin or SPR1 and pancornulins. Other envelope proteins include SKALP/elafin and keratolinin/cystatin. Some precursors of the cornified envelope are delivered by granules: small, smooth, sulfur-rich L granules contain the cysteine-rich protein loricrin, and accumulate in the stratum granulosum.2 Loricrin is the major component of the cornified envelope. Profilaggrin in F granules may make a minor contribution to the envelope. Membrane-associated proteins that contribute to the cornified envelope include the plakin family members, periplakin, envoplakin, epiplakin, desmoplakin as well as plectin. Formation of the cornified cell envelope is triggered by a rise in intracellular calcium levels.3 This leads to cross-link formation between plakins and involucrin catalyzed by transglutaminases. Other desmosomal proteins are then also cross-linked, forming a scaffold along the entire inner surface of the plasma membrane. Ceramides from the secreted contents of lamellar bodies are then esterified onto glutamine residues of the scaffold proteins. The cornified cell envelope is reinforced by the addition of a variable amount of SPRs, repetin, trichohyalin, cystostatin α, elafin and LEP/XP-5 (skin-specific protein). Although most desmosomal components are degraded, keratin intermediate filaments (mostly K1, K10 and K2e) may be cross-linked to desmoplakin and envoplakin remnants. In the upper stratum spinosum and stratum granulosum lipid is synthesized and packaged into lamellated membrane-bound organelles known as membrane-coating granules, lamellar granules or Odland bodies (Fig. 1.28).4 They are found adjacent to the cell membrane with alternating thick and thin dense lines separated by lighter lamellae of equal width, consistent with packing of flattened discs within a membrane boundary. These granules contain phospholipids, glycolipids and free sterols and move towards the plasma membrane as the cells move through the granular layer where they cluster at

Fig. 1.28 Granular cell layer: note the keratohyalin and membrane coating granules (arrowed).

the cell membrane. They fuse with the plasma membrane, dispersing their contents into the intercellular space. Polar lipids from the lamellar granules are remodeled into neutral lipids in the intercellular space between corneocytes, thereby contributing to the barrier. Within the granular layer of the epidermis, the main keratinocyte proteins are keratin and filaggrin, which together contribute approximately 80–90% of the mass of the epidermis and are ultrastructurally represented by the keratohyalin granules (Fig. 1.29). Filaggrin is initially synthesized as profilaggrin, a ≈500-kDa highly phosphorylated, histidine-rich polypeptide. During the post-translational processing of profilaggrin, the individual filaggrin polypeptides, each ≈35 kD, are proteolytically released. These are then dephosphorylated, a process that assists keratin filament aggregation and explains the origin of the name ‘filaggrin’ (filament aggregating ­protein) (Fig. 1.30). Typically, there are 10 highly homologous filaggrin units, although the number of filaggrin repeat units is variable and genetically determined, with

Fig. 1.29 Stratum corneum: keratohyalin granules are present just beneath the keratin lamellae.

Skin immunity Epidermal barrier: mechanical strength; prevent water loss; restrict allergen penetration Stratum corneum

Keratohyalin granules composed of profilaggrin

Micro-organisms

External allergens Stratum corneum

Filaggrin deaminated and degraded

Fig. 1.32 Granular layer

Granular layer

Upper spinous layer Inflammatory cells

Spinous layer

Constitutive anti-microbial peptides (psoriasin) Inducible anti-microbial peptides (β-defensins, RNASE7, LL-37) Pro-inflammatory cytokines (IL-1, TNFα, etc)

Basal layer Dermalepidermal junction

Profilaggrin cleaved into 10-12 filaggrin peptides

Keratinocyte Langerhans cell Melanocyte

Fig. 1.30 Function of filaggrin in human skin: this is the major component of keratohyalin granules. In the granular layer profilaggrin is cleaved into filaggrin peptides subsequent deamination and degradation provides the skin with mechanical strength and restricts transepidermal water loss. Filaggrin also prevents allergen penetration. In the absence of filaggrin, for example caused by common mutations in the filaggrin gene, external allergens may penetrate the epidermis and encounter Langerhans cells. This may lead to the development of atopic dermatitis as well as other atopic manifestations and systemic allergies.

duplications of filaggrin repeat units 8 and/or 10 in some individuals. Fewer filaggrin repeats leads to dryer skin. Loss-of-function mutations in filaggrin are very common, occurring in up to 10% of the European population. These mutations lead to reduced or absent keratohyalin granules, and are the cause of ichthyosis vulgaris as well as constituting a major risk factor for atopic dermatitis (Fig. 1.31).5

Skin immunity Skin possesses both innate and adaptive immune responses to defend against microbial pathogens and thereby prevent infection. One of the primary mechanisms is the synthesis, expression and release of antimicrobial peptides (Fig. 1.32).1 There are more than 20 antimicrobial peptides in the skin, including cathelicidins, β-defensins, substance P, RANTES, RNase 2, 3, and 7, and S100A7. Many of these peptides have antimicrobial action against bacteria, viruses, and fungi. In the stratum corneum there is an effective chemical barrier maintained by the expression of S100A7 (psoriasin).2 This antimicrobial substance is very effective at killing Escherichia coli. Subjacent to this in the skin there is another class of antimicrobial peptides, such as RNASE7, which is effective against a broad spectrum of microorganisms, especially enterococci.3 Below this in the living layers of the skin are other antimicrobial peptides including the β-defensins.4 The antimicrobial activity of most

May cause hyperlinearity of the palms

Occur in up to 10% of the population

Are not associated with psoriasis or non-atopic asthma

Are the cause of ichthyosis vulgaris

Are a major risk factor for atopic dermatitis

Loss-of function mutations in the FLG gene

Can modify clinical expression of other diseases

Are implicated in development of systemic allergies

Innate immunity in the skin: the physical barrier is complemented by an innate immune response that targets bacteria, viruses and fungi and prevents them from invading the skin. These peptides include constitutive and inducible substances against a broad range of organisms.

peptides occurs as a result of unique structural characteristics that enable them to disrupt the microbial cell membrane while leaving human cell membranes intact. The antimicrobial peptides can have immunostimulatory and immunomodulatory capacities as well as being chemotactic for distinct subpopulations of leukocytes and other inflammatory cells.5 Some peptides have additional roles in signaling host responses through chemotactic, angiogenic, growth factor and immunosuppressive activity. These peptides are known as alarmins.6 Alarmins may also stimulate parts of the host defense system, such as barrier repair and recruitment of inflammatory cells. Skin immunity is also provided by a distinct population of antigen presenting cells in the epidermis known as Langerhans cells (Fig. 1.33). These are ­dendritic cells that were first described by Langerhans, who demonstrated their existence in human epidermis by staining with gold chloride. Without stimulation, Langerhans cells exhibit a unique motion termed ‘Dendrite Surveillance Extension And Retraction Cycling Habitude (dSEARCH)’.7 This is characterized by rhythmic extension and retraction of dendritic processes between intercellular spaces. When exposed to antigen, there is greater dSEARCH motion and also direct cell-to-cell contact between adjacent Langerhans cells which function as intraepidermal macrophages, phagocytosing antigens among keratinocytes. Langerhans cells then leave the epidermis and migrate via lymphatics to regional lymph nodes. In the paracortical region of lymph nodes the Langerhans cell expresses protein on its surface to present to a T lymphocyte that can then undergo clonal proliferation. Langerhans cells, in combination with macrophages and dermal dendrocytes, represent the skin's mononuclear phagocyte system.8 By electron microscopy, Langerhans cells have a lobulated nucleus, a relatively clear cytoplasm and well-developed endoplasmic reticulum, Golgi complex and lysosomes. They also possess characteristic granules which are rod or racquet-shaped (Fig. 1.34). These ‘Birbeck’ granules represent subdomains of the endosomal recycling compartment and form at sites where the protein Langerin accumulates. Besides antigen detection and the processing role by epidermal Langerhans cells, cutaneous immune surveillance is also carried out in the dermis by an array of macrophages, T cells and dendritic cells. These immune sentinel and effector cells can provide rapid and efficient immunologic back-up to restore tissue homeostasis if the epidermis is breached. The dermis contains a very

Are associated with atopic dermatitis persisting into adulthood

Are a major risk factor for asthma with atopic dermatitis

Are associated with increased severity of atopic asthma

Fig. 1.31 Functional consequences of loss-of-function mutations in the filaggrin gene, which can affect up to 10% of the people in some populations.

9

10

The structure and function of skin large number of resident T cells. Indeed, there are approximately 2 × 1010 resident T cells, which is twice the number of T cells in the circulating blood. Dermal dendritic cells may also have potent antigen-presenting capacities or the potential to develop into CD1a-positive and Langerin-positive cells. Dermal immune sentinels are capable of acquiring an antigen-presenting mode, a migratory mode or a tissue resident phagocytic mode.9

Melanocytes

Fig. 1.33 Langerhans cells express S-100 protein: note the conspicuous dendritic processes.

Melanocytes are pigment-producing cells and are found in the skin, inner ear, choroid and iris of the eye. In skin, melanocytes are located in the basal keratinocyte layer. The ratio of melanocytes to basal cells ranges from approximately 1:4 on the cheek to 1:10 on the limbs. They appear as vacuolated cells in hematoxylin and eosin stained sections (Fig. 1.35). Ultrastructurally, melanocytes have pale cytoplasm and are devoid of tonofilaments and ­desmosomes (Fig. 1.36). They are easily recognized by their specific cytoplasmic organelles (melanosomes) which are derived from the smooth endoplasmic reticulum. Melanosomes are believed to represent a specialized variant of lysosome (Fig. 1.37). The function of melanocytes is the production of melanin, a ­pigment that varies in color from yellow to brown or black and accounts for the various skin colors within and

Fig. 1.34

A

B

(A, B) Langerhans cell: (A) note the characteristic lobulated nucleus. Dendritic processes are evident, (B) typical rod forms with the characteristic trilaminar structure.

Fig. 1.35

A

B

(A, B) Normal epidermis: melanocytes are seen along the basal layer of the epidermis. The cytoplasmic vacuolation is a fixation artifact; (B) melanocytes can be highlighted with S100-protein immunohistochemistry. Note the dendritic processes.

Melanocytes

Fig. 1.36 Normal melanocyte: it has abundant pale cytoplasm and scattered solitary melanosomes. Note the absence of tonofibrils and desmosomes.

Melanin is transferred from melanocytes in melanosomes to neighboring keratinocytes in the epidermis and into the growing shaft in hair follicles and can be identified by silver techniques such as the Masson-Fontana reaction (Fig. 1.38). Transport occurs along the dendritic processes of the melanocytes and the melanosomes are engulfed as membrane-bound (lysosomal) single or compound melanosomes by a group of adjacent largely basally located keratinocytes (epidermal melanin unit) where they are typically seen in an umbrella-like distribution over the outer aspect of the nucleus (Fig. 1.39). A compound melanosome typically contains from three to six single melanosomes. In heavily pigmented skin and dark hair, melanosomes remain solitary and are longer than those seen in melanogenesis in paler races. Other cells that may contain compound melanosomes include macrophages (melanophages), melanoma cells and, occasionally, Langerhans cells, the other type of epidermal dendritic cell. Macromelanosomes (giant melanosomes) measure several microns in diameter and therefore are readily visible in hematoxylin and eosin stained sections (Fig. 1.40). They may be encountered in normal skin, in lentigines, dysplastic nevi, Spitz nevi, in the café-au-lait macules of neurofibromatosis and in albinism. A key protein involved in melanosome assembly is NCKX5, encoded by the gene SLC24A5.4 Loss of expression of this gene in mice results in marked changes in skin color with loss of pigment.

Fig. 1.38 Fig. 1.37 Melanosome: note the typical striated internal structure.

among races. Melanin protects the mitotically active basal epidermal cells from the injurious effects of ultraviolet light, which accounts for individuals with less pigmentation (fair-haired and light-skinned) having a much greater risk of sunburn and developing cutaneous malignancies (squamous cell and basal cell carcinomas, and melanoma). The mechanism involves absorbing or scattering ultraviolet radiation and/or its photoproducts. Other functions of melanin include control of vitamin D3 synthesis and local thermoregulation. In skin and hair, two forms of melanin pigment are produced; eumelanin and pheomelanin. Eumelanin is a brown or black pigment and is synthesized from tyrosine; it is particularly found in dark-colored races, whereas, pheomelanin has a yellow-red color and is synthesized from tyrosine and cysteine; it predominates in Caucasian skin. Melanocytes also possess melanocyte-specific receptors including melanocortin-1 (MC1R) and melatonin receptors.1 The activation or the inhibition of melanocyte-specific receptors can augment normal melanocyte function, skin color, and photoprotection. Moreover, receptor polymorphisms are known to underlie red hair phenotypes.2 Hair graying reflects abnormalities in melanocyte signaling. Notably, Notch transcription factor signaling in melanocytes is essential for the maintenance of proper hair pigmentation, including ­regeneration of the melanocyte population during hair follicle cycling.3

Normal epidermis: this section of black skin has been stained by the Masson– Fontana reaction for melanin. Note the heavy pigmentation, which is present in both melanocytes and keratinocytes.

Fig. 1.39 Melanin pigment: actinically damaged skin. Note that the melanin pigment is located in a ‘cap’ overlying the keratinocyte nuclei.

11

12

The structure and function of skin

Fig. 1.41 Fig. 1.40 Macromelanosomes: note the large spherical melanosomes in the cytoplasm of the melanocytes.

Merkel cells: separated human epidermis showing a striking linear arrangement (troma-1 antibody). By courtesy of J.P. Lacour, MD, and J.P. Ortonne, MD, University of Nice, France.

Mature melanosomes of eumelanin are ellipsoidal in shape, while pheomelanin-producing melanosomes are spherical.

Merkel cells Merkel cells are postmitotic cells scattered throughout the epidermis of vertebrates and constitute 0.2–0.5% of epidermal cells.1 Merkel cells represent part of the affector limb in cutaneous slowly adapting type-1 (SA1) mechanoreceptors and are therefore particularly concerned with touch sensation. They are located amongst basal keratinocytes and are mainly found in hairy skin, tactile areas of glabrous skin, taste buds, the anal canal, labial ­epithelium and eccrine sweat glands. In glabrous skin, the density of Merkel cells is ≈50 per mm2. Sun-exposed skin may contain twice as many Merkel cells as nonsun-exposed skin.2 Numerous Merkel cells can be found in actinic keratoses.3 Merkel cells cannot be recognized in conventional hematoxylin and eosin stained sections. Rather, immunocytochemistry, particularly using antikeratin antibodies, or electron microscopy, is necessary for their identification (Figs 1.41 and 1.42). Ultrastructurally, Merkel cells appear oval with a long axis of ≈15 μm orientated parallel to the basement membrane (Fig. 1.43). They also have a large bilobed nucleus and clear cytoplasm which reflects a relative scarcity of intracellular organelles. Merkel cells contain numerous neurosecretory granules, each 50 nm to 160 nm across; these are found opposing the junctions with the sensory nerve ending (Fig. 1.44). Merkel cells contain keratin filaments, particularly keratin filament types 8, 18, 19, and 20, which are characteristic of simple epithelium and fetal epidermis. Immunocytochemically, Merkel cells also express neuropeptides including synaptophysin, vasoactive intestinal peptide (VIP) and calcitonin gene-related polypeptide (CGRP).4,5 They contain neuron-specific proteins including neuron-specific enolase (NSE) and protein gene product (PGP) 9.5.6 In addition, Merkel cells express desmosomal proteins, membranous neural cell adhesion molecule and nerve growth factor receptor.7–9 Merkel cells show a positive uranaffin reaction.10 Merkel cells form close connections with sensory nerve endings and secrete or express a number of these peptides.11 The close contact between Merkel cells and nerve fibers represents a Merkel cell–neurite complex, but there is no clear evidence of synaptic transmission, although numerous vesicles can be identified in neurons apposed to Merkel cells.12

Fig. 1.42 Merkel cell: positive labeling for CAM 5.2 identifies Merkel cells in this obliquely sectioned epidermal ridge.

Human skin contains an extensive neural network that contains cholinergic and adrenergic nerves and myelinated and unmyelinated sensory fibers. Moreover, the skin also contains several transducers involved in the perception of touch, pressure, and vibration, including Ruffini organs surrounding hair follicles, Meissner's corpuscles, Vater–Pacini corpuscles located in the deep layer of the dermis, and nerve endings which pass through the epidermal basement membrane. Some of these contain Merkel cells which form the Merkel cell–neurite complex, while others are free nerve endings. The cell bodies for all these neurons reside in the dorsal root ganglion. The Merkel cell–neurite complexes are thought to serve as mechanoreceptors and to be responsible for the sensation of touch. They are clustered near unmyelinated sensory nerve endings, where they group and form ‘touch spots’ at the bottom of rete ridges. These complexes are also known as hair discs, touch domes, touch corpuscles, or Iggo discs. The complex is innervated by a single, slowly adapting type 1 nerve fiber. In hairy skin, Merkel cells also cluster in the rete ridges and in the outer root sheath of the hair follicle where the arrector pili muscles attach. The function of Merkel cells in hair follicles is unclear, although they may be involved in the induction of new anagen cycles. There are two hypotheses for the origin of Merkel cells: one possibility is that they differentiate from epidermal keratinocyte-like cells and the other

Intercellular junctions

Intercellular junctions Desmosomes are the major intercellular adhesion complexes in the epidermis. They anchor keratin intermediate filaments to the cell membrane and link adjacent keratinocytes (Fig. 1.45). Desmosomes are found in the epidermis, myocardium, meninges and cortex of lymph nodes. Ultrastructurally, desmosomes contain plaques of electron-dense material running along the cytoplasm parallel to the junctional region, in which three bands can be distinguished: an electron-dense band next to the plasma membrane, a less dense band, and then a fibrillar area (Fig. 1.46).1 Identical components are present on opposing cells which are separated by an intercellular space of 30 nm within which there is an electron-dense midline. There are three main protein components of desmosomes in the epidermis: the desmosomal cadherins, the armadillo family of nuclear and junctional proteins, and the plakins (Fig. 1.47).2 The transmembranous cadherins comprise mostly heterophilic ­associations of desmogleins and desmocollins. There are four main ­epidermis-specific desmogleins (Dsg1–4) and three desmocollins (Dsc1–3). These show differentiation-specific expression. For example, Dsg1 and Dsc1 Fig. 1.43 Merkel cell: a heavily granulated Merkel cell is present in the midfield. This is located immediately adjacent to a small nerve fiber.

Fig. 1.45 Mid-prickle cell layer of normal epidermis: there are complex interdigitations between adjacent cell membranes with numerous desmosomal junctions.

Fig. 1.44 Merkel cell granules: they are membrane bound and measure approximately 150 nm in diameter. By courtesy of A.S. Breathnach, MD (1977) Electron microscopy of cutaneous nerves and receptors. Journal of Investigative Dermatology 69, 8–26. Blackwell Publishing Inc., USA.

is that they arise from stem cells of neural crest origin that migrated during embryogenesis, in similar fashion to melanocytes.13 Merkel cell hyperplasia is a common histological finding and may accompany keratinocyte hyperproliferation as well as being frequently seen in adnexal tumors such as nevus sebaceus, trichoblastomas, trichoepitheliomas, and nodular hidradenomas.14 Merkel cell hyperplasia is associated with hyperplasia of nerve endings that occurs in neurofibromas, neurilemomas, nodular prurigo, or neurodermatitis. It is not clear whether Merkel cell carcinoma originates from Merkel cells or their precursors but the latter may be more likely given that many dermal Merkel cell carcinomas do not connect with the epidermis.

Fig. 1.46 Mid-prickle cell layer of normal epidermis showing the stratified nature of the desmosome.

13

14

The structure and function of skin Autosomal dominant

Arrhythmogenic right ventricular cardiomyopathy

Autosomal recessive Plakophilin 1

Ectodermal dysplasia Skin fragility syndrome

Plakophilin 2

Arrhythmogenic right ventricular cardiomyopathy Woolly hair, keratoderma, +/- cardiomyopathy

Woolly hair, keratoderma, cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy

Desmoplakin Lethal acantholytic epidermolysis bullosa

Striate palmoplantar keratoderma Desmoglein

Plakoglobin

Desmoplakin

Desmocollin

Plakophilin

Keratin

Fig. 1.47 Protein composition of a desmosome junction between adjacent keratinocytes. The keratin filament network of two keratinocytes is linked by a series of desmosomal plaque proteins and transmembranous molecules to create a structural and signaling bridge between the cells.

Arrhythmogenic right ventricular cardiomyopathy

Plakoglobin

Striate palmoplantar keratoderma

Desmoglein 1

Arrhythmogenic right ventricular cardiomyopathy

Desmoglein 2

Arrhythmogenic right ventricular cardiomyopathy

Desmoglein 4

Localized recessive hypotrichosis

Naxos disease

Recessive monilethrix

are found predominantly in the superficial layers of the epidermis whereas Dsg3 and Dsc3 show greater expression in basal keratinocytes. The intracellular parts of the cadherins interact with the keratin filament network via the desmosomal plaque proteins, mainly desmoplakin, plakoglobin and plakophilin.1 Clues to the biologic function of these desmosomal components have arisen from various inherited and acquired human diseases.3,4 Naturally occurring human mutations have been reported in ten different desmosome genes with variable skin, hair and heart abnormalities and several desmosomal proteins serve as autoantigens in immunobullous blistering skin diseases such as pemphigus (Figs 1.48 and 1.49).5 Antibodies to multiple desmosomal proteins may develop in diseases such as paraneoplastic pemphigus through the phenomenon of epitope spreading.6 Cleavage of the extracellular domain of Dsg1 has also been demonstrated as the basis of staphylococcal scalded skin syndrome and bullous impetigo.7 Adherens junctions are recognized ultrastructurally as electron-dense transmembrane structures, with two opposing membranes separated by approximately 20 nm, that form links with the actin skeleton.8 They are 0.2–0.5 μm in diameter and can be found as isolated cell junctions or in association with tight junctions and desmosomes. Adherens junctions are expressed early in skin development and contribute to epithelial assembly, adhesion, barrier formation, cell motility and changes in cell shape. They may also spatially coordinate signaling molecules and polarity cues as well as serving as docking sites for vesicle release. Adherens junctions contain two basic adhesive units: the nectin-afadin complex and the classical cadherin complex.9,10 The nectins form a structural link to the actin cytoskeleton via afadin (also known as AF-6) and may be important in the initial formation of adherens junctions. The cadherins form a complex with the catenins (α-, β-, and p120 catenin) and help mediate adhesion and signaling. Cell signaling via β-catenin can activate several pathways linked to morphogenesis and cell fate determination. Inherited gene mutations of the adherens junction proteins plakoglobin and P-cadherin have been reported. Plakoglobin mutations result in Naxos disease (woolly hair, keratoderma, cardiomyopathy).3 P-cadherin mutations underlie autosomal recessive hypotrichosis with juvenile macular dystrophy as well as ectodermal dysplasia-ectrodactyly-macular dystrophy (EEM) syndrome, in which there is hypotrichosis, macular degeneration, hypodontia and limb defects, including ectrodactyly, syndactyly and camptodactyly.11,12 Gap junctions represent clusters of intercellular channels, known as ­connexons, which form connections between the cytoplasm of adjacent ­keratinocytes (and other cells).13 Formation of a connexon involves ­assembly of six connexin subunits within the Golgi network. This complex is then transported to the plasma membrane where connexons associate with other

Desmocollin 3 Arrhythmogenic right ventricular cardiomyopathy

Desmocollin 2

Hypotrichosis simplex

Corneodesmosin

Hypotrichosis with scalp vesicles

Fig. 1.48 Genetic disorders of desmosomes: autosomal dominant or autosomal recessive mutations in ten different structural components of desmosomes may give rise to specific diseases that can affect skin, hair or heart or combinations thereof.

Immunobullous diseases Desmoglein 3 Desmoglein 1 Desmocollin 3 Desmocollin 1

Pemphigus vulgaris Pemphigus foliaceus Endemic pemphigus Atypical pemphigus Atypical pemphigus IgA pemphigus (sub-corneal type)

Fig. 1.49 Immunobullous diseases of desmosomes: intraepidermal blistering can arise through autoantibody disruption of four separate desmosomal proteins which leads to different clinical variants of pemphigus.

connexons (homotypic or heterotypic) to form a gap junction. To date, 13 different human connexins have been described. The formation and stability of gap junctions can be regulated by protein kinase C, Src kinase, calcium concentration, calmodulin, adenosine 3′,5′-cyclic monophosphate (cAMP) and local pH.14 The connexins are classified into three groups (α, β and γ) according to their gene structure, overall gene homology and specific sequence motifs.15 Apart from the connexins, vertebrates also contain another class of gap junction proteins, the pannexins, which are related to the innexins found in nonchordate animals. The function of gap junctions is to allow sharing of low molecular mass metabolites (IFAR Plectin

CM

Epidermis

LL LD

BP230 a6

HD BP180

Dermis

b4

LL NaCL split skin Laminin-5 Epidermis

LD AF AP

Fig. 4.2 Basement membrane constituents: blisters can be classified into those that develop within the lamina lucida (LL) and those that arise below the lamina densa (LD). (AF, anchoring fibrils; AP, anchoring plaque; CM, cell membrane.)

In this chapter, only those conditions in which subepidermal blister formation represents an inherited or autoimmune primary event are considered. Other conditions, which may be associated with subepidermal blistering, are dealt with in more appropriate chapters.

Split skin immunofluorescence This technique represents a modification of indirect immunofluorescence (IMF) where normal skin is split through the lamina lucida of the basement membrane region to produce an artificial blister cavity (with the lamina densa lining the floor) for use as substrate. Artificial separation can be achieved by the suction technique (in vivo) or by immersion of normal skin in 1 M NaCl for 48 hours at 4°C (Fig. 4.3). In general, the latter technique is preferred.2 As such a split is invariably through the lamina lucida region ­(confirmed by

A

Artificial blister cavity LD Dermis

Fig. 4.3 Split skin immunofluorescence.

­electron microscopy or immunofluorescence) (Figs 4.4, 4.5), the technique enables precise localization of a circulating basement membrane zone antibody to either the floor or the roof of the artificial blister cavity. In bullous pemphigoid, pemphigoid gestationis, and the majority of cases of mucous membrane pemphigoid, linear immunofluorescence is found along the roof of the artificial blister whereas in diseases characterized by a sublamina densa split (e.g., epidermolysis bullosa acquisita, antilaminin mucous membrane ­pemphigoid, anti-p105 pemphigoid, anti-p200 pemphigoid, and bullous dermatosis of bullous lupus erythematosus), the immunofluorescent signal is found along the floor of the blister (see references 3 and 4 for a review) (Fig. 4.6). In some diseases, positive immunofluorescence may be found on either the roof or the floor or even at both sites simultaneously (e.g., ­linear IgA disease and some variants of mucous membrane pemphigoid). Such variable labeling reflects the antigen heterogeneity in a number of bullous dermatoses.

B

Fig. 4.4 (A, B) Split skin immunofluorescence: the split is through the lamina lucida, the lamina densa lining the floor of the artificial blister cavity.

Epidermolysis bullosa

Fig. 4.5

Fig. 4.7

Split skin immunofluorescence: type IV collagen lines the floor of the split skin artificial blister which therefore forms within the lamina lucida. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK.

Paraffin-embedded immunoperoxidase antigen mapping: in bullous pemphigoid, type IV collagen is present along the floor of the blister.

Fig. 4.6 Split skin immunofluorescence: (left) linear IgG at the basement membrane; (middle) in epidermolysis bullosa acquisita (EBA), the antibody binds to the floor of the blister cavity; (right) in bullous pemphigoid (BP), the antibody binds to the roof of the blister. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK.

Immunoperoxidase antigen mapping As an alternative to split skin immunofluorescence, paraffin-embedded sections of lesional skin have been proposed in a direct immunoperoxidase antigen mapping technique to identify the level of the epidermodermal separation.5–8This procedure localizes known basement membrane region constituents such as keratins 5/14, laminin, and type IV collagen to the roof or floor of the blister cavity. The site of blister formation can therefore be characterized as intrabasal, within the lamina lucida or deep to the lamina densa. For example, in epidermolysis bullosa simplex variants, all of these immunoreactants are present along the floor of the blister cavity. In bullous pemphigoid, keratin is present along the roof of the blister while laminin and type IV collagen are found along the floor (Fig. 4.7). In dystrophic epidermolysis bullosa, epidermolysis bullosa acquisita, and bullous systemic lupus erythematosus, all three immunoreactants are present in the roof of the blister (Fig. 4.8). However, in many hereditary and acquired blistering diseases the relevant antibodies against the target antigens do not work well in paraffin-embedded material and false-positive and false-negative results are common, making this method unreliable for use in routine diagnosis. For example, antigen mapping of the group of hereditary subepidermal blistering diseases is done exclusively on frozen sections with excellent results.

Fig. 4.8 Paraffin-embedded immunoperoxidase antigen mapping: in epidermolysis bullosa acquisita, type IV collagen is present along the roof of the blister cavity.

Epidermolysis bullosa Epidermolysis bullosa (EB) refers to a heterogeneous group of diseases in which the skin and sometimes the mucous membranes blister easily in response to mild trauma, hence the alternative title ‘mechanobullous dermatosis’, which has sometimes been applied.1 All are rare conditions; the estimated incidence for the group as a whole is in the order of 1:20 000. Apart from the acquired autoimmune variant (epidermolysis bullosa acquisita), they are all autosomal inherited disorders. EB was initially described as a defined entity in 1886.2 This group of conditions has been classified in several ways over the years. The three major types were defined in a groundbreaking electron microscopy study in 1962.3 In 1988, the contemporary classification and subtyping of the major variants commenced with the first consensus meeting of the Steering Committee of the National EB Registry (established in 1986) held in conjunction with the American Academy of Dermatology.4,5 At that time, 23 seemingly clinically distinct variants were recognized (Table 4.1).5 In the following decade, a second consensus conference was held.6 As a result of the considerably increased number of cases available for study, a much greater degree of clinical overlap between the various subtypes was recognized. For this reason and because of a much better understanding of the molecular basis for many of

101

102

Inherited and autoimmune subepidermal blistering diseases Table 4.1 First consensus conference (1988): classification of subepidermal blisters

Table 4.2 Second consensus conference (1999): classification of epidermolysis bullosa

EB simplex Localized EB simplex of hands and feet (Weber-Cockayne variant) EB simplex with anodontia/hypodontia (Kallin syndrome) Generalized EB simplex, Koebner variant EB simplex herpetiformis (Dowling-Meara variant) EB simplex with mottled or reticulate hyperpigmentation with or without punctate keratoderma EB simplex superficialis EB simplex, Ogna variant Autosomal recessive EB simplex (letalis) with or without neuromuscular disease EB simplex, Mendes da Costa variant Reproduced with permission from Fine, J.D. et al (1991) Pediatrician, 18, 175–187. DDEB, dominant dystrophic EB; DEB, dystrophic EB; RDEB, recessive dystrophic EB. Junctional EB Localized Junctional EB, inversa Junctional EB, acral/minimus Junctional EB, progressiva variant Generalized Junctional EB, gravis variant (Herlitz variant) Junctional EB, mitis variant (non-Herlitz variant; EB atrophicans generalisata mitis; generalized atrophic benign EB) Cicatricial junctional EB Dystrophic EB Localized RDEB, inversa DDEB, minimus DDEB, pretibial RDEB, centripetalis Generalized Autosomal dominant forms of DEB DDEB, Pasini variant DDEB, Cockayne-Touraine variant transient bullous dermolysis of the newborn Autosomal recessive forms of DEB RDEB, gravis (Hallopeau-Siemens variant) RDEB, mitis

the variants of EB, a considerably simplified classification system was recommended at that time (Table 4.2).7,8 Most recently, at the Third International Consensus Meeting on Diagnosis and Classification of EB, the classification scheme was further revised and this current proposed scheme forms the framework for the discussion in this chapter (Tables 4.3, 4.4).9 Research over the past two decades has generated a wealth of literature ­specifically addressing the molecular basis of the various subtypes of EB. As a result, it is now possible to subgroup EB on the basis of the level of ­separation within the ­basement membrane region as well as on specific molecular findings. Though molecular classification now drives our understanding of this disease group, knowledge of the traditional clinical subtypes can be helpful in explaining the disease course to patients, despite the often overlapping ­spectrum of manifestations. Traditionally, EB has been classified into three major groups based on ­clinical differences, antigen mapping, and electron microscopic observations: • simplex (epidermolytic; in which the level of split is within the basal keratinocyte), • junctional (lucidolytic; where the level of split is within the lamina lucida), • dystrophic (dermolytic; where the level of split is deep to the lamina densa).

Major EB subtype

Protein/gene systems involved

EBS (‘epidermolytic EB’)

EBS-WC EBS-K EBS-DM EBS-MD

K5, K14 K5, K14 K5, K14 Plectin

Junctional EB

JEB-H HEB-nH JEB-PA†

Laminin-5* Laminin-5; type XVII collagen α6β4 integrin‡

DEB (‘dermolytic EB’)

DDEB RDEB-HS RDEB-nHS

Type VII collagen Type VII collagen Type VII collagen

Major EB type

Reproduced from Fine et al (2000) J Am Acad Dermatol, 42, 1051–1066 from American Academy of Dermatology. DDEB, dominant dystrophic EB; EBS-DM, EBS Dowling-Meara; EBS-K, EBS, Koebner; EBS-MD, EBS with muscular dystrophy; EBS-WC, EBS, Weber-Cockayne; JEB-H, junctional EB, Herlitz; JEB-nH, junctional EB, non-Herlitz; JEB-PA, junctional EB with pyloric atresia; RDEB-HS, recessive dystrophic EB, Hallopeau-Siemens; RDEB-nHS, recessive dystrophic EB, non-Hallopeau-Siemens. *Laminim-5 is a macromolecule composed of three distinct (α3, β3, γ2) laminin chains; mutations in any of the encoding genes result in a junctional EB phenotype. †Some cases of EB associated with pyloric atresia may have intraepidermal cleavage or both intralamina lucida and intraepidermal clefts. ‡α β integrin is a heterodimeric protein; mutations in either gene have been 6 4 associated with the JEB-PA syndrome.

In 1999, a fourth category – hemidesmosomal EB (where the level of split is within the hemidesmosome) – was added.10 This provisional category has now been removed and Kindler syndrome now constitutes a fourth major category. The most recent classification, which takes into account the current precise molecular data which is now known for virtually all of the subtypes of this disease, is particularly valuable when considering the pathological basis of EB and forms the basis for this account. There have been some changes in nomenclature based on an attempt to produce names that are more accurately descriptive of the diseases and concordant with current molecular classification of this disease. Mutations of sundry types in a variety of genes encoding plakophilin-1 (PKP1), desmoplakin (DSP), keratins 5 and 14 (KRT5, KRT14), plectin (PLEC1), BP180, α6 and β4 integrin subunits (ITGA6, ITGB4), laminin-5 (now termed laminin-332 and encoded by LAMA3, LAMB3, LAMC2), types XVII and VII collagen (COL17A1, COL7A1) and kindling-1 (KIND1) currently account for the different subtypes of EB (a more detailed account of these basement membrane proteins is given in Chapter 1).10–12 Molecular studies including Western blot and ­immunoprecipitation, ­however, are not always available for every case of EB, particularly at ­presentation, and therefore initially at least the patient may well be ­provisionally subclassified on the basis of: • clinical variation, • presence or absence of extracutaneous manifestations, • mode of inheritance, • immunoepitope mapping and/or electron microscopy. Clinical evaluation of a patient with suspected EB should include the age of onset and nature and distribution of the cutaneous lesions and whether or not scarring and contractures are present. In addition, the family pedigree should be studied and the patient investigated for the presence or absence of extracutaneous involvement (eyes, oropharynx, larynx, gastrointestinal and genitourinary tracts, and musculoskeletal system) and other specific lesions (including enamel hypoplasia, anodontia or hypodontia, pyloric atresia, and muscular dystrophy) that might point towards a particular variant.4,5 Four major subtypes of EB are now recognized: simplex, junctional, ­dystrophic and Kindler Syndrome: 4–7,9 • EB simplex (historically also known as the epidermolytic variant) is characterized by the level of separation within the epidermis, usually as a

Epidermolysis bullosa Table 4.3 Third consensus conference (2007): classification of epidermolysis bullosa Major EB type

Major EB subtype

Protein involved

EBS

Suprabasal Lethal acantholytic EB Plakophilin deficiency EBS superficialis (EBSS)

Desmoplakin Plakophilin-1 ?

Basal EBS, localized (EBS-loc)+ EBS, Dowling-Meara (EBS-DM) EBS, other generalized (EBS, gen-nonDM; EBS, gen-nDM)^ EBS with mottled pigmentation (EBS-MP) EBS with muscular dystrophy (EBS-MD) EBS with pyloric atresia (EBS-PA) EBS, autosomal recessive (EBS-AR) EBS, Ogna (EBS-Og) EBS, migratory circinate (EBS-migr)

K5, K14 K5, K14 K5, K14 K5 Plectin Plectin, α6β4 integrin‡ K14 Plectin K5

Junctional EB

DEB (‘dermolytic EB’)

JEB, Herlitz (JEB-H) JEB, other (JEB-O) JEB, non-Herlitz, generalized (JEB-nH gen)$ JEB, non-Herlitz, localized (JEB-nH loc) JEB with pyloric atresia (JEB-PA)† JEB, inversa (JEB-I) JEB, late onset (JEB-lo)# LOC syndrome (laryngo-onycho-cutaneous syndrome) Dominant dystrophic EB (DDEB) DDEB, generalized (DDEB-gen) DDEB, acral (DDEB-ac) DDEB, pretibial (DDEB-Pt) DDEB, pruriginosa (DDEB-Pr) DDEB, bullous dermolysis of the newborn (DDEB-BDN) Recessive dystrophic EB (RDEB) RDEB, severe generalized (RDEB-sev gen)@ RDEB, generalized other (RDEB-O) RDEB, inversa (RDEB-I) RDEB, pretibial (RDEB-Pt) RDEB, pruriginosa (RDEB-Pr) RDEB, centripetalis (RDEB-Ce) RDEB, bullous dermolysis of the newborn (RDEB-BDN)

Kindler syndrome

Laminin-332 (laminin-5)* Laminin-332; type XVII collagen (BP180) Type XVII collagen α6β4 integrin‡ Laminin-332 ? Laminin-332 α3 chain Type VII collagen Type VII collagen Type VII collagen Type VII collagen Type VII collagen Type VII collagen Type VII collagen Type VII collagen Type VII collagen Type VII collagen Type VII collagen Type VII collagen Kindlin-1

Adapted from Fine et al (2008) J Am Acad Dermatol, 58, 931–50 from American Academy of Dermatology. Rare variants are italicized. +Previously termed EBS, Weber-Cockayne ^Includes cases previously termed EBS-Koebner ‡α β integrin is a heterodimeric protein; mutations in either gene have been associated with both EBS-PA and JEBS-PA. Some cases of EB associated with pyloric atresia may have 6 4 intraepidermal cleavage or both intralamina lucida and intraepidermal clefts. *Laminin-332 (laminin-5 is a macromolecule composed of three distinct (α3, β3, γ2) laminin chains; mutations in any of the encoding genes result in a junctional EB phenotype. $Previously termed generalized atrophic benign EB (GABEB). #Previously termed EB progressiva. @Previously termed RDEB, Hallopeau-Siemens. Dominant dystrophic EB; EBS-DM, EBS Dowling-Meara; EBS-K, EBS, Koebner; EBS-MD, EBS with muscular dystrophy; EBS-WC, EBS, Weber–Cockayne; JEB-H, junctional EB, Herlitz; JEB-nH, junctional EB, non-Herlitz; JEB-PA, junctional EB with pyloric atresia; RDEB-HS, recessive dystrophic EB, Hallopeau-Siemens; RDEB-nHS, recessive dystrophic EB, ­ non-Hallopeau-Siemens. †Some cases of EB associated with pyloric atresia may have intraepidermal cleavage or both intralamina lucida and intraepidermal clefts. ‡α β integrin is a heterodimeric protein; mutations in either gene have been associated with the JEB-PA syndrome. 6 4

•

consequence of cytolysis. Traditionally, all variants have been associated with mutations in the genes encoding keratin 5 or 14.8,9 However, the most current classification scheme divides this group into suprabasal and basal forms, and now certain rare variants are known to be associated with mutations in the genes encoding desmoplakin, plakophilin-1, plectin, and α6 and β4 integrin subunits.9 Epidermolysis bullosa with late-onset muscular dystrophy, which had traditionally been included in the simplex category, is now known to result from a mutation in the plectin gene and was included in the provisional hemidesmosomal group of EB as delineated by Pulkkinen and Uitto in the 1999 classification scheme.10,13 Hemidesmosomal EB was

distinguished by the split through the hemidesmosome. The group included EB with late-onset muscular dystrophy (previously included in the simplex group), some examples of generalized atrophic benign EB (others associated with laminin-332 mutations are included within the junctional group) and EB with pyloric atresia (previously included in the junctional group).10,14–16 These three variants of EB develop as a consequence of mutations of genes encoding the hemidesmosomal proteins plectin, BP180, and the α6 and β4 integrin subunits respectively.10 In the newest classification scheme, these are now included in the suprabasal and basal types of EB simplex (Table 4.4). The hemidesmosomal group designation is no longer used as the

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Table 4.4 Simplified classification of epidermolysis bullosa Subtype

Mutation

Simplex

Suprabasal Basal

Plakophilin-1; desmoplakin Keratin 5 or 14; plectin; α6β4 integrin

Junctional

Herlitz Non-Herlitz

Laminin-332 (laminin-5) Laminin-332; type XVII collagen; α6β4 integrin

Dominant Recessive

Type VII collagen Type VII collagen

Dystrophic Kindler syndrome

•

•

Kindlin-1

consensus conference considered its application to be less useful than the current scheme. The main reason for this decision is that it is a somewhat artificial category. It separated non-Herlitz junctional EB into two categories namely, junctional EB and hemidesmosomal EB, based only on the presence of mutations in the genes encoding either laminin-332 or type XVII collagen, respectively. Both conditions have very similar clinical features and cannot be separated on clinical grounds, making this distinction confusing for clinicians, patients, and their parents. Thus all the diseases in the hemidesmosomal category are now reclassified into either the junctional or simplex types of EB. Junctional EB is characterized by the development of cleavage within the lamina lucida. It results from mutations in one of the three genes encoding the hetrotrimeric subunits of laminin-332 (laminin-5), α6 and β4 integrin subunits, and type XVII collagen.17 As mentioned above, some of these cases were deamed in the provisional hemidesmosomal category in the previous classification scheme (e.g., α6 or β4 integrin subunits with EB with pyloric atresia). Dystrophic EB (also known as the dermolytic variant) is defined by a split developing immediately below the lamina densa in the region of the anchoring fibrils. This type is composed of genetically dominant and recessive subtypes invariably due to type VII collagen gene mutations.18,19

Clinical features EB simplex (EBS) Two major types of EB simplex (with 12 subtypes) are now recognized: • suprabasal, • basal.

Suprabasal EBS Three suprabasal subtypes are recognized; all of them are rare variants. Lethal acantholytic EB Lethal acantholytic EB has been described in two cases with severely defective skin and mucosal epithelia.19 The disease was lethal in the neonatal period due to epidermolysis that was first noted during parturition leading to uncontrollable loss of fluid from the skin. Additional defects included universal alopecia and complete shedding of nails and the presence of neonatal teeth. Histology revealed clefting of the suprabasal layer producing a tombstone-type appearance reminiscent of pemphigus vulgaris. Molecular investigation revealed that the patient had inherited two different nonfunctional copies of the gene encoding desmoplakin (DSP, a desmosomal protein that links the transmembrane cadherins to the various proteins of the cytoplasmic intermediate filaments), one from each parent, indicating that the disease is autosomal recessive. The mutations both lead to truncation of the desmoplakin protein and an inability to act as a linker. Additional cases will be necessary to further define this syndrome. Plakophilin deficiency (ectodermal dysplasia-skin fragility syndrome, McGrath syndrome) Plakophilin is a required component of desmosomes and an important protein in ectodermal development. The rare deficiencies in this protein result in

a recently described inherited disease known as ectodermal dysplasia-skin fragility syndrome. Plakophilin-1 (PKP1) deficiency is an autosomal recessive disease that is associated with skin fragility and an inflammatory response resulting in erosions, scale-crust, and progressive palmoplantar keratoderma. Ectodermal effects such as sparse hair and anhidrosis and astigmatism are also noted.20 While initially described in a single child, approximately ten cases with mutations in this gene have now been described.20,21 Epidermolysis bullosa simplex superficialis This rare form of EB transmitted in an autosomal dominant fashion was first described in 1989. It specifically differs from the other simplex variants by the site of epidermal cleavage: variable subcorneal split between the stratum corneum and granular cell layer or sometimes within the stratum spinosum rather than intrabasal.22 Patients present at birth or within the first 2 years of life with erosions and crusts sparing the palms and soles. Atrophic scarring, nail dystrophy, and milia are additional common features; oral and ocular epithelia can be affected.23 As well as the cutaneous manifestations, anemia and gastrointestinal lesions affect a minority of patients. Some cases are associated with mutations causing structural dysfunction of type VII collagen.23 The condition may be clinically confused with peeling skin syndrome but in the latter there are no blisters and peeling is continous and spontaneous.

Basal EBS Nine subtypes of basal EBS are currently recognized, five of which are very rare. EB simplex, localized (Weber-Cockayne; EB simplex of the hands and feet) This is the most common form of epidermolysis bullosa and has an ­autosomal dominant mode of inheritance.4 5 Lesions are limited to the palms and soles and are usually detected in infancy or the first few years of life (Fig. 4.9). Occasionally, in patients with mild involvement, blisters and erosions may not develop until childhood or even early adulthood in association with strenuous activity. The lesions, which sometimes heal with atrophic scarring, show seasonal variation, often occurring only in the summer months. Hyperhidrosis may sometimes be present. Milia, atrophic scarring, and nail dystrophy are uncommon features.5,7 The teeth are uninvolved and there is no evidence of any systemic involvement, except perhaps for oral erosions, which may affect an appreciable number of patients in infancy.7 Ocular lesions are not a feature. Repeated episodes of secondary infection may occur in some patients. Postinflammatory hyper- and hypopigmentation may sometimes be a cosmetic problem.8 EBS, Dowling-Meara (EBS herpetiformis) This variant, which is the second commonest form of EB simplex, shows clinical features resembling dermatitis herpetiformis and has an autosomal dominant mode of inheritance (Fig. 4.10).7,24–27 Herpetiform grouping of blisters is characteristic. Lesions are usually present at birth and have a distribution sometimes mimicking severe dystrophic or junctional disease.7 Some patients die in early infancy due to infection, fluid loss or electrolyte imbalance.1 Milia formation is common, but atrophy and scarring are rare.7 Distal flexural contractures are occasionally present.25 Nail dystrophy is often found and palmoplantar keratoderma is characteristic. Anodontia and hypodontia have also been described. Normalization during episodes of high fever is a typical finding but seasonal variation is not a feature.26 Blistering significantly improves with advancing years.27 Mutations in keratins 5 and 14 underlie this disease.28–31 Death as a result of complications of the disease is rare and generally occurs by age 1 as a result of sepsis or respiratory failure.32 EBS, other generalized (includes Koebner variant) This group has an autosomal dominant mode of inheritance and includes primarily those cases previously termed Koebner-type and all other generalized subtypes of EBS.5 In the Koebner variant, blisters are present at birth or shortly thereafter and, although the entire body may be affected, lesions are particularly severe on the extremities, where the dorsal surfaces tend to be involved (Fig. 4.11).5 The blisters usually heal without scarring or atrophy and milia are very uncommon.5 The eruption often worsens in the summer months. The nails are rarely dystrophic and teeth abnormalities are typically

Epidermolysis bullosa

B

A

Fig. 4.9 EB simplex (Weber-Cockayne): typical lesions affecting (A) the fingers and (B) the toes. The pale color of the latter is due to the marked thickness of the roof of the blister. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.11 EB simplex (Koebner): intact blisters are present in the axilla and on the chest. By courtesy of M.J. Tidman, MD, Guy's Hospital, London, UK.

Fig. 4.10 EB bullosa simplex: Dowling-Meara variant showing characteristic grouping of blisters and erosions. By courtesy of R.A.J. Eady, MD, Institute of Dermatology, London, UK.

absent. Although oral lesions may be present in infancy, systemic involvement is not a feature of this variant. EBS with mottled pigmentation This autosomal dominant variant was originally described in six members of a single kindred.33 The cutaneous lesions are similar to the Dowling-Meara variant with the addition of mottled or reticulate pigmentation, particularly affecting the neck and trunk. Atrophic scarring, milia, and nail dystrophy are uncommon. Punctate keratoderma affecting the palms and warty hyperkeratotic lesions involving the hands, elbows, and knees may be additional features.33–35 Dental caries is also sometimes present and intraoral lesions are occasionally seen. EBS with muscular dystrophy (pseudojunctional EB) This is an autosomal recessive variant in which patients concomitantly develop muscular dystrophy or exceptionally myasthenia gravis and even cardiac

involvement.36–38 Blisters and erosions present at birth or soon ­thereafter and are usually generalized. Patients may also suffer from atrophic ­scarring, milia, nail dystrophy or anonychia, alopecia, and oral lesions36,37 Severe mucose membrane involvement is rare.39 The mortality of this variant is high.6 Mutations in plectin are associated with these forms of the disease.40–42 Plectin is a large (greater than 500 kD) intermediate filament binding protein that provides mechanical rigidity to cells by acting as crosslinking adaptor to the cytoskeleton.43 The PLEC1 gene bears a domain structure similar to BPAG1, indicating they belong to a common family and may have similar functions. A lethal variant of EBS with mutations in plectin at the level of the plakin domain may occur exceptionally and it is associated with aplasia cutis of the limbs and developmental impairment.42 EBS with pyloric atresia This category was placed in the provisional hemidesmosomal category in the prior edition of this book. Cases with pyloric atresia are currently considered in two groups: EBS discussed here, and another category in junctional EB discussed below. This is a rare variant of epidermolysis bullosa in which affected infants are at risk of ureterovesical junction obstruction with fibrosis involving the entire urinary tract and aplasia cutis congenita in addition to pyloric atresia (Figs 4.12, 4.13).44–47 Polyhydramnios is also seen. The pyloric atresia may be due to a diaphragm or stenosis (Fig. 4.14). The mortality rate of this variant is very high, up to 78% of affected infants succumbing.46 It appears to be the most lethal form in the EBS category. Mutations in both plectin and

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A

Fig. 4.12 EB with pyloric atresia: stillborn infant with widespread blistering. By courtesy of M.J. Tidman, MD, Institute of Dermatology, London, UK.

B

Fig. 4.14 (A, B) EB with pyloric atresia: pyloric canal is obliterated by fibrous connective tissue.

Fig. 4.13 EB with pyloric atresia: in addition to blistering there is also deep ulceration. By courtesy of M.J. Tidman, MD, Institute of Dermatology, London, UK.

α6β4 integrin subunits (junctional EB) have been described.48 Since both α6β4 integrin and plectin are expressed in villous trophoblast from the first trimester of pregnancy this feature has been used successfully for the prenatal diagnosis of this group of conditions.49 EBS, autosomal recessive Autosomal recessive EBS is generalized with onset at birth. Blistering is prominent with mild atrophic scarring. Ichthyotic plaques and focal palmoplantar keratoderma are sometimes encountered. Nails may be dystrophic or absent. Anemia, growth retardation, dental caries, and constipation can be complications.9 Mutations in keratin 14 underlie this disease; keratin 5 mutations have not been described.50,51

EBS, Ogna This form is autosomal dominant and presents at birth. It primarily involves acral sites, but can become widespread. Blistering is prominent and onychogryphosis is common. A tendency to bruise has been described.9,52 Lack of muscular involvement distinguishes this form of disease from EBS with muscular dystrophy described above; the mutation genotype may be predictive of disease expression.42,53 Mutations in plectin underlie this syndrome.39,52 EBS, migratory circinate This generalized form of EBS presents at birth with an autosomal dominant inheritance pattern. Blistering is very prominent and associated with a migratory circinate erythema and postinflammatory hyperpigmentation.9 Mutations in keratin 5 have been described, but none is currently reported in keratin 14.39,54,55

Hemidesmosomal EB This group previously included three variants: • patients with generalized atrophic benign EB (GABEB) (others were included in the junctional group; see below), • EB with late-onset muscular dystrophy (formerly included in the simplex group), • EB with pyloric atresia (formerly included in the junctional category). This subtype is of historical interest only as it no longer exists in the most current classification scheme.

Epidermolysis bullosa

Junctional epidermolysis bullosa Two major subtypes of this variant are recognized: junctional EB-Herlitz and junctional EB-non-Herlitz (Other). This later group encompasses both localized and generalized forms, cases with pyloric atresia, and three additional very rare variants under the newly revised classification scheme.9 Junctional EB with pyloric atresia was classified in the hemidesmosomal group in the prior classification scheme. All have an autosomal recessive mode of inheritance.

Junctional EB, Herlitz (Herlitz, gravis variant of junctional EB, EB hereditaria letalis, EB atrophicans generalisata gravis) Within this generalized variant, no additional subtypes are recognized. Blisters and erosions are present at birth accompanied by scarring and atrophy (Fig. 4.15).56–58 Milia may be a feature.7 Healing with the formation of ­exuberant, vegetative or tumorous granulation tissue is a pathognomonic ­feature (Fig. 4.16).5 This is found particularly around the mouth, sides of the neck, trunk, and about the nails.4 The nails may be dystrophic or absent and scarring alopecia is sometimes evident.5 Severe oral involvement (including ­scarring and microstomia) is usually present and pitted dystrophic enamel is characteristic (Fig. 4.17). Dental caries are frequently severe. Other ­features may include musculoskeletal deformities, gastrointestinal lesions, laryngotracheal stenosis, and genitourinary and ocular involvement. Esophageal involvement may result in stenosis. Perforation with resultant infection is an important cause of death. Severe growth retardation and anemia are usually evident. Infantile mortality is high (42.2%).7 Mutations in one of the three subunits of ­laminin-332 underlie this syndrome.59–61

Junctional EB, Other The category contains six subtypes, two common and four rare. JEB, non-Herlitz, generalized (generalized non-Herlitz junctional EB, EB atrophicans generalisata mitis, generalized atrophic benign EB (GABEB), hemidesmosomal EB, junctional EB mitis) This somewhat milder form, in which the cutaneous features are similar to the gravis form, includes some patients with laminin-332 gene mutations and others with mutations in type XVII collagen previously classified in the hemidesmosomal group.9,62 Systemic involvement is typically mild or absent.63–66 Patients present at birth with extensive blistering and erosions accompanied by mild scarring and widespread cigarette paper-like atrophy. Variable

Fig. 4.16 Junctional EB (Herlitz): infant showing granulation tissue at the edge of a healing blister. By courtesy of the Institute of Dermatology, London, UK.

­ yperpigmentation and hypopigmentation are characteristic.63 Skin lesions h may be exacerbated during summer. Milia are variably present. Exuberant ­granulation tissue is less common than in the Herlitz variant. Other features include dystrophic or absent nails (Fig. 4.18), oral erosions with mild scarring, pitted dystrophic enamel, and severe dental caries. Ocular lesions include recurrent corneal erosion, blistering, and corneal scarring.64 Follicular atrophy with resultant alopecia involving the scalp, axillary, and pubic hair in addition to sparse eyelashes and eyebrows is common (Fig. 4.19).63 Large or multiple melanocytic nevi have also been described as part of the phenotype58 but this is not currently believed to be a specific feature.5 Contractures do not develop. Systemic involvement is usually limited to mild laryngeal and/or esophageal lesions.4 Growth may be retarded and anemia is present in some patients. Infantile mortality is high (up to 44.7%).7,32 JEB, non-Herlitz, localized This milder and localized form of JEB is associated with mutations in type XVII collagen rather than laminin-332.67,68 Genotypic correlations and immunofluorescence antigen mapping may allow distinction of this form from the more several generalized form.68 JEB with pyloric atresia All EB with pyloric atresia was previously placed in the now defunct hemidesmosomal category. These cases are now divided into two categories within EBS and JEB. While both plectin and α6β4 integrin subunit mutations have been noted in EBS with pyloric atresia, only the latter is believed associated with JEB with pyloric stenosis.69–71 The clinical features are similar, with generalized blisters present from birth associated with atrophic scarring, dystrophic or absent nails, and milia on occasion. Large areas of aplasia cutis have been described.67 This disease is usually fatal at an early age.

Fig. 4.15 Junctional EB (Herlitz): newly born infant with blistering and nail involvement. By courtesy of J. McGrath, MD, Institute of Dermatology, London, UK.

JEB inversa Lesions, which are present at birth or develop in early infancy, are initially generalized, but later are predominantly localized to inverse (flexural) sites including the axillae and groin.5 Blisters and erosions are accompanied by atrophic scarring and nails may be dystrophic or absent. Other features that are sometimes evident include mouth erosions, maldeveloped teeth with enamel hypoplasia, and occasional gastrointestinal lesions, particularly affecting the esophagus and anus. Mutations in the subunits of laminin-332 are noted.9,58 JEB-late onset (progressiva) In this variant, lesions do not present until late childhood, and consist of blisters and erosions affecting the hands, elbows, knees, and feet.5 Nails may be dystrophic or absent and enamel hypoplasia is characteristic. Mouth erosions may be evident. Mild finger contractures are sometimes a complication.3,5 The mutation underlying this form of the disease is unclear.9

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Fig. 4.17 Junctional EB (Herlitz): note the scarring with microstomia and severe dental involvement. By courtesy of J. McGrath, MD, St John's Dermatology Centre, London, UK.

Fig. 4.19 Generalized atrophic benign EB: note the sparsely distributed eyebrows and eye lashes. By courtesy of the Institute of Dermatology, London, UK.

Dominant dystrophic EB Five subtypes are recognized; four of these are rare. Dominant dystrophic EB, generalized Autosomal dominant EB, generalized includes both the Cockayne-Touraine and Pasini variants. This is because the two conditions are characterized by identical type VII gene mutations and the albopapuloid lesions (white perifollicular papules and plaques) have been found to be an inconsistent finding (Fig. 4.20).6,7 Generalized blisters are seen at birth (Fig. 4.21a).4,8 Alopecia may be present and milia, atrophic scarring, and dystrophic or absent nails are typical features (Fig. 4.21b). Oral involvement may be mild or absent. Enamel hypoplasia is sometimes evident. Gastrointestinal and genitourinary tract involvement is seen in a minority of patients. There is a slightly increased risk of basal cell carcinoma and melanoma.75

Fig. 4.18

Dominant dystrophic EB, acral In this mild autosomal dominant localized variant, lesions present at birth or in early childhood, particularly in an acral distribution. Blisters and erosions in the absence of other significant lesions except for atrophic scarring, milia,

Generalized atrophic benign EB: there is scarring and complete absence of nails. By courtesy of the Institute of Dermatology, London, UK.

Laryngo-onycho-cutaneous (LOC) syndrome A mutation in the gene encoding the laminin-332 α3 chain resulting in an unusual N-terminal deletion underlies this syndrome.72 It was first described by Shabbir and colleagues in 22 patients of Punjabi extraction and about 10 additional cases have been described.73,74 So far, this autosomal recessive condition has not been described outside of this population. It can occur in a nonconsanguineous context. It consists of epithelial defects resulting in cutaneous erosions, nail dystrophy, and chronic conjunctival and laryngeal granulation tissue. Symblepharon and blindness are serious complications. Airway obstruction and infection can also be problematic. The degree of skin fragility is less than that seen in other variants of JEB. Under the new classification system, based on molecular and clinical similarities to JEB, this syndrome has been added as a rare variant.9,59

Dystrophic EB Two major subtypes – dominant dystrophic EB and recessive dystrophic EB (Hallopeau-Siemens) – are recognized and these are categorized into three major subtypes (one dominant and two recessive) and nine rare dominant or recessive groups. All subtypes are associated with mutations in the gene encoding type VII collagen. 9

Fig. 4.20 Dystrophic EB: albopapuloid lesions on the lumbosacral area. These are an inconstant finding in dystrophic EB. The lesions are not preceded by blistering and probably represent connective tissue nevi. By courtesy of M.J. Tidman, MD, Guy's Hospital, London, UK.

Epidermolysis bullosa

Fig. 4.21

A

Dominant dystrophic EB (Cockayne-Touraine): (A) truncal involvement is present in addition to the more typical limb lesions; (B) hemorrhagic blisters, scarring, milia and nail dystrophy. By courtesy of the Institute of Dermatology, London, UK.

B

and nail dystrophy may cease altogether after childhood.1 Extracutaneous manifestations have not been recorded. Dominant dystrophic EB, pretibial This is a mild, localized, and typically symmetrical autosomal dominant form. An autosomal recessive variant has recently been described (see below).76 The onset is often delayed, patients usually presenting in early ­childhood.77 Blisters and erosions accompanied by atrophic scarring and milia are ­particularly seen on the pretibial region and dorsal aspects of the feet (Figs 4.22, 4.23). The scarring may have a violaceous appearance reminiscent of hypertrophic lichen planus.76 Lesions are also sometimes seen on the forearms and trunk.76 Pruritus and nail dystrophy are common. There are no teeth or hair changes.77 Dominant dystrophic EB, pruriginosa This variant, which presents in childhood, includes dominant and ­recessive variants (see below).78 Patients present with highly pruritic, violaceous

Fig. 4.23 Dystrophic EB–pretibial: close-up view. By courtesy of the Institute of Dermatology, London, UK.

­ odular prurigo-like nodules developing against a background of blisters, n milia, nail dystrophy, and albopapuloid lesions. Dominant dystrophic EB, bullous epidermolysis of the newborn This exceptionally rare, self-limiting condition presents in the newborn with blisters that usually resolve within the first 2 years and heal with mild atrophy, milia, and scarring.79,80 Most cases have been inherited as an autosomal dominant, although recessive variants have also been documented.6

Recessive Dystrophic EB This category is composed of seven subtypes, of which five are rare.

Fig. 4.22 Dystrophic EB–pretibial: extensive erosions with scarring are localized to the front of both shins. By courtesy of the Institute of Dermatology, London, UK.

Recessive dystrophic EB, severe generalized (Hallopeau-Siemens; polydysplastic EB; EB gravis) This autosomal recessive variant is a much more serious form than its autosomal dominant counterpart.4,8 Blisters and erosions are present at birth and, atrophy, scarring, anemia, and growth retardation are consistently present (Figs 4.24, 4.25). Nikolsky's sign is positive. Destructive involvement of the distal peripheries results in contractures and severe deformities including the characteristic ‘mitten lesions’ (pseudosyndactyly) of the hands and feet (Figs 4.26–4.28).81 If the latter is left untreated, there may eventually be resorption of the underlying bones (autoamputation). Nail dystrophy and milia are marked, and scarring alopecia is common (Fig 4.29). Oral involvement is severe, with blisters, erosions, and scarring. Excessive caries are usual.

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A

Fig. 4.24 Recessive dystrophic EB (Hallopeau-Siemens): extensive blistering present at birth. The disease process has involved the nails and those of the first two toes are absent. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

B

Fig. 4.27 (A, B) Recessive dystrophic EB (Hallopeau-Siemens): in addition to the gross mitten deformity, there is very severe scarring and scaling. (A) By courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London; (B) by courtesy of the Institute of Dermatology, London, UK.

Fig. 4.25 Recessive dystrophic EB (Hallopeau-Siemens): note the scarring and extensive erosions. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.26 Recessive dystrophic EB (Hallopeau-Siemens): weblike folds enveloping the toes have resulted in a clublike appearance. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.28 Recessive dystrophic EB (Hallopeau-Siemens): there is gross deformity of the knees. By courtesy of J. McGrath, MD, Institute of Dermatology, London, UK.

Epidermolysis bullosa

Fig. 4.30 Recessive dystrophic EB: extensive esophageal involvement with complete separation of the mucosa has resulted in this dramatic, but fortunately very rare, manifestation. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.29 Recessive dystrophic EB (Hallopeau-Siemens): note the conspicuous milia. By courtesy of the Institute of Dermatology, London, UK.

Gastrointestinal and renal complications are common.82,83 There is often conjunctival involvement with keratitis and scarring, and lesions of the mucous membranes result in difficulty in opening the mouth, dysphagia, and esophageal stricture formation, with some infants eventually succumbing to terminal respiratory infections (Fig. 4.30).84 Anal and genitourinary involvement may also be present. Squamous cell carcinoma is a common complication of the cutaneous scarring (occurring in 39.6% of cases) and is a significant cause of mortality (Figs 4.31–4.33).85,86 Tumors are frequently multiple, have an aggressive behavior, and may be associated with extensive metastatic spread. Melanoma much less commonly develops. This variant of EB has a high mortality: 38.7%.7 Recessive dystrophic EB, generalized other This type is often referred to as non-Hallopeau-Siemens type. In contrast to the severe generalized form, anemia and mental retardation are less common and dental caries are not increased. In this variant the features are similar to the Hallopeau-Siemens variant except that the extracutaneous lesions and complications (e.g., anemia, mental retardation, and dental caries) are less severe and the risk of developing cutaneous squamous cell carcinoma is diminished (14.3%).4,8 The mortality for this variant of EB is 10.0%.87 Genotypic differences in mutational types and sites in the gene encoding type VII collagen likely underlie differences in the phenotypic expression of this disease.88 Recessive dystrophic EB, inversa In this autosomal recessive form, lesions are present at birth and consist of blisters, erosions, milia, and atrophic scarring, found particularly about the flexural sites, including the inguinal regions, axillae, neck, and the lower back.89,90 Nail dystrophy is usually evident and sometimes scarring alopecia is seen. Severe oral and esophageal involvement (erosions and scarring) is characteristic.91

Fig. 4.31 Recessive dystrophic EB (Hallopeau-Siemens): in this patient numerous large keratoses are evident. Many of these progress to squamous cell carcinoma. Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK.

Recessive dystrophic EB, pretibial The pattern of involvement is similar to the dominant form (see above), but can be more severe.

Recessive dystrophic EB, centripetalis This autosomal recessive localized form has been described in a single patient. Presentation was at birth with widespread blisters. In adulthood, however, the distribution became acral. The blisters, milia, and severe scarring with atrophy then showed a characteristic centripetal spread. Nail dystrophy and/or absence were also present. Despite the severe scarring, contractures and deformities were not features.92 There were no extracutaneous manifestations.

Recessive dystrophic EB, pruriginosa The pattern of involvement is similar to the dominant form (see above), but can be more severe.

Recessive dystrophic EB, bullous dermolysis of the newborn The pattern of involvement is similar to the dominant form (see above), but can be more severe.

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Pathogenesis and histological features

Fig. 4.32 Recessive dystrophic EB (Hallopeau-Siemens): in addition to severe scarring accompanied by autoamputation of the fingertips, there is a large ulcerated squamous cell carcinoma. Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK.

Fig. 4.33 Recessive dystrophic EB (Hallopeau-Siemens): in this patient there is a massive squamous carcinoma, which has destroyed much of the knee. Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK.

Kindler syndrome Kindler syndrome has been added to the EB classification scheme due to similarities to EB, and the hope that patients with this disease may benefit from the greater molecular and pathogenetic understanding of EB as a whole. It does not readily fit into any of the EB types as the level of blistering separation can be intraepidermal, junctional or below the lamina densa. This disease is caused by a mutation in the KIND1 gene that encodes the protein kindlin-1, a component of contact foci in basal keratinocytes.93,94 First described in 1954, more than 50 cases are now published in the literature.95,96 Significant heterogeneity is noted, but this rare autosomal recessive disease is associated with skin fragility similar to other forms of EB associated with the symptoms of poikiloderma and photosensitivity not seen in other forms of EB. Trauma-induced blistering and photosensitivity often improve with age. Squamous cell carcinoma and transitional cell carcinoma of the bladder have been described.97 All types of hereditary epidermolysis bullosa (simplex, junctional, and ­dystrophic) may rarely present with large nevi that often simulate melanoma on clinical grounds. Histology, however, shows no evidence of mali­gnancy.98,99

The investigation of a patient with suspected EB should ideally include immunofluorescence antigen mapping, ultrastructural, and molecular genetic ­studies. In general, routine histopathology often contributes little, other than to confirm the presence of a subepidermal blister. Immunofluorescent antigen mapping of basement membrane determinants is a method of identification of the plane of cleavage in the various types of EB that can sometimes avoid the need for ultrastructural studies.100,101 Essentially, the location of three antigens – type IV collagen, laminin-332, and bullous pemphigoid antigen-1 – is determined by standard indirect immunofluorescence of lesional (either naturally occurring or mechanically induced) skin:7 • In simplex variants, all three antigens are found along the floor of the blister. • In junctional lesions, bullous pemphigoid antigen-1 is identified mainly in the roof of the blister, whereas laminin-332 and type IV collagen are present along the floor. • In dystrophic EB, the plane of cleavage is below the lamina densa and therefore all three basement membrane antigens are present in the roof of the blister. The immunofluorescent investigation of skin samples for a wide range of recognized basement membrane constituents known to be absent or ­diminished in the various subtypes of epidermolysis bullosa has proved to be particularly valuable, and has also been shown to be of use in antenatal (16–18 weeks' gestation) diagnosis.102–104 The monoclonal antibody KF-1, which localizes to the lamina densa, shows an absence of labeling in nonlesional skin from patients with the severe recessive dystrophic form of EB, whereas in the dominant variant it is reduced.105,106 The monoclonal antibodies AF1 and AF2, which recognize antigens in and immediately below the lamina densa (probably constituents of anchoring fibrils), show an absence of immunolabeling in both normal and lesional skin from the recessive dystrophic form, but appear normal in dominant dystrophic EB.107 LH7:2 is a monoclonal antibody directed against the NC-1 globular domain of type VII collagen, which binds to the lamina densa and attached anchoring fibrils.108,109 Labeling is absent or markedly reduced in the severe recessive dystrophic form, patchily reduced in mild or localized recessive dystrophic variants, and normal in the dominant dystrophic variant.110,111 Immunolabeling with the monoclonal antibody GB3, which recognizes laminin-332 (nicein/kalinin/epligrin), is reduced or absent in the junctional (Herlitz) form of EB. It may be normal, reduced or absent in the non-Herlitz junctional variants.112,113 Laminin-332 is a major constituent of the anchoring filaments, which stretch from the hemidesmosomes to the lamina densa. Two further antibodies, 19-DEJ-1 and AA3, characteristically fail to label the basement membrane zone in all patients with junctional epidermolysis bullosa and are therefore of additional diagnostic value.114 19-DEJ-1, which recognizes uncein, has been recommended as the most reliable antibody for evaluation and diagnosis of the major junctional variants.115,116 Bullous pemphigoid 180-kD antigen is demonstrably diminished or absent as determined by immunofluorescence in many patients with generalized atrophic benign EB.117

EB simplex In EB simplex variants, blisters develop as a consequence of basal cell ­cytolysis (Fig. 4.34). The plane of cleavage lies deep to the nuclei of the keratinocytes such that wispy remnants of basal cell cytoplasm may be identified along the floor of the blister cavity, which is therefore intraepidermal in location (Figs 4.35, 4.36).118 In older lesions the blister often appears to be subepidermal due to continued lytic changes of the residual keratinocyte cytoplasm (Fig. 4.37). By direct immunoperoxidase antigen mapping on paraffin-embedded sections, keratin, laminin, and type IV collagen staining may be identified along the floor of the blister, confirming its intraepidermal location (Fig. 4.38). Ultrastructural studies have shown that the earliest change is loss of keratin filaments (tonofilaments).118,119 As a consequence, there is structural instability and fragility of the keratinocytes. Keratin clumps similar to those described in the Dowling-Meara variant (see below) have been a rare finding in EB simplex Koebner.120 Loss of keratin filaments is subsequently followed by dissolution

Epidermolysis bullosa

Fig. 4.34 EB simplex: the earliest histological feature in the development of a blister is marked vacuolation of the basal keratinocytes, so-called cytolysis.

Fig. 4.37 EB simplex: old lesion; the features are those of a cell-free subepidermal blister and are not specific.

Fig. 4.35 EB simplex: established lesion showing ‘subepidermal’ vesiculation.

Fig. 4.38 EB simplex: paraffin immunoperoxidase displays type IV collagen along the floor of the blister cavity (same case as Fig. 4.37).

Fig. 4.36 EB simplex: basal keratinocyte cytoplasmic remnants are visible along the floor of the blister cavity.

of the other keratinocyte cytoplasmic constituents. Suprabasal desmosomes appear unaffected. The lamina densa and anchoring fibrils are normal. While the hemidesmosomes generally appear normal, reduplication and increased electron density have been described in a recent case report.121 The Dowling-Meara variant (including the subset with mottled pigmentation) is characterized by 1–5-μm homogenous intracytoplasmic clumps of keratin filaments in addition to cytolysis (Fig. 4.39).122 These are present in the basal keratinocytes and extend into the overlying prickle cell layer. They may also be identified in the follicular outer root sheaths, dermal eccrine sweat ducts, and sebaceous glands. The clumps are composed of keratins 5 (type II) and 14 (type I).122 In addition to intraepidermal vesiculation, ­intrakeratinocyte cleavage may also be found in the follicular infundibula. The other skin appendage structures are not affected. The dermis may contain an infiltrate of lymphocytes and eosinophils.

113

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Inherited and autoimmune subepidermal blistering diseases

Fig. 4.39

A

EB simplex (Dowling-Meara): (A) electron micrograph showing intrakeratinocyte splitting; (B) close-up view of tonofilament clumps. By courtesy of J.A. McGrath, MD, and R.A.J. Eady, MD, Institute of Dermatology, London, UK.

B

The keratoderma shows hyperkeratosis and acanthosis. Clumps of keratin may also be evident. Ultrastructurally, the level of cleavage is low within the basal keratinocytes, just above the level of the hemidesmosomes (Figs 4.40, 4.41). In ­addition to cytolysis, however, acantholysis may also sometimes be evident. The keratin filament abnormalities include irregular whorled bundles in addition to homogeneous clumps. They are present in normal skin in addition to lesional material (Fig. 4.42).122,123 Desmosomes may appear diminished in number in the keratinocytes showing tonofilament clumps. Basement membrane zone constituents are normal. In EB simplex superficialis the plane of cleavage is in the upper epidermis just beneath the stratum corneum.22 Additional clefts may also be evident in the lower third of the epidermis. It is now apparent that the majority of EB simplex develop as a direct ­consequence of keratin gene mutation, but mutations in desmoplakin, ­plakophilin, plectin, and α6β4 integrin subunits are seen in some of the rare subtypes (see Table 4.2).124,125 Following the initial discovery of keratin ­filament clumps in Dowling-Meara EB and their subsequent identification as keratins 5 and 14, it was shown that keratinocyte cultures from patients with this disease exhibited an identical morphological abnormality.120 Genetic linkage studies showed that EB simplex was associated with keratin gene

Fig. 4.40

M

EB simplex (Koebner): the blister cavity forms within the basal keratinocyte. Note the cytoplasmic remnants along the floor of the blister. (M, melanosome.)

clusters on chromosomes 12 and 17.126–130 The gene for keratin 5 is carried on chromosome 12q and that for keratin 14 is located on 17q. Truncated mutant human keratin 14 gene induces the EB phenotype when introduced into transgenic mice and similarly causes an identical keratin abnormality when expressed in ­transfected human keratinocytes.131,132 Specific missense mutations or ­deletions have now been identified in patients with Dowling-Meara (K5 and K14), localized (K5 and14), other generalized (K5 and14) subtypes, and the the rare EB simplex subtypes with mottled pigmentation (K5), autosomal recessive (K14), and migratory circinate (K5).133–138 The highly conserved end domains of the keratin rod are particularly susceptible to significant mutation with resultant instability of the filament assembly and consequent fragility of basal keratinocytes following mild trauma.124 Plectin, which localizes to the inner plaque of the hemidesmosome, is a member of the plakin family and in concert with BP230 is believed to be of importance in keratin filament anchorage.10,14 Recently, mutation of the gene PLEC1 encoding this protein has been described in patients with the muscular dystrophy-associated, pyloric atresia, and Ogna subtypes.39 Plectin is associated with the Z-lines in the desmin cytoskeleton and this explains its importance in myocyte adhesion and their role in the pathogenesis of EBS with muscular dystrophy.139 Mutations in the genes encoding desmoplakin and plakophilin-1, respectively, are associated with lethal acantholyic EB and ­plakophilin deficiency.19,20 EB (both the simplex and junctional forms) associated with pyloric atresia results from α6β4 integrin missense mutations resulting in premature termination codons with synthesis of defective or nonfunctional α6 or β4 subunits.140–142 As a result, hemidesmosomes are hypoplastic or reduced in number.10 Mutations in the gene encoding plectin are also noted in the simplex form.48,143 Exceptionally, amlyoid has been described in the Weber-Cockayne type of EB.144 Dyskeratosis has been reported as a histologic feature in Dowling-Meara EB but not in other variants, including Koebner EB or Weber Cockayne EB.145 The sample in this study, however, was small and further investigation is required to confirm the specificity of this finding.

Junctional EB Junctional EB variants are also characterized by subepidermal ­blistering, usually unaccompanied by any substantial inflammatory cell infiltrate (Fig. 4.43).146 Ultrastructurally, the site of cleavage is through the lamina lucida (Fig. 4.44). The hemidesmosomes may appear malformed, be ­diminished in number or

Epidermolysis bullosa

Fig. 4.41

Fig. 4.43

EB simplex (Koebner): this high-power view shows the floor of the blister cavity. Note the lamina densa (arrowed), hemidesmosomes (arrowheads) and basal keratinocyte cytoplasm. (A, blister; B, cytoplasm; C, dermis.)

Junctional EB: subepidermal cell-free blister.

Fig. 4.42

Fig. 4.44

Epidermolysis bullosa simplex (Dowling-Meara): numerous tonofilament clumps are present in the adjacent clinically normal skin (arrowed). By courtesy of J.A. McGrath, MD, Institute of Dermatology, London, UK.

Junctional EB: lesional skin showing separation within the lamina lucida of the dermoepidermal junction. By courtesy of R.A.J. Eady, MD, Institute of Dermatology, and M.J. Tidman, MD, Guy's Hospital, London, UK.

absent.147–150 Hemidesmosome alterations as detected by electron microscopy, however, are heterogeneous. In a morphometric study of numbers of hemidesmosomes per unit length of basement membrane, one of five patients with the Herlitz variant and two of three patients with non-Herlitz variants had normal results.151 The same authors recorded an association between junctional EB and a reduction in the numbers of hemidesmosomes with associated sub-basal plates. Junctional EB is characterized by mutations in the genes that encode the α3, β3 or γ2 chains of laminin-332 (laminin-5).152–158 Mutations resulting in premature termination codons in the laminin-332 genes are present, for example, in all cases of the Herlitz lethal variant.7,10 Nonsense mutations, out-of-frame deletions or insertions and splicing errors affect both alleles, resulting in reduced synthesis and defective assembly of trimeric laminin-5 molecules.10 The majority of mutations have affected the LAMB3 gene although LAMA3 and LAMC2 gene abnormalities have also been documented. Non-Herlitz junctional EB variants, including some cases of generalized atrophic benign EB, are associated with milder missense mutations or deletions in the laminin-332 genes.152,159,160 Laminin-332 is located within anchoring filaments and in the lamina densa. The abnormal laminin-332 results in defective anchoring filaments with resultant instability at the basement membrane region.

Junctional EB, non-Herlitz (generalized and localized) is most commonly a result of BP180 mutations (BPAG2/type XVII collagen).161–163 Nonsense mutations or insertions/deletions with resultant premature termination codons result in absence of type XVII collagen. This is a transmembrane collagen that is thought to contribute to the anchoring filaments via its carboxy-terminal segment.10 The amino-terminal globular domain resides within the cytoplasm of the basal keratinocyte localizing to the outer plaque of the hemidesmosome. Less often, laminin-332 mutations are responsible for this clinical phenotype.

Dystrophic EB In the dystrophic variants the histological features are those of subepidermal vesiculation or blister formation in the absence of any significant inflammatory content (Fig. 4.45). The clinical subtypes show no particular distinguishing features. The adjacent dermis is often markedly scarred due to previous episodes of blistering. The squamous carcinoma that develops in association with recessive dystrophic EB is very often well differentiated (Fig. 4.46) and occasionally its appearance suggests a verrucous variant. Whether this latter form has the good prognosis usually evident with verrucous carcinoma is uncertain.

115

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Inherited and autoimmune subepidermal blistering diseases

Fig. 4.45

Fig. 4.47

Dystrophic EB (Hallopeau-Siemens): in addition to obvious subepidermal blistering there is dermal scarring and chronic inflammation.

Dystrophic EB (Hallopeau-Siemens): lesional skin demonstrates cleavage immediately beneath the lamina densa of the dermoepidermal junction (arrowed). By courtesy of R.A.J. Eady, MD, Institute of Dermatology, and M.J. Tidman, MD, Guy's Hospital, London, UK.

A

B

Fig. 4.46 (A, B) Dystrophic EB (Hallopeau-Siemens): biopsy from the forearm of a 30-year-old patient showing a cell-free subepidermal blister. In addition, a well-differentiated squamous cell carcinoma extends into the subcutaneous fat.

Ultrastructurally, the site of cleavage is immediately below the lamina densa (Fig. 4.47).164,165 In the autosomal dominant and some localized recessive groups, anchoring fibrils are decreased in number, but may appear ­morphologically normal, whereas in the generalized recessive ­variants (and occasionally in severe dominant cases), the fibrils are very sparse or more often absent.166–168 Frequently, thin wispy filaments immediately adjacent to the lamina densa are all that are visible. In a recent morphometric study of basement membrane in various dystrophic forms, using nonblistered skin, anchoring fibrils were completely absent in generalized recessive dystrophic EB. Reduced numbers of morphologically normal anchoring fibrils were found in localized recessive and dominant dystrophic variants.169 Type VII collagen expression in dystrophic EB, however, as determined by LH7:2 immunolabeling, is not an all-or-none phenomenon. Even in the recessive variant, some positive staining of thin, ­ill-formed filamentous structures may be seen immediately below the lamina densa. Collagenolysis in the superficial dermis may also be seen in the more severe variants. In transient bullous dermolysis of the newborn, in addition to reduced numbers of anchoring fibrils, intracytoplasmic inclusions are seen in the basal keratinocytes. These have a stellate appearance and represent retained type VII and type IV collagen.170–172 Dystrophic EB variants are all caused by mutations in the type VII collagen gene COL7A1.173–175 Over 100 distinct mutations have been identified.10 The Hallopeau-Siemens severe recessive variant is characterized by nonsense mutations, insertions, deletions or splicing errors, which cause premature termination codons affecting both alleles, resulting in very low levels of mRNA and virtual absence of type VII collagen synthesis.10,172,173 Premature termination codon, missense, deletion, and substitution mutations have been identified in a number of the less severe dystrophic variants.7 Dominant dystrophic EB is caused by a glycine substitution mutation resulting in a less severe variant in which type VII collagen, although defective, is still produced and anchoring filaments are present albeit in reduced numbers.176,177 Transient bullous dermolysis of the newborn also results from a mutation in COL7A1.79,80 Milia, which are most commonly seen in dystrophic EB, are small cysts within the upper dermis, consisting of a mass of keratinized squames surrounded by a wall of squamous epithelium, thereby representing miniepidermoid cysts. They are not specific to epidermolysis bullosa, being found in a variety of conditions associated with damage to the cutaneous adnexal structures (e.g., severe burns and porphyria cutanea tarda) and other blistering disorders.

Bullous pemphigoid

Differential diagnosis With the appropriate clinical information the histological diagnosis of EB should not pose any problems. With the exception, however, of the Dowling-Meara variant, it is not usually possible to predict which subtype the patient suffers from although, in specimens from early lesions, it is sometimes possible to identify the simplex variants of the basis of cytolysis. Cell-free subepidermal blisters, however, may be seen in a variety of conditions including autolysis, EB acquisita, cell-free pemphigoid, suction blisters, bullous cutaneous amyloidosis, bullous lichen sclerosus, porphyria cutanea tarda, and pseudoporphyria. Because the genetic defects for so many of the EB subtypes are now known, prenanatal testing is possible.178 It is hoped that understanding of the molecular pathobiology of this disease may eventually lead to successful gene therapy as was recently described for a patient with junctional EB using transplanted epidermal stem cells genetically modified to express wildtype LAMB3.179,180

Bullous pemphigoid

117

(Fig. 4.51). Often they contain clear or bloodstained fluid. Any area of the body may be affected, but the blisters are most commonly located about the lower abdomen, the inner aspect of the thighs and on the flexural surfaces of the forearms, the axillae, and groin (Fig. 4.52).14 Grouping of lesions as seen in dermatitis herpetiformis is not usually a feature and symmetry is characteristically absent. A ‘cluster of jewels’ appearance of new blisters arising at the edge of resolving lesions as seen in linear IgA disease may, however, ­occasionally be a feature of bullous pemphigoid (Fig. 4.53).15 The lesions are often pruritic and a burning sensation is sometimes a feature. Nikolsky's sign is usually negative. In contrast to mucous membrane pemphigoid, generalized bullous pemphigoid is not associated with scarring. Reported mucosal involvement (frequently as ulcers) is highly variable, ranging from 8% to 58%.16–18 In a series of 115 patients, 24% had oral involvement and 7% had genital lesions.18 Lesions are found most often on the palate, the cheeks, lips, and tongue (Fig. 4.54). Other sites less commonly involved include mucosae of the nose, pharynx, conjunctiva and, rarely, the urethra and vulva (see below) (Fig. 4.55).17 In contrast to mucous membrane pemphigoid, mucosal involvement in generalized bullous pemphigoid is not associated with scarring.

Clinical features Bullous pemphigoid is not a single disease entity. Rather, there are many subtypes, which have been classified into primary cutaneous and mucosal variants and into generalized and localized forms (Fig. 4.48).1–4 Bullous pemphigoid (BP) is the most frequently encountered autoimmune bullous dermatosis with an annual incidence of 6.6 new cases per one million of the population.5,6

Generalized cutaneous pemphigoid Any age group may be affected, but the generalized variant demonstrates a predilection for the later years of life, showing a maximum incidence in the seventh decade and over. Rarely, however, children and even infants may be affected.7,8 The disease is associated with a worldwide distribution and shows no racial propensity. There are no significant human leukocyte antigen (HLA) associations and the sex incidence is approximately equal. Prodromal events are numerous and include erythematous, urticarial and, rarely, eczematous phases.9,10 Erythroderma, either preceding the bullous phase or occurring simultaneously, is a very rare manifestation (erythrodermic pemphigoid).11,12 Similarly, patients may present with a history of generalized pruritus in the absence of visible skin lesions (pruritic pemphigoid). In such circumstances, immunofluorescence investigations are essential to establish the correct diagnosis.13 The characteristic lesions of established disease are tense and often intact blisters arising on normal or erythematous skin (Figs 4.49, 4.50). They may measure up to several centimeters in diameter and are typically dome-shaped

Widespread

Generalized Vesicular Polymorphic Vegetans Nodularis Erythrodermic Seborrheic

Localized

Pretibial Brunsting-Perry

Widespread

Mucous Membrane

Localized

Desquamative Gingivitis Oral

Cutaneous

Mucosal

Fig. 4.48 Bullous pemphigoid: classification.

Fig. 4.49 Erythrodermic BP: blistering has developed against a background of generalized erythroderma. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.50 BP: early tense blister arising on an erythematous base. By courtesy of the Institute of Dermatology, London, UK.

118

Inherited and autoimmune subepidermal blistering diseases

Fig. 4.51

Fig. 4.53

BP: tense, dome-shaped blisters. The flexures are typically affected. By courtesy of the Institute of Dermatology, London, UK.

BP: new blisters arising at the edge of a healing lesion (‘cluster of jewels’ sign). Although typically seen in childhood linear IgA disease, this is sometimes a feature of bullous pemphigoid. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.54 Fig. 4.52 BP: widespread, fluidfilled, hemorrhagic blisters on the arms and legs of an elderly female. By courtesy of the late M. Beare, MD, Royal Victoria Hospital, Belfast, N. Ireland.

Although bullous pemphigoid has been reported in association with a variety of internal malignancies, this may just be coincidental, merely reflecting the age incidence of these two diseases.19 In a series of almost 500 patients from Sweden, no increased incidence of cancer was observed.20 Other studies, however, have shown that there may be a positive correlation between internal malignancy and seronegative bullous pemphigoid patients.21 Generalized bullous pemphigoid is a serious condition with a significant mortality ranging from 10% to 20%.1 Since the advent of steroid therapy and immunosuppressive agents, patients are more at risk of developing severe iatrogenic disorders than of dying from their disease.22 Morbidity from this disease may be related more to the age and general state of health of the patient than to the severity of blistering.23 Although mortality from the disease is low, there has been a reported increase in mortality in the last 20 years of the twentieth century.24

BP: oral erosions are an occasional finding. Intact blisters are rare. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.55 BP: conjunctival injection is present. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Bullous pemphigoid

Fig. 4.56

Fig. 4.57

Bullous pemphigoid: occasionally erythematous urticarial lesions may be the presenting feature. Blisters may not evolve until several weeks later. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Bullous pemphigoid: close up view. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Clinical variants of generalized pemphigoid Urticarial bullous pemphigoid presents with large persistent erythematous plaques, which sometimes display an annular or gyrate peripheral component (Fig. 4 56, 4.57).1 Rarely, small vesicles are also to be found. Vesicular pemphigoid is a rare clinical variant in which the cutaneous manifestations show a striking overlap with dermatitis herpetiformis.25–28 Patients present with numerous small tense vesicles that may be symmetrical, intensely pruritic, and therefore associated with conspicuous excoriation. Polymorphic pemphigoid is a somewhat confusing entity, which is similar to vesicular pemphigoid, but probably shows overlap with linear IgA disease.29–31 Patients present with burning and itching lesions predominantly affecting the extensor aspects of the limbs, back, and buttocks. Symmetry, grouping, and a polymorphic clinical appearance of papules, vesicles, and variably sized bullae emphasize a similarity to dermatitis herpetiformis. It has been suggested that polymorphic pemphigoid is not an entity sui generis, but represents a potpouri of conditions including vesicular pemphigoid, linear IgA disease, and mixed subepidermal bullous disease in which patients show both linear IgG and linear IgA or dermal papillary granular IgA on direct immunofluorescence.30 Pemphigoid vegetans is an exceedingly rare vegetative intertriginous variant that may be associated with chronic inflammatory bowel disease.32–39 Fewer than 10 cases have been documented. Patients present with vegetative, crusted, purulent, and sometimes eroded lesions in the groin, axillae, neck, hands, eyelids, inframammary, and perioral regions (Fig. 4.58). Vesicles and bullae may also be evident. Scarring has been described.39 The etiology of the vegetative lesions is unknown. Seborrheic pemphigoid is a variant in which the clinical features are suggestive of pemphigus erythematosus.31 Pemphigoid nodularis represents the extremely rare association of lesions of bullous pemphigoid with intensely pruritic papules and nodules of nodular prurigo predominantly affecting the trunk and extremities (Fig. 4.59).40–42 The association of pemphigoid nodularis with immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is the subject of a single case report.43 Exceptionally, patients may show immunofluorescent evidence of bullous pemphigoid in the absence of clinical blistering.42 The cause of this unusual phenomenon is unknown although in some patients at least, chronic scratching probably damages the basement membrane region with exposure of bullous pemphigoid antigens. There is a female predilection (2:1).42 The age range of this variant extends from 24 to 80 years but, as with classical bullous pemphigoid, the majority of patients are elderly.

Dyshidrosiform pemphigoid is a rare variant of pemphigoid in which patients develop 1–2-mm, tense ‘sago-grain-like’ vesicles on the palms and soles resembling dyshidrosiform dermatitis (pompholyx).44–50 Lesions may be localized, or precede or occur simultaneously with generalized disease. Overlap with pemphigoid nodularis has been described.51 Childhood pemphigoid exhibits lesions that are similar to their adult counterparts, but there is some tendency for lesions to be localized around the face, lower trunk, thighs, and genitalia, reminiscent of linear IgA disease in childhood (Fig. 4.60).7,8,52–61 Similarly, a ‘cluster of jewels’ ­appearance is sometimes evident.7 Palmar, plantar, and oral lesions are often present and may be the sole site of involvement in infants (Fig. 4.61). The mucous membranes may be affected but scarring is absent. A number of children with primary localized penile and vulval lesions have also been described (Fig. 4.62).47,48,59,62,63 This is of particular clinical importance since it may be mistaken for evidence of sexual abuse. Childhood pemphigoid has a good prognosis and, as in adults, is usually self-limiting. Although the etiology is generally unknown, in some infant cases there appears to be a relationship to prior vaccination or immunization.59,64 Differences between childhood and infant cases have been described, but the importance of further subdividing this group is unclear.64

Localized cutaneous pemphigoid Although classical bullous pemphigoid not uncommonly presents initially as localized lesions that after a few months become generalized, occasional patients present with localized blisters that do not subsequently disseminate (localized bullous pemphigoid).65 Traditionally, this group has been ­subdivided into two variants: • Brunsting-Perry pemphigoid predominantly affects the head and neck and is associated with scarring.66 • Localized cutaneous nonscarring bullous pemphigoid (Eberhartinger and Niebauer variant)67 predominantly affects the lower legs (in particular the pretibial region) of females. The former variant is considered in the section on mucous membrane pemphigoid. Although the latter nonscarring cutaneous form particularly affects the lower legs (Fig. 4.63), it may also present at a variety of other sites including forearms and hands, breasts, chest, buttocks, and umbilicus. Lesions in localized bullous pemphigoid may be related to trauma.67 This variant shows a peak incidence in the sixth decade. As with generalized bullous pemphigoid, patients present with tense, sometimes hemorrhagic, bullae that arise on normal or erythematous-appearing skin. Localized cutaneous nonscarring bullous pemphigoid is generally associated with a good prognosis.67

119

120

Inherited and autoimmune subepidermal blistering diseases

Fig. 4.58

B

A

(A, B) Pemphigoid vegetans: presentation as verrucous lesions in the flexures may result in considerable diagnostic difficulties. By courtesy of R.K. Winkelmann, MD, The Mayo Clinic, Scottsdale, Arizona, USA.

Fig. 4.60 Fig. 4.59 Pemphigoid nodularis: in addition to bullous lesions, this patient also developed these pruritic nodules. By courtesy of H. Shimizu, MD, Keio University School of Medicine, Tokyo, Japan.

Rare patients present with localized bullous pemphigoid at the site of trauma without much evidence of disease elsewhere.68

Mucosal pemphigoid/desquamative gingivitis Localized oral pemphigoid is a recently described variant of desquamative gingivitis.69–71 The latter, of multifactorial etiology by definition, affects the marginal and attached gingivae. It shows a female predominance (9:1) and presents most frequently in the middle aged. Desquamative gingivitis may also be a

Childhood BP: very rarely this disease affects young children and infants. There is a widespread distribution of bullae, which characteristically arise on an erythematous base. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

manifestation of lichen planus, mucosal pemphigoid, and pemphigus.41 The diagnosis of localized oral pemphigoid depends upon the presence of a linear band of immunoreactants at the epithelial basement membrane region on direct immunofluorescence.69 Clinical features include erythema, edema, erosions, and ulcers.72 The oral lesions are nonscarring. Bullous pemphigoid-associated desquamative gingivitis may remain confined to the gingiva (the localized oral pemphigoid type), but approximately an equal proportion of patients goes on to develop full-blown cutaneous pemphigoid (Fig. 4.64).69

Bullous pemphigoid

Fig. 4.63 Localized pemphigoid, nonscarring variant: lesions are found particularly on the lower legs of females. The prognosis is usually good, but occasionally the condition can become generalized. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.61 Childhood BP: plantar involvement is sometimes the only site of disease. By courtesy of M. Liang, MD, The Children's Hospital, Boston, USA.

Fig. 4.62 Childhood BP: note the perineal scarring and isolated blister. By courtesy of M. Liang, MD, The Children's Hospital, Boston, USA.

Pathogenesis and histological features The histological features of bullous pemphigoid depend to some extent upon the age of the lesion biopsied. Early erythematous and urticarial lesions most often show upper dermal edema associated with a perivascular lymphohistiocytic infiltrate accompanied by usually conspicuous eosinophils (Figs 4.65 and 4.66). Eosinophilic spongiosis is sometimes evident and occasionally, if eosinophils are present in sufficient numbers, flame figures may be a feature. Mild interface changes characterized by basal cell hydropic degeneration can be seen in early or prodromal lesions. If the biopsy is taken from an established blister, the changes are most often those of an inflammatory (cell-rich) variant.73 The blister, which is subepidermal, is typically unilocular and covered by attenuated epithelium (Fig. 4.67). In early lesions the roof epidermis may appear unaffected or show occasional to even confluent necrotic basal keratinocytes. The blister contents include coagulated serum, fibrin strands, and large numbers of inflammatory cells including conspicuous eosinophils (Fig. 4.68). Variable numbers of neutrophils may be present. A typical finding in bullous pemphigoid is retention of the dermal papillary outline (festooning) which project like sentries into the vesicle cavity (Fig. 4.69). The underlying dermis is inflamed and usually shows widespread

Fig. 4.64 Desquamative gingivitis: note the intense gingival erythema and retraction. Such features may also be seen in mucous membrane pemphigoid and pemphigus. By courtesy of P. Morgan, FRCPath, London, UK.

severe edema. An infiltrate of eosinophils and mononuclears surrounds the blood vessels and extends between the adjacent collagen bundles. Leukocytoclasis is not seen and features of vasculitis are absent. The adjacent papillary dermis is often edematous and, very occasionally, eosinophil microabscesses are a feature (Fig. 4.70). Exceptionally rarely, neutrophil microabscesses may be seen (see vesicular pemphigoid), raising diagnostic confusion with dermatitis herpetiformis. Eosinophilic spongiosis is also sometimes evident in the adjacent epidermis (Fig. 4.71).74 Cell-poor (noninflammatory) features are occasionally seen if biopsies are taken from lesions arising on noninflamed skin (Fig. 4.72). Because inflammatory cells are sparse or, exceptionally, even absent in such cases, there may be considerable problems with the differential diagnosis, particularly if adequate clinical information and immunofluorescence findings are not available.

121

122

Inherited and autoimmune subepidermal blistering diseases

Fig. 4.65

Fig. 4.68

Prebullous pemphigoid: there is upper dermal edema and a perivascular lymphohis­ tiocytic infiltrate with conspicuous eosinophils.

BP: the blister cavity contains large numbers of eosinophils.

Fig. 4.69 Fig. 4.66

BP: preservation of the dermal papillary outline (festooning) is a characteristic feature.

Prebullous pemphigoid: there are numerous eosinophils.

Fig. 4.67 BP: an established lesion showing a subepidermal tense, dome-shaped blister containing edema fluid, fibrin, and inflammatory cells.

Fig. 4.70 BP: the presence of eosinophil microabscesses in the dermal papillae is a useful although rare diagnostic marker.

Bullous pemphigoid

A

Fig. 4.71 BP: eosinophilic spongiosis is sometimes seen in the epidermis adjacent to the blister.

B

Fig. 4.73 Vesicular pemphigoid: (A) low-power view showing a multilocular blister; (B) the blister contains a neutrophil-rich infiltrate.

Fig. 4.72 Cell-poor pemphigoid: this is a very uncommon variant and is most often seen if a very early lesion is sampled. The blister contains only a little edema fluid and there is a light chronic inflammatory cell infiltrate in the superficial dermis.

Vesicular/polymorphic pemphigoid is characterized by subepidermal vesicles with features suggesting either bullous pemphigoid or dermatitis herpetiformis or both (Fig. 4.73). Neutrophil dermal papillary microabscesses, which are often regarded as pathognomonic of dermatitis herpetiformis, may be seen in this variant (Fig. 4.74). Pemphigoid vegetans is characterized by acanthosis, often with pseudoepitheliomatous hyperplasia, papillary dermal edema with subepidermal clefting or frank vesicle formation and an inflammatory cell infiltrate of eosinophils, mononuclears, and occasional neutrophils. Pemphigoid nodularis exhibits pruriginous lesions which are characterized by hyperkeratosis and acanthosis, and which may amount to pseudoepitheliomatous hyperplasia and dermal fibrosis (Fig. 4.75). In the dermis, a perivascular infiltrate of lymphocytes and eosinophils is present. The blisters show typical features of bullous pemphigoid (Fig. 4.76).

Localized nonscarring (pretibial) bullous pemphigoid usually shows the histology of cell-rich bullous pemphigoid. Localized oral pemphigoid is typified by a subepithelial vesicle (when present) and cannot be distinguished histologically from oral involvement in mucous membrane pemphigoid (see below). Ultrastructurally, in early lesions of bullous pemphigoid, the dermoepidermal cleavage is seen to have developed between the plasma membrane of the basal keratinocyte and the lamina densa, through the lamina lucida.75 The lamina densa is therefore located along the floor of the blister (Figs 4.77, 4.78). Degenerative changes in the basal cells, including villous ­process formation, mitochondrial swelling, and cytoplasmic vacuolization, are frequently found. Hemidesmosomes may appear reduced in number or may even be absent.76 Intercellular edema between adjacent basal cells is a common finding.77 If specimens from established inflammatory lesions are examined, the lamina densa is sometimes fragmented or entirely absent.48 Bullous pemphigoid is characterized by a linear antibasement membrane zone antibody using the indirect immunofluorescent technique.78 Although IgG is invariably present (and most commonly of the IgG4 subclass), other immunoglobulins, including IgE, may be represented.79 Such antibodies are present in around 75–80% of patients.80–83 Sensitivity can, however, be increased to 90% if split skin is used as substrate.18 Although the antibody titer does not correlate with disease activity or severity, more recently it has been shown that serum antibodies to the NC16A domain of BP180 (a subunit of the bullous pemphigoid antigen) do correlate with disease activity (see below).84,85 Split skin indirect studies are essential in the investigation of a patient in whom a linear IgG antibasement membrane antibody has been detected.86–88

123

124

Inherited and autoimmune subepidermal blistering diseases

A

B

Fig. 4.74 Vesicular pemphigoid: (A) neutrophil microabscesses in the adjacent dermal papillae heighten the resemblance to dermatitis herpetiformis. It would be impossible to establish the diagnosis of bullous pemphigoid without appropriate immuno-fluorescent findings; (B) preservation of the dermal papillae may be a clue to the correct diagnosis of pemphigoid.

Fig. 4.75 Pemphigoid nodularis: this is a biopsy of a pruritic nodule showing hyperkeratosis, irregular acanthosis, dermal chronic inflammation, and scarring.

Fig. 4.77 BP: electron micrograph showing the lamina densa lying along the floor of the blister cavity.

Fig. 4.76 Pemphigoid nodularis: this subepidermal blister comes from the same patient as shown in Figure 4.75. Pemphigoid nodularis is of particular importance because the nodular lesions may precede clinical evidence of blistering.

Fig. 4.78 BP: high-power view of the lamina densa.

Bullous pemphigoid Such antibodies are also characteristic of mucous membrane pemphigoid, herpes (pemphigoid) gestationis, inflammatory epidermolysis bullosa, and bullous systemic lupus erythematosus. The antibodies in pemphigoid variants (with the exception of the anti-p105 and anti-p200 variants discussed below) bind to the epidermal side of 1 M NaCl-split skin whereas those of inflammatory epidermolysis bullosa and bullous systemic lupus erythematosus bind to the floor. In those patients in whom indirect fluorescent studies are not available, similar information may sometimes be obtained through the localization of lamina densa constituents such as type IV collagen or laminin-1 using ­paraffin-embedded direct immunoperoxidase techniques. In pemphigoid, the staining is found along the floor of the blister, whereas in inflammatory ­epidermolysis bullosa and bullous systemic lupus erythematosus it is located along the roof (see Figs 4.7 and 4.8). Bullous pemphigoid antibodies are capable of complement fixation in as many as 75% of patients.89,90 Most of complement fixation in bullous pemphigoid antibody resides in the IgG4 subclass.91 Linear in vivo-bound immunoglobulin at the epidermodermal interface on direct immunofluorescence is present in 90% or more of patients (Fig. 4.79).18,92 Complement (C3) is also usually present and is sometimes the sole immunoreactant (Fig. 4.80).93 Other immunoglobulin subclasses including IgM, IgA, and IgE may be detected occasionally.83,89,94 In addition to C3, the other components of the classical complement pathway, in particular C5b-9 (the membrane attack complex) and members of the alternative complement pathway, including properdin, factor B and B-1H-globulin, may also be identified.83,95 There is therefore evidence that both the classical and alternate complement pathways are involved in the pathogenesis of bullous pemphigoid.96 The classical complement pathway, however, predominates. A recent mouse model underscores the necessity of an intact innate immune system, as depletion of complement or neutrophils or blockage of mast cell activation prevents blister formation.97 The immunofluorescence findings in erythematous, pruritic, urticarial, and eczematous prodromal lesions and childhood, dyshidrosiform, vesicular, nodular, and vegetans variants are similar to those seen in the conventional generalized disease.25–28,32–49,98,99 In polymorphic pemphigoid either linear IgG or IgA deposits may be identified along the basement membrane region.29–31 The serum may contain either IgG or IgA antibodies.30 Immunofluorescence findings in localized cutaneous disease are variable. In some reports, patients show positive direct immunofluorescence for IgG and C3 at the epidermodermal junction and a positive indirect immunofluo-

Fig. 4.79 BP: direct immunofluorescence of perilesional skin showing intense linear basement membrane zone staining (IgG).

Fig. 4.80 BP: direct immunofluorescence showing C3 deposition (left), no staining is seen in the negative control (right). By courtesy of B. Boghal, FIMLS, Institute of Dermatology, London, UK.

rescent test for bullous pemphigoid antibody, while others may be positive for in vivo-bound complement, but negative on indirect examination.66,67,99 One series has shown that almost 70% of patients with localized pemphigoid have circulating IgG antibodies in their sera and the presence of these can be relevant for serum-based testing, as discussed below.67,100 A caveat is that in one study, antibodies were also detected in more than half of normal subjects who did not subsequently develop the disease.101,102 This finding is further discussed below. By direct immunoelectron microscopy, the immunoreactants (IgG and C3) are seen to be located within the hemidesmosomal plaque and upper lamina lucida (Fig. 4.81).103–107 Indirect immunoelectron microscopic ­studies show that the bullous pemphigoid antigen is most often detected ­intracellularly in the region of the cytoplasmic face of the hemidesmosome (Fig. 4.82).104,108–110 The immunoelectron microscopic observations in childhood bullous pemphigoid, vesicular pemphigoid, polymorphic pemphigoid, pemphigoid nodularis, pemphigoid vegetans, and localized pemphigoid are identical to those of classic bullous pemphigoid.111,112 Two principal bullous pemphigoid antigens are recognized by Western blot and immunoprecipitation studies: one is 230 kD (BPAG1) and the other is approximately 180 kD (BPAG2) (Fig. 4.83).113–119 These represent products of distinct genes.120–123 BP230 maps to the short arm of chromosome 6, locus 6p11-12.121 It belongs to the plakin family and shows homology with plectin and the ­desmogleins.122 It is wholly intracellular and localizes to the hemidesmosome. BP230 is not involved in the early stages of the pathogenesis of blistering but is of importance as a secondary event; antibodies against this antigen are not required for blister formation in most cases.124–126 BP180 (collagen type XVII) is the major pathogenic antigen in bullous pemphigoid. The BPAG2 (COLI7A1) maps to the long arm of chromosome 10, locus 10q24.3.121 It is a transmembrane adhesion molecule comprising an ­intracytoplasmic N-terminal fragment, a transmembrane region, and a collagenous ­extracellular C-terminal ectodomain.127 The latter constitutes part of the anchoring ­filament and distally merges with the lamina densa. The antibodies directed against BP180 in bullous pemphigoid most commonly react with a short extracellular noncollagenous locus – NC16A (regions MCW0-MCW3) – located within the upper lamina lucida proximal to the collagenous segment (Fig. 4.84).127–130 It now appears that antibodies specific to this area are ­generally required for blister formation and, while antibodies may also target BP180 non-NC16A domains, these latter antibodies do not appear to be pathogenic in most cases.124–26 This finding reconciles the fact that antibodies to both BP180 and BP230 can be seen in a significant portion of the population without blister formation as these are not against the critical NC16A region of BP180.84

125

126

Inherited and autoimmune subepidermal blistering diseases

Fig. 4.81

Fig. 4.83

BP: direct immunoperoxidase reaction using frozen tissue substrate showing electron-dense deposits in the lamina lucida.

BP: Western blot demonstrating the two quite separate bullous pemphigoid antigens. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.

More recently, two patients with a nonscarring, bullous pemphigoid-like illness characterized by neutrophil-rich subepidermal blisters resembling ­dermatitis herpetiformis and antibodies to a unique 105-kD protein – ­so-called anti-p105 pemphigoid – have been documented.141–143 This antigen localizes to the dermal side of split skin on indirect immunofluorescence. Its precise nature has not yet been determined. Anti-p200 pemphigoid is characterized by antibodies to a lower lamina lucida basement membrane antigen.144–146 Patients generally present with a

Basal keratinocyte HD plaque NH2

Fig. 4.82 BP: immunogold electron microscopic preparation. Note that the immunoreactant to BP180 and BP230 is particularly located on the hemidesmosomes (open arrows). However, deposits are also present within the lamina lucida, black arrows. (BC, basal cell; DER, dermis.) By courtesy of H. Shimizu, MD, Keio University School of Medicine, Tokyo, Japan.

Between 50% and 90% of patients with generalized bullous pemphigoid have antibodies that react with BP230 and 35–50% have antibodies that react with BP180 that are readily detected by immunoblotting.131 However, the sera in 100% of patients react with BP180 NC16A domain recombinant protein.131 This latter finding underscores the usefulness of recent testing for anti-NC16A domain antibodies from peripheral blood to distinguish bullous pemphigoid from other disorders.100,132–134 Circulating antibodies against BP180 or BP230 have also been defined in many of the other less common variants of bullous pemphigoid, including localized and vesicular forms, pemphigoid vegetans, erythrodermic pemphigoid, and pemphigoid nodularis.131,135–139 In childhood pemphigoid, the antibodies also react against the same antigens.140 In addition, rarely there may also be antibodies that react with the linear IgA 120-kD antigen.140 The BP180 antigen is most often ­targeted, and immunoblot analyses have shown that the antibodies react ­specifically with the NC16A domain as in adult patients. In some children at least, the IgG subclasses differ from adult disease, consisting of all IgG subclasses or IgG2 in isolation.18 IgE antibodies are not a feature of c­ hildhood disease.

Transmembranous domain

NC16a

Cell membrane

Rod-like interrupted collagenous domain

Lamina lucida

COL1 Lamina densa

Globular cytoplasmic domain

Flexible ‘tail’ COOH

Fig. 4.84 A schematic representation of the BP180 molecule showing the globular intracellular NH2 domain, the membrane proximal NC16A domain and the flexible rod-like interrupted collagenous structure of the extracellular domain. (HD, hemidesmosome). Collagen XVII/BP180: a collagenous transmembrane protein and component of the dermoepidermal anchoring complex. (Powell AM, ­ Sakuma-Oyama Y, Oyama N, Black MM. Department of Immunodermatology, St John's Institute of Dermatology, St Thomas' Hospital, London, UK.)

Pemphigoid gestationis nonscarring bullous pemphigoid-like illness although linear IgA disease-like and dermatitis herpetiformis-like variants have also been reported.144 The disease has also been described in association with psoriasis.145 With split skin indirect IMF, the antibodies bind to the floor of the blister cavity.144 With indirect immunoelectron microscopy, the antibodies bind to the lower lamina lucida.147,148 The identity of the 200-kD antigen has yet to be determined but it is neither laminin nor type VII collagen.148 Anti-p450 pemphigoid has been documented in a single patient. The antigen, which has been localized to the basal keratinocyte, belongs to the plectin family.149 Its precise nature has yet to be determined. Exceptionally, bullous pemphigoid may be associated with antiplectin antibody.150 Bullous pemphigoid has been described following PUVA therapy for mycosis fungoides. More recently, a case arising in the setting of radiation therapy has also been noted, perhaps suggesting a role for tissue damage in the pathogenesis of this disease.151 A mechanism for blister development in bullous pemphigoid has been proposed by Jordon et al.80,152 and is outlined as follows. Following antibody– antigen interaction and complement fixation, various chemotactic agents including C3a and C4a are produced.153 Mast cells degranulate under the influence of the latter or IgE, and release ECF-A, NMW-NCF, ESM, histamine, and enzymes.154 Eosinophils and neutrophils, so recruited, bind (possibly via C3b receptors) to the basement membrane region. By direct cytotoxic action (eosinophils are capable of antibody-dependent cellular cytotoxicity) or via released proteases, particularly elastase, damage at the basement membrane region results in the development of a vesicle. Lymphocytes elaborate histamine-releasing factor (HRF), which increases mast cell degranulation and perpetuates the process. A broad range of cytokines are involved in this inflammatory reaction including interleukin (IL)-1, IL-4-IL-8, IL-10-IL-13, IL-15 and interferon gamma (IFN-γ).155 As yet, their relative importance and time sequences are unknown. Bullous pemphigoid is therefore a true autoimmune disease in which ­antigen–antibody reaction and complement fixation results in a characteristic and reproducible train of events, which is inevitably accompanied by the development of subepidermal blister formation. The etiology or ­initiator (other than those associated with drugs or PUVA therapy, which are the ­minority) is unknown. The question as to why self-tolerance breaks down with the ­formation of symptomatic autoantibodies in patients with this d ­ isease is an important question for further investigation.

Differential diagnosis The inflammatory cell-rich variant of bullous pemphigoid must be distinguished from other subepidermal blistering dermatoses in which a heavy inflammatory cell component is a typical finding. These include dermatitis herpetiformis, linear IgA disease, inflammatory epidermolysis bullosa acquisita, and bullous systemic lupus erythematosus (see Table 4.5).

Successful differentiation depends upon careful clinicopathologic correlation and immunofluorescent studies or, more recently, serum-based immunologic (ELISA) testing. Split skin indirect immunofluorescence or lamina densa antigen mapping by type IV collagen or laminin-1 direct immunoperoxidase is essential to determine the level of the split. Although electron microscopy, immunoelectron microscopy, and immunoprecipitation or Western blotting provide definitive information, such techniques are not necessary in the majority of cases. The cell-poor variant of bullous pemphigoid has a very wide range of ­differential diagnoses including epidermolysis bullosa (congenital and acquired), porphyria cutanea tarda, bullous amyloidosis, bullosa diabeticorum, and autolysis.

Pemphigoid gestationis Pruritus is a very common symptom in pregnancy, occurring in up to 18% of gravid females.1–4 When it occurs in the absence of significant cutaneous stigmata it is known as pruritus gravidarum. This may occasionally be associated with a cholestatic pathogenesis. The specific pregnancy eruptions have long been a source of considerable confusion and controversy in the literature, largely due to a diverse range of terminologies and classifications. Recently, Holmes has attempted to clarify the situation with the introduction of a new and much simplified classification and others have proposed similar schemes.2,5 Therefore the specific dermatoses of pregnancy may be divided into: • polymorphic eruption of pregnancy, where the predominant lesions are urticarial; in the United States, the term pruritic urticarial papules and plaques of pregnancy (PUPPP) has achieved greater popularity; • pregnancy prurigo in which the lesions consist of itchy papules; • pemphigoid (herpes) gestationis, an autoimmune dermatosis belonging to the bullous pemphigoid group of diseases. Pemphigoid gestationis is a bullous dermatosis of pregnancy and the puerperium. It may be exacerbated by the use of oral contraceptives and rarely complicates hydatidiform mole and gestational (but not nongestational) choriocarcinoma. The current evidence implicates an autoimmune-mediated pathogenesis in which hormonal influences play a significant role.6,7

Clinical features The term herpes (gestationis) is neither appropriate nor satisfactory. It is not of viral etiology, nor has it anything to do with creeping (Gr. herpes, to creep). It was originally so named because of the tendency of the disease to show ‘progressive involvement by peripheral extension’.3 Because of its intimate relationship to bullous pemphigoid, the designation pemphigoid gestationis is preferred. As the major larger series have consisted of patients derived from a variety of sources, estimates of incidence have been very variable, ­ranging from 1:3000 to 1:50 000 pregnancies.4,8–10 The more recent figures where cases have had immunofluorescent confirmation would suggest that the latter figure is the most accurate.3

Table 4.5 Differential diagnosis of cell-rich pemphigoid Parameter

BP

EBA

BSLE

LAD

DH

DIMF

Linear IgG, C3

Linear IgG, C3

Linear IgG, C3

Linear IgA

Granular IgA

IIMF

IgG antibodies 75–80%

IgG antibodies 25–50%

IgG antibodies 60%

IgA antibodies 30%

Antitransglutaminase antibodies

Split skin IMF

Roof

Floor

Floor

Roof or floor or both

N/A

Type IV collagen

Floor

Roof

Roof

Roof or floor

N/A

EM: site of split

LL

Sub-LD

Sub-LD

LL, sub-LD or both

Papillary dermis

Western blot

BP180 kD BP230 kD

290 kD (type VII collagen)

290 kD (type VII collagen)

BP180 kD BP230 kD 200/280 kD 285 kD 250 kD 290 kD

Antigen uncertain

BP, bullous pemphigoid; BSLE, bullous systemic lupus erythematosus; DH, dermatitis herpetiformis; DIMF, direct immunofluorescence; EBA, epidermolysis bullosa acquisita; EM, electron microscopy; IIMF, indirect immunofluorescence; IMF, immunofluorescence; LAD, linear IgA disease; LL, lamina lucida; sub-LD, sub-lamina densa.

127

128

Inherited and autoimmune subepidermal blistering diseases Pemphigoid gestationis may present in the first or any subsequent pregnancy.3 It may first also rarely present in the postpartum period. In one series, 30% of patients were primigravidae.9 In addition to developing in pregnant or postpartum patients, pemphigoid gestationis has rarely been described following a hydatidiform mole and gestational choriocarcinoma.11,12 It has not, however, been reported in nongestational variants such as those occurring in the ovary, mediastinum, and testis, or complicating malignant teratoma. Pemphigoid gestationis is predominantly a disease of white females, being exceedingly rare in blacks.13,14 Presentation is usually in the second or third trimester, most often developing in the sixth or seventh month, but the range is variable from 2 months to 4 days postpartum.10,15 Although the disease may rarely completely remit before delivery, most patients (up to 75%) develop an exacerbation, which is frequently severe, in the immediate puerperium when progesterone levels have fallen.15,16 Exceptionally, the infant may show transient urticated erythema and blistering.4 Pemphigoid gestationis usually complicates subsequent pregnancies, frequently presenting earlier on and with more severe symptomatology.10 Sometimes, however, it may skip intervening pregnancies.3 This may be related to a change in paternity, or else due to compatibility at the HLA-D locus. Pemphigoid gestationis may develop into a very protracted ‘postpartum’ illness associated with considerable morbidity and lasting up to 12 years.17,18 In the majority of patients, however, the disease resolves by about 6 months postpartum.4 The disease may first present following a change in sexual partner.3,19 Alternatively, recurrent disease may persist even when there has been a change of sexual partner.7 This obviously calls into question the role of specific paternal antigens. Exacerbation following the use of the oral contraceptive is a common complication,10,20–23 affecting 20–50% of patients.3 Estrogens in particular have been implicated.22 The condition may also relapse during menstruation for some weeks or months postpartum and the return of symptoms (pruritus) has also been noted to coincide with ovulation (again suggesting an estrogen influence), although this is rare.3,10,22 Evidence has been published relating the duration of symptoms postpartum to the practice of breast-feeding. Bullous lesions lasted only 5 weeks in those who breast-fed compared to 24 weeks in those who bottle-fed. Although hormonal factors must be implicated, the precise pathogenetic implications underlying this observation are not fully understood.22 Pemphigoid gestationis is associated with intense pruritus, which may be present for days or weeks before the onset of typical cutaneous manifestations.1 The dermatosis is characteristically polymorphous, consisting of erythematous or urticarial papules and plaques, some with a polycyclic ­pattern, and later vesicles and bullae develop at the periphery of spreading erythematous plaques (Fig. 4.85).3,10,24 When fully evolved, the blisters are tense and

Fig. 4.85 Pemphigoid gestationis: prebullous phase showing erythema and small papules. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.86 Pemphigoid gestationis: the blisters are tense and dome-shaped. By courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK.

contain clear fluid, but at times the fluid may become hemorrhagic (Fig. 4.86). They typically heal without scarring. The umbilicus is frequently the site of initial involvement; spread to the trunk and extremities then follows (Figs 4.87, 4.88).3 Surprisingly, lesions on the face and mucous membranes are distinctly uncommon. Eventually palmar and plantar manifestations may appear. Other than pruritus, symptoms are usually mild, with stinging, burning, and pain being relatively infrequent.10

Fig. 4.87 Pemphigoid gestationis: slightly raised erythematous lesions with a propensity to cluster on the abdomen. By courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK.

Pemphigoid gestationis

Fig. 4.89 Fig. 4.88 Pemphigoid gestationis: umbilical involvement is a common mode of presentation. By courtesy of the Institute of Dermatology, London, UK.

Occasionally, the presence of target or iris lesions may mimic erythema multiforme.25 Less commonly, features may initially suggest classical bullous pemphigoid.25 Very occasionally, there is clinical overlap with dermatitis herpetiformis. Pemphigoid gestationis is not associated with pre-eclamptic toxemia and there is no related maternal mortality. Pemphigoid gestationis is accompanied by a significant increased risk of developing Graves' disease and an increased risk of autoantibodies.26 The literature concerning the incidence and nature of fetal morbidity and mortality is a source of some confusion. Kolodney therefore considered that there was no evidence of an increased incidence of stillbirths or abortions; however, his report predates the immunofluorescence era.5 An investigation by Lawley et al.20 of a large series of cases where immunofluorescent confirmation was available, suggested that there was an increased risk of fetal morbidity and mortality. More recently, evidence has been presented that patients with pemphigoid gestationis are liable to deliver low weight and small-fordates infants, prematurely.27 In contrast, however, Shornick et al. failed to show any evidence of significant fetal complications.7 It has been shown that the onset of the disease in the first and second trimester and the presence of blisters is associated with higher morbidity including premature birth and low birth weight children.28 Morbidity, however, still remains low. The antibody can cross the placenta and, in approximately 5% of cases, this may be associated with a mild and transient vesiculobullous eruption.29–32

Pemphigoid gestationis: early erythematous lesion showing marked edema of the papillary dermis and conspicuous eosinophils.

Fig. 4.90 Pemphigoid gestationis: early erythematous lesion showing eosinophilic spongiosis.

Pathogenesis and histological features The histopathologic features seen in biopsies from patients with pemphigoid gestationis are variable, depending upon whether early erythematous lesions, urticarial papular lesions, or fully established vesicles and bullae are studied.33 In early lesions, the major pathological features are seen in the superficial dermis where there is a perivascular inflammatory cell infiltrate consisting of lymphocytes, histiocytes, and typically very large numbers of eosinophils. This is associated with edema of the papillary dermis, which when marked may result in a ‘teardrop’ appearance (Fig. 4.89).33 Sometimes there is accompanying spongiosis and this may be associated with large numbers of eosinophils (eosinophilic spongiosis, Fig. 4.90). Occasionally the infiltrate of lymphocytes, histiocytes, and eosinophils is present in a linear distribution along the dermoepidermal junction.3 Vacuolar degeneration of the basal keratinocytes, sometimes accompanied by individual cell necrosis, may be a feature of the early lesions, but is often more evident in the fully established vesicular or bullous stage.33 In the latter, the blister is subepidermal in location and frequently contains large numbers of eosinophils (Figs 4.91, 4.92).33 The underlying and adjacent

Fig. 4.91 Pemphigoid gestationis: established subepidermal blister.

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Inherited and autoimmune subepidermal blistering diseases

Fig. 4.92

Fig. 4.93

Pemphigoid gestationis: the blister cavity contains a heavy eosinophil infiltrate.

Pemphigoid gestationis: indirect complement immunofluorescence showing linear deposition of IgG.

dermis is edematous and contains a predominantly perivascular lympho/histiocytic infiltrate with large numbers of eosinophils. Leukocytoclasis and eosinophil dermal papillary microabscesses are only rarely identified.33,34 Ultrastructural studies show that the cleavage plane lies within the lamina lucida.33,35 Direct immunofluorescence of perilesional skin in pemphigoid gestationis shows a linear basement membrane zone deposition of C3 in all patients.3,36–41 About 30–50% of cases also have an IgG band (less frequently IgM or IgA).36 They are present in nonlesional (perilesional) as well as in lesional skin.36 Recently, it has been suggested that demonstration of linear C3d deposition at the dermoepidermal junction may be a useful tool in the diagnosis of the disease.42 The authors of this study used immunohistochemistry in paraffinembedded, formalin-fixed material with good results. Complement pathway components including properdin and properdin factor-B may also be identified.1 IgG and complement can often be detected along the amniotic basement membrane region using direct immunofluorescence.38,43,44 Pemphigoid gestationis antigen has been detected in the placenta from early in the second ­trimester onwards.45 The antibody may also be found in the skin of infants of affected mothers.29 Interestingly, serologic evidence of pemphigoid gestationis without manifestation of the disease may be seen, An exceptional case of neonatal pemphigus in a child whose mother had clinical and serologic evidence of pemphigus vulgaris but only serologic evidence of pemphigoid gestationis has been described.46 Circulating complement-fixing (via the classical pathway) IgG antibodies (pemphigoid (herpes) gestationis (HG) factor) can be detected in 50–75% of cases by indirect complement immunofluorescence (Fig. 4.93).20,36,47–51 The socalled HG factor is nothing more than a low titer IgG complement-fixing antibasement membrane antibody.36 The antibody can be of any IgG subclass; IgG1 and IgG4 have been reported as predominent.38,51 If monoclonal antibodies directed against IgG are used, 100% of patients can be shown to possess circulating HG factor.38 Approximately 25% of patients have ­antibasement membrane zone antibodies detectable by conventional ­techniques.51 These bind to the roof of 1 M NaCl-split skin.36 The antibody also reacts with amnion and chorion basement membrane.42,44 The autoantibodies in the disease are directed against collagen XVII which is the BP ­180-kD protein (BPAG2). The latter plays a major role in cell adhesion and signaling. It has been demonstrated that collagen XVII is present in the epithelial cells of the amniotic membrane and in syncitial and cytotrophoblastic cells.52 Although the exact pathogenetic mechanism of the disease is still unknown (see below), the presence of collagen XVII in these tissues seems to play a major role in the mechanism of the disease. With immunoelectron microscopy the immunoreactants are deposited within the upper lamina lucida where they are most probably associated with the sub-basal dense plate.53,54 In pemphigoid gestationis the antibody recognizes BPAG2 (collagen type XVII) on Western ­immunoblot and localizes to the

same NC16A domain as described in bullous pemphigoid.55–62 This can be detected in serum using the same test employed for bullous ­pemphigoid.60–62 Antibodies that recognize the 230-kD bullous ­pemphigoid antigen are present in 10–26% of cases.56,57 Experimental models indicate that antibodies against the NC16A domain of BP180 are the ­pathogenic antibodies in pemphigus gestationis just as they are for bullous pemphigoid 7,62 Patients with pemphigoid gestationis have an increased incidence of HLAB8 (43–79%), HLA-DR3 (61–80%) and HLA-DR4 (52–53%). The paired haplotypes HLA-DR3 and -DR4 are present in 54% of patients compared with 3% in the general population.1,3,22,63,64 The phenotype, however, does not appear to correlate with the clinical features of pemphigoid gestationis.3,65 Patients with pemphigoid gestationis also have a high incidence (100%) of anti-HLA cytotoxic antibodies, particularly directed against the paternal ­antigens.36,63–66 These are, however, found in 25% of normal multiparous women and therefore their possible role in the pathogenesis of pemphigoid gestationis is uncertain.26 The pathogenesis of pemphigoid gestationis relates to antibody-associated complement fixation with the production of leukocyte chemotactic factors, mast cell degranulation, and associated dermoepidermal separation.36 The presence of pemphigoid gestationis antigen in both skin and amnion raises the possibility that an initial antiplacental antibody cross-reacts with skin, giving rise to the clinical features of pemphigoid gestationis.29 Support for this theory has been the discovery that the HLA antigens -DP and -DR are consistently expressed in the placentas of patients with this condition.64,67 The main antigen present in both the skin and placenta seems to be collagen type XVII and this, associated with genetic predisposition and specific HLA ­genotype, appears to trigger the disease.68

Differential diagnosis The differential diagnosis includes epidermolysis bullosa acquisita, dermatitis herpetiformis, linear IgA disease, and bullous systemic lupus erythematosus (see Table 4.4). Pemphigoid gestationis must also be distinguished from pruritic urticarial papules and plaques of pregnancy (PUPPP) and pregnancy prurigo. PUPPP is predominantly a disorder of first pregnancies. Lesions particularly develop around abdominal striae, and periumbilical sparing is a characteristic feature (Fig. 4.94). Eosinophilic spongiosis and subepidermal blistering may be seen in established lesions and therefore, in the absence of clinical details and immunofluorescence findings, distinction from pemphigoid gestationis may be impossible. Pregnancy prurigo, which typically develops in the third trimester, ­presents with pruritic papules and nodules (Fig. 4.95). Blisters are not a feature. Histologically, the changes are those of a low-grade, non-specific spongiotic dermatitis.

Lichen planus pemphigoides

Fig. 4.94 Pruritic papules and plaques of pregnancy: note the erythematous papules particularly related to the abdominal striae, and characteristic umbilical sparing. By courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK.

Fig. 4.96 Lichen planus pemphigoides: typical lichenoid papules are present on the anterior aspect of the wrist. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.

Fig. 4.95 Pregnancy prurigo: there are erythematous papules and excoriations. Blisters are not a feature of this condition. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Lichen planus pemphigoides Clinical features Lichen planus (lichen ruber) pemphigoides (Kaposi) must be distinguished from the vesicles occasionally seen in lichen planus as a consequence of severe hydropic degeneration (lichen planus vesiculosis).1,2 Rarely, lichen planus is associated with a generally benign, bullous pemphigoid-like disease: lichen planus pemphigoides. This represents a heterogeneous condition characterized by basement membrane antibodies directed towards a number of antigens. Clinically, the pemphigoid-like lesions are usually preceded by typical lichen planus although rarely the blisters may develop first (Fig. 4.96). The bullae, which are most numerous on the extremities, may arise on normal skin, in areas of erythema or on lichenoid papules (Figs 4.97 and 4.98). In some patients the blisters are generalized. Exceptionally, the blisters are localized with typical lichen planus-like lesions elsewhere. A case with single blisters on the soles has been described.3 They are tense, dome-shaped and hemorrhagic or contain clear fluid. Evolution to pemphigoid nodularis-like lesions has been described.4 Lichen planus pemphigoides more commonly affects males and presents most often in the fourth and fifth decades.5,6 Exceptionally, however, cases have been documented in childhood.7–9 All races may be affected.

Fig. 4.97 Lichen planus pemphigoides: note the blisters and erosions arising on an erythematous base. Atypical target lesions are present. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.

Pathogenesis and histological features The lichenoid lesions show the typical histopathological and immunofluorescent changes of lichen planus, but the bullae have features more suggestive of bullous pemphigoid (Fig. 4.99). A variety of findings have been described. Early erythematous lesions show intense dermal edema with a dense ­perivascular and interstitial eosinophil infiltrate; eosinophilic spongiosis may also sometimes be evident. Established blisters are subepidermal and both inflammatory (cell-rich) and cell-poor variants have been documented (Figs 4.100, 4.101).5 Eosinophils are variably present but often may be numerous. Immunofluorescent examination of biopsies from peribullous skin reveals linear deposition of IgG and complement.10–13 The serum contains an IgG antibasement membrane antibody in up to 50–60% of patients. With NaCl-split skin, the antibody generally labels the roof of the blister cavity. Ultrastructural investigations have shown that the level of separation is ­usually through the lamina lucida. By immunoelectron microscopy, the immunoreactants ­typically localize to the hemidesmosome and lamina lucida.5,13,14 Mucous membrane pemphigoid and epidermolysis bullosa acquisita ­(EBA)-like variants have, however, also been documented.15

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Fig. 4.98 Lichen planus pemphigoides: note the intact dome-shaped tense blister. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.

Fig. 4.100 Lichen planus pemphigoides: there is a subepidermal blister.

Fig. 4.99 Lichen planus pemphigoides: the lichenoid papules show typical features of lichen planus.

A number of antigens have been recognized in lichen planus pemphigoides including BP180, BP230, and an as yet uncharacterized 200-kD protein of keratinocyte derivation.1,15–23 The segment of the NC16A domain recognized in lichen planus pemphigoides differs from BP, localizing to MCW-4 (the more C-terminal end of the domain) as opposed to MCW-0 to MCW-3.24,25 Type VII collagen has also been implicated in the EBA-like variant although the immunoblot was negative.15 Although the pathogenesis of lichen planus pemphigoides has not been fully unraveled, it is likely that the basement membrane zone damage associated with lichen planus results in antigen exposure with subsequent autoantibody production and resultant bullous disease. So far, it is uncertain why only a small percentage of patients with lichen planus are affected. The pathogenesis in those patients in whom the blisters develop first is unknown although a different antigen may be involved. Exceptionally, cases have been documented as an adverse drug reaction (e.g., to angiotensin-converting enzyme inhibitors, complicating PUVA therapy, or in a patient taking paracetamol, ibuprofen, and having narrowband UVB).26–35 There has been a suggestion that lichen

Fig. 4.101 Lichen planus pemphigoides: the blister contains eosinophils.

planus pemphigoides might be associated with internal malignancy but the diagnosis lacked substantiation by immunofluorescence studies.36 Two additional cases involving a patient with multiple keratoacanthomas and colonic adenocarcinoma indicating a Torre-Muir-like syndrome and association with retroperitoneal Castleman disease have been noted more recently.37,38

Differential diagnosis Lichen planus pemphigoides differs from typical bullous pemphigoid clinically by its earlier age of presentation and predilection for the lower limbs. In those cases associated with antibodies to BP180, epitope mapping may make the distinction.

Mucous membrane pemphigoid (cicatricial pemphigoid)

Mucous membrane pemphigoid (cicatricial pemphigoid) Mucous membrane pemphigoid represents a spectrum of diseases (e.g., ocular pemphigoid, oral pemphigoid, benign mucous membrane pemphigoid) which affect the mucosa and skin.1–4 With the advent of molecular studies identifying the antigens involved, it is becoming clear that there are a number of ­relatively well-defined clinicopathological variants that arise as a consequence of autoimmune diseases directed against a number of different basement ­membrane antigens. Although multiple systems are often affected, there is increasing ­evidence that pure ocular and oral variants may also be encountered.1,2

Clinical features Mucous membrane pemphigoid is a rare blistering disorder in which mucosal lesions predominate and in which scarring is a characteristic feature (although not generally in the oral lesions).1,2,5 It is often associated with severe morbidity, largely due to the effects of the scarring. As ocular and oral lesions predominate, many patients come to the attention primarily of the dental and oral surgeons or ophthalmologists rather than dermatologists. The incidence is estimated as being between 1:12 000 and 1:20 000 of the population per year.2 It is associated with a female preponderance (2:1) and it not uncommonly presents in the seventh decade. Very rare instances of childhood involvement have been reported.3,6–10 Mucous membrane pemphigoid is a chronic disease and is rarely self-limiting. It shows no racial or geographic predilection. Oral lesions occur in 85–95% of patients and commonly follow mild trauma.11 Bullae, erosions, and erythema most commonly affect the gingival or buccal mucosa, but the hard and soft palate, tongue, and lips are also frequently involved (Figs 4.102, 4.103). Desquamative gingivitis is the most common manifestation.12,13 Patients with this condition present with painful, swollen, erythematous lesions of the gums, which may be associated with bleeding, blistering, erosions, and ulceration.14 Most cases of desquamative gingivitis have lichen planus and only in a low percentage, around 9%, is the process a manifestation of mucous membrane pemphigoid.15 Lesions limited to the oral cavity is a distinctive subset, usually associated with a good ­prognosis although characterized by chronicity.1 Pharyngeal (19% of patients) and esophageal (4% of patients) lesions may be complicated by scarring, resulting in stenoses. Aspiration pneumonia is sometimes a fatal complication. Nasal lesions, which may occur in up to 15% of patients, lead to obstruction and occasionally cicatricial stenoses and septal ­perforation.16 Laryngeal involvement, which occurs in 8% of patients, is sometimes ­complicated by such severe stricture formation and edema that tracheotomy may be a lifesaving necessity.14

Fig. 4.102 Mucous membrane pemphigoid: there is erosion of the buccal mucosa. By courtesy of P. Morgan, FRCPath, London, UK.

Fig. 4.103 Mucous membrane pemphigoid: in addition to erosions, intact blisters are evident. By courtesy of P. Morgan, FRCPath, London, UK.

Ocular lesions, which occur in approximately 64% of patients, are a source of considerable morbidity.17–19 The eye (in particular the conjunctiva) may be a sole site of involvement.14 Early symptoms are those of a non-specific ­conjunctivitis. In more advanced lesions, subconjunctival fibrosis ­develops.20,21 Patients may therefore present with fibrous bands (symblephara) stretching between the fornices and the globe (Fig. 4.104). Eventually, ­contractures may obliterate the conjunctival sac. An essential feature of ocular cicatricial ­pemphigoid is the production of an abnormal tear film. This develops because of diminished lacrimal gland secretion (due to ductal stenosis), impaired ­goblet cell mucus secretion and ocular exposure due to impaired eye ­closure.20 The end result is ocular drying and eventual keratinization of the ocular surface epithelium. Other important sequelae include entropion, trichiasis (maldirected eyelashes, which can result in corneal abrasion), ­erosions and perforation, corneal neovascularization and scarring with opacification (Figs 4.105, 4.106). Primary corneal bullae have been described but are very rare, and erosions are more typical.11 Corneal lesions manifest as ­foreign body ­sensation, photophobia, and eventual ­blindness, which may be bilateral, occurring in up to 16% of patients.9 Ocular involvement may be classified into a number of stages of ­progression (modified Foster staging system).22

Fig. 4.104 Mucous membrane pemphigoid: there is a dense fibrous adhesion (symblepharon) between the conjunctiva lining the eyelid and that covering the globe. By courtesy of the Institute of Dermatology, St Thomas' Hospital, London, UK.

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Fig. 4.105 Mucous membrane pemphigoid: in this advanced case there is entropion and trichiasis (inwardly directed eyelashes). By courtesy of D. Kerr-Muir, MD, St Thomas' Hospital, London, UK.

Fig. 4.107 Mucous membrane pemphigoid: in addition to erosions, marked scarring of the vulva is present. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.106 Mucous membrane pemphigoid: here there is dense corneal scarring with complete opacification. By courtesy of D. Kerr-Muir, MD, St Thomas' Hospital, London, UK.

Ocular involvement should not be confused with drug-induced pemphigoid (pseudo-ocular mucous membrane pemphigoid).2 This is a self-limiting unilateral scarring disease of the eye, which most commonly develops as a consequence of long-term use of eyedrops containing pilocarpine, echothiophate iodide, idoxuridine, timolol, and adrenaline (epinephrine) in the treatment of glaucoma.23,24 Lesions of the female genitalia, which occur in 20% of patients, predominantly affect the labia majora and minora.14 Scarring is common and may occasionally be associated with labial fusion (Fig. 4.107). In males, genital lesions most often affect the prepuce and the glans penis and are occasionally complicated by urethral stricture formation. Anal lesions affect up to 4% of patients and sometimes cause stenosis.14 Cutaneous lesions are found in approximately 25–33% of patients with mucous membrane pemphigoid and most often affect the scalp, face, and neck.2,14,15 In some patients, presentation is similar to that of bullous pemphigoid, and fibrosis is not a feature.2 Lesions are generally few in number and present as itchy, sometimes burning, tense bullae situated on an erythematous or urticated base (Fig. 4.108). They tend to recur on previously affected sites. Rarely, patients may suffer from a transient generalized bullous eruption.14 Nikolsky's sign is negative.21

Fig. 4.108 Mucous membrane pemphigoid: note the localized blistering and erosion with scarring on the lower leg of an elderly female. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

In the Brunsting-Perry variant of localized mucous membrane pemphigoid, scarring lesions are found predominantly on the head and neck (Fig. 4.109).25,26 This condition shows a male predominance (2:1) and presents most often in the sixth decade. The lesions are slowly enlarging, ­atrophic or scarred plaques measuring several centimeters or more in diameter and ­showing vesiculation and/or bullae formation, both centrally and at the enlarging margin.27 The anterior portion of the scalp, the face ­(forehead, ­temporal regions, and cheeks), and the anterolateral aspects of the neck are most often affected.27 In some patients, lesions are few in ­number and, because of crusting, they may be clinically treated as actinic keratosis, thereby ­delaying the diagnosis. Transient mucous membrane lesions may be a feature, but ­scarring is not seen.25

Mucous membrane pemphigoid (cicatricial pemphigoid)

Fig. 4.110 Fig. 4.109 Brunsting–Perry localized pemphigoid: there is extensive alopecia in addition to multiple erosions with scarring. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Mucous membrane pemphigoid: in this example of a recurrent lesion, the subepidermal blister is cell free and there is dermal scarring.

An exceptional case of anti-BP180 mucous membrane pemphigoid ­ resenting with concomitant pemphigus vulgaris limited to mucosal surfaces p has been described.28 Autoimmune blistering diseases are very rarely associated with HIV infection and only a single exceptional case of mucous membrane pemphigoid has been reported in association with HIV.29

Pathogenesis and histological features Mucous membrane pemphigoid has been described as a complication of D-penicillamine therapy for rheumatoid arthritis, practolol and clonidine.14,30 Immunologically, characteristic cicatricial pemphigoid has also been described following acute, severe, ocular inflammation in patients with Stevens-Johnson syndrome.31 Although the results of HLA associations have been variable, an increased frequency of HLA-DR4 and -DQw3 (DQB1*0301) correlates with a heightened risk of developing ocular disease.32 The cutaneous lesions of mucous membrane pemphigoid are often indistinguishable from those of cell-rich (inflammatory) bullous pemphigoid, comprising a subepidermal vesicle containing fibrin, edema fluid, and variable numbers of inflammatory cells. Although eosinophils are usually evident, they tend to be much less numerous than in generalized bullous pemphigoid. The dermis contains a perivascular lymphohistiocytic infiltrate, sometimes with conspicuous plasma cells and accompanied by neutrophils and eosinophils. In older or recurrent lesions, scarring may be a feature (Fig. 4.110). Less commonly, a cell-poor subepidermal blister is seen (Fig. 4.111). In late lesions all that may be observed is a band of scarring in the superficial dermis with or without a subepidermal split. If the latter is present, this is a good clue to the diagnosis, especially in localized variants where the diagnosis is not suspected on clinical grounds. The histopathology of lesions in antilaminin 332 mucous membrane pemphigoid has been studied in a small number of cases.33 The features are nondiagnostic and do not allow distinction from other autoimmune blistering diseases. There is subepidermal blistering and a mild to moderate, superficial mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and neutrophils and/or eosinophils. Scarring is not often seen as biopsies are taken from early lesions. Oral lesions may rarely be characterized by vesiculation developing between the stratified squamous epithelium (mucosa) and lamina propria (Figs 4.112, 4.113). The latter is usually edematous and contains a mixed inflammatory cell infiltrate consisting of lymphocytes, histiocytes, plasma cells, and varying numbers of eosinophils and neutrophils (Fig. 4.114). More commonly, however, the features seen are those of erosions or ulcers lined by granulation tissue or fibrous tissue and showing non-specific acute or chronic inflammation. The histology is frequently modified by intense acute inflammatory changes due to secondary infection.

Fig. 4.111 Mucous membrane pemphigoid: high-power view of a similar lesion

Fig. 4.112 Mucous membrane pemphigoid: oral lesion showing an intact subepithelial blister.

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Fig. 4.113 Mucous membrane pemphigoid: note the preservation of the papillae.

Fig. 4.114 Mucous membrane pemphigoid: in this example the infiltrate consists of lymphocytes and histiocytes. Eosinophils are not a feature.

Conjunctival vesicles or bullae are very rarely seen in ocular cicatricial pemphigoid. Although erosions may be a feature, more commonly one may anticipate conjunctival squamous metaplasia with foci of hyperkeratosis and parakeratosis accompanied by goblet cell depletion (Fig. 4.115).14 The lamina propria is infiltrated by a mixed inflammatory cell population consisting of lymphocytes, plasma cells, mast cells, and occasional eosinophils and neutrophils.21 Granulation tissue may be seen in early lesions, but dense scarring is a feature of the later stage. In more severely affected patients, a variety of intraocular manifestations, including iridocyclitis, rubiosis iridis, and the development of synechiae, may be seen (Figs 4.116–4.118). Laryngeal, pharyngeal and esophageal lesions occasionally show subepithelial bullae, erosions, ulcers, inflammatory changes, and fibrosis are more likely to be seen (Fig. 4.119). Chronic involvement may result in serious stenosis. The histological features of the localized cutaneous scarring (BrunstingPerry) variant are indistinguishable from those of mucous membrane pemphigoid.27 Electron microscopic observations are variable. In some patients, the split is in the lamina lucida with the lamina densa lining the floor of the blister cavity whereas in others, lamina densa is found along the roof of the blister, and occasionally the lamina densa may be split, lining the roof and the floor.2,34 Direct immunofluorescent findings in cicatricial pemphigoid are similar to those found in generalized bullous pemphigoid. Therefore a linear deposit of IgG (and sometimes IgA) and C3 is found at the basement membrane region

Fig. 4.115 Mucous membrane pemphigoid: this specimen of conjunctiva shows complete squamous metaplasia. Neovascularization of the lamina propria is evident. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.

Fig. 4.116 Mucous membrane pemphigoid: section of cornea. The overlying pannus shows squamous metaplasia, chronic inflammation, and neovascularization. Blood vessels are also present in the cornea. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.

Fig. 4.117 Mucous membrane pemphigoid: this section shows iris impaction with anterior synechiae. Iritis and posterior synechiae are also present. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.

Epidermolysis bullosa acquisita (dermolytic pemphigoid)

Fig. 4.118 Mucous membrane pemphigoid: this field shows anterior uveitis. There is inflammation of the iris and ciliary body. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.

Fig. 4.119 Mucous membrane pemphigoid: postmortem specimen showing laryngeal erosion, ulceration, and scarring.

of perilesional mucosa (the site of choice) or perilesional skin in approximately 80–97% of patients.35–39 The presence of IgA at the basement membrane region accompanied by IgG and C3 is a diagnostic pointer towards cicatricial pemphigoid.2 Examination of the oral mucosa is also of value in the diagnosis of ocular disease.2 Direct immunoperoxidase of paraffin-embedded tissue can be a satisfactory alternative if a specimen has not been taken for direct immunofluorescence studies.40 Circulating antibasement membrane zone autoantibodies (IgG and/or IgA) are sometimes present (26–36%) and are usually of low titer.36,41,42 Substitution of normal buccal mucosa as substrate does not increase the yield of circulating antibodies.41 The antibody consists predominantly of IgG4 and IgG1 ­subclasses, the presence of the latter conferring complement-­fixing ­ability.43 The presence of IgA may be linked to the mucosal membrane ­distribution of this disease.44 Investigations of cicatricial pemphigoid antibodies using 1 M NaCl-split skin have yielded variable results.45–47 Circulating antibodies may be detected

in from 50% to 100% of cases with active disease.48,49 Although the majority of sera have reacted with the epidermal side of the split, some have labeled the floor (dermal side, subsequently shown to be due to antilaminin 332 antibodies: see below), and exceptionally both the roof and the floor have been labeled.45–49 There is also variation in indirect immunofluorescence findings depending upon the predominant site of involvement. Thus, for example, split skin indirect immunofluorescence may be positive in up to 81% of patients with combined skin and mucosal disease whereas much lower figures have been found in patients with mucosal disease only (18%) or isolated ocular disease (7%).2,50 The immunofluorescent findings in the Brunsting-Perry variant are the same as those described for mucous membrane pemphigoid.51–54 Immunoelectron microscopic observations in mucous membrane pemphigoid have revealed two patterns of immune reactant deposition. IgG and C3 may be localized to the lower lamina lucida and lamina densa or else ­identified overlying the hemidesmosome.55–61 There is no involvement of the sublamina densa region. The variation can be explained by the different ­target antigens involved, i.e., BP180, laminin 332 or β4 integrin. In the Brunsting-Perry variant of localized chronic pemphigoid the immunoreactants are localized within the lamina lucida and on the undersurface of basal keratinocytes.62 In a single case it was demonstrated that the ­antibodies in the serum reacted with the C-terminal domain of the BP180 (BPAG2) protein.63 Additionally, however, the complement components C3 and C4 may also be detected within the lamina densa and the upper papillary dermis. It is ­suggested that this latter finding might account for the scarring characteristic of this disease process.62 A number of subsets of cicatricial pemphigoid have been delineated by antigen analysis including variants characterized by antibodies to BP180, laminin-332, and β4 integrin.43,47,57,64–74 Traditionally, this group of diseases has been classified together, but the increasing demonstration of autoimmune reactions to different cell adhesion molecules will likely ultimately lead to subtyping of this disease similar to the cutaneous forms. For now, since the clinical features are more uniform than those seen in the skin, these mucosal cases are considered together. BP180 (collagen XVII) antibodies react with at least two different sites on the extracellular domain of BP180. One is located on the noncollagenous domain NC16A; the other is located within the carboxy-terminal region.68,75–78 Antilaminin-332 (also called epiligrin) antibodies to the γ3 subunit (sometimes accompanied by antilaminin type-6 antibodies) are present in a minority of cases and, although the antibodies are usually IgG, IgA, and IgE, antibodies against laminin-332 may also be found in a subset of patients.79 Patients with antilaminin-332 antibodies have been classified as having antiepiligrin mucous membrane pemphigoid (AEMMP). Some of such cases are associated with internal malignancies (including lung, colon, endometrium, stomach, ovary, pancreas, prostate, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and acute myeloblastic leukemia).80–84 Integrin has been implicated in patients with ocular disease and an as yet unidentified 45-kD antigen, which binds to the epidermal side on split skin immunofluorescence, has been identified in some patients with IgA antibodies.70,72,73 Autoantibodies to type VII collagen is of importance in some cases of Brunsting-Perry cicatricial pemphigoid (these patients might be better classified within the epidermolysis bullosa acquisita spectrum, see below).85

Differential diagnosis Apart from the presence of scarring in older lesions, mucous membrane pemphigoid is indistinguishable from bullous pemphigoid.

Epidermolysis bullosa acquisita (dermolytic pemphigoid) Epidermolysis bullosa acquisita (dermolytic pemphigoid) is a rare, chronic blistering disease, which is characterized by variable clinical presentations and which may therefore be mistaken for a number of other blistering disorders including congenital epidermolysis bullosa and the other acquired autoimmune bullous dermatoses.1,2 Annual incidence figures from France and Central Germany are 0.17–0.26 per million of the population.3,4 In contrast to its congenital counterpart, epidermolysis bullosa acquisita (EBA) usually

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Inherited and autoimmune subepidermal blistering diseases develops in adult life although cases in childhood have been documented.5,6 Initially it was characterized as a porphyria cutanea tarda-like mechanobullous dermatosis. More recently, however, patients have been described in whom the disease has presented as a generalized inflammatory bullous dermatosis.1 For many decades the diagnosis of EBA was one of exclusion. As a result of immunofluorescence and immunoultrastructural techniques ­combined with immunoblotting and immunoprecipitation, EBA is now ­recognized as an autoimmune dermatosis, type VII collagen (290 kD) representing the target antigen.1,8 A 145-kD antigen is also sometimes identified. This represents a cleavage product of the 290-kD antigen.

Clinical features EBA was defined in 1971 by Roenigk and colleagues5 as follows: • clinical lesions resembling dystrophic epidermolysis bullosa (blisters developing on the hands, feet, elbows, and knees following mild trauma and complicated by atrophic scarring, milia formation and nail dystrophy), • an adult onset, • a negative family history of epidermolysis bullosa, • exclusion of all other recognized bullous dermatoses including porphyria cutanea tarda, bullous pemphigoid, dermatitis herpetiformis, pemphigus, erythema multiforme, and bullous drug reactions.9 It has a wide age incidence ranging from 11 to 77 years, with a mean age of 47 years. It is associated with a slight female predominance. In addition to the mechanobullous classical form of EBA, inflammatory variants, including bullous pemphigoid-like, mucous membrane pemphigoidlike, and linear IgA disease-like variants, may also be encountered.1,10,11 A case of familial EBA has been described.12

e­ pidermolysis bullosa. Scarring may then be extreme with resultant contractures and syndactilism. Rarely, esophageal involvement has been documented with resultant stricture formation.10,13,14

Bullous pemphigoid-like EBA This is the most commonly encountered inflammatory variant.15 On the basis of split skin indirect immunofluorescence (see below) it has been suggested that a BP presentation may account for up to 50% of cases of EBA and that 10–15% of patients diagnosed as BP, in fact, have EBA.15 Other authors, however, have found that EBA is very rare compared to BP, the relative incidence being approximately 25–50 cases of BP for every one case of EBA diagnosed.16,17 Patients present with a generalized eruption of large tense blisters, which are often associated with erythema and show a predilection for the flexural and intertrigenous areas.18,19 Pruritus is common.15 Skin fragility is typically absent and scarring and/or milia are not usually features unless the patient concomitantly shows or evolves towards a mechanobullous phase.1,15 Infrequently, the clinical manifestations may resemble dermatitis herpetiformis (Fig. 4.122). Exceptionally, prurigo nodularis-like lesions may be seen.20

Classical variant The classical variant is the most commonly encountered variant of EBA. Patients present with a porphyria cutanea tarda-like illness showing extreme skin fragility, developing erosions, blistering and crusting in response to mild trauma including shearing forces.5 Lesions are located on the backs of the fingers and hands in particular and at other sites that are susceptible to trauma, including the knees, elbows, and buttocks, but virtually any site may be affected (Fig. 4.120).1,5 The blisters are characteristically noninflammatory, painless, and tense, and may contain clear or bloodstained fluid. Healing is usually associated with postinflammatory hyperpigmentation, considerable scarring, and atrophy. Milia are frequently conspicuous, and nail changes, including distal onycholysis, dystrophy, and anonychia with nail bed scarring, are common complications (Fig. 4.121). More widespread involvement may resemble dominant or more often recessive dystrophic

Fig. 4.120 Epidermolysis bullosa acquisita: there is a tense fluid-filled blister on the ankle. An old lesion is also evident. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.121 Epidermolysis bullosa acquisita: conspicuous milia are present on the back of the hand. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.122 Epidermolysis bullosa acquisita: in this patient with the dermatitis herpetiformis-like inflammatory variant, blisters, erosions, and erythematous plaques are evident on the elbow. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Epidermolysis bullosa acquisita (dermolytic pemphigoid)

Mucous membrane pemphigoid-like variant Some patients present with a mucous membrane pemphigoid-like variant, characterized by mucous membrane involvement. The oral cavity is commonly affected. Erosions, ulcers, and blisters may be seen on the tongue, gums, ­palate, and buccal mucosa.11 Rarely, the larynx and esophagus are affected with ­resultant stricture formation.10 The anus, vulva, vagina, and bladder can very occasionally be involved.21 Conjunctival lesions are an important, but infrequent, cause of morbidity.10,11,22 Symblepharon, epiphora, and even blindness may occur. Alopecia is sometimes an additional feature.7,13

Brunsting-Perry variant Some patients with the Brunsting-Perry variant of mucous membrane pemphigoid (characterized by blistering and scarring confined to the head and neck) have antibodies against type VII collagen and therefore might better be classified within the epidermolysis bullosa acquisita spectrum.7,23,24 Facial involvement predominates.24,25 A very unusual localized case with periorbital papulovesicular blisters has been reported.26

Linear IgA disease-like variant (IgA-EBA)

Fig. 4.123 Epidermolysis bullosa acquisita (classical variant): there is a cell-free subepidermal vesicle. Note the dermal scarring.

Epidermolysis bullosa acquisita may also present as a linear IgA disease-like variant in which both adult and childhood patients have IgA autoantibodies directed against type VII collagen (see below).27–29 In adults, ocular involvement is often severe and blindness is not uncommon.28

Childhood EBA Childhood EBA is extremely rare. Mucosal disease is often severe, and clinical manifestations have included classical bullous pemphigoid and linear IgAlike variants.6,8,30–33

Systemic disease Epidermolysis bullosa acquisita has long been known to be associated with a number of systemic illnesses, many with an immunologically mediated pathogenesis. Most important are inflammatory bowel disease and diabetes mellitus.2,10,15,34–45 Approximately 30% of patients with EBA manifest inflammatory bowel disease, predominantly Crohn's disease.42,46 Control of this improves the skin condition in some patients. Interestingly, although up to 68% of patients with inflammatory bowel disease have antibodies against collagen type VII, only very few develop EBA.47 Presentation as a paraneoplastic phenomenon in association with internal malignancy has also on occasion been described.48,49

Fig. 4.124 Epidermolysis bullosa acquisita (classical variant): high-power view. There is fibrin along the floor of the blister cavity. Note the absence of inflammatory cells.

Pathogenesis and histological features The histological features are somewhat variable depending upon whether a mechanobullous or an inflammatory lesion is biopsied. The mechanobullous lesion is characterized by a bland, ‘cell-free’ ­subepidermal vesicle containing only a few erythrocytes and a little fibrin (Figs 4.123, 4.124). Usually, no significant inflammatory cell infiltrate is present either within the blister cavity or in the adjacent or underlying dermis. Sometimes, however, a small number of neutrophils, histiocytes, and eosinophils may be present. The basement membrane lines the roof of the blister. Marked scarring of the adjacent dermis is often a feature and milia are ­frequently identified. The inflammatory variant is characterized by a subepidermal vesicle accompanied by a mixed inflammatory cell infiltrate comprising lymphocytes, histiocytes with prominent neutrophils, and eosinophils. Neutrophils are usually the predominant cell type and in incipient lesions they may be identified in a linear distribution adjacent to the epidermodermal junction.15 Occasionally, however, eosinophils predominate.24 Such inflammatory lesions may resemble bullous pemphigoid or dermatitis herpetiformis (Figs 4.125, 4.126).2,50 Oral lesions show similar features of submucosal vesiculation with an erythrocyte and inflammatory cell content. By direct immunoperoxidase using paraffin-embedded material, type IV collagen is found in the roof of the blister cavity (see Fig. 4.8). Ultrastructurally, the level of the split in EBA is situated within the superficial dermis immediately below the lamina densa (Fig. 4.127).51–53 The basal

keratinocytes appear normal. Anchoring fibrils have been variably reported as reduced in number or absent.47–53 An occasional finding is the presence of electron-dense, amorphous granular material within the superficial papillary dermis close to, but separated from, the lamina densa (Fig. 4.128).9,35 When present, the split is usually below the electron-dense amorphous material, which is therefore located within the roof of the blister. By direct IMF, IgG and C3 are present in a linear distribution along the basement membrane region (identical to BP) in a very high proportion of cases of EBA (Fig. 4.129).9,10,36 Less commonly, IgM, IgA, properdin, and factor B may also be identified.1,52,53 In linear IgA disease-like patients, IgA may be present in the absence of IgG.27–29 Positive direct immunofluorescence has also been reported at a variety of other sites including the oral mucosa, conjunctiva, cornea, esophagus, duodenum, and bladder.9,28,34 IgG antibasement membrane antibodies may be identified in 25–50% of patients, thereby increasing the similarity to BP.2,47,51,54 In many patients the antibasement membrane antibodies are associated with complement-fixing properties.55 With split skin indirect IMF, which is more sensitive than conventional indirect IMF, the immunoreactants line the floor of the induced blister cavity.56–59 Direct and indirect immunoelectron microscopic studies have determined that the immunoreactants lie on or below the lamina densa, corresponding to the site of the electron-dense amorphous material mentioned above

139

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Inherited and autoimmune subepidermal blistering diseases

A

A

B

B

Fig. 4.125 (A, B) Inflammatory epidermolysis bullosa acquisita: in this bullous pemphigoid-like variant, subepidermal blistering is associated with an eosinophil-rich infiltrate.

Fig. 4.127 (A, B) Epidermolysis bullosa acquisita: electron micrograph showing the lamina densa in the roof of the blister. (BC, blister cavity.)

Fig. 4.126 Inflammatory epidermolysis bullosa acquisita: dermatitis herpetiformis-like variant, with a neutrophil-rich infiltrate.

Fig. 4.128 Epidermolysis bullosa acquisita: occasional deposits of finely granular electrondense material (immunoreactant) as seen in this field may be a useful diagnostic pointer.

Epidermolysis bullosa acquisita (dermolytic pemphigoid)

Fig. 4.129

Fig. 4.131

Epidermolysis bullosa acquisita: (left) direct immunofluorescence shows linear IgG deposition along the basement membrane region; (right) with split skin the immunoreactant lines the floor of the induced lesion. By courtesy of Department of Immunofluorescence, Institute of Dermatology, London, UK.

Epidermolysis bullosa acquisita: immunogold preparation showing localization of the immunoglobulin to the anchoring fibrils. By courtesy of H. Shimizu, MD, Keio University School of Medicine, Tokyo, Japan.

Fig. 4.132 Fig. 4.130 Epidermolysis bullosa acquisita: direct immunoelectron microscopy showing reactant deposition below the lamina densa.

(Fig. 4.130).1,51,52,60,61 Immunogold labeling confirms that the immunoglobulin deposits are related to the anchoring fibrils (Fig. 4.131).62 As a consequence of these additional observations, a modified set of criteria for the diagnosis of EBA has been recommended:1,63 • clinical lesions of trauma-induced bullae occurring over the joints of the hands, feet, elbows and knees, atrophic scars, milia and nail dystrophy, or else presentation as a clinically inflammatory bullous or mucous membrane pemphigoid-like process, • postinfancy onset of the disease, • no family history of EBA, • exclusion of other bullous diseases, • IgG at the basement membrane zone on direct immunofluorescence, • demonstration of blister formation beneath the lamina densa, • demonstration of IgG associated with anchoring fibrils beneath the basal lamina by immunoelectron microscopy, • localization of the immunoreactants to the floor of 1 M NaCl-split skin by direct and or indirect immunofluorescence. The EBA antigen (290 kD) is the globular (noncollagenous) carboxyl terminus of type VII procollagen (Fig. 4.132).64–68 Type VII collagen is the major constituent of anchoring fibrils which anchor the basement membrane

Epidermolysis bullosa acquisita: there are two distinct antigens: one the 290-kD major antigen; the other the 145-kD minor antigen. By courtesy of I. Leigh, MD, Royal London Hospital Trust, London, UK.

through the lamina densa to the connective tissue constituents of the adjacent dermis and is composed of three identical alpha-chains (each 290 kD). It is synthesized by both human keratinocytes and fibroblasts in culture, and is found in other mammalian skin including dog, cat, guinea pig, rat, mouse, and hamster, but not in avian, reptilian, amphibian, or fish skin.69–72 Type VII collagen has also been identified within the esophagus, mouth, anus, and vagina. It has a high affinity for fibronectin, which is thought to be responsible (at least in part) for adhesion between cells and matrix within the dermis.73 The interaction between the EBA antibody and type VII collagen is thought to somehow upset this delicate relationship with consequent dermoepidermal separation.74 Passive transfer of human EBA autoantibodies to mice and immunization of mice with type VII collagen both lead to EBA disease models, confirming the importance of this autoantibody.75–78 An animal model and human antibody characterization indicate that the pathogenic antibodies of epidermolysis bullosa acquisita are often against the cartilage

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Inherited and autoimmune subepidermal blistering diseases matrix protein subdomain of the N-terminal noncollagenous domain of type VII collagen.79 In some cases of inflammatory EBA the antibodies react against epitopes in the triple-helical collagenous domain.80 The parallel between EBA and BP is obvious and it is tempting to extrapolate a similar downstream pathogenesis after autoantibody binds to its protein target.81 Although the current concept for EBA points to such a similarity, additional confirmatory evidence is required. Recent studies have shown that the pathogenesis is related, at least in part, to neutrophil recruitment mediated by complement activation, and the generation of complement-derived chemotactic activity (C5A) at the epidermal basement membrane region.74 Experimental models in which immune complexes are produced by treating normal skin in organ culture with EBA complement-fixing antibodies has been shown to result in complement-dependent neutrophil migration to the basement membrane region and eventual dermoepidermal separation.55,82 Lack of complement-fixing function in the autoantibodies does not result in tissue injury in one model.83 The precise mechanism whereby such blisters evolve is unknown, but it has been suggested that leukocyte-derived proteases and reactive oxygen intermediates may be important.54 The pathogenesis of the ‘cell-free’ mechanobullous variant is poorly understood. It is also associated with antibasement membrane antibody, but there is little if any evidence for neutrophil chemotactic activity. It has been proposed that separation at the dermoepidermal junction may result from an abrogation of affinities between the type VII collagen and laminin-332 in addition to matrix proteins such as fibronectin due to a direct effect of autoantibody deposition at that site.1,84–86 An additional potential mechanism proposed is a direct effect of the autoantibody on type collagen VII antiparallel dimer assembly leading to diminished anchoring fibril formation.1,87 The finding of domain specificity in EBA autoantibodies will direct focus toward the function of this cartilage matrix protein subdomain.81 It is intriguing that the pathogenetic autoantibodies in EBA are against type VII collagen, the same protein genetically interrupted in dystrophic epidermolysis bullosa, leading to nonfunctional anchoring fibrils. Nonetheless, the clinical presentation of EBA is broad and includes features not seen in dystrophic EB, such as bullous pemphigoid-like lesions.

Differential diagnosis ‘Cell-free’ EBA must be distinguished from congenital EB, porphyria cutanea tarda, pseudoporphyria, and cutaneous bullous amyloidosis. Diagnosis can be achieved easily with the use of immunofluorescence. Inflammatory EBA can be distinguished from bullous pemphigoid, mucous membrane pemphigoid, and linear IgA disease by split skin IMF and, when necessary, by Western blot (see Table 4.4). It is also important that dermoepidermal separation due to autolysis is not confused with in vivo blister formation. In autolysis the epithelium typically shows marked eosinophilia and the nuclei are often lost.

Fig. 4.133 Bullous systemic lupus erythematosus: West Indian female with perioral blistering. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

both sexes may develop the disease (Fig. 4.133).4,6–11 Presentation in children is exceptional.12,13 Patients present with a widespread, sometimes pruritic, tense, vesiculobullous eruption that may affect both sun-exposed and nonsun-exposed skin (Figs 4.134–4.136). The eruption can precede the onset of SLE or develop subsequently.8,14 Lesions develop on flexural and extensor surfaces, and mucosal (mouth and pharynx) lesions have been documented.4,8,15 A predilection for involvement of the upper trunk and supraclavicular regions has been reported.4 Lesions may arise against a background of ­erythema or less commonly urticaria. Unlike EBA with which this disease shares much in common, mechanobullous lesions are not seen, nor is there ­evidence of scarring.4 Milia formation, although rare, has been recorded on two occasions and in both instances affected children.9,10 Postinflammatory ­hyperpigmentation is a not uncommon complication. Surprisingly, patients with bullous SLE do not usually develop other cutaneous manifestations of lupus. Bullous SLE has been recorded in a patient whose primary ­disease developed as a consequence of hydralazine therapy and identical features (including immunological) have been recorded in a patient with mixed ­connective tissue disease.16

Bullous systemic lupus erythematosus Blisters may rarely develop as a manifestation of systemic lupus erythematosus (SLE). They can therefore arise in a background of vasculitis or complicate sunburn and photosensitivity.1,2 Occasionally vesicles form after extreme basal cell hydropic change and consequent dermoepidermal separation.3 Patients with SLE manifest a wide range of antibodies resulting in numerous complications, which include the development of autoimmune bullous dermatoses such as bullous pemphigoid, dermatitis herpetiformis, pemphigus vulgaris, pemphigus foliaceus, linear IgA disease, and ­epidermolysis bullosa acquisita.4,5 More recently, an apparently unique dermatosis ­comprising a widespread vesiculobullous eruption characterized by a ­dermatitis herpetiformis-like histology, linear basement ­membrane zone ­antibody deposition (reacting with type VII collagen), and a striking response to dapsone has been described in patients with SLE.6 This c­ onstitutes bullous SLE.

Clinical features Bullous SLE – also termed bullous eruption of SLE, vesiculobullous SLE, SLE with herpetiform blisters – tends to present in the second and third decades and although young black women are most often affected, all ages, races, and

Fig. 4.134 Bullous systemic lupus erythematosus: in this example there is a conspicuous inflammatory background. By courtesy of the Institute of Dermatology, London, UK.

Bullous systemic lupus erythematosus

Fig. 4.135

Fig. 4.137

Bullous systemic lupus erythematosus: numerous erosions are present over the chest, shoulders, and upper arms. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Bullous systemic lupus erythematosus: this shows the typical features of a subepidermal, neutrophil-rich vesicle.

Fig. 4.138 Fig. 4.136 Bullous systemic lupus erythematosus: tense bullous pemphigoid-like lesions. By courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features Patients with bullous SLE (and EBA) have a significantly higher incidence of HLA-DR2 compared to the normal population.4 This is thought to be associated with an increased risk of developing autoimmune diseases.17 The histological features of bullous SLE (BSLE) are those of a subepidermal vesicle, often indistinguishable from dermatitis herpetiformis. The roof is usually intact and the blister cavity contains fibrin with large numbers of neutrophils and karyorrhectic debris (Fig. 4.137). Occasionally ­lymphocytes, histiocytes, and eosinophils are also evident.4 The adjacent, nonbullous skin characteristically shows subepidermal neutrophil microabscesses (Fig. 4.138). The upper dermis contains a perivascular mixed inflammatory cell infiltrate consisting of neutrophils, occasional eosinophils, lymphocytes, and histiocytes. Sometimes the features of a leukocytoclastic vasculitis are also present (Figs 4.139–4.141). Electron microscopy shows that the site of the split is below the lamina densa.4

Bullous systemic lupus erythematosus: the presence of a neutrophil abscess in the papillary dermis increases the histological similarity of this condition to dermatitis herpetiformis.

Using direct immunofluorescence, the disease is characterized by the presence of immunoglobulin and complement at the epidermal basement membrane region of both lesional and perilesional skin. Immunoglobulins are frequently multiple: IgG is present in 100% of patients, IgA in 67%, and IgM in 50%.4,7,8,17,18 Two patterns are recognized: granular in 40% of cases and linear in 60%.8 Sometimes immunoreactants are also present within the walls of the upper dermal vasculature, particularly venules.4 Indirect immunofluorescence using 1 M NaCl-split skin as substrate shows the presence of a low titer antibasement membrane antibody in those patients who demonstrate linear positive direct IMF (type 1 BSLE).1,4,8,15,16,19–22 The antibodies generally label the floor of the blister cavity although a roof (epidermal) variant has rarely been described.8 Those that are negative on indirect IMF have been classified as type 2 BSLE.4 Type 3 BSLE refers to those cases in which the ­target antigen is an epidermal rather than dermal epitope.6 Direct immunoelectron microscopy shows that the immunoreactants are present on and immediately below the lamina densa, obscuring the anchoring

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Inherited and autoimmune subepidermal blistering diseases

Fig. 4.139 Bullous systemic lupus erythematosus: this scanning view shows a central focus of subepidermal vesiculation. Striking inflammatory changes outline the dermal vasculature.

fibrils, and also occasionally somewhat deeper in the papillary dermis similar to those seen in nonbullous SLE.4, 23–25 The antibody binds to the lamina densa and sublamina densa in a manner identical to that seen in epidermolysis bullosa acquisita.4,24 Western immunoblot has shown that these antibodies bind to antigens of 290 kD and 145 kD as described for EBA (i.e., type VII collagen).19 Recently, rare patients with SLE have been shown to have circulating antibodies to type VII collagen in the absence of blisters, and occasional patients with bullous SLE have been shown to have antibodies which bind to both the roof and the floor of NaCl-split skin, suggesting that a number of different basement membrane antigens may be involved.1,4 The target antigen in the epidermal variant of bullous SLE has not yet been identified although bullous pemphigoid antigen 1 was identified in addition to type VII collagen and laminins-332 and -311 in one patient with combined epidermal and dermal staining on NaCl-split skin indirect IMF, most likely representing a manifestation of postinflammatory epitope spreading.25 The bullous SLE antibodies are associated with complement activation activity, which results in neutrophil migration and adherence to the basement membrane region.4 Neutrophil enzyme release is associated with basement membrane damage and subsequent dermoepidermal separation.

Differential diagnosis Bullous SLE shows obvious overlap with EBA. There are, however, a number of discriminatory features. Bullous SLE is not associated with a mechanobullous pathogenesis and scarring is not a feature. It develops most often in a younger age group than EBA. The dermatitis herpetiformis-like histological features are rarely seen in EBA and probably of greatest importance; bullous SLE responds dramatically to dapsone therapy, but EBA does not.3

Dermatitis herpetiformis Clinical features

Fig. 4.140 Bullous systemic lupus erythematosus: this view shows florid leukocytoclastic vasculitis.

Fig. 4.141 Bullous systemic lupus erythematosus: this is a close-up view of the subepidermal vesicle shown in Figure 4.139.

Dermatitis herpetiformis and celiac disease are highly interrelated conditions and best regarded as variable expressions of a common inherited tendency to autoimmune disease. Dermatitis herpetiformis (Duhring-Brocq disease) is a widespread, intensely pruritic, papulovesicular eruption affecting all ages, but particularly people in their second to fourth decades.1–4 The male to female ratio is 2:1. The incidence of dermatitis herpetiformis is highest in Northern Europe, Scotland, and Ireland.2,5,6 It is less frequently seen in the United States. Caucasians are mainly affected, the disease being rare in Asians and blacks. Case clustering is common and familial involvement (either dermatitis ­herpetiformis or celiac disease), possibly autosomal dominantly inherited, has been documented in up to 10.5% of cases.2,7 Relatives of patients with ­dermatitis herpetiformis have an increased risk of developing celiac disease.2 The lesions, which may be symmetrical, are grouped mainly on the ­posterior scalp, shoulders, back, buttocks, and extensor aspects of the limbs (Figs 4.142, 4.143). Scratching is often severe and therefore excoriation and/ or lichenification typically predominate with intact vesicles rarely being seen. However, occasionally, larger blisters similar to those found in bullous ­pemphigoid may be evident. Patients sometimes present with urticarial plaques and crusted erosions.2 Oral involvement is rare.3 Rarely, the initial presentation may be with localized lesions in areas such as the scalp.8 The latter is not infrequently involved in more generalized disease. In one patient, the presenting symptom was petechiae on the fingertips.9 The clinical response to dapsone (50–200 mg/day) is dramatic; therefore, the drug is commonly administered for diagnostic as well as ­therapeutic ­purposes. Relief from pruritus occurs within a few hours of commencing treatment and is soon followed by clearing of the rash. The eruption returns 2–3 days after dapsone is discontinued. The disease persists for many years and is usually lifelong. A gluten-free diet may result in prolonged remission in some patients or lowering of the daily dapsone requirement in others. At least 65–75% of patients with dermatitis herpetiformis show histological evidence of celiac disease (gluten-sensitive enteropathy, GSE). However, only

Dermatitis herpetiformis

Pathogenesis and histological features

Fig. 4.142 Dermatitis herpetiformis: excoriations are present on the elbow and back of the arm. Intact blisters are uncommon in dermatitis herpetiformis because of the intense pruritus. By courtesy of the Institute of Dermatology, London, UK.

Patients with dermatitis herpetiformis (and celiac disease) have a high incidence of HLA-B8 (80–90%), HLA-DR3 (90–95%) and HLA-DQ2 ­(95–100%) compared to a normal control population (21%, 23%, and 40%, respectively).3,24–27 More recent studies, however, have demonstrated that the increased incidence of HLA-B8 and -DR3 are due to positive linkage disequilibrium. 28 The most current data suggest that the significant positive HLA association in dermatitis herpetiformis lies with the class II antigen DQ2.2,29 These HLA associations can be helpful diagnostically.30 All patients with dermatitis herpetiformis have granular deposits of IgA in the dermal papillae of perilesional skin, and many also show in vivobound fibrin (Fig. 4.144).31,32 IgA has also been identified in the oral mucosa.33 A  granular linear pattern may be seen and it seems to be more common than previously reported.34 In patients with a linear pattern, careful attention should be paid to the presence of granularity to avoid a misdiagnosis of ­linear IgA disease. Recently, a fibrillar pattern has also been documented.35 Two of the three patients reported with this pattern had clinical features of dermatitis herpetiformis but lacked antitransglutaminase and antiendomysial antibodies. Other immunoglobulins are not usually found, but C3 is often present.36 This is associated with formation of the membrane attack complex (C5–C9), which is thought to result in neutrophil chemo­ taxis and the evolution of subepidermal vesiculation.3,37 Cutaneous IgA

A

Fig. 4.143 Dermatitis herpetiformis: the buttocks are frequently affected. By courtesy of the Institute of Dermatology, London, UK.

about 20% have clinical manifestations of malabsorption, these being usually mild.10–15 The actual incidence of celiac disease is likely to be higher because the mucosal abnormality in dermatitis herpetiformis is patchy and may be missed unless multiple jejunal biopsies are taken.16–18 Interestingly, patients who apparently do not have enteropathy may develop the ­condition when challenged with large doses of gluten (latent GSE).13 It is therefore believed that all patients with dermatitis herpetiformis have GSE to a greater or lesser extent.1–3 Relatives of patients with dermatitis herpetiformis may show no evidence of the skin disease, but can have subclinical or overt s­ ymptoms of the enteropathy. Patients with dermatitis herpetiformis may have antigastric parietal cell antibody (10–25%), gastric hypochlorhydria (50–90%), and gastric ­atrophy (50–70%).3 They may also have antithyroid antibodies and show an increased incidence of thyroid disease, insulin-dependent diabetes mellitus, and connective tissue diseases including systemic lupus erythematosus and Sjögren's syndrome.19,20 As with isolated celiac disease, there is an increased risk of intestinal lymphoma.21 Exposure to iodine may trigger or flare the disease.22,23

B

Fig. 4.144 Dermatitis herpetiformis: direct immunofluorescence showing (A) deposits of granular IgA in the dermal papillae; (B) fibrin deposition in the dermal papillae. (A) By courtesy of the Department of Immunofluorescence, Institute of Dermatology, London, UK.

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146

Inherited and autoimmune subepidermal blistering diseases deposits may still be detected after dapsone therapy. They do, however, sometimes disappear after a prolonged gluten-free diet.2 Cutaneous IgA deposition is not seen in patients with celiac disease.2 Electron microscopy reveals electron-dense, amorphous granular deposits in the superficial dermis showing no particular relationship with the basement membrane region or any other specific structure.38,39 Immunoelectron microscopic observations initially suggested that the IgA deposits were associated with elastic-containing microfibrillar bundles, but more recently published work using antifibrillin antibodies has discounted this theory.38,40 Antigliadin antibodies, which are often used to assess celiac disease status, are of limited value in the diagnosis of dermatitis herpetiformis.13 They have high specificity, but low sensitivity.13 Anti-smooth muscle endomysial antibody correlates with the gluten-sensitive state and appears before the development of any small intestinal histological abnormality in patients with dermatitis herpetiformis.13,41,42 Such endomysial antibodies are present in up to 70% of patients and are highly specific; they react with tissue transglutaminase (tTG) (antitransglutaminase antibodies).43 Antibodies against epidermal transglutaminase are found more frequently than the latter. Antitransglutaminase antibodies, particularly those to epidermal tranglutaminase, seem to be the most sensitive serological marker of dermatitis herpetiformis.33,44 Patients with high levels of IgA and IgG transglutaminase antibodies usually have more prominent mucosal villous atrophy and more severe clinical disease.45 Gliadin is an important substrate for tissue transglutaminase forming gliadin–gliadin or gliadin–tTG complexes.46 Circulating IgA antibodies to tTG are pathognomonic of dermatitis herpetiformis and celiac disease.47 The gut subtype of transglutaminase is TG2 while that in the skin is TG3. Cross-reactivity between these homologous proteins or antigenic drift may underlie some of the mucosal and cutaneous features of this condition.48,49 Whatever the underlying mechanism, the IgA in some way ‘fixes’ in the skin, resulting in complement activation via the alternative pathway.50–52 Neutrophil chemotaxins are then released and the ensuing inflammatory reaction leads to dermal papillary edema, fibrin deposition, and eventual vesiculation. There may be a role for cell-mediated ­immunity in this disease as well, perhaps involving γ/δ T cells.53 The histological hallmark of dermatitis herpetiformis is the dermal papillary neutrophilic microabscess, best seen in early erythematous lesions or well away from the blister in an established eruption (Fig. 4.145).54–56 Occasionally,

many levels of the biopsy will have to be examined before a microabscess is found. Abscess evolution depends upon the initial presence of fibrin and ­polymorphs within the tips of the dermal papillae (Fig. 4.146), both of which are associated with degenerative changes of the collagen and the development of edema. Development of small subepidermal microvesicles follows, leading on to the formation of multilocular subepidermal blisters. Typically, the blister cavity contains edema fluid, a reticular network of fibrin, and numerous polymorphs (Figs 4.147, 4.148). In contrast to bullous pemphigoid, the floor of the blister cavity usually shows effacement of the dermal papillary outline. Within the dermis is a mixed inflammatory cell infiltrate consisting of lymphocytes, histiocytes, and abundant neutrophils. Leukocytoclasis (nuclear dust, Fig. 4.149) is characteristic. Although blood vessels frequently show endothelial swelling, there is no evidence of vasculitis. Occasionally, eosinophils are quite numerous in the infiltrate, but usually they are late arrivals, appearing 24–48 hours after the neutrophils. On occasions, biopsies from typical dermatitis herpetiformis may show acantholysis, a cause of considerable confusion (Fig. 4.150).

Fig. 4.146 Dermatitis herpetiformis: in this early lesion, there are thin strands of fibrin visible above the neutrophilic infiltrate.

Fig. 4.145 Dermatitis herpetiformis: biopsy from an early lesion showing conspicuous neutrophil microabscesses.

Fig. 4.147 Dermatitis herpetiformis: an established subepidermal blister. Although early lesions are usually multilocular, by 24–48 hours the lesion becomes unilocular.

Linear IgA disease

A

Fig. 4.148 Dermatitis herpetiformis: floor of the blister in Figure 4.147 showing an intense neutrophil infiltrate.

B

Fig. 4.150 (A, B) Dermatitis herpetiformis: in this example acantholysis may result in diagnostic confusion with pemphigus. Note that the blister is subepidermal.

Linear IgA disease

Fig. 4.149 Dermatitis herpetiformis: nuclear debris (karyorrhexis) within the dermis is a characteristic feature.

Jejunal biopsy may reveal villous blunting, intestinal crypt elongation, flattening of surface epithelial cells with loss of microvilli, and intraepithelial γ/δ lymphocytic infiltration to a degree ranging from partial to subtotal villous atrophy.57 If gluten is withheld from the diet, these changes revert to normal.

Differential diagnosis A neutrophil-predominant subepidermal vesicle accompanied by neutrophil dermal papillary microabscesses in addition to dermatitis herpetiformis may also be seen in the following conditions: vesicular pemphigoid, bullous systemic lupus erythematosus, inflammatory epidermolysis bullosa, and linear IgA disease. Distinction depends upon clinical information and the results of immunofluorescent studies (see Table 4.4).

Linear IgA disease of adults by definition presents after puberty. It is ­characterized by the development of a sometimes self-remitting dapsone or ­sulfonamide-responsive dermatosis typified by subepidermal vesicles and blisters in association with in vivo deposition of linear (homogeneous) IgA at the basement membrane region on direct immunofluorescence of normal or ­perilesional skin.1–3 Childhood linear IgA disease (chronic bullous dermatosis of childhood) is almost identical to the adult counterpart; however, there are differences in clinical presentation and therefore these particular aspects are described separately. Linear IgA disease of adults is a rare disease, which was originally thought to represent a variant of dermatitis herpetiformis4–6 or bullous pemphigoid.7,8 Some cases were reported under the rubric polymorphic pemphigoid (see above) or intermediate (mixed) forms of bullous disease.9,10 More recently, particularly following the application of immunoelectron microscopic and immunoblotting techniques, it has been confirmed as a disease (or at least a disease spectrum) sui generis.11–15 Its approximate incidence in the south of England is 1:250 000.16 In France and central Germany, the incidence is 0.5 per million of the population.17,18 In Singapore, the incidence has been estimated at 0.26 per million population.19 Although data for the United States are limited, the incidence in Utah has been reported as 0.6 per 100 000.20 Some consider that this disease is underdiagnosed.

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Inherited and autoimmune subepidermal blistering diseases

Clinical features Linear IgA disease of adults affects the sexes equally and, while the age distribution is wide, there are peaks in teenagers and young adults and in patients in their sixties.1 It may present as a somewhat atypical bullous eruption showing features suggestive of dermatitis herpetiformis or more commonly bullous pemphigoid (Fig. 4.151). Occasionally, it may initially resemble and be ­mistaken clinically for erythema multiforme.21 Pruritus and/or a burning sensation are common manifestations and early lesions may include urticarial, ­annular, ­polycyclic, and targetoid eruptions.15,22 The established dermatosis may be vesicular or more often frankly bullous; blisters arising at the edge of erythematous annular lesions (‘string of beads’ sign) are said to be characteristic.15 Sites affected in decreasing order of frequency include the trunk, limbs, hands, scalp, face, and perioral region. The perineum and vagina may also be affected with erosions and blisters.1 Mucous membrane involvement, which is common, is of particular importance because it can be associated with scarring. Important sites that may be affected include the eyes (conjunctivitis, symblepharon, trichiasis, corneal opacification, and rarely blindness; Fig. 4.152), the mouth (erosions, blisters, and chronic ulceration), nasal cavity (crusting and bleeding) and the pharynx (hoarseness).1,23–25 When these mucosal symptoms are severe there is clinical overlap and diagnostic confusion with mucous membrane pemphigoid. Childhood linear IgA disease (chronic bullous disease of childhood) not uncommonly develops after an upper respiratory tract illness, often following treatment with penicillin.26–29 Females are affected more often than males (1.6:1) (Fig. 4.153). The average age of onset is 6 years, but very rare cases in neonates have been described.30 Lesions, which can be pruritic or burning in the early stages, may be urticated, annular or polycyclic in appearance and usually arise on normal skin. Vesicles and large bullae (sometimes hemorrhagic) then predominate, and although the perioral regions and genitalia are particularly affected, the face, ears, trunk, limbs, hands, and feet are also often involved (Fig. 4.154). Usually, the new lesions appear around those that are resolving (the ‘cluster of jewels’ sign, Fig. 4.155). In older and black African children the clinical appearances can suggest bullous pemphigoid. Healing is sometimes associated with postinflammatory hyper- or hypopigmentation. Mucous membrane lesions are common (64%). Ocular symptoms of pain, grittiness, discharge and redness are found in 40% of children; conjunctival scarring is present in approximately 21%; oral lesions are found in up to 57%.

Fig. 4.152 Adult linear IgA disease: there is marked conjunctival injection and blepharitis. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.153 Childhood linear IgA disease: in this case widespread erosions on an erythematous background are present on the buttocks and legs. Occasional intact vesicles are also evident. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.151 Adult linear IgA disease: in this example the clinical appearances of excoriated lesions are suggestive of dermatitis herpetiformis. By courtesy of the Institute of Dermatology, London, UK.

Although linear IgA disease in children was originally thought to be selflimiting, it is now appreciated that symptoms may last over 5 years (25%) and occasionally extend beyond puberty into adult life. Exceptionally, an association with IgA nephropathy may be seen.31 Linear IgA disease is associated with increased expression of HLA-Cw7, -B8, -DR2, -DR3 and -DQ2.32 The incidence of HLA-B8 association is variable, with reported figures varying from 28% to 56% (normal range 20–25%).15,22 There is no evidence of an increase in HLA-B12.15 Linear IgA disease is also associated with HLA-Cw7 and -DR3.1 Although in the earlier literature as many as 24% of patients with linear IgA disease were thought to have associated gluten-sensitive enteropathy, the incidence is almost certainly considerably lower.1 There are, however, ­occasional recent references documenting occasional patients with linear IgA disease with clinical and histological evidence of gluten-sensitive enteropathy in the presence of antiendomysial and antitransglutaminase antibodies.33,34

Linear IgA disease

A

Fig. 4.154 Childhood linear IgA disease: groups of blisters are present on the vulva and inner thighs. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

B

Fig. 4.156 (A, B) Linear IgA disease: in this example the features are those of a neutrophil-rich subepidermal vesicle reminiscent of dermatitis herpetiformis.

Fig. 4.155 Childhood linear IgA disease: the arrangement of blisters called the ‘cluster of jewels’. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

It is possible that these cases represent dermatitis herpetiformis with linear granular deposits of IgA in which the granularity has not been detected. There are a number of reports documenting an association between linear IgA disease and internal malignancy, including lymphoma and leukemia, although whether this has significance is uncertain.35–38

Pathogenesis and histological features Histologically, linear IgA disease is characterized most frequently by dermatitis herpetiformis-like features (Fig. 4.156).26,39,40 Occasionally, however, the histological changes suggest bullous pemphigoid or sometimes a mixture of both diseases (Fig. 4.157). Eosinophilic spongiosis may rarely be a feature.26 Ultrastructurally, the site of cleavage may be through the lamina lucida or below the lamina densa.21

A homogeneous linear deposition of IgA along the basement membrane region is found by direct immunofluorescence in 100% of patients (Fig. 4.158).26,41–43 Uninvolved skin (particularly of the back) is suitable.1 Oral mucosa and conjunctiva may also show IgA deposition.1 The linear IgA antigen is present in all stratified squamous epithelia and amnion but, in contrast to the bullous pemphigoid antigen, is not found in bladder mucosa.42 IgG may also be demonstrable in up to 25% of cases.12,15 IgM and C3 are occasionally present.43 A low titer circulating IgA antibasement membrane zone antibody is present in approximately 30% of patients.1 Use of conjunctiva as substrate may, however, substantially increase this figure (up to 50%).23 Circulating IgG or C3-binding antibasement membrane antibodies are seen only in those patients with overlap syndrome.44 The IgA antibody is of pathogenetic significance since it causes dermoepidermal separation after incubation with whole skin cultures.45 Passive transfer of antibodies into a mouse model with human skin graft also produces characteristic lesions.46 Blister fluid is also satisfactory for indirect IMF.1 With split skin immunofluorescence, the titer may be higher and sensitivity is increased. The IgA antibasement membrane zone antibody variably labels the epidermal side, the dermal side or both sides of the artificial ­blister ­cavity.47–49 Immunoelectron microscopy has shown similar results, with IgA being present within the lamina lucida or below the lamina densa in association with anchoring fibrils, and sometimes in both locations (Fig. 4.159).50–55 Studies by Western immunoblotting indicate that linear IgA disease is a heterogeneous condition. Thus, in those cases associated with dermal binding on indirect NaCl-split skin IMF, the dermal antigens include 285-kD and

149

150

Inherited and autoimmune subepidermal blistering diseases

A

B

Fig. 4.157 (A, B) Linear IgA disease: in this field the presence of eosinophils is more suggestive of bullous pemphigoid.

Fig. 4.158 Linear IgA disease: direct immunofluorescence showing linear IgA deposition. By courtesy of the Department of Immunofluorescence, Institute of Dermatology, London, UK.

250-kD proteins and type VII collagen.14,49,56,57 Epidermal binding ­antibodies react with BP230 (BPAG1), BP180 (BPAG2), and 200/280-kD antigens distinct from either of the BP antigens.58–60 The antigens 120 kD (LAD1) and 97 kD described in earlier reports represent proteolytic cleavage products of BP180.61–64 Linear IgA disease 180-kD antibodies recognize the NC16A domain of collagen XVII (BPAG2) also critical for bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, and lichen planus pemphigoides described above.65–68 This fact is remarkable considering the variable

Fig. 4.159 Linear IgA disease: direct immunoperoxidase reaction using frozen tissue substrate. There is an abundance of granular IgA beneath the basal lamina.

clinical features of these various ­autoimmune bullous disorders. LAD1 has been identified as ladinin localizing to the extracellular domain of BP180 kD.69 Those patients with mixed IgA and IgG antibody-mediated disease also target BP180.44 Recent reports suggest that antibodies against the NC16A domain may be more important than those against the LAD1 cleavage product of BP180, but not all cases contain the anti-NC16A antibodies.70–72 Drug-induced linear IgA disease is considered in chapter 14.

Differential diagnosis The diseases from which linear IgA disease must be differentiated are dermatitis herpetiformis, bullous pemphigoid, and inflammatory epidermolysis bullosa. Points of distinction are considered in Table 4.4.

See www.expertconsult.com

Acantholytic disorders

Chapter

for references and additional material

Introduction  151 Pemphigus  151 Pemphigus vulgaris  152 Pemphigus vegetans  156 Pemphigus foliaceus  157 Endemic pemphigus foliaceus (fogo selvagem)  160 Pemphigus herpetiformis  162 Pemphigus erythematosus  162

Paraneoplastic pemphigus  163 IgA pemphigus  165 Drug-induced pemphigus  167 Contact pemphigus  167

Acantholytic dermatoses with dyskeratosis  167 Hailey-Hailey disease  167 Relapsing linear acantholytic dermatosis  169 Darier's disease  169

Introduction The term acantholysis derives from the Greek akantha, a thorn or prickle, and lysis, a loosening. In its simplest definition, the term is used to reflect a primary disorder of the skin (and sometimes the mucous membranes) ­characterized by separation of the keratinocytes at their desmosomal junctions (Fig. 5.1). A wide range of conditions are characterized by this feature, from inherited disorders such as Darier's disease and Hailey-Hailey disease in which a calcium pump gene mutation results in desmosomal instability through to the autoimmune pemphigus group of diseases whereby autoantibodies directly damage desmosomes with resultant keratinocyte separation and blister formation (Table 5.1). Desmosomes may also be damaged by secondary phenomena, for example following severe edema, either ­intercellular (spongiosis) or intracellular (e.g., ballooning degeneration as is seen in ­various viral infections). Such processes, however, are not included in the acantholytic ­category

5

Linear Darier's disease  173 Transient acantholytic dermatosis  174 Acantholytic dermatosis of the genitocrural area  176 Warty dyskeratoma  176 Familial dyskeratotic comedones  177 Acantholytic acanthoma  178 Acantholytic dyskeratotic acanthoma  179 Focal acantholytic dyskeratosis  179

Table 5.1 Antigens targeted in the pemphigus variants Pemphigus variant

Autoantigen

Pemphigus vulgaris

Dsg3 (mucosal), Dsg1 (cutaneous), desmocollins, pemphaxin, α9-acetylcholine receptor

Pemphigus vegetans

Dsg3, Dsc1, and Dsc2 in some patients

Pemphigus foliaceus

Dsg1

Pemphigus erythematosus

Dsg1

Fogo selvagem

Dsg1, rarely also Dsg3

IgA pemphigus

Dsc1, Dsg1 or Dsg3

Herpetiform pemphigus

Dsg1, rarely also Dsg3

Paraneoplastic pemphigus

Desmoplakins I and II, envoplakin, periplakin, BP230, plectin, Dsg1, and Dsg3

Drug-induced pemphigus

Dsg1 or Dsg3

Dsc, desmocollin; Dsg, desmoglein. Modified from Martel, P., Joly, P. (2001) Pemphigus: autoimmune diseases of keratinocyte's adhesion molecules. Clinical Dermatology, 19, 667.

and are discussed elsewhere. The histological features of the conditions described in this chapter show considerable overlap. The diagnosis is therefore dependent upon adequate clinical information and the results of immunofluorescence investigations.

Pemphigus

Fig. 5.1 Acantholysis: the keratinocytes are rounded and separated from each other to form an intraepidermal blister. Villi formed from the underlying dermal papillae typically project into suprabasal cavities.

Pemphigus (Gr. pemphix, blister) refers to a group of chronic blistering diseases which develop as a consequence of autoantibodies directed against a variety of desmosomal proteins.1–5 The condition as a whole is rare, with an annual incidence ranging from 0.1–0.7 per 100 000 of the general ­population.2 It is commoner in the Jewish population in which the annual incidence rises to 1.6–3.2 per 100 000.6 Ashkenazi Jews are the most frequently affected.6 The incidence in India also appears to be higher than in other countries.7 There is no sex predilection.

152

Acantholytic disorders The clinical features and, therefore, classification of these disorders depends upon the level of separation within the epidermis: • In pemphigus vulgaris (p. vulgaris) and pemphigus vegetans (p. vegetans) the blisters are suprabasal. • In pemphigus foliaceus (p. foliaceus), pemphigus erythematosus (p. erythe­ matosus) and fogo selvagem, the blisters are situated more superficially. Pemphigus vulgaris is by far the most common variant, accounting for 80% of cases.8,9 In addition to affecting humans, pemphigus has been described in a variety of animals including dogs, cats, goats, and horses.10

Pemphigus vulgaris Clinical features Pemphigus vulgaris (p. vulgaris) particularly affects the middle aged (onset typically at 40–60 years of age) although occasionally (up to 2.6%) children are affected.1–7 Self-limiting neonatal disease through transplacental transfer of maternal autoantibodies has also rarely been documented (see pathogenesis).8–11 The disease begins in the mouth (Figs 5.2, 5.3) in 50–70% of patients with painful erosions or bullae and, after a period of weeks or months, the

blisters spread to involve the skin.12–15 Oral lesions most commonly affect the buccal, palatine, and gingival mucosae.1,15–17 Pemphigus vulgaris is only rarely confined to the skin.18,19 The typical skin lesion is a fragile, flaccid blister, which develops on normal or erythematous skin, and readily ruptures, leaving a painful, crusted, raw, bloody erosion (Figs 5.4, 5.5). Lesions are most often seen on the scalp, face, axillae, and groin, although in some patients they are generalized (Figs 5.6–5.8).1–3,20 Blisters can be induced by rubbing the adjacent, apparently normal skin with a finger – the Nikolsky sign. Direct pressure applied to the center of the blister is also followed by lateral extension – the AsboeHansen sign.2 Healing is often accompanied by postinflammatory hyperpigmentation but scarring is not a feature.2 Before the introduction of corticosteroid therapy, the lesions usually became more extensive and in the past often led eventually to death. Treatment with high doses of corticosteroids, immunosuppressants, such as azathioprine and more recently biologicals has significantly reduced the mortality to 5–15% and prolonged remissions without treatment are now being reported.2 A considerable proportion of the deaths that do occur, however, are due to the side effects of therapy and include staphylococcal infections and, to a lesser extent, pulmonary embolism.2 Severe opportunistic infections due to a wide range of organisms including listeria, nocardia, enterococci, herpes virus, cryptococcus and candida may further complicate the disease.21–27

Fig. 5.2 Pemphigus vulgaris: painful erosions are present on the buccal mucosa. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 5.3 Pemphigus vulgaris: in this patient there is an intact blister on the floor of the mouth. Pemphigus commonly presents in the mouth. By courtesy of the Institute of Dermatology, London, UK.

Fig. 5.4 Pemphigus vulgaris: since the blisters are superficial, erosions are more commonly encountered. By courtesy of the Institute of Dermatology, London, UK.

Fig. 5.5 Pemphigus vulgaris: extensive erosions and blisters are present on the shin. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Pemphigus

Fig. 5.6 Pemphigus vulgaris: umbilical lesions showing intact blisters as well as raw erosions. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 5.8 Pemphigus vulgaris: extensive disease can be very disfiguring. By courtesy of the Institute of Dermatology, London, UK.

Fig. 5.7 Pemphigus vulgaris: extensive trauma-induced blisters. By courtesy of the Institute of Dermatology, London, UK.

Nail involvement seems to be more common than previously reported. Patients may present with hemorrhagic paronychia, chronic paronychia, trachyonychia, onycholysis or onychomadesis.17,28 Paronychia and onychomadesis are the most common nail changes encountered. Nail involvement is more common in the nails of digits affected by periungual blisters and also in patients with large number of skin blisters.29 Occasional modes of presentation include linear lesions and pemphigus arising after surgery, burns, vaccination, and radiation therapy.30–39 Development after exposure to pesticides and a possible association with cocaine snorting has also been reported.40,41 A very exceptional case has been described in which blisters were initially confined to melanocytic nevi.42 P. vulgaris may also be rarely induced by a variety of drugs. In addition to oral and cutaneous involvement, lesions have been described at a wide variety of sites including the nasopharynx, larynx, ear, esophagus, eye, external genitalia, urethra, and anal and colonic mucosa.1,43–45 Esophageal lesions, although originally thought to be rare, have more recently been

documented in as many as 63–87% of patients.46,47 Erosions and ulcers are t­ ypically found and intact blisters are rare. Exceptionally, the whole mucosa may be affected with subsequent sloughing – esophagitis dissecans superficialis.48 Ocular lesions are usually restricted to the conjunctiva, presenting as conjunctivitis or small vesicles that rapidly rupture.2,49,50 Very rarely, scarring may develop and corneal ulceration with perforation has been described.51 Vulval, vaginal, and cervical lesions are well recognized.52–56 Exceptionally, the vagina may be the sole site of involvement.57 Penile lesions most commonly affect the glans.58 They are not usually followed by any significant sequelae. The development of pemphigus may be associated with a variety of disorders including other autoimmune bullous dermatoses, particularly bullous pemphigoid, lupus erythematosus, thymoma, and myasthenia gravis as well as Hashimoto's thyroiditis, vitiligo, minimal change nephropathy, and ulcerative colitis.59–66 It has also been described in a patient with the 1p36 deletion syndrome.67 As in the many other diseases with an immunological pathogenesis, pemphigus is accompanied by an increased incidence of internal malignancy including thymoma, lymphoma, and multiple myeloma (see paraneoplastic pemphigus).68,69 It has also been reported in association with Kaposi's sarcoma.70

Pathogenesis and histological features Pemphigus is an immunologically mediated disease.71,72 Examination of perilesional skin by direct immunofluorescent techniques reveals in vivo-bound immunoglobulin (usually IgG) and often complement (C3) in the intercellular region of the epidermis (Fig. 5.9).73 Abundant antigen in the follicular outer root sheath and germinal matrix may account for the marked scalp involvement typical of pemphigus, and plucked hair follicles may serve as an adequate substrate for direct immunofluorescence analysis.74,75 The in vivobound IgG is mainly of the IgG1 and IgG4 subclasses.76 Indirect immunofluorescent techniques show that the serum of patients with pemphigus contains an IgG antibody that reacts with the intercellular region of normal squamous epithelium – the intercellular substance (pemphigus) antibody.77 This antibody is, however, not entirely specific as it may be found in a variety of other conditions, such as severe burns, penicillin drug reactions, and following radiation therapy.78–80 Presumably, pemphigus antigens are released into the circulation following such trauma with resultant antibody production. Circulating antibodies are predominantly of the IgG1 and IgG4 subclasses; IgG3 is i­dentified much less often.81

153

154

Acantholytic disorders

Fig. 5.9 Pemphigus vulgaris: direct immunofluorescence. By courtesy of the Institute of Dermatology, London, UK.

Circulating IgG is pathogenic.71,72 The level of the antibody titer closely parallels the clinical state of the disease.82–85 IgG4 titers diminish during remission whereas circulating IgG1 may continue to be present.72,83 Relapse is commonly preceded by rising IgG4 antibody titers.83 P. vulgaris very occasionally may be evident in a neonate born of a mother with active pemphigus vulgaris.8,86 Such autoantibodies cross the placenta, inducing disease in the infant. The condition is, however, short lived, with lesions disappearing, as the maternal antibodies are catabolized. Passive transfer of IgG4 into neonatal mice results in the development of blisters.87 Purified IgG from pemphigus induces acantholysis in human skin explants and keratinocyte cultures.88,89 The pemphigus antibody binds to the full thickness of the epidermis. Compared with p. vulgaris, immunofluorescence studies on the sera of p. foliaceus patients tend to show more staining in the superficial epidermis, correlating with the level of the split.90,91 Conversely, the sera from patients with p. vulgaris show more affinity for the lower epidermis. Despite these trends, we generally do not base diagnoses on these (often subtle) differences in immunofluorescence staining distribution. The p. vulgaris antibody is directed at the extracytoplasmic domain of the 130-kD epithelial desmosomal cadherin, desmoglein 3 (Dsg3), which forms a complex with plakoglobin (85 kD).92–98 The p. vulgaris antibody, however, does not recognize the latter. Many patients also have antibodies that bind to the p. foliaceus antigen, desmoglein 1 (Dsg1), a 160-kD polypeptide.99,100 Dsg3 is expressed primarily in the oral mucosa and, therefore, antibodies directed against this antigen result in mucosal pemphigus. In contrast, Dsg1 is a cutaneous antigen and, therefore, antibodies directed against it result in lesions affecting the skin but not the mucosa (cutaneous pemphigus).90 Anti-Dsg1 antibodies also show cross-reactivity against Dsg4, a recently identified member of the desmoglein family.101,102 While patient sera contain antibodies against nonconformational epitopes of Dsg3, active disease correlates with the presence of antibodies directed against the NH2terminal aspect of Dsg3, in particular ectodomains 2–4.103–105 Oral disease is particularly associated with reactivity to ectodomains 1-4, which is reduced in cutaneous pemphigus.103 Antibodies reactive to a number of other proteins including desmoplakin, desmocollins, pemphaxin, and acetylcholine receptor have also been demonstrated in the sera of p. vulgaris patients.106–110 Sera from patients with pemphigus vulgaris not infrequently contain additional IgA antibodies, in particular against Dsg1 and Dsg3.111–113 Although the combination of both IgG and IgA antibodies has in some instances been referred to as IgG/IgA pemphigus in the literature, this appears to be an ­ill-defined and heterogeneous disease group.111,114 In addition to ­pemphigus vulgaris, the additional presence of anti-Dsg IgA antibodies has also been demonstrated in pemphigus foliaceus, pemphigus

vegetans, pemphigus ­herpetiformis, and paraneoplastic pemphigus.111,115,116 Furthermore, so-called IgG/IgA pemphigus may show an atypical clinical presentation, histological features more reminiscent of IgA pemphigus, and the presence of IgA antibodies against desmocollins in a subset of patients.114,117–123 The pathogenesis of the acantholysis is uncertain. Direct binding of antibody to the desmosomal cadherins is of major importance and results in internalization of Dsg3 and degradation by the endolysosomal pathway.71,114,124 Plakoglobin has been implicated in mediating intracellular events following IgG binding to Dsg3.125,126 In particular, the role of plakoglobin is signal transduction to the nucleus.125,127 There is also some evidence to suggest that the process may involve, at least secondarily, the action of local proteolytic enzymes.70 Pemphigus antibody induces expression of plasminogen activator receptor on the surface of keratinocytes.128 Binding of plasminogen activator to its keratinocyte cell membrane receptor results in plasminogen activation with resultant production of plasmin.129,130 This latter has non-specific proteolytic activity, which may be responsible at least in part for the dissolution of the desmosomes.71 P. ­vulgaris antibodies stimulate production of keratinocyte phospholipase C, inositol 1,4,5-triphosphate, and increase intracellular calcium. Protein kinase C activation results in release of keratinocyte plasminogen activator and increased expression of plasminogen activator receptor.131–133 Other factors, however, must be of greater importance since p. vulgaris IgG can induce acantholysis in plasminogen activator knockout mice.134 An additional phenomenon is rapid phosphorylation of heat shock protein 27 and p38MAPK resulting in reorganization and collapse of the cytoskeleton as a result of IgG binding to Dsg3.135,136 This process is mediated by upstream events involving EGF receptor kinase and src.137 Complement appears not to be essential for acantholysis and it is thought that any involvement is secondary, perhaps accelerating or extending the process.71 Although it has been suggested that apoptosis may be induced by p. vulgaris IgG, and that this mechanism may be important in the pathogenesis of the disease, a recent study has shown that apoptosis is not a prerequisite for blistering and may be a secondary phenomenon.138 T cells are also critical to the development of the antibody-mediated acantholysis.70 CD4+ memory T cells are predominantly involved and both T-helper 1 (Th1) and Th2 Dsg3-specific subtypes are represented.139,140 Th1 T-cell-derived interferon-γ stimulates production of IgG1, and Th2 cells produce interleukin (IL)-4 and IL-13 which are responsible for secretion of B-cell-derived IgG4.141 Both populations are therefore of importance in stimulating production of p. vulgaris antibody.72 In addition, there is evidence that tumor necrosis factor 1 (TNF-1), Fas-ligand and IL-1 are also of importance in the development of acantholysis.142 Knockout mice for both these cytokines show diminished acantholysis in passive antibody transfer experiments.143 There is considerable evidence of a genetic background influencing susceptibility to pemphigus as shown by strong associations with human leukocyte antigen (HLA)-DRβ1*0402, HLA-DRβ1*1401 and HLA-DQβ1*0503.144–147 Perhaps surprisingly, however, there are only occasional documented reports of familial occurrence.148–151 Pemphigus blisters rupture easily. It is therefore essential to biopsy an early lesion to establish the correct diagnosis. The characteristic acantholysis develops because of damage to the intercellular bridges. Acantholytic cells are rounded and have intensely eosinophilic cytoplasm, pyknotic nuclei, and perinuclear halos. An early lesion of p. vulgaris shows a slitlike ­suprabasal cleft or vesicle containing occasional acantholytic cells. The established blister contains acantholytic cells in clumps and in isolation (Figs 5.10 and 5.11). Characteristically, the floor of the cavity is lined by a single layer of intact basal cells, the so-called ‘tombstone’ pattern (Fig. 5.12).152 The acantholytic process frequently involves the epithelium of the adnexae, which can be a useful diagnostic clue in those lesions which lack the roof of the blister (Fig. 5.13).153 The dermal papillary outline is usually maintained and, frequently, the papillae protrude into the blister cavity. Sometimes the features of eosinophilic spongiosis are seen on biopsy, particularly in early lesions.154 The blister cavity often contains a few inflammatory cells (notably eosinophils) and, in the dermis, there is a moderate perivascular

Pemphigus

Fig. 5.10

Fig. 5.12

Pemphigus vulgaris: established blister showing marked acantholysis and scattered neutrophils. The dermal papillae project into the cavity as villi.

Pemphigus vulgaris: cell-free example showing a linear palisade of intact basal keratinocytes – the so-called ‘tombstone’ appearance.

A

Fig. 5.13 Pemphigus vulgaris: follicular involvement distinguishes pemphigus from Hailey-Hailey disease in which it is not a feature.

chronic inflammatory cell infiltrate with conspicuous eosinophils, although ­sometimes these are scanty or even absent. Mucous membrane lesions show similar histology. Ultrastructurally, there is dilatation of the intercellular space with consequent stretching of the desmosomal attachment points (Figs 5.14, 5.15).155 With progression, these separate and eventually disappear, residual cell membranes often showing a pseudovillous morphology. Hemidesmosomes are morphologically normal. Immunoelectron microscopy confirms that the immunoreactants are located within the intercellular space.

Endemic pemphigus vulgaris Fig. 5.11

B

Pemphigus vulgaris: (A) perianal mucosa showing acantholysis and conspicuous villi; (B) highpower view.

Patients with clinical and histological presentation of pemphigus vulgaris but epidemiological features of fogo selvagem were identified in the Goiania and Brasilia regions of Brazil, known endemic areas of pemphigus foliaceus. These patients demonstrate classical mucocutaneous disease and antibodies to both Dsg1 and Dsg3, but are remarkable for early onset of disease, frequently before the age of 20.156

155

156

Acantholytic disorders or without immunofluorescence studies, it may be impossible to establish a definitive diagnosis. Darier's and Hailey-Hailey diseases are not associated with immunoreactants. Dyskeratosis in the form of corps ronds and grains is typical of Darier's disease, but is rarely seen in Hailey-Hailey disease, and is not a feature of pemphigus. In Hailey-Hailey disease, the perivesicular epithelium is likened to a dilapidated brick wall, an effect sometimes seen in p. vulgaris. More frequently, however, the epithelium overlying and adjacent to the blister is essentially intact. Acantholysis involving the follicular epithelium is often seen in pemphigus, but usually not in Hailey-Hailey disease. The pemphigus-like variant of Grover's disease is histologically indistinguishable from pemphigus, but the clinical history, minute size of the lesions as viewed by the microscope, and negative immunofluorescence findings make distinction relatively easy. Extreme degrees of acantholysis in acantholytic solar keratosis may on rare occasions be confused with the previously mentioned acantholytic disorders. Similarly, it is important not to misinterpret the trivial finding of incidental focal acantholytic dyskeratosis in a skin specimen removed or biopsied for an unrelated finding.

Fig. 5.14 Pemphigus vulgaris: electron photomicrograph of an early lesion showing suprabasal, intraepidermal vesiculation. Residual cytoplasm of basal keratinocytes lines the floor of the blister. The lamina densa is clearly visible.

Fig. 5.15 Pemphigus vulgaris: electron photomicrograph of an early lesion showing marked dilatation of the intercellular space. Cytoplasmic ‘villus’ formation is conspicuous and only occasional desmosomes are apparent.

Differential diagnosis The differential diagnosis of p. vulgaris includes a variety of conditions such as Darier's disease, Hailey-Hailey disease, and transient acantholytic dermatosis (Grover's disease) (Table 5.2). In the absence of clinical information

Pemphigus vegetans Clinical features Pemphigus vegetans (p. vegetans), a chronic variant of p. vulgaris, has a somewhat better prognosis than p. vulgaris with occasional cases associated with spontaneous remission documented.1–3 It accounts for 1–2% of all cases of pemphigus.1 As with the vulgaris variant, p. vegetans typically presents in adults. There has, however, been a small number of cases described in childhood including a dapsone-responsive IgA-mediated variant.4–7 The lesions, which present as blisters and erosions, are particularly prolific in the flexures, especially the axillae, the groin, the inframammary region, the umbilicus and at the margins of the lips. The scalp is also said to be a site of predilection.8,9 Soon thereafter, patients characteristically develop hypertrophic vegetations and pustules at the blistered edges (Fig. 5.16).1 The oral cavity is commonly affected and a cerebriform or ‘scrotal’ tongue is said to be a diagnostic clue in cases of early involvement.10–13 An exceptional case of the disease restricted to the tongue has been reported.14 Esophageal involvement presenting as erosions and white plaques has been described in a number of patients and the nasal mucosa, larynx, vulva, vagina, penis, and anus may also be affected.7,15–19 Nail involvement including onycholysis and pustules is sometimes seen.20 Acral involvement can clinically be mistaken for acrodermatitis continua suppurativa.21 A case has been described developing after and restricted to a split-thickness skin graft.22 A further exceptional case developed in association with intranasal heroin abuse and was restricted to the nasal mucosa.23 Peripheral blood eosinophilia is commonly present. Two clinical subtypes are recognized:24,25 • In the Neumann variant (the more serious form), lesions usually begin as described in p. vulgaris, but the ensuing erosions develop vegetations. The course of this variant is similar to that of p. vulgaris. • In the Hallopeau variant (‘pyodermite vegetante’), the eruption begins as pustular lesions that rapidly evolve into verrucous vegetating plaques.2 Bullae are usually not seen. This is a milder variant in which spontaneous remission is not uncommon.

Table 5.2 Differential diagnosis of suprabasal pemphigus Pemphigus vulgaris*

Darier's disease*

Hailey-Hailey disease*

Types of lesion

Intraepithelial bullae

Suprabasal clefts

Intraepithelial bullae

Adjacent epithelium

Intact

Intact

Disintegrating

Involvement of adnexae

Yes

Yes

No

Corps ronds and grains

No

Yes

Rarely

Dermal inflammation

Mononuclears, eosinophils

Mononuclears

Mononuclears

IMF

Positive

Negative

Negative

*The lesions of Grover's disease may histologically mimic any of these and can only be distinguished by immunofluorescence.

Pemphigus

Fig. 5.16 Pemphigus vegetans: axillary ulceration and vegetative lesions. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Fig. 5.17 Pemphigus vegetans: the epidermis is hyperplasic and there are scattered abscesses.

Pathogenesis and histological features Support for the thesis that p. vegetans is a variant of p. vulgaris is based on the finding that both subtypes are associated with IgG and C3 deposition in the epidermal intercellular space on direct immunofluorescence, and circulating ‘pemphigus’ antibody.25 P. vegetans is characterized by an antibody directed at the desmosomal cadherin, desmoglein 3.26–28 Antibodies against desmocollins 1 and 2 as well as periplakin have also been documented.29,30 Rarely, additional IgA antibodies to Dsg3 may also be detected.31 Precipitating factors for this variant of pemphigus are largely unknown. Exceptionally, however, p. vegetans has been linked with the angiotensin­converting enzyme (ACE) inhibitors, captopril and enalapril.32,33 Lesions localized to the nasal mucosa in a patient with longstanding nasal heroin abuse have been reported and an association with human immunodeficiency virus (HIV) infection documented.19,34,35 There are few reports relating p. vegetans with an underlying malignancy and in one patient a p.vegetans-like lesion was a manifestation of paraneoplastic pemphigus.33,36–40 Although a variant of p. vulgaris, p. vegetans shows strikingly different histological features. Suprabasal acantholysis is present but is often subtle, being masked by an exuberant proliferation of squamous epithelium which may sometimes show pseudoepitheliomatous hyperplasia (Fig. 5.17). The epithelial proliferation involves both the epidermis and the infundibular follicular epithelium. Characteristically, there is an intense inflammatory cell infiltrate containing numerous eosinophils, and intraepidermal microabscesses are often seen (Figs 5.18, 5.19). Eosinophilic spongiosis is a feature.41,42 The inflammatory changes and epithelial proliferation are sometimes so marked that the true nature of the lesions is obscured. Very occasionally, 10–40-μm eosinophilic hexagonal Charcot-Leyden crystals have been described within the eosinophil-rich microabscesses.32,43 The diagnosis of p. vegetans is easily overlooked and is made only by the pathologist with a high index of suspicion.

Differential diagnosis Since early lesions may be similar, or identical, to p. vulgaris, the same differential diagnosis as discussed for that variant should be considered. In established lesions associated with squamous epithelial hyperplasia, the suprabasal cleft formation is often focal and easily overlooked. Infections, ­particularly fungal and bacterial, that are associated with ­pseudoepitheliomatous

Fig. 5.18 Pemphigus vegetans: follicular involvement is seen on the right.

­hyperplasia and microabscesses may be confused with p. vegetans. In particular, pyostomatitis vegetans must be excluded in patients presenting with oral involvement. The latter is usually associated with inflammatory bowel disease and although it may mimic p. vegetans clinically and histologically, direct immunofluorescence is invariably negative. Halogenoderma may also show similar histological features.

Pemphigus foliaceus Clinical features Pemphigus foliaceus (p. foliaceus) is considerably more uncommon than p.  vulgaris and although it most often affects the middle aged and elderly, it has a very variable age of onset, sometimes affecting younger adults and even, occasionally, children.1–8 Very exceptionally, maternal antibodies have been known to cross the placenta, resulting in neonatal disease.9–11 In general, ­nonendemic p. foliaceus in children is relatively benign and of short duration.6

157

158

Acantholytic disorders

Fig. 5.21 Pemphigus foliaceus: crusted lesions are evident on the back of this young male. From the collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Fig. 5.19 Pemphigus vegetans: there are numerous eosinophils. Note the acantholysis.

The superficial blisters of p. foliaceus are exceedingly fragile and therefore much less obvious; erosions and large leafy scales or crusts are often predominant (Figs 5.20–5.22). The lesions may remain localized to the scalp, nose, face, and trunk for many months or years, leading to a ­mistaken diagnosis of seborrheic dermatitis, seborrheic keratosis, or even lupus ­erythematosus. Sometimes the eruption involves the entire surface of the body or produces a clinical resemblance to exfoliative dermatitis (erythroderma) (Fig. 5.23).12,13 Mucous membrane involvement is rare.1 Exceptionally, patients may present with localized disease, typically restricted to the face.14,15 The development of pustular lesions is exceptional.16 P. foliaceus often has a much more benign course than p. vulgaris, although patients with severe

A

Fig. 5.20 Pemphigus foliaceus: multiple erosions are present with background erythema and postinflammatory hyperpigmentation. Courtesy of The Institute of Dermatology, London, UK.

B

Fig. 5.22 Pemphigus foliaceus: (A) there are numerous crusted lesions on the lower abdomen and in the groin, (B) high-power view. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Pemphigus

Pathogenesis and histological features

Fig. 5.23 Pemphigus foliaceus: in this patient, there is generalized erosion with scaling and erythroderma. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

­ isease, requiring ­corticosteroid and immunosuppressant therapy, still have d an appreciable ­mortality. The ­disease may be complicated by Kaposi's varicelliform eruption.17 Very occasionally, patients may develop p. foliaceus during or after a previous episode of p. vulgaris and vice versa.18–20 The development of bullous pemphigoid following an episode of p. foliaceus has also been described.21,22 This is accompanied by an antigen shift, possibly as a result of intermolecular epitope spreading.19,23–25 A case of a blistering disorder displaying ­features of bullous pemphigoid and pemphigus foliaceus has been described in ­association with consumption of Spirulina algae.26 The coexistence of both p. ­vulgaris and p. foliaceus in one patient has also been reported.27 A further case of paraneoplastic pemphigus with concomitant clinical features of ­pemphigus foliaceus and the presence of antibodies against desmoglein 1 was recently reported.28 In addition to idiopathic p. foliaceus, drug-induced variants, notably due to penicillamine, may also be encountered (Fig. 5.24). A localized form may also be associated with topical drugs such as imiquimod and has been reported following radiation therapy.29–32 Pemphigus foliaceus is rarely associated with an underlying malignancy including ­non-Hodgkin's lymphoma and esophageal cancer.33,34

A

Similar to other variants of pemphigus, p. foliaceus is an immunologically mediated disease. Examination of perilesional skin by direct ­immunofluorescent techniques reveals in vivo-bound immunoglobulin (usually IgG) and often complement (C3) in the intercellular region of the epidermis.1 Abundant antigen in the follicular outer root sheath and germinal matrix may account for the marked scalp involvement typical of pemphigus.35 Indirect immunofluorescent techniques show that the sera of patients with p. foliaceus contain an IgG antibody that reacts with the intercellular region of normal squamous epithelium.36 IgG4 predominates followed by IgG1.37,38 IgG3 is also sometimes present. This may be of importance since IgG3 is the most efficient activator of complement.37 Some 60–70% of patients have ­positive indirect immunofluorescence.39 The p. foliaceus antibody binds to a 160-kD desmosomal cadherin, designated desmoglein 1 (Dsg1).40,41 The sera of p. foliaceus patients bind to the extracellular amino terminal domain of bovine Dsg1 whereas sera from both p. vulgaris and p. vegetans patients react with the intracellular domain of Dsg1.42,43 Compared with p. vulgaris, immunofluorescence studies on the sera of p. foliaceus tend to show more staining in the superficial epidermis, correlating with the level of the split.44,45 Conversely, the sera from patients with p. vulgaris show more affinity for the lower epidermis. Anti-Dsg1 antibody is pathogenic.46 Injection of purified anti-Dsg1 antibodies from sera of patients with p. foliaceus into neonatal mice induces subcorneal acantholysis in a pattern typical of p. foliaceus.47 Acantholysis is thought to be the result of an antibody-mediated cellular response rather than purely the result of steric hindrance.48 Internalization of nonclustered Dsg1 has been put forward as a possible mechanism resulting in lack of newly formed desmosomes rather than a disruption of pre-existing structures.49 Increasing evidence suggests that the blistering is the result of the activation of p38 mitogen-activated protein kinase-dependent signaling by the p. foliaceus IgG antibodies.50 Rarely, patient sera contain additional IgG antibodies directed against desmoglein 3 (Dsg3) and the presence of additional IgA antibodies against Dsg1 as well as Dsg3 has also been detected.3,51,52 Furthermore, three patients have been reported with clinical and histological features of p. foliaceus but direct immunofluorescence findings reminiscent of p. erythematosus. Antibodies recognizing bullous pemphigoid antigen1 (BP230) as well as a 190-kD ­protein co-migrating with periplakin were detected in these patients in addition to anti-Dsg1 antibodies.53 The use of D-penicillamine may be associated with the acquisition of a pemphigus-like antibody and the development of p. foliaceus.54 Since the blisters of p. foliaceus are superficial, they are therefore fragile and it is often very difficult to obtain an intact lesion for diagnosis. Patients commonly have erosions without blisters, and frequently the clinician does not suspect a bullous disorder. Usually, the cleft or blister lies within the

B

Fig. 5.24 Pemphigus foliaceus: (A) in this patient, the eruption was induced by penicillamine therapy; (B) close-up view of intact blisters, erosions and crusting. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

159

160

Acantholytic disorders

A

B

Fig. 5.25 Pemphigus foliaceus: (A) in this example, there is a cell-free, subcorneal blister; (B) occasional acantholytic cells are present adjacent to the roof.

g­ ranular layer or beneath the stratum corneum (Fig. 5.25). The roof of the fragile blister is often not present, having sloughed either before or after biopsy. Acantholysis is frequently difficult to detect, but usually a few acantholytic cells can be found attached to the roof or floor of the blister. In those cases where the blister is missing, a careful inspection of the hair follicles may reveal focal acantholysis. Sometimes the blister contains numerous acute inflammatory cells (Fig. 5.26), particularly neutrophils, which can make distinction from subcorneal pustular disorders, including bullous impetigo, a dermatophyte infection, candidiasis, pustular psoriasis, and subcorneal pustular dermatosis especially difficult.55,56 Eosinophilic spongiosis may also be seen.57

Table 5.3 Differential diagnosis of superficial pemphigus: conditions characterized by subcorneal pustules Superficial pemphigus IgA pemphigus Subcorneal pustular dermatosis Pustular psoriasis Reiter's syndrome Pustular drug reaction Bullous impetigo Staphylococcal scalded skin syndrome Pustular fungal infection

Differential diagnosis The histological features in the superficial forms of pemphigus may be easily overlooked and, since bullae are often not appreciated by the clinician, the unwary pathologist may not consider a bullous disorder when evaluating the biopsy. A high index of suspicion is therefore critical. The differential diagnosis of superficial pemphigus includes bullous impetigo, staphylococcal scalded skin syndrome, IgA pemphigus, and subcorneal pustular dermatosis (Table 5.3). Distinction depends upon a careful consideration of the clinical information, the results of bacterial culture, and immunofluorescent studies.

Fig. 5.26 Pemphigus foliaceus: in this example, the blister cavity contains numerous neutrophils. Acantholytic cells are conspicuous.

Endemic pemphigus foliaceus (fogo selvagem) Clinical features Fogo selvagem (Brazilian pemphigus foliaceus, ‘wild fire’, endemic pemphigus foliaceus) is endemic in regions of Brazil and has also been documented in other areas of Central and South America including Colombia, El Salvador, Paraguay, Venezuela, and Peru.1–11 An endemic area has also been described in Tunisia.12,13 The condition is associated with poverty and malnutrition and particularly affects children and young adults. Results from a more recent epidemiological study demonstrated disease manifestation also in patients of higher socioeconomic class and urban areas.14 There is a striking familial incidence.4 Most cases are found along major rivers, and people especially at risk include farmers and workers involved in land clearing and road construction.2 It appears that the majority of patients live at an altitude of between 500 and 800 meters, and that their homes are generally within 10–15 kilometers of running fresh water and in the path of prevailing winds, thus suggesting a likely insect vector.4,15 In support of this, a case-controlled epidemiological study has provided evidence that bites by the black fly (family Simuliidae) are a significant risk factor for development of the disease and it has been proposed that a component of the saliva may trigger an antibody response in susceptible individuals.16–18 Simulium nigrimanum, which is found in the same areas in which Brazilian fogo selvagem occurs, has been identified as being the likely species involved.17 The clinical presentation of fogo selvagem has been divided into a number of categories including localized and generalized forms:2,4 • Localized disease presents in a variety of ways including small blisters and erosions or violaceous papules and plaques distributed mainly in the seborrheic areas. Such lesions may be clinically misdiagnosed as discoid lupus erythematosus.

Pemphigus

Fig. 5.27 Brazilian pemphigus foliaceus: this woman with chronic disease shows very severe scaling. Blisters are not apparent. By courtesy of S.A. Pecher, MD, Amazonas, Brazil.

were detected.32,33 Patients have circulating CD4+ memory T cells with a Th2 cytokine profile that proliferate in response to the extracellular domain of Dsg1 and are thought to be of importance in the initiation and progression of the disease by stimulating B-cell production of autoantibodies.34–36 The systemic kinin system appears to be activated in patients with fogo selvagem but the significance of this finding and its mechanism of action in blister formation are unclear.37 Patients often share the HLA phenotype DRB1*0102 and lack DQB1*0201 which is thought to represent a dominant protective gene found in unaffected persons living in endemic regions.38,39 HLA-DRB1*0404, *1402 and *1406 may also confer susceptibility.4,28,34 The histological changes of fogo selvagem are identical to the other forms of superficial pemphigus (p. foliaceus and p. erythematosus).40 Since the blisters are superficial, often only nonbullous erosions are present for histological examination. It is very difficult to obtain an intact lesion for diagnosis. Typically, the cleft or blister lies within the granular layer or beneath the stratum corneum. Acantholysis is frequently subtle but usually a few acantholytic cells can be found attached to the floor of the blister. The blister roof is often missing. Blisters may contain numerous inflammatory cells, particularly neutrophils. This feature may cause confusion with infection or other subcorneal pustular disorders. Eosinophilic spongiosis is also sometimes present, ­particularly if biopsies of early lesions are examined (Figs 5.28, 5.29).

• Generalized presentation includes bullous exfoliative, exfoliative

erythrodermic, and disseminated plaque and nodular (resembling nodular prurigo) variants (Fig. 5.27).4 With resolution, patients may sometimes develop hyperpigmentation.19 The antibody does not cross the placenta and therefore neonatal disease is not a feature.20 Patients with fogo selvagem appear to have no increased risk for other concomitant autoimmune disorders.21 In contrast to Brazilian fogo selvagem, endemic disease in the area of El Bagre, Colombia, shows several unusual and distinguishing features.22 The disease affects an older population with a strong male predilection and clinical features reminiscent of pemphigus erythematosus. In addition to the more ­classical presentation, patients develop hyperkeratotic plaques on the face, chest, and back reminiscent of discoid lupus erythematosus as well as an erythematous macular lesion in a butterfly-like distribution in the central face.22 Active disease is also accompanied by conjunctivitis. The disease also shows characteristic immunological and histological changes, which are discussed below.

Pathogenesis and histological features The immunological features of fogo selvagem are similar to p. foliaceus. Indirect immunofluorescent techniques show that the sera of patients with fogo selvagem contain an IgG4 antibody that reacts with desmoglein 1.15,23 Passive transfer of this antibody to BALB/c neonatal mice results in acantholysis and subcorneal blistering clinically indistinguishable from that of human disease.24–26 Low-titer IgG1 and IgG2 antibodies may also be present and nonpathogenic IgG1 antibodies are present in unaffected individuals and in the preclinical stages of patients from endemic areas.15,24 IgG antibodies may be accompanied by IgM antibodies, a finding seen more frequently in individuals from rural rather than urban areas. Furthermore, additional IgM antibodies are detected more frequently associated with fogo selvagem than pemphigus foliaceus.27 Fogo selvagem is otherwise histologically and by immunofluorescence indistinguishable from nonendemic foliaceus and, like the latter, the antibody recognizes epitopes in the ectodomain of Dsg1.28,29 Epitope recognition is conformation specific and calcium dependent, and recently intramolecular epitope spreading has been implicated in the pathogenesis of the disease. Epitope spreading appears to be related to onset of disease as well as disease modulation with remission and relapse.30 Specifically, it has been shown that sera from patients in the preclinical stage or in remission recognize epitopes in the COOH-terminal region of the ectodomain of Dsg1 while antibodies against epitopes in the NH2-terminal region of the ectodomain are detected at disease onset.15,30 Interestingly, a study has suggested that the presence of serum IgG4 antidesmoglein-1 in asymptomatic individuals may suggest preclinical disease.31 A subset of patients may also have antibodies to Dsg3, and in up to 36% of sera from individuals from the Terena reservation of Liao Verde, Brazil, additional anti-Dsg3 ­antibodies

Fig. 5.28 Brazilian pemphigus foliaceus: in this example of an early lesion, the features of eosinophilic spongiosis are evident.

Fig. 5.29 Brazilian pemphigus foliaceus: there is superficial dermal edema and a perivascular inflammatory cell infiltrate with conspicuous eosinophils.

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162

Acantholytic disorders The verrucous plaques and nodules seen occasionally in localized or chronic fogo selvagem show acanthosis, hyperkeratosis, parakeratosis, and papillomatosis.41 Acantholysis is invariably present. The hyperpigmentation characteristic of remission is a direct result of ­pigmentary incontinence. The histological findings in the endemic form described in the El Bagre area in Colombia are identical to those of fogo selvagem in active disease. In addition, liquefactive degeneration of the epidermal basal cell layer is observed in a quarter of biopsies.22 By direct immunofluorescence, a positive lupus-band test is detected in 40% of patients in addition to IgG deposition on the surface of keratinocytes. Reactive antibodies are of the IgG4 subtype with Dsg1 being the major antigen. Sera from patients also contained additional antibodies against antibasement membrane zone as well as further IgG1 anticell-surface antibodies, which may represent desmoplakin1, envoplakin, and periplakin.42 Recently, criteria have been proposed to establish a diagnosis of fogo ­selvagem as distinct from nonendemic p. foliaceus:4 • clinical evaluation, • presence of subcorneal acantholysis, • positive direct and indirect immunofluorescence and/or immunoprecipitation or ELISA assays, • confirmatory epidemiological data.

Differential diagnosis As with p. foliaceus, the histological features in fogo selvagem may be easily overlooked and a high index of suspicion is critical to making the diagnosis. The differential diagnosis includes p. foliaceus, p. erythematosus, bullous impetigo, staphylococcal scalded skin syndrome, and subcorneal pustular dermatosis. Careful clinical correlation, immunofluorescence studies, and sometimes bacterial culture are necessary to establish a definitive diagnosis.

Pemphigus herpetiformis Clinical features Pemphigus herpetiformis (p. herpetiformis, herpetiform pemphigus, acantholytic dermatitis herpetiformis) is a variant of pemphigus which shows clinical features resembling dermatitis herpetiformis with the histology and immunofluorescent findings of pemphigus.1–6 It is rare, accounting for only up to 7.3% of cases of pemphigus.2 The sexes are affected equally and there is a wide age range varying from 31 to 83 years.3 Patients typically present with intensely pruritic, grouped, erythematous papules and plaques, vesicles and blisters, sometimes associated with mucous membrane involvement.2 Urticaria may also be a presenting feature.7 The Nikolksy sign is variably present. Although lesions are often generalized, there is a tendency for the extensor surfaces of the extremities to be particularly involved. Exceptionally, herpetiform pemphigus may be associated with psoriasis, systemic lupus erythematous or with an underlying malignancy including prostate and lung cancer (see paraneoplastic pemphigus).8–12 Although in some patients the clinical manifestations remain herpetiform throughout, in others, the features evolve into more typical p. foliaceus, fogo selvagem and, less commonly, p. vulgaris.2,4–6 Contrariwise, patients with typical p. foliaceus and p. vulgaris may go on to develop a herpetiform eruption.13 IgA pemphigus may also present with herpetiform lesions.14,15 In ­general, p. herpetiformis has a benign course, most patients responding well to sulfones or steroids.2,3,16

t­ argets a different epitope although this has yet to be confirmed. Recently, two patients with neutrophil-rich histology were shown to co-localize ­pemphigus antibody and the neutrophil chemoattractant IL-8. In addition, circulating IgG antibody up-regulated cultured keratinocyte IL-8 expression, thereby offering an explanation for the neutrophil recruitment.20,21 The biopsy findings are variable and often non-specific. Although eosinophilic spongiosis is most typical, spongiosis associated with either a mixed eosinophilic and neutrophilic, or a neutrophil-predominant infiltrate may also be encountered.4,22 Intraepidermal vesicles and pustules, also of variable composition, are often present and dermal papillary neutrophil microabscesses have been described.2,6,16 Acantholytic cells are usually (but not invariably) identified. A requirement for multiple biopsies before a diagnosis can be established is a common theme in the literature.

Differential diagnosis There is both clinical and histological overlap with IgA pemphigus and ­dermatitis herpetiformis. Immunofluorescence allows for distinction between these entities. It should also be noted that, exceptionally, dermatitis herpetiformis may histologically show occasional acantholytic cells in the absence of any evidence of pemphigus herpetiformis. In those cases where eosinophilic spongiosis is the predominant histological feature, the differential diagnosis also includes hypersensitivity reactions and infection (bacterial and fungal). Immunofluorescence studies and special stains for microorganisms will eliminate these possibilities.

Pemphigus erythematosus Clinical features Pemphigus erythematosus (p. erythematosus, Senear-Usher syndrome) is a mild localized form of superficial pemphigus with the histological and immunofluorescent findings of p. foliaceus combined with features of lupus ­erythematosus.1–6 In general, the latter is subclinical, being suggested only by laboratory findings, but there are also rare reports of full-blown systemic disease being present.4 The condition shows a worldwide distribution and a slight female predominance.5 Exceptionally, it has been described in children although immunological confirmation of the diagnosis is available in only one case.7–10 Clinically, it is commonly confined to the head, neck, and upper trunk, and typically resembles p. foliaceus. Lesions are erythematous, scaly, and crusted, with or without superficial vesicles, blisters or erosions. Facial ­involvement often shows a butterfly distribution reminiscent of lupus erythematosus or seborrheic dermatitis (Fig. 5.30).1 Mucous membrane involvement is ­exceedingly rare.2

Pathogenesis and histological features Immunofluorescence testing shows IgG in an intercellular pattern characteristic of the pemphigus group of disorders on both direct and indirect techniques.1,2,4,16 In most patients, Dsg1 (p. foliaceus antigen) is the target autoantigen.4,6,17,18 However, in some patients, antibodies against Dsg3 (p. vulgaris antigen) have also been documented.18,19 A single patient has been reported with both IgG as well as IgA antibodies against Dsg1 in addition to anti-Dsc (desmocollin) 3 IgG.15 Why antibodies to Dsg1 in patients with p. herpetiformis often fail to induce appreciable acantholysis compared with p. foliaceus is uncertain. It is postulated that the p. herpetiformis antibody

Fig. 5.30 Pemphigus erythematosus: there is scaliness and erythema affecting both cheeks. By courtesy of the Institute of Dermatology, London, UK.

Pemphigus There are reports of p. erythematosus developing after treatment with a number of drugs, notably D-penicillamine, and there are also instances attributed to therapy with propranolol, captopril, pyritinol, thiopronine, ceftazidime, and cefuroxime.11–15 P. erythematosus has also been described as a complication of heroin abuse.16 P. erythematosus may rarely be associated with thymoma.3,17–19 Typically, the thymoma precedes the onset of cutaneous lesions, which often present following thymectomy.18 Most tumors have been benign but one malignant variant has been documented.19 P. erythematosus may also be a manifestation of paraneoplastic pemphigus.3

Pathogenesis and histological features Pemphigus erythematosus, in addition to intercellular staining, also shows granular deposition of IgG and complement along the basement membrane region (positive lupus band test) (Figs 5.31 and 5.32).2,20,21 Typically

the ­latter deposits are found within sun-exposed skin but in some patients normal, nonsun-exposed skin may also be positive.2 Pemphigus antibody is ­generally present on indirect immunofluorescence, and antinuclear factor may also be identified.20,21 Anti-DNA antibodies and antibodies to extractable nuclear antigens are negative except in those patients with features of systemic lupus erythematosus.4 In common with p. foliaceus, the antibody reacts with Dsg1.22 P. erythematosus has histological changes that are identical to those seen in p. foliaceus and fogo selvagem. As the blisters are superficial, it is often very difficult to obtain an intact lesion for diagnosis. Usually, the cleft or blister lies within the granular layer or beneath the stratum corneum. As with the other forms of superficial pemphigus, acantholysis is frequently difficult to detect, but usually a few acantholytic cells can be found attached to the roof or floor of the blister. The blister may contain numerous acute inflammatory cells, particularly neutrophils, which can make distinction from subcorneal pustular disorders especially difficult.

Differential diagnosis The differential diagnosis includes the other forms of superficial pemphigus (p. foliaceus and fogo selvagem), bullous impetigo, and staphylococcal scalded skin syndrome, in addition to subcorneal pustular dermatosis. Distinction depends upon a careful consideration of the clinical information, the results of bacterial culture, and immunofluorescence studies.

Paraneoplastic pemphigus Clinical features

Fig. 5.31 Pemphigus erythematosus: typical intercellular immunofluorescence with granular staining (IgG) at the basement membrane region. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK.

Fig. 5.32 Pemphigus erythematosus: immunoelectron micrograph showing immunoreactant beneath the lamina densa in addition to occupying the intercellular space. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK.

Paraneoplastic pemphigus is a variant of pemphigus, quite distinct from p. vulgaris and p. foliaceus.1 Paraneoplastic pemphigus may be associated with a variety of tumors, such as B-cell lymphoproliferative disorders and hematopoietic malignancies, Castleman's disease, Waldenström's macroglobulinemia, thymoma (occasionally with myasthenia gravis), Hodgkin's lymphoma, carcinomas (e.g., carcinoma of bronchus, pancreas, liver, uterus, breast, and liver), and sarcomas (including dendritic follicular cell sarcoma, round cell liposarcoma, leiomyosarcoma, and inflammatory myofibroblastic tumor).2–47 We have seen an exceptional association with systemic mastocytosis. Lymphoma is most often the coexistent neoplasm.1 In a case of a patient with non-Hodgkin's lymphoma, the disease developed only after six cycles of fludarabine, raising the possibility of an association with the medication.48 In a further exceptional case, a patient presented with a disease fulfilling the diagnosis of paraneoplastic pemphigus by histology, immunoblotting, and immunoprecipitation. However, no neoplasm was found in 8 years of follow-up.49 Paraneoplastic pemphigus has been defined by Sapadin and Anhalt as follows:50 • painful mucosal erosions and a polymorphous skin eruption in the context of an occult or confirmed neoplasm (Fig 5.33), • histopathological changes of keratinocyte necrosis, intraepidermal acantholysis, and vacuolar-interface dermatitis, • direct immunofluorescence showing intercellular IgG and complement accompanied by linear or granular complement at the dermal–epidermal junction (Fig 5.34), • indirect immunofluorescence showing circulating antibodies to simple, columnar, and transitional epithelia in addition to a more typical pemphigus pattern of binding to skin and mucosa, • circulating autoantibodies that immunoprecipitate a high molecular weight complex of polypeptides from keratinocyte extracts weighing 250, 230, 210, 190, and 170 kD. Although the disease may develop in a wide age range (7–83 years), the majority of patients have been in the fifth to eighth decades and there is a male predominance.5 Exceptionally, children may be affected.4,51–54 Lesions are seen in both the mucosa and the skin. Patients present with refractory, painful, persistent erosions of the oral mucosa and vermilion border of the lips. In addition, the tongue, gingiva, floor of mouth, palate, oropharynx, and nasopharynx can be affected.5 Manifestation confined to the skin or oral mucosa is exceptional.22,55,56 Esophageal disease has been described and the

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Fig. 5.33 Paraneoplastic pemphigus: there are numerous erosions and crusted lesions. Courtesy of The Institute of Dermatology, London, UK.

Fig. 5.34 Paraneoplastic pemphigus: IgG is evident in an intercellular distribution.

trachea and bronchi may be affected.57–59 The latter is sometimes accompanied by an invariably fatal bronchiolitis obliterans-like disorder.46,58,59 Colonic involvement is unusual.60 Frequently, patients also have severe pseudomembranous conjunctivitis with symblephara, and eventual blindness may occur.5 The vulva, vagina, and penis are sometimes affected.4 Rarely, the disease is accompanied by other autoimmune disorders including myasthenia gravis and alopecia areata.46,56 Cutaneous lesions are typically polymorphic and often present as a pruritic papulosquamous dermatosis with subsequent blistering. The trunk, proximal extremities, palms, and soles are characteristically affected.61 Nail involvement may occur. Although the eruption typically resembles p. vulgaris, it may also mimic p. foliaceus, IgA pemphigus, bullous pemphigoid, linear IgA disease, lichen planus pemphigoides, erythema multiforme, and toxic epidermal necrolysis.39,62–67 P. vegetans-like lesions have been described.49 Paraneoplastic pemphigus is associated with a very high mortality.5

Pathogenesis and histological features In paraneoplastic pemphigus, circulating antibodies bind to desmosomal and hemidesmosomal plakin family members including 250-kD (desmoplakin I), 230-kD (bullous pemphigoid antigen), 210-kD (a doublet originally thought to be desmoplakin II but later determined to represent envoplakin) and a 190-kD antigen (periplakin).68–71 The presence of antibodies to envoplakin

and periplakin (both cornified envelope constituents) is believed to be highly specific for paraneoplastic pemphigus and the linker domain of plakins may be of particular significance.72,73 There are also antibodies to an as yet undetermined 170-kD antigen.66 Antibodies to Dsg1 and 3 are also usually present and plectin (another plakin family member) antibodies may be found.74,75 Anti-Dsg antibodies are thought to be of particular importance in the initiation of lesions, disrupting the cell membrane and thereby exposing desmosomal and hemidesmosomal plakin proteins with resultant autoantibody formation.68,76 Direct immunofluorescence shows IgG deposition affecting the whole thickness of the epidermis whereas C3 is found only on the lower layers.68,77–79 Characteristically, the intercellular staining is often focal and faint.77,78 In addition, complement is present along the basement membrane region. Immunoglobulin deposition in the respiratory epithelium has also been documented.57–59 Indirect studies confirm the presence of a circulating antibody although the membrane deposition is often masked by strong cytoplasmic labeling.68 This latter can be reduced or abolished by serum dilution.68 In paraneoplastic pemphigus, in addition to binding to stratified squamous epithelium, the antibody labels transitional epithelium, pseudostratified respiratory epithelium, small and large intestinal mucosa, and thyroid epithelium.78 It also reacts with myocardium and skeletal muscle. Rat bladder epithelium is said to be highly specific for paraneoplastic pemphigus.79 Up to 25% of cases, however, are negative.80 Recently, there has been accumulating evidence demonstrating considerable heterogeneity within disorders designated as paraneoplastic pemphigus in addition to overlap with other immunobullous diseases. Patient sera frequently contain additional IgA antibodies against Dsg3 and a patient with IgA antibodies to desmocollins analogous to IgA pemphigus has recently been reported.66,81 Immunophenotypic variability among paraneoplastic pemphigus patients has thus been established. The documentation of patients displaying p. vulgaris-like or p. foliaceus-like features has led some authors to suggest that immunobullous disorders arising in association with malignancy would be best viewed as representing a spectrum rather than a distinct entity.62 Included within this spectrum are other nonpemphigus immunobullous disorders resembling erythema multiforme, graft­versus-host disease, and lichen planus. The description of antibodies reactive with desmoplakin I and II in some patients with erythema multiforme raises the possibility that these autoantibodies play a pathogenic role in a ­subset of patients.82 However, further study will be necessary to determine the ­significance of this finding. Analogous to other forms of pemphigus, recent studies have suggested a genetic predisposition. HLA typing has identified HLA-Cw*14 as the predisposing allele in a Chinese population while DRB1*03 was identified in a French study.83,84 The histological findings in paraneoplastic pemphigus are highly variable but are characterized by an admixture of suprabasal acantholysis, often resembling p. vulgaris, with cleft or vesicle formation (sometimes involving adnexal epithelium), and interface changes with basal cell liquefactive degeneration, dyskeratotic keratinocytes, and lymphocytic exocytosis (Figs 5.35–5.37).69,85 Spongiosis is often present.3 A perivascular and lichenoid chronic inflammatory cell infiltrate is typically seen in the superficial dermis.77 In some cases, the histological features may closely simulate lichen planus. Eosinophils, however, are rare. Pigmentary incontinence is frequently evident.85 Acantholysis-like change has also been described affecting the bronchial lining epithelium and brochiolitis obliterans-like features may be seen.57,59

Differential diagnosis The biopsy findings of admixed acantholysis and interface change appear to be relatively non-specific. This contention is demonstrated by skin lesions in patients with typical autoimmune pemphigus without evidence of neoplasia that have histological features considered typical of paraneoplastic pemphigus.79 The differential diagnosis includes mainly interface dermatitides (e.g., drug eruption, lichen planus, erythema multiforme, graft-versus-host disease) rather than other variants of pemphigus. A very high index of suspicion on the part of the pathologist and clinician alike and confirmatory immunofluorescence studies are prerequisites to achieving a correct diagnosis.

Pemphigus

Fig. 5.35

Fig. 5.37

Paraneoplastic pemphigus: this medium-power view shows suprabasal acantholysis and interface change. Note the hyperkeratosis and hypergranulosis. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA.

Paraneoplastic pemphigus: note the basal cell hydropic degeneration and cytoid bodies. There is an intense lymphohistiocytic infiltrate. A single eosinophil is evident. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA.

• Patients with SPD-like IgA pemphigus present with superficial flaccid

•

pustular lesions, often arising on an erythematous base and typically affecting the trunk and proximal limbs, although the intertriginous sites are predilected.11 Very uncommonly, there is exclusive involvement of the oral mucosa and perianal skin.23 Occasionally, there is generalized skin involvement. Lesions are crusted and progress with peripheral extension to form ringlike and rosette patterns.15 The features may be indistinguishable from classical non-IgA-associated SPD. Patients with the IEN IgA dermatosis variant present with generalized pustules and crusts and erythematous macules with peripheral vesicles forming the so-called sunflower-like configuration (Figs 5.38, 5.39).7 A dermatitis herpetiformis-like presentation with grouped edematous papules may also be encountered.11,12,15 Pruritus is common and is sometimes severe.8

Fig. 5.36 Paraneoplastic pemphigus: higher-power view of acantholysis with suprabasal cleft formation. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, Virginia, USA.

IgA pemphigus Clinical features IgA pemphigus is a rare dapsone-responsive variant of pemphigus that, as its name suggests, is characterized by intercellular IgA deposition and presents clinically with pustular rather than bullous or vesicular lesions.1–6 This disease has been described under a number of different names, such as intraepidermal neutrophilic IgA dermatosis, IgA pemphigus foliaceus, IgA herpetiform pemphigus, intraepidermal IgA pustulosis, intercellular IgA dermatosis, and intercellular IgA vesiculopustular dermatosis.7–16 Most patients are middle aged or elderly but children may also be affected.8,17–21 The sex incidence is equal. There is no racial or geographic predilection.8,11 Drug-induced variants have occasionally been documented.22 IgA pemphigus is divided into two major subtypes: subcorneal pustular dermatosis (SPD) variant (IgA pemphigus foliaceus) and intraepidermal neutrophilic IgA dermatosis (IEN) variant (IgA pemphigus vulgaris).7 Other less readily classifiable variants may also be encountered.

Fig. 5.38 IgA pemphigus: erythematous lesions and an intact vesicle are present. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

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Fig. 5.39

Fig. 5.40

IgA pemphigus: high-power view showing pus-filled intact blisters and an erosion. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

IgA pemphigus: this biopsy is from the edge of an established blister. Note the heavy inflammatory cell infiltrate and focal acantholysis.

The lesions in occasional patients resemble classic p. vulgaris or p. f­ oliaceus. In one childhood case, a p. vegetans-like presentation associated with ­α1-antitrypsin deficiency was documented.18 Mucous membrane involvement in either variant is exceptional.17 Nikolsky's sign has been reportedly negative at least in a subset of patients.2,12,13 IgA pemphigus tends to be a chronic relapsing but relatively benign disorder.11,12,15 A significant number of patients (approximately 20%) may have an associated monoclonal gammopathy, usually of the IgA class.11,24–26 Two documented cases have been benign and the others have represented B-cell lymphoma or multiple myeloma.11

Pathogenesis and histological features SPD IgA pemphigus is characterized by intercellular IgA deposition in the upper epidermis, and circulating IgA antibodies which preferentially bind to the upper epidermis are typically present.4 In contrast, in the IEN variant, IgA is deposited preferentially in the lower epidermis, and circulating antibodies also generally bind to the lower epidermis. In some patients, however, the IgA antibody binds to the entire thickness of the epithelium. A linear subcorneal distribution has also been documented.9 Complement is not usually present and IgG and IgM are absent.7 The antibodies are of the IgA1 subclass and are usually of low titer.4,17 They have been identified in approximately 50% of patients.12 By immunoelectron microscopy performed on a limited number of cases, the immunoglobulin has been identified within the intercellular space, on the keratinocyte cell membrane, in some cases showing desmosomal accentuation.27–29 In the SPD type, labeling has been predominantly detected in extracellular spaces between keratinocytes at desmosomes while labeling is mainly in intercellular spaces in nondesmosomal areas in the IEN variant.30 The two subtypes result from autoantibody production to different ­desmosomal proteins.31 Patients with the SPD variant show reactivity with desmocollin 1.32–35 In contrast, anti-Dsg1 or anti-Dsg3 IgA antibodies are present in the IEN variant.19,36–38 One patient with the SPD variant showed both anti-Dsc1 as well as anti-Dsg1 IgA.39 In some patients, however, neither desmocollins nor desmogleins appear to be involved, suggesting that IgA pemphigus is a heterogeneous group of conditions.13,18,35,38 Histologically, in the SPD variant, vesicles are typically found in a subcorneal location associated with a neutrophil infiltrate. It is thought that the presence of IgA is responsible for the striking neutrophil response of this disorder since IgA is associated with neutrophil chemotaxis and neutrophils bear IgA receptors.40,41 In the IEN variant, the pustules can be distributed throughout all ­layers of the epidermis and may also involve the hair follicles (Figs 5.40, Figs 5.41).18

Fig. 5.41 IgA pemphigus: the blister cavity contains neutrophils and eosinophils.

Acantholytic cells are usually (but not always) present. Typically, they are sparse and, as such, this diagnostic clue may be very easily overlooked.11–13 Prominent dyskeratotic cells have been described in a single case of IgG/IgA pemphigus.42 Significant numbers of eosinophils may also be seen in occasional IEN cases.20,43 Neutrophil dermal papillary microabscesses have also been described, sometimes accompanied by neutrophil spongiosis.12,20 A perivascular infiltrate of neutrophils, lymphocytes, and histiocytes surrounds the superficial vascular plexus and eosinophils may also sometimes be present. In addition to the major variants characterized by pustules, some patients with IgA pemphigus show histological features typical of classic p. vulgaris, p. foliaceus or even, exceptionally, p. vegetans.4,18

Differential diagnosis The differential diagnosis includes subcorneal pustular dermatosis, typical p. foliaceus, and infections such as bullous impetigo. Although clinically subcorneal pustular dermatosis tends to be more restricted to the flexural sites, absolute distinction from the subcorneal variant of IgA pemphigus depends upon immunofluorescent studies. Gram stain and a periodic acid-Schiff (PAS) should always be included in the histological workup to exclude an infective process.

Acantholytic dermatoses with dyskeratosis

Drug-induced pemphigus There are at least 25 drugs that have been shown to be associated with the development of pemphigus.1 Penicillamine and captopril are the most common offenders; however, enalapril, propranolol, bisoprolol, glibenclamide, cilazapril, penicillins, cephalosporins, rifampicin, pyrazolon derivatives, and lisinopril, among others, have also been implicated.1–8 Some drugs such as penicillamine may elicit either p. foliaceus or p. vulgaris, but the former is much more common. Symptoms disappear in most patients following withdrawal of causative drugs that contain a sulfhydryl group (thiol drugs). Non-thiol drugs are much less likely to be associated with remission following withdrawal.2 Histologically, drug-induced pemphigus resembles sporadic counterparts with positive direct immunofluorescence in most, but not all, patients.9 As expected, given the different variants of pemphigus that drugs may induce, antibodies against both Dsg1 and Dsg3 have been documented.10 It has been suggested that a monoclonal antibody against desmogleins 1 and 3 may be useful in the diagnosis and prognosis of drug-induced pemphigus.11 Staining with this antibody is usually patchy in idiopathic pemphigus and diffuse in drug-induced pemphigus. Furthermore, cases of drug-induced pemphigus with diffuse pattern tend to have a poorer prognosis.

Contact pemphigus Clinical features There is a growing body of literature documenting contact with topical substances preceding the onset of pemphigus. The pathogenesis is not understood, but in some cases the exposure is thought somehow to trigger or induce pemphigus. The term ‘contact pemphigus’ has been proposed as a designation for this phenomenon, which has been described in the vulgaris, vegetans, foliaceus and erythematosus variants.1,2 Substances that have been implicated include nickel, pesticides, chromium sulfate, tincture of benzoin, phenol, diclofenac, dihydrodiphenyltrichlorethane, ketoprofen, feprazone, and imiquimod.1–14 Clearly, further study is necessary to elucidate the relationship between exposure to topical agents and contact pemphigus.

Pathogenesis and histological features Whether this phenomenon relates to systemic absorption, contact allergy or a direct ‘toxic’ effect on epidermal antigens is as yet unknown. It is interesting to note that in the majority of documented cases, the patient has been exposed to the offending agent for a considerable period of time before the onset of the blistering eruption.6 Biopsy of contact pemphigus shows histological features similar to those of p. vulgaris, although one patient developed features more reminiscent of pemphigus vegetans. Immunofluorescent studies show intercellular IgG and sometimes C3.

Fig. 5.42 Hailey-Hailey disease: erythematous and scaly lesions are present in the groin and on the labia majora. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

as the genitalia, umbilicus, inframammary regions and scalp, may also be affected. Rarely the disease may be generalized.4,5 Nikolsky's sign is sometimes positive.3 Vesicles and bullae, arising on normal or erythematous skin, are soon replaced by erosions, crusting and scaly plaques sometimes resembling impetigo (Figs 5.43, 5.44).2,6 Healing is accompanied by hyperpigmentation, but scarring is not a feature.3 Lesions are frequently itchy and malodorous. Sometimes pain is a considerable problem, particularly if fissuring is present.3 Symptoms often improve with advancing age.1 Superinfection by Candida albicans, herpes virus, and Staphylococcus aureus are frequent complications.7,8 Segmental involvement has rarely been reported as a result of type 1 or type 2 mosaicism according to the classification by Happle, and it has now become clear that at least some of the cases of relapsing linear acantholytic dermatosis represent type 2 segmental Hailey-Hailey disease.9–13 The development of the lesions is related to mechanical trauma, stress, and ultraviolet radiation and exacerbation of the disease has been reported due to scabies, contact irritation, and patch testing.14–18 An exceptional case of a patient developing the disease while on efalizumab for psoriasis has been reported.19 Symptoms often improve or even disappear during winter, but tend to worsen in summer.1,20 Mucosal involvement is unusual. Anogenital disease, however, occasionally presents as multiple 3–5-mm diameter warty

Differential diagnosis The main differential diagnosis is with classic pemphigus. Only clinical information will allow distinction of contact pemphigus from other members of the pemphigus family of disorders.

Acantholytic dermatoses with dyskeratosis Hailey-Hailey disease Clinical features Hailey-Hailey disease (benign familial pemphigus) is a rare, episodic, acantholytic disorder with an autosomal dominant mode of inheritance.1,2 In only about two-thirds of patients, however, is a family history obtained. There is an equal sex incidence.2,3 Lesions usually present in the second to fourth decades and appear particularly at sites of minor trauma or friction, especially flexural, around the neck, and in the axillae and groin (Fig. 5.42). However, other sites, such

Fig. 5.43 Hailey-Hailey disease: lesions are most often seen in the flexures as a consequence of friction. By courtesy of the Institute of Dermatology, London, UK.

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Fig. 5.44 Hailey-Hailey disease: close-up view of keratotic warty lesions. By courtesy of the Institute of Dermatology, London, UK.

papules.21 This occurs most often in females, particularly blacks, and sometimes may be a presenting feature. In such instances there is overlap with papular acantholytic dyskeratosis of the vulva.22 Asymptomatic white longitudinal bands may be present on the fingernails in up to 70% of affected patients.1,23 The other nail changes of Darier's disease are absent. Significant associated conditions have not been documented with the possible exception of a bipolar disorder and a patient with affective disorder (see Darier's disease).24,25 An association with supernumerary nipples has been documented in one Tunisian family.26 Exceptionally, squamous carcinoma has been documented as a complication in patients with Hailey-Hailey disease.27 It is likely, however, that those arising on the vulva have a human papillomavirus-associated basis.28,29 Condylomatous change and evidence of HPV infection has recently been detected in genital lesions of the disease.30,31 While it has rarely been reported that Darier's disease may coexist with Hailey-Hailey disease, the available evidence supports the contention that these two conditions represent completely different entities.32

Pathogenesis and histological features Hailey-Hailey disease is primarily an abnormality of cell adhesion. Development of this disease has recently been shown to be caused by multiple mutations in ATP2C1 on chromosome 3q21–24, a gene that encodes the calcium pump SPCA1.33,34 SPCA1 is a Ca2+/Mn2+ ATPase present within the membrane of the Golgi apparatus and responsible for the transport of Mn2+ as well as Ca2+ ions into the Golgi.35,36 Over 100 mutations have been identified spanning the entire ATP2C1 gene including missense, frameshift, splice site as well as nonsense mutations.37–46 However, no clear genotype–phenotype correlation has emerged as yet. Studies have shown that calcium regulation in cultured keratinocytes is impaired.33 In addition, there is evidence that integrity of intercellular junctions may be dependent on intracellular calcium stores.47–50 The precise mechanism by which the abnormality in the calcium pump causes acantholysis is not known. However, the addition of calcium to monolayers of squamous cells in culture elicits stratification.48 In contrast, cells grown in low calcium medium fail to stratify.50 It should be noted that Darier's disease, another disorder showing acantholysis, is also associated with a mutation in another calcium pump – ATP2A2. That both of these disorders of acantholysis are associated with mutations in a calcium pump is strong evidence for an important role in maintaining cell–cell cohesion. Immunohistochemical studies have confirmed that the major desmosomal proteins and glycoproteins are synthesized in Hailey-Hailey disease and distributed along the plasma membranes in uninvolved epidermis.51 In lesional skin there is marked cytoplasmic labeling for the desmoplakins (DpI, DpII), desmogleins (Dsg2, Dsg3) and the desmocollins.51–55 Studies on keratinocyte

differentiation demonstrate premature expression and reduced levels of involucrin due to increased mRNA degradation, and it has been proposed that intact ATP2C1 is necessary for basal cell layer keratinocytes to maintain their undifferentiated state.56,57 A number of interesting observations have been made recently in both Hailey-Hailey and Darier's disease that provide further insight into how the alteration in the calcium gradient affects ATP receptors and keratin expression.58 In both diseases there is a lower level of calcium in the basal cell layer of the epidermis compared to normal skin, the ATP receptor P2Y2 is not identified at the cellular membrane in affected cells whereas P2X27 which is usually not present on the cellular membrane is expressed in these cells probably mediating apoptosis. Furthermore, both keratins 14 and 10 are expressed in diseased cells whereas these keratins are mutually exclusive in normal keratinocytes. While early lesions show suprabasilar lacunae, established Hailey-Hailey disease is characterized by massive acantholysis associated with suprabasal vesicle or bulla formation.3 Typically, however, the acantholysis is incomplete, the cell retaining some connections and giving an appearance often ­likened to a ‘dilapidated brick wall’ (Figs 5.45–5.47). The adnexal epithelium is usually spared. Occasionally, dyskeratotic cells resembling the corps ronds and grains of Darier's disease are seen.

Fig. 5.45 Hailey-Hailey disease: early lesion showing the characteristic ‘dilapidated brick wall’ appearance.

Fig. 5.46 Hailey-Hailey disease: in this example, there is marked hyperkeratosis, parakeratosis, and acanthosis. Villi project into the blister cavity.

Acantholytic dermatoses with dyskeratosis The disease has been shown to be a type-2 mosaicism according to Happle, resulting in homozygosity for the mutated gene and pronounced disease in a segmental distribution superimposed on more classical disease in a heterozygous individual.4–7

Histological features The features are indistinguishable from Hailey-Hailey disease.

Darier's disease Clinical features

Fig. 5.47 Hailey-Hailey disease: in contrast to Darier's disease, dyskeratosis is usually minimal or even absent.

Ultrastructural studies have primarily disclosed abnormalities of the desmosome-tonofilament units, characterized by diminished numbers of desmosomes and clumped tonofilaments.59–62 The latter have a linear distribution in the basal keratinocytes, but develop a whorled configuration in the suprabasal layers.60,62 The cell membranes show microvillus formation.59 An electron microscopic study of artificially induced early lesions suggests the desmosomal splitting precedes the tonofilament clumping.61 Dyskeratotic cells are characterized by condensed tonofilaments surrounding pyknotic nuclei.

Differential diagnosis The histological features of Hailey-Hailey disease must be distinguished from those of Darier's disease, p. vulgaris, and Grover's disease. Pemphigus is distinguished from Hailey-Hailey disease by the presence of relatively intact epithelium in the adjacent epidermis (versus disintegrating ‘dilapidated brick wall’) and involvement of adnexal structures. In difficult cases, positive immunofluorescence staining supports a diagnosis of pemphigus. Darier's disease tends to show prominent suprabasal cleft formation with involvement of adnexae and is associated with numerous corps ronds and grains. These points of distinction are summarized in Table 5.2. Immunofluorescence studies for immunoglobulin and complement are invariably negative, aiding in the distinction from immunobullous disorders. Distinction from acantholytic dermatosis of the genital area can, however, be extremely difficult. In fact, the relationship between these disorders is not well understood. The combination of clinical features of a lesion or lesions localized to the vulvogenital area and a negative family history favors acantholytic dermatosis of the genital area.

Darier's disease (keratosis follicularis, morbus Darier), which is characterized by abnormal keratinocyte adhesion, is a rare hereditary disorder, usually transmitted in an autosomal dominant pattern. In a large series, however, 47% of patients had no clear family history of Darier's disease.1 Presumably these cases represent new mutations or evidence of incomplete penetrance. Its documented incidence is variable. In Oxfordshire (UK), the incidence is 1:55 000, in the north of England it is 1:36 000, in the west of Scotland it is 1:30 000, whereas in Denmark it is 1:100 000.2–5 The sex incidence is equal, although males appear to be more severely affected than females. The disease usually presents in the first or second decade (with a peak around puberty) and often follows exposure to ultraviolet light.1 Exceptionally, patients may not present until their sixth or seventh decade.6 Darier's disease is a long-term illness. Remissions do not occur, although some patients show improvement with increasing age.6 The lesions are frequently itchy and, less commonly, painful.1,6 They are characterized by greasy, crusted, keratotic yellow-brown papules and plaques found particularly on the ‘seborrheic’ areas of the body – the scalp, forehead, ears, nasolabial folds, upper chest, back, and supraclavicular fossae (Figs 5.48–5.52).1,5 There is mild involvement of the flexures in the majority of patients although sometimes this distribution predominates.1,6 Lesions may be induced or exacerbated by stress, heat, sweating, and maceration.1,7 In some areas the lesions have a warty appearance, while in the flexures they are often vegetative, malodorous (a particularly distressing problem), and often secondarily infected (Figs 5.53, 5.54).6 Bullous lesions generally following sun exposure can occur, albeit rarely.8–10 Leukodermic macules in black patients have also been described.11–14 Additional features including cutaneous horns and hemorrhagic palmar lesions have also been documented.15–18 Patients with Darier's disease are susceptible to bacterial (particularly Staphylococcus aureus), dermatophyte, and viral infections.1,19,20 There are rare case reports of eczema vaccinatum and eczema herpeticum complicating

Relapsing linear acantholytic dermatosis Clinical features Relapsing linear acantholytic dermatosis (Hailey-Hailey-like epidermal nevus) is an exceptionally rare nevus-like condition characterized by erythematous plaques with vesicles and erosions arranged in a linear distribution along Blaschko's lines.1–3 It typically undergoes spontaneous resolution followed by recurrence and has a chronic course. Insufficient cases have been documented to precisely determine its relationship to Hailey-Hailey disease. Recent data, however, demonstrate that at least some of the patients harbor mutations in the gene responsible for Hailey-Hailey disease, the ATP2C1.

Fig. 5.48 Darier's disease: in this patient keratotic brown papules are present on the back of the neck. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

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Fig. 5.49

Fig. 5.51

Darier's disease: close-up view of keratotic papules. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Darier's disease: lesions may be induced by heat, sweating, and maceration. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Fig. 5.50 Darier's disease: this patient shows a striking symmetrical distribution. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Darier's disease and a patient who developed localized anogenital cowpox has also been reported.21–23 Life-threatening Kaposi's varicelliform eruption is a rare but important complication.24–26 No consistent abnormality of immune function has been found to explain this.27,28 Recently, however, persistence of intracellular S. aureus small-colony variants in a patient with Darier's disease has been shown to be of importance in chronic cutaneous infection and resistance to antibiotic therapy.29 Whether this mechanism is involved in other patients awaits confirmation. Other cutaneous manifestations of Darier's disease include unilateral, linear or zosteriform variants, which some regard as acantholytic, dyskeratotic epidermal nevi rather than true Darier's disease (see below).30,31 It is more likely that these variants, at least in part, result from genetic mosaicism.32 The hands are affected in 96% of patients.1 Pits and punctate keratoses with focal disruptions of the skin ridges of the palms and soles are characteristic features (Fig. 5.55).1,6,33 Acrokeratosis verruciformis-like lesions are common on the backs of the hands.1 Indeed, acrokeratosis verruciformis of Hopf, a localized disorder of keratinization of distal extremities, is closely related to Darier's disease and appears to be caused by mutations in the same gene.34,35 Nail changes are a particularly important diagnostic feature.1,2,6,36,37 Longitudinal white or red streaks (often both), some of which ­terminate

Fig. 5.52 Darier's disease: close-up view. From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

in a small nick on the free margin, are typical findings (Figs 5.56, 5.57).1 Painful splitting and subungual hyperkeratoses are additional ­manifestations.1 The toenails are affected less often (and less severely) than the ­fingernails.1 Subtle hand and nail manifestations may sometimes be a ­presenting feature.6 The mucous membranes of the mouth, pharynx, larynx, esophagus, and female genitalia can also be affected.38–41 Oral lesions are present in up to 50% of patients and consist of small white papules on the hard palate.42,43 Large nodular and verrucous plaques are also sometimes present and occasionally there are gingival, buccal mucosal, and tongue lesions.15 Involvement of the salivary ducts is said to be uncommon and results in ­salivary gland swelling with obstruction and sialadenitis.44,45 Recently, however, one series reported an incidence of 30% involvement of the parotid gland.42 Anal ­involvement may present as pruritus ani or less often as ­vegetating ­malodorous plaques.46

Acantholytic dermatoses with dyskeratosis

Fig. 5.53 Darier's disease: skin involvement as severe as this is fortunately extremely rare. By courtesy of M. Greaves, MD, the Institute of Dermatology, London, UK.

Fig. 5.55 Darier's disease: palmar pits are a helpful diagnostic clue. By courtesy of J. Wilkinson, MD, Wycombe General Hospital, High Wycombe, UK.

Fig. 5.56

Fig. 5.54 Darier's disease: severe involvement can be very disfiguring and a source of considerable disability and embarrassment. By courtesy of M. Greaves, MD, the Institute of Dermatology, London, UK.

Ocular lesions, particularly affecting the cornea, are seen in up to 76% of patients.47 Peripheral corneal opacities and central epithelial irregularity are the usual findings. Pannus formation may rarely be present. Lesions are ­typically asymptomatic. Associated systemic abnormalities are unusual, but include epilepsy, ­pulmonary lesions, bone cysts, low intelligence, and small stature.1 Various neuropsychiatric problems including depression and bipolar disorder have been linked with Darier's disease.6,48 There is some evidence to suggest that there is familial cosegregation of bipolar disorder with Darier's disease, at least in a proportion of cases.48,49 Rare and likely incidental associations include visceral malignancy, horseshoe kidney, hemodialysis, gynecomastia, cutis verticis gyrate, and Fanconi anemia.50–55 Spontaneous remissions in Darier's disease are rare, and in the majority of patients the disease persists throughout life.

Darier's disease: parallel white and red longitudinal streaks are pathognomonic features. By courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features Positional cloning studies of different families have all shown the gene of Darier's disease to be located at 12q23-q24.56,57 Mutations in ATP2A2, a gene that encodes for SERCA2 (type 2 sarcoendoplasmic reticulum CA2+ATPase), cause the disease and have been identified in the majority of patients screened.57 So far, over 100 different mutations have been reported. They are predominantly missense mutations, but frameshift and splice site mutations as well as mutations resulting in a premature stop codon have also been identified.58–67 However, no clear genotype–phenotype correlation has emerged. The disease is likely a result of haploinsufficiency since only one correct copy of the ATP2A2 gene is expressed.68 The mutant copy may furthermore lead to enhanced proteasome-mediated degradation and/or protein dimerization resulting in complete loss of SERCA2 activity.68,69 The precise mechanism of how mutations in the ATP2A2 gene lead to disease is unknown although

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Fig. 5.58 Fig. 5.57 Darier's disease: notches on the free margin of the nail are common findings. By courtesy of the Institute of Dermatology, London, UK.

there is emerging evidence to suggest that the integrity of intercellular junctions is dependent on the intracellular calcium stores.70 SERCA is a ubiquitously expressed calcium-ATPase and its function is the transport of cytosolic calcium ions into the endoplasmic reticulum.68 There are three different genes encoding these proteins, resulting in a total of nine different isoforms. Of the different isoforms only SERCA2b appears to be expressed in keratinocytes.71 Loss of SERCA2 function can therefore not be compensated for, explaining the severe skin manifestations in the absence of further systemic involvement in most patients with Darier's disease.68 Ultimately, intact intracellular calcium ion homeostasis has been identified as a major factor in the complex process of desmosome assembly and is necessary for intracellular interactions between desmosomal cadherins and intracellular plaque proteins such as plakoglobin.68,72 Apoptosis in Darier's disease resulting in dyskeratotic cells is likely directly related to the imbalance in calcium homeostasis, and immunohistochemical studies have revealed reduced expression of antiapoptotic proteins of the bcl-2 gene family in lesional epidermis.73–75 No single specific ultrastructural abnormality has been identified in Darier's disease. Changes described have included complete loss of desmosomes in foci of acantholysis with formation of cell membrane microvilli, cytoplasmic vacuolization, cell membrane defects, abnormal tonofilament aggregation, clumping and distribution, premature and abnormal formation of keratohyalin granules and membrane coating (Odland) bodies, and excessive lipid lamellae between the flattened keratinocytes of the stratum corneum.76–80 Hemidesmosomes and the lamina densa usually appear morphologically normal, although discontinuities of the latter have been described. Ultrastructurally, corps ronds are characterized by large dense keratohyalin masses, numerous membrane coating granules, and tonofilament clumps.76 They are distributed particularly around the nucleus, often surrounding a perinuclear cytoplasmic halo containing distended vesicles. Grains of Darier are composed of nuclear remnants with surrounding dyskeratotic debris.76 Acantholysis develops as a consequence of desmosomal breakdown and dissociation of tonofilaments, although which comes first is uncertain. The histological features of Darier's disease depend upon a variable ­interplay between acantholysis and abnormal keratinization (dyskeratosis), the acantholysis resulting in suprabasal cleft formation (and rarely vesicles or even blisters), and the dyskeratosis manifesting as corps ronds and grains of Darier. • Corps ronds are large structures, usually most conspicuous in the granular layer, and consist of an irregular eccentric and sometimes

Darier's disease: very early lesion showing multiple characteristic corps ronds.

pyknotic nucleus surrounded by a clear halo enclosed within a basophilic or eosinophilic ‘shell’ (Fig. 5.58). Variable amounts of highly irregular keratohyalin granules may also be evident. • Grains are located within the horny layer and consist of somewhat flattened oval cells with elongated cigar-shaped nuclei and abundant keratohyalin granules. In the fully established lesion there is hyperkeratosis and often parakeratosis, sometimes arranged in a clearly defined tier (Figs 5.59–5.61). The epidermis may appear acanthotic or atrophic and typically shows acantholysis with suprabasal cleft formation in which the underlying dermal papillae, covered by a single layer of epithelium, project into the cavity (villus formation). The roof contains variable numbers of grains and the adjacent epithelium has variable numbers of corps ronds. Occasionally, epithelial proliferation can be marked, resulting in pseudoepitheliomatous hyperplasia. Bullous lesions are illustrated in Figures 5.62 and 5.63. There may be a perivascular chronic inflammatory cell infiltrate in the superficial dermis, although this is not a common finding. The histological features of the oral, pharyngeal, laryngeal, and esophageal lesions are similar to those described in the skin although dyskeratosis is said to be less conspicuous.42 Salivary gland lesions show ductal dilatation and squamous metaplasia of the lining epithelium with acantholysis and dyskeratosis.44,45

Fig. 5.59 Darier's disease: scanning view through a typical lesion. Note the keratotic tier and suprabasal cleft formation.

Acantholytic dermatoses with dyskeratosis

Fig. 5.60

Fig. 5.63

Darier's disease: higher-power view showing the well-developed vesicle with suprabasal acantholysis and well-developed corps ronds and grains.

Darier's disease: high-power view of Figure 5.62 showing multiple corps ronds.

Corneal lesions are characterized by corneal epithelial edema, subepithelial granular deposits, and basement membrane thickening. Acantholysis and dyskeratosis are not seen.47

Differential diagnosis Although warty dyskeratoma, Hailey-Hailey disease, and pemphigus are ­considered in the differential diagnosis of Darier's disease, their distinction is not challenging when clinical information is considered. Warty dyskeratoma is a single umbilicated lesion that typically forms more pronounced papillary structures. Hailey-Hailey disease is characterized by full-thickness epidermal acantholysis and does not show extensive dyskeratosis. Grover's disease may be indistinguishable from Darier's disease in a given biopsy, but the lesions are usually small, spanning only a few rete ridges. The presence of some combination of spongiosis, and changes mimicking more than one of the ­acantholytic dermatoses, is characteristic of Grover's disease. In cases that show only Darierlike changes, clinical information should allow for ­definitive diagnosis.

Linear Darier's disease Fig. 5.61 Darier's disease: in this example both corps ronds and grain of Darier are evident.

Clinical features Linear Darier's disease (acantholytic dyskeratotic epidermal nevus, unilateral Darier's disease, zosteriform Darier's disease, segmental Darier's disease) is a rare acquired condition characterized by the development of grouped, keratotic, sometimes pruritic, yellow-brown papules which affect the trunk, trunk and limbs, limbs, scalp, vulva, and face in decreasing order of frequency (Fig 5.64).1–9 Their linear distribution corresponds to the lines of Blaschko. Lesions may be aggravated by sunlight, heat, and sweating. Although a wide age range may be affected, the majority of patients are in the third or fourth decade. There is an equal sex incidence. There is no family history of Darier's disease. Usually, patients are free from other stigmata of Darier's disease but there are very occasionally reports of patients with linear lesions associated with ipsilateral nail changes and palmar pits typical of Darier's disease.10,11

Pathogenesis and histological features

Fig. 5.62 Darier's disease: bullous variant showing suprabasal acantholysis, epidermal regeneration and a subcorneal blister.

The precise nature of this lesion remains conjectural. Although many authors prefer to regard it as a variant of epidermal nevus with superimposed acantholytic dyskeratosis, there is an alternative school of thought which believes that many, if not all, such lesions represent localized or unilateral Darier's disease, arguing that the condition develops as a consequence of genetic mosaicism. Certainly, the late age of onset is unlike a typical epidermal nevus, which usually presents in childhood. The distribution along the lines of Blaschko and the occasional reports of additional Darier-like features on the ipsilateral side of the body offers support to a concept of localized Darier's disease. Recently,

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Fig. 5.64

Fig. 5.65

Linear Darier's disease: the trunk is a commonly affected site. Note the small papules. Courtesy of the Institute of Dermatology, London, UK.

Grover's disease: innumerable erythematous papules are present on the chest wall. By courtesy of the Institute of Dermatology, London, UK.

ATP2A2 mutations have been identified in lesional tissue but not unaffected skin patients with linear acantholytic epidermal nevi, confirming the relationship of these lesions to Darier's disease.12,13 Histologically, these lesions are indistinguishable from Darier's disease.

Differential diagnosis Very rarely, true epidermal nevus may show histological features of acantholysis and dyskeratosis presenting against a background of a verrucous plaque characterized by marked acanthosis and papillomatosis.14,15 Such lesions, which are present at birth, would be best classified as epidermal nevus ­showing acantholysis and dyskeratosis rather than being included in the spectrum of acantholytic dyskeratotic epidermal nevus.

Transient acantholytic dermatosis (Grover's disease) Clinical features Transient acantholytic dermatosis (persistent acantholytic dermatosis) is a primary acquired, self-limiting, acantholytic disease of unknown etiology, seen predominantly in the middle aged or elderly although there are rare reports of the disorder in children.1–5 Males are affected more often than females (3:1).2,3 The white races are predominantly affected.5 Cases involving blacks are exceptionally rare.6 The disease shows a predilection for the winter months in nonhospitalized patients.7 Although the disease is usually transient, persistent and recurring variants have also been described (persistent acantholytic dermatosis) in the literature.8–10 The development of Kaposi's varicelliform eruption is a rare and unusual complication of the disease and occult colonization by herpes simplex virus has also been documented.11,12 The skin lesions are usually rather polymorphic, consisting of 1–3-mm erythematous, red-brown or flesh-colored papules, vesicles, and eczematous plaques with a predilection for the chest, back, and thighs (Figs 5.65 and 5.66).2 The palms and soles are unaffected. Superimposed excoriations are associated with the intensely pruritic eruption. Pustular, bullous, nummular, follicular herpetiform, and zosteriform variants have all been ­documented.2,13–16 The mucous membranes, palms, and soles are commonly spared although there are rare reports of oral, nasal, and laryngeal involvement.2,17,18 Postinflammatory pigmentary changes following resolution of the acute phase are common. Transient acantholytic dermatosis has been described in ­association with leukemia and lymphoma in addition to numerous solid tumors including carcinoma of kidney, renal pelvis, bladder, and prostate.2,19–24 In one study, 25% of patients had some form of malignancy.21 Other rare associations include scabies, renal failure, peritoneal dialysis,

Fig. 5.66 Grover's disease: close-up view. By courtesy of the Institute of Dermatology, London, UK.

and renal as well as bone marrow transplantation.25–29 It is likely, however, that the majority of these associations are coincidental. Transient acantholytic ­dermatosis shows a positive correlation with asteatotic eczema, allergic ­contact dermatitis, and atopic dermatitis.3,30,31

Pathogenesis and histological features The pathogenesis of Grover's disease is incompletely understood. There are, however, a number of important known etiological factors including: • sun exposure, • excessive heat and sweating, • ionizing radiation, • adverse reaction to drugs. Transient acantholytic dermatosis has long been known to be associated with sun exposure.2,3,32–35 The lesions are photodistributed and the patients commonly give a history of having recently spent time in the sun.36 There is also a well-established relationship to excessive heat and sweating.35,37–39

Acantholytic dermatoses with dyskeratosis Bedridden, febrile patients are particularly at risk and as a result it has been proposed that the pathogenesis might be analogous to that of miliaria. Occlusion of sweat ducts and increased sweating resulting in acantholysis mediated by high concentrations of sweat urea has been proposed, although this has yet to be proven.40 More recent immunohistochemistry studies have not generally offered support for this hypothesis although bedridden, febrile patients may occasionally show prominent involvement of the eccrine duct; this has been termed sudoriferous acrosyringeal acantholytic disease.21,41,42 Associations with sunlamps, sun parlors, PUVA therapy, steam bath, hot tub, hot water bottle, and polyester jogging suits have also been documented.1,2,21 Despite these well-recognized associations, there must be other important predisposing factors, since overexposure to sunlight and excessive sweating are extremely common yet this disease is rare. Very occasional reports have described transient acantholytic dermatosis developing after radiotherapy for cancer, exceptionally with lesions confined to the area of the port.2,22,43,44 Only a small number of drugs have been associated (rarely) with the development of transient acantholytic dermatosis.2 There are reports of lesions following treatment with sulfadoxine-pyrimethamine, 2-chlorodeoxyadenosine, D-penicillamine, recombinant interleukin-4, cetuximab, and induction chemotherapy for allogeneic bone marrow transplantation.45–50 The presence of eosinophils in the dermal inflammatory cell infiltrate has raised the possibility of a hypersensitivity reaction.21 Occasional cases arising in patients with HIV infection have been recorded.21 Despite the histological similarity to Darier's and Hailey-Hailey diseases, there is no evidence of a mutation in the ATP2A2 gene.51 There have been a variety of both direct and indirect immunofluorescence observations including lupus erythematosus-like, bullous pemphigoidlike, and pemphigus-like findings.21,52 These are reviewed in reference 2. They are the exception rather than the rule and are unlikely to be of any great significance. Immunohistochemistry observations have included a reduction or absence of desmosomal staining with cytoplasmic redistribution of the proteins, ­desmoplakins I and II, plakoglobin, and desmoglein.53–55 Redistribution and dissolution of desmosomal attachment plaques have been demonstrated as the first stage in the development of Grover's disease.55 Instead of featuring specific histopathological changes, transient acantholytic dermatosis mimics three other diseases: Darier's disease, Hailey-Hailey disease, and pemphigus (p. vulgaris and p. foliaceus) (Figs 5.67–5.70).21 The first is by far the most commonly encountered. Thus, in the typical case, there is hyperkeratosis, parakeratosis, acanthosis, and acantholysis ­accompanied by corps ronds formation and grains of Darier. In the Hailey-Hailey pattern, the acantholysis is much more pronounced such that the dilapidated brick wall appearance is seen. Follicular involvement may be present. In the ­pemphigus-like ­variant,

Fig. 5.68 Grover's disease: high-power view showing acantholysis.

Fig. 5.69 Grover's disease: this example is indistinguishable from pemphigus vulgaris.

Fig. 5.67

Fig. 5.70

Grover's disease: low-power view showing an intact intraepidermal vesicle.

Grover's disease: early lesion showing intraepidermal vesiculation.

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Acantholytic disorders ­ yskeratosis is typically absent. Multiple specimens from any one patient d may disclose differing histological variants, and superimposed spongiosis is often present. Occasional bullae are encountered. A variable dermal mononuclear infiltrate is usual and significant numbers of eosinophils are seen in some cases.21 Patients with sudoriferous acrosyringeal acantholytic disease show, in addition to typical features of Grover's disease, acantholysis of the ­superficial portion of the eccrine duct.

Differential diagnosis Clinically, transient acantholytic dermatosis is easily differentiated from Darier's disease, Hailey-Hailey disease, and pemphigus. However, the biopsy findings often mimic these diseases. A histological clue to the diagnosis is the small size of the lesion. Usually only one or two small discrete lesions that span a few rete ridges are noted. This is in contrast to other acantholytic­ dermatoses, which tend to involve the entire biopsy. Biopsies from a patient with Grover's disease often show varying features mimicking more than one of the acantholytic dermatoses and occasionally a number of patterns are seen in a single biopsy specimen. Sometimes, a biopsy will show non-specific features of spongiotic dermatitis. The association of both spongiosis and acantholysis may be a useful pointer to the diagnosis of Grover's disease (see also Table 5.2).

Acantholytic dermatosis of the genitocrural area Clinical features In acantholytic dermatosis of the genitocrural area (papular acantholytic dermatosis of the vulvocrural area) focal dyskeratosis and/or acantholysis may present as an isolated phenomenon on the vulvocrural region of young or middle-aged females.1–10 Lesions sometimes extend on to the thigh and perineum.5 Patients present with variably pruritic, multiple, 0.1–0.4-mm isolated or groups of white papules, solitary keratotic nodules or, less often, with erythematous or white plaques measuring up to 1.0 cm in diameter involving the labia majora or inguinal region. More recently, cases with histologically similar findings have been described in males, presenting on the penis, scrotum, thigh, perianal region, and in the anal canal.11,12 Family history is invariably negative for either Darier's or Hailey-Hailey disease and, by definition, there is no evidence of similar lesions elsewhere on the body.4 Two cases have developed in the presence of syringomas.1

Pathogenesis and histological features The pathogenesis is unknown although it is likely that the moist environment of the body folds is of importance. Candida albicans infection has accompanied a number of cases although this may have been coincidental.4,6 With the exception of one case showing intracellular IgG and C3 staining, immunofluorescence (when performed) has been negative.3–5,8 The lesions show features of hyperkeratosis, parakeratosis, acanthosis, and acantholysis, sometimes with dyskeratosis, resembling Darier's or Hailey-Hailey disease. Warty dyskeratoma-like features associated with follicular involvement may also be encountered.2,4 Typically, minimal or no inflammation is present.

Fig. 5.71 Warty dyskeratoma: scaly nodule on the scalp, a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.

in the literature.2,3 Although the cutaneous lesions are believed to be of follicular derivation, histologically similar nodules have been described affecting the oral and vulval mucosa.8–11 The former occur most often on ­keratinized mucosa of the palate, alveolar ridge, and gingiva.9 Subungual warty dyskeratoma-like lesions have also been documented.12

Pathogenesis and histological features The etiology of warty dyskeratoma is unknown, although in the past authors have suggested an effect of actinic radiation or possibly a viral infection. Neither of these has been substantiated. There is no relationship with Darier's disease. Multiple lesions have been associated with chronic renal disease.5,6 Warty dyskeratoma is most probably of follicular derivation. Thus, many examples appear in continuity with a dilated hair follicle and, less frequently, a sebaceous gland may be evident.3,6 The recent observation of positive staining with antibodies directed towards cortex and inner root sheath provides additional support. Mucosal and subungual variants must have a different derivation. Histologically, warty dyskeratoma is composed of a widely dilated cupshaped or cystic lesion containing keratinous debris and often associated with a hair follicle (Fig. 5.72). Superficially, the keratinous debris contains ­conspicuous corps ronds and grains of Darier. The adjacent and deeper ­epithelium shows marked acantholysis and suprabasal villi are a prominent feature (Figs 5.73 and 5.74). The underlying dermis is often infiltrated by lymphocytes and histiocytes, and sometimes plasma cells are evident.

Warty dyskeratoma Clinical features Warty dyskeratoma is a peculiar hyperkeratotic, umbilicated, persistent nodule that usually presents on the sun-exposed skin of the head and neck of middleaged adults, although lesions on the trunk and extremities have ­occasionally been documented (Fig. 5.71).1–4 Most cases are solitary, but occasional patients with multiple tumors have been reported, particularly in Japanese patients.3,5–7 Lesions are commonly asymptomatic but ­occasionally discharge and bleeding may be encountered.2 There are conflicting data ­regarding gender distribution

Fig. 5.72 Warty dyskeratoma: typical scanning view of a cystic nodule with acantholysis.

Acantholytic dermatoses with dyskeratosis nodule should not be confused with any of the above disorders with the ­possible exception of familial dyskeratotic comedones; however, villi are not ­conspicuous in the latter. There is also considerable overlap with both focal acantholytic dyskeratosis and acantholytic acanthoma; however, in neither of these conditions is there a deeply penetrating crateriform lesion.

Familial dyskeratotic comedones Clinical features Although thought to be common, familial dyskeratotic comedones have been extremely rarely documented in the literature. To date, fewer than 10 families have been reported.1–8 The condition is characterized by an autosomal dominant mode of inheritance. Lesions develop in childhood or adolescence and are permanent.5 Patients present with 1–3-mm diameter papules containing small hard keratotic plugs, which on removal leave crateriform lesions resembling comedones (Fig. 5.75). Cutaneous horns may also sometimes be apparent (Fig. 5.76).2 Lesions are often generalized but show a predilection for the extremities, particularly the forearms and thighs. The face, scalp, palms, soles, and mucous membranes are typically unaffected. Some patients complain of pruritus or inflammation. There is no evidence of ectodermal dysplasia and systemic lesions are absent. Fig. 5.73 Warty dyskeratoma: note the acantholysis and villi.

Histological features The lesions are characterized by a follicle-like crateriform cystic cavity containing laminated hyperkeratotic and parakeratotic debris and lined by squamous epithelium showing dyskeratosis and sometimes acantholysis at the base (Figs 5.77, 5.78).4 Grains of Darier are typically present but corps ronds are sparse and poorly developed. Villi, as seen in Darier's disease, are not a feature. Hair shafts and sebaceous glands are absent.

Differential diagnosis The consistent folliculocentric nature of the eruption and absence of nail and oral mucosal changes help to distinguish familial dyskeratotic comedones from Darier's disease. Corps ronds, a characteristic finding in Darier's disease, are usually not prominent in familial dyskeratotic comedones. Villus formation and well-developed corps ronds within a solitary lesion distinguish warty dyskeratoma.

Fig. 5.74 Warty dyskeratoma: corps ronds are conspicuous.

Oral lesions can be morphologically indistinguishable although a number of cases more likely represent focal acantholytic dyskeratosis arising in a background of a benign trauma-related keratosis. A single case report has documented verruciform xanthoma-like features within a typical oral lesion.13

Differential diagnosis Although there are histological similarities with familial dyskeratotic comedones, Darier's disease, Hailey-Hailey disease, and Grover's disease, deeply penetrating crateriform lesions with villus formation are not associated with these entities. In addition, the clinical findings of a solitary umbilicated

Fig. 5.75 Familial dyskeratotic comedones: numerous comedones are present on the penis and foreskin. By courtesy of B.J. Leppard, MD, Royal South Hants Hospital, UK.

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Fig. 5.76

Fig. 5.78

Familial dyskeratotic comedones: a small cutaneous horn is seen arising on the scrotum. By courtesy of B.J. Leppard, MD, Royal South Hants Hospital, UK.

Familial dyskeratotic comedones: note the superficial dyskeratosis. By courtesy of B.J. Leppard, MD, Royal South Hants Hospital, UK

Perforating folliculitis presents in adults and shows a predilection for the extremities. It is characterized by a crateriform lesion containing a distorted and often curled-up hair shaft.

Acantholytic acanthoma Clinical features

Fig. 5.77 Familial dyskeratotic comedones: this section comes from the edge of a lesion. Note the dell with associated hyperkeratosis and parakeratosis. The acanthosis is in part due to the oblique angle of the cut. By courtesy of B.J. Leppard, MD, Royal South Hants Hospital, UK.

Diffuse familial comedones differ by the absence of dyskeratosis.9,10 Familial dyskeratotic comedones may also be mistaken for Kyrle's and Flegel's diseases: • Kyrle's disease typically presents on the extensor aspect of the lower extremities and presents in adulthood. There is no familial incidence. Histolo­gically, it is characterized by transepidermal elimination of parakeratotic and inflammatory debris. There is no dyskeratosis. • Flegel's disease typically presents in older adults and is characterized by epidermal atrophy, interface change, and dyskeratosis. A keratin-filled crateriform lesion is absent.

Acantholytic acanthoma is a common entity consisting of a solitary, usually asymptomatic, keratotic papule or plaque, 0.5–1.5 cm in diameter, often with overlying scale/crust. It usually presents on the trunk, arm or neck and is clinically thought to be a seborrheic keratosis or actinic keratosis.1–5 A  case with central umbilication reminiscent of molluscum contagiosum has also been described.6 Very occasionally multiple lesions have been documented.7 Some patients report pruritus. Patients are usually elderly (median age 60 years) and there is a predilection for males (2:1).2,4 Lesions are not seen about the head, palms, and soles and the mucous membranes appear to be spared.2

Pathogenesis and histological features The pathogenesis of this lesion is unknown. Although one case has been documented in association with immunosuppression, it is likely that this was coincidental.7 Diagnosis is one of exclusion and depends upon the solitary nature of the lesion. The histological features are those of hyperkeratosis, acanthosis, and papillomatosis accompanied by acantholysis affecting all or any layer of the epidermis (Figs 5.79 and 5.80).1 Dyskeratosis may be evident. A perivascular lymphohistiocytic chronic inflammatory cell infiltrate, sometimes with occasional eosinophils, may be present in the superficial dermis.

Differential diagnosis In acantholytic seborrheic keratosis the acantholysis is typically focal and the lesion elsewhere shows the typical features of horn cysts and squamous eddies.8 Darier's disease, acantholytic dermatosis of the genitocrural area, warty dyskeratoma and pemphigus, Hailey-Hailey disease, and Grover's disease may show similar histological features but are easily ­distinguished clinically. Acantholytic actinic keratosis also shows dysplasia in addition to acantholysis.

Acantholytic dermatoses with dyskeratosis Histological characteristics include regular epidermal acanthosis ­showing acantholytic dyskeratosis with grains and corps ronds.1,2 Acantholytic acanthosis is typically confluent, affecting varying levels of the epidermis. Occasionally, it may be confined to the granular and corneal layers or it may be nonconfluent and multifocal.1 Cup-shaped endophytic growth and ­follicular involvement are not observed.

Differential diagnosis Acantholytic dyskeratotic acanthoma differs from acantholytic acanthoma by the presence of marked dyskeratosis. Focal acantholytic dyskeratosis shows identical histological features but is an incidental finding rather than a clinically distinct lesion. Warty dyskeratoma is characterized by its cup-shaped and endophytic growth. Pemphigus, Darier's disease, and Grover's disease differ in their clinical presentation.

Focal acantholytic dyskeratosis Fig. 5.79 Acantholytic acanthoma: low-power view showing hyperkeratosis, parakeratosis, intraepidermal vesiculation, and multiple foci of acantholysis.

Clinical features By definition, this is an incidental histological feature without a clinical correlate.

Pathogenesis and histological features Focal acantholytic dyskeratosis is a descriptive histopathological term ­referring to the finding of Darier-like features within the epidermis overlying or adjacent to an otherwise unrelated pathological lesion.1,2 The pathogenesis is not known. The histological features comprise hyperkeratosis, parakeratosis with suprabasal cleft formation, acantholysis, and dyskeratosis.3 These changes may be seen in the overlying or adjacent epithelium in a variety of lesions, such as basal cell carcinoma, melanocytic nevi, chondrodermatitis nodularis helicis, malignant melanoma, dermatofibroma, and as part of an epidermal nevus (Fig. 5.81). Focal acantholytic dyskeratosis has recently been described in a patient with pityriasis rubra pilaris.4 It is important to ­recognize this as an incidental finding to avoid misdiagnosis as Darier's disease.

Fig. 5.80 Acantholytic acanthoma: high-power view showing acantholysis and dyskeratosis.

Acantholytic dyskeratotic acanthoma Clinical features Acantholytic dyskeratotic acanthoma is a recently described entity with ­clinical features similar to acantholytic acanthoma. There is a predilection for the trunk of middle-aged to elderly adults with an equal gender distribution.1 They are solitary lesions characteristically measuring less than 1 cm with a clinical impression of basal cell carcinoma, actinic keratosis or squamous cell carcinoma in situ.1,2 Fig. 5.81

Pathogenesis and histological features The pathogenesis of acantholytic dyskeratotic acanthoma is unknown.

Focal acantholytic dyskeratosis: this example showing the changes of Darier's disease was an incidental finding adjacent to a completely unrelated lesion. There was no clinical evidence of Darier's disease.

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Chapter

Spongiotic, psoriasiform and pustular dermatoses

ECZEMATOUS DERMATITIS  180 Eczema – general considerations  180 Endogenous dermatitis  180 Atopic dermatitis  180 Seborrheic dermatitis  182 Discoid dermatitis (nummular eczema)  183 Hand eczema (dyshidrotic eczema, palmoplantar eczema, pompholyx)  183 Autosensitization (Id) reaction  184

Exogenous dermatitis  184 Contact dermatitis  184 Infective dermatitis  186 Asteatotic dermatitis  186 Lichen simplex chronicus  188 Nodular prurigo and prurigo nodule  190 Stasis dermatitis and acroangiodermatitis  192 Pityriasis alba  193

Actinic prurigo  194 Eosinophilic spongiosis  194 Erythroderma  194 Sulzberger-Garbe syndrome  195 Vein graft site dermatitis  195 Papular acrodermatitis of childhood  195 Pityriasis rosea  196 Juvenile plantar dermatosis  199 Miliaria  199 Fox-Fordyce disease  200 Transient acantholytic dermatosis with prominent eccrine ductal involvement  200

PSORIASIFORM DERMATOSES  201 Psoriasis  201

See www.expertconsult.com

for references and additional material

Inflammatory linear verrucous epidermal nevus  214 Bazex syndrome  215 PUSTULAR DERMATOSES  215 Pustular drug reactions  215 Subcorneal pustular dermatosis  215 Toxic erythema of the neonate  217 Infantile acropustulosis  217 Transient neonatal pustular melanosis  218 Eosinophilic pustular folliculitis of infancy  218

Reiter's syndrome  211 Pityriasis rubra pilaris  211

Eczematous dermatitis This chapter discusses a number of disorders under the rubric eczematous dermatitis, also called eczema and spongiotic dermatitis. The term eczema refers to a group of disorders that share similar clinical and histological features but may have different etiologies. Some object to a diagnosis of eczema since it does not reflect a specific disease but is a non-specific term that simply can be used for any clinical lesion that exhibits spongiosis, which clinically manifests as moist, often ‘bubbly’ papules or plaques superimposed on an erythematous base. The pathogenesis of some forms is poorly understood. The histopathologist usually cannot render a more specific diagnosis other than ‘spongiotic dermatitis ­consistent with eczematous dermatitis’ and precise classification within the differential diagnosis of spongiotic dermatitis is often not possible. For these reasons, this class of disorders is discussed as a group. Distinguishing clinical, pathogenetic, and histological features are presented in the appropriate sections.

Eczema – general considerations Eczema encompasses a number of disorders with variable etiologies and ­clinical manifestations and is one of the most common complaints of patients visiting dermatology clinics. The earliest clinical lesions are erythema and aggregates of tiny pruritic vesicles, which rupture readily, exuding clear fluid, and later become encrusted (Fig. 6.1). More chronic lesions become scaly and thickened (lichenification), resulting in lichen simplex chronicus (Fig. 6.2). Lichenification occurs if the skin is continually scratched or rubbed as, for example, in atopic dermatitis. Therefore, the clinical features of dermatitis depend upon the duration of the lesions, site(s) involved, and the amount of scratching.

For instance, in pompholyx (acute vesicular dermatitis of the hands and feet), the fluid is trapped beneath the thickened horny layer as small tense white blisters resembling rice grains. In other regions where the skin is loosely attached, as on the eyelids, scrotum, and backs of hands, tissue edema is often marked. Eczematous dermatitis has two major etiological classifications: • endogenous dermatitis, related to major constitutional or hereditary factors, • exogenous dermatitis, involving environmental factors.

Endogenous dermatitis Atopic dermatitis Clinical features Although atopic (infantile or flexural) dermatitis may begin at any age, it usually commences from about the sixth week onwards. It is characterized by a chronic, relapsing course.1 In the infantile phase lesions are present mainly on the head, face, neck, napkin area, and extensor aspects of the limbs (Fig. 6.3). As the patient grows older and enters childhood, the eruption shifts to the flexural aspects of the limbs. Chronic atopic cheilitis may also be evident.1 Pruritus is intense and constant scratching and rubbing leads to lichenification and frequent bouts of secondary bacterial infection (Fig. 6.4).2,3 Atopic eczema is commonly associated with dry skin (xerosis). Vesiculation is uncommon. There is an increased risk of dermatophyte and viral infections.1

Endogenous dermatitis

Fig. 6.1 Eczema: this is a plaque of discoid eczema. Small vesicles are present at the edge of the lesion. By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.3 Atopic dermatitis: lesions on the face and trunk are particularly seen in infants and young children. This child has bilateral involvement of the cheeks. By courtesy of J. Dayrit, MD, Manila, The Philippines.

Fig. 6.4 Atopic dermatitis: these crusted, exudative and infected lesions with lichenification are characteristic. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 6.2 Lichenification: pronounced pebbly lichenification on the dorsum of the hand of a patient with atopic dermatitis. Bizarre forms, as seen here, are not uncommon in black children. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

The disease improves during childhood and, in over 50% of cases, clears completely by the early teens. Approximately 75% of patients with atopic dermatitis have a family history of atopy and up to 50% have associated asthma or hay fever.4,5 The condition typically worsens in the winter months. It is associated with an increased incidence of contact dermatitis, ­particularly affecting the hand.6 Other features that may be seen include ichthyosis (50%), nipple eczema, conjunctivitis, keratoconus, bilateral anterior cataracts, sweat-associated itching, wool intolerance, perifollicular accentuation, food intolerance and white dermatographism.5 Infraorbital folds (DennieMorgan folds) are said to be characteristic of atopic dermatitis, particularly when double.1

Pathogenesis Atopy is defined as a genetically determined disorder encompassing dermatitis, asthma, and hay fever. It is associated with excess immunoglobulin E (IgE) antibody formation in response to common environmental antigens. A subset of patients with ‘intrinsic atopic dermatitis’ represents perhaps 10–30% of

patients with atopy; this does not appear to be due to a response to an environmental antigen.7 Atopic dermatitis is a multifactorial disease. Its pathogenesis is complex and, despite recent advances, only incompletely understood. In addition to a genetic susceptibility, the main elements responsible for the initiation and maintenance of the disease state include abnormal skin barrier function, abnormal activity of the innate and adaptive immune systems, as well as environmental factors and infectious agents.7–15 Since patients with atopic dermatitis often have a personal or family history of asthma or allergies, a genetic predisposition to the disease has long been suspected. Recent studies have demonstrated that loss-of-function ­mutations in the FLG gene, encoding the cornified envelope protein profilaggrin, are present in a significant subset of patients with atopic dermatitis and represent the highest risk factor for development of the disease.16 Together with involucrin and loricrin, filaggrin is a major constituent of the cornified envelope during terminal keratinocyte differentiation responsible for intact epidermal barrier function. Disruption of the skin barrier function appears to be of particular significance in the initiation and early stages of the disease. Nevertheless, 40% of patients with FLG mutations never develop atopic ­dermatitis and FLG mutations have been identified in only 14–56% of patients, indicating that other factors may also play an important role in the pathogenesis of the disease. In addition to the cornified envelope, epidermal barrier function is maintained also by other factors such as proteases and protease inhibitors as well as direct keratinocyte–keratinocyte interaction. Increased expression of kallikrein-related peptidases has been observed in the stratum corneum in atopic dermatitis and in one study a 4-bp ­insertion

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Spongiotic, psoriasiform and pustular dermatoses into the 3′ untranslated region of KLF7 leading to increased levels of this protease was identified in patients with atopic dermatitis.13,17,18 However, this finding has not been substantiated in further studies.13 Linkage has also been demonstrated to the gene SPINK5, encoding the serine protease inhibitor LEKTI. LEKTI, expressed at the granular cell layer, is an important inhibitor of the kallikrein-related peptidases KLK5 and KLK7 and is responsible for controlling desquamation. Linkage to SPINK5 is, however, significantly weaker than to profilaggrin.13 A further mechanism involved in skin barrier function is the presence of intercellular junctions, and recent data have demonstrated reduced expression of the tight junction protein claudin-1 in atopic dermatitis.15 Many lines of evidence also implicate an abnormal immune response as pivotal in the pathogenesis of atopy. It is interesting to note that atopy is cured by bone marrow transplantation in patients with Wiskott-Aldrich syndrome, an immunological disorder characterized by susceptibility to infection and thrombocytopenia, in addition to eczematous dermatitis.19 Wiskott-Aldrich syndrome shows an X-linked recessive pattern of inheritance and is characterized by depletion of nodal and circulating T lymphocytes. Contrariwise, patients without a prior history of atopy may develop atopic disease following transplantation of bone marrow from an atopic individual.20 Patients with atopic dermatitis have an abnormal immune reaction to a variety of environmental antigens leading to production of IgE antibodies and a T-cell response.9,21–23 There is evidence that certain subpopulations of T cells selectively circulate to and perform immune surveillance for the skin and lymph nodes that drain cutaneous sites.9,23 This subset of lymphocytes is characterized by a unique immunophenotype and is defined by expression of cutaneous lymphocyte antigen (CLA). In patients with atopic dermatitis, antigens such as dust mites and bacteria activate CLA T cells, resulting in the production of cytokines, which stimulate eosinophils to produce IgE, which, in turn, promotes mast cells and basophils to release cytokines and chemotactic factors in what has been termed the intermediate-phase response.8 The so-called late-phase reaction is characterized by migration of eosinophils, lymphocytes, histiocytes, and neutrophils from the circulation into the dermis and epidermis. Factors released by the various cells present in the dermis certainly play a role in the generation of the clinical appearance and induction of pruritus, leading to scratching and rubbing. In the early phase, mechanical trauma and skin barrier disruption lead to release of proinflammatory cytokines (IL-1α, IL-1β, TNF-α, GM-CSF) which activate cellular signaling and induce expression of vascular endothelial cell adhesion molecules after receptor binding to endothelial cells.15,24,25 These steps subsequently initiate transvascular migration of inflammatory cells.8,26 Chemokines released by inflammatory cells attract a more directed cellular immune response. In particular, CCL27, CCL22, and CCL17 are increased in patients with atopic dermatitis and levels correlate with disease activity.14,25 Disease onset is related to TH2 cytokines IL-4, IL-13, and IL-31 while disease maintenance (chronic phase) is associate dwith TH1 cytokines. Other T cells, such as Treg and TH17, are also present in cutaneous lesions but their precise role is uncertain.14 The demonstration that squamous cells in patients with atopic dermatitis show increased production of GM-CSF, a cytokine thought to play a role in Langerhans/dendritic cell function, further suggests that a keratinocyte defect may be involved in the pathogenesis of atopy.27 Another area of interest has been the role of superantigens in the pathogenesis of atopy as well as other immunologically mediated cutaneous and noncutaneous disorders.28–33 Although superantigens have been implicated in the pathogenesis of psoriasis and Kawasaki's disease, in addition to atopic dermatitis, their precise role in these and other diseases is not well understood and is controversial.29,30 Further research is necessary to clarify the role of superantigens in immunologically mediated diseases. Superantigens are microbiological (viral, bacterial, fungal) toxins that ­stimulate CD4+ T cells. They bind to T-cell receptors and to the class II major histocompatibility complex (MHC), thus stimulating lymphocyte proliferation, activation and release of cytokines, as well as T-cell-mediated tissue damage. They may also stimulate B cell activation. Superantigens are powerful mediators of the immune system by virtue of their ability to stimulate a large population of T cells in a non-specific manner. Staphylococcal superantigens have, in particular, been an area of research.32 The skin of most patients

with atopic dermatitis is colonized with Staphylococcus aureus. In contrast, S. aureus is found on the skin of only a minority of control subjects.33 Disease severity has been shown to correlate with the presence of toxigenic S. aureus.34 It is thought that staphylococcal superantigens SEA and SEB (staphylococcal enterotoxins A and B, respectively) activate T cells.34–37 In a study of children with atopic dermatitis, there was a correlation of disease severity and presence of SEA and SEB antibodies.35 Recently, application of SEB was shown to be associated with T-cell activation in both normal and atopic patients.38 In summary, there is mounting evidence that staphylococcal superantigens play a role in the symptomatology of atopic dermatitis. Whether superantigens play a key role in the development of disease or simply exacerbate symptoms in atopic patients requires further study.

Seborrheic dermatitis Clinical features Seborrheic dermatitis is a common dermatosis which affects up to 1–3% of the population.39–41 There is a male predominance. It presents in infants, with a second peak affecting adults.42 There is often a family history of the disease. It particularly affects those areas where sebaceous glands are most numerous, i.e., the scalp, forehead, eyebrows, eyelids, ears, cheeks, presternal and interscapular areas (Figs 6.5, 6.6).43 Occasionally, the flexural regions are affected (intertrigo). Often the lesions of seborrheic dermatitis are sharply marginated, dull red or yellowish, and covered by a greasy scale.43 They are therefore easily confused with psoriasis. Dandruff and cradle cap are also sometimes included within the spectrum of seborrheic dermatitis. Seborrheic dermatitis is one of the most common dermatoses seen in patients with acquired immunodeficiency syndrome (AIDS). Seborrheic dermatitis has also been associated with stress and neurological disorders including Parkinson's disease, syringomyelia, and trigeminal nerve injury.44

Pathogenesis The precise pathogenesis of this condition is unknown. Surprisingly, and in spite of the distribution (and the name) of the disease, sebaceous gland activity and sebum composition appear to be normal.44 Seborrheic dermatitis is associated with heavy colonization of the skin by the lipophilic yeast Malassezia furfur (Pityrosporum ovale) while more recent data have identified a predominance of Malassezia restricta and Malassezia globosa.41,45–50 Although many workers in the field believe this to be of etiological importance, an almost equal number are unconvinced. The body of evidence favoring a significant relationship relates to the successful treatment

Fig. 6.5 Seborrheic dermatitis: there is diffuse erythema and scaling of the scalp. By courtesy of B. Al Mahmoud, MD, Doha, Qatar.

Endogenous dermatitis

Fig. 6.8

Fig. 6.6 Seborrheic dermatitis: note the marked scaling. By courtesy of the Institute of Dermatology, London, UK.

Discoid eczema: the lesion is sharply defined and there is a pronounced scale. By courtesy of the Institute of Dermatology, London, UK.

of seborrheic dermatitis with antifungal therapy.39,40,51 Whether this implies a causal relationship or merely an exacerbating factor is, however, uncertain.

Discoid dermatitis (nummular eczema) Clinical features The presence of single or multiple pruritic, coin-shaped, erythematous plaques with vesiculation, particularly involving the lower legs, forearms, and backs of hands (Figs 6.7–6.9) characterize this chronic form of dermatitis.52 The absence of a raised border clinically distinguishes it from ringworm.52 There are two peak ages of onset: it affects young women (15–30 years of age) and middle-aged adults of both sexes. The disease tends to chronicity. Fig. 6.9 Discoid eczema: there is extensive involvement of the leg. A sharply demarcated erythematous and scaly circular lesion is present just below the knee. By courtesy of R.A. Marsden, St George's Hospital, London, UK.

Pathogenesis

Fig. 6.7 Discoid eczema: circumscribed, erythematous lesions on the forearm, a characteristic site. By courtesy of the Institute of Dermatology, London, UK.

The pathogenesis is poorly understood. A participatory role for organisms in the pathogenesis has been suggested but not been widely accepted.53 Discoid dermatitis may follow irritants such as soap, acids or alkalis (Fig. 6.10).52 Sometimes it may be a manifestation of atopy and, occasionally, it develops as a consequence of nickel, chromate or cobalt allergy.54,55 Generalized disease has also been documented in the setting of interferon alpha-2b plus ribavirin treatment for hepatitis C infection.56

Hand eczema (dyshidrotic eczema, palmoplantar eczema, pompholyx) Clinical features Hand eczema is characterized by a recurrent pruritic vesicular eruption of the palms, soles or digits. Because of the increased thickness of the keratin

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Fig. 6.10 Discoid eczema: lesions localized to the fingers most often represent a contact irritant reaction. By courtesy of R.A. Marsden, St George's Hospital, London, UK.

Fig. 6.12 Hand eczema: more chronic example showing marked scaling. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Autosensitization (Id) reaction Clinical features On occasion, patients will develop generalized spongiotic dermatitis in response to a dermatosis or infection at a distant site. The eczematous dermatitis resolves if the underlying infection or specific dermatosis is successfully treated. This phenomenon has also been designated an autoeczematization or Id reaction. The lesions that characterize the Id reaction may be a localized pompholyx-like eczematous dermatitis of the hands and feet or scattered papules on the trunk and limbs.65–69 Disorders that may be associated with the Id reaction include fungal infection (e.g., dermatophyte infection), scabies infestation, molluscum contagiosum, tick bite, pediculosis capitis, and bacterial and mycobacterial infections.65–69 A generalized nummular dermatitis has been reported in association with localized dental infection.70

Pathogenesis The pathogenesis of the Id reaction is poorly understood but some data suggest that an abnormal T-cell-mediated immune response directed against skin antigens is responsible for this curious disorder.71 Fig. 6.11 Hand eczema: tense yellow vesicles are present. By courtesy of B. Al Mahmoud, MD, Doha, Qatar.

Exogenous dermatitis Contact dermatitis

layer at these sites, the vesicles appear as small pale papules before rupturing (Figs 6.11, 6.12). Occasionally, frank bullae can form. With the passage of time, the affected parts may show scaling and cracking. The nails sometimes become dystrophic, with discoloration and transverse ridging.57 In the majority of cases the cause is unknown, although heat or psychological stress may precipitate an attack.57 In some patients there is a personal or family history of atopy or coexisting tinea pedis. Rubber, latex, chromium, cobalt or nickel sensitivity may be the trigger.58–62 The condition can be exacerbated by heat and, rarely, it is photoinduced.63 Pompholyx is often associated with hyperhidrosis.58 Females are affected slightly more often than males and patients are predominantly in the second to fifth decades.59 A familial autosomal dominant form has been reported where the candidate gene has been mapped to chromosome 18q22.118q22.3.64

Pathogenesis The pathogenesis is obscure. It has been noted that serum IgE levels are often raised.58

This form of dermatitis is due to external agents and is divided into two variants: allergic contact and irritant contact.

Allergic contact dermatitis Allergic contact dermatitis is an idiosyncratic cell-mediated immunological reaction to an environmental allergen, which may be present in very low concentration. Common examples seen in clinical practice include sensitivity to nickel (found in items such as jewelry, buttons, watches, and suspenders), constituents of synthetic rubber (e.g., thiuram in rubber gloves), primula, poison ivy, topical medicaments (e.g., neomycin, antihistamines, local anesthetics), and chromates found in cement and leather (Figs 6.13–6.15).72–82 Dinitrochlorobenzene (DNCB) is a potent contact sensitizer and this is used as a test of cell-mediated immunity.83,84 A growing understanding of allergic contact dermatitis has emerged over the last decade with the preponderance of evidence pointing to a T-cellmediated hypersensitivity reaction.3,85–88 It is thought that antigens causing allergic contact dermatitis are often unstable (haptens) and need to bind to

Exogenous dermatitis

Fig. 6.13

Fig. 6.15

Contact dermatitis: this early erythematous predominantly macular eruption developed as a reaction to fabric softener. By courtesy of J. Dayrit, MD, Manila, The Philippines.

Contact dermatitis: a severe reaction to poison ivy. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Occasionally, exposure to strong haptens may result in the development of allergic contact dermatitis in previously unsensitized individuals (primary allergic contact dermatitis).89 Ingested or inhaled allergens in a person who has been previously sensitized by cutaneous absorption may result in a clinical picture similar to allergic contact dermatitis (e.g., ingested nickel, chromium or cobalt may result in the appearances of hand eczema).93 Much less commonly, systemic allergic contact dermatitis may be histologically associated with an erythema ­multiforme-like eruption, vasculitis or urticarial morphology.93 This is thought to result from systemic exposure of a hapten via hematogenous transport to the skin.94 It may occur with or without prior sensitization, and a large number of drugs have been implicated in the pathogenesis.94 Fig. 6.14 Contact dermatitis: bilateral involvement in a patient using a watch on the right wrist and a leather bracelet on the left wrist. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

epidermal host proteins.3,85 These hapten–protein interactions are formed via covalent binding of electrophilic residues of the chemical with amino acids, especially cysteine.89–91 In contrast, metal ions, such as nickel, are thought to form noncovalent protein–metal chelate complexes.89 In the sensitization/ initiation phase of the disease, hapten-specific T cells are generated in lymph nodes after the initial contact of the skin with a potent hapten.91 Langerhans cells in skin and dendritic cells in lymph nodes process antigen and stimulate appropriate naive CLA T cells. CLA-positive T cells are a subset of T cells that express a skin-selective homing receptor and perform immune surveillance for the skin and lymph nodes that drain cutaneous sites.92 CLA-positive T cells proliferate when stimulated by the appropriate antigen or antigen– protein complex. The number of CLA-positive memory T cells increases with repeated exposures to its antigen.3,85 When the patient is exposed to the antigen, the elicitation phase, the CLA-positive T cells are activated and release cytokines which lead to the immune reaction responsible for the clinical and histological features associated with allergic contact dermatitis.87 CD8+ T cells appear to be the main effector cell in the elicitation phase.89 Keratinocytes are also thought to play a role through the release of cytokines after hapten exposure and binding.88

Irritant contact dermatitis Irritant contact dermatitis, which is much more common than allergic contact dermatitis, follows exposure to physical or chemical substances capable of direct damage to the skin. Mechanisms of damage are variable and include keratin denaturation, removal of surface lipids and water-holding substances, damage to cell membranes, and/or direct cytotoxic effects.95 Acute irritant dermatitis usually results from a relatively short single exposure to a potent irritant, such as strong acid or alkali, whereas chronic cumulative insult or ‘wear and tear’ dermatitis is due to more prolonged contact with one or more weaker irritants, for example, soap and water, detergents or industrial oil and plants (Fig. 6.16).96–100 Most forms of occupational dermatitis of the hands, including ‘housewives’ and ‘wedding ring’ dermatitis are of the irritant contact type. A diagnosis of contact dermatitis is made from the history and distribution of lesions and, in the case of allergic dermatitis, is confirmed by patch testing to the suspected allergen. Although both forms of contact dermatitis tend to be confined to exposed areas, the reaction may eventually spread to involve nonexposed sites and can persist even when the causative agent is removed from the environment. Similar to atopic dermatitis, loss-of-function mutation in the FLG gene, encoding filaggrin, may confer an increased susceptibility to chronic irritant contact dermatitis evoking an underlying skin barrier defect in the pathogenesis of the disease.101

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Fig. 6.16

Fig. 6.18

Contact dermatitis: there is a superimposed pustular element due to an infection in this patient with a contact reaction to a domestic antiseptic. By courtesy of B. Al Mahmoud, MD, Doha, Qatar.

Asteatotic dermatitis: these typical appearances are the result of scaling and fissuring. By courtesy of B. Al Mahmoud, MD, Doha, Qatar.

Infective dermatitis

ity, all of which tend to dry the skin.111 The affected regions are inflamed and criss-crossed by scaly lines and superficial fissures (Fig. 6.18). Asteatotic dermatitis may be associated with internal malignancy, including lymphoproliferative disorders and solid tumors.112–115

Infective dermatitis is a severe chronic and recurrent eczematous dermatitis showing pronounced exudation and crusting and presenting in children with human T-cell lymphotropic virus type 1 (HTLV-1) infection.102–105 Adult onset is exceptional.106,107 The disease has a predilection for the scalp, flexures, the ears and feet, and sometimes around wounds and ulcers (Fig. 6.17), and is frequently associated with Staphylococcus aureus and beta-hemolytic Streptococcus infection of the skin and nasal vestibule. It occurs in regions where HTLV-1 is endemic. It has frequently been reported in Jamaica, while presentation in Japan appears relatively rare.108 Development of the disease may be associated with a defective immune system and may be a risk factor for the development of other HTLV-1-related diseases such as adult T-cell leukemia and tropical spastic paraparesis.109,110

Asteatotic dermatitis Commonly seen in the elderly, particularly in winter and in those with minor degrees of ichthyosis, asteatotic dermatitis (eczema craquelé) may be precipitated by excessive washing, exposure to detergents, cold winds or low humid-

Fig. 6.17 Infective dermatitis: lesions affecting the foot web spaces are often due to staphylococci or streptococci and are associated with excess sweating. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Pathogenesis and histological features The histopathological features of spongiotic dermatitis include both dermal and epidermal changes. Their relative proportions vary to some extent with the subtype, but perhaps more importantly, with the stage of evolution of the disease. It is essential not to consider the changes of spongiotic dermatitis as static: different features are seen at different stages.116–118 Attempting to distinguish the various clinical subtypes based on histological features alone is generally futile. Instead, once the disorder has been recognized as spongiotic in nature, clinical examination is a much more satisfactory method of determining the particular variant. The histological hallmark of spongiotic dermatitis is the presence of intercellular edema or spongiosis (L., Gr. spongia, sponge). Slight degrees of intracellular edema may also be evident but may easily be overlooked. In the early stages of development, spongiosis results in widening of the intercellular spaces, rendering the intercellular bridges conspicuous (Fig. 6.19). Further accumulation of fluid leads to the eventual development of an intraepidermal vesicle. A common finding in association with the intercellular edema is lymphocytic infiltration of the epidermis (exocytosis). In severe contact irritant dermatitis, the epidermis may be infiltrated by large numbers of neutrophil polymorphs in association with necrotic keratinocytes.119 In addition, such reactions may be accompanied by dermoepidermal separation resulting in a vesicle or blister. The lesions very often become traumatized and may show marked crusting. Spongiotic dermatitides not uncommonly become infected with bacterial or fungal organisms. Superimposed infection may dramatically alter the histological picture by causing marked acute inflammation with subepidermal, intraepidermal, and subcorneal pustules. Such changes may dominate the histological picture and obscure the underlying spongiotic dermatitis. Use of stains for organisms – Gram, periodic acid-Schiff (PAS) – or cultures are necessary to evaluate for infection. Concomitant with these changes are varying degrees of epithelial proliferation, ranging from mild acanthosis in early acute dermatitis to marked psoriasiform epidermal hyperplasia in chronic variants. Parakeratosis is frequently seen overlying spongiotic foci, while hyperkeratosis is a usual accompaniment of chronic spongiotic dermatitis that has been scratched or rubbed (lichenification). The dermis is often congested and edema is usually marked in active lesions. The vessels of the superficial vascular plexus are surrounded by a

Exogenous dermatitis

Fig. 6.19 Dermatitis: the earliest visible manifestation of intercellular edema is widening of the intercellular spaces with accentuation of the intercellular bridges.

Fig. 6.21 Acute dermatitis: the vesicle contains lymphocytes and occasional eosinophils.

mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and occasional eosinophils or neutrophils. The degree and composition of dermal inflammation is highly variable. Eosinophils may be numerous in allergic contact dermatitis.119 Traditionally, spongiotic dermatitis is subclassified histologically into acute, subacute, and chronic variants: • In acute lesions, vesiculation and blister formation may be seen (Figs 6.20–6.22). • Acanthosis and spongiosis, often with vesiculation, also characterize subacute spongiotic dermatitis (Fig. 6.23). • In chronic spongiotic dermatitis, although spongiosis is evident, it may be subtle, and vesicles are uncommon. Epithelial acanthosis is marked and often shows a psoriasiform pattern (Fig. 6.24). Systemic contact dermatitis may be associated with the features of vasculitis or erythema multiforme.120 As with other forms of spongiotic dermatitis the histological appearances can be divided into acute, subacute, and chronic forms. Spongiosis is more conspicuous in the acute phase although it is never marked. In contrast, the epidermal hyperplasia becomes more conspicuous and psoriasiform towards the chronic end of the spectrum.

Fig. 6.22 Acute dermatitis: in contact reactions, Langerhans cell-rich vesicles are often present, as shown in this picture. These should not be mistaken for the Pautrier microabscesses of mycosis fungoides.

Fig. 6.20 Acute dermatitis: fluid-filled vesicle due to intense spongiosis.

The features of seborrheic dermatitis are often non-specific and subtle. It is characterized by hyperkeratosis and parakeratosis, the latter particularly related to hair follicles and typically associated with neutrophil exocytosis (Figs 6.25, 6.26). Yeasts may sometimes be found in the stratum corneum particularly if PAS stained sections are examined. Epidermal acanthosis with thickened rete ridges is present and often marked in chronic lesions. It is, however, somewhat irregular in contrast to the uniform hyperplasia characteristic of psoriasis. Variable spongiosis with lymphocyte exocytosis is common. The dermis may be edematous and mild vascular dilatation is usually seen. A mixed inflammatory cell infiltrate consisting of lymphocytes, histiocytes, and small numbers of eosinophils surrounds the superficial vascular plexus.

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Fig. 6.23 Subacute dermatitis showing patchy parakeratosis, crusting, marked acanthosis with considerable elongation (and fusion) of the epidermal ridges, and focal spongiotic vesiculation. The dermis contains an intense lymphocytic infiltrate.

Fig. 6.25 Seborrheic dermatitis: in this field, there is perifollicular psoriasiform hyperplasia. Parakeratosis is present on either side of the follicular ostium.

Fig. 6.24 Chronic dermatitis (lichenification): there is hyperkeratosis with hypergranulosis and psoriasiform hyperplasia. The papillary dermis is fibrosed and there is a patchy chronic inflammatory cell infiltrate.

Differential diagnosis Although spongiosis is a characteristic feature of spongiotic dermatitis, it is also encountered in many other inflammatory dermatoses (Table 6.1), particularly superficial dermatophytoses. A diagnosis of spongiotic dermatitis should never be made until a stain for fungus (e.g., PAS reaction) has been performed to exclude this possibility. This is especially important since the common treatment of spongiotic dermatitides – topical corticosteroids – would exacerbate a fungal infection (tinea incognito) (Figs 6.27–6.29).

Lichen simplex chronicus Clinical features The term lichen simplex chronicus (circumscribed neurodermatitis) refers to the development of localized areas of thickened scaly skin complicating prolonged and severe scratching in a patient with no underlying dermatological

Fig. 6.26 Seborrheic dermatitis: there is parakeratosis, and occasional neutrophils are present.

condition (Fig. 6.30).1 Lichenification is an identical process in which an underlying intensely pruritic dermatosis such as atopic eczema is present.2 Dermatophyte infections, stasis dermatitis, and chronic allergic contact dermatitis may also predispose to lichenification. Picker's nodules and nodular prurigo are related conditions (see below).3 Patients present with profound pruritus and localized scaly plaques with accentuated skin markings described as resembling tree bark. There is a predilection for females, and young to middle-aged adults are predominantly

Exogenous dermatitis Table 6.1 Conditions featuring spongiosis • • • • • • • • • • • • •

Pityriasis rosea Superficial fungal infections Herpes gestationis (early lesions) Polymorphic eruption of pregnancy Erythema multiforme Miliaria rubra Erythema annulare centrifugum Guttate parapsoriasis Acral papular eruption of childhood Eczema Lichen striatus Insect-bite reaction Prurigo nodularis

Fig. 6.29 Spongiotic superficial dermatophyte infection: numerous fungal hyphae are seen in this PAS-stained section.

Fig. 6.27 Spongiotic superficial dermatophyte infection: there is marked subcorneal vesiculation.

Fig. 6.30 Lichen simplex chronicus: thick, scaly erythematous plaques are present on the shins, a commonly affected site. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Histological features and pathogenesis

Fig. 6.28 Spongiotic superficial dermatophyte infection: higher-power view.

affected. Accessible skin is particularly affected and the nape and sides of the neck, the thighs, the lower legs and ankles, vulva, and scrotum are sites generally involved.2 Pebbly lichenification refers to a distinct variant in which lichenoid papules follow intense scratching in patients with inflammatory dermatoses such as atopic eczema.2

Although the etiology and pathogenesis of lichen simplex chronicus remains elusive, psychological factors may play an important role.4,5 Recent data further suggest that an underlying neuropathy may be of importance in at least a subset of patients.6 Histologically, lichen simplex chronicus is characterized by marked hyperkeratosis, sometimes with small foci of parakeratosis, and a usually prominent granular cell layer (Fig. 6.31).7 The epidermal ridges are elongated and irregularly thickened. Mild spongiosis is variably present depending upon the cause. A perivascular and sometimes interstitial inflammatory cell infiltrate consisting of lymphocytes, histiocytes, and small numbers of eosinophils is present in the superficial dermis. Enlarged, angulated myofibroblasts are sometimes evident and, as in many other chronic skin conditions, scattered small, multinucleated cells, so-called Montgomery giant cells, are identified. Papillary dermal fibrosis is

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Fig. 6.33

Fig. 6.31

Nodular prurigo: typical globular nodules; the intervening skin appears normal. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Lichen simplex chronicus: there is hyperkeratosis, patchy parakeratosis, and elongation of the rete ridges.

Fig. 6.32 Lichen simplex chronicus: there is hypergranulosis. Note the vertically orientated collagen fibers, a characteristic feature.

a characteristic feature and in some cases nerve hyperplasia is seen (Fig. 6.32).3 In our experience, however, the latter feature is distinctively uncommon.

Nodular prurigo (prurigo nodularis) and prurigo nodule (picker's nodule) Clinical features Nodular prurigo is characterized by the development of chronic, intensely pruritic, lichenified, and excoriated nodules.1,2 It occurs over a wide age range, from 5 to 75 years, with a mean of 40 years. Rarely, children are affected.3 Disease duration ranges from 6 months to 33 years, with a mean of 9 years. Nodular prurigo occurs equally in men and women. It shows significant overlap with lichen simplex chronicus, although this is not uniformly accepted.1,2

Fig. 6.34 Nodular prurigo: there are scattered, excoriated discrete nodules on the buttocks and thighs. Note the postinflammatory hyperpigmentation. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Individual lesions are often described as globular with a warty and excoriated surface and may measure up to 2 cm in diameter (Fig. 6.33).2 They are often grouped, symmetrical, and occur predominantly on extensor aspects of the (distal) limbs (Figs 6.34, 6.35).1 The trunk may also be affected.2 Occasional disseminated cases have been described.2 The palms and soles are typically uninvolved.2 The intervening skin usually appears normal. Similarlooking lesions are sometimes seen in patients with eczema (see below). The majority of patients with nodular prurigo are perfectly well and investigations are unhelpful; however, occasionally nodular prurigo is found in patients with gluten enteropathy.4 Psychosocial disorders have been reported in a high proportion of patients.5 In some cases the eruption occurs after an insect bite, but subsequent lesions develop spontaneously.5

Exogenous dermatitis

Fig. 6.35 Nodular prurigo: in this patient there is very severe involvement of the shins and dorsal surface of the feet. By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.36 Nodular prurigo: there is hyperkeratosis, hypergranulosis, and pseudoepitheliomatous hyperplasia. The dermis is scarred and there is a perivascular and interstitial chronic inflammatory cell infiltrate.

The pruritus is episodic and may be precipitated or aggravated by heat and anxiety.5 Significant laboratory abnormalities may include anemia, eosinophilia, and raised serum IgE levels.5 Nodular prurigo (eczema) is defined as lesions of nodular prurigo arising on a background of overt eczema.5 While this distinction is of academic interest it has no clinical or prognostic importance. A prurigo nodule is a solitary variant that develops as a consequence of localized scratching and picking. On occasion, nodular prurigo is accompanied by the features of bullous pemphigoid (pemphigoid nodularis).6

Pathogenesis and histological features Classical nodular prurigo, which is focal and characterized by hyperplasia, has recently been related particularly to follicular epithelium.2,7 In the epidermis this manifests as orthohyperkeratosis, hypergranulosis and acanthosis, sometimes to the degree of pseudoepitheliomatous hyperplasia (Figs 6.36, 6.37).8 Superficial mild spongiosis and focal parakeratosis is occasionally present and the features may resemble chronic eczema.5 Subepidermal fibrin deposition is sometimes a feature.9 In the dermis there is vascular hyperplasia, with dilated vessels in both the papillary and reticular dermis. New vessel formation is apparent and there is a surrounding perivascular mild inflammatory cell infiltrate, consisting mainly of lymphocytes and some histiocytes, plasma cells, occasional eosinophils and scattered, superficial, small multinucleated cells (Montgomery giant cells) (Fig. 6.38).8 Mast cells are present in normal numbers.1 The infiltrate has been described as having an inverted triangular configuration extending from the superficial dermis.2 This has not been the present author's experience. Occasionally, the dermal features include lymphoid follicles with germinal center formation, thereby resembling a persistent insect bite reaction.5 An additional finding is the presence of fibrosis of the papillary dermis.8 With light microscopy the nerves may appear normal, increased in number or occasionally hyperplastic (Fig. 6.39).1,5 Special neural stains or S-100 protein immunocytochemistry may accentuate mild proliferative changes. Nerve changes, however, do not appear to be essential for the diagnosis.1 Studies have shown no evidence of true neuroma formation and it is thought by some authors that the neural changes are secondary to chronic trauma and scratching of the intensely pruritic nodules.1,5,7 This intense pruritus may have been partly responsible for the large amount of attention given to ­neural changes in

Fig. 6.37 Nodular prurigo: higher-power view.

Fig. 6.38 Nodular prurigo: note the conspicuous eosinophils.

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Spongiotic, psoriasiform and pustular dermatoses Acroangiodermatitis (pseudo-Kaposi's sarcoma, congenital dysplastic angiopathy, arteriovenous malformation with angiodermatitis) refers to the clinical manifestation of purple macules, nodules, and sometimes verrucous plaques typically developing on the dorsal aspects of the feet and toes in patients with severe and longstanding venous insufficiency.7 Varicose veins are often present. The condition is of particular importance in that it may be clinically mistaken for Kaposi's sarcoma.8 Identical lesions have been described complicating Klippel-Trénaunay, Stewart-Bluefarb, and PraderWilli syndromes, surgical arteriovenous fistulae as seen for example in hemodialysis patients, complicating poorly fitting suction socket prostheses on amputation stumps and on paralysed limbs.9–22

Pathogenesis and histological features

Fig. 6.39 Nodular prurigo: in our experience, nerve hyperplasia is an uncommon observation.

nodular prurigo in the past. Very rarely, however, hyperplastic nerve trunks are associated with Schwann cell proliferation, giving rise to small neuromata.10 Electron microscopy has shown vacuolation of Schwann cell cytoplasm, together with loss of definition of internal structure of the mitochondria.5,10,11

The pathogenesis of stasis dermatitis and acroangiodermatitis is unknown although it may be related to the tissue anoxia that typically results from increased venous pressure or circulatory disturbance.13 Stasis dermatitis shows, in addition to the epithelial changes of spongiotic dermatitis, marked hemosiderin deposition in the dermis accompanied by fibrosis and a characteristic lobular pattern of superficial and/or deep dermal neovascularization (Figs 6.41–6.45). Inflammatory cells – including lymphocytes, histiocytes, and variable numbers of plasma cells – are often numerous, and erythrocyte extravasation is usually prominent.

Stasis dermatitis and acroangiodermatitis Clinical features Stasis (varicose) dermatitis usually involves the medial aspect of the lower leg or ankle, but may be more widespread, and develops as a complication of impaired venous return from the lower limbs.1 Superficial varicose veins are a frequent predisposing factor. The lesion appears as an itchy, scaly, often swollen and hyperpigmented area. Such changes are often seen around chronic stasis ulcers (Fig. 6.40). Malignant tumors (both squamous and basal cell carcinomas) may occasionally develop at the edge of these ulcers.2–5 Furthermore, in the early stages of the disease, the lesion may present singly and can be clinically mistaken for a cutaneous malignancy, i.e., squamous cell carcinoma.6

Fig. 6.41 Stasis dermatitis: there is hyperkeratosis, focal parakeratosis and marked epidermal hyperplasia. The dermis is chronically inflamed and scarred.

Fig. 6.40 Stasis dermatitis: there is vesiculation, exudation, and crusting on the lower leg around a stasis ulcer, which was precipitated by allergy to the antibiotic dressing. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 6.42 Stasis dermatitis: note the increased vascularity.

Exogenous dermatitis

Fig. 6.43 Stasis dermatitis: there is marked mural fibrin deposition. The features often overlap with atrophie blanche.

Fig. 6.46 Acroangiodermatitis showing lobular capillary proliferation, red cell extravasation, and a chronic inflammatory cell infiltrate.

In acroangiodermatitis, the vascular proliferation is often so exuberant that it may mimic a vascular neoplasm, most often Kaposi's sarcoma (Fig. 6.46).23

Differential diagnosis Acroangiodermatitis differs from Kaposi's sarcoma by the absence of a spindle cell population or irregular lymphatic-like vascular channels dissecting the dermal collagen. In addition, the promontory sign (tumor vessels partially surrounding normal vessels and the adnexae) is absent. In acroangiodermatitis, the hallmark is the presence of lobular capillary proliferation. In cases where the diagnosis is in doubt, CD34 immunocytochemistry is of value. The spindle cells in Kaposi's sarcoma express this antigen whereas those in acroangiodermatitis do not.24 Smooth muscle actin emphasizes the pericytes in acroangiodermatitis and a reticulin stain can be used to highlight the lobularity.

Pityriasis alba Fig. 6.44 Stasis dermatitis: in this view, there is marked new blood vessel formation and abundant hemosiderin is present.

Clinical features Pityriasis alba is a very common form of chronic dermatitis usually affecting preadolescent children of either sex.1 In the United States, the prevalence is 1.9% in a healthy population.2 The lesions are seen on the face in particular, but the shoulders, upper extremities, and legs may also be involved (Figs 6.47–6.49).1,3 Early lesions present as slightly scaly, mildly pruritic, round to oval pink plaques measuring from 0.5 to 5.0 cm or more in diameter, which later appear as scaly hypopigmented lesions.1 The races are equally affected although lesions are more prominent in dark-skinned persons.1,4 The condition usually resolves spontaneously after months or years.

Pathogenesis and histological features

Fig. 6.45 Stasis dermatitis: the hemosiderin can be highlighted with a Prussian blue reaction for iron.

The etiology is unknown although some authors believe it may be a form of atopic dermatitis since many patients also have features of classic atopic dermatitis or a family history of atopy.5 However, some patients with pityriasis alba lack typical features of atopy. An association with xerosis has also been postulated and the condition has also been linked to copper deficiency.6,7 The histological features of the early stage include follicular dilatation and plugging with infundibular spongiosis, parafollicular parakeratosis, and sebaceous gland atrophy accompanied by a superficial perivascular lymphocytic infiltrate and edema.8 In the later stages, the changes are those of chronic non-specific dermatitis including hyperkeratosis, parakeratosis sometimes accompanied by mild acanthosis, and slight spongiosis.8–10 There is variable hypo- and hyperpigmentation of the basal keratinocytes with reduced or normal numbers of melanocytes and pigmentary incontinence.8,11

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Fig. 6.47 Pityriasis alba: there are multiple hypopigmented, scaly patches on the arms. Lesions are more obvious in the colored races. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.

Fig. 6.49 Pityriasis alba: lesions in white-skinned patients are much more subtle. By courtesy of the Institute of Dermatology, London, UK.

eruption. Lesions may form nodules and plaques and there may be evidence of lichenification and excoriation due to repeated scratching and postinflammatory scarring.1–3 Sun-exposed areas of the face, neck, upper chest, forearms, and hands are predominantly involved. The lips and conjunctiva are also frequently affected.1,3 Associated cheilitis particularly affecting the lower lip is characterized by edema, fissuring, ulceration, and chronic dry scaling and may be the sole manifestation.6 Conjunctival involvement results in photophobia, hyperemia, and formation of a pseudopterygium.1,3 The disease course of actinic prurigo is chronic with significant adverse impact on the quality of life.7 Remission may be observed in the winter months in patients living in geographic areas with significant variation of sunlight throughout the year.1,3 In a subset of patients with childhood onset, symptoms will improve in adulthood with occasional spontaneous remission.3

Pathogenesis and histological features

Fig. 6.48 Pityriasis alba: there is striking leukoderma on the cheek and chin, which are commonly affected sites. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Actinic prurigo Clinical features Actinic prurigo is a rare familial photodermatitis with a female predilection and disease onset in childhood (4–5 years of age) although disease manifestation has also been documented in adulthood.1–4 The disease is most commonly observed in Native Americans as well as Latin Americans. Caucasians, Asians, and Australians are less frequently affected.1,2,4,5 The clinical presentation is varied. Patients typically present with intense pruritus and an erythematous papular

Using phototesting, the majority of patients show increased sensitivity to a broad spectrum of UVA as well as UVB radiation.1,2 The disease has strong associations with HLA haplotypes, in particular DRB1*0407 (60–70% of patients) and DRB1*0401 (20% of patients).3 The histological features are often nondiagnostic and areas of excoriation are frequently biopsied. In late lesions changes include regular epidermal acanthosis with overlying hyperparakeratosis and some degree of hypergranulosis. There is an associated marked superficial to mid-dermal perivascular chronic inflammatory cell infiltrate composed predominantly of lymphocytes. In the papillary dermis focal fibrosis may be seen and there is often pigment incontinence. Lymphoid follicles can be present especially in areas of ulceration, particularly in lesions on the lip. Eosinophils are frequently noted. Biopsies from the lip show similar epidermal features in addition to spongiosis and basal cell vacuolar change. Dermal edema and prominent telangiectatic vessels are further characteristic features. An associated lymphoplasmacytic infiltrate may be bandlike or show lymphoid follicles with germinal centers. The latter is mainly seen in conjunctional biopsies.

Eosinophilic spongiosis Eosinophilic spongiosis is the histopathological term used to describe spongiosis in which eosinophils are the predominant cell type.1–5 Eosinophilic spongiosis is a non-specific finding with which a considerable number of dermatoses may be associated. Table 6.2 lists dermatoses in which eosinophilic spongiosis is commonly encountered. Detailed discussion of each of these disorders is found in the appropriate chapters.

Erythroderma Spongiotic dermatitis is one of the causes of erythroderma. Sometimes incorrectly called exfoliative dermatitis, erythroderma is applicable only when the

Exogenous dermatitis Table 6.2 Diseases featuring eosinophilic spongiosis

• • • • • • • • • •

Incontinentia pigmenti Pemphigus Bullous pemphigoid Linear IgA disease Pemphigoid (herpes) gestationis and polymorphic eruption of pregnancy Insect-bite reactions Atopic eczema Contact dermatitis Grover's disease Drug reactions

Table 6.3 Causes of erythroderma

• • • • • • • •

Dermatitis Lymphoma (mycosis fungoides, T-cell leukemia, Hodgkin's lymphoma) Drugs (gold, penicillin, etc.) Psoriasis Pityriasis rubra pilaris Ichthyosiform erythroderma Scabies Lichen planus

to lichenoid lesions and vice versa is also thought to be a typical feature. The lesions are chronic, lasting from months to years, but eventually resolving.

Pathogenesis and histological features The existence of Sulzberger-Garbe syndrome as a distinctive entity is controversial. Some authors consider patients classified under this designation as having nummular dermatitis.3 Biopsy of exudative lesions shows a non-specific spongiotic dermatitis. Biopsy of lichenoid lesions is characterized by a bandlike lymphocytic infiltrate. Variable numbers of eosinophils may be present.

Vein graft site dermatitis Occasionally, patients undergoing coronary artery bypass develop an eczematous dermatitis in the region of the scar from the saphenous vein donor site.1, 2 The pathogenesis is unclear. Since patients often have objective evidence of neuropathy, some authors believe that the neuralgia may play a pathogenic role.1 It is also possible that stasis changes play a role in this disorder. Biopsy shows non-specific spongiotic dermatitis.

Papular acrodermatitis of childhood Clinical features

Fig. 6.50 Erythroderma: the entire skin surface is erythematous and slightly scaly. The appearances are relatively non-specific and give no indication of the cause. By courtesy of the Institute of Dermatology, London, UK.

entire skin surface is inflamed, erythematous, and scaly (Fig. 6.50).1–5 The clinical features are remarkably consistent irrespective of the underlying disease and therefore often pose a diagnostic challenge. Pruritus is variable, being particularly severe in the Sézary syndrome and in mycosis fungoides. Lymphadenopathy is usually present (dermatopathic lymphadenopathy). Prolonged erythroderma, particularly in the elderly, may be complicated by cardiac failure, peripheral circulatory collapse, hypothermia, and infection. Patients with erythroderma are frequently biopsied since the clinical examination findings are often nonspecific. Diagnosis without clinical information is often not possible.1 Table 6.3 lists the various causes of erythroderma. The specific diseases that cause ­erythroderma are discussed in detail in the appropriate chapters.

Sulzberger-Garbe syndrome Clinical features Sulzberger-Garbe syndrome (distinctive exudative discoid and lichenoid chronic dermatosis) was originally described as a widespread pruritic eruption associated with discoid lesions in middle-aged Jewish males.1–3 Involvement of the penis was said to be characteristic. Transformation from eczematous

Papular acrodermatitis of childhood (Gianotti-Crosti syndrome, infantile papular acrodermatitis) is a rare disease representing a cutaneous response to a number of viral infections. It is characterized by the acute onset of monomorphic, symmetrical flat-topped papules or papulovesicles, 1–10 mm across, which range in color from pink to red or brown and are located primarily on the face (particularly the cheeks), buttocks, and extensor surfaces of the forearms and legs, with the trunk typically being spared (Figs 6.51–6.53).1–4 Lesions are usually blanchable although petechial and hemorrhagic variants can be rarely encountered.4 A positive Koebner phenomenon is sometimes elicited.4 The lesions are occasionally pruritic and are self-limiting, lasting up to 3 weeks. Mucous membranes are not affected. Infants and children are predominantly affected although there are occasional reports of the condition developing in adults.4–9 Systemic signs include hepatosplenomegaly and axillary and inguinal lymphadenopathy. Sometimes a fever is evident. There may be an anicteric acute hepatitis and occasionally patients progress to chronic liver disease.

Pathogenesis and histological features In the original and early reports, Gianotti-Crosti syndrome was documented following infection with hepatitis B virus.10–12 More recently cases have been reported in association with hepatitis A virus, coxsackievirus, influenza virus, Epstein-Barr virus, cytomegalovirus, parainfluenza virus, human herpesvirus-6 (HHV-6), poxvirus, parvovirus, and rotavirus.13–25 In addition, the disease had been associated with HIV infection.26 Gianotti-Crosti syndrome has also been reported following Mycoplasma infection, Lyme borreliosis, and immunization.27–35 The pathogenesis is unknown although viral antigenemia and immune complex-mediated mechanisms have been proposed.36 Biopsies of skin lesions show entirely non-specific histological features. The epidermis often appears normal or it may be mildly acanthotic with ­parakeratosis. Lymphocytic exocytosis is usually present.3 The upper dermis contains a lymphohistiocytic infiltrate in a perivascular distribution and there

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Fig. 6.53 Gianotti-Crosti syndrome: the papules are very uniform. A viral etiology is often identified. By courtesy of C. Gelmetti, MD, Milan University, Italy.

In cases with hepatitis, the appearances are those of an acute viral hepatitis, which usually resolves over a period of up to 6 months. Rarely, chronic disease ensues. Fig. 6.51 Gianotti-Crosti syndrome: the eruption is present on the face and arms, there is sparing of the trunk. By courtesy of C. Gelmetti, MD, Milan University, Italy.

Fig. 6.52 Gianotti-Crosti syndrome: note the widespread erythematous papules on the cheeks of this young girl. By courtesy of C. Gelmetti, MD, Milan University, Italy.

is also swelling of endothelial cells sometimes accompanied by marked papillary dermal edema.31 Scattered eosinophils may be present.36 Occasionally, a more lichenoid pattern of inflammation is encountered. There is no evidence of vasculitis. Direct immunofluorescence is negative.3 By immunohistochemistry, the infiltrate consists of an admixture of CD4+ helper T cells and CD8+ cytotoxic T cells.19,36,37

Pityriasis rosea Clinical features Pityriasis rosea (‘rose-colored scale’) presents as an acute inflammatory dermatosis characterized by self-limiting oval papulosquamous lesions on the trunk and extremities.1–3 The disease appears to be more common in females, and 75% of cases occur between the ages of 10 and 35 years.4 It is characterized by seasonal variation, being most common in the months of December to February.5 Although pityriasis rosea typically presents as a solitary episode, recurrent disease may occur in up to 2% of patients.6,7 In the majority of cases the disease first manifests itself with the appearance of a ‘herald patch’, a single red scaly lesion that increases in size over 48 hours up to 2–10 cm in diameter (Fig. 6.54).8 A significant proportion of patients report symptoms, including pyrexia, headache, malaise, arthralgia, chills, vomiting, diarrhea, and lymphadenopathy, up to 2–3 weeks before the onset of the eruption.9 After the appearance of the herald patch there is a ‘secondary incubation period’ of 7–14 days before the generalized eruption of pink to salmon-colored elliptical scaly lesions (Fig. 6.55).10 The latter are approximately 1 cm in length and their longest axes occur along the Blaschko skin tension lines, producing the characteristic ‘fir’ or ‘Christmas tree’ effect. There is usually an erythematous center, the periphery of the macule being slightly brown and scaly. In dark-skinned patients the macules tend to be darker than the surrounding skin (Fig. 6.56). The lesions spread from the chest to the abdomen, thighs, arms, and back, generally within 2 weeks, persist for 2—4 weeks, and fade over a further 2 weeks. Pityriasis rosea may be pruritic. Oral lesions have been described in up to 16% of patients.4 They may take the form of a single large erythematous plaque, bullae, multiple hemorrhagic puncta, round erythematous macules and plaques or erythematous annular lesions.4,11–14 Several morphological variants may occur: a papular variant is seen in young children, pregnant women and those of Afro-Caribbean descent; a vesicular or bullous variant may occur in infants and children; and an urticarial form has also been noted.5,14,15 Occasionally, pityriasis rosea has a purpuric, hemorrhagic component.5,14,16 Localized and unilateral forms, and an ‘inverse’ form presenting on the face and extremities, have also been documented.17

Exogenous dermatitis

A

B

Fig. 6.54 Pityriasis rosea: (A) the ‘herald patch’ which marks the onset of this dermatosis, is marked by an arrow; (B) close-up view. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Pathogenesis and histological features The exact etiology of pityriasis rosea is unknown; however, most of the evidence points to an infectious, probably viral, cause. It sometimes complicates an upper respiratory tract infection.18 The herald patch may develop at the site of an insect bite, particularly fleas, but patches have also occurred in areas

A

of old trauma and scars, suggesting an isomorphic (Koebner's) response.17 Atypical pityriasis rosea has also been described in bone marrow transplant recipients and following treatment with interferon-alpha (IFN-α) as well as Hodgkin's disease, and a pityriasis rosea-like eruption has been documented due to drugs such as imatinib mesylate, ACE inhibitors, and hydrochlorothi-

B

Fig. 6.55 Pityriasis rosea: (A) the secondary rash presents as small pink slightly scaly macules; (B) close-up view. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

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Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.56 Pityriasis rosea: in pigmented skin, there is often postinflammatory hyperpigmentation and the erythematous nature of the eruption is not apparent. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

azide.19–23 Case clustering in establishments with communal living supports an infectious etiology. Recently, HHV-7, as well as HHV-6 and HHV-8, has been identified in peripheral blood mononuclear cells in addition to plasma and skin of patients with pityriasis rosea, and herpes virus-like particles have been identified in cutaneous lesions of pityriasis rosea by electron microscopy.24–33 Other workers, however, have failed to confirm this observation.28,34,35 Rarely, a pityriasis rosea-like eruption may be a manifestation of HIV/AIDS.36 The histopathological features are those of a non-specific subacute or chronic dermatitis and comprise focal hyperkeratosis and angulated parakeratosis with slight acanthosis (Figs 6.57–6.60).37 The granular cell layer may be absent beneath the foci of parakeratosis. Intraepidermal cytoid bodies are present in as many as 50% of cases.38,39 Focal acantholytic dyskeratosis has occasionally been documented.40 A lymphohistiocytic infiltrate surrounds the vessels of the superficial vascular plexus and there is slight spongiosis. Rarely, spongiotic vesiculation may be evident.5 Occasionally, scattered eosinophils are present. Red cell extravasation is a not infrequent feature and occasional erythrocytes may be seen within the epidermis. Immunocytochemical staining has demonstrated that the dermal infiltrate consists mainly of T cells, including helper and suppressor cells, together with

Fig. 6.58 Pityriasis rosea: small foci of parakeratotic scale are a characteristic finding. The epidermis shows mild spongiosis.

large numbers of Langerhans cells.41 Human leukocyte antigen DR (HLA-DR, Ia-like antigen) has been demonstrated on the surface of keratinocytes, and this has been interpreted as showing that they are taking an active role in cellular immunity.42–44 HLA-DR antigen may also be expressed on the surface of the T-helper cells.43

Differential diagnosis Guttate psoriasis shows considerable overlap with pityriasis rosea. The presence of neutrophils within the parakeratotic mounds favors a diagnosis of psoriasis. A wide range of drugs has been associated with a pityriasis rosea-like eruption including barbiturates, ketotifen, clonidine, captopril, isotretinoin, gold, bismuth, arsenic, organic mercurials, methoxypromazine, D-penicillamine, tripelennamine hydrochloride, metronidazole, and salvarsan.15,17 In such cases, the distinction depends upon clinicopathological correlation. The presence of large numbers of eosinophils is a clue to a hypersensitivity reaction. Acute and subacute eczematous dermatitis may also be confused with pityriasis rosea. The presence of lens-shaped parakeratosis and limited spongiosis favors pityriasis rosea. Again, clinical findings should help make this distinction.

Fig. 6.59

Fig. 6.57 Pityriasis rosea: low-power view showing multiple foci of scale with psoriasiform hyperplasia.

Pityriasis rosea: there is spongiosis and a perivascular lymphocytic infiltrate. The angulated tier of parakeratosis (teapot lid sign) is characteristic.

Exogenous dermatitis

Fig. 6.60

Fig. 6.62

Pityriasis rosea: in this field, there is red cell extravasation.

Juvenile plantar dermatosis: close-up view showing scaling and fissuring. By courtesy of the Institute of Dermatology, London, UK.

Pityriasis lichenoides chronica is characterized by interface change and vacuolar degeneration of the basal layer of the epidermis, features not seen in pityriasis rosea. A PAS stain is mandatory in all cases to exclude a dermatophyte infection.

Juvenile plantar dermatosis

years before resolving.1,3 However, many patients develop features of classic eczema of the hands later in life.2

Clinical features Scaly palms and soles with loss of a normal epidermal rete pattern characterize juvenile plantar dermatosis. The affected area often has a shiny red appearance with fissures (Figs 6.61, 6.62).1–4 As its name suggests, the disease is seen in prepubertal children with a mean age of 9.6 years.1 The most common sites affected are the volar aspect of the great toe and the ball of the foot.1 The hand is only rarely affected. Patients often have a personal or family history of atopy.2,4 The disorder usually lasts for 6 months to several

Pathogenesis and histological features The pathogenesis of this disorder is not understood; however, it has been suggested that synthetic footwear may play a role in its development.3 Biopsy shows epidermal acanthosis and subacute to chronic spongiosis.1 Variable parakeratosis and hypogranulosis may be seen. A lymphocytic infiltrate centered on the eccrine duct is said to be characteristic.1

Differential diagnosis The histological changes are probably non-specific but the presence of chronic inflammation centered on the sweat duct should suggest juvenile plantar dermatosis in the appropriate clinical setting and allow distinction from other spongiotic dermatitides, which typically spare the acrosyringium. One group could not identify PAS-positive material occluding sweat ducts in multiple histological sections of juvenile plantar dermatosis (compare with miliaria).1 A PAS stain with diastase digestion should also be performed to evaluate for fungal infection.

Miliaria Clinical features

Fig. 6.61 Juvenile plantar dermatosis: multiple erythematous lesions are present on the soles of the feet. By courtesy of the Institute of Dermatology, London, UK.

This common disorder, although most often seen in children, may affect any age group but congenital presentation is rare.1 It develops as a consequence of obstruction to the outflow tract of the intraepidermal component of the eccrine sweat duct and is associated with excessive sweating and exposure to high humidity. Traditionally, the condition is subdivided into three subtypes: miliaria crystallina, miliaria rubra, and miliaria profunda.2,3 • In miliaria crystallina the level of obstruction is within the stratum corneum, and results in the formation of small, clear vesicles, located particularly on the trunk (Fig. 6.63). There are accompanying symptoms of a high fever and pronounced sweating. • Miliaria rubra (prickly heat) is particularly common in hot, humid climates and is due to obstruction within the prickle cell layer, resulting in erythematous papules and vesicles, usually located about the trunk and intertriginous regions (Fig. 6.64). This form of miliaria is particularly common in infants. The term miliaria pustulosa has been applied to the above subtypes when pustules develop. Miliaria rubra

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Spongiotic, psoriasiform and pustular dermatoses both variants the lesions can be seen to be centered upon an intraepidermal eccrine sweat duct. Miliaria pustulosa is characterized by features of miliaria in addition to an intraepidermal or subcorneal pustule. Miliaria profunda is characterized by spongiosis of the dermal portion of the eccrine duct, often associated with dermal chronic inflammation adjacent to the affected duct.

Fox-Fordyce disease Clinical features

Fig. 6.63 Miliaria crystallina: tiny vesicles resembling water droplets are scattered over the abdomen of this young male. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fox-Fordyce disease (apocrine miliaria, chronic itching papular eruption of the axillae and pubic region) presents as a chronic papular eruption, associated with pruritus, and located in areas containing apocrine sweat glands (i.e., the axillae, the pubic area, the vulval labia, the perineum, and areola) (Fig. 6.65).1–3 The papules are discrete, firm, and flesh-colored or pigmented. Associated hair loss is often present. The disease is uncommon and over 90% of reported cases have occurred in women, usually aged 13–35 years. Rarely, prepubescent and postmenopausal patients have been described.4,5

Pathogenesis and histological features Patients with Fox-Fordyce disease have apocrine anhidrosis. Although eccrine sweating is normal, apocrine sweating does not occur due to the keratotic plugging of the apocrine duct orifice. The continued secretion of sweat, however, causes the duct to rupture and an apocrine sweat retention cyst forms in the epithelium. The exact cause of the follicular plugging is unknown, but a hormonal link has been postulated. Occasional instances of coexistent hidradenitis suppurativa have been recorded.6 Follicular infundibular plugging is present in association with acanthosis, parakeratosis, spongiosis, and an underlying non-specific chronic inflammatory cell infiltrate. Dilation of the apocrine glands may be present and the presence of perifollicular foamy histiocytes is a frequent and diagnostically helpful feature.7–9 Further reported findings include vacuolar change, dyskeratosis, and parakeratotic lamellae affecting the follicular infundibulum.10 The keratinous obstruction prevents the outflow of apocrine secretion and leads to the diagnostic feature of an intrafollicular sweat retention vesicle; serial sections may be needed to demonstrate this lesion.11,12

Transient acantholytic dermatosis with prominent eccrine ductal involvement Fig. 6.64 Miliaria rubra: the characteristic appearance is of large numbers of minute papules and vesicles. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.

•

and its pustular variant have also been found in association with pseudohypoaldesteronism, type I.4,5,6 In miliaria profunda, also typically seen in tropical climates, the obstruction is at level of the sweat duct. Small papules are seen on the trunk and occasionally the extremities.

Pathogenesis and histological features The pathogenesis of miliaria is poorly understood. It has been suggested that bacteria play a role in the development of the disease. There is evidence that extracellular polysaccharide substance (EPS), a PAS-positive material produced by some strains of Staphylococcus epidermidis, obstructs the sweat duct and causes the disease.7 Normal controls who had S. epidermidis swabbed on to the volar aspect of their forearms followed by occlusion and heat developed miliaria. These results have not been replicated with other bacteria.7 Biopsy revealed EPS in lesions from several patients. A subcorneal vesicle containing a few neutrophils characterizes miliaria crystallina, while rubra involves an intraepidermal spongiotic vesicle. In

Grover's disease (transient acantholytic dermatoses) is discussed more comprehensively elsewhere; however, since it is commonly associated with spongiosis (often in the absence of acantholysis), it deserves mention in this chapter. Recent studies of Grover's disease have shown a strong correlation with high temperature and sweating and it has been suggested that its pathogenesis may be analogous to that of miliaria.1–3 Supporting this concept is the development of Grover's disease in bed-ridden and febrile patients. The lesions are usually present on the back. These patients often have prominent involvement of the eccrine duct and the lesions have been termed sudoriferous acrosyringeal acantholytic disease (sudoriferous Grover's disease).4 Biopsies taken from patients with sudoriferous acrosyringeal acantholytic disease often show, in addition to typical features of Grover's disease, acantholysis of the superficial portion of the eccrine duct. When acantholysis is present and a clinical history is provided, the diagnosis is usually straightforward. However, not uncommonly, biopsies taken from patients with Grover's disease show spongiosis only (often eosinophilic spongiosis). In these patients, a diagnosis of Grover's disease may still be made in the appropriate clinical setting. It is important to note that myriad cutaneous disorders may show some degree of spongiosis. For example, such disparate conditions as mycosis fungoides and psoriasis are not uncommonly associated with a degree of spongiosis. In this chapter, we have focused our discussion on entities for which spongiosis is a dominant and fairly consistent histological finding. Other entities that may occasionally be associated with some degree of spongiosis are discussed in the appropriate chapters.

Psoriasis

Fig. 6.65

A

Fox-Fordyce disease: (A) there are numerous white papules. The axilla is a characteristic site; (B) close-up view. By courtesy of the Institute of Dermatology, London, UK.

B

Psoriasiform dermatoses The psoriasiform reaction pattern is defined by the presence of epidermal hyperplasia with fairly uniform and marked enlargement of the rete ridges. Although confluent parakeratosis with neutrophil exocytosis is characteristic of psoriasis (the prototype of this group of conditions), this feature is not included within the definition, which would otherwise become too restrictive. Diseases in addition to psoriasis which may manifest a psoriasiform pattern include Reiter's syndrome, pityriasis rubra pilaris, lichen simplex chronicus, psoriasiform drug reactions, subacute and chronic spongiotic dermatitis, parapsoriasis, and pityriasis rosea (herald patch). Other conditions in which psoriasiform hyperplasia may sometimes be a feature include dermatophyte infections and candidiasis, secondary syphilis, scabies infestation, inflammatory linear verrucous epidermal nevus, necrolytic migratory erythema, acrodermatitis enteropathica, and pellagra. Neoplastic conditions such as Bowen's disease and mycosis fungoides, which often show marked epidermal hyperplasia, are not included in this definition.

(Fig. 6.69). The scalp, the extensor surfaces (mainly the knees and elbows), the lower back, and around the umbilicus are particularly affected. The clinical features, however, show regional variation: scalp involvement often shows very marked plaque formation, whereas on the penis scaling is commonly minimal and the features may be mistaken for Bowen's disease (Figs 6.70– 6.72). Linear lesions (linear psoriasis) follow previous trauma (koebnerization) (Fig. 6.73). Psoriasis may manifest in a variety of other ways. • Guttate (eruptive) psoriasis presents as small (0.5–1.5 cm in diameter) papules over the upper trunk and proximal extremities, typically in younger patients (Figs 6.74–6.76).

Psoriasis Clinical features Psoriasis is a chronic relapsing and remitting disease of the skin that may affect any site.1 It is one of the commonest of all skin diseases, with a reported incidence of 1–2% in Caucasians.2,3 It is rare among blacks, Japanese, and native North and South American populations.4 Males and females are affected equally. Although psoriasis may occur at any age, it most frequently presents in the teens and in early adult life (type I psoriasis).5 A second peak in which the disease is often milder appears around the sixth decade (type II psoriasis).5 The classic cutaneous lesion of psoriasis vulgaris (plaque psoriasis), developing in about 85–90% of patients with psoriasis, is raised, sharply demarcated, with a silvery scaly surface (Figs 6.66–6.68).6,7 The underlying skin has a glossy, erythematous appearance. If the parakeratotic scales are removed with the fingernail, small droplets of blood may appear on the surface (Auspitz's sign); this is diagnostic. Plaques, when multiple, are often symmetrical and annular lesions due to central clearing are a common finding

Fig. 6.66 Psoriasis: typical plaque disease showing bilateral and fairly symmetrical distribution. In this example, the silvery scale is well demonstrated. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

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Fig. 6.67

Fig. 6.69

Plaque psoriasis: note the symmetry of these lesions. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Annular psoriasis: central clearing of plaques results in annular lesions. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

• Psoriasis inversa is characterized by the development of plaques in the flexures (Fig. 6.77).

• Generalized pustular psoriasis (von Zumbusch) is an acute variant,

characterized by fever of several days' duration, together with the sudden appearance of sterile pustules, 2–3 mm across, over the trunk and extremities (Fig. 6.78).8 The surrounding skin is erythematous and confluence may result in a generalized erythroderma (Fig. 6.79). Usually, recurrent episodes of fever occur, followed by fresh outbreaks of pustules (Fig. 6.80). Systemic signs include weight loss, weakness, and hypocalcemia, with a raised white cell count and high erythrocyte sedimentation rate (ESR). Although the precipitating factor is often unknown, pustular psoriasis may follow a streptococcal or viral infection. Withdrawal of systemic steroid therapy is also a known predisposing cause.9 Treatment with systemic steroids or intensive topical regimens has also been incriminated.10 Other risk factors for developing a pustular episode include drugs, pregnancy, hypocalcemia,

Fig. 6.70 Plaque psoriasis: the scalp is a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.71 Fig. 6.68 Plaque psoriasis: close-up view showing the thick scale. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Plaque psoriasis: in this extreme case, the initial diagnosis was Norwegian scabies. Surprisingly, alopecia is an uncommon complication. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Psoriasis

Fig. 6.74 Guttate psoriasis: this infant shows a characteristic distribution over the trunk. By courtesy of M. Liang, MD, Children's Hospital, Boston, USA.

Fig. 6.72 Psoriasis: penile lesion showing a sharply demarcated, erythematous, eroded, slightly scaly plaque. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.

Fig. 6.75 Guttate psoriasis: this close-up view shows the erythema and scaling. By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.73 Plaque psoriasis: linear involvement is a manifestation of koebnerization following trauma. By courtesy of the Institute of Dermatology, London, UK.

•

and sunlight or phototherapy.11 Uncommon variants of pustular psoriasis include an annular form, exanthematous pustular psoriasis, juvenile and infantile pustular psoriasis.12,13 The annular variant is a somewhat less serious variant in which, due to central clearing, lesions develop an annular or gyrate morphology.11 Often, the systemic manifestations are less florid. The exanthematous variant, which tends to develop de novo, may sometimes follow an infection or represent a pustular drug reaction.11 Impetigo herpetiformis most probably represents pustular psoriasis of pregnancy although some authors classify it as a separate entity.14 In psoriatic erythroderma, there is an intense generalized erythema affecting the entire skin surface, associated with desquamation (Fig. 6.81). Ectropion may be present and scalp involvement is sometimes followed by hair loss. Erythroderma may be precipitated in patients with psoriasis vulgaris by infection with Staphylococcus aureus, abrupt curtailment of steroid or methotrexate therapy, and sunburn.11 Systemic symptoms including fever, chills, shortness of breath, fatigue, and

Fig. 6.76 Guttate psoriasis: as with plaque disease, guttate psoriasis is associated with a Koebner phenomenon. By courtesy of the Institute of Dermatology, London, UK.

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Fig. 6.79

Fig. 6.77

Pustular psoriasis: early stage showing intense erythema. By courtesy of the Institute of Dermatology, London, UK.

Flexural (inverse) psoriasis: this is a rare variant in which the lesions develop on flexural skin.

Fig. 6.78 Pustular psoriasis (von Zumbusch): note the extreme generalized erythema and pustulation. This variant is rare and may sometimes prove fatal. By courtesy of R.A. Marsden, St George's Hospital, London, UK.

•

•

•

myalgia are commonly present.11 Biochemical abnormalities include hypoalbuminemia, anemia, and dehydration.15 High-output cardiac failure is an important complication. Localized (mixed) pustular psoriasis represents the development of pustules on pre-existent plaques.9 This variant most often develops in acute flares of psoriasis or following treatment.11 It sometimes represents a harbinger of a more generalized process. Palmoplantar pustular psoriasis of Barber (pustulosis palmaris et plantaris) refers to a chronic recurrent pustular dermatosis localized to the palms and soles (Figs 6.82, 6.83). It shows a strong predilection for females (9:1) in the fourth to fifth decade of life and the disease is associated with a history of smoking.6,16,17 In about 25% of patients there is coexistent chronic plaque psoriasis.6 Acrodermatitis continua (acropustulosis) of Hallopeau is a rare sterile pustular eruption of the fingers or toes, involving the nails and slowly extending proximally (Figs 6.84, 6.85).

Fig. 6.80 Pustular psoriasis: close-up view showing typical pustules arising on a background of intense erythema. By courtesy of the Institute of Dermatology, London, UK.

The nail is frequently affected in psoriasis; lesions may include pitting, discoloration, onycholysis, subungual hyperkeratosis, nail grooving, splinter hemorrhages and complete loss in pustular psoriasis.18 Patients with psoriasis have a higher incidence of certain comorbidities including, depression, obesity, type 2 diabetes mellitus, hyperlipidemia, hypertension, metabolic syndrome, cardiovascular disease, Crohn's disease, and multiple sclerosis, as well as cutaneous and visceral malignancies.6,19

Psoriatic arthritis Psoriatic arthritis has a prevalence of 0.02–7% but more recent data suggest that it could be as high as 30%.20 It may take a number of different forms (Fig. 6.86):21 • The most common is an asymmetrical involvement of a few joints of the fingers or toes; this accounts for over 70% of cases. • In 15% of cases a symmetrical polyarthritis, clinically indistinguishable from rheumatoid arthritis, but seronegative, is seen.

Psoriasis

Fig. 6.83 Palmoplantar pustular psoriasis: close-up view of palmar pustules. By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.81 Psoriatic erythroderma: there is generalized erythema. Patients are at risk of dehydration, hypoalbuminemia, and anemia. By courtesy of R.A. Marsden, St George's Hospital, London, UK.

Fig. 6.84 Acropustulosis continua: there is pustulation with erythema and scaling, the nail has been shed, and there is damage to the nail plate. By courtesy of R.A. Marsden, St George's Hospital, London, UK.

Fig. 6.82 Palmoplantar pustular psoriasis: there is intense erythema, scaling, and numerous pustules. By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.85 Acropustulosis continua: a particularly severe example. By courtesy of S. Dalziel, MD, University Hospital, Nottingham, UK.

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Fig. 6.86 Psoriatic arthropathy: joint involvement is a rare manifestation. Lesions of the interphalangeal joints, while said to be characteristic, are an uncommon finding. In this patient there is gross deformity. By courtesy of R.A. Marsden, St George's Hospital, London, UK.

Fig. 6.88 Psoriatic arthropathy: sacroiliitis. Note the virtual obliteration of the sacroiliac joints. By courtesy of R.A. Marsden, St George's Hospital, London, UK.

Fig. 6.87 Psoriatic arthropathy: classic type. Note the destruction of the distal interphalangeal joint of the first finger. By courtesy of the Institute of Dermatology, London, UK.

• In approximately 5% of cases the distal interphalangeal joints are

involved, the classical picture of psoriatic arthropathy (Fig. 6.87).

• A further 5% have a destructive and severely deforming arthritis, arthritis mutilans.

• The remaining cases have ankylosing spondylitis, with or without

peripheral joint involvement (Fig. 6.88). Psoriatic arthritis is associated with a high incidence of mitral valve prolapse with resultant incompetence.22 The peak age of onset is 36–45 years of age, although the destructive form may occur earlier. A high incidence of immunoglobulin gene polymorphism has been identified in patients with psoriatic arthritis, suggesting an inherited predisposition.23 Psoriatic arthritis in children, although uncommon, is of importance because frequently the arthritis precedes the onset of the skin lesions. A careful examination for nail changes and questioning about a family history may be of value in establishing the diagnosis.

Pathogenesis and histological features Although the etiology of psoriasis remains incompletely understood, considerable advances have been made in the past two decades to unravel the complex mechanisms involved in the pathogenesis of this common dermatosis. For many years psoriasis was considered to represent a primary epidermal hyperproliferative disorder. More recent studies, however, have shown that a T-lymphocyte-driven immune process is central to the development of the psoriatic plaque and, in fact, may represent the earliest stage in its evolution. Other important factors include genetic influences, the environment, and the contribution of keratinocyte-derived mediators of the inflammatory process.

The inherited predisposition to develop psoriasis has long been known. A positive family history is common. Documented prevalence rates in firstdegree relatives have ranged from 7.8% to 17.6%.24,25 Monozygotic twins have a concordance of 64–70% while that of dizygotic twins is in the order of 14–23%.26 Linkage analysis has identified at least nine separate loci (PSORS1– 9).6,7,27–30 PSORS1 shows the strongest genetic susceptibility, being implicated in 35–50% of familial psoriasis. 6,7,31,32 The locus is present on chromosome 6p within the major histocompatibility complex and more recent data have demonstrated HLA-Cw6 as the susceptibility allele on PSORS1.31,32 Genetically, psoriasis is a heterogeneous disease at the level of PSORS1 and two distinct types have been identified:5 • Type I disease which affects young adults and includes guttate psoriasis is characterized by a familial segregation involving HLA-Cw6.5,33 • Type II disease includes psoriasis vulgaris presenting at an older age (over 50 years) as well as palmoplantar pustulosis and shows no familial segregation and no association with the PSORS1 locus.4,33,34 Patients with pustular psoriasis have a higher incidence of HLA-B27, as do those with psoriasis and peripheral arthritis, and this is most marked if spondylitis is present.35 Further genes related to increased genetic susceptibility for psoriasis include the interleukin-23 receptor gene on chromosome 1p, the interleukin-12B gene on chromosome 5q, zinc finger protein 313 on chromosome 20q, the CDKAL1 gene on chromosome 6p, the PTPN22 gene on chromosome 18p, the IL-4–IL-13 cytokine gene cluster on chromosome 5q, the LCE3B/3C gene on 1q, and the PSORS2 locus on chromosome 17q.7 The IL-23 receptor is of interest as it is also associated with ankolysing spondylitis and psoriatic arthritis while the CDKAL1 gene has also been ­associated with Crohn's disease and type-2 diabetes mellitus.7 Certain factors are known to induce psoriasis in a person who is genetically predisposed. There is a tendency for lesions to develop at sites of previous skin trauma (e.g., mechanical friction, sunburn or childhood illnesses such as varicella); this is termed the isomorphic or Koebner's phenomenon.36–38 Infections are well known as predisposing factors in the onset of psoriasis. In children in particular, upper respiratory tract infections frequently trigger psoriasis, while infections with Streptococcus pyogenes are implicated in the development of acute guttate psoriasis, together with an exacerbation of other forms of psoriasis.39–42 Specific streptococcal serotypes, however, do not appear to be implicated. Other factors known to exacerbate psoriasis include stress, bereavement, HIV/AIDS, withdrawal of corticosteroids after prolonged use, and treatment

Psoriasis with a number of drugs including lithium, antimalarials, and beta-blocking agents.6,43 The development of the psoriatic plaque results from a complex interplay between keratinocyte hyperproliferation with loss of differentiation, changes in the superficial dermal vasculature, and a T-lymphocyte-mediated inflammatory component.44 The relative roles of keratinocyte hyperplasia, vascular changes, and immunological reactions have been the subject of much discussion in the recent literature.45 Most recently, the focus has been particularly directed towards the importance of the innate as well as adaptive immune systems.7 In the skin there is an increased epidermal proliferation rate: the transit time of keratinocytes through the epidermis in normal skin is 56 days; in psoriatic skin it is shortened to 7 days.46,47 The epidermal cell cycle is probably shortened, and there is a large increase in the number of proliferating generative cells in the basal layers, where up to three layers of proliferating cells may be seen compared with only one in normal resting epidermis. Vascular proliferation predominantly affecting the postcapillary venules of the dermal papillae appears to be one of the earliest manifestations of psoriasis.48 This is mediated by upregulation of αVβ3 integrin and vascular endothelial growth factor (VEGF).49–51 The current weight of evidence suggests that a T-cell-mediated immune reaction is central to the pathogenesis of psoriasis.44,52 Clinical studies supporting this hypothesis include the response to antilymphocyte therapies such as ciclosporin.53 More recently, remission in patients with severe psoriasis has resulted from treatment with an activated T-lymphocyte selective toxin DAB389 IL-2 that interacts with the receptor-binding domain of IL-2.54 Successful responses to therapy with monoclonal anti-CD3 and anti-CD4 antibodies adds further support.55,56 Additional evidence has come from bone marrow transplantation studies. Unaffected patients develop psoriasis following a transplant from an affected donor whereas patients are cured of their disease following transplantation from an unaffected donor.57 In vitro studies in which intradermal injection of T-helper lymphocytes from an affected patient into severe combined immunodeficient mice results in the development of typical psoriasis further supports a T-lymphocyte-driven pathogenesis.58 The innate immune system appears to play an important part in the early stages of the disease and increased numbers of activated plasmacytoid dendritic cells are present in early psoriatic lesions.59 Production of interferon alpha by plasmacytoid dendritic cells and TNF-α and INF-γ by natural killer cells leads to activation of myeloid dendritic cells and subsequent proliferation of T cells through IL-12 and IL-23 release.7,60 Although CD4 T-helper (Th) lymphocytes are probably of importance in the earliest stages of plaque development, the major population is characterized by CD8 expression. The immunophenotype of the T cells includes CD45RO+, HLADR+, CD25+ and CLA+, indicating activated skin-specific memory cells.61 The lymphocyte cytokine profile, which includes IL-2, IL-17, interferon gamma (IFN-γ), and absence of IL-4, IL-10, and tumor necrosis factor alpha (TNF-α), reflects a predominantly Th1-mediated inflammatory reaction as well as IL-17-A producing type 17 helper T (Th17) cells.7,62–64 Th17 cells are of particular importance for epithelial immunosurveillance and produce IL-22, a molecule involved in keratinocyte differentiation and proliferation.65,66 IFN-γ is central to the development of the plaque. In vitro studies have shown that the keratinocyte proliferation is IFN-γ dependent.67 Also, IFN-γ injection in normal human skin results in epidermal proliferation.68 In addition to the lymphocyte-derived cytokines discussed above, the keratinocytes themselves are a rich source of inflammatory mediators, which are likely to be of importance in initiating the inflammatory reaction and the development and maintenance of the psoriasiform plaque.69 In particular, keratinocytes secrete IL-1α, IL-1β, and TNF-α. These cytokines play a major role in angiogenesis, in recruitment of circulating lymphocytes, and inducing expression of a number of endothelial cell adhesion molecules including E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1).69–71 These last are of particular importance in facilitating the extravasation of lymphocytes through the endothelium.52 Keratinocytes are also a valuable source of chemokines including IL-8, melanoma growth stimulatory activity alpha (MGS/GRO-α), gamma inducible protein 10 (IP-10), and molecule chemoattractant protein 1 (MCP-1).69 IL-8 is of importance in both neutrophil and T-lymphocyte chemotaxis.72 It also

promotes keratinocyte proliferation and induces angiogenesis.73,74 IL-8 is predominantly derived from superficial keratinocytes and the associated neutrophils within the psoriatic plaque. MGS/GRO-α is an additional powerful neutrophil chemoattractant.69 The pathogenesis of psoriasis therefore involves interaction between injured keratinocytes and activated lymphocytes through the release of various cytokines developing in a background of genetic predisposition.71 The precise relationship between the T-cell-driven immune reaction and epidermal hyperplasia, however, remains unclear. Similarly, the initiator(s) of this process are uncertain. Although autoantigens and bacterial superantigens are currently favored, the possibility of a direct consequence of lymphocyte–keratinocyte interaction has not yet been disproved.74 In biopsies of the early lesions, the histological features consist primarily of dermal changes.75–79 The evolution of the psoriatic plaque consists initially of the development of tortuous, dilated, and frequently congested capillaries in the superficial papillary dermis accompanied by edema and a perivascular mononuclear cell infiltrate (Fig. 6.89).75 This vascular change is common to all forms of psoriasis and may even be seen in biopsies from clinically resolved lesions following treatment.78 Lymphocytes then migrate into the lower epidermis, which becomes spongiotic. Subsequently, the upper epidermis shows focal vacuolation and eventual loss of the granular cell layer with the resultant formation of parakeratotic mounds. Migration of neutrophils from capillaries in the dermal papillae through gaps in the epidermal basement membrane and hence to the stratum corneum completes the process. Psoriasiform hyperplasia of the affected epidermis then follows. Classical plaque psoriatic lesions show marked and characteristic acanthosis of the epidermal ridges, which are evenly elongated and club-shaped at their bases, alternating with long edematous papillae, which are club-shaped at their tips (Figs 6.90–6.93). Fusion of adjacent ridges is commonly present in established lesions. The suprapapillary plate is typically thinned and the epidermal surface is covered by confluent parakeratosis associated with diminution or loss of the granular cell layer. The lower suprabasal layers of the epidermis can frequently be seen to be actively dividing. Large tortuous capillaries are present in the papillary dermis and there is a slight perivascular lymphocytic infiltrate in the subpapillary dermis. Palmar and plantar lesions may sometimes cause diagnostic difficulty as spongiosis can be marked, and occasionally vesiculation is evident.78 The diagnostic features of active lesions include the ‘Munro microabscess’ and ‘spongiform pustule of Kogoj’. Munro microabscesses represent an accumulation of polymorphs within the parakeratotic stratum corneum. Spongiform pustules are seen beneath the keratin layer and consist of small accumulations of neutrophils and occasional lymphocytes intermingled with the epidermal cells in foci of spongiosis.

Fig. 6.89 Evolving psoriasis: in the early stages, there is capillary dilatation, with spongiosis, as shown in this field. A small parakeratotic mound is also demonstrated.

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Fig. 6.90

Fig. 6.93

Plaque psoriasis: scanning view showing extensive parakeratosis, regular acanthosis, club-shaped epidermal ridges, and ridge fusion.

Plaque psoriasis: tortuous and dilated capillaries.

Fig. 6.91 Plaque psoriasis: closer view showing parakeratosis with neutrophil aggregates (Munro microabscess). There is marked dilatation and tortuosity of the capillaries within the dermal papillae. Spongiosis is also present.

Fig. 6.92 Plaque psoriasis: Munro microabscess, spongiform degeneration, and parakeratosis.

In guttate psoriasis, the histological features overlap with those of evolving disease.78 Parakeratosis associated with loss or diminution of the granular cell layer is limited to small foci contrasting with a background of orthokeratosis (Figs 6.94, 6.95). Neutrophils are seen surmounting the parakeratotic tiers. Acanthosis is much less marked than in fully established plaque disease. Neutrophils and lymphocytes are commonly present in the superficial papillary dermis and mild spongiosis is often a feature, particularly if biopsies of early lesions are examined.80 In generalized pustular psoriasis and its three variants the histological picture is slightly different in that the spongiform pustule occurs as a macropustule and is the characteristic lesion (Figs 6.96, 6.97).79 As the spongiform pustule increases in size, the epidermal cells die, with resulting central cavitation. At the edges, a shell of thinned epidermal cells remains. Eventually there is migration of neutrophils into the horny layer and the picture resembles that of a large Munro abscess. Although the epidermal and dermal features may be similar to those of psoriasis vulgaris, particularly if the pustule has developed against a background of plaque-type disease, more often the features are much less well developed (Fig. 6.98). Frequently, therefore, there is no or only minimal epidermal hyperplasia although tortuous and dilated capillaries accompanied by a lymphocytic or mixed lymphocytic and neutrophil infiltrate are usually seen.11

Fig. 6.94 Guttate psoriasis: the multiple discrete, parakeratotic mounds are characteristic. Hyperplasia is not as well developed as in plaque disease.

Psoriasis

Fig. 6.95 Guttate psoriasis: close-up view.

Fig. 6.96 Pustular psoriasis: a macropustule is present. Typical psoriasiform hyperplasia with parakeratosis is seen in the adjacent epidermis.

Fig. 6.97 Pustular psoriasis: close-up view.

Fig. 6.98 Pustular psoriasis: in this patient, the lesions developed dramatically in the absence of significant plaque disease. There is only mild hyperplasia of the underlying epidermis.

In palmar/plantar pustular lesions, the initial changes are those of spongiosis with lymphocytic exocytosis in the lower epidermis.80 As the lesion ­progresses, neutrophils infiltrate the epidermis and a macropustule develops. In psoriatic erythroderma the histological features are variable but in the majority of cases a positive diagnosis can be established.81 Most commonly, the features are those of evolving psoriasis similar to guttate psoriasis, i.e., slight epidermal hyperplasia, focal diminution or loss of the granular cell layer, and mild spongiosis (Fig. 6.99). Parakeratosis is often limited to slight change overlying the hyperplastic epithelium and neutrophils are variably present (Fig. 6.100). A lymphohistiocytic infiltrate is present in an edematous papillary dermis and dilated, tortuous, spiraling vessels are regularly evident. Extravasated red blood cells are a constant finding. Less commonly, the features are those of psoriasis vulgaris and sometimes the changes overlap regressing psoriasis. In resolving lesions, foci of hyperkeratosis overlying hypergranulosis are scattered through the parakeratotic scale and the epidermal hyperplasia is less marked (Fig. 6.101). Current treatment for severe widespread plaque psoriasis may include the use of PUVA therapy. Over the recent years it has been shown that this is associated with an increased risk (albeit low) of cutaneous squamous cell carcinoma and dysplastic keratoses.82–85 Patients at most risk include

Fig. 6.99 Psoriatic erythroderma: there is only very focal parakeratosis with scattered neutrophils. The epidermal hyperplasia is only slight.

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Fig. 6.100

Fig. 6.102

Psoriatic erythroderma: close-up view of parakeratosis and neutrophil karyorrhectic debris.

Bullous pemphigoid and pustular psoriasis: on the left is a subcorneal pustule while on the right is a subepidermal blister.

Fig. 6.101

Fig. 6.103

Resolving psoriasis: newly formed basket-weave orthokeratin is seen underlying focal residual parakeratosis.

Bullous pemphigoid and pustular psoriasis: higher-power view of the blister.

those who have had more than 200 PUVA treatments and/or a cumulative dose in excess of 1000 J/cm2. There is some evidence to suggest that these tumors behave in a low-grade fashion, with little risk of metastatic spread.85 Psoriasis may rarely coexist with a number of autoimmune bullous dermatoses including bullous pemphigoid, pemphigus vulgaris, linear IgA disease, and epidermolysis bullosa acquisita.86–92 Although not in all cases, there is often a relationship to treatment, particularly with PUVA therapy. In some instances, the histology may show features of both conditions (Figs 6.102–6.104).

Differential diagnosis The differential diagnosis of psoriatic lesions includes a number of conditions: • Pityriasis rubra pilaris differs from psoriasis by the presence of alternating parakeratosis and hyperkeratosis in both vertical and horizontal directions (spotty parakeratosis). Neutrophil infiltration of the stratum corneum is not a feature of pityriasis rubra pilaris unless there is secondary infection.

Fig. 6.104 Bullous pemphigoid and pustular psoriasis: higher-power view of the pustule.

Pityriasis rubra pilaris

• Lichen simplex chronicus typically shows scarring of the dermal papillae

• •

•

due to persistent rubbing, and there is no thinning of the suprapapillary plate. Hyperkeratosis and hypergranulosis are often marked and there is minimal parakeratosis unless there is a background of spongiosis. Papulosquamous drug eruptions (e.g., due to lithium or propranolol) may appear similar to psoriasis, but a moderate to high number of eosinophils is usually present in the infiltrate. Seborrheic dermatitis typically shows psoriasiform hyperplasia and corneal neutrophil infiltration may sometimes be a feature. It differs from psoriasis by the presence of a more conspicuous spongiotic component, which in psoriasis only occurs in early lesions and is usually not marked. In those cases where the distinction is not possible, the term ‘sebopsoriasis’ is sometimes used. Pustular psoriasis and its variants are all similar; they must be distinguished from other pustular eruptions, including conditions such as pustular dermatophytoses, bacterial impetigo, and pustular drug eruptions. Pustular psoriasis may be differentiated from subcorneal pustular dermatosis by the absence of spongiform change or degeneration in the latter condition. Gram and PAS stains and culture will exclude infective conditions. Superficial pemphigus can be distinguished by the presence of acantholysis and the usual absence of psoriasiform hyperplasia. In IgA pemphigus, acantholytic cells are usually, but not always, present and this diagnostic clue may be very easily overlooked, but should allow distinction from psoriasis. In lesions of IgA pemphigus that lack acantholytic cells, immunofluorescence studies may be necessary to make the distinction from pustular psoriasis if the clinical diagnosis is in doubt.

Fig. 6.105 Pityriasis rubra pilaris: there is characteristic hyperkeratosis and surrounding erythema. At the edges individual follicular lesions are evident. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.

Reiter's syndrome The skin lesions of Reiter's syndrome typically show psoriasiform hyperplasia with parakeratosis. The epidermis is markedly acanthotic with elongation and hypertrophy of the epidermal ridges. The suprapapillary plates are thinned and there is infiltration of the epidermis by neutrophils, associated with the formation of spongiform pustules, microabscesses, and ultimately macropustules indistinguishable from pustular psoriasis. A perivascular lymphohistiocytic infiltrate with neutrophils is seen in the upper dermis.

Pityriasis rubra pilaris Clinical features Pityriasis rubra pilaris is an erythematous papulosquamous disorder characterized by follicular plugging (often best seen on the dorsal aspects of the hands and feet), perifollicular erythema that becomes confluent, palmoplantar hyperkeratosis, and pityriasis capitis.1–3 It is an uncommon disease, accounting for approximately one of every 5000 new dermatological referrals in the United Kingdom.3 Males and females are affected equally and the age distribution tends to peak in the first and fifth decades.3 Although the majority of cases documented have affected Caucasian patients, occasional reports describing pityriasis rubra pilaris in black African patients have recently been published.4 Pityriasis rubra pilaris has been classified clinically into five types:3 • Type I, classical adult pityriasis rubra pilaris, is seen in over 50% of patients. Initially, a single erythematous patch appears on the upper half of the body (typically the face and scalp) and gradually spreads as large areas of sometimes pruritic or burning follicular hyperkeratosis with erythematous perifollicular halos (Fig. 6.105).4 The erythematous areas coalesce and many patients develop generalized erythroderma (Fig. 6.106). Characteristically, occasional islands of unaffected skin are present (Fig. 6.107). Follicular papules on the dorsal aspects of the fingers and extensor surfaces of the wrists, arms, and thighs are said to be characteristic.5 Fine and powdery scaling occurs on the face and scalp, with coarser scaling on the lower body (Fig. 6.108). The erythema has an orange–yellow tint, which is more noticeable on the palms and soles, together with marked hyperkeratosis (Fig. 6.109).

Fig. 6.106 Pityriasis rubra pilaris: confluence of lesions leads to extensive erythroderma. By courtesy of the Institute of Dermatology, London, UK.

•

•

The nails are also affected, showing distal yellow–brown discoloration, subungual hyperkeratosis, nail thickening, and splinter hemorrhages.6 Ectropion is often present,7 and there may be diffuse alopecia.8 Oral lesions are uncommon and include diffuse hyperkeratosis and macular erythema with white streaks reminiscent of lichen planus.5 Prognosis for patients in this group is good, with up to 80% resolving within 3 years. Type II, atypical adult pityriasis rubra pilaris, occurs in approximately 5% of patients and is manifested by atypical morphological features and a lengthy duration, often up to 20 years. The scaling is more ichthyosiform and there are often areas of eczematous change. The prognosis in this group is poor, with only 20% resolving within 3 years. Type III, classical juvenile pityriasis rubra pilaris, resembles the classical adult form except for its age distribution; it affects children up to 2 years of age, accounting for approximately 10% of patients (Fig. 6.110). More often, however, the eruption commences on the lower half of the body.

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Fig. 6.110 Fig. 6.107 Pityriasis rubra pilaris: characteristic, scattered islands of unaffected skin are evident. By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.108 Pityriasis rubra pilaris: in this patient, the scale is conspicuous. By courtesy of the Institute of Dermatology, London, UK.

Pityriasis rubra pilaris: classical juvenile type. Note the very extensive distribution of the lesions. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.

The prognosis in this group is good, most patients clearing within 1 year but a recurrence rate of up to 17% has been reported.9 • Type IV, circumscribed pityriasis rubra pilaris, affects 25% of patients and presents in prepubertal children. Sharply defined areas of follicular hyperkeratosis and erythema are seen on the knees and elbows, together with occasional scaly erythematous patches on the rest of the body and palmoplantar hyperkeratosis.10 • Type V, atypical juvenile pityriasis rubra pilaris, accounts for approximately 5% of patients; presentation occurs early in life and this type has a lengthy duration. Characteristic follicular hyperkeratosis is present, together with a mild erythema. Ichthyosiform features are sometimes seen.5 The skin of the feet and hands may become thickened and scleroderma-like. Familial variants, which account for 0–6.5% of cases, mostly present with atypical features as described in type V pityriasis rubra pilaris.5 In most families, inheritance has been via an autosomal dominant mechanism with variable expression and reduced penetrance although a recessive form has also been postulated.11 Pityriasis rubra pilaris has been reported in association with HIV ­infection.12,13 Nodulocystic acneiform or furuncle-like lesions and lichen spinulosus may also be present. This is a particularly severe variant, which responds poorly to therapy.13 Further associations include rheumatological disease, in particular arthritis, dermatomyositis, and underlying malignancy possibly representing a paraneoplastic phenomenon.14–25

Pathogenesis and histological features

Fig. 6.109 Pityriasis rubra pilaris: palmar and plantar erythema with hyperkeratosis are frequent manifestations. Sometimes, there is an orange–yellow tint, as seen in this patient. By courtesy of the Institute of Dermatology, London, UK.

The etiology of pityriasis rubra pilaris is largely unknown. It has been associated with abnormal vitamin A metabolism but there is little evidence in support for this other than a frequent response to vitamin A or retinoid therapy.5 Linkage to autoimmune disease, immune dysfunction, internal malignancy, infections and, particularly in recent years, to human immunodeficiency virus, have also been described.5,13,26,27 In the majority of cases, however, there is no preceding or associated condition. Pityriasis rubra pilaris is associated with an increased rate of epidermopoiesis.28–32 Fully developed follicular papules show characteristic features comprising conical follicular plugging, with marked uniform acanthosis of the epidermis and broad epidermal ridges and dermal papillae (Fig. 6.111).28,29,33 There is hyperkeratosis, with foci of parafollicular parakeratosis. In the dermis there is a mild to moderate inflammatory cell infiltrate and sebaceous atrophy. Although the histological features may be non-specific, biopsies from established, nonfollicular lesions comprise alternating orthokeratosis and parakeratosis in both vertical and horizontal directions, focal or confluent hypergranulosis, thick suprapapillary plates, broad epidermal ridges, narrow

Pityriasis rubra pilaris

Fig. 6.113 Fig. 6.111

Pityriasis rubra pilaris: alternating hyperkeratosis and parakeratosis.

Pityriasis rubra pilaris: follicular lesion showing the conical keratin plug. Parakeratosis is present above the adjacent epithelium.

dermal papillae, and a perivascular lymphocytic infiltrate in the superficial dermis (Figs 6.112–6.114).34 Small numbers of plasma cells and eosinophils are sometimes present.26 Superficial blood vessels may appear slightly dilated. Occasionally there is also mild spongiosis with scattered intraepidermal lymphocytes.27 Neutrophil infiltration as seen in psoriasis is not usually a feature of pityriasis rubra pilaris and its presence may indicate a bacterial or fungal superinfection. Acantholysis with or without dyskeratosis involving follicular and interfollicular epithelium has recently been emphasized, and exceptionally a lichenoid infiltrate has been documented.26,35–38 In early lesions, the diagnosis is often problematical. Parakeratosis is usually poorly developed and lamellar orthohyperkeratosis predominates.34 Hypergranulosis is present and the rete ridges are broadened and slightly elongated. The suprapapillary plates may be mildly thickened. In erythrodermic lesions, the keratin layer may be thinned or lost and the granular cell layer diminished.34 Palmar and plantar lesions show hyperkeratosis, focal parakeratosis, and mild acanthosis (Fig. 6.115). Fig. 6.114 Pityriasis rubra pilaris: close-up view.

Fig. 6.115

Fig. 6.112 Pityriasis rubra pilaris: there is hyperkeratosis with focal parakeratosis and psoriasiform hyperplasia.

Pityriasis rubra pilaris: plantar lesion showing hyperkeratosis, focal parakeratosis, and regular acanthosis with a rounded lower border.

213

214

Inflammatory linear verrucous epidermal nevus

Spongiotic, psoriasiform and pustular dermatoses

Differential diagnosis Pityriasis rubra pilaris may be confused both clinically and histologically with psoriasis. Features in favor of pityriasis rubra pilaris include follicular plugging with parakeratosis of the adjacent epithelium, focal parakeratosis, broad rete ridges, thickened suprapapillary plates, increased granular cell layer, and an absence of tortuous dilated capillaries immediately adjacent to the epidermis. In psoriasis the acanthosis is typically more marked and often strikingly regular, the rete ridges are thin and often fused, the suprapapillary plate is thinned, parakeratosis is usually confluent, and characteristic collections of neutrophils are seen in the overlying parakeratotic stratum corneum in association with spongiform degeneration of the underlying superficial epidermis.

Inflammatory linear verrucous epidermal nevus Clinical features Inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon condition which usually presents in infants or young children as an intensely pruritic, persistent, scaly, unilateral, linear erythematous lesion following the lines of Blaschko.1 Individual lesions are discrete, scaly papules, which coalesce to form plaques.2 Superimposed lichenification and excoriations are commonly present. Although lesions may be widely distributed, the leg, thigh, and buttock are sites of predilection (Fig. 6.116).1,3 Females are more often affected than males (4:1).2 The left side of the body is most often involved.2,4,5 Much less commonly, the disorder is bilateral and, exceptionally, the condition is generalized.6–8 Familial cases have been documented and adults may sometimes be affected.7–11 Occasionally inflammatory linear verrucous epidermal nevus coexists with psoriasis and rarely it presents as part of the epidermal nevus syndrome.12,13 Exceptionally, the condition is associated with arthritis.14

Fig. 6.117 Inflammatory linear verrucous epidermal nevus (ILVEN): in this view there is marked psoriasiform epidermal hyperplasia with massive hyperkeratosis. Mild chronic inflammation is seen in the superficial dermis.

Histological features Histologically, the nevus is characterized by sharply demarcated, alternating parakeratosis and orthohyperkeratosis (Figs 6.117–6.119).2,5,15 The epidermis shows papillomatosis with psoriasiform hyperplasia and absence of the

Fig. 6.118 Inflammatory linear verrucous epidermal nevus (ILVEN): alternating hyperkeratosis and parakeratosis is characteristic.

Fig. 6.116 Inflammatory linear verrucous epidermal nevus (ILVEN): patients present with scaly, erythematous, itchy papules and plaques in a linear distribution, showing a predilection for the legs. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 6.119 Inflammatory linear verrucous epidermal nevus (ILVEN): close-up view.

Subcorneal pustular dermatosis granular layer below the foci of parakeratosis contrasting with a thickened granular cell layer underneath the orthohyperkeratosis. Occasionally, Munro microabscesses are a feature. The rete ridges are elongated and thickened. Focal slight spongiosis is present, accompanied by lymphocytic exocytosis. A mild perivascular lymphocytic infiltrate is seen in the superficial dermis.

Differential diagnosis ILVEN must be distinguished from linear psoriasis.16 In ILVEN, parakeratosis alternates with orthohyperkeratosis in contrast with psoriasis where the parakeratosis is confluent. Similarly, the thickened rete ridges of ILVEN contrast with the thinned ones of psoriasis. By immunocytochemistry, in ILVEN, involucrin expression is markedly diminished in the epithelium deep to the parakeratosis, while it is increased in the epithelium underlying the hyperkeratosis.17 In psoriasis, there is a general increase in involucrin expression throughout the entire lesion. Rare cases of ILVEN showing histiocyte infiltration of the underlying ­dermis reminiscent of verruciform xanthoma have been documented.18–21

Bazex syndrome (acrokeratosis paraneoplastica)

Fig. 6.120 Bazex syndrome: note the violaceous discoloration of the ear. By courtesy of J.L. Bolognia, MD, Yale Medical School, CT, USA.

Clinical features Bazex syndrome denotes an acral psoriasiform dermatosis in association with internal malignancy.1–3 Elderly patients, usually males, present with a symmetric erythematous or violaceous, scaly eruption affecting the ears, nose, fingers, and toes (Fig. 6.120).1 The knees and elbows may sometimes be involved. Vesicles and bullae are less common manifestations.4 In patients with black or dark-brown skin, the lesions can present with hyperpigmentation.2 Palmoplantar lesions are keratodermatous and nail involvement ranges from paronychia, horizontal or vertical ridging, yellow discoloration and thickening to onycholysis and subungual keratotic debris (Fig. 6.121).1 Patients with Bazex syndrome invariably have an associated systemic malignancy, most often affecting the oropharynx, larynx, esophagus, and lung, in descending order of frequency.1 Cervical lymph node metastases are commonly present. Persistence of the cutaneous lesions is rare and they commonly regress following successful treatment of the underlying malignancy.2,5

Histological features Histologically, there is considerable overlap with psoriasis and chronic spongiotic dermatitis, the epidermis showing hyperkeratosis, parakeratosis, and acanthosis. In addition however, dyskeratosis and interface changes reminiscent of lichen planus are also commonly present.1 A perivascular or less commonly lichenoid chronic inflammatory cell infiltrate is present in the superficial dermis. Bullous lesions may be subepidermal or, less often, intraepidermal.1,6

Fig. 6.121 Bazex syndrome: keratoderma. By courtesy of J.L. Bolognia, MD, Yale Medical School, CT, USA.

Pustular dermatoses Pustular drug reactions This topic is discussed in the chapter on adverse reactions to drugs.

Subcorneal pustular dermatosis Clinical features Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) is a rare chronic, relapsing, and apparently noninfective eruption of unknown etiology.1,2 It predominantly affects females (4:1) and is usually diagnosed during the middle years of life. Pediatric cases have, however, occasion-

ally been described.3,4 It may be associated with a benign or malignant IgA paraproteinemia (up to 40% of cases) or multiple myeloma, and sometimes pyoderma gangrenosum is also present.5–15 Other associations include rheumatoid arthritis, systemic lupus erythematosus, hyperthyroidism, Crohn's disease, multiple sclerosis, IgG cryoglobulinemia, bullous pemphigoid, morphea, diffuse scleroderma, Sjögren syndrome, marginal zone lymphoma, chronic lymphocytic leukemia, squamous carcinoma of the bronchus, and metastatic gastrinoma, although it is doubtful whether these are of any great significance.15–26 Clinically, patients present with waves of superficial flaccid pustules in circinate or serpiginous groups and sheets, particularly in the folds of the body, such as the axillae (Figs 6.122, 6.123) and groins, beneath the breasts,

215

216

Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.122 Subcorneal pustular dermatosis: typical example showing a succession of pustules spreading outwards from the axilla. At the periphery the lesions are healing with crust formation. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 6.123 Subcorneal pustular dermatosis: close-up view of early lesions characterized by numerous pustules arising on an erythematous background. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

and on the abdomen. Fluid levels are sometimes evident. Typically, the mucous membranes, face, scalp, and peripheries are spared. Healing is rapid, usually within a few days or weeks, and the condition responds to dapsone, although not as dramatically as dermatitis herpetiformis. Postinflammatory hyperpigmentation is common. Canine subcorneal pustular dermatosis, particularly affecting Miniature Schnauzers, has been reported.27

Pathogenesis and histological features The etiology of subcorneal pustular dermatosis is unknown. Intercellular IgA deposits have been identified in a significant number of cases by direct immunofluorescence and many patients have a circulating IgA pemphigus antibody. These cases have been documented in the literature as IgA pemphigus.28–33 Subcorneal pustular dermatosis should be restricted to the immunofluorescence-negative group. The characteristic lesion is a subcorneal pustule, which appears to sit on the skin surface (Fig. 6.124). The contents of the pustules are predominantly neutrophils, although an occasional eosinophil may be identified. The epidermis beneath the pustule shows surprisingly little change except for polymorphs in transit and perhaps slight intercellular edema (Fig. 6.125). Older lesions may contain acantholytic cells (Fig. 6.126). In the dermis, superficial blood vessels are surrounded by a non-specific mixed inflammatory cell infiltrate consisting of neutrophil polymorphs and mononuclear cells.

Fig. 6.124 Subcorneal pustular dermatosis: situated immediately below the stratum corneum is a blister cavity containing edema fluid and numerous neutrophils. The epidermis shows neutrophils in transit. Within the papillary dermis is a neutrophil and lymphocytic infiltrate.

Differential diagnosis The histological features of subcorneal pustular dermatosis cannot be reliably distinguished from those of bullous impetigo, staphylococcal scalded skin syndrome, pemphigus foliaceus, and IgA pemphigus. Impetigo is, however, a disease of young children and, although a Gram stain is often negative, cultures should grow staphylococci or streptococci. The staphylococcal scalded skin syndrome (Ritter's disease) is predominantly a disease of infants, but rarely it may present in adults. Clinically it is different from subcorneal pustular dermatosis, being characterized by the development of large flaccid blisters, which rupture, leaving extensive areas of denuded skin. Although acantholysis is typical of the pemphigus group of diseases, it may occasionally be seen in impetigo, staphylococcal scalded skin syndrome,

Fig. 6.125 Subcorneal pustular dermatosis: close-up view.

Infantile acropustulosis during delivery was initially thought to be of pathogenetic importance, more recent data favor an immunological response to the initial colonization of the skin by commensal microorganisms.11–16 Early erythematous lesions show a somewhat nondescript perivascular inflammatory cell infiltrate with conspicuous eosinophils, which may be seen penetrating the epidermis in close proximity to hair follicles. In an established lesion, the pustules are follicular, lie subcorneally, and contain large numbers of eosinophils and occasional neutrophils.17 The external root sheath of the infundibulum may also be affected.

Differential diagnosis

Fig. 6.126 Subcorneal pustular dermatosis: in addition to neutrophils there are scattered acantholytic keratinocytes. These features are indistinguishable from those of pemphigus foliaceus.

subcorneal pustular dermatosis, and pustular psoriasis. In difficult cases the demonstration of positive immunofluorescence will establish the diagnosis of pemphigus (however, see IgA pemphigus). There has been considerable controversy in earlier literature concerning the relationship between subcorneal pustular dermatosis and pustular psoriasis, with some authors claiming them to be one and the same condition and others equally determined that they are quite different. In our view, these are two distinct diseases. Thus, in subcorneal pustular dermatosis, there is no family history and there is no evidence of more typical psoriasiform lesions elsewhere. Subcorneal pustular dermatosis responds to dapsone in the vast majority of cases and histologically spongiform change deep to the pustule (typical of psoriasis) is characteristically absent. Psoriasis is not associated with monoclonal gammopathy or multiple myeloma.

Toxic erythema of the neonate must be distinguished from incontinentia pigmenti. The latter, however, is characterized by eosinophilic spongiosis, a feature not seen in toxic erythema. In miliaria rubra the vesicles are related to sweat ducts rather than hair follicles and typically contain mononuclear cells rather than eosinophils. Toxic erythema of the neonate must also be distinguished from infantile acropustulosis, transient neonatal pustular melanosis, and infantile eosinophilic pustular folliculitis (see below).

Infantile acropustulosis Clinical features This uncommon condition usually presents in the first year of life and is sometimes evident at birth.1–4 There is a marked male predilection. Although it is most often seen in black children, it has occasionally been reported in Asians and whites.5–8 The disorder presents as crops of intensely itchy, erythematous papules 1–5 mm in diameter, vesicles, and pustules, which are found most often on the palms and soles, but the volar surfaces of the wrists, the ankles, the face, and scalp may occasionally be affected (Fig. 6.127).6 The mucous membranes are spared.1 Lesions are often present for 1–2 weeks and tend to recur every 2–4 weeks. With progression, the duration of the eruption diminishes and the remission lasts for gradually increasing periods of time. Spontaneous resolution has usually occurred by 2–3 years of age.

Pathogenesis and histological features The etiology and pathogenesis of this condition are unknown. However, infantile acropustulosis may be associated with atopy and hypereosinophilia.6,9–11 Sometimes, a history of prior or concurrent scabies infection is present but whether this is causal is uncertain.4

Toxic erythema of the neonate Clinical features Toxic erythema of the neonate (erythema toxicum neonatorum, erythema neonatorum) is a very common self-limiting disorder affecting from 48% to 72% of all newborn infants.1–7 There is no racial predilection but males appear more commonly affected.2,8 It presents as an asymptomatic erythematous macular rash usually in the first 3 days of life.1,9 Occasionally, it may be evident at birth and, exceptionally, the onset is delayed until the second week after birth.5,6,10 Sometimes there are papules and vesicles and, in some patients, pustule formation is evident. The condition most often affects the forehead, face, chest, trunk, and extremities.1 The palms and soles are typically uninvolved. The eruption is asymptomatic and very typically transient, with lesions often lasting only a number of hours or days.1 Full resolution is usually achieved by 1–5 days although recurrences may occur in up to 11% of neonates.2 Toxic erythema of the neonate is frequently associated with a peripheral blood eosinophilia.

Pathogenesis and histological features The etiology of this condition is completely unknown.2 While an acute graftversus-host type of reaction resulting from transfer of maternal lymphocytes

Fig. 6.127 Infantile acropustulosis: typical small pustules centered about the base of the thumb. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

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218

Spongiotic, psoriasiform and pustular dermatoses Histology reveals a subcorneal pustule containing predominantly ­ eutrophils, although occasionally small numbers of mononuclears and n eosinophils are evident. Eosinophil-rich pustules have also been described but with hindsight most such cases probably represent eosinophilic pustular folliculitis.11 Slight acantholysis of the adjacent epidermis has been described.12 The underlying dermis often contains a perivascular chronic inflammatory cell infiltrate, sometimes with scattered neutrophils and eosinophils. Direct and indirect immunofluorescence tests are negative.

Differential diagnosis The diagnosis of infantile acropustulosis depends upon careful clinicopathological correlation. Conditions that may enter the differential diagnosis include scabies, pompholyx, Candida and dermatophytosis, herpes simplex, juvenile dermatitis herpetiformis, toxic erythema of the neonate, bullous impetigo, eosinophilic pustular folliculitis occurring in infancy, and transient neonatal pustular melanosis.

Transient neonatal pustular melanosis Clinical features Transient neonatal pustular melanosis is an uncommon condition which presents with vesicles and pustules on the forehead, under the chin, on the nape of the neck, chest, back, and buttocks.1–4 In contrast to eosinophilic pustular folliculitis of infancy, the scalp is rarely involved. It affects 4–5% of black infants and 0.1–0.3% of white infants.2 There is no sex predilection.3 Lesions, which present at birth or during the first day of life, heal rapidly to leave small brown macules with a peripheral scale, and have usually disappeared by 3 months of age.3

Histological features Histologically, the features are identical to those of infantile acropustulosis: i.e., a subcorneal neutrophil-rich pustule sometimes accompanied by small numbers of eosinophils.1

Eosinophilic pustular folliculitis of infancy Clinical features Eosinophilic pustular folliculitis (Ofuji's disease), which is largely a condition of adults and presents as recurrent episodes of itchy follicular papules and pustules on the face, trunk, and extremities, may rarely develop in infants.1–6 There is a predilection for males.1 In the infantile form, lesions, which may be present at birth or develop during the first 24 hours, are found particularly on the scalp, hands, and feet.1,7–10 The trunk and limbs can also be affected.2 Patients present with 1–3-mm white to yellow crusted pustules arising on an erythematous base.1,2 A blood eosinophilia is often present.7,11 The condition persists from 3 months to up to 5 years.2

Pathogenesis and histological features The etiology is unknown, although in a small number of cases an association with atopy has been documented.12 In contrast to the adult disease, HIV infection is very rarely present.13 The histological features are those of an eosinophil-rich ‘spongiotic’ pustule related to the outer root sheath of the hair follicle from the stratum corneum to the level of insertion of the sebaceous duct.14–18 A heavy inflammatory cell infiltrate consisting of eosinophils, lymphocytes, and histiocytes is present in the adjacent dermis. The reported histological features are, however, less distinctive and specific compared to classic, adult-type, eosinophilic pustular folliculitis.10,19 Numerous other pustular dermatoses may be encountered including superficial pemphigus, particularly IgA pemphigus, pustular drug reactions, bullous impetigo and staphylococcal scalded skin syndrome, pustular dermatophyte infections, pustular lesions in pyoderma gangrenosum, and necrolytic migratory erythema. These are discussed elsewhere in this book.

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for references and additional material

Lichenoid and interface dermatitis Wei-Lien Wang and Alexander Lazar

Lichenoid dermatoses  219

Interface dermatoses  237

Lichen planus  219 Lichen nitidus  229 Lichenoid keratosis  231 Lichen striatus  232 Adult Blaschkitis  233 Keratosis lichenoides chronica  234 Erythema dyschromicum perstans  236 Lichenoid and granulomatous dermatitis  236

Erythema multiforme  238 Toxic epidermal necrolysis and Stevens-Johnson syndrome  241 Paraneoplastic pemphigus  245 Poikiloderma  245 Poikiloderma of Civatte  245 Mitochondrial DNA syndrome-associated poikiloderma  246

The term ‘lichenoid’ refers to inflammatory dermatoses which are characterized by a bandlike lymphohistiocytic infiltrate in the upper dermis, hugging and often obscuring the dermoepidermal interface. Lichen planus is the prototypic lichenoid dermatitis (Box 7.1). Interface dermatitis refers to the presence of basal cell vacuolization (hydropic degeneration) and is often accompanied by single-cell keratinocyte apoptosis (Box 7.2). These two terms are by no means mutually exclusive as most lichenoid infiltrates are accompanied by interface change. However, some dermatoses are characterized primarily by interface change without a lichenoid infiltrate such as lupus erythematosus and erythema multiforme.

Lichenoid dermatoses Lichen planus Clinical features Lichen planus (Gr. leichen, tree moss) is a common, usually intensely pruritic, symmetrical, papulosquamous dermatosis.1,2 Its prevalence in the general population is approximately 1%, and it most often presents in the fourth to sixth decades with a slight female predominance.3,4 It is uncommon in childhood.5,6 Occasional familial cases have been reported.7,8 The disease is characterized by small, smooth, shiny, flat-topped polygonal papules measuring several millimeters to 1 cm in diameter and often having a violaceous color (Fig. 7.1). Delicate white lines known as Wickham's striae typically cross the slightly scaly surface (Fig. 7.2). The lesions are found most commonly on the flexor aspect of the wrists, the forearms, the extensor aspect of the hands and ankles, the lumbar area and the glans penis (Fig 7.3). Lichen planus is associated with a positive Koebner's phenomenon. It is a usually self-limiting although sometimes protracted disorder, patients clearing of lesions within weeks to 1 or 2 years. Oral involvement, which is very common (affecting up to 60% of patients with cutaneous disease), shows a marked female preponderance and presents most often in the seventh decade. It may sometimes be the sole manifestation (an estimated 15–35% of patients with oral lichen planus never develop skin lesions).9–14 The buccal mucosa, vestibule, tongue, and

Chapter

7

Rothmund-Thomson syndrome  246 Blooms' syndrome  247 Cockayne's syndrome  248 Dyskeratosis congenita  248 Graft-versus-host disease  249 Pityriasis lichenoides  255

gingivae are most often affected, in decreasing order of frequency.12 Patients frequently present with a white lacelike pattern, but papules, plaques and erosions, ulcerated, atrophic, and bullous variants may also be found (Figs 7.4–7.6).1,15 Lesions are usually asymptomatic, although erosions and bullae are sometimes tender and painful. Chronic ulcerated oral lichen planus is of particular importance because it has been related to an increased risk, albeit low, of developing squamous cell carcinoma (Fig 7.7). The risk of developing malignancy is debated, with current literature suggesting that 0–12.5% of affected patients will develop an oral malignancy.12,16–22 Oral involvement in lichen planus and its relationship to cutaneous squamous cell carcinoma is discussed in greater depth elsewhere. Involvement of the gums may present as desquamative gingivitis.1 Other mucous membranes that may be involved include those of the pharynx, larynx, esophagus, nose, anus, and genitalia.23 Familial cases of lichen planus limited to oral involvement are noted.24 Ocular involvement is rare and may include eyelid lesions, blepharitis, conjunctivitis, keratitis, punctate corneal opacities, iridocyclitis, and chorioretinitis.25,26 Esophageal involvement, although rare, is an important potential cause of morbidity, and is the most frequently involved gastrointestinal site.27 Concomitant oral lesions are invariably present. To date, middleaged or elderly females are typically affected.28–31 Complications include chronic dysphagia and stricture formation affecting the mid or upper esophagus.28,32–35 Patients with esophageal lichen planus may have a risk of developing squamous cell carcinoma. The role of surveillance is uncertain.27,28,30,31,36,37 Genital lesions in lichen planus are common (particularly in males), being present in up to 25% of patients, and sometimes adopting an annular configuration (Fig. 7.8).1 Similar annular lichen planus may be found elsewhere on the body, including intertriginous areas.38 Occasionally, penile lesions are the sole expression of the disease.39 Vulval lesions may be found in up to 51% of females with cutaneous involvement.40 Sometimes gingival and female genital lesions may coexist as a variant of erosive lichen planus, the so-called vulvovaginal-gingival syndrome.41–44 Patients present with dyspareunia and intense burning vulval pain. The vulva appears congested and there may be erosions, which are often surrounded by a white reticulate border. Vaginal involvement similarly presents as dyspareunia

220

Lichenoid and interface dermatitis Box 7.1 Causes of lichenoid dermatitis

• • • • • • • • • • • • •

Lichen planus Lichenoid graft-versus-host disease Lichen nitidus Lichenoid keratosis Lichenoid drug reaction Fixed drug reaction Lichen planopilaris Lichen striatus Adult Blaschkitis Lichen aureus Lichenoid mycosis fungoides Ashy dermatoses Lichenoid and granulomatous dermatitis

Box 7.2 Causes of interface dermatitis

• • • • • • • • •

A

Lichenoid dermatoses (see Box 1.) Erythema multiforme Stevens-Johnson syndrome/toxic epidermal necrolysis Connective tissue disorders: lupus erythematosus, dermatomyositis, and mixed connective tissue disorders Graft-versus-host disease Poikiloderma including those related to rare inherited disorders Interface drug reactions Interface viral exanthem Pityriasis lichenoides

and often postcoital bleeding due to inflammatory, desquamative, and erosive changes. More typical features of lichen planus may be encountered elsewhere on the body. Squamous carcinoma is an important complication of chronic vulval lichen planus.45 The development of penile cancer is rare.46 Genital involvement in lichen planus is discussed elsewhere. The nails are affected in about 10% of patients with lichen planus; manifestations include thinning of the nail plate, longitudinal ridging, striations, pterygium formation, subungual hyperkeratosis and, very rarely, complete destruction of the nail (Figs 7.9).1 Although nail involvement in children is said to be rare, some authors regard twenty-nail dystrophy of childhood as a variant of localized lichen planus, although not all accept this hypothesis.47–51

B

Fig. 7.2 Lichen planus: (A) note the characteristic Wickham's striae at the edge of these pigmented lesions; (B) Wickham's striae are evident on these lesions, which have arisen on the back, an uncommonly affected site. (A) From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. (B) Courtesy of J. Dayrit, MD, Manila, The Philippines.

Fig. 7.1

Fig. 7.3

Lichen planus: there are typical flat-topped polygonal papules on dorsum of the hand. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Lichen planus: there is extensive bilateral involvement of the flexor aspect of the forearms. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Lichenoid dermatoses

Fig. 7.4 Lichen planus: this lace-like pattern is characteristic. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig 7.6 Lichen planus: the tongue is commonly affected. By courtesy of M. Blanes, MD, Alicante, Spain

Fig. 7.5 Lichen planus: there is extensive ulceration of the buccal mucosa. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 7.7 Lichen planus: there is an ulcerated squamous carcinoma on the lower lip. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

• Lichen planus actinicus (lichen planus subtropicus, summertime actinic Most lesions of lichen planus heal within 6–18 months of onset. However, oral and hypertrophic variants and lichen planopilaris tend to have a chronic course. Postinflammatory hyperpigmentation, which may be very disfiguring, is not uncommon, particularly in colored races (Fig. 7.10). A number of variants of lichen planus merit specific mention: • Lichen planopilaris (follicular lichen planus), presents as single or multiple plaques of scarring alopecia associated with a spectrum of lesions including typical lichenoid papules involving the scalp to brown or violaceous keratotic follicular papules affecting the trunk and extremities (Figs 7.11–7.13).52–55 Nonscarring plaques with prominent follicular papules may also be present. Linear lesions have rarely been described.56–58 Some authors suggest that scalp lichen planus represents pseudopélade of Brocq.59,60 Children can also be affected. 61 • Atrophic lichen planus, the clinical features of which merely reflect resolution of the more typical active phase.

lichenoid eruption (SALE)), develops in patients with prolonged exposure to sunlight and, therefore, usually manifests in spring or summer,62–66 with improvement or remission in the autumn or winter. It occurs particularly in the Middle East (especially Egypt) and the Far East and affects younger people, with a maximum incidence in the second and third decades and a slight female predominance (Fig 7.14). Affected sites include the lateral aspects of the forehead, the dorsum of the hands, the forearms, face, and neck. The eruption can include a mixture of lichen planus-like and lichen nitidus-like lesions, whereas in others, the lesions appear as purely one or the other (see actinic lichen nitidus, below). Typically, the lichen planus lesions have an annular configuration with a bluish-brown, rather atrophic center and slightly raised border. They may sometimes coalesce to form circinate plaques. Occasionally, a melasmalike appearance has been documented.66 There is usually little pruritus and Koebner's phenomenon is commonly absent. The nails are often unaffected.

221

222

Lichenoid and interface dermatitis

A

Fig. 7.9 Lichen planus: there is longitudinal ridging and striation affecting the thumbnail, with inflammatory changes in the nail folds. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

B

Fig. 7.8 Lichen planus: (A) typical papules are present on the shaft of the penis; (B) note the erythematous erosions around the vulval introitus and labia minora. (A) From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK; (B) By courtesy of S. Neill, MD, Institute of Dermatology, London, UK.

• Lichen planus pigmentosus, most commonly encountered in the tropics

•

in dark-skinned patients, is characterized by the development of variably pruritic pigmented dark-brown macules predominantly affecting exposed skin and the flexures (Figs 7.15, 7.16). The most common affected sites include the face and neck.67–72 There is no sex predilection. The disorder is characterized by periods of exacerbation and remission.4 Exceptionally, involvement of the oral mucosa has been documented.5 Hypertrophic lichen planus, which represents superimposed lichen simplex chronicus, commonly affects the lower limbs, particularly the shins, and manifests as highly pigmented warty plaques (Fig. 7.17).73 Familial lichen planus shows an increased incidence of this variant.74 The lesions are intensely itchy and very persistent. There may be an attendant (albeit very slight) risk of neoplastic transformation although the evidence is weak and based largely on case reports.75

Fig. 7.10 Lichen planus: postinflammatory hyperpigmentation is a common manifestation. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

• Ulcerative lichen planus, a chronic variant affecting the fingers, hands,

soles, and toes, is often associated with permanent loss of the nails (Figs 7.18, 7.19). Squamous cell carcinoma may complicate this variant of

lichen planus.76 Other variants include lichen planus linearis, which occurs predominantly in children, and the rare vesicular or bullous variants, which must be distinguished from lichen planus pemphigoides. Bullous lichen planus implies the development of vesicles or bullae on pre-existent lichenoid lesions as a consequence of severe basal cell hydropic degeneration. It is more often a histological finding rather than a clinical observation. In contrast, lichen planus pemphigoides is characterized by the development of large tense bullae arising on normal or erythematous skin in a patient with typical lichen planus elsewhere. It represents the combined expression of lichen planus and bullous pemphigoid.77 Childhood lichen planus shows a modest male predominance (2:1).5,6,61,78 Although mucosal involvement is said to be rare, recent series report a frequency of 14–39%.6,61,78 Hypertrophic lesions may be seen in up to 26% of cases.6

Lichenoid dermatoses

Fig. 7.13 Lichen planopilaris: follicular lichenoid papules are clearly seen in this patient. By courtesy of the Institute of Dermatology, London, UK.

Fig. 7.11 Lichen planopilaris: there are characteristic hyperpigmented follicular papules, which are confluent in some areas. The limbs are commonly affected. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 7.14 Lichen planus actinicus: there is marked facial hyperpigmentation representing postinflammatory changes. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 7.12 Lichen planopilaris: marked inflammatory changes with scarring and secondary hair loss. These changes are difficult to distinguish from those of pseudopélade and chronic discoid lupus erythematosus. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Pathogenesis and histological features The etiology of lichen planus is unknown. Theories of infectious (bacterial and viral), autoimmune, metabolic, psychosomatic, and genetic causes have all had their proponents. Currently, however, it is thought that lichen planus represents an abnormal delayed hypersensitivity reaction to an as yet undetermined epidermal neoantigen, possibly to a combination of an external antigen coupled with an internal self-antigen.79,80 The association of lichen planus with a number of viral infections including hepatitis B and C and human

Fig. 7.15 Lichen planus pigmentosus: there are coalescent pigmented papules. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

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Fig. 7.19 Fig 7.16 Lichen planus pigmentosus: the face is a commonly affected site. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 7.17 Hypertrophic lichen planus: raised, warty, violaceous plaques on the shin of an elderly man. These lesions had been present for 30 years. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 7.18 Ulcerative lichen planus: there is marked atrophy of the skin around this crusted ulcer. By courtesy of the Institute of Dermatology, London, UK.

Ulcerative lichen planus: the digits are often affected. This variant is associated with a slightly increased risk of squamous cell carcinoma. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

­immunodeficiency virus (HIV), combined with the well-recognized relationship to numerous drugs, adds support to this hypothesis.81–83 Lichen planus is associated with a variety of liver cell abnormalities including aberrant liver function tests and serology.84,85 An increased incidence of chronic active hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis has also been recorded.86–91 Not all documented series, however, have confirmed these observations, suggesting that the reported relationship may be dependent upon the background level of hepatitis B virus infection.89 Lichen planus has also followed hepatitis B vaccination.92–95 More recently, lichen planus (particularly oral disease) has been linked to hepatitis C virus and chronic liver disease. The incidence of hepatitis C virus in patients with lichen planus is, however, very variable, ranging from effectively zero in some populations, including the United Kingdom, India, and Slovenia, to as high as 100% in Japan.96–101 Evidence of other disorders including thyroid disease, dyslipidemia, and impaired carbohydrate metabolism including overt diabetes mellitus has also been documented in lichen planus, particularly the oral variant.102–110 A recent study from Japan suggests a possible association of hepatitis C infection with both diabetes and lichen planus.109 A significant association between lichen planus and human leukocyte antigen (HLA)-DR1 and HLA-DQ1 has been noted by a number of authors.111–117 This association pertains to patients with or without mucosal lesions but does not extend to patients with the drug-induced variant. It is suggested that this association relates to antigen presentation by HLA-DR1+ cells to T-helper cells with the resultant development of an autoimmune response.111 Although it is generally accepted that the pathogenesis of the basal cell damage in lichen planus primarily involves the cellular immune response, the precise mechanism(s) require further elucidation. It is unlikely that autoantibody and immune complex-mediated damage have a significant role in the lichenoid tissue reaction.79,80 The initial event in the evolution of the lichen planus papule is destruction of the basal epidermal layer (keratinocytes and melanocytes).118,119 In the earliest stage of development, increased numbers of Langerhans cells are present within the epidermis and it is believed that these cells process modified epidermal antigens for presentation to T lymphocytes.120 Keratinocytes express HLA-DR and this is likely to be of pathogenetic importance. Subsequent migration with resultant CD8+ T-cell activation results in basal keratinocyte death due to the combined effects of interferon-gamma (IFN-γ), interleukin (IL)-6, granulocyte-macrophage colony stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-α).81–83,121 The expression of FasR/FasL by the basal keratinocytes suggests that apoptosis is an important mode of cell death in lichen planus.122 The dermal infiltrate consists predominantly of Ia+, CD4+ lymphocytes.120,123 CD8+ lymphocytes are also present in close apposition to the dermoepidermal junction adjacent to foci of basal keratinocyte necrosis and are said to predominate in early lesions.121,123–125 B lymphocytes are scarce and plasma cells are characteristically absent in cutaneous lesions, except in the hypertrophic variant.

Lichenoid dermatoses Development of the typical papule appears to be due to a combination of continued keratinocyte destruction and regenerative activity, with the latter depending upon the migration of epithelium from the edge of the lesion and from adjacent eccrine ducts, rather than from increased mitotic activity. There is little uptake of tritiated thymidine at the site of basal cell damage, but conspicuous uptake at the edges of the lesion and, as a reflection of regeneration, keratin 17 expression is also up-regulated in the suprabasal epithelium.126 The typical features of lichen planus therefore depend upon a variable interplay between basal cell liquefactive degeneration and irregular epidermal regeneration. The earliest identifiable change in lichen planus is the presence of cytoid bodies and associated pigmentary incontinence. Cytoid bodies (colloid or Civatte bodies) are round or oval, homogeneous, eosinophilic bodies identifiable within the basal epithelium and the papillary dermis (Fig. 7.20). They display diastase-resistant periodic acid-Schiff (PAS) positivity, and may be identified within papules, perilesional skin, and even apparently uninvolved skin. Although they may be seen in a variety of dermatoses (including lupus erythematosus, graft-versus-host disease, and poikiloderma) and seemingly normal skin, where their presence, if either in large numbers or in a cluster, suggests lichen planus. Ultrastructurally, cytoid bodies are composed of tightly arranged aggregates of filaments 6–8 nm in diameter; immunocytochemically they are composed of keratin. Characteristic histological features of an established papule can usually be recognized at scanning magnification (Fig. 7.21). They comprise hyperkeratosis, typically wedge-shaped hypergranulosis (clinically presenting as Wickham's striae) related to the intraepidermal components of sweat ducts and hair follicles, and irregular acanthosis (Figs 7.22, 7.23). The acanthosis often has a saw-toothed appearance (Figs 7.24, 7.25). The presence of prominent parakeratosis argues strongly against a diagnosis of lichen planus. Lymphocytes and histiocytes may sometimes be seen in the epidermis and very occasionally satellite cell necrosis is a feature. Liquefactive degeneration of the basal layer of the epithelium is characteristic and often subepidermal clefts are present (Max Joseph spaces). Pigmentary incontinence is common (Fig. 7.26). A lymphohistiocytic bandlike infiltrate occupies the upper dermis and obscures the dermoepidermal junction. Hyperkeratosis persists in resolving lichen planus, but the acanthosis regresses, leaving a flattened epidermis (Fig. 7.27); there may be focal scarring and the dermal infiltrate is less conspicuous (Fig. 7.28). Lesions may become completely atrophic and histologically there is flattening of the epidermis, variable number of colloid bodies, and pigment incontinence with almost no inflammation. If colloid bodies are rare, distinction from poikiloderma may be very difficult.

Fig. 7.21 Lichen planus: this scanning view is characteristic and highlights the hyperkeratosis, hypergranulosis, and irregular acanthosis. Note the typical bandlike inflammatory cell infiltrate and pigment incontinence.

Fig. 7.22 Lichen planus: note the hyperkeratosis, hypergranulosis, and irregular acanthosis.

Fig. 7.20

Fig. 7.23

Lichen planus: this view shows characteristic eosinophilic cytoid bodies associated with basal cell liquefactive degeneration and a lymphohistiocytic infiltrate.

Lichen planus: the hypergranulosis is clearly related to the acrosyringium. There is marked basal cell liquefactive degeneration. Note the fibrin deposition.

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Fig. 7.24

Fig. 7.27

Lichen planus: the acanthosis is irregular and often has a saw-toothed appearance.

Atrophic (resolving) lichen planus: there is hyperkeratosis, epidermal flattening, and a slight residual lymphohistiocytic infiltrate.

Fig. 7.25 Lichen planus: close-up view of Figure 7.24 showing basal cell liquefactive degeneration and cytoid bodies.

Fig. 7.28 Atrophic (resolving) lichen planus: in addition to the lymphohistiocytic infiltrate, there are excessive numbers of fibroblasts and increased papillary dermal collagen.

Fig. 7.26 Lichen planus: melanin pigment is present within macrophages (pigmentary incontinence).

In lesions of annular lichen planus the typical histologic features are only seen in the periphery at the advancing edge of the lesion. In micropapular lichen planus the changes are so focal that the diagnosis may be missed if serial sections are not examined. Lichen planopilaris in its early stages shows an infiltrate surrounding the lower hair follicle and papilla, follicular dilatation, and keratin plugging (Fig. 7.29).52,54 The adjacent interfollicular epithelium may or may not show a typical lichenoid infiltrate (Fig. 7.30). Basal cell hydropic degeneration, cytoid body formation, and pigmentary incontinence are also sometimes evident. In advanced scalp lesions, the hair follicles are destroyed and replaced by vertically orientated fibrous scars, reminiscent of the fibrous streamers seen in pseudopélade of Brocq. Lichen planoporitis represents a rare variant in which lichenoid/interface changes are centered on the acrosyringium and eccrine sweat duct as it enters the epidermis. Squamous metaplasia of the ductal lining epithelium may be a feature.127 In lichen planus actinicus, the annular borders of the macules show typical features of lichen planus. In the center of the lesions, however, the epithelium is atrophic, thin, and flattened, although the lymphohistiocytic infiltrate

Lichenoid dermatoses

A

B

Fig. 7.29 Lichen planopilaris: (A, B) there is marked follicular dilatation and plugging accompanied by a bandlike folliculocentric infiltrate. This patient presented with scarring alopecia and typical lichen planus lesions elsewhere.

A

B

Fig. 7.30 Lichen planopilaris: (A, B) there is a strikingly folliculocentric bandlike infiltrate associated with keratin plugging. The interfollicular epidermis is unaffected.

remains. Foci of parakeratosis and eczematization within the follicular epithelium have also been described. Lichen nitidus-like lesions may sometimes be seen (see below). Lichen planus pigmentosus is characterized by epidermal thinning accompanied by basal cell vacuolization, pigmentary incontinence, and a superficial dermal lichenoid lymphohistiocytic infiltrate.4 Hypertrophic lichen planus is characterized by more marked hyperkeratosis and acanthosis, with the epithelium sometimes showing pseudoepitheliomatous hyperplasia such that misdiagnosis as squamous cell carcinoma is a distinct possibility, particularly if clinical information is not available (Figs 7.31–7.33).73 A number of changes not seen in ordinary lichen planus may be observed and include parakeratosis, spongiosis, necrotic keratinocytes above the basal cell layer, and eosinophils and plasma cells in the dermal infiltrate. These changes may raise the possibility of a lichenoid drug eruption. The differential diagnosis is not difficult, as lichenoid drug eruptions tend to be more generalized and are not usually associated with hypertrophic changes. The oral lesions of lichen planus, although often displaying the classical features, may show parakeratosis; occasionally, alternate foci of both are evident. In contrast to the cutaneous lesions, the epithelium is sometimes rather thin and the saw-toothed pattern indistinct. There is typically basal

Fig. 7.31 Hypertrophic lichen planus: note the hyperkeratosis, focal wedge-shaped hypergranulosis, very marked irregular acanthosis, and superficial dense bandlike infiltrate.

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Fig. 7.32

Fig. 7.34

Hypertrophic lichen planus: there is very marked irregular acanthosis. Note the hypergranulosis.

Bullous lichen planus: oral lesion showing separation of the squamous epithelium from the lamina propria. Note the bandlike infiltrate.

Fig. 7.35

Fig. 7.33 Hypertrophic lichen planus: there is basal cell liquefactive degeneration with cytoid bodies.

cell hydropic degeneration. Basement membrane thickening due to the deposition of fibrin-rich eosinophilic amorphous material is commonly present. The cellular infiltrate, in addition to lymphocytes and histiocytes, frequently contains plasma cells. Dysplasia may be seen. Unlike skin involvement, esophageal lesions show parakeratosis. Variable epithelial atrophy and/or mild thickening are usually seen and the saw-toothed pattern of acanthosis is not a feature.28,32–34 As with oral lesions, plasma cells often accompany the lymphocytic infiltrate. Vesicular or bullous lesions are subepidermal and occur due to excessive edema developing in association with the basement membrane zone damage complicating basal cell hydropic degeneration (Fig. 7.34).

Lichen planus: brilliant green fluorescence indicates the presence of fibrin. By courtesy of the Department of Immunofluorescence, Institute of Dermatology, London, UK.

Direct immunofluorescence studies on skin biopsies from patients with lichen planus usually reveal a linear fibrillar band of fibrin at the dermoepidermal junction (Fig. 7.35). The cytoid bodies may be highlighted non­specifically by the use of antisera, mainly to IgM, but also to IgG, IgA and C3 (Fig. 7.36). A lichen planus ‘specific antigen’, which is present in the prickle cell and granular cell layers, has been demonstrated by indirect immunofluorescence of patients' serum with fetal skin.128 Whether this is of pathogenetic significance is unknown. Direct immunofluorescence of lichen planopilaris reveals follicular, linear basement membrane zone labeling with immunoglobulin (primarily IgG or IgA).129 Fibrin may also be present. The nosological implications of this observation are uncertain. Indirect immunofluorescence for circulating antibasement membrane zone antibodies is negative.

Lichenoid dermatoses i­nterferon-alpha therapy.8,9 Occasionally, papules may be encountered on the palms and soles.3–12 Familial cases have been rarely described.13,14 Lichen nitidus can spontaneously resolve within a few months or persist indefinitely.2 Mucous membrane involvement presenting as grayish-yellow papules has also been described.4 Nail involvement, which is extremely rare, presents as thickening with ridges, rippling, terminal splitting, striations, and pits.2,4 Keratodermic, vesicular, hemorrhagic, purpuric, and perforating variants may rarely be encountered.2,15–19 Perforating lichen nitidus shows a predilection for the forearms and fingers and may be trauma related.17,20 Actinic lichen nitidus refers to the development of lichen nitidus on sunexposed sites, usually during the summer months. In some cases, involvement is predominantly facial and it may present in black patients.21 It shows considerable overlap with actinic lichen planus (see above).22,23

Fig. 7.36 Lichen planus: cytoid bodies labeled positively for IgM. By courtesy of the Department of Immunofluorescence, Institute of Dermatology, London, UK.

Differential diagnosis Lichen planus should be differentiated from other diseases showing a lichenoid infiltrate and hydropic degeneration of the basal layer of the epithelium.130 Thus lichen planus may be indistinguishable from lichenoid keratosis and their distinction is entirely dependent on clinicopathological correlation. In many cases of lichenoid keratoses, there are other associated changes including focal spongiosis and parakeratosis. Atrophic lesions may be confused with poikiloderma and chronic discoid lupus erythematosus. A lichen planus-like morphology is typical of the early stages of chronic graftversus-host disease (GVHD). Poikiloderma shows epidermal atrophy, with loss of the ridge pattern and no tendency to a saw-toothed appearance. In those examples associated with mycosis fungoides, the lichenoid infiltrate contains variable numbers of atypical lymphocytes and mycosis fungoides cells. Chronic discoid lupus erythematosus is associated with epidermal atrophy and follicular plugging. The inflammatory cell infiltrate is patchy with a tendency to periappendageal location. A positive lupus band test is a helpful discriminator. Lichen planus may easily be mistaken for a lichenoid drug reaction, particularly in the absence of clinical information. Histological features favoring the latter include high-level cytoid bodies and eosinophils within the dermal infiltrate.

Fig. 7.37 Lichen nitidus: numerous tiny papules are present on the chest of a young child. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Lichen nitidus Clinical features Lichen nitidus is a rare but distinctive dermatosis, which shows an equal sex incidence.1 Children and young adults are predominantly affected. It presents clinically as an eruption of pinhead-sized, flesh-colored, shiny, flat-topped or dome-shaped papules and shows a predilection for the arms, chest, abdomen, and genitalia (Figs 7.37, 7.38).1–5 A positive Koebner's phenomenon is typically present.5 The condition is usually localized and asymptomatic, although occasionally there may be mild or even intense pruritus.2 Rarely, generalized lesions have been described.2,6,7 An association with generalized lesions and Down's syndrome has been documented, as has been a case after

Fig. 7.38 Lichen nitidus: numerous tiny papules are present on the penis. The genitalia are commonly affected. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

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Histological features Lichen nitidus is recognizable by a characteristic histology in many cases. The classic papule is sharply circumscribed and occupies the space of only four or five dermal papillae. It is often depressed in the center and composed of atrophic epidermis, frequently covered by a parakeratotic tier and overlying a cellular infiltrate (Figs 7.39–7.42). Clawlike extensions of epidermal ridges mark the lateral boundaries of the lesion. The epithelium shows basal cell hydropic degeneration, and cytoid bodies may be a feature. The inflammatory component consists of lymphocytes, histiocytes, and variable numbers of epithelioid cells. Giant cells are sometimes a feature and true granulomata may occasionally be found, although caseation is never present.24 In addition to red blood cell extravasation, purpuric variants may show increased vascularity with vessel wall thickening and hyalinization.18 In rare cases, a prominent lymphocytic inflammatory infiltrate can extend down the hair follicle and eccrine glands, making the distinction from lichen striatus challenging.24 A follicular variant of lichen nitidus may be seen and mimics lichen spinulosus histologically.25 However, rarely, lichen nitidus and lichen spinulosus may coexist clinically.26 Fig. 7.41 Lichen nitidus: the infiltrate consists of lymphocytes, histiocytes, and epithelioid cells. Ill-defined noncaseating granulomata are not uncommon.

Fig. 7.39 Lichen nitidus: scanning view showing a typical small, circumscribed lesion occupying only a couple of dermal papillae. Note the clawlike epidermal lateral borders.

Fig. 7.42 Lichen nitidus: there are multiple lesions of lichen nitidus with an associated granulomatous component. The patient also had typical lichen planus lesions. By courtesy of R. Margolis, MD, St Elizabeth's Hospital, Boston, USA.

Palmar lesions may be identical to those seen elsewhere or show a more diffuse bandlike upper dermal lymphohistiocytic infiltrate with associated giant cells and focal parakeratosis.3,10–12,27 Fibrin can be detected at the basement membrane zone by immunofluorescent techniques, but immunoglobulin deposition is not a feature.28,29 Immunophenotypic studies show that there is a marked excess of CD4+ cells (helper/inducer T cells) over CD8+ cells (cytotoxic/suppressor T cells).28 Langerhans cells are conspicuous.30 These findings are similar to those described for lichen planus. Ultrastructural examination reveals rather non-specific findings including epidermal intercellular edema, subepidermal edema, colloid bodies, decreased numbers of desmosomes, and disruption or reduplication of the lamina densa.31–33 Perivascular electron-dense deposits (the nature of which is unknown) have been described in purpuric variants.8

Comment Fig. 7.40 Lichen nitidus: note the parakeratosis and bandlike infiltrate.

Lichen nitidus may coexist with lichen planus or predate it and lichen nitidus-like lesions may be found in patients with typical lichen planus, but it is unlikely that the conditions are closely related.34,35 Wickham's striae are not

Lichenoid dermatoses a feature of lichen nitidus and mucosal involvement is exceptional.2,4 Lichen nitidus is associated with parakeratosis and epidermal atrophy, in contrast to the orthohyperkeratosis and acanthosis seen in lichen planus. The sawtoothed appearance of the lower border of the epidermis seen in lichen planus is not a feature of lichen nitidus and immunofluorescence for immunogloblins is negative. Epithelioid cells and giant cells are characteristic of lichen nitidus and are not typically a feature of lichen planus. Three patients with Crohn's disease were reported to develop lichen niditus; however it remains to be seen if lichen nitidus is truly an extragastrointestinal finding of this disease.36 Another patient developed lichen nitidus after hepatitis B vaccine injection.37 The significance of this is uncertain.

Lichenoid keratosis Clinical features Lichenoid keratosis (benign lichenoid keratosis, lichen planus-like keratosis, solitary lichen planus) is not uncommon and usually presents as a solitary, 0.3–2-cm diameter, sharply demarcated, erythematous, violaceous, tan or brown papule or plaque (Fig. 7.43).1,2 Occasionally, multiple lesions may be present.2,3 It is usually of short duration and shows a predilection for the face (particularly the cheeks and nose), neck, upper trunk (especially the presternal area), forearm, and dorsum of the hand.2,4–8 The surface is often scaly. Lesions are commonly asymptomatic, but mild pruritus has sometimes been documented.8 Patients are frequently Caucasian, but occasionally blacks are affected.2,7,8 Females develop these lesions more commonly than males, usually in their fourth to seventh decades.2,5 Lichenoid keratosis is often clinically misdiagnosed as a seborrheic ­keratosis, superficial basal cell carcinoma, squamous cell carcinoma, actinic keratosis or Bowen's disease.5

expression, suggesting the absence of localized antigenic stimulation as seen in lichen planus.2,12 These studies suggest that lichenoid keratosis is an entity distinct from lichen planus despite the similarities in histology. Despite this, histologically, as its name suggests, the features are similar to those of lichen planus. Thus there is hyperkeratosis, wedge-shaped hypergranulosis, variable acanthosis, and basal cell liquefactive degeneration sometimes accompanied by lymphocytic exocytosis (Figs. 7.44, 7.45).2,3,5 Foci of parakeratosis are also frequently seen.1,2 Although the saw-toothed acanthosis of lichen planus is sometimes evident, more often the epithelium merely shows broadened, widened, and irregular epidermal ridges.4 The basal epidermal layers may sometimes show very minor degrees of cytological atypia, including cellular and nuclear enlargement with conspicuous nucleoli, but these changes represent regenerative phenomena.3 Dysplasia as seen in lichenoid actinic keratosis is not a feature of a lichenoid keratosis. Colloid bodies are usually conspicuous in both the epidermis and dermis and pigmentary incontinence is often marked (Figs 7.46–7.48).1,2,7 Apoptotic keratinocytes can be prominent and may be associated with inatraepidermal blister formation with subepidermal vesiculation. Epidermal pallor and dermal edema can be seen in cases with only slight or no acanthosis and an interface population of lymphocytes along the junction with vacuolar degeneration. Foci of atrophy can be occasionally encountered.2 In some cases a combination of lichenoid and spongiotic changes may be seen.

Pathogenesis and histological features The precise nature of lichenoid keratosis is uncertain. In the past, it was regarded as a solitary lesion of lichen planus or thought to have an actinic pathogenesis.9–11 It was also proposed to represent an immunological or regressive response to a pre-existent epidermal lesion similar to the phenomenon encountered with a ‘halo’ nevus.2 The frequent association of solar lentigines or, less commonly, seborrheic keratoses in the adjacent epithelium has been cited as evidence in favor of this hypothesis.4–6,8 Recent studies have shown that the lymphocytic infiltrate in lichenoid keratosis to be immunophenotypically distinct from lichen planus. The lymphocytes in lichenoid keratosis are predominantly CD8-reactive in contrast to lichen planus. More CD20-positive B cells are usually seen in lichenoid keratosis. Furthermore, the lymphocyte infiltrate in lichenoid keratosis lacks the cutaneous ­lymphocyte antigen (CLA)

Fig. 7.44 Lichenoid keratosis: scanning view showing hyperkeratosis, hypergranulosis, irregular acanthosis, and a bandlike chronic inflammatory infiltrate.

Fig. 7.43

Fig. 7.45

Lichenoid keratosis: there is scaling overlying a slightly raised erythematous plaque. By courtesy of the Institute of Dermatology, London.

Lichenoid keratosis: in this field there is basal cell liquefactive degeneration. Cytoid bodies are present.

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Lichenoid and interface dermatitis A dense chronic inflammatory cell infiltrate is typically present in the superficial dermis. Although this characteristically has a lichenoid distribution, on some occasions it may be more discrete and predominantly perivascular in location.4,7 The infiltrate consists largely of lymphocytes and histiocytes, but small numbers of plasma cells and eosinophils are occasionally present. Exceptionally, a few atypical lymphocytes (enlarged with hyperchromatic, irregular, contoured nuclei) which are CD30 and CD3 reactive can be also seen.2 The adjacent dermis sometimes shows lentigo and solar elastosis, which is usually mild if present. Features suggestive of mycoses fungoides such as Pautrier abscesses, dermal–epidermal tagging and mild lymphocytic atypia have been rarely noted in benign lichenoid keratosis.13 Clinicopathological correlation and careful follow-up are essential in such cases to avoid misdiagnosis. Immunofluorescence findings, which are similar to those of lichen planus, comprise deposits of IgM and, less commonly, IgG outlining cytoid bodies.5

Differential diagnosis Many conditions show lichenoid histology and therefore come into the differential diagnosis. Most prominently, these include lichen planus and lichenoid drug reactions. If clinical information is available, differentiation from lichen planus should present little difficulty. Lichen planus is characterized by large numbers of lesions in contradistinction to the single papule or plaque of lichenoid

Fig. 7.48 Lichenoid keratosis: basal cell liquefactive degeneration is evident in addition to cytoid bodies. Note the parakeratosis.

keratosis. In addition, lichen planus is usually itchy. Parakeratosis and dermal plasma cells with eosinophils are not a feature of lichen planus, but are typical of lichenoid keratosis.7 Both actinic keratoses and squamous cell carcinoma in situ may sometimes show a lichenoid inflammatory cell reaction. Dysplasia by definition is not a feature of lichenoid keratosis.1,2 Inflamed seborrheic keratosis and porokeratosis can have a prominent lichenoid reaction. The absence of horn cyst formation, squamous epidermal eddies, and laminated stratum corneum keratin helps distinguish these lesions from seborrheic keratosis, while the absence of cornoid lamella excludes porokeratosis. Melanocytic lesions with halo phenomenon can become a diagnostic consideration and require examination of the dermis and dermoepidermal junction for melanocytic nests. In difficult cases, additional step sections or S-100 protein immunohistochemical study can prove useful. Finally, the presence of scattered CD30-positive lymphocytes in some cases of lichenoid keratosis may raise the histological differential diagnosis of lymphomatoid papulosis. However, the paucity of these enlarged CD30-positive cells, the absence of a deep infiltrate, and the clinically history of a solitary lesion is reassuring for lichenoid keratosis.2 Fig. 7.46 Lichenoid keratosis: in this early lesion, there is more uniform acanthosis.

Lichen striatus Clinical features

Fig. 7.47 Lichenoid keratosis: there is interface change with cytoid bodies.

Lichen striatus (Blaschko linear acquired inflammatory skin eruption (BLAISE)) is an uncommon, usually asymptomatic, dermatosis of unknown etiology, affecting the limbs or neck in which lesions typically follow Blaschko's lines.1–8 Infrequently, the condition is pruritic.6–9 It is self-limiting, normally disappearing within months to a year of onset. It shows a female predominance (2–3:1) and, although it may occur at any age, it most often presents in children aged 5–15 years.2,5,7,8 Rarely, lichen striatus has been described in adults (adult Blaschkitis, see below).4,10,11 Occurrence during pregnancy is very rare.12 A family history is rarely encountered, suggesting a genetic predisposition and/or a common environmental etiology in such cases.2,6,8,13,14 It is associated with seasonal variation with most series reporting the majority of patients presenting in spring and summer,2,7 with the exception of one large series where the majority of patients presented in the winter 8,13 Case clustering has been documented.2 Lesions, usually solitary and unilateral, present as erythematous or fleshcolored lichenoid or sometimes psoriasiform scaly papules, which coalesce into a continuous or interrupted linear or curved band, 1–3 cm wide and often covering the whole length of a limb, either lower or upper extremities (Figs 7.49, 7.50).2,8 Occasionally, multiple lesions have been recorded, as has bilaterality.8,15,16 Presentation at two different sites and at multiple

Lichenoid dermatoses sites may exceptionally occur.17 Nail changes, which may affect a single nail, include onycholysis, longitudinal ridging, splitting, and nail loss.8,1,18,19 An exceptional case of lichen striatus with bilateral nail dystrophy has been described.20 Lichen striatus is not associated with Koebner's phenomenon. Hypo- or hyperpigmentation sometimes follows resolution, which may be marked in people with pigmented skin.8 Lichen striatus is associated with atopy in up to 60% of patients.1,6–8

Pathogenesis and histological features The etiology of this condition is unknown although case clustering and seasonality raises the possibility of an environmental or infective basis in conjunction with an abnormal host response.2,21 The development of lesions along Blaschko's lines also raises the possibility of a cell-mediated autoimmune reaction to an abnormal clone of cells. Blaschko's lines are believed to represent the direction along which epidermal growth centers expand during early skin development.1 It has been suggested that the distribution of lesions in lichen striatus may reflect a postzygotic abnormality such as somatic mutation affecting localized stem cells.1 An intriguing case following trauma in an adult has been reported.22 Further exceptional cases associated with solarium use, varicella infection, and hepatitis B vaccine have been described.23–25 The histological features of lichen striatus may be non-specific and show changes of mild chronic non-specific dermatitis.26 In an established lesion, however, the changes often consist of an admixture of spongiotic dermatitis with lichenoid and interface features (Fig. 7.51).27 Thus, there is often parakeratosis with a normal or slightly acanthotic epidermis accompanied by intercellular edema, lymphocytic exocytosis, and keratinocyte necrosis (Figs 7.52–7.54). Satellite cell necrosis may sometimes be a feature and transepidermal elimination of keratinocyte debris (perforating lichen striatus) has occasionally been documented.4,28 Intraepidermal Langerhans cell vesicles have exceptionally been described.27 A heavy lymphohistiocytic infiltrate is present in the superficial dermis and also surrounds the vessels of the superficial and deep vascular plexuses and sometimes also the cutaneous adnexae.4,27 Eosinophils and plasma cells are uncommon.27

Fig. 7.50 Lichen striatus: the arms are sometimes affected. The condition most often presents in children. By courtesy of the Institute of Dermatology, London, UK.

Some biopsies may be indistinguishable from lichen planus. In those cases where there is follicular involvement, the features can resemble those of lichen planopilaris, and old lesions sometimes simulate lichen nitidus. By immunohistochemistry, the majority of the intraepidermal lymphocytes are of a CD8+ cytotoxic phenotype.4,27 The dermal lymphocytes consist of an admixture of CD4+ and CD8+ subtypes. CD7 is typically conserved.25 Intraepidermal Langerhans cells may be normal, increased or decreased.27 Nail changes include slight spongiosis with exocytosis, focal hypergranulosis, dyskeratosis, and a bandlike lymphohistiocytic infiltrate affecting the proximal nail fold, nail bed, and nail matrix dermis.18

Adult Blaschkitis Clinical features

Fig. 7.49 Lichen striatus: a linear band of scaly hyperpigmented papules is present on the inner aspect of the leg, a commonly affected site. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Adult Blaschkitis (acquired relapsing self-healing Blaschko dermatitis) is a rare, relapsing linear eruption with a mean age of onset of 40 years, predominantly affecting males.1–14 Lesions, which are pruritic papules and vesicles, affect multiple sites, particularly the trunk, following Blaschko's lines and typically resolve in days or weeks.1 The condition, which may be unilateral or more commonly bilateral, recurs over the ensuing months or years.

Pathogenesis and histological features The etiology is unknown. Abnormalities in chromosome 18 in cells from involved skin in comparison to normal-appearing skin has been described in a female patient with adult Blaschkitis, supporting a link with cutaneous genetic mosaicism.13 Association with a drug has been cited in one case and emotional stress has been reported to precede relapses.11,12

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Fig. 7.51

Fig. 7.53

Lichen striatus: scanning view showing hyperkeratosis, focal parakeratosis, and irregular acanthosis. A heavy inflammatory cell infiltrate is present in the upper dermis. There is conspicuous pigmentary incontinence. Case courtesy of S. Lyle, MD, Beth Israel Deaconess Medical Center, Boston, USA.

Lichen striatus: there is spongiosis and marked lymphocytic exocytosis. Case courtesy of S. Lyle, MD, Beth Israel Deaconess Medical Center, Boston, USA.

Fig. 7.54

Fig. 7.52

Lichen striatus: note the spongiosis, basal cell liquefactive degeneration, and pigmentary incontinence. Case courtesy of S. Lyle, MD, Beth Israel Deaconess Medical Center, Boston, USA.

Lichen striatus: in this field, there is parakeratosis, hyperkeratosis, spongiosis, and interface change. Note the pigment incontinence and intense chronic inflammatory cell infiltrate. Case courtesy of S. Lyle, MD, Beth Israel Deaconess Medical Center, Boston, USA.

Histologically, adult Blaschkitis is characterized by spongiotic changes; lichenoid features are absent and no deep involvement of adnexal structures is seen.6,8 A rare case with interface changes has been reported.10

Differential diagnosis It resembles lichen striatus and it has been suggested that there is no justification for separating the two entities.15 However, it differs clinically by the presence of vesicles, its truncal distribution, and relatively rapid resolution. Relapsing courses are typical. Pruritus is rare in lichen striatus. Lichen striatus predominantly affects young children although rare cases similar to adult Blaschkitis but affecting children have been described.

Keratosis lichenoides chronica Clinical features Keratosis lichenoides chronica (Nekam's disease, lichen ruber verrucosus et reticularis) is a very rare, chronic inflammatory dermatosis that combines the features of a seborrheic dermatitis-like eruption of the scalp and face with a progressive lichenoid papulonodular dermatosis affecting the trunk, buttocks, and limbs.1–6 Patients usually present in the third to fifth decades although exceptionally reports of pediatric involvement have been documented, some with possible familial association.7–9 It is usually persistent and

Lichenoid dermatoses typically does not respond to treatment although improvement in the summer may sometimes be seen.5 Facial and scalp lesions are erythematous, greasy and scaly, and bear no resemblance to those found on the trunk and extremities, which are erythematous or violaceous lichenoid scaly papules in a confluent, reticulate, or linear distribution. The latter may suggest Koebner's phenomenon (Figs 7.55, 7.56). Papulonodular and infiltrated plaques are sometimes also present. Lesions are typically bilateral, symmetrical, and usually asymptomatic although rarely pruritus may be intense. Scarring is not a feature. Associated features include oral papules and ulceration, ocular lesions (blepharitis, conjunctivitis, anterior uveitis, and iridocyclitis), laryngeal nodules, palmoplantar keratoderma, and nail changes including yellow discoloration and dystrophy (longitudinal ridging, nail plate thickening, onycholysis, and paronychia) (Fig. 7.57).1,10–14 Genital involvement including penile and scrotal papules, chronic balanitis, and phimosis has been documented.6,10,11 Keratosis lichenoides chronica has been described in association with a number of systemic diseases including chronic infections (toxoplasmosis, tuberculosis, and viral hepatitis), kidney disease, and lymphoma.3,15–17

Pathogenesis and histological features Although the precise nature of keratosis lichenoides chronica is uncertain, some authors regard it as a variant of hypertrophic lichen planus.10,18 Histologically, the lichenoid eruption is characterized by hyperkeratosis and parakeratosis, variable acanthosis, and epidermal atrophy associated with a bandlike lymphohistiocytic infiltrate in the superficial dermis, often with conspicuous melanophages.11 Neutrophils may be prominent in the stratum corneum. Perifollicular/acrosyringotropic and perivascular chronic inflammation may also be evident. Epidermal basal keratinocytes show hydropic degeneration, and cytoid body formation has been described.11,18 Many necrotic keratinocytes are present.1 Exceptionally, amyloid deposition has been documented.19 The dermal infiltrate consists of lymphocytes, histiocytes, and variable plasma cells and eosinophils.11 Direct immunofluorescence highlights the cytoid bodies.18 The scalp and facial lesions show the features of a chronic dermatitis, namely spongiosis with exocytosis and patchy parakeratosis. A perivascular chronic inflammatory cell infiltrate of lymphocytes, histiocytes, and plasma cells may be present in the upper dermis.5

Fig. 7.56 Keratosis lichenoides chronica: close-up view of solitary lichenoid papules and a confluent plaque. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 7.55 Keratosis lichenoides chronica: there are erythematous hyperkeratotic lichenoid lesions in a linear and reticular distribution. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 7.57 Keratosis lichenoides chronica: plantar involvement showing disfiguring exophytic, hyperkeratotic verrucous plaques. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

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Erythema dyschromicum perstans Clinical features Erythema dyschromicum perstans (dermatosis cenicienta, ashy dermatosis) is an acquired, usually asymptomatic, disfiguring dermatosis which occurs particularly in Latin American (especially Mexican) populations and in Asians.1–7 It was originally named dermatosis cenicienta after the clinical appearance of affected patients – los cenicientos (the ash-colored ones).1 However, whiteskinned races may rarely be affected.8 It is of unknown etiology, shows a female predilection, and can develop at any age although the majority of patients are in their first three decades.2,9 Presentation in infancy has been documented.10 Patients develop oval, irregular or polycyclic, gray macules with erythematous, indurated, inflammatory borders of 1–2 mm. The lesions extend peripherally, show a tendency to coalesce, and often affect large areas of the integument (Figs 7.58–7.60). With progression, the eruption develops a grayblue color and loses the erythematous border, which is sometimes replaced by a hypopigmented periphery. It is usually symmetrical, and particularly affects the trunk, proximal extremities and, to a lesser extent, the face and neck.2 The palms and soles, scalp, nails, and mucous membranes do not appear to be involved.6

Fig. 7.58 Erythema dyschromicum perstans: this patient shows irregularly distributed gray macules. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Pathogenesis and histological features The etiology is unknown. Cases have followed HIV infection and there is a report of simultaneous development of vitiligo and erythema dyschromicum perstans. The significance of these observations is doubtful.11,12 Increased susceptibility with HLA-DRB1*0407 in Mexican patients has been reported.13 Sections from the inflammatory border show hyperkeratosis and an epidermis of normal thickness or somewhat atrophic, accompanied by basal cell hydropic degeneration and cytoid body formation (Fig. 7.61). Pigmentary incontinence is marked and a mild perivascular or lichenoid inflammatory cell infiltrate is present in the superficial dermis (Fig. 7.62). Sections from the central gray area show epidermal atrophy, follicular hyperkeratosis, and pigmentary incontinence. The dermal inflammatory infiltrate is composed of both CD4 and CD8 T cells, usually with CD8 forms slightly predominating.14 Direct immunofluorescence reveals non-specific staining of the cytoid bodies with IgG, IgM, and C3.15–17 Fibrinogen may be present at the dermoepidermal junction.16 The immunocytochemical studies are therefore similar to lichen planus. The epidermal keratinocytes express Ia antigen and the ­lymphocytic population comprises both helper/inducer and suppressor/cytotoxic phenotypes similar to lichen planus.17,18 Ultrastructural findings are non-specific, comprising intra- and interepidermal edema with cytoplasmic vacuolation, separation of keratinocytes, retraction of desmosomes, cytoid body formation, focal gaps in the keratinocyte basal lamina, and pigment-laden histiocytes in the papillary dermis.16,19,20

Differential diagnosis The precise relationship of erythema dyschromicum perstans to lichen planus is uncertain. The histological, immunological, and ultrastructural findings certainly suggest that they are closely related.15,16 Typical lichen planus may precede the development of erythema dyschromicum perstans and sometimes the two conditions have presented simultaneously, although some of the documented cases may have represented lichen planus pigmentosus.21,22

Lichenoid and granulomatous dermatitis Clinical features These lesions were described in 2000 by Magro and Crowson to have features of both lichenoid and granulomatous dermatitis.1 There is a slight female predominance (21:15) affecting a broad range of ages (5–86 years old).

Fig. 7.59 Erythema dyschromicum perstans: in this patient there is extensive involvement of the face, neck, and trunk. By courtesy of J. Tschen, MD, Baylor College of Medicine, Houston, USA.

The extremities and trunk are most often involved, followed by the head and neck region. Clinically, the lesions present as lichenoid papules

Pathogenesis and histology Various etiologic agents included drug, coexisting medical illnesses, and infections have been implicated. Similar to any lichenoid disorder, there is a

Interface dermatoses

Fig. 7.60 Erythema dyschromicum perstans: in this patient with more advanced disease, there is a generalized bluish discoloration. By courtesy of the Institute of Dermatology, London, UK.

Fig. 7.62 Erythema dyschromicum perstans: note the hydropic degeneration, cytoid body, and pigment incontinence.

Interface dermatoses Definitions

Fig. 7.61 Erythema dyschromicum perstans: there is hyperkeratosis and marked pigmentary incontinence.

bandlike infiltrate of lymphocytes and histiocytes. The histiocytes are variably described as loosely aggregated and superficially located, cohesive granulomata, diffuse interstitial granulomatous inflammation, scattered solitary giant cells, and granulomatous vasculitis.1 Cases associated with drugs also may display parakeratosis, keratinocyte necrosis, acrosyrinogeal accentuation, red cell extravasation, granulomatous vasculitis, eosinophils, and plasmacellular infiltrate sparing the deep dermis.1,2 Lymphocyte atypia may also be a feature in examples associated with cutaneous lymphoma or lymphomatous drug reactions.1

There is such considerable variation in the literature as to the exact definitions and interrelationships between erythema multiforme (particularly the ‘major’ variant), Stevens-Johnson syndrome, and toxic epidermal necrolysis that it is often difficult or impossible to be certain to which disease the authors are actually referring!1–5 The consensus paper published in 1993 by Bastuji-Garin is used as a basis for classification since the authorship included most of the major players at that time in this difficult subject.1 Classification of an individual patient depends upon the precise morphology and pattern of individual lesions and the extent of skin involvement (detached and detachable epidermis) as a percentage of total body surface area at the worst stage of the illness. • Target lesions are defined as sharply demarcated and round, less than 3.0 cm in diameter and comprising three distinct zones, namely a central erythematous or purpuric disc with or without a blister, surrounded by a raised edematous ring, in turn bordered by an erythematous rim (Fig. 7.63).1 Target lesions are typically distributed in an acral location, are often seen following a herpetic infection, and are characteristic of erythema multiforme. Typical target lesions are not seen in patients with widespread epidermal detachment. • Raised atypical target lesions are ill-defined, round, palpable lesions with only two zones including a central raised edematous area with an erythematous border. • Flat, atypical target lesions are ill-defined, round lesions with only two nonpalpable zones. The center may be blistered (Fig. 7.64). • Macules with or without blisters are defined as nonpalpable, erythematous or purpuric macules with irregular shape and size and often confluent. Blisters often occur on all or part of the macule. This lesion is characteristically seen in patients with widespread epidermal detachment who have a history of drug ingestion. Working on this basis, the following definitions have been proposed:1 • Bullous erythema multiforme is characterized by  60% of cases) arise in elderly women against a background of a chronic scarring dermatosis, usually lichen sclerosus but less often lichen planus. In these patients, the tumors develop directly within the background dermatosis and may be preceded by differentiated VIN. They are not usually associated with HPV.4–11 Squamous cell carcinoma arising in the background of differentiated VIN appears to have a higher tendency for local recurrence.12 • The second group consists of younger women with a background of undifferentiated VIN (usual type) which is associated with HPV16 and -18, smoking and a previous or current history of squamous intraepithelial lesion (SIL/CIN). HPV-16 is the most common type of HPV found in association with vulval squamous cell carcinoma.13 Interestingly, a recent study of human papillomavirus genotypes in invasive vulval squamous cell carcinoma found HPV in 70% of cases (mainly HPV-16) and the average age of the patients was 65. Patients with no evidence of HPV were older than those with proven HPV but these differences were not statistically significant.14 In addition, much more rarely, vulval carcinoma has been described in association with chronic granulomatous disease, hidradenitis ­suppurativa, Fanconi’s anemia, and the genodermatosis Netherton’s syndrome.15–19 A tumor in a young woman with Cohn’s disease and one developing within a localized vulvar lesion of Hailey-Hailey disease after tacrolimus therapy have been documented.20,21 Patients with the warty and basaloid histological subtypes of vulval SCC tend to be younger than those with conventional keratinizing SCC and in one series there seems to be a predominance of black patients with this histological subtype.22 The majority of vulval SCCs develop on the inner aspect of the labia majora and periclitorally.23 Patients present with a mass that is sometimes associated with pruritus, ulceration, bleeding, discharge or pain (Fig. 12.186). Multifocal tumors are very rare.24 Vulval SCC usually spreads via lymphatics to inguinal, femoral and pelvic lymph nodes. Midline tumors are often associated with bilateral lymph node spread.25 The overall 5-year survival for patients with vulval SCC depends on the depth of stromal invasion and the presence or absence of lymph node metastasis.26–32 A study has found that patients with stromal invasion of more than 9 mm had higher risk of local recurrence.33 In the absence of lymph node spread, the 5-year survival is up to 90% but this rate falls to less than 70% in patients with inguinal lymph node metastasis and to less than 25% in those with pelvic lymph node spread.27 The presence or absence of lymph node metastasis is the single most important factor determining prognosis.34 Other factors that have been found to be independently associated with prognosis include older age, advanced stage, size of the tumor, positive margins and degree of differentiation. It has been suggested that HPV-positive tumors have a worse prognosis than those that are HPV negative.35,36 Warty and basaloid SCCs of the vulva are often associated with HPV infection and there is some suggestion that the prognosis of the basaloid subtype may be worse than that of conventional SCC (see below).6,22 Warty squamous cell carcinoma of the vulva is more often associated with high risk HPV other than HPV-16.14

Genital intraepithelial neoplasia and squamous carcinoma

Fig. 12.188 Verrucous carcinoma: this tumor arose in the gluteal cleft of an elderly female. Note the characteristic sharply demarcated lower border.

Fig. 12.186 Vulval squamous cell carcinoma: this tumor arose against a background of long-standing carcinoma in situ (Bowen’s disease). By courtesy of the Institute of Dermatology, London, UK.

Tumors with less than 1-mm stromal invasion do not require lymph node dissection and the appropriate surgery is curative.

Verrucous carcinoma Clinical features Verrucous carcinoma is a low-grade, slow-growing squamous cell carcinoma (SCC) first described in 1948.1 The precise incidence of verrucous carcinoma is difficult to assess accurately because of the confusing number of different terms that have been applied to this tumor in the past. There has been some debate as to whether verrucous carcinoma, well-differentiated epidermoid SCC, epithelium cuniculatum and giant condyloma of Buschke-Löwenstein are all one and the same or separate entities. It is now generally accepted that they are identical lesions.2,3 The tumor presents as a warty exophytic plaque and usually occurs at three anatomical sites: the oropharynx, sole of the foot and the anogenital skin (Figs 12.187, 12.188).2,4–6 Verrucous carcinoma of the vulva may arise on a background of lichen sclerosus or lichen planus.7–9 Oral and lower limb neoplasms may be associated with various types of HPV.10–13 Similarly, genital

verrucous carcinoma may be associated with human papillomavirus albeit in a minority of cases.14 The benign histological appearances of this tumor often lead to an incorrect histological report of condyloma or squamous papilloma, with resulting undertreatment. Vulval verrucous carcinoma can coexist with ordinary squamous cell carcinoma.15 A case of vulval verrucous carcinoma in an HIV-positive patient has been documented.16

Histological features Verrucous carcinoma is characterized by an exophytic and endophytic growth pattern.17,18 The latter, which may extend deeply into subcutaneous tissues or beyond, has a bulbous and sharply delineated lower border, lacking the infiltrative characteristics of conventional SCC (Figs  12.189–12.191). The epithelium is well differentiated, showing no appreciable cytological atypia; mitoses, which are generally sparse, are confined to the lower layer. Intraepithelial neutrophil abscesses are commonly present. In some tumors, koilocytes may be seen, supporting an HPV-associated etiology. One study describes a distinctive triad of marked epithelial acanthosis, loss of the granular cell layer with superficial epithelial cell pallor, and multilayered parakeratosis.19 It has been suggested that this could be a precursor to verrucous carcinoma and is designated vulvar acanthosis with altered differentiation.

Fig. 12.189

Fig. 12.187 Verrucous carcinoma: note the keratotic warty tumor mass. By courtesy of the Institute of Dermatology, London, UK.

Verrucous carcinoma: low-power view showing the characteristic growth pattern comprising deeply penetrating, blunt, fingerlike processes.

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• squamous intraepithelial lesion of low and high grade, • dysplasia, • penile intrepithelial neoplasia grade 3.

Fig. 12.190 Verrucous carcinoma: the epithelium is uniformly well differentiated and often displays a groundglass cytoplasmic pallor.

Taking into account similarities in morphology and pathogenesis between vulval and penile carcinoma, we have recently proposed a new ­nomenclature for penile preinvasive lesions.7,8 In this section, we present a simplified ­version taking into account the etiopathogenetic correlation of precursor HPV and non-HPV-related lesions with their invasive counterparts.9 The term penile intraepithelial neoplasia (PeIN) is preferred over older terminology.10–13 PeIN is classified into differentiated (non-HPV-related), undifferentiated ­(HPV-related) and mixed differentiated–undifferentiated categories. Undifferentiated PeIN may be further subclassified into warty, basaloid, mixed warty/basaloid and other variants. PeIN may be solitary or ­multifocal, and may or may not be associated with infiltrative SCC. PeIN unassociated with invasive cancer occurs in younger patients and tends to be of the undifferentiated type, positive for HPV. Patients with HPV may also develop warty or basaloid PeIN. Conversely, when PeIN is associated with invasive SCC, the predominant histological subtype is the differentiated variant, presenting in 65% of the cases and usually negative for HPV. The explanation for this apparent paradox may be the clinical and pathological underrecognition or underdiagnosis of differentitated PeIN. Differentiated PeIN tends to affect the foreskin of older patients whereas undifferentiated PeIN generally affects the glans of younger patients. The gross appearance of PeIN is heterogeneous and does not allow a clear distinction between the two main types. Differentiated PeIN tends to be white, whereas undifferentiated PeIN is typically reddish or darkly pigmented. Lesions vary from flat to slightly elevated, and can be pearly white or moist erythematous, dark brown or black and present as macules, papules, or plaques. They may be warty, granular or villous (Figs. 12.192–12.195). The contours are sharply delineated or subtle and irregular.

Histological features Microscopically, differentiated PeIN is characterized by hyperkeratosis, parakeratosis, variable hypergranulosis and acanthosis with elongated and anastomosing rete ridges. There is subtle abnormal maturation (enlarged keratinocytes with abundant eosinophilic cytoplasm) (Fig. 12.196), whorling and keratin pearl formation (usually in deep rete ridges), prominent intercellular bridges (spongiosis) and sometimes acantholysis. Atypical basal or prickle layer cells are present and a prominent nucleolus may be seen (Fig.  12.197). At low power, the atypia may seem to be present only in lower levels of the epidermis; however, at higher magnification, there is subtle but abnormal maturation in all levels of the epithelium (Figs 12.198–12.200).

Fig. 12.191 Verrucous carcinoma: intraepithelial neutrophil abscesses are often present.

Penile squamous cell carcinoma Penile intraepithelial neoplasia (PeIN) In this text, penile intraepithelial neoplasia refers to purely squamous lesions and excludes Paget’s disease and melanoma in situ. There is a wide spectrum of morphological lesions reflecting the diverse pathogenesis of penile squamous cell carcinoma (SCC). Historically, there has been variable nomenclature and multiple classifications of penile precursor lesions have been proposed:1–6 • Bowen’s disease, • erythroplasia of Queyrat, • carcinoma in situ,

Fig. 12.192 Intraepithelial neoplasia: multiple eroded lesions are present. By courtesy of the Institute of Dermatology, London, UK.

Genital intraepithelial neoplasia and squamous carcinoma

Fig. 12.193 Intraepithelial neoplasia: in this example, viral warts are present in addition to multiple small papules on the glans (bowenoid papulosis). By courtesy of the Institute of Dermatology, London, UK.

Fig. 12.194 Intraepithelial neoplasia: this patient presented with multiple ulcerated lesions and a thick, scaly plaque. By courtesy of the Institute of Dermatology, London, UK.

Fig. 12.195 Intraepithelial neoplasia: there is intense erythema of the glans penis and the distal shaft. This lesion is also referred to as Bowen’s disease and in the older literature as erythroplasia of Queyrat. By courtesy of the Institute of Dermatology, London, UK.

Fig. 12.196 Differentiated PeIN: with acanthosis, hyperkeratosis, retained squamous maturation, and minimal atypia.

Fig. 12.197 Differentiated PeIN: with marked atypia, more prominent at the bottom layers.

Fig. 12.198 Differentiated PeIN: atypia are seen throughout the epithelium; note the presence of dyskeratosis.

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Fig. 12.199

Fig. 12.201

Differentiated PeIN: squamous hyperplasia (left field ) merging into differentiated PeIN (center field ), the latter in continuity with invasive squamous cell carcinoma (right field).

Differentiated PeIN: with underlying lichen sclerosus characterized by dense hyalinized subepithelial tissue.

Fig. 12.200

In basaloid PeIN, the epithelium is replaced by a monotonous population of small or intermediate-sized immature cells with high nuclear:cytoplasmic ratio (Figs  12.202–12.205). Short spikes or spindle-shaped cells may be noted. Apoptosis and mitotic figures are numerous. Basaloid PeIN should be distinguished from transitional cell urethral carcinoma in situ, which may secondarily involve the penile meatal region.15 In the warty variant, the epithelium has an undulating/spiky surface with atypical parakeratosis. There is cellular pleomorphism and koilocytosis (multinucleation, nuclei with irregular contours, perinuclear halos and dyskeratosis) (Figs 12.206–12.208). Mitosis may be numerous. Basaloid lesions are monotonous and flat, whereas warty lesions are spiky and pleomorphic with prominent koilocytosis. Frequently, lesions show overlapping features of both, namely mixed warty–basaloid PeIN. These mixed lesions have an irregular surface with koilocytic changes while the lower half of the epithelium is predominantly composed of small basaloid cells. This is not a surprising finding, taking into consideration that warty and ­basaloid carcinomas are both HPV-related tumors. Warty PeIN should be ­distinguished from the common condyloma which does not display atypia except at the level of the upper koilocytotic layer.

Differentiated PeIN: the presence of nuclear atypia (right field) allows the distinction of differentiated PeIN from squamous hyperplasia (left field)

The differential diagnosis is squamous hyperplasia which, by definition, shows no atypia. In the absence of specific penile dermatological conditions which may be associated with hyperplasia, it is likely that most acanthotic squamous lesions represent differentiated PeIN. It is not surprising that the precursor lesions of well-differentiated invasive tumors show such a high degree of differentiation. It is important to recognize this lesion because it appears to be the most frequent precursor lesion of penile carcinoma, especially of the keratinizing and well-differentiated variants. Unfortunately, most studies on differentiated PeIN are retrospective and have been based on penectomies performed for invasive carcinoma. There is a preferential association for differentiated PeIN and lichen sclerosus (Fig. 12.201).14 It is therefore important to maintain a high index of suspicion when dealing with hyperkeratotic/hyperplastic epidermal lesions with subtle keratinocytic atypia arising in the setting of long-standing lichen sclerosus. Undifferentiated PeIN (the HPV-related type) shows distinctive morphological features. Lesions can be subclassified into basaloid, warty and mixed warty–basaloid PeIN. In accordance with their common pathogenesis, it is frequent to find mixtures of warty and basaloid patterns in the same specimen. We classify a lesion as either warty or basaloid when there is more than 90% predominance of one type over the other.

Fig. 12.202 Basaloid PeIN: with acanthosis, parakeratosis, and slightly irregular surface.

Genital intraepithelial neoplasia and squamous carcinoma

Fig. 12.203

Fig. 12.206

Basaloid PeIN: with epithelial thickening, parakeratosis, and an overall ‘blue’ appearance due to altered squamous maturation.

Warty PeIN: with prominent parakeratosis and abundant koilocytes, more prominent at upper layers.

Fig. 12.204 Basaloid PeIN: the epithelium is replaced by a monotonous proliferation of small to medium-sized cells with basal-like features

Fig. 12.205 Basaloid PeIN: with abundant mitoses and apoptotic figures throughout the epithelium.

Fig. 12.207 Warty PeIN: showing its characteristic spiky, parakeratotic surface.

Fig. 12.208 Warty PeIN: nuclear atypia is discernable throughout the epithelium, with conspicuous, sometimes pleomorphic koilocytosis (right field ) and marked parakeratosis.

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Diseases of the anogenital skin Rarely, a mixed lesion composed of differentiated and undifferentiated PeIN is encountered. If an associated invasive cancer is present it also shows mixed morphology of more than one subtype of invasive squamous cell carcinoma. Other exceptional and less well-studied morphologic patterns of precursor lesions include pleomorphic, spindled cell, clear cell, pagetoid and small cell. All of these are likely to represent variants of the undifferentiated group. With few exceptions there is good correlation between the microscopic appearance of the preinvasive lesion and the associated invasive carcinoma. Usual and differentiated subtypes of SCC are associated with differentiated PeIN while warty and basaloid invasive carcinomas are associated with warty or basaloid PeIN. These observations further support the concept of a bimodal pathway of penile tumorigenesis.9

Bowenoid papulosis Patients with bowenoid papulosis are younger (mean age 30 years) than those with penile cancer and present with multiple papules affecting the skin of the shaft, glans, sulcus or foreskin. Some lesions regress spontaneously.16–21 Histologically, at low-power magnification there is acanthosis and either a spiky or flat appearance. High power shows a proliferation of small ­basophilic cells with a spotty distribution of atypical forms. Hyperkeratosis, ­parakeratosis and melanin pigmentation may be present. Human ­papillomavirus types 16 and 18 have been associated with bowenoid papulosis; hence, sexual ­transmission is suspected. The histological appearance of bowenoid papulosis is similar to that of basaloid or mixed warty–basaloid PeIN and the diagnosis should be suggested only when there is a clinical presentation of multiple papular lesions in younger patients.

Flat ‘acetowhite’ penile lesions Peniscopic studies of male sex partners of women with HPV-associated squamous intraepithelial lesion (SIL/CIN) have revealed a clinical lesion described by Bleeker et al. as ‘flat penile lesion’.22 It was identified in 60% of 230 cases and affected the inner foreskin surface, frenulum and coronal ­sulcus. HPV was identified in the majority of the lesions by in situ ­hybridization. Grossly (only evident after acetic acid reaction), 2–4 or more well-demarcated 1–2-cm white flat lesions with a mosaic vascular pattern were seen. Microscopically, there was squamous hyperplasia or low grade PeIN. In a minority of cases high-grade PeIN was present. Follow-up of 118 men with flat lesions showed a benign clinical course and regression in 90% of the cases in 5 years, usually within 12 months.

Invasive squamous cell carcinoma Squamous cell carcinoma arises on the mucosal surface of the penis ­extending from the preputial orifice to the urethral meatus, comprising the inner ­surface of the foreskin, coronal sulcus and glans.23 Squamous cell carcinoma ­presenting on the outer skin of the penis is very unusual. Distal urethral tumors, ­morphologically similar to some penile tumors, are not discussed in this text. Penile cancer incidence rates in the West are in the range of 0.3–1.0/100 000 of the population although there is considerable variation amongst the ­different countries. The incidence of penile SCC varies from a high incidence in Uganda, Kenya and some regions of South America, to a lower incidence in Northern Europe and the United States, Japan and Israel.2 Comparing cases from the United States and Paraguay, we have found no geographical ­differences in the morphology, relative incidence of histologic subtypes or in the presence or absence of HPV according to histologic subtype.9,24 Differences in geographical distribution of penile cancer are attributed to environmental factors. Several epidemiological studies have indicated the ­following risk factors: 25–28 • socioeconomic deprivation, • poor hygiene, • lack of access to running water, • phimosis, • smegma retention, • lack of circumcision,

• chronic inflammation, • history of tear or injury to the penis, • physical inactivity, • history of warts, • ultraviolet irradiation, • partner with cervical cancer, • immunosuppression, • smoking, • HPV, • lichen sclerosus.

Early circumcision appears to be associated with a lower incidence of penile cancer when compared to later circumcision. Penile carcinoma in ­circumcised men is very rare; it has been reported in association with irregular scarring in patients undergoing ritual circumcision. Postcircumcision penile cancer appears to be biologically aggressive.29 High incidences of both penile and cervical cancers are seen in some areas of the world. However, pathologically, penile cancers are similar to vulval cancers. The overall prevalence of HPV DNA in penile carcinoma (42%) is lower than that seen in cervical carcinoma (near 100%) and is similar to ­vulval carcinoma.7 Subtypes of penile cancer such as basaloid and condylomatous are consistently associated with HPV, whereas the virus is infrequent in the usual, verrucous, papillary and sarcomatoid squamous cell carcinoma.9,24 These two groups of tumors appear to develop along different pathogenetic pathways. HPV-16 is the most common type of HPV associated with penile cancer. HPV-related anogenital cancers, including penile ­carcinoma, are ­significantly more frequent in HIV-infected patients when compared with the general population.30,31

Clinical features The mean age of patients with penile SCC is around 60 years. HPV-related tumors such as condylomatous and basaloid cancers affect younger patients (45–55 years) while verrucous and pseudohyperplastic carcinomas occur at an older age (70–80 years).32 An exophytic or non-ulcerated lesion is the usual presenting sign. In non-Western countries, up to 40% of patients present with inguinal lymph node metastasis and 10% with disseminated disease. This high figure contrasts with a significantly lower incidence of regional and systemic metastasis in North American patients (13 and 2.3% respectively).33 The frequency of in situ and invasive carcinoma varies according to geographical region. In areas of high frequency, the majority of tumors are initially dignosed as invasive tumors whereas in regions of low incidence, most cases are diagnosed as in situ lesions. In a series of 500 invasive carcinomas diagnosed in Paraguay, we found only 20 cases of carcinoma in situ (4%), whereas in 1605 cases from the SEER database in USA the figure was 37%.33 Geographical differences may reflect the incidence of invasive cancers.

Usual squamous cell carcinoma Grossly, SCC of the usual type displays wide morphologic appearances varying from white–gray exophytic to flat or reddish, ulcerated endophytic masses. The cut surface shows white–gray neoplastic tissues invading variable penile anatomical levels (lamina propria, corpus spongiosum or corpus cavernosum in the glans and dartos or skin in the foreskin). In the fresh state or after fixation there may be a contrast between the white color of the tumor and the reddish, darker penile tissue. The boundaries between tumor and stroma are usually jagged and irregular. Adjacent associated squamous hyperplasia or PeIN can be visualized as a deeply white line measuring 1–2 mm in thickness in the adjacent epithelium.

Histological features Microscopically, tumors vary from well-differentiated keratinizing to solid anaplastic carcinomas with scant keratinization (Figs  12.209–12.211). Most tumors are highly keratinized and of moderate differentiation. Poorly ­differentiated carcinomas may have variable and usually focal amounts of spindled cell, giant cell, solid, acantholytic, clear cell, small cell, warty, basaloid or glandular components. When these features predominate, there is a morphological justification for separation of the neoplasm as a special ­subtype of squamous cell carcinoma.

Genital intraepithelial neoplasia and squamous carcinoma

499

Subtypes of squamous cell carcinoma Table 12.2 Subtypes of squamous cell carcinoma

TS2

Papillae

Koilocytosis

Interphase

HPV

Warty

Condylomatous

Present pleom

Jagged

+ High risk

Verrucous

Noncondy­ lomatous

Absent

Broad

Absent

Papillary

Complex

Absent

Jagged

Absent

Giant condyloma

Condylomatous

Superficial

Broad

+ Low risk

Fig. 12.209 Usual squamous cell carcinoma: well-differentiated (grade 1) usual SCC with keratinizing tumor nests composed of neoplastic cells showing minimal atypia limited to the basal/parabasal layers. A

B

C

D

(A) Verrucous carcinoma: tight papillae separated by keratin (in red ). Broadly based boundaries between tumor and stroma. (B) Papillary carcinoma: irregular papillae without koilocytosis. Jagged tumor–stroma limits. (C) Giant condyloma: condylomatous papillae, surface koilocytosis (white dots) and broad non invasive base. (D) Warty (condylomatous) carcinoma: irregular condylomatous papillae, diffuse koilocytosis and jagged boundary between tumor and stroma.

Fig. 12.210 Usual squamous cell carcinoma: moderately differentiated (grade 2) usual SCC with more evident atypia (upper right field ) but retained squamous maturation.

Fig. 12.211 Usual squamous cell carcinoma: poorly differentiated (grade 3) usual SCC with prominent atypia but evidence of squamous differentiation.

Clinical features Verrucous carcinoma Verrucous carcinoma (VC) is a slowly growing, well-differentiated tumor, with a papillomatous appearance and a broad bulbous invasive border ­contrasting with the irregular infiltrating margin of usual squamous cell ­carcinoma. Described by Dr. Lauren Ackerman in 1948 in the buccal mucosa, verrucous carcinoma continues to pose diagnostic problems with other verruciform tumors sharing some of its characteristics.34 Condyloma, papillary and condylomatous carcinoma have all been published under the designation of verrucous carcinoma or Buscke-Löwenstein tumor. We have proposed a classification of verruciform neoplasms that helps to differentiate verrucous carcinoma from other similar lesions.35 It is important to follow strict diagnostic criteria since classic penile verrucous carcinoma is associated with virtually no metastatic potential.36,37 There is a spectrum of combined tumors with focal or significant verrucous features, which need to be distinguished from typical verrucous carcinoma. The most frequent combination is that of a verrucous carcinoma with usual invasive SCC. These mixed or hybrid ­verrucous carcinomas have a metastatic rate of about 25%.38–40 Verrucous carcinoma may also be associated with sarcomatoid carcinoma sporadically or after radiation therapy.41 HPV has been consistently rare or absent in ­various studies.9,24,42 Verrucous carcinoma is rare, accounting for 7% of all penile SCC.2 It presents during the sixth to seventh decades and the average duration of the ­disease is 56 months, the longest amongst all penile malignant tumors. Any penile epithelial compartment may be affected and it is equally frequent in

500

Diseases of the anogenital skin the foreskin or glans penis. Most tumors are unicentric but multicentric cases or association with other subtypes such as the pseudohyperplastic variant has been observed. Grossly, it is an exophytic papillomatous tumor with some variation in the configuration of the papillae, from multinodular with cobblestone morphology to filiform with a spiky appearance. The cut surface reveals a white serrated tumor and a broad demarcation between the lesion and stroma. Verrucous carcinoma is superficial, rarely penetrating beyond lamina propria or superficial dartos or corpus spongiosum.

Histological features Microscopically, the tumor is diffusely well differentiated, resembling nomal squamous epithelium except for the presence of occasional atypical nuclei in the basal or parabasal layers. Features include papillomatosis, hyper- to orthokeratosis, acanthosis and a broad-based interface between the tumor and stroma, the latter considered pathognomonic for this tumor. Koilocytosis is not present. Although some papillae may harbor fibrovascular cores, this is not a characteristic feature. The space between papillae is occupied by a keratin-filled crater that on a tangential cut appears as keratin-filled pseudocysts. The stroma may show a dense lymphocytic infiltrate, sometimes blurring the interface between the tumor and the underlying connective tissue (Figs 12.212–12.216). Microscopic small nests of well-differentiated invasive keratinized SCC in the lamina propria (1–3 mm in depth) may rarely be observed. We have not observed metastasis in these cases. A designation for such a lesion could be microinvasive verrucous carcinoma. This entity differs from hybrid verrucous carcinoma where large areas of the tumor show features of a moderately to poorly differentiated invasive typical squamous cell carcinoma (Figs 12.217–12.219). Associated lesions which may be seen in the adjacent epithelium include squamous hyperplasia and differentiated PeIN. The hyperplasia often adopts the features of verrucous hyperplasia. Lichen sclerosus is a further frequently found associated condition and may be pathogenetically related to verrucous carcinoma.43 Verrucous carcinoma, if insufficiently resected, is prone to local recurrence. Regional metastases are not seen in typical (pure) lesions.

Fig. 12.213 Verrucous carcinoma: showing acanthosis, parakeratosis, papillomatosis, and a broad-based tumor–stroma interface.

Condylomatous (warty) carcinoma

Clinical features Condylomatous carcinoma is a slowly growing, verruciform low- to intermediate-grade HPV-related tumor, grossly similar to giant condyloma but with malignant histology and potential for nodal metastasis.35 It accounts for 7% of all penile SCC affecting patients younger than those with the usual SCC. A history of previous viral warts is frequently obtained. The foreskin, coronal sulcus and glans are usually involved. Macroscopically, the cut surface shows

Fig. 12.214 Verrucous carcinoma: neoplastic cells are extremely well-differentiated with minimal atypia limited to the basal/parabasal layers.

Fig. 12.212

Fig. 12.215

Verrucous carcinoma: exophytic, verruciform proliferation with papillae showing inconspicuous fibrovascular cores.

Verrucous carcinoma: with epithelial thickening, minimal atypia, parakeratosis, and a well-defined, rounded tumor front.

Genital intraepithelial neoplasia and squamous carcinoma

Fig. 12.216

Fig. 12.219

Verrucous carcinoma: with slightly irregular tumor front and foci suspicious for microinvasive verrucous carcinoma (upper right field).

Hybrid verrucous carcinoma: usual SCC component composed of poorly differentiated neoplastic cells.

a papillomatous growth generally penetrating into the corpora spongiosa and cavernosa. The interface of tumor and stroma varies from broadly based to jagged and irregular.

Histological features

Hybrid verrucous carcinoma: composed of a typical verrucous carcinoma (left field) and a usual SCC (right field).

Microscopically, the tumor papillae are condylomatous and of various shapes (round, ovoid or spiky, long or short) but always with a prominent central fibrovascular core and koilocytotic changes (Figs  12.220–12.224). Unlike benign condyloma, koilocytosis is not restricted to the surface epithelial cells but is also present in deep invasive portions of the tumor (Fig.  12.225). Hyper- and parakeratosis, cellular pleomorphism and clear cell change may be prominent. The biological behavior of condylomatous carcinoma is intermediate between that of other types of low-grade verruciform tumors (verrucous and papillary) and squamous cell carcinoma of the usual type. Deeply invasive, high-grade condylomatous carcinoma may be associated with inguinal nodal metastasis. The differential diagnosis is with other verruciform tumors, verrucous and papillary carcinoma and giant condyloma. The histologic evaluation of type of papillae, presence of koilocytosis, interface of tumor and stroma and presence of HPV helps in the differentiation of these neoplasms (see Tables 12.1 and 12.2).

Fig. 12.218

Fig. 12.220

Hybrid verrucous carcinoma: verrucous component with pushing tumor borders and well-differentiated neoplastic cells; note the underlying stromal reaction.

Condylomatous carcinoma: exhibiting an exophytic, papillomatous pattern of growth with conspicuous fibrovascular cores.

Fig. 12.217

501

502

Diseases of the anogenital skin

Fig. 12.221

Fig. 12.224

Condylomatous carcinoma: showing an irregular, jagged infiltrative tumor front (right field).

Condylomatous carcinoma: showing abundant koilocytes, more prominent at the upper layers, and marked parakeratosis.

Fig. 12.222

Fig. 12.225

Condylomatous carcinoma: with papillomatosis, evident fibrovascular cores, and irregular tumor–stroma interface.

Condylomatous carcinoma: deep infiltrative nests with koilocytes and surrounding stromal reaction.

Koilocytosis, condylomatous papillae and jagged irregular boundaries between tumor and stroma are present in warty but not in verrucous carcinomas. In papillary carcinomas, papillae are complex and show no koilocytosis. Giant condylomas are broadly based noninvasive tumors with surface koilocytosis (see Table 12.2).35,44 Associated precursor lesions of condylomatous carcinoma include PeIN of the warty or basaloid types.

Papillary carcinoma, NOS

Clinical features Papillary carcinoma, NOS is the third type of penile low-grade verruciform carcinoma.2,3,45 Patients are on average around 60 years old. The tumor is grossly exophytic, large and irregular and involves the glans, coronal sulcus and foreskin. The cut surface shows a papillary neoplasm involving corpus spongiosum or dartos. Papillary carcinoma is a slowly growing tumor with a low but definite incidence of inguinal nodal metastasis.

Histological features Fig. 12.223 Condylomatous carcinoma: papillae with conspicuous koilocytosis, slight parakeratosis, and underlying chronic stromal reaction.

Microscopically, the appearance is that of a well-differentiated papillary squamous neoplasm. There is hyperkeratosis and papillomatosis. Papillae are variable and complex, short or long, with or without a fibrovascular core

Genital intraepithelial neoplasia and squamous carcinoma (Figs 12.226–12.228). The tips may be straight, undulated, spiky or blunt. Hyperkeratosis and acanthosis are prominent. Keratin cysts or intraepithelial abscesses are sometimes present. The base of the lesion is irregular and infiltrative. The interface between tumor and stroma is characteristically jagged (Fig.  12.229). Koilocytotic-like changes are usually absent. Differentiating features from verrucous and condylomatous carcinoma are based on the heterogeneity of the papillae, the lack of koilocytosis and the jagged irregular interface between tumor and stroma. The latter feature is crucial to distinguish papillary from verrucous carcinoma. HPV studies may be necessary to differentiate papillary neoplasms, usually negative for HPV, from low-grade condylomatous carcinoma. Another tumor to be distinguished from papillary carcinoma NOS is the infrequent papillary basaloid SCC.2 In this tumor, papillae harbor a thin fibrovascular core and the cells are small and anaplastic, resembling basaloid or transitional carcinoma. This unusual penile neoplasm is often deeply invasive. Low-grade squamous intraepithelial lesion and lichen sclerosus are frequently associated with papillary carcinoma.

Fig. 12.228 Papillary carcinoma, NOS: showing an irregular, jagged tumor front of invasion and prominent stromal reaction.

Fig. 12.226 Papillary carcinoma, NOS: showing papillomatosis with complex papillae and irregular fibrovascular cores.

Fig. 12.229 Papillary carcinoma, NOS: irregular tumor nests at the tumor base surrounded by intense chronic inflammation.

Basaloid carcinoma

Clinical features

Fig. 12.227 Papillary carcinoma, NOS: with rounded and tipped papillae, hyperkeratosis, and irregular fibrovascular cores.

Basaloid carcinoma is an aggressive, HPV-related variant of SCC occurring in the fifth decade and preferentially affecting the glans.46 It has been proposed that it originates within the squamous–transitional junction of the meatal region. Rarely, basaloid carcinoma may develop in the foreskin. It accounts for 4% to 10% of penile SCCs. The median age is 53 years. More than half of patients show inguinal metastasis at clinical diagnosis. Grossly, there is an ulcerated irregular mass. The cut surface reveals a tan, solid tumor, deeply invasive into the corpus spongiosum or cavernosum.

Histological features Microscopically, there are separate or confluent solid nests composed of small basaloid cells, usually with central necrosis (comedonecrosis) or ­central abrupt keratinization (Figs  12.230–12.233). Nuclei are anaplastic

503

504

Diseases of the anogenital skin

Fig. 12.230

Fig. 12.233

Basaloid carcinoma: at low-power view showing deeply infiltrative tumor nests.

Basaloid carcinoma: composed of neoplastic cells with indistinctive cellular borders, high mitotic/apoptotic rate, and central (comedo-like) necrosis.

and ­nucleoli inconspicuous. There are numerous mitotic figures. Occasional ­palisading at the nest periphery may be noted but it is usually not as prominent as is seen in basal cell carcinoma of the skin. Basophilic intermediate or large cell nuclei may be noted in some cases. Pseudoglandular features are sometimes present (Figs  12.234, 12.235) (adenoid–basaloid carcinomas). PeIN of the warty–basaloid type is often found in the epithelium adjacent to the invasive cancer.

Unusual morphological features of basaloid carcinomas

Basaloid carcinoma: with tumor nests showing central, abrupt parakeratosis, and retraction artifact.

In accordance with their common HPV etiology, some tumors show mixed basaloid–condylomatous features. The condylomatous component is superficial and papillary and the deep counterpart a typical basaloid carcinoma. There are deeply invasive nests with central keratinization or comedonecrosis surrounded by clear cells with koilocytotic-like changes and peripheral small basaloid cells. These mixed tumors behave as basaloid carcinomas, with ­frequent nodal metastasis. Another unusual morphological presentation is that of a papillary lesion composed entirely of small basaloid cells (transitional-like papillary basaloid carcinoma). Deep portions of the tumor show the classic features of a basaloid carcinoma. Unlike other penile ­papillary tumors, the papillae are entirely composed of small cells simulating a ­transitional urothelial carcinoma.

Fig. 12.232

Fig. 12.234

Basaloid carcinoma: tumor nest composed of a monomorphic population of cells with evident atypia and central parakeratotic debris.

Basaloid carcinoma: with tumor nests exhibiting open central areas due to central necrosis, simulating a glandular space.

Fig. 12.231

Genital intraepithelial neoplasia and squamous carcinoma

Fig. 12.235

Fig. 12.237

Basaloid carcinoma: with central, necrotic debris and a pseudoglandular appearance.

Sarcomatoid carcinoma: high-grade pleomorphic cells intermingled with spindled cells.

Sarcomatoid carcinoma (carcinoma with heterologous differentiation, metaplastic carcinoma)

Clinical Features Sarcomatoid carcinoma is an aggressive penile neoplasm composed predominantly of spindled cells. It may arise de novo, follow a recurrence of usual squamous cell carcinoma or develop after irradiation therapy of a verrucous carcinoma. It accounts for about 1–4% of all penile carcinomas and preferentially involves the glans penis although the foreskin may also be affected.47 As with usual SCC, the mean age is around 60. Grossly, it presents as a bulky 5–10-cm ulcerated or rounded polypoid mass, which on sectioning shows almost invariably deep invasion into the corpus cavernosum. Regional metastases occur in 85% of sarcomatoid carcinomas and mortality is high.

Histological features Microscopically, there are variable proportions of squamous and spindled cell carcinoma but the latter usually predominates. The sarcomatoid component includes leiomyosarcoma, fibrosarcoma, myxosarcoma, epithelioid angiosarcoma, classic angiosarcoma and so-called pleomorphic malignant fibrous ­histiocytoma (Figs  12.236–12.240). Heterologous bone and ­cartilage formation is sometimes focally present. Rarely, the tumor shows pseudoglandular and/or pseudovascular differentiation (Figs 12.241, 12.242).

Fig. 12.236 Sarcomatoid carcinoma: composed of neoplastic spindle cells simulating a high-grade sarcoma.

Fig. 12.238 Sarcomatoid carcinoma: pleomorphic and spindled malignant cells in a myxoid background.

Fig. 12.239 Sarcomatoid carcinoma: differentiated PeIN with underlying sarcomatoid carcinoma.

505

506

Diseases of the anogenital skin The squamous component typically shows the morphology of usual SCC but areas of ­verrucous, papillary or basaloid carcinoma may also be observed, indicating that sarcomatoid transformation may occur in practically any tumor type. HPV is usually absent. Differential diagnosis includes sarcoma and melanoma. Immunohistochemistry is essential for tumors with little or no epithelial component and for small biopsy specimens. The spindled cells are usually positive for vimentin, various cytokeratins and p63. In our ­experience, cytokeratin 34betaE12 and p63 appear to be the more specific and sensitive markers to categorize these tumors as epithelial. AE1/ AE3 and Cam 5.2 tend to be more variable and often only focally positive, sometimes highlighting scattered single cells. Smooth muscle actin can be focally positive; ­however, desmin, muscle-specific actin, myogenin and S-100 are negative. Tumors which display specific sarcomatous components such as ­leiomyosarcoma or angiosarcoma display the expected immunohistochemistry.

Pseudohyperplastic carcinoma

Clinical features Fig. 12.240 Sarcomatoid carcinoma: neoplastic cells in sarcomatoid carcinomas showing nuclear positivity for p63 immunohistochemistry.

Pseudohyperplastic carcinoma is a clinicopathologic entity characterized by a low-grade ordinary squamous carcinoma preferentially affecting the foreskin of older patients (eighth decade) in association with lichen sclerosus.48 The tumor is well differentiated (resembling normal squamous epithelium) and in small biopsy specimens it may mimic pseudoepitheliomatous hyperplasia. It is often multicentric and the second or third independent lesion is sometimes verrucous. We have observed similar cutaneous tumors in association with severe solar elastosis or in scars after burns. Grossly, it is a flat or slightly elevated lesion measuring about 2 cm. In a series of 10 cases, recurrence was noted in the glans of one patient who was circumcised for a multicentric carcinoma of the foreskin 2 years after diagnosis. No metastases developed in any of these cases.

Histological features Characteristic microscopic features are keratinizing nests of squamous cells with minimal atypia surrounded by a reactive stroma (Fig.  12.243). The ­consistent association with lichen sclerosus suggests that this inflammatory condition may play a pathogenetic role.

Carcinoma cuniculatum

Clinical features Sarcomatoid carcinoma: low-power view of a sarcomatoid carcinoma with irregular spaces simulating vascular lumina.

This tumor was originally documented on the sole of the foot. It is a deeply penetrating, albeit low-grade squamous cell carcinoma which, because of its burrowing growth pattern, was designated epithelioma cuniculatum by Ayrd in 1954.49 Seven cases of this unusual variant of SCC have been reported in

Fig. 12.242

Fig. 12.243

Sarcomatoid carcinoma: high-grade pleomorphic cells mimicking the pattern of growth of angiosarcomas (‘pseudoangiosarcomatoid carcinoma’).

Pseudohyperplastic carcinoma: showing a downward proliferation of irregular tumor nests composed of extremely well-differentiated neoplastic cells.

Fig. 12.241

Genital intraepithelial neoplasia and squamous carcinoma the penis.50 The mean age of presentation was 77 years. Grossly, the tumor is white–gray, exo–endophytic and papillomatous with a cobblestone or spiky appearance. It affects the glans and often extends to the coronal sulcus and foreskin (average size 6 cm). The hallmark of the lesion is visible on the cut surface where deep invaginations of the tumor form irregular, narrow and elongated neoplastic sinus tracts that connect the surface of the tumor to deep anatomical structures. Despite the deep penetration, none of the reported cases of carcinoma cuniculatum has shown nodal or systemic disease at time of diagnosis.

Histological features Microscopically, the tumor partially resembles verrucous carcinoma with a bulbous front of invasion. There may, however, be irregular foci of invasive squamous cell carcinoma of the usual type (Figs 12.244–12.246). Carcinoma cuniculatum should be distinguished from classical verrucous carcinoma, which is also well differentiated, but rarely invades beyond the lamina propria and has a sharply delineated front.

Clear cell carcinoma Clear cell features may be noted in squamous cell carcinoma. We have observed some examples of solid, poorly differentiated SCC composed largely of PAS-positive clear cells and have attributed the appearance to cytoplasmic

Fig. 12.246 Carcinoma cuniculatum: with its characteristic verruciform pattern of growth (left field ) associated with an invasive usual SCC (right field).

hyperglycogenation, similar to cervical lesions.2,3 Clear cells may also be conspicuous in some condylomatous carcinomas. A purported different penile tumor composed exclusively of clear cells, and designated clear cell carcinoma, has recently been reported from Austria.51 The tumors were large, exophytic, partially ulcerated and widely invasive, all located in the foreskin inner surface.

Histological features Microscopically, clear cell carcinoma is composed of large neoplastic cells with clear, PAS-positive cytoplasm (Fig.  12.247). HPV-16 is consistently present. Follow-up information in the Austrian series showed that all five patients had groin cystic clear cell metastases. Two patients were reported as alive and the others either dead or with evidence of disease at last follow-up.

Adenosquamous carcinoma

Clinical features Fig. 12.244 Carcinoma cuniculatum: at low-power view showing its verruciform pattern of growth extending deep into penile erectile tissues.

Adenosquamous carcinoma is an exceedingly rare variant thought to arise within misplaced glandular cells within the perimeatal region of the penis. It consists of squamous cell carcinoma with foci of mucinous glandular differentiation. It is believed to arise from the epithelial surface of the glans, where

Fig. 12.245

Fig. 12.247

Carcinoma cuniculatum: with a broad-based tumor front, intense stromal reaction, neoplastic cells with minimal atypia, and prominent parakeratosis.

Clear cell carcinoma: composed of polygonal cells with evident atypia and a clear, faintly eosinophilic cytoplasm.

507

508

Diseases of the anogenital skin foci of squamous cell carcinoma in situ may be noted. Clinicopathologic ­features and outcome are similar to usual SCC. Grossly, a large firm granular neoplasm deeply invading penile corpora is present. The few reported cases of adenosquamous carcinomas have behaved aggressively with frequent nodal metastasis.

Histological features Microscopically, there is an admixture of squamous cell carcinoma and mucin secreting adenocarcinoma (Figs  12.248, 12.249). The squamous component generally predominates.52 The glandular epithelium expresses carcinoembryonic antigen (CEA). Differentiated PeIN is usually present in the adjacent glans mucosa. Adenosquamous carcinomas should be distinguished from mucoepidermoid, adeno-basaloid and pseudoglandular SCCs. In ­mucoepidermoid ­carcinomas, there are isolated cells or group of squamous cells containing mucin without forming glandular structures.53 In adenobasaloid tumors, there are well-formed mucin secreting glands but the solid component is a basaloid carcinoma. Pseudoglandular (adenoid or acantholytic) SCC most frequently represents SCC of the usual type in which there is considerable ­dyskeratosis and acantholysis with secondary pseudolumen ­formation ­simulating ­glandular structures. The lack of mucin production

Fig. 12.248 Adenosquamous carcinoma: showing neoplastic nests composed of cells with glandular and squamous differentiation.

aids in their distinction. Another important differential diagnosis is adenocarcinoma arising in Littre glands. This tumor is ventrally located around the penile urethra.

Acantholytic (adenoid, pseudoglandular) carcinoma

Clinical Features This unusual variant of SCC is characterized by prominent acantholysis and the formation of pseudoglandular spaces.54 The median age of the patient is 54 years. Tumors are generally large, involve multiple penile anatomical compartments and deeply invade into erectile corpora.

Histological features The pseudoglandular spaces contain keratin, acantholytic cells and necrotic debris (Figs 12.250, 12.251). CEA and mucin stains are negative. Compared with usual SCC, pseudoglandular SCC shows higher-grade foci, invades deeper anatomical structures and is associated with a higher incidence of regional metastasis and mortality. The differential diagnosis includes gland-forming penile tumors (surface adenosquamous, mucoepidermoid and urethral adenocarcinomas) and the angiosarcomatous variant of sarcomatoid carcinoma.

Fig. 12.250 Acantholytic carcinoma: deeply infiltrative tumor nests with extensive areas of central acantholysis, giving the lesion a glandular appearance.

Fig. 12.249

Fig. 12.251

Adenosquamous carcinoma: tumor nest with a high-grade squamous component associated with areas of glandular differentiation.

Acantholytic carcinoma: tumor nest with central acantholysis showing an admixture of neutrophils, necrotic debris, and desquamated cells.

Cloacogenic carcinoma

Giant condyloma Described by Buschke and Löwenstein, this is an exophytic tumor which reaches a very large size after many years of evolution.55 There has been much confusion in the correct classification of this lesion which has been confused with verrucous carcinoma. In our opinion, verrucous carcinoma is a different tumor (see above). In giant condylomas, patients are older than those with condyloma acuminatum and younger than those with condylomatous (warty) carcinoma. Grossly, it presents as a cauliflower-like tumor showing a papillomatous growth with a sharp demarcation between the lesion and stroma on the cut surface. The deep border may affect lamina propria, dartos or corpus spongiosum. Histologically, it may have an exo- add/or endophytic growth pattern with morphology identical to condyloma acuminatum. However, in our recent experience, there is a morphological spectrum: • entirely benign, composed of differentiated squamous cells and indistinguishable from condyloma acuminatum, • focally atypical, • entirely atypical but without invasion, • associated with superficial microinvasive squamous cell carcinoma, • associated with overtly invasive squamous cell carcinoma (see diagram). The condylomatous papillae show a central fibrovascular core and superficial koilocytotic changes (Figs 12.252–12.255). The differential diagnosis

Fig. 12.252 Giant condyloma: showing a papillomatous, exophytic pattern of growth, conspicuous fibrovascular cores, and a broad tumor base.

Fig. 12.254 Giant condyloma: with a pushing, downward proliferation extending into penile erectile tissues.

Fig. 12.255 Giant condyloma: with koilocytosis, easily recognized in the upper layers, and mild atypia at the base of the papillae (‘atypical condyloma’).

includes condyloma acuminatum and noninvasive condylomatous carcinoma (see Table 12.1). Condyloma acuminatum affects younger patients, is smaller and lesions are usually multiple, affecting not only the squamous epithelium of penile mucosal epithelial compartments but also the outer skin of the foreskin and shaft. Giant condyloma affects older patients, is usually bulky and unicentric. The distinction of giant condyloma from well-differentiated condylomatous carcinoma may be difficult. Identification of low-risk HPV in giant condyloma and HPV-16 in condylomatous carcinomas may aid in the differential diagnosis.

Cloacogenic carcinoma

Fig. 12.253 Giant condyloma: with overt koilocytosis, slight parakeratosis, and no cellular atypia.

This rare tumor presents in middle-aged women as a superficial ulcerated adenocarcinoma composed of colonic-type glands arising in direct continuity with vulval surface epithelium (Figs 12.256–12.258).1–5 It is independent of the perivulval glands and, by definition, direct extension or metastasis from an underlying large intestinal or visceral adenocarcinoma has been excluded. The clinical features are not distinctive but tumors may present as lesions simulating Bartholin’s gland infection.6 In a single case, the neoplastic glands also contained Paneth cells.5 The origin of this tumor is not known but it is thought most probably to arise from an area of gastrointestinal metaplasia

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Fig. 12.256

Fig. 12.258

Cloacogenic vulval adenocarcinoma: scanning view showing vulval squamous epithelium on the far right. Colonic epithelium is present on the left. Mucus-secreting carcinoma extends throughout the underlying connective tissue.

Cloacogenic vulval adenocarcinoma: close-up view showing the tumor cells distended by intracytoplasmic mucin.

Fig. 12.257 Cloacogenic vulval adenocarcinoma: the tumor is associated with abundant mucin secretion forming large lakes.

or from heterotopic intestinal tissue (Fig. 12.259).7 Vulval cloacogenic carcinoma should not be confused with the similarly named tumor of the anal canal. Tumor cells are positive for CK7 and CK20 and negative for estrogen and progesterone receptors.8

Adnexal tumors Papillary hidradenoma (mammary-like gland adenoma of the vulva) Clinical features Papillary hidradenoma (hidradenoma papilliferum, mammary-like gland adenoma of the vulva) occurs almost exclusively in females.1–6 A single example of a perianal variant has been described in a male.7

Fig. 12.259 Cloacogenic vulval adenocarcinoma: highpower view of the junction between squamous and colonic epithelium.

Papillary hidradenoma typically presents in middle-aged women as a small (1–2 cm diameter) solitary asymptomatic nodule in a vulval, perineal or ­perianal location.4,6 Rare lesions attain a large size.8,9 Ulceration is ­exceptional. Most often it affects the labium majus, but on occasion it arises on the lateral aspect of the labium minus, fourchette or clitoris (Fig. 12.260).6,10 Perianal lesions are very uncommon.11 It is often associated with the anogenital glands (see below).6,12 Lesions may present with bleeding or pruritus and some are ulcerated.6 Exceptionally, tumors are multiple and such cases tend to be located on the same side of the vulva.1,2,13 Very rarely lesions may have been described on the nipple, eyelid and external auditory canal.3,4

Pathogenesis and histological features This tumor is now believed to be derived from anogenital mammary-like glands and the name mammary-like gland adenoma of the vulva has been proposed.6 The epidermis may be normal, acanthotic or ulcerated. The tumor forms a fairly well-demarcated nodule in the dermis or lamina propria and ­sometimes

Cloacogenic carcinoma

Fig. 12.260 Papillary hidradenoma: the lesion presents as a warty nodule. By courtesy of the Institute of Dermatology, London, UK.

Fig. 12.262 Papillary hidradenoma: the papillae have a fibrovascular core.

shows foci of continuity with the overlying epithelium.5 The growth pattern consists of a mixture of tubular, papillary and solid areas.6 It is composed of epithelium-covered papillary processes projecting into cystic spaces (Fig.  12.261). The epithelial lining is typically double layered, comprising outer small myoepithelial cells with oval hyperchromatic nuclei and inner tall columnar cells with eosinophilic cytoplasm, sometimes manifesting decapitation secretion (Figs  12.262, 12.263). Squamous cells can be identified. Oxyphilic metaplasia of tumor cells is common.14 Tumor cells are epithelial and myoepithelial, and the latter can display clear cell change.6 Occasionally, the lining is only one cell thick (columnar). Diastase-resistant, PAS-positive intracytoplasmic granules are usually present. The occasional finding of a normal mitotic figure has no sinister implication. The larger villi have a fibrous core in which occasional ductal structures may be identified. Often, the fibrous tissue surrounding the tumor is compressed to form a pseudocapsule. Some tumors have a pattern identical to those of breast tumors including syringocystadenoma papilliferum, erosive adenomatosis, sclerosing adenoma and ductal adenoma.6 An inflammatory cell component is not a significant feature but foamy histiocytes can be seen.6 Exceptionally rarely, Fig. 12.263 Papillary hidradenoma: the papillae are covered by a double layer of epithelial cells, the inner showing typical decapitation secretion.

a malignant variant may be encountered.15,16 The malignant component is ­usually an apocrine carcinoma but an adenosquamous carcinoma has also been documented.15 HPV has only occasionally been detected in this tumor.14

Benign tumors of Bartholin’s gland Clinical features

Fig. 12.261 Papillary hidradenoma: whole mount preparation showing sharply circumscribed papillary tumor.

Benign tumors of the Bartholin gland are very rare and the vast majority are nodular hyperplasias.1 They occur mainly in young women. Occurrence in postmenopausal women is exceptional.2 Adenomas are exceptionally rare, as are adenomyomas.1,3,4 They all present as a small asymptomatic mass on the ­posterolateral aspect of the vulva and are usually diagnosed clinically as a cyst. Bilateral lesions are very rare.5 Both hyperplasia and adenomas may be ­associated with pain.5,6 Nodular hyperplasia often presents in younger patients.

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Histological features Nodular hyperplasia is well circumscribed and lobular with preservation of the normal duct–acinar relationship.1 Focal inflammation and squamous metaplasia of the ducts is commonly seen. Dilated ducts and sometimes ruptured ducts with extravasated mucin can be noted.7 Adenomas are well circumscribed and composed of small- to mediumsized glands with focal papillary projections and lined by columnar, mucin-producing cells with no cytological atypia and very rare mitotic figures. Tubules and acini proliferate in a haphazard way in contrast to the hyperplasias, where the normal architecture is preserved.1 A single case of a papilloma arising from the duct of a Bartholin’s cyst has been reported.8 In one case of hyperplasia, clonality was demonstrated, suggesting that the process may be neoplastic rather than reactive.7

Basal cell carcinoma Clinical features Basal cell carcinoma can arise on the anogenital skin (Figs 12.264, 12.265). Prior genital irradiation for cancer or ringworm is a theoretical risk factor that appertains to basal cell carcinoma at other sites. Vulval and penile tumors are seen mainly in elderly patients.1 They usually present as an eroded plaque, which may be pigmented. Less commonly, the tumor forms a nodule or an ulcer. Symptoms vary from discomfort to pruritus.2,3 Neoplasms occur most frequently on the labia majora, and sometimes can be multiple.4 Tumors

Adenoma of minor vestibular glands Clinical features Adenoma of minor vestibular glands (paravestibular tumor) is exceedingly rare and occurs in the vulvar vestibule.1–3 It is likely that it represents a ­hyperplasia rather than a true neoplasm. The lesion is very small and usually ­represents an incidental finding in a biopsy taken for another reason.4

Histological features Histologically, it consists of a small nodular aggregate of mucin-secreting glands lined by columnar cells.

Bartholin’s gland carcinoma Clinical features This rare tumor accounts for only between 2% and 7% of vulval ­neoplasms.1–8 It presents as a painless hard deep subcutaneous nodule, which, as it expands, becomes fixed and painful. The lesion measures from 1 cm to several centimeters and is located in the posterior aspect of the labium majus. It often invades deeply into fat, muscle or bone and may be associated with a Bartholin’s gland abscess. The diagnosis is often delayed because of the latter association. Adult and elderly women are usually affected. Exceptional cases have been described during pregnancy.4 It is often difficult to decide when a tumor has originated from Bartholin’s gland and particular attention should be paid to exclude a metastasis from elsewhere. Distinction from a sweat gland carcinoma can also be a ­diagnostic problem. Rarely, the tumor is associated with extramammary Paget’s ­disease.9,10 In recent years, a consistent association has been found between these tumors and HPV-16.11,12 Recurrence rates vary and have been reported to be as high as 54%.13 Up to 40% of patients present with inguinofemoral metastases. In these the 5-year survival is less than 50% but this decreases to around 18% when two or more lymph nodes are involved.5,7,8 Adenoid cystic carcinoma of Bartholin’s gland has a high local recurrence rate and ­occasionally presents with metastatic disease.14–17

Fig. 12.264 Vulval basal cell carcinoma: erythematous, keratotic plaque on left labium majus. By courtesy of the Institute of Dermatology, London, UK.

Histological features About 40% of Bartholin’s gland carcinomas are adenocarcinomas.4,7 A ­further 40% are squamous cell carcinomas and 15% are adenoid ­cystic ­carcinomas.18–21 The remainder are transitional, adenosquamous or ­anaplastic carcinomas.5,8 A case of lymphoepithelioma-like carcinoma and two ­low-grade epithelial– myoepithelial carcinoma of the Bartholin gland have been documented.22,23 A case of high-grade squamous intraepithelial neoplasia in a Bartholin’s cyst has also been reported.24 Exceptional cases of neuroendocrine carcinoma have also been described.2,25 Malignant mixed tumor very rarely originates from Bartholin’s gland.26 A neoplasm can only be accepted as originating from the gland if there is continuity with it. Adenocarcinomas may be mucinous or papillary.5 Cytogenetic analysis of a single case of adenoid cystic carcinoma of Bartholin’s gland revealed complex chromosomal abnormalities involving chromosomes 1, 4, 6, 11, 14 and 22.27

Fig. 12.265 Perianal basal cell carcinoma: ulcerated perianal nodule with a pearly white rolled border. By courtesy of the Institute of Dermatology, London, UK.

Soft tissue tumors can rarely occur in the context of Gorlin’s syndrome.5 Inadequate excision accounts for a high recurrence rate and exceptional metastases to regional lymph nodes.6,7 Mohs surgery is often recommended to ensure adequate local ­excision and acceptable cosmetic results.

Histological features Histologically, the appearances are identical to basal cell carcinomas occurring elsewhere. There has been one case report of the variant fibroepithelioma of Pinkus affecting the base of the penis.8

Metastatic tumors The anogenital skin is a rare site for metastatic tumors.1–4 Those that are described are usually from a nearby primary site; for example, vulval metastases may be derived from vaginal, cervical, endometrial, ovarian, renal cell carcinoma and choriocarcinoma. A large study of metastatic vulvar tumors found that about 46.9% arise from gynecological primaries and 43.9% from nongynecological primary tumors. The rest of the tumors were metastases from an unknown primary.4 Vulval metastases usually present as a mass or, less commonly, with pain or ulceration.4 Penile metastases most often arise from the prostate, colon, bladder and kidney. Rarely, they derive from elsewhere including pulmonary carcinoma, squamous cell carcinoma of the tongue and cutaneous melanoma.5 The metastases are most commonly sited on the labia majora or periclitorally and in the corpus cavernosum of the penis. Tumor thrombi are often found in the erectile tissue of the penis, predominantly in the corpora cavernosa.5 Penile metastasis may result in priapism.6 They usually represent an ominous sign.5 Metastases may also arise in an episiotomy scar. An exceptional metastasis to a Bartholin gland has been reported.7,8

Lymphoma and leukemia Although lymphoma is the most frequent secondary tumor of the testis, it is rare in other parts of the urogenital tract and few case reports exist.1,2 Primary anal lymphomas are also extremely rare and the cases described have been anorectal, mainly of the plasmablastic variant, associated with EBV and AIDS.3 Dehner and Smith included two cases of primary lymphoma in their series of soft tissue tumors of the penis, both presenting as painless subcutaneous nodules without evidence of systemic lymphoma.4 One case presented with painless priapism and erythematous nodular ulceration of the shaft of the penis, another case with progressive swelling of the glans penis and another with chronic penile ulceration.5,6 Doll and Diaz-Arias described a fungating nodular tumor of the scrotum in an HIV-negative homosexual that was shown to be immunoblastic T-cell lymphoma.7 Ulceration of the penis due to leukemic infiltration secondary to chronic lymphocytic leukemia has been reported.8,9 Scrotal ulceration due to leukemia cutis in acute myelogenous leukemia has also occurred.10,11 Lymphoma may present with perianal ulceration abscess and suppuration.12 Perianal infiltration, ulceration or abscess occurs in 5% of hematological malignancies.13 The histopathology of genital lymphomas is identical to that occurring elsewhere in the skin. The most commonly reported anogenital B-cell lymphoma is of the diffuse large cell type.

Juvenile xanthogranuloma This lesion usually affects the head and trunk but can involve the genitalia (Fig. 12.266).1 Multifocal penile presentation has been documented,2 also a solitary perineal papule,3 and a scrotal swelling.4 Clinicopathologically ­identical solitary lesions may be seen in adults. The histology is of lipid-laden histiocytes and giant cells, negative for CD1 and S-100 which are found in Langerhans cell histiocytosis. Juvenile xanthogranuloma is not associated with abnormal lipids but there may be a relationship with urticaria pigmentosa, diabetes mellitus, neurofibromatosis, cytomegalovirus infection and leukemia.

Fig. 12.266 Juvenile xanthogranuloma: lesions are present on the lateral shaft of the penis. Courtesy of R. Haufmann, Ulm, Germany. Reproduced with permission from Haufmann RE, Bachor, R. Juvenile xanthogranuloma of the penis. J Urol. 1993: 150: 456–457. From Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.

Langerhans cell histiocytosis This condition is regarded as an abnormality of immune function. It usually affects the genital area as part of disseminated disease but can rarely appear at this site alone.1–5 Females are affected much more often than males and presentation can occur at any age from infancy to old age. Anogenital lesions may present as ulcers, erosions, papules, nodules or plaques. Involvement of the penis is very rare.6 Presentation as a fleshy papule on the dorsal penis7 and primary penile ulceration8 have been reported. In infants, the diaper area may be affected, typically with a seborrheic-like dermatitis or purpuric papules.

Soft tissue tumors Keloid It has been asserted that the skin of the penis never forms keloid,1,2 but it has been reported after circumcision3 and other forms of trauma4,5 and may be commoner than suspected.6 Keloid has been simulated on the ­dorsum of the penis (Fig. 12.267) by chronic edema caused by a condom catheter.7

Fibroepithelial stromal polyp Clinical features Fibroepithelial stromal polyp (mesodermal stromal polyp, pseudosarcoma botryoides), which presents in women of reproductive age, predominantly affects the vagina and, less commonly, the vulva.1–9 Involvement of the ­cervix is rare.2 In the vagina, the lower third is the most frequent location. Presentation in the very young (including a congenital lesion) or the elderly is uncommon.10,11 Interestingly, about one-third of patients are pregnant, suggesting that hormonal influences play a significant role in the pathogenesis of these tumors.5 Lesions can be single or, more rarely, multiple and bilateral,12 the latter occurrence being most frequently seen in pregnancy. Tumors are usually less than 2 cm in diameter and are often pedunculated. Giant lesions are exceptional.13,14 Local recurrence may occur following incomplete ­excision but the behavior is benign.

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Fig. 12.267 Chronic edema simulating edema: note the dorsal proximal swelling and ventral urethral fistula. Courtesy of Dr. Rameshwar Bang, Safat, Kuwait. Reproduced from Bang RL. Penile oedema induced by continuous condom catheter use and mimicking keloid scar. Scand J Urol Nephrol 1994;28:333–5. From Bunker C: Male Genital Skin Disease. Saunders Ltd./Elsevier 2004.

Fig. 12.269 Fibroepithelial stromal polyp: in this field, there is striking nuclear atypia. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Histological features Low-power examination reveals a polypoid and often pedunculated lesion with fibrovascular stroma and showing variable cellularity. Small to medium-sized blood vessels with thick walls are conspicuous (Fig. 12.268). Hypocellular tumors contain abundant collagen and only scattered spindleshaped or stellate cells displaying mild focal or no cytological atypia and occasional to frequent multinucleated cells. With increasingly cellular tumors, there is more prominent cytological atypia and mitotic figures may be conspicuous (Figs 12.269, 12.270).8,9,15 Occasional atypical forms may be seen. Such variants are more frequent in pregnant patients. Multinucleated tumor cells become more prominent with a tendency to concentrate in the stroma adjacent to the epithelium. The cellularity is more prominent towards the center of the lesion.8 Small collections of mononuclear inflammatory cells are also commonly present. Tumor cells are positive for desmin, vimentin and estrogen and progesterone receptors.9,16,17 Positivity for actin is rare and macrophage markers are negative.12

Fig. 12.270 Fibroepithelial stromal polyp: the presence of multiple mitoses as shown in this field can be a source of concern to the unwary. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Ultrastructural studies show cells with features of fibroblasts and myofibroblasts.17,18

Differential diagnosis The main differential diagnosis, particularly for lesions presenting in the vagina, is sarcoma botryoides. The latter lesion, in contrast, tends to occur at a much younger age, lacks a cambium layer, displays invasion of the epithelium by tumor cells, and is composed of small, undifferentiated tumor cells.19

Lymphedematous fibroepithelial polyp of the glans penis and prepuce Clinical features Fig. 12.268 Fibroepithelial stromal polyp: there are thick-walled vessels associated with a variably cellular loose connective tissue stroma. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Only a handful of cases of this distinctive entity have been reported.1 Patients developed polypoid or cauliflower-like, usually long-standing, lesions on the glans penis or prepuce associated with chronic catheter use and phimosis. All reported cases are in adults with a median age of 40 years. There may be local recurrences.

Soft tissue tumors

Histological features Lesions are polypoid with a hyperplastic epidermis and an edematous stroma with telangiectasia and sometimes focal proliferation of vascular channels. In the background there are mono- or multinucleated stromal cells and scattered mononuclear inflammatory cells, mainly lymphocytes. The stromal cells are focally positive for actin and desmin.

Prepubertal vulval fibroma Clinical features This distinctive vulval lesion has been also described under the rubric childhood asymmetric labium majus enlargement.1,2 Lesions involve the labium majus and present as a unilateral and exceptionally bilateral swelling. Patients are girls between the ages of 3 and 13. A similar case in a postmenopausal patient has been documented.3

Histological features The lesion is poorly circumscribed, lies within the dermis and subcutis and consist of a poorly cellular mass with abundant collagen, edema and focal myxoid change. The cells within the tumor are positive for CD34.

Angiomyofibroblastoma

Fig. 12.271 Angiomyofibroblastoma: low-power view showing a richly vascular tumor. In this example, there is a strikingly myxoid stroma. By courtesy of M. Nucci, MD, and C.D.M. Fletcher, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Clinical features This is a distinctive benign soft tissue tumor of the external genitalia and perineum that must be distinguished from aggressive angiomyxoma (see below).1–5 Rare cases have been documented in the vagina, fallopian tube, urethra and retroperitoneum.6–9 It most commonly affects females of reproductive age but has also been described in the elderly.4 Cases in males are exceptional.10 A tumor sharing many clinical and histological features with angiomyofibroblastoma has been reported in the male genital tract as angiomyofibroblastoma-like tumor. These are described in the scrotum and groin and histologically show hybrid features between angiomyofibroblastoma and spindle cell lipoma.11,12 Angiomyofibroblastoma presents as a slowly growing, small (usually less than 5 cm diameter), asymptomatic subcutaneous mass in the vulva or, less commonly, in the vagina. Polypoid morphology is exceptional.13 They are frequently confused with a Bartholin’s gland cyst. In males, tumors occur on the scrotum and rarely in the perineum, groin and spermatic cord.14–16 Behavior is generally benign with little or no tendency for recurrence although a single malignant case has been reported.17,18 This tumor consisted of typical areas of angiomyofibroblastoma with areas of high-grade myxoid sarcoma.

Histological features Angiomyofibroblastoma is well circumscribed and surrounded by a fibrous pseudocapsule. Scanning magnification reveals a tumor with hypo- and hypercellular areas and a prominent vascular network composed of thinwalled dilated vascular channels (Figs  12.271, 12.272). The hypocellular areas display prominent myxoid change. Tumor cells are plump, epithelioid or ­spindle-shaped with imperceptible to abundant pink cytoplasm, finely ­dispersed chromatin and inconspicuous nucleoli. They tend to concentrate around the vascular channels. Multinucleated forms are frequent. Epithelioid cells with hyaline cytoplasm often have a plasmacytoid appearance. Cytological atypia is absent and mitotic figures are usually rare or exceptionally more prominent.19 Scattered lymphocytes and mast cells are often present. Intratumoral mature adipocytes are present in a number of cases and may represent most of the tumor (lipomatous variant of angiomyofibroblastoma).5,20 Degenerative nuclear hyperchromatism may sometimes be present. The tumor cells are diffusely and strongly positive for desmin but in only occasional cases are they positive for either smooth-muscle actin or panmuscle actin. Estrogen and progesterone receptor can be positive.5 CD34 is only exceptionally positive. Epithelial markers, S-100 and myoglobin are negative. Ultrastructural studies suggest myofibroblastic differentiation.1,3,4

Fig. 12.272 Angiomyofibroblastoma: the tumor cells have eosinophilic cytoplasm and small nuclei. Nucleoli are not apparent. By courtesy of M. Nucci, MD, and C.D.M. Fletcher, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Differential diagnosis Distinction from aggressive angiomyxoma is not usually difficult as the latter is larger (usually more than 5 cm), infiltrative, less cellular and vascular and contains vessels with thicker walls. However, tumors with hybrid features of angiomyofibroblastoma and aggressive angiomyxoma have been reported.21 Despite this, it is controversial whether both entities are related. Aggressive angiomyxoma has rearrangements of HMGA2, a member of the high-mobility-group protein family involved in alteration of chromatin structure and in the transcription of many genes. The latter feature has not been found in angiomyofibroblastoma.22 The rare cases of hybrid tumors are best classified and treated as aggressive angiomyxoma, and, if possible, cytogenetic analysis or immunohistochemistry for HMGA2 should be performed. By immunohistochemistry, nuclear staining for this protein is seen in the majority of (but not all) aggressive angiomyxomas and it tends to be negative in angiomyofibroblastoma.23,24 However, it is important to take into consideration that there is not always correlation between the translocation and protein expression.

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Aggressive angiomyxoma Clinical features This tumor presents as a slowly growing asymptomatic mass involving the pelvis and perineum.1–6 Exceptionally, the lesion can present in the retroperitoneum.7 It mainly affects females in the third or fourth decade of life. Only a single case has been reported in a child.8 Less than 5% of cases occur in males, with predilection for the scrotum, perineum or groin.9–11 In males, lesions may mimic a hydrocele or an inguinal hernia.12,13 Tumors are often 10 cm or more in diameter and can sometimes attain a very large size. Genitourinary and anorectal symptoms usually ensue due to external compression by the tumor. In females, lesions present mainly in the vulva or perineum followed by the vagina and the pelvis. Because of its extensive infiltrative growth, complete surgical excision is often difficult; local recurrences are therefore frequent and occur in up to 30% of cases. Metastasis are exceptional.14,15 Rare case reports have been published of tumors displaying prominent reduction in size after treatment with gonadotrophin releasing hormone agonists.16,17

Histological features Macroscopic examination reveals a soft, ill-defined, lobulated tumor with myxoid change. Microscopically, the lesion is infiltrative, with numerous small- and medium-sized blood vessels and a small number of tumor cells in a myxoid stroma (Figs 12.273–12.275). The blood vessels have thick walls, which are often hyalinized. Tumor cells are small, spindle-shaped or stellate with ill-defined pale pink cytoplasm and vesicular nuclei. Cytological atypia is absent and mitotic figures are rare. Bundles of smooth muscle are frequently seen adjacent to blood vessels, a finding that can be highlighted by a desmin stain.9 Residual normal structures including glands and smooth muscle are often entrapped by the tumor. Scattered mast cells are often present. Multinucleated giant cells similar to those found in stromal polyps are occasionally found. Some cases overlap histologically with angiomyofibroblastoma (see above). Immunohistochemically, tumor cells are positive for smooth-muscle actin and desmin. Positivity for estrogen and progesterone receptors is also seen and in men androgen receptors are positive.5,7,18 Cytogenetic analysis of a number of aggressive angiomyxomas has often shown rearrangements of chromosome 12q13–15. The latter results in an aberrant expression of HMGA2 (a member of the high-mobility-group protein family previously known as HMGIC).19–23 Interestingly, the area involved (12q14–15) is the same as that reported in a number of other tumors including leiomyoma and lipomatous neoplasms. Staining for HMGA2 may be useful to distinguish aggressive

Fig. 12.274 Aggressive angiomyxoma: in this view, a smooth muscle bundle is evident in the upper field. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Fig. 12.275 Aggressive angiomyxoma: high-power view showing a uniform cellular population. There is no pleomorphism. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

angiomyxoma from potential mimics, mainly angiomyofibroblastoma (see under the latter), but this marker, although sensitive, is not very specific.24,25 Electron microscopy shows cells with features of fibroblasts and myofibroblasts.5

Differential diagnosis See angiomyofibroblastoma. Chronic lymphedema of the vulva may give rise to a lymphedematous pseudotumor that can mimic aggressive angiomyxoma.26 In the former, however, there is massive edema rather than myxoid change, and telangiectatic lymphatics focally surrounded by lymphocytes. Identical changes may be seen in massive localized lymphedema secondary to morbid obesity.

Cellular angiofibroma Fig. 12.273 Aggressive angiomyxoma: there are conspicuous blood vessels dispersed in a myxoid stroma. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Clinical features Cellular angiofibroma is a distinctive tumor that occurs mainly on the vulva of middle-aged women.1–7 Very rare cases occur in the vagina.6,7 Presentation

Soft tissue tumors in males is less common, with lesions occurring in the inguinoscrotal region or rarely in the perianal region.1,2,6,7 Exceptional cases have been reported in the retroperitoneum and in the subcutaneous tissue of the chest, abdomen, knee, retroperitoneum, urethra, anus, upper eyelid and oral mucosa.2,7–10 Tumors tend to be small and behavior is benign, with almost no tendency for local recurrence except very rarely.1,7,11 Sarcomatous change has been reported but so far this has not been associated with aggressive behavior.7,12,13

Pathogenesis and histological features Cytogenetic analysis of cellular angiofibroma has shown loss of chromosome 13q14, a feature also seen in spindle cell lipoma and mammary-type myofibroblastoma.7,14,15 In conjunction with histological similarities, this gives further support to a link between these neoplasms. Tumors are well circumscribed but unencapsulated, with only occasional extension into the surrounding soft tissues (Figs 12.276–12.278).1 An infiltrative pattern is rare.7 Most lesions are fairly cellular and composed of short, bland, spindle-shaped cells with poorly defined pale eosinophilic cytoplasm and vesicular nuclei. Nuclear grooves and intranuclear inclusions are common. The number of mitotic figures varies but sometimes they may be prominent. Thick-walled, medium-sized hyalinized blood vessels are frequent in

Fig. 12.278 Cellular angiofibroma: the tumor cells are small, uniform and have round to oval vesicular nuclei. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

addition to slender collagen bundles and mast cells. Pseudovascular spaces are sometimes seen. Mature adipocytes are frequently present (in up to 30% of cases). Focal cytological atypia resembling symplastic changes seen in other tumors are described and sarcomatous transformation can be ­identified.7,12,13,16 Malignant areas usually show high cellularity, cytologic ­atypia and multinucleated cells.7 Tumors may rarely show features of a pleomorphic liposarcoma or of an atypical lipomatous tumor.6,13 Tumor cells are positive for vimentin and are positive for CD34 in up to 50% of cases. Staining for actin, desmin, caldesmon, S-100 protein and ­epithelial markers is negative.1, 2

Differential diagnosis

Fig. 12.276 Cellular angiofibroma: the tumor is characterized by thick-walled, hyalinized blood vessels associated with a densely cellular stroma. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Fig. 12.277 Cellular angiofibroma: note the associated collagen fibers. By courtesy of M. Nucci, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Distinction is mainly with angiomyofibroblastoma. The latter consists of more epithelioid desmin-positive cells with a nested pattern and a tendency for perivascular distribution. Cellular angiofibroma is negative for desmin and is often positive for CD34.

Genital leiomyoma Clinical features Genital leiomyoma comprises those lesions arising from the vulva, scrotum and nipple. Tumors arising in the vulva and scrotum are distinctive from other cutaneous leiomyomas including pilar leiomyoma and angioleiomyoma.1 Leiomyomas arising in the nipple are similar to pilar leiomyoma. Vulval leiomyomas are relatively rare and present mainly in women of reproductive age or slightly older as an asymptomatic swelling.1–5 Clinical features are not distinctive. Tumors are subcutaneous, well circumscribed and are often clinically diagnosed as a cyst. The majority of benign lesions are less than 5 cm in diameter and present in the labia. Rare cases arise in the ­clitoris.6 Tumors may increase in size during pregnancy and also in ­association with estrogen/progesterone replacement therapy.7 Benign tumors are typically ­circumscribed and small, but only histological examination allows for ­distinction between benign, low-grade malignant and malignant tumors. In the male8 it presents as a painless, slow-growing, palpable mass (papule or nodule), and/or difficulty with micturition9 if it affects the penis; or swelling of the scrotum where it arises from the tunica dartos scroti.1,10–12 Scrotal tumors are less common and tend to be larger than their vulval ­counterparts.13,14 They present as an asymptomatic mass that may occasionally be polypoid.14 Rare cases are associated with prominent warty epidermal hyperplasia and resemble condyloma acuminatum.15 Other benign smooth muscle lesions of the scrotum such as hamartoma of the dartos muscle are ­exceedingly rare.16

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Histological features Tumors are well circumscribed and noninfiltrative with variable cellularity.1–3 They are composed of admixed spindled and epithelioid cells, often with a single cell type predominating.4,17,18 Lesions with a spindled cell component are very similar to those found in the uterus and consist of bundles of cells with welldefined eosinophilic cytoplasm, vesicular cigar-shaped nuclei and an inconspicuous nucleolus. Focal myxoid change and hyalinization are commonly seen and sometimes this results in a plexiform appearance. Epithelioid tumor cells have abundant eosinophilic or pale-staining cytoplasm. Because of the rarity of vulval smooth muscle tumors, it is often difficult to separate benign lesions from those with potential for local recurrence or metastasis (see below). It has been suggested that a tumor with any evidence of mitotic activity, nuclear pleomorphism or an infiltrative margin should be regarded as having at least the potential for local recurrence.4 In such cases, excision with a margin of at least 1 cm should be recommended.4 Because of their rarity, there is even less information relating to histological evaluation of scrotal leiomyoma. Degenerative cytological atypia is accepted in these tumors but these changes occur in noncellular, well­circumscribed lesions that lack mitotic activity.19

Leiomyosarcoma

Fig. 12.279 Vulval leiomyosarcoma: this low-power view shows fascicles of tumor cells with eosinophilic cytoplasm. By courtesy of C. Crum, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Clinical features Vulval leiomyosarcoma is rare and presents in middle-aged to elderly patients as an asymptomatic mass mainly affecting the labia.1–6 Malignancy is not usually suspected on clinical examination unless the mass is large and poorly circumscribed. Lesions may be confused with a Bartholin’s gland cyst.6,7 Scrotal leiomyosarcomas are exceptional and present as an asymptomatic, rapidly growing mass in elderly patients.8,9 Wide local excision is the treatment of choice. It is difficult to predict the outcome because of their rarity and the lack of large studies with adequate follow-up information.

Histological features Accepted criteria for the histological diagnosis of leiomyosarcoma include (Figs 12.279–12.281):1,2,10 • size larger than 5 cm in diameter, • infiltrative margins, • more than 5 mitoses/10 high-power fields (HPF), • moderate to severe cytological atypia. More recently, it has been suggested that tumor necrosis should also be regarded as evidence of malignancy.10

Vulvar leiomyomatosis

Fig. 12.280 Vulval leiomyosarcoma: note the nuclear pleomorphism. By courtesy of C. Crum, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Clinical features This rare condition is characterized by multiple leiomyomas in the vulva associated with esophageal leiomyomas.1–8 The vulval tumors may appear before, concomitantly or after the development of esophageal lesions. Involvement of the clitoris is sometimes noted. Patients can also present with Alport’s syndrome, characterized by inherited glomerulonephritis, ocular abnormalities and deafness.5

Pathogenesis and histological features The pathogenesis of the disease is unknown but deletions and mutations in the COL4A6 and COL4A5 genes have been described.5,7 These genetic alterations are associated with defects in type IV collagen in Alport’s syndrome. Vulval and esophageal leiomyomas are identical to those occurring sporadically.

Myointimoma Clinical features This is a rare, recently described tumor involving the corpus spongiosum of the glans penis.1 The original series consisted of adult patients, but a recent small series in children and adolescents has been reported.1,2 Few single case

Fig. 12.281 Vulval leiomyosarcoma: high-power view showing a mitotic figure in the center of the field. By courtesy of C. Crum, MD, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA.

Soft tissue tumors reports have been presented.3–5 Lesions are small (usually less than 1 cm) and asymptomatic. It does not seem to be related to trauma. The behavior is benign with no tendency for local recurrence.1,2

Histological features Low-power examination reveals a diffuse myointimal proliferation of the blood vessels of the corpus spongiosum of the glans penis in a plexiform growth pattern (Figs 12.282–12.284). The proliferating cells are bland and spindled with abundant pink cytoplasm and vesicular nuclei. A minority of the cells display features more reminiscent of fibroblasts. The background stroma is sclerotic and myxoid. Focal degenerative changes may be seen and mitotic figures are absent. The spindled cells are positive for smooth-muscle actin, muscle-specific actin and calponin but negative for desmin.

Differential diagnosis This tumor must be distinguished from myofibroma, intravascular nodular fasciitis and vascular leiomyoma.

Postoperative spindle-cell nodule Clinical features

Fig. 12.283 Myointimoma: the vascular lumina are compressed by the proliferation of spindleshaped cells.

This rare reactive lesion presents as a small nodule at the site of a previous surgical procedure on the genitourinary tract including the bladder, vulva and the vagina.1–4 It grows rapidly and is usually asymptomatic.1–3 Local ­recurrence is usually not seen.

Fig. 12.284 Myointimoma: areas of hyalinization may be seen.

Pathogenesis and histological features

Fig. 12.282 Myointimoma: note the multinodular and plexiform growth pattern.

The lesion is regarded as a non-neoplastic reparative phenomenon, Interestingly, trisomy 7 has been reported in two cases.5 The nodule is poorly circumscribed and resembles nodular fasciitis.1–3 It is composed of bundles of plump myofibroblast-like cells dispersed in a myxoid or edematous background. Nuclei may be bland or hyperchromatic. Small blood vessels, foci of hemorrhage, lymphocytes and neutrophils are additional features. Mitotic figures are common.

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Degenerative and metabolic diseases Nooshin Brinster and Eduardo Calonje

The hyperlipidemias  520

Porphyria  549

Eruptive xanthomata  522 Tendinous xanthomata  523 Tuberous xanthomata  525 Planar xanthomata  527 Verruciform xanthoma  528

Congenital erythropoietic porphyria  550 Erythropoietic protoporphyria  551 Hereditary coproporphyria  553 Porphyria cutanea tarda  553 Hepatoerythropoietic porphyria  555 Variegate porphyria  555

Angiokeratoma corporis diffusum  530 The amyloidoses  532 Primary and myeloma-associated systemic amyloidosis  534 Secondary amyloidosis  536 Hemodialysis-associated amyloidosis  536 Heredofamilial amyloidoses  537 Amyloid elastosis  537 Primary localized cutaneous amyloidosis, lichen and macular types  537 Secondary localized cutaneous amyloidosis  541 Familial primary cutaneous amyloidosis  541 Nodular amyloidosis  541

Colloid milium  543 Juvenile colloid milium  543 Adult colloid milium  544

Hyalinosis cutis et mucosae  546 Cutaneous macroglobulinosis  548

See www.expertconsult.com

for references and additional material

Pellagra  565

Lichen myxedematosus/scleromyxedema  574 Acral persistent papular mucinosis  578 Cutaneous mucinosis of infancy  579 Self-healing juvenile cutaneous mucinosis  579 Reticular erythematous mucinosis  580 Scleredema  580 Papular and nodular cutaneous mucinosis of systemic lupus erythematosus  581 Myxoid cyst  582 Cutaneous focal mucinosis  582 Mucinous nevus  583 Neuropathia mucinosa cutanea  583 Self-healing infantile familial cutaneous mucinosis  583 Localized mucinosis secondary to venous insufficiency  583 Secondary cutaneous mucinosis  583

Scurvy  566

Acanthosis nigricans  583

Calcinosis cutis  566

Acrodermatitis enteropathica  586

Pseudoporphyria  559 Gout  562 Ochronosis  564 Alkaptonuria  564 Exogenous ochronosis  564

Hartnup disease  565

Dystrophic calcinosis cutis  566 Metastatic calcinosis cutis  568 Idiopathic calcinosis cutis  568

Necrolytic migratory erythema  587 Bullosis diabeticorum  589

The mucinoses  571 Generalized myxedema  572 Localized (pretibial) myxedema  573

The hyperlipidemias The hyperlipidemias may present as cutaneous xanthomata, which are localized aggregates of histiocytes containing accumulated lipid (primarily free and esterified cholesterol), in the form of five main clinical types: • eruptive, • tendinous, • tuberous, • planar, • disseminated.1 The last, xanthoma disseminatum, in which serum lipid levels are normal, is discussed in Chapter 29 (see xanthogranuloma). Xanthoma cells express CD4, CD11c, CD14b, and CD68 in addition to human leukocyte antigen (HLA) class II antigens.2 Hyperlipidemias may be primary, or secondary to conditions such as diabetes mellitus, obesity, pancreatitis, renal disease (the nephrotic syndrome or chronic renal failure), hypothyroidism, alcohol consumption, pregnancy, cholestatic liver disease (e.g. primary biliary cirrhosis) and paraproteinemias. Drug-induced hyperlipidemia also occurs as a result of administration of estrogens, corticosteroids or 13-cis-retinoic acid. It is often associated with serious, potentially life-threatening disorders such as atherosclerosis (low density lipoproteins) and pancreatitis (hypertriglyceridemia).3

The presence of xanthomata commonly represents a cutaneous manifestation of systemic disease, and their recognition should therefore be followed by an intensive investigation to exclude the latter (Table 13.1).2,4 Although not a hard and fast rule, xanthoma morphology and distribution can ­sometimes point towards specific hyperlipidemia variants. The plasma lipids are composed of triglycerides and cholesterol; these are insoluble and their transport is facilitated by their aggregation into lipoproteins. The latter are macromolecular complexes composed of an outer shell of hydrophilic phospholipids, nonesterified cholesterol and apo(lipo)proteins, which emulsify the associated hydrophobic core of triglycerides and cholesterol ester.5 There are a large number of apoproteins, with variable structure and function (e.g. ApoB-48, which is required for the secretion of chylomicrons into the thoracic duct).3 In addition to giving structure to the lipoprotein, apoproteins also represent ligands for specific receptors (e.g. ApoE is a ligand for liver chylomicron receptors). They also act as cofactors for a ­number of lipid-modifying enzymes (e.g. ApoCII activates lipoprotein lipase).5 Lipoprotein metabolism, which is summarized in Figure 13.1, involves both exogenous (dietary) and endogenous pathways.6 For more detailed information the reader is particularly referred to references 1 and 6. The classification of hyperlipidemias is based upon the electrophoretic separation, on paper or agarose gel, of abnormal quantities of lipoprotein in the plasma (Fig. 13.2). There are seven main classes of lipoprotein, with ­differing electrophoretic mobilities:

The hyperlipidemias Table 13.1 Classification of xanthomatous disorders Hyperlipidemic xanthomatoses: disorders characterized by elevated plasma triglycerides or cholesterol

Normolipidemic xanthomatoses: disorders characterized by normal plasma triglycerides and cholesterol

Primary hyperlipoproteinemias

Elevated plasma triglycerides lipoprotein lipase deficiency familial hyperlipoproteinemia, type V familial hypertriglyceridemia Elevated plasma triglycerides and cholesterol familial dysbetalipoproteinemia, type III Elevated plasma cholesterol familial hypercholesterolemia

Disorders characterized by altered lipoprotein content or structure

Accumulation of unusual sterols in LDL cerebrotendinous xanthomatosis(cholestanol) sitosterolemia (sitosterol, campesterol, stigmasterol, etc.) Deficiency of HDL plantar and buccal mucosal xanthomas diffuse plane xanthomas Normocholesterolemic dysbetalipoproteinemia tuberous xanthelasmas Hyperapobetalipoproteinemia tendon xanthomas xanthelasmas

Secondary hyperlipoproteinemias

Elevated plasma triglycerides diabetes mellitus drug-induced chylomicronemia alcohol estrogens retinoids hypothyroidism nephrotic syndrome type I glycogen storage disease (von Gierke’s disease) Elevated plasma cholesterol hepatic cholestasis primary biliary cirrhosis biliary atresia hypothyroidism dysglobulinemias or paraproteinemias multiple myeloma

Disorders associated with antibodies directed against lipoprotein components

Multiple myeloma Other paraproteinemias

States with no demonstrated lipoprotein abnormalities

Underlying lymphoproliferative disease multiple myeloma cryoglobulinemia Waldenström’s macroglobulinemia leukemia lymphoma other Xanthomatosis antedated by local tissue alterations normolipemic eruptive xanthomas (after erythema) xanthelasmas and planar xanthomas (after erythroderma) fiverruciform xanthomas (in areas of dystrophic epidermolysis bullosa) Other hereditary tendinous and tuberous xanthomas normolipemic tendon and tuberous xanthomas normolipemic subcutaneous xanthomatosis

HDL, high density lipoprotein; LDL, low density lipoprotein. Reprinted from Cruz, P.D., East, C., Bergstresser, P.R. (1988) Journal of the American Academy of Dermatology, 19, 95–111 with permission from the American Academy of Dermatology, Inc.

• chylomicrons, which are composed predominantly of exogenous

triglycerides produced by small intestinal mucosal epithelium in response to dietary lipid, • very low density (pre-beta) lipoproteins (VLDL) of hepatic derivation, which are particularly involved in the transportation of endogenous triglyceride, • intermediate density lipoproteins (IDL), which are thought to be VLDL remnants, • low density (beta) lipoproteins (LDL), which are mainly involved in cholesterol transport and derived from IDL or else produced by the liver, • high density (alpha) lipoproteins (HDL) composed predominantly of lipoprotein and equal quantities of cholesterol and phospholipid, • high density lipoprotein variant HDL2,1,5 • high density lipoprotein variant HDL3.1,5 The hyperlipidemias are classified into six types according to the lipoprotein anomaly present (Table 13.2). However, it should be noted that each of these six types may result from a variety of pathogeneses, including those of a known or presumed genetic basis and others that complicate a diverse group of disease processes (secondary hyperlipidemia).7–9 High density lipoproteins are not atherogenic.3 Indeed, their function is to remove cholesterol from the tissues and high levels serve to protect against vascular disease.5 Conversely, HDL deficiency (e.g. Tangier disease) is associated with cholesterol accumulation.10

The lipid content of xanthomata is probably mostly derived from the plasma, presumably by lipoprotein (particularly LDL and VLDL) permeation of blood vessel walls with the release of lipid and its subsequent phagocytosis by histiocytes, although localized lipogenesis may also be of importance.10–13 The subgroups and proportions of lipid deposited within xanthomata are similar to those found in atheromatous plaques, raising the possibility of a shared pathogenesis.1 Xanthomata are, however, not always associated with hypercholesterolemia or hyperlipoproteinemia.14 Under such circumstances, they may evolve as a consequence of altered lipoprotein content or structure, represent local tissue changes or develop as a consequence of systemic disease including lymphoma, multiple myeloma, and Waldenström's macroglobulinemia.15 Normocholesterolemic xanthomata can therefore arise as a consequence of the accumulation of cholesterol-like substances within histiocytes (e.g. ­cerebrotendinous xanthomatosis and β-sitosterolemia). Cerebrotendinous xanthomatosis represents an abnormality of bile acid metabolism inherited in an autosomal recessive pattern.16–18 As a ­consequence of mitochondrial enzyme sterol 27-hydroxylase deficiency and resultant impaired oxidation of the cholesterol side chain during the production of cholic acid, cholestanol (and cholesterol) accumulates in the tissues, ­especially the tendons, lungs, and brain. The xanthomata particularly affect the Achilles tendons and the tendons of the knees, elbows, and the interphalangeal joints.19 In addition to tendinous xanthomata, patients develop j­uvenile cataracts and progressive neurological dysfunction including mental ­retardation, dementia, pyramidal signs,

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Fig. 13.1 Lipoprotein metabolism. (LDL, low density lipoprotein; VLDL, very low density lipoprotein.) Reproduced with permission from Cruz, P.D., East, C., Bergstresser, P.R. (1988) Journal of the American Academy of Dermatology, 19, 95–111.

Eruptive xanthomata Clinical features

Fig. 13.2 Hyperlipidemia: electrophoretic separation of serum lipids. (Chylo, chylomicron; HDL, high density lipoprotein; LDL, low density lipoprotein; VLDL, very low density lipoprotein.) By courtesy of B. Lewis, MD, St Thomas’ Hospital, London, UK.

cerebellar ataxia, spinal cord paresis, and sensory changes due to dysmyelination.18,20,21 Coronary ­atherosclerosis, endocrine ­abnormalities, and diarrhea may also be present. In addition to cholestanol accumulation, cerebrotendinous xanthomatosis has been shown to be ­characterized by abnormal high density ­lipoproteins, which result in impaired cholesterol (and cholestanol) transport and contribute to the ­consequent xanthomatization.16 The mortality is high, patients usually dying in the fourth to sixth decades, most often from progressive neurological ­dysfunction, pseudobulbar paralysis or myocardial infarction.21 Tendinous and tuberous xanthomata may also represent a manifestation of β-sitosterolemia. This is an autosomal recessive condition in which increased intestinal absorption of the plant sterols β-sitosterol, campesterol, and stigmasterol results in tissue deposition along with cholesterol and subsequent xanthoma formation.22–24 Normally these sterols are almost completely unabsorbed from the gastrointestinal tract. β-Sitosterolemia is associated with an increased risk of atherosclerosis.3 Xanthomata may occur in extracutaneous locations mimicking tumors in patients with hyperlipidemia. Sites include deep soft tissues and mediastinum.25

Eruptive xanthomata are small (1–4 mm) yellowish papules with a red halo that have a predilection for the buttocks, shoulders, and extensor surfaces of the limbs (Fig. 13.3).1 They may also present in the antecubital and popliteal fossae, axillae, lips, eyelids, and ears.2 They often appear in crops and may wax and wane with plasma lipoprotein levels.3 Lesions usually resolve spontaneously over a period of weeks. Pruritus is frequently present and the papules are sometimes tender.2 Eruptive xanthomata may rarely display a Koebner phenomenon.4,5 Healing is occasionally associated with the development of hyperpigmented scars.2 Cutaneous lesions of Langerhans cell histiocytosis may mimic eruptive xanthoma.6 Eruptive xanthomata are associated with hypertriglyceridemia and most often occur in hyperchylomicronemic states. Sometimes their presence ­correlates with increased levels of very low density lipoproteins. The most ­common cause, however, is secondary hyperlipoproteinemia, especially in those cases associated with diabetes mellitus and alcohol ingestion, or in those that are drug induced (e.g. due to exogenous estrogens, corticosteroids or retinoids).2,7 They may also develop as a consequence of decreased lipoprotein lipase activity, ApoCII deficiency or increased synthesis of VLDL, which effectively blocks chylomicron access to lipoprotein lipase.2,8 Eruptive xanthomata are therefore often accompanied by other features of hyperlipidemia, ­including lipemia retinalis, hepatosplenomegaly, abdominal pain, and pancreatitis. They may also rarely develop as a manifestation of primary hyperlipoproteinemia (HPL), particularly autosomal recessive lipoprotein lipase deficiency (HLP type I) in children and familial HPL type V in adults.9,10 An exceptional association with β-sitosterolemia, a condition usually presenting with tuberous or tendinous xanthomata, has been documented.11 Much rarer ­associations include familial hypertriglyceridemia, the nephrotic syndrome, chronic pancreatitis, von Gierke's disease, and hypothyroidism.7,12,13 An association with acanthosis nigricans has also been reported.14

Histological features The histological features are seen predominantly within the superficial reticular dermis. In early lesions histiocytes are numerous and the fully developed

The hyperlipidemias Table 13.2 Classification of hyperlipidemias Type

Anomaly

Primary cause

Secondary cause

I

Raised chylomicrons

Familial lipoprotein lipase deficiency Apoprotein Cll deficiency

−

IIA

Raised LDL

Familial hypercholesterolemia Familial multiple type hyper lipoproteinemia Common hypercholesterolemia

IIB

Raised LDL and VLDL

III

Atherogenesis

Xanthoma

Associations

−

Eruptive

Hepatomegaly Pancreatitis Lipemia retinalis Abdominal pain

Hepatoma Porphyria Myxoedema Anorexia nervosa Nephrotic syndrome Cushing’s syndrome

+

Tendinous Xanthelasma Arcus Tuberous (rare)

−

Familial hypercholesterolemia Familial multiple type hyperlipidemia

Nephrotic syndrome Cushing’s syndrome

+

Tendinous Xanthelasma Arcus Tuberous

−

Raised IDL

Familial dysbetalipoproteinemia

Paraproteinemia

+

Palmar Tendinous Tuberous

Diabetes Gout Obesity

IV

Raised VLDL

Familial multiple type hyperlipidemia Familial hypertriglyceridemia Sporadic hypertriglyceridemia

Diabetes Uremia Paraproteinemia Alcoholism Lipodystrophy Obesity

+

Eruptive Tendinous Tuberous

−

V

Raised chylomicrons and VLDL

Familial multiple type hyperlipoproteinemia Familial lipoprotein lipase deficiency Apoprotein Cll deficiency Familial hypertriglyceridemia Famial type V hyperlipoproteinemia

Diabetes Obesity Pancreatitis

+

Eruptive

Hepatomegaly Pancreatitis Lipemia retinalis

IDL, intermediate density lipoprotein; LDL, low density lipoprotein; VLDL, very low density lipoprotein.

Eruptive xanthomata often develop rapidly over the course of several days and occasionally are associated with spontaneous resolution. The quantity of ­intracytoplasmic lipid (predominantly triglyceride in contrast to other xanthomata, which contain mostly cholesterol) is in a state of flux and may be associated with extracellular deposition, a phenomenon that is rare or absent in the other types of xanthomata. In all xanthomata the lipid within the macrophage stains positively with fat stains such as oil red O, scarlet or Sudan red (Fig. 13.7).

Differential diagnosis There can be confusion with granuloma annulare histologically as both conditions have certain features in common, namely a dermal interstitial ­histiocytic infiltrate with variably increased mucin.12,17 Although extracellular lipid may disrupt dermal collagen, necrobiosis is not characteristic of ­eruptive ­xanthoma. Additionally, it contains few giant cells and the ­perivascular infiltrate is ­lymphocytic, in contrast to the histiocytes seen in granuloma annulare.12 Fig. 13.3 Eruptive xanthoma: numerous small yellow papules are present on the buttocks. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Tendinous xanthomata Clinical features

‘foam cells’, which characterize xanthomata, are sometimes few in number. The infiltrate may also contain an admixture of lymphocytes and ­neutrophils.15,16 In an established papule, xanthoma cells with characteristic clear or foamy cytoplasm form the predominant cell type (Figs 13.4–13.6).

Tendinous xanthomata, which are associated with raised low density lipoprotein levels, are slowly enlarging subcutaneous tumors that occur in tendons (especially those of the hands, knees, elbows, and the Achilles tendon), ligaments, fascia, and periosteum (Figs 13.8, 13.9).1 The overlying skin,

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Fig. 13.6 Eruptive xanthoma: the histiocytes express CD68.

Fig. 13.4 Eruptive xanthoma: biopsy of an established lesion. The histiocytes have abundant vacuolated cytoplasm.

Fig. 13.7 Eruptive xanthoma: the lipid within the macrophages stains positively with oil red O.

Fig. 13.5 Eruptive xanthoma: high-power view showing an admixture of vacuolated xanthoma cells and nonlipidized variants with abundant eosinophilic cytoplasm.

which appears normal, is freely moveable over the surface and small tendon xanthomata may be difficult to palpate.1 The lesions characteristically ‘move with the tendons’ and are thought to be trauma related.2 The ­presence of these xanthomata is most frequently a feature of heterozygous familial (LDL receptor deficiency) hypercholesterolemia.2–4 There is a high risk of associated coronary atherosclerosis. A recent meta-analysis demonstrated a threefold increased risk of cardiovascular disease in patients with familial hypercholesterolemia and tendinous xanthomata compared to those without cutaneous lesions.5 Tendinous xanthomata are also seen in familial combined hyperlipidemia, normocholesterolemic states such as cerebrotendinous xanthomatosis (cholestanolosis) and β-sitosterolemia, and the nephrotic syndrome.2,6–10 Clinically, the lesions, which may be mistaken for gouty tophi and rheumatoid nodules, are sometimes found in association with tuberous xanthomata and xanthelasmata.

Fig. 13.8 Tendinous xanthoma: typical nodules on the heels. These lesions are often related to trauma; the Achilles tendon is a classical site. By courtesy of A.F. Lant, MD, and J. Dequeker, MD, London, UK.

The hyperlipidemias Four other conditions may also be characterized by tuberous xanthomatosis: • homozygous familial hypercholesterolemia, • cerebrotendinous xanthomatosis, • β-sitosterolemia,1 • type IV hyperlipoproteinemia.4 Tuberous xanthomata also occur in secondary hyperlipidemia (e.g. due to the nephrotic syndrome or hypothyroidism). Protease inhibitors may cause hyperlipidemia, and ritonavir has been reported to induce tuberous and tendinous xanthoma lesions.5 Clinically, tuberous xanthomata occasionally resemble the lesions of erythema elevatum diutinum. Tuberous and tendinous normolipemic xanthomata have been described but it seems that, with adequate follow-up, patients usually develop some form of hyperlipidemia.6

Fig. 13.9 Tendinous xanthoma: xanthomata are present overlying the knuckles. By courtesy of the Institute of Dermatology, London, UK.

Histological features Tendinous xanthomata are composed of multiple nodules containing ­ anthoma cells, accompanied in early lesions by an admixture of inflamx matory cells including histiocytes, lymphocytes, and neutrophil polymorphs. The deposits in tendinous xanthoma are doubly refractile to polarized light (Fig. 13.10). Older lesions are characteristically ­associated with fibrosis.

Tuberous xanthomata Clinical features

Fig. 13.11 Tuberous xanthoma: firm erythematous nodules over the elbow. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Tuberous xanthomata are firm yellow–red papules and nodules, which are found most frequently on the extensor aspect of the knees, elbows, and buttocks (Figs 13.11–13.13).1 Lesions sometimes also occur on the hands and palms.2 They are most characteristically seen in familial dysbetalipoproteinemia type III, and there is a particular risk of peripheral ­vascular disease.3

Fig. 13.10 Tendinous xanthoma: intense birefringence of deposits in polarized light (oil red O).

Fig. 13.12 Tuberous xanthoma: erythematous nodule on the back of the arm. By courtesy of the Institute of Dermatology, London, UK.

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A

Fig. 13.13 Tuberous xanthoma: in this example, eruptive lesions are present on the elbows. By courtesy of the Institute of Dermatology, London, UK.

Cholesterotic fibrous histiocytomas may be associated with hyperlipidemia and often simulate a tuberous xanthoma clinically and histologically.7 A rare case of malignant fibrous histiocytoma clinically presenting as a tuberous xanthoma in a patient with type IIA hyperlipoproteinemia has been documented.8

Histological features Tuberous xanthomata consist of multiple nodules in the reticular dermis and sometimes the subcutaneous fat (Fig. 13.14). Their appearance varies, depending upon their stage of evolution (Fig. 13.15). Xanthoma cells predominate in early lesions, but with maturity fibrosis supervenes (Fig. 13.16). On occasion, foreign body giant cell granulomata containing cholesterol clefts are seen and a ­perivascular chronic inflammatory cell infiltrate is ­sometimes evident (Fig. 13.17).

Differential diagnosis

B

Fig. 13.15

Heavily lipidized fibrous histiocytomas that tend to occur mainly around the ankle may histologically mimic tuberous xanthoma.9

Tuberous xanthoma: (A) the infiltrate is composed of uniform xanthoma cells characterized by pale, foamy cytoplasm and small central vesicular nuclei; (B) occasional normal mitoses are commonly present.

Fig. 13.14

Fig. 13.16

Tuberous xanthoma: several nodules are present in the reticular dermis.

Tuberous xanthoma: there is marked scarring.

The hyperlipidemias

A

B

Fig. 13.17 (A, B) Tuberous xanthoma: in addition to xanthoma cells, occasionally there are foreign body giant cells containing cholesterol clefts. The lipid has been dissolved out during processing.

Planar xanthomata Clinical features Planar xanthomata are typically soft yellow dermal macules or plaques that occur most frequently around the eyes, where they are known as xanthelasmata (Fig. 13.18).1,2 About 50% of patients with xanthelasmata have associated hyperlipidemia (hypercholesterolemia or hyperlipoproteinemia type III) which is often accompanied by a cholesterol corneal arcus.3–5 Many of those who appear biochemically normal on routine testing, however, are shown to have subtle abnormalities of lipid metabolism on more detailed analysis.6 There is a particularly increased risk of coronary artery atherosclerosis in younger patients.1 When very extensive (diffuse or generalized plane xanthomatosis) and associated with orange–yellow planar xanthomata around the head and neck, and occasionally the upper trunk and arms, there may be an associated systemic disorder such as multiple myeloma with paraproteinemia, cryoglobulinemia, benign paraproteinemia or, less commonly, leukemia and rheumatoid arthritis (necrobiotic xanthogranuloma) (Fig. 13.19).1,3,7–13 More exceptional associations include idiopathic Bence Jones proteinuria,

A

B

Fig. 13.19 Fig. 13.18 Xanthelasmata: note the yellow, periorbital plaques. These are a common manifestation of hypercholesterolemia. By courtesy of the Institute of Dermatology, London, UK.

Planar xanthoma: (A) widely distributed lesions over the forehead, eyelids, and cheeks; (B) extensive yellow plaques on the scalp. This appearance should prompt a search for an associated paraproteinemia. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

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Degenerative and metabolic diseases Sézary's syndrome, Castleman's disease, relapsing polychondritis, acquired palmoplantar keratoderma, adult T-cell leukemia/lymphoma, and Takayasu's disease.14–20 A patient with monoclonal gammopathy and cutaneous lesions with features of both plane xanthoma and amyloidosis has been ­documented.21 The latter case was also associated with myeloma. In cases of myeloma and plane xanthoma, it has been demonstrated that complexes form between serum lipoproteins and paraprotein, suggesting that this interaction may induce a hyperlipidemia and xanthoma formation.22,23 The serum lipid levels of patients with diffuse plane xanthomata are normal or raised. Plane xanthomata may present in the gingiva and, in this location, are usually associated with hyperlipidemia.24 An exceptional case has been described in an infant presenting with normolipemic papular and nodular lesions progressing to plane xanthomata and resulting in spontaneous resolution.25 Diffuse plane normolipemic xanthomata with mucosal and conjunctival involvement and aortic valve xanthomatosis may occur exceptionally.26 Lesions have been reported that clinically resembled plane xanthomata in a patient with systemic lupus erythematosus but histologically showed degeneration of collagen bundles with secondary fat deposition.27 Intertriginous xanthomata seen in patients with raised low density lipoproteins and pathognomonic of homozygous familial hypercholesterolemia present as yellow papules and plaques, often with a cobblestone appearance. These occur in the finger webspaces and to a lesser extent in the axillae and antecubital and popliteal fossae.2,28 They have a particularly high association with early and severe atherosclerosis. Intertriginous xanthomata may also rarely be seen in heterozygous familial hypercholesterolemia.29 Planar xanthomata presenting as yellow–orange macules in the skin creases of the palm and fingers (xanthoma striatum palmare) are diagnostic of familial dysbetalipoproteinemia (HLP type III, broad beta disease) (Fig. 13.20), which is due to an abnormality of the apoprotein ApoE (homozygous ApoE2/ E2).1,2,30 This results in impaired uptake of lipoprotein remnant particles by the liver and macrophages with resultant hyperlipoproteinemia and increased atherogenesis.29 Interestingly, the tendency to familial dysbetalipoproteinemia is present in 1% of the population, but a second lipid abnormality appears to be necessary to induce symptoms.29 Plane xanthomata of cholestasis, for example due to primary biliary cirrhosis and biliary atresia, present as well-demarcated, beige–orange plaques that are particularly found on the hands and feet, but may occur elsewhere.2 They can also develop in patients with diabetes mellitus and have been described in the setting of cholestasis resulting from chronic graft-versus-host disease.31 Planar xanthomata have also been described as a feature of HDL deficiency.32

Histological features In planar xanthomata, the characteristic lipid-laden foam cells are ­situated within the superficial dermis (Figs 13.21–13.23). There is minimal fibrosis. In rare cases, the histology may overlap with that of necrobiotic xanthogranuloma.33

Verruciform xanthoma Clinical features The verruciform xanthoma is an uncommon, asymptomatic lesion, which occurs predominantly in the oral cavity of adults in their fifth or sixth decade and shows a male predilection (1.7:1).1–5 It is most often found on the ­premolar gingiva of the mandible or maxilla.1 At this site it usually ­produces a ­solitary, well-circumscribed, asymptomatic, erythematous or yellow–tan lesion, 3–20 mm in diameter, which may be papillomatous or ulcerated. The patients are normolipidemic. The clinical differential diagnosis includes viral warts, leukoplakia, and squamous cell carcinoma. Verruciform xanthomata of the skin, which are extremely rare, have been described at a variety of sites including the ear, nose, and digits.6–9 Most cases described, however, have arisen on anogenital skin (Fig. 13.24).10–16 It may also develop as a reactive phenomenon within epidermolytic acanthoma,

Fig. 13.21 Planar xanthoma: a dense infiltrate is present in the upper dermis.

Fig. 13.20 Planar xanthoma: palmar lesions presenting as discrete macules with accentuation in the skin creases. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.22 Planar xanthoma: there is an admixture on nonlipidized and lipidized histiocytes.

The hyperlipidemias Although most studies have not demonstrated definitive evidence to support this hypothesis, there are isolated reports demonstrating HPV DNA by polymerase chain reaction (PCR) in the lesions.32–35 Additionally, it has been suggested that keratinocyte necrosis may lead to the release of intracellular lipids, with resultant macrophage influx and xanthomatization.3,34,36 The inciting event leading to keratinocyte necrosis has not been identified. Immunohistochemical and electron microscopic studies tend to give support to this latter hypothesis (see below). Verruciform xanthoma is an exophytic lesion characterized by massive but regular epidermal proliferation, parakeratosis, and hyperkeratosis (Fig. 13.25).32 Neutrophils, neutrophilic debris, and bacterial colonies may be ­evident in the parakeratotic stratum corneum. The acanthosis is associated with uniform, bulbous epidermal ridges, all of which penetrate to the same depth, giving a characteristically level lower border. The expanded ridges are associated with marked central keratinocyte necrosis and a heavy ­neutrophil polymorph inflammatory cell infiltrate (Fig. 13.26). There is no

Fig. 13.23 Planar xanthoma: in addition to xanthoma cells, there are scattered lymphocytes.

Fig. 13.25 Verruciform xanthoma: there is marked acanthosis, hyperkeratosis, and a level lower border.

Fig. 13.24 Verruciform xanthoma: in this unusual gross example, there are numerous warty and polypoid lesions showing extensive involvement of the vulva, perineum, and thighs. A viral etiology was initially suspected clinically.

­seborrheic keratoses, and epidermal nevi (including patients with inflammatory linear verrucous epidermal nevus or with the epidermal nevus syndrome) and has been recorded as a complication of lymphedema.9,17–22 It has been described in association with longstanding discoid lupus erythematosus, complicating ulceration in epidermolysis bullosa, and in association with squamous cell carcinoma of the penis.23–27 Occasionally, verruciform xanthomata are multifocal.6 Such a case has been described as multiple lesions in the upper aerodigestive tract of a child with a systemic lipid storage disease.28 Multiple verruciform xanthomata have also been reported in the anogenital region several years following necrotizing fasciitis of the perineum and in the oral mucosa in a patient with chronic graft-versus-host disease.29,30 A rare case of disseminated lesions has been described on the hands, feet, and anogenital region.31 In the skin, verruciform xanthoma usually presents as a gray or pink nodule or as a plaque with a variably warty surface. Untreated, the lesions have a long duration and behave in a benign fashion, recurrence being very uncommon after local excision.

Pathogenesis and histological features The etiology and pathogenesis of the verruciform xanthoma are unknown. Originally, a viral infection by human papillomavirus (HPV) was suspected.

Fig. 13.26 Verruciform xanthoma: there is extensive keratinocyte necrosis associated with a polymorph infiltrate.

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Degenerative and metabolic diseases epithelial atypia and viral inclusions are invariably absent. The ­accentuated papillary dermis between the elongated epidermal ridges contains large numbers of eosinophilic foamy to granular xanthoma cells, which stain positively with lipid stains, but not usually with the diastase–periodic acidSchiff (PAS) technique (Fig. 13.27). No foreign body or Touton giant cells are present. At the base of the lesion the epidermis may show focal basal cell hydropic degeneration associated with patchy loss of basement membrane. The reticular dermis deep to the lesion often contains a moderately dense lymphocyte–plasma cell infiltrate, which at the edge of the lesion sometimes adopts a lichenoid distribution. Typically,vascular ectasia is seen beneath the lesion. By immunohistochemistry, fully formed foamy cells are negative for histiocytic markers including factor XIIIa, Mac 387, Ham-56, and KP1.34,37 Cells with incompletely lipidized cytoplasm show diffuse positivity for KP1 and weak positivity for FXIIIa and keratin. Cells with little cytoplasmic lipid are diffusely positive for FXIIIa and weakly positive for keratin. Nonlipidized cells located in the periphery of the infiltrate are diffusely positive for FXIIIa only. This staining pattern has led to the suggestion that FXIIIa-positive dermal dendritic cells play an active role in the formation of the lipid cells seen in this condition.34 It also tends to give further support to the role of damaged keratinocytes in the pathogenesis of verruciform xanthoma.34 The mechanism of keratinocyte damage is not fully elucidated. One theory proposes that the macrophages play an active role in keratinocyte cleavage and keratinolysis with secondary release of epithelial lipid. Macrophage recruitment is postulated to occur as a consequence of CD8-positive T cells present in the submucosa.38,39 Ultrastructural studies have revealed histiocytes containing numerous nonmembrane-bound lipid droplets, lysosomes, and myelin figures.11,40 Smaller numbers of these lipid inclusions may be found in the overlying keratinocytes and in the intercellular space. In one report, basal melanocytes were found to contain conspicuous lipid droplets.41 This was accompanied by evidence that the latter had been released into the basal intercellular space in association with disruption of the basal lamina, thereby providing a source for the lipid within the dermal macrophages.

Differential diagnosis Verruciform xanthoma must be distinguished from viral warts, granular cell tumor, and verrucous carcinoma:

Fig. 13.27 Verruciform xanthoma: in the papillary dermis there is an infiltrate of uniform xanthoma cells.

• Viral warts: verruciform xanthoma lacks the vacuolation, clumped •

•

keratohyalin granules and tiers of parakeratosis seen in a viral wart. Inclusions are not a feature. In granular cell tumor the hyperplastic overlying squamous epithelium often shows an infiltrative growth pattern, in contrast to the exophytic nature of verruciform xanthoma. The granular cells are larger, often have a syncytial appearance, and typically stain positively with the PAS reaction. Verrucous carcinoma has both exophytic and endophytic components, the latter appearing as deeply penetrating bulbous epithelial processes. The epithelium often has a ‘watery’ appearance and xanthoma cells are not a feature.

Angiokeratoma corporis diffusum Clinical features Angiokeratoma corporis diffusum (Anderson-Fabry's disease) is a sex-linked recessive disorder of glycosphingolipid metabolism with a high mortality. It is very rare with an approximate incidence of 1 in 200 000.1 Deficiency of the lysosomal enzyme α-galactosidase A leads to the widespread accumulation of neutral glycolipids, mainly globotriaosylceramide (GB3, ceramidetrihexoside), and elevated urinary trihexoxylceramide levels.1–6 Globotriaosylceramide is normally broken down by α-galactosidase A to produce galactose and lactosylceramide. The full-blown syndrome is normally seen only in men, since female carriers have 15–40% greater enzyme activity than their male siblings or offspring. Heterozygotes, however, usually ­display abnormal ophthalmological and ultrastructural features.7 Occasionally, heterozygous females may manifest signs and symptoms due to extreme X inactivation (lyonization) of the healthy X chromosome.7,8 Cutaneous lesions are believed to occur in about 20% of heterozygous females.9 In males, the disease normally presents in childhood as episodes of excruciating intermittent pain, frequently in the fingers and toes.10 The attacks may be accompanied by fever, edema, and malaise. Patients may also have hypohidrosis, acroparesthesiae, and peripheral vasomotor disturbance affecting the heart, kidney, and central nervous system. Heat intolerance and telangiectases of the ears are often present early in the course of the disease.11 The characteristic angiokeratomata develop after puberty and present as tiny red–black bilaterally symmetrical papules, 0.5–2 mm in diameter, with slight hyperkeratosis.10 Lesions are typically seen in the bathing trunk ­distribution including the thighs, buttocks, lower back, penis, and ­scrotum, although occasional lesions may also be seen on the trunk or buccal mucosa (Figs. 13.28, 13.29). The number of angiokeratomata is highly variable. Atypical cases can present with an oligosymptomatic phenotype which includes only very few cutaneous angiokeratomata and asymptomatic involvement of organs such as the kidney and the heart.12 A female heterozygote with multiple nonkeratotic cutaneous angiomas has also been described.13 Nonvascular proliferations have been reported in patients with Fabry's ­disease, ­including polyarteritis nodosa and leg ulcers.14,15 Telangiectasias develop in up to ­one-fourth of affected males.16,17 A recent study correlated the presence of angiokeratomas and telangiectasias with disease severity.16 In a patient in whom the diagnosis is suspected, confirmation can usually be obtained by an ophthalmic examination. The conjunctival vessels may be tortuous or aneurysmal, as may the retinal vessels, and slit-lamp examination of the eyes reveals characteristic whorled, corneal linear opacities (verticillate cornea) (Fig. 13.30). Enzyme assay of α-galactosidase A can be performed using peripheral leukocytes or cutaneous fibroblasts. Hair root analysis has been recommended for the detection of heterozygotes.18 Affected males can develop transient cerebrovascular accidents, but one of the most common causes of death is renal failure.19,20 In the early stages, proteinuria is seen and microscopy of the urinary sediment sometimes reveals characteristic lipid-laden cells even before proteinuria develops (Fig. 13.31). Electron microscopy may reveal the typical inclusions (Fig. 13.32). Cardiac involvement is found in approximately 20% of patients.21 Glycosphingolipid deposits in the conducting system, myocardium, endocardium, and valves may give rise to angina, electrocardiographic ­abnormalities, hypertrophic cardiomyopathy, hypertension, mitral valve incompetence, and

Angiokeratoma corporis diffusum

A

Fig. 13.28 Angiokeratoma corporis diffusum: tiny grouped red papules are present on the buttocks, a characteristic site. By courtesy of the Institute of Dermatology, London, UK.

B

Fig. 13.30 Angiokeratoma corporis diffusum: (A) tortuous conjunctival vessels; (B) tortuous retinal vessels. By courtesy of S. Parker, MD, St Thomas’ Hospital, London, UK.

Fig. 13.29 Angiokeratoma corporis diffusum: conspicuous angiokeratomata on the penis, a commonly affected site. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

aortic medial degeneration.22–25 Cardiovascular disease was found to be the most common cause of death in patients in a recent study of the Fabry registry.26 Oral and dental abnormalities are more common than previously realized and include the presence of cysts/pseudocysts of the maxillary sinuses and maxillary prognathism.27

Pathogenesis and histological features A variety of genetic defects has been identified including point mutations, gene rearrangements, and deletions.28–31 A symptomatic heterozygous female Fabry's disease patient without detectable mutation in the α-galactosidase gene has recently been described.32

Fig. 13.31 Angiokeratoma corporis diffusum: urinary sediment stained with toluidine blue. The metachromasia (purple coloration) is due to the presence of intracytoplasmic sulfatides.

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Degenerative and metabolic diseases

Fig. 13.32 Angiokeratoma corporis diffusum: electron micrograph of urine sediment, showing typical concentrically lamellated inclusions.

Fig. 13.34 Angiokeratoma corporis diffusum: close-up view.

Fig. 13.33 Angiokeratoma corporis diffusum: ectatic blood-filled vascular channels expand the papillary dermis. Note the hyperkeratosis.

The skin lesions are composed of ectatic blood-filled vessels in the papillary dermis, associated with slight hyperkeratosis (Figs. 13.33, 13.34). A characteristic feature is vacuolation of endothelial cells due to lipid deposits. The latter are doubly refractile and can usually be demonstrated in frozen material tissue ­sections. They may also be identified in toluidine blue-stained material. On electron microscopy, lamellar electron-dense inclusion bodies are present within endothelial cells, pericytes, smooth muscle cells, fibroblasts, sweat gland epithelium, and ­macrophages. It is believed that these are due to lipid deposition within lysosomes (Fig. 13.35). Lamellar bodies have also been identified in the endothelial cells of affected vessels with polyarteritis nodosa in a patient with Fabry's disease.14

Differential diagnosis Other forms of angiokeratomata, for example those of Mibelli or Fordyce, should be clinically distinguishable by their site and distribution although their histopathological appearances are identical. It should be noted, however, that diffuse angiokeratomata may also be seen in fucosidosis, α-galactosidosis, sialidosis, aspartylglycosaminuria, α-N- acetylgalactosaminidase deficiency (Kanzaki disease), human beta-mannosidosis, adult-onset GM1 gangliosidosis, and indeed, diffuse angiokeratomata of a benign type may occur in patients with normal enzyme activities.33–38 Widespread angiokeratomata have also been described as an exceptional finding in tuberous sclerosis.39

Fig. 13.35 Angiokeratoma corporis diffusum: the endothelial cells of this small blood vessel contain typical inclusions (L, lumen; E, endothelial cell).

The amyloidoses Amyloidosis is characterized by the extracellular deposition of a protein ­associated with particular tinctorial and ultrastructural properties. The amyloidoses are classified according to whether the amyloid deposition is ­systemic or localized (Table 13.3). The most characteristic staining patterns of amyloid are seen with Congo red or Dylon (cotton dye pagoda red No. 9), which show apple-green ­birefringence under polarized light (Fig. 13.36).1 Unfortunately, this is not ­specific, and green birefringence may also be seen with collagen and in ­colloid milium, porphyria, and lipoid proteinosis. Amyloid deposits, which are PAS positive, may also be identified by the cotton dye Sirius red, or ­metachromatically using methyl or cresyl violet.2 Further confirmatory evidence can be obtained by staining with thioflavine-T and examination using fluorescence ­microscopy or by immunocytochemistry (see below) (Fig. 13.37).

The amyloidoses Table 13.3 Classification of the amyloidoses Systemic amyloidosis

Localized amyloidosis

Primary (due to an occult plasma cell dyscrasia)

Organs other than the skin*

Myeloma associated

Primary cutaneous

Secondary

Lichen, macular and biphasic

Hemodialysis associated

Secondary cutaneous

Heredofamilial

Associated with neoplasms, porokeratosis and PUVA therapy

Amyloid elastosis

Familial cutaneous Nodular

†

*Not discussed further in this chapter. †Including familial Mediterranean fever, Muckle–Wells syndrome, familial amyloidotic polyneuropathy.

Fig. 13.37 Cutaneous amyloidosis: positive immunofluorescence just beneath the epidermis in a case of macular amyloid (thioflavine-T).

A

Fig. 13.38

A

B

Fig. 13.36 Cutaneous amyloidosis: (A) positive staining with Congo red; (B) there is intense apple-green birefringence when viewed with polarized light.

Amyloid shows characteristic and specific electron microscopic features of rigid, straight, nonbranching amyloid filaments with a diameter of 6–10 nm showing a hollow core on cross-section (Fig. 13.38).3 They are haphazardly distributed, lack the cross-banding of collagen, and are embedded in an ­electron-dense amorphous ground substance, which is probably composed of polysaccharides.

B

Cutaneous amyloidosis: (A) electron micrograph of macular amyloidosis showing nodular deposits in the superficial dermis; (B) the characteristic randomly orientated, straight, nonbranching appearance of amyloid filaments.

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Degenerative and metabolic diseases X-ray diffraction and infrared spectroscopy reveal a beta-pleated a­ ntiparallel configuration.4,5 Fibrils with a beta-pleated configuration are insoluble and highly resistant to proteolysis. This, combined with a lack of immunogenicity, results in their persistence at the site of deposition and ­subsequent tissue-damaging effects. All forms of amyloid contain up to 14% by dry weight of a nonfibrillary protein, the serum amyloid P (SAP) component.2,6 The function of SAP is unknown, but it has been suggested that it may be primarily involved in the deposition and maintenance of the fibrillary components.2 Its presence, identified immunohistochemically, is a useful adjunct to the diagnosis of amyloidosis.7 However, it should be appreciated that the antibody also labels degenerate elastic fibers. The fibrillary component, however, may be derived in very different ways in each of the recognized types of amyloidosis: 8 • In primary and myeloma-associated amyloidoses it consists of immunoglobulin light chains (most often of lambda type, or a part thereof). • In the secondary form the fibrillary component is composed of amyloid A protein, which is derived from a normal serum constituent known as serum amyloid A protein. This serum protein, which is an HDL3-associated apolipoprotein, is an acute phase reactant.2,8 • Primary cutaneous amyloidosis is derived from filamentous degeneration of keratin filaments (amyloid-K) (see below).9,10 The capacity to form amyloid in the primary and myeloma-associated variants appears to be dependent upon the inherent ability of a segment of the variable region of the light chain to adopt a beta-pleated configuration.3 This capability is only evident in a proportion of (so-called amyloidogenic) Bence Jones proteins, which explains why not all patients with multiple myeloma develop amyloidosis. Primary and myeloma-associated amyloidoses can be distinguished histochemically from secondary amyloidosis using the potassium permanganate reaction.11 The former are potassium permanganate resistant whereas the latter is sensitive and loses its affinity for Congo red following exposure. ‘Endocrine’ amyloid is also resistant to the effects of potassium permanganate solution, as is senile cardiac amyloid. Therefore, although the amyloidoses all include, by definition, amyloid deposition, they in fact ­represent a very diverse group of conditions.

Fig. 13.39 Primary systemic amyloidosis: a waxy nodule is present behind the ear. Note the purpura. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Primary and myeloma-associated systemic amyloidoses Cutaneous disease occurs in up to 40% of patients with primary (due to occult plasma cell dyscrasia) and myeloma-associated systemic amyloidosis.1–5

Clinical features Primary and myeloma-associated systemic amyloidoses predominantly affect the elderly (mean onset at 65 years of age) and show a slight predilection for males.2 Up to 15% of patients with myeloma have coexisting primary amyloidosis. Occasional patients present with primary systemic amyloidosis and only develop multiple myeloma later.6 The early clinical changes, which are often mild, non-specific, and very difficult to diagnose, include weight loss, hoarseness, dyspnea, fatigue, paresthesia, and lightheadedness.7 Subsequently, the most frequent features are development of the carpal tunnel syndrome and edema due to renal and cardiac involvement. Bilateral carpal tunnel syndrome may be the first symptom of the disease.8 The commonest cutaneous manifestation is hemorrhage (purpura, ­petechiae, and frank ecchymoses) due to deposition of amyloid within blood vessel walls, with resultant fragility (Figs 13.39–13.42). It occurs most typically on the hands (often posttraumatic) and around the eyes, when the purpura may follow proctoscopy or vomiting (Fig. 13.43). Lesions are sometimes also evident in the nasolabial folds, the neck, axillae, umbilicus, ­anogenital region, and within the oral cavity.4,9–11 Prominent hemorrhagic bullae may be present.11 Rarely, systemic amyloidosis presents with solitary vulval lesions which may mimic a condyloma acuminatum.12,13 Blistering is sometimes an additional feature, which occurs due to ­cleavage developing within the amyloid deposits as a consequence of ­shearing stresses.14–23 The blisters are often hemorrhagic, and occur most often on the tongue, buccal or labial mucosa although they may be more widespread and thus mimic those of bullous pemphigoid.14 Blisters can sometimes arise on the

Fig. 13.40 Primary systemic amyloidosis: hemorrhagic bullous lesion on wrist. By courtesy of the Institute of Dermatology, London, UK.

dorsal surfaces of the hands and fingers and the extensor aspect of the forearms and epidermolysis bullosa acquisita then enters the differential diagnosis (Fig. 13.44). Healed lesions are sometimes associated with the development of milia.19 Bullous amyloidosis most often develops in patients with systemic disease, particularly myeloma associated.16 Rarely, however, it may complicate primary cutaneous amyloidosis.14 Rare cases present an elastolytic appearance and development of cordlike indurations associated with intermittent claudication. Prominent perivascular deposition of amyloid has been documented in these patients.24,25 In more advanced cases, waxy, smooth, shiny papules, plaques, and even nodules develop. Cystic nodular lesions have also been reported.26 The papules are skin-colored or yellow and have a dome-shaped appearance.9,27 They

The amyloidoses

Fig. 13.41

Fig. 13.44

Primary systemic amyloidosis: papular mucosal lesions with hemorrhage on the inner aspect of the lower lip. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Primary systemic amyloidosis: blood-filled blisters on the dorsal aspect of the fingers. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.42

Fig. 13.45

Primary systemic amyloidosis: erythematous and purpuric lesions on the face of an elderly male. By courtesy of the Institute of Dermatology, London, UK.

Primary systemic amyloidosis: nail dystrophy as seen in this example is a very rare manifestation. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.43 Primary systemic amyloidosis: small macular purpuric lesions at a classical site. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

are found predominantly on the face (especially the eyelids), head and neck, axillae, umbilicus, inguinal region, and the perineum.4,9 In severely affected patients the clinical appearances with taut skin, particularly affecting the face, hands, and digits, may mimic scleroderma.9,27 Alopecia and nail dystrophy are sometimes evident (Fig. 13.45). Chronic paronychia, palmodigital erythematous swelling, and induration of the hands have been described.28 The presence of these features in conjunction with macroglossia and the carpal tunnel syndrome is highly suggestive of primary or myeloma-associated systemic amyloidosis (Fig. 13.46). In addition to macroglossia, the tongue may be covered with waxy papules, nodules, and plaques and occasionally it is ulcerated or fissured.4 As a consequence, speaking and swallowing difficulties are not infrequently encountered. The sicca syndrome may also be a manifestation of primary systemic amyloidosis.29 Exceptionally, association with normolipemic xanthoma has also been documented.30 Hepatomegaly is found in about 50% of cases and there may also be evidence of cardiomyopathy with arrhythmia or heart failure, peripheral neuropathy, and renal failure or the nephrotic syndrome. Splenomegaly is a feature in less than 10% of cases.5 Intestinal involvement can lead to malabsorption or an ulcerative colitis-like picture, sometimes with hemorrhage.4 ­Pseudo-obstruction,

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Fig. 13.46

Fig. 13.48

Primary systemic amyloidosis: macroglossia. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

diarrhea, and constipation can also occur.7 There is no effective treatment for systemic primary amyloidosis and the prognosis is therefore grave. Mortality relates primarily to cardiac and renal involvement.2,3

Histological features Masses of eosinophilic, amorphous, fissured material are present in the ­ ermis and subcutaneous tissues.9,31 The overlying epidermis is often d stretched and flattened, but – in contrast to the macular and lichenoid variants – shows no evidence of amyloid deposition. In mild cases the changes may be ­limited to the perivascular tissues, but in more extensive disease large aggregates are usually evident. Involvement of blood vessel walls, arrector pili muscles, skin adnexa, and subcutaneous fat (amyloid rings) is frequently present (Figs. 13.47, 13.48).4,9,27 Amyloid deposits around the pilosebaceous units may be accompanied by follicular atrophy with resultant hair loss.9 There is usually little secondary inflammatory cell infiltration.

Primary systemic amyloidosis: high-power view of Figure 13.47. Note the red cell extravasation.

In those cases associated with blistering, the vesicle appears in an i­ntradermal or less commonly subepidermal location. The dermis, in addition to showing amyloid deposits, often in association with blood vessel walls, also shows a fragmented appearance due to the presence of cleftlike spaces.13 Purpura is frequently marked. Clinically normal skin shows histological evidence of amyloid deposition in up to 50% of patients.27

Secondary amyloidosis Secondary amyloidosis develops as a consequence of chronic inflammatory conditions or infections. Cutaneous involvement has not been recognized as a clinical feature of secondary systemic amyloidosis. Yet in one publication it was described in eight out of nine patients with amyloidosis complicating rheumatoid arthritis.1 It is of interest to note that a considerable number of chronic dermatoses may be associated with the development of secondary amyloidosis including psoriasis, lepromatous leprosy, hidradenitis suppurativa, chronically infected burns, and dystrophic epidermolysis bullosa.2–4 In patients with no cutaneous lesions and symptoms suggestive of systemic amyloidosis, the diagnosis can be confirmed by Congo red staining of abdominal fat aspirates.5 Although frank clinical lesions are not commonly a feature of secondary amyloidosis, sometimes small deposits are found in specimens of ­normal skin.1,6 Usually these are present in a perivascular location, but may ­occasionally be present elsewhere in the dermis or even in subcutaneous fat.7 Deposition of amyloid around sweat glands may also be seen. Deposits are said to be focal and abdominal subcutaneous fat has been recommended as the site that is most likely to be positive.1,5,8 Hemodialysis-associated amyloidosis is a distinctive form of secondary amyloidosis and is described below.

Hemodialysis-associated amyloidosis Clinical features Fig. 13.47 Primary systemic amyloidosis: the superficial blood vessels are thickened due to amyloid deposition.

This variant of amyloidosis, induced by beta-2-microglobulin, occurs in patients on long-term hemodialysis.1–5 Exceptionally, cases may present after short-term hemodialysis.6 The most commonly involved organs are the heart, gastrointestinal tract, and lungs.1 Interestingly, the disease does not seem to

The amyloidoses involve the spleen.1 Carpal tunnel syndrome, polyarthralgia, and ­destructive spondyloarthropathy have also been documented.4,7 The walls of blood ­vessels are often involved whereas bone lesions are relatively rare, although pathological fractures may occur.7,8 Cutaneous involvement, which is very uncommon, has been reported to present as subcutaneous masses in the buttocks and shoulder, lichenoid papules and a wrinkled appearance of the skin of the palmar aspect of the fingers. 6–11

Histological features In cases with skin involvement, the amyloid deposits have been found either in the subcutaneous tissue or in the papillary and reticular dermis, around sweat glands and hair follicles.6–11 Occasionally, special stains are unhelpful in demonstrating amyloid and confirmation of the diagnosis by electron microscopy is necessary.

Heredofamilial amyloidoses Familial Mediterranean fever

Clinical features This is a rare variant of autosomal recessive inherited systemic amyloidosis. It is characterized by episodes of fever associated with pleuritis, peritonitis, and synovitis.1–4 Cutaneous lesions are rare and consist of Henoch-Schönlein purpura and erythema of the lower limbs mimicking erysipelas.1,5 Panniculitis and recurrent urticaria may also occur.6,7 Nail fold capillary abnormalities consisting of increased tortuosity and enlargement of capillary loops have also been documented.8 Cutaneous amyloid deposition has not been described.

Pathogenesis and histological features A serum precursor protein forms the amyloid in this condition. This precursor is a high density lipoprotein known as serum amyloid A. The erysipelas-like lesions are characterized by a perivascular mixed infiltrate of lymphocytes, histiocytes, and neutrophils with leukocytoclasia.5 Vasculitis is not seen, although on direct immunofluorescence perivascular C3 and, less consistently IgM and fibrinogen, have been reported.5

Muckle-Wells syndrome and familial cold autoinflammatory syndrome Muckle-Wells syndrome is an autosomal inherited disease with variable penetrance. It is characterized by urticaria, deafness, conjunctivitis, and systemic amyloidosis.1,2 The disease has been mapped to chromosome 1q44. The gene is called CIAS1 and encodes a pyrin-like protein that appears to play a role in regulation of inflammation and apoptosis.3,4 Familial cold autoinflammatory syndrome (familial cold urticaria) is very similar to Muckle-Wells syndrome but, in the former, there is no deafness and the episodes of urticaria are precipitated by cold. The same serum precursor protein (serum amyloid A) produces the amyloid in both conditions. Cutaneous amyloidosis is not typically seen in Muckle-Wells syndrome. Recently, six patients with this syndrome were described as having sclerotic, hyperpigmented plaques with hypertrichosis on the extremities and abdomen.5 Cold-induced urticarial lesions are characterized by an upper to mid-dermal infiltrate of neutrophils with a few eosinophils and dermal edema.6 Neutrophils are seen intravascularly and in vessel walls. Although ­vasculitis has not been described, some vessels may contain fibrinoid deposits. Histological features of the sclerotic lesions include dermal thickening with sclerosis of collagen bundles, fragmentation and thickening of elastic fibers, focal calcification of degenerated elastic fibers, superficial and deep perivascular and interstitial infiltrate of lymphocytes and histiocytes, numerous plasma cells and admixed eosinophils and mast cells.

Familial amyloidotic polyneuropathy

Clinical features Familial amyloidotic polyneuropathy is an autosomal dominant disease in which the deposition of amyloid occurs predominantly in peripheral nerves. The amyloid deposits in this disease consist in most cases of variant transthyretin with single amino acid substitutions.1–3 Clinical manifestations include

sensory then motor peripheral neuropathy predominantly affecting the limbs and autonomic dysfunction manifesting as alternating diarrhea and constipation, urinary incontinence, orthostatic hypotension, and sexual dysfunction.3 The cutaneous manifestations comprise nonhealing ulcers, multiple atrophic scars, and anhidrosis of the lower limbs.4,5 In some patients petechiae can be induced by gentle stroking of the skin.

Histological features Histologically, biopsies from clinically normal skin reveal the presence of amyloid in blood vessel walls, sweat glands, and arrector pili muscle.4

Amyloid elastosis Clinical features Amyloid elastosis is a very rare disease, characterized by systemic and cutaneous deposits of amyloid. Only three cases have been reported to date. Two patients presented with papular and nodular lesions, a sclerodermatous facial appearance, a pseudoxanthoma-like appearance of the neck, cordlike thickening of superficial blood vessels, livedo reticularis-like changes on trunk, Raynaud's phenomenon, venous and arterial thrombosis, and the nephrotic syndrome.1,2 One of the patients had a lambda light chain paraprotein.2 The third patient developed xanthomatous, yellow macules and patches in the intertriginous areas of the axilla, neck, submammary, and abdomen. She was subsequently diagnosed with systemic AL amyloidosis.3

Histological features Amyloid is seen in the dermis, around adnexal structures, surrounding elastic fibers, sometimes forming small globules, and in blood vessel walls, together with striking deposits in the dermal, subcutaneous, and serosal ­elastic tissue.1–3

Primary localized cutaneous amyloidosis, lichen and macular types Clinical features Lichen and macular amyloidoses (skin-limited amyloidoses) represent different manifestations of the same process and both entities may coexist (biphasic amyloidosis) or one may transform into the other.1–4 A recent large study of primary localized cutaneous amyloidosis found that 67% of cases represented lichen amyloidosis, 8% macular amyloidosis, and 25% biphasic variants.5 Although most cases are sporadic, up to 10% of patients demonstrate an autosomal dominant inheritance pattern (see familial primary cutaneous amyloidosis).6,7 Macular primary cutaneous amyloidosis This is most commonly seen in patients from the Middle East, Asia, and Central and South America.1,8 It affects females more often than males (3:1), is seen in younger age groups, and is usually a chronic condition.9,10 Patients present with a macular, dark brown or grayish, symmetrical pigmentation, which occurs most frequently on the upper chest and back, although the extremities and face may also be affected (Fig. 13.49).1,9 The lesions sometimes have a very characteristic reticulated or rippled appearance, which can be quite subtle, and they are usually moderately pruritic (Fig. 13.50). More commonly, however, macular amyloid appears as small, 2–3 mm diameter lesions or else as confluent macular foci, which sometimes have superimposed micropapules.8 Lesions sometimes follow Blaschko's lines, resembling incontinentia pigmenti.11,12 Exceptionally, widespread diffuse pigmentation occurs.13 Predominantly hypopigmented macules have been described, mimicking guttate morphea and vitiligo.14 Papular or lichen amyloidosis In papular or lichen amyloidosis, discrete papules and/or plaques occur, which are often scaly, persistent, and pigmented. They are usually severely pruritic (Fig. 13.51). Excoriations, lichenification, and nodular prurigo-like lesions due to chronic scratching are sometimes evident.10 Lesions are ­especially

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Degenerative and metabolic diseases c­ ommon on the front of the shins and extensor aspect of the ­forearms (Figs 13.52, 13.53).15,16 The calves, ankles, dorsa of the feet, thighs and trunk may also be affected.17–19 Presentation is most often in young adults. The sex incidence is equal.1,20 Lichen amyloidosis shows a predilection for the Chinese race and familial cases have been recorded.18,19 An association with Epstein-Barr virus infection has been reported in a single case but this was not confirmed in a larger study.21 Association with systemic disease is probably coincidental but there have been a number of cases described with progressive systemic sclerosis.22,23 Other primary cutaneous amyloidoses These include anosacral and poikilodermatous variants: • Anosacral amyloidosis presents as scaly hyperpigmented macules and lichenoid papules spreading out from the perianal skin.24,25 It is seen in patients from Japan and China and is very rare. The disease may present early in life and its cause has not been established, although a relationship to keratinocyte apoptosis has been suggested.25 Clinically, lesions can be confused with lichen simplex chronicus, a dermatophyte infection or even postinflammatory hyperpigmentation. Fig. 13.49 Macular amyloid: hyperpigmented lesion in a characteristic site. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.50 Macular amyloid: close-up view of a lesion showing the typically rippled appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.52 Lichen amyloidosis: scaly lichenoid papules on the shin. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.51 Lichen amyloidosis: pigmented papules on the chest. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.53 Lichen amyloidosis: grouped, erythematoviolaceous papules, with a lichenoid surface and showing excoriations in some areas. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

The amyloidoses

• Poikiloderma-like cutaneous amyloidosis is an extremely rare

manifestation of localized cutaneous amyloidosis.26,27 Patients present with poikilodermatous skin lesions and lichenoid papules. It may be associated with photosensitivity, short stature, and palmoplantar keratoderma.27 Blisters are rarely seen. The condition presents early in life or in young adults. Confusion with other conditions associated with poikiloderma including poikiloderma atrophicans vasculare is possible.

Pathogenesis and histological features Chronic irritation to the skin has been proposed as the cause of amyloid deposition in the macular and lichenoid variants although this has never been proven.28,29 The documentation, however, of friction amyloidosis due to nylon brush skin massage and towels does offer some support to this hypothesis.30–33 It may be that chronic trauma in a susceptible or ‘primed’ individual may be associated with an increased risk of developing cutaneous amyloidosis. It has been suggested that amyloid deposition in lichen amyloidosis is a consequence of scratching, as pruritus tends to be the presenting symptom even before amyloid is detected in skin biopsies.34 The chronic damage to the epidermis induces apoptosis of keratinocytes and this leads to amyloid deposition in the papillary dermis. A similar mechanism has been proposed in notalgia paresthetica. This is a condition characterized by pruritus, a burning sensation, and paresthesia or hyperesthesia in an area of the back between dermatomes D2 and D6.35,36 The resultant irritation and scratching induce cutaneous hyperpigmentation and amyloid deposition. It has even been suggested that the cutaneous amyloidosis observed in patients with multiple endocrine neoplasia type 2A is secondary to notalgia paresthetica (see below).37 In both variants the amyloid is deposited high in the papillary dermis, often immediately adjacent to the epidermis.8,9,17,38,39 In the macular type, the amount of amyloid present is often very small and focally distributed. It frequently has a faceted appearance (Figs 13.54–13.56).2,9 Special stains and/or immunocytochemistry are sometimes necessary as the deposits can easily be missed. Intraepidermal cytoid bodies are present in about 33% of cases.8 Typically, there is associated pigmentary incontinence, but only minor epidermal changes of hyperkeratosis and acanthosis are generally evident. Melanin pigment may be present in the stratum corneum. A slight perivascular chronic inflammatory cell infiltrate is often found in the superficial dermis.9 Mild vacuolar interface alteration can be present.14

Fig. 13.55 Macular amyloidosis: close-up view of faceted deposits.

Fig. 13.56 Macular amyloidosis: pigmentary incontinence is typically present.

Fig. 13.54 Macular amyloidosis: typical eosinophilic faceted deposits are present in the papillary dermis.

In papular or lichen amyloidosis, the histopathological changes are similar and cannot be reliably distinguished from those of the macular variant, except that the quantities deposited are greater and there is often more marked epidermal acanthosis, hypergranulosis, and hyperkeratosis. Basal cell hydropic degeneration may be evident and colloid bodies are usually visible (Figs 13.57, 13.58).1 Satellite cell necrosis is sometimes a feature.1 A superficial perivascular chronic inflammatory cell infiltrate is typically present. When special stains fail to demonstrate the presence of amyloid, ultrastructural studies are usually successful in detecting the presence of the protein.40 In contrast to skin involvement in systemic disease, blood vessel deposits are not a feature of primary cutaneous localized lesions. In earlier literature it was postulated that the amyloid might have been derived from mast cells or fibroblasts. The application of newer technology, however, has shown that it is indisputably of keratinocyte derivation, and amyloid deposits have been shown to contain disulfide bonds and bullous pemphigoid antigen.8 Numerous recent publications confirm the presence of

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K

Fig. 13.59

Fig. 13.57 Lichen amyloidosis: there is hyperkeratosis, acanthosis, and basal cell hydropic degeneration; small eosinophilic globules are present in the papillary dermis. A mild chronic inflammatory cell infiltrate is present. Note the pigmentary incontinence.

A

Fig. 13.58

Lichen amyloidosis: (A) early filamentous degeneration is seen in this basal keratinocyte (K), lamina densa is arrowed; (B) compare the organized appearance of the tonofilaments with the haphazardly orientated amyloid immediately adjacent to the lamina densa.

B

Lichen amyloidosis: in this view, there is interface change and a lymphocytic infiltrate.

epidermal keratin in the deposits in both macular and lichenoid forms using monoclonal immunocytochemistry.3,41–49 The amyloid of the skin-limited ­variants, so-called amyloid-K, has been shown to contain 50 and 67 kD keratin filaments.28,48 Apolipoprotein E, one of the proteins found in the amyloid plaque of Alzheimer's disease and in systemic amyloidosis, has also been demonstrated in the amyloid present in localized cutaneous amyloidosis.50,51 Electron microscopic studies have provided further evidence that amyloid-K is of keratinocyte origin by showing tonofilament filamentous (apoptotic) degeneration into amyloid filaments both within the epidermis and in the immediately adjacent dermis.52 Under normal circumstances apoptotic keratinocytes (cytoid bodies) are either shed as a consequence of epidermal upward migration or are released into the dermis where they are removed by an inflammatory response as is seen, for example, in lichen planus. In macular and lichenoid cutaneous amyloidosis it appears that the above disposal mechanism is either overwhelmed or nonfunctioning. Early ultrastructural changes consist of loss of tonofilament electron density and development of a wavy morphology accompanied by internalization of desmosomes, thickening of the keratinocyte cell membrane, and the acquisition of hemidesmosome-like attachments to neighboring cells.28 Cytoplasmic and nuclear remnants are frequently present in the more superficial deposits.

It is thought that on entering the dermis, fibroblasts and macrophages ­convert the degenerate keratin into amyloid filaments (Fig. 13.59).52 The ­precise mechanism is unknown, but it must involve the conversion of the normal alpha tertiary structure of tonofilaments into the beta-pleated ­configuration of amyloid. The filaments of amyloid and cytoid bodies show ultrastructural differences. Amyloid fibrils are irregularly distributed whereas the filaments in cytoid bodies are arranged in bundles or whorls.53 It is postulated that the development of localized cutaneous amyloidosis is dependent upon mild chronic trauma resulting in excessive production of cytoid bodies and their subsequent conversion into amyloid deposits. It would seem that despite a normal humoral response as shown by the presence of IgM and IgG in association with complement fixation, the normal cellular response whereby apoptotic keratinocytes are removed is lacking.28,54–56 Amyloid deposits are frequently found in intimate association with dermal elastic fibers and the deposits in macular amyloidosis have been shown to contain fibrillin.57 Whether this is of pathogenetic significance or is merely a secondary phenomenon is uncertain. The apoptotic theory of amyloidogenesis in the cutaneous variants has, however, been challenged. On the basis of finding amyloid deposits ­immediately below the basal keratinocyte, separating its cell membrane from the lamina

The amyloidoses densa in the absence of any evidence of filamentous degeneration, it has been suggested that cutaneous amyloid deposits may also be a direct secretory ­product of keratinocytes.58,59 It could be that both mechanisms are in operation.

Secondary localized cutaneous amyloidosis Microscopic foci of amyloid have been described in a number of cutaneous neoplasms including basal cell carcinoma, sweat gland tumors, syringocystadenoma papilliferum, pilomatrixoma, trichoepithelioma, trichoblastoma, intradermal nevus, dermatofibroma, seborrheic keratosis, solar keratosis, and Bowen's disease (Fig. 13.60).1–7 The amyloid in most cases appears to be derived from tumor cells. Porokeratosis has also been reported in association with dermal amyloid deposition as a result of apoptosis of keratinocytes.8,9 Mycosis fungoides and discoid lupus erythematosus may exceptionally be seen associated with localized cutaneous amyloidosis.10,11 Cutaneous amyloid deposition may also rarely be seen as a consequence of chronic epidermal damage following PUVA therapy.12,13 So-called concha amyloidosis due to chronic actinic damage to the ear has also been documented.14,15 Repeated insulin injections at the same site have been reported as inducing amyloid in the skin.16

Familial primary cutaneous amyloidosis Familial primary cutaneous amyloidosis is a very rare autosomal dominant variant of amyloidosis that presents with manifestations of either macular and/or lichenoid amyloidosis.1–5 Lichen amyloidosis is also seen in patients with multiple endocrine neoplasia type 2A (Sipple's syndrome).6–8 Germline mutations of the RET proto-oncogene on chromosome 10 involving cysteine residues have been consistently described in Sipple's ­syndrome. However, familial primary cutaneous amyloidosis without Sipple's ­syndrome does not show RET mutations, clearly indicating that they are different conditions.6,9 Recent genetic studies in a small subset of patients with familial primary cutaneous amyloidosis have isolated a mutation in the OSMR gene on chromosome 5.10,11 This encodes the oncostatin M receptor beta which is expressed in various tissues including keratinocytes, cutaneous nerves, and in the dorsal root ganglion. This is a cytokine receptor complex, and it is speculated that mutations in it lead to dysfunctional cell signaling resulting in apoptosis of keratinocytes, amyloid deposition, and reduction of nerve fibers, which causes pruritus.10,12 Not all patients with familial primary cutaneous ­amyloidosis have been shown to have the same mutation in chromosome 5, indicating genetic heterogeneity in this disease.13 The histopathological findings are identical to those described in the ­primary nonfamilial variants of localized cutaneous amyloidosis.

Amyloidosis cutis dyschromica (vitiliginous) is another familial ­variant of primary cutaneous amyloidosis characterized by reticulate ­hyper- and hypopigmentation of the trunk and limbs, with onset typically in ­childhood.14–19 Papules, atrophy, and telangiectasia are usually not ­present. One patient with concomitant morphea has been described.18 It has been suggested that the disease is caused by hypersensitivity to ultraviolet B light with possible DNA repair defects.16 Histologically, the amyloid is present in the papillary dermis. Amyloidosis cutis dyschromica may represent the same disease described as X-linked reticulate pigmentary disorder in which cutaneous amyloidosis occurs as a secondary phenomenon in patients with a disease characterized by failure to thrive, chronic respiratory disease, photophobia with corneal dystrophy, and gastrointestinal disease.20,21

Nodular amyloidosis Clinical features In this rare variant, which is more common in females, pink–brown single or multiple nodules develop on the trunk, extremities, genitalia, face or scalp (Fig. 13.61).1–7 Bilateral nodular amyloidosis of the eyelids in the absence of systemic amyloidosis has rarely been documented.8 The lesions often have a waxy appearance and the surface may be atrophic or ulcerated. Most cases of nodular amyloidosis are limited to skin and only 7% show progression to systemic amyloidosis.7,9 Occasional reports have documented monoclonal paraproteinemia, lymphoplasmacytoid lymphoma, Sjögren's syndrome, proteinuria, bone marrow abnormalities, and a positive rectal biopsy.10–15 Nodular cutaneous amyloidosis has also been described in association with carpal tunnel syndrome induced by the amyloidogenic transthyretin His 114 variant.16 An unusual variant of nodular ­amyloidosis with bilateral plantar involvement is very occasionally encountered.17

Histological features The histological appearances cannot be distinguished from those of systemic amyloidosis and, indeed, as in primary amyloidosis, the amyloid consists of light chain-derived AL protein.18–21 It is thought likely that this nodular variant results from local production of light chains by a localized group of plasma cells.1 PCR studies have demonstrated that the infiltrating plasma

Fig. 13.61 Fig. 13.60 Tumor-associated amyloid: amyloid deposits in a basal cell carcinoma.

Nodular amyloidosis: an irregular infiltrated plaque limited to the nose.

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Degenerative and metabolic diseases cells in cases of nodular amyloidosis are usually monoclonal.22,23 Polyclonality, ­however, has also been reported.11 In all patients with nodular amyloidosis, it is important to exclude systemic disease.2,7 The deposits of amyloid are present in both the papillary and ­reticular dermis and may involve the subcutaneous fat (Figs 13.62–13.64). Sometimes the vasculature and nerve sheaths are affected ­(Figs 13.65–13.67).2

Fig. 13.64 Nodular amyloid: the amyloid deposits fill the papillary dermis.

A

B

Fig. 13.62 Nodular amyloidosis: (A) massive deposits of amyloid are present in the dermis; (B) there is a heavy associated plasma cell infiltrate.

Fig. 13.65

Fig. 13.63

Fig. 13.66

Nodular amyloidosis: in this example there is a broad bandlike deposit in the upper dermis.

Nodular amyloid: the deposits are strongly Congo red positive.

Nodular amyloidosis: amyloid deposits have thickened the blood vessel walls.

Colloid milium

Fig. 13.69 Fig. 13.67 Nodular amyloid: in this example, vessels in the subcutaneous fat showing striking involvement.

Juvenile colloid milium: there is papular thickening of the skin, particularly involving the cheeks, nose, and forehead. By courtesy of S. Hendfield-Jones, MD, Institute of Dermatology, London, UK.

Fig. 13.70 Fig. 13.68 Nodular amyloidosis: there is a conspicuous plasma cell infiltrate.

Characteristically, plasma cells are seen around blood ­vessels and at the ­margin of the amyloid deposits (Fig. 13.68).4,24 Rarely, an ­associated foreign body giant cell reaction and/or calcification are evident.4,6

Juvenile colloid milium: this less severely affected child shows typical yellow–brown translucent papules on the nose and upper lip. By courtesy of S. Hendfield-Jones, MD, Institute of Dermatology, London, UK.

Colloid milium Colloid milium, which is characterized by the deposition of amorphous, eosinophilic granular deposits in the superficial dermis, has a number of subtypes including the juvenile and adult variants. It may also develop as a ­manifestation of ochronosis due to use of the skin bleaching agent hydroquinone.1 Two other variants – nodular colloid degeneration and paracolloid of the skin – are probably variants of nodular amyloidosis.2–4 An alternative name proposed for adult colloid milium is that of papular elastosis.5

Juvenile colloid milium Clinical features The juvenile variant, which is exceedingly rare, develops in children before puberty and sometimes has a familial incidence.6 Patients present with ­discrete, or sometimes confluent, papules measuring 0.2–1.5 cm in diameter.7 Lesions, which are yellow–brown in color, appear translucent and when

­ unctured characteristically express gelatinous material. The underlying p tissues often feel indurated. Juvenile colloid milium predominantly affects the face, in particular the cheeks, nose, and around the mouth (Figs 13.69– 13,71). Induction of purpura after stroking has been described in both ­juvenile and adult colloid milium.8 This phenomenon has been attributed to vascular fragility due to infiltration of the blood vessel walls by colloid material. Exceptionally, ­juvenile colloid milia may present with gingival ­deposits and ligneous conjunctivitis as a result of infiltration of these tissues by ­colloid-like material.9–11

Pathogenesis and histological features Although the etiology remains unknown, in some cases at least, sunlight plays an important role. The pathogenesis, however, shows considerable overlap with macular and lichenoid amyloidosis. Juvenile colloid milium represents a primary degenerative disorder of epidermal keratinocytes, which through the process of apoptosis are transformed into colloid bodies within the superficial dermis.

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Fig. 13.71 Juvenile colloid milium: close-up view from the brother of the patient shown in Figure 13.70. By courtesy of S. Hendfield-Jones, MD, Institute of Dermatology, London, UK.

Fig. 13.72 Juvenile colloid milium: this shows an apoptotic keratinocyte, the cytoplasm of which is filled with fascicles of pale-staining filaments that contrast strikingly with adjacent tonofilaments.

The initial change is one of filamentous transformation whereby the ­relatively straight electron-dense keratin filaments are converted into shortened, curved 8–10 nm filaments arranged in weaved or whorled fascicles (Fig. 13.72).7 Occasionally, both types of filament may be identified simultaneously within the cytoplasm of basal keratinocytes. With progression, filamentous transformation comes to affect the entire cell, and nuclear, cytoplasmic, and desmosomal remnants may be identified within the filamentous mass (Fig. 13.73). Residual desmosomes are sometimes present around the border of the colloid deposit. Finally, the apoptotic cell is extruded into the adjacent dermis. In addition to the transformed filaments characteristic of all cytoid bodies, amyloid filaments have also been identified in juvenile colloid milium, thereby prompting the authors to classify this entity along with other amyloid-K dermatoses.2 Positive labeling of the deposits for epidermal keratin gives support to this hypothesis.2,12 Juvenile colloid milium has also been shown by direct immunofluorescence to be accompanied by immunoglobulin, complement, and fibrin ­deposits.7 Whether this represents an autoimmune-mediated reaction as is seen in ­macular-lichenoid amyloidosis or a secondary non-specific reactive phenomenon has yet to be determined.

Fig. 13.73 Juvenile colloid milium: internalized desmosomes are evident within this degenerate keratinocyte.

Fig. 13.74 Juvenile colloid milium: the papule consists of an intradermal deposit of eosinophilic material. There is no inflammatory response.

Histologically, the deposits are present in the superficial dermis where they impinge on the overlying and often somewhat frayed epidermis (Figs 13.74– 13.77). The colloid is composed of eosinophilic amorphous aggregates, often showing a fractured appearance. The overlying epithelium shows prominent cytoid bodies, while laterally, acanthosis associated with downward and inward growth results in cuffing or even encirclement of the colloid islands by an epidermal collarette.2 An admixture of fibroblasts and mast cells may be evident and pigmentary incontinence is sometimes present. Juvenile colloid milium is histochemically indistinguishable from amyloid: it is diastase-­ resistant, PAS positive, thioflavine-T positive and shows positive staining with Congo red with apple-green birefringence.

Adult colloid milium Clinical features This variant, which is much commoner than the childhood form, affects middleaged patients and shows a predilection for males. Outdoor workers are most often affected and lesions seen on sun-exposed skin are often ­accompanied by the features of solar elastosis, giving rise to the synonym of papular elastosis.

Colloid milium

Fig. 13.77 Fig. 13.75

Juvenile colloid milium: the amorphous material that characterizes this condition is of epidermal derivation. Tonofilaments undergo filamentous degeneration (apoptosis). Note the keratin positivity of the colloid aggregates (pankeratin).

Juvenile colloid milium: this high-power view shows the faceted nature of the deposit.

Fig. 13.78 Adult colloid milium: predominantly unilateral, streaked, orange plaque involving the forehead and nose. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.76 Juvenile colloid milium: the adjacent epidermis shows massive apoptosis.

Adult colloid milium presents as dome-shaped yellowish translucent ­ apules measuring 0.1–0.5 cm in diameter and, in common with juvenile p ­colloid milium, they contain gelatinous material. Lesions are most often seen on the face, ears, neck, and the dorsum of the hands (Fig. 13.78) and may be skin colored to brown.2,13 Adult colloid milium affects fair-skinned patients and follows excessive sun exposure. This has been dramatically illustrated in patients whose lesions are limited to sun-exposed areas of the body.14,15 Adult colloid milium has also been reported following the excessive use of cosmetic ultraviolet A (UVA) sunbed exposure.16 A rare association with multiple myeloma has been described.17 A further report described a patient who developed lesions of adult colloid milia in areas exposed to

mineral oils.18 A single case has also been described in a patient with beta thalassemia major.19 Rare cases of pigmented colloid milium have been documented as a consequence of exogenous ochronosis due to ­bleaching creams and fertilizers.1,13

Pathogenesis and histological features In contrast to the keratinocyte changes seen in the juvenile variant, adult colloid milium represents an extreme degree of actinic damage centered upon the upper dermal elastic fibers. Although earlier studies suggested that the colloid might have represented abnormal collagen or a fibroblast secretory product, more recent studies suggest that it derives from actinic elastoid.14,20–22 Ultrastructural studies have shown that there is direct continuity between actinic elastoid and the colloid deposits and that, within the electron-dense colloid, remnants of both normal and elastotic fibers may sometimes be ­identified.21,23 Amyloid filaments are not present. Further support for this hypothesis is given by the identification of serum amyloid P component within the colloid deposits.21 Although this protein is characteristically present within amyloid, it is also a constant component of normal elastic tissue and has also been identified in actinic elastoid.24,25 Adult colloid milium does not label with antikeratin antibodies, and immunoglobulins and complement are absent.

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Fig. 13.79 Adult colloid milium: deposits of eosinophilic material are present in the superficial dermis. There is adjacent solar elastosis.

Fig. 13.80

The gene for lipoid proteinosis has been mapped to chromosome 1q21 and the disease is caused by mutations in the extracellular matrix protein 1 gene (ECM1) which lead to partial or complete loss of function of the protein.12 ECM1 is thought to play a critical role in dermal structure and organization by binding to dermal ground susbstance (molecules such as perlecan and matrix metalloproteinases), in the formation and maintenance of the basement membrane, and in stromal signaling.13 It has been called ‘­biological super-glue’.13,14 It is also overexpressed in cancers, influencing tumor growth and metastasis.13 Over 40 different mutations in this gene have been reported in association with lipoid proteinosis, and studies thus far have not demonstrated a relationship between the specific type of mutation and ­clinical ­phenotype.13,14 Interestingly, patients with lichen sclerosus have auto­ antibodies to ECM1.15 The initial symptom, a hoarse cry, develops in infancy and results from incomplete closure of the vocal cords, which are thickened and irregular due to the hyaline deposits. Induration of the oral mucosa (including the inner aspect of the lips, the gingivae, uvula, palate, and floor of the mouth) begins in childhood and is progressive, so that adults have extensive yellow infiltration (Fig. 13.81).4,16 The lower lip often assumes a cobblestone appearance. The tongue also tends to be thick and immobile with sublingual frenulum thickening and ankyloglossia. Recurrent ulcers on the tongue have been described.5 Nail growth is frequently abnormal and the upper incisors, premolars or molars can be hypoplastic or aplastic.6 Early inflammatory skin lesions (bullae, pustules, and crusts) are followed by acneiform infiltrated scars on the face and limbs (Fig. 13.82).10 Papulonodular lesions develop on the face, fingers, and around the eyelashes, where they produce the pathognomonic ‘string of beads’ appearance (moniliform blepharosis) (Fig. 13.83). Thicker xanthoma-like plaques, which sometimes become verrucous, later develop on the areas of trauma including the knees, elbows, feet, and hands.17 With chronicity in severely affected patients the entire skin becomes yellow, waxy and thickened, particularly the flexures.18 Similar lesions in the scalp may produce alopecia, which can be patchy or diffuse.6,8 Intracranial disease sometimes occurs, associated with calcification, which is thought to complicate deposition of hyaline material around cerebral blood vessels and basal ganglia.4 Epilepsy is a not uncommon result.17,19,20 Other neurological manifestations include memory loss, rage attacks, and mild mental retardation.21 Involvement of the small bowel by the disease may lead to intestinal bleeding.22 The disease is usually associated with normal life expectancy although there might be some increase in the mortality rate during childhood due to respiratory insufficiency.2

Adult colloid milium: the typical faceted appearance.

Histologically, the eosinophilic amorphous, autofluorescent clefted deposits are typically separated from the epidermis by a grenz zone containing normal collagen (Figs 13.79, 13.80).21 Fibroblasts often occupy the fissures between the fragmented deposits.21 Histochemically, adult colloid milium is diastase-resistant, PAS positive, thioflavine-T positive and demonstrates apple-green birefringence with Congo red.14 It is also Dylon positive.2 Colloid milium can be ­difficult to ­distinguish from amyloidosis, and electron microscopy may be necessary.26,27

Hyalinosis cutis et mucosae Clinical features Hyalinosis cutis et mucosae (Urbach-Wiethe disease, lipoid proteinosis), is a very rare, autosomal recessive condition first described in 1929 in which hyaline material is deposited in virtually any organ in the body, but particularly the skin, the pharyngeal mucosa, and the larynx.1–7 It has been reported most frequently in South Africa (descendants of German and Dutch immigrants) and Sweden, and it has been suggested that up to 35% of documented cases have had South African lineage.8–11

Fig. 13.81 Lipoid proteinosis: small pale papules are present on the mucosal aspect of the lower lip. By courtesy of the Institute of Dermatology, London, UK.

Hyalinosis cutis et mucosae

Fig. 13.82 Lipoid proteinosis: marked thickening of the skin is present with conspicuous scarring. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.84 Lipid proteinosis: the blood vessel walls are thickened by pale-staining, eosinophilic homogeneous material.

Fig. 13.83 Lipoid proteinosis: note the waxy nodules on the lower eyelid, producing the typical ‘string of beads’ appearance. By courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features The epidermis is acanthotic and occasionally papillomatous, with overlying hyperkeratosis. Homogeneous eosinophilic material is distributed in a very characteristic pattern in the dermis.8 Initially, it is found around capillaries and concentrically around sweat coils (Figs 13.84, 13.85); later, more extensive deposits are seen, which tend to be vertically orientated within the dermis. The hair follicles and arrector pili muscles are often surrounded by a hyaline mantle.23 In advanced cases, the perineurium of nerves can also be affected.24 This material stains very strongly with PAS (diastase-resistant) and only very weakly with Congo red and thioflavine-T (Fig. 13.86). The name lipoid is used because the hyaline material usually has a lipid component.25 Ultrastructurally, the deposit is amorphous, electron dense, and may contain ill-defined, anastomosing amyloid-like (5–10 nm) filaments and delicate collagen fibers (Figs 13.87, 13.88).23 Reduplication of basal lamina is evident around blood vessels, hair follicles, and sweat glands, and excess type IV collagen has been demonstrated immunohistochemically.8,17,18,26 The ­fibroblasts contain abundant rough endoplasmic reticulum and numerous mitochondria. Intracytoplasmic inclusions, probably lysosomal in nature, have also been described.

Fig. 13.85 Lipoid proteinosis: in this advanced example, there is considerable involvement of eccrine sweat glands which, as a result, are atrophic.

The etiology of bullous lesions in lipoid proteinosis is unclear. A recent report sheds light on a possible pathogenesis. It describes subcorneal and intraepidermal acantholysis without dyskeratosis in a child with lipoid ­proteinosis.27 Subepidermal clefting was also noted but thought to be artifactual. Direct immunofluorescence studies were negative. Despite considerable research, the precise pathogenesis of lipoid proteinosis remains an enigma. Quantitative abnormalities of dermal collagen have been clearly demonstrated, but little is known about the nature of the hyaline deposits other than that they are probably composed of an admixture of ­glycoproteins, glycosaminoglycans, and lipids, as may be determined by s­ pecial staining techniques.8 Numerous mechanisms have been hypothesized, but none has satisfactorily unraveled the nature of the primary disturbance in this disease. The identification of lipid droplets within the hyaline deposits therefore led to the suggestion that lipoid proteinosis might represent a systemic lipoidosis.8 However, the lipid deposition is very variable and lesional chemical analyses have not demonstrated any consistent abnormalities. Fibroblast tissue culture experiments

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Fig. 13.88 Lipoid proteinosis: high-power view of amorphous electron-dense material containing occasional collagen fibers.

Fig. 13.86 Lipoid proteinosis: the deposit is strongly periodic acid–Schiff positive (diastase-resistant).

A

have not supported this concept.25 It probably denotes a secondary phenomenon. The ultrastructural finding of intracytoplasmic inclusions – including myelin figures and lysosomes accompanied by an increased fibroblast hexuronic acid content – has raised the possibility of a lysosomal storage disorder.28 This has recently been given further support by the demonstration of abnormal lysosomes in eccrine cells and histiocytes in two patients with this disease.29 These lysosomes were found to contain amorphous granular material, zebra bodies, and curved tubular profiles. The curved tubular profiles are similar to those found in Farber's disease and it has been suggested that lipoid proteinosis represents a disease with not only impaired production of collagen but also with alterations in ceramide metabolism. A number of recent publications have described a variety of changes in the dermal collagen content.30 The reduplicated basement membrane laminae noted ultrastructurally have been shown to be composed of laminin accompanied by collagen types III and IV.31 This feature, however, is of doubtful significance as similar appearances have been described in a wide variety of conditions including psoriasis, systemic lupus erythematosus, and diabetes mellitus.8 Basement membrane replication most likely represents a non-specific secondary response to a range of stimuli. Dry weight studies of lipoid proteinosis dermis have shown an apparent decrease in collagen content although there appears to be a relative increase in collagen types III and V compared with collagen type I.32 Immunofluorescence data, however, suggest that there are reduced absolute levels of both type I and type III collagen.8 In vitro studies of fibroblast collagen synthesis as determined by radioactive hydroxyproline synthesis have revealed no significant abnormality.17 Fibroblasts, however, have reduced replicative capacity. Recent investigations have disclosed reduced fibroblast type I procollagen mRNA and a diminished type I:III procollagen mRNA ratio.17 Type IV procollagen mRNA levels have been shown to be raised.33 No DNA abnormalities or chromosomal alternations have yet been identified in lipoid proteinosis. It is likely that the collagen changes are not directly responsible for the accumulation of the granular hyaline material so characteristic of this ­disorder. It is, however, most probably of fibroblast derivation.34

Cutaneous macroglobulinosis Clinical features B

Fig. 13.87 (A, B) Lipoid proteinosis: transverse section through blood vessel showing reduplication of the basement membrane.

Cutaneous macroglobulinosis (IgM storage papules) is a rarely documented manifestation of Waldenström's macroglobulinemia.1–7 The latter is a chronic lymphoproliferative condition that typically presents in the fifth and sixth decades and shows a slight predilection for males.5 It is characterized by ­proliferation of lymphoplasmacytoid cells in the bone marrow, lymph node, and spleen and IgM paraproteinemia.5 Patients present with weakness, fatigue, weight loss, anemia,

Porphyria mucous membrane bleeding, retinal hemorrhages, lymphadenopathy, hepatosplenomegaly, peripheral neuropathy, and the hyperviscosity syndrome.7,8 Skin involvement is very uncommon and includes tumors, plaques, and macroglobulinosis cutis. Additional features that sometimes encountered include purpura, xanthomata, cryoglobulinemia, and Raynaud's phenomenon.7 Clinically, macroglobulinosis presents as sometimes pruritic, skin-colored, erythematous or translucent papules measuring up to 1.0 cm in diameter distributed predominantly on extensor sites including knees, elbows, buttocks, and the arms and legs..7 Umbilication, erosion, and crusting and hyperkeratosis are commonly seen.5,9,10 Cutaneous tumor deposits present as violaceous nodules and plaques.

Histological features The papules are characterized by homogeneous eosinophilic material in the papillary and reticular dermis (Fig. 13.89).2 Hair follicles may be encased.2 The deposits are PAS positive but are Congo red negative (Fig. 13.90). A ­lymphoplasmacytoid infiltrate is variably present.7 The plasma cells may contain intracytoplasmic IgM-rich vacuoles.4

Direct immunofluorescence shows that the deposits stain strongly for IgM.2,5,7 Ultrastructurally, the deposits are composed of amorphous or granular and sometimes filamentous material which by immunoelectron microscopy consists of IgM.1–3,7 The periodicity of amyloid is absent in the filamentous component.7 The plaques and tumor nodules are composed of lymphoplasmacytoid infiltrates.

Porphyria The porphyrias constitute a heterogeneous group of conditions characterized by the excessive production of porphyrins or their precursors resulting from defects in the activity of the enzymes regulating heme synthesis (Fig. 13.91).1–12 Porphyrin synthesis occurs mainly in the erythropoietic system and the liver.

Fig. 13.89 Macroglobulinosis cutis: these are nodular deposits of eosinophilic material in the superficial dermis. By courtesy of A. Wang, MD, Brigham and Women’s Hospital, Boston, USA.

Fig. 13.90

Fig. 13.91

Macroglobulinosis cutis: the material is strongly periodic acid–Schiff positive. By courtesy of A. Wang, MD, Brigham and Women’s Hospital, Boston, USA.

Biochemistry of porphyria. Reproduced with permission from Young, J.W., and Conte, E.T. (1991) International Journal of Dermatology, 30, 399–406.

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Degenerative and metabolic diseases Deficiency of a specific enzyme results in an accumulation of heme ­precursors due to stimulation of the rate-limiting enzyme aminolevulinic acid synthetase as a consequence of diminished heme concentration.10,13 Genetic mutations account for the enzyme deficiencies seen in the various types of porphyria. These mutations have all been delineated at a molecular level, are very heterogeneous, and often result in enzyme deficiencies that may remain silent throughout life.13 If a patient is homozygous for a specific mutation, however, symptoms usually develop even in early life. Patients may present with acute porphyria (abdominal pain with neurological and/or psychiatric symptoms) often induced by drugs, fasting, alcohol or sex hormones.14–17 The enzyme defect leads to the accumulation in the skin of a photosensitizing porphyrin, which absorbs light predominantly in the 400–410 nm range. The energy absorbed may then be released to adjacent nucleic acids or proteins, either directly or indirectly by involving acceptor molecules such as oxygen, and toxic changes causing damage to lysosomal and cellular membranes result.16,17 There is also some evidence to suggest that activation of the complement cascade may be involved in the phototoxic reaction mechanism.16,17 The cutaneous manifestations in acute attacks consist of prominent erythema in sun-exposed areas with a burning sensation. Subacute or chronic skin involvement consists of skin fragility, blister formation, and progressive scarring. Exceptional cases of a photosensitive bullous eruption associated with transient elevation of porphyrin levels have been described in neonates during phototherapy for ­treatment of hyperbilirubinemia due to hemolytic disease.18,19 Porphyria is primarily classified into erythropoietic and hepatic types depending upon which tissue is predominantly affected. The erythropoietic porphyrias (congenital erythropoietic porphyria and erythropoietic protoporphyria) are characterized by altered heme synthesis mainly in the bone

­ arrow. In the hepatic porphyrias the altered synthesis mainly occurs in the m liver (porphyria cutanea tarda, hepatoerythropoeitic porphyria, acute intermittent porphyria, aminolevulinic acid (ALA) dehydratase deficiency, variegate porphyria, and hereditary coproporphyria). Of the eight major types of porphyria, six are associated with cutaneous disease (Table 13.4). The clinical and biochemical findings are very different in these six types of ­porphyria, although the cutaneous histology is similar in all.20–23 Type II porphyria ­cutanea tarda, hereditary coproporphyria, variegate porphyria, and erythr­ opoietic protoporphyria are all inherited as autosomal dominants with incomplete penetrance. Fewer than 20% of affected individuals display ­symptoms and patients often deny a family history.2

Congenital erythropoietic porphyria Clinical features Congenital erythropoietic porphyria (Gunther's disease) is the most severe and mutilating of the erythropoietic porphyrias. It is inherited as an autosomal recessive and develops as a consequence of deficiency of the fourth enzyme of the heme pathway (uroporphyrinogen III synthase) resulting in excessive production of uroporphyrin I and coproporphyrin I, which give the urine a pink–burgundy color.1–3 Patients with the more severe form of the disease may present with fetal hydrops.4 The diapers of affected children usually show a characteristic pink stain. Uroporphyrin I accumulates in the bone marrow, peripheral blood, and other organs. It has been demonstrated that there is a clear correlation between the degree of porphyrin excess and disease severity.5 There is increased production of uroporphyrins and ­coproporphyrins in the urine and coproporphyrins in the feces.

Table 13.4 Classification of porphyria Condition

Mode of inheritance

Enzyme defect

Site of metabolic expression Erythroid cells

Laboratory abnormality

Non-acute porphyrias producing cutaneous lesions Congenital erythropoietic porphyria Porphyria cutanea tarda inherited sporadic toxic Erythropoietic protoporphyria

Autosomal recessive

URO-S

Autosomal dominant Acquired/sporadic Acquired Autosomal dominant

URO-D URO-D Ferrochetalase

Erythroid cells and hepatocyte

Hepatoerythropoietic porphyria

Autosomal recessive

URO-D (severe)

Erythroid cells and hepatocyte

Hepatocytes

Elevated uroporphyrin Coproporphyrin in urine and feces Urinary uroporphyrin:coproporphyrin = 3:1 Elevated urinary uroporphyrin Urinary and stool isocoporphyrins Normal urine Elevated plasma, RBC and stool protoporphyrin Elevated fecal and RBC coproporphyrin Increased urine and stool URO Elevated stool coproporphyrin and isocoproporphyrin Elevated RBC protoporphyrin

Acute porphyrias (porphyrias producing abdominal, neurological and psychiatric symptoms) Acute intermittnt porphyria

Autosomal dominant

ALA dehydratase deficiency

Autosomal recessive

Porphobilinogen deaminase ALA dehydratase (porphobilinogen synthase)

Hepatocyte ?

Stool and blood usually normal Elevated urinary ALA and PBG ALA alone elevated

Porphyrias producing abdominal, neurological, psychiatric and cutaneous manifestations Variegate porphyria

Autosomal dominant

Protoporphyrinogen oxidase

Hepatocyte

Hereditary coproporphyria

Autosomal dominant

Coproporphyrinogen oxidase

Hepatocyte

ALA, aminolevulinic acid; PBG, porphobilinogen; RBC, red blood cell; URO, uroporphyrinogen. Reproduced with permission from Young, J.W., Conte, E.T. (1991) International Journal of Dermatology, 30, 399–406.

Urine normal between attacks Increased stool protoporphyrins and coproporphyrin Increased urinary ALA and PBG during attacks Increased stool and urine coproporphyrins

Porphyria Affected patients develop intense photosensitivity to sunlight as well as to fluorescent light, typically in infancy (Fig. 13.92). Symptoms include painful and pruritic erythema and swelling which occurs within minutes of sun exposure. Vesicles and bullae are supervened by a mutilating scarring process on the face and hands, where autoamputation may occur (Figs 13.93, 13.94). A rare case of metastatic squamous cell carcinoma has been reported in an amputation stump.6 Sclerodermoid change is sometimes seen.7 Coarse hair may be found on the face, and lanugo hair develops on the limbs. Pigmentary changes are sometimes evident. In addition, patients develop cicatricial alopecia of the scalp, nail changes, conjunctivitis, ectropion, keratoconjunctivitis, symblepharon, blepharitis, or brown staining of the teeth (erythrodontia).8,9 The teeth characteristically fluoresce intense orange–red with Wood's light (400 nm). The sclera also demonstrates pink fluorescence under Wood's light.10

Fig. 13.94 Congenital erythropoietic porphyria (Gunther’s disease): adult patient showing very severe photodamage. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.92 Congenital erythropoietic porphyria (Gunther’s disease): this variant is associated with severe photosensitivity. There is marked erythema and edema of the backs of the hands and fingers. Scarring frequently supervenes. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Hemolytic anemia and splenomegaly occur in a large proportion of the patients and hypersplenism is sometimes a feature. Patients with congenital erythropoietic porphyria have an increased risk of bone fragility with ­resultant fractures and developmental defects.2 Acro-osteolysis, soft ­tissue calcifications, and widening of the diploic space have also been documented.11 Early death may result, often in the third decade. Rare cases are associated with the nephrotic syndrome, probably secondary to renal siderosis.12 A delayed ­late-onset variant has rarely been described.13–15 Some of these patients ­present with thrombocytopenia and others with myelodysplasia.14–17 The URO-synthase gene has been mapped to chromosome 10q25.3q26.3,15 The molecular defects in this disease are very heterogeneous and up to 38 mutations in the URO-synthase gene have already been described.18–23 These include single base substitutions, insertions and deletions, and splicing defects. By far the most common mutation is C73R, which has been found in up to 40% of patients with the disease. Two other relatively common mutations include L4F and T228M, seen in 8% and 7% of patients, respectively.19 Prenatal diagnosis of the disease is possible not only by ­measurement of uroporphyrin I levels in amniotic fluid but also by DNA mutation analysis.24

Erythropoietic protoporphyria Clinical features Fig. 13.93 Congenital erythropoietic porphyria (Gunther’s disease): in this severely affected patient, there is marked hyperpigmented scarring on the cheeks, nose, and around the mouth. The brownish discoloration of the teeth is characteristic. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Although this condition was not recognized until 1961, it is now known to be the second commonest type of porphyria. It results from increased production of protoporphyrin due to diminished ferrochelatase (heme synthase) activity.1–3 Ferrochelatase is the enzyme responsible for the combination between protoporphyrin IX and iron to form heme. Urinary porphyrins are normal because protoporphyrins are insoluble in water. Protoporphyrin is elevated in plasma, erythrocytes, and occasionally in the feces.1 Coproporphyrins may be found in erythrocytes and feces. The mode of inheritance is predominantly autosomal dominant with incomplete penetrance although an autosomal recessive inheritance has also rarely been reported.4,5 The gene for ferrochelatase has been mapped to the long arm of chromosome 18 (18q21.3).6 The variable clinical manifestations of this disease are probably the result of heterogeneity of the ferrochelatase gene defects.7 Acute photosensitivity usually presents in early childhood.8 A painful burning erythema

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Degenerative and metabolic diseases with edema occurs immediately after exposure to sunlight.9 Petechiae can occur, ­particularly with prolonged exposure. Vesicles are uncommon, but a scaly, erythematous reaction may be seen, leading to circular or linear depressed scars on the face (particularly on the bridge of the nose and around the mouth) and over the knuckles (Figs 13.95–13.99).1 Purpura and urticaria are sometimes seen. There may also be a waxlike thickening of the skin, particularly of the dorsum of the hands and, more rarely, the face (Fig. 13.100).1 Bullae and milia have been documented exceptionally.3 A further case presented with pseudoainhum.10 An association with lupus erythematosus is very rare.11 Hypertrichosis and hyperpigmentation are not typically seen.2 In the majority of cases the disease is limited to the skin, but some affected patients develop protoporphyrin-rich gallstones, and 5–10% of patients develop liver disease, which may progress to liver failure in fewer than 5% of

patients and rarely to cirrhosis.6,12–14 Patients who develop liver failure have a different form of the disease with an autosomal recessive form of transmission.15 Neurological manifestations are not common. Anemia is rare and if present is very mild. Recently, a late-onset variant has been described, which is more commonly associated with hematological malignancy, where the disease occurs secondary to an acquired somatic mutation in the malignant clone within the bone marrow.16–19 Exacerbation of the disease by blood transfusion and by iron ingestion has been described.20,21

Fig. 13.97

Fig. 13.95 Erythropoietic protoporphyria: crusted lesions are present on the cheeks, nose, and around the mouth. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Erythropoietic protoporphyria: there are characteristic, depressed, small linear scars on the bridge and sides of this patient’s nose. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.98

Fig. 13.96 Erythropoietic protoporphyria: there is marked scarring. Note the depressed linear lesions. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Erythropoietic protoporphyria: there is very severe actinic damage. By courtesy of the Institute of Dermatology, London, UK.

Porphyria with jaundice, severe chronic hemolytic anemia starting in the neonatal period, hepatosplenomegaly, and photosensitivity. Neuropsychiatric ­symptoms or abdominal pain are not seen. These patients usually have a specific mutation (K404E) on one or both alleles of the coproporphyrinogen gene.11

Porphyria cutanea tarda Clinical features

Fig. 13.99 Erythropoietic protoporphyria: note the characteristic scaly scars over the knuckles. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.100 Erythropoietic protoporphyria: there is characteristic waxy thickening of the skin of the hands. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Hereditary coproporphyria Clinical features This very rare autosomal dominant form of porphyria develops as a result of a deficiency of coproporphyrinogen oxidase.1,2 This enzyme catalyzes the sixth step in the heme biosynthetic pathway. It has been mapped to the long arm of chromosome 3 (3q11.2).3 A number of different mutations have been documented.4,5 Heterozygous patients often do not manifest symptoms of the disease.6 In those who develop symptoms, these usually appear after puberty. Affected patients develop intermittent attacks of abdominal pain in association with neurological and psychiatric manifestations. About 30% of cases develop photosensitivity, usually at the time of the acute attacks. The cutaneous changes are similar to those described for porphyria cutanea tarda. The disease may be precipitated by pregnancy, the contraceptive pill, fasting, infections, and the anabolic steroid methandrostenolone.3,7–9 Diagnosis is confirmed by the presence of increased excretion of coproporphyrinogen III in urine and feces. Porphobilinogen and aminolevulinic acid are increased during the episodic attacks. Harderoporphyria is regarded as a variant form of hereditary coproporphyria in which hematological alterations predominate.2,10 Patients ­present

This is the commonest type of porphyria and usually manifests in middle age.1–3 It shows a marked male predominance.4 The highest incidence is found in the South African Bantu.4 Cases are also often seen in Europe and North America. There are two main forms of porphyria cutanea tarda: familial and sporadic.1 Both variants have in common a reduced activity of uroporphyrinogen decarboxylase (URO-D), which catalyzes the decarboxylation of uroporphyrinogen to coproporphyrinogen. In the familial variant there is decreased URO-D activity in erythrocytes and most other tissues while in the ­sporadic form there is decreased URO-D activity restricted to the liver.5,6 In rare ­familial cases, normal URO-D activity has been reported in erythrocytes.7 The rare familial form exhibits an autosomal dominant inheritance. The onset tends to be earlier than that of the sporadic form and the exceptional cases occurring in childhood are usually familial. The disease is related to many different mutations in the URO-D gene.8,9 There is no clear correlation between disease severity and the type of mutation.10 Porphyria cutanea tarda may be precipitated by many exogenous factors including alcohol abuse, iron overload, childbirth, and sun exposure.11 Pregnancy may exacerbate the symptoms of the disease during the first trimester.12 Multiple factors often contribute to precipitate the disease in a given patient.13 Rare cases of familial porphyria cutanea tarda present with constrictive pericarditis.14 The second much more common form is sporadic or acquired. Up to 80% of patients with porphyria cutanea tarda have the sporadic form of the disease. It has been demonstrated that sporadic porphyria cutanea tarda is a multifactorial disorder involving a combination of genetic and environmental factors. Recent studies have demonstrated that the hemochromatosis gene mutations C282Y and H63D represent a susceptibility factor in Western European and Australian patients affected by this form of the disease.15–19 These mutations probably induce the disease through iron overload. It has also been suggested that the IVS4+198 T allele in the human transferrin receptor-1 may play an independent role in the development of the disease.15 However, this has not been substantiated in other studies.18 Coinheritance of mutations in the uroporphyrinogen decarboxylase and in the hemochromatosis genes appears to accelerate the onset of porphyria cutanea tarda.20 Sporadic cases mainly occur in patients exposed to a variety of hepatotoxic chemicals, such as ethanol, estrogens, griseofulvin, vitamin B12, sulfonamides, tamoxifen, pravastatin, barbiturates, hydantoins, and chlorinated hydrocarbons: for example, an epidemic form occurred in Turkey due to exposure to the fungicide hexachlorobenzene.21–25 Rare associations include diabetes ­mellitus, Wilson's disease, myelofibrosis, the CREST syndrome, and hepatocellular carcinoma.26–29 Increased hepatic iron stores are a major predisposing factor.6,30 The mechanism by which this happens is not well understood. Iron catalyzes the formation of reactive oxygen species and this may enhance uroporphyrin formation by increasing the rate at which uroporphyrinogen is oxidized to uroporphyrin, leading to the manifestations of the disease. A second possible proposed mechanism considers the indirect inhibition of uroporphyrinogen decarboxylase by iron. Whatever the mechanism, the iron overload has important ­therapeutic implications as venesection can induce a remission. Hepatitis C virus infection is often associated with porphyria cutanea tarda.31–33 A frequent association is also the acquired immunodeficiency syndrome (AIDS).34–39 AIDS patients with porphyria cutanea tarda are often hepatitis C virus-positive.40 Patients who have had both acquired and familial variants have developed the typical features of increased skin fragility, blistering, hyperpigmentation, and hypertrichosis, but scarring and milia have rarely been evident.41 Often, the development of porphyria has preceded the ­diagnosis of HIV infection.41 In many instances this has been related to ­excessive alcohol consumption and/or infectious hepatitis, particularly

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Degenerative and metabolic diseases ­ epatitis C.38,42 The association has been reported too often to be merely h ­fortuitous and liver damage seems to be the common denominator. The causal agent (be it hepatitis C virus or HIV) seems to have a direct effect upon hepatocyte porphyrin metabolism. It has been demonstrated that elevated serum porphyrin levels occur in early-stage HIV infection and hepatitis C infection.43 Porphyria cutanea tarda has also been described in association with nonalcoholic liver disease, chronic hemodialysis, noninsulin dependent diabetes mellitus and lupus erythematosus.1,44,45 An autoantibody study in a large series of patients with lupus erythematosus suggests that the association is fortuitous.46 The association with hematological malignancies including leukemia and lymphoma is usually related to the treatment, particularly repeated blood transfusions.47,48 Typically, blisters occur on light-exposed skin and are traumatic or actinically induced (Figs 13.101–13.103).4 Cutaneous fragility is usually marked. The blisters are slow to heal and leave superficial atrophic scars with milia. Although they are most often seen on the backs of the hands, they may also be found on the palms, face, scalp, forearms, trunk, and under the finger nails.4 Hypertrichosis and premature aging with chronic actinic damage are usual and sclerodermatous changes may be marked (Fig. 13.104). The hypertrichosis is characterized by long dark lanugo hair developing about the

cheeks and temples, the eyebrows, ears, and arms (Fig. 13.105).4 The ­sclerodermatous features, which are more common in females, are found on both light-exposed and unexposed skin. Sites that are particularly affected include the face, neck, scalp, chest, and backs of hands, and often there is hyper- or hypopigmentation or both.4,49 Hyperpigmentation, if present, may be diffuse, reticulate or spotty. Preauricular calcification is a common ­complication. The dermal fibrosis appears to be related particularly to high uroporphyrin ­levels.49 Uroporphyrin has been shown to stimulate fibroblast collagen synthesis independent of ultraviolet light.50 Uncommon cutaneous manifestations of porphyria cutanea tarda include alopecia affecting the frontoparietal, temporal, and occipital regions of the scalp, and centrofacial papular lymphangiectasis.51,52 Hair darkening has also been reported.53 Very rare cases have been documented presenting with plaques or simulating solar urticaria.54,55

Fig. 13.103 Porphyria cutanea tarda: note the scarring and milia. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.101 Porphyria cutanea tarda: in addition to a blood-filled vesicle there are numerous milia. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Fig. 13.104

Fig. 13.102 Porphyria cutanea tarda: there are numerous ruptured blisters. Milia are also evident. By courtesy of the Institute of Dermatology, London, UK.

Porphyria cutanea tarda: there is marked facial scarring with sclerodermiform features. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Porphyria

Fig. 13.106

Fig. 13.105

Variegate porphyria: numerous ruptured vesicles are present on the back of the hand and fingers. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Porphyria cutanea tarda: hypertrichosis as seen in this patient is a very typical feature. By courtesy of the Institute of Dermatology, London, UK.

Acute attacks are not a feature of this variant. Biochemical evidence of liver involvement is common, but clinical manifestations are unusual.1 Urinary porphyrin levels are increased and result in pink–red fluorescence with a Wood's lamp.56 The diagnosis is confirmed by the presence of uroporphyrin and hepta­ carboxylic porphyrins in urine and plasma and by the presence of ­isocoproporphyrin in feces.

Hepatoerythropoietic porphyria Clinical features Hepatoerythropoietic porphyria is very rare and, in fact, represents the homozygous form of familial porphyria cutanea tarda.1 Both diseases share some of the mutations that have been described.2 This form of porphyria is also heterogeneous and different mutations in the URO-D gene may occur.3,4 The activity of uroporphyrinogen decarboxylase is much lower than in ­porphyria cutanea tarda. As a consequence, disease manifestations are ­typically severe. Recently, mild variants have been reported in association with certain genetic mutations.5,6 Extreme immediate photosensitivity occurs in infancy.7–9 Erythema, edema, and vesicles lead to severe scarring, with hypertrichosis and sclerodermatous changes in exposed areas.10 Ocular features include photophobia, conjunctivitis, and scleromalacia perforans.11 Hepatitis, cirrhosis, and normochromic anemia may also occur.

Variegate porphyria Clinical features This familial type of porphyria manifests the cutaneous features of porphyria cutanea tarda and the acute abdominal and neurological attacks of acute intermittent porphyria, both of which usually become apparent in the second or third decade (Figs 13.106–13.109).1,2 It is particularly common in South Africa where it can be traced to the descendants of a single Dutch family.2,3 It is an autosomal dominantly inherited condition and more severely affected homozygotes have been recognized (Figs 13.110, 13.111). Variegate porphyria is associated with diminished activity of protoporphyrinogen oxidase, the penultimate enzyme in the heme biosynthetic pathway.4 Several different mutations have been demonstrated in the protoporphyrin oxidase gene on

Fig. 13.107 Variegate porphyria: there are ruptured blisters with scarring and milia. By courtesy of the Institute of Dermatology, London, UK.

chromosome 1q22-23.5,6 The genotype is not a significant determinant of the clinical manifestations.7–9 Usually, there is approximately a 50% reduction in the activity of the enzyme.9 Acute attacks may be precipitated by a wide range of drugs that induce hepatic microsomal activity including barbiturates, alcohol, oral contraceptives, pregnancy, anticonvulsants, and sulfonamides.10–13 Acute variegate porphyria has also presented during an episode of viral hepatitis.10 The cutaneous manifestations are sometimes mild or absent during the acute attack and the condition may therefore be misdiagnosed as acute intermittent porphyria.2

Histological features of the porphyrias Direct immunofluorescence reveals immunoglobulin (particularly IgG and to a lesser extent IgM), fibrinogen, and C3 outlining characteristic donutshaped blood vessels in the papillary dermis (Fig. 13.112). Although this is particularly evident in erythropoietic protoporphyria, it is also a feature of

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Degenerative and metabolic diseases

Fig. 13.110

Fig. 13.108

Homozygous variegate porphyria: there is marked scarring of the dorsal surface of the forearms, hands, and fingers. By courtesy of the Institute of Dermatology, London, UK.

Variegate porphyria: note the blistering over the toes and dorsum of the foot. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.109 Variegate porphyria: an intact blister is present on the left little finger. Elsewhere, there is marked scarring and milia are present. By courtesy of the Institute of Dermatology, London, UK.

the other ‘cutaneous’ variants.1,2 Immunoreactants are also frequently present at the dermoepidermal junction and have been identified within the basement membrane region of eccrine sweat glands and ducts.1–4 This finding is believed to be due to the non-specific binding of serum components rather than an immunologically mediated reaction.3 In addition, both type IV collagen and laminin are present in increased amounts, thereby contributing to the vessel wall thickening.5 Cytoid bodies are also commonly evident.3 Recently, direct immunofluorescence studies have demonstrated granular and homogenous deposition of the membrane attack complex C5b-9 in vessel walls of the superficial and mid dermis in patients with porphyria cutanea tarda. It is proposed that UV light activated uroporphyrins in turn activate complement, possibly playing a pathological role.6 Indirect immunofluorescence is invariably negative for basement membrane zone autoantibodies. The histological changes for all types of porphyria are very similar. The characteristic feature is the presence of a PAS-positive, diastase-resistant, hyaline material around the blood vessels of affected skin (Figs 13.113, 13.114). In mild disease the deposits are delicate and are usually limited to the papillary dermal capillaries, but in more severe cases the deposits are widespread, occur more deeply in the dermis, and give the vessel walls a characteristic

Fig. 13.111 Homozygous variegate porphyria: note the perioral erosions and scarring. By courtesy of the Institute of Dermatology, London, UK.

lamellated appearance. These appearances are particularly conspicuous in erythropoietic protoporphyria.1,7 Alcian blue-positive mucin is sometimes evident around the blood vessels and to a lesser extent at the dermoepidermal junction in both porphyria cutanea tarda and erythropoietic protoporphyria.1 Lipid droplets are sometimes also demonstrable. A false-positive Congo red stain for amyloid may be evident in the lower dermis.1 Electron microscopic observations include considerable basement membrane reduplication around the dermal vasculature and to a lesser extent at the dermoepidermal junction (Fig. 13.115).1,7 This is consistent with the effects of repetitive endothelial cell injury and regeneration with subsequent new basement membrane formation. In addition, finely fibrillar material is typically present both around the vessels and at the epidermal basement membrane region. Irregular electron-dense amorphous deposits may also be evident.1

Porphyria There may be subepidermal blisters, characteristically associated with slight mononuclear inflammatory cell infiltration (Figs 13.116, 13.117). Neutrophil polymorphs showing leukocytoclasis have been described in acute lesions of erythropoietic protoporphyria and red cell extravasation is ­sometimes evident.8 Festooning of the dermal papillae is often, though not invariably, present.

The plane of cleavage appears to be variable.9 Some blisters arise beneath the lamina densa in the superficial dermis similar to ­epidermolysis bullosa acquisita. In others, they develop within the reduplicated basement membrane constituents. Most often, however, as shown by antigen mapping experiments, blistering commences in the lamina lucida.9,10 Type IV collagen and laminin are therefore usually present along the floor of the blister while bullous pemphigoid antigen is evident in the roof. Linear segmented structures composed of type IV collagen and laminin have been identified in the roof of blisters from patients with porphyria cutanea tarda.11 These so-called caterpillar bodies may also be seen in specimens from patients with erythropoietic protoporphyria and drug-induced pseudoporphyria (Fig. 13.117b).12 They are PAS positive and appear as globules arranged in a linear fashion in the epidermis overlying the subepidermal blisters. Ultrastructural studies suggest that these bodies ­represent a combination of degenerating keratinocytes, colloid bodies, and basement membrane fragments formed by repeated blistering and re-epithelialization.13 A recent study of caterpillar bodies demonstrated their presence in 43% of

Fig. 13.112 Porphyria cutanea tarda: the superficial blood vessels show striking IgG circumferential deposition.

Fig. 13.114 Erythropoietic protoporphyria: the appearances are much more dramatic in this periodic acid–Schiffstained section. A

B

Fig. 13.113 (A, B) Porphyria cutanea tarda: the superficial vessels are thickened and appear hyalinized.

Fig. 13.115 Porphyria cutanea tarda: there is striking basement membrane reduplication surrounding this small dermal vessel.

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Degenerative and metabolic diseases ­ orphyria cutanea tarda specimens.14 ‘Caterpillar body-like clusters’ have also p been identified in patients with porphyria cutanea tarda, erythropoietic protoporphyria, bullous ­pemphigoid, and junctional and dystrophic epidermolysis bullosa. These clusters were histologically identical to classical caterpillar bodies but did not stain for type IV collagen or PAS stains.14

Rarely, a lichenoid tissue reaction has been documented in porphyria ­cutanea tarda.15 The histological features of the blisters seen in variegate porphyria are identical to those described for porphyria cutanea tarda.16 A secondary sclerodermatous change is frequently present in more chronic lesions, characterized by thickened collagen bundles and reduced numbers of cutaneous adnexae (Fig. 13.118).3,7,17 Diastase-resistant, ­PAS-positive material may be identified throughout the involved dermis.1 This is particularly marked in porphyria cutanea tarda. Its distinction from the dermal changes of scleroderma may be very difficult, but it has been said that the texture of the collagen bundles is somewhat looser in ­porphyria.1 Basement membrane thickening due to diastase-resistant, PASpositive material is usually present, particularly in porphyria cutanea tarda.1,7 Solar elastosis is often evident in the latter condition, but this is probably largely a consequence of the age of the patient and is unlikely to be a fundamental process (Fig. 13.119). It is not a feature of ­erythropoietic protoporphyria.1,7 In the alopecia associated with porphyria cutanea tarda, the initial changes are those of swelling and homogenization of the perifollicular connective ­tissue

Fig. 13.116 Porphyria cutanea tarda: a bland subepidermal blister is present.

Fig. 13.118 Porphyria cutanea tarda: there is intense scarring of the entire dermis. The fat entrapment is reminiscent of scleroderma. A

B

Fig. 13.117

Fig. 13.119

Porphyria cutanea tarda: (A) the blister is cell free; (B) the superficial vessels are thickened (periodic acid–Schiff). Note the caterpillar bodies in the overlying epidermis.

Porphyria cutanea tarda: there is colloid milium-like solar elastosis deep to this blister.

Pseudoporphyria sheath.18 Later, the features of sclerodermatous transformation of the ­reticular dermis supervene. Centrofacial papular lymphangiectasis is ­characterized by the presence of dilated lymphatics in the superficial dermis.19 The hepatic changes of porphyria cutanea tarda are variable and include needle-shaped uroporphyrin crystals, hepatitis, liver cell degeneration and regeneration, fatty change, hemosiderosis, and scarring, sometimes amounting to cirrhosis (Fig. 13.120).18,20,21 There is an increased risk of hepatocellular carcinoma.21 Hepatic changes of erythropoietic protoporphyria include birefringent, dark brown, protoporphyrin crystal deposition in the hepatocytes and Kupffer cells, hepatocyte necrosis, portal and periportal fibrosis, cholestasis and, less commonly, cirrhosis (Fig. 13.121).22

Differential diagnosis The major differential diagnosis histologically is between porphyria, pseudoporphyria, epidermolysis bullosa acquisita and congenita, and bullous amyloidosis. All produce cell-poor or cell-free subepidermal blisters. Their distinction is readily made in the majority of cases with clinical information, immunofluorescence studies, and Congo red staining.

Pseudoporphyria Clinical features Pseudoporphyria (drug-induced pseudoporphyria, drug-induced pseudoporphyria cutanea tarda, pseudoporphyria cutanea tarda, bullous dermatosis in end-stage renal failure, bullous dermatosis of hemodialysis) refers to a photodistributed blistering dermatosis resembling porphyria cutanea tarda but in the absence of any serum, urine or stool porphyrin abnormality (Figs 13.122– 13.125).1 It is now recognized as having many causes including drugs, excessive UVA (including the use of sunbeds), and sunlight exposure and may develop in patients undergoing hemodialysis for chronic renal failure.1–20 Pseudoporphyria occurs in up to 6% of patients receiving hemodialysis.21 Small tense blisters develop on the backs of the hands and fingers, and occasionally involve the face, upper chest, and legs.1,2 Milia, skin fragility,

Fig. 13.122 Pseudoporphyria: there is extensive purpura with freckling and conspicuous excoriations. The patient had used a sunbed for a number of years. By courtesy of G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Fig. 13.120 Porphyria cutanea tarda: in addition to fatty change and mild chronic inflammation, brown uroporphyrin crystals are evident.

Fig. 13.121

Fig. 13.123

Erythropoietic protoporphyria: the Kupffer cells contain abundant brown pigment. By courtesy of D.R. Davies, MD, St Thomas’ Hospital, London, UK.

Pseudoporphyria: small tense grouped vesicles are present on the arm. By courtesy of G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.

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Degenerative and metabolic diseases photosensitivity, and scarring are often present. Hypertrichosis, hyperpigmentation, sclerodermoid changes, and dystrophic calcification as seen in porphyria cutanea tarda are not features of pseudoporphyria.1 In children affected with this condition (usually receiving naproxen for juvenile arthritis), facial scarring reminiscent of erythropoietic protoporphyria has been ­documented.7,22 In general, hepatic abnormalities appear to be absent.1

Pathogenesis and histological features Pseudoporphyria is a UVA-related phototoxic dermatosis.1 It may develop following both hemodialysis and peritoneal dialysis and also in patients with chronic renal failure in the absence of dialysis. Suggested risk factors in such patients include iron overload, aluminum intoxication, PVC-induced photosensitivity, drugs, and ethanol.1,2 The condition has also been documented ­following use of non-steroidal anti-inflammatory medications including naproxen and cyclooxygenase inhibitors.7–10 A wide variety of other drugs

including ­various antibiotics (e.g. nalidixic acid, tetracyclines, and cipro­ floxacin), antifungals (e.g. voriconazole) and diuretics (e.g. furosemide (frusemide), torsemide) have also been incriminated (for details see references 1 and 2).13–18,23–25 Recent case reports also implicate the tyrosine kinase inhibitor imatinib, ciclosporin, and oral contraceptive pills.27 The use of UVA suntanning beds is also a well-recognized cause of pseudoporphyria.12,27 Young females are almost exclusively affected and PUVA therapy has also rarely been incriminated.1 A rare case of narrow-band UVB-induced ­pseudoporphyria has been reported in a patient being treated for psoriasis. 20 The blisters are subepidermal and rather bland, containing perhaps a little fibrin and, occasionally, red blood cells (Fig. 13.126).7,11,27,28 The floor of the blister is typically lined by well-preserved dermal papillae (festooning). There is usually no significant inflammatory component although occasionally, a light perivascular lymphocytic infiltrate may be seen in the superficial dermis. Thickening of the superficial vessels (highlighted by a PAS stain) and dermal sclerosis with elastosis may be apparent. Direct immunofluorescence reveals Ig (usually IgG, IgM, and sometimes IgA) with C3 around the superficial vasculature in a donut distribution and as a fine granular deposit at the epidermal basement membrane region (Fig. 13.127).2,7,22,23,26–29 Indirect immunofluorescence is invariably negative.2

Fig. 13.124 Pseudoporphyria: note the hemorrhagic blister overlying the knuckle. By courtesy of G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Fig. 13.126

A

Fig. 13.125 Pseudoporphyria: there are multiple erosions and milia. By courtesy of the Institute of Dermatology, London, UK.

B

Pseudoporphyria: (A) there is a subepidermal blister; (B) the superficial dermal vessels are thickened with a hyaline deposit. (B) By courtesy of G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.

Pseudoporphyria

A

Fig. 13.127 Pseudoporphyria: the vessel wall thickening is in part due to excess type IV collagen, as shown in this field. By courtesy of G.M. Murphy, MD, Beaumont Hospital, Dublin, Eire.

On electron microscopic examination, the plane of cleavage is variable: in some it has been shown to be within the lamina lucida, whereas in others it has been deep to the lamina densa (Fig. 13.128).7,30,31 As in porphyria ­cutanea tarda, basement membrane reduplication is typically present both at the dermoepidermal junction and also around the superficial vasculature (Fig. 13.129).7

Differential diagnosis The invariably negative indirect immunofluorescence and absence of ­porphyrin abnormalities distinguish this disease from autoimmune bullous ­dermatoses and porphyria cutanea tarda.32,33

A

B

Fig. 13.129 (A, B) Pseudoporphyria: note the striking basement membrane duplication.

B

Fig. 13.128 (A, B) Pseudoporphyria: in this example, the blister is located in the superficial papillary dermis deep to the lamina densa (arrowed).

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Degenerative and metabolic diseases

Gout Clinical features Gout represents a group of disorders of purine metabolism in which elevated levels of uric acid occur.1–4 The majority of affected patients have reduced excretion of purines which may be caused by diuretic therapy or renal disease. Hyperuricemia may also complicate diabetic ketoacidosis and starvation, and can develop in patients with sarcoidosis and psoriasis.5,6 Some have increased purine synthesis and this type of disturbance can occur dramatically in the myeloproliferative diseases, particularly following therapy with cytotoxic drugs. Less commonly, gout represents a primary inherited disorder of purine metabolism. A number of enzymatic defects are recognized including hypoxanthine guanine phosphoribosyltransferase activity (X-linked recessive), abnormal phosphoribosylpyrophosphate synthetase variants (X-linked dominant) and glucose-6-phosphatase deficiency.4 These defects represent a small proportion of patients with gout. More recent genome-wide association studies have rapidly expanded the knowledge of other genetic defects responsible for the disease.7–9 Many of the implicated genes are believed to function as urate transporters in the renal tubules.8,9 Males are affected more often than females and presentation is usually in the fourth to sixth decades. However, the incidence in females is rising, particularly in those on diuretics and those with altered renal function.10 The prevalence of the disease is higher in black patients.11 Gout produces recurrent, acute, exceedingly painful monoarticular arthritis, classically of the great toe, but also of the large joints of the legs. Many patients present initially with acute inflammation of the first metatarsophalangeal joint (podagra).12 The affected joint is characteristically exceedingly tender, hot, and erythematous, and cellulitis may therefore enter the differential diagnosis. Precipitating factors include trauma, excessive alcohol consumption, dietary excess (particularly red meat consumption), lead exposure, hypertension, renal insufficiency, surgery, and infections.4,12–14 Alcohol and obesity are associated with increased nucleotide catabolism and decreased urate excretion.15–17 Not surprisingly, more recent studies indicate a close relationship with the metabolic syndrome, and as a consequence patients with gout also have an increased risk of diabetes, myocardial infarction, and premature death.8,18 Certain medications, including diuretics (loop and thiazide), low-dose aspirin, and ciclosporin increase the risk of gout.14,19 With chronicity, a disabling and often crippling arthritis may develop, particularly affecting the hands and feet.3 Subsequently, uric acid crystal deposition in skin and soft tissues produces gouty tophi; these nodules are seen most commonly on the external ear, but also over the elbows and on the digits (Fig. 13.130). When large, they often discharge a chalky material. Rare clinical presentations include bullous lesions, a fungating mass, and sparing of hemiplegic limbs by the tophi.20–22 Nowadays, only a minority of patients present with tophi because of ­improvement in the ­diagnosis and treatment of the disease.23 Tophi are rarely the first manifestation of the ­disease.24,25 They have exceptionally been described in the mitral valve, breast, nose, ­cervical spine, sacroiliac joint, larynx, and eyes.26–32 Bone involvement gives rise to characteristic lytic lesions in the distal subchondral region of the digits.4 Fracture due to bone erosion has been reported.33 Renal disease, which is an important complication, presents as urate nephropathy and/or uric acid nephrolithiasis.18,34,35 In secondary types associated with increased cell turnover, including myeloproliferative disease and multiple myeloma, acute precipitation of uric acid crystals sometimes occurs in the collecting ducts of the kidney during chemotherapy. Uric acid nephropathy may also develop in patients with the inherited variants. Patients present with acute renal failure. More commonly, in primary gout, renal stones are a feature, and chronic urate nephropathy (due to deposition of monosodium urate monohydrate salt crystals in the interstitial tissues of the kidney), presenting as mild proteinuria and hypertension, occasionally develops.4 Uric acid stones develop in about 40% of patients with gout secondary to myeloproliferative diseases and in 10–25% of patients with the primary variants.4

Fig. 13.130 Gout: massive deposit on the dorsal aspect of the hand.

The diagnosis of gout rests primarily on the identification of uric acid c­ rystals within joint fluid or tophi rather than on serum uric acid levels, which can be unreliable. Acute attacks of gout can be associated with normal uric acid levels.12

Histological features The demonstration of uric acid crystals in tophi requires alcohol fixation and anhidrous processing because monosodium urate is water ­soluble (Fig. 13.131).36 In formalin-fixed sections, uric acid crystals appear as amorphous material in the dermis or subcutaneous tissues, surrounded by a marked ­granulomatous response in which many giant cells are usually ­evident (Figs 13.132, 13.133). Calcification may be a late complication. In secondarily infected lesions, a neutrophil polymorph infiltrate is sometimes present.37 In alcohol-fixed sections, the deposits are seen to be composed of ­needle-shaped brown crystals, which lie in bundles and show negative ­birefringence with polarized light and a first-order red compensator filter (Figs 13.134, 13.135).38

Fig. 13.131 Gout: characteristic needle-shaped crystals. By courtesy of G.T. McKee, MD, Massachusetts General Hospital, Boston, USA.

Gout

A

A

B

B

Fig. 13.132 Gout: (A) circumscribed deposits of uric acid are scattered within the dermis, note the accompanying fibrosis; (B) formalin fixation has destroyed the uric acid crystals to leave amorphous eosinophilic material.

Fig. 13.133 Gout: multinucleate giant cells are present.

Fig. 13.134 (A, B) Gout: characteristic needle-shaped uric acid crystals are seen in alcohol-fixed and anhydrous processed material.

Fig. 13.135 Gout: the crystals display striking birefringence when viewed with polarized light.

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Degenerative and metabolic diseases

Ochronosis The term ‘ochronosis’ was first used by Virchow in 1866 to describe a clinical condition in which blue–black cutaneous pigmentation in the skin was associated with the microscopic deposition of an ochre-colored pigment. There are two main types: alkaptonuria and exogenous ochronosis.

Alkaptonuria Clinical features This is an autosomal recessively inherited condition (with an approximate incidence of 1:106) in which deficiency of homogentisate 1,2-dioxygenase (HGD) in the liver and kidneys (necessary for the catabolism of phenylalanine and tyrosine) leads to the accumulation of homogentisic acid (2,5-hydroquinone acetic acid) in cartilage, tendon, skin, and fibrous tissue.1–4 The condition is particularly seen in patients of Eastern European origin, mainly those from Slovakia where the incidence is as high as 1:19 000.5 Clinical features relate particularly to joint and cardiovascular involvement, renal and prostatic stones, and ocular and cutaneous lesions. Alkaptonuria, or blackening of the urine after standing or alkalinization due to oxidation of homogentisic acid, usually becomes obvious in childhood. Most patients present with either dark urine or early-onset arthritis. The blue–black discoloration of the tissues (known as ochronosis) is due in part to the Tyndall effect. The cutaneous changes develop later, at about 30–40 years of age. They are seen particularly on sun-exposed skin and areas with maximum numbers of sweat glands.1–4 Deposition of polymerized oxidase pigment in the ear cartilage produces painful thickening and blue–black speckled discoloration. Involvement of the eardrum and ossicles may result in tinnitus and deafness.4 Subsequently, discoloration of the sclera, conjunctiva, tendons, and skin of the face, hands, and flexures occurs.6 A rare case of vaginal hyperpigmentation has been reported.7 The skin pigmentation may be more prominent on the palms and soles.8 Finally, a characteristic arthritis, which is often severe, develops in almost all patients.9 Low back pain is followed by involvement of the large joints of the limbs. Spinal involvement leads to disc herniation, spondylosis, and osteophytosis with resultant limitation of movement and loss of height.1,10 Musculoskeletal disease caused by alkaptonuria can be severe and result in significant disability.12 Despite widespread morbidity, alkaptonuria is not associated with significant mortality, and life expectancy is typically normal.1 Osteoarticular involvement – which is particularly evident in the knees, shoulders, and hips, and in advanced cases the vertebral column – is characterized by pigmentation of the articular cartilage, synovium, and capsule associated with fibrillation, fragmentation, calcification, and erosion. 11,12 Osteoarthritis may also be evident and chronic ­n on-specific synovitis is commonly present. Cardiovascular involvement occurs in up to 50% of patients and mainly consists of pigmentation and calcification of the aortic valve, which may lead to stenosis. 13–15 Cardiovascular pigmentation, which is especially seen on the endocardium and valves (aortic and mitral), also affects the intima and media of arteries. Surprisingly, even with heavy pigment deposition and smooth muscle cell degeneration, aneurysm formation is not a feature of ­vascular involvement.16 In up to 60% of patients the kidneys typically show very marked pigmentation, especially involving the pyramids and calculi.17 Ochronotic prostatic stones are a nearly invariable feature, but bladder calculi are much less frequent.4,16 Asymptomatic ocular involvement is seen in up to 70% of patients.18 Pigmentation particularly affects the sclera and to a lesser extent the conjunctiva and cornea.6,16 The lesions are typically noninflammatory. Ochronotic pigmentation is frequently seen in the hyaline cartilage of the larynx, trachea, and bronchi.16,19 Involvement of endocrine organs, central nervous system, and teeth is rare.20–22

Exogenous ochronosis Clinical features Deposition in the skin of an identical pigment to that seen in alkaptonuria may occur as a result of the application of phenol (carbolic acid) to leg ulcers, therapy with resorcinol and picric acid, the oral and intramuscular ­administration of antimalarials such as chloroquine, and the application to dark skin of bleaching creams containing hydroquinone, most often in black women.23–32 Antimalarials result in slate-gray pigmentation affecting the knees, face, palate, and subungual regions.33 In hydroquinone-induced ochronosis, lesions occur particularly over bony prominences such as the forehead, temples, nose, and lower jaws and also on the sides of the neck (Fig. 13.136).34 Time to onset of lesions is approximately 6 months. The first stage is characterized by erythema and mild hyperpigmentation.24 Subsequently, the hyperpigmentation intensifies and patients develop widespread ‘­caviar-like’ black papules; cutaneous atrophy and colloid milia may also occur.34 In longstanding disease, nodules develop.24,35–37 Hydroquinone-induced ochronosis is a major problem in the black population of South Africa. In one series the prevalence among users of skin lighteners was almost 70%.28 The reason for the high incidence of ochronosis in this population is not entirely clear but is thought to be due in part to high concentrations of hydroquinone used in their products and the synergistic effect of multiple compounds used in combination with hydroquinone such as mercury and resorcinol, which can also cause ochronosis.24 Exogenous ochronosis due to hydroquinone is thought to be photoactivated. Exogenous ochronosis tends to chronicity. In addition to causing ochronosis, hydroquinones containing bleaching creams have been shown to be carcinogenic in rodents. As a result, in 2006, the US Food and Drug Administration proposed a ban on all over-the-counter bleaching creams containing hydroquinone.29

Pathogenesis and histological features In alkaptonuria, as a result of the deficiency of homogentisate 1,2-dioxygenase, homogentisic acid is oxidized and polymerized by polyphenol ­oxidase to form benzoquinone acetic acid. This results in a black pigment that binds irreversibly to collagen. Polyphenol oxidase is particularly common in cartilage and skin and this reflects in their preferential ­involvement.

Fig. 13.136 Exogenous ochronosis: hyperpigmented plaque with numerous colloid milia in a Bantu female. The lesions developed as a consequence of the application of hydroquinone bleaching cream.

Pellagra The pigment formed has not been characterized but there are some similarities to ­melanin.38 It appears that the pigment deposition occurs both in previously damaged ­collagen and in normal collagen. The gene responsible for alkaptonuria has been localized to chromosome 3q.23-21.39–41 The human homogentisate 1,2-dioxygenase gene has been cloned and it has been shown that patients with alkaptonuria carry two copies of a loss-offunction homogentisate 1,2-dioxygenase allele.42 Over 91 different genetic mutations have been identified thus far in the HGD gene.41 A study of patients with ­alkaptonuria has demonstrated that they have a significantly higher prevalence of HLA-DR7 than those without the disease.43 The exact pathogenesis of exogenous ochronosis is not known. Proposed mechanisms include: • the inhibition in the skin of homogentisate 1,2-dioxygenase by hydroquinone with formation of pigment, 44 • increased tyrosinase activity induced by hydroquinone.23 Ochronosis presents as yellow–brown, sharply defined, irregularly shaped and frequently fragmented fibers in the superficial dermis (Fig. 13.137).1,26 The ochronotic pigment is autofluorescent, appears black with methylene blue, but does not stain with van Gieson, Perl's stains or the Masson-Fontana reaction.1 Pigment granules are often present in the epithelium and basement membrane of sweat glands, in endothelial cells, and within dermal macrophages.16,19 In ochronosis due to hydroquinones the skin may, in addition, show ­melanophages in the upper dermis associated with depigmentation of the ­epidermal melanocytes.35 In early lesions the collagen fibers appear basophilic and swollen before developing the characteristic yellow ochronotic morphology (Fig. 13.138). With chronicity, large amorphous eosinophilic granules may develop, resembling colloid milium.35 Solar elastosis and foreign body granulomata (sometimes indistinguishable from sarcoidosis) are less common features.26,27,37,45 An actinic granuloma-like variant has been described.36 Transepidermal and transfollicular elimination of ochronotic fibers has occasionally been documented.37,46 Antimalarial pigmentation is due to melanin and hemosiderin deposition in addition to the classical ochronotic fibers.1 Electron microscopic studies have shown that initially electron-dense ochronotic pigment is deposited around swollen collagen fibrils that characteristically lose their banding pattern.35 These fibrils subsequently degenerate until the whole collagen fiber is replaced by amorphous ochronotic pigment. Rupture of the fibrils also occurs, so that the pigment comes to lie scattered free in the dermis. Phagocytosis of the latter by macrophages and giant cells may be seen.16,26 The colloid milium-like deposits in hydroquinone-associated ochronosis consist of electron-dense granular material lacking a significant fibrillar component.35

Fig. 13.138 Exogenous ochronosis: early lesion showing markedly swollen collagen fibers.

Hartnup disease Clinical features Hartnup disease is an autosomal recessive disorder characterized by defective gastrointestinal absorption and renal reabsorption of monoamine and monocarboxylic amino acids due to a defect in the neutral brush border system.1 One of the effects is tryptophan deficiency.2 The disease typically presents in childhood. In addition to a pellagra eruption (see below), patients also have a characteristic aminoaciduria and cerebellar ataxia.3,4 An uncommon cutaneous manifestation is an acrodermatitis-like eruption involving the perioral region, perineum and acral skin.5 The disease may, however, sometimes be so mild as to remain asymptomatic.6 Additional symptoms include diarrhea and central nervous system dysfunction ranging from mild apathy to psychosis and frank dementia.7 An exceptional case of a patient with identical symptoms and signs of Hartnup disease in the absence of a recognized metabolic abnormality or aminoaciduria has been described.8 The disease has been mapped to chromosome 5p15 and the defective gene is SLC6A19, a sodium dependent neutral amino acid transporter.9–11

Histological features The cutaneous histology is identical to that of pellagra (see below).

Pellagra Clinical features

Fig. 13.137 Ochronosis: typical swollen, irregular, goldenbrown fibers are seen (bottom left).

Pellagra develops as a consequence of deficiency of nicotinic acid (niacin, vitamin B3) or its precursor tryptophan.1–3 The cause may be dietary. It has traditionally been associated with high consumption of corn.3 In developed countries it is most frequently observed in alcoholics, in those living in conditions of socioeconomic deprivation, and in patients with anorexia nervosa or malabsorption due to extensive gastrointestinal disease (e.g. partial gastrectomy, gastroenterostomy, and Crohn's disease).1,4 A severe case of cytomegalovirus colitis in an immunocompetent patient has also been associated with pellagra.5 It is sometimes also a feature of the carcinoid syndrome because the tumor cells consume available tryptophan to produce serotonin.5,6 Pellagra occasionally develops after therapy with a number of drugs ­including

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Degenerative and metabolic diseases i­soniazid, 6-mercaptopurine, and 5-fluorouracil.6–10 Finally, it can occur in Hartnup disease and in association with defects in the metabolism of tryptophan.11 Pellagra is particularly prominent in parts of Africa and Asia where nutritional deficiencies are prevalent.1 A rare case has been described in association with the intake of alternative medicines.12 A further report describes an association with amyloidosis secondary to multiple myeloma.13 The classic triad of pellagra is ‘dermatitis, diarrhea, and dementia’. The skin eruption of pellagra is photosensitive in nature. An initial painful sunburn-like erythema subsides to leave a dusky brownish discoloration with a dry scaly appearance (Figs 13.139, 13.140). Blisters may sometimes be ­evident. The eruption is typically sharply demarcated, symmetrical, and occurs on the backs of the hands (most commonly), the forearms, the knees, ­central chest, neck, and face.7 The thickened skin around the photoexposed skin of the neck typically resembles a necklace (Casal's necklace). Other ­features sometimes present include cheilosis, glossitis, angular stomatitis, and oral or perianal sores.3,7 Gastrointestinal disease in pellagra manifests as nausea, vomiting, abdominal pain, gastritis, and diarrhea. Neurological involvement evolves, with headache, depression, and ataxia initially and more severe symptoms of ­disorientation, delirium, and coma and eventually death.3

Histological features The appearances in pellagra are usually non-specific. There is ­hyperkeratosis, parakeratosis, and acanthosis associated with increased melanin pigmentation and, in early lesions, keratinocyte vacuolation in the upper reaches of the epidermis.7,8 Telangiectasia and a perivascular chronic inflammatory cell infiltrate in the upper dermis may also be evident. Older lesions sometimes show epidermal psoriasiform hyperplasia.14 In some instances the histology can resemble that of necrolytic migratory erythema and acrodermatitis enteropathica.

Differential diagnosis The diagnosis is very much dependent upon clinicopathological correlation, particularly in those cases that resemble necrolytic migratory erythema and acrodermatitis enteropathica.

Scurvy Clinical features Scurvy, due to vitamin C deficiency, results from a diet inadequate in fresh fruit and vegetables and is nowadays most often encountered following inappropriate dieting, food fads, and in alcoholics and socially isolated individuals.1 Scurvy is rare in children but does occur in those with developmental and psychiatric disorders. It may also be secondary to drinking boiled or evaporated milk which is deficient in vitamin C.2 Cutaneous manifestations include dry skin, follicular hyperkeratoses particularly affecting the forearms, legs and abdomen, perifollicular hemorrhages especially affecting the legs, petechiae and subungual splinter hemorrhages, leg edema, alopecia, erythematous, swollen and bleeding gums with tooth loss, and clinical evidence of poor wound healing.1–4 Painful subperiosteal hemorrhage, ‘Barlow's disease’, is characteristically seen in infants.2 Less specific manifestations which may cause a delay in diagnosis include fatigue, arthralgia, and myalgias.3

Pathogenesis and histological features

Fig. 13.139 Pellagra: scaling and hyperpigmentation are present on the dorsal aspect of the knuckles and fingers. By courtesy of the Institute of Dermatology, London, UK.

Vitamin C is necessary for hydroxylation of proline and lysine residues during the conversion of procollagen into collagen fibers. As a result of impaired collagen synthesis, basement membrane synthesis is defective, with consequent loss of blood vessel wall integrity. This, combined with impaired dermal connective tissue constituents, results in a bleeding tendency. The cutaneous features include follicular dilatation and keratin plugging, perifollicular hemorrhages with chronic inflammation, and hemosiderin deposition.4–7 The alopecia is characterized by hair shaft fracture and ­corkscrew hairs within a dilated and plugged follicle (Fig. 13.141).1,4,8

Calcinosis cutis Calcinosis cutis may occur when connective tissue is abnormal (dystrophic) or where calcium or phosphate levels in the blood are high ­(metastatic); alternatively, there may be no obvious underlying cause (idiopathic) (Table 13.5).1–3

Dystrophic calcinosis cutis Clinical features

Fig. 13.140 Pellagra: close-up view of hyperpigmentation and scaling. By courtesy of the Institute of Dermatology, London, UK.

In this, the most common variant of calcinosis, the changes are limited to the dermis and subcutaneous tissues and there is no involvement of internal organs. This form of calcinosis always occurs in tissue that has been previously damaged either by external agents or as the result of a disease. Under this variant, iatrogenic calcinosis cutis induced by local application of ­chemicals or medications is also included. In the localized form of dystrophic ­calcinosis cutis, the underlying anomaly may be inflammatory or traumatic in nature, for example acne scars, burns, fat necrosis or subcutaneous and ­intramuscular injections.4,5 Calcification and necrosis have been reported ­following electroencephalography and electromyography.6,7 Calcification is a

Calcinosis cutis

Fig. 13.141 Scurvy: the hair follicle is dilated and there is a typical corkscrew hair cut in multiple planes. Note the surrounding chronic inflammation and red cell extravasation. By courtesy of S. Tahan, MD, Beth Israel and Deaconess Medical Center, Boston, USA.

Fig. 13.142 Dystrophic calcinosis cutis: calcification has developed in this ruptured cyst.

Table 13.5 Classification of calcinosis cutis Type

Distribution

Clinical features

Dystrophyic

Localized Widespread

Acne scars; fat cell necrosis; epidermoid cysts; pilomatrixoma; infantile calcinosis of the heel Dermatomyositis; systemic lupus erythematosus; Ehlers-Danlos syndrome; pseudoxanthoma elasticum

Metastatic

Hypercalcemic

Hyperparathyroidism; sarcoidosis; vitamin D excess; milk alkali syndrome; destructive bone disease Chronic renal failure; pseudohypoparathyroidism

Normocalcemic Idiopathic

Generalized Localized

Calcinosis universalis Subepidermal calcified nodule; localized idiopathic dermal calcinosis; tumoral; scrotal

characteristic feature of pancreatic disease-associated panniculitis and in older lesions of subcutaneous fat necrosis of the newborn. Auricular calcification (also known as ‘petrified ear’) may occur as a result of chondritis, trauma or frostbite.1,8,9 Less commonly, it is associated with hypercalcemia associated with systemic disorders and endocrinopathies.8,9 A distinct example of dystrophic calcification is infantile calcinosis cutis of the heel, in which calcific dermal nodules develop approximately 1 year after birth in infants who have had multiple heel punctures for venesection.10,11 Localized dystrophic calcinosis may also complicate epithelial cysts or neoplasms (Fig. 13.142).12 It is particularly seen within the keratin of trichilemmal cysts. Calcification may occur in many adnexal tumors, for ­example pilomatrixoma and trichoepithelioma. It is much more common in basal cell carcinoma than in squamous cell carcinoma.13,14 Subungual epidermoid ­inclusions are rare tumors of the nail bed in which calcification may occur.15 Calcinosis cutis has also been documented following the intravenous administration of calcium chloride, phosphate, and gluconate (iatrogenic calcinosis cutis) (Fig. 13.143).16–18 Lesions consist of multiple, erythematous

Fig. 13.143 Iatrogenic calcinosis cutis: this widespread dermal calcification followed calcium gluconate infusion.

nodules which can ulcerate. They usually develop within a few weeks of exposure.18 Deep soft tissue calcification has been described in association with pentazocine and pitressin.19,20 Similar reactions following calcium-containing heparin in patients with renal insufficiency have also been reported.21,22 Widespread dystrophic calcification occurs most commonly as a sequel to connective tissue disease (Figs 13.144, 13.145). Localized dystrophic calcification with bone formation has also been described in mixed connective tissue disease.23 Dermatomyositis, especially in children, may be complicated by extensive deposits of calcium in the skin and subcutaneous tissues, as well as in muscles and tendons. Scleroderma, especially the CREST variant, tends to show localized deposition of calcium, particularly on the digits and over bony prominences. Fingertip lesions are a common presentation in patients with Raynaud's phenomenon (with or without underlying connective tissue disease) and have also been reported in a patient with Sjögren's syndrome who did not have Raynaud's.24,25 Systemic lupus erythematosus is infrequently associated with calcinosis.26,27 It is usually an incidental radiological observation, most commonly seen in the buttocks and extremities and unassociated with panniculitis. Mostly it develops in patients with severe acute disease including cardiac, renal or central nervous system (CNS) manifestations.2 It also appears to correlate with high doses of corticosteroids and myositis.28,29

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Fig. 13.144 Dystrophic calcinosis cutis: this large deposit is associated with focal ulceration and transepidermal elimination. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.146 Metastatic calcinosis cutis: there are gross deposits, many ulcerated. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Metastatic calcinosis cutis Clinical features

Fig. 13.145 Dystrophic calcinosis cutis: multiple digital deposits are present. By courtesy of the Institute of Dermatology, London, UK.

Calcification complicating discoid lupus erythematosus and subacute lupus erythematosus is limited to a few case reports.30,31 Lupus panniculitis and other types of panniculitis (including pancreatic fat necrosis) may also be associated with calcification.32 Patients with porphyria cutanea tarda rarely develop calcinosis cutis. Lesions are most common on the scalp, neck, preauricular area, and hands, and are more likely to develop in patients with sclerodermoid disease.33 Calcium is also deposited in inherited connective tissue disorders, especially Werner's syndrome, pseudoxanthoma elasticum (PXE), and Ehlers- Danlos syndrome, in which small calcific nodules typically develop within atrophic scars over bony prominences. Alternatively, dystrophic calcification in PXE may occur as large, painful, pruritic nodules in areas involved by the underlying disease.34 Calcification has recently been described in patients with nephrogenic systemic fibrosis, associated with the cutaneous lesions as well as in fascia and muscle.35,36 The etiology of calcification in this disease is debated. Some believe it occurs secondarily as part of a dystrophic process while others contend that calcification is intrinsic to the pathological process, particularly as it is also seen in vessels, in patterns resembling calciphylaxis.37

Metastatic calcification occurs as a result of hypercalcemia or hyperphosphatemia as may be seen in chronic renal failure, hyperparathyroidism, and sarcoidosis.38–41 Calcium deposits occur in the skin, subcutaneous tissues, muscle, tendon, and internal organs. In the skin, the clinical appearances are of hard nodules and plaques, which may ulcerate to liberate chalky material and ultimately leave a scar (Fig. 13.146). This may be particularly frequently seen over large joints, the iliac crest or in the flexures. Fingertip lesions are usually very painful. A case report describes a patient with vulvar cystic nodules and hyperphosphatemia.42 Albright's hereditary osteodystrophy is a genetic disorder associated with end-organ resistance to parathyroid hormone. Patients present in infancy or childhood with obesity, short stature, mild mental retardation, shortened fourth and fifth metacarpals, and cutaneous calcification.43,44 The skin lesions are typically multiple erythematous to purpuric papules, plaques, and nodules on the trunk and extremities. Vascular calcification with thrombosis may lead to livedo reticularis, ulceration, and gangrene, particularly affecting the hands, fingers, toes, and lower legs (so-called clinical calciphylaxis).41,45,46 A frequent complication is sepsis and this often results in death. Patients usually have chronic renal failure in association with hyperphosphatemia and hyperparathyroidism.47–49 Other conditions associated with calciphylaxis include hypervitaminosis D and A, hypercalcemia, primary or secondary hyperparathyroidism, AIDS, and protein C deficiency.50,51 The exact mechanism of calciphylaxis is not clear but it seems to be related to an imbalance in calcium and/or phosphorus metabolism.52 Rarely, the condition occurs in patients with normal levels of calcium and phosphorus.52

Idiopathic calcinosis cutis Clinical features There are six main clinical types of calcinosis in which there is no known predisposing condition: • In calcinosis universalis, there is progressive deposition of calcium in the skin and subcutaneous tissue, producing discharging hard nodules and plaques very similar clinically to those seen in metastatic calcification. Some cases may represent dermatomyositis in which the acute phase was not diagnosed. • In contrast, idiopathic calcinosis may occur as a solitary nodule on the extremities and face, particularly the eyelids (subepidermal calcified

Calcinosis cutis

Fig. 13.147 Tumoral calcinosis: bilateral nodules over the elbows, with perforation on the patient’s left. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.149 Tumoral calcinosis: subcutaneous deposits are present overlying the thigh and lateral border of the knee. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

• Finally, milia-like idiopathic calcinosis cutis is a rare condition seen in

children (usually under the age of 21 years).61,62 Lesions are multiple, skin colored to whitish papules with a generalized distribution. Perforation may occur. Two-thirds of cases have been associated with Down's syndrome and up to one-third of patients have coexisting syringomata. Lesions resolve spontaneously without scarring.

Pathogenesis and histological features

Fig. 13.148 Tumoral calcinosis: these small deposits are undergoing transepidermal elimination. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

•

•

•

nodule, cutaneous calculus).53,54 It usually presents in early childhood and is more common in males; the majority of the nodules are hyperkeratotic and tender on palpation. Rarely, it may be present at birth and occasionally multiple lesions are present.55 Localized idiopathic dermal calcinosis may also occur as a solitary nodule on the limbs.56,57 The fingers and elbows are particularly affected.1 An equivalent lesion, designated oral mucosal calcified nodule, which affects the gingiva and tongue, has recently been documented.58 In tumoral calcinosis, large deposits of calcium are present in the skin and subcutaneous tissues, typically over bony prominences (hip, elbow, and scapula) (Figs 13.147, 13.148). It is rare in Europe and North America, but is not uncommon in South, Central and East Africa and Papua New Guinea, where it is known as hip stone. It shows a female preponderance (2:1) and affects younger age groups. These deep deposits may be visualized radiologically (Fig. 13.149). Scrotal calcinosis may occur spontaneously. Patients present in childhood or early adulthood with multiple, asymptomatic, flesh-colored or yellow nodules of varying sizes, which often release granular chalky material.59 A similar finding on the penis has also been reported in young men with no prior history of trauma and without a known underlying adnexal lesion.60

Calcium stains blue with hematoxylin and eosin. In calcinosis cutis a rather homogeneous deep blue material is seen, either as small superficial deposits or as deeper globular ones (Fig. 13.150). Owing to the concomitant presence of phosphate and carbonate, the deposit stains black with the Von Kossa stain (Fig. 13.151). The presence of calcium in the skin variably excites a foreign body reaction, so giant cells are sometimes seen at the edge of the deposit. On other occasions a chronic inflammatory cell infiltrate is present. Transepidermal elimination of calcified debris is sometimes a feature.4 Dystrophic calcification due to extravasation of intravenous solutions containing calcium is characterized by dermal calcium surrounding degenerated collagen bundles.18 Lesions caused by calcium-containing heparin also demonstrate calcium in fat lobules, surrounding adipocytes, in septae as well as within the media of small vessels in the subcutaneous fat and dermis.22 There may be fibrosis of vessel walls; however, thrombosis is not a usual feature.20,22 In calciphylaxis, there is prominent calcification of walls of dermal and subcutaneous small blood vessels (Fig. 13.152).52 Often, the findings also include some degree of intimal proliferation and thrombosis. These changes result in prominent ischemic necrosis. Calcification of the subcutaneous fat accompanied by lipophagic necrosis may also be seen. The pathogenesis of calciphylaxis is not completely understood. Recent studies point to osteopontin as a possible factor.63 Osteopontin is a phosphoprotein adhesion molecule with a high affinity for calcium. It is normally expressed by various cell types, including osteoblasts, osteocytes, fibroblasts, macrophages, and smooth muscle cells. It plays an important role in bone remodeling. Previous studies have suggested a role for osteopontin in calcification of heart valves and pilomatrixoma.64,65 A recent study examined its presence in calciphylaxis and demonstrated expression in the media and, less often, the intima of vessel walls and surrounding adipocytes in the subcutaneous fat in areas involved by calcification.63 The authors speculate that calciphylaxis may be caused by osteogenic differentiation of vascular smooth muscle cells.

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Fig. 13.150 A

Calcinosis cutis: (A) small deposits of intensely basophilic material are present in the superficial dermis; (B) these calcium deposits are associated with scarring.

B

Fig. 13.151 Calcinosis cutis: the calcified deposit stains positively with the Von Kossa reaction.

Calcification deposits in nephrogenic systemic fibrosis occur in the dermis, associated with CD34-positive spindled cells and in the media of small arteries in the deep dermis and subcutaneous fat, similar to that seen in calciphylaxis.37 A report of an exceptional case of metastatic calcification showed calcification only of sweat ducts.66 There may be histological evidence of the underlying disease process. In localized dystrophic calcinosis, for example, there is sometimes evidence of a preceding epidermoid cyst. In widespread dystrophic calcinosis cutis ­secondary to connective tissue disease, there is occasionally evidence of ­preceding collagen degeneration. In a subepidermal calcified nodule, there is sometimes pseudoepitheliomatous hyperplasia, associated with transepidermal elimination of calcium. In tumoral calcinosis the histological features depend upon the stage of evolution of the lesion (Figs 13.153–13.155).67 In early examples, multiple cystic spaces lined by epithelioid and giant cells are seen. The cyst lumina contain

Fig. 13.152 Calciphylaxis: note the subendothelial calcification and thrombosis.

eosinophilic debris undergoing calcification. In advanced lesions, densely calcified material is seen embedded in hyalinized connective tissue. The occasional finding of necrobiosis and vasculitis may have pathogenetic significance. The pathogenesis of the scrotal variant is most probably calcification of the contents of pre-existent dermal cysts, mostly epidermoid, but occasionally pilar.62,68–72 Some authors have failed to detect an epithelial component;43 however, this may be a reflection of the age of the lesion. A recent study of 20 cases identified residual epidermal cysts in 14.71 In many examples, typical epidermoid lining epithelium surrounds the calcified deposit and sometimes residual keratinous contents are visible. A foreign body giant cell reaction is not uncommon. The etiology of milia-like calcinosis cutis is unclear. Theories include increased calcium content of excreted sweat and calcification of a pre-existing cyst.61 Histologically, there is a focus of calcium in the papillary dermis surrounded by a lymphocytic infiltrate and giant cells. Perforation may be ­present.61,62 Cyst epithelium is not present.

The mucinoses

The mucinoses

Fig. 13.153 Tumoral calcinosis: this low-power view shows a dense hyalinized stroma with numerous cystic cavities containing necrotic and calcified debris.

The mucinoses are a group of conditions in which accumulation of acid glycosaminoglycans (mucin), particularly hyaluronic acid and to a lesser extent chondroitin (-4 and -6) sulfate and heparin, occurs either diffusely or focally in the dermis (Table 13.6).1–6 Mucinosis also may occur as a secondary phenomenon in dermatoses such as lupus erythematosus, scleroderma, dermatomyositis, Degos' disease, granuloma annulare, and chronic graft-versus-host disease.5,7 In this chapter, however, only primary cutaneous mucinoses are discussed. The glycosaminoglycans, which are secreted by fibroblasts, are constituents of normal cell membranes and connective tissue. This substance is usually secreted in only small amounts by fibroblasts. It is not clear why mucin production is increased in pathological states. Although the cause is probably multifactorial, it has been suggested that cytokines and/or immunoglobulins and unidentified factors in the serum of affected patients can induce synthesis of glycosaminoglycans.5,8–10 Cytokines that play an important role in this process include tumor necrosis factor, interleukin-1, and transforming growth factor beta (TGF-β).5,11,12 Actively secreting fibroblasts have a characteristic stellate shape and contain intracytoplasmic secretory vesicles; their presence in sections should therefore prompt a careful search for mucin deposition (Figs 13.156–13.158).

Table 13.6 Classification of the dermal mucinoses Diffuse lichen myxedematosus – generalized form (scleromyxedema) scleredema reticular erythematous mucinosis generalized myxedema pretibial myxedema Focal lichen myxedematosus – discrete papular form acral persistent papular mucinosis papular and nodular mucinosis associated with lupus erythematosus self-healing juvenile cutaneous mucinosis cutaneous mucinosis of infancy cutaneous focal mucinosis myxoid cyst Follicular follicular mucinosis

Fig. 13.154 Tumoral calcinosis: early lesions characteristically show a histiocytic and giant cell palisade around eosinophilic, degenerate connective tissue.

Fig. 13.155

Fig. 13.156

Tumoral calcinosis: in older lesions, calcified deposits lie within lacunae.

Myxoma: Note abundant stromal mucin.

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Fig. 13.157 Mucinosis: this electron micrograph from a patient with acral persistent papular mucinosis shows collagen bundles widely separated by a faintly electron-dense granular deposit.

Hyaluronic acid stains with colloidal iron (blue–green), Alcian blue at pH 2.5 (blue) (but not at pH 0.4), and mucicarmine (red) but it is negative for PAS. It also stains metachromatically with toluidine blue, methylene blue, and thionine.13 Sulfated acid mucins stain with Alcian blue at pH 0.5 and aldehyde-fuschin.2 Hyaluronic acid absorbs enormous amounts of water, which accounts for the induration and thickening common to this group of conditions.14 Routine fixation and processing results in an anhydrous state so that mucin presents as basophilic strands and granules in hematoxylin and eosin stained sections.3 In normal skin it is found particularly around appendages and the vasculature (Fig. 13.159). In the cutaneous mucinoses the deposits are hyaluronidase sensitive because most of the mucin present is hyaluronic acid. The excessive mucin disrupts the collagen fibers, giving them a frayed appearance. In general, with the exception of scleromyxedema, there is considerable histological overlap within this group of conditions. Diagnosis depends considerably upon clinical features and the results of biochemical investigations.14 There are five major mucinoses: • generalized myxedema, • pretibial myxedema, • lichen myxedematosus, • reticular erythematous mucinosis, • scleredema. Follicular mucinosis is considered in Chapter 29.

Generalized myxedema Clinical features

A

Generalized myxedema occurs as a consequence of severe hypothyroidism. Patients with myxedema may appear pale yellow due to the combined effects of edema, anemia, and carotenemia.1,2 The last, which is due to defective conversion of betacarotene to vitamin A in the liver, is seen particularly on the palms, soles, and in the nasolabial folds.3 Rarely, the color change is generalized.4 The skin is cool, dry, coarse, waxy, and puffy, especially around the eyes and cheeks, and the hands and feet may show nonpitting edema (Fig. 13.160).3,5–7 The face is often expressionless. Eccrine and sebaceous gland secretions are reduced and this may result in xerosis, an ichthyotic appearance or asteatotic eczema.4 Hyperkeratosis over bony prominences resembling avitaminosis A is also sometimes evident.8 Alopecia is a common finding and the outer third of the eyebrows is typically affected. There is usually thinning of the beard and sexual hair in addition to loss of the scalp hair. Myxedema is associated with a greatly increased percentage of hair follicles in the telogen phase.9 The rate of hair growth is also diminished. Residual

B

Fig. 13.158 Mucinosis: (A) actively secreting fibroblasts contain abundant rough endoplasmic reticulum; (B) numerous intracytoplasmic vesicles containing amorphous material are commonly present.

Fig. 13.159 Eccrine sweat gland: this section of normal skin from the sole of the foot shows abundant dermal mucin when stained with Ehrlich’s hematoxylin.

The mucinoses

Fig. 13.161

Fig. 13.160 Generalized myxedema: note the waxy infiltrated plaques on the eyelid. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

A

(A, B) Generalized myxedema: this patient has widespread xanthomata. By courtesy of the Institute of Dermatology, London, UK.

hair is dry, coarse, and brittle.3 The nails often become thin, brittle, and striated.1 Additional cutaneous manifestations have included pruritic papular lesions, purpura and ecchymoses, impaired healing, generalized follicular mucinosis, and multiple focal cutaneous mucinoses.1,5,9–11 Oropharyngeal and laryngeal involvement is common and many patients are hoarse. Patients with myxedema have an increased risk of developing hyperlipidemia with resultant eruptive and tuberous xanthomata (Fig. 13.161).

Histological features The epidermis may show mild hyperkeratosis with occasional follicular plugging.3 Most frequently, the dermal changes are subtle and nondiagnostic. However, in cases of greater severity, there is slight swelling and separation of the collagen bundles with edema, and special stains show that small quantities of mucin are present within the dermis and occasionally in the subcutaneous fat.12 Fibroblastic proliferation is not a feature of generalized myxedema.13

B

Localized (pretibial) myxedema Clinical features Localized (pretibial) myxedema is most often associated with hyperthyroidism.1 It occurs in 3–5% of cases.2 It is one of three processes classically seen in autoimmune thyroid (Graves') disease, the other two being exophthalmos and thyroid acropachy (clubbing of the digits associated with ­subperiosteal new bone formation). Pretibial myxedema, also known as ‘Graves’ or thyroid dermopathy', is usually a late manifestation of Graves' disease and follows the development of Graves' ophthalmopathy.3 It has only been reported exceptionally preceding the diagnosis of Graves' disease and in the absence of ophthalmopathy.4 In 10% of cases of Graves' disease, patients are not clinically hyperthyroid.5 They may be hypothyroid or euthyroid.5 Pink or yellow waxy plaques, nodules, and sometimes ‘tumors’ develop, most frequently first on the anterolateral aspects of the lower legs (Fig. 13.162). Lesions are classically nonpitting. In some patients there is induration with prominence of the follicles, giving rise to a peau d'orange appearance, and secondary hypertrichosis is occasionally marked. Localized hyperhidrosis at the site of the myxedema may also rarely occur.6 The disease may progress to involve much of the lower leg, which rarely becomes grossly elephantiasiform (Fig. 13.163).2,7–9 The feet and toes sometimes can

be involved.9 Small lesions are usually asymptomatic or mildly p ­ ruritic; the larger plaques are often painful.10 Infrequently, localized myxedema occurs on other sites such as the arms, shoulders, abdomen, neck, face, and even the ears (Fig. 13.164).11 Nodular lesions rarely occur on the hands.12 Deposition on the forearm has been described as ‘preradial myxedema’.12 Occurrence at atypical sites is most likely related to trauma.13 For example, it has been described localized to scar tissue.14–16 The latter includes the site of a smallpox vaccination scar.17 Presentation at the site of a thigh donor graft site has also been reported.18 Rare patients with pretibial myxedema have no evidence of thyroid disease. Biopsies from these patients tend to show changes associated with stasis and this feature is useful in the histological differential diagnosis.19 One such variant has been described in morbidly obese patients with ­lymphedema.20,21 Lesions occur as papules, vesicles, and nodules on the pretibial surfaces. Pretibial myxedema is sometimes self-limiting, involution occurring after a number of years. Complete remission occurs in up to 26% of cases but this depends on the severity of the disease.5,22 An exceptional form of pretibial mucin deposition that may be confused with pretibial myxedema associated with Graves' disease has been documented

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Fig. 13.162

A

Fig. 13.163

Pretibial myxedema: (A) erythematous, somewhat translucent plaques are present over the shin; (B) close-up view. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

B

in association with Sjögren's syndrome under the name acral ichthyosiform mucinosis.23 In the cases described, the patients had normal thyroid function tests and the mucin deposition was predominantly in the papillary dermis.

Pathogenesis and histological features The etiology is uncertain; the presence of pretibial myxedema is usually associated with detection of long-acting thyroid stimulator (LATS) in the serum, but LATS is not believed to be causal.24 It was suggested in 1978 that a fibroblast stimulating factor associated with mucigenic properties isolated from the serum of patients with pretibial myxedema might play a role in the pathogenesis of the disease.25 More recent studies have shown that fibroblasts in pretibial skin and in the orbit of affected patients contain sequences identical to those of the thyroid stimulating hormone receptor.26,27 It has also been proposed that the fibroblasts might contain a cross-reacting protein rather than the true receptor, which binds with the autoantibodies against thyroid stimulating factor receptor.28,29 Based on these observations, it has been proposed that autoantibodies against thyroid-stimulating hormone receptor react with fibroblasts containing these sequences, resulting in production of cytokines and induction of increased glycosaminoglycan secretion.28,29

Pretibial myxedema: in this extreme example, the features resemble elephantiasis. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Localization to the legs most typically is thought to be due to dependency and mechanical factors.3 Additionally, tobacco is a known risk factor for the development of pretibial myxedema and Graves' ophthalmopathy; however, the precise mechanism for this is presently unknown.3 The epidermis is often hyperkeratotic, with follicular plugging; in gross cases it may be papillomatous and acanthotic. The reticular dermis shows separation of collagen bundles by large quantities of mucin (Figs 13.165, 13.166).1 Fragmentation of collagen fibers can be seen.3 Stellate ­fibroblasts are evident, but there is usually no increase in their number except ­perhaps in the more elephantiasiform examples. Lesions seen in the setting of ­lymphedema and obesity are also characterized by small vessel angiogenesis, vessel wall thickening, edema, and hemosiderin deposition.20,21 Immunofluorescent studies are usually negative, although granular deposits of IgM have been identified within the superficial papillary dermis.10 Electron microscopic studies show amorphous granular material both within fibroblast endoplasmic reticulum, coating the surface of the fibroblast, and in the interstitium surrounding the widely separated collagen and elastic fibers.8 Tubuloreticular structures have been identified in the cytoplasm of endothelial cells in one case and in the dermis of another.10,14

Lichen myxedematosus/scleromyxedema Clinical features As originally classified, there were four variants of this rare disease of adults.1 These were: • generalized lichenoid papular eruption (Figs 13.167, 13.168). • discrete papular variant presenting as much smaller numbers of flesh-colored papules on the trunk and extremities (Fig. 13.169), • localized and generalized lichenoid plaques mimicking lichen planus, • urticarial or nodular lesions, which often evolved into the generalized papular form.2,3 With the subsequent delineation of new entities, the validity of this classification was called into question.4 Lichen myxedematosus is now divided into three forms:5–8 • a localized form, which includes several variants: discrete papular lesions occurring at any site, acral persistent papular mucinosis (see below), ­

The mucinoses

Fig. 13.164

A

(A, B) Localized myxedema: these pictures came from same patient shown in Figure 13.162. Following a road traffic accident, the patient developed additional mucinous deposits on her arm close to the site of a fracture. By courtesy of P.G. Goodwin, MD, The Royal Bournemouth Hospital, UK.

Fig. 13.165 Pretibial myxedema: there is loss of collagen fibers associated with mucin deposition.

B

self-healing papular mucinosis (see below), papular mucinosis of infancy (see below) and nodular mucinosis, • a generalized form (scleromyxedema) characterized by lichenoid papules, indurated and thickened skin and a monoclonal gammopathy; by definition, thyroid function is invariably normal. • an atypical or intermediate form where patients may have generalized lesions without systemic symptoms/gammopathy, localized lesions with systemic symptoms/gammopathy or other manifestations that do not strictly fulfill criteria for either the localized or generalized variants. The generalized form of lichen myxedematosus (scleromyxedema) occurs equally in males and females and is seen most often in the fourth and fifth decades.3 It often presents on the hands and wrists, but soon becomes generalized although lesions are particularly seen on the hands, elbows, neck, face, and upper trunk.9,10 Prominent linear papules may be evident on the forehead, neck, axillae, and behind the ears.11 The papules are small, 2–3 mm in diameter, white or erythematous, and often have a waxy consistency. They tend to coalesce to form infiltrated plaques and, when associated with ­hardening and thickening of the underlying skin (scleromyxedema), result in ­tethering and limitation of movement, so that sclerodactyly, microstomia,

Fig. 13.166 Pretibial myxedema: the mucin (hyaluronic acid) stains positively with Alcian blue.

and a ­mask-like facies may result (Fig. 13.170).4 Gross involvement of the glabellar skin sometimes causes a leonine appearance.12 A rare patient with leonine facies and tumor-like nodules mimicking lymphoma has been reported.13 The lack of acral calcification and absence of Raynaud's phenomenon help to ­distinguish this condition from scleroderma. The mucous membranes are not usually affected.3 The lesions are variably pruritic. There are occasional reports of systemic symptoms. Esophageal aperistalsis, peripheral neuropathy, proximal myopathy, and cardiac and cerebrovascular diseases have all been described.4,14 There has been little postmortem confirmation of visceral involvement and therefore it is likely that many of

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Fig. 13.169 Fig. 13.167 Lichen myxedematosus: erythematous papules are widely distributed over the forearms. A more diffuse plaque is present over the dorsum of the left hand.

Lichen myxedematosus: this is an example of the discrete papular form showing small numbers of papules on the anterior wrist. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

inflammatory myopathy not dermatomyositis has been described in association with sclerom­yxedema.30 It has been suggested that the development of myopathy is associated with a poor prognosis.30 Scleromyxedema is usually (but not invariably) associated with a paraproteinemia; most often this is IgG with lambda light chains.15,31–34 Occasionally it has been of the IgM or IgA class.3 An occasional association with multiple myeloma has also been noted but occurs in less than 10% of patients.5,9

Pathogenesis and histological features

Fig. 13.168 Lichen myxedematosus: numerous papules are present in the antecubital fossa. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

these associations are no more than coincidental. Neurological ­manifestations have, however, been reported most often and are probably of significance. They have included acute psychoses, encephalopathy and coma, epileptiform seizures, aphasia, memory loss, depression, and motor dysfunction.9,14–16 Dermatoneuro syndrome describes a rare manifestation of central nervous system disease where patients develop high fever, flulike symptoms followed by seizures, and coma.17,18 Carpal tunnel syndrome has also been reported fairly frequently.19–21 Pulmonary involvement is not uncommon and consists of restrictive or obstructive disease and pulmonary hypertension.22 Renal disease similar to that seen in scleroderma is rare.23 There is usually no ­relationship between lichen myxedematosus and neoplasia. An exceptional case of lichen myxedematosus and hepatocellular carcinoma has been reported.24 Rare cases associated with HIV infection have also been ­documented.25,26 Further associations include chronic hepatitis C and ­dermatomyositis.27–29 The latter finding is interesting because in the past

The pathogenesis of lichen myxedematosus is unknown. There is no evidence to suggest that the paraprotein is responsible for the fibroblastic proliferation. However, serum from scleromyxedema patients has been shown to contain a nonparaprotein-associated fibroblast growth factor. This requires further characterization.8,35 There is some evidence to suggest that the paraprotein may, however, have mucinogenic properties.36,37 Fibroblasts grown in tissue culture produce greater quantities of hyaluronic acid and sulfated glycosaminoglycans than normal controls.38 Collagen synthesis, as determined by H3-hydroxyproline estimations, is diminished. Immunofluorescent studies have revealed immunoglobulin (IgG and to a lesser extent IgM) in the reticular dermis or just below the epidermis in 35% of cases.12 Indirect immunofluorescence is invariably negative. The epidermis may be normal, acanthotic or atrophic, and sometimes hyperkeratosis with parakeratosis is evident. In early lesions stellate ­fibroblasts are seen between disorganized collagen fibers in the reticular ­dermis (Figs 13.171, 13.172).3,7 The papillary dermis is not affected. Increased numbers of mast cells are sometimes present.29 Focal deposits of mucin are readily identifiable (Fig. 13.173).2 A slight perivascular chronic ­inflammatory cell infiltrate is often seen in the superficial dermis. In the more severe scleromyxedema variant, fibroblasts are numerous and there is consequent fibrosis and thickening of the dermis (Figs 13.174– 13.176).4 Mucin deposits may be less evident or even absent.12 Decreased elastic fibers have occasionally been reported.3 A chronic inflammatory cell infiltrate is frequently present surrounding the superficial vasculature. Recently, a less common granulomatous variant of scleromyxedema has been described in which there is an interstitial histiocytic infiltrate with giant cells, similar to granuloma annulare or interstitial granulomatous dermatitis.39,40 Although there is increased mucin, prominent stellate fibroblasts and dense bundles of collagen are not a feature.

The mucinoses

Fig. 13.170

A

(A, B) Scleromyxedema: this severely affected patient shows sclerosis and linear papules on the forehead. Note the pinched, mask-like facies. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

B

Ultrastructural studies show active fibroblasts characterized by abundant rough endoplasmic reticulum and Golgi apparatus, increased numbers of mitochondria, and cytoplasmic inclusions accompanied by collagen deposition.41 Systemic involvement has only rarely been documented. Mucin deposition has been described in the adventitia of visceral blood vessels and in the renal papillae in single case reports.9,41 It has also been described within­

A

r­ ectal mucosa and in muscle in one patient with scleromyxedema. Whether this ­represents true primary involvement or a secondary unrelated phenomenon is uncertain. In a particularly unusual case the features of systemic sclerosis were found in the kidney.9 In the absence of any autopsy evidence of further sclerodermatous lesions, it may be that the renal vascular and glomerular changes reflected unrecognized scleromyxedematous pathology. Demyelination and focal gliosis have also been reported.12,42 Nevertheless,

B

Fig. 13.171

Fig. 13.172

Lichen myxedematosus: increased mucin is evident in the superficial dermis.

(A, B) Lichen myxedematosus: the collagen fibers are widely separated by mucin deposits. Fibroblasts are increased in number.

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Degenerative and metabolic diseases

Fig. 13.175

Fig. 13.173 Lichen myxedematosus: staining with colloidal iron emphasizes the mucin deposits.

Scleromyxedema: delicate strands of mucin separate the collagen fibers.

Fig. 13.176 Scleromyxedema: Alcian blue.

Fig. 13.174 Scleromyxedema: the dermis is markedly thickened. There is fibrosis and increased numbers of fibroblasts are evident.

autopsy studies have usually shown no evidence of widespread mucinosis and it is likely that in the great majority of cases the pathological changes are limited to the skin.

Differential diagnosis It may be impossible to distinguish scleromyxedema from nephrogenic ­systemic fibrosis based solely on histopathological features.43 Both conditions demonstrate an intradermal proliferation of spindled cells associated with increased mucin. The spindled cells stain for CD34, factor 13a, and procollagen I in both disorders. Although correlation with clinical parameters is critical for ultimate distinction between the two disorders, a recent study suggests that the depth of the infiltrate may be a helpful differentiating feature.44 In scleromyxedema the infiltrate is confined to the mid to deep dermis, whereas in nephrogenic systemic fibrosis the process begins in the dermis but also extends into the septa of the subcutaneous fat.

Acral persistent papular mucinosis Clinical features This rare condition, which predominantly affects females, is characterized by the development of persistent multiple discrete and often symmetrical smoothsurfaced small papules (2–7 mm) on the dorsal aspects of the hands and wrists, sometimes extending on to the forearms (Fig. 13.177).1–4 The condition is generally regarded as a localized variant of lichen myxedematosus.5–11 The papules are ivory or flesh-colored and translucent, and on puncture characteristically contain clear viscous fluid.2 Lesions do not occur on the face or trunk and there is no thickening or induration of the skin.12 Pruritus is exceptional.13 Occurrence in two sisters has been reported, raising the possibility of a familial form of the disease.14 Acral persistent papular mucinosis is not usually known to be associated with any systemic abnormalities such as thyroid disease or paraproteinemia.15,16 An exceptional case associated with IgA monoclonal gammopathy has been reported.17

Histological features The papules show extensive mucin deposition in the upper reticular ­dermis separated by a grenz zone from the overlying epidermis (Figs 13.178, 13.179).10,12,18 Increased numbers of spindled or stellate-shaped fibroblasts

The mucinoses

Fig. 13.177 Acral persistent papular mucinosis: discrete papule on the dorsal surface of a forefinger. This patient had similar lesions on the arms. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.179 Acral persistent papular mucinosis: close-up view showing mucin deposits.

The eruption consists of densely grouped, firm, 1–2 mm papules on the elbows and smaller numbers of more dispersed lesions about the forearms and dorsa of the hands.1 Congenital linear papules on the backs of two ­fingers have been reported in one infant and another was born with clustered ­papules on the lower back.2,3 More recently, a patient with multiple congenital papules on the fingers and toes has been described.6 Owing to the paucity of cases, the natural history and prognosis of this condition are unknown.

Histological features Excessive mucin (hyaluronic acid) is present in the papillary dermis under an acanthotic epidermis. Sectioning artifact may make the deposits appear to have an intraepidermal location. Biopsies from late lesions show features identical to those of lichen myxedematosus with fibrosis and proliferation of dermal fibroblasts.4 A perivascular chronic inflammatory cell infiltrate is ­evident in the superficial dermis.

Self-healing juvenile cutaneous mucinosis Clinical features

Fig. 13.178 Acral persistent papular mucinosis: note the presence of a discrete superficial papule with a well-developed collarette.

may occasionally be evident.19 Fibrosis, however, as seen in lichen myxedematosus, is not a ­feature of this condition. Direct immunofluorescence has revealed granular IgM at the dermoepidermal junction and linear IgG around the eccrine glands in one case.2 Ultrastructural studies reveal active fibroblasts with prominent dilated rough endoplasmic reticulum. The collagen bundles are widely separated and focal deposits of electron-dense amorphous material are evident.5 Conspicuous lamellated electron-dense lysosomes have been described in one case.19 This probably represents a non-specific secondary change.

Cutaneous mucinosis of infancy Clinical features This variant of papular mucinosis is very rare.1–3 It has recently been suggested that the condition might represent a pediatric localized form of lichen myxedematosus.4,5 Familial cases have been documented.4

This is an extremely rare condition, only a handful of cases having been documented.1–17 It most commonly presents in children, with a rapid onset of asymptomatic erythematous papules and plaques, which show a predilection for the face, neck, scalp, abdomen, and extremities, accompanied by deep nodules on the face and periarticular regions.1 The plaques have a characteristic appearance as linear groups of papules, giving the skin a corrugated appearance.3 The deep nodules can mimic fasciitis.11 The eruption resolves within a period of weeks to months. Mild arthritis involving the elbows, knees, and interphalangeal joints has been documented as has possible polychondritis.1,3 These latter manifestations may be persistent.1 In one patient bilateral carpal tunnel syndrome was present. Non-specific features of fatigue, weight loss, and myalgia may also be evident. The age of those who are typically affected ranges from infancy to teenagers. Exceptionally, the disease presents in adults.14–17 There is no evidence of thyroid dysfunction or paraproteinemia.

Pathogenesis and histological features The etiology is unknown although it has been suggested that the fibroblast activity may have been stimulated by a preceding viral infection.3 Histologically, the epidermis is normal or may show mild hyperkeratosis. Mucin deposition is seen in the papillary and upper reticular dermis separating and splitting the collagen bundles. In one case the mucin was PAS positive and identified as a sialomucin, whereas in others it was found to consist of hyaluronic acid.1,3,9,10,12,14,16 Fibroblasts are slightly increased in number and a mild chronic inflammatory cell infiltrate surrounds the superficial ­vasculature.

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Degenerative and metabolic diseases Deeper nodules demonstrate similar involvement of the septa and lobules of the subcutaneous fat which can also extend into the fascia. Epithelioid, ­ganglion-like histiocytes can be seen and may cause confusion with proliferative or nodular fasciitis.11,12

Reticular erythematous mucinosis This condition is described in Chapter 8.

Scleredema Clinical features Scleredema (Buschke) is a rare primary mucinosis that presents with nonpitting indurated edema and associated dermal hardening in the absence of any significant clinical abnormality of the overlying skin.1,2 Three distinct ­subtypes are recognized:2–5 • Most commonly seen is an acute variant predominantly affecting children and characterized by a rapid onset arising a few weeks after an infection, most often of the upper respiratory tract. Streptococcal infections are particularly implicated, but cases have followed a variety of viral illnesses including measles, mumps, influenza, cytomegalovirus infection, and chickenpox.6–8 Scleredema has also occurred in the setting of chronic scabies and secondary streptococcal infection.9 Although many of these cases resolve spontaneously within a period of months and years, a significant number are persistent and exacerbations are not uncommon.10 Females are affected more often than males and the disease is more common in the winter months.11 Sometimes there is a prodromal illness of malaise, myalgia, generalized myasthenia, and arthralgia.10 Some patients develop a variety of cutaneous manifestations including transient erythema, urticarial or annular eruptions and dermographism before the onset of the more typical features.4 Scleredema in children may exceptionally present overlapping features with eosinophilic fasciitis.12 • Secondly, scleredema may have an insidious onset unaccompanied by any previous acute illness.2 • Lastly, scleredema sometimes develops in association with late-onset diabetes mellitus. Patients, more often males, are often obese and there are usually other manifestations of diabetes including nephropathy, hypertension, coronary and peripheral vascular insufficiency, retinopathy and peripheral neuropathy.2,13,14 The diabetes commonly precedes the development of scleredema, which is usually widespread and associated with a chronic course.1,15,16 This variant of scleredema does not tend to resolve spontaneously or with treatment. Scleredema is occasionally associated with a paraproteinemia (usually IgG, but sometimes IgA) and rarely multiple myeloma.17–19 There is no evidence that the paraprotein results in the skin lesions; hence it is probably a secondary phenomenon. Evolution to systemic amyloidosis has been reported in one patient.20 It should be noted that despite the original nomenclature of scleredema adultorum, many of the patients are in fact children.10,11,21 Only very rarely are childhood cases associated with diabetes.21 An exceptional case of congenital scleredema has been reported.22 Rare cases have had associated primary and secondary hyperparathyroidism, rheumatoid arthritis, Sjögren's syndrome, and sarcoidosis.23–26 Scleredema has also been described in HIV infection, in association with a nuchal fibroma, following exposure to organic solvent, in the setting of a malignant insulinoma and carcinoid, with acanthosis nigricans, with generalized hyperpigmentation, and as an adverse consequence of infliximab.13,18,27–32 The cutaneous manifestations are similar for all three subtypes, differences being merely a matter of degree. Patients present with symmetrical nonpitting edema and dermal hardening, which particularly affects the posterior and lateral aspects of the neck (Fig. 13.180).2 The face, anterior neck, upper trunk, and upper limbs are also frequently affected.1 Rarely, the disease may spread to the lower abdomen and legs. Confinement of the changes to the thighs has been described.33 The palms and soles are rarely affected and genital involvement is ­uncommon.10 Lesional skin is shiny and feels hard, and wrinkling is impossible due to involvement of the papillary dermis (Fig. 13.181). In severely affected patients reduced ­mobility

Fig. 13.180 Scleredema: a diffuse, firm thickening of the tissues is present over the neck and shoulders. By courtesy of G. Murphy, MD, Institute of Dermatology, London, UK.

A

B

Fig. 13.181 (A, B) Scleredema: there is marked thickening and induration of the skin of the upper back. By courtesy of G. Murphy, MD, Beaumont Hospital, Dublin, Eire.

The mucinoses is often a problem. The face may be expressionless, the lines of ­cleavage lost, and smiling and mouth opening may be difficult.1 The overlying skin may demonstrate erythema, hyperpigmentation and/or a peau d' orange ­appearance. An unusual case with hyperkeratosis has been described.8 In some patients systemic disease may be evident, including pericardial, pleural, and peritoneal effusions, dysarthria and dysphagia due to tongue and pharyngeal lesions, hepatosplenomegaly, cardiac and skeletal muscle manifestations, parotid gland involvement and ocular changes presenting as induration of the eyelids and conjunctivae.10,11,34 Periorbital edema can be the sole presentation.35 In cases with systemic involvement, mucin deposition has been demonstrated in the bone marrow, liver, nerve, salivary gland, and heart.36,37 Cardiac and pulmonary disease may exceptionally lead to death.38

Pathogenesis and histological features The pathogenesis of scleredema is unknown. The serum from one patient with scleredema and a paraprotein markedly stimulated collagen production in normal skin fibroblast cultures, suggesting that a circulating factor(s) probably related to the paraprotein might induce the dermal fibrosis.39 The involved skin shows increased synthesis of type I collagen, which appears to be responsible, at least in part, for the dermal fibrosis.40,41 The fibroblasts in involved skin from individuals with scleredema show increased protein production, collagen synthesis, and glucosamine incorporation. This correlation is associated with increased levels of type I and type III collagen.42 Biochemical analysis of involved skin in scleredema has confirmed an increase in glycosaminoglycans, the main component being hyaluronic acid.43 The histological features are often subtle and the diagnosis is difficult. The epidermis may be slightly thinned or appear normal. The reticular dermis is greatly thickened, often at the expense of the subcutaneous fat, and the eccrine glands therefore become abnormally situated within the upper third or mid dermis (Figs 13.182, 13.183).1 The collagen fibers are broadened and, ­particularly in the earlier stages, are abnormally separated by clear spaces ­(dermal fenestration).2 The latter may contain small quantities of mucin, but often special stains (Alcian blue, colloidal iron) and multiple biopsies are ­necessary for their demonstration (Fig. 13.184).16,44 Up to one-third of cases may not demonstrate mucin even with the aid of special stains.45 Fibroblasts are present in normal numbers. A mild chronic inflammatory cell infiltrate is sometimes evident in the superficial dermis and mast cells may be increased in number (Fig. 13.185).1 Direct immunofluorescence studies are negative.2,17

Fig. 13.183 Scleredema: the collagen fibers appear swollen. There is excess mucin.

Fig. 13.184 Scleredema: the abundant mucin is highlighted by Alcian blue/chromotrophe 2R staining.

Differential diagnosis Scleredema may be distinguished clinically from scleroderma by the absence of Raynaud's phenomenon, acral sclerosis with calcification, pigmentary changes, and telangiectasia.2 Histologically, the appendages are atrophic and compressed or absent in scleroderma and there is diffuse dermal sclerosis rather than the fenestrated appearance seen in scleredema.

Papular and nodular cutaneous mucinosis of systemic lupus erythematosus Clinical features

Fig. 13.182 Scleredema: early lesion showing collagen bundle separation.

Mucin deposition as a specific clinical manifestation of lupus erythematosus has been recorded only rarely in the literature yet is said to occur in up to 1.5% of dermatological patients with this disease.1–3 The condition presents as asymptomatic, flesh-colored, occasionally umbilicated papules and nodules on the neck, trunk, and upper limbs.4–12 Presentation with massive cutaneous mucinosis has also rarely been reported.13 The papules may rarely be hyperpigmented.14 Lesions are best appreciated using tangential light, which gives the skin a lumpy appearance.5 Mucin deposition occurs most often in patients

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Fig. 13.186 Myxoid cyst: the translucency is typical. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 13.185 Scleredema: superficial dermal lymphohistiocytic infiltrate.

with the systemic variant, usually with diffuse antinuclear ­factor and antiDNA antibodies, and is particularly associated with joint and kidney lesions.4,11,15 There are, however, occasional reports of its occurrence in patients with discoid and subacute cutaneous lupus erythematosus 4,7–9 An inconstant relationship to sunlight has been recorded.4,16 Exceptionally, systemic sclerosis may present with similar papular and nodular mucinous lesions.17

Histological features The epidermis shows no significant features; in particular, the changes of lupus erythematosus are usually absent. However, an interface change has been described in a single case.18 The mucin is present in the papillary and upper reticular dermis associated with a slight perivascular chronic inflammatory cell infiltrate.4,19 Fragmentation of collagen bundles has been noted in one case in association with mucin accumulation.11 Direct immunofluorescence may show linear or granular immunoglobulin (IgG, IgM) deposits and complement at the dermoepidermal junction.

Fig. 13.187 Myxoid cyst: localization over the distal interphalangeal joint is characteristic. By courtesy of the Institute of Dermatology, London, UK.

Myxoid cyst Clinical features Cutaneous myxoid cyst, sometimes inappropriately referred to as synovial cyst, presents as a soft or fluctuant cystic nodule on the dorsal aspect of the distal interphalangeal, the metacarpophalangeal and, less frequently, the metatarsophalangeal joints (Figs 13.186, 13.187).1,2 An exceptional case occurring on the lateral aspect of the knee has been described.3 Occasionally, lesions are multiple.4 Cutaneous myxoid cysts may present at any age and are more common in females. The surface is usually smooth, although verrucous variants are occasionally encountered. The cyst contains yellow, clear viscous fluid. Lesions are often painful or tender. Myxoid cyst involving the proximal nail fold can be associated with longitudinal grooving of the nail.5 Although the precise cause is not well elucidated, underlying osteoarthrosis is sometimes evident, and repetitive trauma is proposed to be one possible mechanism.1,4

Histological features The cyst is devoid of any lining and consists of a large pool of mucin containing spindled/stellate fibroblasts with prominent cytoplasmic processes (Fig. 13.188). The overlying epidermis is often atrophic and ­hyperkeratotic,

and acanthosis may be seen at the edges. Early lesions are sometimes ­indistinguishable from cutaneous focal mucinosis. There is no evidence of any ­connection with an underlying joint.

Cutaneous focal mucinosis Clinical features Cutaneous focal mucinosis presents as an asymptomatic, usually solitary, ­dermal papule or nodule most commonly on the face, neck, trunk or extremities of adults.1–5 It is not seen in relation to the joints of the hands, feet or wrists. The lesion is usually dome-shaped, white or flesh-colored and ­sometimes has an erythematous halo.2 Occasional verrucous variants have been documented.1 There is usually no evidence of an associated thyroid abnormality. Exceptional cases, however, are associated with reticular ­erythematous ­mucinosis or scleromyxedema.6 Multiple lesions are rare.7

Acanthosis nigricans Patients present with papules, nodules and/or plaquelike lesions, usually with a linear or dermatomal distribution.4 Large pedunculated lesions are rare.6 A familial case has been described in two young brothers.7

Histological features Histologically, the mucin is located in the superficial dermis where it replaces the collagen and elastic fibers.5 Some cases are associated with epidermal hyperplasia and these may represent a combined epidermal and mucinous nevus.3,8 A recent immunohistochemical evaluation demonstrated that the stromal cells are CD34 positive, with rare cells staining for factor 13A.9

Differential diagnosis These lesions must be distinguished from the mucinous eccrine nevus, which comprises abundant mucin surrounding eccrine glands and ducts.10

Neuropathia mucinosa cutanea A

There is only one case report of this condition, which presented in a young male with hyperesthesia and livedoid lesions on the lower limbs. A biopsy of these lesions revealed hypertrophic nerves surrounded by mucin.1

Self-healing infantile familial cutaneous mucinosis This very rare entity has been reported only once, in two brothers. Multiple lesions developed during the first few months of life and in one patient regressed spontaneously over a few years.1

Localized mucinosis secondary to venous insufficiency

B

Fig. 13.188 (A, B) Myxoid cyst: excessive mucin deposition has resulted in this fluid-filled cyst. The overlying epithelium may appear attenuated or verrucous and occasionally the cyst is, in part, intraepidermal in location.

Histological features The lesion is usually located in the mid and upper dermis, often separated from the epidermis by a grenz zone of dermal sparing.2 It consists of a localized, but usually poorly delineated, focus of mucin deposition containing increased numbers of spindled cells and stellate fibroblasts with elongated cytoplasmic processes.2 Sometimes these contain conspicuous intracytoplasmic vacuoles.3 Collagen fibers are usually diminished in number.4 A mild perivascular chronic inflammatory cell infiltrate is often present in the adjacent dermis. There may be an increase in the number of small-caliber blood vessels. The overlying epidermis is typically ­uninvolved; however, immature follicular germlike induction can occur.8 Ultrastructurally, the fibroblasts contain prominent rough endoplasmic reticulum and membrane-bound intracytoplasmic vesicles containing abundant granular electron-dense material.3

Differential diagnosis Cutaneous focal mucinosis must be distinguished from superficial angiomyxoma, a benign myxoid cutaneous and subcutaneous lesion with a tendency for local recurrence, associated with Carney complex.

Mucinous nevus Clinical features Mucinous nevus (nevus mucinosis) is a rare lesion that may be congenital or acquired.1–5 The most common site affected is either the trunk or lower limbs.

A recent case report describes two elderly patients with violaceous plaques and coalescing papules on the lower extremities.1 The lesions were painful and occurred in the setting of venous stasis. There was no history of thyroid disease, connective tissue disease or antecedent treatment with ultraviolet light. The histological features consisted of large amounts of mucin deposition in the papillary and reticular dermis with characteristic extension around the eccrine glands. There was a slight increase in the number of blood vessels which demonstrated thickened walls. However, an inflammatory infiltrate was not present. The pathogenesis of this condition is unknown.

Secondary cutaneous mucinoses Clinical features Mucinous lesions on the skin have been described as part of a reactive process associated with various triggers. A patient recently developed multiple erythematous to skin-colored papules following infection with varicella-zoster virus.1 The lesions occurred in the same dermatome affected by postherpetic neuralgia and resolved as the pain improved. Mucinosis complicated by cutaneous necrosis can occur following injection with interferon. Recombinant interferon-beta-1b and interferon alfacon-1 have been implicated in the setting of treatment for multiple sclerosis and hepatitis C, respectively.2,3 Erythematous ulcerative plaques develop at injection sites. Additionally, mucinosis papules and plaques have been described in the vicinity of a recently replaced joint.4

Histological features These mucinous disorders are characterized by intradermal mucin without a significant increase in dermal fibroblasts. 1–4 Ulcerative lesions associated with interferon injections can also demonstrate intravascular thrombi.3

Acanthosis nigricans Clinical features Acanthosis nigricans develops under a variety of circumstances.1–3 In addition to the well-recognized tumor-associated variant, acanthosis nigricans may present with benign familial forms, endocrinopathy and drug-related ­variants,

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Degenerative and metabolic diseases and the condition can be seen in association with a range of congenital conditions including lipoatrophy, leprechaunism and the type A and type B syndromes described below. Genetic conditions associated with acanthosis nigricans include: • Alstrom syndrome (retinopathy, progressive sensorineural hearing loss, truncal obesity), • Crouzon syndrome (facial palsy, sensorineural hearing loss with skeletal and mental retardation), • Seip-Lawrence syndrome (congenital lipodystrophic diabetes), • Costello syndrome (postnatal growth deficiency, coarse facies, redundant skin of the neck, palms, soles, and fingers, dark skin, and papillomas), • Bannayan-Riley-Ruvalcaba syndrome (subcutaneous lipomas, vascular malformations, lentigines of the penis and vulva, warty lesions, macrocephaly, mental retardation, intestinal polyposis, skeletal abnormalities, vascular malformations of the central nervous system, and thyroid tumors),4–8 • Lelis syndrome (ectodermal dysplasia with hyptrichosis, hypohidrosis, hypodontia, palmar-plantar hyperkeratosis, perioral furrows).9 Acanthosis nigricans has been described in association with a missense mutation of the fibroblast growth factor receptor.4 This disease is also associated with severe neurological impairment and severe achondroplasia.10 Additional rare associations include Wilson's disease (hepatolenticular degeneration) and primary biliary cirrhosis.11,12 In the latter case, the acanthosis nigricans resolved after liver transplantation. In an exceptional family with several members affected by acanthosis nigricans, absence of the eyebrows and eyelashes and sparse hair elsewhere has been reported.13 Development of acanthosis nigricans may also antedate or present concomitantly with a variety of connective tissue diseases including systemic lupus erythematosus, systemic sclerosis, and dermatomyositis.14–16 The condition is characterized by the presence of symmetrical brown velvety or verrucous plaques with a predilection for intertriginous sites such as the back of the neck, groin, and axillae (Figs 13.189, 13.190). In more extreme forms the changes may be generalized.17 Involvement of the eyelids also rarely occurs.18 In addition, there is sometimes brown thickening of the skin over the dorsum of the fingers or, rarely, the palms of the hands (tripe palms) (Fig. 13.191). The latter is a distinctive appearance due to broadened epidermal ridges and deep sulci giving the skin a velvety rugose texture.19 Tripe palms are usually associated with internal malignancy and often (but not invariably) accompany acanthosis nigricans. However, the lesion may

Fig. 13.190 Acanthosis nigricans: there is velvety thickening of the axillary skin. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.191 Acanthosis nigricans: tripe palms. The palmar skin is thickened and the creases are accentuated. By courtesy of the Institute of Dermatology, London, UK.

Fig. 13.189 Acanthosis nigricans: thickening of the skin of the groin. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

also represent a benign reversible phenomenon unassociated with neoplasia. Less frequently, there are similar changes on mucosal surfaces such as the mouth (particularly the tongue and upper lip) or genitalia (Fig. 13.192).20,21 The latter changes are more common in cases related to malignancy. Oral lesions have been reported in 25–50% of all cases of acanthosis nigricans and in at least 35% of patients with associated malignancy.20,22,23 The tongue lesions consist of hypertrophied filiform papillae producing a deeply fissured papillomatous surface and the lips develop papillary and verrucous lesions.20 The palate and buccal mucosa may also be involved.23 Oral lesions are usually nonpigmented. Involvement of the esophagus is rare and is almost invariably associated with malignancy, particularly in the gastrointestinal tract.24 A drug-induced variant has been documented, and glucocorticoids, nicotinic acid, oral contraceptives, and diethylstilbestrol have been implicated.25 Acanthosis nigricans has also been reported in association with ­somatotrophin therapy.26

Acanthosis nigricans

• In type A, the patients are young (particularly black) women with

Fig. 13.192 Acanthosis nigricans: the skin of the groins and vulva is thickened and hyperpigmented. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Rarely, the disease presents as an autosomal dominant nevoid lesion, which may present at birth, in childhood or at puberty.27,28 The condition has also been reported in association with Cohen's syndrome (truncal obesity, ­hypotonia, mental retardation, microcephaly, and ocular abnormalities).29 So-called benign familial acanthosis nigricans occurs more commonly in females. This autosomal dominantly inherited condition usually presents in early childhood with lesions that particularly affect the face, dorsal surfaces of the fingers, and the flexures.30 There are usually no associated endocrinopathies or congenital abnormalities. Acanthosis nigricans presents in up to 51% of patients with Down's syndrome and is probably due to insulin resistance.31 It has also been described in up to 5% of patients with severe atopic dermatitis but the pathogenesis in this setting is unknown.31 It may occur as a sign of occult malignancy and obesity. The sex incidence is equal. Malignant acanthosis nigricans is often severe, widely disseminated, and has a rapid course. Lesions may also be pruritic and are more difficult to treat. Tumors that are particularly associated include gastric adenocarcinoma, and, less often, malignancies of the extrahepatic biliary tree, breast, pancreas, bladder, and colon.24,32,33 Ovarian and uterine tumors, bronchial squamous and adenocarcinoma, and lymphoma have also been implicated.34 Acanthosis nigricans as an indicator of insulin resistance has been reported in HIV-positive patients receiving treatment with protease inhibitors.35 The malignant form sometimes develops in association with other cutaneous markers of internal malignancy including palmoplantar hyperkeratosis, eruptive seborrheic keratoses (Leser-Trélat sign), and florid cutaneous papillomatosis.36 The last condition presents as numerous viral wartlike itchy papillomata, which show a predilection for the trunk and extremities and invariably accompany an internal malignancy, most often gastric adenocarcinoma. The course of malignant acanthosis nigricans usually parallels that of the underlying neoplasm, which is generally aggressive and associated with a high mortality. Lesions may sometimes abate following surgical removal of the tumor, only to return with its recurrence. Acanthosis nigricans is also associated with a wide range of endocrine diseases, including Cushing's disease, acromegaly, gigantism, Addison's disease, polycystic ovary syndrome, diabetes mellitus, acromegaly, and thyroid disorders. The association between hyperandrogenism (HA), insulin resistance (IR), and acanthosis nigricans (AN) is known as HAIR-AN syndrome. There appears to be an association between acanthosis nigricans, obesity, hypertension, ischemic heart disease, and type 2 diabetes, the inheritance of which is autosomal dominant.37 Acanthosis nigricans may also occur in nonobese patients in association with diabetes mellitus and insulin resistance due to diminished receptor binding.38–43 Patients with this sporadic syndrome are divided into two groups:

acanthosis nigricans, primary amenorrhea with hypertestosteronemia, virilization, increased somatic growth, hyperglycemia and hyperinsulinemia, with insulin resistance due to a congenital defect of insulin receptors. • In type B, the patients are older and have features suggesting other autoimmune diseases, including raised erythrocyte sedimentation rate (ESR), proteinuria, and hypocomplementemia with antinuclear and anti-DNA antibodies. Antibodies directed against the insulin receptor may be detected. • A third type, type C, has recently been proposed, in which acanthosis nigricans and insulin resistance are associated with a postinsulin receptor defect. Studies have found that the presence of acanthosis nigricans in AfricanAmericans and Native Americans is a cutaneous marker of hyperinsulinemia and insulin resistance.44,45 Obesity-associated acanthosis nigricans, previously called pseudoacanthosis nigricans, develops in the flexures of obese patients. This is the most common type of acanthosis nigricans in children and adults and is associated with insulin resistance.46 Transient acanthosis nigricans-like lesions have been described at the sites of healing lesions of pemphigus vulgaris and pemphigus foliaceous.47,48 Acanthosis nigricans-like lesions have been described after local application of fusidic acid.49

Pathogenesis and histological features The pathogenesis is uncertain, although in the diabetes-associated patients hyperinsulinemia is likely to be of importance.41 In malignancy-related acanthosis nigricans, peptide or hormonal secretion appears to be of significance in at least a proportion of cases.32 It has been demonstrated that some malignant tumors secrete transforming growth factor alpha (TGF-α) in large quantities and this stimulates proliferation of keratinocytes.50 The histopathological findings are subtle, comprising delicate, elongate papillomatosis, hyperkeratosis and slight acanthosis, sometimes alternating with foci of atrophy (Fig. 13.193). The occasional presence of keratin-filled cysts may result in a seborrheic keratosis-like appearance.20 Despite the clinically obvious brown appearance of the lesions, there is normally little increase in the amount of melanin present. A non-specific perivascular chronic inflammatory cell infiltrate is sometimes evident in the superficial dermis. Distinguishing this type of benign acanthosis from others such as epidermal nevi may be difficult. Oral lesions show hyperkeratosis and patchy parakeratosis associated with marked acanthosis and epithelial papillary hyperplasia.20 Tripe palms are characterized by hyperkeratosis, acanthosis, and papillary dermal hypertrophy.19 Florid cutaneous papillomatosis is also characterized by hyperkeratosis, papillomatosis, and acanthosis.36

Fig. 13.193 Acanthosis nigricans: there is hyperkeratosis, papillomatosis, and slight acanthosis.

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Acrodermatitis enteropathica Clinical features Acrodermatitis enteropathica is a rare autosomal recessive inherited disorder of zinc malabsorption, which predominantly affects infants and responds dramatically to dietary zinc supplements.1–4 It presents with diarrhea, stomatitis, irritability, and failure to thrive, accompanied by erythematous scaly and crusted lesions with vesicles, pustules, and erosions, predominantly affecting the extremities, perineal, and periorificial region (Figs 13.194, 13.195). Frankly bullous lesions have been described. 5 Nonscarring alopecia may also be present. Additional features include nail dystrophy, prolonged wound healing, impetiginization, short stature, psychiatric symptoms, and photophobia.1–7 Corneal lesions and decreased visual acuity have also exceptionally been reported.8,9 Patients are also prone to developing infections, particularly by bacteria and fungi, illustrating the importance of normal zinc levels in maintaining the integrity of the immune system.10–13 The disease can persist into adulthood or rarely be diagnosed for the first time in adult life.14–16 An acquired variant may complicate artificially fed or, rarely, breast-fed infants either full term or premature.17–28 This is due to the low concentration

Fig. 13.194 Acrodermatitis enteropathica: extensive crusted erosions in a characteristic distribution. By courtesy of Z.S. Tannous, MD, Harvard Medical School, Boston, USA.

of zinc in breast milk secondary to a defect in zinc uptake from maternal serum into the breast.28 In premature infants, the problem is aggravated by the low gastrointestinal absorption of zinc and low body stores of zinc that were transferred from mother to fetus in the last 10 weeks of pregnancy.28 Many other conditions with acquired zinc deficiency have been associated with signs and symptoms of acrodermatitis enteropathica including Crohn's disease, alcoholic cirrhosis, alcoholic pancreatitis, intestinal bypass operation, chemotherapy for hematological malignancies, anorexia nervosa, lymphoma, biotin deficiency, dialysis, cystic fibrosis, Hartnup disease, essential fatty acid deficiency, citrullinemia, deficiency of ornithine transcarbamylase, and following total intravenous hyperalimentation.9,29–49 A similar picture has also been described in a number of aminoacidopathies and organic acidemias. The latter include methylmalonic acidemia, propionic acidemia, glutaric aciduria type I, and nonketotic hyperglycinemia.50–56 The changes are due not only to zinc deficiency, but also to a deficiency in branched chain amino acids including isoleucine. This is induced by the low protein diet that these patients receive. Acrodermatitis enteropathica has also been described in ­relation to HIV infection.57

Pathogenesis and histological features The manifestations of acrodermatitis enteropathica result from insufficient absorption of zinc by the intestine. The mechanism of the disease involves a defect in a zinc transporting protein. Initial studies of genes that encode for proteins important in the transport of zinc including SLC30A4 and ZNT4 did not show association with the disease.58–60 More recently, the gene for acrodermatitis enteropathica has been identified on chromosome 8q24.3.61 This gene, designated SLC39A4, encodes a histidine-rich transmembrane protein known as hZIP4 which is involved in zinc uptake.62–69 The mutation in acrodermatitis enteropathica also affects zinc metabolism in fibroblasts and reduces the activity of 5′-nucleotidase.70,71 Over 30 different mutations in this gene have been described thus far in association with acrodermatitis enteropathica.67 The vast majority of patients carry a homozygous or compound heterozygous mutation in SLC39A4. However, there are some without such an identifiable genetic mutation, indicating that other genetic factors may possibly play a causative role in the disease.67 The mechanism of infections in acrodermatitis enteropathica is related to alterations in the immune system due to zinc deficiency.12,13 Zinc is critical to the development and function of lymphoyctes, neutrophils, macrophages, NK cells, and cytokine production. It also functions as an antioxidant and ­prevents cellular damage by free radicals.13 Lymphopenia and thymic atrophy are ­frequent findings in acrodermatitis enteropathica and are due to the loss of­ B- and T-cell precursors in the bone marrow. The zinc deficiency induces apoptosis mediated by glucocorticoids with resultant decrease in lymphopoiesis. The histopathology varies according to the stage of evolution.72 Very early lesions show subtle changes consisting of focal parakeratosis alternating with orthokeratosis. As lesions advance, the parakeratosis becomes more prominent and confluent and the stratum granulosum is decreased or absent. The keratinocytes in the upper layers of the epidermis display marked cytoplasmic pallor (Figs 13.196, 13.197). In addition there is focal spongiosis. Dyskeratotic cells are rarely seen. In late stages there is cytoplasmic vacuolation and necrosis which may result in intraepidermal vesicles or occasionally progress to blister formation.73,74 Subcorneal pustules may be seen and usually indicate secondary infection. An atypical case of bullous acrodermatitis enteropathica with a lichenoid infiltrate has been reported.75

Differential diagnosis

Fig. 13.195 Acrodermatitis enteropathica: in this infant, there is very extensive involvement with widespread erosion. By courtesy of Z.S. Tannous, MD, Harvard Medical School, Boston, USA.

Histologically, acrodermatitis enteropathica is indistinguishable from necrolytic migratory erythema and pellagra. Very similar histological features are also seen in necrolytic acral erythema, a condition that occurs on the dorsum of the feet and legs of patients with hepatitis C infection.76–79 Lesions are erythematous and psoriasiform plaques and decreased serum and lesional zinc levels have been associated with this condition.78,79 Prominent pallor of ­keratinocytes in the upper layers of the epidermis is also seen in deficiency of the M subunit of lactate dehydrogenase.80,81 The cutaneous manifestation of the latter condition has been described as annually recurring acroerythema.82

Necrolytic migratory erythema

Fig. 13.196 Acrodermatitis enteropathica: lowpower view showing hyperkeratosis and marked epidermal eosinophilia on the right side.

anemia, nausea, diarrhea, abdominal pain, neurological symptoms (ataxia and fecal and urinary incontinence), thromboembolic pathology (deep vein thrombosis and pulmonary thromboembolism), and weight loss in addition to the cutaneous manifestations.10 About 57% of patients present with the ­typical visceral, cutaneous, and laboratory abnormalities.11 Exceptional cases of ­glucagonoma arise from the duodenum, ­kidney, and lung.12–14 Necrolytic migratory erythema, so-called because of its superficial resemblance to toxic epidermal necrolysis and the waxing and waning nature of the eruption, is seen most frequently on the central face, particularly around the mouth, on the perineum and other intertriginous sites, the thighs, buttocks, and distal limbs (Fig. 13.198).3 Patients most often present in their sixth decade (median 52 years) with intense erythema, which progresses to flaccid bullae that rupture readily and develop crusting.11,15 Pressure, friction, and trauma have occasionally been noted to precipitate the eruption.8 Central healing with active borders gives rise to annular and serpiginous lesions. Lesions are often painful and pruritic. Postinflammatory hyperpigmentation follows resolution. Individual lesions usually last 1–2 weeks and, characteristically, lesions in varying stages of evolution are evident at any one time.8,15 Additional features may include stomatitis, angular cheilitis, blepharitis, conjunctivitis, hair loss, and nail changes.9–11 Laboratory investigations commonly reveal an abnormal glucose tolerance test, normochromic normocytic anemia, hypoproteinemia, hypoalbuminemia, and hypoaminoacidemia.9,16 Low amino acid levels were detected in 96% of patients in one reported series.17 However, in larger series, the percentage of patients with low amino acid levels has been lower, ranging between 41% and 78%.10,11 Glucagonoma syndrome may constitute part of the multiple endocrine neoplasia syndrome.18 Rarely, necrolytic migratory erythema has been described in the absence of a glucagonoma, so-called ‘pseudo-glucagonoma syndrome’.19–25 Abnormal liver function tests have usually been present and it has been suggested that this may have resulted in impaired glucagon catabolism with resultant hyperglucagonemia or raised levels of one of the glucagon immunofractions.20 Patients have had associated gastrointestinal malabsorption disorders such as celiac disease, ulcerative colitis, Crohn's disease, short bowel syndrome, liver diseases including cirrhosis and hepatitis, as well as chronic pancreatitis, cystic fibrosis, and other malignancies.23,26–30 A study of 24 patients with nonglucagonoma-associated necrolytic migratory erythema found increased glucagon in 52% of patients and low zinc levels in 37% of patients.23 Despite its relatively indolent growth characteristics, a large majority of tumors have metastasized by the time of diagnosis.

Fig. 13.197 Acrodermatitis enteropathica: keratinocyte necrosis is seen in this high-power view.

Necrolytic migratory erythema Clinical features Necrolytic migratory erythema is a distinctive dermatosis that is classically seen in patients with the glucagonoma syndrome.1–9 The latter, due to a slowly progressive malignant tumor of the pancreatic islets, consists of hyperglucagonemia, diabetes mellitus, glossitis, normochromic ­normocytic

Fig. 13.198 Necrolytic migratory erythema: note the intense erythema in a characteristic distribution. By courtesy of the Institute of Dermatology, London, UK.

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Pathogenesis and histological features The precise etiology of necrolytic migratory erythema is unknown. Although it is certainly related to hyperglucagonemia, this is not necessarily causal. Therefore, although the signs and symptoms rapidly abate following surgery or the use of glucagon secretion inhibitors such as somatostatin, ­hyperglucagonemia does not readily explain the intermittent nature of the eruption.20 The topical or intradermal application of glucagon does not produce the dermatoses.8 Similarly, there are alternative causes of hyperglucagonemia including burns and acute trauma, diabetes mellitus, septicemia, cirrhosis, renal failure, Cushing's syndrome, and primary hyperglucagonemia, in which necrolytic migratory erythema is not a feature.16 Hypoaminoacidemia is an extremely common manifestation and it may have pathogenetic significance for the cutaneous lesions. It has been proposed that the diminished amino acid availability may result in epidermal protein depletion and eventual necrosis.15 Certainly, treatment with intravenous amino acids has been shown to control the eruption, but this, of course, may have been coincidental, considering the characteristic fluctuating course of the dermatoses.20 Fatty acid and zinc deficiency and abnormal arachidonic acid distribution have also been proposed as pathogenetic mechanisms.9,31 It has been suggested that diminished tryptophan levels may be the cause of the dermatoses.9 A further hypothesis points to hepatic dysfunction as having a role in the pathogenesis of the disease.20,21,23,25,32 This is mainly based on the fact that patients with necrolytic migratory erythema and absence of glucagonoma often have liver dysfunction. The model of ‘multifactorial malnutrition’ has been suggested as an explanation for the several disorders associated with this disease.25 It is proposed that deficiencies in zinc, amino acids, fatty acids, and protein result in a metabolic alteration which affects a final common pathway that manifests clinically with epidermal inflammation and necrosis in areas of trauma. The precise pathways involved remain unknown. Histological examination reveals parakeratosis accompanied by vacuolation and pallor of the mid and upper keratinocytes (Figs 13.199–13.201).33 Dyskeratosis has been described as a clue to early diagnosis.34 This is accompanied by necrosis and separation of the upper layers of the epidermis, giving rise to intraepidermal clefting or vesiculation.33 A neutrophil polymorph infiltrate may be evident, particularly in well-established lesions.35 Subcorneal pustulation has also been described.16 This may develop in a background of epidermal necrosis or, less often, represents an isolated phenomenon.35 Suprabasal acantholysis has exceptionally been described.36 The dermis shows a lymphohistiocytic chronic inflammatory cell infiltrate surrounding dilated blood vessels. In lesions associated with pustulation, neutrophils may also be

Fig. 13.200 Necrolytic migratory erythema: close-up view of Figure 13.199.

Fig. 13.201 Necrolytic migratory erythema: high-power view showing marked overlying parakeratosis.

present. Older lesions may show parakeratosis, marked acanthosis, and papillary dermal angiogenesis, and psoriasis may therefore enter the ­differential diagnosis.7,33,35 Pustular folliculitis in association with more typical features has also been described.35 Immunofluorescence studies are invariably negative.13,15,31,35,37 An ultrastructural study revealed widening of the intercellular space with reduced numbers of desmosomes in the absence of acantholysis.38 Cytoplasmic vacuolation with lysed organelles and dyskeratotic cells was also present. These changes are largely degenerative and non-specific.

Differential diagnosis

Fig. 13.199 Necrolytic migratory erythema: low-power view showing extensive vacuolation with vesiculation.

Necrolytic migratory erythema shows considerable clinicopathological overlap with acrodermatitis enteropathica, and niacin and zinc deficiencies, suggesting a possible shared pathogenesis.9 Pellagra can also show similar histological features. The histology of necrolytic acral erythema is that of necrolytic migratory erythema. This condition is, however, associated with hepatitis C infection and clinically tends to be restricted to the dorsum of the feet, with less common involvement of the lower legs and dorsal hands.39

Bullosis diabeticorum If subcorneal pustules are evident, impetigo, dermatophyte infection, ­ ustular psoriasis, subcorneal pustular dermatosis, and pemphigus foliaceus p enter the differential diagnosis. Multiple biopsies are sometimes necessary before the correct diagnosis can be established.

Bullosis diabeticorum Clinical features There are numerous cutaneous manifestations of diabetes mellitus. These include vascular complications such as peripheral gangrene, especially ­affecting the foot, and infective lesions including candidiasis and dermatophytosis. Other dermatological features include necrobiosis lipoidica ­diabeticorum, ­disseminated granuloma annulare, acanthosis nigricans, ­eruptive ­xanthomata, scleredema, diabetic dermopathy (shin spots), waxy skin, and bullous lesions.1–4 Bullosis diabeticorum (bullous eruption of diabetes mellitus) is rare, affecting approximately 0.16% of diabetics, and affects men more commonly (male:female ratio 2:1).5 It usually presents as spontaneous blisters, typically without underlying inflammation, affecting the periphery. Lesions, which are sometimes mildly painful or associated with a burning sensation, are found most often on the feet and lower legs although the hands may also be affected.6–10 Blisters range in size from a few millimeters to a few centimeters and can evolve rapidly and become hemorrhagic.4 The lesions, which are often recurrent, commonly heal in a few weeks and are not associated with scarring. Rarely, secondary ulceration and infection can occur. 5 Osteomyelitis has been reported recently.11

Fig. 13.202 Bullous eruption of diabetes: this example from the fingertip shows a subepidermal vesicle.

Pathogenesis and histological features The cause of blistering in diabetic patients is unknown, but theories implicating a vascular or neurological mechanism have been favored in the literature. The occasional finding of epidermal infarction overlying the blister cavity favors the former in at least some patients.6 The discovery that diabetic patients have a diminished threshold for suction-induced blisters may have pathogenetic significance.12 Others have suggested an abnormality of calcium and magnesium metabolism as a consequence of diabetic nephropathy.13 Despite lesions being predominantly acral in distribution, trauma does not seem to be generally implicated. In all likelihood, the cause is probably multifactorial. The reported histopathological features have been variable and include subcorneal, suprabasal, and subepidermal vesiculation, sometimes associated with spongiosis (Figs 13.202, 13.203).13–15 Some of the discrepancies may be due at least in part to variable ages of the lesions, biopsies with re-epithelialization resulting in an apparent intraepidermal location. Electron microscopic studies in two cases have shown that the plane of separation is through the lamina lucida in the subepidermal lesions.6,13 Absence of hemidesmosomes and anchoring filaments has also been described.13 Immunofluorescence studies are almost invariably negative, although one report described IgM and C3 around the superficial vasculature in ­uninvolved skin.16

Fig. 13.203 Bullous eruption of diabetes: in this field, the epidermis shows the changes of infarction. Note the intense cytoplasmic eosinophilia and absence of nuclei.

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Chapter

14

Cutaneous adverse reactions to drugs

Adverse drug reactions – introduction  590 Type A drug reactions  591 Type B drug reactions  591 Type C drug reactions  591

Nooshin Brinster

Vasculitic drug reactions  604 Purpuric drug reactions  605 Granulomatous drug reactions  605 Drug-induced erythema nodosum  606 Drug-induced alopecia  606

Adverse drug reactions – clinical manifestations  592

Drug-induced lupus erythematosus  607

Exanthematous reactions  592

Drug-induced linear IgA disease  607 Drug-induced bullous pemphigoid  608 Drug-induced epidermolysis bullosa acquisita  609 Drug-induced pemphigus  609 Drug-induced pseudoporphyria  609

Urticarial reactions, angioedema and anaphylaxis  594 Serum sickness/serum sickness-like drug reactions  594

Bullous drug reactions  607

See www.expertconsult.com

for references and additional material

Penicillamine  617 Gold  618 Silver  619 Mercury  619 Bismuth  620 Voriconazole  620 Lithium  620 Barbiturates and coma blisters  621

Chemotherapeutic agents  621 Chemotherapy-induced acral erythema  623

Chemotherapy-associated eccrine gland reactions  623 Neutrophil eccrine hidradenitis  623 Eccrine squamous syringometaplasia  624

Psoriasiform drug reactions  609

Adverse reactions to cytokine therapy 625

Phototoxic and photoallergic reactions  595

Pityriasiform drug reactions  610

Anticonvulsant hypersensitivity syndrome  597

Pustular drug reactions  611

Cutaneous reaction of lymphocyte recovery  626

Lichenoid and interface drug reactions  598 Fixed drug eruptions  599 Erythema multiforme  601 Stevens-Johnson syndrome and toxic epidermal necrolysis  601 Drug-induced hyperpigmentation  601

Ichthyosiform drug reactions  612 Drug-induced pseudolymphoma  612 Specific drug reactions  614 Arsenic  614 Iododerma  615 Bromoderma  615 Warfarin  616 Heparin  617

Dental amalgam tattoos  626 Tumor necrosis factor-a inhibitors  626 Esthetic microimplants  627 Alpha-melanocyte stimulating hormone analogues (melanotan I and II)  629 EMLA cream  630

Adverse drug reactions – Introduction Adverse drug reactions are unintended and undesired effects of drugs used for prevention, diagnosis or treatment of disease.1,2 In light of the ever-increasing number of medications available, it should come as no surprise that such reactions are extremely common. The incidence statistics vary considerably depending upon the method by which the data are derived and the nature of the population under study.3 Estimates, however, range from 2% to 7% of hospital inpatients.4–8 Although most reactions are mild, they are sometimes severe and a source of considerable morbidity and occasional mortality.6,7 The diagnosis of an adverse drug reaction is frequently problematical, the clinical appearances often being similar, if not identical, to a number of primary dermatoses and infectious conditions (particularly viral exanthems) and, in the context of transplantation patients, graft-versus-host disease (GVHD). The histological diagnosis can also be extremely difficult, as drug reactions can demonstrate several inflammatory histological patterns that mimic other dermatoses (i.e. spongiotic, psoriasiform, lichenoid, pityriasiform).9 The problem is exacerbated in the immunologically compromised patient. Frequently, the

diagnostic difficulties are worsened by the multitude of drugs prescribed. The problem is further compounded by the multiplicity of different eruptions that any one particular drug may induce. Contrariwise, a given clinical appearance may be caused by a large number of unrelated drugs.10 The prevalence of agents responsible for adverse drug reactions reflects the prescribing tendencies for any given population as much as the relative risks ascribed to any particular drug.11 It should come as no surprise, therefore, that – in a hospital environment – antibiotics, nonsteroidal antiinflammatory agents (NSAIDs) and psychotropic drugs are commonly reported as being the most frequently incriminated.8 In a large hospital survey, penicillin and sulfonamides accounted for over 80% of all adverse drug reactions.8 Experience in general practice has been much less often documented. In a survey from the Netherlands, sulfonamide-trimethoprim combinations, fluoroquinolones, and penicillin were the most common antibacterials causing drug-related eruptions.3 In the series of approximately 150 000 patients, 1% developed a reaction.

Type C drug reactions Adverse drug reactions are mostly nonimmunologically mediated. They develop either as a result of an unwanted but known property of the drug (and hence are entirely predictable) or as a consequence of drug intolerance/ idiosyncrasy (and are completely unpredictable).5,12–15 The former are by far the more common, accounting for approximately 80% of all adverse drug reactions. Less often, adverse drug reactions represent a manifestation of an immunological phenomenon, so-called allergic drug reactions.5,15 Although in theory the above subdivisions are sharply defined, in many patients the underlying pathogenetic mechanisms are far from clear.13 Adverse drug reactions are particularly encountered in certain population groups, for example the elderly, females, patients with Sjögren's syndrome, and those suffering from the effects of immune deficiency including patients receiving immunosuppressive therapy and those suffering from the acquired immunodeficiency syndrome (AIDS).5 Adverse drug reactions can be divided into three categories: type A, type B, and type C.1,12,16

Type A drug reactions Type A reactions, which are predictable and are related to the pharmacological actions or metabolism of the drug, include:1 • side effects, • drug toxicity, • drug interactions.

Side effects Side effects, which occur with almost all drugs, represent unwanted pharmacological actions. For example, methotrexate, cyclophosphamide and nitrosourea commonly result in anagen alopecia by inducing Bax proteinmediated apoptosis.17–21 Gold may be associated with cutaneous pigmentation (chrysiasis) and penicillamine can be associated with the development of skin laxity and fragility.22–25

Drug toxicity Drug toxicity develops as a consequence of the gradual accumulation of a drug or its metabolite (e.g., minocycline or amiodarone deposition with resultant abnormal pigmentation).15,26–29 Delayed toxicity may take months to many years before expression (e.g., arsenical keratoses).30–33

Drug interactions Drug interactions develop when one drug alters the pharmacological efficacy of another that is given concurrently.12,13,34,35 The effect may enhance or diminish the effect of the drug with resultant toxicity or loss of therapeutic value.13,14 Drug interactions are thought to arise when one drug affects clearance of the other as a consequence of several mechanisms including:3,4 • alteration in the rate of absorption resulting in diminished drug levels, • alteration in the renal excretion resulting in inappropriately high drug levels, • plasma protein or tissue drug binding site competition resulting in displacement and inappropriately high drug levels, • alterations in hepatic cytochrome P-450-mediated drug metabolism. The last is believed to be of particular importance and includes increased enzyme synthesis with excessive drug degradation and diminished circulating or tissue levels and inhibition of drug breakdown with increased circulating and tissue levels.34,36 Drug interactions are of particular importance in the elderly, the immunosuppressed, and in those patients receiving multiple medications.3,4

Type B drug reactions Type B reactions are uncommon and unpredictable. They do not have an allergic pathogenesis and include: 1 • idiosyncratic drug reactions, • exacerbation of a pre-existing condition, • pseudoallergic drug reactions.

Idiosyncratic drug reactions Idiosyncratic reactions (drug intolerance) develop as a result of genetic or metabolic influences. They may represent the effects of abnormal or altered hepatic drug metabolism. For example, a lupus erythematosus-like condition is a rare complication of hydralazine therapy in the average population but the risk is greatly increased in patients who metabolize the drug slowly.3,7 Drug-induced lupus erythematosus may also be caused by procainamide, chlorpromazine, isoniazid, methyldopa, penicillamine, minocycline, quinidine, and sulfasalazine.36–38 Cefaclor-induced serum sickness-like eruptions and the antiepileptic hypersensitivity syndrome are also believed to result from reactive intermediate metabolic products.39,40

Exacerbation of a pre-existing condition This is a not uncommon problem; for example, lithium, beta-blockers, antimalarial drugs, NSAIDs, and tetracycline may precipitate, aggravate or induce a psoriatic eruption.4,41–45

Pseudoallergic drug reactions Pseudoallergic reactions result from the nonimmunologically mediated release of effector substances such as histamine from tissue-bound mast cells or circulating basophils with resultant urticarial reactions, angioneurotic edema, and anaphylaxis.1,4 The complement system can also be activated by similar nonimmune mechanisms, and there is evidence that perturbation of arachidonic acid metabolism may be involved in some cases.1,3,17 Drugs which have been incriminated in such pseudoallergic reactions include radiocontrast media, NSAIDs, acetyl salicylic acid, opium derivatives, codeine, curare, d-tubocurare, polymyxin B, and angiotensin-converting enzyme (ACE) inhibitors.46–50

Type C drug reactions Type C reactions are rare, immunologically mediated, and develop as a consequence of previous exposure to the drug with resultant allergy.1 The majority of drugs are of low molecular weight (less than 1000 Daltons) and therefore on their own are incapable of eliciting an immune response. By functioning as haptens and forming conjugates with carrier plasma proteins or cell membrane constituents they develop immunogenic potential.1,2,17 The ability of the majority of drugs to cause an immune response is therefore dependent on whether it is able to bind to circulating or tissue protein.51 A number of drugs are likely to induce allergic reactions, including antibiotics, anticonvulsants, chemotherapeutic agents, heparin, insulin, protamine, and biological response modifiers such as interferons and growth factors.1 A variety of mechanisms may be involved in cutaneous drug-induced hypersensitivity reactions including:12 • IgE mediated type 1 reactions, • immune complex-associated type 3 reactions, • type 4 delayed hypersensitivity reactions.

IgE-mediated type 1 cutaneous reactions In type 1 reactions, the release of histamine and other chemical mediators from tissue-fixed mast cells results in increased vascular permeability with development of edema in the dermis or deeper tissues.5,17 Immediate reactions which develop within an hour or less of drug exposure present as urticaria, angioedema or anaphylaxis whereas accelerated reactions which develop from 1 to 72 hours following the administration of the drug are usually urticarial.17 Urticaria following treatment with penicillin is a typical type 1 reaction. Certain other antibiotics, antisera, and gammaglobulin are also common offenders.12 The most common cause of anaphylaxis is penicillin.52 Other causes include foods, stings, anesthetics, muscle relaxants, latex, contrast material, antibiotics, and allergenic extracts.52–54 In addition to histamine, anaphylaxis is mediated through a number of substances including prostaglandin D2, ­leukotriene C4, interleukin (IL)-4 and IL-13, and tumor necrosis factor alpha (TNF-α).51

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Immune complex-associated type 3 reactions Type 3 reactions are expressed as urticaria, the Arthus reaction, serum sickness, and leukocytoclastic (allergic) vasculitis.12 The disease manifests a week or more after exposure to the drug, by which time sufficient circulating antibody has been generated to result in immune complexes of an appropriate size to avoid phagocytosis. Their deposition in the tissues or within blood vessel walls is accompanied by complement fixation and resultant acute inflammatory reaction.

Delayed hypersensitivity type 4 reactions Delayed hypersensitivity reactions are T-lymphocyte mediated and exemplified in acute allergic contact dermatitis.12,17 Cytotoxic T-cell-mediated

reactions are of importance in many other adverse allergic drug reactions including exanthematous/morbilliform, bullous, and interface variants.55–58 Although most delayed hypersensitivity reactions are immune responses to the hapten-carrier complex, recent studies indicate that some drugs may be capable of directly activating the immune system, independent of a covalent drug–peptide complex.59 Certain medications may directly bind T-cell receptors and MHC molecules and trigger the release of cytokines which recruit specific leukocytes. The delayed hypersensitivity reactions may be subclassified based on the cell type recruited: monocytes (type 4a), eosinophils (type 4b), T cells (type 4c), and neutrophils (type IVd). The resultant clinical phenotype may be determined by which cells are involved.59

Adverse drug reactions – clinical manifestations Although the range of drugs that may result in adverse drug reactions is extensive, the variety of clinical responses encountered is fairly limited. Many drugs may cause more than one clinical response and any given reaction pattern may result from a wide range of drugs. There are, however, a number of clinicopathological responses that are fairly unique to a particular drug and these are dealt with individually, later in this chapter.1–8 Adverse drug reactions may therefore present with a considerable number of clinical manifestations as outlined in Box 14.1.1,2

Exanthematous reactions Clinical features Exanthematous (morbilliform, maculopapular) reactions are the most frequently encountered adverse drug reaction, accounting for 51% to 95% of skin reactions, and mimic a variety of infective conditions including scarlet fever, measles, and rubella (Figs 14.1, 14.2).1–5 Patients present with erythematous macules and papules that may become confluent or gyrate/ polycyclic. Pruritus, low-grade fever, and eosinophilia are sometimes present.2 The eruption is often symmetrical and usually presents on the trunk and extremities or sites of pressure and trauma.1 The palms and soles are sometimes affected but the mucous membranes are not usually involved.

Fig. 14.1 Exanthematous drug reaction: typical erythematous maculopapular eruption on the lower extremities due to ampicillin. By courtesy of the Institute of Dermatology, London, UK.

Box 14.1 Clinical manifestations of adverse drug reactions

• • • • • • • • • • • • • • • • • • • • • • •

Exanthematous reactions Urticaria, angioedema and anaphylaxis Serum sickness Phototoxic/photoallergic eruptions Hypersensitivity syndrome Lichenoid drug reactions Fixed drug eruptions Erythema multiforme Stevens-Johnson syndrome/toxic epidermal necrolysis Pigmentary abnormalities Vasculitis Purpura Granulomatous drug reactions Erythema nodosum Drug-induced alopecia Lupus erythematosus-like drug reactions Bullous drug reactions Psoriasiform drug reactions Pityriasis rosea-like eruptions Pustular drug reactions Ichthyosiform drug reactions Pseudolymphomatous drug reactions Eczematous drug reactions

Fig. 14.2 Exanthematous drug reaction: more extensive lesions on the abdomen associated with amoxicillin therapy. By courtesy of the Institute of Dermatology, London, UK.

Exanthematous reactions Exanthematous eruptions typically develop within 1–2 weeks of starting the drug.1 Occasionally, the eruption is delayed and may even present after the treatment has ceased.1,6 In more seriously affected patients the eruption can progress to erythroderma (exfoliative dermatitis) in which the erythema becomes generalized and is often accompanied by scaling.7 Resolution of exanthematous drug reactions is characterized by exfoliation and sometimes is followed by postinflammatory hyper- or hypopigmentation.1 Penicillin, sulfonamides, ampicillin, amoxicillin, phenylbutazone, isoniazid, barbiturates, phenytoin, carbamazepine, benzodiazepines, gold, and trimethoprim are especially incriminated.1,8–10 Patients who suffer from infectious mononucleosis are at risk of developing an exanthematous reaction following therapy with ampicillin or amoxicillin.11

Pathogenesis and histological features The pathogenesis of exanthematous drug reactions is not fully understood, although a cytotoxic T-cell-mediated reaction is likely in most cases (see Immunohistochemistry). The histological features are often subtle. Although the epidermis may appear normal, focal parakeratosis is commonly present. The characteristic changes include lymphocytic exocytosis with mild spongiosis, typically accompanied by basal cell liquefactive degeneration and a few dyskeratotic keratinocytes (Figs 14.3–14.7).12,13 The dermis shows a perivascular infiltrate of lymphocytes and histiocytes with variable numbers of eosinophils. Eosinophils – although often emphasized in the literature as an important feature of drug reactions – can, in our experience, be very scanty or even absent. Sometimes marked edema is seen, particularly if an urticarial element is clinically evident. Red cell extravasation may also be a feature in those lesions that include a purpuric component. By immunohistochemistry, the lymphocytes are largely CD3+ T-cells with a predominance of CD4+ cells in the superficial perivascular infiltrate.14 Lymphocytes at the dermoepidermal junction and within the epidermis consist of approximately equal numbers of CD4+ and CD8+ forms.14–19 These latter cells regularly express human leukocyte antigen (HLA)-DR and a subpopulation also expresses CD25.19 There is an admixture of T-helper Th1 and Th2 cells.18 Occasionally, the infiltrate is almost entirely composed of the CD4+ lymphocytes and, contrariwise in human immunodeficiency virus (HIV) positive patients, the infiltrate may consist of CD8+ cells alone.14,17 CD1a+ dendritic cells and CD68+ histiocytes are also present.18 CD56+ natural killer (NK) cells may be identified.17 Cytotoxic pathways mediated by

Fig. 14.4 Exanthematous drug reaction: in this example due to carbamazepine therapy, there is spongiosis, dyskeratosis, and interface change associated with lymphocytic exocytosis.

Fig. 14.5 Exanthematous drug reaction: low power view showing focal parakeratois, mild acanthosis and a heavy upper dermal inflammatory cell infiltrate.

Fig. 14.3 Exanthematous drug reaction: early lesion due to penicillin showing slight interface change, spongiosis, and lymphocytic exocytosis. There is a superficial perivascular lymphocytic infiltrate, and one or two plasma cells are present.

perforin and granzyme B have been shown to be of particular importance in exanthematous drug reactions.16,18,19 Fas/Fas-L cytotoxic mechanisms are not thought to be of relevance.14 The features of drug-induced erythroderma are rather non-specific and include parakeratosis and psoriasiform hyperplasia, sometimes accompanied by mild spongiosis. Eosinophils may be identified within the dermal chronic inflammatory cell infiltrate.

Differential diagnosis Exanthematous adverse drug reactions are a frequent feature in transplantation patients who are usually taking multiple medications and, therefore, must be distinguished from acute GVHD. In reality, it is difficult, if not impossible, to make this distinction histologically. Traditionally, the presence of eosinophils has been thought to support a drug reaction. However, a recent study found tissue eosinophils in both graft-versus-host disease and drug reactions,

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Cutaneous adverse reactions to drugs submucosal layers are affected, angioedema results.2–4 Urticaria can also be a manifestation of serum sickness and anaphylaxis. Urticarial reactions may be caused by a large number of drugs. Aspirin, penicillin, ACE inhibitors, and blood products are particularly incriminated.5,6 Drugs which directly stimulate mast cell release of vasoactive substances such as histamine can cause urticaria, include opiates, curare, vancomycin, and polymyxin B.3,7,8 Radiocontrast media may have a similar effect.3 Urticarial reactions due to aspirin and NSAIDs are thought to sometimes be a result of abnormal arachidonic acid metabolism.3

Pathogenesis and histological features

Fig. 14.6 Exanthematous drug reaction: in this high power view there is parakeratosis, focal spongiosis and lymphocytic exocytosis. A heavy dermal infiltrate is present with one or two eosinophils.

The pathogenesis of urticarial drug reactions includes IgE-mediated type 1 reactions, immune complex mechanisms, and pseudoallergic phenomena (non IgE-mediated).5,9,10 Histologically, urticaria is characterized by dermal edema and vascular dilatation accompanied by a perivascular infiltrate consisting of lymphocytes and eosinophils (Fig. 14.8). Edema is often difficult to appreciate histologically but may be inferred by separation of collagen bundles. Mast cell degranulation may be present.3 Vasculitis is not a feature. Angioedema is characterized by edema extending into the deeper dermis and subcutaneous fat.

Serum sickness/serum sickness-like drug reactions Clinical features Serum sickness develops within 1–3 weeks after taking the serum or vaccine.1–8 It presents with an erythematous maculopapular or urticarial response or with palpable purpura variably accompanied by fever, arthralgia, myalgia, arthritis, lymphadenopathy, glomerulonephritis, myocarditis, and neuritis (Fig. 14.9).1–4 The cutaneous manifestations often commence on the sides of the fingers, toes, and hands before becoming more generalized.2 A wide range of drugs has been implicated in the development of serum sickness-like drug reactions including phenytoin, phenylbutazone, and carbamazepine. Antibiotics are also a common offender, with cefaclor featured most prominently along with other antibiotics such as cefprozil, ciprofloxacin, minocycline, penicillin V, amoxicillin, flucloxacillin, and cotrimoxazole.6,9–19 More recently, therapy with monoclonal antibodies such as rituximab, infliximab, and natalizumab has been associated with serum sickness-like reactions.20–22

Fig. 14.7 Exanthematous drug reaction: note the interface change and cytoid bodies.

making histological distinction impossible.20 A viral exanthem also commonly enters the differential diagnosis – the histological findings are often indistinguishable although the presence of eosinophils may favor a drug reaction.

Urticarial reactions, angioedema and anaphylaxis Clinical features Urticaria is the second most common adverse drug reaction.1 It is characterized by pruritic, erythematous, and edematous wheals. If accompanied by marked edema involving the deeper dermis and subcutaneous fat, or if the

Fig. 14.8 Urticarial drug reaction: high-power view showing a predominately perivascular lymphohistiocytic infiltrate with one or two eosinophils.

Phototoxic and photoallergic reactions

Fig. 14.9 Serum sickness: there is a widespread erythematous and urticarial eruption.

Fig. 14.11 Phototoxic drug reaction: in this example there are well-developed blisters arising on an erythematous base.

Pathogenesis and histological features Serum sickness is thought to represent an immune complex-mediated type 3 reaction although the possibility of direct toxicity against vessel wall, autoimmunity, and cell-mediated cytotoxicity have been proposed as alternative pathogenetic mechanisms.2 Direct immunofluorescence reveals immunoglobulin and C3 in relation to blood vessel walls.6 The histological features are those of leukocytoclastic vasculitis (Fig. 14.10).23

Phototoxic and photoallergic reactions Clinical features There are two types of photosensitive drug reactions: phototoxic and photoallergic. Phototoxic reactions are more common; however, they are not necessarily mutually exclusive and are not always clinically distinguishable.1–30 The clinical appearances of acute phototoxic reactions mimic severe sunburn and include erythema, edema, and blistering with subsequent desquamation and postinflammatory hyperpigmentation (Figs 14.11, 14.12).6,7 Typically, only exposed skin is affected and it occurs minutes to hours after sun exposure. Phototoxicity has also been associated with onycholysis.21,25 Chronic phototoxicity presents with poikilodermatous features including hyper- and hypopigmentation, epidermal atrophy, and telangiectasia. It is an important feature of the porphyrias and the inherited ­photodermatoses such Fig. 14.12 Phototoxic drug reaction: the lesions in this patient followed PUVA therapy. By courtesy of the Institute of Dermatology, London, UK.

Fig. 14.10 Serum sickness: there is a florid leukocytoclastic vasculitis.

as xeroderma pigmentosum, Rothmund-Thomson syndrome, and Bloom's syndrome. It rarely results from drug treatment but may follow long-term therapy with psoralen and UVA (PUVA therapy) where there is also an increased incidence of actinic keratosis, basal cell carcinoma, squamous cell carcinoma and, more rarely, melanoma.6,31–34 Drugs that are incriminated in acute phototoxic reactions include thiazide diuretics, sulfonamides, tetracycline antibiotics, NSAIDs (including naproxen, diclofenac, and ketoprofen), phenothiazines (particularly chlorpromazine), amiodarone, tars, and psoralens.6–13,19,20,23,24,29 Phototoxicity has also been described with use of St. John's wort and following photodynamic therapy.22,26 Porphyrins are potent phototoxic sensitizers.6 In this instance, the damage affects the dermal constituents including the vasculature, leaving the epidermis relatively unaffected. The clinical appearances of photoallergic drug reactions are variable and include eczematous and lichenoid dermatitides (Figs 14.13, 14.14).14 The rash usually develops 24 hours or more after sun exposure. Unlike phototoxic

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Fig. 14.15 Fig. 14.13 Photoallergic drug reaction: note the obvious sparing of covered skin. By courtesy of the Institute of Dermatology, London, UK.

Phytophotodermatitis: this variant represents an allergic reaction to a plant chemical. Linear lesions on the limbs are characteristic and usually follow gardening. By courtesy of the Institute of Dermatology, London, UK.

(Fig. 14.15).35 Members of the Umbelliferae, Rutaceae and Moraceae families are implicated.36,37

Pathogenesis and histological features

Fig. 14.14 Photoallergic drug reaction: this example resulted from treatment with tetracycline. By courtesy of the Institute of Dermatology, London, UK.

reactions, unexposed skin may also be affected in addition to exposed skin.7 Typically, the dermatitis resolves after withdrawal of the offending agent. Rarely, a persistent light reaction may occur in which the photodermatitis persists despite removal of the photosensitizing chemical. This usually occurs in the setting of photoallergic contact dermatitis. The majority of photoallergic reactions are induced by the application of topical medicaments and chemicals (contact photoallergy) including antihistamines, local anesthetics, chlorpromazine, hydrocortisone sunscreens containing p-aminobenzoic acid, and halogenated phenolic compounds in soaps and fragrances (e.g., 6-methylcoumarin and musk ambrette).2,7,15,17 Photoallergy can also follow systemic administration of drugs including sulfonamides, griseofulvin, phenothiazines, tetracyclines, NSAIDs, chloroquine, and thiazides.8,18 Diagnosis is best confirmed by a photopatch test. Phytophotodermatitis represents a phototoxic drug reaction due to contact with plants containing furanocoumarins.35–37 Patients develop erythema followed by postinflammatory hyperpigmentation. Rarely, blisters may develop

Photosensitization has been described as a process whereby 'a reaction to non-ionizing radiation occurs as a consequence of the introduction of a radiation-absorbing reagent (the sensitizer), which induces another substance (the substrate) to undergo chemical change'.1–6 There are two basic mechanisms: phototoxic and photoallergic. While an enormous range of drugs has been implicated in photosensitivity reactions, NSAIDS, phenothiazines, amiodarone, antibiotics, and antifungal agents such as griseofulvin appear to be of particular importance.30 Two types of phototoxic reactions are recognized: photodynamic and nonphotodynamic.6 • Photodynamic reactions are oxygen-dependent and result in singlet oxygen or superoxide anions which cause injury to cellular constituents such as cell membranes, cytoplasmic proteins and nucleic acids. • Nonphotodynamic reactions are oxygen independent and damage DNA or RNA directly. Many drug reactions are photodynamic, whereas psoralen represents a nonphotodynamic reaction. Phototoxic reactions do not depend on prior exposure to the drug and will affect all patients of the same skin type provided that sufficient bound drug is available for reaction with the appropriate radiation.1 The action spectrum for phototoxicity is UVA, and less often UVB and visible light. Photoallergic drug-induced photosensitivity is immunologically mediated and represents a delayed papular, vesicular or eczematous response.6 It is a lymphocyte-mediated delayed hypersensitivity type 4 reaction. It typically requires previous exposure to the drug or chemical.1,5 Only a proportion of patients taking the drug will develop a reaction. Photoallergic reactions are usually induced by UVA.1,2 The histological appearances of acute phototoxic reactions include conspicuous apoptotic keratinocytes (sunburn cells) which in severe cases may affect the entire epidermis, with variable neutrophil exocytosis, dermal edema, and a perivascular lymphohistiocytic infiltrate with small numbers of neutrophils and eosinophils (Figs 14.16, 14.17).38 Chronic lesions are characterized by hyperkeratosis, hypergranulosis, variable acanthosis and epidermal atrophy, increased melanin pigmentation, melanocyte hyperplasia, and pigmentary incontinence.38 Elastosis and

Anticonvulsant hypersensitivity syndrome It can also be caused by other medications including allopurinol, azathioprine, dapsone, minocycline, sulfonamides, terbinafine, and more recently efalizumab.12–17 The syndrome has been predominantly described in black patients. There is no sex predilection.4 Children may be affected.18–22 Symptoms appear 1 to 8 weeks after starting the offending drug. Clinical features include pyrexia, a maculopapular or erythrodermatous eruption, facial or periorbital edema, strawberry tongue, tender lymphadenopathy, myositis and hepatitis associated with leukocytosis and eosinophilia (Figs 14.18, 14.19).4,5 Less often the cutaneous manifestations include localized or generalized follicular pustules, erythema multiforme, and toxic epidermal necrolysis.4,6,22,23 In patients with the pustular variant, lesions present on the scalp before becoming generalized.8,23,24 Conjunctivitis and/or pharyngitis may also be present.2 Renal, pulmonary (interstitial pneumonitis), and hematological (atypical lymphocytosis) involvement sometimes occur.5 The prognosis of this syndrome is variable.25,26 The majority of patients recover but in those with hepatitis, the mortality is approximately 20%.5,27

Fig. 14.16 Phototoxic drug reaction: this is a very severe reaction. Dermal edema has resulted in subepidermal vesiculation.

Fig. 14.18 Anticonvulsant hypersensitivity syndrome: there is striking facial edema with periorbital accentuation. By courtesy of C.C. Kim, MD, Department of Dermatology, Harvard Medical School, Boston, USA.

Fig. 14.17 Phototoxic drug reaction: note the multiple necrotic keratinocytes (sunburn cells). The blister cavity is cell-free and the dermal papillae are preserved (festooning).

t­ elangiectatic vessels may be conspicuous, and in severely affected patients stellate atypical myofibroblasts can be a feature. Epidermal disorganization and dyskeratosis may also be present.6 The histological appearances of drug induced photoallergic reactions includes spongiosis (often with vesiculation, lymphocytic, and eosinophil exocytosis), accompanied by papillary dermal edema and an upper dermal lymphohistiocytic infiltrate with variable numbers of eosinophils.38

Anticonvulsant hypersensitivity syndrome Adverse drug reactions to phenytoin – which include erythematous maculopapular lesions, erythroderma, acneiform lesions, hypo- and hyperpigmentation, vasculitis, erythema multiforme, and toxic epidermal necrolysis – affect up to 19% of patients taking this drug.1–7 Pseudolymphomatous drug reactions may also occur and these are discussed later in the chapter. A potentially fatal hypersensitivity syndrome develops in approximately 1 in 3000 patients receiving phenytoin.5,6 This is defined by a triad of pyrexia, exanthematous skin rash, and evidence of systemic involvement.6 The acronym DRESS describes drug rash with eosinophilia and systemic symptoms. Administration of other antiepileptics including phenobarbital, carbamazepine, primidone, and lamotrigine may result in an identical ­condition.8–11

Fig. 14.19 Anticonvulsant hypersensitivity syndrome: there is a maculopapular eruption and pustules are present. By courtesy of C.C. Kim, MD, Department of Dermatology, Harvard Medical School, Boston, USA.

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Pathogenesis and histological features The precise etiology of this syndrome is uncertain. It is thought to result from an inability to detoxify arene oxide anticonvulsant metabolites due to absence, possibly genetically determined, of specific hydrolases. The condition has been associated with reactivation of human herpes virus 6 and 7, Epstein-Barr virus, and cytomegalovirus.28–33 The histological features vary from spongiotic dermatitis to those of erythema multiforme or toxic epidermal necrolysis. Pustular lesions are characterized by a subcorneal pustule associated with follicular infundibular dilatation (Figs 14.20, 14.21).8

Lichenoid and interface drug reactions Clinical features Lichenoid drug reactions are clinically similar to lichen planus although lesions are often larger, Wickham's striae are usually not apparent, and mucosal involvement is commonly absent.1–4 In contrast to lichen planus, where lesions are characteristically on the flexural surfaces of the forearms, the legs, and the genitalia, in lichenoid drug reactions the trunk and extremities are more often affected (Figs 14.22, 14.23 ).4,5 The eruption may sometimes be photodistributed and predominantly affect the hands and forearms although other sun-exposed sites can be involved.4,6,7 The latent period between starting the drug and the onset of the eruption is often long, months or even years.4 Atypical features including eczematous and psoriasiform lesions are sometimes seen and bullous or ulcerative variants are occasionally encountered.3,4,8 Postinflammatory hyperpigmentation may be very marked and is

Fig. 14.20 Anticonvulsant hypersensitivity syndrome: this example shows a subcorneal pustule.

Fig. 14.22 Lichenoid drug reaction: lichenoid papules are widely distributed about the patient’s face and upper chest.

Fig. 14.21 Anticonvulsant hypersensitivity syndrome: the underlying dermis shows a superficial dermal perivascular lymphohistiocytic infiltrate with scattered eosinophils.

Fig. 14.23 Lichenoid drug reaction: lichenoid papules on the back. By courtesy of B Al-Mahmoud, MD, Doha, Qatar.

Fixed drug eruptions often persistent. Scarring alopecia is sometimes present and some patients may develop anhidrosis.4 Although many drugs can cause a lichenoid reaction, those of particularly importance include gold, antimalarials such as quinine and quinidine, penicillamine, captopril, various beta-blockers (e.g., propranolol), lithium, thiazide diuretics, furosemide (frusemide),spironolactone, and ethambutol.4,7–19 More recently, the TNF-alpha inhibitors infliximab, adalimumab, and etanercept have been associated with lichenoid eruptions.20–22 Contact with p-phenylenediamine by workers in the photographic color developing process and hairdressers may also result in a cutaneous lichenoid reaction. This is of two types: • Continuous exposure to small amounts results in the appearance of typical lichen planus. • If exposed to a single large dose, the features are those of a lichenoid contact dermatitis.4 Other causes of a contact lichenoid eruption include dental restorative materials, musk ambrette, nickel, and gold.4 Captopril and cinnarizine may cause lichen planus pemphigoides-like eruptions (see bullous drug reactions below).23,24

Histological features The histological features are frequently indistinguishable from typical lichen planus although focal parakeratosis and spongiosis are sometimes present and interface change may be patchy (Figs 14.24–14.26). The epidermis is often thinner and hypergranulosis less marked.15 Cytoid bodies may be found in the upper granular cell layer or even in the stratum corneum.5,7 Sometimes, eosinophils and occasionally plasma cells are found in the dermal infiltrate.5 Focal interruption of the granular cell layer, exocytosis of lymphoid cells into the upper epidermis and a perivascular infiltrate in the deeper dermis are said to be additional helpful diagnostic pointers.7 Photodistributed lichenoid drug reactions are said to more closely resemble idiopathic lichen planus than nonphotodistributed variants.5 The changes that allow distinction from lichen planus are often seen in hypertrophic lichen planus. However, in lichenoid drug eruptions, prominent hyperplasia is hardly ever present. With some drug reactions, interface changes are present in the absence of a background of epidermal lichenoid features (Figs 14.27, 14.28).

Fig. 14.25 Lichenoid drug reaction: In this example, the changes of hypertrophic lichen planuslike lesions are evident. There is pseudoepitheliomatous hyperplasia and a dense upper dermal lymphohistiocytic infiltrate.

Fixed drug eruptions Clinical features Fixed drug eruptions present as one or more circumscribed erythematous to violaceous or brown plaques that show a predilection for the extremities including the hands, feet, and external genitalia (Figs 14.29, 14.30).1–8

Fig. 14.26

Fig. 14.24

Fig. 14.27

Lichenoid drug reaction: there is hyperkeratosis, hypergranulosis with interface change. Note the superficial bandlike infiltrate. The appearances are indistinguishable from idiopathic lichen planus.

Interface drug reaction: more extensive lesion due to propranolol showing hyperkeratosis, widespread apoptosis, upper dermal edema, and a superficial chronic inflammatory cell infiltrate.

Lichenoid drug reaction: focal interface change is present. Eosinophils are conspicuous.

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Fig. 14.30

Fig. 14.28 Interface drug reaction: there are numerous apoptotic keratinocytes and severe interface change is evident.

Fixed drug eruption: early, sharply delineated erythematous lesion. By courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features The  mucous membranes may be affected, either alone or in association with cutaneous manifestations.3 Lesions – which may be pruritic or present with a burning sensation – typically recur at the same site on rechallenge with the offending drug. They usually develop within 30 minutes to 8 hours after ­taking the drug.3 Vesiculation and blistering are common. Resolution is typically marked by postinflammatory hyperpigmentation varying from brown to brown-violet or even black.6 In cases with multiple lesions the multiple pigmented patches result in an appearance described as ‘Dalmatian dog’. Occasionally, the eruption is generalized and resembles toxic epidermal necrolysis.9 Although the number of drugs that are capable of eliciting a fixed reaction is very large, those that are said to be more commonly incriminated include barbiturates, phenylbutazone, ibuprofen, acetyl salicylic acid, sulfonamides, trimethoprim-sulfamethoxazole, tetracyclines, dapsone, phenolphthalein, and quinine.2,3,6

Fig. 14.29 Fixed drug eruption: typical localized brown plaque with a small central blister. By courtesy of the Institute of Dermatology, London, UK.

Fixed drug eruption is unique owing to the precise localization of the eruption and its recurrence at the same site on rechallenge. To understand this process, initial research was directed towards identifying the site of cutaneous memory. Autotransplantation experiments in which normal skin was grafted to a previously affected site and vice versa, followed by rechallenge with the causative drug, produced conflicting results. Some workers found that following challenge, grafted normal skin was unaffected, whereas transplanted previously affected skin developed erythema and became symptomatic.10 Others experienced quite the opposite results.11 Immunofluorescence studies have been equally conflicting. While some authors have documented in vivo bound immunoglobulin and complement in the intercellular region of the epidermis or at its basement membrane, the majority of investigations have been negative.12,13 It seems unlikely, therefore, that humoral immunity has a significant part to play in the pathogenesis of fixed drug eruption. Current research is directed towards understanding the role of cellular immunity. On initial exposure, the drug appears to bind to the epidermal keratinocytes (thereby functioning as a hapten) and is presented by Langerhans cells to lymphocytes within the dermis or in local lymph nodes. This stimulates an effector CD8+ lymphocyte population which, on returning to the epidermis, produces various cytokines including interferon-gamma (IFN-γ) and TNF-α which result in epidermal necrosis.14,15 Keratinocyte death is believed to be mediated by both cytolytic pathways (e.g., perforin, granzyme A, and granzyme B) and FAS-mediated apoptosis.14–16 Resolution of the disease is thought to be due to recruitment of CD4+ T cells into the epidermis which suppress CD8+ T-cell activation and limit cell destruction, possibly via production of IL-10.17 Although the precise mechanism by which memory in fixed drug eruption is achieved is incompletely understood, there is now considerable evidence to suggest that an intraepidermal effector-memory CD8+ T-cell population residing in the epidermis after the initial drug reaction is of particular importance.13–20 Such cells are defined immunohistochemically by expression of CD3, CD45RA, TCR-alpha beta, CD11a, and CD11b, and absence of CD27, CD28, and CD62L.19,21 It has been demonstrated that they remain in a state of activation (CD69+) in the unchallenged state and, following exposure to the drug, rapidly up-regulate IFN-γ expression and induce FAS and FASligand expression, soon followed by epidermal necrosis.16,20 Histologically, the acute fixed drug eruption is characterized by marked basal cell hydropic degeneration, with lymphocyte tagging along the dermoepidermal junction and individual keratinocyte necrosis (Figs 14.31–14.33).22 Marked pigmentary incontinence is typical. Subepidermal vesiculation may be a feature of advanced lesions. Lymphocytes, histiocytes, and neutrophils are evident in the upper dermis. Eosinophils may sometimes be prominent. In late lesions, pigmentary incontinence may be the sole histological finding.

Drug-induced hyperpigmentation

Erythema multiforme Although infectious agents (herpes simplex virus, Mycoplasma species) are the most common cause of erythema multiforme (EM), medications, or a combination of medications and viral infections, are implicated in a subset of patients. Drugs with the strongest association include antibiotics, anticonvulsants, and nonsteroidal antiinflammatory agents.1 Sulfonamides, specifically trimethoprim-sulfamethoxazole, carry the highest relative risk. Other causative antibiotics include aminopenicillins, quinolones, cephalosporins, and tetracyclines. The anticonvulsants associated with EM most often are phenobarbital, carbamazepine, phenytoin, and valproic acid. EM due to a combined viral infections and drug exposure has been described with cytomegalovirus and Epstein-Barr virus.2,3

Stevens-Johnson syndrome and toxic epidermal necrolysis Fig. 14.31 Fixed drug eruption: there is epidermal hyperplasia, interface change, and a superficial dermal chronic inflammatory cell infiltrate.

In contrast to erythema multiforme, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are strongly associated with medication use.1 The profile of implicated drugs is similar to that seen in EM (see above).2 Studies on newer medications cite strong associations for nevirapine, lamotrigine and weaker but significant associations for sertraline, pantoprazole and tramadol.3

Drug-induced hyperpigmentation Clinical features Cutaneous hyperpigmentation is a frequent complication of drug therapy. It may result from increased melanin synthesis or deposition of the drug or its metabolite within the skin.1–5 Heavy metals can also result in skin pigmentation.4 Most often, however, it results from postinflammatory hyperpigmentation.3 Long-term treatment with minocycline might result in usually reversible (types I and II) cutaneous pigmentation.6–13 Three clinical variants of cutaneous minocycline pigmentation are generally recognized (Figs 14.34–14.36): • Type I: blue-black macules localized to areas of scarring and inflammation (e.g., facial acne scars),

Fig. 14.32 Fixed drug eruption: high-power view showing apoptosis and interface change.

Fig. 14.34

Fig. 14.33 Fixed drug eruption: in this example, the infiltrate has a predominantly perivascular distribution.

Minocycline pigmentation: extensive lesions involving the cheek and periorbital region. By courtesy of the Institute of Dermatology, London, UK.

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• Type II (most common): blue-black, brown or slate-gray pigmentation on the shins, ankles and arms,

• Type III: generalized muddy-brown pigmentation which may be

exacerbated on sunlight-exposed regions. A fourth variant affecting the lips and possibly representing a fixed drug eruption has been described.14 Nail pigmentation most often presents as a persistent slate-gray coloration of the proximal nail bed.15 Additional features include longitudinal melanonychia, diffuse nail pigmentation, and photo-onycholysis.15 Minocycline may involve the teeth (causing a green–gray or blue–gray discoloration) predominantly affecting the middle and occasionally the incisal

thirds of the crown.16 Lesions of the oral mucosa are rare although pigmentation has been described on the buccal mucosa, gingiva, tongue, and lips.17–21 The bones underlying the oral cavity (black bone disease) represent the single site most commonly affected by minocycline pigmentation.22 This is best visualized by inspecting the maxillary and mandibular anterior alveolar mucosa.14 The hard palate and lingual alveolar bone are also commonly affected.14 The conjunctiva, sclera, thyroid (black thyroid), aorta, endocardium, and atherosclerotic plaques may also be involved in minocycline pigmentation.23–29 Many other tetracyclines including methacycline and tetracycline hydrochloride have also been associated with cutaneous pigmentation.30, 31 Amiodarone, which is used primarily in the treatment of cardiac arrhythmias, is associated with a phototoxic/photosensitivity reaction in up to 50% of patients.32–38 In addition, cutaneous golden-brown to slate-gray or blue/violaceous pigmentation predominantly affecting the exposed surfaces including the face and the backs of the hands may develop, especially in those receiving high doses over a protracted period of time (Fig. 14.37).32 Pigmentation is also sometimes seen in the sclera and cornea.35 Antimalarials also result in abnormal skin pigmentation.39–42 Mepacrine (quinacrine) typically produces a yellow coloration although localized blue–black mucocutaneous lesions have been described (Figs 14.38, 14.39).42 Chloroquine and hydroxychloroquine cause yellow–brown to gray

Fig. 14.35 Minocycline pigmentation: these blue–black lesions have developed in a patient with pyoderma gangrenosum. By courtesy of the Institute of Dermatology, London, UK.

Fig. 14.37 Amiodarone pigmentation: note the slate-gray discoloration on the forehead, a characteristic site. By courtesy of the Institute of Dermatology, London, UK.

Fig. 14.36 Minocycline pigmentation; typical pigmentation affecting the shin. By courtesy of the Institute of Dermatology, London, UK.

Fig. 14.38 Mepacrine pigmentation: a yellow discoloration is characteristic. By courtesy of the Institute of Dermatology, London, UK.

Drug-induced hyperpigmentation

Pathogenesis and histological features

Fig. 14.39 Mepacrine pigmentation: in this patient the drug resulted in black lesions. By courtesy of the Institute of Dermatology, London, UK.

­ igmentation.2,39–41 Sun-exposed skin is predominantly affected, although p mucosal pigmentation may also occur.43 In addition to causing photosensitivity and contact dermatitis, chlorpromazine therapy (particularly when protracted and in high doses) can result in cutaneous pigmentation, especially on sun-exposed skin such as the face, dorsum of the hands, and the neck.2,44–47 Patients may present with a goldenbrown, tanned appearance while others develop a slate-gray, bluish or purple appearance. The cornea and lens of the eye can also be involved.2 Long-term treatment with imipramine may result in photodistributed hyperpigmentation affecting the face, neck, ‘V’ of chest, arms, and hands (Fig. 14.40).48–50 The coloration varies from golden-brown to blue-gray or slate-gray. The irises may also darken. Photodistributed blue-gray pigmentation has been documented following treatment with desipramine.51 Heavy metals including gold, silver, and mercury can all result in cutaneous pigmentation (see below).

The histological features of minocycline pigmentation are variable.7,10,11,14 In types I and II variants, golden-brown to brown–black granules are found predominantly within macrophages distributed mainly around the vasculature and sweat gland coils (Fig. 14.41). The pigment, which fluoresces yellow under ultraviolet light, stains positively with both Masson-Fontana and Perl’s Prussian blue reactions in type II variants (Figs 14.42, 14.43).11 The pigment is periodic acid-Schiff (PAS) negative. In contrast, in type I, the pigment only stains with Perl's reaction. It is believed to represent minocycline or its breakdown product chelated with hemosiderin, ferritin or iron.7 Calcium, sulfur, and chlorine are also present but melanin is absent.11 Melanocytes and the epidermis show no increase in melanin pigmentation in types I and II variants. Type III hyperpigmentation is characterized by an increase in epidermal basal cell melanin pigmentation.6 The Perl’s stain is negative. Minocycline pigmentation of the subcutaneous fat has recently been described in the clinical setting of type II disease.52,53 Histologically, there is pigment within macrophages and giant cells in the subcutaneous fat, with positive staining for Masson-Fontana and variable staining with Perl’s reaction. One study also described green–gray nonrefractile globules within macrophages in the fat.53 Histologically, amiodarone pigmentation is characterized by macrophages containing PAS-positive, yellow–brown lipofuscin-like granules located in a perivascular distribution (Figs 14.44, 14.45).32 Melanin pigmentation of the

Fig. 14.41 Minocycline pigmentation: note the presence of perivascular granular brown pigment.

Fig. 14.40 Imipramine pigmentation: note the intense brown pigment of the hands and forearms in comparison with the chest. By courtesy of L. Cohen, MD, Cohen Dermatopathology, Massachusetts, USA.

Fig. 14.42 Minocycline pigmentation: the pigment stains positively with Masson-Fontana.

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Fig. 14.43 Minocycline pigmentation: the pigment also stains with Prussian blue.

Fig. 14.44 Amiodarone pigmentation: pigmented macrophages are present in a perivascular distribution.

Fig. 14.46 Imipramine pigmentation: typical golden-brown granules. Note that the Prussian blue reaction is negative. By courtesy of L. Cohen, MD, Cohen Dermatopathology, Massachusetts, USA.

epidermis is not increased; indeed its absence in involved skin has recently been documented.38 By electron microscopy, the granules are located within lysosomes.33,37 Lamellar myelin bodies may also be identified.23 Similar inclusions may be found in the hepatocytes, Kupffer cells, pulmonary macrophages, and neutrophils. In mepacrine (quinacrine) pigmentation, yellow–brown pigment is found within the cytoplasm of histiocytes throughout the dermis.42 The pigment is weakly positive with the Perl’s Prussian blue reaction for iron and is Masson-Fontana negative.38,43 The histological findings in hydroxychloroquine-related pigmentation have been described as yellow–brown granular deposits within macrophages and extracellularly.54 These granules are nonrefractile and stain positively with Masson-Fontana and are negative for iron.54 Histologically, chlorpromazine hyperpigmentation is characterized by golden-brown macrophage-bound granules surrounding the superficial vasculature. The granules are positive with the Masson-Fontana reaction but do not stain with Perl’s Prussian blue.47 Ultrastructurally, the pigment is lysosome bound and present in endothelial cells, fibroblasts, Schwann, and smooth muscle cells, in addition to macrophages.44,45 Increased melanin also contributes to the cutaneous pigmentation.44 Histologically, imipramine and desipramine hyperpigmentation contain Masson-Fontana positive golden-brown granules within the upper dermis, lying both free and within macrophages (Fig. 14.46).48,49,51 Perl’s Prussian blue is negative. Ultrastructurally, histiocytes contain melanosomes in addition to lysosomal-bound electron-dense granules.48

Vasculitic drug reactions

Fig. 14.45 Amiodarone pigmentation: high-power view.

Adverse drug reactions are a common cause of vasculitis.1,2 An immune complex mechanism mostly represents the pathogenesis in the majority of cases. A wide range of drugs has been implicated, including anti-infective agents, cancer chemotherapeutic agents and adjuvants, psychoactive and cardiovascular drugs, diuretics, anticoagulants, beta-adrenergic receptor agonists, and anticonvulsants.2 The more important agents include trimethoprim, penicillin, sulfonamides, NSAIDs, and aspirin.3 Other implicated drugs include cimetidine, clarithromycin, coumadin, furosemide (frusemide), hydralazine, ibuprofen, iodides, phenacetin, phenothiazines, procainamide, rifampin, propythiouracil, and streptokinase (Figs 14.47, 14.48).4–13 More recently, antiTNF-alpha therapies have been linked to vasculitic reactions.14,15 Granulomatous vasculitis has been described following treatment with chlorothiazide, allopurinol, phenytoin, and carbamazepine.4,16–18

Granulomatous drug reactions

Fig. 14.47 Vasculitic drug reaction: hemorrhagic papules and plaques with central necrosis complicating treatment with propylthiouracil. By courtesy of M. Mailberger, MD, Virginia Commonwealth University, Richmond, Virginia, USA.

Fig. 14.49 Purpuric drug reaction: there is massive subepidermal edema with red cell extravasation.

reaction.2,3 This reaction pattern may also be related to a variety of systemic illnesses including rheumatoid arthritis, hepatobiliary disease, diabetes mellitus, Crohn’s disease, and chronic infections such as hepatitis C, herpes simplex/varicella-zoster, Epstein-Barr virus (EBV), and HIV.2 Patients present with erythematous to violaceous, nonpruritic, irregular and sometimes annular papules or plaques predominantly affecting the inner arms, inner thighs, and the groins (Fig. 14.50).1 Erythroderma in a case of anticonvulsant-induced hypersensitivity syndrome has also been described.4

Histological features

Fig. 14.48

Histologically, the eruption is characterized by an interstitial infiltrate of lymphocytes, histiocytes, eosinophils, plasma cells, and multinucleate giant cells, sometimes associated with increased dermal mucin and showing more than a superficial resemblance to interstitial granuloma annulare (Figs 14.51, 14.52). Fragmentation of collagen fibers and elastic tissue is commonly evident and phagocytosis of connective tissue debris by giant cells is typically seen (Figs 14.53, 14.54). Discrete granulomata may also be identified and granulomatous vasculitis has been documented.5 Flame figures and ChurgStrauss-like granulomata have also been described.6,7 Atypical lymphocytes with hyperchromatic, irregular and variably enlarged nuclei showing

Vasculitic drug reaction: there is acute vasculitis with thrombosis.

Purpuric drug reactions Clinical features Purpura may be a manifestation of an adverse drug reaction. Causes include NSAIDs, diuretics, meprobamate, zomepirac sodium, ampicillin, pseudoephedrine, linezolid, and lidocine/prilocaine cream.1–4

Histological features The histological features are those of red cell extravasation in the absence of changes of vasculitis (Fig. 14.49).

Granulomatous drug reactions Clinical features Interstitial granulomatous drug reactions are rare and have been associated with a number of drugs including calcium channel blockers, ACE inhibitors, beta-blockers, lipid-lowering agents, diuretics, NSAIDs, antihistamines, anticonvulsants, and antidepressants.1 More recently, IL-1 inhibitor (anakinra) and adalimumab have been associated with an interstitial granulomatous

Fig. 14.50 Lichenoid and granulomatous dermatitis: note the flat-topped lichenoid papules. This reaction developed during rituximab therapy. By courtesy of J. Francis, MD, Virginia Commonwealth University, Richmond, Virginia, USA.

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Fig. 14.53 Fig. 14.51

Granulomatous drug reaction: there is extensive elastophagocytosis (elastic van Gieson).

Granulomatous drug reaction: there is a marked infiltrate involving the full thickness of the dermis.

Fig. 14.54 Granulomatous drug reaction: phagocytosis of collagen may also be seen (Masson’s trichrome).

Fig. 14.52 Granulomatous drug reaction: in this example there is an obvious interstitial distribution reminiscent of granuloma annulare.

e­ pidermotropism are present in up to 50% of cases.1 The changes of interface dermatitis, sometimes with an associated lichenoid infiltrate, are found in the majority of cases.1,5

Differential diagnosis Interstitial granulomatous drug reactions must be distinguished from granuloma annulare and systemic disease-associated lesions as described above. Granuloma annulare is not usually associated with interface dermatitis, and necrobiosis and mucin deposition are not features of granulomatous drug reactions. Systemic disease-associated granulomatous dermatitis is usually associated with vasculitic and/or thrombotic phenomena.7 In cases where significant lymphoid atypia is present, cutaneous T-cell lymphoma enters the differential diagnosis. When elastophagocytosis is marked, granulomatous slack skin or an elastolytic granuloma may be important diagnostic considerations.

Drug-induced erythema nodosum This topic is discussed in the chapter on panniculitis.

Drug-induced alopecia Drug-induced alopecia is usually reversible, predominantly nonscarring, and affects females more often than males.1–4 Anagen effluvium, in which hair growth stops due to cessation of mitotic activity, is a common feature of anticancer therapy and often develops days or a few weeks after starting the drug.1,2 The scalp and beard areas, which contain a high percentage of anagen follicles, are particularly affected. It especially complicates combination chemotherapy and is likely to be severe.5 Although all anticancer drugs may be associated with some degree of alopecia, particular offenders include bleomycin, cyclophosphamide, dactinomycin, daunorubicin, doxorubicin, 5-fluorouracil, ifosfamide, and vindesine.1,2 There is some variation in drug effect. Some cause alopecia in all individuals whereas others affect only a minority of patients.5 Telogen effluvium, in which hairs are transformed into the telogen phase, develops several months after commencing therapy.1 Anticoagulants, including

Bullous drug reactions heparin and warfarin and dextran sulfate, cause telogen effluvium in up to 50% of patients.3,5–11 Other causes include antithyroid drugs such as iodine, thiouracil and carbimazole, oral contraceptives, lithium, interferons and retinoids.5,12,13 Alopecia areata may develop as a consequence of TNF-alpha inhibitors such as adalimumab and etanercept.14,15

Drug-induced lupus erythematosus Clinical features Drug-induced systemic lupus erythematosus was first described as a complication of hydralazine.1–8 It has also been reported in association with procainamide, quinidine, sulfasalazine, chlorpromazine, penicillamine, methyldopa, carbamazepine, acebutalol, isoniazid, captopril, propylthiouracil, and minocycline.2,3 Therapy with TNF-alpha inhibitors has been associated with a lupus-like syndrome.9,10 With the exception of hydralazine and procainamide (high risk) and quinidine (medium risk), the other associations are low risk.2 Laboratory investigations reveal anti-Ro, anti-La, and antinuclear antibodies (ANA) in the majority of cases.1 Subacute cutaneous lupus erythematosus-like features have been described following treatment with terbinafine.11–13 More recently, localized cutaneous lupus lesions were described occurring at the site of IFN injection.14 Cutaneous lesions including malar erythema, discoid lesions, photosensitivity, oral ulceration, and alopecia are rare.2 Anti-TNF-alpha therapy-induced lupus may result in a higher incidence of cutaneous lesions, hypocomplementemia, and positive serology for double-stranded DNA as compared to other medications.13 Symptoms typically develop months to years after initiating therapy.15 Diagnostic criteria have been defined as follows:2 • continuous treatment with the suspected drug for 1 month or longer, • common presenting symptoms include arthralgias/arthritis, myositis, serositis, malaise and fever, • antihistone antibodies frequent, particularly IgG anti-([H2A-H2B]-DNA), • most importantly, clinical improvement within days or weeks after stopping the suspected drug.

Histological features The histological features of cutaneous lesions are indistinguishable from those seen in the idiopathic forms.16

Bullous drug reactions Blisters may develop within the setting of an adverse drug reaction either as a consequence of severe spongiosis or marked interface change or they may reflect drug-related autoimmune bullous disorders (Fig. 14.55). In this section, only the last are discussed. These include drug-induced linear IgA disease, bullous pemphigoid, epidermolysis bullosa acquisita, pemphigus variants, and drug-induced pseudoporphyria. Many alleged drug reactions are single case reports, particularly in patients taking multiple medications. It is often difficult to determine which associations are therefore coincidental and which are genuine. In occasional reports, recrudescence following reexposure to the offending agent has been documented. The precise mechanism of drug-induced blistering is unknown, although multiple factors have been suggested:1 • direct toxicity to basement membrane constituents or intercellular junctions with resultant autoantibody production, • the drug may function as a hapten, • the drug may be antigenically similar to a basement membrane or intercellular junction constituent, • perturbation of the immune system with inappropriate production of anti-basement membrane antibodies, • drug-induced abnormality of cell membrane calcium metabolism.

Drug-induced linear IgA disease Drug-induced linear IgA disease is most often associated with intravenous therapy with vancomycin.1–7,8–10 Similar eruptions, however, have also been

Fig. 14.55 Bullous drug reaction: this subepidermal blister arose against a background of an exanthematous drug reaction.

described following treatment with trimethoprim- sulfamethoxazole, penicillin, phenytoin, somatostatin, lithium, amiodarone, captopril, cefamandole, ceftriaxone, cyclosporin, IL-2, IFN-alpha, penicillin, amoxicillin, vigabatrin, and diclophenac.2,11–21 Cutaneous manifestations of vancomycin-induced linear IgA disease include pruritic, erythematous, urticarial, targetoid and bullous lesions with a predilection for the trunk, extremities, palms, and soles (Figs 14.56, 14.57).1 Morbilliform lesions have also been described.8 Mucosal involvement is present in up to 40% of cases. As such, there can be considerable clinical overlap with EM and TEN.2,9,10 Laryngeal involvement has been documented.20

Pathogenesis and histological features By definition, linear IgA deposition along the basement membrane region is present in all cases (Fig. 14.58). C3 is seen in approximately 20% of cases.7 Linear IgG may also very exceptionally be present, although distinction from drug-induced bullous pemphigoid can then be problematical.3,17 Such cases may, in fact, represent examples of drug-induced IgA-mediated bullous pemphigoid.21 Circulating IgA anti-basement membrane zone antibodies are found in 25% of cases.1 Split skin studies predominantly localize to the floor of the blister cavity.1,2 By immunoelectron microscopy, the results

Fig. 14.56 Drug-induced linear IgA disease: these blisters developed following treatment with vancomycin. By courtesy of B.A. Solky, MD, Department of Dermatology, Harvard Medical School, Boston, USA.

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Fig. 14.57 Drug-induced linear IgA disease: oral lesions were also present. By courtesy of B.A. Solky, MD, Department of Dermatology, Harvard Medical School, Boston, USA.

Fig. 14.58 Vancomycin-induced linear IgA disease: immunofluorescence showed strong basement membrane deposition of IgA.

Fig. 14.59 Vancomycin-induced linear IgA disease: this case showed a neutrophil-rich subepidermal blister.

Fig. 14.60 Vancomycin-induced linear IgA disease: the adjacent skin showed neutrophil dermal papillary microabscesses.

are heterogeneous, IgA having been detected within the lamina lucida, lamina densa, and in the sublamina densa.18–20 Western immunoblotting has detected a number of antigens including a 230-kD antigen (bullous pemphigoid antigen 1), a 97-kD antigen (an anchoring filament protein) and also a 250-kD antigen corresponding to type VII collagen.19,20 Histologically, a neutrophil-rich subepidermal blister is seen in the majority of cases but sometimes eosinophils are conspicuous (Figs 14.59–14.61).2

Drug-induced bullous pemphigoid Clinical features A variety of drugs including captopril, ciprofloxacin, chloroquine, furosemide (frusemide), ibuprofen, mefenamic acid, nifedipine, penicillamine, penicillins, phenacetin, sulfasalazine, spironolactone, and enoxaparin have been incriminated in alleged drug-induced bullous and mucosal pemphigoid.1–14 Of these, antirheumatics, cardiovascular drugs, and antimicrobial drugs are the most important.6 Penicillamine is among the most commonly incriminated (mucosal more than bullous), usually in rheumatoid arthritis patients.6,15–17 Furosemide (frusemide) is believed to be an important cause of drug-induced bullous pemphigoid although recently this has been challenged, the author suggesting that diagnoses of pseudoporphyria or epidermolysis

Fig.14.61 Vancomycin-induced linear IgA disease: conspicuous eosinophils may raise suspicion for bullous pemphigoid if the clinical information is unavailable.

Psoriasiform drug reactions bullosa acquisita may be more appropriate.6,18 The ACE inhibitors, captopril and enalapril, have both been associated with immunologically proven bullous pemphigoid.2,8 The penicillins including amoxicillin and procaine penicillin G are the most frequently implicated antibiotics.6 Clinically, drug-induced bullous pemphigoid is similar to idiopathic disease although the lesions are often polymorphic, mimicking other drug-induced bullous dermatoses such as erythema multiforme, eczematous dermatitis, and porphyria cutanea tarda.6 In drug-induced disease, mucous membranes are often involved, thereby blurring the distinction between bullous and mucosal variants of pemphigoid. In some patients there appears to be overlap between bullous pemphigoid and pemphigus vulgaris.6

Histological features Drug-induced variants are characterized by linear IgG and C3 along the basement membrane region on direct immunofluorescence.7,8 By indirect immunofluorescence, the antibodies bind to the epidermal side (roof) of split skin.2,5,6 Western immunoblotting has demonstrated that the antibodies react with both the 230 kD and 180 kD bullous pemphigoid antigens.2,3 Histologically, drug-induced variants are similar to typical bullous pemphigoid, being characterized by an eosinophil-rich subepidermal blister.

Drug-induced epidermolysis bullosa acquisita Drug-induced epidermolysis bullosa acquisita has been described following treatment with granulocyte–macrophage colony stimulating factor (GM-CSF) and in a patient receiving vancomycin and gentamicin therapy.1,2 In both patients, the blisters were subepidermal and eosinophil rich; direct immunofluorescence disclosed linear IgA and IgG deposits at the basement membrane region. Split skin indirect immunofluorescence in the former patient labeled the floor of the blister cavity and by immunoelectron microscopy the deposits were localized to the lamina densa and the sublamina densa region.1 In the latter patient, IgG antibodies against type VII collagen were recognized by an enzyme-linked immunosorbent assay (ELISA).2 An epidermolysis bullosa acquisita-like reaction has also been described after treatment with penicillamine. Histological features included a pauci-inflammatory subepidermal blister. Linear deposition of C3, IgG and IgM are seen on direct immunofluorescence, and IgG labels to the base of the blister on salt-spilt direct immunofluorescence.3 A significant number of cases of vancomycin-induced linear IgA disease are characterized by antibodies which label the floor of split skin on indirect immunofluorescence. Many of these might represent examples of drug-induced epidermolysis bullosa acquisita.2 An epidermolysis bullosa acquisita-like blistering dermatosis has been described with penicillamine therapy but this has not been confirmed with immunofluorescent or molecular data.3

a change in prescribing habits to non-thiol related drugs, vulgaris-type cases are more frequently seen.4 In most cases of imiquimod-induced pemphigus foliaceus, disease is localized to the sites of application, although there is one report of both localized and distant lesions.16 In the setting of radiotherapy, all patients developed pemphigus at the site of radiation.18–21 One patient also had distant lesions.22

Pathogenesis and histological features Histologically, drug-induced and idiopathic variants are indistinguishable.23 Intercellular IgG and circulating antibodies are variable in drug-induced pemphigus, although in a series of 10 patients all had positive direct immunofluorescence and 80% had circulating antibodies.4 Such antibodies may recognize desmoglein 3 and/or 1.1,22

Drug-induced pseudoporphyria Clinical features Pseudoporphyria is a rare blistering disease which clinically and histologically mimics porphyria but which develops in the setting of normal porphyrin metabolism (Fig. 14.62). There are many causes including drugs, chronic renal failure usually in the setting of dialysis, excessive sun exposure and UVA. It has also been described following excessive use of sunbeds.1–15 The most common medications include diuretics such as furosemide (frusemide) and NSAIDs, particularly naproxen. Other drugs include isotretinoin and the oral contraceptive. More recently imatinib (tyrosine kinase inhibitor) and voriconazole have been implicated.14,15

Pathogenesis and histological features The pathogenesis of pseudoporphyria is unknown but it may (at least in some patients) represent a phototoxic photosensitivity reaction.12 Histologically, pseudoporphyria is characterized by a subepidermal cellfree blister, typically with preservation of the dermal papillae (festooning). By immunofluorescence, immunoglobulin (most commonly IgG) is present at the dermoepidermal junction and also outlining the superficial dermal vasculature.

Psoriasiform drug reactions Clinical features Psoriasis and psoriasiform dermatoses can be caused by a number of drugs including lithium, beta-blockers, NSAIDs, synthetic antimalarials, and tetracycline.1–5 Drug-induced disease may have variable presentations including:1,2

Drug-induced pemphigus Clinical features Pemphigus may be related to a wide range of drugs, either directly as a causative factor or indirectly as a precipitating or triggering factor.1–14 The range of drugs is quite wide but many belong to the thiol group of compounds (characterized by the presence of an -SH group) including penicillamine, captopril, bucillamine, and thiopronine.1,4 Thiol-induced acantholysis is mediated by both immune and direct biochemical mechanisms.5 Penicillamine most often induces pemphigus in the setting of rheumatoid arthritis.6 Although foliaceus is most commonly encountered, vulgaris, erythematosus, and herpetiform variants may occur.2,6–8 Other drugs that contain sulfur, which can also form -SH groups, include gold compounds, penicillins, rifampicin, and cephalosporins.4 Topical application of imiquimod has been reported to cause pemphigus foliaceus and vegetans.15–17 Additionally, both pemphigus foliaceus and vulgaris lesions have been described as a consequence of radiotherapy.18–21 Clinically, drug-induced pemphigus can resemble vulgaris, foliaceus, erythematosus, and vegetans variants, the first being most often encountered.4 In the older literature, foliaceus variants were typical but with

Fig. 14.62 Pseudoporphyria: trauma-induced blisters on the backs of the hands and fingers are characteristic. By courtesy of the Institute of Dermatology, London, UK.

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• exacerbation of pre-existing psoriasis, • induction of new lesions in uninvolved psoriatic skin, • precipitation of psoriasis de novo, • resistance to treatment.

Lithium-induced psoriasis varies from exacerbation of pre-existing psoriasis to development of new disease.2 Manifestations vary from plaque disease to generalized pustular psoriasis, palmoplantar pustulosis, scalp psoriasis, and psoriatic erythroderma.2,6–8 Latency varies from 1 week to years or more.2 Beta-blockers (e.g. propranolol, oxprenolol, pindolol, alprenolol, and the now discontinued practolol), antimalarials (e.g. chloroquine and hydroxychloroquine) and NSAIDs (e.g. indometacin, phenylbutazone, oxyphenylbutazone, and ibuprofen) can also induce psoriasiform eruptions or result in exacerbations and flares.1,2,9–15 The increasing use of TNF-alpha inhibitors is associated with new-onset or exacerbated psoriasiform eruptions.16–21 Most patients develop palmoplantar pustulosis or plaque-type psoriasis.18–20 The average time to onset of lesions is 6–10 months, although the range is variable.16–21 It is speculated that inhibition of TNF-alpha increases levels of type 1 interferons which result in psoriasiform lesions.21 A large number of other drugs have been linked with exacerbation of psoriasis or development of new disease. These include the antifungal agent terbinafine, antibiotics such as penicillin and tetracycline, digoxin, amiodarone, IFN-α, recombinant IFN-α, and erlotinib (tyrosine kinase inhibitor).2,22–31

Fig. 14.64 Psoriasiform drug reaction: the capillaries in the dermal papillae are tortuous and dilated.

Histological features The histological features overlap lichen simplex chronicus and psoriasis. Occasionally, they are indistinguishable from psoriasis vulgaris (Figs 14.63– 14.65). Psoriasis secondary to TNF-alpha inhibitors may also demonstrate lichenoid inflammation and spongiosis.21

Pityriasiform drug reactions Clinical features Pityriasiform drug reactions may be particularly caused by ACE-inhibitors and gold.1–4 Less often, terbinafine, omeprazole, benfluorex, arsenicals, bismuth compounds, isotretinoin, naproxen, acetaminophen, barbiturates, and bacille Calmette-Guérin (BCG) therapy have been implicated.5–11 The tyrosine kinase inhibitor imatinib has been associated with pityriasiform dermatitis.12–14 Patients present with small erythematous lesions accompanied by a peripheral scale, which may follow Langer's lines, giving rise to the typical ‘fir tree’ appearance. The trunk and extremities are predominantly affected.

Fig. 14.65 Psoriasiform drug reaction: neutrophils are present in the stratum corneum.

Histological features

Fig. 14.63 Psoriasiform drug eruption: there is confluent parakeratosis with elongated, broadened, and partially fused rete ridges.

Histologically, pityriasiform drug reactions are typically characterized by patchy parakeratosis, focal spongiosis with lymphocytic exocytosis, and a superficial perivascular lymphocytic infiltrate, sometimes associated with red cell extravasation (Fig. 14.66)3,6 On occasions, clinically typical pityriasiform drug eruptions may demonstrate a more psoriasiform histology.9

Pustular drug reactions

Fig. 14.66 Pityriasiform drug reaction: there is a focal parakeratotic scale associated with acanthosis and spongiosis. A perivascular chronic inflammatory cell infiltrate surrounds the superficial vasculature.

Pustular drug reactions Clinical features Drug-induced pustules are a manifestation of reactions to corticosteroids, anabolic steroids, oral contraceptives, isoniazid, haloperidol, and lithium therapy (Fig. 14.67).1 In addition, they are a feature of the halogenodermas (see below). Pustules are also the main feature of acute generalized exanthematous pustulosis (AGEP, toxic pustuloderma) (Fig. 14.68). This rare condition is characterized by the sudden onset of numerous small, nonfollicular pustules arising against a background of pruritic or burning edematous erythroderma.2–11 The eruption often starts on the face or in the intertriginous regions but soon becomes generalized.3 The mucous membranes are affected in a minority of patients.3 Facial edema, purpura, vesicles, blisters, and erythema multiformelike lesions have also been described.3,6 Pyrexia is usually present. Although in the majority of patients there is no history of significant previous skin disease, in some there is a background of psoriasis.3 The eruption usually resolves rapidly and is followed by widespread desquamation.9 Peripheral leukocytosis with high neutrophil levels and sometimes eosinophilia can be present.3,9

Fig. 14.67 Pustular drug reaction: numerous pustules are present on an erythematous background. By courtesy of the Institute of Dermatology, London, UK.

Fig. 14.68 Acute generalized exanthematous pustulosis: tiny pustules are evident. There is intense erythema. By courtesy of B.A. Solky, MD, Department of Dermatology, Harvard Medical School, Boston, USA.

While this disorder may occur as a feature of mercury toxicity or follow a viral infection (particularly enteroviruses) or spider bite, in the majority of cases it represents an adverse drug reaction.3,12,13 In most patients, the eruption has followed antibiotic therapy including penicillin, amoxicillin, ampicillin, metronidazole, trimethoprim, and erythromycin.3,9 Analgesics (e.g. acetaminophen), antiepileptics (e.g. carbamazepine), antidiabetics (e.g. carbutamide), antifungals (e.g. terbinafine), antimalarials (e.g. hydroxychloroquine), and many other drugs have also been implicated.3,11–19 The condition often develops rapidly following the administration of the drug – sometimes in a matter of hours.3,7

Histological features The pustules are present in a subcorneal and/or intraepidermal location and sometimes contain a few acantholytic keratinocytes in addition to large numbers of neutrophils (Figs 14.69, 14.70).3,9 A background of spongiosis is usually evident. The dermal papillae are often edematous and occasionally subepidermal vesiculation is a feature. A perivascular infiltrate of lymphocytes and histiocytes with conspicuous neutrophils and variable numbers of eosinophils is generally present in the superficial dermis. Leukocytoclastic vasculitis may be a feature in a significant proportion of cases.3,9,11

Fig. 14.69 Acute generalized exanthematous pustulosis: there is a subcorneal pustule. The dermis is intensely inflamed.

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Fig. 14.70

Fig. 14.71

Acute generalized exanthematous pustulosis: high-power view of pustule. Note the acantholysis.

Drug-induced pseudolymphoma: this patient developed a maculopapular eruption following treatment with phenytoin.

Differential diagnosis

Nonanticonvulsant-related pseudolymphomatous reactions present similarly with single lesions or multiple papules, plaques, and nodules. Associated drugs include antihypertensives, antidepressants, tranquilizers, beta-blockers, calcium channel blockers, diuretics, NSAIDs, and antibiotics.2,18–22 Sézary’s syndrome-like features have also been documented.23 Lymphomatoid contact dermatitis is much less common and usually represents a T-cell reaction to a contact allergen that histologically shows features reminiscent of mycosis fungoides.2,24–31 Patients present with pruritic, localized to generalized scaly papules and plaques.2 A number of antigens have been incriminated including matchbox striking surface antigens, ethylenediamine dihydrochloride, isopropyl-diphenylenediamine, phosphorus, nickel, cobalt naphthenate, and para-phenylenediamine. B-cell lymphomatoid drug reaction is rare but has been described in association with fluoxetine hydrochloride and amitriptyline hydrochloride.2,21,22 Patients present with solitary nodules, multiple infiltrative plaques, or multiple papules. B-cell lymphomatoid contact reactions may be seen with gold and nickel earrings. Patients present with one or more firm, erythematous nodules at the site of piercing.32–34 B- and, less commonly, T-cell pseudolymphomatous reactions may develop within tattoos.35–39 Papules and nodules localized to the tattoo occur months to years after tattoo placement. The most common culprit is red pigment, although reactions to blue and green dyes have been reported.38,39 Both metals and organic synthetic pigments are implicated as antigens in such reactions.

The differential diagnosis includes pustular psoriasis, subcorneal pustular dermatosis, IgA pemphigus, pustular necrotizing angiitis, and acute generalized pustular bacterid.20,21

Ichthyosiform drug reactions Clinical features Exceptionally, acquired ichthyosis following lipid-lowering agents (including triparanol and diazacholesterol) and kava consumption has been documented.1–3 The clinical features may resemble ichthyosis vulgaris or lamellar ichthyosis.

Histological features In ichthyosis vulgaris-like drug-induced variants, there is mild hyperkeratosis associated with a diminished to absent granular cell layer. A mild superficial perivascular lymphohistiocytic infiltrate with occasional eosinophils may be present. In the lamellar ichthyosis-like variant, there is marked hyperkeratosis, mild acanthosis, and a normal or thickened granular cell layer.

Drug-induced pseudolymphoma Clinical features

Pathogenesis and histological features

Drug-induced pseudolymphoma includes pseudolymphomatous reactions to systemically administered medications (lymphomatoid drug eruption) and the much less frequent contact variant associated with locally administered agents (lymphomatoid contact dermatitis).1–3 Lymphomatoid drug eruptions are commonly a T-cell type, although B-cell lymphomatoid drug eruptions are also recognized. T-cell variants are divided into anticonvulsant-related and nonanticonvulsant-related variants.2 Anticonvulsant-related T-cell lymphomatoid drug eruption typically develops within weeks or months of commencing treatment. Patients present with pyrexia, lymphadenopathy, and an eruption of single or generalized lesions comprising erythematous, morbilliform maculopapules, plaques, nodules or tumors often associated with leukocytosis, circulating Sézary cells, eosinophilia, hepatosplenomegaly, and variable liver dysfunction (Fig. 14.71).2,4–16 Vesicles and purpuric lesions have also been described.14 Sézary’s syndromelike features may rarely be seen.17 A number of anticonvulsants have been implicated including phenytoin, primidone, mephenytoin, carbamazepine, Phenobarbital, and trimethadione.2

The pathogenesis of lymphomatoid drug reactions is not completely understood, but is thought to be secondary to immune dysregulation. Studies show that medications implicated in drug-induced pseudolymphoma can induce proliferation of T cells and inhibit suppressor T cells, both in vivo and in vitro.40,41 This may lead to an increase in helper T cells as well as B cells, resulting in T-cell and B-cell pseudolymphoma, respectively. Drug-induced T-cell pseudolymphoma most often presents as a dense superficial perivascular or bandlike infiltrate composed of lymphocytes, histiocytes, and atypical lymphoid cells with irregular, enlarged, and hyperchromatic nuclei (Figs 14.72–14.76).42 Cerebriform variants may be seen and there is often associated epidermotropism. Pautrier-like microabscesses reminiscent of mycosis fungoides, however, are only occasionally identified. Eosinophils are frequently evident and often the epidermis shows significant spongiosis. Giant cells, collections of histiocytes, and epithelioid granulomata may also be evident. Dense nodular and tumor-like variants more suggestive of pleomorphic T-cell lymphoma may also be encountered (Figs 14.77–14.79). A follicular mucinosis-like variant has rarely been described.22

Drug-induced pseudolymphoma

Fig. 14.72 Drug-induced pseudolymphoma: there is an atypical superficial perivascular lymphocytic infiltrate. Note the marked epidermotropism. The histological features are suggestive of mycosis fungoides.

Fig. 14.74 Carbamazepine-induced pseudolymphoma: in this example, there is a dense bandlike upper dermal lymphocytic infiltrate.

Fig. 14.73 Drug-induced pseudolymphoma: the lymphocytes are surrounded by a welldeveloped retraction artifact and there is a small Pautrier microabscess.

By immunohistochemistry, the infiltrate consists of CD3+ T cells. CD4+ cells most often outnumber CD8+ forms, and CD20+ B cells are either extremely sparse or absent. A CD8+ variant has, however, been recently described following treatment with gemcitabine.35 CD30 expression with resultant confusion with an anaplastic large cell lymphoma has exceptionally been described.11,43–45 Reported T-cell receptor gene rearrangement studies have disclosed a clonal population in only a small minority of patients.5,6,12,14 Lymphomatoid contact dermatitis most often is reminiscent of mycosis fungoides and is characterized by a superficial dermal bandlike infiltrate composed of atypical lymphocytes and histiocytes with variable lymphocyte epidermotropism. The epidermis is typically acanthotic, and spongiosis may sometimes be present. Immunohistochemical analysis has been reported in a small number of cases. The atypical lymphocytes usually express CD3 and CD4 with no loss of CD5 and CD7. A CD8 predominant variant has been documented.29

Fig. 14.75 Carbamazepine-induced pseudolymphoma: there is marked lymphocytic atypia. Cerebriform cells are present. The features are very suggestive of plaque stage mycosis fungoides.

In the limited number of cases in which T-cell receptor (TCR) gene rearrangements have been documented, two have disclosed a polyclonal pattern while one has displayed a weak monoclonal band.26,29,31 B-cell lymphomatoid drug reactions are characterized by a nodular or ­diffuse pandermal infiltrate, often accompanied by extension into the subcutaneous fat. The infiltrate consists of lymphocytes and histiocytes with variable numbers of plasma cells and eosinophils. Mitoses are sometimes numerous. Blasts are often present and lymphoid follicles with germinal centers may be evident. By immunohistochemistry, the majority of the lymphocytes are CD20+ B cells although a subpopulation of CD3+ T-cells is also present. Identification of CD21+ follicular dendritic cells may be helpful in confirming the presence of poorly developed follicles. Kappa and lambda immunohistochemistry invariably show no evidence of light chain restriction. Tattoo-associated pseudolymphomas may be of the B- or T-cell type, with a B-cell pattern being more common. In addition to the features described

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Fig. 14.78 Drug-induced pseudolymphoma: scattered multinucleated giant cells are evident.

Fig. 14.76 Carbamazepine-induced pseudolymphoma: diagnosis depends upon careful clinicopathological correlation.

Fig. 14.79 Drug-induced pseudolymphoma: there is marked lymphocytic atypia. The nodules melted away following withdrawal of drug.

Fig. 14.77 Drug-induced pseudolymphoma: this very dense dermal infiltrate developed following treatment with an antidepressant. Multiple cutaneous nodules were present.

is withdrawal of the suspected drug. It is important that correlation always be undertaken in any case of an unanticipated lymphoma in order that reactive conditions do not receive inappropriate lymphoma treatment.

Specific drug reactions Arsenic Clinical features

above, there is tattoo pigment extracellularly and within macrophages. Rarely, a lichenoid infiltrate is present.39

Differential diagnosis Distinction between cutaneous lymphoma and a drug-induced pseudolymphoma can be exceedingly difficult. Features that favor a drug-induced process over mycosis fungoides include vacuolar alteration, keratinocyte necrosis, spongiosis, and papillary dermal edema.40 However, there can be considerable histological overlap and rare instances of a T-cell receptor gene rearrangement necessitate close clinicopathological correlation. If cutaneous pseudolymphoma is suspected, the most effective way to make the distinction

Arsenic exposure can be encountered under a variety of circumstances.1–7 It may be a constituent of proprietary medicines and is an active component of pesticides and herbicides.3 Fowler's solution – once used in the treatment of psoriasis and other dermatological disorders – contained 1% potassium arsenate.1,3 The most common source of arsenic exposure now is through contaminated ground water. For many years (as a consequence of its use as an insecticide) it was an ingredient in cigarette tobacco.2,4 High levels of arsenic occur in the mining and smelting industries.3 Exposure to arsenic may cause acute arsenical dermatitis, although more commonly patients are seen with long-term sequelae.2–7 The former presents with a diffuse erythematous papular or pustular/bullous dermatosis that can

Specific drug reactions progress to exfoliative dermatitis.5 Transverse white nail striations may be a feature.5 Chronic complications of arsenic exposure include pigmentary disturbances and cutaneous tumors. Patients are also at increased risk of internal malignancies.1,7 Other systemic manifestations include atherosclerosis, hepatic fibrosis, peripheral neuropathy, respiratory disease, and diabetes mellitus.7 Characteristic of arsenicism is the ‘rain drops on a dusty road’ appearance in which patients develop hyperpigmented macules containing foci of hypopigmentation and areas of darker pigmentation.7–10 Lesions are often seen on the trunk and in heavily pigmented regions such as the areola and flexural creases.3 The cutaneous pigmentary changes are especially seen in Asian populations.3 Palmar and plantar keratoses are common and present 2 years or more after exposure.5 After many years they may be associated with malignant transformation.7 Skin tumors are a late manifestation, are often multiple, and are particularly found on non-sun-exposed sites. Bowen’s disease, squamous cell carcinoma, and superficial basal cell carcinoma may develop.1,2 Patients with evidence of arsenic exposure should be investigated for visceral malignancies, particularly carcinoma of the lung, bladder, and kidney.7,11,12 There are occasional reports documenting an association between arsenic and hepatic angiosarcoma.13,14

Fig. 14.80 Iododerma: ulcerated vegetative plaques are present on the backs of the hands and fingers. By courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features The mechanism of arsenic carcinogenesis is multifactorial. Arsenic is methylated as part of the metabolization process.6 This results in free radicals which damage DNA, contribute to chromosomal aberrations, and increase sister chromatid exchange.7 Arsenic also impairs the DNA repair process and diminishes p53 activity.15 Transcription factors, cytokines, and cell signaling pathways critical to regulation of cellular proliferation and differentiation are also affected by arsenic and lead to uncontrolled cell growth and de-differentiation.7,15,16 Histologically, cutaneous hyperpigmentation demonstrates increased melanin synthesis, with excess pigment being present at all levels of the epidermis.3 There is no evidence of melanocytic proliferation. Skin cancers arising as a result of arsenic exposure show no distinguishing features histologically and are described elsewhere.

Iododerma Clinical features Potassium iodide is encountered in various settings. It is often included in expectorants/bronchodilators and is used for treatment of thyroid disease and as a radiocontrast medium. Adverse reactions are rare.1–9 Acneiform papulo/pustular lesions are most common and affect the face, neck, and back.3,4 Erythematous, urticarial, vesiculobullous, and pustular psoriasis-like lesions have been described.1,7 Rarely, chemical burnlike changes develop in patients, often post-surgical, when there is concomitant occlusion and maceration.9 Lesions affecting the lower limbs may be petechial, hemorrhagic or resemble erythema nodosum.1,2 Nodular and ulcerated vegetative plaques constitute more extreme forms. This latter variant affects the face, shoulders, trunk, and extremities and presents as 1–7 cm disfiguring, crusted, erythematous lesions, sometimes with central umbilication (Figs 14.80, 14.81).3 Healing may be complicated with scarring. Iododerma is associated with multiple myeloma, polyarteritis nodosa, lymphoma, and glomerulonephritis.3,7,10 Renal insufficiency may be a predisposing factor.

Pathogenesis and histological features Although delayed hypersensitivity is believed to represent the underlying pathogenesis, the precise mechanism is unknown. Acute lesions are characterized by an intense dermal neutrophil-rich infiltrate. With chronicity, pseudoepitheliomatous hyperplasia and ulceration are common. Neutrophil microabscesses may be seen in the epidermis and the dermis; in some cases, there is focal leukocytoclastic vasculitis.3,5

Fig. 14.81 Iododerma: in this patient, nodules are conspicuous. Superimposed pustules are evident. By courtesy of the Institute of Dermatology, London, UK.

Differential diagnosis Histologically, the nodular lesions of iododerma resemble an infective process such as blastomycosis or an atypical mycobacterial condition. The presence of occasional eosinophils within the infiltrate and epidermal degeneration in association with the abscesses may result in confusion with pemphigus vegetans. In early lesions, when the epidermis is normal thickness, the features can be mistaken for Sweet’s syndrome and pyoderma gangrenosum.

Bromoderma Clinical features Methyl bromide has been used as a pesticide and disinfectant and in the pharmaceutical, film, and dye industries.1–5 It may be found in sedative syrups and expectorants. Although occupational exposure is associated with severe respiratory effects including pulmonary edema, occasional reports of skin

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Cutaneous adverse reactions to drugs contact have also been documented.3,4 Potassium bromide is used as an anticonvulsant in many parts of the world. Other sources of exposure include brominated pool disinfectants and brominated vegetable oil, a product used in citrus-flavored drinks.6 Patients present with sharply circumscribed erythematous lesions containing vesicles and bullae.4 Intertriginous regions and sites of mechanical pressure are predominantly affected. Ingested bromide may give rise to hyperpigmentation, urticaria, acneiform/pustular lesions (acne bromica), vegetative and ulcerated plaques (vegetant bromoderma, tuberous bromoderma), necrotizing panniculitis, and pyoderma gangrenosum-like ulcers (Fig. 14.82).7–12 Lesions may be multiple or solitary. Vegetant bromoderma most often presents on the face, scalp, and legs and predominantly affects infants.7 It is commonly mistaken for an infection. A case which complicated bromine secretion in breast milk has been documented.13

Histological features Cutaneous lesions that develop following acute exposure to methyl bromide are characterized by spongiosis, keratinocyte necrosis, papillary dermal edema, and subepidermal blister formation.4 A perivascular inflammatory cell infiltrate containing neutrophils, eosinophils, and smaller numbers of lymphocytes and histiocytes is present in the superficial dermis. In vegetating lesions, there is striking pseudoepitheliomatous hyperplasia with intraepidermal and dermal abscesses accompanied by an intense neutrophil, eosinophil, and lymphohistiocytic infiltrate in the underlying dermis. Urticarial lesions show papillary dermal edema accompanied by a neutrophil and eosinophil-rich infiltrate.4

Differential diagnosis Vegetating lesions may be easily confused with deep fungal and atypical mycobacterial infections. Pemphigus vegetans also enters the differential diagnosis. The diagnosis may be most easily reached by careful clinicopathological correlation.11

Warfarin Warfarin (coumadin) may be associated with a number of adverse reactions including hemorrhage, alopecia, urticaria, maculopapular eruptions, dermatitis, purple toe syndrome, and leukocytoclastic vasculitis.1–8 Cutaneous necrosis develops in 0.01–0.1% of patients and may cause severe morbidity and significant mortality.5

Fig. 14.82 Bromoderma: vegetant plaques and nodules are seen around the eye. Ulceration is present. By courtesy of the late M. Beare, MD, Royal Victoria Hospital, Belfast, N. Ireland.

Clinical features Warfarin necrosis typically develops 3 to 6 days after starting anticoagulation therapy. Paresthesia is present initially and is followed by a painful, well-­circumscribed, edematous, and erythematous plaque resembling peau d’orange with purpura.1,5 Large blood-filled blisters that rapidly break down, accompanied by progressive necrosis of the underlying dermis and subcutaneous fat, are later sequelae. Tissue destruction is often considerable and the resultant scarring is very disfiguring. Occasionally, the onset of this condition is delayed for weeks or months although in most instances this reflects an interrupted therapeutic regimen.9,10 The condition shows a predilection for obese females (85%) and predominantly affects the breasts, buttocks, and thighs.2 The reason for the female predominance is unknown. In males, the thighs and buttocks are also affected and sometimes the penis is involved. Occasionally, lesions are seen on the hands. Deeper soft tissues and internal viscera are not affected. Patients almost invariably have received anticoagulation for thrombophlebitis (deep venous thrombosis) and/or pulmonary embolism. Patients who receive warfarin for treatment of cardiovascular disorders such as atrial fibrillation only very exceptionally develop this condition.5

Pathogenesis and histological features Cutaneous necrosis rarely complicates therapy with warfarin. Although hypersensitivity reactions and direct toxicity have been postulated as etiological factors, an imbalance in the ratio of procoagulative and anticoagulative factors is currently thought to be most important.5 In addition to depressing the vitamin K-dependent clotting factors II, VII, IX, and X, warfarin reduces the levels of naturally occurring anticoagulants including protein C, protein S, and antithrombin III. It first affects protein C, which has an extremely short half-life, and until the anticoagulative effect comes into play with depressed levels of coagulating factors, the patient is paradoxically at increased risk of thrombosis. Why this should so rarely result in skin necrosis is uncertain. Congenital protein C deficiency is an important predisposing factor in some patients. This is a relatively common autosomal dominant condition that affects between 1:200 and 1:300 of the population. Protein C is activated by thrombin under the influence of the cofactor thrombomodulin.5 The activated form inactivates factors VIIIa and Va, which inhibit conversion of factor X to factor Xa and prothrombin to thrombin with resultant inhibition of coagulation.5 Protein C deficiency is, therefore, associated with a thrombotic tendency.11 Approximately 30% of patients who develop warfarin necrosis have an underlying protein C deficiency.2 Warfarin therapy, therefore, tips the balance in an already protein C-deficient patient. The proposed mechanism, however, by no means offers an explanation in the majority of cases. Acquired or congenital deficiency of protein S may also be of importance in a small number of cases.12–15 Protein S is a vitamin K-dependent cofactor for activated protein C.5 Acquired protein S deficiency may be encountered in patients with renal failure or antiphospholipid syndrome, or who are undergoing hemodialysis.16,17 An episode of thrombophlebitis and/or pulmonary embolism leading to the warfarin therapy seems to be of major etiological importance.1,2 It is proposed that the vascular inflammatory changes play a role in precipitating the thrombotic tendency by reducing endothelial cell thrombomodulin levels, inactivating protein S and decreasing fibrinolytic activity.1–4 Protein C or protein S deficiency (inherited or developing as a consequence of warfarin therapy) may then represent an additional predisposing factor. Other conditions that predispose to the development of warfarin necrosis include reduced antithrombin III levels, lupus anticoagulant syndrome, factor V Leiden, and prothrombin gene mutation.18–20 Histologically, warfarin-associated skin necrosis is characterized by fibrin thrombi in the small veins and venules of the dermis and subcutaneous fat, with widespread erythrocyte extravasation (Figs 14.83, 14.84). In advanced lesions, subepidermal blood-filled blisters are seen. In older lesions, the changes of infarction are superimposed; however, vasculitis is not a feature. Arteries are not affected.

Specific drug reactions

Fig. 14.83 Coumadin necrosis: there are thrombosed vessels throughout the superficial dermis associated with epidermal regeneration.

occur at the injection site. There is a striking female predominance.2,11 Rarely, blisters may develop, and exceptionally the erythema becomes generalized.10 Hemorrhagic vesicles have also been described in patients given low molecular weight heparin.12,13 Reported patients have been elderly and received the medication while hospitalized. Lesions develop distant from injection sites and occur on the extremities. HIT syndrome – in addition to definitional thrombocytopenia – is characterized by thrombosis (venous more often than arterial) which account for the high morbidity and potential mortality.4,6 Venous thrombosis results in deep venous lesions in the lower legs in up to 50% of patients, and of these 25% may develop pulmonary embolism.6 Additional complications include ­warfarin-induced limb gangrene, adrenal hemorrhage, and DIC.6 Arterial thrombosis is more likely in catheterized or traumatized arteries and may affect the aorta and ileofemoral arteries, resulting in peripheral gangrene, myocardial infarction or stroke.4,6 Cutaneous necrosis develops in 10–20% of patients with the HIT syndrome.6,14 The injection site is predominantly involved but more distant areas (thighs, abdomen, and buttocks) may also be affected in a minority of patients.1,2,15–24 Initial lesions are painful or burning erythematous plaques followed by ulceration and tissue necrosis.2 The condition shows a predilection for middle-aged females and the obese.2,15 Thrombocytopenia and thromboembolism are potentially life-threatening complications.

Pathogenesis and histological features

Fig. 14.84

Coumadin necrosis: high-power view of Figure 14.83.

Differential diagnosis Identical histological features may be seen in a number of conditions including antiphospholipid antibodies, hereditary hypercoagulation disorders (factor V Leiden mutations, protein C or S, and antithrombin III deficiencies) in the absence of warfarin therapy, heparin-induced thrombocytopenia syndrome and disseminated intravascular coagulation (DIC). Cryoglobulinemia and cryofibrinogenemia may also have to be excluded. Calciphylaxis can be excluded by the absence of vascular calcification. The diagnosis ultimately depends upon adequate clinicopathological correlation.

Heparin Adverse side effects of heparin include hemorrhage, urticaria, anaphylaxis, macular erythema, and alopecia.1–3 Of greater significance, patients may develop thrombocytopenia, paradoxical thrombosis, and skin necrosis – ­heparin-induced thrombocytopenia syndrome (HIT syndrome).1–6

Clinical features Urticarial reactions are exceptionally rare.7–9 Delayed hypersensitivity reactions are the most common of the adverse cutaneous responses to heparin, occurring in 7.5% of patients.9,10 Macular erythema and eczematous lesions

The heparin-induced thrombocytopenia syndrome results from platelet activating HIT/PF4 antibodies induced in response to a platelet factor 4-heparin complex.1,22,23 The resulting immune complexes bind to platelet Fc receptors and activate platelets. In addition, the antibody reacts with surface endothelial cell platelet factor 4-inducing endothelial cell injury and thrombosis.4,23 Only a minority of patients with HIT antibodies develops skin necrosis, and it is postulated that additional prothrombotic factors such as protein C or S deficiency are necessary for the development of thrombosis and its sequelae.1 Adverse side effects are more common and more severe in patients receiving unfractionated as opposed to low molecular weight heparin.24 The histological features of the macular erythema are those of spongiotic dermatitis. Within the superficial dermis is a perivascular lymphohistiocytic infiltrate with variable numbers of eosinophils. The lymphocytes are predominantly of the T-helper subclass.25 Heparin-induced cutaneous necrosis is characterized by widespread superficial small vessel (capillary and venule) thrombi accompanied by hemorrhage and necrosis.16,17 The presence of leukocytoclastic vasculitis is variable.2 Bullous hemorrhagic lesions are intraepidermal blisters filled with extravasated red blood cells.12,13 Perivascular lymphocytes, histiocytes, and eosinophils are variably present. Leukocytoclastic vasculitis is absent. Direct immunofluorescence studies are negative.

Penicillamine Clinical features Penicillamine therapy is associated with various adverse reactions including exanthematous eruptions, urticaria, lichenoid reactions, papulosquamous dermatoses, alopecia, hypertrichosis, nail changes, dermatomyositis, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus erythema, and bullous and mucosal pemphigoid.1–12 The autoimmune blistering dermatoses complicating penicillamine therapy are not dose dependent and are seen particularly in patients with other immunologically mediated diseases including rheumatoid arthritis and systemic sclerosis.9 Pemphigus is by far the most common bullous disorder associated with penicillamine, pemphigus foliaceus being the most frequent variant encountered.4,9 Herpetiform pemphigus has also rarely been described as complicating the use of penicillamine.10,11 Additional manifestations – particularly seen in patients taking high doses in the treatment of Wilson’s disease and cystinuria – include penicillamine dermopathy, elastosis perforans serpiginosa, skin fragility with hemorrhages and milia formation on the extensor surfaces, wrinkling and anetoderma-like changes, cutis laxa, and pseudoxanthoma elasticum-like

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Cutaneous adverse reactions to drugs appearances.13–19 Patients on long-term therapy may present with small yellow papules resembling a plucked-chicken appearance or disfiguring loose folds of skin particularly affecting the flexures.16,17

Histological features Penicillamine acts by impairing cross-linking in newly formed collagen and elastic fibers.13 The histological features include increased numbers of abnormally formed elastic fibers in the reticular dermis (Fig. 14.85). These are thickened with irregular serrated appearance on cross-section. When viewed in a longitudinal plane, the fibers show conspicuous lateral projections (Figs 14.86, 14.87). Evidence of similar elastic tissue damage has been documented in the joint capsules, lungs, intestine, and large elastic arteries.13

Gold Clinical features Gold therapy may result in eczematous, lichenoid, pityriasiform, and psoriasiform dermatoses and stomatitis. Cutaneous pigmentation which results from parenteral treatment with gold salts is known as chrysiasis (auriasis, chrysoderma, hautaurosis).1–5 It is a pho-

Fig. 14.87 Penicillamine dermopathy: the changes can be highlighted by an elastic tissue stain.

todependent, irreversible condition most often documented in patients with rheumatoid arthritis.2,3 Patients are at risk once a threshold of 50 mg/kg of gold is reached.1 Disease severity correlates with the cumulative dose of gold.6 Coloration varies from mauve/blue to blue to slate-gray.2 The ­sun-exposed skin of the face is particularly affected. In severe cases lesions may be seen on the neck, front of chest, and backs of the forearms and hands (Fig. 14.88).2 In bald patients, scalp involvement is sometimes apparent. Pigmentation has also been described in the sclera and buccal mucosa.2

Pathogenesis and histological features

Fig. 14.85 Penicillamine dermopathy: there are thickened, intensely eosinophilic elastic fibers throughout the reticular dermis.

Fig. 14.86 Penicillamine dermopathy: the serrated appearance is characteristic.

The pathogenesis of chrysiasis is uncertain. It is probably related to an effect of UV radiation on tissue-bound gold particles. Support for this hypothesis is the observation that skin lesions can be induced by UVB irradiation of ­sunlight-protected skin.7 Similarly, typical skin lesions have been described following Q-switched ruby laser treatment in patients treated with gold.8–10 Chrysiasis is characterized by deposits of small black macrophagebound particles surrounding the vessels in the deeper reticular dermis and around the sweat gland coils (Fig. 14.89).2 Perl’s Prussian blue (hemosiderin) and Masson-Fontana staining for melanin are negative. The gold particles show orange–red birefringence with cross-polarized light.11 There is no inflammatory response. Epidermal melanin pigmentation usually appears normal.2

Fig. 14.88 Chrysiasis: multiple foci of blue discoloration are present on the cheek. By courtesy of J. Kerner, MD, Department of Dermatology, Harvard Medical School, Boston, USA.

Specific drug reactions

Fig. 14.89 Chrysiasis: there are fine black granules both within macrophages and lying free around the superficial vasculature. By courtesy of S. Lyle, MD, Beth Israel Deaconess Medical Center, Boston, USA.

Fig. 14.90 Argyria: there is striking slate-blue pigmentation; the eyes are also affected. By courtesy of the Institute of Dermatology, London, UK.

By electron microscopy, the gold appears as granular, particulate, and filamentous material, sometimes showing a starlike morphology within phagolysosomes (aurosomes). The diagnosis can be confirmed by electron/X-ray probe microanalysis.2,4,12–14

Differential diagnosis Gold pigment must be distinguished from silver deposits (argyria), mercury, and tattoo pigment.5,10 Silver pigment is predominantly deposited in relation to basement membranes, particularly of the sweat glands. It does not show orange–red birefringence with cross-polarized light.10 Mercury particles are large (up to 340 μm in diameter) and brown-black in color. Tattoo usually consists of a variety of different pigments of varying colors. Clinical history should readily establish the diagnosis in the majority of cases.

Silver Clinical features Generalized tissue accumulation of silver (argyria) follows dietary, medicinal, and industrial exposure to silver compounds.1–9 Occupational exposure may be encountered in silver mining and smelting, electroplating, and in the photographic industries.3 Silver deposits are found in the skin and mucous membranes in addition to internal viscera, particularly liver, spleen, adrenals, muscle, and brain (Fig. 14.90).1 Argyria initially presents in the gingivae as a slate-blue line due to deposition of metallic silver and silver sulfide.1–3 Cutaneous manifestations affect the sun-exposed sites of the face, neck, and backs of hands.6 The nails may also be involved. Ocular involvement presents as a bluish-gray to brownish-black coloration. Localized argyria has been documented due to silver earrings, orthodontic surgery, acupuncture, silver polishing, and the application of topical silver sulfadiazine.10–19 In the absence of clinical information, a diagnosis of blue nevus may mistakenly be made.11

Histological features Argyria results from deposition of metallic silver and silver sulfide. Pigmentation is intensified by sunlight due to silver reduction analogous to photographic processing.6 There is also increased epidermal melanin synthesis. Silver granules are found in association with the vascular and adnexal basement membranes and adjacent to dermal elastic fibers (Fig. 14.91).2 They measure less than 1.0 μm in diameter and appear brown–black in hematoxylin and eosin stained sections.6 Ultrastructurally, the silver granules may be membrane bound within macrophage lysosomes or lie freely in the dermis.8 The diagnosis can be confirmed by X-ray microanalysis.6,9

Fig. 14.91 Argyria: note the fine silver granules outlining the basement membrane of the sweat gland epithelium.

Mercury Clinical features Mercury exposure is encountered under a variety of circumstances.1–3 It occurs in three different forms: metallic, inorganic, and organic mercury.1 • Metallic mercury, which is a liquid at room temperature, is present in vapor from heating amalgam and paints and in mercury thermometers.4 • Inorganic mercurial salts may be present in laxatives, pesticides, antiseptics and germicides.1,5 • Organomercurials are used as industrial antifungal agents.4 Dermatological reactions to metallic mercury include mercury granuloma and mercury exanthem (acute generalized exanthematous pustulosis). Mercury granuloma follows penetrating skin wounds as might result from a broken thermometer, attempted homicide or suicide. Patients present with a flesh-colored to red or hyperpigmented nodule at the site of implantation.6–10 Membranous fat necrosis following subcutaneous mercury injection has also been documented.11 Mercury exanthem follows exposure to metallic mercury (as may follow breaking a thermometer) in a previously sensitized patient.12–22

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Cutaneous adverse reactions to drugs The eruption presents as a vivid erythema, which particularly affects the flexural sites of the body (so-called ‘Baboon syndrome’).17 An inverted V-shaped erythema affecting the upper anteromedial aspects of both thighs is characteristic.12,16 Sterile pustules commonly develop and a purpuric element may develop. Pyrexia and peripheral leukocytosis are typically present. The dermatosis resolves by desquamation. Topical mercury cream has been used as a skin-bleaching agent.6,23,24 Continuous and protracted use results in slate-gray pigmentation affecting the flexures. The eyelids, nasolabial folds, and neck creases are sites of predilection.25,26 Parenteral use of mercury results in pigmentation of the gingivae.26 A  lichenoid drug reaction has been documented following acute mercury poisoning.27 Dental workers are at risk of allergic contact dermatitis from exposure to mercury or mercury salts.28 Mercury may also be associated with palmar/plantar peeling in children (pink disease, acrodynia, erythredema), palmar/plantar hyperkeratosis, and acanthosis nigricans-like skin lesions.29 Pink disease is rarely encountered nowadays due to control of mercury in medications and in the environment.30–32 The condition is still occasionally seen and may be a problem in developing countries. It presents in infants and young children following chronic mercury exposure, for example in diaper powders, laxatives, paint, fluorescent light bulbs or other household sources.1 It is characterized by the development of characteristic painful swelling and pink coloration of the tip of the nose, fingers, and toes.1,11 As the condition resolves, the palms and soles show intense sweating and desquamation.1 Sterility in males is a potential long-term sequel.31 Lichenoid and granulomatous inflammatory reactions may complicate use of mercuric sulfide (cinnabar) to provide the red color in tattoos.33–35 Pseudolymphomatous reactions to mercury have also been documented.36,37 Amalgam tattoo reactions are discussed elsewhere.

Histological features Mercury pigment is brown–black, round and opaque, and measures up to 340 μm in diameter (Fig. 14.92).5–7,38 The granules are found within macrophages in addition to extracellular dermal deposition. They are localized around the superficial vasculature and in association with the connective tissue elements.38 Mercury granulomata are characterized by local necrosis associated with free mercury globules surrounded by an intense foreign body granulomatous reaction with lymphocytes, histiocytes, plasma cells, and varying numbers of eosinophils.6,7,9 Ulceration is common and the epidermis may show pseudoepitheliomatous hyperplasia.

Mercury exanthem is characterized by subcorneal and/or intraepidermal pustules which may contain acantholytic keratinocytes in addition to large numbers of neutrophils.13 Background spongiosis is usually evident. The dermal papillae are often edematous and occasionally subepidermal vesiculation is a feature. A perivascular infiltrate of lymphocytes and histiocytes with conspicuous neutrophils and variable numbers of eosinophils is present in the superficial dermis. Leukocytoclastic vasculitis may be a feature in a significant proportion of cases.13 Cutaneous pigmentation following chronic local exposure to mercury is characterized by increased melanin pigment in the epidermis accompanied by mercury granules in the papillary dermis.26 Iron stains are negative.1 Pink disease is characterized by sweat gland hyperplasia and a non-specific dermal inflammatory cell infiltrate.1

Bismuth Clinical features Bismuth may be used for gastrointestinal complaints including gastritis and peptic ulceration.1–3 Adverse cutaneous reactions include erythroderma, exanthemata, purpuric eruptions, stomatitis, and urticaria.2,3 Generalized pigmentation may follow prolonged parenteral and oral use. Patients develop a generalized blue–gray pigmentation, which also affects the conjunctivae and oral mucosa.1 A blue–black line at the gingival margin is pathognomonic.1 Transient black lingual pigmentation has also been reported.4

Histological features Bismuth appears as small dark granules in the dermis and within sweat gland basement membranes.3 Transfollicular elimination has been documented.2

Voriconazole Clinical features Voriconazole is a second-generation broad-spectrum triazole antifungal that acts by inhibiting fungal cytochrome 450 enzymes. It is well tolerated and it is commonly used to treat fungal infections, particularly in immunocompromised patients. It may be associated with a number of side effects including nausea, vomiting, diarrhea, visual disturbances, cheilitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, pseudoporphyria, blistering, facial erythema, and mucocutaneous retinoidlike effects.1–4 One of the most important side effects is photosensitivity, initially reported to occur in around 1–2% of patients and after long-term therapy.5–7 Although the photosensitivity subsides when the treatment is stopped, photoaging also occurs and it persists. The latter is associated with multiple lentigines and premature dermatoheliosis.5–7 Furthermore, some patients, even children, have developed aggressive squamous cell carcinomas and, most recently, melanomas in-situ have been reported in two adults.8–11

Histological features All the cutaneous manifestations of voriconazole therapy show the same histological features of their counterparts not induced by drugs.

Lithium Clinical features

Fig. 14.92 Mercury pigmentation: there are multiple round black deposits of mercury associated with abscess formation.

Lithium therapy is associated with cutaneous side effects in up to 45% of patients.1,2 It is known to precipitate or aggravate psoriasis, in particular pustular lesions.3–6 Other cutaneous adverse affects include maculopapular eruptions, seborrheic dermatitis, exfoliative dermatitis, atypical acneiform lesions (predominantly affecting the forearms and legs), pustular eruptions, hidradenitis suppurativa, keratosis pilaris-like lesions, palmoplantar hyperkeratosis, bullous disorders, and hair, nail and mucosal changes.7–12 Exacerbation and the development of Darier’s disease has rarely been documented.13

Chemotherapeutic agents

Barbiturates and coma blisters Clinical features Barbiturates may be associated with a wide range of adverse drug reactions including erythema multiforme, toxic epidermal necrolysis, hypersensitivity syndrome, and pseudolymphoma.1,2 In company with many other sedative drugs, including chlorpromazine, imipramine, and meprobamate, barbiturates, particularly when taken in overdose, may result in blisters (coma blisters), related especially to sites of trauma.3–8

Pathogenesis and histological features These lesions probably develop as a result of focal persistent hypoxia and ischemia due to chronic localized pressure. They may develop in a comatose patient whatever the cause. Direct toxic effect may be of importance in some patients, since similar blisters have complicated localized barbiturate extravasation. Histologically, the blisters are subepidermal in location and are often accompanied by infarction of the overlying epidermis (Fig. 14.93). Sweat gland necrosis is characteristic.

Chemotherapeutic agents Clinical features The rapid rate of epidermal and mucosal turnover results in a high degree of susceptibility to the effects of chemotherapeutic agents. Among the most commonly encountered adverse responses are stomatitis, alopecia, and pigmentary changes.1–8 Stomatitis is very common and presents as burning erythema, followed by the development of extremely painful erosions and ulcers.2 Commonly implicated drugs include cyclophosphamide, methotrexate, bleomycin, cytarabine, doxorubicin, daunorubicin, dactinomycin, 5-fluorouracil, IL-2, hydroxyurea, and mercaptopurine.5,7 Secondary infection, such as with herpes simplex virus or Candida albicans, is an important complication. Proliferating hair follicles are highly susceptible to chemotherapeutic agents and as a consequence anagen effluvium (in which there is loss of much of the body hair) is a common and distressing complication.7,8 This is reversible once treatment is completed although subsequent regrowth of hair may be accompanied by a change in color or texture.1 Concomitant premature catagen and telogen effluvium can result in total baldness.2 Drugs most often implicated include bleomycin, cyclophosphamide, daunorubicin, docetaxel, doxorubicin, etoposide, ifosfamide, mechlorethamine, methotrexate, mitoxantrone, and paclitaxel.1 Nail changes, including pale transverse ridges (Beau’s lines)

Fig. 14.93 Coma blister: there is a subepidermal blister. Re-epithelialization along the floor is present.

develop as a result of mitosis inhibition with consequent temporary growth arrest and may be due to bleomycin, cyclophosphamide, and doxorubicin.5 Onycholysis can follow treatment with docetaxel, fluorouracil, and mitoxantrone.7 Transverse striate leukonychia (Mees’ lines), which result from periodic disruption of nail plate keratinization, classically have been described in association with arsenic poisoning.9 Similar lesions have been documented with a number of agents including ciclosporin and daunorubicin.10,11 Maculopapular eruptions may be caused by several chemotherapeutic drugs including azathioprine, 5-fluorouracil, chlorambucil, melphalan, and hydroxyurea.6 These are frequently a source of clinical diagnostic difficulty, as infectious diseases – including viral exanthemas and, in patients who have undergone transplantation, acute GVHD – are often within the differential diagnosis. Cutaneous hyperpigmentation is a common complication of chemotherapeutic agents and often affects the hair, nails, and mucosae in addition to the skin.1–8,12–14 Hypopigmentation is less commonly seen.5 The mechanism for increased melanin synthesis by melanocytes is unknown. Alkylating agents including busulfan, cyclophosphamide, ifosfamide, hydroxyurea, 5-fluorouracil, and methotrexate are among the most often implicated agents.5,15,16 Nail changes (including diffuse pigmentation, longitudinal and transverse banding or streaks) are particularly seen with cyclophosphamide, daunorubicin, doxorubicin, 5-fluorouracil, and hydroxyurea.2,9 Cyclophosphamide also causes hyperpigmentation of the palms and fingers.14 Immediate or delayed tanning following sun exposure is a frequent complication of 5-fluorouracil. Rarely, patients may develop linear erythema, complicated by pigmentation around an injection site, so-called serpentine supravenous hyperpigmentation.7,16,17–19 Similar lesions have followed treatment with actinomycin and nitrosourea.20,21 Hair pigmentation can result from tamoxifen therapy.1,22 Bleomycin therapy is associated with cutaneous pigmentation affecting between 30% and 60% of patients.2,23 Pathognomonic linear flagellate streaks may develop on the skin of the trunk and proximal extremities.24–31 It is suggested that lesions develop as a consequence of trauma-induced vasodilatation with resultant local increased concentration of bleomycin. An early inflammatory phase, due to scratching, has occasionally been documented, suggesting that the pigmentation occurs as a consequence of postinflammatory changes. A similar problem of patterned hyperpigmentation has been documented following treatment with thio-TEPA (triethylene thiophosphoramide). Localized occlusion during treatment (as for example with adhesive bandages) may cause retention of thio-TEPA-rich sweat and subsequent reversible hyperpigmentation confined to the occluded surfaces.32,33 Transverse banding of hair shafts following therapy with methotrexate – the so-called ‘flag sign’ – has also been documented.34 Chemotherapeutic agents may interact with radiation therapy to result in various unusual manifestations including photosensitivity, radiation enhancement, radiation recall, and reactivation. Photosensitivity may be induced by dacarbazine, 5-fluorouracil, hydroxyurea, and vinblastine.7 Radiation enhancement, which may be a feature of both dactinomycin and doxorubicin therapy, is due to impaired repair of radiation-induced sublethal cellular damage.2,5 As a consequence, the effects of radiation therapy are amplified. Clinical manifestations include increased erythema, hyperpigmentation, erosions, blistering, and necrosis at the site of radiation therapy.32 Radiation enhancement has also been encountered following therapy with adriamycin, bleomycin, cisplatin, 5-fluorouracil, hydroxyurea, and methotrexate.5,7 Radiation recall presents as erythema, vesiculation, and desquamation at the site of previous irradiation and may develop months or years after completion of treatment.2 The mechanism is unknown. Dactinomycin is particularly incriminated.2 A similar response has also been reported following therapy with adriamycin, bleomycin, cytarabine, doxorubicin, etoposide, 5-fluorouracil, hydroxyurea, melphalan, methotrexate, tamoxifen, and vinblastine.7,35,36 Recently, radiation recall reactions have been described following treatment with paclitaxel, gemcitabine, docetaxel, IFN-α2b, dacarbazine, acyclovir, and capecitabine.37–45 Reactivation of ultraviolet light-induced erythema has been described as a complication of methotrexate and suramin therapy.7,46 Manifestations include vesiculation and erythema.

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Cutaneous adverse reactions to drugs Inflammatory changes affecting pre-existing actinic keratoses and seborrheic keratoses have been described following treatment with cisplatin, cytarabine, dacarbazine, dactinomycin, doxorubicin, 5-fluorouracil, 6-thioguanine, and vincristine.4,5 The affected keratoses become pruritic and erythematous. It is suggested that such changes are analogous to radiation recall phenomena.4 Hypersensitivity reactions (including urticaria, angioedema, serum sickness, anaphylaxis, generalized dermatitis, and fixed drug eruption) are uncommon complications of chemotherapy. Although a wide range of agents may result in these responses, L-asparaginase, intravenous melphalan, and cisplatin have been particularly incriminated.2,47,48 Cyclophosphamide, daunorubicin, doxorubicin, methotrexate, and procarbazine have also been implicated.48 Dacarbazine and procarbazine may cause fixed drug reactions.1 Immune complex-mediated reactions including vasculitis and some cases of erythema multiforme or toxic epidermal necrolysis may rarely be a result of treatment with hydroxyurea and mechlorethamine.5 Contact dermatitis is an uncommon but important complication of topical mechlorethamine (mustard) therapy.49 An interstitial granulomatous maculopapular eruption following low-dose methotrexate in the treatment of collagen vascular diseases including lupus erythematosus and rheumatoid arthritis has been described.50 The buttocks and limbs are commonly affected. Newer chemotherapeutic agents have emerged which selectively target specific cellular pathways. Their increasing use has also resulted in diverse cutaneous side effects.51 One class of such drugs is the epidermal growth factor receptor (EGFR) inhibitors which are used to treat non-small cell lung cancer, breast, colon, pancreatic, and squamous cell carcinoma of the head and neck.52 Examples include cetuximab, gefitinib, and erlotinib. Since EGFR is expressed in keratinocytes, follicular epithelium, eccrine glands, and sebaceous cells, adverse effects on the skin and appendages are common.53 Acute folliculitis on the face and trunk is most common.51,52,54 Other potential side effects include dry skin, nail alterations (paronychia, ingrown nails, nail fold fissures, onycholysis, splinter hemorrhages, pyogenic granulomas), and hair changes (frontal alopecia, trichomegaly of eyelashes, altered hair texture).51,52,55–57 Another class of medication is the tyrosine kinase inhibitor. Imatinib, dasatinib, and nilotinib treat chronic myeloid leukemia (CML).51 Imatinib is also approved for treatment of gastrointestinal stromal tumor (GIST) and some cases of dermatofibrosarcoma protuberans. A wide range of cutaneous effects have been reported with these medications, the more common being hyper-, hypo- and de-pigmentation and macular–papular exanthems.51,58,59 Sorafenib and sunitinib are multikinase inhibitors currently approved for treatment of renal cell carcinoma.51,60 Additional uses include hepatocellular carcinoma and imatinib-resitant GIST for sorafenib and sunitinib, respectively. A distinct cutaneous finding with both of these medications is hand– foot reaction developing in up to two-thirds of patients, typically 2 to 4 weeks after initiating treatment, and characterized by painful erythema and edema of the palms and soles (Fig. 14.94).51,53,61–63 There may be associated paresthesia and desquamation. The lesions are discrete and accompanied by hyperkeratosis, in contrast to the acral erythema associated with traditional chemotherapeutic agents.53 Other cutaneous reactions linked to sorafenib include pruritus, alopecia, actinic keratoses, and squamous cell carcinoma.51,60,64,65

Fig. 14.94 Chemotherapy-related drug reaction: there are discrete palmar bullae with a rim of erythema. The patient had been taking sorafenib. By courtesy of R. Lee, MD, Virginia Commonwealth University, Richmond, Virginia, USA.

Fig. 14.95 Chemotherapy-related drug reaction: there are interface changes with basal cell hydropic degeneration and apoptosis.

Histological features Interface dermatitis represents the most frequently encountered histological appearance in chemotherapy adverse drug reactions (Figs 14.95–14.97).66–69 In addition to the epidermis, both follicular and sweat gland/duct epithelium may be affected. Appearances are variable, ranging from lichen planuslike changes (including hyperkeratosis, hypergranulosis, acanthosis, basal cell hydropic degeneration, and apoptosis) to lupus erythematosus-like reactions in which the epidermis is markedly atrophic. The combination of interface changes with severe maturation arrest (dysmaturation) is pathognomonic of chemotherapy-related reactions. It is particularly a feature of patients receiving long-term chemotherapy, high-dose chemotherapy, and multiagent chemotherapy. In addition to impaired maturation, the epidermis appears disorganized and individual keratinocytes are enlarged with pleomorphic nuclei containing conspicuous nucleoli. These changes are particularly

Fig. 14.96 Chemotherapy-related drug reaction: there is striking dyskeratosis and abnormal maturation. The latter is a common feature of chemotherapy reactions.

Chemotherapy-associated eccrine gland reactions Pustular folliculitis secondary to EGFR inhibitors demonstrates a dilated, hyperkeratotic follicular infundibulum.63 The perifollicular infiltrate initially contains lymphocytes and later becomes neutrophilic. The histological features of hand–foot eruption seen with multikinase inhibitors sorafenib and sunitinib include vacuolar interface alteration along the dermal–epidermal junction, dyskeratotic keratinocytes, and a thin to absent granular cell layer with variable parakeratosis.53,62 Mitotic figures may also be seen predominantly in the spinous layer. Intraepidermal cleavage occurs as a consequence of epidermal cell necrosis. Intradermal perivascular inflammation is sparse and contains mononuclear cells with inconspicuous eosinophils. Vasculitis is not seen.

Chemotherapy-induced acral erythema Clinical features

Fig. 14.97 Chemotherapy-related drug reaction: close-up view.

associated with bleomycin, busulfan, and hydroxyurea. Squamous metaplasia of the dermal sweat ducts may be seen with methotrexate therapy.69 Etoposide, a podophyllin derivative, in addition to causing maturation abnormalities, can cause metaphase arrest with characteristic fragmented nuclear chromatin resulting in so-called ‘starburst cells’.70 Hyperpigmentation complicating busulfan therapy predominantly affects the basal layer of the epidermis but also may extend throughout the full thickness and is often accompanied by pigmentary incontinence due to melanocyte toxicity.71 Similarly, bleomycin-induced hyperpigmentation is characterized by epidermal hyperpigmentation and pigmentary incontinence.72 Melanocytes are present in normal numbers. The early inflammatory phase is characterized by a superficial perivascular infiltrate of lymphocytes, histiocytes, occasional neutrophils, plasma cells, and eosinophils. Some authors, however, have described basal cell pigmentation in the absence of pigmentary incontinence.27,73 Lymphocytic vasculitis has also been reported.28 Thio-TEPA-induced pigmentation is similarly characterized by melanin pigment within all layers of the epidermis including the stratum corneum, accompanied by basal cell hydropic degeneration and pigmentary incontinence.32 A mild perivascular lymphohistiocytic infiltrate is present in the superficial dermis. The melanocyte concentration is normal. Radiation recall is characterized by epidermal atrophy, basal cell hydropic degeneration, and superficial dermal vascular ectasia. In addition to anagen alopecia and interface changes, pustular folliculitis and allergic contact dermatitis (5-fluorouracil) may be a feature of chemotherapy-associated adverse reactions, particularly with dactinomycin and 5-fluorouracil.74,75 Hypersensitivity reactions including urticaria, angioedema, and maculopapular eruptions are histologically no different from other drug-induced lesions (see above). Dermal sclerosis may be a feature of bleomycin and docetaxel therapy.76 Extravasation of chemotherapeutic agents including cisplatin, dactinomycin, daunorubicin, doxorubicin, etoposide, idarubicin, mechlorethamine, mithramycin, paclitaxel, vinblastine, and vincristine may result in chemical cellulitis and tissue necrosis.1 Spongiotic dermatitis is rarely seen as a complication of systemic chemotherapy but has been described following treatment with methotrexate, 5-fluorouracil, and dacarbazine.67,68 It is much more commonly encountered following topical chemotherapeutic agents including 5-fluorouracil and mechlorethamine. The interstitial granulomatous reaction associated with low-dose methotrexate therapy is characterized by a largely histiocytic interstitial infiltrate with small numbers of neutrophils.46 Vasculitis is not a feature. The histiocytes may surround neutrophil aggregates, and a characteristic feature is histiocytes forming a palisade around collagen fibers.65

Chemotherapy-induced acral erythema (acral erythema, hand-foot syndrome, palmoplantar erythrodysesthesia syndrome, toxic erythema of the palms and soles) in which the patient presents with circumscribed, extremely painful and tender erythematous macules on the palms, fingertips and soles has been described following treatment with 5-fluorouracil, cyclophosphamide, cytarabine, daunorubicin, doxorubicin, and vincristine.1–12 Etoposide, mercaptopurine, methotrexate, and vinblastine have also been incriminated. Patients subsequently develop blisters followed by desquamation.

Histological features The histological features include basal cell liquefactive degeneration, keratinocyte necrosis, and mild spongiosis.1–3,13 There is papillary dermal edema, vascular dilatation, and a mild superficial perivascular lymphohistiocytic infiltrate. Features of syringosquamous metaplasia and eccrine neutrophilic hidradenitis are rarely seen.14,15 In one case, immunohistochemistry of the dermal lymphocytes disclosed a CD3+, CD16+, CD56+, leukocyte function antigen-1 positive phenotype suggestive of natural killer T-cells.16 The eccrine ducts expressed HLA-DR and intercellular adhesion molecule-1 (ICAM-1).16

Differential diagnosis The features are indistinguishable from graft-versus-host disease. Distinction is dependent upon clinicopathological correlation. Compared to hand–foot reaction associated with multikinase inhibitors, there is no diminution of the granular cell layer, parakeratosis or intraepidermal mitoses.17

Chemotherapy-associated eccrine gland reactions Although there is some histological overlap between neutrophil eccrine hidradenitis and eccrine syringosquamous metaplasia, more often they present independently of one another and, as such, they are considered separately.

Neutrophilic eccrine hidradenitis Clinical features This rare eccrine gland reaction was initially reported in a patient receiving induction chemotherapy including doxorubicin and cytarabine in the treatment of acute myelogenous leukemia.1 Subsequently, a similar eruption was described in patients with a number of other malignancies such as Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, breast carcinoma, Wilms’s tumor, osteosarcoma, and testicular tumors including embryonal carcinoma and teratoma.2–7 Further cases developing in association with acute myelogenous leukemia have also been documented.8,9 It was soon appreciated that additional chemotherapeutic agents including bleomycin, chlorambucil, daunorubicin, dactinomycin, vincristine, lomustine, mitoxantrone, thioguanine, cis-platinum, vinblastine, topotecan, cyclophosphamide, and 5-fluorouracil might be responsible, although cytarabine has been most commonly implicated.10 A case following the use of GM-CSF has been reported.11

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Cutaneous adverse reactions to drugs It should be noted, however, that neutrophilic eccrine hidradenitis has also been described as a prodromal manifestation of acute myelogenous leukemia in the absence of chemotherapy.12 The condition has been described in ­HIV-positive patients receiving zidovudine and as a complication of treatment with acetaminophen.13–16 Clinically, patients (who are commonly febrile) develop a polymorphous eruption consisting of variably asymptomatic or tender erythematous to violaceous macules, papules, plaques, nodules, and pustules which most often presents within 1 or 2 weeks of starting chemotherapy.4 Lesions may be very numerous and, although there does not appear to be a site predilection, the trunk and upper limbs are most often affected.5 Facial involvement may also occur, manifesting as periorbital edema, violaceous plaques, and lesions that mimic cellulitis.17–19 Ear involvement seen as bilateral tender erythema has been documented.20 An atypical presentation with symmetrical, erythematous plaques isolated to the breasts has also been reported.21 The lesions desquamate and usually heal spontaneously within 1–3 weeks.4 Postinflammatory hyperpigmentation and scarring are not usually features. Recurrence following the reintroduction of chemotherapy has been documented.1,8 Clinically, an infectious condition, leukemia cutis, bullous pyoderma, atypical pyoderma gangrenosum or Sweet’s disease is most often suspected.8

Pathogenesis and histological features The pathogenesis of this condition is unknown but it has been proposed that the drug may be concentrated in the sweat glands, thereby exerting a direct toxic effect on the secretory epithelial cells.1,2 Alternatively, the condition may represent part of the spectrum of acute neutrophilic dermatoses which also includes Sweet’s syndrome and pyoderma gangrenosum.4 Presentation as a prodromal manifestation of leukemia before the introduction of chemotherapy and its development in an otherwise healthy person as a probable complication of prolonged pressure suggests that the etiology is likely to be multifactorial.12,16 The most significant histological features are seen in the deeper reticular dermis and subcutaneous fat where a dense neutrophil polymorph infiltrate surrounds the eccrine secretory coils (Fig. 14.98). The coiled and straight dermal ducts are typically unaffected. Leukocytoclasis is sometimes evident.4,22 The glandular epithelium shows neutrophil infiltration, nuclear pyknosis, cytoplasmic eosinophilia or vacuolation and often appears sloughed off into the lumen of the gland.7 Syringosquamous metaplasia may additionally be present; rarely, necrosis of the eccrine gland is seen in the absence of significant inflammation.8,17,23,24 The periadnexal fibroadipose tissue stroma typically shows mucinous degeneration and a variable infiltrate of neutrophils, lymphocytes, histiocytes, and eosinophils.8 Recently, it has been shown that the apocrine glands may be affected in addition to the eccrine glands.25 There is no evidence of vasculitis.

Fig. 14.98 Neutrophil eccrine hidradenitis: there is a neutrophil infiltrate involving the eccrine gland. Note the sparing of the duct in the center of the field.

Differential diagnosis Idiopathic plantar hidradenitis (idiopathic recurrent palmoplantar hidradenitis in children, neutrophilic eccrine hidradenitis in children) is a rare dermatosis in which tender, painful, erythematous papules, plaques, and nodules, 0.5–3.0 cm in diameter, develop on the soles of the feet of children.26–30 Pustular lesions have been reported.31 Less often, concomitant palmar involvement has been documented.27 Recurrences are not uncommon. The condition shows a predilection for females (2:1).26 Incidence shows seasonal variation, lesions developing most often in spring and autumn. Adults may also rarely be affected.32 Although trauma does not appear to be an etiological factor, chronic pressure is probably of importance. Prolonged immersion in hot bath water preceded the development of lesions in a number of cases. Pyrexia is not usually present and the patients are otherwise well. The condition generally clears spontaneously. In contrast to eccrine neutrophilic hidradenitis, the changes are centered on the coiled duct and proximal straight duct, the secretory apparatus usually being spared or only minimally affected.26 There is an intense neutrophil infiltrate surrounding and involving the ductal epithelium associated with epithelial degenerative changes and necrosis. Abscess formation may also be a feature. Eccrine syringosquamous metaplasia is not seen. Rarely, neutrophilic eccrine hidradenitis may represent a primary infectious process, for example Serratio spp., Enterobacter cloacae, Staphylococcus aureus, and Nocardia asteroides.33–35

Eccrine squamous syringometaplasia Clinical features Eccrine squamous syringometaplasia (syringosquamous metaplasia) is a histologically distinctive eruption that may rarely develop following chemotherapy.1–3 Patients present with erythematous papules often in a generalized distribution following the administration of a number of chemotherapeutic agents including bleomycin, cytarabine, daunorubicin, doxorubicin, and cisplatinum (Fig. 14.99). A similar response has been seen more recently with the kinase inhibitors sunitinib and imatinib.4,5 Pustules and vesicles are sometimes seen. Presentation as acral erythema has also been documented.6,7

Histological features The changes primarily affect the upper portion of the eccrine duct and consist of squamous metaplasia associated with apoptosis of the lining epithelium (Figs 14.100, 14.101).1 Periductal edema and fibrosis may also be seen. A perivascular infiltrate consisting of lymphocytes and occasionally neutrophils is present in the surrounding dermis.

Fig. 14.99 Eccrine squamous syringometaplasia: there is an erythematous patch with a dusky center on the thigh and in the inguinal fold.

Adverse reactions to cytokine therapy

Fig. 14.100 Eccrine squamous syringometaplasia: the eccrine ductal wall is replaced with squamous epithelium.

Fig. 14.101 Eccrine squamous syringometaplasia: high-power view.

Differential diagnosis Eccrine squamous syringometaplasia may occur in a wide variety of settings. It may be found adjacent to cutaneous ulcers, following severe burns, as a feature in panniculitis, linear scleroderma, and pyoderma gangrenosum, in fibrous hamartoma of infancy, in recall phenomenon, in association with tumors including squamous cell carcinoma and keratoacanthoma, and in infections including herpes virus, cytomegalovirus, and human immunodeficiency virus.8–15 It has also been described as a complication of benoxaprofen therapy.16

Adverse reactions to cytokine therapy Clinical features A very wide range of adverse reactions to the large number of recombinant cytokines available as therapeutic agents has been described.1 These are very comprehensively documented in the review article of Asnis and Gaspari.2 The majority of these agents have to a greater or lesser extent been associated with local injection site reactions (painful or pruritic erythematous wheals).2 Only a limited number of cytokines, which may be associated with more specific dermatological manifestations, are included in this section.

Granulocyte colony-stimulating factor (G-CSF, filgrastim; a glycoprotein that stimulates proliferation and differentiation of neutrophils) therapy has been associated with a number of dermatological conditions including bullous pyoderma gangrenosum, folliculitis, leukocytoclastic vasculitis, and Sweet’s syndrome.2–9 G-CSF and GM-CSF have also been incriminated in exacerbation of pre-existent leukocytoclastic vasculitis, psoriasis, a generalized erythematous eruption, erythematous plaques, and a localized lichenoid reaction.10–15 A number of adverse reactions have been described following treatment with GM-CSF (a growth factor which stimulates proliferation and differentiation of neutrophils, monocytes, and eosinophils) including localized angioedema, facial flushing, and generalized erythematous, maculopapular, exfoliative, urticarial, pruritic and pustular cutaneous reactions.2,16–19 Localized pustular and vasculitic reactions, generalized folliculitis, epidermolysis bullosa acquisita, and alopecia have also followed treatment with GM-CSF.2,7,18–21 The use of IFN-α may be followed by localized erythema and less often skin necrosis. It is followed by the development of alopecia in up to 10% of patients.22 Psoriasis, pyoderma gangrenosum, localized granulomatous and suppurative lesions, ulcers, vasculitis, systemic lupus erythematosus, eosinophilic fasciitis, eczematous lesions, photosensitivity, and paraneoplastic pemphigus have also complicated its use.2,23–29 Sarcoidosis induced by IFN-α is also well documented.30,31 Cutaneous and systemic disease may occur as a consequence of enhanced helper T-cell type 1 (Th1) immune response, resulting in granulomatous inflammation. Pegylated IFN-α, used increasingly for its improved bioavailabity compared to traditional interferon, has been linked to hyperpigmentation.32–34 Expression of α-melanocyte stimulating hormone receptors is increased by interferon, and is thought to be the cause of lingual and cutaneous darkening. Cutaneous lesions are reported to occur at sites of injection and elsewhere, including the face, trunk, extremities, and nails. Lesions develop weeks to months after starting therapy. Single case reports have documented instances of fatal pemphigus vulgaris and allergic facial contact dermatitis following treatment with IFN-β.35,36 Erythematous plaques, cutaneous ulceration, necrosis, vasculitis, sclerodermiform lesions, and lobular panniculitis have also been documented.37–43 IFN-γ may induce psoriatic plaques at the injection site and its use has been shown to induce erythema nodosum leprosum in patients with leprosy.44,45 IL-2, which is produced by activated T lymphocytes, stimulates the production of a number of cytokines including IFN-γ, tumor necrosis factor and GM-CSF in addition to inducing differentiation of an activated killer cell population which has a cytotoxic effect on tumor cells.46,47 Dermatological complications of recombinant IL-2 (r IL-2) therapy include a desquamating, diffuse erythematous macular eruption, pruritus, purpura, telogen effluvium, mucositis with aphthous ulcers, and glossitis.2,46 Toxic epidermal necrolysislike blistering dermatoses, pemphigus vulgaris, linear IgA disease, vitiligo, and erythema nodosum have also been reported.2,29,48–52 IL-2 therapy may be associated with exacerbation of psoriasis.53,54 Pruritus, facial edema, and a transient acantholytic dermatosis-like eruption affecting the chest, back, and proximal extremities have been described following treatment with IL-4 and there is a case report describing the development of vitiligo in association with recombinant IL-4 therapy.55,56

Histological features Histologically, the erythematous lesions associated with G-CSF show epidermal acanthosis, parakeratosis, eosinophilic spongiosis with abscess formation, and interface changes.14 The lichenoid eruption is characterized by hyperkeratosis, dyskeratosis, and interface change accompanied by a lymphocytic infiltrate.15 An atypical dermal histiocytic infiltrate characterized by nuclear pleomorphism and mitotic activity has recently been documented.57 The erythematous maculopapular eruption associated with GM-CSF is characterized by edema and a superficial perivascular and interstitial inflammatory cell infiltrate composed of T-helper lymphocytes, histiocytes, eosinophils, and conspicuous neutrophils accompanied by epidermal spongiosis and lymphocyte/neutrophil exocytosis.16–18 Focal dyskeratosis may also be a feature.16

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Cutaneous adverse reactions to drugs The histological features of hyperpigmentation from pegylated IFN-α include increased melanin along the basal layer of the epidermis and papillary dermal melanophages.33 There is no associated iron deposition. Lobular panniculitis associated with IFN-β demonstrates a spectrum of changes.43 Early on, there is a neutrophil-rich lobular panniculitis with sterile microabcess formation. Intravascular thrombi without vasculitis, increased interstitial mucin, and microcalcification may be seen. Areas of fat saponification with microcalcification are typical and must be distinguished from pancreatitis-associated panniculitis. As lesions become longstanding, there is less inflammation, predominantly comprised of mononuclear cells with septal fibrosis and calcification surrounding adipocytes. IL-2 skin reactions are characterized by interface vacuolar degeneration with rare necrotic keratinocytes accompanied by lymphocyte exocytosis and focal spongiosis.3,46,54 Papillary dermal edema is present with a superficial perivascular lymphohistiocytic infiltrate. Rarely, epidermal necrosis may be extensive.46 The infiltrate consists predominantly of CD3+/CD4+/CD25-/HLA-DR+ T-helper cells with a small subpopulation of CD8+ lymphocytes. Endothelial cells and keratinocytes express ICAM-1.46 Histologically, the transient acantholytic dermatosis-like eruption associated with IL-4 therapy is characterized by acantholysis and suprabasal cleft formation with dyskeratosis, spongiosis, and a superficial perivascular lymphohistiocytic infiltrate with rare eosinophils.55 Immunofluorescence studies have not been performed.

Cutaneous reaction of lymphocyte recovery Clinical features This unusual condition follows return of lymphocytes to the general circulation and skin after induction or augmentation chemotherapy.1,2 It has been described most often following combined cytarabine and daunorubicin treatment and also following treatment with amsacrine, etoposide, interferon, cyclophosphamide, and vincristine.3 Patients present with a pruritic, erythematous maculopapular eruption associated with pyrexia.1 The eruption resolves with desquamation.2

Histological features The histological features include mild spongiosis with lymphocyte exocytosis associated with interface change, keratinocyte atypia with impaired maturation (chemotherapy effect) and minimal dyskeratosis.1,2 There is vascular dilatation and a perivascular lymphocytic infiltrate is present in the superficial dermis. Eosinophils are absent.2 Exceptionally, epidermal lymphocyte infiltration may be very marked so as to mimic mycosis fungoides.4 The infiltrate is composed of CD3+/CD4+ T-helper cells with a smaller subpopulation of CD8+ cells.2 The lymphocytes may also express CD25.4 Epidermal Langerhans cells are reduced in number and there is minimal to absent keratinocyte HLA-DR and ICAM-1 expression.2,4 Nuclear pleomorphism with hyperchromatism and expression of CD30, CD25, and HLA-DR has been described in the eruption of lymphocyte recovery in patients who have also received human recombinant cytokines including GM-CSF and IL-3.5

Histological features Amalgam tattoos, which consist of mercury and silver, sometimes accompanied by tin, present as fine to globular, brown to black deposits lying free or within macrophages and also deposited on the elastic tissue fibers and blood vessels within the lamina propria.2–4

Tumor necrosis factor-a inhibitors The use of tumor necrosis factor-α (TNF-α) inhibitors has rapidly expanded over the past decade. Etanercept, infliximab, and adalimumab are FDA approved for treatment of plaque-type psoriasis, rheumatoid arthritis, and ankylosing spondylitis. Other indications for its use include Crohn’s disease, ulcerative colitis, and juvenile idiopathic arthritis. As use of these medications has increased, so too has the side effect profile. The most common adverse dermatological effect is injection site reaction, occurring in up to one-third of patients.1,2 Erythematous, edematous, eczematous lesions are described most commonly, although discoid lupus erythematosus and localized vasculitis have been reported.1–3 Generalized vasculitis may also occur, either following localized lesions or de novo, involving the skin and other organ systems (kidneys, central and peripheral nervous systems, serosa, myocardium, lung, gall bladder).4,5 Paradoxically, a common cutaneous side effect seen distant from the injection site is psoriasis.6 Both psoriasis vulgaris and palmar-plantar pustular psoriasis have been described, predominantly in patients treated for rheumatoid arthritis, ankylosing spondylitis and Crohn’s disease (Figs 14.102–14.104).7 Most psoriasiform reactions occur 6 to 10 months after starting therapy.7,8 The proposed mechanism is increased IFN-α production by plasmacytoid dendritic cells (PDC) as a consequence of TNF-α inhibition, which has been shown to induce psoriasis lesions.9–11 There is clinical overlap between the psoriasiform and lichenoid dermatitides associated with the TNF-α inhibitors. The clinical appearance of the lichenoid eruptions may resemble lichen planus, psoriasis, or be non-specific erythematous macules and papules.12 The mechanism for development of these lesions is not well understood but is thought to be a consequence of cytokine imbalance.13 The eruption begins weeks to months after starting TNF-α inhibition therapy. Cutaneous infections are a well known risk with TNF-α inhibitor therapy and include folliculitis, herpes simplex, tinea corporis, and tinea versicolor.14–16 An emerging reaction seen in the setting of TNF-α inhibition is granulomatous inflammation. Case reports describe cutaneous, pulmonary, and

Differential diagnosis The features are indistinguishable from exanthematous drug reactions, viral infections, and acute graft-versus-host disease.6

Dental amalgam tattoos Clinical features Dental amalgam tattoos develop following the accidental implantation of dental amalgam into the soft tissue of the mouth following a dental procedure. Lesions, which are most commonly found on the buccal, gingival, and alveolar mucosa, measure from 0.10 to 1.5 cm and present as flat gray to blue–gray or slate-colored lesions.1

Fig. 14.102 Tumor necrosis factor-α inhibitor reaction: there are thin psoriasiform plaques on the lower legs.

Esthetic microimplants

Fig. 14.103 Tumor necrosis factor-α inhibitor reaction: erythematous, psoriasiform plaques are present on the lower leg. Courtesy of J. Nunley, MD, Virginia Commonwealth University, Richmond, Virginia, USA.

Fig. 14.104 Tumor necrosis factor-α inhibitor reaction: there are tense palmar pustules identical to those seen in palmar-plantar psoriasis.

nodal sarcoidosis which improves upon discontinuation of therapy.17,18 Additional reports include interstitial granulomatous dermatitis and granuloma annulare.19,20 Lupus-like syndromes may also occur as a consequence of therapy with TNF-α inhibitors.21

Histological features Injection site reactions are characterized by dermal edema, a perivascular lymphocytic infiltrate with eosinophils.1–3 Immunohistochemical studies demonstrate CD8-predominant T cells.1 Vasculitis in the setting of TNF-α inhibitor therapy may involve small or medium sized vessels with leukocytoclastic changes.7 Necrotizing features and extravascular granulomatous inflammation have been described. Psoriasis induced by TNF-α inhibitors resembles typical psoriasis, with variable presence of spongiosis and lichenoid inflammation.10 The dermal infiltrate contains mononuclear cells, although eosinophils may be present.10 The few histological descriptions of TNF-α inhibitor-associated lichenoid dermatitis available closely resemble lichen planus, with a lichenoid

Fig. 14.105 Tumor necrosis factor-α inhibitor reaction: there is hyperkeratosis, hypergranulosis, psoriasiform hyperplasia, and interface change with a superficial perivascular lymphohistiocytic infiltrate.

Fig. 14.106 Tumor necrosis factor-α inhibitor reaction: in this example, the features are indistinguishable from sarcoidosis.

infiltrate of mononuclear cells, melanophages involving a hyperplastic epidermis, hyperkeratosis, and hypergranulosis.12 Psoriasiform hyperplasia may be superimposed (Fig. 14.105). TNF-α inhibitor associated sarcoidosis is characterized by noncaseating granulomata in the dermis and/or subcutis (Figs 14.106, 14.107).17 Necrotizing foci are rarely described. Interstitial granulomatous dermatitis demonstrates a diffuse intradermal infiltrate of histiocytes and lymphocytes with a variable number of eosinophils and occasional neutrophils.19 There is no increased dermal mucin or vasculitis. Interface changes occur but are not common.

Esthetic microimplants Cosmetic dermatology is a rapidly evolving industry. The demand for ‘nonsurgical’ rejuvenation has seen a rise in the number of implants and injectable materials available to patients. Unfortunately, inflammatory reactions to these agents occur.

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Fig. 14.107 Tumor necrosis factor-α inhibitor reaction: high-power view.

There are several categories of fillers which may be permanent or resorbable (Table 14.1). Fillers are either polymers, which function as volumizers, creating effect by taking up space, or a combination of degradable polymer and microparticles.1 The microparticles serve as a lattice upon which the host’s response (often collagen induction) contributes partially or completely to the filler’s effect. The microparticles may or may not be degraded over time. Silicone was one of the first agents used for soft tissue augmentation, in the 1950s. It was banned in the United States in 1982 due to concerns over adverse effects such as migration to distant locations.2,3 Inflammatory nodules (‘siliconomas’) may also develop, sometimes years later. Presently, two new forms of liquid silicone are available, Silikon 1000 and Adatosil 5000, for treatment of retinal detachment.1 The former is more easily injected and is used off-label for cosmetic purposes. Polydimethylsiloxane/polyvinyl pyrrolidone (Bioplastique) contains particles of solid silicone and is available for injection into the subcutaneous fat (Fig. 14.108).4 Table 14.1 Esthetic microimplants Chemical Ingredient Resorbable: Bovine collagen Human collagen Porcine collagen Hyaluronic acid (non-animal) Hyaluronic acid (animal) Poly-L-lactic acid Hydroxy-polyethylene/ hydroxyl-polypropylene Calcium hydroxylapatite Permanent: Bovine collagen/polymethyl methacrylate microspheres (PMAA) Hyaluronic acid/ polyhydroxyethylmethacrylate (HEMA) / ethylmethacrylate (EEMA) Silicone (dimethyl polysiloxane) Polydimethylsiloxane /polyvinyl pyrrolidone Polyacrylamide gel (PAAG) Polyacrylamide and polyvinyl acid Polyalkylimide gel Polytetrafluoroethylene

Product Name(s) Zyderm, Zyplast Cosmoderm, Cosmoplast, Cymetra Evolence Restylane, Captique, Perlane, Juvederm Hylaform, Hylaform plus Newfill, Sculptra Profill Radiesse, Radiance Artecoll, Arteplast, Artefill, Metacril DermaLive, DermaDeep

Silikon 1000, Silskin, Adatosil 5000 Bioplastique Aquamid Evolution BioAlcamid Gore-Tex

Fig. 14.108 Restylane nodules: linear arrangement of nodules along the neck creases.

As a consequence of the ban on silicone, bovine collagen was developed. There is a 1–3% rate of allergic reactions, despite double skin testing.4 Many such reactions are localized erythema and edema which occur in the first weeks to months after injection, although recurrent inflammation, years later, has been described. Other potential complications include localized glabellar necrosis, granulomata, and abscess formation.5 Granulomata present as erythematous nodules at the site of treatment and are seen within a few months following injection. Sometimes, lesions are seen years later. Abscesses typically occur weeks to months after injection.4 Hyaluronic acid is commonly used to correct facial creases and wrinkles. There are two types of hyaluronic acid fillers: nonanimal, derived from fermentation of bacteria (Streptococcus equi) and animal, derived from chicken combs.6 Hypersensitivity reactions, although rare, have been reported in up to 0.8% of patients.4,7 Injection site reactions are most common, with temporary erythema, edema, and bruising within the first 14 days following injection.8 Delayed reactions are less common and present as erythematous, firm nodules along the sites of injection weeks to months later.6–11 There are two types of nodules: granulomatous and nongranulomatous. The etiology of the granulomatous response is unclear. There is speculation that it could be secondary to impurities related to the fermentation process in the ­nonanimal-derived form.12 Additional side effects to hyaluronic acid include sterile abscesses, hyperpigmentation, and a livedoid, reticular pattern in the area of injection.7 Foreign-body granulomata have also been seen following injection with poly-L-lactic acid (Newfill, Sculptra) and polyacrylamide gel (Aquamid).4,5 Hydroxy-polyethylene/hydroxyl-polypropylene (Profill) is also associated with lipoatrophy.4 Polytetrafluoroethylene (Gore-Tex) has been used for lip augmentation and has resulted in ulcerated nodules with pustules.14 Immediate-type reactions such as erythema, edema, and bruising have also been described with other fillers, including hydroxy-polyethylene/hydroxylpolypropylene (Profill), polyacrylamide-containing products, and poly-L-lactic acid.4,13 Infection is a potential complication following any cosmetic procedure.13 Early infections, occurring within 2 weeks, are typically secondary to bacteria such as Staph. aureus or Streptococcus.3,13 Later infections may be due to atypical mycobacteria such as Mycobacteria chelonae, M. fortuitum, and abscesses.13

Histological features Silicone nodules contain multiple vacuoles in the dermis, subcutis, and skeletal muscle.3,4,13 Vacuoles are variable in size and shape and resemble Swiss cheese. These are actually empty spaces where silicone was lost during processing. They are surrounded by giant cells and histiocytes which

Esthetic microimplants contain intracytoplasmic vacuoles. Additionally, impurities in the silicone result in birefringent foreign material within giant cells.3,4 Surrounding fibrosis may also be noted.3 The silicone particles in polydimethylsiloxane/ polyvinyl pyrrolidone are too large to be phagocytosed by histiocytes.1 The material induces a foreign body giant cell reaction and fibrosis. The particles are identified as translucent, jagged structures within cystic spaces.4 Bovine collagen is distinguished from human collagen by its lighter eosinophilic color, thicker bundles, and more amorphous, acellular appearance.4 When recurrent inflammatory reactions develop in hypersensitive patients, there is a perivascular mononuclear cell infiltrate with a mixture of neutrophils, mononuclear cells, and eosinophils within implanted collagen.4 Early granulomatous nodules are comprised of a mixture of ­mononuclear cells, giant cells, eosinophils, neutrophils, and plasma cells surrounding but not infiltrating the collagen implant.4 Later lesions have a denser and deeper infiltrate. Birefringent material is not seen. In contrast, nodules due to bovine collagen with polymethyl methacrylate microspheres (PMAA) (Artecoll) contain a diffuse and nodular granulomatous infiltrate which surrounds cystic spaces, mimicking fat cells and with a Swiss cheese appearance.3 Located in the center of the spaces are nonbirefringent, round, translucent, well-­circumscribed foreign bodies (Fig. 14.109). This foreign material is the PMMA microsphere which also induces surrounding fibrosis. The fibrosis contributes to the filling-effect. Hyaluronic acid with polyhydroxyethylmethacrylate (HEMA)/ethylmethacrylate (EEMA) (DermaLive, DermaDeep) reactions are very similar histologically to Artecoll, as they also contain methacrylate microspheres.3 Calcification of the foreign material has been described with DermaLive.1 Asteroid bodies may be present in both reactions. Abscesses seen as a consequence of collagen implants show a dense neutrophilic infiltrate with admixed plasma cells, histiocytes, and mononuclear cells.4 Giant cells surround implanted collagen, and granulomata may be present. Nongranulomatous inflammatory nodules related to hyaluronic acid injection are characterized by a superficial and deep perivascular and periadnexal infiltrate of mononuclear cells with several eosinophils.13 Implanted hyaluronic acid is not seen. In contrast, the granulomatous nodules contain a striking nodular infiltrate of foreign body giant cells, histiocytes, and eosinophils surrounding pools of basophilic foreign material which stain with Alcian blue (pH 2.7).4,13 Polyacrylamide gel (PAAG) (Aquamid) has similar features, but is distinguished from injected hyaluronic acid by the presence of necrotic tissue admixed with the basophilic foreign material.13 Poly-L-lactic acid (Newfill, Sculptra) nodules are granulomatous and are distinguished by spiky, long translucent bodies within giant cells.4,13 They are irregular in shape and birefringent. Reactions to bioAlcamid (polyalkylimide gel) display palisading granulomas with scattered giant cells and a central area of amorphous material that may mimic deep granuloma annulare or rheumatoid nodule (Fig. 14.110).

Fig. 14.109 Reaction to Artecoll: note the foreign body granulomatous reaction and the typical swiss cheese appearance.

Ulcers caused by polytetrafluoroethylene (Gore-Tex) demonstrate variably sized threads of material surrounded by neutrophils and granulation tissue (Fig. 14.111).14 Infectious lesions demonstrate variable findings depending on the causative organism. Mycobacterial infections may present as granulomatous nodules, and appropriate tissue stains and culture are necessary.

Alpha-melanocyte stimulating hormone analogues (melanotan I and II) Melanotan I and II are superpotent analogues of alpha-melanocyte stimulating hormone that have photoprotective effects. They appear to be increasingly used by patients who want to develop a prominent tan. Although they are not licensed for this purpose, they can be obtained through the Internet. Their administration not only induces prominent tanning but also induces enlargement and darkening of pre-existing nevi. Histology of these nevi has not been described in detail but the few removed lesions in two patients did not show evidence of malignancy.1

Fig. 14.110 Reaction to Bioalcamid: the central necrobiosis with a surrounding rim of histiocytes shows a striking resemblance to granuloma annulare.

Fig. 14.111 Reaction to Gore-Tex: the mesh is surrounded by dense fibrous tissue.

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Cutaneous adverse reactions to drugs

EMLA cream (prilocaine-lidocaine emulsion) Clinical features

latter changes may mimic epidermolysis bullosa (Fig. 14.112). By electron microscopy, the appearances mimic a lysosomal storage disorder with empty lisosomal inclusions.6 The latter change has been attributed to the castor oil contained in EMLA cream.

EMLA is a eutectic mixture of prilocaine and lidocaine that is used widely as a cream to provide local anesthesia, particularly in children and in adults in genital areas. Very few side effects occur with its application, among them a petechial eruption, contact urticaria, allergic contact dermatitis, and irritant contact dermatitis.1–4 For dermatopathologists, however, what is more important about EMLA are the subtle changes that it can cause at a microscopic level, leading to difficulties in interpretation.5 These changes appear to be related to the time that the cream is applied to the patient and they may be more common in skin in which the biopsy is performed as a result of an inflammatory process.

Histological features In cases of irritant contact dermatitis, the features consist of confluent necrosis of the upper layers of the epidermis, focal interface change with hydropic degeneration of basal cells and clefting at the dermoepidermal junction and an upper dermal mixed inflammatory cell infiltrate with neutrophils.4 The changes mimic a necrolyic erythema or graft-versus-host disease. In cases with no clinical evidence of a side effect, there is vacuolization of the granular cell layer and upper stratum spinosum and focal areas with hydropic degeneration of basal cells and clefting at the dermoepidermal junction.5 The

Fig. 14.112 Reaction to EMLA cream: in this example, there are multiple small foci of subepidermal vesiculation.

See www.expertconsult.com

for references and additional material

Neutrophilic and eosinophilic dermatoses

Pyoderma gangrenosum  631 Acute febrile neutrophilic dermatosis  636 Neutrophilic dermatoses associated with gastrointestinal and hepatobiliary disease  639 Rheumatoid neutrophilic dermatitis  640 Arthropod and arachnid bite reactions  641

Seabather’s eruption and coelenterate stings  643 Erythema marginatum rheumaticum  644 Still's disease  644

Chapter

15

Eosinophilic cellulitis  649 Eosinophilic pustular folliculitis  651 Incontinentia pigmenti  652 Toxic erythema of the neonate  655

Urticaria  645

Hidradenitis suppurativa  655

Papular urticaria  649 Hypereosinophilic syndrome  649

Pyoderma gangrenosum Clinical features Pyoderma gangrenosum is an uncommon disease of obscure etiology.1–11 It appears to be somewhat more common in women and, although it may occur at any age, most patients are in their fourth or fifth decade.4 Presentation in children is uncommon, but it has been seen even in infants,12–21 and rare ­familial cases have been documented.22–24 The disease may also present in pregnancy and in this setting it is associated with an underlying disease ­process in about 50% of the cases.25–28 Large, necrotic ulcers, often 10 cm or more in ­diameter, characterize the disease (Fig. 15.1). Lesions may arise from ­acneiform ­pustules or on a background of erythematous nodules. Typically, the ulcers have undermined edges and red–purple borders (Fig. 15.2).

They may be ­solitary or multiple, and occur most often on the lower limbs, although other sites such as the trunk, face, arms, and buttocks are sometimes affected (Fig. 15.3).29–30 Rare sites of involvement include the oropharyngeal region, hand, eyelid, eye, vulva, penis, scrotum, and the ­cervix.31–44 The ulcers are ­painful and tender, and may persist for months or years. Complications ­usually result from the site of the lesion and include cranial osteolysis and nasal ­perforation.17,45 Recurrent attacks are not uncommon.2 Cribriform ­scarring often follows healing. Systemic involvement has rarely been ­documented, affecting the lungs, liver, bone, joints, pancreas, and heart.46–51

Fig. 15.2

Fig. 15.1 Pyoderma gangrenosum: this unusually severe example is associated with very extensive tissue destruction resembling necrotizing fasciitis. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Pyoderma gangrenosum: this shows an area of ulceration with a typical undermined purplish border. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

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Neutrophilic and eosinophilic dermatoses

Fig. 15.3 Pyoderma gangrenosum: an extensive lesion with marked crusting and undermining in the proximal and medial margins. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Occasionally bullous or pustular variants are encountered.4,52–60 One large study found that bullous lesions are more common on the upper ­extr­emities and they appear to be more frequently associated with hematological ­malignancy.4 Such lesions are sometimes designated atypical pyoderma gangr­ enosum.4,53 A vegetative form has also been described.61–65 A particularly interesting feature seen in as many as 50% of cases is ­development of lesions in traumatized areas (pathergy).4,66,67 Lesions may occur at sites of surgery and have been reported after cholecystectomy, breast reduction or augmentation, splenectomy, hysterectomy, cesarian section, fol­ lowing aortic valve replacement, at the site of a fasciocutaneous flap, a lap­ aroscopic port insertion site, and in an amputation stump (Fig. 15.4).68–81 They also occur following rather trivial trauma such as injection or intrave­ nous access site, ­arteriovenous dialysis shunt, blood-drawing, ­acupuncture

Fig. 15.4 Pyoderma gangrenosum: multiple early lesions at the site of previous surgery. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

or a tattoo.4,82–85 Pressure from use of seat belts in automobiles has been ­associated with subsequent lesion development.86 Presentation has even been documented at the location of a spider bite.87 One case reports involvement of the scalp after receiving hair highlights at a salon, which could be due to physical and/or chemical trauma.88 A few publications have implicated drugs in the etiology of the disease, including: • alpha-2b interferon (IFN-α2b), • isotretinoin, • sulpiride, • propylthiouracil.89–94 In a single case report, pyoderma gangrenosum developed after ­combination therapy with cytosine arabinoside, aclarubicin, and granu­ locyte colony-stimulating factor for myelodysplastic syndrome.95 Another single report associates gefitinib, an EGFR inhibitor, with pyoderma gan­ grenosum.96 A granulomatous and suppurative dermatitis that may mimic pyoderma gangrenosum has been documented at the site of interferonalpha (IFN-α) ­injections.97 Sclerotherapy has also been complicated by pyoderma gangrenosum on rare occasions.98 Association with sunitinib was reported in a single case study.99 Of particular importance is the known association of pyoderma gangreno­ sum with a variety of conditions4,11,100 (in up to 50% of patients2) as outlined in Table 15.1. Of these, inflammatory bowel disease (both Crohn’s disease and ulcerative colitis) and arthritis show the most well-established links.101–103 Pyoderma gangrenosum is reported to complicate around 1–2% of inflam­ matory bowel disease patients.104–106 In one study, 27% of patients had asso­ ciated inflammatory bowel disease and 20% of patients had arthritis.4 In this same study, 27% of patients with superficial ‘atypical’ pyoderma gangrenosum had an associated hematological disorder.4 In another large study, idiopathic pyoderma gangrenosum and that associated with chronic inflammatory bowel disease were found to be more common in females, whereas pyoderma gangrenosum associated with hematological malignancy was more common in males.5 While pyoderma gangrenosum can fluctuate with inflammatory bowel disease activity, it may also be a presenting or heralding feature. The presence of pyoderma gangrenosum as a complication of inflammatory bowel disease does not appear to be an independent ­predictor of severity of the bowel disease.107,108 Although pyoderma gangrenosum lesions may improve as inflammatory bowel disease is brought under control, specific treatment is usually required.109 Most of the other numerous, rare associations men­ tioned in Table 15.1 are likely to be fortuitous, as a report of simple coex­ istence does not strictly imply a meaningful association.110 In any event, a diagnosis of pyoderma ­gangrenosum should always prompt an evaluation for an underlying disease association. Pyoderma gangrenosum-like lesions have been reported as the presenting feature of antiphospholipid antibody syn­ drome.111 Other underlying conditions causing lesions that mimic pyoderma gangrenosum are also well described including inflammatory and infectious processes, vasculopathies, and malignancies, stressing the importance of care­ ful c­ linical investigation.112–122 The disease may also occur in association with other neutrophilic derma­ toses including Sweet’s syndrome.123–125 Pyoderma gangrenosum is one of the components of a recently described autosomal dominant syndrome known as PAPA (pyogenic ster­ ile arthritis, pyoderma gangrenosum and acne).126 This syndrome has been mapped to chromosome 15q and is associated with mutations in the gene CD2BP1/PSTPIP1.127–131 These mutations increase the binding affinity of this gene product to pyrin, overcoming the autoinhibition of this homotrimer and allowing activation of the downstream innate immune response.132–134 Ultimately, this mutation leads to an increase in caspase-1 activation, an underlying feature of multiple inherited autoinflammatory syndromes.135 Cases lacking a mutation in this gene have also been reported.136 These find­ ing indicate that pyoderma gangrenosum may be best regarded as an autoin­ flammatory or autoimmune disease and the pathways being studied in PAPA syndrome may also eventually shed light onto the pathogenic mechanisms of sporadic pyoderma gangrenosum. Para- and peristomal involvement in patients with ileostomy or colostomy for inflammatory bowel disease is a well-recognized phenomenon.4,137–141 In a large series, 13% of patients had peristomal pyoderma.4 Both Crohn’s disease

Pyoderma gangrenosum Table 15.1 Conditions associated with pyoderma gangrenosum (alphabetical order)

• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • •

Acne fulminans, acne conglobata and hidradenitis suppurativa184–188 Acquired ichthyosis189 Acute myeloid leukemia190 Allergic contact dermatitis from rubber191 Anaplastic large cell lymphoma192 Antineutrophil cytoplasmic antibodies193–195 Arthritis (either seronegative or rheumatoid arthritis), ankylosing spondylitis and osteoarthrosis 4,196–198 Autoimmune neutropenia of infancy199 Behçet’s disease200 Bullous systemic lupus erythematosus201 Burns / scalding202,203 C7 deficiency204 Chronic idiopathic myelofibrosis205 Chronic myelomonocytic leukemia206 Chronic renal failure207 Chlamydia pneumoniae208 Cogan’s syndrome (interstitial keratitis and vestibuloauditory dysfunction) 209 Collagenous colitis210, 211 Colorectal carcinoma212 Cutaneous T-cell lymphoma213 Cryofibrinogenemia214 Cryoglobulinemia6 Diverticular disease215 Essential thrombocythemia 216 Fanconi’s anemia217 Factor V Leiden deficiency214 Gastric carcinoma154,218 Grave's disease219 Glomerulonephritis220 Hepatitis, autoimmune and viral156, 221–225 Human immunodeficiency virus (HIV) infection226–228 Hypertrophic osteoarthropathy229 Hypogammaglobulinemia230, 231 Inflammatory bowel disease: both ulcerative colitis and Crohn’s disease2,4,104 Juvenile idiopathic arthritis232 Kartagener’s syndrome233 Klinefelter's syndrome234 Lupus anticoagulant235 Monoclonal gammopathy (most often IgA); usually benign but may lead to multiple myeloma2,54,196,236 Multiple sclerosis237 Myelodysplastic syndrome238,239 Myelofibrosis240 Myeloid leukemia54,56,155,241 Osteomyelitis12,242 Paroxysmal nocturnal hemoglobulinuria243 Polycythemia rubra vera198 Psoriasis244 Renal transplant245,246 SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis)247,248 Sarcoidosis249 Sjogren syndrome250 Subcorneal pustular dermatosis251,252 Systemic lupus erythematosus253 Systemic sclerosis254 Tuberculosis255 Varicella (chickenpox)256 Vasculitis, including Takayasu’s disease, erythema elevatum diutinum and Wegener’s granulomatosis257–263

and ulcerative colitis are associated with this complication.4,140,142 It should be noted that peristomal pyoderma gangrenosum has been seen in the absence of inflammatory bowel disease.137,138 It has been documented in patients with ostomy for gastrointestinal carcinoma and diverticular ­disease.137,138 Pyoderma gangrenosum may also occur at urostomy sites following ­cystectomy for ­bladder carcinoma.138

Superficial granulomatous pyoderma is believed to represent a ­superficial and rare variant of pyoderma gangrenosum.3,143–148 Patients develop single or sometimes multiple superficial ulcerated lesions with vegetative borders (for this reason this variant is sometimes referred to as ‘vegetative variant of ­pyoderma gangrenosum’) as a consequence of trauma, frequently ­surgical (Fig. 15.5). Pain is an occasional feature. The ulcers have a cleaner base than those seen in classic pyoderma. Lesions are most commonly found on the trunk and upper extremities and heal with cribriform scarring (Fig. 15.6). Draining sinuses are occasionally evident. Often there is no evidence of under­ lying systemic disease. Superficial granulomatous pyoderma is more likely to follow a chronic course compared with classic pyoderma gangrenosum.149 So-called ‘malignant pyoderma’ is a controversial designation which we believe should be avoided. Some authors have used the term to describe a vari­ ant of pyoderma gangrenosum predominantly affecting the head and neck.150– 152 More recently, however, it has been postulated that at least some cases of so-called malignant pyoderma more likely represent cutaneous Wegener’s granulomatosis.153 One study found that over 50% of patients with pyoderma gangreno­ sum required long-term therapy to control their disease.5 The disease may be

Fig. 15.5 Superficial granulomatous pyoderma: crusted superficial lesion with a cribriform appearance. By courtesy of the Institute of Dermatology, London, UK.

Fig. 15.6 Superficial granulomatous pyoderma: this field shows extensive ulceration of the breast. By courtesy of R.K. Winkelmann, MD, Mayo Clinic, Scottsdale, Arizona, USA.

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Neutrophilic and eosinophilic dermatoses fatal in some cases, particularly if diagnosis is delayed.6,154 In another study, 2 of the 21 patients reported died of pyoderma gangrenosum secondary to ­pulmonary involvement.6

Pathogenesis and histological features The precise pathogenesis of pyoderma gangrenosum is uncertain. The current state of knowledge suggests that it is due to immune dysfunction, perhaps innate, and/or that it develops on a vasculitic basis.10,128,155–160 A variety of immunological abnormalities have been described including: • absent delayed hypersensitivity reactions to common antigens such as mycobacteria and Candida albicans, • defective neutrophil chemotaxis, • impaired neutrophil phagocytosis, • diminished lymphokine (migration inhibition factor) production,155,156,158 • overexpression of interleukin-8, a potent chemotactic polypeptide for neutrophils, has been reported in lesional tissue and may be an important pathogenetic factor,161,162 • reduction in interleukin-8 and related molecules has been noted following successful therapy,163 • aberrant neutrophil trafficking and metabolic integrin β2-CR3 and -CR4 oscillations in lesional tissue,164,165 • elevated levels of HIF2a and downstream effectors VEGF and Ang-2 have been noted in disseminated disease, suggesting that angiogenesis in improper control of the neutrophil oxidative burst may be involved,166 • elevated TNF-α, MMP-9, and MMP-10 have also been noted,167 • TNF-α may have some of its effects mediated by keratinocyte secretion of elafin, an elastase inhibitor.168 Indeed anti-TNF-α therapy has been described to show some efficacy;169–173 however, a case has also been described in association with TNF-α antagonists used to treat rheumatoid arthritis and the relationship may be complex.174 The results of immunofluorescence studies in large series of patients have revealed both immunoglobulins (usually IgM) and complement in blood ves­ sel walls in the dermis of the leading edge of the ulcer.175,176 Another study, however, failed to substantiate this finding.2 There is no evidence to support an infective pathogenesis.177 Expanding T-cell clones in both the skin and circulation have been described in a small series of patients indicating that T-cell response plays a role in the disease and may be triggered by a local stimulus in the skin.178 T-cell clonality has been described in pyoderma gangrenosum in the absence of an underlying myeloproliferative disease.179 In general, the histopathology is that of non-specific ulceration with abscess formation (Fig. 15.7). The adjacent dermis shows acute and chronic inflam­ mation. A pseudo-Pelger-Huet phenomenon with hyposegmented neutrophils

A

Fig. 15.8 Pyoderma gangrenosum: early acneiform lesion showing a subcorneal pustule.

­ aking recognition difficult has been described in one patient.180 Early lesions m may present with subcorneal pustulation (Fig. 15.8). Although the histological features of both leukocytoclastic and lymphocyte-mediated vasculitis have been described, it is our experience that any vasculitis present is usually located within the floor of the ulcer or in the immediate adjacent tissues and is, therefore, more likely to be a consequence, rather than a cause, of the lesion (Fig. 15.9).1,181 Giant cells appear to be a common feature of pyoderma gangreno­ sum in patients with Crohn’s disease.7 In one study, they were present in 6 of 13 patients with associated inflammatory bowel disease; of these, 5 had Crohn’s disease and 1 had ulcerative colitis.7 Giant cells were not found in any ­biopsies from 22 patients without associated inflammatory bowel disease. Superficial granulomatous pyoderma is characterized by a zoned inflamma­ tory infiltrate in the superficial dermis.3 Focal and sterile abscesses are surrounded by a zone of granulomatous inflammation bordered by a rim of lymphocytes and plasma cells (Figs 15.10–15.12).3 Hemorrhage is often present and eosinophils may be evident. Any vasculitic change is thought to be secondary. The adjacent tissues may show scarring. Acanthosis and pseudoepitheliomatous hyperplasia are frequently noted. Foreign material including starch, sutures, vegetable mat­ ter, wood, and hair has been identified in a large proportion of these cases.3 It should be noted that not all cases of pyoderma gangrenosum with granu­ lomatous inflammation are limited to the superficial dermis. Some cases show involvement of the deep dermis and even subcutaneous tissue.

B

Fig. 15.7 (A, B) Pyoderma gangrenosum: in this biopsy from the edge of an ulcer, there are massive intradermal inflammatory changes, with abscess formation.

Pyoderma gangrenosum

Fig. 15.9 Pyoderma gangrenosum: acute necrotizing vasculitis. It is likely that any active inflammation of the blood vessel walls is a result of the surrounding inflammation rather than its cause.

Fig. 15.12 Superficial granulomatous pyoderma: high-power view showing multinucleate giant cells. There are also conspicuous plasma cells.

Differential diagnosis

Fig. 15.10 Superficial granulomatous pyoderma: low-power view showing an undermining ulcer.

Fig. 15.11 Superficial granulomatous pyoderma: the zoned inflammatory reaction is clearly seen. Note the central abscess and surrounding granulomatous inflammation.

The histopathological findings in pyoderma gangrenosum are non-specific and the diagnosis is primarily one of exclusion.182 Since surgery is used to manage some of the disorders considered in the histological and clinical dif­ ferential diagnosis – but is contraindicated in the treatment of pyoderma gangrenosum – early and accurate diagnosis is critical. Surgery, which tends to exacerbate the disease, is generally contraindicated in pyoderma cases because of the pathergic response. The mainstay of therapy is medical man­ agement, such as corticosteroids. Unfortunately, patients with pyoderma are often misdiagnosed early in the course of their disease and the diagnosis is sometimes made only after multiple unsuccessful (and damaging) surgeries have been performed. In one study, an average of five physicians had exam­ ined the patient before a correct diagnosis was rendered.29 To avoid this error, obtaining accurate clinical information on wounds and debridement speci­ mens is essential. Culture is required to exclude infection (bacterial, mycobacterial, fun­ gal). Necrotizing fasciitis tends to affect deeper fascial and subcutaneous tissue, while pyoderma is centered in the dermis (albeit some spillover into the subcutis may be seen). Usually, sheets of bacteria are evident in untreated necrotizing fasciitis. Distinguishing these two conditions is critical since the treatments are diametric opposites with surgery and antibiotics for necrotizing fasciitis and avoidance of surgery with sys­ temic anti-immune treatment and supportive wound care for pyoderma gangrenosum.183 Sweet’s syndrome is generally not associated with ulceration and shows more prominent karyorrhexis relative to the number of neutrophils. Bite reactions, particularly resulting from the brown recluse or other spiders, may show similar histological features. Clinical information is necessary to distinguish pyoderma from many other forms of ulcer such as those due to trauma. Although some authors have noted lymphocytic or neutrophilic vascu­ litis in lesions of pyoderma gangrenosum, this finding, in our experience, is limited to areas adjacent to the ulcer and likely represents a second­ ary finding.5 Indeed, it has been our experience that ‘secondary’ vasculitis is frequently present at the border of ulcers of many different etiologies in patients without any genuine underlying ‘primary’ vasculitic process. Evaluation for vasculitis as a cause of ulceration therefore depends upon examination of blood vessels in areas of dermis and subcutaneous tissue away from the ulcer. It cannot be overemphasized how important accurate clinical information is in establishing the correct diagnosis. Failing to recognize this disease early in its course can be disastrous for the patient.

635

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Neutrophilic and eosinophilic dermatoses

Acute febrile neutrophilic dermatosis Clinical features Acute febrile neutrophilic dermatosis (Sweet’s syndrome) is an uncommon disease of unknown etiology and pathogenesis.1–11 It is associated with a marked female predilection (5:1) and most patients affected are in their third through sixth decades. It may, however, occasionally be seen in children and a few cases presenting in infancy have been documented.12–22 Infant broth­ ers who both had Sweet’s syndrome have been reported.23 Patients present with variable numbers of asymmetrically distributed, frequently bilateral, cir­ cumscribed, tender and painful red plaques or nodules, particularly on the face, neck, and upper and lower limbs (Figs 15.13–15.15). An acral form of this condition is now termed neurophilic (or pustular) dermatosis of the dorsal hands (Fig 15.16).24–31 Whether this represents a distinct disease or a ­peculiarly localized variant of Sweet’s syndrome is uncertain.

Occasionally, the lesions may become bullous or pustular.32,33 The plaques vary from about 1 to 4 cm in diameter and typically heal without scarring. Recurrences develop in approximately one-third of patients and postinflammatory hyperpigmentation is sometimes seen.34,35 Pathergy and ­koebnerization are occasional features and necrosis with ulceration may rarely be encountered.7,36–38 Sweet’s syndrome may present with lesions mimicking ­palmoplantar pustulosis and sometimes erythema nodosum-like lesions are present.32,39,40 A Sweet’s syndrome-like eruption has been described in a­ ssociation with exposure to light.41 Sweet’s syndrome often follows an upper respiratory tract infection. In some cases it is a complication of drug treatment, for example carbamazepine, furosemide, hydralazine, co-trimoxazole, abacavir, azathioprine, ofloxacin, doxycycline, clindamycin, minocycline, trimethoprim-sulfamethoxazole, bort­ ezomib, lenalidomide, imatinib mesylate, nilotinib, etanercept, granulocyte ­colony-stimulating factor (G-CSF), radiocontrast agent, some vaccines, oral contraceptives, all-trans retinoic acid, isotretinoin, nitrofurantoin, diazepam, clozapine, and celecoxib.32,33,42–69 The temporal relationship with administra­ tion, development of symptoms, and resolution with withdrawal of the offend­ ing drug establishes the cause in drug-induced cases.42,65 The disease has also been reported after chemotherapy in patients with acute ­myeloid ­leukemia.70,71

Fig. 15.13 Sweet’s syndrome: an erythematous plaque on the forearm. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 15.15 Sweet’s syndrome: close-up view of typical plaques. By courtesy of the Institute of Dermatology, London, UK.

Fig. 15.14 Sweet’s syndrome: characteristic edematous red plaques (some showing ulceration and pustulation) are widely distributed on the trunk and proximal limbs. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Fig. 15.16 Sweet’s syndrome: acral lesions on the dorsal surface of the hands and fingers, some with a hemorrhagic appearance. By courtesy of J.C. Pascual, MD, Alicante, Spain.

Acute febrile neutrophilic dermatosis Sweet’s syndrome can be broadly reviewed as falling into three general categories: • classic (and often idiopathic), • malignancy-associated (paraneoplastic), • drug-induced.10 Patients may also have conjunctivitis, episcleritis, iritis, polyneuropathy, oral involvement (superficial ulcers), and arthralgias.32,72–76 The larger joints are usually affected and involvement tends to be migratory.5 Patients with concurrent Sweet’s syndrome and erythema nodosum have been described and it is possible that these two disorders share common pathogenetic mecha­ nisms.77 Dyssynchronous and synchronous Sweet’s syndrome and erythema nodosum may occur.78–81 Sweet’s syndrome is of particular importance since 10–40% of cases are associated with hematological malignancy such as leukemia (monocytic or myelomonocytic, including leukemia cutis), myelodysplasia, lymphoma, and multiple myeloma.82–93 Development of the disease may herald a relapse of the leukemia.94 Sweet’s syndrome has also been reported in patients with mono­ clonal gammopathy and myelodysplasia in the absence of frank leukemia or lymphoma.95 Hemophagocytic syndrome is also a reported association.96 The clinical lesions of Sweet’s syndrome are said to be more severe in patients with underlying hematological disease.88 An association with urticaria pigmentosa has also been documented.7 Solid tumors may also be associated with Sweet’s syndrome in up to 7% of patients, including: • testicular, • bladder, • gastrointestinal, • breast, • lung, • ovary, • prostate.7,32,35,79,82–85,88,95,97–99 Association with oral squamous cell carcinoma has been reported,36,100 as has a rare case following treatment of herpes simplex in a patient with metastatic breast carcinoma.101 Sweet’s syndrome has been described in conjunction with numerous conditions, some of which are listed in Table 15.2. While its association with hematologic and internal malignan­ cies, upper respiratory tract infections, drugs, and certain inflammatory ­disorders such as erythema nodosum, rheumatoid arthritis, and sarcoido­ sis appears repeatedly, many of the others listed in the literature could be coincidental. Systemic involvement may be a feature of Sweet’s syndrome with lesions described in the eye, lung, kidney, central nervous system, vagina, liver, gas­ trointestinal tract and skeletal muscle.7,86,102–110 Neural involvement appears to be strongly associated with HLA-Cw1.110 An exceptional case with gin­ gival hyperplasia and myositis in the absence of cutaneous involvement has been documented.111 Associated features include pyrexia, neutrophilia, and a raised ESR. In one study, six of seven patients had antineutrophil cytoplasmic antibodies (ANCA).112 Other studies, however, have not found an association between Sweet’s syndrome and ANCA.7 This finding has not been further explored in the more recent literature.

Pathogenesis and histological features The etiology of Sweet’s syndrome is unknown; however, the disease most prob­ ably represents an unusual hypersensitivity reaction.113 Cytokine mediation is likely, as anti-inflammatory agents are generally useful.113 The occasional presence of immune complexes in blood vessel walls may have pathogenetic significance.32 It has been suggested that neutrophils are activated by interleu­ kin (IL)-1 and that Sweet’s syndrome represents a cytokine-mediated inflam­ matory reaction to a wide variety of different antigens including bacteria, viruses, drugs, and malignancies.114–116 Demonstration of elevated serum IL-1α, IL-1β, IL-2, and interferon-gamma (IFN-γ) but not IL-4 suggests that type 1 (but not type 2) helper T cells (Th) play a role in the pathogenesis.117 Not surprisingly, since exogenous treatment with G-CSF is associated with Sweet’s syndrome, endogenous G-CSF has been shown to be elevated in some cases.118

Table 15.2 Conditions associated with Sweet’s syndrome Common associations Drugs58 Hematologic malignancies (and myelodysplastic syndrome)91 Hepatitis B142 Inflammatory bowel disease (including ulcerative colitis and Crohn’s disease) 143,144 Non-tuberculous mycobacterial infection145,146 Pregancy147 Sarcoidosis148,149 Scrofuloderma150 Sjögren’s syndrome151 Tuberculosis152 Upper respiratory tract infection10 Rare associations Bacille-Calmette–Guérin (BCG) vaccination153 Pigmented villonodular synovitis154 Behçet’s disease155,156 Bronchiolitis obliterans157 Celiac disease158 Chronic granulomatous disease159 Dermatomyositis160, 161 Encephalitis162 Erythema nodosum80 Generalized granuloma annulare163 Hashimoto thyroiditis164 Infection with Apnocytophaga canimorsus, Chlamydia pneumoniae, Coccidiodes immitis, Cytomegalovirus, Francisella tularensis, Helicobacter pylori, Hepatitis C, human immunodeficiency virus (HIV), Pasteurella multocida, Salmonella enteritidis, and Staphylococcus epidermidis and Staphylococcus aureus165–178 Polycythemia rubra vera179,180 Prothrombin gene (G20210A) mutation181 Relapsing polychondritis182, 183 Sarcoidosis184 Solid tumor malignancy87, 97 Still’s disease185 Surgery186 Subacute and systemic cutaneous lupus erythematosus187–189 Thyroid disease (Grave’s disease and Hashimoto’s thyroiditis)190 Urticaria pigmentosa7

One study demonstrated clonality in the skin infiltrate of a patient with Sweet’s syndrome and acute myelogenous leukemia, undergoing treatment with G-CSF.119 The authors concluded that Sweet’s syndrome in patients with myelogenous leukemia may result from therapy-induced differentiation of neoplastic cells.119 However, a further study has demonstrated clonality in four patients in the absence of myeloproliferative disease.120 Histologically, the epidermis in Sweet’s syndrome is usually unaffected although occasionally slight spongiosis is present; rarely, vesiculation and spongiform pustules have been described.32 Necrotic keratinocytes are also sometimes evident.32 The cardinal feature, however, is an intense neutrophil polymorph infiltrate within the reticular dermis (Fig. 15.17).3,121 This may be diffuse or perivascular in distribution and often surrounds the sweat ducts. Typically, leukocytoclasis is marked (Fig. 15.18). Admixed with the neutro­ phil polymorphs are variable numbers of eosinophils, lymphocytes, and his­ tiocytes. Ingestion of nuclear debris by histiocytes is sometimes a conspicuous feature. A histiocyte-rich form of the disease has increasingly been recog­ nized.32,122–130 This is more likely to represent a stage in the evolution of the disease rather than a specific variant of Sweet’s syndrome. It has been pos­ tulated that the histiocyte-like cells seen represent immature granulocytes.130 Awareness of this form of presentation is important to avoid a misdiagno­ sis. Given the presence of a ­mononuclear cell infiltrate in these cases, it is extremely important to exclude leukemia cutis. Often, the papillary dermis shows very marked edema, which sometimes results in subepidermal vesiculation (Fig. 15.19). Rarely, the presence of

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Neutrophilic and eosinophilic dermatoses

Fig. 15.17 Sweet’s syndrome: an intense inflammatory cell infiltrate is present in the dermis.

Fig. 15.20 Sweet’s syndrome: the occasional presence of dermal papillary neutrophil microabscesses can result in confusion with dermatitis herpetiformis.

Fig. 15.18 Sweet’s syndrome: the infiltrate consists largely of neutrophils. There is edema and marked leukocytoclasis.

dermal papillary neutrophil microabscesses may cause diagnostic confusion with dermatitis herpetiformis (Fig. 15.20).121 In Sweet’s syndrome the blood ­vessels are dilated and may show endothelial swelling but changes of frank vasculitis are generally absent in our experience (and certainly not promi­ nent). However, others have reported features of vasculitis such as nuclear dust, extravasation of erythrocytes, and fibrin deposition in and around ves­ sels walls in the majority of their series of 31 cases and thus argue that the presence of vasculitis should not exclude this diagnosis.131–133 Purpura, how­ ever, is sometimes evident.134 Immunofluorescence examination of skin biop­ sies in Sweet’s syndrome is usually negative for immunoreactants in the walls of the vasculature. Recently, a case associated with leukocytoclastic neutro­ philic lobular panniculitis has been reported.135 In some cases, an inflammatory infiltrate is noted within subcutaneous tis­ sue. This infiltrate may be composed of lymphocytes and histiocytes and, less commonly, neutrophils.121,129 Sweet’s syndrome has also been associated with an erythema nodosum-like panniculitis.136 Elastophagocytosis and cutis laxa have been reported with resolution of Sweet’s syndrome lesions.137–140

Differential diagnosis

Fig. 15.19 Sweet’s syndrome: marked papillary dermal edema is commonly present and sometimes this is associated with subepidermal vesiculation.

The presence of prominent fibrinoid vascular change can distinguish necrotiz­ ing vasculidities such as leukocytoclastic vasculitis, erythema elevatum diuti­ num, and granuloma faciale from Sweet’s syndrome; the clinical presentation and distribution of disease are also extremely helpful. In granuloma faciale, fibrinoid necrosis is often minimal and eosinophils tend to be prominent. Late lesions of erythema elevatum diutinum and granuloma faciale show fibrosis, a feature not seen in Sweet’s syndrome. Clinically, the presence of character­ istic large ulcers helps distinguish pyoderma gangrenosum from Sweet’s syn­ drome. Also, pyoderma gangrenosum does not usually show the extent of karyorrhexis that is a typical feature of Sweet’s syndrome. A Gram stain and periodic acid-Schiff (PAS) or culture may be necessary to exclude ­infection. Distinction from some other forms of neutrophilic dermatosis including bowel bypass syndrome may be a definitional issue since the clinical setting determines the terminology applied.7 Behçet’s disease may also be associated with lesions similar to those seen in Sweet’s syndrome. Clinical correlation should ensure the correct diagnosis. CD30-positive forms can sometimes be found in Sweet’s syndrome, raising the possibility of lymphomatoid papulosis. However, neutrophils are usually rare in the latter condition and the ­number of CD30-positive cells in lymphomatoid papulosis is not prominent.141

Neutrophilic dermatoses associated with gastrointestinal and hepatobiliary disease

Neutrophilic dermatoses associated with gastrointestinal and hepatobiliary disease Clinical features Pyoderma gangrenosum, the most common neutrophilic dermatosis affect­ ing patients with gastrointestinal disease (particularly ulcerative colitis), is discussed above. The spectrum of lesions described in this section shares many histological (and likely pathogenetic) features with pyoderma gan­ grenosum but lack the characteristic progressive ulceration. Neutrophilic dermatoses associated with gastrointestinal disease may best be regarded as a continuum, with pyoderma gangrenosum representing an extreme end of the spectrum. A syndrome of arthritis and pustular skin lesions was initially described in patients with inflammatory bowel and liver disease, and also in patients who have undergone jejunoileal bypass or Billroth II surgery for morbid obesity, but now has been described in other gastrointesti­ nal disorders.1–7 Up to 20% of patients with jejunoileal bypass develop this condition.4,8 It has also been noted in association with peptic ulcer­ ation, appendicitis, and diverticular disease.9,10 An increasing number of papers call this process bowel-associated dermatosis-arthritis syndrome (BADAS); this terminology currently appears to be that preferred by the majority of authors. The skin lesions may be papular or vesicular, or form large necrotic lesions resembling pyoderma gangrenosum. They are usually found on the trunk or extremities. Oral involvement has also been described.2 Associated panniculitis, which may resemble erythema nodosum, is a fea­ ture in some patients. Cutaneous manifestations often recur with exacer­ bation of the associated gastrointestinal disease.4 Some patients have an elevated ESR.4 The disease occasionally responds to antibiotic or steroid therapy. A recurring vesiculopustular eruption may be seen in patients with hepa­ tobiliary disease.11 The lesions – which can be pruritic and sometimes heal with an atrophic scar – often present on the extremities. In some patients the ­eruption represents a necrotizing folliculitis.11 Occasionally, the cutaneous lesions precede the features of the hepatobiliary disease. Of interest, patients with Crohn’s disease complicated by disseminated abscesses (involving the spleen, lymph nodes, liver, pancreas, and brain) have recently been described.12 In some of these, the abscesses occurred before the diagnosis of Crohn’s disease. Histologically, a granulomatous ele­ ment was commonly present. Successful treatment with immunosuppressive therapy suggests that such lesions may represent an unusual extraintestinal ­manifestation of Crohn’s disease.12 The description of these entities suggests that they are overlapping or ­perhaps represent a disease continuum. BADAS is the most rigorously defined among these and this terminology can probably be employed for all of the conditions mentioned above.

Pathogenesis and histological features The presence of circulating immune complexes in occasional patients has led some authors to postulate a pathogenic role.13,14 It is postulated that bacterial overgrowth may play a role in the development of such circulating immune complexes.4 The histopathological findings, which are non-specific, are those of a neu­ trophilic dermatosis. The lesions show variable dermal edema and necrosis associated with a perivascular and interstitial neutrophilic infiltrate. Variable numbers of lymphocytes and histiocytes may also be present. Abundant kary­ orrhexis gives rise to a histological pattern similar to acute febrile neutrophilic dermatosis (Sweet’s syndrome) (Fig. 15.21). Leukocytoclastic vasculitis and pustular vasculitis have also been documented.15,16 The inflammation is often limited to the dermis but in some patients it may be seen to involve the sub­ cutaneous fat, resulting in erythema nodosum or an erythema nodosum-like panniculitis. The small number of cases described in patients with hepatobiliary disease has shown bullae associated with a dermal neutrophilic infiltrate, sometimes accompanied by eccrine hidradenitis or folliculitis.11

Fig. 15.21

A

(A, B) Neutrophilic dermatosis associated with gastrointestinal disease: there is an intense dermal neutrophilic infiltrate indistinguishable from Sweet’s syndrome.

B

Differential diagnosis The main differential diagnoses include infection, Sweet’s syndrome, ­pyoderma gangrenosum, and rheumatoid neutrophilic dermatitis. Clinical history is essen­ tial to distinguish these conditions. The literature relating to bowel-associated dermatosis-arthritis and Sweet’s syndromes is often confusing and it seems likely that some patients who have been reported as the former would actually have been better clas­ sified as the latter. Contrariwise, occasional patients who presented with features more typical of bowel-associated dermatosis-arthritis syndrome have, in fact, been reported as Sweet’s syndrome.17,18 In many patients such a distinction is semantic. In others, however, the clinical lesions are quite inconsistent with Sweet’s syndrome and in these patients a designa­ tion of bowel-associated dermatosis-arthritis syndrome is probably more appropriate. Pyoderma gangrenosum is another neutrophilic dermatosis which patients with gastrointestinal disease are at risk of developing. Clinically, it may be distinguished by the progressive expansile nature of the cutaneous ulcers.4 Since the biopsy findings may be similar, clinical correlation is ­essential to distinguish this condition from bowel-associated dermatosis-arthritis syndrome.

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Neutrophilic and eosinophilic dermatoses It is likely, given the histological and clinical spectrum encountered in the neutrophilic dermatoses associated with gastrointestinal and hepatobiliary disease, that they result from similar or shared pathogenetic mechanisms. Clearly, more research may clarify their precise pathogenesis and contribute to a more satisfactory classification system.

Rheumatoid neutrophilic dermatitis Clinical features Rheumatoid neutrophilic dermatitis is an uncommon eruption seen in patients with rheumatoid arthritis.1 It presents most often as papules, nod­ ules, and plaques on the extensor surfaces of the extremities, neck, and trunk. In some patients it may clinically resemble urticaria.2–7 Bullous lesions have also been described.8,9 The lesions, which can ulcerate, are often pru­ ritic or painful, and sometimes show an annular configuration.3,10 The dis­ ease is uncommon, as evidenced by documentation in just two of 142 and two of 215 patients with rheumatoid arthritis seeking medical attention for skin disorders in academic clinics in Japan and Turkey, respectively.4,11 The presence of rheumatoid neutrophilic dermatitis correlates with the severity of the patient’s joint disease.4 Typically, lesions last for up to several weeks.2 In some patients, the condi­ tion resolves spontaneously; in others, it responds to steroid, dapsone or sul­ famethoxypyridamine therapy.2,5,10 Patients with seronegative arthritis but with cutaneous findings similar to rheumatoid neutrophilic dermatitis have recently been reported.12–15 Magro and Crowson have described sterile neutrophilic folliculitis associated with a Sweet’s syndrome-like histology in a setting of systemic disease including rheumatoid arthritis, Crohn’s disease, connective tissue disease, hepatitis, Behçet’s disease, atopy, hematological dyscrasia, and mycobacterial infection.16,17 A similar folliculocentric acute ­inflammatory process has also been documented in patients with ulcerative ­colitis.18,19 It would seem probable that these reports reflect a similar ­condition or ­spectrum of disease that likely shares common histopathogenic mechanisms.

Pathogenesis and histological features The pathogenesis of rheumatoid neutrophilic dermatitis is not understood but some authors have suggested that it may represent an immune complexmediated disease.3,5 Histologically, it is characterized by a dermal neutrophilic infiltrate with variable karyorrhexis (Fig. 15.22). In some cases, however, karyorrhe­ xis is ­minimal or absent. Variable numbers of histiocytes, plasma cells, and

A

e­ osinophils may be present; abscess formation is sometimes a feature.2,3,5 Occasionally, the inflammatory infiltrate extends into the subcutaneous fat.3,7 The overlying epidermis may show spongiosis and intraepidermal vesiculation.5

Differential diagnosis Infection must be considered in the differential diagnosis, particularly as patients are often at risk of infection as a result of immunosuppressive ther­ apy. Furthermore, the cutaneous eruption may be treated with steroids, and failure to diagnose an underlying infective process could have disastrous consequences. Gram, AFB/acid fast, and silver stains for microorganisms should be routinely performed and the diagnosis made only after infection has been excluded. We have encountered several patients with rheumatoid arthritis on steroid therapy who developed pustular infiltrates associated with Mycobacterium chelonei infection. Pyoderma gangrenosum may show similar, if not identical, features but differs by progressive ulceration. It should be remembered that patients with rheumatoid arthritis may also develop pyoderma gangrenosum.4 Clinical correlation is necessary to distinguish these entities. Pyoderma gangrenosum may form part of a continuum that may eventually prove to share similar pathogenetic mechanisms. To those who hold this view, documentation of a patient with concurrent typical features of both ­pyoderma gangrenosum and rheumatoid neutrophilic dermatitis should not be surprising.20 Some authors have pointed out that rheumatoid neutrophilic derma­ titis might be classified as a variant of Sweet’s syndrome.2 Certainly, the biopsy findings may be very similar. The lack of fever and the general mal­ aise that accompany Sweet’s syndrome are distinguishing clinical findings. The presence of gastrointestinal disease distinguishes rheumatoid neutro­ philic dermatitis from bowel-associated dermatosis-arthritis syndrome. As with pyoderma gangrenosum, one might consider Sweet’s syndrome and rheumatoid neutrophilic dermatitis to form a spectrum of disease.2 It is the characteristic clinical settings that allow these disorders to be distinguished. Patients with rheumatoid arthritis may sometimes develop lesions which show histological overlap with rheumatoid neutrophilic dermatitis but which can be distinguished by the presence of a palisading necrobiotic and granulomatous component (termed palisaded neutrophilic granuloma­ tous dermatitis).21 This spectrum, also includes interstitial granulomatous dermatitis encountered in a setting of systemic disease (including rheuma­ toid arthritis). Patients, predominantly adults, present with papules and nodules which particularly affect the extremities or trunk; these are often distributed in a linear pattern.22,23 The presence of necrobiosis associated

B

Fig. 15.22 (A, B) Rheumatoid neutrophilic dermatitis: there is an intense upper dermal neutrophilic infiltrate with conspicuous karyorrhexis. By courtesy of J. Cohen, MD, Dermatopathology Laboratory, Tucson, USA.

Arthropod and arachnid bite reactions with a histiocytic response reminiscent of granuloma annulare or necrobi­ osis lipoidica in addition to acute inflammation and ­variable ­karyorrhexis helps distinguish these lesions from typical ­rheumatoid ­neutrophilic dermatitis. Lesions in which the neutrophilic infiltrate is associated with dermal pap­ illary abscess formation may be mistaken for dermatitis herpetiformis, linear IgA disease, and bullous systemic lupus erythematosus. Immunofluorescence staining may be necessary in problematic cases. The presence of vascular necrosis and fibrinoid change distinguishes rheu­ matoid neutrophilic dermatitis from vasculitis.24 It must be emphasized that a careful search for evidence of vasculitis is not simply an academic exercise, since patients with rheumatoid arthritis are also at risk of developing vas­ culitis. In fact, patients with rheumatoid arthritis may present with lesions histologically showing extravascular palisading granulomas, diffuse neutro­ philic infiltrates or vasculitis (neutrophilic, lymphocytic or granulomatous). The different patterns may overlap and classification should be based on the dominant histological pattern.

Arthropod and arachnid bite reactions Clinical features The vast majority of insect bites pose little more than a minor annoyance. The reaction that results from a given bite depends on the nature of the offend­ ing insect and the patient’s immune response. The clinical response to a bite may vary from a trivial erythematous papule to a large nodule associated with marked pruritus and ulceration. Vesicles are sometimes seen in severe ­reactions (Fig. 15.23). Careful inspection will often reveal a punctum at the site where insect mouth parts entered skin. While arthropod bites are rarely of clinical importance, reactions ­following the bite of certain arachnids can lead to a more serious clinical lesion (Fig. 15.24). Many different species of spiders may bite humans, and reac­ tions to the most significant and well described – the brown recluse and the black widow – are detailed below.1–4

Brown recluse spider The brown recluse spider (Loxosceles reclusa) bite begins as a painful ­bluish macule, papule or nodule, often with a bruise-like appearance. A central punctum is commonly observed. The lesion is often trivial. The thigh was the involved site in almost 50% of cases with the arm and abdomen accounting for most of the remainder in a large series from a single center of more than 50 patients with presumed bites.5 However, in some patients, blistering and

Fig. 15.24 Spider bite: note the central eschar and surrounding erythema. Courtesy of Al Mahmoud, MD, Doha, Qatar.

ulceration, often progressing to a large necrotic lesion, is a feature.6 Chronic ulceration mimicking pyoderma gangrenosum may rarely ensue.7 The brown recluse is most commonly encountered in rural areas of the Midwest, southcentral, and southeastern United States and is easily identified by a violinshaped marking on the cephalothorax that gives it its vernacular name of ‘fiddleback’ spider.8 However, other spiders are often misidentified as brown recluse and the diagnosis may be overused as the spider is often not identi­ fied at the time of the bite.9–13 This makes much of the existing literature suspect.14 Sphingomyelinase-D in the venom of the brown recluse spider is thought to be responsible for the extensive necrosis that results in some patients.15 Spider bites may be associated with morbilliform rash, malaise, fever, nausea, hemoglobinuria, arthralgias, and vomiting.6,16–18 More seri­ ous complications (e.g., renal failure, shock, disseminated intravascular coagulation, acute hemolytic anemia, and intravascular hemolysis) have also been described.16,19,20 Many of the effects of the venom appear to be dose-dependent rather than idiosyncratic.21,22 ELISA-based assays to detect the Loxosceles venom at the site of the bite are available and can be helpful to confirm the diagnosis, as detectable toxin may persist for more than 2 weeks.23–27 Anti-loxoscelic sera are available for use in severe cases.28,29

Widow spiders

Fig. 15.23 Bullous insect bite reaction: there are large fluid-filled bullae in this close up view from the lower leg. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

The five species of widow spiders found in the United States, including the notorious black widow (Latrodectus mactans), are most commonly encoun­ tered in the southern states. Compared with the brown recluse, bites by widow spiders are much less commonly encountered by healthcare provid­ ers. Many presumed or self-reported arachnid bites are ultimately discov­ ered to be skin and soft tissue infections.30 The bite often shows a targetoid appearance with a pale center surrounded by an outer erythematous rim.31 A bite from a black widow spider is commonly associated with severe pain in the vicinity of the bite as well as systemic symptoms such as general mal­ aise, abdominal pain, nausea, headache, and muscle spasms.6,16,31 Priapism has been noted as a rare complication.32 Occasionally, patients die as a result of the bite.19,33 Alpha-latrotoxin is an active component of the venom that binds to pre­ synaptic nerve terminals and stimulates massive neurotransmitter release. The neurological symptoms are termed latrodectism and consist of pain, diaphoresis, and non-specific systemic symptoms sometimes combined with additional autonomic or neurological dysfunction.34 Equine-derived antisera is available and effective as a treatment.35 Recombinant antisera are under development.36

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Neutrophilic and eosinophilic dermatoses

Hobo spider Recently, the Hobo spider (Tegenaria agrestis) has been implicated as a cause of significant bite reactions in the Pacific Northwest with migration to Montana and Colorado and evidence of continuing eastward expansion.37,38 While bites from this spider are believed to cause dermonecrotic injuries, additional study is necessary to confirm this impression.39,40

Histological features Just as there is a spectrum of clinical response to an insect bite, the histo­ pathological features also vary. The typical arthropod bite reaction, such as follows a mosquito bite, is characterized by a wedge-shaped polymorphic inflammatory cell infiltrate composed of lymphocytes, histiocytes, eosinophils, and sometimes neutro­ phils (Figs 15.25, 15.26). Spongiosis (occasionally with vesicle formation) and variable dermal edema are also seen (Figs 15.27–15.30). Ulceration with scale-crust commonly forms in excoriated lesions. In some cases, insect mouth parts are identified in the center of the lesion. In our experi­ ence, this is more common in biopsies from tick bites than arachnid bites (Figs 15.31–15.33). As with arthropod bite reactions, the histological sequelae from arach­ nid bite are variable. Compared with the former, arachnid bite reactions are typically associated with more extensive necrosis and suppurative inflam­ mation. Necrosis may extend to involve the subcutaneous fat and muscle.6 Variable numbers of eosinophils and lymphocytes are present and marked dermal edema is often a feature.6 Secondary vasculitis, involving vessels within the lesion or in the immediate surrounding tissue, may be a feature in some cases. Injection of brown recluse spider venom into rabbits results in ‘mummified’ coagulation necrosis, a mixed inflammatory cell infiltrate, and vasculitis.41

Fig. 15.26 Arthropod bite reaction: note the conspicuous eosinophils.

Differential diagnosis The histological findings in biopsies of insect bites, short of identifying mouth parts in the specimen, are non-specific. The main differential diagno­ sis includes hypersensitivity reactions. The characteristic wedge shape of the infiltrate is an important clue to the diagnosis. The presence of large ­atypical lymphocytes helps distinguish lymphomatoid papulosis from an arthropod bite reaction. Bite reactions with a dense eosinophil-rich infiltrate may be Fig. 15.27 Bullous arthropod bite reaction: massive subepidermal edema has resulted in a multiloculated subepidermal blister.

Fig. 15.25 Arthropod bite reaction: there is a heavy perivascular and interstitial infiltrate.

Fig. 15.28 Bullous arthropod bite reaction: eosinophilic spongiosis is present at the edge of the lesion.

Seabather’s eruption and coelenterate stings

Fig. 15.29

Fig. 15.32

Bullous arthropod bite reaction: there is a lymphocytic and eosinophilic perivascular and interstitial infiltrate.

Tick bite reaction: high-power view showing tick parts and multiple flame figures.

Fig. 15.30

Fig. 15.33

Bullous arthropod bite reaction: high-power view showing a flame figure.

Tick bite reaction: there is a dense infiltrate of lymphocytes, histiocytes, and conspicuous eosinophils.

indistinguishable from Wells’ syndrome. The occasional presence of flame figures heightens the similarity. Clinical correlation may be necessary to ­distinguish these two conditions. The histological findings associated with arachnid bite are also non-spe­ cific. Arachnid bites must be distinguished from pyoderma gangrenosum, factitial disease, primary vasculitis, and infections including cellulitis and necrotizing fasciitis. Arachnid envenomation appears to be over-reported; thus, some cases have been reported in regions where the spiders have never been documented to exist. ELISA-based assays may be helpful to confirm the ­diagnosis. Without definitive evidence of involvement of an arachnid, the diagnosis must be considered one of exclusion so as not to overlook ­important clinical alternatives with a different treatment approach.

Seabather’s eruption and coelenterate stings Fig. 15.31 Tick bite reaction: low-power view showing a heavy dermal inflammatory cell infiltrate. Tick parts are seen in the center of the field.

Clinical features Seabather’s eruption, sometimes referred to as ‘sea lice’, is attributed to stings from larval forms of coelenterates, often the thimble jellyfish

643

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Neutrophilic and eosinophilic dermatoses (Linuche unguiculata scyphomedusae).1–4 Typically, patients develop a papular eruption in areas covered by the bathing suit, often accentuated where the suit is tight fitting, such as the waistline.5 The eruption is usu­ ally pruritic and may cause a burning sensation. Patients sometimes expe­ rience systemic symptoms such as malaise, fever, nausea, diarrhea, and vomiting. Reactions to coelenterates such as jellyfish vary from minor irritation to fatal reactions following stings by highly venomous species such as the ‘box jellyfish’ (Chironex fleckeri and Chiropsalmus quadrigatus).6 Jellyfish stings are often erythematous and show a ‘whiplash-like’ appearance.6,7 Certain spe­ cies may have more serious consequences, such as the Portugese man-ofwar (Physalia physalis), where systemic effects from neurotoxins can be seen, including cramping of muscles, respiratory distress, profound ­hypotension, and even death in extreme cases.8–11 A topically applied envenomation inhibitor based on the mucous coat of clown fish is effective in dramatically reducing both some coelenterate stings and seabather’s eruption, though it may lack efficacy against certain coelen­ terate species.12,13

Histological features Biopsy of papules of seabather’s eruption shows a non-specific perivascular inflammatory cell infiltrate composed of variable numbers of lymphocytes, eosinophils, and neutrophils.2 Epidermal changes are apparently not usually a feature.2 Only few authors have reported the histological findings following reac­ tion to coelenterate stings. Non-specific perivascular inflammation with lymphocytes and variable numbers of eosinophils appear to be characteris­ tic. Some cases show dense, sheetlike aggregates of lymphocytes and histio­ cytes.14 Variable dermal edema may be an additional feature. Spongiosis and vesicle formation are also sometimes described.14–16 One fatal case showed only vascular congestion without significant inflammation, a ­histological picture that likely reflects the fact that the patient died only 40 minutes after being stung.6 Only occasionally are nematocyst capsules and tubes identified.6,16

Differential diagnosis The histological differential diagnosis of reactions to coelenterates includes other hypersensitivity reactions. Short of finding nematocysts, the diagnosis depends entirely on clinical correlation.

Erythema marginatum rheumaticum Clinical features Once a common disease, it was thought that, with the effective antibiotic treatment of the causative infection, rheumatic fever would become of histor­ ical interest only. However, there has been a resurgence of the condition over the past few decades, particularly in developing countries.1–5 Rheumatic fever is an immunologically mediated disease that follows an infection with Lancefield group A beta-hemolytic streptococcus. The infec­ tion causes pharyngitis and carditis. Additional features include polyarthritis, a neurological movement disorder known as Sydenham’s chorea, and sub­ cutaneous nodules.6 Carditis, characterized by a valvular disease, is a major cause of morbidity and mortality. Erythema marginatum rheumaticum is the designation given to the dis­ tinctive annular or polycyclic eruption of rheumatic fever. The lesions are nonpruritic, multiple, flat, erythematous maculopapules which change and spread over hours, and are often recurrent. The trunk and proximal extremities are most frequently affected.2 The hands and face may also be involved.4 By definition, erythema marginatum rheumaticum is associated with rheumatic fever, but occurs in only 1–18% of patients.1 Some studies have failed to identify significant human leukocyte antigen (HLA) associa­ tions.3,7 However, there are conflicting reports of certain HLA subtypes and the disease.8

Pathogenesis and histological features

The pathogenesis of rheumatic fever is incompletely understood. It appears likely that it results from a hypersensitivity reaction triggered by streptococ­ cal infection. Specifically, patients develop autoantibodies that cross-react with streptococcal antigen due to molecular mimicry.9 For example, autoan­ tibodies cross-react with cardiac muscle, causing carditis. Mice immunized with the streptococcal M protein develop myocarditis.9 Bradykinin in dense deposits can be seen in stromal and endothelial tissues, suggesting it may mediate some facets of this condition.10 Variable numbers of neutrophils (sometimes associated with leukocyto­ clasis) and mononuclear cells are present in the infiltrate.7,11 Importantly, however, there is no evidence of vasculitis. Dermal papillary neutrophil microabscesses have occasionally been described.7 It has been reported that rare cases are devoid of neutrophils and the ­infiltrate is instead composed of lymphocytes and histiocytes.12

Differential diagnosis The biopsy findings in erythema marginatum are non-specific. Similar his­ tological features may be seen in patients with Still’s disease and acute lupus erythematosus. Careful search for vascular damage is necessary to exclude leukocytoclastic vasculitis. Special stains and culture to rule out an infec­ tious etiology are sometimes required. Urticaria can demonstrate ­perivascular ­neutrophils but additionally it shows significant dermal edema, and an ­interstitial inflammatory cell infiltrate, including neutrophils, eosinophils, and lymphocytes

Still's disease Clinical features Juvenile rheumatoid arthritis or systemic juvenile idiopathic arthritis (Still’s disease) is a heterogeneous group of disorders which share in common an inflammatory arthritis with many features similar to rheumatoid arthritis in adults. Juvenile rheumatoid arthritis patients, however, are seronegative for rheumatoid factor.1 There are marked differences in prevalence from region to region. Whites in Europe, the United States, and Australia (4 per 1000) have the highest prevalence.2,3 One study has suggested that the incidence of the disease is decreasing.4 This same study also documented incidence peaks indicating a possible cyclical pattern.4 Other studies have found seasonal ­variation in certain regions such as the Canadian prairies.5 However, such seasonal onset has not been apparent in other areas of Canada, in Denmark or in Japan.5–8 Juvenile rheumatoid arthritis is classified into three variants: ­pauciarticular, polyarticular, and systemic onset. • The pauciarticular (oligoarticular) form is characterized by arthritis involving up to a maximum of four joints. Systemic manifestations are uncommon. Uveitis, however, is frequently present. • The polyarticular form is manifest by symmetrical arthritis typically involving the knees, wrists, and ankles. Fever and hepatosplenomegaly are sometimes present. • The systemic-onset form is a severe variant in which lymphadenopathy, fever, and rash precede development of polyarteritis which most often affects the knees, ankles, and wrists.9 Additional features may include hepatosplenomegaly and effusions. In general, the term Still’s disease is restricted to this form of juvenile rheumatoid arthritis; however, some authors use it for any of the variants. The majority of patients with the systemic form have the characteristic rash in contrast to the pauci- and polyarticular variants in which only 20–40% are affected.9 The rash of Still’s disease is evanescent, and is characterized by a faint erythematous (salmon-colored), sometimes pruritic, macular eruption involv­ ing the trunk, extremities, head, and neck.9–11 Often, there is an association between onset of rash and febrile episodes, particularly in the late afternoon or evening.9,11 The rash is typically present for only a short period of time, usually a matter of a few hours; however, some lesions persist for more than 24 hours.9,11 It characteristically reappears without regard for its former dis­ tribution.11 Macules are often only a few millimeters in size but frequently

Urticaria become confluent to form larger lesions. Central pallor is sometimes a feature of the latter.10 The eruption – which may persist for weeks to years – tends to localize to areas of mild trauma and pressure.9,11 Laboratory abnormalities include elevated ESR and C-reactive protein. Serum immunoglobulins may also be raised. Patients sometimes have leuko­ cytosis, anemia, and thrombocytosis. Occasional patients have rheumatoid factor and some authors consider this to represent bona fide juvenile rheu­ matoid arthritis. Antinuclear antibodies are commonly found in patients with pauci- and polyarticular variants of the disease.8 In contrast, antinuclear anti­ body is usually not present in the systemic-onset form. It is very difficult to predict the outcome of this disease in the individual patient. Approximately 50% of patients experience symptoms into adulthood. Progression of juvenile rheumatoid arthritis to systemic lupus ­erythematosus (SLE) has been documented.12 Serious complications ­including uveitis, ­cardiac tamponade, portal vein thrombosis, liver failure, and ­disseminated ­­intravascular coagulation have been documented.13–17 Despite the name juvenile rheumatoid arthritis, Still’s disease is not lim­ ited to the pediatric population. Adult onset is well described in the literature (Fig. 15.34).18–22 Patients with the adult form of the disease may develop per­ sistent papules and plaques and hyperpigmentation.23 Lesions are mainly seen on the face, neck, trunk, and extensor surfaces of the extremities.

The influence of various HLA alleles and their association with juve­ nile rheumatoid arthritis has been an area of considerable interest and has yielded a complex picture of the relationship between certain HLA alleles and risk of disease.29 HLA-A2, DR8, DR5, and DPB1*0201 are associated with increased risk of pauciarticular disease early in life.31 While B27 and DR4 may be protective in the early years, these alleles seem to confer increased risk of disease later in life.30 CD4-reactive T lymphocytes are the predominant cell type in the inflamed synovium.31 As with other autoimmune disorders, production of predomi­ nantly Th1 cytokines (IFN-γ and IFN-β) has been observed in the synovium of juvenile rheumatoid arthritis patients.31,32 The biopsy findings are non-specific and variable. There is often a perivas­ cular neutrophilic infiltrate.10 In some cases, mononuclear cells are the pre­ dominant cell type.9,11 A neutrophilic panniculitis may be associated with the disease.33 In adult-onset Still’s disease, distinctive histologic features have been described particularly in the persistent papules and plaques sometimes seen in the disease.24 The epidermis displays dyskeratotic keratinocytes in single units or aggregates. They tend to be present mainly in the upper layers of the epidermis and even in the stratum corneum.23,34 Other changes include subcorneal pustules, upper dermal lymphocytes and neutrophils and, in a single case report, excess dermal mucin.23,34

Pathogenesis and histological features

Differential diagnosis

The pathogenesis of juvenile rheumatoid arthritis is poorly understood. It would seem likely, however, that the various subtypes have different etiologies. Thus: • IL-2 mRNA is detected more often in pauciarticular juvenile rheumatoid arthritis than in the polyarticular form.24 • IFN-γ mRNA may be detected in 33% of systemic-onset juvenile rheumatoid arthritis in contrast to 85% in the other forms.24 IL-6 and other cytokines can also be involved.25 Recently, it has been suggested that nucleotide-binding and oligomerization domain (NOD)-like receptors (NLR) that detect microbes and help constitute the inflammasome (a complex of proteins which initiates an inflammatory reaction) may be involved in autoimmune disease generally and in Still’s dis­ ease in particular.26 Data suggesting that the incidence of the disease is decreasing with cyclical peaks raise the possibility that environmental factors could play a role in the pathogenesis.4 Demonstration of T-cell oligoclonal expansions within synovial tissue suggests that an antigen or group of antigens may trigger the disease.27 The nature of such triggering factors, however, has not yet been identified. The prevalence of autoimmune disease is increased in relatives of patients with juvenile rheumatoid arthritis compared with control subjects, suggesting that shared susceptibility genes may be of importance in the pathogenesis of juvenile rheumatoid arthritis and other autoimmune diseases.28

The histological findings, as indicated above, are variable and non-specific. Clinical correlation is necessary to establish the diagnosis. The differential diagnosis includes infection, and culture and stains for microorganisms should be performed when necessary. The absence of fibrinoid change and necrosis of blood vessel walls distinguishes the lesions from leukocytoclastic vasculitis.

Fig. 15.34

Fig. 15.35

Still’s disease in an adult: there are multiple erythematous macules. By courtesy of J.C. Pascual, MD, Alicante, Spain.

Urticaria: erythematous, edematous, coalescing plaques on the trunk and proximal extremities of an infant. By courtesy of J.C. Pascual, MD, Alicante, Spain.

Urticaria Clinical features Urticaria is an extremely common group of disorders that share common clinical and histological features.1 The lifetime incidence approaches 1 in 5 people.2 As will be seen later, urticaria has many different etiologies but, more often than not, the cause remains unknown and the disease is then classi­ fied as idiopathic. In some patients, more than one stimulus may elicit symp­ toms.3 The clinical common denominator in urticaria is the development of ‘hives’ or ‘wheals’ – raised edematous lesions – which are often surrounded by a zone of erythema and are commonly pruritic (Figs 15.35–15.37).4,5 Dermatographism – pressure or light scratching resulting in linear urti­ carial lesions – is a common symptom. Urticaria may develop in only sec­ onds. Lesions usually resolve in less than a few hours. By definition, lesions

645

646

Neutrophilic and eosinophilic dermatoses

Solar urticaria Solar urticaria is characterized by development of wheals and pruritus at sites exposed to light (Fig. 15.38).7 A sensitizing agent, such as a drug, may be necessary.8 In some patients lesions even arise in areas covered by light cloth­ ing.9 ‘Fixed solar urticaria’ is a designation given to a rare form of urticaria seen in patients who develop lesions at the same sites with repeated light exposure.10,11 Solar urticaria has also been described following exposure to infrared and ultraviolet radiation.12,13

Aquagenic urticaria

Fig. 15.36 Urticaria: in this patient, the erythematous border is well demonstrated. By courtesy of the Institute of Dermatology, London, UK.

‘Aquagenic urticaria’ is a bizarre variant of physical urticaria in which patients develop lesions following exposure to water (regardless of temperature).14,15 Extracutaneous manifestations such as migraine headache and familial occur­ rence has been described on rare occasion.16–18 Thankfully, patients do not develop symptoms from drinking water.5,19 Application of petrolatum oint­ ment or other barrier cream prior to water exposure helps to prevent lesion development.14,20 It has been postulated that a water-soluble epidermal anti­ gen may be responsible for such symptoms, since aqueous extracts of callus cause symptoms in patients’ skin but not in that of controls.21 Increased water salinity has also been implicated.22

Cold urticaria Placing an ice cube on the skin of patients may elicit a wheal – a condition desig­ nated ‘cold urticaria’.5,23 Some patients, however, develop symptoms only after generalized cooling of the body.5,24 Occasionally, drinking cold liquids or bath­ ing in cold water elicits symptoms.5 The condition can be associated with other types of physical urticaria. Very rarely, there is associated cryoglobulinemia and in some cases the condition follows a viral infection or drug ingestion.23,25,26 Familial cold urticaria (familial cold autoinflammatory syndrome) which ­follows exposure to cold is an autosomal dominant condition characterized by:27–30 • urticaria, • fever, • arthralgias, • arthritis, • conjunctivitis, • leukocytosis. Patients with this syndrome develop symptoms with a decrease in body temperature but do not develop wheals at the site of an ice cube applied to skin. Recently, patients have been shown to have mutations in the NLRP3 gene (also known as CIAS1) on chromosome 1q44 encoding the protein cryo­ pryin. This protein is part of the cytosolic inflammasome protein complex and involved in its activation.31–38 Interestingly, Muckle-Wells syndrome is associ­ ated with the same gene and consists of periodic fever, frequent ­sensorineural

Fig. 15.37 Urticaria: in this extreme example there is intense erythema. By courtesy of the Institute of Dermatology, London, UK.

in patients with chronic urticaria, however, persist over a period in excess of 6 weeks.5,6 In addition, individual lesions in patients with chronic urticaria often last longer – up to 36 hours.4 Given that urticaria is best viewed not as a single disease but as a group of related disorders, it comes as no surprise that the natural history of ­urticaria is highly variable.2 Resolution is seen in 50% of patients within a few years of onset; however, in some patients the disease persists for decades.2,5 The severity of symptoms is also variable. For many patients, the disease is a minor annoyance; for others, however, severe reactions may be associated with ­life-threatening anaphylaxis. Physical causes of urticaria include sunlight, cold, heat, pressure, and vibration.

Fig. 15.38 Solar urticaria: in this patient, urticaria developed after exposure to sunlight. By courtesy of the Institute of Dermatology, London, UK.

Urticaria hearing loss, amyloidosis, and recurrent urticaria not linked to cold expo­ sure.32,39 In addition, neonatal-onset multisystem inflammatory disease also maps to this gene.40 The spectrum of autoinflammatory disorders is now referred to as the cryopinopathies.41 Urticaria induced by heat has rarely been documented.42–44

Delayed pressure urticaria Patients with ‘delayed pressure urticaria’ develop lesions at sites of pressure, such as areas of tight clothing.5,45 This form of urticaria is seen in 40% of patients with chronic urticaria (see below).5,46,47

Cholinergic urticaria Cholinergic urticaria – one of the most common subtypes of urticaria – is thought to result from release of cholinergic substances by nerves.48–50 Evidence in support of this theory includes the observation that wheals may be elicited by the injection of cholinergic compounds, and injection of anticholinergic agents blocks wheal formation.48 Furthermore, wheals do not develop in skin innervated by nerves injected with local anesthetic, and application of sco­ polamine to skin prevents aquagenic urticaria.19,48 Common causes of cho­ linergic urticaria include increase in body temperature (e.g., following a hot bath or shower), emotional stress, exercise or consumption of spicy food (Fig. 15.39).5,48,51 Familial cases of cholinergic urticaria have been reported.52

Contact urticaria Contact urticaria may be divided into two main subtypes: allergic and irritant.5 • Allergic contact urticaria is a hypersensitivity reaction following exposure to an allergen such as chemicals, foods, latex, plants, fruits and vegetables, and animal-derived antigens.53,54 Not surprisingly, this form of urticaria often occurs in patients with a history of atopy.53,55 • Irritant contact urticaria is a nonimmunologically mediated form of urticaria secondary to a wide variety of substances found in cosmetics, food and medications.53

Urticarial angioedema Patients with urticaria often develop angioedema characterized by edematous swelling of the lips, eyelids, and tissues of the oropharynx.5,56,57 Two main sub­ types of angioedema are recognized: hereditary and nonhereditary (acquired). • Hereditary angioedema is rare, autosomal dominantly inherited, and due to C1-esterase inhibitor deficiency.58 • Acquired angioedema is caused by drug reactions, allergic reactions, reaction to physical agents, hypereosinophilia, and acquired (nonhereditary) C1-esterase deficiency.57 An idiopathic variant is also recognized.

Physical urticaria, secondary to vibration, cold, and sunlight, as well as contact (type I) hypersensitivity reaction and cholinergic urticaria may be associated with angioedema.57

Urticarial vasculitis Urticarial vasculitis is an uncommon condition which combines clinical ­features of chronic urticaria and histological findings of leukocytoclastic venulitis.59–62 A type III hypersensitivity reaction (caused by antibody–antigen complexes) appears to be the underlying etiology in a subset of patients.63,64 In many patients, however, no underlying cause is discovered. Urticarial vasculitis is associated with a female predominance (2:1) and is most often seen in young to middle-aged adults. Urticarial lesions tend to last 24–72 hours and may be associated with pruritus, a burning ­sensation or pain.65,66 The frequency of attacks varies from daily to monthly. Hyperpigmentation can be present at resolution. The spectrum of illness ranges from mild symptoms to a serious ­systemic ill­ ness.67 In addition to urticarial skin lesions, patients can also have angioedema, gastrointestinal symptoms, and evidence of renal involvement. Necrotic skin lesions are not usually seen. Other systemic manifestations/associations include joint pain, stiffness, and swelling; however, frank arthritis is extremely rare. Some patients have proteinuria and hematuria. Rarely, renal biopsy reveals the features of focal or diffuse proliferative glomerulonephritis. Crescentic glomerulonephri­ tis and mesangial and membranous nephropathy have been described in some patients.67–69 The erythrocyte sedimentation rate (ESR) is frequently raised. Rarely, urticarial vasculitis has been documented in association with malig­ nancy, a relationship which may be coincidental.67,70–75 Hypocomplementemia is seen in many patients and the presence of this sign correlates with systemic involvement and a high prevalence of autoantibod­ ies to endothelial cells.63,67,76–78 Patients with Schnitzler’s syndrome have urti­ carial vasculitis and monoclonal IgM gammopathy.79–86 Hepatosplenomegaly, elevated ESR, raised white blood cell count, fever, and joint pain are charac­ teristic features.80–82 Occasional patients have an associated lymphoprolifera­ tive disorder.79 This disease is associated with anti-C1q autoantibodies which likely mediate the disease.87 Urticarial vasculitis (especially the hypocomplementemic variant) is often asso­ ciated with or precedes development of a variety of systemic ­diseases, including myeloma, hepatitis B and C, SLE, arthritis, interstitial lung ­disease, peri­carditis, mixed connective tissue disease, inflammatory bowel ­disease, serum sickness, polyarteritis nodosa, Wegener’s granulomatosis, viral ­infections, Sjögren’s syn­ drome, cryoglobulinemia, polycythemia rubra vera, ­reaction to drugs, and as a response to sunlight.67,76,77,88–96 Urticarial vasculitis has also been documented in association with pregnancy, exercise, and cocaine use.97–99 Ocular disease (includ­ ing uveitis, scleritis, conjunctivitis or episcleritis) is a very common ­feature.67,100 Patients with hypocomplementemia appear to be at risk of developing more severe disease.88 Obviously, a diagnosis of urticarial ­vasculitis in any patient should initiate an evaluation for underlying disease.101

Drug-induced urticaria Drug-induced urticaria is fairly common. It is present in 0.16% of medical inpatients and in 9% of cases of chronic urticaria or angioedema seen in der­ matology outpatient departments.102,103 The drugs most commonly implicated are sulfonamides, penicillins, and non-steroidal anti-inflammatory medica­ tions.102 Aspirin may induce acute urticaria, worsen chronic urticaria or act as a cofactor to induce anaphylaxis.104 Other less common drug associations include antipsychotics, alendronate, recombinant IFN-β, cetirizine, bleomycin, and IL-3.105–110 Many of these reactions are mediated by IgE antibodies, but some result from direct activation of mast cells or interact with another path­ way that augments the urticaria reaction.111 In this last category, modulation of arachidonic acid metabolites by aspirin and other agents can help initiate or exacerbate urticaria.112 Specifically, in some cases polymorphism in the leukot­ riene C4 synthase gene can be associated with aspirin-induced urticaria.113–115

Other urticarial associations Fig. 15.39 Cholinergic urticaria: in this variant, urticaria follows heat, emotional stress or a spicy meal. By courtesy of the Institute of Dermatology, London, UK.

Urticaria has also been documented in association with autoimmune pro­ gesterone dermatitis, dermatophytosis, candidiasis, parasites (anisakiasis), consumption of tonic water, nicotine, alcohol consumption, and hepatitis B vaccination (Table 15.3).116–122

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Neutrophilic and eosinophilic dermatoses

Table 15.3 Classification of urticaria subtypes (presenting with wheals and/or angioedema) Types

Subtypes

Definition

Spontaneous urticaria

Acute spontaneous urticaria Chronic spontaneous urticaria

Spontaneous wheals and/or angioedema < 6 weeks Spontaneous wheals and/or angioedema > 6 weeks

Physical urticaria

Cold contact urticaria

Eliciting factor: cold objects/ air/fluids/wind Eliciting factor: vertical pressure (wheals arising with a 3-12 h latency) Eliciting factor: localized heat Eliciting factor: UV and/or visible light Eliciting factor: mechanical shearing forces (wheals arising after 1-5 min) Eliciting factor: vibratory forces, e.g. pneumatic hammer

Delayed pressure urticaria Heat contact urticaria Solar urticaria Urticaria factitia/ dermographic urticaria Vibratory urticaria/ angioedema Other urticaria types

Aquagenic urticaria Cholinergic urticaria

Contact urticaria Exercise induced anaphylaxis/urticaria

Eliciting factor: water Elicitation by increase of body core temperature due to physical exercises, spicy food Elicitation by contact with urticariogenic substance Eliciting factor: physical exercise

Table 2 from Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA2LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. Allergy 2009; 64:1417–1426.

Pathogenesis and histological features As has been stated above, urticaria is probably best viewed as a group of dis­ orders sharing common clinical and histological features. The pathogenesis of some forms of urticaria (e.g., allergic contact urticaria) is well understood; however, the precise pathogenesis of many cases of urticaria is obscure.123 Mast cell degranulation with perhaps some involvement of basophils appears to be a common denominator in the pathway of most types of urticaria.124,125 Release of histamine following a hypersensitivity reaction after exposure to an allergen is the basis for allergic contact urticaria.56 In sensitized patients, an allergen binds to IgE on mast cells causing degranulation and the release of

A

histamine, eosinophil chemotactic factor, prostaglandin, leukotrienes, ­platelet activating factor, and enzymes.53,123,124,126,127 Similarly, IgE-mediated mast cell degranulation also underlies the pathogenesis of allergic contact urticaria in which direct contact with allergens on skin bind to the surface IgE on mast cells causing release of histamine and other inflammatory mediators. Autoantibodies against the IgE high-affinity receptor (FcεRI) or to IgE itself are present in about 30% of patients with chronic urticaria, designated auto­ immune urticaria, a type II hypersensitivity reaction.123,128–131 Patients with physical urticaria or with connective tissue or autoimmune bullous disease may also have anti-FcεRI. However, in the last group of patients, the autoan­ tibodies are nonfunctional (nonhistamine releasing), whereas in chronic urti­ caria, the antibodies are functional (histamine releasing).131,132 A type III hypersensitivity reaction, caused by circulating antigen–antibody immune complexes, underlies a form of urticaria associated with serum sickness. A role for Helicobacter pylori in the causation of chronic urticaria has been suggested but other studies have challenged this theory.133–138 The pathogenesis of irritant contact urticaria is not well understood but evidence suggests that degranulation of mast cells due to direct, nonimmu­ nologically mediated contact causes release of vasogenic mediators.53,124 Similarly, it is thought that the physical urticarias (heat, cold, pressure, vibration, water) also result from a direct effect on mast cells in susceptible individuals.127 Some investigators have suggested that solar urticaria results from a type I hypersensitivity reaction to a photoinduced antigen eliciting IgE-mediated mast cell degranulation.9 An intriguing study has shown that most patients (77%) develop an urticarial reaction when challenged with autologous serum that has been irradiated using the same spectrum of light that induces lesions in each particular patient.139 Furthermore, patients with ‘fixed’ urticaria develop lesions at the same specific sites that are affected by light exposure following injection with irradiated plasma.14 Consistent with these observa­ tions, some patients with severe solar urticaria may be effectively treated by plasma exchange.140,141 A type III hypersensitivity reaction (caused by antibody–antigen com­ plexes) appears to be the underlying etiology in some patients with urti­ carial vasculitis; however, no underlying cause is discovered in many patients.64,67 More recently, urticarial vasculitis has been excluded from the formal urticaria group of disorders by some authors due to its variant pathogenic mechanism, but is still considered in this section for historical purposes.2 The biopsy findings in urticaria are non-specific. Dermal edema may be mild or severe and its presence is confirmed by separation of dermal retic­ ular collagen fibers. An often sparse dermal perivascular and interstitial mixed inflammatory infiltrate composed of variable numbers of lympho­ cytes, ­neutrophils, and eosinophils is present (Fig. 15.40). Of interest, mast­

B

Fig. 15.40 Urticaria: (A) at low-power examination, the features are easily overlooked. There is a light perivascular infiltrate and the collagen fibers appear separated; (B) at high power, there is edema and a light perivascular infiltrate of lymphocytes with scattered eosinophils.

Eosinophilic cellulitis cells – which play such an important role in the pathogenesis of urticaria – do not appear to be increased in number except in chronic urticaria.130,142 Usually, more inflammatory cells are seen in lesions of chronic urticaria com­ pared to those of acute urticaria.142 Urticarial vasculitis combines histological features of urticaria with super­ imposed vascular damage. The vasculitis affects the superficial vascular plexus and shows features of a leukocytoclastic subtype; however, compared with typical leukocytoclastic vasculitis, the histological findings tend to be subtle and are easily overlooked. Mild or focal fibrinoid change apparent on only a few sections associated with few neutrophils and sparse karyorrhexis is typical. Some authors have shown that endothelial ­necrosis is unusual.64 Occasionally, impressive necrotizing vasculitis (features of ­typical leukocy­ toclastic vasculitis) may be seen. In summary, urticarial vasculitis appears as a continuum, ranging from urticaria with very mild vascular injury to frank necrotizing vasculitis.143

Differential diagnosis The diagnosis requires careful clinical correlation. The biopsy findings are often very subtle: the dermal edema and sparse inflammatory infiltrate may be easily overlooked. A definitive diagnosis sometimes requires test­ ing for response to particular antigens. Other forms of hypersensitivity reaction such as arthropod bite and drug eruption can show similar fea­ tures and require clinical correlation to distinguish them from ­urticaria. Clinical correlation is necessary to distinguish urticarial vasculitis from other forms of leukocytoclastic vasculitis. Although urticarial vasculi­ tis is often associated with subtle low-grade vascular injury, this pattern should not be relied upon in the distinction from other forms of vasculitis. In short, the pathologist’s role in diagnosis is to confirm the presence of vasculitis.

Papular urticaria Clinical features Although papular urticaria (prurigo mitis) is often described as a variant of urticaria, and the histologic picture is that of an urticarial dermatitis, the lesions are persistent and patients do not fulfill the criteria for the diagnosis of urticaria. In the latter, lesions are self-limited even in cases of chronic urticaria. The condition is generally regarded as a variant of an insect bite reaction.1–4 Papular urticaria has no sex predilection and although the age range is wide, it tends to be more frequent in children. It presents as small, itchy, red papules that tend to appear in crops. Most lesions are no more than a few millimeters in diameter but larger lesions may be seen. They are more usually seen on exposed areas of the body and tend to be more prevalent during the summer months. Changes secondary to scratching including excoriations are frequent. There are no associations with systemic disease.

Pathogenesis and histological features The pathogenesis is not entirely clear but it is generally believed that the condition is triggered by a hypersensitivity reaction to insect or arthropod bites.5,6 Many insects and arthropods have been implicated in the disease including fleas, carpet beetles, lice, bedbugs, mosquitoes, and even caterpil­ lars. This is further supported by the rash clearing after the patient returns from ­holidays or after moving to a new house. A recent study found evidence of IgG against bedbugs (Cimex lectularius) in affected patients suggesting a role in the pathogenesis of the disease.6 The histological features are fairly non-specific. In intact lesions the epi­ dermis is unremarkable or slightly acanthotic. Changes of excoriation may be evident. In the dermis there is a mild to moderate, superficial and deep, often wedge-shaped, mainly perivascular inflammatory cell infiltrate composed of lymphocytes, histiocytes, and eosinophils.7 Neutrophils can be seen in some cases.7 The presence of the latter is required for a histological ­diagnosis of ­papular urticaria to be made. A few CD30-positive lymphocytes are some­ times present.

Hypereosinophilic syndrome Clinical features The hypereosinophilic syndrome is defined as an idiopathic condition ­characterized by persistent eosinophilia (more than 1.5 × 109/L) for at least 6 months and with involvement of one or more organs.1–4 The diagnosis should be made only after other causes of eosinophilia, particularly parasitic infec­ tions, have been excluded. The heart, lungs, central and peripheral nervous system, liver, and skin are commonly affected. The disease, which may some­ times prove fatal, generally presents in adults. Cutaneous lesions are seen in up to 53% of patients and usually consist of either pruritic papules and nodules or urticaria and angioedema.5 Rarely, skin lesions represent an initial manifestation and in this setting, annular ery­ thema and erythroderma have been reported.6–10 Oral and genital erosions are quite characteristic and can be the first manifestation of the disease.11,12 Other rare cutaneous features include livedo reticularis, cutaneous infarction, deep vein thrombosis, blisters, aquagenic pruritus, erythema gyratum repens, and Wells’ syndrome.13–19 Hypereosinophilic syndrome has been reported in ­association with lymphomatoid papulosis, T-cell lymphoma, systemic mast cell disease, SLE, and HIV infection.20–25

Pathogenesis and histological features The etiology is unknown. It has sometimes been categorized into: • idiopathic, • clonal, • secondary types.26 Some forms of clonal eosinophilia (malignancy-associated) harbor activat­ ing mutations or rearrangements of fibroblast or platelet derived growth fac­ tor receptors (FGFR1, PDGFRA, PDGFRB) and are amenable to targeted therapies.27,28 Secondary causes result from other causes such as an under­ lying infection. Idiopathic is what remains when these first two categories are excluded. Elevated serum levels of IL-10 and soluble IL-2 receptor have been documented.29 IL-2 stimulates release of eosinophilic cationic protein from eosinophils which contain IL-2 receptor (CD25) and this results in tis­ sue damage. The histological findings vary according to the type of lesion biopsied. Urticarial and papular lesions show a superficial and deep perivascular and interstitial mixed inflammatory cell infiltrate with variable numbers of eosinophils and scattered lymphocytes, histiocytes, and occasional plasma cells. Rare flame figures may be present. Dermal edema is seen particularly in urticarial lesions. Eosinophils are not always prominent and the findings can be entirely non-specific. Microthrombi are present in some cases and ­sometimes correlate with the severity of the disease.13,30

Eosinophilic cellulitis Clinical features Eosinophilic cellulitis (Wells’ syndrome) is an uncommon disorder, character­ ized by recurrent erythematous and edematous plaques.1–6 It occurs with an equal sex ratio and there is a large age range, with a mean age of 37 years.7 It is sometimes also encountered in children and rare cases have been docu­ mented in neonates.7–11 It appears that cases occurring in childhood may be particularly severe. Scalp involvement, with alopecia and scarring, is a feature in some patients.7,8 The disease particularly affects the extremities and trunk. Although it pres­ ents most commonly as well-defined (cellulitis-like) annular erythematous plaques, which are edematous and firm, a wide variety of clinical ­appearances have been described including blistering, nodular, papulovesicular ­eruptions, and itchy excoriated inflammatory papules (Figs 15.41–15.43).7,12–14 The plaques, which cause pain and pruritus in some patients, typically heal with­ out scarring.7 Eosinophilic cellulitis has been associated with urticaria.15 Dermatographism can be a feature.16 With progression, the lesions sometimes adopt a greenish hue. Clinically, the lesion may occasionally be mistaken for an infective process.17 The disease tends to be episodic, with remissions and relapses, which can last from months to years.

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Neutrophilic and eosinophilic dermatoses Large bullae are seen in rare patients.18 An unusual pattern of involvement following Blaschko's lines has been reported and it has been proposed that this form represents cutaneous mosaicism.19 Rarely, eosinophilic cellulitis is associated with a malignant neoplasm. Cases accompanied by eosinophilic leukemia, colonic carcinoma, squamous cell carcinoma of the lung, and non-Hodgkin’s lymphoma have been described.20–23 Associations with HIV, hypereosinophilic syndrome, ulcerative colitis, tetanus or thiomersal-containing vaccine and varicella infection have occasionally been documented.24–30 Exceptional familial cases have been reported.31,32 In one family, the ­disease showed an autosomal dominant pattern of inheritance and was associated with mental retardation and dysmorphic body habitus.31 In another family, the lesions were first noted during infancy.33

Pathogenesis and histological features

Fig. 15.41 Eosinophilic cellulitis: there is a large erythematous swollen plaque. The limbs are commonly affected. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 15.42 Eosinophilic cellulitis: in this patient, there is striking symmetry. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

The pathogenesis is unknown and may simply represent an eosinophil-rich inflammatory reaction to a variety of insults. The only consistent associa­ tion appears to be a peripheral eosinophilia, manifested either as an elevated total eosinophil count or as an increased percentage of eosinophils. Clinical activity appears to correlate with increased eosinophil cation protein and IL-5 levels in the peripheral blood in addition to blood and bone marrow eosinophilia.31,32 An elevated ESR is occasionally present. It is possible that some patients represent the benign end of the spectrum of the hypereosinophilic syndrome discussed in the previous section. Histologically, early lesions of eosinophilic cellulitis are characterized by a diffuse and heavy dermal infiltrate of eosinophils: this occurs either in the superficial dermis, as a bandlike infiltrate, or in the deep dermis with exten­ sion into the underlying subcutaneous tissue, fascia, and muscle (Figs 15.44, 15.45).2,34 In addition, lymphocytes and plasma cells may be present. There is sometimes edema of the papillary dermis to such an extent that subepi­ dermal bullae develop (Fig. 15.46).35 The epidermis can be spongiotic and occasionally intraepidermal vesicles are present.35 Over a period of 1–3 weeks the eosinophils degranulate and degenerate, and eosinophilic material and nuclear debris are deposited on collagen fibers to produce ‘flame figures’ (Fig. 15.47).35, 36 Sometimes these are surrounded by histiocytes and multinucleated giant cells (Fig. 15.48). There is no evidence of primary collagen degenera­ tion. It is likely that flame figures represent a non-specific eosinophil reaction pattern to a variety of different provoking stimuli.36 Later, the lesion becomes more granulomatous and giant cells are occasionally prominent.37 Vasculitis is not usually a feature, although extravasation of red blood cells is sometimes evident.35 Indirect immunofluorescence studies have shown that flame figures con­ tain extracellular eosinophil granule major basic protein.36,38 Ultrastructural

Fig. 15.43

Fig. 15.44

Eosinophilic cellulitis: bullous lesion with a hint of greenish discoloration in the adjacent skin. From the collection of the late N.P. Smith, MD, Institute of Dermatology, London, UK.

Eosinophilic cellulitis: there is a light, deep dermal chronic inflammatory cell infiltrate. A flame figure is present.

Eosinophilic pustular folliculitis

Fig. 15.45

Fig. 15.48

Eosinophilic cellulitis: the infiltrate is composed of lymphocytes and histiocytes with conspicuous eosinophils and extends into the subcutaneous fat.

Eosinophilic cellulitis: in this example, a flame figure is surrounded by an intense granulomatous infiltrate.

investigation confirms that the eosinophil granules invest the associated ­collagen fibers.39 Direct immunofluorescence has demonstrated immu­ noglobulins and/or complement in blood vessel walls in a minority of cases.2,7,17,36

Differential diagnosis

Fig. 15.46 Eosinophilic cellulitis: subepidermal vesiculation as seen here is not uncommon. The blister cavity may contain numerous eosinophils reminiscent of bullous pemphigoid.

The histological features of eosinophilic infiltration with 'flame figures', although characteristic of Wells’ syndrome, are not pathognomonic.40 Similar features may be seen in arthropod bite reactions, spider bites, onchocerciasis, drug hypersensitivity reactions, diffuse erythema, tinea infection, atopic eczema, allergic contact dermatitis, urticarial vasculi­ tis, eosinophilic pustular folliculitis, bullous pemphigoid, herpes gestatio­ nis, the hypereosinophilic syndrome, and cutaneous mastocytoma.2,36,41–47 Prominent flame figures are also seen in eosinophilic ulcer of the oral mucosa.48–50 It should be emphasized that in regions where parasitic infec­ tions are endemic, lesions with the histological appearance of eosinophilic cellulitis have a high likelihood of representing parasitic infection such as giardiasis, toxocariasis, and onchocerciasis.51–53 In eosinophilic fasciitis, diffuse fibrosis of the deep dermis with extension into the fibrous septa of the subcutaneous fat and involvement of the fascia allow for easy distinc­ tion from Wells’ syndrome.

Eosinophilic pustular folliculitis Clinical features

Fig. 15.47 Eosinophilic cellulitis: flame figures are typically present.

Eosinophilic pustular folliculitis (Ofuji’s disease) is a rare dermatosis seen primarily in Japanese and Chinese, although occasional reports from Europe and the USA are encountered.1–5 It is a disease which particularly affects the seborrheic regions and, therefore, lesions are predominantly present on the face and back.6 The extensor surfaces of the upper limbs are also fre­ quently affected. Acral involvement is exceptional.7–9 Patients present with crops of occasionally pruritic, sterile follicular papulopustules measuring 1–2 mm in diameter, grouped to form small plaques, which characteristi­ cally spread centrifugally to produce an annular or serpiginous lesion.1,6 The disease is typically recurrent and spontaneous resolution within months to several years is characteristic.10,11 Healing is often associated with residual postinflammatory hyperpigmentation.1 Males are predominantly affected (5:1) and the peak incidence is in the third and fourth decades, although children and infants can be affected.12,13 Sometimes there is a past or present history of acne vulgaris. Extensive laboratory investigations reveal leukocytosis with hypereosino­ philia.14 Serum IgE levels may be increased.5,15

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Neutrophilic and eosinophilic dermatoses Similar cases have been reported in Caucasians in association with HIV infection.3,4,16–23 However, based on the clinical and histological findings, many authors regard HIV-associated eosinophilic folliculitis as a separate entity.20,22 Pruritus, which is always present in patients with HIV-associated eosinophilic folliculitis, is seen only in occasional patients with Ofuji’s disease.24 A small number of childhood cases of eosinophilic pustular folliculitis, including several in neonates, have also been reported.15,25–31 Some authors prefer to categorize these as a separate entity, others feel that this category does not form a distinct condition.5,12,28,32 In children, the scalp is particularly involved. There is less of a tendency to affect the seborrheic regions and poly­ cyclic patterns are not evident.25 Eosinophilic pustular folliculitis has been described in association with non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, polycythemia rubra vera, myelodysplastic syndrome, bone marrow transplant for aplastic ane­ mia, eosinophilic cellulitis, hepatitis C viral infection, and the nevoid basal cell ­carcinoma ­syndrome.13,33–41 A few cases induced by allopurinol, time­ pidium bromide, and chemotherapy for breast carcinoma has also been documented.42–44

Pathogenesis and histological features The etiology and pathogenesis of eosinophil pustular folliculitis are unknown. The possibility of an inherited or contagious cause for the disease has been raised by the observation of the disease in siblings.45 However, there is no firm evidence of an infective cause. A variety of immunological abnormalities have been described including: • raised IgE levels, • low immunoglobulin levels, • defects of neutrophil motility.6,28 A pemphigus-like antibody and an antibasal keratinocyte antibody have also been recorded in patients with this disease.46,47 The seborrheic distribution raises a possible role for sebaceous glands in the pathogenesis.10 A lipid-soluble eosinophil chemotactic factor has been iden­ tified from epidermal surface lipids.48 The association of eosinophil pustular folliculitis with AIDS (if indeed this is the same disease) raises the interesting possibility of a diminished T-helper lymphocyte-mediated pathogenesis. An increased number of mast cells has been described around hair follicles and sebaceous glands, suggesting a role for these cells in the development of the disease.49 In early lesions, spongiosis of the outer root sheath of the infundibulum with an accompanying eosinophil and mononuclear cell infiltrate is char­ acteristic.6 As the disease progresses, vesiculation and pustulation are seen deep to the stratum corneum, often extending into the sebaceous gland (Fig. 15.49). The epithelium is infiltrated by large numbers of eosinophils with an admixture of neutrophils and mononuclear cells. In the superficial dermis there is a perivascular mononuclear and eosinophil infiltrate. Follicular muci­ nosis has been described.50–54

Differential diagnosis As mentioned above, there is considerable overlap between eosinophilic folli­ culitis associated with HIV infection and Ofuji’s disease. The latter condition tends to form arcuate plaques. Histologically, well-developed large eosino­ philic pustules in the pilar canals are characteristic of Ofuji’s disease but are less common in HIV-associated eosinophilic folliculitis.55 Identical histology may be seen in epidermal fungal infections and special stains are essential to exclude this possibility.49,56–59

Incontinentia pigmenti Clinical features Incontinentia pigmenti (Bloch-Sulzberger syndrome) is a rare systemic illness with a striking female bias (in excess of 37:1), as affected males usually die in utero.1–3 It has an X-linked dominant mode of inheritance.4 Cutaneous ­manifestations usually present at birth or during the first few weeks of life.1 There may also be lesions affecting the hair, teeth, nails, eyes, skeleton and the central nervous system in up to 80% of patients.1,4 The phenotype in

Fig. 15.49

A

(A, B) Eosinophilic pustular folliculitis: there is spongiosis associated with an eosinophil-rich abscess.

B

females is variable, manifestations being dependent on the effects of mosa­ icism resulting from X-chromosome lyonization.5 It has occasionally been described in identical twins.6 The disease is rarely transmitted from father to daughter.7 Most males with incontinentia pigmenti die in utero and only very rare patients survive. As with females, it is associated with the same phenotypic mosaicism.8 In the majority of cases of male involvement it develops in asso­ ciation with Klinefelter’s syndrome.9,10,32 Half chromatid mutation, or more recently an unstable pre-mutation, has been offered as explanations for affected males with a normal karyotype.11,12 Typically, the condition has four stages: 13,14 • Stage 1, comprising erythema and linear vesiculation on the trunk and extremities, is apparent at birth or during the first 2 weeks of life (Fig. 15.50).15 Characteristically, the face is unaffected. Patients usually show associated leukocytosis and eosinophilia. On average, the blistering stage completely resolves within 4 months.5 • Stage 2, which is uncommon and usually transitory, consists of hyperkeratotic verrucous papules and plaques most frequently found on the extremities (Fig. 15.51). The verrucous lesions develop at sites of previous blistering.15 They may resemble linear epidermal nevi.16 This

Incontinentia pigmenti

Fig. 15.50 Incontinentia pigmenti: the inflammatory stage is characterized by erythema, linear clusters of intact vesicles, crusts, and scaling. By courtesy of J.C. Pascual, MD, Alicante, Spain.

stage (when present) appears during the second to sixth weeks of life and usually resolves completely by 6 months.5 • Stage 3, which is pathognomonic of incontinentia pigmenti, presents as bizarre reticulated pigmentation, generally between the twelfth and twenty-sixth weeks after birth. It sometimes occurs de novo. The brown to slate-gray pigmentation appears as splashes, streaks, and whorls (sometimes referred to as ‘Chinese lettering’) on the torso and extremities (Fig. 15.52). The nipples are typically hyperpigmented and involvement of the groin and axillae is characteristic.5 The pigmentation appears to develop independently of the bullous lesions or verrucous plaques and follows Blaschko's lines.15,16 Resolution of lesions is associated with atrophy and the pigmentation is usually imperceptible by adulthood. • Stage 4, usually present in adulthood, shows only residual changes that may be visible as occasional atrophic, hypopigmented, hairless, reticulated patches and streaks best seen on the lower legs.1,5,17 Additional cutaneous lesions include mild nail dystrophy (40%), scalp alo­ pecia at the vertex, and the woolly hair nevus.4,5 A whorled scarring alopecia following the lines of Blaschko has been documented.2 At this point, the skin lesions cease to be problematic and other issues such as ocular involvement are the focus of concern.18,19

Fig. 15.52 Incontinentia pigmenti: the whorl-like distribution of the pigment is characteristic. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Painful subungual digital verrucous nodules are occasional late ­features of incontinentia pigmenti.17,20 They are usually multiple, affect the hands more often than the feet and, in addition to nail destruction, they can also be asso­ ciated with scalloped resorption of the underlying phalanx.21 Spontaneous regression is sometimes seen. Clinically, these nodules may be mistaken for a wart, subungual fibroma, keratoacanthoma or squamous cell carcinoma.22 Dermatoglyphic patterns presenting in patients and also in nonaffected family members have been described.23 Some patients develop episodes of late reactivation of the disease in hyperpig­ mented streaks and this appears to be related to a preceding infection.24 It sug­ gests that the mutated cells persist in the epidermis for a long period of time. There can be widespread systemic involvement (Table 15.4). Dental abnormalities include hypodontia, delayed eruption, impaction, and crown malformations such as conical forms and accessory cusps.5,16,25–27 The most characteristic ocular changes are strabismus, ­microphthalmos, cataract, and optic atrophy.28 Retinal detachment with a fibrovascular ­retrolental membrane is the commonest intraocular abnormality.29–32 Central nervous system involvement may result in encephalopathy, ­seizures, mental retardation, microcephaly, cerebellar ataxia, and motor effects including spastic quadriplegia, hemiplegia, slow motor develop­ ment, and psychomotor retardation.1,33–35 There is some evidence to suggest that incontinentia pigmenti can be associated with chromosomal instabil­ ity and a slightly increased susceptibility to cancer; cutaneous squamous cell ­carcinoma has been described in a 16-year-old.36,37 A unique case associated with t­ wenty-nail dystrophy has been reported.38 Table 15.4 General manifestations of incontinentia pigmenti

Fig. 15.51 Incontinentia pigmenti: verrucous lesions, seen in the second stage, predominantly affect the extremities. By courtesy of the Institute of Dermatology, London, UK.

System

Abnormality

Scalp

Scarring Alopecia of variable severity

Nails

Occasional dystrophy

Teeth

Partial/complete absence Conical (pegged)

Eyes

Strabismus Blindness Cataracts Atrophy of optic nerve

Central nervous system

Spastic paralysis Mental retardation Convulsions

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654

Neutrophilic and eosinophilic dermatoses

Pathogenesis and histological features Considerable new data have been published which sheds much light on the pathogenesis of this disease: • Linkage analysis has demonstrated two incontinentia pigmenti loci that reside within the long arm of the X chromosome at Xq11 (IP1) and Xq28 (IP2).5,39,40 • Mutations in the gene for the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG) also called nuclear factor (NF)-κ,B gene modulator (NEMO), which plays a role in inhibiting tumor necrosis factor (TNF)-induced apoptosis, has been shown to be responsible for development of the disease.41–44 • A mouse model has been created by disruption of NEMO, which leads to lethality in males and heterozygous females with skin and eye lesions similar to incontinentia pigmenti.45,46 Biopsy of skin lesions of diseased animals shows increased keratinocyte apoptosis, inflammation, and pigment incontinence.45 • A relationship between incontinentia pigmenti and the osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, immunodeficiency (OL-EDA-ID) syndrome has recently been suggested in a patient who presented with the latter syndrome born to a mother with features of incontinentia pigmenti.47 Both diseases are associated with mutations in NEMO / IKBKG.48,49 Male patients with the disease often have less deleterious mutations and present with ectodermal dysplasia and immunodeficiency.10 • Eotaxin (an NF-kappaB-activated chemokine) is strongly expressed in the suprabasal epidermis of involved skin in patients with the disease.50 This expression is concomitant with the upper epidermal accumulation of eosinophils, suggesting a pathogenetic role for this chemokine. Histological examination of lesions in the vesicular stage (stage 1) shows eosinophilic spongiosis (Fig. 15.53). Occasionally, aggregates of dyskeratotic cells are evident (Fig. 15.54).4 A chronic inflammatory cell infiltrate with conspicuous eosinophilia may be present within the dermis. The verrucous lesions (stage 2) are characterized by hyperkeratosis, acan­ thosis, papillomatosis, and focal dyskeratosis (Fig. 15.55).21 The dyskeratotic cells are typically arranged in a whorled configuration. Stage 3 lesions manifest marked pigmentary incontinence with numerous melanophages in the dermis associated with epidermal basal cell degeneration. End-stage lesions display epidermal atrophy and there may be loss of the adnexae.45 Melanocytes appear to be present in reduced or normal num­ bers and ultrastructurally have shown no significant lesion except for one report in which small nondendritic forms with degenerate melanosomes were described.6,51 Some authors have recommended biopsy of these late lesions in adulthood as helpful for diagnosis.52

Fig. 15.54 Incontinentia pigmenti: there is dyskeratosis and an upper dermal eosinophil-rich infiltrate.

A

B

Fig. 15.53

Fig. 15.55

Incontinentia pigmenti: vesicular stage showing a subcorneal eosinophil pustule and intraepidermal eosinophils.

(A, B) Incontinentia pigmenti: verrucous stage showing massive hyperkeratosis, papillomatosis, acanthosis, and numerous dyskeratotic cells.

Hidradenitis suppurativa Molecular testing is available for confirmation of difficult cases and such techniques can also be applied to prenatal testing.3,53–55 The subungual verrucous nodules show hyperkeratosis, hypergranulosis, pseudoepitheliomatous hyperplasia, and striking dyskeratosis throughout the epidermis.21,22

Differential diagnosis Clinically, incontinentia pigmenti may be confused with hypomelanosis of Ito (incontinentia pigmenti achromians), and the central nervous system involve­ ment in both diseases is similar.56 The latter condition, however, is character­ ized by cutaneous pigmentary changes in the absence of either vesicular or verrucous lesions. Many conditions are associated with eosinophilic spongiosis, but with ade­ quate clinical information none should pose diagnostic problems. Toxic erythema of the neonate can be distinguished histologically from incontinentia pigmenti by the absence of spongiosis in the former condition.

Toxic erythema of the neonate Clinical features Toxic erythema of the neonate (erythema toxicum, erythema toxicum neonato­ rum) is a very common, self-limiting disorder that presents as an asymptomatic erythematous macular rash usually in the first few days of life. Very rarely, the eruption occurs a week or more after birth.1 It affects up to 50% of neonates. In survey studies from Japan, Australia, China, and India, toxic erythema was found in 40.8%, 34.8%, 33.7% and 20.6% of infants, respectively.2–5 It may be associated with papules, and occasionally pustule formation is evident. It most often involves the forehead, face, chest, trunk, and extremi­ ties.6 Lesions usually resolve in a few days.

Fig. 15.56 Hidradenitis suppurativa: early lesion presenting as an erythematous nodule discharging clear fluid. The axilla is a commonly affected site. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Pathogenesis and histological features The etiology of this condition is obscure, but some have suggested an immune reaction to postnatal cutaneous comensural microbial colonization, perhaps partially mediated by mast cells.7,8 Early erythematous lesions show a somewhat nondescript perivascular inflammatory cell infiltrate with conspicuous eosinophils, which can be seen penetrating the epidermis in close proximity to hair follicles. The pustules are characteristically intrafollicular, sometimes subcorneal or intraepidermal, and contain large numbers of eosinophils and occasional neutrophils.9

Differential diagnosis Toxic erythema of the neonate must be distinguished from incontinentia pig­ menti. The latter, however, is characterized by eosinophilic spongiosis, a fea­ ture not seen in toxic erythema. In miliaria rubra the vesicles are related to sweat ducts rather than hair follicles and typically contain mononuclear cells rather than eosinophils.

Hidradenitis suppurativa Clinical features Hidradenitis suppurativa (acne inversa, apocrine acne) is a common dis­ ease.1–3 Studies from Denmark have found the prevalence to be around 4%, while that in France is approximately 1%.4–6 It is a chronic relapsing suppurative inflammation of regions where apo­ crine glands occur, i.e., the axilla, inguinal folds, perineum, genitalia, and periareolar region (Fig. 15.56).7,8 It occurs postpubertally in both sexes, but is more common in women.5 Karl Marx was famously afflicted.9–11 The ­disease is seen most frequently in young adults, although its first presentation may be in older individuals and also before puberty.12,13 Initially, there is a firm painful nodule in the groin or axilla. The nodule can involute slowly or else discharge pus through the skin; the discharge of pus is not copious, but is chronic and often malodorous. In the late stages a complex interconnecting system of sinuses extends deeply into the dermis and subcutaneous fat with extensive dense fibrosis (Fig. 15.57).14

Fig. 15.57 Hidradenitis suppurativa: in this very severe example, there is marked scarring and numerous sinuses are present. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.

Axillary lesions are more common in women and genitoinguinal lesions are more common in men. Changes may be confined to one region or occur in both, but the axillary region is involved in over 70% of cases.15 Some reports have attached etiological importance to axillary shaving and the use of deodorants, but this is not generally accepted.15,16 In women, obesity appears to be a predisposing factor and smoking is closely associated, but it is not clear whether this is a cause or effect.6,17–19 In one study, nearly 90% of German patients were smokers (expected prevalence rate 27%).12 Whether cessation of smoking improves the course of the disease is unknown.20 Patients with the hidradenitis suppurativa appear to be at increased risk of developing ­nonmelanoma skin cancer.21

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Neutrophilic and eosinophilic dermatoses The lesions are clearly maintained by bacterial infection as various ­ rganisms are often grown. Symptomatic improvement can be achieved with o long-term antibiotics. Perineal lesions are often severe and complicated by abscesses, fistulae, and draining sinus tracts.15 Lesions are also rarely seen on the malar region of the face and even on the eyelids (glands of Moll), sites with modified apocrine glands. Hidradenitis suppurativa can be present in association with conditions which are said to be pathologically similar, namely acne conglobata and dis­ secting folliculitis of the scalp. These three conditions have been referred to collectively as the ‘follicular occlusion triad’.22 Any one condition, however, may occur separately. Acne conglobata, an extremely severe nodulocystic variant of acne, occurs extensively on the trunk, buttocks, and limbs with predilection for males.23 The disease has been described in association with HIV and following pregnancy.24,25 Dissecting folliculitis (folliculitis capitis abscedens et suffodiens) is centered on the vertex of the scalp and is char­ acterized by boggy tender lesions that tend to become confluent with for­ mation of draining sinuses and suppuration.26–29 The disease presents more commonly in black males and it is very rarely familial.30 Radical surgery is often the only satisfactory means of terminating the process. All the dis­ eases in the follicular occlusion triad can occasionally be complicated by progression to cellulitis and septicemia. Squamous carcinoma (including the verrucous variant) is a rare and late additional complication.31–38 As with Marjolin’s ulcer–cancer, the carcinomas are capable of aggressive invasion and metastasis (50%) and are generally associated with a poor prognosis.15 Such tumors arise most frequently on the buttocks and are more often seen in males.34 Hidradenitis has been shown to be rarely associated with sys­ temic granulomatous lesions, in particular Crohn’s disease.17,39–41 An associa­ tion with spondyloarthropathy, Dowling-Degos disease, and lithium therapy has also been documented.42–44 Treatment of this disease is difficult due to its chronic relapsing nature. Surgery is often used to remove affected areas but the cure rate in some studies is very low.45 Nevertheless, occasional patients are satisfied with the relief of symptoms, albeit temporary, afforded by surgery.45 Other studies have shown a low recurrence rate following wide excision.46,47 Early surgical treatment appears to increase the chance of success.48 Recently, new-generation immunosuppressive agents have shown some efficacy.49 Hormonal regulation has also been employed with more ­limited success.50

Pathogenesis and histological features The pathogenesis of hidradenitis suppurativa remains poorly understood.51–56 It has generally been thought that the earliest lesion is an acute inflamma­ tory process involving the apocrine duct and gland, which extends into the surrounding connective tissue with subsequent abscess and sinus formation

A

(Fig. 15.58).51 Other authors, however, believe that eccrine hidradenitis is more commonly found than apocrine involvement and yet others think that the primary event is follicular obstruction.34,53 Some data suggest overacti­ vation of the innate immune system, but a deeper underlying cause remains elusive.57,58 The provocation for the initial ‘apocrinitis’ is believed by some to be keratin occlusion of the corresponding hair follicle. Certainly, keratin plug­ ging of follicles and sinuses and inflammation in and around the hair fol­ licle are regularly seen.52 In one study, follicular occlusion was present in all of 118 specimens examined in patients with disease duration that ranged from as little as 1 month to many years.54 The anatomic distribution of the lesions also supports the concept of an underlying apocrine gland defect. The condition has some similarity to Fox-Fordyce disease, which is more convincingly associated with an inflammatory process of the apocrine duct. Fox-Fordyce disease has the same sex predilection, age incidence, and ana­ tomic distribution, and it too is alleviated by pregnancy. Interestingly, some cases of Fox-Fordyce disease have been reported to progress to hidradenitis suppurativa. The other members of the follicular occlusion triad – acne conglobata and dissecting folliculitis – are both clearly associated with keratin plugging. There is no doubt that the main symptoms and chronic disability are related to the sinuses and fibrosis; these are largely due to the chronic second­ ary infection, since injection of sterile apocrine sweat into tissues does not induce an inflammatory response. Organisms that may be found include Staphylococcus aureus, Streptococcus viridans, Escherichia coli, Proteus mirabilis, Klebsiella spp, Pseudomonas aeruginosa, Streptococcus milleri and anaerobic organisms. Coagulasenegative S. aureus is the most common bacterium isolated from the depth of the lesions.59 Anaerobic organisms are responsible for the offensive smell, which can be a major problem for the patient. Generally, no immune defi­ ciency is detectable, but there have been occasional reports of a functional neutrophil deficiency. In considering the pathogenesis of this condition it must also be noted that some cases clearly develop as an autosomal dominantly inherited ten­ dency.60,61 Others have no suggestion of familial incidence. The disease has been simulated in 3 of 12 normal volunteers by occlu­ sion of axillary skin with atropine tape following depilation.62 The latter in itself could be expected to produce some pathology, which is clearly not seen in the normal individual. The absence of lesions in 75% of these volunteers shows at least that there is some variation in susceptibility to developing the disease. This experimental induction of the disease has not been repeated. In a study of 42 women with hidradenitis suppurativa, the authors noted premenstrual exacerbation of symptoms in two-thirds of patients

B

Fig. 15.58 (A, B) Hidradenitis suppurativa: early lesion showing acute inflammation involving the apocrine gland.

Hidradenitis suppurativa and over one-third of patients reported menstrual irregularities.63 In this same study, testosterone and free androgen index were higher compared with control patients.63 In contrast, another study was not able to correlate ­hyperandrogenism and development of hidradenitis in women.8,64 Pregnancy may relieve the ­symptoms of the disease. In summary, the precise pathogenesis of hidradenitis suppurativa is not well understood. It seems likely, however, that while many patients have a tendency to follicular occlusion with resultant acne-like lesions, some indi­ viduals show an additional, occasionally inherited, tendency for follicular obstruction to cause, or be associated with, inflammation of the apocrine duct. With the additional occlusive effects of obesity and secondary infec­ tion, often by mixed organisms, there is a resultant florid destructive fol­ liculitis centered on, or also involving, the apocrine glands. The secondary bacterial infection perpetuates the chronic inflammatory and scarring nature of the process. A defect in the immune system would be expected to exac­ erbate this vicious circle, but no consistent abnormality has yet been identi­ fied.65,66 The changes with pregnancy and menstrual cycle can be attributed to the hormonal effects on the apocrine gland and do not appear to be of primary importance. Biopsies of established hidradenitis suppurativa show sinus tracts with marked suppuration and frank abscess formation. The sinus tracts are lined by a mixture of granulation tissue and squamous epithelium (Fig. 15.59). The latter extends from the associated follicular epithelium. These inflam­ matory sinus tracts usually contain desquamated keratin and sometimes hair shafts, and are surrounded by dense fibrosis.54 The suppuration may extend into adjacent connective tissue where there can also be a chronic inflam­ matory infiltrate frequently including histiocytes and giant cells that are sometimes related to keratin fragments. At this stage apocrine glands are conspicuously absent in the scarred and inflamed area, although ­adjacent apocrine glands often appear quite normal. Although some authors have emphasized the presence of acute inflammation of apocrine glands, in our

Fig. 15.59 Hidradenitis suppurativa: the sinuses are lined by stratified squamous epithelium and surrounded by fibrosis and inflammation.

experience, this is an uncommon finding in routine surgical specimens. Others have also found primary inflammation of apocrine glands in only a minority of specimens.53,67

Differential diagnosis The main differential diagnoses are primary infection, a response to a ­ruptured epidermal inclusion cyst, or wounds. Clinical correlation and special stains for microorganisms are necessary to establish the correct diagnosis.

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Chapter

16

Vascular diseases

See www.expertconsult.com

for references and additional material

Introduction  658

Thromboangiitis obliterans  688

Disseminated intravascular coagulation  701

Leukocytoclastic vasculitis  658

Temporal arteritis  689

Cryoglobulinemia  703

Henoch-Schönlein purpura  664

Juvenile temporal arteritis  692

Infantile acute hemorrhagic edema  665

Takayasu's arteritis  692

Antiphospholipid antibody syndrome and Sneddon's syndrome  705

Urticarial vasculitis  666

Infection-related vasculitis  694

Polyarteritis nodosa and microscopic polyangiitis  667

Paraneoplastic vasculitis  695

Wegener's granulomatosis  673 Allergic granulomatosis with angiitis  677 Mucocutaneous lymph node syndrome  679

Vasculitis associated with palisaded neutrophilic and granulomatous dermatitis  696 Lymphocytic vasculitis  696 Malignant atrophic papulosis  697 Atrophie blanche  699

Erythema elevatum diutinum  684

Dermatological manifestations of cholesterol crystal embolism and embolism from atrial myxoma  700

Introduction Vasculitis and other forms of vascular damage are the subjects of this chapter. Although minimal criteria for the diagnosis of vasculitis may differ among experts, the presence of inflammation and some evidence of vascular damage in the form of vessel wall/endothelial cell necrosis or fibrinoid change fulfill most authorities' criteria for a diagnosis of vasculitis. Some, however, apply the term less restrictively to vascular inflammation associated with nonspecific histological features such as extravasated red cells, endothelial swelling, or karyorrhexis but without fibrinoid change or necrosis. When encountering such cases, we prefer to designate them as ‘low-grade vascular damage’ and include a comment that, although the findings may represent very early vasculitis, they do not meet strict criteria for necrotizing vasculitis. That inflammatory vascular disease is represented by a broad spectrum of histological changes cannot be overemphasized. The histological features of most forms of vasculitis are not specific for an entity per se. A specific diagnosis requires careful clinical, histological, and serological (i.e. presence of antineutrophil antibodies) correlation.1 The role of the pathologist in evaluating a biopsy is to confirm or deny the presence of vasculitis, and to describe the nature of the inflammatory infiltrate and the type(s) and size(s) of the vessel(s) involved. A histological differential diagnosis is established to guide patient evaluation. Correct biopsy technique and timing are important to allow for adequate assessment for vasculitis. Incisional biopsies to include sufficient subcutis and larger subcutaneous vessels within the first 48 hours after development of the lesion yield the best results.1 A pathological diagnosis of vasculitis may indicate a primary or secondary disease (i.e. in the setting of connective tissue disease). Secondary forms

Immune thrombocytopenic purpura  707 Factor V Leiden mutation  708 Hypergammaglobulinemic purpura  708 Hyperimmunoglobulinemia D syndrome  709 Superficial thrombophlebitis  709

Granuloma faciale  681

Behçet's disease  686

Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome  706

Sclerosing lymphangitis  709 Senile purpura  710

of vascular disease may manifest as diverse histological patterns. For example, connective tissue diseases may be associated with either a smallvessel leukocytoclastic disease or a large vessel vasculitis. Likewise, different histological patterns may be seen in association with a given primary vasculitis. As an example, Wegener's granulomatosis may be linked with either leukocytoclastic or granulomatous vasculitis. The myriad schemata for the classification of the vasculitides are a reflection of the complexity of this controversial class of diseases. Over the last decade or so, several new classifications have emerged that attempt to combine both histological and clinical information (Table 16.1).2 Undoubtedly, these will continue to be refined as a more complete understanding of the pathogenesis of these diseases is gained.

Leukocytoclastic vasculitis Clinical features Leukocytoclastic vasculitis (allergic vasculitis, hypersensitivity vasculitis, leukocytoclastic angiitis) is the commonest form of vasculitis.1–6 It is not a disease entity but represents a vascular reaction pattern due to circulating immune complexes that may either be idiopathic or caused by a number of underlying disorders. The antigens possibly involved are summarized in Table 16.2.1–7 The most frequent associations are drugs in addition to infections.8,9 In over 40% of cases, however, no underlying condition can be identified.10 Although the condition may be limited to the skin, it is important to recognize that it can also be associated with systemic manifestations involving the joints, kidneys, and gastrointestinal system in between 15% and 50% of patients.5,10–12 The disease occurs equally in men and women, and may present in any age group.

Leukocytoclastic vasculitis Table 16.1 Types and definitions of vasculitis adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis* Type of vasculitis

Essential components/nonessential components

Large vessel vasculitis Giant cell (temporal) arteritis

Takayasu arteritis

Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery. Often involves the temporal artery. Usually occurs in patients older than 50 and often is associated with polymyalgia rheumatic. Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger than 50.

Medium-sized vessel vasculitis Polyarteritis nodosa† (classic polyarteritis nodosa) Kawasaki disease

Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Arteritis involving large, medium-sized and small arteries, and associated with mucocutaneous lymph node syndrome. Coronary arteries are often involved; aorta and veins may be involved. Usually occurs in children.

Small vessel vasculitis Cutaneous leukocytoclastic angiitis Henoch–Schönlein purpura

Microscopic polyangiitis† (microscopic polyarteritis)‡ Wegener's granulomatosis‡

Churg-Strauss syndrome‡ Essential cryoglobulinemic vasculitis

Isolated cutaneous leukocytoclastic angiitis without systemic vasculitis or glomerulonephritis. Vasculitis, with IgA-dominant immune deposits, affecting small vessels (i.e. capillaries, venules or arterioles). Typically involves skin, gut, and glomeruli, and is associated with arthralgias or arthritis. Necrotizing vasculitis, with few or no immune deposits, affecting small vessels (i.e. capillaries, venules or arterioles). Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels (e.g. capillaries, venules, arterioles and arteries). Necrotizing glomerulonephritis is common. Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, and associated with asthma and eosinophilia. Vasculitis, with cryoglobulin immune deposits, affecting small vessels (i.e. capillaries, venules or arterioles), and associated with cryoglobulins in serum. Skin and glomeruli are often involved.

Reproduced with permission from Jennette, J.C., et al. 1994 Seminars in Diagnostic Pathology, 18, 3–13. * Large vessel refers to the aorta and the largest branches directed toward major body regions (e.g. to the extremities and the head and neck); medium-sized vessel refers to the main visceral arteries (e.g. renal, hepatic, coronary, and mesenteric arteries); small vessel refers to venules, capillaries, arterioles, and the intraparenchymal distal arterial radicals that connect with arterioles. Some small and large vessel vasculitides may involve medium-sized arteries, but large and medium-sized vessel vasculitides do not involve vessels smaller than arteries. Essential components are represented by normal type; italicized type represents usual, but not essential, components. † Preferred term. ‡ Strongly associated with antineutrophil cytoplasmic autoantibodies.

Skin lesions are typically polymorphic, but palpable purpura (nonblanching erythematous papules) is the commonest manifestation (Fig. 16.1). Urticarial, bullous or vesicular, ulceroinfarctive, nodular, pustular, livedoid, and annular lesions may also be encountered (Figs 16.2–16.8).13–17 The lesions measure from 1 mm to several centimeters in diameter. Occasionally, annular erythema multiforme-like lesions occur (Fig. 16.9). The lower legs are affected most often, but lesions can present at a wide variety of sites, including the buttocks, arms, feet, ankles, trunk, and face, particularly in more seriously affected patients (Figs 16.10, 16.11). Lesions may be noted in the skin of dependent areas of bedridden patients, such as the back and buttocks. A frequent accompaniment is edema of the lower legs or ankles (Fig. 16.12). Patients either experience a single occurrence or develop frequent recurrences over months or years. The eruption often occurs in episodes at irregular intervals, each lasting 1–4 weeks. Lesions usually heal completely, although on occasions atrophic scars and hyperpigmentation may occur. Rarely, leukocytoclastic vasculitis shows an erythema gyratum repens gross morphology.18 Although occasional cases are asymptomatic, patients not uncommonly complain of pruritus or burning; less frequently, pain is a feature. Additional features, which are sometimes present, include abdominal pain and gastrointestinal bleeding, joint pains with associated erythema and swelling, and evidence of renal involvement.19 In severe cases, the features resemble acute glomerulonephritis and the nephrotic syndrome may even supervene. Rarely, patients have respiratory involvement (nodular or diffuse infiltrative lesions on X-ray examination), and very exceptionally the central or peripheral nervous system is affected, causing symptoms such as headache, diplopia, and dysphagia.

In one study, drug therapy, often following an upper respiratory tract infection, was the inciting event in 45% of patients.20 Numerous drugs have been implicated as a trigger including non-steroidal anti-inflammatory drugs (aspirin, ibuprofen, naproxen, phenylbutazone), phenytoin, quinidine, amiodarone, potassium iodide, allopurinol, sulfonamides, griseofulvin, penicillin, erythromycin, clindamycin, oxacillin, vancomycin, ofloxacin, clarithro­ mycin, furosemide (frusemide), thiazides, cimetidine, omeprazole, gabapentin, orlistat, zidovudine, indinavir, efavirenz, lisinopril, sotalol, insulin, retinoids, propy­lthiouracil, thiouracil, mefloquine, methotrexate, azathioprine, sirolimus, granulocyte colony-stimulating factor, haloperidol, cytarabine, erlo­ tinib, rituximab, cinacalcet, famciclovir, rifampin, pyrazinamide, insulin aspart, metformin, gold and disulfiram.2,21–63 Levamisole has been described as producing a vasculitis localized to the ears in children.64, 65 Localized leukocytoclastic vasculitis may occur at the site of interferon alpha injection.66, 67

Collagen vascular disease (most often rheumatoid arthritis and lupus erythematosus) is commonly associated with leukocytoclastic vasculitis, 2,68 and in one study it was found in 21% of patients.2 The presence of leukocytoclastic vasculitis in a patient with dermatomyositis raises the possibility of associated malignancy.69 Infection is also commonly associated with leukocytoclastic vasculitis, with bacterial, fungal, and viral infection all being implicated.70 Associated bacterial infections include streptococci, Klebsiella pneumoniae, Mycobacterium tuberculosis, and Mycoplasma pneumoniae.71–73 Systemic cat scratch disease presenting as leukocytoclastic vasculitis has been documented.74 Hepatitis C infection is a particularly frequent association. It should be noted that

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Table 16.2 Possible causes of allergic vasculitis •  Infection –  bacterial: Streptococcus –  mycobacterial: Mycobacterium tuberculosis –  viral: hepatitis, influenza –  cytomegalovirus –  HIV infection –  leprosy •  Drugs –  aspirin, phenacetin, sulfonamides, penicillin, iodides, phenothiazines •  Chemicals –  insecticides, weed killers, petroleum products •  Foreign proteins –  serum sickness –  hyposensitization antigens •  Associated diseases – autoimmune diseases: systemic lupus erythematosus, inflammatory bowel disease –  hemolytic anemia –  Hodgkin's lymphoma, carcinoma –  rheumatoid arthritis –  mixed connective tissue disease –  dermatomyositis –  relapsing polychondritis –  Sjögren's syndrome –  Henoch-Schönlein purpura –  cryoglobulinemia –  polyarteritis nodosa –  Wegener's granulomatosis –  Churg-Strauss disease –  granuloma faciale –  erythema elevatum diutinum –  Waldenström's hypergammaglobulinemia –  sarcoidosis

Fig. 16.2 Leukocytoclastic vasculitis: close-up view showing small erythematous lesions. By courtesy of the Institute of Dermatology, London, UK.

Fig. 16.3 Leukocytoclastic vasculitis: in this patient an extensive purpuric eruption showing central necrosis is evident. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 16.1 Leukocytoclastic vasculitis: typical erythematous maculopapular lesions are present on the medial aspect of the ankle. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

hepatitis C is also often associated with cryoglobulins (see section on cryoglobulinemia).75–77 Inflammatory bowel disease, both ulcerative colitis and Crohn's disease, may be coupled with leukocytoclastic vasculitis.78,79 Further rare associations include sarcoidosis, α1-antitrypsin deficiency, cystic fibrosis, and the WiskottAldrich syndrome.15,80,81

Fig. 16.4 Leukocytoclastic vasculitis: here confluent purpura with ulceration is present. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Leukocytoclastic vasculitis

Fig. 16.5 Leukocytoclastic vasculitis: this patient presented with bullous lesions which developed as a consequence of thrombosis with epidermal infarction. By courtesy of the Institute of Dermatology, London, UK.

Fig. 16.7 Leukocytoclastic vasculitis: in this patient, there are extensive ulceroinfarctive lesions. By courtesy of the Institute of Dermatology, London, UK.

Fig. 16.8 Leukocytoclastic vasculitis: close-up view of a hemorrhagic blister. By courtesy of the Institute of Dermatology, London, UK.

Fig. 16.6 Leukocytoclastic vasculitis: Nodular lesions. By courtesy of the Institute of Dermatology, London, UK.

Physical exercise has also been related to the development of leukocytoclastic vasculitis. Outdoor activities in hot weather such as walking, running, and golfing (Golfer's vasculitis) have especially been implicated and middle-aged to elderly individuals are more frequently affected.82–84 Leukocytoclastic vasculitis rarely represents a paraneoplastic manifestation of an underlying malignancy, especially leukemia and lymphoma.85 Hairy cell leukemia is particularly often associated with leukocytoclastic vasculitis but other forms of vasculitis may also be seen. In one study of 42 patients with hairy cell leukemia and vasculitis, 21 had leukocytoclastic vasculitis and 17 had polyarteritis nodosa.86 In addition, four patients had direct infiltration of vessel walls by leukemic cells (see also section on paraneoplastic vasculitis). Although uncommon, leukocytoclastic vasculitis may also be seen in patients with a variety of solid tumors including non-small cell carcinoma of lung, and adenocarcinoma of breast, colon, prostate, and kidney.87, 88 Leukocytoclastic vasculitis can be a manifestation of human immuno­ deficiency virus (HIV) infection.89 Unusual associations of this condition

include the use of a nicotine patch, drug additives, sodium benzoate, protein A column pheresis, interleukin-12 receptor beta-1 deficiency, prolonged exercise, and as a complication of an infected hip prosthesis.90–96 Laboratory investigation may reveal an elevated erythrocyte sedimentation rate (ESR), proteinuria or hematuria. In some idiopathic cases and in those associated with systemic disease (e.g. rheumatoid arthritis, systemic lupus erythematosus (SLE), and Sjögren's syndrome), hypocomplementemia is sometimes evident.5 Urinalysis may reveal proteinuria or hematuria. Cryoglobulins have been found in up to 25% of patients.2 Perinuclear staining antineutrophil antibodies are present in about 20% of patients.2,97 The outcome of leukocytoclastic vasculitis is variable, ranging from a mild, self-limiting illness through to a serious, potentially fatal disorder due particularly to renal involvement.19 About 1.9% of patients die of systemic disease.2 Most patients have a benign outcome. An acute clinical course is seen in approximately 50% of patients.2,10 A chronic course or one characterized by relapses and remissions is seen in some patients.2 In one study of patients with hypersensitivity vasculitis, 54 did not require therapy, 26 were treated with non-steroidal anti-inflammatory medications, and 14 required immunosuppressive agents, most often corticosteroids.20 Specific syndromes associated with leukocytoclastic vasculitis, such as urticarial vasculitis and Henoch-Schönlein purpura, are discussed under separate headings in this chapter.

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Fig. 16.9

Fig. 16.10

Fig. 16.11

Leukocytoclastic vasculitis: these urticarial lesions on the back of the arm resemble those of erythema multiforme. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Leukocytoclastic vasculitis: lesions may be widely disseminated in severely affected patients. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Leukocytoclastic vasculitis: this patient has serological evidence of systemic lupus erythematosus.

Fig. 16.12 Leukocytoclastic vasculitis: in addition to the typical maculopapular eruption there is marked swelling of the legs. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Pathogenesis and histological features Leukocytoclastic vasculitis is an immune complex-mediated disorder similar to the classic Arthus reaction.98 Immune complexes are deposited in the walls of small blood vessels.5 This is associated with activation of the complement cascade and the production of C5a (a neutrophil polymorph chemotactant). The resultant polymorph influx is associated with release of

lysosomal enzymes, including elastases and collagenases, resulting in blood vessel wall damage, fibrin deposition, and the release of red blood cells (purpura) into the perivenular connective tissue. Thrombosis may ensue and, in particularly severe examples, epidermal ischemic damage results. Lesions are particularly seen on the lower legs because of hydrostasis and blood vessel flow sludging.5 Evidence for an immune complex-mediated pathogenesis is convincing.1 Patients have been clinically proven to have high levels of circulating immune complexes, and these are shown to correlate with vasculitic lesions. Immunoglobulin and complement can be identified in vitro, by immunofluorescence or immunoperoxidase techniques, and in biopsies from blood vessel wall lesions less than 24 hours old (Fig. 16.13).99 Immune complexes can be identified ultrastructurally as clumps of electron-dense material, usually within the basement membrane between endothelial cells and pericytes of postcapillary venules. Examination of apparently uninvolved skin from patients with leukocytoclastic vasculitis sometimes shows immunoglobulin and complement within the walls of dermal blood vessels. If histamine is injected into uninvolved skin 3–4 hours previously, all the features of leukocytoclastic vasculitis are evident at biopsy, including neutrophil degeneration; this suggests that the immunoreactants are a cause rather than a consequence of the vasculitis.1 The findings of immunofluorescence studies vary according to the age of the lesion. Immunoglobulins have been described in up to 81% of patients.8 In early lesions, C3 and IgM predominate, in fully developed lesions there is predominance of fibrinogen and IgG, and in late lesions fibrinogen and C3 are detected.8 Some authors, noting that early lesions may contain abundant CD3+, CD4+ and CD1a+ cells, have suggested that cell-mediated immune mechanisms may also play a role in the pathogenesis of leukocytoclastic vasculitis.8 Consistent with this hypothesis is the demonstration of Langerhans cells in the late phase of vasculitis.100 Expression of 72 kD heat shock protein and the presence of gamma/delta T cells in patients with vasculitis associated with infection have led one group of authors to postulate that the cell-mediated immune response plays an important role in that subset.101

Leukocytoclastic vasculitis

Fig. 16.13 Leukocytoclastic vasculitis: IgM is present in the blood vessel walls (direct immunofluorescence). By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK.

In leukocytoclastic vasculitis, it is the postcapillary venule and the capillary loops (and not the arteriole) which are primarily affected, usually within the superficial dermis (Figs. 16.14, 16.15). In severe cases, particularly those associated with malignancy or connective tissue disease, the inflammatory changes extend into the vasculature of the deep reticular dermis or even the subcutaneous fat.9 The histological features are similar irrespective of the underlying etiology. The histological features of leukocytoclastic vasculitis are those of fibrinoid necrosis associated with endothelial cell swelling and infiltration of the blood vessel walls by neutrophils and conspicuous nuclear dust (Fig. 16.16).2,102,103 Variable numbers of mononuclear cells and eosinophils may be seen. In early lesions, nuclear dust is associated with a perivascular neutrophilic infiltrate but multiple tissue sections may be needed to identify fibrinoid vascular changes. The former features, even without unequivocal fibrinoid change, are suggestive of an evolving leukocytoclastic vasculitis. Intravascular thrombi and ischemic necrosis of the overlying epidermis (often with bullae formation) may sometimes be seen (Figs 16.17–16.19). Occasionally, one may encounter intradermal or subepidermal pustules. In patients with associated hypocomplementemia, neutrophils are predom­ inant with far fewer lymphocytes; patients who are normocomplementemic

Fig. 16.15 Leukocytoclastic vasculitis: high-power view showing complete vessel wall destruction.

Fig. 16.16 Leukocytoclastic vasculitis: high-power view showing fibrinoid necrosis and a mixed inflammatory cell infiltrate composed of neutrophils, eosinophils, and lymphocytes. There is marked leukocytoclasis (karyorrhexis, nuclear dust).

Fig. 16.14

Fig. 16.17

Leukocytoclastic vasculitis: the blood vessels show florid fibrinoid necrosis and intense inflammation.

Leukocytoclastic vasculitis: vascular thrombosis as seen in this field is not uncommon.

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Fig. 16.18

Fig. 16.20

Leukocytoclastic vasculitis: in this example, there is incipient subepidermal vesiculation.

Leukocytoclastic vasculitis: note the marked red cell extravasation.

vasculitis. An inadequate biopsy that does not include deep dermis and subcutaneous tissue containing large vessels can produce misleading results. The presence of leukocytoclastic vasculitis in a superficial biopsy does not exclude an associated large-vessel vasculitis; therefore the report of a superficial biopsy from a patient suspected of having large-vessel vasculitis should comment on the lack of larger vessels for evaluation. Sweet's syndrome may resemble leukocytoclastic vasculitis; however, the presence of a diffuse (rather than predominantly perivascular) neutrophilic infiltrate without fibrinoid vascular change or necrosis favors the former condition.

Henoch-Schönlein purpura Clinical features

Fig. 16.19 Leukocytoclastic vasculitis: vascular thrombosis is accompanied by epidermal infarction. Note the cytoplasmic eosinophilia and loss of nuclei.

may show lymphocyte predominance. In the surrounding connective tissue, red cell extravasation, edema, and an inflammatory neutrophil infiltrate associated with karyorrhexis (leukocytoclasis) are typically present (Fig. 16.20). The severity of the histopathological changes in the cutaneous lesions of leukocytoclastic vasculitis does not predict extracutaneous involvement.104

Differential diagnosis The diagnosis is relatively straightforward. It is critical to understand that leukocytoclastic vasculitis is not a disease sui generis. Rather, it represents a reaction pattern due to circulating immune complexes that may be caused by myriad underlying disorders. Furthermore, leukocytoclastic vasculitis is frequently encountered in association with other forms of vasculitis. For example, it is much more commonly encountered in patients with Wegener's granulomatosis than granulomatous vasculitis. Therefore, a biopsy showing leukocytoclastic vasculitis does not exclude diseases that may be associated with other forms of vasculitis. Sometimes it coexists with a large-vessel

Henoch-Schönlein purpura is a syndrome characterized by abdominal pain, joint symptoms, and palpable purpura secondary to leukocytoclastic vasculitis, and caused by circulating IgA immune complexes. The disease typically involves children (males more often than females), although adults may also be affected.1–4 Occurrence during pregnancy has only rarely been documented.5 In a large study of children with Henoch-Schönlein purpura, 92% of patients were less than 10 years of age.6 It often complicates an upper respiratory tract infection and is characterized by a seasonal incidence with a peak in winter.1 Clustering of cases has been described, leading one group of authors to postulate that person-toperson spread of an infectious agent plays a role in the pathogenesis of this syndrome.7 Although it may follow a streptococcal throat infection, it sometimes develops after a wide variety of other infective conditions including amebiasis, chickenpox, hepatitis, HIV, yersiniosis, and infection by Toxocara canis, Helicobacter pylori, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and erythrovirus (formerly parvovirus) B19.8–13 Additional causes include adverse reactions to drugs such as ampicillin, penicillin, erythromycin, and clarithromycin.14,15 An association with cocaine inhalation has also been described.16 In one study, drug therapy may have been a precipitating cause in 26% of patients.17 As noted above, classic Henoch-Schönlein purpura is characterized by a triad of purpura, abdominal pain, and arthralgia. The cutaneous clinical findings are those of leukocytoclastic vasculitis. Cutaneous lesions are most frequently the presenting symptom and comprise palpable purpura predominantly affecting the lower limbs, thighs, and buttocks (Fig. 16.21).1,18–20 Targetoid lesions are often present.21 Hemorrhagic bullae are rare.22–24 Subcutaneous nodules have also been documented.25 A prodrome of itchy urticaria is sometimes described.2 Children often have edema, particularly of the feet and lower legs, although it may be more widespread. In one large study, arthritis was seen in 82% of patients and was the presenting feature in 24%.6 Joint involvement consists of migratory arthralgia

Infantile acute hemorrhagic edema

A

Low serum C3, leukopenia, and thrombocytopenia are rare findings.33 Henoch-Schönlein purpura in children is generally associated with a good prognosis, with less than 2% suffering long-term morbidity.34,35 However, patients do occasionally die from renal failure, gastrointestinal infarction or respiratory involvement. In contrast to pediatric patients, adults are thought to have a worse prognosis. However, one study found that, although older patients had more severe symptoms including frequent renal involvement, prognosis was equally good in young and older patients.36 In another study, complete recovery was seen in 67% of adults after a median follow-up period of 36 months.10 In a further series, a third of patients suffered at least one recurrence of symptoms, usually within a few months of initial presentation.6 Recurrences were also found to be more frequent in patients > 8 years of age and in those with nephritis.18 Solid tumors including breast cancer and hematological malignancy have been associated with Henoch-Schönlein purpura.37–41 One study found that nearly a third of adults with Henoch-Schönlein purpura had an associated tumor.37 For this reason, the authors concluded that physicians should suspect an underlying malignancy in older patients (especially males of 40 years or more) with Henoch-Schönlein purpura.38 Pulmonary hemorrhage is a rare complication that may prove fatal.42,43

Pathogenesis and histological features

B

Fig. 16.21 (A, B) Henoch-Schönlein purpura: palpable purpura in the classical distribution on the buttocks and thighs. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

predominantly affecting the large joints of the lower limbs. In one study, 37% also had involvement of the upper extremities, with the hand and wrist being more often affected than the elbow.6 Intestinal involvement with resultant red cell extravasation or hemorrhage leads to abdominal pain and gastrointestinal bleeding. Abdominal pain was noted in 63% of patients in one study of 100 consecutive children presenting with the condition.6 Gastrointestinal disease develops as a consequence of acute vasculitis. Bleeding may be either occult or in the form of bloody or melanotic stools.6 Intussusception is an occasional complication.26,27 Abdominal pain was the presenting complaint in 19% of patients in one study.6 Endoscopy may reveal hemorrhage, ulceration, and erosions.28 IgA is often noted in capillaries of the gastrointestinal tract but frank necrotizing vasculitis was not seen in any patients in two series.28,29 Rarely, gastrointestinal involvement with minimal skin lesions is encountered.30 Renal symptoms are variable and include microscopic hematuria, acute nephritic syndrome, nephrotic syndrome, and acute or chronic renal failure. The pathological features seen on renal biopsy range from mild focal glomerulo­ nephritis to necrotizing or proliferative glomerulonephritis.1,6 In a consecutive series of 100 pediatric patients, a single patient required transplantation.6 Patients older than 7 years are at increased risk of renal involvement.31 Orchitis is a recognized complication of Henoch-Schönlein purpura, affecting 14% of male patients.6,18 Neurological involvement may be manifested by headaches, seizures, mental status changes and, less frequently, ataxia and peripheral neuropathy.32

An incomplete picture of the pathogenesis of Henoch-Schönlein purpura has emerged. As noted above, it seems a wide variety of infective agents may trigger this disease. Henoch-Schönlein purpura is associated with IgA deposition in blood vessel walls, both in the dermis and in the renal glomerulus (mesangium). IgA1 is the major IgA subclass found in the cutaneous blood vessels.44 Fibrinogen and C3 are also usually present. Raised levels of serum IgA and IgE are present in some, but not all, patients.6 IgA antineutrophil cytoplasmic antibodies (ANCA) and IgA anticardiolipin antibodies have also been documented.45,46 There is evidence that patients have an increased number of IgA-type B cells.47 More recently, IgA-binding regions from streptococcal M proteins have been identified in a significant subset of skin and renal biopsies from patients with Henoch-Schönlein purpura.48 The finding of IgA deposition by immunofluorescence is not equivalent to a diagnosis of Henoch-Schönlein purpura. A vasculitis with the presence of IgA deposition in patients lacking other typical features of HenochSchönlein purpura has been described in association with cancer, Wegener's granulomatosis, and inflammatory bowel disease.49 The observation of an association between DRB1*01 and DRB1*11 and Henoch-Schönlein purpura suggests a genetic susceptibility in some patients.50,51 Other authors have suggested that DQA1*0301 and C4 deletion may also represent risk factors for IgA nephropathy as well as HenochSchönlein nephritis.52 Biopsies of cutaneous lesions show features of typical leukocytoclastic vasculitis (Fig. 16.22).

Differential diagnosis The histological differential diagnosis includes other forms of leukocytoclastic vasculitis. Since IgA deposition can be seen in the blood vessel walls of patients with leukocytoclastic vasculitis but without evidence of Henoch-Schönlein purpura, this finding is not diagnostic in isolation.53 In one study, only 24% of patients with vascular IgA deposition had Henoch-Schönlein purpura.53 Careful clinical correlation is necessary to establish the diagnosis.

Infantile acute hemorrhagic edema Clinical features Infantile hemorrhagic edema is a form of leukocytoclastic vasculitis that is mostly seen in newborns but has also been described in the first 3 years of life and occasionally in older children.1–11 The disease is usually limited to the skin but mucosal involvement may be an additional feature.10 Transient renal involvement with microscopic hematuria and proteinemia, hypocomplementemia, abdominal pain, and elevated transaminases are exceptional additional findings.12,13 It frequently follows vaccination or

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Fig. 16.22

Fig. 16.23

Henoch-Schönlein purpura: this small venule shows striking fibrinoid change. There is considerable red cell extravasation.

Urticarial vasculitis: this very large lesion has developed a bizarre outline due to central clearing. By courtesy of the Institute of Dermatology, London, UK.

infection including otitis, upper respiratory tract infection or conjunctivitis.1,10,11 An association with cytomegalovirus, herpes simplex virus-1 or rotavirus infection has been documented.14–16 Since many children had received antibiotics for infection prior to development of lesions, a subset of cases may represent reaction to medication.1 This disease has a peak incidence in the winter months. Skin lesions are widely distributed, and often involve the head and neck, and limbs. They present as purpuric lesions that often have a rosette or targetoid configuration.2,3 The cheeks and ears seem to be sites of predilection.3,11 Resolution within a few weeks is typical and recurrences are not reported.1,11,17 An elevated ESR and leukocytosis are usually present.

Pathogenesis and histological features The pathogenesis of infantile hemorrhagic edema is unknown; however, it is likely that the disease is immune mediated. Biopsy shows features of leukocytoclastic vasculitis with variable fibrinoid necrosis.3

Differential diagnosis Some authors consider infantile hemorrhagic edema to be a variant of Henoch-Schönlein purpura. Others do not agree, arguing that the absence of perivascular IgA on immunofluorescence staining, absence of systemic involvement in most patients, and the benign clinical course do not support this view.3,18 However, a very interesting hypothesis possibly linking the two diseases has been postulated.19 Goraya and Kaur note that, since the IgA immune system in infants is immature, if acute hemorrhagic edema were related to Henoch-Schönlein purpura, the patient would be incapable of mounting an IgA-mediated immune response and this would explain the lack of IgA on immunofluorescence studies in the majority of patients.19 Clearly, further study of this disorder is necessary to elucidate its pathogenesis and to clarify its nosological position in the classification of leukocytoclastic vasculitis.

Urticarial vasculitis Clinical features Urticarial vasculitis is an uncommon condition characterized clinically by urticaria and histologically by leukocytoclastic venulitis.1–5 In addition to urticarial skin lesions, patients may also experience angioedema, arthralgia, gastrointestinal symptoms, and evidence of renal involvement.6,7 The term encompasses a spectrum of illness, with some patients experiencing only mild symptoms while others develop serious systemic involvement.7,8 Urticarial vasculitis is most often seen in the third to fifth decades and shows a female predominance.7 The cutaneous lesions are urticarial in appearance, consisting of edematous, raised, erythematous plaques associated

Fig. 16.24 Urticarial vasculitis: close-up view. By courtesy of the Institute of Dermatology, London, UK.

with nonblanchable purpura (Figs 16.23, 16.24). However, in contrast to uncomplicated urticaria, cutaneous lesions of urticarial vasculitis often last 24–72 hours.9 Patients commonly complain of pruritus, burning or pain. The frequency of cutaneous symptoms varies considerably, from daily to monthly. Joint pain, stiffness, and swelling, particularly of the hands, elbows, feet, ankles, and knees, are seen; however, frank arthritis is extremely rare.10 Hypocomplementemia, which correlates with systemic involvement, is a feature in many patients.4,7,8,11,12 Proteinuria and hematuria may also be noted. Rarely, patients develop focal or diffuse proliferative glomerulonephritis. Crescentic glomerulonephritis, mesangial glomerulonephritis, and membranous nephropathy have also been documented.8,13–16 Gastrointestinal symptoms can include abdominal pain, nausea, vomiting and diarrhea, and an associated peripheral neuropathy has been reported.17 The ESR is raised in many patients with hypocomplementemia. There may also be depression of the early classic pathway components C1q, C4 and C2. Patients with hypocomplementemic urticarial vasculitis have a high prevalence of autoantibodies to endothelial cells.18,19 Schnitzler's syndrome is a term that has been applied to patients with urticarial vasculitis and monoclonal IgM gammopathy.20–25 Hepatosplenomegaly, elevated ESR, and white blood cell count, fever and joint pain are characteristic features.21–23 An associated monoclonal IgA gammopathy has been reported and an underlying lymphoproliferative disorder is present in some patients.20,26,27

Polyarteritis nodosa and microscopic polyangiitis Importantly, urticarial vasculitis (especially the hypocomplementemic variant) is often associated with, or heralds the onset of, a variety of systemic diseases, including SLE, arthritis, interstitial lung disease, pericarditis, mixed connective tissue disease, systemic sclerosis, relapsing polychondritis, hepatitis, inflammatory bowel disease, serum sickness, polyarteritis nodosa and Wegener's granulomatosis, viral infection, Sjögren's syndrome, cryoglobulinemia, polycythemia rubra vera, reaction to drugs (including cocaine and diltiazem), and as a response to sunlight.8,13,28–38 The condition may be exacerbated by methotrexate.39 In one study, more than 50% of patients had uveitis, scleritis, conjunctivitis or episcleritis.8 It appears that patients with hypocomplementemia have more severe disease.28 Some authors have postulated that hypocomplementemic urticarial vasculitis represents a subset of SLE. Others, however, have failed to confirm this observation.8,40 Urticarial vasculitis has been documented in association with malignancy.8,41 Given the rarity of this association, this may well be coincidental. Nevertheless, a diagnosis of urticarial vasculitis should always initiate an evaluation for possible underlying disease. Urticarial vasculitis usually has a benign outcome.8

Pathogenesis and histological features In many patients, no underlying cause is discovered. In others, antibody– antigen complexes (a type III hypersensitivity reaction) is implicated.4,5 The vasculitis affects the superficial vascular plexus and is characterized by a leukocytoclastic pattern (Fig. 16.25). Extravasation of red blood cells is evidence of vascular damage. A background of dermal edema may be seen. Often, the histological features are subtle and are easily overlooked, with only focal fibrinoid vascular change, few neutrophils, and sparse karyorrhexis. In our experience, the vasculitis is usually low grade or subtle in nature; however, more impressive necrotizing vasculitis is seen in some patients. Others have shown that endothelial necrosis is unusual.5 In summary, urticarial vasculitis may show a spectrum of histological changes ranging from urticaria with very mild vascular injury to frank necrotizing vasculitis.42

Differential diagnosis Clinical correlation is necessary to distinguish urticarial vasculitis from other forms of leukocytoclastic vasculitis. Although urticarial vasculitis is often associated with subtle low-grade vascular injury, this feature should not be relied upon in its distinction from other forms of vasculitis. In short, the pathologist's role in diagnosis is to confirm the presence of vasculitis.

Fig. 16.25 Urticarial vasculitis: the changes are unusually florid in this example.

Polyarteritis nodosa and microscopic polyangiitis Classic polyarteritis nodosa (Kussmaul-Maier disease) is a rare systemic vasculitis involving medium-sized and small arteries.1 Some view the disorder not as a disease sui generis but, less restrictively, as a syndrome with many triggering causes and disease associations. Classic polyarteritis nodosa overlaps both clinically and histologically with microscopic polyangiitis (microscopic polyarteritis nodosa, microscopic polyarteritis). Distinction between these entities may be difficult and criteria for their distinction are controversial. Nevertheless, they seem to represent distinctive syndromes that warrant separate classification to facilitate appropriate treatment.2 In order to maintain a usable working classification, we – while admitting they are separate diseases – prefer to describe them in the same section to facilitate comparisons between them.

Clinical features Classical polyarteritis nodosa Classic polyarteritis nodosa is a multisystem disease with protean clinical manifestations (Table 16.3).1,3–5 It should be noted that the 1990 criteria from the American College of Rheumatology do not distinguish polyarteritis nodosa from microscopic polyarteritis. However, in the more recent Chapel Table 16.3 1990 criteria for the classification of polyarteritis nodosa (traditional format)* Criterion

Definition

Weight loss ≥ 4 kg

Loss of 4 kg or more of body weight since illness began not due to dieting or other factors

Livedo reticularis

Mottled reticular pattern over the skin of portions of the extremities or torso

Testicular pain or tenderness

Pain or tenderness of the testicles not due to infection, trauma or other causes

Myalgias, weakness, or leg tenderness

Diffuse myalgias (excluding shoulder and hip girdle) or weakness of muscles or tenderness of leg muscles

Mononeuropathy or polyneuropathy

Development of mononeuropathy, multiple mononeuropathies or polyneuropathy

Diastolic BP > 9  mmHg

Development of hypertension with the diastolic BP higher than 90 mmHg

Elevated BUN or creatinine

Elevation of BUN > 40 mg/dL or creatinine > 1.5 mg/dL not due to dehydration or obstruction

Hepatitis B virus

Presence of hepatitis B surface antigen or antibody in serum

Arteriographic abnormality

Arteriogram showing aneurysms or occlusions of the vesical arteries not due to arteriosclerosis, fibromuscular dysplasia, or other non-inflammatory causes

Biopsy of small or mediumsized artery

Histological changes showing the presence of granylocytes or granulocytes and mononuclear leukocytes containing PMN in the artery wall

*For classification purposes, a patient shall be said to have polyarteritis nodosa if at least three of these 10 criteria are present. The presence of any three or more criteria yields a sensitivity of 82.2% and a specificity of 86.6%. BP, blood pressure; BUN, blood urea nitrogen; PMN, polymorphonuclear neutrophils. Reproduced with permission from Lightfoot, D.W. (1991) Current Opinion in Rheumatology, 3, 3–7.

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A

is also a common cutaneous manifestation (Fig. 16.29). Cutaneous nodules may also be seen. A maculopapular rash, vesiculation, and pustular lesions are occasional features (Figs 16.30–16.33). Joint involvement (arthralgias and arthritis) is often present; arthritis is usually asymmetrical and particularly affects the lower limbs. Non-specific muscle pain and weakness are additional features. Muscle wasting is commonly found. Both peripheral and central nervous system involvement are often encountered. The former presents as sensory neuropathies (numbness or paresthesias), motor neuropathies (wrist or foot drop) and combined

B

Fig. 16.26

Fig. 16.27

Polyarteritis nodosa: (A) a sharply defined ulcer with an indurated purplish border on the shin; (B) multiple ulcers, nodules, and foci of livedo reticularis. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Polyarteritis nodosa: this patient presented with large hemorrhagic lesions on the legs. By courtesy of the Institute of Dermatology, London, UK.

Fig. 16.28

Fig. 16.29

Polyarteritis nodosa: epidermal infarction has resulted in these digital ulcers. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Polyarteritis nodosa: this patient shows florid livedo reticularis. By courtesy of the Institute of Dermatology, London, UK.

Polyarteritis nodosa and microscopic polyangiitis

Fig. 16.30

Fig. 16.33

Polyarteritis nodosa: erythematous macules are occasionally seen. By courtesy of the Institute of Dermatology, London, UK.

Polyarteritis nodosa: in some patients, an intense neutrophil infiltrate results in pustular lesions as seen in this patient. By courtesy of the Institute of Dermatology, London, UK.

Fig. 16.31 Polyarteritis nodosa: erythematous papules are present around this patient's ankles. By courtesy of the Institute of Dermatology, London, UK.

Fig. 16.32 Polyarteritis nodosa: this patient presented with acral erythematous lesions. By courtesy of the Institute of Dermatology, London, UK.

sensorimotor lesions (mononeuritis multiplex and polyneuropathy). Central nervous system involvement may present as confusion, disorientation or delirium. Eye involvement is a rare feature of polyarteritis nodosa.11 Complications include choroidal infarction, ischemic optic neuropathy, retinal artery occlusion, episcleritis, ulcerative keratitis, uveitis, and orbital pseudotumor.11–13 Involvement of the kidney is very common and is of major importance because its sequelae – renal failure and hypertension – are among the commonest causes of death in this disease. Patients on occasion have episodes of loin pain due to renal infarction. Hypertension is often present in patients with classical polyarteritis nodosa and in some patients it may enter the malignant phase. Urinalysis for proteinuria, hematuria and red cell casts, and serum creatinine estimations are therefore mandatory early investigations. Gastrointestinal involvement is also an important cause of morbidity and mortality.14,15 Symptoms include nausea, vomiting, and abdominal pain. Serious complications include gastrointestinal hemorrhage, perforation, and infarction, the last being a not uncommon cause of death. Involvement of the hepatobiliary tract may also be seen.16,17 Involvement of the gallbladder and pancreas has also been reported and can represent an incidental finding or patients may present with symptoms of acute cholecystitis.18,19 Cardiac manifestations include pericarditis, arrhythmias, and myocardial infarction due to coronary artery involvement (Fig. 16.34). Although it is often stated that polyarteritis nodosa does not involve the lung, in exceptional cases pulmonary involvement is seen and patients occasionally complain of asthma, hemoptysis, and effusions. Although clinical involvement of the lungs is rare, autopsy evaluation has shown that arteritis affecting the bronchial arteries is not uncommon, being seen in 70% in one small series.20 Orchitis, usually unilateral, is a characteristic feature of polyarteritis nodosa.21–23 Affected patients present with symptoms of acute orchitis or features that suggest a testicular neoplasm.21,23 Laboratory investigations often reveal anemia, leukocytosis, and a raised ESR. Low-titer rheumatoid factor and antinuclear antibody are sometimes features and, in occasional patients, a cryoglobulin is identified. Diminished serum complement levels may also be detected. ANCAs are uncommonly seen in patients with classic polyarteritis nodosa. One group with extensive experience estimates that less than 5% of patients with the classic form of the disease have ANCAs.24 Others have found a somewhat higher frequency. Nevertheless, this is in contrast to microscopic polyangiitis, a form of vasculitis that is usually associated with ANCAs (see below). Polyarteritis nodosa in children may present in two forms: the infantile variant, which may be related to Kawasaki syndrome, and a childhood form, which is similar to adult polyarteritis nodosa (see also section on Kawasaki syndrome).25

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Fig. 16.34 Polyarteritis nodosa: coronary arteries showing conspicuous aneurysmal dilatation are now very rarely seen (museum specimen). By courtesy of the Department of Pathology, St Thomas' Hospital, London, UK.

Cutaneous polyarteritis nodosa In addition to classic polyarteritis nodosa, ‘localized (cutaneous) polyarteritis nodosa’ has also been described.26–32 This is a relatively benign variant in which patients develop cutaneous lesions, often over very prolonged periods, but serious visceral involvement is, by definition, never a feature. In one study, none of 79 patients with cutaneous polyarteritis nodosa who were followed for an average of 6.9 years developed systemic vasculitis.26 It may occur at any age, including childhood, and shows no sex predilection. The disease has occasionally been associated with minocycline treatment.33–35 Patients have recurrent episodes during which tender, painful nodules develop, particularly on the lower legs, although these may sometimes be quite widespread. Individual lesions vary from 2 mm to 2 cm in diameter. In the early stages they are pink or red, while more established nodules may have a purplish coloration. Patients sometimes also manifest livedo reticularis, usually on the lower legs and often related to groups of nodules. Other complications include ulceration and, rarely, gangrene. Very occasionally, patients develop lesions reminiscent of atrophie blanche.30 Other features include fever, malaise, arthralgias, and myalgias, and peripheral nerves may be affected, but there is never any evidence of more widespread visceral involvement.28,32 Immunofluorescence often reveals IgM and/or complement in the walls of cutaneous arteries, suggesting a possible immune complex pathogenesis.36 Rare reports of infants of mothers with cutaneous polyarteritis developing the disease and experiencing subsequent resolution are suggestive of a pathogenic circulating factor.37

Microscopic polyangiitis Microscopic polyangiitis (microscopic polyarteritis) is a more recently described entity, which involves the skin in a significant proportion of patients.2,38–40 Its definition and relationship to classic polyarteritis nodosa are somewhat controversial. The disease essentially consists of small vessel vasculitis in association with glomerulonephritis. In contrast, renal involvement in classic polyarteritis is a vascular nephropathy. Lung capillaritis is sometimes seen in patients with microscopic polyangiitis. By way of distinction, classic polyarteritis nodosa is very rarely associated with clinical manifestations of pulmonary involvement (although pathological involvement of large vessels may be more common than suspected: see above) and this, clinical difference is helpful in distinguishing these entities.24 However, since many patients

Fig. 16.35 Microscopic polyarteritis: p-ANCA. By courtesy of G. Swana, MD, St Thomas' Hospital, London, UK.

with either disease have neither pulmonary nor renal involvement, precise classification can be difficult.24 Microscopic polyangiitis is a diagnosis of exclusion; other conditions that may manifest similar renal features include Wegener's granulomatosis, rapidly progressive glomerulonephritis, ChurgStrauss syndrome, SLE, classic polyarteritis nodosa, and Henoch-Schönlein purpura.18 Microscopic polyangiitis is usually associated with positive neutrophil cytoplasmic antibodies, typically of the antimyeloperoxidase (perinuclearantineutrophil cytoplasmic antibody, p-ANCA) subtype (Fig. 16.35).40 Since most (but not all) patients with classic polyarteritis nodosa do not have ANCAs, this is useful in distinguishing these conditions. This disease is of particular importance due to its high morbidity and mortality, with a 5-year survival of approximately only 65%.38 As a result of improved medical treatment outcome has significantly improved over the past few decades, with a quoted 5-year survival of 81%.41 Severe renal disease and disease relapse are the best indicators for poor prognosis.41 Patients often present with non-specific constitutional symptoms including malaise, fever, and myalgia. There may be a past history of sore throat or a flulike illness, which obviously raises the possibility of an iatrogenic pathogenesis for the subsequent vasculitic process.38 Renal involvement may manifest as microscopic hematuria, proteinuria or acute renal failure. Hypertension is present in a large proportion of patients. Pulmonary lesions present as hemoptysis, pulmonary fibrosis, and intrapulmonary hemorrhage, which can prove fatal.42,43 Dermatological signs, which are found in approximately 40% of patients, include purpura, erythema, splinter hemorrhages, and leg ulceration.10,39,44 Bullous presentation or urticaria are occasionally encountered but cutaneous nodules and livedo are rare features of this disease due to absence of involvement of larger vessels.10,44–46 Other manifestations such as nervous system lesions, gastrointestinal bleeding with pain, and diarrhea, are sometimes evident.47–50 Laboratory findings in microscopic polyarteritis include a raised ESR, normochromic normocytic anemia, leukocytosis with neutrophilia and thrombocytosis, raised C-reactive protein, and raised α-1 and α-2 globulins. Rheumatoid factor and immune complexes are present in less than 50% of patients.38 Anti-DNA antibodies are not a feature. Cutaneous immunofluorescence is usually negative.

Pathogenesis and histological features Polyarteritis nodosa The pathogenesis of polyarteritis nodosa is poorly understood. Classic polyarteritis nodosa has been suggested to be immune-complex mediated, on the basis of serum immune-complex levels, immunofluorescence investigations and ultrastructural studies. However, in many patients immune complexes

Polyarteritis nodosa and microscopic polyangiitis cannot be demonstrated and their role in the development of this disease is controversial. Important suspect antigens include hepatitis B virus (HBV) surface antigens and cryoglobulins.51–54 It has been shown that a significant number of patients with polyarteritis nodosa have circulating HBV antigen.9,54 Furthermore, circulating immune complexes containing HBV antigen and immunoglobulin have been characterized in occasional patients.9 HBV surface antigen has also been identified within affected vessels in a small number of patients.9 A decrease in HBV-associated cases of polyarteritis nodosa in France has been reported and it has been suggested that this phenomenon is the result of vaccination programs.55 Rarely, however, polyarteritis nodosa may also develop following hepatitis B vaccination.56 Human immunodeficiency viral infection has also been reported in cases of polyarteritis nodosa or a polyarteritis nodosa-like syndrome.57–63 Evidence of hepatitis C viral infection has been documented in some patients. In one study, 20% of patients had antibodies against hepatitis C virus.62,64 Erythrovirus (parvovirus) infection has been associated with polyarteritis nodosa in occasional cases.65,66 In childhood polyarteritis nodosa, there appears to be a striking association with group A streptococci.67 Although there is some evidence to suggest a role for immune complexes generated during infection, such a relationship cannot be demonstrated in many cases. Therefore, the pathogenesis of classic polyarteritis nodosa is unclear in many patients. As with other ANCA-associated vasculitides, the presence of ANCAs (usually p-ANCAs) in most patients with microscopic polyangiitis suggests that these antibodies may play a pathogenic role. In contrast, ANCAs are not usually seen in patients with classic polyarteritis nodosa. Additionally, again in contrast to classic polyarteritis nodosa, immune complexes are not thought to play a role in the pathogenesis of microscopic polyarteritis nodosa. The presence of ANCAs suggests a shared pathogenic relationship with other ANCA-associated vasculitides (i.e. Wegener's granulomatosis, Churg-Strauss syndrome) and there is recent evidence to suggest that different but overlapping epitopes of myeloperoxidase (MPO) are recognized by ANCAs in Wegener's granulomatosis and microscopic polyangiitis.68 HIV infection has been documented in patients with microscopic polyangiitis.58 The histological features of the cutaneous lesions in both the classic and localized variants of polyarteritis nodosa are similar and changes are variable.38,69,70 In some instances, the changes are indistinguishable from leukocytoclastic vasculitis involving the superficial dermal vessels (Fig. 16.36). More characteristic, however, is the finding of necrotizing vasculitis involving the muscular arteries of the deep dermis or subcutaneous fat; these are the changes that are also seen in the internal viscera, often associated with

infarction (Fig. 16.37). Although the whole circumference and thickness of the vessel wall is often affected, sometimes the changes are focal. Typically in polyarteritis nodosa, the vascular changes are discontinuous, with uninvolved skip lesions between affected segments (Fig. 16.38). The acute changes, those of fibrinoid necrosis, involve the muscle coat and often destroy the internal elastic lamina; this is often best appreciated by the use of a stain for elastic tissue (Fig. 16.39). Associated with the necrosis is an inflammatory cell infiltrate of neutrophils, eosinophils, and mononuclear cells. Leukocytoclasis is sometimes an additional feature. Thrombosis is common and may be complicated by ischemic necrosis of the surface epithelium. Healing lesions are associated with fibroblastic proliferation and eventual fibrous scarring. Endarteritis is often evident and any disruption of the internal elastic lamina is permanent. A characteristic feature often present in wedge biopsies that contain multiple vessels is the presence of lesions at varying stages of evolution. Deep, surgical incisional biopsies are essential for the diagnosis of cutaneous involvement in polyarteritis nodosa. A punch biopsy will often not sample larger vessels that are typically affected. Furthermore, the diagnosis is subject to sampling error due to the multifocal nature of the disease. Aneurysm formation may sometimes be appreciated microscopically.1

Fig. 16.36

Fig. 16.38

Polyarteritis nodosa: in this case the features are those of a superficial leukocytoclastic vasculitis. It is important to remember that this histological lesion may represent a serious systemic disease.

Polyarteritis nodosa: while fibrinoid necrosis involves both lateral extremities of this vascular segment, the middle portion is relatively unaffected.

Fig. 16.37 Polyarteritis nodosa: high-power view showing fibrinoid necrosis.

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A

Fig. 16.40 Polyarteritis nodosa: in this kidney section an arcuate artery shows necrotizing vasculitis and fibrointimal thickening. The inflammatory cell infiltrate contains conspicuous eosinophils.

B

Fig. 16.39 Polyarteritis nodosa: (A) there is marked red cell extravasation; (B) elastic–van Gieson staining shows disruption of the internal elastic lamina.

Internal visceral involvement is based upon the effects of necrotizing arteritis. Interestingly, nodular swellings (aneurysms) are much more obvious. The effects depend upon the relative interplay of infarction and hemorrhage. Renal involvement in classical polyarteritis nodosa is predominantly due to large-vessel vasculitis, with resultant thrombosis and infarction, coupled with the effects of hypertension (Fig. 16.40).71 Patients may also manifest focal, segmental proliferative or necrotizing glomerulonephritis similar to that seen in patients with microscopic polyarteritis nodosa (Fig. 16.41).

Fig. 16.41 Polyarteritis nodosa: segmental necrotizing glomerulonephritis.

Microscopic polyangiitis Microscopic polyangiitis (microscopic polyarteritis) is characterized by smallvessel vasculitis, which may predominantly affect the muscular arteriole, capillaries, and venules (Fig. 16.42).2,40,72 Given the spectrum of vessel types involved and the absence of arteriolar involvement in some patients, the term ‘microscopic polyangiitis’ is preferred by some authors.2,73 The absence of involvement of capillaries and venules in classic polyarteritis nodosa is a major point of distinction from microscopic polyarteritis nodosa. Necrotizing vasculitis with fibrinoid necrosis and variable numbers of neutrophils and monocytes is seen. In early lesions, neutrophils associated with karyorrhexis predominate, while lymphocytes and histiocytes dominate the infiltrate in older lesions. In some patients, acute lesions are indistinguishable from leukocytoclastic vasculitis. Renal lesions include focal segmental necrotizing glomerulonephritis (often with crescents), vasculitis, interstitial inflammation, and tubular atrophy. Large-vessel disease, visceral infarction, and granulomatous inflammation are not features.

Fig. 16.42 Microscopic polyarteritis nodosa: acute necrotizing vasculitis of a small muscular arteriole is evident. Numerous eosinophils are present.

Wegener's granulomatosis

Differential diagnosis Since other vasculitides may show similar histological features, particularly cases with only small-vessel involvement (leukocytoclastic vasculitis pattern), the biopsy findings must never be used in isolation to determine the diagnosis. Only after careful clinical, serological, and histological correlation should a definitive diagnosis be rendered. Criteria are admittedly definitional and as we learn more about this disease (or group of diseases), criteria are likely to change. Careful clinical investigation is required to evaluate for underlying causes/disease associations. As noted above, distinction between classic polyarteritis nodosa and polyangiitis is based on the size of vessels involved, spectrum and type of organ involvement, and presence of ANCAs. Microscopic polyangiitis may also be confused with Wegener's granulomatosis and Churg-Strauss syndrome. The presence of granulomatous inflammation in the lung favors the first of the last two conditions. The presence of blood eosinophilia and asthma favors a diagnosis of Churg-Strauss syndrome. As can be seen, microscopic polyangiitis is a diagnosis of exclusion. In fact, with clinical follow-up, the diagnosis may be revised. For example, patients who appear to fit criteria for microscopic polyangiitis may eventually develop manifestations that allow for classification as Wegener's granulomatosis.2 Diagnostic criteria are likely to change as we understand more about these disorders.

Wegener's granulomatosis Clinical features Wegener's granulomatosis is a multisystem vascular disease associated with high morbidity and mortality.1,2 Before the introduction of cyclophosphamide therapy it was associated with a dismal prognosis. Mean survival was of the order of 5 months following diagnosis and approximately 80% of patients died within 1 year, most as a consequence of renal involvement. Although it may present in a wide variety of age groups, from infancy to the elderly, it is the middle-aged that are predominantly affected, with a peak incidence in the fourth decade.1–4 There is a slight predilection for males (3:2). In one large study, 97% of patients were Caucasians.5 Wegener's granulomatosis comprises a triad of characteristics: • necrotizing, destructive, granulomatous lesions in the upper respiratory tract (nose, nasal sinuses, nasopharynx, and larynx) and/or in the lower respiratory tract (trachea, bronchi or lungs); frequently, both are present. Similar lesions may also be found in virtually any organ in the body, • a generalized focal vasculitis occurring in a wide variety of sites, but particularly affecting the lungs, • glomerulonephritis.6,7 Early in the disease, when patients may not have developed the full clinical triad, definitive diagnosis can be difficult or impossible (see Table 16.4). The most common presenting symptoms relate to involvement of the nose and nasal sinuses, and include severe and often purulent nasal discharge or evidence of sinusitis with pain and discharge. Clinical examination may reveal mucosal ulceration, perforated septum, paranasal sinusitis or a saddlenose deformity. Serous or purulent otitis media is occasionally a presenting feature. Middle and inner ear involvement is also a common manifestation of disease.8–10 Pulmonary lesions are invariably present and patients may have cough, chest pain or hemoptysis. Radiological examination frequently reveals solitary or more commonly multiple nodular opacities, which are often bilateral, may be diffuse or sharply delineated, and are typically transient. Cavitation is frequently a feature. Lesions may present as large nodules that are clinically and radiologically suspicious for malignancy. Renal involvement is common and urinalysis typically reveals hematuria (often microscopic), proteinuria, and red cell casts. Joint involvement may present as arthralgia or, less commonly, frank arthritis. In one large series, 34% of patients developed neurological involvement.11 Peripheral neuropathy was seen in 16%.11 Central nervous system lesions are

Table 16.4 1990 criteria for the classification of Wegener's granulomatosis (traditional format)* Criterion

Definition

Nasal or oral inflammation

Development of painful or painless oral ulcers or purulent or bloody nasal discharge

Abnormal chest radiograph

Chest radiograph showing the presence of nodules, fixed infiltrates or cavities

Urinary sediment

Microhematuria (> 5 red blood cells per high power field) or red cell casts in urine sediment

Granulomatous inflammation on biopsy

Histological changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)

* For purposes of classification, a patient shall be said to have Wegener's granulomatosis if at least two of these four criteria are present. The presence of any two or more criteria yields a sensitivity of 88.2% and a specificity of 92.0% Reproduced with permission from Leavitt, R.Y. (1990) Arthritis and Rheumatism, 33, 1101–1107.

not uncommon and occur either as a consequence of direct extension through the base of the skull from sinus involvement or as a result of meningeal or intracerebral necrotizing granulomata. Patients may experience myelopathy or neuropathy.12 Vasculitis involving intracerebral vessels can also result in cerebral lesions. Patients develop cranioneuropathy, cerebrovascular accidents or seizures.11 Involvement of the vasa nervora may give rise to mononeuritis multiplex. Ocular lesions result in a variety of complications including conjunctivitis, granulomatous keratitis, sclerouveitis, and orbital pseudotumor. Proptosis is sometimes a feature.13 Involvement of the temporal artery results in features (i.e. vision loss, jaw claudication) similar to those seen in temporal arteritis.14 Cutaneous manifestations are common, occurring in about 14–50% of patients.15–18 Several different types of skin lesion may be encountered, including vasculitic lesions with purpura, bruising, and nodule formation (Figs 16.43–16.45). Pyoderma gangrenosum-like lesions with necrosis and ulceration that have a predilection for the lower limbs are sometimes encountered. The presence of skin lesions appears to correlate with disease activity. Oral ulceration is common.18,19

Fig. 16.43 Wegener's granulomatosis: multiple purpuric macules and papules. By courtesy of D. McGibbon, MD, St Thomas' Hospital, London, UK.

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Fig. 16.44

Fig. 16.46

Wegener's granulomatosis: cutaneous nodules as seen in this patient are a not uncommon manifestation. By courtesy of the Institute of Dermatology, London, UK.

Pathergic granulomatosis: gross necrosis and ulceration have resulted in very disfiguring tissue damage.

Fig. 16.45

Fig. 16.47

Wegener's granulomatosis: this patient has ulcerating plaques and nodules. By courtesy of the Institute of Dermatology, London, UK.

Wegener's granulomatosis: c-ANCA. By courtesy of G. Swana, MD, St Thomas' Hospital, London, UK.

In addition to the organ-specific features noted above, patients also often have a variety of constitutional symptoms, including anorexia, weight loss, fever, and general malaise. Two limited forms of Wegener's granulomatosis are recognized: pathergic granulomatosis and limited pulmonary granulomatosis.20–22 • Pathergic granulomatosis is of particular importance because mucosal and cutaneous lesions may predominate and persist for very long periods of time before intractable renal failure develops. In the absence of evidence of pulmonary and renal involvement, there may be a delay in establishing the diagnosis and administration of appropriate chemotherapy, with resultant increased morbidity and mortality. Patients with this variant are at particular risk of facial mutilation; sites especially involved include the nose, nasopharynx, sinuses, and middle ears (Fig. 16.46). • In limited pulmonary granulomatosis patients have respiratory symptoms with associated fever and weight loss. Radiologically, multiple bilateral discrete nodular infiltrates and thin-walled cavitating lesions are seen, usually in the lower lobes. No evidence for renal involvement is present. Patients with this variant appear to have a somewhat better prognosis than those with classic (generalized) Wegener's granulomatosis. A further development is the proposed purely granulomatous Wegener's granulomatosis (PGWG), in which it has been suggested that the presence of extravascular granulomata (particularly affecting the ears, nose, throat,

orbit or lung) in association with a positive serum cytoplasmic-antineutrophil cytoplasmic antibody (c-ANCA) represents the earliest stage in the evolution of Wegener's granulomatosis.23 Such a concept, if proven viable, should result in diagnosis at a stage before the development of more serious multisystem disease and, hence, earlier treatment. The vast majority of patients with Wegener's granulomatosis have ANCA detected in their sera; rising titers have been shown to correlate with disease activity and are a valuable method of predicting relapse.2,24 Typically, the indirect immunofluorescence shows a cytoplasmic pattern of staining (c-ANCA) (Fig. 16.47).1 In the majority (70–80%) of patients with active disease ANCAs are directed against proteinase 3 (PR3) while ANCAs against myeloperoxidase (MPO) are detected in approximately 10% of patients.25,26 ANCAs have also been detected in patients with Takayasu's arteritis, ChurgStrauss syndrome, Kawasaki's arteritis, microscopic polyangiitis, and idiopathic crescentic glomerulonephritis.24,27,28

Pathogenesis and histological features This rare disease is thought to represent a hypersensitivity reaction to an as yet unidentified allergen. Response to immunosuppressive therapy is consistent with this hypothesis. The presence of ANCAs against PR3 and to a lesser amount MPO in most patients with Wegener's granulomatosis and the correlation

Wegener's granulomatosis of circulating levels of ANCAs with disease activity suggest a role in the pathogenesis of this disease. Additionally, although immune complexes have not been demonstrated, disease activity is ameliorated with plasma exchange. Thus, there is compelling anecdotal evidence suggesting ANCAs are central to pathogenesis, most likely through activation of neutrophils, lymphocytes, and macrophages.29 In particular, abnormal numbers and function in regulatory T cells (Treg) have been demonstrated in patients with Wegener's granulomatosis and appear to also correlate with disease activity.30–32 However, the precise mechanism action of ANCAs is not yet fully understood.29 It is postulated that exposure to an antigen (or antigens) may trigger ANCAs that have pathophysiological effects leading to tissue destruction.33 Infectious agents have received some attention as potentially playing a role in the pathogenesis of Wegener's granulomatosis. It is interesting to note that relapses of the disease may follow infection.29 In some patients, a complete or partial remission is achieved with antibiotic treatment combined with immunosuppressive agents.29,34 Trimethoprim-sulfamethoxazole has also been used to reduce the frequency of relapses in Wegener's patients.35 Patients who are chronic nasal carriers of Staphylococcus aureus seem to have a higher relapse rate compared with noncarriers.36 Furthermore, antibodies against hepatitis C virus, Epstein-Barr virus, and Helicobacter pylori as well as IgG antibodies against Toxoplasma gondii and IgM antibodies against cytomegalovirus are significantly more common in patients with Wegener's granulomatosis than in unaffected individuals.37 Gastrointestinal and renal manifestation correlate well with the presence of IgG antibodies to cytomegalovirus while otolaryngeal manifestation is more common in patients with IgG antibodies to the EBV early antigen.37 Despite considerable research to establish a possible relationship between Wegener's granulomatosis and infection, a categoric role in the disease is elusive.38 In addition to that for infectious agents, a search for putative roles for physical agents in the environment has also been undertaken. Perhaps most attention has focused on silicon compounds.39–41 One case-control study showed that exposure to silicon-containing compounds conferred a sevenfold risk for the development of Wegener's granulomatosis.40 It has been postulated that silica-induced apoptosis of inflammatory cells may release lysosomal enzymes that stimulate ANCAs.29,39 Pulmonary lesions are characterized by necrotizing granulomatous inflammation that may bear more than a superficial resemblance to the caseation of pulmonary tuberculosis (Fig. 16.48).42 The similarity is increased by the presence of large numbers of Langhans giant cells at the periphery

of the necrotic focus (Fig. 16.49). In addition, the features of an active angiitis are present; this may involve both arteries and veins and frequently has a granulomatous component (Fig. 16.50). The adjacent parenchyma is chronically inflamed and often shows severe, diffuse, interstitial fibrosis. Early renal lesions are characterized by focal segmental glomerulonephritis. In more advanced cases the glomerulitis becomes generalized, with fibrinoid necrosis and widespread epithelial crescent formation.43 The renal interstitial tissue may contain necrotizing granulomata, and vasculitis is sometimes a feature. Immunofluorescence occasionally reveals granular deposits of immunoglobulin and complement along the glomerular capillary walls. This is taken as evidence for possible immune complex involvement. Similar granulomata and evidence of vasculitis have been described in all organ systems of the body, but are particularly often seen in the spleen. Cutaneous lesions reveal a variety of features including necrotizing vasculitis, in which small or medium-sized dermal vessels display fibrinoid necrosis, a neutrophil polymorphonuclear infiltrate, and nuclear dust (Figs 16.51, 16.52). In one series, 80% of biopsies from patients with cutaneous lesions (of 244 patients in this series, 14% had cutaneous lesions) showed leukocytoclastic vasculitis.17 In another study, nearly a third showed leukocytoclastic vasculitis and another third showed non-specific chronic

Fig. 16.49 Wegener's granulomatosis: this lung section shows extensive necrosis associated with a granulomatous infiltrate containing Langhans giant cells. These appearances resemble pulmonary tuberculosis.

Fig. 16.48 Wegener's granulomatosis: this postmortem lung specimen shows consolidation and numerous abscesses. By courtesy of B. Corrin, MD, Brompton Hospital, London, UK.

Fig. 16.50 Wegener's granulomatosis: a branch of the pulmonary artery shows necrotizing arteritis with fibrointimal thickening.

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Fig. 16.51 Wegener's granulomatosis: leukocytoclastic vasculitis as shown in this field is the most frequently encountered cutaneous lesion.

Fig. 16.52 Wegener's granulomatosis: large vessel showing intense chronic inflammation, thrombosis, and intimal fibrosis.

inflammation.44 In this study, nearly 50% of patients had entirely non-specific findings. Extravasated red blood cells are invariably present.15,16 In severe cases, the epidermis may show ischemic necrosis. Bone fide granulomatous vasculitis of skin appears to be a very rare feature. In fact, one study failed to demonstrate granulomatous vasculitis in 75 skin biopsies from 46 patients.44 In other patients, there may be granulomatous infiltration of the dermis, which may be related to foci of collagen necrosis and sometimes resembles the Churg-Strauss granuloma (Figs 16.53, 16.54). In some cases, extensive geographic zones of necrosis are present, associated with a mixed inflammatory cell infiltrate including variable numbers of histiocytes, giant cells, lymphocytes, eosinophils, and plasma cells. Erythema nodosum and granuloma annulare-like lesions may also be encountered.44

Differential diagnosis As mentioned above, early in the course of the disease, when patients may not have developed the full clinical triad, definitive diagnosis is sometimes impossible. In those instances where a granulomatous dermal infiltrate occurs in the absence of vasculitis, a host of conditions enters the differential

Fig. 16.53 Wegener's granulomatosis: low-power view of a necrotizing dermal granuloma.

Fig. 16.54 Wegener's granulomatosis: high-power view of an ill-defined granuloma.

diagnosis including sarcoidosis and infections, particularly mycobacterial and fungal. Granulomatous vasculitis may also be seen in association with lymphoproliferative diseases including lymphoma, angioimmunoblastic lymphadenopathy, and leukemia.45 Microscopic polyangiitis can be confused with Wegener's granulomatosis. The presence of granulomatous inflammation in the lung would favor the latter. Microscopic polyangiitis is approached as a diagnosis of exclusion. In fact, a diagnosis may be revised as the pattern of clinical involvement changes. For example, patients that appear to fit criteria for microscopic polyangiitis may eventually develop manifestation allowing for classification as Wegener's granulomatosis.46 When granulomata and/or allergic vasculitis are the only features, it may not be possible to histologically distinguish Wegener's granulomatosis from the Churg-Strauss syndrome. A high eosinophil content, however, is somewhat suggestive of the latter condition but certainly not diagnostic, as this finding may sometimes be seen in Wegener's granulomatosis.44 Therefore, distinction of Wegener's granulomatosis from other forms of granulomatous inflammation and leukocytoclastic and granulomatous vasculitis requires careful clinicopathological and serological correlation.

Allergic granulomatosis with angiitis On CT scan, pulmonary infiltrates may take the form of opacification, nodules, or bronchial wall and interlobular septal thickening.17 Bronchoalveolar lavage reveals alveolar eosinophilia.1 Certain patients develop an eosinophilrich pleural effusion.1 In addition to pulmonary lesions, systemic involvement most commonly affects the heart, nervous system, gut, and kidneys.6 Cardiac lesions may be a cause of dysrhythmia or sudden death. Cardiac manifestations also include valvulopathy, ventricular insufficiency, global cardiac insufficiency, and endomyocarditis.1,18–20 Pericardial effusion was seen in 23% of patients in one study.1 Complications relating to cardiac involvement are the most common cause of death in patients with Churg-Strauss syndrome. Nearly 40% of deaths are due to cardiac involvement.1 Neurological manifestations are frequent, particularly mononeuritis multiplex and symmetric polyneuropathy.21,22 In one large study, 72% of patients developed mononeuritis multiplex.1,23 Intracerebral hemorrhage or infarction sometimes develops.21 Ischemic optic and bilateral trigeminal neuropathy are rare complications.22 Myalgia, epilepsy, hydrocephalus, chorea, and vertigo are further occasional features.24 Evidence of gastrointestinal involvement, such as nausea, bleeding, vomiting, and abdominal pain, is often found. In one study, one-third of patients experienced gastrointestinal symptoms, usually abdominal pain.1 Diffuse bowel ischemia is an uncommon but serious complication.1 Renal disease in Churg-Strauss syndrome is usually manifest as glomerulonephritis, most often a focal segmental glomerulonephritis.1,25 Patients with renal involvement show hematuria, proteinuria, and increased creatinine.1 Renal infarction appears to be a rare complication.1 Rheumatological involvement in the form of polyarthralgia and consti­ tutional symptoms, including fever, anemia, and weight loss, is common.1 Amyloidosis is a rare complication.26,27 Exceptionally, Churg-Strauss syndrome may present with temporal nongiant cell arteritis.28 Involvement of the breast occurs exceptionally as eosinophilic mastitis.29 A limited form of the disease has been described.30,31 Cutaneous lesions are seen in 40–70% of patients and include petechiae, purpura, papules, vesicles, facial erythema, urticaria, and ulceration.32–37 Cutaneous infarction and bullae are less common manifestations.35,38 Livedo reticularis involving the lower limbs is occasionally a feature. Patients may also develop tender nodules, which particularly affect the extensor aspects of the arms, legs, hands, and feet (Fig. 16.55). The sacrum, buttocks, and scalp can also be involved. The cutaneous lesions tend to appear in crops with spontaneous relapses and remissions. Churg-Strauss syndrome has been seen in association with HIV infection, hepatitis B, Wells' syndrome, and bronchopulmonary candidiasis.39–42 The disease has also been described in association with drugs including fluticasone and cocaine.43,44 Laboratory investigation usually reveals leukocytosis and a raised ESR in association with peripheral blood eosinophilia.35 Blood eosinophilia often decreases with treatment but some authors stress that such a response should not be taken as evidence that disease activity is under control.45 ANCAs are demonstrated in many patients (see below).

Allergic granulomatosis with angiitis Clinical features Allergic granulomatosis with angiitis (Churg-Strauss syndrome) is a very rare disease that combines the features of asthma, fever, multisystem necrotizing vasculitis, extravascular granulomata, and hypereosinophilia.1,2 Although there is clinical overlap, it can be distinguished from polyarteritis nodosa and Wegener's granulomatosis (Table 16.5). The criteria published by the Chapel Hill Consensus conference differ somewhat.3 In this scheme, Churg-Strauss syndrome is defined as ‘eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized arteries, and associated with asthma and eosinophilia’.3 Given differences in classification criteria, it comes as no surprise that inconsistencies between these classification schemes exist.4,5 One study found good concordance between classification schemes for the diagnosis of Wegener's granulomatosis but not Churg-Strauss syndrome.4 As we gain further understanding of this disease, refinement of diagnostic criteria is likely. Churg-Strauss syndrome may present in a wide range of age groups, but most patients are adults, those in the third and fourth decades being most commonly affected. The disease has a slight male predominance.6–9 Presentation in children is very rare.10–12 Asthma and necrotizing vasculitis are invariably present. Asthma often precedes the onset of vasculitis, sometimes by many years, or these features develop simultaneously. In one large study, asthma preceded definitive diagnosis in 94% of patients.1 Asthma may be associated with transient pulmonary infiltrates (Loeffler's syndrome) or there can be fullblown chronic eosinophilic pneumonitis.6 There is some evidence to suggest that patients in whom vasculitis occurs rapidly after presentation of asthma have a particularly poor prognosis. It has been suggested that, in some cases, treatment for allergic rhinitis with steroids suppresses the full-blown syndrome.13,14 Recently, an association between treatment of asthma with antileukotrienes and development of Churg-Strauss syndrome has been suggested.2,15 The association is controversial and what role, if any, antileukotrienes play in development of disease in these patients is unclear. However, it has also been proposed that it is the withdrawal of the steroids and not the administration of antileukotrienes that leads to disease.2 Further investigation is required to resolve this controversy. Churg-Strauss syndrome has also been described following treatment with anti-IgE antibodies (omalizumab) for asthma and may represent unmasking of the disease while reducing steroid treatment.16 Common manifestations of upper respiratory tract involvement include allergic rhinitis (which is sometimes associated with polyp formation and sinusitis) and hay fever. A family history of atopy and allergic reactions to inhaled antigens and drugs is often present. Chest radiography frequently confirms the presence of pulmonary involvement, which takes a variety of forms including transient patchy infiltrates, discrete noncavitating nodular masses, or diffuse interstitial disease.

Table 16.5 1990 criteria for the classification of Churg–Strauss syndrome (traditional format)* Criterion

No. of CSS patients (n = 20)

Sensitivity (%)

No. of control patients (n = 787)

Specificity (%)

Asthma

19

100

782

96.3

Eosinophilia > 10%

20

95

708

96.6

Neuropathy (mono or poly)

20

75

781

79.8

Pulmonary infiltrates, non-fixed

20

40

736

92.4

Paranasal sinus abnormality

14

85.7

366

79.3

Extravascular eosinophils

16

81.3

385

84.4

* For classification purposes, a patient shall be said to have Churg-Strauss syndrome (CSS) if at least four of these six criteria are positive. The presence of any four or more of the six criteria yields a sensitivity of 85% and a specificity of 99.7%. Reproduced with permission from Masi, A.T. (1990) Arthritis and Rheumatism, 33, 1094–1100.

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Fig. 16.55 Churg-Strauss syndrome: this patient presented with painful nodules on the limbs. By courtesy of the Institute of Dermatology, London, UK.

Fig. 16.56 Churg-Strauss syndrome: this early lesion shows a swollen collagen fiber in the superficial dermis. Note the surrounding multinucleate giant cells.

Pathogenesis and histological features The etiology and pathogenesis of Churg-Strauss syndrome is poorly understood. The presence of perinuclear-antineutrophil cytoplasmic antibodies (p-ANCA) in many patients is of considerable interest.46–49 ANCAs are detected in approximately 40% of patients.50–52 The ANCAs seen in these patients usually target myeloperoxidase.52 However, the various types of ANCA are non-specific, being present in a spectrum of disease.53 Their presence is associated with higher risk of developing renal disease and peripheral neuropathy, while absence of ANCAs is linked to heart disease and fever.51,52,54 ANCAs may activate neutrophils, causing degranulation and vascular injury.55 T lymphocytes can also be stimulated, leading to endothelial cell injury.55 As with other ANCA-associated vasculitides, it is suspected that they play a role in the pathogenesis of Churg-Strauss syndrome; however, the precise mechanism, particularly triggering factors, is not yet known. Persistence of ANCAs with therapy may be of limited value in making treatment decisions.56 One group has found that, although there is poor correlation between ANCA titer and disease activity, disappearance of ANCA can reflect absent disease activity.57 Pulmonary lesions comprise variably sized (up to 1.5 cm) nodules, ranging from only a few lesions to hundreds which may coalesce. Histologically, they are composed of granulomata with central necrosis and surrounding epithelioid histiocytes with occasional giant cells. Large numbers of eosinophils with an admixture of lymphocytes, neutrophils, plasma cells, and histiocytes infiltrate the adjacent lung parenchyma. Vasculitis involving small arteries and sometimes veins is also present. Cutaneous lesions are variable. A common feature is the so-called ‘ChurgStrauss (extravascular) granuloma’. Early lesions are characterized by focal collagen degeneration in association with a varying and mixed inflammatory cell infiltrate comprising neutrophils, lymphocytes, and histiocytes (Figs 16.56, 16.57). Eosinophils may be sparse or numerous. Leukocytoclasis is often a feature. In more advanced examples the granuloma is more mature in appearance, consisting of a central zone of collagen necrosis surrounded by a peripheral palisade of epithelioid and giant cells (Figs. 16.58,16.59). In some examples, the features are those of a rather diffuse and ill-defined granulomatous inflammatory process without obvious collagen degeneration. Commonly, features of necrotizing vasculitis are evident: fibrinoid necrosis accompanied by an eosinophilic and neutrophilic infiltrate with leukocytoclasis involving the more superficial small blood vessels (Fig. 16.60). There may be epidermal ischemic necrosis. In one study, 16 of 37 biopsies (taken from 29 patients) showed leukocytoclastic vasculitis.34 Occasionally, the arteries in the dermis and subcutaneous fat show changes similar to those seen in polyarteritis nodosa.35 Additionally, acute and chronic panniculitis with eosinophils has been described.35

Fig. 16.57 Churg-Strauss syndrome: medium-power view showing swelling of the dermal collagen fibers and a perivascular chronic inflammatory cell infiltrate.

Differential diagnosis The histological features encountered in skin biopsies of patients with Churg-Strauss syndrome are not diagnostic. Careful clinicopathological and serological evaluation is necessary to establish a definitive diagnosis. Although Churg-Strauss syndrome, polyarteritis nodosa, and Wegener's granulomatosis show both clinical and histological overlap, research over the last several decades leaves no doubt that they represent distinctive entities. Nonetheless, they form a spectrum of disease with similar pathogenesis, although there are sufficient differences to justify their separate classification: • Asthma may be seen in both polyarteritis nodosa and Churg-Strauss syndrome, but characteristically polyarteritis affects medium-sized and small arteries, while Churg-Strauss syndrome typically affects small arteries and veins. • The neutrophil dominates the inflammatory cell infiltrate in polyarteritis nodosa, whereas in Churg-Strauss syndrome it is the eosinophil. • Necrotizing extravascular granulomata are not a feature of polyarteritis nodosa.

Mucocutaneous lymph node syndrome

Fig. 16.58 Churg-Strauss syndrome: in this field there is a more obvious granulomatous infiltrate.

Fig. 16.60 Churg-Strauss syndrome: the features of smallvessel leukocytoclastic vasculitis are evident.

by both endemic and epidemic variants.4 The incidence among Japanese children is 16–150/100 000/ year whereas in white children the incidence is 6–10/100 000/year.4,6 The incidence of reported disease in the United States is rising but has been attributed to increased physician awareness.7,8 The syndrome shows a male predominance and occurs most frequently in children aged 6–18 months.9 Adults are only rarely affected.10–12 Kawasaki syndrome is thought to have an infectious etiology on the basis of symptoms of fever and exanthem, age distribution, seasonality (peaks in winter and spring), and occurrence of community-wide epidemics.13

Clinical features Fig. 16.59 Churg-Strauss syndrome: this florid example shows a granulomatous infiltrate containing prominent giant cells. By courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK.

The diagnostic features of Kawasaki syndrome are summarized in Table 16.6 and include: • a spiking fever unresponsive to antibiotic therapy, • an erythematous polymorphic cutaneous eruption (Fig. 16.61), • erythema, edema, and induration of the extremities followed by cutaneous desquamation of the tips of the fingers and toes (Fig. 16.62),

• Patients with Wegener's granulomatosis present with ulceroproliferative

lesions of the upper respiratory tract, chest pain, and hemoptysis rather than asthma. • Marked eosinophilia is uncommon in Wegener's granulomatosis. Churg-Strauss granulomata may be seen in Wegener's granulomatosis; however, the necrosis is more often of the tuberculocoagulative type. Granulomatous vasculitis is not a feature of Churg-Strauss syndrome. It must be stressed that Churg-Straus granulomata should not be taken as pathognomonic for Churg-Strauss syndrome. Churg-Strauss granulomata, or nearly identical lesions, have been described in the setting of other systemic diseases including rheumatoid arthritis, lupus erythematosus, other forms of vasculitis (Wegener's granulomatosis, polyarteritis nodosa, Takayasu's arteritis), lymphoproliferative disorders, Crohn's disease and ulcerative colitis, bacterial endocarditis, and hepatitis.35,58–62

Mucocutaneous lymph node syndrome Mucocutaneous lymph node syndrome (Kawasaki syndrome) is a multisystem disease that predominantly affects infants and young children.1–5 Although it was first described, and shows a marked preponderance, in Japan, it has been diagnosed worldwide and in all races. Kawasaki syndrome is characterized

Table 16.6 Kawasaki syndrome: diagnostic guidelines •  Fever lasting ≥ 5 days plus •  Polymorphous rash •  Bilaterial conjunctival injection •  At least one of the following changes of the mucosal membranes: –  erythema or fissuring of the lips –  strawberry tongue –  diffuse injection of oral and pharyngeal mucosa •  Acute non-purulent cervical lymphadenopathy (at least one node ≥ 1.5 cm) •  At least one of the following changes of the peripheral extremities: –  erythema of palms and soles –  indurative edema of hands and feet –  membranous desquamation from fingertips Fever plus four of the above criteria must be present for a secure diagnosis; other illness that can present with similar clinical findings must be excluded. Reproduced with permission from Wortman, D.W. (1992) Seminars in Dermatology, 11, 37–47.

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Fig. 16.61

Fig. 16.63

Kawasaki syndrome: erythematous macular eruption. By courtesy of W.G. Phillips, MD, Institute of Dermatology, London, UK.

Kawasaki syndrome: the lips are erythematous and swollen. Angular cheilitis is evident. By courtesy of J. Ross, MD, Lewisham Hospital, London, UK.

Fig. 16.62 Kawasaki syndrome: desquamation of the skin of the toes is a characteristic finding. By courtesy of J. Ross, MD, Lewisham Hospital, London, UK.

• oropharyngeal mucosal changes including edema, erythema, and fissuring

of the lips, erythema of the cheeks, and a strawberry (scarletiform) tongue (Figs 16.63, 16.64), • bilateral, nonexudative conjunctivitis, • nonsuppurative cervical lymphadenopathy. In an appropriate clinical context, children are judged to have Kawasaki syndrome if they show a high fever plus four of the signs described above.4,14 More recently, this has been amended to include coronary artery aneurysm plus three of the above features.4 The cutaneous findings are variable and include erythematous, macular, maculopapular (morbilliform), urticarial, pustular, erythema multiformelike (targetoid), and erythema marginatum-like lesions.2,15 A vesiculopustular eruption has also been reported.16 The skin lesions show a propensity for the trunk and extremities, but may be more generalized. A diffuse, erythematous macular or plaquelike eruption involving the perineum is said to be characteristic.5 This can be pruritic or painful and typically desquamates.

Fig. 16.64 Kawasaki syndrome: the tongue shows intense erythema. By courtesy of J. Ross, MD, Lewisham Hospital, London, UK.

Cervical lymphadenopathy affects 50–75% of patients and may be unilateral or bilateral and involves one or a group of nodes. Cardiovascular involvement is characteristic and is the most important cause of morbidity and mortality.2 Some 50% of patients show evidence of myocarditis, which may progress to congestive cardiac failure. Pericardial effusion (subclinical) is not uncommon. Of particular significance is the development of coronary artery ectasia or aneurysm, a feature that develops in 15–25% of patients, which may be complicated by coronary artery ischemia, thrombosis, and infarction. In 2% of patients, it proves fatal.12 In a very large follow-up study of 594 patients, the incidence of coronary artery aneurysm was 25%.17 Angiographic evidence of regression was seen in 55% of patients.17 There is an inverse relationship between the size of the aneurysm and the likelihood of resolution: large aneurysms, especially giant aneurysms (defined as greater than 8.0 mm), tend to persist, or become obstructed or stenotic.18 Gastrointestinal involvement presents as abdominal pain, vomiting, and diarrhea. Liver lesions may result in abnormal liver function tests and, less often, jaundice. Pancreatitis and hydrops of the gallbladder are seen in approximately 10% of patients.2 Neurological symptoms develop in about 30% of patients and include features of aseptic meningitis, seizures, and transient paralyses.2 Arthralgias

Granuloma faciale

Fig. 16.65 Kawasaki syndrome: disease in an adult is very rare. In this patient, the erythema particularly affects the buttocks and thighs. By courtesy of W.G. Phillips, MD, Institute of Dermatology, London, UK.

Fig. 16.66 Kawasaki syndrome: in this example, the features of severe, acute leukocytoclastic vasculitis are present in the superficial dermis. This is an uncommon finding. By courtesy of W.G. Phillips, MD, Institute of Dermatology, London, UK.

and arthritis are present in up to 30–40%, although chronicity is not a feature. Renal involvement manifests as sterile pyuria, hematuria, and infarction. The features of adult Kawasaki syndrome are essentially those described above and are illustrated in Figure 16.65. Coronary artery aneurysm, however, appears to be a less common complication.10 It is important to differentiate this condition from staphylococcal toxic shock syndrome.19 Occasionally, patients develop a relapse, which may occur years after initial disease and resolution.20

The histopathological features of cutaneous lesions in Kawasaki disease are often non-specific and comprise severe edema of the papillary dermis accompanied by vascular dilatation, endothelial cell swelling and degeneration associated with a superficial perivascular mononuclear infiltrate.5 Immuno­ pathological studies have shown the infiltrate is usually composed of CD4+ T lymphocytes and macrophages.30 Occasionally, however, the features of a leukocytoclastic vasculitis are evident (Fig. 16.66). The epidermis may show mild basal cell degeneration.5 Vesiculopustular lesions develop on the basis of subcorneal spongiform pustulation.9 Systemic lesions are characterized by necrotizing vasculitis.19,31,32 Aneurysm with mural thrombus formation may be evident in advanced lesions. Lymph node involvement includes vasculitis, focal necrosis, and infarction.

Pathogenesis and histological features

Differential diagnosis

The etiology of this disease is unknown. Recent evidence points to an immunoregulatory defect of T cells stimulated by superantigen-producing strains of Streptococcus pyogenes and Staphylococcus aureus.19,21,22 Superantigens are a class of microbial antigens that are thought to be capable of stimulating a large number of naive T cells in a non-specific manner by binding to histocompatibility antigens on antigen-presenting cells leading to T-cell activation. Superantigens have been postulated to play a role in the pathogenesis of a number of skin diseases in addition to Kawasaki syndrome, such as atopic dermatitis, psoriasis and toxic shock syndrome. However, in one study, superantigen-producing bacteria were found in 56% of cultures (taken from throat, rectum, and groin) from patients with Kawasaki syndrome compared with 35% of controls with positive culture.23 These differences did not achieve statistical significance. Another study found strains of streptococci and staphylococci in the jejunum of patients with Kawasaki syndrome but not in controls.24 These same authors, in a follow-up study, found V beta 2+ T cells selectively increased in small bowel mucosa of Kawasaki patients compared with control subjects.25 Clearly, further research is necessary to elucidate the precise pathogenesis of Kawasaki disease. Other infectious agents that have been implicated in the pathogenesis of Kawasaki disease include retroviruses, rickettsiae, spirochetes and Propionibacterium acnes.5,26 Additionally favored hypotheses include exposure to house mites and recently cleaned or shampooed carpet, living in close proximity to open water or complicating a recent respiratory illness.13 It is possible that Kawasaki syndrome represents a vasculitic disorder developing as a consequence of multiple infectious agents. Of interest, there is a growing body of literature reporting Kawasaki disease, or a Kawasaki-like syndrome, in patients infected with the human immunodeficiency virus.27–29

The mucocutaneous manifestations of Kawasaki disease show considerable overlap with those seen in the toxic shock syndrome, which is not surprising, given that they appear to share a similar pathogenesis. Palmoplantar erythema, cutaneous desquamation, conjunctivitis, and pharyngitis are therefore common to both.33 The toxic shock syndrome (which is due to a staphylococcal exotoxin complicating constant tampon use in menstruating females) is, however, not associated with systemic vascular involvement. Histologically, it is characterized by a mild, superficial, perivascular lymphocytic infiltrate associated with edema of the papillary dermis and no evidence of vasculitis.34

Granuloma faciale Clinical features Granuloma faciale is a localized form of leukocytoclastic vasculitis of uncertain pathogenesis. Although children may be affected, most cases occur in people who are middle aged or older. There is predilections for males.1 Lesions occur most commonly on the face and are single or more often multiple, erythematous or brownish red, soft discrete papules, plaques or nodules up to several centimeters in diameter (Fig. 16.67).2–4 The surface often shows dilated follicles and fine telangiectasia (Fig. 16.68). Common sites include the nose, malar prominence, forehead, and ear (Fig. 16.69). A case simulating rhinophyma has been documented.5 Extrafacial lesions may occur on the extremities, neck, chest, and scalp (Fig. 16.70).1,6–13 Although often asymptomatic, patients sometimes report symptoms of mild pruritus or stinging. There is no evidence of associated systemic involvement. Granuloma faciale tends to chronicity and is typified by periods of relapse and partial

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Vascular diseases

Fig. 16.67 Granuloma faciale: multiple brown nodules. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 16.69 Granuloma faciale: the lesions are frequently multiple. By courtesy of K. Liddell, MD, Eastbourne District Hospital, East Sussex, UK.

Fig. 16.68 Granuloma faciale: the face is a commonly affected site. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

remissions. Treatment is very difficult and recurrences manifest after surgical excision, even at the site of full-thickness grafting.14 A histologically similar lesion affecting the mucosa of the upper respiratory tract has been designated ‘eosinophilic angiocentric fibrosis’. Concurrent cases of granuloma faciale and eosinophilic angiocentric fibrosis have been described.15–17 This suggests that the two diseases represent part of the same spectrum. Granuloma faciale has been documented in a patient with prostate carcinoma.18 Any relationship with tumors is likely to be coincidental.

Pathogenesis and histological features Examination of lesional biopsies by immunofluorescence reveals granular IgG and complement along the epidermal–dermal junction, outlining the hair follicles, and also within the walls of blood vessels; less often IgA and IgM are present, and there is abundant fibrin.19–21 Granuloma faciale is, therefore, a chronic vasculitis and may be immune complex mediated. However, some authors consider the above immunofluorescence findings

Fig. 16.70 Granuloma faciale: there are multiple lesions on this patient's neck. By courtesy of the Institute of Dermatology, London, UK.

non-specific. Immunohistochemistry shows the presence of abundant eosinophilic cationic protein.22 T-helper lymphocytes represent the main nonmyelocytic cell in the infiltrate and it has been suggested that they play a role in the pathogenesis of the disease, being attracted to the site by gammainterferon.23 Histologically, granuloma faciale is characterized by a dense cellular infiltrate, which often has a nodular outline (Fig. 16.71).24 This infiltrate usually occupies the mid dermis, although the deep dermis and the subcutaneous fat may be involved; it typically spares the immediate subepidermis and hair follicles, forming a ‘grenz zone’ (Fig. 16.72). The infiltrate is polymorphic, being composed of large numbers of eosinophils, neutrophils (often displaying leukocytoclasis), and an admixture of plasma cells, mast cells, and lymphocytes (Fig. 16.73).25 Red cell extravasation is often present. Blood vessels, which often appear increased in number, are dilated and may show infiltration of their walls by eosinophils with fibrin deposition (Fig 16.74). Diagnostic features of vasculitis, namely inflammation of vessel walls associated with

Granuloma faciale

Fig. 16.71

Fig. 16.74

Granuloma faciale: a dense inflammatory cell infiltrate is present in the dermis. Note the conspicuously spared grenz zone.

Granuloma faciale: this dilated blood vessel shows marked endothelial swelling, fibrin deposition, and disruption of its wall.

Fig. 16.72

Fig. 16.75

Granuloma faciale: close-up view of grenz zone.

Granuloma faciale: there is a well-developed storiform pattern.

fibrinoid change, may be difficult to identify in some lesions. In other cases, fibrin is widely distributed in the dermis. Older lesions may show fibrosis and hemosiderin deposition.1 The microscopic picture in late stages overlaps with that seen in erythema elevatum diutinum (Fig 16.75).1 An ultrastructural study of a case of granuloma faciale has shown that the cytoplasmic granules in the eosinophils display alterations and Langerhans cells are absent.26

Differential diagnosis

Fig. 16.73 Granuloma faciale: the infiltrate contains large numbers of eosinophils as well as lymphocytes, histiocytes, and occasional polymorphs and plasma cells.

The morphological features of granuloma faciale are distinctive. The presence of a mixed infiltrate with a grenz zone distinguishes it from neutrophilic dermatoses and leukocytoclastic vasculitis. Erythema elevatum diutinum, another form of localized vasculitis, tends to be located on the extensor surfaces of the extremities and shows more sclerosis, more neutrophils, and fewer eosinophils. The presence of large numbers of eosinophils may raise the possibility of a Langerhans cell proliferative disorder; however, the presence of only scattered Langerhans cells and a grenz zone (Langerhans cell proliferative disorders tend to be epidermotropic) with significant numbers of neutrophils favors granuloma faciale. The grenz zone also helps to distinguish granuloma faciale from hypersensitivity reactions such as to an arthropod bite. Angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma) is distinguished by the presence of highly unusual thick-walled blood vessels

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Vascular diseases with prominent endothelial cells. An exceptional case of infection by Trichophyton rubrum with histology mimicking that of granuloma faciale has been documented.27 Histological features identical to those of granuloma faciale may be seen in patients presenting with a solitary lesion (papule, nodule or plaque) that does not have the clinical appearance or location typical of the disease. The histological picture in these cases has been described as chronic fibrosing vasculitis. As there is also histological overlap with erythema elevatum diutinum, it has been suggested that the microscopic appearances represent a non-specific inflammatory reaction pattern.28 Therefore, establishing the diagnosis requires close clinicopathological correlation.

Erythema elevatum diutinum Clinical features This uncommon disease represents a localized variant of leukocytoclastic vasculitis.1–3 Although it can occur in any age group, patients are usually in their third to fifth decade.4 Incidence is equal in men and women. Patients present with papules and nodules measuring up to about 1 cm in diameter; they may also develop round or oval, indurated, elevated plaques 5–6 cm in diameter. Lesions are red or purple, although some have a yellowish tinge, which may be confused with a xanthomatous process. Bullous lesions are occasionally present and an annular distribution has been reported.1,5,6 The disease is characteristically persistent and the distribution of the lesions often symmetrical. Large nodules resembling keloids or tumor are sometimes found.7,8 Lesions are located particularly in relation to the extensor surfaces of the joints and are, therefore, seen on the backs of the hands and fingers, wrists, elbows, knees, ankles, and toes (Figs 16.76, 16.77). The buttocks may also be affected, but the trunk is usually spared.9 We have observed a case with oral involvement. Although lesions are often asymptomatic, some patients complain of itching and pain, and symptoms are frequently made worse in a cold environment. Patients sometimes also have arthralgia. Eye involvement includes keratolysis and ulcerative keratitis with positive rheumatoid factor.10,11 Although the disease is chronic and progressive, resolution usually occurs by 5–10 years. The disease characteristically responds to dapsone. Systemic involvement does not usually occur but pulmonary infiltrates have exceptionally been documented.12

Fig. 16.77 Erythema elevatum diutinum: the extensor surfaces are commonly affected. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

An association with paraproteinemia is frequently present, often of the IgA subtype.1,13,14 Hyperimmunoglobulinemia D syndrome is a further rare association.15 An underlying myelodysplastic syndrome or a hematological malignancy (e.g. multiple myeloma, B cell lymphoma, and chronic lymphocytic leukemia) has been found in some patients.1,16–19 Often, the skin lesions precede development of the hematological disorder.1 In one study, an average of 7.8 years separated onset of skin lesions and development of a myeloproliferative disorder.1,20 Erythema elevatum diutinum has rarely also been associated with other malignancies such as pulmonary lymphoepithelioma-like carcinoma and breast carcinoma.21,22 Inflammatory bowel disease – both Crohn's disease and ulcerative colitis – has also been associated with erythema elevatum diutinum.23–25 Interestingly, in one patient with Crohn's disease, skin lesions seemed to appear during exacerbation of bowel symptoms.23 In another patient with ulcerative colitis, onset of erythema elevatum diutinum lesions coincided with presentation of bowel disease, and skin lesions resolved following colectomy.24 Erythema elevatum diutinum has also been reported in association with celiac disease.26–28 In one patient with celiac disease, skin lesions resolved with the introduction of a gluten-free diet.27 Rheumatoid arthritis has been described in conjunction with erythema elevatum diutinum.29–31 Other reported associations include Wegener's granulomatosis, relapsing polychondritis and pyoderma gangrenosum, cutaneous lupus erythematosus, nodular scleritis and panuveitis, Hashimoto's thyroiditis, juvenile idiopathic arthritis, and Sjögren's syndrome.32–40 Erythema elevatum diutinum is also seen in patients with HIV infection.41–46 In HIVinfected patients, lesions may mimic Kaposi's sarcoma.41 Extensive acroosteolysis has been described in a single case.47 The exceptional association with pityriasis rubra pilaris and mosquito bites is probably coincidental.48 A condition described as ‘neutrophilic dermatosis of the dorsal hands’ is likely to be part of the spectrum of erythema elevatum diutinum.49

Pathogenesis and histological features

Fig. 16.76 Erythema elevatum diutinum: tuberose nodules present on the elbow. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Erythema elevatum diutinum is possibly immune complex mediated. Both a streptococcal antigen and Escherichia coli have been implicated.2,50 As mentioned above, the disease has also been recorded in association with cryoglobulin IgA, monoclonal or biclonal gammopathy, multiple myeloma, hairy cell leukemia, and polycythemia rubra vera.1,51–53 In addition, IgA antineutrophil cytoplasmic antibodies (ANCA) and less frequently IgG ANCA have been identified in patient's serum.54 In early lesions, there is increased expression of the beta (2)-integrins CR3 and LFA-1 and this diminishes in older lesions.55 Peripheral blood neutrophils show increased migration in response to interleukin-8 (IL-8) and decreased responsiveness to the bacterial peptide analogue N-formyl-methionyl-leucyl-phenylalanine. These findings

Erythema elevatum diutinum

Fig. 16.79 Fig. 16.78 Erythema elevatum diutinum: early lesion showing leukocytoclastic vasculitis in a background of a Sweet's syndromelike neutrophil infiltrate.

suggest that in erythema elevatum diutinum the recruitment of neutrophils occurs as a result of activation of cytokines such as IL-8.55 Immune complexes and bacterial peptides sustain the persistent local inflammatory response.55 Biopsy of early lesions reveals typical features of leukocytoclastic vasculitis (Fig. 16.78).1,56 The epidermis may show acanthosis and parakeratosis. Fibrinoid necrosis and infiltration of the superficial vessels by neutrophil polymorphs are present. The perivenular connective tissue contains abundant fibrin and a dense inflammatory cell infiltrate of neutrophils, histiocytes, lymphocytes, and eosinophils. Leukocytoclasis is usually evident. Older lesions are characterized by the development of granulation tissue and fibrous scarring, although even then, foci of neutrophilic vasculitis may

Erythema elevatum diutinum: older lesion showing scar tissue with a vaguely storiform growth pattern.

be found after examination of multiple sections (Fig. 16.79). In ‘burnt out’ lesions, vasculitis may not be present. Granulation tissue and dense scarring mark the site of the previous acute inflammatory process. In older lesions the scarring often shows a storiform pattern (Fig. 16.80). Interstitial lipid deposition described in the past as extracellular cholesterolosis is uncommon. In ocular lesions, leukocytoclastic vasculitis with focal granulomatous inflammation has been described.11 Rare histopathological features described include palisaded necrotizing granuloma and pyogenic granuloma-like features.48

Differential diagnosis Erythema elevatum diutinum typically involves the dermis and must, therefore, be distinguished from granuloma faciale. Granuloma faciale usually shows an eosinophil predominance whereas in erythema elevatum diutinum neutrophils are much more numerous. However, the histological

B

Fig. 16.80

A

(A, B) Erythema elevatum diutinum: this example was clinically thought to represent a keloid. There is a circumscribed dermal nodule composed of spindle cells in a hyalinized stroma. Focally perivascular nuclear debris is evident and there are scattered eosinophils.

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Vascular diseases features of late lesions in both entities often overlap and similar appearances are found in chronic fibrosing vasculitis. The latter represents a non-specific reaction pattern that is occasionally seen in solitary lesions from patients who have no clinical features of either granuloma faciale or erythema elevatum diutinum.57 Distinction from Sweet's syndrome is afforded by the presence of neutrophilic vasculitis. Older sclerotic lesions, particularly when they present as mass lesions, may be mistaken for a neoplastic process or dermatofibroma.8 The presence of a leukocytoclastic vasculitis and neutrophilic infiltrate with karyorrhexis favors erythema elevatum diutinum.

Behçet's disease Clinical features This rare disease was originally described as a combination of recurrent oral and genital ulceration associated with uveitis. However, it is now known to represent a systemic illness with lesions involving the joints and central nervous, vascular, respiratory, gastrointestinal, and urogenital systems, in addition to mucous membranes and integument (Table 16.7).1–7 Although it is seen worldwide, it has a high incidence in Japan, Southeast Asia, the Middle East, Turkey, and some countries bordering the Mediterranean. Behçet's disease shows a male predominance and most commonly presents in young adults with a peak incidence of onset in the third decade.8 Children may also be affected with an approximately equal sex incidence.9 One study has suggested that the disease is less aggressive in children.10 Some data appear to indicate that males have a higher mortality rate.11 The International Study Group established diagnostic criteria for Behçet's disease in 1990 and these are summarized in Table 16.8.4 It should be kept in mind that these criteria are somewhat controversial.12 More research is necessary before we can fully understand this complex disease. Recurrent oral ulceration is an invariable feature. Some patients have a long history of oral ulceration before developing other features that allow for a definitive diagnosis of Behçet's disease. Ulcers typically measure up to 1 cm across but may be larger. They develop anywhere in the oral cavity, in the pharynx, and even in the larynx (Fig. 16.81).13 They are exquisitely painful, and usually regress spontaneously within 14 days although they can persist for much longer. A yellow, necrotic crust covers the ulcer floor. Some patients develop ulcerations in a herpetiform configuration.14 Patients with larger ulcers tend to have greater severity of oral disease with more frequent relapses.14 Cutaneous lesions are common, recurrent, and comprise a wide variety of manifestations including erythema nodosum-like lesions, usually on the lower extremities.15,16 Patients may also develop acneiform papules and pustules, furuncles, pyoderma, and thrombophlebitis (Fig. 16.82). In one very large study, papulopustular lesions (followed by erythema nodosum-like nodules) were the most commonly encountered skin manifestation.7 Patients have also been described with Sweet's syndrome-like features.17 Table 16.7 Behçet's disease: frequency of organ involvement Sign or symptom

Incidence (%)

Oral ulcers

90–100

Genital ulcers

64–88

Ocular lesions

27–90

Cutaneous lesions

48–88

Joint manifestations

18–64

Neurological features

10–29

Intestinal manifestations

0–59

Thrombophlebitis

10–37

Reproduced with permission from Arbesfield, S.J. and Kurban, A.K. (1988) Journal of the American Academy of Dermatology, 19, 767–779. Copyright © The American Academy of Dermatology, Inc.

Table 16.8 Behçet's disease: diagnostic criteria* Criterion

Definition

Recurrent oral ulceration

Minor aphthous, major aphthous, or herpetiform ulceration observed by physician or patient, and recurrent at least three times in one 12-month period

Plus two of: Recurrent genital ulceration

Aphthous ulceration or scarring, observed by physician or patient

Eye lesions

Anterior uveitis, posterior uveitis or cells in vitreous on slit lamp examination or Retinal vasculitis observed by ophthalmologist

Skin lesions

Erythema nodosum observed by physician or patient, pseudofolliculitis or papulopustular lesions; or acneiform nodules observed by physician, patient not on corticosteroid treatment

Positive pathergy test

Read by physician at 24–48 hours

* Findings applicable only in the absence of other clinical explanations. Reprinted with permission from Elsevier (International Study Group for Behçet's Disease (1990) Lancet, 335, 1078–1080).

Fig. 16.81 Behçet's disease: superficial ulcers are present on the inner aspect of both lips. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Typical of Behçet's disease, and an important diagnostic clue, is development of sterile pustules at sites of mild skin trauma such as injection sites (pathergic response) (Fig. 16.83).18,19 Paradoxically, some authors have found that wound healing after 4 mm punch biopsy does not seem to differ compared with control subjects.20 Genital lesions, similar in appearance to those of the oral mucosa, occur on the scrotum, penis, vagina, and vulva (Figs 16.84, 16.85).7 Ocular involvement is important because, if left untreated, it may progress to cataracts and blindness. Both eyes are affected in the majority of patients. Almost any part of the eye is affected and bilateral inflammation of the anterior segment (anterior uveitis), posterior uveitis with hypopyon and vitritis are said to be pathognomonic.21,22 Uveitis is more common and is associated with a more severe clinical course in males potentially leading to loss of vision.22 Conjunctivitis, corneal ulceration, choroiditis, and retinal vessel involvement (arterial and venous vasculitis) are sometimes additional features.

Behçet's disease

Fig. 16.82 Behçet's disease: typical pustules on the lower leg. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 16.84 Behçet's disease: there is a typical scrotal ulcer with central slough. By courtesy of D.A.H. Yates, MD, St Thomas' Hospital, London, UK.

Fig. 16.83 Behçet's disease: this ruptured pustule developed at the site of a previous venipuncture. Such a positive provocation test is virtually pathognomonic for Behçet's disease. By courtesy of D.A.H. Yates, MD, St Thomas' Hospital, London, UK.

Joint involvement is not uncommon and usually affects the knees, ankles, elbows, and wrists.23 A mono- or oligoarticular pattern is typical. The affected joints are swollen, red, tender, and painful. It is of interest that despite many years of arthritic symptoms, joint deformities do not develop. Vascular disease in Behçet's disease takes the form of both thromboocclusive disease and frank vasculitis. Vascular involvement is an important cause of both morbidity and mortality and is seen in approximately one-third of patients.24,25 Males appear to be at an increased risk.25 Thrombophlebitis is common and can affect both superficial and deep veins of the limbs. Superior and inferior vena caval obstruction are not uncommon complications. A particularly perilous form of vascular involvement is hepatic vein occlusion (Budd-Chiari syndrome), which is associated with a high mortality.26 Pulmonary artery aneurysm occurs in approximately 1% of patients and is associated with a 50% mortality rate.27,28 The inflammation may affect virtually any artery and the development of an aneurysm with subsequent rupture is an important cause of death. Respiratory involvement presents as dyspnea, cough, pleuritic chest pain, and hemoptysis.29 The last, due to pulmonary artery–bronchial fistula formation, is an important cause of death. Lung involvement occurs in up to 5% of patients.29

Fig. 16.85 Behçet's disease: multiple superficial vulval ulcers are present. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Intestinal involvement particularly affects the ileocecal region; ulcers may be complicated by perforation, presenting as an intra-abdominal emergency necessitating surgical intervention.30 The esophagus is uncommonly affected by ulcers and erosion, stenosis or esophagitis.31 Involvement of the nervous system, which is associated with a poor prognosis, occurs in up to 25% of patients.24 Lesions develop anywhere in the central and peripheral components and, therefore, virtually any neurological sign or symptom may be seen, including sensory losses, strokes, and spinal cord, cranial and peripheral nerve lesions. Dural sinus thrombosis is a ­wellrecognized complication.32

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Vascular diseases The kidney is affected in up to 55% of patients and manifestations include amyloidosis, glomerulonephritis, interstitial nephritis, and vasculitis.33 A study of relative organ system involvement has led to a subclassification of a spectrum of Behçet's disease.34,35 The mortality of Behçet's disease is, however, surprisingly low, of the order of 2–4%.

Pathogenesis and histological features The precise etiology and pathogenesis are unknown. Recent interest has focused on the possibility of an altered immune response in patients with Behçet's disease. It has been suggested that heat shock proteins may play an important role in its pathogenesis.36,37 They have been found to be elevated in serum together with increased levels of vascular endothelial growth factor (VEGF) and antiphospholipid antibodies independent of disease activity.38 Heat shock proteins reactive in Behçet's patients induce uveitis in rats.37 Increased VEGF levels correlate significantly with the presence of vascular or ocular disease.38 Oligoclonal expansion of T cells in some patients with Behçet's disease has been documented.39 In one study, serum IL-12 and peripheral Th1 lymphocyte levels correlated with disease activity.40 Complement components C3 and C9 have been identified in blood vessel walls in oral biopsies.35 Increased interleukin levels associated with increased B-cell activity have also been described.41 Of possible importance in the pathogenesis is the frequent presence of high levels of circulating immune complexes and the common detection of immunoglobulins (particularly IgM) and complement in blood vessel walls.42–44 Behçet's disease is associated with human leukocyte antigen (HLA)-B5, -B12, -B27, and particularly with HLA-BW51.24 Anticardiolipin antibodies have been described.24 Despite the accumulation of considerable immunological and genetic data, the underlying antigen or other stimulus that drives these changes, and is ultimately responsible for the disease, remains elusive. The histological features are in themselves largely non-specific.35,41,45,46 The diagnosis of Behçet's disease is essentially clinical. The pathological features that may be detected include both lymphocytic and necrotizing vasculitis affecting the superficial postcapillary venules with associated fibrinoid necrosis (Fig. 16.86).45 In one study, nearly 50% of patients had evidence of vasculitis.47 Often, however, such vasculitic changes appear to be a consequence, rather than a cause, of the dermal or mucosal inflammatory changes.46 Endothelial swelling may be a feature and there is often an associated lymphocytic perivascular infiltrate although sometimes neutrophils are abundant.48 Venulitis and phlebitis were the most common forms of vasculitis seen in one series of patients.12 In this study, phlebitis/venulitis was seen in 48% of patients while leukocytoclastic vasculitis and lymphocytic vasculitis were seen in 17% and 31% of patients, respectively.47 Non-specific features include a diffuse neutrophil polymorph dermal infiltrate with or without abscess formation, corresponding clinically to pustular

Fig. 16.87 Behçet's disease: there is florid suppurative acute folliculitis.

lesions, acute folliculitis, and acneiform folliculocentric pustular changes (Fig. 16.87).12,49,50 Biopsy after needle trauma in one study showed a neutrophilic infiltrate with intraepidermal pustules. Vasculitis was not seen in pathergic lesions in this study.51 Other authors have found that the pathergic lesions may show leukocytoclastic vasculitis or Sweet's syndrome-like features.18 The erythema nodosum-like lesions correspond to necrotizing vasculitis of the subcutaneous vessels, usually associated with thrombosis. Septal and lobular panniculitis have also been described.13 Superficial thrombophlebitis is present in up to 30% of patients (Fig. 16.88).34 Oral lesions and genital ulcers show non-specific ulceration, accompanied in some instances by leukocytoclastic or lymphocytic vasculitis. Pulmonary involvement is characterized by pulmonary artery vasculitis, sometimes also affecting the veins and capillaries.29 Thrombosis, infarction, hemorrhage, and the development of aneurysm are important sequelae. The inflammation is usually transmural and may be associated with damage to the associated elastic tissue. Older destructive vascular lesions are characterized by fibrous scarring. Cerebral lesions in the early stage are characterized by a perivenular lymphocytic infiltrate. In the more advanced lesions there is extensive demyelination resembling multiple sclerosis.24

Differential diagnosis Given the myriad non-specific histological manifestations that Behçet's disease may produce, it comes as no surprise that the histological differential diagnosis is usually broad. The authors of one large study stated that clinical data are most important in establishing a diagnosis and suggested that the role of biopsy is to confirm the clinical impression.7 Others propose that biopsy is critical to evaluate for vessel-based pathology as clinical distinction from pustular (non-vascular) lesions may be important.12 It is likely that the criteria for diagnosis of Behçet's disease will continue to be refined. The differential diagnosis includes other causes of folliculitis, infection, erythema nodosum, connective tissue disease, neutrophilic and lymphocytic vasculitis, and neutrophilic dermatoses. There are no pathognomonic histological changes. Both clinical and pathological data must be considered before arriving at a final diagnosis.7

Thromboangiitis obliterans Clinical features Fig. 16.86 Behçet's disease: this field shows a superficial vulval ulcer with an intense neutrophilic infiltrate and changes of acute vasculitis.

Thromboangiitis obliterans (Buerger's disease) is most often seen in young adults and is much more common in males than in females.1 However, the ratio of men to women is shifting, with the disease becoming more common in women.2,3 In one large study, 23% of patients were female.2 In addition, the disease is seen more frequently in older patients.2 Buerger's disease occurs

Temporal arteritis

A

Fig. 16.89 Buerger's disease: digital gangrene is present in this amputation specimen.

B

Fig. 16.88 (A, B) Behçet's disease: this section shows thrombophlebitis involving a vein in the subcutaneous fat. The vessel is infiltrated by large numbers of lymphocytes.

almost exclusively in smokers. Although most patients are considered ‘heavy’ smokers, some smoke less than a pack of cigarettes a day.4 In fact, some authors view a history of smoking a necessary criterion for diagnosis. In one study from Japan, nonsmokers with Buerger's disease were more likely to be women.5 In Bangladesh, smoking bidis (a hand-rolled, additive-free, unprocessed form of tobacco) is particularly associated with this disease.6 The worldwide incidence of Buerger's disease differs dramatically from region to region. For example, the incidence is 50-fold greater in Nepal compared with North America.7 This disease has its highest prevalence in Eastern Europe, the Middle East, and Asia. Patients most often present with painful cyanotic lesions of the extremities, especially the fingers or toes, which may ulcerate and become gangrenous (Fig. 16.89). Sensitivity to cold is a common complaint. Resolution of disease usually follows cessation of smoking.8,9 Patients who continue to smoke suffer autoamputation of digits and distal extremities. In one study, only 2% of patients who quit smoking had amputations. In contrast, 42% of those that continued to smoke required amputation.2 In most patients, the disease is limited to the extremities; however, some patients develop visceral involvement,10–13 and this can prove fatal.10 The vessels of the brain, intestine, heart, kidney, and lung may therefore be affected.14–17 Occasional patients have involvement of multiple organs.18

Pathogenesis and histological features The pathogenesis of Buerger's disease is poorly understood. Clearly, the strong association with smoking suggests that this habit plays an important role in eliciting thrombosis and resultant ischemia.19 It is unclear if tobacco

products are toxic to endothelial cells or elicit immune reactions that damage vessels. Of interest, the disease has been described in patients who use smokeless tobacco.20 Antiendothelial antibodies are elevated in a subset of patients with Buerger's disease.21 Furthermore, disease activity correlates with antiendothelial cell antibody titers.21 Response to acetylcholine, an endothelium-dependent vasodilator, is diminished in ‘nondiseased’ extremities of Buerger's patients compared with control subjects.22 IgG, IgM, and IgA are present along the internal elastic lamina.23 Lesions are characterized by thrombosis of small or medium-sized arteries and, less commonly, veins associated with a variable inflammatory infiltrate composed of a mixture of neutrophils, lymphocytes, eosinophils, histiocytes, and giant cells.19,24 Immunohistochemical studies have confirmed the heterogeneous nature of the infiltrate. T cells, B cells, macrophages, and dendritic cells may all be present.23 CD4-positive T cells outnumber CD8positive cells and T cell-mediated inflammation appears to be of significance in the development of the disease.25 A characteristic finding is the presence of a microabscess associated with an intraluminal thrombus. Inflammatory cells may be seen in all layers of the vessel wall (Fig. 16.90). Preservation of the internal elastic lamina is a typical feature.19 As lesions age, thrombi become organized and are replaced by fibrosis, and eventually the vessel is recanalized (Fig. 16.91). A definitive diagnosis based on biopsy findings is not possible during the later stages of organization.

Differential diagnosis The histopathological features are probably not specific for Buerger's disease, and differential diagnosis includes other thrombotic vasculopathies. Clinical correlation is advised before rendering a definitive diagnosis. Preservation of the internal elastic lamina is a characteristic feature and is said to help in distinction from other vasculitides.19,26

Temporal arteritis Clinical features Temporal arteritis (giant cell arteritis) is a disease of the elderly that shows a marked female predominance (3:1).1,2 It is a generalized vasculitis that predominantly affects large and medium-sized arteries.3 It is mainly seen in Caucasians and its etiology is unknown.2,3 Five of the American College of Rheumatology 1990 criteria are outlined in Table 16.9.1 Classically, the temporal arteries are primarily affected, but giant cell arteritis may also affect the occipital or facial arteries and, in fact, has the potential to involve virtually any medium-sized or large vessel, including the aorta and its branches.3 Patients with giant cell arteritis present with pyrexia, severe headache, and throbbing scalp pain. Clinical

689

690

Vascular diseases

A

A

B

B

Fig. 16.90  (A, B) Buerger's disease: this acute lesion shows pan-mural inflammation with abscess formation and thrombosis.

examination may reveal scalp tenderness and the skin overlying the affected vessel may be erythematous, edematous or appear bruised.4 Palpation often reveals a cordlike and nodular vessel. Pulsation can be diminished or absent. Visual disturbance due to involvement of the ophthalmic or retinal vessels is an important complication which sometimes results in blindness. Lesions of the central nervous system may result in stroke, subarachnoid hemorrhage or mental confusion, and aural involvement can cause deafness. In one large study, neurological problems were present in nearly one-third of patients.5 Peripheral neuropathic syndromes are evident in 14% of patients.4 Often the associated lymph nodes are enlarged and tender. Symptoms of polymyalgia rheumatica (i.e. stiffness, weakness, aching and pain in the muscles of the neck, limb girdles, and upper limbs) are extremely common, occurring in up to 75% of patients.6 Laboratory investigations typically reveal mild anemia, neutrophilia, and a very high ESR. Elevated levels of von Willebrand factor are characteristic.7 Cutaneous lesions other than those mentioned above are uncommon, presumably reflecting the vast collateral circulation of the integument.8,9 Patients may occasionally manifest ulcers (sometimes quite widespread), massive necrosis, bullae, and gangrene (Fig. 16.92).10,11 Involvement of the lingual artery can cause glossitis or gangrene of the tongue.12,13 Masticatory claudication is an additional feature. Rare patients with disseminated visceral arteritis with giant cell arteritislike histological features have been described.14 The heart, lungs, kidneys, stomach, pancreas, and liver may be involved.14 It is debatable what terminology should be applied to such rare and unusual cases. Life expectancy does not seem to be adversely affected by having temporal arteritis.15

Fig. 16.91  (A, B) Buerger's disease: old lesion showing luminal obliteration and recanalization. Note the intact elastic lamina.

The vast majority of patients have an elevated ESR.16 C-reactive protein is also typically elevated.16 Elevated levels of anticardiolipin antibodies are frequently present.17–20 Some studies suggest that the presence of anticardiolipin antibodies correlates with more severe vascular damage.19,20 In most patients, anticardiolipin antibody titers return to normal range with steroid therapy.18

Table 16.9 1990 criteria for the classification of giant cell (temporal) arteritis (traditional format)* Criterion

Definition

Age at disease onset ≥ 50 years

Development of symptoms or findings beginning at age 50 or older

New headache

New onset of or new type of localized pain in the head

Temporal artery abnormality

Temporal artery tenderness to palpation or decreased pulsation, unrelated to arteriosclerosis of cervical arteries

Elevated ESR

ESR ≥ 50 mm/hour by the Westergren method

Abnormal artery biopsy

Biopsy specimen with artery showing vasculitis characterized by a predominance of mononuclear cell infiltration or granulomatous inflammation, usually with multinucleated giant cells

*For purposes of classification, a patient shall be said to have giant cell (temporal) arteritis if at least three of these five criteria are present. The presence of any three or more criteria yields a sensitivity of 93.5% and a specificity of 91.2%. Reproduced with permission from Hunder, G.G. (1990) Arthritis and Rheumatism, 33, 1122–1128.

Temporal arteritis

A

Fig. 16.92 Giant cell arteritis: severe ischemic necrosis with ulceration has destroyed most of this patient's scalp. By courtesy of D. McGibbon, MD, St Thomas' Hospital, London, UK.

Pathogenesis and histological features The pathogenesis of temporal arteritis is poorly understood. Although an immunological mechanism has been suggested, it has not been proven. Evidence of familial aggregation and an increased incidence of the HLA-DR4 antigen have raised the possibility of a genetic influence.3 However, consistent reproducible HLA associations have not been demonstrated in all populations. It has been suggested that giant cell arteritis is an autoimmune disease perhaps directed, at least in part, against the vascular elastic lamina.3 T cells in the infiltrate are predominantly of the helper subclass and expression of HLA-DR has been recorded, thereby suggesting that they are activated.3 The lymphocytes have been shown to respond to antibodies against transferrin and IL-2 receptors.21 Proliferation of mononuclear cells following incubation in cultures containing elastin-derived peptides is increased compared with control subjects.22 This finding suggests elastinderived peptides are the targets of T cells in giant cell arteritis.22 Disease activity has been shown to correlate with plasma concentrations of IL-6.23 The demonstration by some authors of a fluctuating cyclical pattern of incidence has raised the possibility of an infectious agent or other triggering factor playing a significant pathogenetic role.24–26 A study from the Mayo Clinic showed a variation in incidence with peak periods occurring approximately every 7 years.24 Similarly, a study from Denmark demonstrated marked variation in the incidence of temporal arteritis with five peak periods.26 Of these, there appeared to be association with two epidemics of Mycoplasma pneumoniae infection, two possibly related to erythrovirus (parvovirus) B19 epidemics and one peak that may have been related to an epidemic of Chlamydia pneumoniae.26 Another study showed a threefold increased likelihood of infection in patients with temporal arteritis compared with control subjects.27 An association between temporal arteritis and antibodies to parainfluenza type 1 has been demonstrated.28,29 A different hypothesis implicated altered endogenous material due to age- or sun damage-related changes.30–32 Despite these observations, the precise triggering factors and the pathogenesis of temporal arteritis remain unclear. The lesions of giant cell arteritis are typically focal in distribution; therefore, the vessel should be carefully palpated to find an obviously affected segment before a biopsy is undertaken. Even then, false negatives are not uncommon (see below). The lesion is granulomatous in nature and may affect only part or the whole circumference of the vessel wall (Fig. 16.93).33 The infiltrate, which particularly affects the intima and media, is composed of lymphocytes, plasma cells, histiocytes, and variable numbers of giant cells of both foreign body and Langhans type (Fig. 16.94). Giant cells are sometimes relatively sparse and multiple levels have to be examined before they are identified.

B

Fig. 16.93 (A, B) Giant cell arteritis: this scalp biopsy showed multiple affected vessels. By courtesy of P.A. Burton, MD, Southmead Hospital, Bristol, UK.

Fig. 16.94 Giant cell arteritis: the intima and media are infiltrated by a dense chronic inflammatory cell infiltrate containing conspicuous Langhans giant cells. By courtesy of P.A. Burton, MD, Southmead Hospital, Bristol, UK.

691

692

Vascular diseases On occasion, they are absent. Typical of giant cell arteritis is damage to the internal elastic lamina, which appears swollen and fragmented, and portions may be identified within the cytoplasm of giant cells (Fig. 16.95).4 A second, less common form consists of a panarteritis composed of lymphocytes, macrophages, neutrophils, and eosinophils but giant cells are absent. Varying degrees of vessel wall necrosis are evident and the vessel is often thrombosed. In the late stages of the disease, fibrous scarring takes place and a reconstituted, often multilayered, internal elastic lamina may be identified. In cases of doubt, an elastic tissue stain can prove invaluable. The thrombus is on occasions recanalized. Initiation of corticosteroid treatment before biopsy influences the histological appearances.34 Giant cells are rare or entirely absent, there are large circumferential defects in the elastic lamina, and there is a mantle of lymphocytes and epithelioid histiocytes between the outer muscular layer and the adventitia.34 These changes can be noted as early as 1 week following steroid treatment.34 It is crucial to note that patients with classic symptoms of temporal arteritis may have a negative biopsy, most likely due to the multifocal nature of the arteritis and sampling bias. In one study, 44% of patients who were regarded as having clinical manifestations of temporal arteritis, which improved with steroid treatment, had negative biopsies.35 Therefore, a negative biopsy does not necessarily exclude this disease. Given the consequences of delayed or no treatment, it is often necessary to treat selected patients even without definitive biopsy diagnosis. One study found that patients with temporal arteritis who have constitutional symptoms or an abnormal temporal artery detected by physical examination are more likely to have a positive biopsy.36 Doppler flow studies may be used to improve the sensitivity of biopsy.37 Given the multifocal nature of giant cell arteritis, the diagnostic yield, not surprisingly, is likely improved with longer artery length biopsied and increased number of sections examined.38

Differential diagnosis The histological findings are identical to those seen in some patients with Takayasu's disease, another form of giant cell arteritis. Careful clinical correlation is required to distinguish these conditions and, since overlap exists, many cases are not easily subclassified. Some authors consider these diseases part of a continuum of giant cell vasculitis, with patient age being an important discriminator: patients under age 40 are more likely to have Takayasu's arteritis; those over 50 are more likely to have temporal arteritis. It should be noted that fragmentation of the internal elastic lamina may result from either age-related changes or atherosclerosis and these conditions may be difficult to distinguish from healed arteritis. The presence of medial scarring is suggestive of temporal arteritis. The extent of destruction, particularly confluent loss of the internal elastic lamina, is said to correlate with probability of healed arteritis.6

Juvenile temporal arteritis Clinical features Juvenile temporal arteritis is a rare and poorly defined entity first reported in 1975.1 Thus far, only approximately 20 cases have been reported in the literature.2–10 The disease is unrelated to classic temporal arteritis and is not associated with abnormal erythrocyte sedimentation rate or signs of systemic involvement. It occurs in patients under the age of 40, most commonly manifesting as a unilateral painless nodule or swelling of a few centimeters in the temporal area.1–10 Painful presentation and bilateral involvement are rare features.2–4 The disease may be accompanied by blood eosinophilia and it may be related to or associated with Kimura's disease.4,5,7,9,10

Histological features Juvenile temporal arteritis is characterized by intimal proliferation and disruption of the media of the temporal artery associated with a heavy chronic inflammatory infiltrate composed predominantly of lymphocytes and eosinophils. Endothelial proliferation is an additional finding and formation of lymphoid follicles and germinal centers may be present. Giant cells as seen in classical temporal arteritis are not a feature.

Takayasu's arteritis Clinical features Takayasu's arteritis (pulseless disease, giant cell arteritis) is a rare granulomatous disease that predominantly affects the aorta and its major branches and results in vascular stenoses with bruits and diminished or absent pulses (hence the term ‘pulseless disease’).1,2 Aneurysm formation may be an additional feature. It predominantly affects females (7:1), most often involves the upper limbs, and usually presents in the second or third decade. Although most patients are young adults, the disease is also seen in children.3,4 It is rare in Europe and the United States, occurring more often in Japan, China, Korea, Southeast Asia, India, and Mexico.2 It appears to have two stages: • an acute systemic illness characterized by fever, malaise, arthralgias, myalgias, and ocular lesions including uveitis and episcleritis, • a chronic stage of large-vessel involvement.5 Current diagnostic criteria are shown in Table 16.10. In addition to the obligatory criterion, the presence of two major criteria, one major plus two or more minor, or four or more minor criteria, is associated with a high probability of Takayasu's arteritis.6

Table 16.10 Takayasu's arteritis: diagnostic criteria •  Obligatory criterion –  age  4 mm with ulceration (T4bN0M0)

53

39

IIIA

Single regional nodal micrometastasis**, nonulcerated primary (T1–4aN1aM0) 2–3 microscopic regional nodes, nonulcerated primary (T1–4aN2aM0)

78

68

IIIB

Single regional nodal micrometastasis, ulcerated primary (T1–4bN1aM0) 2–3 microscopic regional nodes, ulcerated primary (T1–4bN2aM0) Single regional nodal macrometastasis***, nonulcerated primary (T1–4aN1bM0) 2–3 macroscopic regional nodes, nonulcerated primary (T1–4aN2bM0) In-transit metastasis(es)/satellite lesion(s) without metastatic lymph nodes (T1–4a/ bN2cM0)

59

43

IIIC

Single microscopic regional node, ulcerated primary (T1–4bN1bM0) 2–3 macroscopic regional nodes, ulcerated primary (T1–4bN2bM0) In-transit metastasis(es)/satellite lesion(s) without metastatic lymph nodes, ulcerated primary(T1–4bN2cM0) 4 or more metastatic nodes, matted nodes/gross extracapsular extension, or in-transit metastasis(es)/satellite(s) and metastatic nodes (anyTN3M0)

40

24

IV

Distant skin, subcutaneous, or nodal metastasis with normal LDH (any T any NM1a) Lung metastasis with normal LDH (any T any NM1b) All other visceral metastasis with normal LDH or any distant metastasis with increased LDH(any T any NM1c)

62 53 33

Breslow thickness is defined as the thickness of the lesion using an ocular micrometer to measure the total vertical height of the melanoma from the top of the granular layer to the area of deepest penetration. The Clark level refers to levels of invasion according to depth of penetration of the dermis. *Clark level is now only used when mitotic rate is not available in a T1 tumor. Level IV or V invasion would meet criterion for T1b. **Micrometastases are defined as following pathologic assessment of sentinel lymph node and/or lymphadenectomy specimen. There is no longer a minimum size lesion for metastasis. Immunohistochemistry may be used to screen for micrometastases, but must include at least one ‘melanoma-specific’ marker (i.e., HMB-45, MART1, MelanA). ***Macrometastasis is clinically detectable with pathologic confirmation or gross extracapsular extension on pathologic examination. Adapted with permission from AJCC Cancer Staging Manual, 7th Edition (2009) Eds: Edge SB, et al. Melanoma of the Skin, pp.325–344. Springer-Verlag, New York. and Balch, C. M., Gershenwald, J. E., Soong, S. J. et al. (2009) Final Version of 2009 AJCC Melanoma Staging and Classification. J Clin Oncol, 27; 6199–6206.

1233

1234

Melanoma assessable in thin melanomas, then Clark level no longer provides additional prognostic information. The 2009 (7th) AJCC staging system no longer ­recommends the use of the Clark level, even for thin melanomas, if a mitotic rate in the dermal component is available.113,114 The presence or absence of ulceration and the width of the ulcer are independent prognostic indicators and should be recorded.92 Ulceration is defined as ‘the absence of an intact epidermis overlying a major portion of the primary melanoma based on microscopic examination of the histologic sections’.113 Trauma and artifactual loss of the epidermis must be excluded. Ulceration is associated with a very significant increased risk of metastasis and was first included as a second determinant in the T classification in the AJCC 6th Edition.113,117–119 Tumor-infiltrating lymphocytes are an important independent prognostic variable and should be recorded as brisk, nonbrisk or absent (Figs 26.44–26.46).79,120–122 The brisk category implies lymphocytes present throughout the whole vertical growth phase or extending across its entire base. Nonbrisk tumor infiltrating lymphocytes implies focal infiltration only. Absent includes two categories: either no lymphocytes at all or lymphocytes are present but do not infiltrate the melanoma. Brisk lymphocytic responses tend to be a feature of thin melanomas whereas absence of a lymphocytic response is generally seen in thick melanomas.110,121 In a study of 285 vertical growth phase tumors, the 10-year survival rates for brisk, nonbrisk, and absent tumor-infiltrating lymphocytes were 55%, 45%, and 27%, respectively.121 Not surprisingly, the absence of tumor-infiltrating lymphocytes also correlated with metastasis to sentinel lymph nodes as a

A

B

Fig. 26.44 (A, B) Melanoma: tumor infiltrating lymphocytes. Category A – Brisk: the lymphocytes infiltrate the tumor and extend along the whole of the base of the lesion.

surrogate marker of melanoma risk in a cohort of 887 patients with full multivariate analysis.122 Assessing tumor-infiltrating lymphocytes in lymph node metastases may also have predictive value.123 In thin melanoma it is important to recognize the features of regression, which may be particularly evident in the dermal component (Figs 26.47, 26.48).79 These include absence or reduced numbers of malignant melanocytes, degenerate (apoptotic) forms, and a chronic inflammatory cell infiltrate (Fig. 26.49).124–126 Melanophages, horizontal scarring, isolated tumor islands, and telangiectatic vessels are also commonly present in the later stage. Clinically, regression presents as macular gray, white or pink areas. Although the importance of regression as a determinant of biological behavior has been the subject of considerable argument in the literature, a number of authors believe that, in thin tumors, it correlates with an impaired prognosis, though this contribution may be minor relative to other factors in many cases.126–134 Complete regression of an undiagnosed primary melanoma may be the explanation for patients presenting with metastatic tumor of indeterminate derivation (Fig. 26.50). Some authors recommend sentinel node biopsy for thin melanomas if there is evidence of extensive (> 50%) regression.93 Mitotic rate is determined by the number of mitotic figures/1 mm2 of tumor in the most mitotically active area. It has become clear that tumors displaying a high mitotic rate are associated with a poorer prognosis and that mitoses are a more robust predictor of outcome than ulceration and thus mitotic rate has been incorporated into the 7th AJCC staging system.79,114,135–140 Despite earlier contrary evidence and the complex interrelations of tumor thickness,

A

B

Fig. 26.45 (A, B) Melanoma: tumor infiltrating lymphocytes. Category B – Nonbrisk: the lymphocytes infiltrate only part of the tumor.

Prognostic indicators

Fig. 26.46 Melanoma: tumor infiltrating lymphocytes. Category C – Absent: lymphocytes are present but they do not invade the tumor. The category also includes complete absence of lymphocytes.

A

B

Fig. 26.47 (A, B) Regression: no residual epidermal component is present. Note the lymphocytic infiltrate, plasma cells, abundant melanin-containing macrophages, scarring, and conspicuous vasculature.

Fig. 26.48 Partial regression: in this variant, the junctional component is still present. Its significance is less certain.

Fig. 26.49 Regression: in this example, there is conspicuous apoptosis. Note the eosinophilic bodies.

­ulceration, and mitotic rate, mitotic rate appears to carry prognostic information independent of both of the other factors.93,141,142 The presence of a microscopic satellite is defined by a distinct tumor nodule measuring 0.05 mm or more in diameter separate from the main tumor mass in the section containing the thickest region of the melanoma. It is found in thicker tumors and is associated with an increased risk of local recurrence, regional lymph node metastases, and diminished survival.143–145 The presence of microsatellites is recorded as N2c (without positive lymph nodes) and N3 when seen in combination with positive lymph nodes in the 2009 AJCC melanoma staging system.113 The presence of lymphatic invasion correlates with the development of intransit metastases (Fig. 26.51).146 Lymphovascular invasion has been shown to represent a predictor of diminished survival in melanoma in a number of studies.122,147–50 The use of immunohistochemistry for D2-40 significantly increases the sensitivity for detection of lymphatic invasion and also correlates with lymph node metastasis and survival.151 More study is needed to validate the application and interpretation of the technique. Contrariwise,

1235

1236

Melanoma

B

Fig. 26.50

A

(A, B) Regression: in this example, there is no residual tumor. The dermis is scarred and there is abundant melanin pigment. The patient presented with an unknown primary. By courtesy of M. Forder, MD, St Anne's Medical Center, Pietermaritzburg, South Africa.

A

B

Fig. 26.51 Melanoma: vascular invasion: (A) pleomorphic tumor cells are adherent to the endothelium; (B) tumor cells are growing into the lumen.

absence of vascular involvement in thick melanomas correlates with increased survival in a number of studies.152,153 Perineural and intraneural infiltration are most often encountered in desmoplastic variants, thereby accounting, in part, for the increased risk of local recurrence (Fig. 26.52). In this context, CD57 immunohistochemistry can be helpful in identifying residual nerve (Fig. 26.53). Angiogenesis, which is defined as the increasing development of new blood vessels at the base of the melanoma, parallels increases in tumor thickness.154–157 Increasing angiogenesis therefore correlates with thick tumors, ulceration, relapse, and tumor-associated death.157,158 Perhaps related to the likelihood of lymphovascular invasion, increased intratumoral lymphangiogenesis as measured by D2-40 or VEGF-C also correlates with metastasis to sentinel lymph nodes and reduced disease-specific survival.159 Sentinel node biopsy also adds extremely valuable prognostic information.160–164 It has been shown to represent the most important factor in determining likelihood of tumor recurrence and patient survival in stage I and stage II disease.161 Whether the procedure has therapeutic value is

uncertain but it can spare the patient unnecessary regional lymph node dissection.163 The latest AJCC staging system recommends incorporation of sentinel lymph node data in cases where it would inform management, as this procedure significantly increases the accuracy and discriminatory power of the stage groups.114 Lymph nodes are bivalved or serially sectioned along their long axis and in addition to the examination of hematoxylin and eosin stained sections, immunohistochemistry – such as S-100 protein, HMB-45 and/or MART-1 (melanoma antigen recognized by T cells 1) – should invariably be performed in those cases where the initial sections are negative. Detection of single or tiny groups of cells using an antibody against a ‘melanoma-specific’ antigen such as HMB-45 or MART1 is now incorporated into the AJCC staging system. More recently, molecular techniques including reverse transcriptase polymerase chain reaction for tyrosinase messenger RNA have been proposed.165,166 A major disadvantage of such procedures is the likelihood of false-positive results due to the common presence of banal capsular nevi, though the use of markers more specific to melanoma over nevus cells could potentially alleviate this problem.167

Immunohistochemistry of melanoma ­pleomorphic, amelanotic ­epithelioid melanoma sometimes has to be distinguished from anaplastic carcinoma and occasionally anaplastic lymphoma. The use of antibodies to keratins, epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), leukocyte common antigen (LCA), T- and B-cell antigens, and CD30 may be necessary to achieve a definitive diagnosis.

Immunohistochemistry of melanoma

Fig. 26.52 Melanoma: intraneural invasion. Note the pleomorphic tumor nuclei within this nerve trunk.

Fig. 26.53 Melanoma: CD57 immunohistochemistry may be particularly valuable when tumor growth has largely destroyed the nerve.

Sentinel node biopsy is currently recommended for all tumors measuring 1.00 mm or more in thickness. Other possible indications include ulcerated tumors, tumors with 50% or more regression, tumors having achieved the vertical growth phase, and those lesions which have been biopsied and involve the deep margin.93,163,168 The procedure should also be considered for tumors that are less than 1.00 mm thick but are Clark level IV or with conspicuous mitotic activity.169

Differential diagnosis Amelanotic spindled cell melanoma may be histologically indistinguishable from other cutaneous spindled cell tumors including leiomyosarcoma, spindled cell squamous carcinoma, atypical fibroxanthoma, and even dermatofibrosarcoma protuberans. In such cases, the use of an appropriate panel of immunohistochemical reagents, including antibodies to S-100 protein, HMB-45 or MART-1, pan-cytokeratin, AE1/AE3, smooth muscle actin, and CD34, is often essential. Similarly, highly

Immunohistochemistry is a valuable adjunct to histology in the diagnosis of melanoma, particularly in amelanotic, epithelioid, and spindled cell variants and their distinction from undifferentiated carcinomas and mesenchymal tumors.1,2 Owing to problems of specificity and sensitivity, it is prudent to use two or even three ‘melanoma markers’ in such problematical cases. Using these markers as part of a panel looking at multiple lines of differentiation is also of practical use, such as inclusion of keratins to exclude epithelial tumors. In morphologically challenging cases, a panel of stains that supports the ultimate diagnosis by their pattern of reactivity or nonreactivity is very helpful. The role of immunohistochemistry is to provide supportive data. It should rarely if ever be used as the sole criterion by which a diagnosis of melanoma is achieved. S-100 protein remains the yardstick in the immunohistochemical diagnosis of melanoma.3–5 Although there are now substantial numbers of new markers available, none as yet, in isolation, measures up to S-100 protein. However, S-100 protein lacks specificity and there are very exceptional S-100 proteinnegative melanomas. In cases where the diagnosis remains in doubt, use of a battery of the newer immunohistochemical markers may be of great value.1 S-100 protein is a calcium binding F-band protein, isolated from brain. It is variably positive in 94–100% of primary and metastatic melanomas.1,2 In addition to melanocytes, Schwann cells, myoepithelial cells, adipocytes, chondrocytes, Langerhans cells, and tumors derived thereof, express S-100 protein. Staining of Langerhans cells can sometimes be a problem, particularly when assessing the extent of intraepidermal melanocyte spread. In such instances, the addition of HMB-45 or MART-1 may be helpful. S-100 protein may also be expressed in a number of breast carcinomas and undifferentiated carcinomas.4,5 The most commonly employed antibody against S-100 is a purified rabbit polyclonal antibody against S-100 protein purified from bovine brain. More than 20 members of this family exist and monoclonal antibodies are available for many of them. While not well established in large series, there may be some selectivity of the isoforms between melanoma and other traditionally S-100 protein reactive neoplasms in the differential diagnosis.6 HMB-45 reacts with the cytoplasmic premelanosome glycoprotein gp100 and is less sensitive than S-100 protein.6 It is expressed by 80–86% of metastatic melanomas and between 90% and 100% of primary tumors.1,3,6 However, expression is often more focal than with S-100. Sensitivity diminishes in spindled cell variants and it is usually negative in desmoplastic melanoma (see below).7,8 The junctional and superficial dermal components of banal nevi also react with HMB-45 but the deeper dermal nevus cells are generally negative. This differential staining pattern may be of value in confirmation of pre-existent banal nevus cells associated with a melanoma and in particular their distinction from small cell and nevoid melanoma, which are typically positive in the deepest nests of cells (Fig. 26.54). It is very important to remember that this pattern is lost in cases where melanocytes are pigmented as the latter are positive for HMB45. Dysplastic nevi are similarly labeled. Blue nevi and deep penetrating nevi are also HMB-45 positive.1 Spitz nevi are often HMB-45 positive in the superficial aspect of the lesion and this is usually, but by no means always, lost with depth. This finding may be of value in its distinction from spitzoid melanoma in which staining is typically present throughout the tumor. Although it is more specific than S-100 protein, HMB-45 also reacts with the group of perivascular epithelioid cell tumors (PEComas) including angiomyolipoma, lymphangiomyomatosis, and clear cell sugar tumor of the lung.9,10 MART-1 (Melan-A) is a melanosomal differentiation antigen recognized by autologous cytotoxic T cells.11–17 Some antibodies raised to this protein

1237

1238

Melanoma

A

B

Fig. 26.54 Melanoma: this tumor has arisen in a background of a banal nevus. (A) Compare the eosinophilic, pleomorphic tumor cells with the small basophilic nevus cells; (B) the melanoma cells are HMB-45 positive; the nevus cells are negative.

(e.g., A103) label a variety of lesions including adrenocortical, Leydig cell, Sertoli cell, and granulosa cell tumors, and tumors in the PEComa group of lesions including angiomyolipoma, lymphangiomyomatosis, and clear cell sugar tumors of the lung in addition to melanoma.15,16 It has a similar sensitivity to S-100 protein in epithelioid melanomas but is less sensitive in spindled cell tumors and is not usually expressed in the desmoplastic variant. A study has shown evidence that diminished MART-1 expression correlates with increasing tumor thickness, reduced disease-free interval, and increased patient mortality.15 MART-1 expression has also been demonstrated in compound, dermal nevi and Spitz nevi with the exception of neurotized variants.12–14 Antityrosinase antibody (e.g., T311) appears to be less sensitive than either S-100 protein, HMB-45 or Melan-A (A103).18–23 It does not appear to label desmoplastic melanoma. Microphthalmia transcription factor (MITF) is a transcriptional regulator important for tyrosinase expression.24 It is strongly positive in nevi and epithelioid melanoma.25–27 Sensitivity is reduced in spindled cell and desmoplastic variants.28 Spitz nevi and neurotized banal nevi show diminished expression. The specificity of MITF is low and this limits its use in the differential diagnosis of mimickers of melanocytic lesions. Recently, a new monoclonal antibody, SM5-1, was created by a subtractive immunization protocol using human melanoma samples and appears to bind a variant of fibronectin.29,30 Initial reports indicated that its sensitivity is similar to S-100 protein with improved specificity for other traditionally

S-100 protein reactive, but the antibody also reacts with hepatocellular carcinoma and breast cancer cells.23,31 SOX10 has recently between described as a novel marker of melanocytic and Schwann cells. While it lacks specificity and stains other cells it may be useful in desmoplastic melanoma.32 Additional study and confirmation of both these new markers is necessary. The bar is high for inclusion of new markers as standards for melanoma in clinical practice. All antibodies have a natural history of decreasing specificity with study of additional tumor types and new antibodies are not as far down this curve as older antibodies, creating potential for misinterpretation if the new reagents are used alone. Melanoma cells can express epithelial markers including keratins, EMA, and CEA.2,33–35 Keratin may be identified in as many as 10% of melanomas, both on frozen and on paraffin-embedded sections.2 CEA is commonly encountered if polyclonal antibodies are utilized.34,35 Metastatic disease more often shows such aberrant staining patterns than primary tumors. Diagnostic difficulties are unlikely to be encountered provided S-100 protein and/or other melanoma markers have been included in the antibody panel. Smooth muscle actin (SMA) and desmin are very rarely expressed in melanoma with the exception of the desmoplastic variant where, as in most spindle cell tumors, SMA can be detected to varying degrees.36 One study with dual labeling for S-100 protein and SMA in desmoplastic melanoma indicates that the SMA reactivity may be in accompanying stromal myofibroblasts.37 Melanoma cells may express histiocytic markers such as CD68 (KP1) in 80% or more of tumors.38,39 Mac 387 and α1-antitrypsin may also be positive. This is of particular significance since the distinction between tumor cells and histiocytes, particularly in sentinel lymph node specimens, can sometimes be problematical. In addition, distinguishing between balloon cell melanocytic lesions and xanthomatous infiltrates may require immunohistochemical confirmation, particularly if no residual recognizable melanocytic component is visible. In such circumstances, positive melanocytic markers are obviously of major diagnostic importance. Recently, there has been an ever-expanding range of reputed immunohistochemical prognostic markers.40 Most of these lack appropriately powered full multivariate analysis linking the marker with specific outcome such as melanoma-specific mortality and supplemented by hazard ratios or do not fully describe the methods utilized as recommended by the NCI-EORTC reporting recommendations for tumor marker prognostic studies.41,42 The more useful of these are very briefly discussed below. Few of these are validated to the level necessary for routine application to clinical samples; virtually all are reported in retrospective cohorts. Use of multiple markers and application of rigorous methods of quantification have efficacy, distinguishing different prognostic groups.43 The markers discussed below are primarily used to help support a diagnosis of melanoma or nevus in the relatively small subset of cases where this determination is challenging on purely histologic grounds. Ki-67 (MIB-1) is a particularly valuable adjunct in the distinction between benign melanocytic nevi (including Spitz nevi) and melanoma.44,45 In nevi, less than 5% of nuclei are positive (and these are usually located in the most superficial aspect of the dermal component) whereas in melanoma 25% or more of cells are labeled (Figs 26.55, 26.56). Its role in predicting biological behavior is controversial; thus, although in earlier studies increased expression in thick tumors was thought to correlate with poor survival, more recently it has been claimed that increased expression in thin tumors ( 80% of the skin surface, with or without scaling.2 It may be seen in cutaneous T-cell lymphoma as well as in a variety of other benign and malignant conditions. The latter include other lymphomas such as B-chronic lymphocytic leukemia, adult T-cell leukemia/lymphoma and T-prolymphocytic leukemia.3 Idiopathic erythroderma refers to cases with no identifiable cause.2 Skin biopsies from patients with Sézary's syndrome often show non-specific or only suspect features of cutaneous T-cell lymphoma, and clinical

Fig. 29.96 Sézary's syndrome: the facial skin is indurated and covered by a scale. Note the alopecia. By courtesy of M. Blanes, MD, Alicante, Spain.

Sézary syndrome

Fig. 29.98 Fig. 29.97 Sézary's syndrome: palmar keratoderma is often present. By courtesy of M. Blanes, MD, Alicante, Spain.

The outcome of the disease is variable but it is often associated with poor prognosis.23,26–32 Median survival figures of 45–48 months are often quoted.29,32 Patients with visceral involvement fare particularly badly. Documented important prognostic indicators have included lymph node status, absolute Sézary's cell count, fast evolution of the disease, and serum lactate dehydrogenase and beta-2-microglobulin levels.29,32 The cause of death may be the tumor itself or overwhelming secondary infection. Visceral spread is similar to that of advanced mycosis fungoides. Erythrodermic cutaneous T-cell lymphoma should be classified as stage 4 disease.

Pathogenesis and histological features The etiology of Sézary's syndrome remains unknown. No consistent viral, environmental or occupational causative factor or hereditary mutation has been found.33 Most cases show evidence of chromosomal instability with complex karyotypes and/or large numbers of chromosomal abnormalities.34–37 Recently, one of three molecular pathways have been implicated in the pathogenesis of Sézary's syndrome; deregulation of cMYC expression, loss of TP53 and genome maintainance genes or changes in IL2 signaling pathway components.34 Amplification and increased transcription and expression of the JUNB gene has also been reported.38,39 JUNB is a member of the activator protein 1 (AP-1) transcription factor complex involved in cell ­proliferation and T-helper-2 cytokine production by T cells. Altered expression of this gene may explain the Th2-type functionality of the neoplastic lymphocytes in Sézary's syndrome and the down-regulation of genes involved in Th1 polari­ zation.39–41 Genomic differences between Sézary's syndrome and mycosis fungoides have recently been described, suggesting that these two entities may not be as closely related as previously thought.42,43 The term Sézary cell is synonymous with ‘mycosis cell’, ‘Lutzner cell’, and ‘cerebriform lymphocyte’.2 On electron microscopy, Sézary cells have characteristic hyperconvoluted (cerebriform) nuclei.44–46 They may be classified into three subtypes in peripheral blood smear according to size (Fig. 29.98):2 • small Sézary cells (Lutzner cells): 8–11 μm, • intermediate-sized Sézary cells: 11–14 μm, • very large Sézary cells: > 14 μm. Very large Sézary cells tend only to be seen in association with lymphoma where they correlate with a worse prognosis, but it is important to remember that circulating Sézary cells of small and intermediate size may be found in a number of benign conditions including contact dermatitis, atopic dermatitis, erythrodermic psoriasis, erythrodermic eczema, actinic reticuloid, and pseudolymphomatous drug reactions.2,47–49 They may even be found in the blood of healthy elderly people.50,51

Sézary's syndrome: peripheral blood smear showing large numbers of Sézary cells. By courtesy of the Institute of Dermatology, London, UK.

Diagnostic biopsies contain significant numbers of atypical lymphocytes with cerebriform nuclei (Sézary cells), although they are often in the minority.52,53 In 20–40% of cases these cells display epidermotropism and the histological features are similar to those seen in mycosis fungoides (Figs 29.99–101).6,52 In the remainder of diagnostic cases epidermotropism is absent and the lymphoid infiltrate assumes a perivascular or superficial dermal bandlike distribution.6,52 Uniform small lymphocytes often predominate but there are sufficient identifiable small, intermediate and/or large Sézary cells to permit a diagnosis of Sézary's syndrome, given the appropriate clinical setting. In a minority of nonepidermotropic cases the dermal infiltrate consists entirely of large atypical lymphocytes and the histological features are those of a large cell lymphoma.6,32,52 In one series, adnexal involvement was frequently seen and included follicular mucinosis in rare cases.32 Biopsies of patients with Sézary's syndrome are reported to show nonspecific and/or nondiagnostic features in around 40% of cases. Earlier studies using less precise diagnostic criteria may have included examples of benign erythroderma leading to an overestimate in the proportion of such cases. However, a significant proportion of cases lack diagnostic features even in more recent studies in which Sézary's syndrome was more stringently defined.4–6,52,53

Fig. 29.99 Sézary's syndrome: there is hyperkeratosis with acanthosis and a dense upper dermal lymphocytic infiltrate.

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Cutaneous lymphoproliferative diseases and related disorders Lymph nodes usually show features of dermatopathic lymphadenopathy but may show partial or complete effacement of the architecture by lymphoma. In contrast to mycosis fungoides, large transformed cells are not usually conspicuous.54,55 By immunohistochemistry, Sézary cells are typically CD2+, CD3+, CD4+, CD5+, CD8−, TCRαβ+, CLA+, CD45RO+ T cells.2,32,52 CD7 is commonly diminished or absent. CD2, CD3, and CD5 are sometimes lost.2 CD4−/CD8+ variants have been described and occasionally a CD4+/CD8+ phenotype is encountered. CD158 can be demonstrated on neoplastic cells if frozen tissue is available.56 Monoclonality may be demonstrated in skin biopsies of patients with Sézary's syndrome. Such finding is best regarded as significant particularly when an identical clone is demonstrated in peripheral blood.3,21,22

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders

Fig. 29.100 Sézary's syndrome: occasional atypical lymphocytes are present within both the epidermis and the dermis.

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders are collectively the second most common group of cutaneous T-cell lymphomas, accounting for approximately 30% of cases.1,2 This category comprises a spectrum of disease with overlapping histologic and immunophenotypic characteristics, and encompasses lymphomatoid papulosis at one end and primary cutaneous anaplastic lymphoma at the other.3 Clinical appearances and disease course are critical for determining the diagnosis. ‘Borderline’ is the term applied to cases in which the distinction between lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma cannot be readily made, usually because of a discrepancy between the clinical and pathological features.2,3 Cases of CD30-positive transformed mycosis fungoides are excluded, as are ALK-positive anaplastic large cell lymphoma and other CD30-positive large T- and B-cell lymphomas involving the skin.

Lymphomatoid papulosis Clinical features

Fig. 29.101 Sézary's syndrome: in this field, there are multiple Pautrier microabscesses.

In some studies, > 50% of biopsies show features that are not diagnostic of lymphoma. These include cases with a predominantly dermal infiltrate with few, if any, recognizable Sézary cells, as well as cases showing features consistent with chronic dermatitis.18–20,54,55 Occasional nondiscriminatory additional features in diagnostic and nondiagnostic biopsies include acanthosis, parakeratosis, spongiosis, basal layer damage, and dermal fibrosis. A mixture of inflammatory cells including histiocytes, eosinophils, neutrophils, and plasma cells is sometimes seen.6,52,53 The difficulty in arriving at a histological diagnosis has in part been attributed to a loss of epidermotropism in Sézary cells. It is speculated that this is due to accumulation of Th2-polarized neoplastic lymphocytes in the skin, resulting in reduced production of interferon-γ, leading to decreased production of interferon-γ inducible protein-10 and intracellular adhesion molecule-1 by keratinocytes.3 Topical treatment prior to biopsy and inadequate sampling may also contribute to the frequent lack of diagnostic features. However, even when both these criteria are satisfied, the diagnosis may remain elusive.

First described in 1968, lymphomatoid papulosis is a chronic, self-healing eruption.1 It is now classified as an indolent lymphoma in the new WHO classification. Lymphomatoid papulosis occurs more frequently in males (2:1). Patients are usually in their fifth decade, although a wide age range, including children, may be affected.2–6 The typical presentation is crops of erythematous papules, 0.5–1.0 cm across, which develop over the course of 3–4 weeks, become hemorrhagic and necrotic, and then heal, forming atrophic scars (Figs 29.102–29.104). The clinical features often overlap with those of pityriasis lichenoides acuta. Other lesions may be larger and nodular, and heal with deep varioliform scars. The condition commonly presents on the trunk and limbs, but occasionally other sites are involved. Numbers of lesions are variable, ranging from several to hundreds and take from a few weeks to several months to regress.7 Rare clinical variants have been described. In regional lymphomatoid papulosis, lesions are limited to one body region for years, and seem to be more common in children.8–11 Mucosal involvement is exceptional.12–15 Oral lesions present as recurring and spontaneously regressing painful ulcers, nodules or erythematous indurated plaques.13,15 Follicular and pustular variants have been described, as has a hydroa vacciniforme-like presentation in Japan.16–19 Pediatric and adolescent disease constitutes 6–10% of cases.3,4 The clinical presentation may be alarming, with the rapid development of large ulcerating lesions in addition to the usual papular eruption. However, the disease is otherwise typical.4,20–22 Lymphomatoid papulosis may run a short self-limiting course, or a more protracted course of 5–10 years or longer. Whatever the scenario, the outcome is generally benign, treatment only being required when lesions are particularly numerous and/or cosmetically disturbing.4 However, between 9% and 19% of cases are associated with another lymphoma, either mycosis fun­ goides, primary cutaneous anaplastic large cell lymphoma, or Hodgkin's lymphoma.3,23–29 The lymphoma may precede, arise concurrently with or succeed lymphomatoid papulosis.

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders

Fig. 29.102 Lymphomatoid papulosis: multiple small papules are present on the wrist and hand. By courtesy of R.A. Johnson, MD, Massachusetts General Hospital, Harvard Medical School, Boston, USA. Reproduced from Liu V. and McKee P.H. Cutaneous T-cell Lymphoproliferative disorders: approach for the surgical pathologist and clarification of confused issues. Advances in Anatomic Pathology. 2002, 9:79–100, with permission from Lippincott Williams & Wilkins.

Fig. 29.104 Lymphomatoid papulosis: in this example, lesions are present on the neck. By courtesy of the Institute of Dermatology, London, UK.

Fig. 29.105 Lymphomatoid papulosis: low-power view showing ulceration and a dense dermal infiltrate.

Fig. 29.103 Lymphomatoid papulosis: close-up view of erythematous papules. By courtesy of R.A. Johnson, MD, Massachusetts General Hospital, Harvard Medical School, Boston, USA.

Pathogenesis and histological features The pathogenesis remains undetermined. Most cases appear to represent clonal proliferations of T lymphocytes, more likely a T-regulatory cell subset.3,26,30–33 Recent studies have shown a high rate of apoptosis probably contributing to regression.34,35 This may be mediated by death-receptor pathway signaling via cell surface Fas (CD95) signaling and/or due to increased levels of the proapoptotic protein bax.3,34,36–39 An autocrine or paracrine growth control mechanism has been proposed, mediated by TGF-β secretion and signaling. Mutations of TGF-β signaling receptor genes results in disease progression.32,40,41 In cases of lymphomatoid papulosis associated with another lymphoma, a common clonal identity can often be demonstrated, suggesting a common stem cell giving rise to both.32,42–46 This theory, supported by cytogenetic findings, holds that different tumor cell phenotypes with distinct histopathologies and behaviors, arise from accumulated genetic alterations in subclones of a common, occult stem cell.32,42–45

The microscopic appearance of lymphomatoid papulosis varies, correlating with the age of the lesion biopsied. Three histological subtypes have been described.4,47,48 • Type A pattern (75–80% of cases) consists of a mixed, wedge-shaped dermal and rarely focally subcutaneous infiltrate containing large anaplastic cells (15–30 μm in diameter) with pleomorphic vesicular nuclei containing prominent nucleoli and abundant cytoplasm (Figs 29.105–29.109). These may be multinucleate, and can resemble Reed-Sternberg cells. Mitotic figures are frequent (Fig. 29.110). In established lesions these cells are scattered or arranged in small clusters, and admixed with neutrophils, eosinophils, plasma cells, lymphocytes, and histiocytes. Epidermotropism of large atypical cells is rare.3 • Type B pattern (5–10% of cases) has a preponderance of small to medium-sized lymphocytes with pleomorphic irregular and enlarged nuclei (Figs 29.111, 29.112). The infiltrate displays a bandlike distribution in the upper dermis. Epidermotropism is prominent and it simulates plaque stage mycosis fungoides, although Pautrier microabscesses, halos, and basal lymphocytic palisades are usually absent.7 • In type C pattern (7–10% of cases) the infiltrate is nodular with large clusters or cohesive sheets of type A cells with relatively few

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Cutaneous lymphoproliferative diseases and related disorders

Fig. 29.106

Fig. 29.109

Lymphomatoid papulosis: the epidermis is infiltrated by atypical pleomorphic lymphocytes.

Lymphomatoid papulosis: multiple mitotic figures are present.

Fig. 29.107

Fig. 29.110

Lymphomatoid papulosis: dense dermal infiltrate. Even at this magnification, the cytological atypia is obvious.

Fig. 29.108 Lymphomatoid papulosis: the lymphocytes have highly irregular hyperchromatic or vesicular nuclei. Note the background population of neutrophils.

Lymphomatoid papulosis: an atypical mitosis is seen just above the center of the field.

Fig. 29.111 Lymphomatoid papulosis: there is a dense infiltrate of type B cells.

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders

Fig. 29.112

Fig. 29.113

Lymphomatoid papulosis: the type B cells have enlarged, irregular hyperchromatic nuclei and scanty cytoplasm reminiscent of mycosis cells.

Lymphomatoid papulosis: numerous CD30+ cells are present.

inflammatory cells. The features may be identical to those seen in primary cutaneous anaplastic large cell lymphoma and the two processes are only distinguished on the basis of clinical features.4 Recently, an epidermotropic CD8-positive variant of lymphomatoid pap­ ulosis that can mimic primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma has been described.48a This variant has been proposed as lymphomatoid papulosis type D. It should be noted that not all cases of lymphomatoid papulosis neatly subclassify into the variants described above. In up to 10% of cases there are overlapping features of two or more subtypes within a single lesion, and lesions displaying different patterns may be present at different sites and/or times within a single patient.3,47,48 Other features are common to all of the subtypes. Dermal edema and hemorrhage are often conspicuous. Some vessels may show fibrin deposition and occlusion. Reactive epidermal changes are variable, depending on the stage of evolution of the papule. Early lesions show intercellular edema and occasional intraepidermal lymphocytes. Intermediate lesions are characterized by variable necrosis of keratinocytes, intercellular edema, and intraepidermal cells, many of which are atypical. Intraepidermal polymorphs and erythrocytes are commonly found. Late lesions are characterized by extensive epidermal necrosis, ulceration, and the formation of a scaly, parakeratotic crust. Occasionally, there is striking pseudoepitheliomatous hyperplasia such that misdiagnosis as a squamous cell carcinoma or keratoacanthoma may result.49 Rare histological patterns described include a myxoid variant with a sarcoma-like appearance, a folliculotropic pattern with follicular mucinosis, and a syringotropic example.3,50–54 Angiocentric and angiodestructive lymphomatoid papulosis may occur.55,56 In all histological patterns the atypical lymphoid cells express the cutaneous lymphocyte antigen and are usually CD4+ and CD8−, although occasionally CD4−/CD8+, CD4−/CD8− and CD4+/CD8+ variants are encountered.3,57 Cytotoxic molecules, such as TIA-1, are usually identifiable, irrespective of the CD4/CD8 status.3,58 There is variable expression of the pan-T-cell antigens, CD2, CD3, CD5, and CD7.4 The anaplastic cells in the types A and C variants express CD45 and CD30, but not CD15, epithelial membrane antigen (EMA) or p80/ALK1: reactivity with CD25 may also be seen (Fig. 29.113).42,59–65 Conversely, in type B lesions, CD30 is often, although not always, negative.3,31 Although earlier studies suggested an absence of CD56, more recently expression of this molecule has frequently been seen.3,64,65 In general, tumors of natural killer (NK)/T cell are generally associated with a very poor prognosis, but this does not appear to be the case in lymphomatoid papulosis. Most cases (75–80%) of lymphomatoid papulosis are also positive for MUM1, and it has been proposed as a useful marker for distinguishing between lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. However, whilst the incidence of positivity was significantly different in one study, MUM1 was not found to be discriminatory in another.65,66

TCR gene rearrangements are detected in approximately 60% of cases.3,26,30,31,42

Differential diagnosis Expression of CD30 is not a reliable discriminator for differentiating cutaneous CD30+ T-cell lymphoproliferative disorders from reactive inflammatory skin conditions or other types of lymphoma. An increasing number of infectious skin diseases have been shown to contain significant numbers of CD30+ cells and mimic lymphomatoid papulosis. These include cutaneous lesions in various viral infections, including herpes virus, molluscum contagiosum, parapox virus (milker's nodule), Epstein-Barr virus, HTLV1, and HIV.62,67–73 Lesions of scabies, syphilis, and superficial fungal infections may also contain CD30+ cells.62,74,75 Noninfectious cutaneous inflammatory processes, such as pityriais lichenoides et varioliformis acuta, atopic dermatitis, and drug reactions (particularly to anticonvulsants) may also harbor CD30+ cells.60,76–79 Cutaneous eruption of lymphocyte recovery may also contain CD30+ cells.62,80 In most of these disorders the CD30+ cells lack the anaplastic features and are present in fewer numbers than in lymphomatoid papulosis. They also tend to be scattered, rather than in small clusters but this is not always the case.62 However, close clinicopathological correlation remains essential. Type B lymphomatoid papulosis displaying epidermotropism may be impossible to distinguish from mycosis fungoides or a lymphomatoid drug reaction, and in this situation clinical correlation is essential.

Primary cutaneous anaplastic large cell lymphoma Primary cutaneous anaplastic large cell lymphoma is a tumor composed of at least 75% of CD30-positive T cells.1,2 These latter may display anaplastic, pleomorphic or immunoblastic morphology, and the outcome is similar irrespective of histologic subtype, and hence the name ‘CD30-positive cutaneous large T-cell lymphoma’ previously preferred by the EORTC.1,3,4 It has an excellent prognosis, particularly when compared to other CD30-positive large cell lymphomas involving the skin. The latter include transformed lymphomatoid papulosis and mycosis fungoides, as well as nodal/systemic ALK-positive and ALK-negative anaplastic large cell lymphoma with cutaneous dissemination. Primary cutaneous CD30-negative large cell lymphomas are also excluded from this category because of their much more aggressive behavior and poorer prognosis.1,4,5

Clinical features Primary cutaneous anaplastic large cell lymphoma occurs mainly in the seventh decade. Although a wide age range may be affected, childhood cases are rare and, unlike systemic anaplastic large cell lymphoma, there is no bimodal age

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Cutaneous lymphoproliferative diseases and related disorders distribution.6–9 There is male predilection. Most cases (approximately 80%) present with a solitary erythematous or violaceous, often ulcerated nodule or group of nodules/papules restricted to a single region (Figs 29.114, 29.115). The extremities are particularly involved. Multifocal disease, defined as two or more lesions at multiple anatomic sites, is seen in around 20% of cases (Fig. 29.116).1–6 Clinical behavior varies: 42% of lesions are associated with partial or complete regression; such variants were described as ‘regressing atypical histiocytosis’ in the older literature.6,10–12 A further 42% are associated with one or more recurrences but only 10–20% are associated with extracutaneous (generally nodal) spread.6 There does not, however, appear to be any significant difference in behavior between those that are confined to the skin and those that spread to one draining lymph node region.6 The 5- and 10-year diseaserelated survival ranges from 91% to 96% for patients with primary disease (depending on whether or not there is concomitant lymph node involvement) compared with 24% for patients with secondary cutaneous involvement by nodal CD30-positive large T-cell lymphoma.6 Risk factors for tumor progression are unknown.6 Fig. 29.116 Primary cutaneous anaplastic large cell lymphoma: multiple lesions affecting different regions are present in this patient. By courtesy of the late N.P. Smith, MD, Institute of Dermatology, London, UK.

Pathogenesis and histological features

Fig. 29.114 Primary cutaneous anaplastic large cell lymphoma: erythematous, ulcerated tumor nodule on the forehead. By courtesy of the Institute of Dermatology, London, UK.

Fig. 29.115 Primary cutaneous anaplastic large cell lymphoma: ulcerated facial nodule. By courtesy of R.A. Johnson, MD, Massachusetts General Hospital, Harvard Medical School, Boston, USA. Reproduced from Liu V. and McKee P.H. Cutaneous T-cell Lymphoproliferative disorders: approach for the surgical pathologist and clarification of confused issues. Advances in Anatomic Pathology. 2002, 9:79– 100, with permission from Lippincott Williams & Wilkins.

Primary cutaneous anaplastic large cell lymphoma is a neoplasm of activated skin-homing T-lymphocytes which appear to show a Th2-type bias of cytokine production.13–15 They have clonally rearranged T-cell receptor genes but are deficient in T-cell receptor and T-cell receptor associated proximal signaling molecules.16 The pathogenesis is unknown.17–22 Consistent cytogenetic abnormalities have been identified and a variety of oncogenes implicated, including JUNB, but specific mechanisms of tumor development have yet to be elucidated.23–25 As with lymphomatoid papulosis, it is possible that expression of the proapoptotic protein bax and/or death-receptor (CD95) signaling may contribute to the spontaneous regression of some cases and the generally favorable outcome.26,27 Primary cutaneous anaplastic large cell lymphomas typically lack the t(2;5) (p23;q35) and resulting overexpression of the NPM-ALK fusion protein normally associated with this translocation.28 Although rare positive cases are documented, some of these may be false-positive results in view of the considerable cross-reactivity of the p80 antibody used to detect the fusion protein and/or the molecular techniques employed to demonstrate the translocation.28 It is possible that some examples represent systemic anaplastic large cell lymphoma presenting primarily in the skin which, if followed, will exhibit early extracutaneous dissemination.29 In addition, cases of primary cutaneous anaplastic large cell lymphoma displaying cytoplasmic ALK expression but lacking evidence of an underlying genetic abnormality are noted.30,31 Thus, even if bona fide cases of ALK-positive primary cutaneous anaplastic large cell lymphoma do exist, they are currently best excluded from this category until there is sufficient information to better understand their biology and predict their behavior (Fig. 29.117). In contrast to lymphomatoid papulosis where the infiltrate is largely restricted to the dermis, in primary cutaneous large cell lymphoma, the tumor (which is often ulcerated) commonly extends into the subcutaneous fat or deeper tissues. Rare cases confined to the subcutis have also been reported and occasionally an angiodestructive growth pattern is evident.32–34 A number of histological variants are recognized, with a similar spectrum of appearances to that seen in systemic ALK-positive anaplastic large cell lymphoma.32,35–37 Most commonly, the tumor cells display an anaplastic morphology with abundant cytoplasm and pleomorphic vesicular nuclei with clumped heterochromatin and prominent nucleoli (Figs 29.118–29.121). Some cells may show cytoplasmic vacuolation and even assume a signet ring appearance.32 Bizarre forms are common and include multinucleated giant cells resembling Reed-Sternberg cells, as well as cells with nuclei arranged in wreath configurations (Fig. 29.122). Lymphophagocytosis may be seen (Fig.29.123). Mitoses including atypical forms are common (Fig.29.124).

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders

Fig. 29.117

Fig. 29.119

Secondary cutaneous anaplastic large cell lymphoma: this example of metastatic disease is ALK positive.

Primary cutaneous anaplastic large cell lymphoma: the tumor is composed of anaplastic cells with vesicular nuclei containing prominent eosinophilic nucleoli.

Fig. 29.118 Primary cutaneous anaplastic large cell lymphoma: low-power view showing the superficial part of a large tumor nodule.

Less often, tumor cells have a pleomorphic or immunoblastic appearance. Small cell (pleomorphic) variants may resemble tumor stage mycosis fungoides, and are rare (Figs 29.125, 29.126).32 They are characterized by an infiltrate of atypical hyperchromatic and only weakly CD30+ cerebriform T-lymphocytes with much smaller numbers of anaplastic large cells and inflammatory cells.4,32,38,39 Rarely, the tumor cells may have a pleomorphic spindle cell morphology, myxoid stroma or a storiform growth pattern, mimicking a sarcoma.40,41 The tumor cells grow in large nests or diffuse sheets (occasionally leading to a mistaken diagnosis of metastatic carcinoma or melanoma) commonly showing areas of necrosis (Figs 29.127, 29.128). Epidermotropism is often absent but may be seen in up to 40% of cases.32 Pseudoepitheliomatous hyperplasia may be marked, closely mimicking malignancy, especially in small biopsies.4,32,42 Inflammatory cells including neutrophils, eosinophils, histiocytes, lymphocytes, and plasma cells are frequent (Figs 29.129, 29.130). Rarely,

Fig. 29.120 Primary cutaneous anaplastic large cell lymphoma: the tumor cells have abundant ill-defined amphophilic cytoplasm and vesicular nuclei.

neutrophils are so conspicuous that an inflammatory process such as a pustular/infective dermatosis may initially be suspected (neutrophil-rich variant, pyogenic lymphoma).32,43,44 It has been suggested that the intense neutrophil infiltrates result from IL-8 production by the tumor cells.45 In other cases, large numbers of eosinophils are present and may represent the disease described as eosinophilic histiocytosis.32,46,47 A lymphohistiocytic variant characterized by the presence of numerous histiocytes, which may display hemophagocytosis, has also been described.32,48 By definition, 75% or more of the tumor cells express membranous and Golgi CD30 (Ber-H2/Ki-1) (Fig. 29.131). Most cases display an activated CD4+ T-cell phenotype although occasionally CD8+ or null cell variants are encountered (Fig. 29.132). There is variable loss of various pan-T-cell antigens. The majority of cells express cytotoxic molecules TIA-1, perforin or granzyme B.2,49,50 CD25, CD71, and HLA-DR are also usually present.51 CD15 is typically absent. In contrast to primary nodal variants, EMA is almost invariably absent in primary cutaneous lesions although it may sometimes

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Cutaneous lymphoproliferative diseases and related disorders

Fig. 29.121

Fig. 29.124

Primary cutaneous anaplastic large cell lymphoma: in this example single, central basophilic nucleoli are conspicuous.

Primary cutaneous anaplastic large cell lymphoma: abnormal mitoses are present.

Fig. 29.122

Fig. 29.125

Primary cutaneous anaplastic large cell lymphoma: note the anaplastic multinucleated tumor cells.

Primary cutaneous anaplastic large cell lymphoma: small cell variant characterized by a uniform population of tumor cells with hyperchromatic nuclei.

Fig. 29.123

Fig. 29.126

Primary cutaneous anaplastic large cell lymphoma: the tumor giant cells show lymphophagocytosis

Primary cutaneous anaplastic large cell lymphoma: small cell variant. The nuclei are darkly staining and cytoplasm is minimal

Primary cutaneous CD30-positive T-cell lymphoproliferative disorders

Fig. 29.127

Fig. 29.130

Primary cutaneous anaplastic large cell lymphoma: in some lesions, the tumor cells grow in cohesive cords such that a carcinoma may first be suspected.

Primary cutaneous anaplastic large cell lymphoma: numerous eosinophils are present in this example.

Fig. 29.128

Fig. 29.131

Primary cutaneous anaplastic large cell lymphoma: widespread necrosis is present.

Primary cutaneous anaplastic large cell lymphoma: the tumor cells are uniformly CD30 positive.

Fig. 29.129

Fig. 29.132

Primary cutaneous anaplastic large cell lymphoma: abundant histiocytes as shown in this field account for misdiagnosis as inflammatory malignant fibrous histiocytoma.

Primary cutaneous anaplastic large cell lymphoma: the cells coexpress CD4 (same case as Fig. 29.131).

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Cutaneous lymphoproliferative diseases and related disorders provisional entity.3,4 It is defined as a neoplasm of small to medium-sized CD4-positive pleomorphic T-cells in patients lacking patches or plaques typical for mycosis fungoides.3 It is rare, accounting for approximately 2% of all primary cutaneous T-cell lymphomas.4 Females appear to be affected more than males.5,6 The age range is wide, but almost all patients are adults with a median age at presentation in the sixth decade.5–9 The majority of patients present with solitary or localized asymptomatic, erythematous to purple papulonodules or plaques, particularly on the head and neck and upper trunk.3,5–7,10,11 A minority of patients present with large tumors or multiple lesions.5,10,11 The prognosis is good, with a 5-year survival of around 80%.3 Patients with solitary or localized lesions at presentation have the best outcome.5,6,11 Those with multiple lesions/large tumors run a more aggressive clinical course.5,6,10,11

Histological features

Fig. 29.133 Cutaneous anaplastic large cell lymphoma: in this example the tumor cells express epithelial membrane antigen. This case proved to represent a metastasis from a nodal primary lesion.

be evident in children (Fig. 29.133). Staining for ALK1 is also usually negative (see above).7 Spindle cell variants may express smooth muscle actin.41 Fascin is expressed in up to 64% of cases of CD30-positive anaplastic large cell lymphoma, compared with only 24% of cases of lymphomatoid papulosis.52 Occasional CD56+ tumors have been documented, but this does not appear to be associated with prognosis.53–55 MUM1 may also be expressed but the true incidence of this marker and its usefulness for distinguishing primary cutaneous anaplastic large cell lymphoma from lymphomatoid papulosis remains to be determined.56,57

Differential diagnosis Clinical correlation is essential in differentiating primary cutaneous anaplastic large cell lymphoma from other CD30+ large cell lymphomas that may arise in, or disseminate to, the skin. The clinical appearance of lesions and course of disease are the only reliable discriminants of primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis types A and C. Primary cutaneous anaplastic large cell lymphoma may also be indistinguishable from transformed CD30+ mycosis fungoides, and this possibility should always be excluded by careful clinicopathologic correlation. Staging, including CT of chest and abdomen and bone examination, is essential in excluding dissemination of nodal CD30+ large T-cell lymphomas, such as ALK+ and ALK- anaplastic large cell lymphoma and some examples of peripheral T-cell lymphoma, unspecified.6 Immunohistochemistry and genetic analysis may facilitate distinction from nodal ALK+ anaplastic large cell lymphoma, with the above caveats. Immunohistochemistry will also permit distinction from rare cases of CD30+ large B-cell lymphoma involving the skin, and will facilitate distinction of spindle cell variants from spindle cell carcinoma, spindle cell melanoma, dermal sarcomas, inflammatory pseudotumor, follicular dendritic cell sarcoma, dendritic reticulum cell sarcoma, and spindle cell leukemic infiltrates.41,58,59 Inflammatory conditions containing CD30+ cells are more likely to be mistaken for lymphomatoid papulosis than cutaneous anaplastic large cell lymphoma.

Primary cutaneous CD4-positive small/ medium T-cell lymphoma Clinical features Although this variant was recognized in the EORTC classification, it was not included in the original WHO classification.1,2 This omission has been rectified in the combined EORTC−WHO classification, although primary cutaneous CD4-positive small/medium T-cell lymphoma is still considered a

Histologically, the tumor is composed of a fairly uniform population of small to medium-sized lymphocytes with pale scanty cytoplasm and hyperchromatic irregular noncerebriform nuclei in a perivascular, bandlike, nodular or diffuse fashion, often involving the entire dermis and sometimes extending into the subcutis (Figs 29.134, 29.135).5,7,10,11 By definition, large cells make up less than 30% of the population.3,6 Mitotic figures are rare and epidermotropism is absent, or focal (Fig. 29.136).5–7,11–13 Folliculotropism is exceptional.8 Lymphocytes, neutrophils, eosinophils, and plasma cells may sometimes be present and rarely there is a granulomatous component. Tumor cells have a T-helper phenotype and there may be loss of CD7 and CD2 (Fig. 29.137).6,7,11,12 CD30 is negative. Cytotoxic molecules and EBV are negative.5 It has been proposed that the neoplastic lymphocytes show features of follicular T-helper cells, since a proportion of tumor cells ( 50 years.7,12–14 Clinically, there are firm, erythematous to violaceous plaques, nodules and/or tumors of variable but sometimes large size. The vast majority of cases (≈ 80%) present with solitary or localized lesions, multifocal lesions being rare.1,2,8,13 There is predilection for the head and neck, particularly the scalp, and trunk; rare cases occur on the legs.1,2,6,8,,11,13–16 Disease should be limited to the skin at presentation in order to qualify as PCFCL. Radiotherapy is the treatment of choice for solitary or localized lesions, and rituximab is used for more generalized disease.17 Cutaneous relapses are frequent (≈ 30% of cases). The overall prognosis is excellent with a 5-year survival of > 95%. Systemic combination chemotherapy is rarely required, when there is very extensive cutaneous disease, rare examples associated with systemic dissemination, and possibly also for cases arising on the leg, since the latter appear to have a less favorable prognosis.2,6,8,15,17

a more sensitive technique. However, this is still at a much lower frequency (i.e., 41%) than seen in nodal follicular lymphoma, and the fact that many FISH-positive cases are PCR negative suggests that different pathogenetic mechanisms are at work in many PCFCLs.27,28 A t(3;14)(q27;q32) has also been documented in a small number of cases.27 The infiltrate shows a perivascular and periadnexal distribution, but may diffusely fill the dermis. The majority of cases lack follicles (64%), but some show a follicular and diffuse pattern of growth or, less commonly, a purely follicular architecture.1–3,14,29 The neoplastic lymphocytes are predominantly medium to large centrocytes, or centroblasts (Figs 29.200–29.203). Centrocytes have angulate, twisted or cleaved nuclei with inconspicuous nucleoli and scant cytoplasm; centroblasts have round or oval nuclei with vesicular chromatin, with one to three nucleoli and a narrow rim of

Pathogenesis and histopathological features The neoplastic lymphocytes are of follicle center origin. Gene expression profiling studies show a pattern similar to that seen in diffuse large B-cell lymphoma of germinal center type, and there is frequent amplification of c-REL.17–20 Follicular lymphoma, which arises predominantly in lymph nodes, is another neoplasm of follicle center cells, and is characterized by a t(14;18) (q32;q21) juxtaposing the BCL2 gene with the immunoglobulin heavy chain.21 This translocation is seen in around 90% of cases of nodal follicular lymphoma, but PCR-based assays fail to identify it in only a relatively low proportion of PCFCL.4–6,10,15,22–26 A higher incidence of t(14;18)(q32;q21) is seen in series of PCFCL studied by fluorescence in situ ­hybridization (FISH),

Fig. 29.199 Primary cutaneous follicle center lymphoma: presentation on the back was once known as reticulohistiocytoma of the dorsum (Crosti's lymphoma). Note the aggregate of erythematous tumor nodules. By courtesy of the Institute of Dermatology, London, UK.

Fig. 29.200 Primary cutaneous follicle center lymphoma: there is a dense nodular infiltrate with a distinctive follicular pattern. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Fig. 20.201 Primary cutaneous follicle center lymphoma: note the conspicuous tumor follicles. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

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Fig. 29.202

Fig. 29.204

Primary cutaneous follicle center lymphoma: the follicles are composed of a uniform population of tumor cells. Note the mitoses. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Primary cutaneous follicle center lymphoma: the tumor cells express CD20. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Fig. 29.205 Fig. 29.203 Primary cutaneous follicle center lymphoma: the tumor consists of centrocytes with irregular, hyperchromatic nuclei. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

­cytoplasm. Follicles have a monotonous appearance, generally have few tingible body macrophages, and show no differentiation into light and dark zones. Mantles are either absent or only poorly formed. Aggregates of neoplastic follicle center cells are present in the interfollicular areas.4,6,14 Cases with a predominantly diffuse growth pattern contain a majority of large centrocytes with scattered polylobated cells and few centroblasts.3,9,12,14,29 A spindle cell morphology is exceptional.30,31 The neoplastic lymphocytes show consistent expression of CD20 and bcl-6 (Figs 29.204, 29.205). CD10 expression varies. It is usually present when follicles are prominent, but negative in cases with a diffuse growth pattern (Fig. 29.206).2,8,15,28,32,33 Staining for bcl-2 is often negative. Although some studies report positive staining in a high percentage of cases, bcl-2 is usually expressed at a lower level than seen in admixed reactive T cells.2,4,6,8,23,27,33,34,35 Strong positivity for both CD10 and bcl-2 should raise suspicion of secondary cutaneous involvement by nodal follicular lymphoma. Staining for CD5 and cyclin D1 is negative and there is rare expression of CD23, MUM1 or FOXP1 (Fig. 29.207).4,10,11,14,32 The expanded follicular nodules can be highlighted with CD21, which can be negative in diffuse lesions (Fig. 29.208).20,32

Primary cutaneous follicle center lymphoma: the tumor cells are bcl-6 positive. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Fig. 29.206 Primary cutaneous follicle center lymphoma: in this example, CD10 is strongly expressed.

Primary cutaneous diffuse large B-cell lymphoma, leg type

Fig. 29.207

Fig. 29.209

Primary cutaneous follicle center lymphoma: CD5 is absent. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Primary cutaneous follicle center lymphoma: this high-grade lesion shows very brisk proliferative activity with MIB-1. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

dark zones, tend to have higher numbers of mitotic figures and tingible body macrophages, and contain a higher proportion of centroblasts and immunoblasts.36 However, in the skin, reactive follicles may lack mantles, especially when associated with B. burgdorferi infection.15,37 Immunohistochemical demonstration of bcl-2 in the follicle center cells confirms a diagnosis of lymphoma. Neoplastic follicles often have a low proliferation fraction compared with reactive follicles, and staining for Ki-67 may also highlight the presence of zonation in the latter. However, bcl-2 expression is often weak or negative in PCFCL and cases composed predominantly of large cells may display a high proliferation fraction (Fig. 29.209). In such situations, a careful search for CD10 and/or bcl-6 positive interfollicular cells is necessary; extrafollicular CD10 B-cells are only seen in lymphoma and are not a feature of reactive lymphoid tissue. Mantle cell lymphoma can be distinguished from PCFCL by the ­expression of CD5 and cyclin D1 in the former.

Fig. 29.208 Primary cutaneous follicle center lymphoma: the tumor follicles are highlighted with CD21 immunohistochemistry. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Clonality may be confirmed by light chain restriction (although this is often difficult due to low levels of surface immunoglobulin expression), IgH gene rearrangement or, in some cases, by the presence of the t(14;18) translocation.32

Differential diagnosis Primary cutaneous follicle center lymphoma with a diffuse growth pattern is usually composed of large cells and is not easily mistaken for reactive conditions. However, cases with a follicular growth pattern may be difficult to differentiate from B-cutaneous lymphoid hyperplasia (B-CLH). It is not possible to reliably discriminate B-CLH from PCFCL on the basis of the architectural features at scanning magnification.36 Determining whether the lymphoid follicles are reactive or neoplastic is the main way of making this distinction. Neoplastic follicles typically have a monotonous appearance, lack well-formed mantles, show no differentiation into light and dark zones, and have relatively few tingible body macrophages. PCFCL are also composed predominantly of large centrocytes. By comparison, reactive follicles usually show differentiation into light and

Primary cutaneous diffuse large B-cell lymphoma, leg type Clinical features The controversial entity of large B-cell lymphoma of the leg, proposed in the original EORTC classification, has gained general acceptance following an increasing number of publications associating location in the lower limb with poor outcome in primary cutaneous lymphomas composed of large B cells.1–5 However, lymphomas displaying similar clinicopathological features also occur above the waist and this has led to the use of the less anatomically restricted term of primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT).6,7 PCDLBCL-LT accounts for around 20% of all PCBCLs.6,8 Most patients are elderly females (male to female ratio 1:3.4), with a median age at presentation > 70 years.7–11 Presentation is usually with multiple red or bluish-red nodules or tumors and, less commonly, deeply infiltrated plaques, subcutaneous tumors, and ulcers.2,4,5,7,9–11 Solitary lesions are relatively infrequent. About 10–15% of cases present at a site different from the leg (trunk, upper limbs, and head and neck).7–11 Multifocal disease is seen in 5–20% of cases.8,9,11 The recommended treatment is as for systemic diffuse large B-cell lymphoma (DLBCL).12 Relapses and extracutaneous dissemination, to lymph nodes and/ or viscera, are common (55–69% and 17–47% of patients, respectively), with relatively frequent CNS involvement.8,9,11 The 5-year ­disease-­specific survival is approximately 50%.2,4,8,10,11 Multiple lesions at diagnosis is a poor ­prognostic indicator.

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Pathogenesis and histological features Primary cutaneous diffuse large B-cell lymphoma is a tumor of postgerminal center B cells that displays a gene expression profile similar to that seen in activated B-cell-like DLBCL, as well as one that suggests constitutive activation and inhibition of the intrinsic apoptosis pathway.13,14 t(14;18)(q32;q21) is not present but there is a high incidence of translocations involving c-MYC, BCL6, and IGH.15,16 In addition, more than half of cases show amplifications of 18q21.31-q21.33, a region encompassing the BCL2 and MALT1 genes, providing an explanation for the high levels of bcl-2 expression seen in this neoplasm. Loss of 9p21.3, harboring the CDKN2A gene encoding p16 and p14ARF, or inactivation by promoter hypermethylation, is also common and may be a poor prognostic indicator.17–19 Biopsies show a diffuse dermal infiltrate composed of sheets of centroblasts and immunoblasts that effaces adnexal structures (Figs 29.210–212). A grenz zone is present and ulceration may be seen. Centroblasts have little

Fig. 29.212 Primary cutaneous diffuse large B-cell lymphoma, leg type: the tumor is composed of an admixture of centroblasts and immunoblasts. Note the mitotic activity.

cytoplasm and round to oval vesicular nuclei typically containing multiple small nucleoli dispersed adjacent to the nuclear membrane. Immunoblasts have more abundant basophilic cytoplasm and the nucleus contains a single large eosinophilic nucleolus. Mitotic figures are plentiful. A few reactive T cells are present.2,4,6–8,11 Tumor cells express CD20 and CD79A, and are almost always strongly positive for bcl-2, MUM1/IRF4, and FOXP1, although negative staining for bcl-2 and MUM1/IRF4 is reported in up to 10% of cases (Fig. 29.213).5,8,10,14,20–22 Staining for bcl-6 is usually positive and CD10 is negative (Fig. 29.214).5,8,22

Differential diagnosis

Fig. 29.210 Primary cutaneous diffuse large B-cell lymphoma, leg type: there is a dense dermal infiltrate which, in this case, abuts the overlying epithelium.

Primary cutaneous diffuse large B-cell lymphoma must be differentiated from DLBCL secondarily involving this skin, which is done by staging, and PCFCL. PCFCL and PCDLBCL-LT are primarily distinguished on the basis of cell morphology, the former containing a predominance of cleaved cells and the latter diffuse sheets of round cells. However, distinction is difficult and is subject to interobserver variation.2 Other factors that suggest a diagnosis of PCFCL are the presence of a significant admixture of T cells, a stromal reaction, and remnants of follicular dendritic cell networks, as demonstrated by antibodies to CD21, CD23 and/or CD35. Strong staining for bcl-2, MUM1, and FOXP1 favors a diagnosis of PCDLBCL-LT.8

Fig. 29.211

Fig. 29.213

Primary cutaneous diffuse large B-cell lymphoma, leg type: the tumor extends into subcutaneous fat.

Primary cutaneous diffuse large B-cell lymphoma, leg type: the tumor cells show uniform expression of CD20.

Mantle cell lymphoma

Mantle cell lymphoma Clinical features

Fig. 29.214 Primary cutaneous diffuse large B-cell lymphoma, leg type: bcl-6 is strongly expressed.

Primary cutaneous diffuse large B-cell lymphoma, other Primary cutaneous diffuse large B-cell lymphoma, other (PCDLBCL-O) was a term introduced in the original EORTC–WHO classification.1 It was used for rare cases of large B-cell lymphoma arising in the skin that could not be comfortably categorized as primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) or primary cutaneous follicle center lymphoma (PCFCL). It was suggested that it would include variants of DLBCL that usually represent a skin manifestation of a systemic lymphoma, such as plasmablastic lymphoma or T-cell/histiocyte-rich large B-cell lymphoma. This approach was slightly modified in the WHO classification of skin tumors published in 2006. In this text, both T-cell/histiocyte-rich large B-cell lymphoma and plasmablastic lymphoma are considered separate from PCDLBCL-O.2 PCDLBCL-O is largely restricted to lymphomas showing features typical of PDLBCL-LT but lacking bcl-2 expression.2 However, recent publications suggest no significant clinical differences between bcl-2-positive and bcl-2negative PCDLBCL-LT, and several authors accept the latter as part of the spectrum of PCDLBCL-LT.3,4 Plasmablastic lymphoma is discussed below as an example of a systemic lymphoma that may present in the skin. T-cell/histiocyte-rich large B-cell lymphoma arising primarily in the skin is exceedingly rare and characterized by scattered large neoplastic B cells with a background of numerous (> 90%) reactive T cells. Clinically, such cases show similarities with PCFCL and PCMZL and may merely represent an exaggerated T-cell infiltrate in association with other, specific forms of PCBCL. Cutaneous T-cell/histiocyte-rich large B-cell lymphoma does not appear to be related to the nodal form of the disease, which is much more aggressive.5–8 PCDLBCL-O is therefore not an entity, but a holding category into which large B-cell tumors can be placed until such time as the diagnosis becomes obvious, or future studies clarify gray areas in the current classification system. In view of its apparent poor prognosis, PCFCL arising on the leg might be viewed in such a light.

Secondary cutaneous involvement by B-cell lymphoma The following lymphomas not infrequently involve the skin. Cutaneous lesions may be the presenting feature, and in some cases disease may remain con­ fined to the skin for lengthy periods. However, such tumors are no different from morphologically identical neoplasms that disseminate to the skin during relapse and/or progression.

Mantle cell lymphoma (mantle zone lymphoma, centrocytic lymphoma, lymphocytic lymphoma of intermediate grade) (MCL) is a rare peripheral B-cell lymphoma thought to be derived from naive pregerminal center B cells of the inner mantle zone.1 It accounts for approximately 3–10% of non-Hodgkin's lymphoma subtypes.2 It is more common in old adults (median 60 years) with predilection for males (2:1 – 4:1).1,3,4 MCL is a nodal disease that frequently disseminates to extranodal sites. Most cases are advanced stage (stage III or IV) at diagnosis. Generalized lymphadenopathy is the most frequent presentation (87–90%). Infiltration of bone marrow (80%), spleen (47–60%), and liver (13%) is frequent. The gastrointestinal tract (18–20%) and Waldeyer's ring (10–12%) are also often affected and most cases of lymphomatous polyposis of the intestine are due to this lymphoma. Neoplastic lymphocytes are typically found in peripheral blood using flow cytometry, and rarely there may be a leukemic picture.5–8 ‘B’ symptoms (clinical symptoms of pyrexia (sometimes periodic), weight loss, and night sweats) are present in 14% to 40% of patients.3,4Anemia, low serum albumin, raised lactate dehydrogenase and β2-microglobulin levels are common.3,4 Cutaneous involvement is exceptional, and although MCL may present in the skin, it is almost invariably associated with systemic disease.9–13 Presentation is with erythematous nodules or tumors on the trunk or extremities, although indurated plaques, macules, and a maculopapular rash may occur.9–12 It can also be associated with cutaneous paraneoplastic phenomena. Several cases of insect bitelike reactions, similar to those more commonly seen in B-chronic lymphocytic leukemia, have been described. These manifest as a polymorphous rash comprising multiple pruritic, erythematous papules, nodules, plaques and/or vesicles, that usually precede, but may follow, the diagnosis of lymphoma.14–18 Hypersensitivity reactions to mosquito bites, similar to those seen in association with NK/T-cell lymphomas, have also been described.19,20 The median survival is only of 3–5 years.1,21 The most consistent prognostic indicators are a high mitotic or Ki-67 index and a blastoid or pleomorphic morphology.1,7,8,22,23

Pathogenesis and histopathological features Mantle cell lymphoma is associated with a t(11;14)(q13;q32) translocation in most cases.1,3,4,24–26 This results in dysregulation of the PRAD1/CCND1 gene with overexpression of cyclin D1, a protein that is critical to cell cycle regulation.27,28 A variant translocation involving CCND1 and light chain genes may also occur.29 Most cases also contain a high number of nonrandom secondary chromosomal aberrations, some of which correlate with more aggressive behavior.30–32 A subset of mantle cell lymphomas lack t(11;14)(q13;q32) and do not overexpress cyclin D1. These cases show identical morphologic and clinical features as cyclin D1-positive cases and share the same gene expression profile, except that they express high levels of cyclin D2 or cyclin D3. Some have a t(2;12)(p12;p13) juxtaposing the cyclin D2 gene with the immunoglobulin lambda light chain gene.33,34 Immunoglobulin light and heavy chain genes are rearranged in many cases, but the V regions are either ­unmutated or show only low levels of somatic hypermutation.35,36 Nodal tumors may show a nodular, diffuse or mixed growth pattern.1–3,5,37,38 In nodular variants, the nodules represent reactive follicles with a surrounding rim of tumor cells (mantle zone pattern) or are composed of a pure tumor cell population.37,38 The infiltrate usually consists of a monomorphic population of small to medium-sized atypical lymphoid cells with irregular, hyperchromatic nuclei, inconspicuous nucleoli and minimal cytoplasm.1,3 Morphologic variants include blastoid, pleomorphic, small cell, and marginal zonelike. In blastoid MCL, the cells are uniformly of intermediate to large size with a lymphoblast-like appearance. They have dispersed chromatin and a very high mitotic index (20–30/10 high-power fields). Pleomorphic MCL also comprises large cells, but these often have irregular nuclear outlines and prominent nucleoli. The neoplastic lymphocytes in the small cell variant resemble those seen in small lymphocytic lymphoma, whilst the marginal zonelike cases have abundant pale cytoplasm.1 Tumors may transform to a more aggressive variant with recurrence.4 Hyalinized vessels, a background population of polyclonal plasma cells, and histiocytes are often seen.1,3

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Cutaneous lymphoproliferative diseases and related disorders Cutaneous lesions vary from superficial perivascular to nodular or ­diffuse dermal/subcutaneous monomorphic infiltrates (Figs 29.215–29.217).9–12 Small/intermediate and blastoid variants may be encountered.11 Insect bitelike reactions seen in MCL show a superficial and deep perivascular and interstitial lymphocytic infiltrate with numerous eosinophils. Neutrophils are also usually plentiful and nuclear dust may be seen, but there is no fibrinoid necrosis of vessel walls. In biopsies of papules, nodules, and plaques, there is either no epidermal involvement or only mild spongiosis. Vesicular lesions show marked subepidermal edema and dermoepidermal separation.14 Tumor cells are of B-cell origin (CD20+ and CD79a+) with coexpression of surface IgM and IgD, and more often show lambda than kappa light chain restriction.1 They typically express CD5, CD43, cyclin D1, and bcl-2 and are usually negative for bcl-6 and CD10 (Fig. 29.218).1 Cases with aberrant CD5 negative or CD10 or bcl-6 positive phenotypes can occur.1,39,40 CD23 is negative or weakly positive. Bcl-2 is positive, as is cyclin D1, in nearly all cases (i.e., those harboring a t(11;14)(q13;q32)). A high proliferation index is usually evident. Fig. 29.217 Mantle cell lymphoma: in this field, nucleolated forms are present and there are multiple mitoses. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Cyclin D1 immunohistochemistry is valuable with paraffin-embedded material (91% sensitivity). However, in those cases that are negative or indeterminate, interphase fluorescent in situ hybridization (FISH) may be of particular value in demonstrating the t(11;14) translocation.12,41,42 Amplification of the t(11;14) genomic breakpoint by PCR suffers from scattering of the breakpoints and it is much less sensitive.41 The diagnosis may also be confirmed by reverse transcription PCR (RT-PCR) demonstration of cyclin D1 transcript overexpression.41 It should also be remembered that rare cases lack t(11;14). Thus, when confronted with a CD5-positive, cyclin D1-negative lymphoma with the morphological features of MCL, consideration should be given to staining for cyclin D2 and cyclin D3 to avoid a misdiagnosis.

Differential diagnosis Mantle cell lymphoma: this lesion presented in the subcutaneous fat. The tumor consists of a monomorphic population of lymphoid cells with hyperchromatic nuclei. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Mantle cell lymphoma must be distinguished from other small B-cell lymphomas that may disseminate to the skin, including follicular lymphoma and B-small lymphocytic lymphoma/chronic lymphocytic leukemia, cutaneous follicle center lymphoma, and primary cutaneous marginal zone lymphoma. Follicular lymphoma and cutaneous follicle center cell lymphoma

Fig. 29.216

Fig. 29.218

Mantle cell lymphoma: nuclei are irregular. Note the mitosis. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Mantle cell lymphoma: the tumor cells uniformly express cyclin D1. By courtesy of G. Pinkus, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Fig. 29.215

B-chronic lymphocytic leukemia/small lymphocytic lymphoma are typically CD5−/CD10+, marginal zone lymphoma is CD5−/CD10− and small cell lymphocytic lymphoma is CD5+CD23+/CD10−. All are cyclin D1 negative.3,43

B-chronic lymphocytic leukemia/small lymphocytic lymphoma Clinical features B-chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a neoplasm of small, antigen-experienced B lymphocytes.1 CLL is defined on the basis of a persistent (≥ 3 months) lymphocytosis of ≥ 5 × 109/L.1,2 SLL is the term applied to cases without a leukemic blood picture, in which there is tissue infiltration by cells displaying morphological and immunophenotypic features of CLL, lymphadenopathy, absence of cytopenias due to bone marrow infiltration, and a peripheral blood lymphocyte count of  2.0 cm in diameter and most commonly affect the upper trunk and proximal limbs, predominantly in girls (5:1).11,13–16 Congenital presentation is common and ulceration is often seen.11 The agminate variant is exceptional, presenting as clustered papules, and may be associated with alopecia.17,18 In contrast to the more usual sites, the arm and leg have been affected. One case of lichenoid JXG has been described.19 Extracutaneous involvement is seen in up to 25% of cases, and may take the form of a solitary lesion without associated skin disease.4,20 Solitary extracutaneous lesions usually present as a large subcutaneous (up to 3 cm in diameter) or soft tissue (usually > 4 cm diameter) mass. The soft tissues of the head and neck are most frequently involved and rarely lesions occur on the trunk and limbs, and in the abdomen–pelvis.4,21–24 The orbit is another common site.2,3,25,26 Patients with ocular involvement are under 2 years of age and most present with a unilateral asymptomatic iris tumor, a red eye with signs of uveitis, unilateral glaucoma, and spontaneous hyphema.12,25,26 Solitary lesions can also occur in bone, tongue, nasal cavity and paranasal sinuses and lung.4

Fig. 29.292 Xanthogranuloma: this child has multiple lesions. By courtesy of the Institute of Dermatology, London, UK.

Fig. 29.293 Xanthogranuloma: this is a rare example of xanthogranulomata presenting in a child with neurofibromatosis type I. By courtesy of the Institute of Dermatology, London, UK.

Visceral disease is usually multifocal and associated with multiple skin lesions.4 Organs involved include liver, spleen, lungs, and CNS, and less commonly in the heart, oropharynx, muscle, kidney, bone, pancreas, peripheral nerve, ovaries, testes, and adrenal gland. Skin lesions tend to flatten, disappearing over months to years, sometimes leaving atrophic or hypopigmented scars. Most systemic lesions also completely regress within 3 to 6 years.1–3 Rare fatalities have occurred in patients with CNS or hepatic involvement.4,27–29 There is a well-documented association between JXG and neurofibromatosis type I and/or juvenile myelomonocytic leukemia (Fig. 29.293).9,30–32 In cases associated with leukemia, JXG usually precedes or presents concurrently. Fig. 29.291

Benign cephalic histiocytosis

Xanthogranuloma: there is a characteristic reddishbrown nodule on the bridge of the nose of this infant. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Benign cephalic histiocytosis is exceptional and presents in early childhood.33–41 The age at onset ranges from 3 to 34 months (mean, 13.5 months).34 The sexes are equally affected. Early lesions are erythematous, round or oval maculopapules that enlarge to form 2–8 mm diameter, brownish–yellow papules distributed most often on the face, particularly the cheeks, eyebrows, and forehead (Fig. 29.294). Not infrequently, they later spread to affect the shoulders, proximal limbs, trunk, and pubic area.34,35

Juvenile xanthogranuloma family Umbilicated lesions in children mimic molluscum contagiosum.55,56,60 Two patients have been described in which an early presentation as generalized eruptive histiocytoma evolved into typical xanthoma disseminatum, emphasizing the considerable overlap in the non-X group of histiocytosis.55,56

Xanthoma disseminatum and scalloped cell xanthogranuloma Xanthoma disseminatum (XD) usually develops in young adults ( 40 years (mean age at presentation, 43 years; range, 6–71 years).3–6 There is female predilection (3:1).2–4 Two-thirds of patients present with arthropathy and invariably develop skin lesions within months to a few years. Cutaneous lesions represent the primary complaint in 20% of patients, and while many go on to develop joint symptoms, in some the disease remains in the skin (referred as generalized cutaneous reticulohistiocytosis).1,2 Cutaneous lesions present on the face (predominantly ears, nose, and paranasal areas), the hands (dorsum and lateral aspects of the fingers, nail folds), neck, and trunk. Multiple reddish-brown to yellow papules and nodules measuring from a few millimeters to 2 cm in diameter are seen.2,3,7–10 Sometimes they coalesce to form plaques with a cobblestone appearance. Nail fold changes present a characteristic ‘coral band’

Fig. 29.322 Reticulohistiocytoma: the dermis is expanded by a dome-shaped nodule composed of large histiocytes.

Hemophagocytic lymphohistiocytosis

Fig. 29.323 Reticulohistiocytoma: the histiocytes have copious eosinophilic cytoplasm.

Fig. 29.326 Reticulohistiocytoma: the giant cells are PAS positive, diastase resistant.

The histiocytes and multinucleate giant cells are consistently positive for CD68, CD163, and Ki-M1p and react variably with antibodies to Ham56 and factor XIIIA. They are negative for CD1a and S-100.1,2,35 The giant cells are diastase-PAS positive (Fig. 29.326). Synovial lesions show similar histology.5

Differential diagnosis In cases with systemic features, the clinical history is paramount. Solitary RH may be distinguished from JXG by the absence of lipidized cells and Touton giant cells and the typical eosinophilic cells with ground-glass cytoplasm. However, JXG may have scattered cells similar to the latter. Distinction from a melanocytic lesion is made by negative staining for melanocytic markers.

Hemophagocytic lymphohistiocytosis Clinical features Fig. 29.324 Reticulohistiocytoma: characteristic multinucleate giant cell with ground-glass cytoplasm.

Fig. 29.325 Reticulohistiocytoma: lymphocytes are also present.

Hemophagocytic lymphohistiocytosis (HLH) (hemophagocytosis syndrome) represents a complex group of disorders that share a final common pathway culminating in hemophagocytosis and associated signs and symptoms. They are divided into primary and secondary HLH. Primary HLH equates with familial forms of the disease and is usually associated with an inherited genetic disorder, although a family history may be negative, and HLH in these patients may be triggered by infections.1,2 Secondary variants include HLH associated with inherited immune deficiencies (e.g., Chediak-Higashi syndrome, X-linked lymphoproliferative syndrome, and Griscelli's syndrome), and acquired HLH in patients with immune system defects. In the latter, HLH is triggered by severe infection with viruses (especially EBV and CMV), other infectious agents (e.g., leishmaniasis) or malignancy (particularly various lymphomas). HLH may also complicate autoimmune disease, including macrophage activation syndrome in systemic juvenile arthritis, adult-onset Still's disease, and lupus erythematosus.3 Familial HLH occurs in around 1 in 50 000 live-born children and usually presents at  5 cm, nonscalp location and/or foci of necrosis or ulceration in addition to histological findings of infiltrative growth, abundant mitotic figures (including atypical forms), and marked cytological atypia.31,42 In a more comprehensive attempt to correlate histologic features with outcome, three distinct groups have emerged in an analysis of 76 tumors. Tumors showing circumscribed silhouettes and pushing borders, mild nuclear atypia and lack of necrosis, atypical mitoses and ­perineural

Fig. 31.44 Pilar tumor: foci of necrosis are commonly present.

or lymphovascular invasion are characterized by benign behavior with no increased risk for local recurrence or distant metastasis, In contrast, tumors showing irregular outlines and infiltrative growth with ­involvement of deep dermis and subcutis may have potential for locally destructive growth, while metastatic potential was observed in tumors with an invasive growth ­pattern

Proliferating trichilemmal (pilar) cyst

Fig. 31.45

Fig. 31.48

Pilar tumor: the presence of free keratin within the dermis commonly evokes a foreign body giant cell reaction.

Pilar tumor: mitotic figures, as shown in this field, are generally inconspicuous.

Fig. 31.46 Pilar tumor: note the clear cells, which result from glycogen accumulation.

Fig. 31.49 Malignant pilar tumor: low-power view showing a typical pilar tumor associated with a carcinomatous infiltrating component.

in addition to marked nuclear atypia, atypical mitoses, and geographic necrosis with or without perineural or lymphovascular invasion.43 Malignant proliferating pilar tumors may display aneuploidy, an increased proliferative index, and loss of staining for CD34 and wild-type p53 protein.44–46 Malignant proliferating pilar tumor has been reported to occur in patients with keratosisichthyosis-deafness (KID) syndrome and shows risk for distant metastasis and associated mortality.31,47

Differential diagnosis

Fig. 31.47 Pilar tumor: this field shows conspicuous squamous eddies.

Usually, proliferating trichilemmal cysts can be distinguished from squamous cell carcinoma by the presence of multiple circumscribed nodules showing a noninfiltrative palisaded border, sometimes accompanied by a hyaline basement membrane and showing abundant trichilemmal rather than epidermoid keratinization.

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Fig. 31.50 Malignant pilar tumor: medium-power view of the carcinomatous component.

Fig. 31.52 Pilomatrixoma: note the small chalky nodule on the cheek of this young girl, a characteristic site. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

­ redominance.2,29,32,33,68–70 More recent studies, however, have documented a p somewhat wider age distribution with a second peak among those in their sixth and seventh decades of life.4,8,71–73 Surgical excision is curative although there is local recurrence in 2–3% of cases.1,32,33,69,74

Pathogenesis and histological features

Fig. 31.51 Malignant pilar tumor: the nuclei are hyperchromatic and irregular, and multiple mitoses are present.

Pilomatrixoma Clinical features Pilomatrixoma (pilomatricoma, calcifying epithelioma of Malherbe) usually represents a solitary lesion, but occasionally multiple tumors are evident as part of an autosomal dominant disorder.1–6 Rarely, it may represent a dermatological marker of systemic disease (e.g., myotonic dystrophy, Gardner's syndrome or MYH-associated polyposis (MAP)).7–20 Multiple pilomatrixomas have also been reported in patients with Turner's syndrome, trisomy 9, Rubinstein-Taybi syndrome, Sotos's syndrome, and spina bifida.21–27 Synchronous appearance of multiple tumors is exceptional.28 It presents as a slowly growing, firm-to-hard nodule of around 0.5–3 cm on the head, upper limbs, neck, trunk, and lower limbs, in decreasing order of frequency (Fig. 31.52).2,19,29–31 The cheek is the most commonly affected site.32,33 Unusual locations include the spermatic cord and paratesticular region.34,35 Large chalky deposits are sometimes evident and calcification may be revealed by radiology. Tumors are rarely extremely large, measuring up to 12 cm in diameter (giant pilomatrixoma).36–42 The overlying skin can be bluish, and show dilated vessels, bullous, anetodermic or perforating changes.43–67 Young people are mainly affected, some 60% of cases being excised before 20 years of age and most before 10 years.3 There is a female

Recently, insights have been gained into the molecular pathogenesis of pilomatrixoma implicating β-catenin as a key molecule. β-catenin is an important intracellular protein with a dual role. It has a structural function and is involved in cell–cell junction formation by binding to cadherins as well as α-catenin, thereby providing a link between adherens junctions and the actin cytoskeleton.75–77 It is also part of the Wnt/wingless signal transduction pathway and mediating transcriptional activation of target genes such as c-myc and cyclin D1.78–80 Cytosolic β-catenin is phosphorylated at its N-terminus and is subsequently subject to ubiquitin-mediated degradation involving the APC gene.81,82 Wnt signaling prevents phosphorylation of β-catenin leading to its cytosolic accumulation. Cytosolic β-catenin then interacts with lymphoid enhancer factor-1/T-cell factor (Lef-1/Tcf) to form a nuclear transcription factor complex.83,84 β-catenin stabilization caused by truncating mutations in its N-terminus (which prevent phosphorylation) has been shown to result in the formation of pilomatrixoma in a mouse model.85 These observations have led to the identification of mutations in the N-terminal portion of β-catenin in human pilomatrixoma predominantly affecting direct sites of phosphorylation.86–93 By immunohistochemistry, pilomatrixoma expresses cyclins D1, D2, and D3 and β-catenin nuclear staining within the basaloid/matrix cells while only cytoplasmic and membranous staining is observed in areas of maturation/transitional area. Staining is absent in ghost cells.94–99 Analogous to the findings in anagen hair follicles, the sequential expression of hair keratins is preserved in the transitional layer of pilomatrixoma and there is subsequent loss of expression in the ghost cell layer.100,101 While cortical differentiation of matrix cells in anagen hair follicles is accompanied by LEF-1/α-catenin induced expression of the hair keratin hHa1, nuclear coexpression of LEF-1 and α-catenin is not observed in the outer transitional layer of pilomatrixoma, arguing that cortical differentiation in pilomatrixoma is not under the control of the Wnt signaling pathway.102,103 Mutations in the β-catenin gene have also been identified in other tumors showing morphological overlap with pilomatrixoma including basal cell carcinoma with ghost cell differentiation, cribriform trichoblastoma, and craniopharyngioma.93

Pilomatrixoma Differentiation of pilomatrixoma towards the hair matrix is supported by a number of studies on keratin, S-100, and gene expression involved in the α-catenin pathway and apoptosis represents the main mechanism leading to ghost cells.86,96,104–110 Pilomatrixoma is a tumor that expresses differentiation towards the hair matrix; hair shaft formation is therefore not a feature. The epidermis is usually normal, although rarely transepidermal elimination of tumor in addition to anetoderma-like changes and blister formation have been documented.3,47–54 Situated within the dermis and sometimes extending into the subcutaneous fat is a multilobulated tumor, which may on occasion be surrounded by a fibrous pseudocapsule of compressed adjacent connective tissue elements (Fig. 31.53). Individual tumor lobules are composed of a variable admixture of basaloid and ghost cells; the former predominate in evolving lesions and the latter in mature lesions.111 Basaloid cells are small and uniform with round vesicular nuclei and prominent nucleoli (Fig. 31.54). Early lesions may show very brisk mitotic activity, but this is never abnormal and is indicative of a rapid growth phase rather than malignant potential (Fig. 31.55). With tumor maturation, the basaloid cells transform into ghost cells, acquiring abundant eosinophilic cytoplasm and developing small hyperchromatic nuclei (Fig. 31.56). Eventually, the nuclei are lost, leaving sheets of intensely eosinophilic keratinous debris in which the ghost outlines of tumor cells are faintly visible, and giant cells are often present

Fig. 31.55 Pilomatrixoma: note the presence of conspicuous mitotic figures. These are often numerous in early lesions and are not a cause for alarm.

Fig. 31.53 Pilomatrixoma: this low-power view shows the typical biphasic population.

A

B

Fig. 31.54

Fig. 31.56

Pilomatrixoma: early lesions are composed predominantly of sheets of germinative basaloid cells with uniform nuclei and small nucleoli.

(A, B) Pilomatrixoma: with maturation, the cells become larger, acquire abundant eosinophilic cytoplasm, and show nuclear pyknosis.

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Fig. 31.57 Pilomatrixoma: a foreign body giant cell reaction is commonly present.

Fig. 31.59 Pilomatrixoma: this tumor shows widespread osseous metaplasia including the formation of marrow spaces.

Fig. 31.60 Fig. 31.58 Pilomatrixoma: note the fine basophilic calcification.

(Fig. 31.57). Keratinization in pilomatrixoma is therefore predominantly pilar, although occasionally small foci of epidermoid keratinization may be found. An additional feature in some tumors is melanin pigment within both basaloid cells and tumor histiocytes.3,112 Calcification is seen in 80% of lesions, more commonly in those that have achieved maturity.71 Basophilic stippling of ghost cells is the most common expression (Fig. 31.58). Rarely, large calcific concretions are present, and in 20% of cases ossification takes place (Figs. 31.59, 31.60).71 Bone morphogenetic protein-2 (BMP-2), an important molecule involved in bone and cartilage formation, has been demonstrated in shadow cells by immunohistochemistry and may play a role in bone formation in pilomatrixoma.113 Stromal amyloid deposition and focal clear cell change are occasionally seen (Fig. 31.61), and differentiation towards other aspects of the hair follicle including the follicular infundibulum and the inner root sheath as well as ­follicular germinal cells is a rare finding.114 Pilomatrixomas in the elderly generally show features similar to those of the childhood variant. Occasionally, however, atypical features include basaloid cell pleomorphism, loss of polarity, nuclear hyperchromatism, and marked mitotic activity including atypical forms.71,115 This variant has

Pilomatrixoma: high-power examination shows foci of ghost cells contrasting with the more eosinophilic osteoid.

Fig. 31.61 Pilomatrixoma: high-power view showing focal clear cell change.

Melanocytic matricoma also been referred to as proliferating pilomatrixoma.115–117 Lymphatic and ­‑perineural spread are not features. These atypical variants do not appear to behave in any way differently from more conventional lesions. Nevertheless, their ­complete removal with careful follow-up is advised. An unusual tumor showing features of pilomatrixoma in an ­intraepidermal location with cutaneous horn formation has been described as pilomatricomal horn.118 This tumor is characterized by papillomatous and thickened epidermis composed of well-defined lobules of matrical cells budding into papillary dermis. Tumor cells mature to produce ghost cells and there is an overlying keratinaceous horn.

Differential diagnosis Although ghost cells are characteristic of pilomatrixoma, they can also be seen in a variety of other follicular neoplasms including infundibular cysts, trichoepithelioma, and its desmoplastic variant.81,82 Matrical differentiation may also sometimes be seen in basal cell carcinoma and ­combined cysts.

Pilomatrix carcinoma Clinical features

Fig. 31.62

Pilomatrix carcinoma (malignant pilomatrixoma, matricial carcinoma) is rare, approximately 100 cases having been documented in the English ­literature.1–40 The tumor, which shows a predilection for males (4:1), most frequently presents in adults as a mass ranging in size from 0.5 to 20 cm (mean: 4 cm) on the posterior neck, back, scalp, and retroauricular region and may rarely be pigmented.1,9,30,39–42 Other locations include the extremities, shoulder, breast, axilla, hip, and groin.9,10,15,16,25,35–38 Pilomatrix carcinoma exceptionally occurs in children.36,37 It has arisen, albeit rarely, in a background of multiple benign pilomatrixomas and also at the site of treatment of a pilomatrixoma.18,35 Recurrences are common, but metastases are limited to a handful of cases that particularly affect drainage lymph nodes and the lung and rarely other sites including bone.1–8,10–14,19–21,38,43–45 In general, therefore, pilomatrix carcinoma appears to be a low-grade neoplasm with wide excision being the treatment of choice.1,9 Careful review of the literature suggests that at least some examples of malignant pilomatrixoma (particularly earlier reports) may represent misdiagnoses resulting from overinterpretation of the often brisk mitotic activity seen in evolving lesions. The biological behavior of these tumors therefore requires ­f urther study.

Pilomatrix carcinoma: lowpower view of irregular tumor lobules.

Pathogenesis and histological features Analogous to pilomatrixoma (see above), the Wnt-signaling pathway and β-catenin have recently been shown to be involved in the molecular pathogenesis of pilomatrix carcinoma. Cytoplasmic and nuclear staining for β-catenin in addition to nuclear staining for cyclin D1 is present in the basaloid cell population and there are mutations in the N-terminus of β-catenin. 38,46 Interestingly, the spectrum of mutations is similar to that reported in benign pilomatrixoma.38,47 This indicates that further molecular alterations in addition to a disturbance of the Wnt-signaling pathway must be necessary for a pilomatrixoma to undergo malignant change.48 Features that raise the possibility of malignant potential include large size (4  cm or more in diameter), an infiltrating border with involvement of fascia or skeletal muscle, basaloid cell predominance, nuclear pleomorphism, conspicuous eosinophilic nucleoli, abnormal mitotic figures, areas of confluent tumor necrosis, stromal desmoplasia, and vascular, lymphatic or perineural invasion (Figs 31.62–31.67). It should be noted that brisk mitotic activity is a common feature in early benign lesions and on its own should not necessarily be a cause for alarm. Many of the documented cases of pilomatrix carcinoma have contained 30 or more mitoses per 10 high-power fields.1 This, however, should not be used as the sole criterion for a diagnosis of malignancy.

Fig. 31.63 Pilomatrix carcinoma: the tumor is composed of basophilic cells. Note the ghost cells.

Pigmentation of pilomatrix carcinoma may occasionally be observed due to increased accumulation of melanin pigment within tumor cells or colonization of the tumor by pigmented dendritic melanocytes.9,30,39,49 Exceptionally, malignant pilomatrixoma has been described in association with MFH-like stromal features.14

Melanocytic matricoma Clinical features Melanocytic matricoma is a recently described entity, less than 10 cases having been reported to date.1–3 It presents clinically as a small (less than 1 cm)

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A

Fig. 31.64 Pilomatrix carcinoma: there is marked nuclear pleomorphism with prominent nucleoli.

B

Fig. 31.67 (A, B) Pilomatrix carcinoma: lymph node metastasis.

Fig. 31.65 Pilomatrix carcinoma: an abnormal mitotic figure is present.

well-circumscribed purple to black papule on sun-damaged skin in the elderly (sixth to seventh decade).1–5 Affected sites have included the nose, preauricular area, chest, back, hand, and forearm.1–3,5 The clinical differential diagnosis includes pigmented basal cell carcinoma, hemangioma, and melanoma. After complete excision, none of the lesions has recurred or harmed the patient (longest follow-up period 2 years).1–3 Further studies, however, will be necessary to determine this lesion's true biological potential.

Pathogenesis and histological features

Fig. 31.66 Pilomatrix carcinoma: there is striking Ki-67 expression.

Melanocytic matricoma presents histologically as a well-circumscribed dermal tumor showing asymmetrical pigmentation (Figs 31.68, 31.69).1–3 It is arranged in solid nests and lobules composed of basaloid cells with scant amounts of cytoplasm and prominent nucleoli reminiscent of matrical and supramatrical cells (Figs 31.70–31.72). Cytological atypia as well as mitotic figures may be present. Dispersed singly and in small aggregates are ghost cells within the tumor and pigmented dendritic melanocytes are admixed. Surrounding the tumor is a sclerotic stromal response containing melanophages. The dermis and overlying epidermis reveal changes of significant sun damage including elastosis, epidermal atrophy, and actinic keratoses.1–3 One tumor was reported as ‘malignant melanocytic matricoma’ because of ­extension of tumor cells into the surrounding fibrous pseudocapsule and the presence of atypical mitotic figures.6 As no clinical follow-up is available it is uncertain at this point whether these histological features are truly signs of malignancy or whether they may be part of a histological spectrum of melanocytic matricoma.

Melanocytic matricoma

A

Fig. 31.68 Melanocytic matricoma: there is a multinodular dermal tumor.

B

Fig. 31.70 Melanocytic matricoma: (A) the tumor is composed of basophilic cells with mild nuclear pleomorphism and conspicuous mitotic activity; (B) high-power view showing melanocytes.

Fig. 31.69 Melanocytic matricoma: focal ghost cell change is present. Note the dendritic melanocytes.

By immunohistochemistry, the basaloid cells show membranous staining for both P- and E-cadherin as well as nuclear and cytoplasmic staining for β-catenin reminiscent of the hair bulb of anagen hair and also implicating β-catenin in its pathogenesis.7

Differential diagnosis The main histological differential diagnoses include pilomatrixoma, pilomatrix carcinoma, and basal cell carcinoma with matrical differentiation. Melanocytic matricoma shows overlapping features with both pigmented pilomatricoma and pilomatrix carcinoma and reliable distinction may not always be possible. Despite the presence of cytological atypia and abundant mitotic figures, the tumors are small, well circumscribed, and lack atypical mitoses, necrosis, lymphovascular invasion, and may thereby be distinguished from pilomatrix carcinoma in many instances. Nevertheless, tumors displaying such features should be viewed with caution, and complete excision would be prudent.

Fig. 31.71 Melanocytic matricoma: the matrical cells express keratin.

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Pathogenesis and histological features It consists of a cystic cavity (dilated hair follicle) lined by stratified squamous epithelium (including a granular cell layer), which can usually be shown to arise from the surface epithelium (Fig. 31.74).1,2 The cavity contains keratinous debris and hair shaft fragments.7 Arising from its wall are numerous hair follicles, each surrounded by a clearly defined perifollicular sheath (Figs 31.75, 31.76). Secondary budding with further abortive pilar differentiation may be seen. Small primitive sebaceous acini and keratocysts are occasionally present. Stromal granulomatous inflammation surrounding hair shaft fragments and focal calcification are sometimes present and focal acantholytic dyskeratosis may be an incidental finding.7,12 A recent analysis of the histological features demonstrates that trichofolliculoma shows a morphological spectrum corresponding to the hair follicle

Fig. 31.72 Melanocytic matricoma: the dendritic melanocytes are highlighted with HMB-45.

Basal cell carcinoma with matrical differentiation is characterized by foci of typical basal cell carcinoma composed of basaloid nests showing ­peripheral palisading and stromal retraction artifact.

Trichofolliculoma Clinical features Trichofolliculoma is a not uncommon hamartoma that usually arises on the face and presents as a single, dome-shaped, 0.5–1.0-cm diameter papule with a central pore.1–6 It is occasionally found on the scalp or neck and has been rarely described on the vulva.7,8 A wide age range is affected, although lesions are very rare in children or infants.7,9,10 Characteristic, although not diagnostic, is the presence of one or more silky, white, thread-like hairs (trichoids) growing out of the central opening (Fig. 31.73).7 Rarely, trichofolliculoma may coexist with a basal cell carcinoma.11

Fig. 31.74 Trichofolliculoma: scanning view showing a cystically dilated follicle communicating with the epidermis. Note the secondary follicles arising from the lateral wall.

Fig. 31.75 Fig. 31.73 Trichofolliculoma: characteristic dome-shaped nodule with protruding trichoids. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Trichofolliculoma: this example emphasizes the numerous secondary follicles.

Folliculosebaceous cystic hamartoma present in young adulthood but the age distribution is wide and lesions present at birth have been described.1,2,5,6,13–15,21 A example has been reported in association with a port-wine stain and multiple tumors have been documented in the setting of a giant nevus lipomatosus superficialis.22–24 There is no association with Torre-Muir syndrome.

Pathogenesis and histological features Folliculosebaceous cystic hamartoma is a dermal-based lesion composed of an infundibular cystic cavity similar to trichofolliculoma (Fig. 31.77). Within the cavity, keratinaceous debris and sebaceous secretions are found.1,2,5,7 Hair shafts may occasionally be identified but are absent in the majority of cases.15,25 Although initially thought to be uncommon, epidermal communication may be present.1,14 Numerous small sebaceous lobules are connected to the cavity via sebaceous ducts (Fig. 31.78). Hair follicles at various stages in the follicular cycle are occasionally observed and sometimes these are malformed (Fig. 31.79).13 Small cystic apocrine

Fig. 31.76 Trichofolliculoma: high-power view of secondary follicles.

cycle and has postulated that the very late stage of trichofolliculoma is identical to folliculosebaceous cystic hamartoma (see below).13,14 The early-stage trichofolliculoma is characterized by several curved vellus hair follicles leading into an infundibulum without cystic dilatation, whereas the late stage shows changes of catagen and telogen hair follicles and more prominent sebaceous differentiation.13

Folliculosebaceous cystic hamartoma Clinical features Folliculosebaceous cystic hamartoma is a rare hamartomatous lesion with follicular, sebaceous, and mesenchymal elements.1–13 Approximately 60 cases have been documented.14,15 It typically presents as a small (around 1 cm in diameter) solitary symmetrical papule or nodule with a predilection for the central face, especially the nose.1,2,14–17 Genital location as well as a giant variant have been described to involve extrafacial sites.3,4,18–21 Patients typically

Fig. 31.78 Folliculosebaceous cystic hamartoma: the sebaceous glands communicate with the cyst through small ductules. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

Fig. 31.77

A

B

Folliculosebaceous cystic hamartoma: (A) scanning view showing cystic cavity with conspicuous sebaceous glands embedded in a dense stroma; (B) oblique section of cyst emphasizing the sebaceous glands. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

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Fig. 31.79

Fig. 31.81

Folliculosebaceous cystic hamartoma: malformed hairs as shown in this field are sometimes present. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

Folliculosebaceous cystic hamartoma: a dense spindle cell stroma is an integral component of the tumor. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

Fig. 31.80 Folliculosebaceous cystic hamartoma: note the cleftlike space, a characteristic feature. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

Fig. 31.82 Folliculosebaceous cystic hamartoma: mature adipocytes are regularly present in this tumor. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

glands may also be present.13 The epithelial component is surrounded by a dense laminated collagenous fibroplasia and the fibroepithelial unit is separated from the adjacent mesenchymal proliferation by cleftlike spaces (Fig. 31.80).1,2,5,7 Mesenchymal elements including collagen, elastic fibers, adipose, and vascular tissue represent an integral component of this tumor and indeed in some examples they may predominate.1,8 The folliculosebaceous elements are embedded in a distinctive, variably collagenous stroma composed of spindled cells with eosinophilic cytoplasm and tapered hyperchromatic nuclei (Fig. 31.81). Abundant mature adipocytes are often present and there is a conspicuous vascular component, often showing perivascular fibroplasia (Fig. 31.82).13 In some tumors, mucin deposition has been noted and this may show striking perivascular accentuation (Fig. 31.83). A neural component has also been described.9,12 Studies on keratin and filaggrin expression demonstrate differentiation towards the follicular infundibulum, the sebaceous duct and sebaceous cells.26

Differential diagnosis Although, at first sight, this lesion bears a similarity to trichofolliculoma, particularly the sebaceous variant, the more usual lack of ­communication

Fig. 31.83 Folliculosebaceous cystic hamartoma: high-power view showing perivascular mucin deposition. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

Trichoepithelioma with the surface epithelium, combined with the conspicuous stromal ­components present in this hamartomatous lesion, serve as helpful ­histological discriminants.

Sebaceous trichofolliculoma Clinical features Sebaceous trichofolliculoma is a rare hamartomatous condition and represents a variant of trichofolliculoma. It presents as a depressed lesion up to 1 cm across, usually on the nose and only rarely on the scrotum and penis (Fig. 31.84).1–3 It is associated with one or more fistulous openings from which protrude terminal hairs, vellus hairs and trichoids. Typically, lateral ­pressure does not express any debris. The lesion neither communicates with the ­paranasal sinuses nor causes any bony destruction.

Histological features

Fig. 31.85

It consists of a multilocular crateriform cavity lined by epidermoid stratified squamous epithelium (Fig. 31.85).1 Additional small laterally orientated sinuses may drain into the central cavity, which contains hairs of varying size as well as keratinous debris. Arising from the wall of the cyst are numerous sebaceous lobules associated with terminal hairs, vellus hairs, and trichoids.

Sebaceous trichofolliculoma: this cystically dilated follicle is lined by squamous epithelium showing infundibular keratinization. Numerous sebaceous lobules are present.

Differential diagnosis Sebaceous trichofolliculoma may be distinguished from sebaceous hyperplasia, the latter merely representing a grossly enlarged solitary sebaceous gland not associated with hair follicle formation. Sebaceous trichofolliculoma must be differentiated from dermoid cyst and median nasal dermoid fistula. • Dermoid cysts do not communicate with the surface epithelium, smooth muscle is often present in proximity to the cyst wall, and eccrine and apocrine glands are sometimes evident. • Median nasal dermoid fistula is a rare developmental abnormality in which nasal fusion is associated with the sequestration of fetal

ectoderm, proliferation of which results in the development of the fistula.4,5 Patients present with an erythematous pit in the midline or dorsum of the nose (Figs 31.86, 31.87). Typically, small hairs protrude from the opening of the fistula. Histologically, the fistula is lined by keratinizing stratified squamous epithelium. Numerous hair follicles are associated with the fistula wall, but sebaceous, apocrine, and eccrine glands are not present (Fig. 31.88). The importance of the median nasal dermoid fistula is that it may communicate with an anterior meningoencephalocele.

Trichoepithelioma Clinical features Trichoepithelioma is a hamartomatous condition that shows less follicular differentiation than a trichofolliculoma. The lesion may be multiple and familial or solitary.

Multiple familial trichoepithelioma

Fig. 31.84 Sebaceous trichofolliculoma: there is a characteristic pitshaped depression on the tip of the nose. Note the protruding hairs. By courtesy of G. Plewig, MD, Düsseldorf, Germany.

Multiple familial trichoepithelioma (epithelioma adenoides cysticum (Brooke)) is inherited in an autosomal dominant fashion with diminished expression in males and onset during puberty.1 Patients present with multiple, small, skin-colored papules in a roughly symmetrical distribution located predominantly on the face (Figs 31.89, 31.90).2 The nasolabial folds, eyebrows, eyelids, and cheeks are most commonly involved.2,3 Other sites including the scalp, neck, extremities, buttocks, and genital area may also be affected.2,4–9 The lesions are usually asymptomatic and commence as translucent skin-colored papules, which sometimes show slight surface telangiectasia. They slowly enlarge to reach a maximum diameter of about 0.5 cm. Rarely, ulceration occurs, ­usually at a very late stage. Lesions are occasionally pigmented. A linear and dermatomal distribution has also been reported.5 Patients with epithelioma adenoides cysticum rarely develop any significant systemic manifestations. An association with renal and pulmonary cysts and with malignant lymphoepithelial lesion of the parotid gland has,

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Fig. 31.86 Median nasal dermoid fistula: on the dorsum of the nose is an erythematous crateriform depression. By courtesy of D. Shuttleworth, MD, University of Wales, Cardiff, UK.

Fig. 31.88 Median nasal dermoid fistula: the fistula, which communicates with the surface epidermis, is lined by hair-bearing epithelium. By courtesy of D. Shuttleworth, MD, University of Wales, Cardiff, UK.

Fig. 31.89 Trichoepithelioma: this patient has familial multiple trichoepitheliomas. Note the presence of multiple skin-colored papules about the nasolabial folds. By courtesy of the Institute of Dermatology, London, UK.

Fig. 31.87 Median nasal dermoid fistula: the presence of protruding white hairs is characteristic. By courtesy of D. Shuttleworth, MD, University of Wales, Cardiff, UK.

­ owever, been documented.10,11 Very rarely, a coexistent basal cell carcinoma h may be found.12–16 Although initial genetic linkage analysis mapped the disease to a region on chromosome 9p21, subsequent studies have failed to confirm this ­observation. Instead, mutations in the CYLD gene on chromosome 16q12-q13 have been consistently identified in multiple families, analogous to Brooke-Spiegler syndrome.17–28 These data emphasize that multiple familial trichoepithelioma may indeed represent part of a disease spectrum that also includes familial cylindromatosis and Brooke-Spiegler syndrome.

Fig. 31.90 Epithelioma adenoides cysticum: note the numerous skin-colored papules and nodules on this girl's scalp and forehead. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Trichoepithelioma

Brooke-Spiegler syndrome The autosomal dominant Brooke-Spiegler syndrome (familial cylindromatosis or turban tumor syndrome) is characterized by multiple cylindromas in addition to spiradenomas, multiple trichoepitheliomas, and milia.29–54 While penetrance is high, there is great variability in presentation among patients. Within the same family some patients may present with either multiple cylindromas or trichoepitheliomas only, or a combination of both. Patients present with skin lesions in early adulthood and there is a female predilection. While cylindromas typically present on the scalp and may grow to large size and confluence (turban tumor), the multiple trichoepitheliomas are largely located centrofacially.2 Tumors frequently show hybrid features such as spiradenocylindromas, and sebaceous differentiation may be a feature.55 Patients also develop other hair follicle tumors such as trichoblastoma and cutaneous lymphadenoma.55 Additional syringomas are rare and may be an incidental association.56 Parotid gland tumors such as membranous-type basal cell adenoma, a histological mimic of cylindroma, may rarely develop as well as cylindroma of the breast parenchyma.57–64 Both the salivary gland tumor as well as the cylindromas infrequently undergo malignant change.31,58,65–67 Recently, malignant transformation in trichoepithelioma (high-grade trichoblastic carcinoma) and development of a carcinosarcoma have also been documented in patients with Brooke-Spiegler syndrome and multiple familial trichoepithelioma.68–70

of solitary trichoepithelioma. Analogous to basal cell carcinoma, somatic mutations and loss of heterozygosity of the patched gene (PTCH) have been detected in a subset of trichoepitheliomas.93,94 Transgenic mice overexpressing GLI-1, a protein involved in the sonic hedgehog signaling pathway, develop basal cell carcinoma as well as adnexal tumors reminiscent of trichoepithelioma and cylindroma, and high GLI-1 transcript levels have been detected in both basal cell carcinomas as well as trichoepitheliomas.95,96 The tumor sometimes shows continuity with the epidermis, which may appear normal or slightly hyperkeratotic and thinned with loss of the rete ridge pattern. Ulceration, however, is exceedingly rare. Typical trichoepithelioma is characterized by numerous horn cysts free within the dermis and within lobules of basaloid cells (Figs 31.91, 31.92).2 Admixed with the horn cysts are lobules of tumor cells indistinguishable from those of basal cell carcinoma, being basophilic with minimal cytoplasm and showing peripheral palisading (Fig. 31.93). In trichoepithelioma, however, the perilobular ­connective tissue sheath is more conspicuous and is frequently associated with the formation of juxtaepithelial round or oval fibroblastic aggregates – papillary mesenchymal bodies (Fig. 31.94).97 These are believed to represent primitive

Rombo syndrome Rombo syndrome comprises multiple trichoepitheliomas, milia, vermiculate atrophy, basal cell carcinoma, vellous hair cysts, peripheral vasodilatation, and cyanosis.71 It is an exceedingly rare condition, with a possible autosomal dominant mode of inheritance.72 Skin lesions present in childhood and basal cell carcinomas develop in early adulthood.72 A further familial form has been associated with nail dystrophy, alopecia, and myasthenia gravis.73–76

Solitary trichoepithelioma Solitary trichoepithelioma usually presents as an 0.5-cm diameter, asymptomatic, flesh-colored nodule on the face of an adult. It is occasionally seen at other sites, including the scalp, neck, back, vulva, mons pubis, and proximal extremities.2,77,78 Trichoepithelioma is occasionally associated with melanocytic (banal or blue) and epidermal nevi.79–82

Fig. 31.91 Trichoepithelioma: this scanning view shows the typical appearances of lobules of basaloid cells and keratocysts.

Pathogenesis and histological features The Brooke-Spiegler syndrome has recently been mapped to chromosome locus 16q12-13 and the candidate gene identified as the tumor suppressor gene CYLD.47–52 Mutations resulting in inactivation of the CYLD gene have been reported, with tumors showing loss of heterozygosity for the wild-type copy, a characteristic finding for tumor suppressor genes.32,33,35,47 CYLD mutations have now also been identified in families with multiple familial trichoepithelioma and familial cylindromatosis, suggesting phenotypic variation of the same underlying disease.18,19,21–28,30,83 However, no genotype–phenotype correlation has emerged thus far. More recently, insights into the molecular function of CYLD have been gained. CYLD is a deubiquinating protein that interferes with the tumor necrosis factor alpha (TNF-α)/NF-κb pathway by targeting multiple important signaling molecules such as TRAF2 (tumor necrosis factor receptor-associated factor 2), NEMO as well as bcl-3, among others. CYLD is therefore involved in the regulation of various important functions including inflammation, cell survival, proliferation, and tumorigenesis.84–86 Lack of CYLD results in constitutive NF-κb pathway activation as well as decreased apoptosis.87–91 The precise mechanism detailing how NF-κb pathway activation is involved in tumorigenesis is, however, not fully understood. Keratin expression profiles in trichoepithelioma demonstrate differentiation towards the outer root sheath.92 In contrast to data on multiple familial trichoepithelioma and the Brooke-Spiegler syndrome, the sonic hedgehog ­signaling pathway appears to be involved in the ­pathogenesis

Fig. 31.92 Trichoepithelioma: the keratocysts show infundibular keratinization.

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Fig. 31.93

Fig. 31.95

Trichoepithelioma: in this area the tumor lobules show conspicuous peripheral palisading and are enveloped in a dense connective tissue sheath. A papillary mesenchymal body is evident in the center of the field.

Trichoepithelioma: in this view, the tumor has a delicate frondlike pattern.

Fig. 31.94

A

Trichoepithelioma: high-power view of a papillary mesenchymal body.

papillary mesenchyme. Sometimes they indent the lobules to ­produce a hair bulb-like appearance. The lobules of basaloid cells are frequently ­associated with thin epithelioid strands resulting in a frondlike appearance (Fig. 31.95). Trichoepitheliomas not uncommonly show a foreign body giant cell reaction to free keratin, and occasionally foci of calcification are evident. Amyloid deposits are uncommon.98–100 Some trichoepitheliomas, however, may show little keratin cyst formation.2 Instead, the tumor is composed of a rather circumscribed lesion in which discrete lobules of basaloid cells are widely dispersed throughout an abundant connective tissue stroma (Figs 31.96, 31.97). Tumors with this particular pattern are likely to have arisen at extrafacial sites. Rarely, epithelial giant cells and multinucleated forms have been observed in tumor lobules.101

Differential diagnosis Sometimes the histological appearances of trichoepithelioma are difficult to distinguish from those of keratotic basal cell carcinoma. The presence of ulceration and/or a marked tumor–stroma retraction artifact with mucin deposits argue in favor of the latter, whereas marked epithelial frond

B

Fig. 31.96 (A, B) Trichoepithelioma: in this example, the tumor is composed of small basophilic lobules surrounded by a dense fibrous stroma. Keratocysts are not present.

Desmoplastic trichoepithelioma (sclerosing epithelial hamartoma)

Desmoplastic trichoepithelioma (sclerosing epithelial hamartoma) Desmoplastic trichoepithelioma was originally thought to represent a syringoid variant of trichoepithelioma. It was subsequently described simultaneously as desmoplastic trichoepithelioma and sclerosing epithelial hamartoma.

Clinical features Desmoplastic trichoepithelioma is an asymptomatic, slowly growing lesion that usually presents on the face or neck of young adults, favored sites being the cheek, chin, and forehead (Figs 31.98, 31.99).1–12 Congenital presentation is rare.13 Lesions are usually solitary, although patients with multiple tumors have occasionally been documented.14,15 It shows a predilection for females (4:1).2 The tumor is 3–8 mm in diameter, hard and annular, white or yellow, with a depressed or atrophic center and an elevated border.2,16 Typically, the lesion does not ulcerate. Occasionally, milia are also present. Desmoplastic trichoepithelioma is not seen in patients with the multiple trichoepithelioma syndromes and familial occurrence is exceptional.17,18

Fig. 31.97 Trichoepithelioma: the tumor is composed of small cells with uniform darkly staining nuclei.

f­ ormation, and more particularly papillary mesenchymal body with hair bulb formation, are indicative of the former.98 Mitotic figures and apoptotic cells may be present in both conditions.98 Immunohistochemistry may play a useful role in the differential diagnosis although the cytokeratin (CK) expression pattern is largely similar.97,102 Only CK15, which is expressed in most ­trichoepitheliomas but not in basal cell carcinoma, appears to be of some value.103,104 Expression of bcl-2 is consistently found to be diffuse in basal cell carcinoma while it is predominantly peripheral in trichoepithelioma.102,105 The MIB-1 proliferative index and p53 nuclear staining are increased in basal cell carcinoma compared to trichoepithelioma, and androgen receptor expression is observed in the majority of basal cell carcinomas while it is absent in trichoepitheliomas.106,107 In addition, the stroma surrounding trichoepithelioma contains CD34+ cells whereas these are largely absent in basal cell carcinoma.108 CD10 staining in trichoepithelioma is predominantly located in the stromal rather than the epithelial component while the opposite is true for basal cell carcinoma (Table 31.1).109 However, none of the above mentioned immunohistochemical stains can be used with complete confidence in the differential diagnosis and should not be relied upon. A clinical history of numerous small facial papules is highly suggestive of epithelioma adenoides cysticum. If the lesion is solitary and the diagnosis is in doubt, it is probably in the patient's safest interests to treat it as a keratotic basal cell carcinoma. Trichoepithelioma shows considerable histological overlap with trichoblastoma and indeed some authors might classify it as such.

Fig. 31.98 Desmoplastic trichoepithelioma: there is a white annular lesion with a rolled upper border reminiscent of basal cell carcinoma. By courtesy of the Institute of Dermatology, London, UK.

Table 31.1 Immunohistochemical profile of basal cell carcinoma, trichoblastoma and trichoepithelium BCC

TB

TE

bcl-2 (epithelium)

+ (diffuse)

± (peripheral)

± (70%; peripheral)

CD10 (epithelium)

+ (86%)

±

± (15%)

CD10 (stroma)

−

+

+ (92%)

CD34 (stroma)

±

±

+

Androgen receptor (epithelium)

+ (78%)

−

−

Intratumoral CK20positive Merkel cells

−

+ (70%)

n/a

Fig. 31.99 Desmoplastic trichoepithelioma: this example on the nose presented as a depressed area of scarring. By courtesy of the Institute of Dermatology, London, UK.

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Histological features Desmoplastic trichoepithelioma is quite different from conventional trichoepithelioma. It consists of a triad of narrow epithelial strands, keratinous cysts, and a desmoplastic stroma (Figs 31.100, 31.101).1,3,4 The epidermis may be normal, atrophic or mildly acanthotic. Occasionally, a central depression is evident. Situated within the upper and mid dermis is a variable admixture of linear and branched epithelial strands and keratinizing cysts embedded in a dense fibrous and often collagenous stroma (Figs 31.102, 31.103). The cysts consist of a peripheral border of small cuboidal basal cells with prominent nuclei and scanty cytoplasm. These mature to form squamous epithelium, which in turn undergoes epidermoid keratinization. Epithelial strands sometimes bud from the cyst walls.1 A foreign body giant cell reaction due to released keratin is very common. Calcification is also frequently seen and occasionally bone formation occurs (Fig. 31.104).19 The epithelial strands (which sometimes unite with the epidermis) are composed of small cuboidal basaloid cells in a layer 1–3 cells thick. Mitotic activity is very rare and pleomorphism is never a feature. Peripheral palisading is absent. Occasionally, aggregates of ghost cells are evident.20 The tumor cells are PAS-negative. The tumor stroma is dense and often appears hyalinized. Merkel cells are numerous and an integral component of the tumor.21,22

Fig. 31.100 Desmoplastic trichoepithelioma: low-power view showing the typical features. Note the keratocysts and epithelial strands embedded in a dense fibrous stroma.

Fig. 31.101 Desmoplastic trichoepithelioma: in this example, a follicular origin is evident.

Fig. 31.102 Desmoplastic trichoepithelioma: note the narrow strands of small basophilic cells embedded in a dense collagenous stroma.

Fig. 31.103 Desmoplastic trichoepithelioma: the cysts show epidermoid keratinization.

Fig. 31.104 Desmoplastic trichoepithelioma: focal calcification as shown in this field is a very common feature.

Desmoplastic trichoepithelioma (sclerosing epithelial hamartoma)

Fig. 31.105 Desmoplastic epithelioma: this example shows a coexistent dermal nevus.

Fig. 31.107 Desmoplastic trichoepithelioma: the tumor cells express EMA but there is no evidence of ductal differentiation.

carcinoma). The presence of duct formation or intracytoplasmic lumina, as determined with the use of diastase–PAS staining or by assessing EMA and CEA immunohistochemistry, excludes a tumor of follicular differentiation (Fig. 31.107).37,38 Furthermore, CD23 expression is not identified in desmoplastic trichoepithelioma.39

Trichoblastoma

Fig. 31.106 Desmoplastic trichoepithelioma: high-power view.

Perineural infiltration is never seen in desmoplastic trichoepithelioma. P53 and bcl-2 are not expressed and the MIB-1 proliferation index is extremely low.23 In contrast to morpheaform basal cell carcinoma there is no expression of the matrix metalloproteinase stromelysin-3 in perilesional fibroblasts and the surrounding stroma contains CD34+ cells.24–26 Occasionally, desmoplastic trichoepithelioma coexists with an intradermal nevus including blue nevus (Figs 31.105, 31.106).19,27–31 Whether this is fortuitous or represents melanocyte-induced epithelial hyperplasia, as has been suggested, is uncertain.28,32 It does, however, occur sufficiently frequently to suggest that the association is not random. Desmoplastic trichoepithelioma has also been described in a varicella scar.33

Differential diagnosis Desmoplastic trichoepithelioma is most likely to be confused with morpheaform basal cell carcinoma.3,4,20 It differs by its symmetry, and absence of peripheral palisading, necrosis, retraction artifact, and mitotic activity. Desmoplastic trichoepithelioma rarely ulcerates. Morpheic basal cell carcinoma is not usually associated with horn cyst formation. By immunohistochemistry, CK20-positive Merkel cells are identified in most desmoplastic trichoepitheliomas but only in a small subset of basal cell carcinomas.34 In contrast, most cases of desmoplastic trichoepithelioma are negative for androgen receptor.34,35 Similar to basal cell carcinoma, desmoplastic trichoepithelioma stains positively for Ber-EP4 and this marker is not useful in the distinction from basal cell carcinoma.36 Occasionally, particularly when only small biopsies are available for study, desmoplastic trichoepithelioma may be mistaken for syringoma, microcystic adnexal carcinoma or eccrine epithelioma (eccrine syringoid

Trichogenic tumors are neoplasms recapitulating the germinative hair bulb and its associated mesenchyme.1 Their nomenclature is, however, exceedingly confusing. Analogous to odontogenic neoplasms, Headington classified these tumors according to the relative amounts of epithelial and mesenchymal components and the presence of stromal inductive change.2 Purely epithelial tumors were labeled trichoblastoma while mixed epithelial and mesenchymal tumors were referred to as trichoblastic fibroma or trichogenic trichoblastoma in the presence of hair follicle differentiation.2,3 Individual neoplasms are, however, capable of showing varying degrees of differentiation and the originally proposed classification is too strict and limited.4 In addition, subsequent reports of trichogenic neoplasms have used a variety of designations, confusing classification of these tumors even further. For example, tumors resembling trichoblastic fibroma have been referred to as giant solitary trichoepithelioma, subcutaneous trichoepithelioma or immature trichoepithelioma. More recently, entities such as trichogerminoma, rippled-pattern trichoblastoma, rippled-pattern trichomatricoma, and melanotrichoblastoma have also been described. These tumors display some unique histological features but also share features of the traditional trichogenic tumors. While it is important to recognize distinct histological patterns within a neoplasm, it is equally important that classification is comprehensible and meaningful. Since the clinical presentation and behavior of the aforementioned entities are similar and a variety of histological patterns may be seen in any one tumor, trichogenic tumors in this text are unified under the single heading trichoblastoma. Cutaneous lymphadenoma has recently been shown to represent a variant of trichoblastoma and is likely synonymous with trichoblastoma with adamantinoid features. Due to its distinctive morphological features it is discussed separately.

Clinical features Trichoblastoma presents clinically as a slowly growing, solitary, well­circumscribed nodule located predominantly in the head and neck area with predilection for the scalp but other anatomic sites including trunk, proximal extremities, perianal, and genital region may also be affected (Fig. 31.108).1,4–38 Lesions rarely present as infiltrative plaques and these are almost invariably

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Fig. 31.108 Trichoblastoma: this ulcerated, polypoid lesion is present between the buttocks, one of the characteristic sites. By courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK.

located on the face, especially the cheeks, where they have been referred to as ‘plaque-variant’ of trichoblastic fibroma.5,6 Trichoblastomas are frequently present for multiple years before initial biopsy and they usually grow to a large size – 3 cm or more in diameter; some examples have reached 8–10 cm across.7–10 Any age group (except young children) may be affected, but most commonly patients are in their fifth to seventh decades.1,4–38 The tumor occurs equally in men and women except for the plaquelike facial lesion where there is a striking female predominance of 9:1.5 There is no relationship with familial multiple trichoepitheliomas but trichoblastoma has been described in a patient Birt-HoggDubé syndrome and in one patient with Curry-Jones syndrome, characterized by multiple malformations involving brain and skull abnormalities, polysyndactyly as well as defects of eyes, skin, and gastrointestinal tract.39,40 Lesions are typically skin colored although a pigmented variant has also been documented.11,12 They are rarely related to a dilated pore.41 Development of trichoblastoma as well as basal cell carcinoma has been reported as a ­complication of radiation treatment for ringworm infection of the scalp.42 Trichoblastoma typically behaves in a benign fashion. Malignant change has, however, been rarely described (see below).13,43–54

Fig. 31.109 Trichoblastoma: low-power view of a pseudoencapsulated multinodular basaloid cell population. Note the absence of a retraction artifact. The stromal component is best seen in the center of the field.

Fig. 31.110 Trichoblastoma: scanning view of a trichoepithelioma-like variant (trichoblastic fibroma) showing an admixture of basophilic tumor lobules and foci of adenoid change. Note the abundant densely cellular stroma.

Histological features Trichoblastoma is a well-circumscribed but unencapsulated nodular tumor spanning the entire dermis, characteristically extending into subcutaneous tissue (Fig. 31.109). A purely subcutaneous location may rarely be ­seen.1,3,15–18,55,56 It is devoid of epidermal or follicular derivation and characterized by variably sized epithelial nests closely resembling basal cell carcinoma. Peripheral palisading is conspicuous but there is stromal condensation around tumor lobules and cleft artifact is not a prominent feature. The amount of surrounding stroma as well as ‘stromal induction’ is variable between different tumors as well as within the same lesion. The tumor described as trichoblastic fibroma is characteristically biphasic, being composed of lobules of basaloid cells intimately associated with a conspicuous fibromyxoid stroma (Fig. 31.110).1,5,19 Larger lobules and their stroma are often arranged in a mosaic pattern, while the smaller islands of tumor cells are set in close clusters with little intervening stroma. Tumor cells are small and basophilic with minimal cytoplasm. They often show peripheral palisading. Pleomorphism is not a feature, but mitotic activity is ­frequently brisk and apoptotic bodies may be evident. Some of the lobules have associated narrow epithelial strands giving rise to ‘antler-like’ patterns (Fig. 31.111).15,17

Fig. 31.111 Trichoblastoma: high-power view showing epithelial strands and stroma.

Trichoblastoma Occasionally, a cribriform appearance is evident (Fig. 31.112).1 Sometimes the large lobules are associated with keratin cyst formation although much less frequently than seen in trichoepithelioma. Keratinization is usually epidermoid in nature, but pilar type may also be represented. The small tumor lobules sometimes form whorls or squamous eddies around a central space or keratinized core and occasionally focal glycogen-rich clear cell change is evident.1 The fibromyxoid stroma is an important, integral component of the tumor (Fig. 31.113). It comprises both stellate and spindled cell fibroblasts and characteristically is associated with primitive hair papilla formation – ­so-called papillary mesenchymal bodies, which often indent the adjacent epithelium (Fig. 31.114).1 At the opposite end of the spectrum, some tumors are predominantly composed of large basaloid epithelial lobules showing peripheral palisading and only scant sclerotic intervening stroma with no or only little evidence of stromal induction (Figs 31.115, 31.116).9,11,12,18,21–25 Within the tumor lobules, cells may take on a spindle appearance and align to form nuclear palisading reminiscent of verrocay body formation. This pattern can be focal or extensive and tumors such as this have been referred to as rippled-pattern trichoblastoma (rippled-pattern trichomatricoma) (Figs 31.117, 31.118).9,21–25 Sebaceous differentiation is sometimes observed in this variant. Tumors described as trichogerminoma show additional distinctive histological features.13,14,57 They are composed of small basaloid epithelial lobules and nests separated by thin fibrous strands. The lobules are composed of densely packed basaloid cells reminiscent of ‘Zellballen’ and closely resemble the hair bulb (Fig. 31.119). A peripheral palisade surrounds them. Trichoblastoma is rarely heavily pigmented and contains abundant intralesional dendritic melanocytes (Figs 31.120–31.122). This variant has been referred to as pigmented trichoblastoma or melanotrichoblastoma.11,12,58 Occasionally, abundant clear cell change (clear cell trichoblastoma) may be evident, and ductal as well as sebaceous differentiation has been described.13,24,25,59–65 Nodular trichoblastoma with adamantinoid features is a distinctive variant thought to be synonymous with cutaneous lymphadenoma.37 Panfolliculoma is an exceedingly rare and unusual tumor.36,66 It falls into the spectrum of trichoblastoma but shows unique histological features with differentiation towards all elements of the hair follicle. It is well demarcated and symmetrical and both solid and cystic with a wide range of differentiation towards germinal hair bulb and papilla as well as follicular matrix and inner and outer root sheath. A mild chronic inflammatory cell infiltrate is sometimes present and mast cells are often conspicuous. Amyloid deposits are commonly found within the stroma and focal calcification is sometimes evident (Figs 31.123, 31.124).11,33 Merkel cells frequently populate trichoblastoma.67,68

A

B

Fig. 31.113 (A, B) Trichoblastoma: in this example, there is a conspicuous stromal component. Note the peripheral palisading.

Fig. 31.112

Fig. 31.114

Trichoblastoma: stromal mucin deposition results in adenoid foci as shown in this field. This feature may cause confusion with adenoid basal cell carcinoma.

Trichoblastoma: condensation of the stroma has resulted in primitive hair papilla formation (papillary mesenchymal body).

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Fig. 31.115

Fig. 31.118

Trichoblastoma: this example, which arose in a nevus sebaceus, consists solely of an epithelial component. There is little stromal induction. In the past such lesions were regarded as basal cell carcinoma.

Trichoblastoma: high-power view.

A

Fig. 31.116 Trichoblastoma: high-power view.

B

Fig. 31.119 (A, B) Trichoblastoma (trichogerminoma): this example consists predominantly of a germinative component comprising basaloid cells admixed with distinct pale micronodules (Zellballen).

Fig. 31.117 Trichoblastoma: rippled-pattern variant showing prominent palisading.

Trichoblastoma may arise within a nevus sebaceus and rarely occurs in a poroma (Fig 31.115).58,61,69–80 Occasionally, areas morphologically reminiscent of basal cell carcinoma may arise within an otherwise typical trichoblastoma, raising concern for malignant change.81

Desmoplastic trichoepithelioma (sclerosing epithelial hamartoma)

Fig. 31.120

Fig. 31.123

Pigmented trichoblastoma: this lesion developed in a background of nevus sebaceus. There is heavy melanin pigmentation.

Trichoblastoma: in this example there are conspicuous amyloid deposits.

Fig. 31.124 Trichoblastoma: focal calcification is a not uncommon feature.

Fig. 31.121 Pigmented trichoblastoma: medium power view. There is abundant pigment.

Immunohistochemical studies of cytokeratin expression have revealed the presence of cytokeratins 6, 8, 14, 17, and 19 and absence of hair keratins in trichoblastoma, trichoepithelioma, and basal cell carcinoma, thereby demonstrating differentiation towards the follicular outer root sheath.82–86 Lack of CK7 expression in trichoepithelioma compared with both trichoblastoma and basal cell carcinoma has been documented.83 Analogous to basal cell carcinoma and pilomatricoma, CD10 is expressed in most trichoblastomas.65,87 In contrast to basal cell carcinoma, however, trichoblastoma does not express androgen receptor and is often colonized by cytokeratin 20-positive Merkel cells (see Table 31.1).81,88 By molecular analysis, a mutation in β-catenin (CTNNB1) has been identified in 1 of 15 trichoblastomas studied.89 In contrast, no mutations in the PTCH gene have been detected.90

Differential diagnosis

Fig. 31.122 Pigmented trichoblastoma: melanin pigment is present within tumor cells, dendritic cells, and macrophages.

Trichoblastoma is most commonly mistaken for conventional trichoepithelioma and nodular basal cell carcinoma. It is much larger than conventional trichoepithelioma, and is situated within deep dermis and subcutaneous tissue while ‘conventional’ trichoepithelioma is centered in mid dermis. Trichoblastoma shows less keratinization and is devoid of epidermal or follicular origin. Lack of epidermal origin, more conspicuous stroma with prominent papillary mesenchymal bodies, and absence of retraction artifact are useful diagnostic features in excluding basal cell carcinoma. It is, however, often extremely difficult to make this distinction with confidence, especially on a small biopsy specimen. Complete excision is therefore the treatment of choice.

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Malignant trichoblastoma Trichoblastoma is a biphasic tumor characterized by an epithelial as well as an intimately associated stromal component in varying proportions. The malignant change in trichoblastoma may be related to its epithelial component (trichoblastic carcinoma), its stromal component (trichoblastic sarcoma) or both (trichoblastic carcinosarcoma).

Clinical features Malignant trichoblastoma is a tumor of the elderly, presenting in the fifth to the eighth decade of life. 1–17 There is no gender predilection and a wide range of anatomic sites is affected. Malignant trichoblastoma has also been documented in the setting of Brooke-Spiegler syndrome and familial ­multiple trichoepithelioma.12,13,18 Tumors in this setting may present at an earlier age.12

Fig. 31.127 Malignant trichoblastoma: ulcerated tumor. Note the epithelial strands and associated stroma. Courtesy of D. Kazakov, MD, Charles University Medical Faculty Hospital, Pilsen, Czech Republic.

Fig. 31.125 Malignant trichoblastoma: scanning view showing a pseudoencapsulated tumor composed of variably sized nests of basaloid cells. Courtesy of D. Kazakov, MD, Charles University Medical Faculty Hospital, Pilsen, Czech Republic.

Fig. 31.128 Malignant trichoblastoma: high-power view showing marked nuclear pleomorphism and mitotic activity. Courtesy of D. Kazakov, MD, Charles University Medical Faculty Hospital, Pilsen, Czech Republic.

Fig. 31.126 Malignant trichoblastoma: high-power view showing nuclear atypia and increased mitotic activity. Courtesy of D. Kazakov, MD, Charles University Medical Faculty Hospital, Pilsen, Czech Republic.

Trichoblastic carcinoma: two distinct forms, low- and high-grade variants have been reported in the literature:1–14 • Low-grade trichoblastic carcinoma: these are characterized by morphological features of trichoblastoma but have an infiltrative growth pattern with involvement of deeper tissues such as skeletal muscle.1–8 They have also been referred to as ‘plaque variant of trichoblastic fibroma’ and ‘aggressive trichoblastoma’.1–3,6,7 Clinical presentation is of a large plaque measuring multiple centimeters with a strong predilection for the face.1–8 There are only few documented examples in the literature and clinical follow-up is limited. Although no adverse outcome such as local recurrence or metastasis has been documented, we have seen a small number of cases of local recurrence. Complete removal and follow-up is advisable. • High-grade trichoblastic carcinoma: the characteristic feature of this tumor is the presence of a high-grade, undifferentiated carcinoma arising in the background of a trichoblastoma or trichoepithelioma. Only seven cases of this rare tumor have been reported to date.9–14 A wide range of anatomical sites is affected, with predilection for the trunk and

Malignant trichoblastoma

A

B

Fig. 31.129 Malignant trichoblastoma: (A) low-power view of a biphasic tumor. Benign trichoepithelioma is seen in the left upper quadrant, Elsewhere there is a cystic and necrotic carcinomatous nodule; (B) high-power view of benign component.

A

B

Fig. 31.130 (A & B) Malignant trichoblastoma: the tumor is composed of multiple nodules of basaloid cells showing central necrosis.

Fig. 31.131 Malignant trichoblastoma: there is nuclear pleomorphism and multiple mitoses are evident.

extremities. The head and neck area appears to be involved less often. The clinical presentation is of a frequently ulcerated tumor measuring multiple centimeters. A deeply pigmented tumor has been reported as malignant melanocytic trichoblastoma.14 Typically, there is a history of a longstanding lesion over many years, which has shown recent and rapid growth.9–12 An additional history of a systemic malignancy has been elucidated in some patients and one tumor arose in a patient with Brooke-Spiegler syndrome and another in the setting of familial multiple trichoepithelioma. High-grade trichoblastic carcinoma has potential for aggressive clinical behavior and distant metastasis and death from disease has been documented in two patients.9,10 Only one case of trichoblastic sarcoma and four cases of trichoblastic carcinosarcoma have been documented in the literature so far. All tumors have affected the elderly. The documented trichoblastic carcinosarcomas have presented as ulcerated tumors affecting the ear, cheek, neck, and sacral area.11,16–18 The trichoblastic sarcoma presented on the neck as a 4-cm mass.15 A history of a longstanding tumor with recent change and rapid growth similar to high-grade trichoblastic carcinoma may be elucidated. A carcinosarcoma has also developed on the back in a patient with Brooke-Spiegler syndrome.18 Follow-up is limited but no adverse outcome has been reported thus far.

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Histological features Low-grade trichoblastic carcinoma: this neoplasm is characterized by an asymmetrical dermal-based tumor with infiltrative margin and extension into deeper structures including skeletal muscle. It is composed of basaloid epithelial nests and strands with intimately associated stroma and papillary mesenchymal body formation.1–8 Cytological atypia is mild but mitotic activity can be present. Keratinization and keratocyst formation may be focal findings (Figs 31.125–31.128). High-grade trichoblastic carcinoma: the characteristic histological feature of this rare neoplasm is the presence of an undifferentiated, morphologically high-grade carcinoma arising in the background of a trichoblastoma or trichoepithelioma.9–13 Tumors involve dermis and subcutis without epidermal connection. The malignant component shows a solid and expansile growth with pushing or infiltrative borders. It is composed of atypical basaloid cells showing varying degrees of nuclear pleomorphism arranged in nests and ribbons. Spindle cell differentiation as well as focal peripheral palisades, squamoid features, and external root sheath differentiation may be additional findings. Mitotic figures are numerous, including atypical forms. Frank necrosis is frequently present. Melanin deposits may rarely be present, leading to the clinical impression of a pigmented tumor.14 Diagnosis rests upon recognition of a pre-existing trichoblastoma or trichoepithelioma (Figs 31.129–31.131). Trichoblastic sarcoma: this circumscribed biphasic tumor involves dermis and subcutis and is characterized by pushing rather than diffusely infiltrative borders.15 It is composed of tumor lobules containing a central benign-appearing epithelial element associated with a bland stromal component reminiscent of trichoblastoma/trichoepithelioma. Focal sebaceous differentiation may also be present. The highly cellular sarcomatous component is located peripherally as a nodular and expansile area sharply demarcated from the rest of the tumor. It lacks epithelial elements and is composed of large pleomorphic and bizarre-appearing cells which frequently are multinucleated. Mitotic activity is brisk and includes atypical forms. In areas, the sarcomatous elements ­infiltrate into the benign epithelial elements of the tumor. By immunohistochemistry, the sarcomatous component focally expresses smooth muscle actin but is negative for cytokeratins, desmin and S-100. Trichoblastic carcinosarcoma: this tumor is characterized by the presence of a malignant epithelial component showing trichoblastic differentiation associated with malignant mesenchyme.11,16–18 These asymmetric and expansile tumors may show exo- and endophytic growth with ulceration of the overlying epidermis. The epithelial component forms tumor nodules of varying size in areas showing a cribriform or fenestrated architecture. Tumor lobules consist of basaloid cells with scant cytoplasm and significant cytological atypia and nuclear pleomorphism. There is nuclear crowding, increased mitotic as well as apoptotic activity, and a peripheral palisade may be evident.16,17 Surrounding the epithelial tumor lobule is a multilayered rim of medium-sized stromal cells with scant cytoplasm and pale, vesicular nuclei. These cells form concentric layers around the epithelial lobules and, in areas, they are arranged to form so-called ‘continuous papillae’.16,17 In other areas, they show diffuse and patternless growth within a slightly myxoid matrix. Nuclear pleomorphism and crowding is prominent and increased and atypical mitotic activity is evident. In a case reported as ‘high-grade’ trichoblastic carcinosarcoma, an additional pleomorphic spindle cell component was present.17 By immunohistochemistry, the stromal component is negative for cytokeratin and EMA as well as actin, desmin, CD31, and CD34. The MIB-1 ­proliferative index is high and p53 expression is observed in both stromal and epithelial components.16

Trichoblastic carcinoma differs from carcinosarcoma by the presence of a benign rather than malignant mesenchymal component. The differential diagnosis of carcinosarcoma further includes primary or secondary sarcomas to the skin and, analogous to ‘high-grade’ trichoblastic carcinoma, the diagnosis rests on recognition of the trichoblastic nature of the epithelial component. Trichoblastic carcinosarcoma shows overlapping features with other cutaneous carcinosarcomas and especially sarcomatoid (metaplastic) basal cell carcinoma. Trichoblastic carcinosarcoma appears to be morphologically ­distinct, based largely on its epithelial–mesenchymal interaction with ­formation of follicular germlike structures.

Cutaneous lymphadenoma (lymphoepithelial tumor of the skin) Cutaneous lymphadenoma is a rare neoplasm of disputed histogenesis. Differentiation towards the pilosebaceous unit has been postulated and recently some authors have included it within the category of trichoblastoma (trichoblastoma with adamantinoid features).

Clinical features It presents as a usually slowly growing, skin-colored, sometimes indurated, papule, nodule or plaque, up to 1 cm in diameter and clinically mistaken for dermatofibroma, sebaceous hyperplasia, and basal cell carcinoma.1–23 It shows a predilection for the head, particularly the face, and only rarely are the legs affected (Fig. 31.132).2,3,13 The sex incidence is equal. Although the age range is wide (newborn–75 years) most patients are in the fourth or fifth decade.2,4,16,22,23 Recurrence and metastasis has not yet been documented and local excision appears curative.5

Pathogenesis and histological features Cutaneous lymphadenoma was originally thought to differentiate towards the pilosebaceous unit.2,3 Arguments in favor of this hypothesis included the presence of occasional sebaceous cells within the tumor lobules and connection with follicular structures.2,3 This view has been challenged by reports proposing sweat gland differentiation due to the presence of ductlike structures.8,9,11,22 It is, however, not clear at this point whether their presence represents true ductal differentiation or entrapment of pre-existing structures, as was originally suggested.2 More recent data, including immunohistochemical profiling, postulate pilar differentiation; these data advocate classification as a variant of trichoblastoma (adamantinoid trichoblastoma.)13,14,24 Cutaneous lymphadenoma is primarily located in the dermis although sometimes the superficial subcutaneous tissue is affected and is characterized by irregularly shaped lobules and trabeculae of epithelial cells enmeshed

Differential diagnosis The main differential diagnosis of ‘low-grade’ trichoblastic carcinoma is with trichoblastoma and basal cell carcinoma as they show morphologic features of trichoblastoma but infiltrative growth more reminiscent of basal cell carcinoma. As discussed above, complete excision may be the treatment of choice until further data regarding clinical behavior become available. ‘High-grade’ trichoblastic carcinoma has a wide differential diagnosis including Merkel cell carcinoma and sebaceous carcinoma as well as cutaneous metastasis from visceral primary carcinomas. The diagnosis is based entirely on identification and recognition of a pre-existing trichoblastoma or trichoepithelioma.

Fig. 31.132 Cutaneous lymphadenoma: this lesion presented as a dome-shaped nodule on the cheek, a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.

Cutaneous lymphadenoma (lymphoepithelial tumor of the skin)

Fig. 31.133 Cutaneous lymphadenoma: scanning view showing multiple epithelial nodules embedded within a dense fibrous stroma.

Fig. 31.134 Cutaneous lymphadenoma: the epithelial component consists of a rim of basaloid cells surrounding a clear or pale-stained cell population.

in a dense fibrous stroma, rarely containing Alcian blue (pH 5.0) positive mucin (Fig. 31.133).2,7 The tumor is well delineated but unencapsulated; occasionally, connection with the epidermis or a hair follicle is evident.2,3,5,6 Lobules are composed of a peripheral rim of one or more layers of small basaloid cells, sometimes showing palisading, surrounding a core of large glycogen-rich cells with vesicular nuclei and often containing large nucleoli­ (Fig. 31.134).2,5 Mitotic activity is not usually a feature. An integral component is the presence of large numbers of small lymphocytes admixed with the epithelial cells; germinal center formation can be seen in the adjacent stroma (Fig. 31.135).4 Occasionally, foci of central keratinization are present and rare isolated sebaceous cells may be identified.2,5 Small duct-like structures are sometimes observed within the lobules.2,8,9,12,22 Their epithelial lining may show decapitation secretion and their luminal surfaces stain positively with antibodies against EMA. Cutaneous lymphadenoma has been described adjacent to an osteoma, and synchronous presentation with syringoid eccrine carcinoma has been reported.6,12 Immunohistochemically, the epithelial cells express keratin and sometimes EMA, but they are consistently CEA negative (Fig 31.136).2,4,5 The infiltrate is composed of a mixture of B and T lymphocytes with a predominance of the latter.2,7 CK20+ Merkel cells may be present and S-100 protein-positive dendritic cells are often conspicuous (Fig. 31.137).4,14

Fig. 31.135 Cutaneous lymphadenoma: the tumor cells have abundant cytoplasm and large vesicular nuclei with prominent nucleoli. Note the conspicuous lymphocytes.

Fig. 31.136 Cutaneous lymphadenoma: the tumor cells express keratin (MNF-118)

Fig. 31.137 Cutaneous lymphadenoma: note the S-100 protein-positive dendritic cells.

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Tumors of the hair follicle These coexpress CD1a and likely represent Langerhans cells.14 The peripheral layer in cutaneous lymphadenoma stains positively for ­bcl-2.14 Scattered within the center of the lobules are CD30+ cells, which have been variably interpreted as representing activated lymphocytes and histiocytes.10,14

Differential diagnosis Cutaneous lymphadenoma should not be confused with lymphoepithelial-like carcinoma of the skin.2 The latter represents a poorly differentiated tumor with a very heavy admixture of lymphocytes, reminiscent of nasopharyngeal lymphoepithelioma.25

Perifollicular fibroma Clinical features Perifollicular fibroma is a very rare nevoid lesion of the perifollicular sheath. It may be single (congenital or acquired) or multiple (late onset) and presents as a 1–5-mm diameter, asymptomatic, flesh-colored or erythematous papulonodule most commonly located on the face or neck.1–5 Occasionally, the trunk is affected.6 Perifollicular fibromas have been documented in association with colonic polyps and may be inherited as an autosomal dominant trait.4,7,8 This association has been referred to as Hornstein-Knickenberg syndrome. The Birt-Hogg-Dubé syndrome is similar if not identical.9,10

Pathogenesis and histological features The lesion consists of concentric layers of cellular fibrous tissue producing an ‘onion skin’ effect around a normal hair follicle (Figs 31.138, 31.139).1,11 An artifactual cleft often separates the fibroma from the adjacent connective tissue. Occasionally, a chronic inflammatory cell infiltrate is present within the lesion and around the blood vessels in the superficial dermis.

Fig. 31.138 Perifollicular fibroma: the hair follicles are surrounded by a dense connective tissue sheath. Note the retraction artifact.

Fibrofolliculoma Clinical features Fibrofolliculoma very rarely presents as a solitary facial papule.1,2 More often, multiple lesions are seen, which represent either an isolated condition or an autosomal dominant syndrome.1,3,4 In one instance, a series of patients with multiple fibrofolliculomas had familial thyroid medullary carcinoma.5 The presence of multiple fibrofolliculomas has also been described in association with a connective tissue nevus.6 Fibrofolliculoma has been reported in association with nevus lipomatosis and in a patient with tuberous sclerosis.7,8 Patients with multiple fibrofolliculomas may have multiple trichodiscomas and acrochorda (Birt-Hogg-Dubé syndrome).9–12 Fibrofolliculomas present as dome-shaped, pale yellow or white papules, 2–4 mm in diameter, with a predilection for the scalp, forehead, face, and neck (Fig. 31.140). Lesions may also be found on the chest and back, and antecubital and popliteal fossae.3 Some papules are umbilicated with a keratinous plug, while others contain hairs. Presentation is most common in the third decade of life.3,6,9

Histological features Fibrofolliculoma is a benign hamartomatous condition combining proliferation of the perifollicular fibrous and external root sheaths.1,13 It has a unique and very distinctive histological appearance, which is centered upon the infundibulum. A section through the middle of a papule reveals a well-formed hair follicle, which is often cystically dilated and contains keratinous debris or a hair shaft (Fig. 31.141). Surrounding the infundibulum is a circumscribed proliferation of loose connective tissue containing fine collagen and excess hyaluronic acid. Elastic fibers are absent.3,6 Epithelial strands, 2–4 cells thick, arise from the infundibulum, anastomose and rejoin the infundibulum or unite with the stratum germinativum of the sebaceous gland, to give an appearance reminiscent of scaffolding (Fig. 31.142). Residual sebaceous glands are often incorporated into the nevus. Some papules show ­histological features combining fibrofolliculoma with trichodiscoma. The acrochorda may show features of a fibroepithelial polyp or focal fibrofolliculomatous change.

Fig. 31.139 Perifollicular fibroma: in addition to fibrous tissue there are excessive glycosaminoglycans.

Fig. 31.140 Fibrofolliculoma: note the numerous pale facial papules. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Trichodiscoma, Birt-Hogg-Dubé, and Hornstein-Knickenberg syndromes

Fig. 31.141 Fibrofolliculoma: this combination of outer root sheath and perifollicular fibrous sheath proliferation is pathognomonic.

Fig. 31.143 Birt-Hogg-Dubé syndrome: note multiple facial papules. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 31.144 Fig. 31.142

Birt–Hogg–Dubé syndrome: neurosis papules are seen some with features of acrochorda. From the collection of the late N.P. Smith, M., the Institute of Dermatology, London, UK.

Fibrofolliculoma: high-power view.

Trichodiscoma, Birt-Hogg-Dubé, and Hornstein-Knickenberg syndromes Clinical features Trichodiscoma is a hamartomatous proliferation of the mesodermal component of the hair disc (haarscheibe), which represents a slowly adapting mechanoreceptor.1 Patients present with hundreds of small (1–5 mm) asymptomatic, round, sharply circumscribed, firm, dome-shaped or flat, flesh-colored papules, which are widely distributed about the body.1,2 Lesions are sometimes associated with vellus hairs. There are no associated systemic abnormalities. In some patients the condition is inherited as an autosomal dominant.3 The association of multiple trichodiscomas with fibrofolliculomas and acrochorda was originally described in 1977 and is now referred to as the Birt-Hogg-Dubé syndrome.4,5 This autosomal dominant genodermatosis is clinically characterized by multiple firm papules on the face, neck, and trunk; pedunculated lesions resembling acrochorda may also be present (Figs 31.143–31.145). Importantly, there is an association with internal disease, especially renal tumors and lung disease including recurrent ­spontaneous

Fig. 31.145 Birt–Hogg–Dubé syndrome: papular lesions can be numerous and confluent. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

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Tumors of the hair follicle pneumothorax, lung cysts, and bullous emphysema.6–13 Renal tumors are frequently bilateral and cosegregate in a dominant fashion. Histologically, their spectrum encompasses oncocytoma and chromophobe in addition to papillary renal cell carcinoma.7–9,14–16 An association with intestinal polyps and intestinal malignancy has been proposed but to date it is uncertain whether this truly represents part of the syndrome since no unequivocal evidence has been documented.7,17–20 A number of other systemic manifestations have been reported including medullary thyroid carcinoma, follicular adenoma of the thyroid, multinodular goiter of the thyroid, oncocytoma of the parotid gland, chorioretinal scars, multiple lipomata and angiolipomata, neural tumors, parathyroid adenoma, connective tissue nevus, and multiple facial angiofibromas.4,6,8,17–22,20–27 The significance of these associations is unclear. Hornstein-Knickenberg syndrome is reminiscent of Birt-Hogg-Dubé syndrome. It is characterized by the presence of multiple perifollicular fibromas presenting as numerous papules on the face, neck, and trunk in association with adenomatous polyps and adenocarcinoma of the colon.28–30 More recent data suggest that perifollicular fibroma and fibrofolliculoma/trichodiscoma likely represent a morphological spectrum and that Hornstein-Knickenberg syndrome and Birt-Hogg-Dubé syndrome are manifestations of the same condition.20,31–33

Pathogenesis and histological features Recent studies have excluded a number of candidate genes for ­Birt-Hogg-Dubé syndrome and the susceptibility locus has been mapped to chromosome 17p11.2.34–37 The candidate gene (BHD) has recently been identified, and this encodes for a novel protein, folliculin.37 Although its precise function and mechanism of action remain unknown, folliculin is likely a tumor suppressor gene and involved in the mammalian target of rapamycin (mTOR) pathway similar to other hamartoma syndromes.38–40 Multiple mutations in the folliculin gene have been identified in patients with Birt-Hogg-Dubé syndrome including insertions, deletions, frame shift, and splice site mutations as well as missense and nonsense mutations.41–49 Trichodiscoma is always topographically related to a hair follicle, although multiple sections may be necessary to confirm this.1 The overlying epidermis is flattened, but laterally there is a collarette (Fig. 31.146). It is composed of an unencapsulated, elliptical, loosely woven admixture of collagen, reticulin and thin elastic fibers with abundant acid mucopolysaccharides and containing bland-appearing spindle cells (Fig. 31.147).1–3 Focal hyalinization may sometimes be evident.3 A regular feature is the presence of multiple thin-walled blood vessels with PAS-positive basement membranes within the substance of the tumor (Fig. 31.148).2 A thick-walled vessel with a narrow lumen and conspicuous endothelial cells often enters the tumor, usually approaching from the vicinity of a hair follicle. Melanin pigment within

Fig. 31.147 Trichodiscoma: the core of the lesion consists of edematous connective tissue. By courtesy of V. Liu, MD, Harvard Medical School, Boston, and E. Page, MD, Lahey Clinic, Burlington, USA.

Fig. 31.148 Trichodiscoma: the tumor characteristically contains admixed thin- and thickwalled blood vessels. By courtesy of V. Liu, MD, Harvard Medical School, Boston, and E. Page, MD, Lahey Clinic, Burlington, USA.

small fusiform and stellate cells (presumably Schwann cells) is characteristic. Occasionally, multinucleate cells are evident.3 Examination of serial sections sometimes reveals a peripheral nerve entering the lesion. In contrast to the hair disc, Merkel cells are not present in trichodiscoma. By immunohistochemistry, spindle cells may react with CD34 antibodies but are negative for S-100, SMA, EMA, and desmin.50,51

Neurofollicular hamartoma (spindle cell predominant trichodiscoma) Fig. 31.146 Trichodiscoma: scanning view showing the raised papule with lateral collarette. By courtesy of V. Liu, MD, Harvard Medical School, Boston, and E. Page, MD, Lahey Clinic, Burlington, USA.

Clinical features Neurofollicular hamartoma is a rare benign tumor that lies within the spectrum of trichodiscoma and fibrofolliculoma. Despite its name, true neural differentiation is not a feature and more recently the term ‘spindle

Neurofollicular hamartoma (spindle cell predominant trichodiscoma) cell ­predominant trichodiscoma’ has been proposed to reflect this.1 The tumor is now thought to represent the cellular end of a morphological spectrum with trichodiscoma.1 It presents clinically as a small, skin-colored, dome-shaped, firm papule, less than 1 cm in diameter.2–5 Lesions are almost invariably located on the face, with a strong predilection for the nose or nasolabial fold.2–5 Adults are affected predominantly in the fourth or fifth decade and there is no gender predilection. The clinical differential diagnosis typically includes fibrous papule, basal cell carcinoma, and dermal nevus.

Histological features Neurofollicular hamartoma is a well-circumscribed, dermal-based tumor composed of epithelial and mesenchymal components.2–5 The epithelial component consists of distorted and hyperplastic pilosebaceous units with prominent sebaceous glands accompanied by a proliferation of basaloid and ductal

epithelium. Surrounding and embedding this epithelial component is a somewhat myxoid and fibrillary stroma containing elongate and wavy spindle cells arranged in loosely formed fascicles. Focal palisading may also be observed. Small nerve twigs are interspersed and mast cells are sometimes prominent.2–5 The stromal and epithelial components appear intimately associated. The features of neurofollicular hamartoma are reminiscent of trichodiscoma and fibrofolliculoma and these entities possibly represent a morphological spectrum.3 Variable expression of S-100 protein is identified within these tumors.2–5 However, S-100 positivity is likely present within intralesional S-100-positive dendritic cells rather than the lesional spindle cells.1,3 Furthermore, there is no significant expression of NSE, synaptophysin, GFAP, NFP, EMA or Leu-7, arguing against true neural differentiation.1–5 Spindle cells express CD13 and CD34 as well as CD10 and are negative for actin, desmin, Melan-A, and factor XIIIa.1,6

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32

Tumors and related lesions of the sebaceous glands

See www.expertconsult.com

for references and additional material

Ectopic sebaceous glands  1488

Sebaceoma  1496

Sebaceous carcinoma  1501

Sebaceous hyperplasia  1488

Superficial epithelioma with sebaceous differentiation  1499

Muir-Torre syndrome  1505

Nevus sebaceus  1489 Steatocystoma and sebocystomatosis  1492 Sebaceous adenoma  1494

Sebomatricoma  1500 Basal cell carcinoma with sebaceous differentiation  1500

Mantleoma  1507 Other cutaneous tumors showing sebaceous differentiation  1507

Sebaceous epithelioma  1496

Ectopic sebaceous glands Clinical features Sebaceous glands are normally found in association with a hair follicle. However, at several mucosal sites, they may develop independently, presenting as small 1–3-mm yellow to white papules (Fordyce spots), which can be accentuated when the mucosa is stretched.1 Lesions of the oral cavity ­commonly present on the vermilion border of the lip and the buccal mucosa.2,3 On the vulva, Fordyce spots affect the medial aspect of the labia majora while in males the glans penis is involved.4 Prevalence varies, but some large studies place the incidence of oral lesions at greater than 25%.2,3,5 Incidence increases with age since Fordyce spots are not commonly seen in infants.2,3 They are of little consequence and likely represent a normal physiological variant since such a large proportion of the adult population is affected.1 Rarely, lesions on the lip become a cosmetic nuisance.6 Similar tiny papules are sometimes seen on the areola of the female breast where they are known as Montgomery's tubercles.7–10 These may be associated with vellus hairs or lactiferous ducts, and occasionally in adolescence they are complicated by the development of a small breast lump, which discharges thin secretions.11 Such lesions tend to resolve spontaneously. Sebaceous hyperplasia of the areola has been reported in both women and men (see below), but its relationship to Montgomery's tubercles (if any) is unclear.12 Occasionally, ectopic sebaceous glands have been identified in the esophagus, gastroesophageal junction, uterine cervix, vagina, sole of the foot, ­thymus, and tongue.13–23 Rarely, these lesions have been described as ­extensively involving the esophagus.

Histological features These lesions are all characterized by the presence of well-formed lobules or small clusters of sebocytes located high in the lamina propria and opening directly onto the epithelial surface.

Sebaceous hyperplasia Clinical features Sebaceous hyperplasia is a common condition which is frequently clinically misdiagnosed as basal cell carcinoma. It most often presents on the face of older adults, particularly males (Fig. 32.1).1 Lesions are, ­however,

Fig. 32.1 Sebaceous hyperplasia: multiple lesions are present on the cheek. Note the central umbilication. By courtesy of the Institute of Dermatology, London, UK.

­ ccasionally encountered in children.2,3 The forehead and cheeks are o ­predominantly affected and occasionally diffuse facial involvement occurs (Fig. 32.2).1,4 Other less common sites include the chest, ocular caruncle, penis, scrotum, and vulva.5–11 A linear variant presenting on the penis has been described.12 Lesions – which may occur individually, in groups, or as a sheet of ­papules – present as yellowish, dome-shaped asymptomatic papules 1–2 mm in diameter.1,13 Larger variants measuring 1.0 cm or more in diameter are occasionally seen (giant solitary/senile sebaceous hyperplasia).14–17 The ­papule is umbilicated, and individual lobules growing out from the center can often be identified with a hand lens. Recently, distinctive dermatoscopic ­features including cumulus sign, crown vessels, and milia-like cysts have been described.18,19 Rarely, postpubertal sebaceous hyperplasia occurs, either as an isolated phenomenon or more rarely in association with anhidrotic ectodermal dysplasia.20,21 Familial cases, sometimes with early onset, have also been described.22–24 Sebaceous hyperplasia is significantly increased in transplant

Nevus sebaceus

Fig. 32.2 Sebaceous hyperplasia: in this example, a group of papules is present on the forehead, a characteristic site. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 32.3 Sebaceous hyperplasia: scanning view showing sebaceous glands grouped around a cystic infundibulum.

patients, particularly in males following renal transplantation, and this may be related to therapy with cyclosporin A.25–28 A case in an immunosuppressed patient with Senear-Usher syndrome (pemphigus erythematosus) has recently been reported.29 Ectopic sebaceous glands with associated hyperplasia have been described in the oral mucosa and on the areola where lesions may be bilateral (areolar sebaceous hyperplasia).30–39

Pathogenesis and histological features Although sebaceous development is profoundly affected by androgens, their mode of action in sebaceous hyperplasia has not yet been determined.40 Since these lesions do not regress, it is unclear that they truly represent hyperplasia, which is a reversible phenomenon. Nonetheless, the name sebaceous hyperplasia is certainly indicative of a well-defined clinicopathologic entity. Studies have indicated that overexpression of the mEDA-A1 splice variant of EDA which encodes ectodysplasin, a member of the tumor necrosis factor (TNF) ligand family, induces sebaceous hyperplasia in transgenic mice.41 This transcription factor is involved in skin adnexal development, acting through the nuclear factor-kappaB (NF-κB) and JNK pathways.41,42 Mutations in EDA cause X-linked anhidrotic ectodermal dysplasia.43 The relevance of this finding to human sebaceous hyperplasia remains to be determined, although interestingly and perhaps incongruously, sebaceous hyperplasia as mentioned above has been reported in the setting of anhidrotic ectodermal dysplasia.20,21 In solitary papules, the individual gland is hyperplastic and situated higher in the dermis than normal (Fig. 32.3).44 Individual lobules are increased in number but are not appreciably different in size compared with normal sebaceous glands. The individual lobules drain into a central duct, which is often associated with a hair follicle, through single or multiple follicular infundibula (Figs 32.4, 32.5).45 In confluent lesions, multiple sebaceous glands are similarly affected. In both variants the dermis is normal, except for a variable degree of elastosis. Oral sebaceous hyperplasia is not associated with a hair follicle and the lobules empty into a single duct that opens directly onto the mucosal surface.31,38 Sebaceous hyperplasia overlying a benign fibrous histiocytoma (dermatofibroma) has been documented.46,47

A

Nevus sebaceus Fig. 32.4

Clinical features Nevus sebaceus (Jadassohn, organoid nevus) is not uncommon and often presents at birth although it usually does not cause the patient to seek medical attention until the second to fourth decades.1–3 Lesions have been described in up to 0.3% of neonates.4 The sex distribution is equal.

B

(A, B) Sebaceous hyperplasia: the sebaceous lobules drain through short ductules into the central duct.

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A

Fig. 32.5 Sebaceous hyperplasia: the hyperplastic sebaceous lobules mirror the normal sebaceous gland and consist of an outer layer of basaloid cells surrounding mature sebaceous cells with eosinophilic bubbly cytoplasm.

Nevus sebaceus is single, round or oval, well circumscribed and usually measures 1–6 cm in greatest dimension. It commonly affects the head and neck, particularly the scalp where it presents as a yellowish, flat or mamillated patch of alopecia (Fig. 32.6). Other sites of predilection include the forehead, temples, around the central face, and behind the ears.1–3 Rarely, lesions have been documented at other sites including the trunk, breast, limbs, oral cavity, external auditory canal, and perianal region.3–8 It becomes rather warty during childhood and in adolescence shows marked enlargement with development of a waxy surface under the influence of pubescent hormonal stimulation.3 In adulthood, any further change is likely to be due to the development of a range of usually benign but sometimes malignant tumors of variable differentiation (Fig. 32.7).1–3 Less frequently, nevus sebaceus presents as a linear lesion, often behind the ear.2 Sometimes the lesion is very extensive and a zosteriform variant has been noted. 9 Few cases of familial nevus sebaceus showing paradominant transmission have been described.10–16 Very rarely, congenital nevus sebaceus is associated with other abnormalities, particularly neurological symptoms.17 Involvement tends to be linear and frequently parasagittal with a wide distribution on the head and scalp, and sometimes it extends to the neck and shoulder.18,19 Most such cases are classified as linear nevus sebaceus syndrome which presents with a triad of nevus sebaceus, seizures, and mental retardation.9,18,19 In practice, however, seizures and mental retardation are not regularly present. Ocular abnormalities are common and other organ systems may also be affected.19 The seizures are sometimes intractable to medical treatment and may require surgical intervention.20 Reported complications include unilateral megalencephaly, hamartomatous intracranial mass, hemimegalencephaly, cerebral arteriovenous malformation, desmoplastic neuroepithelial tumor, hemifacial asymmetry, complex conjunctival colombomas or choristomas, corneal dermoid, macular and optic nerve hypoplasia, optic glioma, nonparalytic strabismus, partial oculomotor palsy, microphthalmia, retinal detachment, sensorineural deafness, inner ear malformation with hearing loss, rickets, uvula bifida, premature tooth eruption, cleft secondary palate, and diffuse pulmonary angiomatosis.21–40 Extensive surgical resection with reconstruction may sometimes be required.41 This condition forms part of the Schimmelpenning syndrome (Schimmelpenning-Feuerstein-Mims syndrome, organoid nevus phakomatosis), which represents a distinct clinicopathological subset of the epidermal nevus syndrome.42–44 More recently, SCALP syndrome has been described consisting of the combination of nevus sebaceus, central nervous system malformations, aplasia cutis congenita, limbal ­dermoid, and pigmented nevus.45

B

Fig. 32.6 Nevus sebaceus: (A) lesions most commonly affect the scalp; (B) this example shows the characteristic yellow cerebriform appearance. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 32.7 Nevus sebaceus: in this example, basal cell carcinoma has developed in a nevus sebaceus. Courtesy of J.C. Pascual, MD, Alicante, Spain.

Nevus sebaceus Nomenclature and classification schemes for the epidermal nevus ­syndrome are complex, with overlapping entities and variable associated defects. Nevus sebaceus can coexist with other epidermal nevi, including verrucous ­epidermal nevus, possibly representing a continuum of manifestations.46 Other rare associations, not clearly syndromic and perhaps incidental, include melorheostosis, mediastinal lipomatosis, and familial retinoblastoma.47–49 Nevus sebaceus has also been reported in a child with nevoid basal cell carcinoma syndrome.50 A nevus sebaceus was reported as a paired phacomatosis pigmentokeratotica with speckled lentiginous nevus of the abdominal wall in which embryonal rhabdomyosarcoma arose in one exceptional case.51

Pathogenesis and histological features Deletion of the PTCH gene has been reported in nevus sebaceus.52 The PTCH pathway is involved in cutaneous patterning and development.53–56 This finding has some relevance, particularly in the context of the disordered epithelium and appendageal structures characteristic of this lesion. However, such PTCH deletions have not been confirmed by others and additional research is necessary.57 A mouse skin graft model with nevus sebaceus-like lesions which appear to have been induced by aberrantly transplanted dermal ­fibroblasts has been described.58 Nevus sebaceus is a complex lesion comprising abnormalities of the epidermis, hair follicle, and sebaceous and sweat glands. The epidermis may be acanthotic or papillomatous and foci of abortive hair papillae-like proliferations are commonly seen (Figs 32.8, 32.9). The epithelium in older lesions

sometimes contains foci of pale-staining glycogen-rich cells, suggesting outer root sheath differentiation reminiscent of trichilemmoma. Sebaceous glands are variably hyperplastic and excessive, diminished in number or even absent (Fig. 32.10). In early infancy the sebaceous glands often show a transient enlargement under the lingering influence of maternal hormones, but they then diminish in size until adolescence when they undergo marked proliferation. This is followed by a tendency to involution with increasing age. Virtually all lesions show irregularities of morphology and distribution of sebaceous glands. Commonly, they are located at an abnormally high level within the dermis, sometimes communicating directly with the surface of the epidermis (Fig. 32.11). Often they appear unrelated to a hair follicle. A punched-out defect at the periphery of a lobule is occasionally seen, presumably representing coalescence of several mature lipid-laden sebaceous epithelial cells. A very common finding is an absence or great reduction in the number of mature hair follicles. This is invariable in scalp lesions. In many cases, ectopic apocrine glands are present within the lower dermis. Nevus sebaceus is frequently complicated by development of a variety of other benign cutaneous neoplasms including syringocystadenoma ­papilliferum,

Fig. 32.9 A

Nevus sebaceus: several primitive hair germlike proliferations arising from the epidermis are seen in this field. Note the peripheral palisading.

B

Fig. 32.8 Nevus sebaceus: (A) there is marked papillomatosis with hyperkeratosis. Note the almost complete absence of hair follicles. Apocrine glands are present in the center of the field; (B) high-power view showing apocrine glands

Fig. 32.10 Nevus sebaceus: in this example there are excessive numbers of sebaceous glands. Note the absence of hair follicles.

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A

Fig. 32.11 Nevus sebaceus: in this field, the sebaceous gland communicates directly with the epidermis.

trichoblastoma-like lesions, trichilemmoma, sebaceous neoplasms, kerato­acanthoma-like lesions, viral wart, seborrheic keratosis, giant cutaneous horn, spiradenoma, pilar leiomyoma, nodular hidradenoma, dermal lipoma, banal melanocytic nevus, combined blue and speckled lentiginous nevus, infundibuloma, apocrine cystadenoma, tubular apocrine adenoma, syringoma, and extramedullary hematopoiesis.1,59–68 A recent large study has shown that syringocystadenoma papilliferum and trichoblastoma-like proliferations are the most commonly encountered lesions (both 5%) while trichilemmoma and sebaceoma are present in 2–3% of cases, with other lesions being less frequent (Figs 32.12–32.16).68 Malignant tumors are much less often seen and include basal cell carcinoma, squamous cell carcinoma, melanoma, sebaceous carcinoma, eccrine porocarcinoma, dermal leiomyosarcoma, apocrine carcinoma, microcystic adnexal carcinoma, and trichilemmal carcinoma.1,69–80 Historically, basal cell carcinoma was thought to represent the most common malignant neoplasm arising in association with nevus sebaceus with incidences reported as high as 20%.1–3 Recent studies, however, indicate that the majority of cases of basal cell carcinoma arising in nevus sebaceus are more accurately classified as benign trichoblastoma-like lesions, although authentic basal cell carcinoma is occasionally seen.68,81,82 Both benign and malignant secondary lesions are more commonly encountered in adults, although children may also rarely be affected.69,82–84 Nonetheless, the currently perceived scarcity of malignancy in childhood nevus sebaceus has called into question the necessity of early prophylactic excision.85,86 Nevus sebaceus not uncommonly shows multiple tumor-like proliferations. Frequently, these defy precise classification.87

Steatocystoma and sebocystomatosis Clinical features Steatocystoma multiplex (sebocystomatosis), characterized by autosomal dominant inheritance, usually presents in adolescence.1,2 Although the sternal region is commonly affected in the male, and the axillae and groins in the female, lesions (which are invariably multiple) may involve most of the upper trunk and face. More localized variants presenting on the face, scalp, nose, and vulva have been described.3–12 A linear form is very infrequently encountered.9,13,14 Early small dome-shaped lesions are rather translucent, changing to a yellowish color with age (Figs 32.17, 32.18). Puncta are not obvious, but

Fig. 32.12

B

Nevus sebaceus: (A) a small evolving trichoblastoma is present in the center of the field; (B) these lesions were previously regarded as basal cell carcinoma.

comedones are often associated features.15 Spontaneous rupture of the cysts sometimes results in steatocystoma multiplex suppurativum characterized by inflammation and scarring reminiscent of acne conglobata.16–18 Rarely reported associations include natal teeth, hidradenitis suppurativa, bilateral preauricular sinuses, multiple trichoblastomas, familial hypobetalipoproteinemia, cerebellar ataxia, intracranial dermoid, LEOPARD syndrome, Alagille syndrome and Lowe (oculocerebrorenal) syndrome.19–26 Spherulocystic disease (myospherulosis) has also been described.27 Steatocystoma simplex, in which patients present with a solitary lesion, shows an equal sex incidence and usually affects adults.28 The cysts are asymptomatic and well circumscribed. They are particularly found on the face or neck, chest, axillae, and arms.29 Involvement of the oral cavity and ocular caruncle has been described, albeit uncommonly.30–33 Rarely, steatocystoma multiplex and eruptive vellus hair cysts have been described in the same patient.34–38

Pathogenesis and histological features Mutations in KRT17 (encoding Keratin 17), which is expressed in the nail matrix, hair follicles, and sebaceous glands, have been documented in

Steatocystoma and sebocystomatosis

A

A

B

Fig. 32.13

B

Nevus sebaceus: (A) multinodular trichoblastoma; (B) the tumor cells have very regular, small, roundto-oval nuclei. Note the absence of mitoses or apoptosis.

­families with steatocystoma multiplex.39–42 Similar mutations have also been described in pachyonychia congenita type II (Jackson-Lawler syndrome).43,44 These shared mutations offer a pathogenetic basis for occasional cases of these two conditions occurring in the same individual.45–49 The presence of a mutation in KRTI7, within a single family cohort can lead to affected members with only pachyonychia congenital type II or only steatocystoma multiplex.35 Mutations in KRTI7 have not been described in steatocystoma simplex. It is of some relevance that eruptive vellus hair cysts have also been described in association with pachyonychia congenita since a number of authors believe that there is significant morphological overlap between eruptive vellus hair cyst and steatocystoma.36,50–53 Although eruptive vellus hair cysts express keratin 17, steatocystoma also expresses keratin 10 and thus other authorities believe that the two conditions can be clearly distinguished.43,54 Their exact relationship (if any) therefore remains to be determined. Steatocystoma probably represents a true sebaceous cyst since its lining mirrors the point where the sebaceous duct enters the hair follicle.55 The thin-walled dermal cyst is usually collapsed and folded, appearing empty except for sebaceous debris and rarely a hair fragment (Figs 32.19, 32.20).28 The lining typically comprises a few cells forming stratified squamous

Fig. 32.14 (A, B) Nevus sebaceus: this example shows a syringocystadenoma papilliferum. Note the villous processes covered by a double layer of epithelium.

Fig. 32.15 Nevus sebaceus: this apocrine papillary adenoma arose in a background of nevus sebaceus.

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A

Fig. 32.18 Steatocystoma multiplex: a rather more extensive case showing involvement of the arms in addition to the chest and abdomen. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

B

Fig. 32.16 (A, B) Nevus sebaceus: desmoplastic trichilemmoma arising in a background of nevus sebaceus.

Fig. 32.19 Steatocystoma multiplex: this low-power view shows a collapsed empty cyst lined by squamous epithelium.

e­ pithelium and maturing into a homogeneous, undulating eosinophilic cuticle ­without the formation of a granular layer (Fig. 32.21).29 Sebaceous glands are an almost invariable feature, either within the squamous lining itself or ­adjacent to it. The lesions of steatocystoma multiplex and simplex are histologically indistinguishable.

Sebaceous adenoma Clinical features Fig. 32.17 Steatocystoma multiplex: numerous small yellowish papules are present on the chest. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Sebaceous adenoma is rare and frequently misdiagnosed clinically as a basal cell carcinoma. It presents most often in older people (mean age 60 years) as a tan, pink-to-red or yellow papulonodule measuring approximately 0.5 cm

Sebaceous adenoma

Fig. 32.20 Steatocystoma multiplex: the presence of sebaceous glands within the cyst wall is a characteristic feature.

Fig. 32.21 Steatocystoma multiplex: a thick, wavy refractile hyaline cuticle covers the surface of the epithelium.

in greatest dimension.1–3 Occasionally, it has a polypoid appearance.2 The face (particularly the nose and cheek) and scalp are most often affected (Figs 32.22, 32.23).2 Less commonly affected sites include the ear and medial canthus and occasionally lesions have been described on the trunk, leg, arm, and penis.2,4,5 Sebaceous adenoma forms part of the spectrum of the Muir-Torre syndrome, particularly those that arise outside the head and neck region.6 Occasional reports have documented its presence in patients with the acquired immunodeficiency syndrome (AIDS).7,8 Rarely, it may develop intraorally, possibly in association with Fordyce papules.3,9–15 Sebaceous adenoma has rarely been described in the submandibular and parotid glands.16–18

Pathogenesis and histological features Recently, inactivating mutations in LEF1, the gene encoding a transcription factor in the Wnt/β-catenin pathway, have been documented in a subset of sebaceous adenomas.19 This pathway is involved in fate selection of follicular stem cells to adopt sebaceous differentiation and may also directly promote tumorigenesis.20,21 The hedgehog and c-Myc pathways may also be involved in tumorigenesis.22,23

Fig. 32.22 Sebaceous adenoma: note the yellow papule on the cheek of this elderly patient. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 32.23 Sebaceous adenoma: this example is domeshaped and has a slightly scaly surface. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

The tumor is multilobulated and sometimes appears to replace the surface epithelium (Fig. 32.24).1,2 Individual lobules, often surrounded by a collagenous pseudocapsule, mirror the structure of a normal sebaceous gland. At the periphery are a variable number of layers of small germinative cells with round or oval vesicular nuclei and scanty cytoplasm.2,3 This increased number of basaloid or germinative cells allows separation from sebaceous hyperplasia, which has at most two layers of basal cells.24 The basaloid cells blend with the usually more centrally located mature sebaceous cells, which are much larger and have pale-staining foamy cytoplasm and central crenated hyperchromatic nuclei.24,25 Occasionally, peripheral palisading is a feature.2 Some lobules show cystic degeneration and others appear to communicate directly with the surface epithelium. By convention, more than half of the lobule in sebaceous adenoma is composed of mature sebaceous cells.24

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Fig. 32.25 A

Sebaceous adenoma: part of an ulcerated giant variant.

B

Fig. 32.24 Sebaceous adenoma: (A) this example has been shelled out. Note the circumscribed border; (B) there is a peripheral layer of basophilic germinative cells and inner sebaceous cells with bubbly cytoplasm and crenated nuclei.

Sometimes, giant sebaceous adenomas are encountered which may show increased mitotic activity in the basaloid cell component (Figs 32.25, 32.26). This should not be interpreted as implying malignant potential. The intervening dermis may contain a chronic inflammatory cell infiltrate including lymphocytes, histiocytes, and plasma cells.26 An overlying cutaneous horn has been described.27

Sebaceous epithelioma Few terms have caused as much confusion in dermatopathology as sebaceous epithelioma. This tumor has been variably recognized as a distinct lesion, as a variant of sebaceous adenoma, as an intermediate stage between sebaceous adenoma and basal cell carcinoma, and as a synonym for basal cell carcinoma with sebaceous differentiation. Troy and Ackerman introduced the term sebaceoma to help clarify this morass and proposed that the term sebaceous epithelioma be abandoned.1 Sebaceoma is clearly defined and distinguishable from sebaceous hyperplasia, sebaceous adenoma, and sebaceous carcinoma. Over time, use of sebaceous epithelioma as a diagnostic term has declined. The publications that have ­documented tumors described as sebaceous epithelioma have illustrations that are clearly not

Fig. 32.26 Sebaceous adenoma: higher-power view showing retention of the architecture with peripheral basaloid cells and inner sebocytes. Note the mitotic figures.

those of basal cell carcinoma with sebaceous differentiation and are indistinguishable from the description of sebaceoma.2–5 While we have sympathy with the view of Dinneen and Mehregan that ‘the term sebaceous epithelioma has merit for historical reasons and because the tumor can be locally destructive’ we believe that its continued use will only perpetuate the confusion in the literature.5 Sebaceoma appears to be established as the diagnostic terminology of choice for this tumor and, as in the third edition, we have adopted the term sebaceoma and no longer recognize sebaceous epithelioma as an entity. The alternative term sebomatricoma, which includes sebaceous adenoma and sebaceoma as opposite ends of a spectrum of benign sebaceous tumors, has not received significant support in the literature.6

Sebaceoma Clinical features Sebaceoma presents as a yellow-to-orange or flesh-colored papule, nodule or tumor measuring approximately 1–3 cm in diameter (Fig. 32.27).1–7 A giant variant measuring up to 6.0 cm in greatest dimension has also been described.2,8

Sebaceoma The tumor presents more often in females (4:1) and, while a wide age range may be affected (29–87 years), the majority of patients are in the sixth to ninth decades. Lesions predominantly affect the face and scalp although a single report has described a case developing on the chest.4 Sebaceoma arising in continuity with a seborrheic keratosis has been documented and some examples have arisen within nevus sebaceus.2,3,9 Importantly, sebaceoma may reflect associated Muir-Torre syndrome.4,5,10 Recurrences or metastasis has not been reported.

Histological features Sebaceoma is centered in the dermis and only rarely affects the subcutaneous fat (Figs 32.28, 32.29).1 Epidermal involvement is often present. It consists of multiple variably sized, discrete nodules, symmetrically distributed and separated by dense eosinophilic connective tissue (Fig. 32.30).1–4 The nodules are composed of an admixture of basaloid cells and mature sebocytes lacking an organized lobular architecture.1 Peripheral nuclear palisading and cleftlike spaces separating the tumor nodules from the adjacent stroma are absent.1

Fig. 32.29 Sebaceoma: the tumor is composed of multiple lobules separated by connective tissue septa

Fig. 32.27 Sebaceoma: yellowish nodule on the forehead of an elderly patient. By courtesy of the Institute of Dermatology, London, UK. A

B

Fig. 32.28

Fig. 32.30

Sebaceoma: there is a multinodular dermal tumor showing multiple points of origin/ contact with the epidermis.

Sebaceoma: (A) scanning view showing conspicuous cyst formation; (B) high-power view of cysts.

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Tumors and related lesions of the sebaceous glands The basaloid cells are small and uniform with minimal indistinct ­cytoplasm and round to oval nuclei, sometimes containing small nucleoli (Fig. 32.31). There is no nuclear pleomorphism and mitotic activity is generally sparse, although as with other basaloid cutaneous neoplasms (e.g., pilomatrixoma) it can sometimes be prominent. The sebaceous cells appear mature with eosinophilic bubbly cytoplasm and scalloped nuclei, but this process is usually distributed in multiple pockets throughout the proliferation rather than being centralized, as seen in sebaceous adenoma. Duct formation is frequently present and cysts containing sebaceous debris lined by an eosinophilic cuticle are often present within the nodule or at it edges (Figs 32.32, 32.33). Focal glandular differentiation with apocrine features has been noted on rare occasion.11,12 While holocrine secretion is regularly present, tumor necrosis in the basaloid component is not a feature. Occasional tumors may show superficial elements reminiscent of seborrheic keratosis or verruca vulgaris.2 Sebaceomas with carcinoid-like, reticulated, cribriform, and rippled or Verocay body-like features have also been described (Fig. 32.34).6,7,13–15

Differential diagnosis Sebaceoma can be distinguished from sebaceous adenoma in which a lobular architecture with distinct and regular maturation (mimicking the normal sebaceous gland) is typically present. Sebaceous adenoma generally presents as a solitary nodular lesion in the superficial dermis, frequently replacing

A

B

Fig. 32.31 Sebaceoma: (A) the tumor consists of a random admixture of basaloid cells and mature sebocytes; (B) in this field, there are two mitoses. There is no significant atypia.

Fig. 32.32 Sebaceoma: ductal differentiation is commonly present.

Fig. 32.33 Sebaceoma: this is a scanning view of a rare cystic variant showing central degenerative features.

the overlying epidermis in whole or in part. It should be noted, however, that focal sebaceous adenoma-like features may sometimes be seen in a background of more typical sebaceoma.2 In such instances, the final diagnosis of sebaceous adenoma or sebaceoma may well be arbitrary. Of more importance is distinction from well-differentiated sebaceous carcinoma and recognition that the lesion could represent a cutaneous marker of Muir-Torre syndrome. Sebaceoma should not be confused with basal cell carcinoma showing sebaceous differentiation which first and foremost is clearly a basal cell carcinoma showing peripheral palisading and cleft formation and in which the sebaceous differentiation is merely an incidental finding. Immunohistochemistry using EMA and D2–40, which are expressed by sebaceoma, and Ber-EP4, which labels basal cell carcinoma, may be helpful in limited biopsies, but the distinction can usually be made morphologically in intact specimens.16,17 Sebaceous carcinoma is characterized by significant nuclear pleomorphism, nucleolar prominence, and conspicuous mitotic activity. Although in well-differentiated variants the tumor may have a distinct lobular architecture with smooth regular margins, thereby resulting in diagnostic confusion, less ­well-differentiated examples typically display an infiltrating growth pattern.

Superficial epithelioma with sebaceous differentiation

A A

B B

Fig. 32.34 Sebaceoma: (A) palisaded variant, which shows considerable histological overlap with rippled-pattern trichoblastoma; (B) stromal hyalinization has resulted in this trabecular pattern (high-power view).

Sebaceoma should also be differentiated from trichoblastoma with sebaceous differentiation.4 This latter tumor invariably shows focal hair germ differentiation, and papillary mesenchymal bodies are often evident. Peripheral nuclear palisading and stromal induction are also generally present. When sebaceoma was originally defined, the authors intended it to replace the confusing term sebaceous epithelioma and to clearly define a novel entity distinct from both sebaceous adenoma and basal cell carcinoma with sebaceous differentiation.1 Others have proposed an alternative term, sebomatricoma, to include lesions previously designated sebaceoma, sebaceous epithelioma, superficial epithelioma with sebaceous differentiation, the sebaceous neoplasms associated with Muir-Torre syndrome, and those arising in nevus sebaceus.18 This alternative designation has not received support in the subsequent literature. Sebaceoma has become a widely adopted and useful diagnostic category. We agree that the term of sebaceous epithelioma is confusing and should no longer be used. Of utmost importance is recognition that a variety of benign sebaceous lesions with variable architecture and proportion of ­basaloid cells form the benign end of the Muir-Torre spectrum. Sebaceoma ­represents a more cellular and less architecturally organized variant (Fig. 32.35). Recognition of this ­cellularity is important to avoid confusion with ­sebaceous carcinoma. The term sebaceoma clearly recognizes this increased cellularity as benign.

Fig. 32.35 Sebaceoma: (A) this example was not associated with Muir-Torre syndrome, (B) MSH-2.

Superficial epithelioma with sebaceous differentiation Clinical features Superficial epithelioma with sebaceous differentiation is a rare tumor, with less than 20 cases having been documented.1–10 Most often, it presents on the face.1–3 Two cases, however, have been described on the back and a single patient with multiple lesions involving the face, axilla, trunk, and thigh has been reported.4–6 Lesions are usually 1 cm or less in diameter but cases of up to 2 cm have been encountered.4 They present as flesh-colored or yellow-tobrownish papules, nodules or plaques. The age distribution is wide (38–79 years) but the mean age is 60 years.4 There is no clear gender predilection.8 The relationship of this tumor to Muir-Torre syndrome is unknown although one patient has had a family and personal history of esophageal and colon carcinoma.1 Recurrences following local excision have not been described.4

Histological features The tumor is characterized by a sharply defined and well-circumscribed, platelike epidermal growth with elongated, thickened rete ridges that ­anastomose in a reticular pattern (Fig. 32.36).1 Merging with the more

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Tumors and related lesions of the sebaceous glands A single case reported as reticulated acanthoma with sebaceous differentiation has been reported, with the squamous portion descending from the surface epithelium and showing a reticulated pattern.12 This lesion may fall within the spectrum of superficial epithelioma with sebaceous differentiation or seborrheic keratosis with sebaceous differentiation.

Sebomatricoma

A

B

The term sebaceous epithelioma has been the source of considerable confusion, largely because different authors have taken it to mean different things while others have used it indiscriminately without precise definition. Thus sebaceous epithelioma has been used as a synonym for basal cell carcinoma with sebaceous differentiation or else to represent a variant of sebaceous adenoma. To overcome this problem, Troy and Ackerman introduced the term sebaceoma which clearly described a tumor distinguishable from sebaceous hyperplasia, sebaceous adenoma, sebaceous carcinoma, and basal cell carcinoma with sebaceous differentiation.1 They recommended that the term sebaceous epithelioma be abandoned. In a similar vein, Sánchez Yus's group proposed the term sebomatricoma to describe a spectrum of tumors ­ranging from ­sebaceous adenoma to sebaceoma.2–4 Although this has some merit, since sebaceous adenoma and sebaceoma do show an element of overlap and may both be associated with Muir-Torre syndrome, the term sebomatricoma has not received great support in the subsequent literature. In addition, the unusual benign sebaceous neoplasms associated with Muir-Torre syndrome were also included in this definition. The issue was a little clouded, however, since the authors also recommended inclusion of superficial epithelioma with sebaceous differentiation and sebaceous neoplasms arising within nevus sebaceus.4 In addition, this term would group sebaceous neoplasms clearly associated with the Muir-Torre syndrome and lesions such as follicular infundibulum tumor that can rarely show sebaceous differentiation but probably have no connection with the Muir-Torre syndrome. As a spectrum, this grouping may not have clinical utility.5

Fig. 32.36 Superficial epithelioma with sebaceous differentiation: (A) there is a circumscribed focus of epidermal thickening with duct formation; (B) foci of sebaceous differentiation are evident. Courtesy of E. Farmer, MD, Virginia Commonwealth University, Virginia, USA.

s­ uperficial ­keratinocytes is a cytologically bland basaloid cell population in which are admixed mature sebocytes, singly and in clusters.1 Mitotic activity may be evident and is sometimes brisk, but cytological atypia is not a feature.1 Ductal differentiation and keratin-filled cystic spaces are also present, and occasionally squamous eddies are a feature.1,4 Melanin pigmentation has been described.1 Peripheral palisading is not a feature and cleftlike spaces separating the tumor from the adjacent dermal connective tissue are absent.

Differential diagnosis Superficial epithelioma with sebaceous differentiation should be distinguished from follicular infundibulum tumor. The latter is also characterized by a platelike epithelial proliferation suspended from the epidermis. However, the tumor trabeculae are characteristically thin, vacuolated, and often ­surrounded by a thickened eosinophilic basement membrane. In ­addition, ­follicular infundibulum tumor does not contain keratin-filled cysts or generally show sebaceous differentiation, although a single published case showed features of both tumors.11 Seborrheic keratosis with sebaceous differentiation also enters the differential diagnosis.9 This lesion, however, shows the features of an acanthotic variant of seborrheic keratosis with only small numbers of mature sebaceous cells scattered randomly throughout the epithelium.

Basal cell carcinoma with sebaceous differentiation Clinical features Basal cell carcinoma with sebaceous differentiation is exceedingly rare, few cases having been published with even fewer photomicrographs.1–4 Despite this fact, the entity is commonly cited in reviews.5,6 It arises in the distribution expected for basal cell carcinoma, with the most common site being the face. Lesions are sometimes multiple.2,3 Its behavior appears no different from other basal cell carcinomas.

Pathogenesis and histological features It is not clear whether basal cell carcinoma with sebaceous differentiation forms part of the spectrum of the Muir-Torre syndrome. Some authors have reported an association with internal malignancy, but diagnostic criteria within this family of neoplasms have evolved significantly since that report.3 In addition, since traditional basal cell carcinomas are associated with mutations in patched (PTCH1), p53, and BAX (bcl-2 associated X-protein) and not the genetic defects in DNA mismatch repair seen in the Muir-Torre syndrome, a true relationship may not be present.7–9 Basal cell carcinomas are increasingly conceptualized as adnexal in origin and thus it is not surprising that numerous adnexal ­elements are reported within this tumor. Basal cell carcinoma with sebaceous differentiation shows features of basal cell carcinoma with proliferation of palisading basaloid cells, usually in a nodular form, retraction artifact, and loose stroma rich in mucin. Within these nodules are foci of variable numbers of mature sebocytes, sometimes with f­ ormation of cysts due to holocrine secretion.

Sebaceous carcinoma

Sebaceous carcinoma Clinical features Sebaceous carcinoma is rare and has traditionally been divided into two groups: an aggressive periocular variant comprising about 75% of cases and an extraocular form considered by some to be less aggressive.1–5 More recent observations, however, indicate that this distinction is inappropriate, since a significant number of extraocular tumors are associated with metastases and appreciable mortality.6–10 Indeed, a recent retrospective review of 1349 sebaceous carcinoma cases followed over a 31-year period from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute indicated no difference in overall survival between groups with ­periocular and nonocular sebaceous carcinoma.11

Periocular sebaceous carcinoma The periocular variant is more common than the cutaneous or extraocular form and presents in the mid sixties.12 It arises in association with the ocular sebaceous glands. At least five types of sebaceous adnexae are recognized in the eye. The meibomian glands (tarsal glands) are modified sebaceous glands that are associated with the tarsal plates of both the upper and lower eyelids.13 They are relatively large structures that are not associated with hair follicles and which discharge through squamous epithelium-lined ductules into a larger central duct that ultimately empties at the margin of the eyelid. These glands contribute to the lipid content of tears.13 The glands of Zeis are associated with the eyelashes at the lid margin. Also recognized are the sebaceous glands of the caruncle, eyebrows, and those of the tiny vellus hairs on the surface of the eyelid.9 Sebaceous carcinoma is the second or third most common malignant tumor of the eyelid after basal cell carcinoma (and probably squamous cell carcinoma), accounting for 1.5% to more than 25% of tumors in several large series from referral centers.9,14–19 It is a significantly more common diagnosis in series from Asia, but it is not clear that Asian populations in the USA have a higher incidence. The difference may well be due to a relatively low incidence of other malignant tumors such as basal cell carcinoma and squamous cell carcinoma in this population.9,11,20 Most series from other regions place the incidence at approximately 1–5% of malignancies of the eyelid.9,12 Tumors generally arise in association with the meibomian gland, and present as a steadily enlarging, nonulcerated mass that usually involves the upper eyelid.21 Occasionally, tumors develop from the glands of Zeis and from the sebaceous glands of the eyelid, caruncle, and eyebrow.1 Sometimes they are multicentric or diffuse.22–24 Occasionally they present in younger patients.23 There was believed to be a slight female preponderance, but this is not clear in the largest studies to date.11,21,25 The tumor is very rarely diagnosed clinically, as presentation is notoriously varied. Many lesions are mistaken for basal cell carcinoma, squamous cell carcinoma, and even as a chalazion or chronic blepharoconjunctivitis.21,26 The metastasis rate with subsequent mortality is high, approaching 25%.11,21 Aggressive local behavior with intracranial extension may also occur.27 The metastatic and mortality rate can be significantly lowered (to 18%) with early detection and treatment.28,29 The organs most often affected include the regional nodes with subsequent involvement of lung, liver, brain, and bone.9 Metastatic disease is a poor prognostic sign with a 50% 5-year mortality in one study.21 Prognosis is particularly poor when both the upper and lower eyelids are involved.21 Sentinel lymph node biopsy may be helpful for disease staging.30 Sebaceous carcinoma has been documented in retinoblastoma patients treated with radiotherapy, although it has also been reported in these patients in the absence of such treatment and occurring in a considerably younger age range.31–33 Tumors associated with HIV infection have also been reported.34

Extraocular sebaceous carcinoma Extraocular sebaceous carcinoma accounts for approximately one-quarter of all cases.6,7,9 It commonly presents on the head and neck where sebaceous glands are more concentrated (Fig. 32.37). Approximately one-quarter of the

Fig. 32.37

A

Sebaceous carcinoma: (A) an encrusted tumor on the scalp of an elderly patient; (B) a more extensive lesion showing a central, erythematous, dome-shaped nodule. By courtesy of D.H. McGibbon, St Thomas' Hospital, London, UK.

B

extraocular tumors arise at other regions including the trunk and thigh and rarely the genitalia.1,7,35–37 Other exceptionally affected sites include the nasal vestibule, breast, nipple, finger, foot, and external auditory canal.38–43 Traditionally, males are thought to be affected more often than females in a ratio of up to 2:1, but this has varied among authors and is less pronounced in the more recent comprehensive reviews and large series.7–9,11,44 The majority of patients are in their seventh decade.7,8 Exceedingly rare cases in children have been described.45 The tumor presents as a sometimes ulcerated pink to yellow-red nodulocystic lesion measuring up to 8 cm in diameter.1 It has usually been present for at least 6 months, and often much longer, before diagnosis. Metastasis and mortality are believed by many authors to approximate to that of periocular tumors and the pattern of metastasis is similar.6–11 Sebaceous carcinoma has been reported in association with ­xeroderma ­pigmentosum and Bowen's disease of the vulva.46,47 A series has been described in immunosuppressed organ transplant patients.48 It can also complicate nevus sebaceus.49 Sebaceous carcinoma may also very rarely arise at noncutaneous sites. Documented cases have been described in the oral and buccal mucosa, ­hypopharynx, pulmonary bronchus, parotid and submandibular glands, ­uterine cervix, and in dermoid cysts or benign cystic teratomas of the ovary.50–60 These presumably arise in association with ectopic sebaceous glands.

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Tumors and related lesions of the sebaceous glands The parotid gland is the most common of the noncutaneous sites and other benign ­sebaceous neoplasms have also been described at this location.8,9,55,61,62 Sebaceous lymphadenoma and the exceedingly rare sebaceous lymphadenocarcinoma are also seen in the parotid, but have not been reported in skin.63,64 Both periocular and extraocular carcinoma represent the malignant end of the spectrum of sebaceous lesions seen in Muir-Torre syndrome; cases from such patients tend to appear at a somewhat younger age.65 Association of periocular sebaceous carcinoma with the Muir-Torre syndrome appears to be less prominent than the extraocular types.25 In particular, sebaceous carcinomas from outside of the head and neck region may be most indicative of the Muir-Torre syndrome.66

Pathogenesis and histological features In general, the etiology of sebaceous carcinoma is unknown although ultraviolet radiation is probably of importance and occasional tumors have followed therapeutic cutaneous irradiation.7,21,67,68 Periocular cases from Asia show a frequent association with human papillomavirus (HPV) infection, but this has not been replicated in series from other regions.69,70 Mutation and nuclear accumulation of p53 and increased expression of the c-erB-2 oncogene have also been noted.70,71 Nuclear accumulation of p53 and c-erB-2 expression may correlate with a poor outcome.72 Dysregulation of the cell cycle as assessed by loss of appropriate compartmentalization of p21 (WAF1) has been described.73 Pathogenesis may differ based on association with the Muir-Torre syndrome.74 Histologically, extraocular tumors are characterized by a variety of irregular lobular patterns or, less frequently, diffuse growth in the upper dermis, usually showing foci of continuity with the overlying epidermis ( Figs 32.38 , 32.39 ). Infiltration of subcutaneous fat or skeletal muscle may sometimes be evident. The lobules are composed of a disorderly admixture of basophilic germinative sebaceous cells with round or oval nuclei, usually containing several eosinophilic nucleoli, and more mature cells with lightly eosinophilic bubbly cytoplasm. Necrosis is frequently present, sometimes giving rise to a comedo-like appearance ( Fig. 32.40 ). 26 In poorly differentiated examples, the tumor cells are more hyperchromatic and may contain minimal lipid (Figs 32.41, 32.42). Peripheral palisading is occasionally seen, but is never marked. Keratinization resulting in diagnostic confusion with squamous cell carcinoma is sometimes a feature and there may be an associated foreign body giant cell reaction. The tumor cells in poorly differentiated lesions usually show marked nuclear and cytoplasmic pleomorphism and frequent, often abnormal, mitoses. Infiltration of the perineural space and lymphatic or vascular invasion are variable features. More recently, intraepidermal or pagetoid spread has been recognized

A

Fig. 32.39 Sebaceous carcinoma: in this high-power view showing an almost pure basaloid cell population, there are conspicuous mitoses.

Fig. 32.40 Sebaceous carcinoma: high-power view showing admixture of basaloid and differentiated cells. Note the tumor necrosis.

B

Fig. 32.38 Sebaceous carcinoma: (A) the tumor consists of irregular lobules and trabeculae composed of an admixture of dark-staining germinative cells and small numbers of differentiated sebaceous cells; (B) high-power view.

Sebaceous carcinoma

Fig. 32.41

Fig. 32.43

Sebaceous carcinoma: poorly differentiated variant composed almost entirely of undifferentiated cells.

Sebaceous carcinoma: a positive lipid stain aids in the differential diagnosis.

A

A

Fig. 32.44

B

Sebaceous carcinoma: (A) ultrastructural examination shows prominent nonmembrane-bound lipid vacuoles; (B) shown in high power. Note the tonofilaments and desmosome.

B

Fig. 32.42 Sebaceous carcinoma: (A) the tumor shows marked mitotic activity; (B) only a very tiny focus of sebaceous differentiation is evident.

in a few cases of extraocular lesions and an in situ form of the disease has been described.75–78 Very rarely, apocrine differentiation has been reported.79 Special staining for lipid is usually positive (Fig. 32.43). If the diagnosis is in doubt, ultrastructural examination typically reveals nonmembrane-bound intracytoplasmic lipid inclusions (Fig. 32.44).26

With immunohistochemistry, sebaceous carcinoma is characterized by strong epithelial membrane antigen (EMA) and adipophilin (see under ­differential diagnosis) expression, but is c­ arcinoembryonic antigen (CEA) negative (Fig. 32.45). The periocular variety has similar histological features, but is further characterized by a striking tendency to show pagetoid spread and/ or bowenoid carcinoma in situ in the overlying conjunctival epithelium or epidermis (Figs 32.46–32.49).21,26,80,81 Initial histopathological misdiagnosis is common despite the presence of sebaceous differentiation.28 Grading systems have been devised stressing classification by either tumor

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Tumors and related lesions of the sebaceous glands

A

Fig. 32.47 Sebaceous carcinoma: the tumor is poorly differentiated. Note the conspicuous mitotic activity.

B

Fig. 32.45 Sebaceous carcinoma: (A) the tumor cells show strong epithelial membrane antigen expression; (B) adipophilin is positive.

Fig. 32.48 Sebaceous carcinoma: the surface epithelium shows striking bowenoid features.

Fig. 32.46 Sebaceous carcinoma: this is a periocular variant.

Fig. 32.49 Sebaceous carcinoma: high-power view superficially showing focal sebaceous differentiation.

Muir-Torre syndrome c­ ytological differentiation or architectural growth pattern.21,26 These ­systems are not uniformly applied and their prognostic significance is not well established. Poor prognostic indicators include multicentricity, size greater than 1 cm in diameter, poor differentiation, extensive tissue infiltration, and vascular or lymphatic involvement.21

Differential diagnosis Sebaceous carcinoma is distinguished from benign sebaceous neoplasms with ­conspicuous germinative basaloid cells by its more irregular architecture, pleomorphism, nucleolar prominence, mitotic activity, and abnormal mitotic figures. Occasionally, however, well-differentiated variants merge into a histological continuum with other sebaceous tumors. In cases of doubt, particularly with periocular lesions, it is probably in the patient's best interests to regard the tumor as a sebaceous carcinoma. It may be differentiated from clear cell squamous carcinoma and clear cell hidradenocarcinoma by positive staining for lipid and negative periodic acid-Schiff, Alcian blue or mucicarmine staining for glycogen and mucin. Others have stressed that a dimorphic staining pattern of basal cells and mature ­sebocytes with cytokeratin, EMA, and Ber-EP4 may be of assistance in demonstrating sebaceous differentiation, particularly in small ­biopsies.82–84 Fat stains can be useful in the rare situation where fresh tissue is available and detection of sebaceous differentiation with immunohistochemistry for ­subclasses of the human milk fat globules has been reported.85 A recent and ­promising immunohistochemical marker applicable to fixed tissue is ­adipophilin, and the related perilipin, which mark proteins associated with intracellular ­vesicles that contain lipids (see Fig 32.45b).20,49,86,87 An additional important ­differential diagnosis is balloon cell melanoma, which may be ­identified by positive S-100 protein, HMB-45 or MART-1 (melanoma ­antigen recognized by T cells 1) reactions.

Muir-Torre syndrome In 1967, Torre and Muir each reported an individual patient with multiple cutaneous tumors and gastrointestinal malignancies.1–3 Where this association has been seen to be familial (autosomal dominant, 59%) the title ‘family cancer syndrome’ has been applied.4,5 There appears to be a high degree of penetrance, but expression of the syndrome is variable.6 More than 200 patients have now been reported. Sebaceous adenoma, sebaceoma, both ocular and extraocular sebaceous carcinoma, keratoacanthoma, and squamous cell carcinoma have all figured in the cutaneous findings (Fig. 32.50).4,6–8 Professor Torre currently defines the syndrome as having at least one ­cutaneous sebaceous neoplasm and at least one visceral cancer – no family history is required.8

Traditionally, sebaceous adenoma is the most specific marker for the syndrome, but sebaceoma may have a similar degree of association, and multiple lesions increase the specificity.8 One series indicates that up to 40% of adenomas are associated with internal malignancy; the association with sebaceous carcinoma appears to be lower.6,8,9 However, a recent study of 664 cutaneous sebaceous carcinomas using the Surveillance, Epidemiology and End Results (SEER) database of the National Cancer Institute over a three decade period indicated that the risk of internal malignancy in those patients was greatly elevated over than seen in a cohort of patients with periocular sebaceous carcinoma.10 The skin tumors may antedate the presentation of the internal malignancies by several years, although more often they are a subsequent or simultaneous development.6,11 Some series show a slight male predominance and presentation ranges from the third to the ninth decade, but is most common in the fifth and sixth decades.6,7 AIDS and other immune deficiencies may induce expression of the syndrome.12–15 The internal neoplasms in the Muir-Torre syndrome, which can be multiple, generally behave less aggressively and overall survival is improved.6,7,15–17 Current emphasis on screening and early detection will likely further improve prognosis. Common associations include gastrointestinal (≈53%), bladder and renal pelvis (≈11%), endometrium (≈10%), breast (≈5%), and hematological malignancies (≈5%).4,11,18,19 Intestinal polyps are present in at least 27% of cases (although not to the degree seen in familial adenosis polyposis coli syndrome) and correlates strongly with the presence or development of colorectal carcinoma.11,16,20,21 The colonic carcinomas tend to be proximal in distribution (60%) and up to 50% of patients will have more than one primary tumor.11 It is important to note that on occasion a single sebaceous tumor, including an ocular lesion, has been found to be associated with a visceral carcinoma.22–25 Since sebaceous tumors (excluding simple hyperplasia) are uncommon, it is prudent to draw the attention of the physician to the ­possibility of an underlying systemic neoplasm when such a lesion is diagnosed. The sebaceous lesions of Muir-Torre syndrome sometimes have unique histopathological features and some authors consider that many tumors cannot be classified using existing categories.26–30 In particular, cystic sebaceous lesions devoid of a connection with the overlying epidermis and sebaceous tumors with keratoacanthoma-like architecture have been described (Figs 32.51, 32.52), but their specificity for the Muir-Torre syndrome in an unselected series is unclear.28,29,31,32 The cystic lesions may show significant proliferative activity in their basaloid rims.29 Cytological atypia has been noted and it has been proposed that these lesions represent low-grade malignancies, although confirmation of an aggressive biological behavior is lacking.30 The sensitivity and specificity of these findings for the Muir-Torre syndrome is unknown. Sebaceous tumors that are readily classifiable also represent m ­ arkers for this syndrome. A cancer syndrome known as hereditary nonpolyposis colorectal carcinoma (HNPCC) or Lynch's syndrome is the most common form of inherited colorectal carcinoma and represents up to 1–3% of all colorectal

Fig. 32.50

Fig. 32.51

Muir-Torre syndrome: this patient has innumerable small tumors on the anterior chest wall and neck. Courtesy of J.C. Pascual, MD, Alicante, spain.

Muir-Torre syndrome: sebaceous tumors showing cystic change as seen in this example are suggestive but far from diagnostic of Muir-Torre syndrome.

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Tumors and related lesions of the sebaceous glands

Fig. 32.52

Fig. 32.53

Muir-Torre syndrome: sebaceous tumors showing a keratoacanthoma-like architecture are also likely to indicate Muir-Torre syndrome. Note the epidermal collarette.

Muir-Torre syndrome: this tumor arose in a patient with known Muir-Torre syndrome.

­ alignancies.33,34 Despite the name, HNPCC is also associated with endom metrial, urological, ovarian, hepatobiliary, and other internal malignancies.35 This syndrome is associated with an inherited defect in one allele or copy of a DNA mismatch repair (MMR) gene.36 Subsequent loss of the other wild-type allele leads to genetic instability during replication at repetitive sequences of DNA known as microsatellites.37 This phenomenon is known as microsatellite instability (MSI) and is characteristic of tumors associated with this syndrome.36 MSI is present in the tumors of approximately 70% of patients with HNPCC; the underlying defect in the remainder is unknown.38 Malignancies associated with MSI are generally less aggressive than their same-stage counterparts.39 The two major MMR proteins involved are hMLH1 and hMSH2, though hMSH6 alone has been rarely reported as well.36,39,39–42 In cases of MSH2 loss, MSH6 is usually also lost due to protein instability or downregulation.32 Loss of hMSH6 alone can occur in isolation on rare occasion. The Muir-Torre syndrome represents a subset of HNPCC syndrome and at least 70% of tumors from these patients also show MSI.38,43–46 Genetic alterations other than those in MMR genes, including fragile histidine triad (FHIT), have been suggested, but further confirmation is required.47–50 In one study, the malignancies in patients with Muir-Torre syndrome associated with MSI presented at a significantly younger age (40 vs 70 years).43 The precise role of MSI in neoplastic transformation is unclear, but loss of tumor suppressor genes may be involved.51–53 Recent work speculates that the cutaneous sebaceous tumors in Muir-Torre syndrome with MSI may be related to dysregulation of the β-catenin and PTCH signaling pathways.54 Similar pathways may also be involved in spontaneous sebaceous neoplasms. MSI can be assessed using a polymerase chain reaction (PCR)-based technique from formalin-fixed, paraffin-embedded tissue and is commonly identified in the sebaceous lesions and keratoacanthomas of Muir-Torre patients.55–57 Immunohistochemistry to demonstrate loss of MMR proteins hMLH1 and hMSH2 is also available with excellent sensitivity and specificity (Figs 32.35, 32.53–32.55).32,58–63 While germline disruption of hMLH1 or hMSH2 is evenly distributed in HNPCC, disruption of hMSH2 is seen in the ­majority of ­Muir-Torre patients (> 90%).36,64–66 The cause of over­representation of the Muir-Torre syndrome among patients with hMSH2 deficiency is not understood, but the precise location and type of mutation in the MSH2 gene may result in a predisposition for sebaceous tumorigenesis.46 Indeed, the great majority of patients with HNPCC and hMSH2-deficient internal tumors do not develop cutaneous tumors characteristic of the MuirTorre syndrome.33,35,36,38,65,66 Features of the Muir-Torre syndrome are recapitulated in a MSH2-deficient transgenic mouse model.67 Other internal malignancies can show MSI as a result of somatic loss of hMLH1, usually by methylation suppression, a finding present in 10–15% of sporadic colonic and endometrial carcinomas.39,53 The occurrence of sporadic cancers with somatic suppression of MMR genes is much more common than HNPCC-associated carcinomas and does not imply heritability.39 Loss

Fig. 32.54 Muir-Torre syndrome: high-power view showing focal sebaceous differentiation.

Fig. 32.55 Muir-Torre syndrome: there is complete absence of MSH2 expression.

Other cutaneous tumors showing sebaceous differentiation of hMLH1 is uncommon in sebaceous neoplasms and somatic suppression of MMR genes does not appear to be an important factor in their development.68 Tumors occurring outside the head and neck region overwhelmingly show loss of MMR protein, particularly hMSH2.32 Somatic loss of hMSH2 is not common; thus the finding of MSI and/or loss of MMR proteins in both the cutaneous and internal tumors of a patient is highly specific for the Muir-Torre syndrome.43,45,59–61,64,65 The demonstration of loss of hMSH2 or (less commonly) hMLH1 by immunohistochemistry is characteristic of the Muir-Torre syndrome and strongly suggests a germline mutation. This may result in the need for further confirmatory genetic testing and subsequent genetic counseling. However, the absence of this finding does not exclude the syndrome.43,59–62 Very rarely, cutaneous lesions other than sebaceous tumors or keratoacanthomas found in Muir-Torre patients may show MSI.69,70 The immunohistochemical and molecular MSI testing of relevant cutaneous sebaceous neoplasms is increasingly recognized as valuable in the work-up of these lesions.68,71–73 We recommend careful investigation for internal malignancy in patients with cutaneous sebaceous neoplasia to evaluate for the presence of ­Muir-Torre syndrome.

Mantleoma Clinical features An intriguing series of four tumors showing possible differentiation toward the follicular mantle has been described in a single report.1 It occurs solely on the face and often represents an incidental finding.1 The tumor is benign.

Pathogenesis and histological features First described by Felix Pinkus, the mantle is situated at the follicular infundibulum and in three dimensions appears like an inverted cup.2 It is formed from thin strands of basaloid cells with variable sebaceous differentiation. Its exact nature is debated, but it may be related to sensory function or the formation of the sebaceous glands.3

Fig. 32.56 Mantleoma: low-power view showing a lacelike proliferation of basaloid cells. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

Although there may be considerable histological variation, in essence mantleoma consist of folliculocentric cords and strands of basaloid cells containing variable numbers of sebocytes, and sometimes forming reticulated structures (Figs 32.56–32.58).1 The associated connective tissue stroma may show mucin deposition and is separated from the adjacent dermis by cleftlike spaces. Additional cases have not been reported in the literature, but we have periodically noted this entity as an incidental finding.

Differential diagnosis There is considerable morphological overlap with a similar benign adnexal tumor termed folliculocentric basaloid proliferation but the relationship between these two lesions is unclear.3 Some authors consider fibrofolliculomas and trichodiscomas, which can be markers for the Birt-Hogg-Dubé ­syndrome, to also show differentiation toward the mantle.4 Mantleoma displays histological overlap with basaloid follicular ­hamartoma.1,5,6 The latter condition, however, presents with multiple lesions and shows no evidence of sebaceous differentiation.

Other cutaneous tumors showing sebaceous differentiation A number of cutaneous epithelial or adnexal tumors can show a sebaceous component or differentiation. This is not surprising since the skin adnexal structures arise from pluripotent stem cells.1,2 Sebaceous differentiation in tumors of follicular derivation is not entirely unexpected given the intimate association of the pilar and sebaceous units. Cutaneous tumors which may show sebaceous elements include cutaneous mixed tumor, microcystic adnexal carcinoma, poroma, porocarcinoma, proliferating trichilemmal cyst, fibrofolliculoma, trichofolliculoma, trichoblastoma, tumor of the follicular infundibulum, and pilar sheath acanthoma.3–13 The entity described as sebocrine adenoma is an alternative name for apocrine poroma and is characterized by sebaceous differentiation.14,15 A variety of unclassifiable mixed adnexal neoplasms with sebaceous ­differentiation have also been reported.16–20

Fig. 32.57 Mantleoma: note the cleftlike space separating the tumor from the adjacent dermis and indented sebaceous gland. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

Fig. 32.58 Mantleoma: the tumor consists of a uniform population of small basaloid cells admixed with sebocytes. By courtesy of C. Steffan, MD, Palm Springs, California, USA.

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33 Chapter

Tumors of the sweat glands

See www.expertconsult.com

for references and additional material

Apocrine nevus  1508

Malignant mixed tumor  1522

Hidradenoma  1545

Apocrine hidrocystoma and apocrine cystadenoma  1508

Myoepithelioma and malignant myoepithelioma  1526

Clear cell hidradenocarcinoma  1546

Hybrid epidermoid and apocrine cyst  1510

Eccrine nevus  1527

Syringocystadenoma papilliferum  1510

Adnexal polyp of neonatal skin  1528

Syringocystadenocarcinoma papilliferum  1512

Eccrine syringofibroadenoma  1528

Hidradenoma papilliferum  1512 Tubular apocrine adenoma  1513 Adenoma and adenocarcinoma of the anogenital mammary-like glands  1515 Nipple adenoma  1515 Syringomatous adenoma of the nipple  1515 Apocrine poroma  1515 Apocrine carcinoma  1516 Ceruminous gland tumors  1518 Mixed tumor of the skin  1519

Malignant cylindroma  1553

Eccrine angiomatous hamartoma  1529 Porokeratotic eccrine ostial and dermal duct nevus  1530 Eccrine hidrocystoma  1530 Hidroacanthoma simplex  1531

Dermal duct tumor  1534

Syringoma  1538

Aggressive digital papillary adenocarcinoma  1543

Histological features The lesion is characterized by excess mature apocrine glands in the reticular dermis, sometimes extending into the subcutaneous fat. Glands and ducts are represented.

Syringoid eccrine carcinoma  1558 Microcystic adnexal carcinoma  1560 Primary adenoid cystic carcinoma  1563 Primary mucinous carcinoma  1566

Squamoid eccrine ductal carcinoma  1570 Polymorphous sweat gland carcinoma  1570

Papillary eccrine adenoma  1541

Apocrine nevus as defined by an excess of normal apocrine glands (apocrine hamartoma, hamartomatous apocrine gland hyperplasia) is a very rare and clinically heterogeneous condition. Most often it presents with a fleshy axillary swelling.1–4 Erythematous or brown nodules on the neck, chest, and inguinal region, a plaque on the cheek, and multiple papules on the chest have also been documented.5–10 Lesions are present at birth or develop in adulthood. Hyperhidrosis is not usually a feature. There is generally no underlying systemic disease although one patient with a background of focal dermal hypoplasia (Goltz syndrome) and another with axillary apocrine carcinoma have been documented.4,5,11 In addition, the development of syringocystadenoma papilliferum has been described within apocrine nevi.12,13

Eccrine spiradenocarcinoma  1556

Eccrine ductal carcinoma  1569

Eccrine porocarcinoma  1535

Clinical features

Eccrine spiradenoma  1554

Endocrine mucin-producing sweat gland carcinoma  1568

Eccrine poroma  1533

Apocrine nevus

Dermal cylindroma  1550

Primary cutaneous signet ring cell carcinoma  1570

Apocrine hidrocystoma and apocrine cystadenoma Clinical features Apocrine hidrocystoma is an uncommon cystic lesion and is most often s­ olitary.1–3 Despite its apocrine derivation it is rare at sites rich in normal ­apocrine glands.3 It is usually found on the head and neck, commonly affecting the cheek (Fig. 33.1).2,3 Multiple lesions have also been documented.4–8 Those on the face are sometimes known as the Robinson variant and these present most often in middle-aged females.4,5,9 Multiple apocrine hidrocystomas are a feature of ectodermal dysplasia (Schöpf-Schulz-Passarge ­syndrome) and focal dermal hypoplasia (Goltz syndrome).10–13 Similar lesions on the eyelids are also known as Moll's gland cysts.6,7 Rarely, it may ­present on the chest, shoulder, axilla, umbilicus, prepuce, vulva, penis, and the ­finger.14–23 Penile variants are now thought at least in part to represent median raphe rather than true apocrine cysts. The cyst shows an equal sex ­incidence and arises most often in the middle aged.15 Exceptionally, it has been described in childhood.24 It presents as an intradermal, moderately firm, dome-shaped, translucent, blue, bluish-black or purple cystic nodule measuring up to about 1 cm across.

Apocrine hidrocystoma and apocrine cystadenoma

Fig. 33.1 Apocrine hidrocystoma: this shows a characteristic bluish translucent swelling on the cheek of a middleaged male patient. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 33.2

A

(A, B) Apocrine hidrocystoma: this example consists of a multilocular cyst.

Giant variants measuring up to 7.0 cm in diameter are exceptionally encountered.25–27 Apocrine hidrocystoma is not associated with a familial incidence. Although solitary apocrine hidrocystoma is said not to show seasonal variation, multiple lesions in some patients worsen in summer or with excessive heat and decrease during the winter months.4,5 Apocrine hidrocystoma is an occasional feature of nevus sebaceus.28

Histological features Apocrine hidrocystoma consists of a large unilocular or multilocular cystic space situated within the dermis (Fig. 33.2).3 A fibrous pseudocapsule is often present. Typically, the cystic spaces are lined by a double layer of epithelial cells: an outer layer of flattened vacuolated myoepithelial cells and an inner layer of tall columnar cells with eosinophilic cytoplasm and basally located, round or oval vesicular nuclei. Ultrastructural observations have confirmed the presence of myoepithelial in addition to secretory cells.29 Decapitation secretion is usually present (Fig. 33.3). Diastase-resistant periodic acid-Schiff (PAS)-positive granules may be evident in the cytoplasm of the inner lining cells and occasionally iron or melanin is also demonstrable.3,15–17,30 In about 50% of lesions, numerous papillary projections are seen growing into the central cavity. Occasionally, the cyst cavity is partially replaced by a papillary or ­adenomatous p ­ roliferation (apocrine cystadenoma) (Fig. 33.4).31 Moll's gland cyst is lined in part by apocrine-type epithelium and elsewhere by keratinizing squamous epithelium.32 The myoepithelial layer can be highlighted with smooth muscle actin (SMA) and p63 immunohistochemistry (Fig. 33.5). Staining with S-100 protein is variable.

B

Differential diagnosis There is often difficulty distinguishing between apocrine hidrocystoma and eccrine hidrocystoma. This results largely from atrophy of the epithelial lining of the apocrine hidrocystoma due to cyst distension by excessive secretions. Eccrine hidrocystoma is thought to derive from cystic dilatation of a sweat duct.33 Whether such a cyst is of eccrine or apocrine derivation is a moot point, since the two ductal systems are generally thought to be identical.4,5 Some authors have proposed the alternative term ductal hidrocystoma to reflect this possible dual histogenesis.5 Recently, however, apocrine ducts have been reported as expressing human milk fat globulin 1 (HMFG-1) whereas eccrine ducts are negative for this protein.33 This may help ­separate

Fig. 33.3 Apocrine hidrocystoma: high-power view of lining epithelium showing decapitation secretion.

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Tumors of the sweat glands true apocrine duct hidrocystoma from that of eccrine derivation. In any event, in hidrocystomas where decapitation secretion is unapparent, S-100 protein and α-SMA immunohistochemistry will readily resolve the problem since eccrine hidrocystoma is negative for both antibodies.33–35 In addition, the luminal epithelial layer in apocrine hidrocystoma expresses keratins K7, K8, and K18 whereas in eccrine hidrocystoma the luminal layer expresses K1, K5, K10, and K14.33,35

Hybrid epidermoid and apocrine cyst Clinical features This rarely documented entity presents as a usually less than 1.0 cm bluish or flesh-colored cystic papule or nodule. Lesions have been described on the nipple, eyelid, and lip.1 A

Histological features The cyst (which contains keratin debris) is lined in part by apocrine ­epithelium with decapitation secretion admixed with squamous epithelium showing a well-developed granular cell layer.

Syringocystadenoma papilliferum Clinical features

B

Fig. 33.4 (A, B) Apocrine papillary cystadenoma: this tumor (which presented on the skin of the neck) was cystic but contained both adenomatous and papillary components.

Syringocystadenoma papilliferum is usually a solitary lesion, which may be present at birth or develop in childhood, and most commonly occurs on the scalp.1–5 It can also be found on the face, neck, trunk, and rarely the lower limbs (Fig. 33.6).3 Surprisingly, it is not often present in the axilla, a site where apocrine glands are abundant. Rarely, lesions have been described on the eyelid, breast, arm, thigh, popliteal fossa, vulva, and scrotum.6–16 Scalp involvement is commonly associated with nevus sebaceous (Fig. 33.7).17–19 Syringocystadenoma papilliferum is thus found in between 5% and 19% of cases of nevus sebaceus, sometimes in association with trichilemmoma.20,21 It has also been described in association with nevus comedonicus and in a patient with focal dermal hypoplasia (Goltz syndrome).22,23 Syringocystadenoma papilliferum most often presents as a gray or darkbrown papillary or rather warty, sometimes crusted, excrescence with a moist appearance. Less commonly, multiple small papules, occasionally in a linear or segmental distribution sometimes following Blaschko's lines are seen.3,24–29 Lesions may be excoriated due to pruritus, and those that develop on the scalp sometimes bleed due to the trauma of hair brushing or combing. Occasionally, there is central umbilication with drainage of serosanguinous secretions.6 Multifocal disease is exceptional.30

Fig. 33.5

Fig. 33.6

Apocrine hidrocystoma: the outer myoepithelial cells express smooth muscle actin.

Syringocystadenoma papilliferum: ulcerated, scaly plaque just prior to surgery. By courtesy of J.C. Pascual, MD, Alicante, Spain.

Syringocystadenoma papilliferum papillae, which communicate with ductlike structures in the deeper aspect of the lesion. At the surface, residual squamous epithelium is often hyperplastic and may show hyperkeratosis and parakeratosis. Superficially, the villi can be covered by stratified squamous epithelium, but this soon gives way to a typical double-layered epithelium consisting of an inner zone of small cells with scant cytoplasm and oval hyperchromatic nuclei, and an outer zone of tall columnar cells with abundant eosinophilic cytoplasm and fairly large vesicular nuclei (Fig. 33.9). Decapitation secretion is often a feature. The glandular spaces are also lined by a double layer of epithelium. The papillary processes are supported by a fibrovascular core, which typically contains large numbers of plasma cells (Fig. 33.10). Although the histological features of syringocystadenoma papilliferum are quite classic and characteristic, the morphological spectrum appears to be broad and there may be at least some morphological overlap with tubular apocrine adenoma.47 Syringocystadenoma papilliferum can show areas reminiscent of classic tubular apocrine adenoma as well as apocrine hidrocystoma and clear cell syringoma, and a tumor with focal sebaceous differentiation has also been reported to arise within a nevus sebaceous.32–34,47–50 Fig. 33.7 Syringocystadenoma papilliferum: scalp tumor, which has arisen within a nevus sebaceus. By courtesy of the Institute of Dermatology, UMDS, London, UK.

Occasionally, syringocystadenoma papilliferum has been described in association with apocrine hidrocystoma, apocrine cystadenoma, hidradenoma papilliferum, tubular apocrine adenoma, apocrine poroma, mixed tubulopapillary hidradenoma, as well as apocrine nevus.18,31–36 It may also present with condyloma accuminatum, apocrine acrosyringeal keratosis, papillary eccrine hidradenoma, cutaneous horn, verrucous carcinoma, verrucous cyst, giant comedone, and poroma folliculare.37–45

Pathogenesis and histological features Although syringocystadenoma papilliferum is generally classified within the apocrine group, the results of electron microscopy, enzyme histochemistry, and immunocytochemistry are conflicting, variably offering support for both eccrine and apocrine derivation/differentiation.3 Perhaps the tumor is truly of apocrine histogenesis or derived from an undifferentiated pluripotential cell as originally postulated by Lever in the 1960s. Deletion at 9q22 (PTCH) and at 9p21 (p16) have been identified in a subset of cases of syringocystadenoma papilliferum.46 Syringocystadenoma papilliferum has a characteristic and readily recognizable appearance. On low-power examination it appears as an invagination from the overlying epidermis or else has an exophytic configuration (Fig. 33.8). Central to the diagnosis are superficially located ­epithelium-covered

Fig. 33.8 Syringocystadenoma papilliferum: this exophytic lesion developed within a nevus sebaceus. Note that the surface is covered with squamous epithelium.

Fig. 33.9 Syringocystadenoma papilliferum: the papillae are covered by an outer layer of tall columnar cells with eosinophilic cytoplasm and an inner layer of small cuboidal myoepithelial cells with hyperchromatic nuclei.

Fig. 33.10 Syringocystadenoma papilliferum: the stroma contains numerous plasma cells.

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Tumors of the sweat glands Syringocystadenoma papilliferum expresses AE1/AE3, CAM 5.2, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA).12,33,51,52 The inner layer is positive for SMA.12 The results of markers of apocrine differentiation are variable. Some authors have found gross cystic disease fluid protein 15 (GCDFP-15) and HMFG-1 negative.10,39 Others have found GCDFP-15 and/or HMFG-2 present.12,51

Syringocystadenocarcinoma papilliferum Clinical features Only very rare cases of syringocystadenocarcinoma have been described.1–6 These have included three in situ variants.1,5,6–8 There are insufficient cases to allow for meaningful clinical data other than documenting that they have been described particularly on the scalp (three cases) but the chest, breast, back, and perianal region have also been affected (one case each). The sex incidence is equal and patients have been middle aged or elderly (range 47–74 years). Patients presented with verrucous nodules or large plaques, usually of many years' duration. When documented, an episode of sudden rapid growth and tumor fixation to the underlying tissues has been evidence of malignant transformation. Occasionally, an association with nevus sebaceous has been documented.8–10 Thus far, these tumors appear to be low grade, only one case having metastasized to regional lymph nodes.3

Histological features The majority of carcinomas have arisen in clearly recognizable benign precursor lesions. The malignant component may be recognized by nuclear atypia, multilayering, increased mitotic activity including abnormal forms, and dermal involvement in those cases associated with an invasive component. Rarely, the development of mucinous adenocarcinoma or apocrine ductal carcinoma presenting in a syringocystadenoma papilliferum which had arisen in a nevus sebaceus has been documented.9,10 The tumor epithelial cells express AE1/AE3, EMA, and CEA.6 HMFG-2 and GCDFP are variably positive.5,6

Fig. 33.11 Hidradenoma papilliferum: this example has caused erythema and ulceration below the right labium minus and around the introitus. By courtesy of the late M. Ridley, MD, Whittington Hospital, London, UK.

Hidradenoma papilliferum Clinical features Hidradenoma papilliferum (papillary hidradenoma) in the vast majority of cases has been described in females.1–9 Almost all cases have been reported in white women.5 Patients are generally young or middle-aged adults (range 20–89 years).6,7 There are only very rare documented cases reported in males and some authors would regard such lesions as representing apocrine papillary cystadenomas.7,10,11 The same might also be said for at least some examples of so-called ectopic hidradenoma papilliferum which have been described on the eyelid, nose, cheek, axilla, upper and lower limbs, chest, back, and external auditory canal.12–17 The examples arising on the eyelid and external auditory meatus are likely derived from the gland of Moll and ceruminous gland, respectively. The tumor presents as a small (1–2 cm in diameter), solitary, usually asymptomatic papule or nodule in a vulval, perineal or perianal location.4 Very occasionally pain, tenderness, pruritus, burning, discharge or bleeding may be encountered.6 Most often it affects the labium majus, but on occasions it has been described as involving the lateral aspect of the labium minus, the interlabial sulcus, the clitoris, posterior fourchette, and mons pubis (Fig. 33.11).6 Lesions are round, solid or cystic and sometimes umbilicated or ulcerated.5

Pathogenesis and histological features Hidradenoma papilliferum arises from apocrine glands or possibly the anogenital mammary-like glands.18 The epidermis may be normal, acanthotic or ulcerated. The tumor forms a fairly well-demarcated nodule in the dermis or lamina propria and may sometimes show foci of continuity with the overlying epithelium (Fig. 33.12).4,19 The lesion consists primarily of epithelium-covered papillary processes that

Fig. 33.12 Hidradenoma papilliferum: low-power view of an exophytic ulcerated nodule. The epidermal collarette is seen in the lower left of the field.

project into cystic spaces. The epithelial lining is typically double layered, comprising inner small myoepithelial cells with oval hyperchromatic nuclei and outer tall columnar cells with eosinophilic cytoplasm, sometimes manifesting decapitation secretion (Fig. 33.13). Prominent oxyphilic metaplasia of the epithelial cells, in areas showing mild nuclear pleomorphism, may be a focal feature.8,9 Occasionally, the lining is only one cell thick (columnar). Diastase-resistant, (PAS)-positive intracytoplasmic granules are usually present. The presence of normal mitotic activity has no sinister implication (Fig. 33.14).20 The larger villi have a fibrous core in which occasional ductular structures may be identified, sometimes forming a cribriform pattern. Often the fibrous tissue surrounding the tumor is compressed to form a ­pseudocapsule.

Tubular apocrine adenoma Human papillomavirus (HPV) types 16, 31, 33, 53, and 56 have been detected in a subset of anogenital lesions but no definite causal role in the pathogenesis of this tumor has been established as yet and the significance of this finding is unclear.8,31

Tubular apocrine adenoma Clinical features

Fig. 33.13 Hidradenoma papilliferum: a double layer of epithelium covers the epithelial fronds. Decapitation secretion is conspicuous.

Tubular apocrine adenoma (apocrine adenoma, tubulopapillary hidradenoma, papillary tubular adenoma) is a rare benign tumor which shows a female predominance (2:1) and a wide age distribution (18–78 years).1–12 The scalp is most commonly affected although lesions have been described at a variety of other sites including the face, eyelid, axilla, leg, and genitalia.3,5,8–11,13,14 The last, however, may represent an adenoma of the anogenital mammary-like glands.10 Those that present on the scalp often arise in a background of nevus sebaceus and are sometimes associated with syringocystadenoma papilliferum.12,15–19 The tumor generally presents as a dermal nodule 1–2 cm in diameter or pedunculated lesion, frequently of many years' duration, particularly those developing within a nevus sebaceus. The lesion is benign and recurrence following excision is uncommon.

Histological features

Fig. 33.14

Histologically, tubular apocrine adenoma presents most often as a circumscribed intradermal nodule although in some cases the subcutaneous fat is involved. Sometimes the tumor communicates with the epidermis through ductlike structures or dilated follicular infundibula (Fig. 33.15). As mentioned above, there may be continuity with a syringocystadenoma papilliferum or an organoid nevus. It is composed of variably sized, well-formed tubules lined by a double or multilayered epithelial cell layer comprising cuboidal or columnar forms with abundant eosinophilic cytoplasm and uniform round to oval nuclei (Fig. 33.16). There is no pleomorphism and mitoses are scanty. In those tubules showing glandular differentiation, the inner lining cells often show decapitation secretion while the outer layer is composed of flattened myoepithelial cells. Cystic change is common and in many tumors intraluminal papillae are present although usually these are devoid of a fibrovascular core. True papillae are, however, sometimes seen although these are generally evident in lesions associated with a syringocystadenoma papilliferum. The tumor has a well-developed connective tissue stroma in which only small numbers of chronic inflammatory cells are present. Areas of follicular and/or sebaceous differentiation may rarely be encountered.20

Hidradenoma papilliferum: in the center of the field are two mitotic figures.

An inflammatory cell component is not a significant feature although aggregates of lymphocytes and plasma cells have been described in the stroma of ectopic lesions.14 Rare observations include a focally solid growth pattern composed of small monomorphous cells with lumen formation, a spindle cell population as well as areas resembling sclerosing adenosis in the breast.8 Uncommonly, focal sebaceous differentiation may be a feature.4,17 Exceptionally rarely, a malignant variant may be encountered including intraductal carcinoma.21–25 In the single example encountered by the authors, focal areas showing an extensive infiltrative growth pattern accompanied by marked nuclear pleomorphism and conspicuous, sometimes abnormal, mitotic activity were identified against a background of typical benign morphology. The outcome in this case is unfortunately not known. Coincidental hidradenoma papilliferum in a patient with vulval Paget's disease has been described.7,26 Ultrastructurally, hidradenoma papilliferum shows features of apocrine differentiation.27 Immunohistochemically, the epithelial cells express low molecular weight keratin, EMA, CEA, HMFG, and GCDFP-15.7,28 Estrogen and to a lesser extent progesterone receptors are positive, and androgen receptor is expressed in up to 20% of tumors.28–30 The myoepithelial cells express S-100 protein and SMA.28

Fig. 33.15 Apocrine tubular adenoma: this example from the face consists of variably sized tubules, many showing cystic dilatation.

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Tumors of the sweat glands of a plasma cell-rich inflammatory cell infiltrate. There may, however, be a ­morphological continuum between the two entities and reliable separation is not always possible.21 Tubular apocrine adenoma can be distinguished from papillary eccrine adenoma in many cases by the presence of apocrine decapitation secretion and the common location on the scalp, especially when developing in association with syringocystadenoma papilliferum or organoid nevus. In some cases, however, the distinction is difficult or impossible (Figs 33.18, 33.19). Occasional tumors show features of both lesions.11 This has led some authors to suggest the alternative terms tubulopapillary hidradenoma and papillary tubular adenoma.11,12,22 Tubular apocrine adenoma differs from papillary apocrine carcinoma by the absence of an infiltrative growth pattern and cytological atypia. Mitoses are generally sparse and abnormal forms are absent.

Fig. 33.16 Apocrine tubular adenoma: the tubules are lined by cuboidal to columnar epithelial cells with copious eosinophilic cytoplasm and focally showing decapitation secretion.

The luminal surface of the tubular lining epithelial cells shows strong expression of EMA and CEA (Fig. 33.17).7,11,12,17 The cytoplasm is also sometimes weakly EMA positive.12 HMFG-1 and GCDFP may be present.11 The myoepithelial cells can be highlighted with SMA or S-100 protein immunohistochemistry.11,12,17 Ultrastructurally, the tubules are lined by cuboidal to columnar epithelial cells with conspicuous luminal microvilli and sometimes showing apical pinching or frank decapitation secretion. The cytoplasm contains prominent Golgi, conspicuous mitochondria, and lipid-rich secretory vacuoles. The outer layer shows features of myoepithelial cells.12

Differential diagnosis

Fig. 33.18 Tubulopapillary hidradenoma: this example, which arose in a background of nevus sebaceus, shows a prominent papillary component.

Tubular apocrine adenoma must be distinguished from syringocystadenoma papilliferum, papillary eccrine adenoma, and papillary apocrine carcinoma. Some tumors, particularly those arising in a background of an organoid nevus, develop in association with a syringocystadenoma papilliferum. Those that are wholly intradermal differ from syringocystadenoma papilliferum by the absence of true papillae with fibrovascular cores and by the absence

Fig. 33.17 Apocrine tubular adenoma: the luminal aspect of the tubules shows striking EMA positivity.

Fig. 33.19 Tubulopapillary hidradenoma: the tubules are lined by double-layered epithelium. The papillae are devoid of a fibrovascular core. It is often impossible to determine whether this tumor is of apocrine or eccrine differentiation.

Apocrine poroma

Adenoma and adenocarcinoma of the anogenital mammary-like glands The anogenital mammary-like glands combine the features of eccrine, apocrine, and mammary glands.1–3 They are present in greatest concentration in the vulval interlabial sulcus. A range of tumors reminiscent of their mammary counterparts including epithelial hyperplasia, adenoma, fibroadenoma, ­phyllodes tumor, and in situ as well as invasive ductal carcinoma have been documented.4–24 Pseudoangiomatous stromal hyperplasia (PASH) has also been documented.25,26 Human papillomavirus (HPV) has been detected in a single case of ­invasive ductal carcinoma.27

Nipple adenoma Clinical features Nipple adenoma (erosive adenomatosis, florid papillomatosis, superficial papillary adenomatosis) is a benign tumor which most often presents in middle-aged females with a peak incidence in the fifth decade.1–8 Rarely, however, girls may be affected and there are exceptional reports of the condition in males.9–13 Patients present with erythematous, scaly or crusted and sometimes eroded lesions clinically mistaken for eczematous dermatitis or Paget's disease (Fig. 33.20).1,6, 14 Pruritus, irritation, pain, and burning are variable complaints.9 An 0.5–1.5 cm tumor nodule and/or an increase in size of the nipple are sometimes present.4,8 Some patients complain of nipple discharge or bleeding.

Histological features The tumor is unencapsulated and consists of adenomatous and papillary areas in varying proportion.1 It usually communicates with the surface epithelium where cysts lined by an admixture of squamous and columnar epithelium are sometimes evident.1 The glandular spaces are lined by tall columnar eosinophilic cells which invariably show decapitation secretion. A myoepithelial cell layer is present. Intraluminal papillomatosis is generally evident and giant cells are sometimes seen.1,9 Normal mitoses may be present. The papillae are devoid of a fibrovascular core and cytological atypia is absent. The stroma can be fibrotic or hyalinized and in some tumors this compresses the epithelium to give rise to a pseudoinfiltrative growth pattern.1 A plasma cell-rich inflammatory cell infiltrate is sometimes evident in the surrounding connective tissue.

Fig. 33.20 Nipple adenoma: the nipple shows an ulcerated crusted lesion. By courtesy of the Institute of Dermatology, UMDS, London, UK.

Syringomatous adenoma of the nipple Clinical features Syringomatous adenoma of the nipple is a rare tumor presenting as a firm unilateral mass of few centimeters on the breast predominantly affecting the nipple and subareolar area.1–9 Development within a supernumerary breast has recently been reported.10 It is a tumor of adulthood with a peak incidence in the fourth decade and a strong female predilection.1–10 Presentation in males is exceptional.9 Syringomatous adenoma of the nipple is a locally aggressive tumor with potential for recurrence if inadequately excised.8,9 However, no distant metastasis or disease-related mortality has been documented and complete excision with negative margins appears to be curative.8,9

Histological features The histological features are reminiscent of sclerosing sweat duct carcinoma to which it may be closely related. The tumor shows an infiltrative growth pattern within dermis, along nipple ducts, and extending into breast parenchyma.9,10 Infiltration of smooth muscle is a frequent feature and ­perineural infiltration may rarely be observed. The tumor is composed of small, ­well-formed ducts and basaloid epithelial strands within a fibrous stroma showing only little cytological atypia.9,10 Tubular and squamous differentiation may be seen and keratocysts as well as dystrophic calcification are common.

Apocrine poroma Clinical features Apocrine poroma (poroma with divergent differentiation, complex poromalike adnexal adenoma, sebocrine adenoma, sebaceous and apocrine adenoma, and poroma with sebaceous differentiation) is an uncommon tumor, which presents as an often slowly growing flesh-colored, erythematous papule, nodule or plaque.1–10 There is no site predilection, lesions having been described on the lip, cheek, eyelid, nose, abdomen, back, and limbs.3,11,12 No cases presenting on the palms and soles have been documented to date. A wide age range may be involved (19–76 years). The sexes are affected equally. The tumor is benign and recurrences are rare.2

Histological features Apocrine poroma in essence is defined as a poroma showing sebaceous differentiation with the occasional presence of follicular differentiation and foci of apocrine-like features. In terms of nomenclature, although sebaceous differentiation is the common link, the literature has focused on the apocrine element – hence the designation apocrine poroma. The presence of sebaceous, follicular, and apocrine features reflects the common embryological ancestry of the three units (the folliculosebaceous- apocrine unit). Apocrine poroma – in common with its eccrine counterpart – is composed of anastomosing trabeculae, displaying multiple points of origin from the ­epidermis and located largely in the papillary and upper reticular dermis.3 The individual cells are small and uniform with scanty cytoplasm and round to oval nuclei united by inconspicuous intercellular bridges. Foci of ductal differentiation with a well-developed eosinophilic cuticle are present. An example showing follicular infundibular origin in a patient with nevoid basal cell carcinoma has been reported.4 An infrequent feature is the presence of sebaceous cells, singly and in clusters with bubbly cytoplasm and crenated nuclei. Sebaceous ductlike tubular or cystic structures lined by squamous epithelium with an eosinophilic, ­scalloped cuticle and containing eosinophilic debris with pyknotic nuclei may also be present.3 In some examples, hair germlike structures manifest as small collections of basaloid cells with peripheral palisading, and ­perifollicular sheathlike connective tissue are seen.3,7,9 Occasional reports have described tubules lined by cells with intensely eosinophilic cytoplasm reminiscent of apocrine ­epithelium.3,7 Although frank decapitation has generally been absent, it is well illustrated in the series of Yamamoto and coworkers.6

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Tumors of the sweat glands Wholly intraepidermal hidroacanthoma simplex-like and largely intradermal variants have been documented.5,9 In addition, there is a report of an example associated with trichoblastoma.10 A case presenting on the areola has also been documented.13 In it, however, there was no evidence of sebaceous, follicular or apocrine differentiation. Although close proximity to the follicular infundibula was demonstrated, it is unclear whether the tumor might not have been better regarded as eccrine poroma.13 A metaplastic or sarcomatoid carcinoma has recently been shown to arise within an apocrine poroma (sarcomatoid apocrine porocarcinoma).11

Differential diagnosis Diagnosis of apocrine poroma depends upon exclusion of entrapped normal adnexae. Intraepidermal variants may be differentiated from seborrheic keratoses with sebaceous differentiation by the presence of ducts, which may be highlighted with diastase–PAS staining or EMA/CEA immunohistochemistry.

A

Apocrine carcinoma Clinical features Apocrine adenocarcinoma is rare and most documented cases have affected the axilla.1–18 Occasionally, the tumor may present at a variety of other sites including the scalp, eyelid (Moll's gland carcinoma), ear (ceruminous gland adenocarcinoma), anogenital region, chest, lip, and wrist, in descending order of frequency.2,14,18–30 Tumors have also been described on the cheek, nipple, and fingertip.11,31,32 Clinical data are limited in the majority of published cases, but most tumors present as single or multiple, sometimes ulcerated, often slowly growing nodules or plaques covered by erythematous or purple skin. A presentation as carcinoma erysipeloides has also been documented.1–3,33 In some instances, tumors have been present for 30 years before diagnosis.12 Occasional tumors have arisen within a nevus sebaceous and invasive as well as in situ carcinoma has been documented to arise in association with apocrine adenoma in the perianal area.18,28,34–38 Patients with bilateral axillary apocrine carcinomas and associated apocrine hyperplasia have been reported in the Japanese literature.16,39 Telangiectatic and inflammatory cutaneous metastatic disease similar to that described with breast carcinoma has been described.24 Age at presentation is variable (18–91 years, mean 60 years) and the sex incidence is approximately equal.1,2,18 There is no racial predilection.2 Apocrine carcinoma is often characterized by a prolonged course and, although recurrences (28%) and nodal metastases (50%) are common, the overall mortality is low. Bone and lung secondary deposits or more disseminated disease and tumor-related deaths have, however, been described.1,2,5,11 ,12,18,22,24,40–43 Disease-related mortality was 24% in a recent study.18 In some patients, metastases are a very late development and therefore a very careful, prolonged follow-up is indicated.

B

Fig. 33.21 (A, B) Apocrine carcinoma: this specimen comes from the vulva and shows diffuse infiltration by poorly differentiated adenocarcinoma. Note the nuclear pleomorphism and prominent nucleoli.

Histological features Apocrine carcinoma is characterized by a variable glandular, tubular, ­papillary, tubulopapillary or diffuse or solid growth pattern centered on the deeper ­dermis and frequently involving the subcutaneous fat (Figs 33.21– 33.24).1–3,18,44 Occasional tumors are cystic, and foci of necrosis are sometimes evident.2 In contrast to apocrine adenoma, the tumor is usually poorly circumscribed and typically an infiltrating border is present. Epidermotropism is sometimes a feature and in some tumors frank Paget's disease is present (Fig. 33.25).2,11,13,18,23,24,45–47 The epithelial cells have abundant eosinophilic cytoplasm, and decapitation secretion (albeit often focal) is invariably present (Fig. 33.26).2,6 Nuclei are round or oval and vesicular and commonly contain a solitary prominent nucleolus (Figs. 33.27, 33.28, 33.29). Focal squamous differentiation may occasionally be seen.2 Exceptionally, sebaceous differentiation has been described.26 Pleomorphism and mitotic activity are variable features, but become more prominent in poorly differentiated variants. The tumor is commonly accompanied by a dense hyaline stroma. A single filing growth pattern

Fig. 33.22 Apocrine carcinoma: focal glandular differentiation and decapitation secretion is evident.

Apocrine carcinoma

Fig. 33.24 Apocrine carcinoma: higher-power view showing multilayering, nuclear hyperchromatism, and pleomorphism.

Fig. 33.23

A

(A, B) Apocrine carcinoma: this example from the face shows a striking papillary growth pattern.

Fig. 33.25 B

may be encountered in poorly differentiated tumors.8–10,18,24 Apocrine carcinoma is characterized by intracytoplasmic diastase-resistant, (PAS)-positive granules and intracytoplasmic iron is sometimes demonstrable.2,16,22 Alcian blue (pH 2.5) and mucicarmine may also be positive but glycogen is uniformly absent.9,13 Normal apocrine glands are often found in close proximity to the tumor and occasionally longstanding pre-existent benign apocrine lesions (including hyperplasia, cystadenoma, cylindroma, syringocystadenoma papilliferum, and tubular adenoma) may be evident, raising the possibility of malignant transformation.2,3,6,14,20,48 The apocrine glands sometimes show tumor infiltration/in situ carcinoma.1,2,13,26 Perineural infiltration and lymphovascular invasion is occasionally seen.18,22,26 A small number of apocrine carcinomas showing signet ring cells ­reminiscent of invasive lobular carcinoma of breast have been reported.18,49,50 These show a striking predilection for elderly males (10:1).10 Although these have most frequently been described on the eyelids, they may also present in the axilla.8–10 Apocrine carcinoma with focal mucinous carcinoma-like ­features has been documented.23 An unusual tumor characterized by more circumscribed borders, epidermal connection, and atypical basaloid cells with duct formation and decapitation secretion has recently been reported.51

Apocrine carcinoma: there is focal decapitation secretion.

Fig. 33.26 Apocrine carcinoma: focal epidermotropism is evident (same case as Figures 33.21 and 33.22).

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Tumors of the sweat glands Immunocytochemically, the tumor shows low molecular weight keratin (CAM 5.2), AE1/AE3, EMA, CEA, CK15, and GCDFP-15 expression.2,3,11,19 Lysozyme, α1-antitrypsin, α1-antichymotrypsin, and in some tumors S-100 protein, are also present.2,10 Myoepithelial cells as demonstrated by SMA are usually lost.13,26 In a significant subset of tumors expression of estrogen receptor, progesterone receptor or androgen receptor is seen.18 If fresh tissue is available, assessment of apocrine enzymes, including acid phosphatase and non-specific esterase, may be of diagnostic value.6 Electron microscopic findings, including luminal microvilli, conspicuous mitochondria, and large electron dense granules, have supported apocrine differentiation.11,23

Differential diagnosis

Fig. 33.27 Apocrine carcinoma: low-power view.

Primary cutaneous apocrine carcinoma is indistinguishable from metastatic mammary ductal apocrine carcinoma. With the exception of those rare lesions arising in a nevus sebaceus or showing focal continuity with an associated apocrine adenoma, careful breast assessment should be advised before accepting the diagnosis of primary cutaneous apocrine carcinoma, ­particularly for those lesions that present at an atypical location.

Ceruminous gland tumors Clinical features

Fig. 33.28 Apocrine carcinoma: the tumor cells have abundant eosinophilic cytoplasm and large vesicular nuclei. Note the nuclear pleomorphism

Ceruminous gland tumors (ceruminoma) are rare and present as an often pedunculated nodule or cystic lesion in the external auditory canal, often associated with deafness and less commonly with tinnitus or otorrhea.1–8 Pain is sometimes a feature as a result of otitis externa, ulceration or malignancy.7 Facial nerve palsy has occasionally been documented.2,9 The age distribution is wide but tumors are most commonly seen in adulthood.8 The sex incidence is equal.5,8 In the earlier literature, the term ceruminoma was often applied to all glandular tumors arising in the external auditory meatus. This resulted in considerable confusion since it lumped together both benign and malignant variants, the latter being the more common. Currently, ceruminous gland tumors are classified as benign, including apocrine adenoma and mixed tumor (pleomorphic adenoma), and malignant – ceruminous gland adenocarcinoma and adenoid cystic carcinoma.1,2,6 In addition, cylindroma, syringocystadenoma papilliferum, and mucoepidermoid carcinoma have exceptionally been documented.2,10

Histological features The ceruminous glands are apocrine glands found predominantly within the dermis of the cartilaginous part of the external auditory canal. Ceruminous apocrine adenoma presents as a circumscribed nodule composed of glands lined by a double layer of epithelium (Fig. 33.30).4,8 The inner are cuboidal to columnar with eosinophilic cytoplasm often showing decapitation secretion. The outer are myoepithelial cells. Cystic change is sometimes present. Solid, acinar, and trabecular variants have been described.5,8 Pleomorphism is absent and mitoses are scarce. Abnormal forms, by definition, are not a feature. Ceruminous gland adenocarcinoma is characterized by an infiltrating growth pattern. Pure glandular and papillary variants are recognized. The cytology varies from deceptive, well-differentiated forms to high-grade tumors with marked pleomorphism and conspicuous mitotic ­activity (Fig. 33.31). Perineural infiltration is sometimes a feature and rarely extramammary Paget's disease is seen.11

Differential diagnosis

Fig. 33.29 Apocrine carcinoma: there is focal decapitation secretion.

Well-differentiated ceruminous gland adenocarcinoma may be difficult to distinguish from adenoma if the infiltrative border is not visible, as may be the case in small biopsy specimens. If there is any doubt, it is recommended that tumors be reported as having uncertain malignant potential with the final diagnosis deferred until the full excision specimen is available for study.5

Mixed tumor of the skin

A

A

B

B

Fig. 33.30

Fig. 33.31

(A, B) Ceruminous gland adenoma: this example shows continuity with the epidermis. The tumor shows tubule formation and multiple small cysts are apparent. The tubules are lined by a double layer of epithelium. The inner layer has abundant eosinophilic cytoplasm; the cells of the outer layer are cuboidal and represent myoepithelial cells. By courtesy of M. Bosenberg, MD, University of Vermont, Vermont, USA.

Ceruminous gland adenocarcinoma: (A) low-power view of part of an ulcerated mass; (B) there is multilayering and nuclear pleomorphism.

Mixed tumor of the skin Clinical features Mixed tumor of the skin (chondroid syringoma) is not uncommon and presents as a slowly growing, firm, circumscribed, lobulated nodule within the dermis or subcutaneous fat. It is usually solitary and asymptomatic and most often affects the head and neck, particularly the nose, cheek, upper lip, scalp, forehead, chin, eyelids, and ear including the external auditory meatus, in descending order of frequency, although on occasions it may involve the axillae, trunk or extremities (Figs 33.32, 33.33).1–9 Scrotal involvement has rarely been described.10,11 Exceptional giant variants affecting the cheek and axilla have been documented.8,12–15 Males are more commonly affected than females and the tumor typically presents in the middle aged.9 Recurrences are rare.

Histological features Although the earlier literature argued variably for an eccrine or apocrine derivation, more recently variants differentiating towards both are recognized.16,17

Fig. 33.32 Mixed tumor: this erythematous nodule is present at a characteristic site. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

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Tumors of the sweat glands

Fig. 33.33 Mixed tumor: lesions are more common in males and occasionally affect the thorax. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 33.34 Mixed tumor: at scanning magnification the tumor is circumscribed and compresses the adjacent dermal connective tissue.

Most tumors are currently classified as apocrine type (apocrine chondroid syringoma). This is usually multilobulated and situated within the deep dermis and/or subcutaneous fat (Fig. 33.34). It forms a well-circumscribed mass in which a dominant component has a chondroid appearance (Figs. 33.35, 33.36). The lobules are separated by fibrous septa. The epithelial component is composed of nests and cords of cuboidal or polygonal cells with copious eosinophilic cytoplasm and basophilic nuclei.1–3,12,17 They are distributed singly, in cords and nests or as irregular tubuloalveolar and ductal structures. The tubuloalveolar foci, which are believed to represent differentiation towards the secretory coil, are lined by two or more rows of epithelial cells, the outer layer being somewhat flattened and of myoepithelial derivation (Fig. 33.37). Apocrine decapitation secretion is sometimes evident and occasionally the epithelium has a lacelike pattern (Fig. 33.38). PAS-positive, diastase sensitive, glycogen-rich clear cells may be present (Fig. 33.39).17 One or occasionally two layers of cells line the ducts, which represent differentiation towards the dermal sweat gland duct (Fig. 33.40). Cystic dilatation is common (Fig. 33.41). Occasionally, keratinous cysts and foci of squamous differentiation are present (Fig. 33.42).1,17 In addition, clear cell change as well as mucinous, columnar, oxyphilic, and hobnail metaplasia of the epithelial component may be evident.9 There is, however, no pleomorphism, mitoses are sparse, and necrosis is absent.

Fig. 33.35 Mixed tumor: this example has a well-developed chondroid stroma. There is conspicuous ductal differentiation and multiple cysts are present.

Fig. 33.36 Mixed tumor: higher-power view of chondroid component.

Fig. 33.37 Mixed tumor: the inner lining cells have abundant cytoplasm and vesicular nuclei; the outer myoepithelial cells have hyperchromatic spindled nuclei.

Mixed tumor of the skin

Fig. 33.38 Mixed tumor: this example shows well-developed decapitation secretion.

Fig. 33.39 Mixed tumor: clear cell change due to cytoplasmic glycogen is sometimes present.

Fig. 33.40 Mixed tumor: the ducts are lined by cuboidal epithelium and show a well-developed cuticle.

Fig. 33.41 Mixed tumor: this example shows marked cystic change.

Fig. 33.42 Mixed tumor: keratocysts, as shown in this field, are sometimes present.

Not uncommonly, mixed tumor shows additional foci of follicular and sebaceous differentiation.1,6,17–21 The former is characterized by the presence of infundibulocystic, isthmic as well as tricholemmal differentiation, hair bulbs and papillary mesenchyme in addition to foci of ghost cells reminiscent of pilomatrixoma.6,9,20,21 Sebaceous differentiation is present as foci of cells showing granular or bubbly cytoplasm and scalloped nuclei or as sebaceous ductlike structures with an eosinophilic, wavy, laminated, keratinized lining.6,9,18 Rarely, pigmented dendritic melanocytes are a feature. The myoepithelial component may show hyaline (plasmacytoid), spindled cell or clear cell differentiation.9,22–26 The hyaline (plasmacytoid) cells are characterized by abundant ground-glass eosinophilic cytoplasm and an eccentric nucleus. They are present singly within the stroma or as distinct noncohesive aggregates (Fig. 33.43).17,22–27,28 Spindled cell myoepithelial cells are also present within the chondroid matrix and are responsible for its production.29–31 Clear cell change of the myoepithelial component may be an additional finding. Transition between polyhedral cells and spindled cells or foci of squamous differentiation may be seen.27 The stroma is of variable appearance. Characteristically, it is composed of homogeneous bluish chondroid (Fig. 33.44). In other areas it is myxoid or densely collagenous, eosinophilic, and hyalinized (Fig. 33.45). Positive Alcian blue or green staining at pH 2.5 indicates the presence of acid mucopolysaccharides (Fig. 33.46).17

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Tumors of the sweat glands

A

Fig. 33.43 Mixed tumor: this example shows conspicuous hyaline/plasmacytoid cells.

Sometimes, abundant mature fat is present (‘lipomatous mixed tumor’) (Fig. 33.47).8,9,32–36 Some tumors may show foci of calcification, and on rare occasions osteoid with marrow spaces has been described.6,16,18,37–42 Less often, the tumor is composed of small gland and ductlike structures lined by a single layer of cuboidal epithelium dispersed in a mucinous and/or chondroid stroma (Figs 33.48, 33.49).16,17 This is sometimes referred to as the eccrine variant (eccrine chondroid syringoma).4,16 Exceptionally, hidrocystoma-like features have been described.43 Cutaneous mixed tumors with atypical histological features but benign clinical behavior have recently been described.44 Atypical architectural features include lesional asymmetry and slightly infiltrative tumor edges without capsular invasion.44 More often, the atypical findings relate to the cytological features. Mild cytological atypia of epithelial cells in ductular structures may be present but the most frequent finding is the presence of scattered multinucleated pleomorphic and bizarre-appearing cells within the myoepithelial component of the tumor. By immunohistochemistry, these cells are characterized by a myoepithelial phenotype.44 There are occasional reports of diagnosis of mixed tumor by fine needle aspiration cytology.45–47 In view of the difficulty sometimes encountered in distinguishing between benign and malignant variants, a complete excision with histological study should always be performed. Immunocytochemically, the inner epithelial cell layer is characterized by high and low molecular weight keratin (AE1/AE3), EMA, CEA, and GCDFP-15 expression (Fig. 33.50).17,48–51 The outer cells express vimentin, S-100 protein, and sometimes SMA and muscle-specific actin (MSA) (Fig. 33.51).39,40,50–53 Stromal cells are vimentin and S-100 protein positive.39,40 A recent, more detailed immunohistochemical study of stromal cells in mixed tumor has shed some light on their likely nature.27 The authors classified them into the following three subtypes: • Hyaline cells express CAM 5.2 but not cytokeratin 10 (CK10), CK14, SMA or MSA, indicative of simple epithelium. A rim of CK14+ cells possibly representing ductal basal cell or myoepithelial differentiation may surround them. The additional presence of S-100 and focal GFAP expression, however, argues for myoepithelial differentiation.54 • Polyhedral cells express CK14 but not CK10, SMA or MSA and may represent myoepithelial cells or sweat duct basal cells. • Spindled cells express CK14, SMA, and MSA but not CAM 5.2 or CK10 and are therefore thought to be of myoepithelial derivation.27 A number of in-depth investigations of keratin expression in mixed tumor have been published.54–56 The results suggest that all elements of the sweat gland are represented although whether the tumor arises in or differentiates towards the apocrine or eccrine sweat gland apparatus remains uncertain.

B

C

Fig. 33.44 Mixed tumor: (A, B) in this field, the stroma has a chondroid appearance; (C) this example shows well developed bone with marrow cavities.

Malignant mixed tumor Clinical features Malignant mixed tumor (malignant chondroid syringoma) is an extremely rare tumor.1–19 Approximately 50 cases have been described to date. Although the majority of tumors have developed de novo, there are some documented

Malignant mixed tumor

A

Fig. 33.45 Mixed tumor: myxoid change due to abundant mucopolysaccharide is commonly present.

B

Fig. 33.48 (A, B) Mixed tumor: eccrine variant showing small, duct-like structures dispersed in a hyalinized stroma.

Fig. 33.46 Mixed tumor: the stroma stains strongly with Alcian green.

Fig. 33.47 Mixed tumor: foci of mature adipocytes are often an integral component of the tumor.

Fig. 33.49 Mixed tumor: focal clear cell change is seen in this example.

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Tumors of the sweat glands

Fig. 33.50

Fig. 33.52

Mixed tumor: the inner layer of epithelial cells shows strong EMA expression.

Malignant mixed tumor: this specimen comes from a longstanding lesion. Residual benign precursor is seen to the right of center.

Fig. 33.51

Fig. 33.53

Mixed tumor: in this example, the myoepithelial cells are highlighted with S-100 protein immunohistochemistry.

Malignant mixed tumor: benign tumor on the left merges with carcinoma on the right.

examples which appear to have arisen within a pre-existent benign mixed tumor.4,6,8,14 The tumor predominantly affects the distal extremities (the foot being the commonest site), shows a predilection for females (2:1), and most often arises in the sixth decade although there is a wide age range (18–89 years).15 Clinically, the tumor is not distinctive and presents as a flesh-colored or erythematous nodule. Malignant mixed tumor is an extremely high-grade neoplasm with a ­metastasis rate of approximately 60% and a mortality of roughly 25%.9 The lymph nodes, lungs, and bone are predominantly affected.4,10–14,17,20

Histological features Ideally, the diagnosis of malignant mixed tumor should depend upon the identification of a benign precursor lesion (Figs 33.52–33.56). This, however, has only rarely been histologically documented.4,6,14 In the majority of cases, diagnosis depends upon identification of foci of mucoid stroma and chondroid differentiation as with its benign counterpart. Criteria suggestive of malignant potential include an infiltrative growth pattern, epithelial nuclear and cytoplasmic pleomorphism, excessive or abnormal mitotic activity, and tumor necrosis (Figs 33.57–33.59). Vascular and lymphatic invasion or metastases obviously confirm the diagnosis. Impaired tubular differentiation, excessive mucoid matrix, and abundant, poorly developed

Fig. 33.54 Malignant mixed tumor: the carcinoma cells have large vesicular nuclei with prominent eosinophilic nucleoli. Multiple mitoses are present.

Malignant mixed tumor

Fig. 33.55 Malignant mixed tumor: focally, the tumor cells show signet ring cell change.

Fig. 33.56 Malignant mixed tumor: this example is a recurrent lesion on the foot. Residual benign tumor is present in the upper-left quadrant. Chondroid stroma is evident in the lower-right field.

Fig. 33.58 Malignant mixed tumor: the malignant component shows focal glandular differentiation.

Fig. 33.59 Malignant mixed tumor: note the nuclear pleomorphism and mitotic activity.

chondroid elements may also point towards a diagnosis of malignancy, and ­frank ­chondrosarcomatous or osteosarcomatous differentiation may be present.3,9,17 Some tumors which have metastasized have been deceptively bland. An infiltrative growth pattern or evidence of satellite lesions in such tumors should be viewed with concern and the tumor widely excised, with careful follow-up recommended.16 The tumor often shows multiple satellite lesions in the adjacent dermis or subcutaneous tissue, which may result in incomplete excision and account for the high risk of recurrence.15 There is one instance of malignant mixed tumor recognized by fine needle aspiration cytology.12 Immunohistochemically, the epithelial cells express pankeratin, AE1/ AE3, CAM 5.2, EMA, CEA, and variably S-100 protein.5,6,8–11 The luminal epithelial cells are also Ulex europaeus positive.10 Intracytoplasmic lumina may be outlined with CEA.9 The stromal cells are S-100 protein positive 9,10 and variably express keratin.9 SMA has been variably reported as present or absent.10,11

Differential diagnosis Fig. 33.57 Malignant mixed tumor: residual benign tumor showing cysts and ducts lined by a double-layered epithelium. Carcinoma is present in the lower field.

Malignancy in mixed tumor relates solely to the epithelial proliferation. If nuclear pleomorphism and mitotic activity affect the chondroid ­component, a diagnosis of metaplastic carcinoma (carcinosarcoma) is more appropriate.

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Tumors of the sweat glands Other tumors in which a mucinous or chondroid matrix is evident, including mucinous carcinoma, extraskeletal myxoid chondrosarcoma, and metastatic skeletal chondrosarcoma, may occasionally have to be excluded.

Myoepithelioma and malignant myoepithelioma Clinical features Myoepithelioma is a rare tumor which arises in the dermis, subcutaneous fat or soft tissues.1–19 Analogous to salivary gland tumors, cutaneous myoepitheliomas are composed of the myoepithelial and stromal components of mixed tumors but lack the ductal epithelial component.7,8 The age range at presentation is wide (newborn–93 years) but there is a predilection for adolescents and young adults.1–3,5–8,18 Males appear more frequently affected than females. Cutaneous tumors present as firm or hard, well-circumscribed, flesh-colored, gray or violaceous nodules ranging in size from 0.5 cm to 2.5 cm (mean: 1.1 cm).7 Tumors located within soft tissue may present as larger masses measuring up to 12 cm (mean: 3.8 cm) while malignant myoepithelioma may reach up to 20 cm.8 There is a predilection for the extremities and limb girdles but the head, neck, and trunk are also affected.2–4,6–8,18 Local recurrence may be a complication, but distant metastasis and disease-related death are rare.3,7,8,15 While few data are available regarding morphologically malignant tumors of skin, those presenting in soft tissue show an increased risk of local recurrence (40–50%), high metastatic potential of 30–50%, and high disease-associated mortality.8,18,10

Fig. 33.61 Myoepithelioma: the tumor cells have eosinophilic cytoplasm and round to oval or spindled vesicular nuclei with prominent nucleoli. By courtesy of L. Cohen, MD, Cohen Dermatopathology, Massachusetts, USA.

Histological features Myoepithelioma is composed of an unencapsulated, often dome-shaped, circumscribed nodule consisting of a pure population of myoepithelial cells with no evidence of glandular or ductal differentiation as is seen in the more commonly encountered mixed tumor (Figs 33.60, 33.61).5–7 The overlying epidermis may be hyperplastic and sometimes a well-developed collarette is present.1 A variety of cell types are encountered, including epithelioid, spindled, histiocytoid, and plasmacytoid (hyaline) cells; occasionally clear cells are a feature.3 These may show a solid sheetlike, reticular or whorled and occasionally fascicular arrangement.2,6,7 Some tumors are characterized by a multinodular growth pattern. There is generally no significant nuclear pleomorphism, nucleoli are inconspicuous, and mitoses usually scanty (Fig. 33.62).1 Intranuclear cytoplasmic pseudoinclusions are sometimes present. The stroma is typically myxoid or hyaline (Figs 33.63, 33.64).3,6–8 Cartilagenous differentiation or osseous metaplasia is only rarely present.8,18 In some tumors conspicuous mature adipocytes are present.1,4,7 Occasionally, radially orientated collagenous crystalloid inclusions are a feature.3

Fig. 33.62 Myoepithelioma: a mitosis is present in the center of the field. By courtesy of L. Cohen, MD, Cohen Dermatopathology, Massachusetts, USA.

Fig. 33.60

Fig. 33.63

Myoepithelioma: scanning view showing a circumscribed upper dermal tumor nodule. By courtesy of L. Cohen, MD, Cohen Dermatopathology, Massachusetts, USA.

Myoepithelioma: in this field, there is marked stromal hyalinization. By courtesy of L. Cohen, MD, Cohen Dermatopathology, Massachusetts, USA.

Eccrine nevus Lymphovascular invasion or perineural infiltration may also be present.18 The behavior of cutaneous and soft tissue myoepitheliomas is, however, unpredictable and local recurrence and even distant metastasis as well as disease-related mortality have been documented in tumors lacking cytological features of malignancy. Reliable criteria for malignancy are therefore difficult to establish. Ultrastructurally, intermediate filaments with focal densities are prominent and the tumor cells are surrounded by a well-developed basal lamina.2 Desmosomes may be present.1 By immunohistochemistry, expression of cytokeratin and/or EMA together with S-100 and/or GFAP in tumor cells is required to document their myoepithelial phenotype. In addition, expression of calponin and SMA may be seen (Fig. 33.65).6–8 Nuclear staining for p63 may be seen but desmin is only rarely expressed.6,7 Malignant variants show an identical profile.6 Cytogenetic studies on one case of malignant myoepithelioma have revealed complex findings with deletion of 3p, gain of 16q, and monosomy of chromosomes 13 and 15.14

Eccrine nevus

Fig. 33.64 Myoepithelioma: myxoid change, as shown in this field, is sometimes present. By courtesy of L. Cohen, MD, Cohen Dermatopathology, Massachusetts, USA.

Clinical features

These are composed predominantly of type I collagen with type III collagen at their periphery.3 Rarely, colonization by dendritic melanocytes may be a feature.17 Malignant myoepithelioma is characterized by marked nuclear pleomorphism, conspicuous nucleoli, a high mitotic rate, and necrosis.6–8,18

Eccrine nevus (nevus sudiferous, sudiferous hamartoma) is a rare hamartoma of the eccrine unit which typically presents in childhood or adolescence.1–15 Clinical manifestations are variable and include localized areas of hyperhidrosis (localized unilateral hyperhidrosis). The condition may also develop in association with cutaneous lesions including solitary papules, nodules, patches or plaques frequently showing brownish discoloration.1–4,6–14

A

B

C

D

Fig. 33.65 Myoepithelioma: immunohistochemistry showing (A) EMA, (B) S-100 protein, (C) smooth muscle actin and (D) GFAP expression.

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Tumors of the sweat glands These cutaneous findings may also present in the absence of hyperhidrosis. There is a predilection for the upper extremities. Lesions may be grouped in a linear arrangement but are rarely multiple and congenital presentation is infrequent.3,6,7,12

erosive palmoplantar lichen planus, epithelioid hemangioendothelioma, and squamous cell carcinoma.3,23,33–48 Recurrences are not a feature but malignant transformation within a longstanding eccrine syringofibroadenoma has been postulated.37,49

Pathogenesis and histological features

Pathogenesis and histological features

Histologically, eccrine nevi are characterized by increased sized or number of eccrine coils. Infrequently, abundant mucin surrounds the coils, when the term mucinous eccrine nevus is applied.15–20

Whether presenting as a solitary tumor or in a nevoid distribution, the histological features are remarkably similar.1,2,5,7,8,30 Arising from the epidermis at multiple points are thin anastomosing strands of uniform, small epithelial cells enclosing a fibrovascular stroma, which is often rich in acid mucopolysaccharides and sometimes contains a prominent lymphocytic and plasma cell infiltrate (Fig. 33.66). The epithelial strands characteristically show ductal differentiation, often associated with a well-formed cuticle (Figs 33.67, 33.68). Aggregates of clear cells may rarely be noted.14,50 The epithelial cells are PAS positive and, in keeping with their eccrine derivation, contain oxidative enzymes, including succinic dehydrogenase, phosphorylase, and leucine aminopeptidase.1

Adnexal polyp of neonatal skin Clinical features Adnexal polyp of neonatal skin presents as a small congenital polypoid and typically solitary cutaneous lesion. It is skin colored and regresses within a few days of birth.1,2 The incidence reported in a large Japanese study is estimated at 4%.2,3 It almost exclusively affects the areola of the breast but other sites such as the eyelid, cheek, periauricular and scapular regions, axilla, arm, hypochondrium, scrotum, and labium majus may also be involved.1–3

Pathogenesis and histological features Histologically, the polyp consists of centrally located adnexal structures including hair follicles, sebaceous glands, and well-formed eccrine units. Arrector pili muscle and apocrine structures are absent. Keratinous cysts are sometimes present.2

Eccrine syringofibroadenoma Clinical features Eccrine syringofibroadenoma (acrosyringeal nevus) is uncommon. It may show a variable presentation, ranging from solitary lesions to multiple papules and nodules arranged in a symmetrical or linear nevoid pattern.1,2 Distribution is wide and includes the face, back, abdomen, buttock, extremities, and rarely the nail.2–4 The age of onset ranges from 16 to 80 years; most patients, however, have been in their seventh and eighth decades.1 More recently, stratification according to five clinically distinct subgroups has been proposed:5,6 • Solitary eccrine syringofibroadenoma: this variant presents as a single, often verrucous-like lesion in the middle aged or elderly.2,5,7–19 The anatomical distribution is wide with a predilection for the lower extremity.5 • Multiple eccrine syringofibroadenoma associated with ectodermal dysplasia: patients in this subgroup typically present with multiple erythematous papules predominantly affecting the limbs and especially the palms and soles.5,20–26 Presentation is in adolescence and is associated with ectodermal dysplasia. The accompanying cutaneous manifestations frequently include eyelid hidrocystoma, hypotrichosis, hypodontia, and nail hypoplasia, a constellation also referred to as the Schöpf syndrome.27 • Multiple eccrine syringofibroadenoma without associated cutaneous findings: the lesions typically occur on the palms and soles of the elderly without associated cutaneous anomalies.1,5,28,29 • Nonfamilial unilateral linear eccrine syringofibroadenoma: this extremely infrequent presentation is nonfamilial and lesions are present unilaterally as multiple papules and plaques in a linear arrangement.2,30–32 A wide age range is affected but patients typically present in adolescence or early adulthood and there is a predilection for the extremities. • Reactive eccrine syringofibroadenoma: eccrine syringofibroadenoma may also be present as an unusual reactive epithelial change complicating other cutaneous disease including inflammatory dermatoses in addition to neoplasia. It has been associated with longstanding venous stasis, nail trauma, chronic ulceration of the foot, burn scar ulcer, leprosy, nevus sebaceus, enterostomy site, bullous pemphigoid, epidermolysis bullosa,

Fig. 33.66 Eccrine syringofibroadenoma: this lesion presented as a solitary tumor. Arising from the epidermis are numerous anastomosing strands of epithelium surrounded by a cellular fibrous stroma.

Fig. 33.67 Eccrine syringofibroadenoma: the epithelium is composed of uniform small cells with eosinophilic cytoplasm and small hyperchromatic nuclei. Ductal differentiation is present.

Eccrine angiomatous hamartoma

Fig. 33.68 Eccrine syringofibroadenoma: high-power view.

Fig. 33.70 Eccrine angiomatous hamartoma: higher-power view of the sweat glands and blood vessels.

Eccrine angiomatous hamartoma Clinical features Eccrine angiomatous hamartoma is a rare benign malformation characterized by both eccrine and vascular components. The clinical presentation is of a slowly enlarging nodule, plaque or papule with blue–purple discoloration and a predilection for the extremities, especially the legs.1–27 Less frequently involved sites include the trunk and the head and neck area.6,7,11,14,15,28 A wide age range from 2 months to 73 years may be affected but presentation is usually in children (median: 10 years).1,29 In more than 50% of patients the lesions are of congenital onset and there is no sex predilection.1,26 Eccrine angiomatous hamartoma may present as single or multiple lesions ranging from very small (3 mm) to large lesions (up to 11 cm in size).1,13,20,30,31 Rarely, patients have multiple, symmetrical lesions.19,26 The cutaneous findings are frequently associated with pain, tenderness, hyperhidrosis, and (less frequently) hypertrichosis.1,4 Eccrine angiomatous hamartoma has also developed in a patient with Cowden's syndrome.32

Histological features

A

Histologically, eccrine angiomatous hamartoma appears as a relatively circumscribed but unencapsulated lesion located within the mid to deep dermis and composed of increased numbers of occasionally dilated but matureappearing eccrine glands (Figs 33.69, 33.70).1,4,19 Clear cell change may be a

B

Fig. 33.71 Eccrine angiomatous hamartoma: high-power views of (A) sweat glands and (B) the vascular component.

Fig. 33.69 Eccrine angiomatous hamartoma: this example involves the subcutaneous fat. There are widespread eccrine sweat gland units intimately associated with small vascular channels.

focal feature.14,17 Eccrine duct formation is present, and intimately associated with the eccrine structures is a benign vascular proliferation (Fig. 33.71). This latter component is composed of small capillaries showing variable dilatation. It appears lobular but may rarely be ill defined.1 Secondary changes such as thrombosis with evidence of recanalization or associated hemorrhage is

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Tumors of the sweat glands

Fig. 33.73

Fig. 33.72

Porokeratotic eccrine osteal and dermal duct nevus: note the linear distribution on the palm of the hand. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Eccrine angiomatous hamartoma: this example shows a conspicuous mucinous component.

sometimes a feature.19 Other unusual findings include a lipomatous component, mucinous change or pilar structures (Fig. 33.72).10,11,15–17,19,33,34 The overlying epidermis is frequently unremarkable but occasionally verrucous features are present.18 In addition, eccrine angiomatous hamartoma rarely may show features reminiscent of verrucous hemangioma or arteriovenous malformation.35,36 It has also been documented adjacent to a spindle cell hemangioma.34 By immunohistochemistry, the vascular component is characterized by positive staining with endothelial markers.5,7,15 Eccrine glands are positive for S-100 protein, CEA, EMA, and cytokeratin as well as GCDFP-15.5,15,19,21,37

Porokeratotic eccrine ostial and dermal duct nevus Clinical features Porokeratotic eccrine ostial and dermal duct nevus is a rare hamartomatous lesion that was first described as ‘comedo nevus of the palm’ in 1979.1 Clinically, it presents at birth or in early childhood as multiple punctuate pits and papules, frequently showing comedo-like plugging (Figs 33.73, 33.74).1–32 The lesions may appear verrucous and are distributed in a linear arrangement. The palms and soles are almost exclusively affected but rarely a generalized, widespread, and occasionally unilateral or dermatomal distribution is observed.12,14,22–24,28–30 Late onset in adulthood is uncommon and there appears to be no gender predilection.23,25 The concurrent occurrence of linear psoriasis has been reported but no other associated anomalies are found.8,19,27 Rarely, the lesions are complicated by the development of squamous cell carcinoma.31,32

Fig. 33.74 Porokeratotic eccrine osteal and dermal duct nevus: each lesion consists of a dilated sweat pore containing keratinous debris. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Histological features The histological features are distinctive and consist of a small epidermal invagination with an overlying prominent parakeratotic cornoid lamella-like tier (Fig. 33.75). This is frequently found in association with, and overlying, an eccrine duct; sometimes it contains the tortuous acrosyringeal duct. Loss of the granular cell layer is seen at the base of the epidermal invagination and keratinocytes often appear vacuolated. Dyskeratotic cells may be evident.1

Eccrine hidrocystoma

very large, reaching up to 8 cm.8,9 Typically, the lesions wax and wane with circumstances that provoke sweat production; they are therefore exacerbated in summer, but may disappear clinically in the winter months.3 There are two modes of presentation: • More often, patients (with a slight female predilection, 3:2) have a solitary lesion. • More rarely, patients (almost all female) develop numerous hidrocystomas, sometimes in the hundreds.1,3,10–15

Pathogenesis and histological features

Clinical features Eccrine hidrocystomas are common and affect adults at any age. Individual lesions vary in size from pinhead to pea-sized and appear as tense vesicles located predominantly on the face, particularly periorbitally, but the trunk, popliteal fossae, external ear, and vulva may rarely be affected (Fig. 33.76).1,4–7 Larger lesions sometimes have a bluish hue. Exceptionally, the cysts may be 1–3

Because of the clinical features and the fact that eccrine sweat ducts may empty into and drain from the cysts, it is thought that the lesion merely represents a massively dilated duct. The cause of the blockage is unknown, but it is not mechanical. The application of topical atropine or botulinum toxin resolves the lesion, lending support to a functional pathogenesis.3,11,16

Hidroacanthoma simplex

Fig. 33.75 Porokeratotic eccrine osteal and dermal duct nevus: there is gross hyperkeratosis with parakeratosis associated with marked dilatation of the acrosyringium and dermal duct. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 33.77 Eccrine hidrocystoma: this tangential section from the eyelid shows a unilocular cyst.

Fig. 33.76

Fig. 33.78

Eccrine hidrocystoma: note the tense swellings adjacent to and below the eyebrow. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Eccrine hidrocystoma: the cyst is lined by cuboidal epithelial cells. In contrast to apocrine hidrocystoma, there are no myoepithelial cells.

Histologically, the hidrocystoma consists of one or several partially collapsed, unilocular cysts in the dermis, which are often situated adjacent to normal eccrine glands (Fig. 33.77). Serial sectioning sometimes shows continuity between the cyst epithelium and the lining of the proximal sweat duct.3 The cyst wall is composed of a double layer of cuboidal epithelium with eosinophilic cytoplasm (Fig. 33.78).3 Papillary projections are not usually evident.1 Myoepithelial cells and decapitation secretion are not present. A PAS-positive, diastase-resistant basement membrane is present and the epithelial cells may contain glycogen. On occasions, compression of the adjacent dermal connective tissue results in a pseudocapsule. In keeping with eccrine derivation, the cyst wall epithelium contains succinic dehydrogenase and phosphorylase.2 The cytokeratin expression pattern in these lesions resembles that of the dermal eccrine ducts.17,18

Hidroacanthoma simplex Clinical features Hidroacanthoma simplex is a rare tumor and is usually clinically misdiagnosed as a seborrheic keratosis, basal cell carcinoma or in situ squamous cell carcinoma (Bowen's disease).1 It presents most often on the distal extremities, although the chest, arm, and face may be affected (Fig. 33.79).2 Lesions are generally hyperkeratotic erythematous or brown plaques.3,4 The condition occurs equally in males and females, predominantly in the elderly.

Pathogenesis and histological features Hidroacanthoma simplex is a benign intraepidermal neoplasm derived from the acrosyringium. At low-power examination the tumor appears as

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Tumors of the sweat glands

Fig. 33.79 Hidroacanthoma simplex: typical erythematous scaly lesion on the ankle. By courtesy of H. Woolfson, MD, Brook Hospital, London, UK.

Fig. 33.81 Hidroacanthoma simplex: the tumor cells are smaller than the adjacent keratinocytes. They are very uniform and form intercellular bridges.

Fig. 33.80 Hidroacanthoma simplex: there is hyperkeratosis. Within the acanthotic epidermis are multiple discrete collections of tumor cells.

­ iscrete circumscribed populations of cells within an irregularly acanthotic d epidermis (Fig. 33.80).2 Hidroacanthoma simplex therefore represents one cause of the intraepidermal epithelioma of Jadassohn. Individual tumor cells resemble those of a poroma, being cuboidal or oval, with a vesicular nucleus containing a small nucleolus (Fig. 33.81). Intracytoplasmic glycogen can usually be demonstrated and in some tumors this is so marked that a clear cell variant results.5 Pigmented lesions associated with melanocyte colonization represent another unusual subtype.6 On occasions, the tumor cells have a spindled appearance (Fig. 33.82).2 Rudimentary duct formation and/or intracytoplasmic lumina are present although multiple levels often have to be examined before they are identified.7,8 By definition, the dermis is unaffected. The tumor cells sometimes express EMA but not CEA although ductal differentiation/intracytoplasmic lumina may sometimes be highlighted with both antibodies.9,10 Occasional tumors showing nuclear and cytoplasmic pleomorphism with mitotic activity are encountered (Figs 33.83, 33.84). These are best classified as in situ variants of eccrine porocarcinoma (malignant hidroacanthoma simplex).11–19 Invasive tumor may result.

Fig. 33.82 Hidroacanthoma simplex: in this field, there is focal spindled cell morphology.

Differential diagnosis Hidroacanthoma simplex must be distinguished from a seborrheic keratosis exhibiting a Jadassohn effect in which basaloid and squamous cells in the malpighian layer may show nesting or squamous eddy formation. Bowen's disease may also rarely manifest an intraepidermal nesting appearance; the dysplasia and dyskeratosis should, however, make the diagnosis obvious, and in addition there is no evidence of ductal differentiation.

Fig. 33.83 Malignant hidroacanthoma simplex: this tumor arose on the shin. The epidermis appears verrucous and there is a distinct, nested basaloid cell population.

Eccrine poroma

A

Fig. 33.85 Eccrine poroma: a dark-red nodule is present on the side of the foot, which is a characteristic site. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

B

Fig. 33.84 (A, B) Malignant hidroacanthoma simplex: the basaloid cells have darkly staining nuclei. Nucleoli are prominent and mitoses conspicuous.

Fig. 33.86

Eccrine poroma

Eccrine poroma: this example is present on the palm of the hand. By courtesy of the Institute of Dermatology, London, UK.

Clinical features Classically, this benign tumor, which presents as a solitary, sessile, skin-colored to red, slightly scaly nodule, has been described most often on the sole or sides of the foot (Fig. 33.85).1–3 More recently this view has been challenged and a much wider distribution documented.4 It may therefore also occur on the head, neck, scalp, chest, abdomen, proximal extremities, and hand (Fig. 33.86).5–7 The external auditory canal has also been affected.8 Lesions, which measure up to 3 cm in diameter, are usually asymptomatic, although bleeding after mild trauma is not uncommon. It is a tumor of adults and affects both sexes equally.3 Presentation in childhood and congenital onset are unusual.9,10 Multiple (poromatosis) and linear nevoid variants have been described and tumors may occur in the setting of chronic scarring.11–15

Pathogenesis and histological features In general, the pathogenesis is unknown. There are, however, very occasional case reports documenting the development of multiple lesions in the site of previous electron beam and X-ray therapy.16,17 One patient developed poromatosis in a background of hidrotic ectodermal dysplasia.13 Eccrine poroma is derived from cells of the outer layer of the acrosyringium and upper dermal eccrine duct. The tumor replaces the epidermis and grows down into the dermis in broad anastomosing bands (Fig. 33.87).3 There is a sharp demarcation between the keratinocytes of the adjacent epidermis and

the monomorphic, slightly smaller cuboidal poroma cells (Fig. 33.88). The tumor cells are united by conspicuous intercellular bridges (Fig. 33.89).2 Peripheral nuclear palisading is not a feature. Confirmation of the diagnosis is provided by features of maturation, either into ductal lumina with a single row of luminal cells covered by an eosinophilic lining or, more frequently, into cystic spaces devoid of any formal lining. Intracytoplasmic lumina with refractile cuticular borders may also be seen (Fig. 33.90). The latter may be highlighted by diastase–PAS staining or EMA and CEA immunohistochemistry.18,19 The tumor is supported by a delicate fibrovascular stroma. Eccrine poroma cells usually contain glycogen, although the staining is often patchy. Occasionally, pigmented variants with associated dendritic melanocytes and tumor cell melanin deposition are encountered.10,20–27 These are of particular importance as they may be clinically mistaken for melanoma. Dystrophic calcification and transepidermal elimination of tumor nests are exceptional findings.28,29 Eccrine poroma shows marked phosphorylase and succinic dehydrogenase activity (Fig. 33.91).2

Comment Benign eccrine ductal tumors – including hidroacanthoma simplex, eccrine poroma, dermal duct tumor, and eccrine hidradenoma – are in most instances readily recognizable as distinct histological entities. Not surprisingly, ­however,

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Tumors of the sweat glands

Fig. 33.89

Fig. 33.87

Fig. 33.88

Eccrine poroma: this scanning view shows interconnected epithelial downgrowths with multiple foci of attachment to the epidermis.

Eccrine poroma: the tumor cells are much smaller than the adjacent keratinocytes.

Fig. 33.90 Eccrine poroma: note the well formed duct and there are conspicuous intracytoplasmic lumina.

considering their similar ancestry, overlap tumors are occasionally seen and sometimes two or more subtypes may coexist in a particular lesion (overlap eccrine ductal tumors).30

Dermal duct tumor Clinical features Dermal duct tumor is a very rare benign tumor that usually occurs on the head and neck or limbs and presents as a nondescript, generally asymptomatic, flesh-colored or erythematous, firm nodule or papule measuring up to 2 cm in diameter.1–3 It is associated with a female preponderance (6:1) and tends to affect the elderly.

Eccrine poroma: note the sharp boundary between the keratinocytes and tumor cells. Intercellular bridges are conspicuous.

Fig. 33.91 Eccrine poroma: eccrine tumors can be identified by the presence of oxidative enzymes such as succinic dehydrogenase, as shown in this lesion. By courtesy of N. Ramnarain, FIMLS, Institute of Dermatology, London, UK.

Pathogenesis and histological features The dermal duct tumor arises from the intradermal segment of the eccrine duct.1 It is composed of large lobules of tumor in the mid and lower dermis; the epidermis is unaffected (Figs 33.92, 33.93). The tumor consists of small uniform cuboidal cells showing maturation towards ductal lumina. The latter may be accentuated by the diastase–PAS reaction. Sometimes intracytoplasmic lumina are a feature, and occasionally cystic spaces are present (Fig. 33.94). Peripheral palisading is not usually a feature, the cells at the edges of the lobules tending to be rather flattened. Mitotic figures are not present. The tumor cells contain variable amounts of glycogen and, as further

Eccrine porocarcinoma evidence of eccrine differentiation, both phosphorylase and succinic dehydrogenase activities may be demonstrated.4 Occasionally, focal continuity with an intradermal eccrine duct has been demonstrated.2

Differential diagnosis Dermal duct tumor is very rarely diagnosed since most apparent examples can be shown on deeper levels to demonstrate at least focal continuity with the epidermis, when a diagnosis of poroma is then rendered.5 Their distinction, in any event, is of little significance.

Eccrine porocarcinoma Clinical features

Fig. 33.92 Dermal duct tumor: this lesion is entirely intradermal. Note the circumscribed tumor nodules and scattered cysts.

Fig. 33.93 Dermal duct tumor: there are multiple cysts and focal ductal differentiation is seen.

Fig. 33.94 Dermal duct tumor: high-power view.

Eccrine porocarcinoma (malignant eccrine poroma), in our experience, is the most frequently encountered malignant sweat gland tumor. It shows a slight predilection for females (1.3:1) and displays a propensity to affect the elderly, with a mean age at presentation of 73 years (range 12–91 years).1–6 Very exceptionally, children are affected.7 Lesions are not usually clinically distinctive, being described as verrucous plaques or polypoid growths measuring 0.4–20.0 cm in diameter (mean: 2.0 cm), often clinically misdiagnosed as squamous cell carcinoma, Bowen's disease, seborrheic keratosis or pyogenic granuloma (Figs 33.95, 33.96).1,6 It presents most often on the lower limb, trunk, head, and upper limb in descending order of frequency.6 However, virtually any site may be affected including the genitalia and nail bed.8–11 Often the tumor has been present for a long time, sometimes as much as 50 years, suggesting malignant transformation in a previous benign eccrine poroma.2,4,6 Tumors are often ulcerated and many bleed on trauma. Eccrine porocarcinoma has also been reported in the setting of chronic arsenism.12 Eccrine porocarcinoma is prone to local recurrence (17%), is sometimes multiple, and is occasionally associated with nodal metastases (19%).6 Some tumors are characterized by very aggressive local spread and occasionally epidermotropic cutaneous metastases are encountered.13–15 Systemic spread is rare (11%).6,16 Although there are many case reports documenting mortality, we believe that this is an uncommon outcome.17–22 In the substantial series published with sufficient follow-up information, the death rate amounts to only 7–11%.1,3,6 Particularly aggressive behavior has, however, been reported from Japan with high rates of lymph node metastasis (50%) and associated mortality (33%).23

Pathogenesis and histological features In general, the pathogenesis of this tumor is unknown although occasional tumors have followed prior radiotherapy and one or two cases have arisen within a pre-existent organoid nevus.6,24,25 Coexistent benign eccrine poroma is encountered in up to 11% of cases.2,6,26 Rarely, a coexistent pigmented hidroacanthoma simplex or seborrheic keratosis is present.27–29 p16 protein has been shown to be overexpressed in eight out of nine cases of eccrine porocarcinoma with absence of retinoblastoma (RB) protein expression.30 No p16 gene mutation was discovered in the single tumor examined. The tumor may remain completely intraepidermal (in situ porocarcinoma) but is more often associated with an invasive intradermal component.31 The in situ variant is recognized by the presence of obvious poroma cells, with typical ductal lumina, associated with cytological features of malignancy including nuclear and cytoplasmic pleomorphism, nuclear hyperchromatism, and mitotic activity (frequently abnormal).1 Invasive malignant eccrine poroma invariably shows continuity with the surface epithelium and may be associated with a broad pushing deep margin or a more obviously infiltrative lower border (Figs 33.97, 33.98). The former is a particular catch for the unwary unless the cytology of the lesion is carefully scrutinized. The tumor is most typically characterized by downgrowths of broad anastomosing bands of epithelium, composed of small cells united by small intercellular bridges and devoid of any tendency towards peripheral palisading (Fig. 33.99).14,32,33 Occasionally, involvement of the surface epithelium manifests as a Borst-Jadassohn effect. Although some tumors

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Tumors of the sweat glands

Fig. 33.95

A

Eccrine porocarcinoma: (A) this erythematous and ulcerated tumor plaque is present on the sole of the foot. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK; (B) the ear is a very unusual site. By courtesy of J.C. Pascual, Alicante, Spain.

B

Fig. 33.96

A

appear deceptively bland and are only recognized as being malignant on the basis of their infiltrative growth pattern, the majority of tumors show nuclear pleomorphism and conspicuous, sometimes abnormal, mitotic activity (Figs 33.100, 33.101). Ductal differentiation and/or intracytoplasmic lumen formation is invariably evident and is often rendered more obvious by the use of the diastase–PAS reaction or the immunocytochemical demonstration of EMA or CEA expression (Figs 33.102, 33.103). It is important not to misinterpret entrapped normal sweat ducts in which the epithelium is devoid of atypia as ­representing

B

Eccrine porocarcinoma: (A) the tumor is composed of numerous warty excrescences; (B) this example has arisen in a preexistent benign poroma. Note the poroma above and invasive tumor below.

tumor ductal differentiation. Similarly, degenerative cytoplasmic vacuolation may initially suggest ductal differentiation but it can be distinguished by the absence of a cuticle and negative EMA/CEA immunohistochemistry. Lymphovascular invasion or spread along the perineural space is sometimes seen and tumor necrosis may be evident (Figs 33.104–106).6,33 The tumor cells frequently contain glycogen, which may be sufficient to produce foci of clear cell change. Rarely, the latter feature predominates – the clear cell variant (Figs 33.107, 33.108).6,34,35 Squamous metaplasia is sometimes present and, uncommonly, the tumor may show foci of frankly

Eccrine porocarcinoma

A

Fig. 33.98 A

Eccrine porocarcinoma (A, B): there is a very striking infiltrative growth pattern.

Fig. 33.97

B

Eccrine porocarcinoma: (A) in this example, the tumor has a broad pushing lower border; (B) the borders are sharply delineated and intracytoplasmic lumina are evident.

bowenoid features with dyskeratosis or more obvious keratinization, usually affecting the more superficial aspect of the tumor (bowenoid porocarcinoma) (Figs 33.109, 33.110).2,6,36 Rarely, squamous features are extensive and these tumors resemble invasive squamous cell carcinoma on cursory examination (squamous variant of eccrine porocarcinoma).37 However, areas of more obviously poromatous differentiation are invariably present. Colonization by melanocytes and pigmentation of tumor cell cytoplasm is sometimes a feature, particularly in the heavily pigmented races (pigmented porocarcinoma) (Fig. 33.111).6,8,38,39 Other very rare variants, including giant cell, spindled cell, mucus cell, and metaplastic or sarcomatoid ­porocarcinoma, may be encountered (Fig. 33.112).6,40–43 Exceptionally, porocarcinoma has been associated with syringoid eccrine carcinoma-like features, eccrine syringofibroadenomalike foci, as well as areas resembling dermal ductular carcinoma.6,40,44,45 Cutaneous metastases show a propensity for epidermal, pagetoid involvement – epidermotropic eccrine carcinoma.14,15 The tumor cells express EMA and CEA. p53 protein has been shown to be overexpressed but as this is also a feature of benign poromas, it would appear to be of no great significance.20,46,47 Prognostic indicators for eccrine porocarcinoma include mitotic activity,­ ­lymphovascular invasion, and tumor thickness.6 Tumors with an ­infiltrating rather than pushing lower border are associated with a greater risk of recurrence.6

B

Fig. 33.99 Eccrine porocarcinoma: in this ulcerated example, the broad anastomosing trabeculae are well demonstrated. Note the necrosis.

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Tumors of the sweat glands

A

A

B

B

Fig. 33.100

Fig. 33.102

(A, B) Eccrine porocarcinoma: the tumor cells have pleomorphic, vesicular nuclei. Note the intracytoplasmic lumina.

(A, B) Eccrine porocarcinoma: ductal differentiation is an essential diagnostic feature.

Differential diagnosis Malignant eccrine poroma may be distinguished from an infiltrating basal cell carcinoma by the presence of intercellular bridges and the absence of peripheral palisading. Ductal differentiation, intracytoplasmic lumina, and the small size of the tumor cells differentiate it from invasive squamous cell carcinoma with which it is frequently confused.

Syringoma Clinical features

Fig. 33.101 Eccrine porocarcinoma: conspicuous mitoses are present.

Syringomas are common tumors and present most often as multiple, symmetrically distributed, usually asymptomatic, small papules (1–3 mm) on the lower eyelids and upper cheeks (Fig. 33.113).1,2 They appear at puberty or in early adult life and show a marked female predominance. Individual papules are firm and skin colored or slightly yellow (Fig. 33.114). Syringomas may, however, manifest a wide variety of clinical presentations. They may occur singly or in multiples on the scalp, forehead, neck, axillae, chest, abdomen, buttocks, extremities or genitalia (male and female), periorally or, rarely, in a linear nevoid unilateral, segmental or plaquelike pattern.1,3,4–26 A giant ­variant measuring up to 1 cm has also been described and presentation as milia is an unusual finding.27–31 Patients with vulval syringomas often have coexisting eyelid lesions, and vulval pruritus is a frequent presenting symptom.12

Syringoma

A

A

B

B

Fig. 33.103 Eccrine porocarcinoma: (A) ductal differentiation and intracytoplasmic lumina can be highlighted with EMA or CEA immunohistochemistry (EMA); (B) the luminal border of the duct is diastase resistant, PAS positive.

Fig. 33.104 (A, B) Eccrine porocarcinoma: lymphovascular invasion.

Fig. 33.105

Fig. 33.106

Eccrine porocarcinoma: lymph node metastasis from the same patient as shown in Figure 33.104b.

Eccrine porocarcinoma: high-grade tumors commonly show areas of necrosis.

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Tumors of the sweat glands

A

A

B

B

Fig. 33.107 Clear cell eccrine porocarcinoma: (A) there is striking cytoplasmic vacuolation; (B) high-power view.

Fig. 33.108 Clear cell eccrine porocarcinoma: (A) the tumor cells are PAS positive; (B) EMA.

An eruptive variant has been described in which successive crops of papules appear on the anterior surfaces of young people.32,33 Characteristic sites of involvement include the neck, chest, axillae, antecubital fossae, upper extremities, lower abdomen, and groins.32,34 Occasional familial examples have been recorded.34–39 Eruptive syringomas are more common in Orientals and are present in 18% of mature patients with Down's syndrome.40–43 They may rarely be associated with milium cysts and vermiculate atrophoderma (Nicolav and Balus syndrome).44

Pathogenesis and histological features Histochemical and electron microscopic studies have shown that the syringoma represents an adenoma of the acrosyringium, the intraepidermal eccrine sweat duct.45,46 Immunohistochemical studies further confirm differentiation of this tumor towards the acrosyringium or dermal eccrine duct.47–51 The epithelium of a syringoma therefore contains succinic dehydrogenase, phosphorylase, and leucine aminopeptidase. The tumor is composed of interconnecting epithelial strands and ducts dispersed in a fibrous stroma within the upper dermis (Fig. 33.115). The ducts are lined by two layers of flattened cuboidal cells. There may be a cuticle lining the lumina, which frequently contains eosinophilic granular debris. Sometimes the ducts are associated with an epithelial strand, giving rise to the characteristic tadpole configuration (Figs 33.116, 33.117). Occasionally, single glycogen-rich ductal cells are seen, and rarely all of the ductal cells ­contain

Fig. 33.109 Eccrine porocarcinoma: this example shows striking squamous differentiation with focal dyskeratosis.

Papillary eccrine adenoma

A

B

C

D

Fig. 33.110 Bowenoid porocarcinoma: (A) low-power view showing obvious poromatous features; (B) junction between the bowenoid and poromatous areas; (C) this field comes from near to the surface and there is squamous differentiation; (D) high-power view near to surface showing marked keratinization. It is very easy to misdiagnose this variant as squamous cell carcinoma.

glycogen, giving rise to the clear cell variant of syringoma. This appears to be particularly associated with diabetes mellitus.52,53 The milium-like variant of syringoma is characterized histologically by large epithelial-lined cysts containing keratinaceous material and located within superficial dermis.28 The features are otherwise characteristic of syringoma and the keratin-filled cysts are immunoreactive against CEA.

Differential diagnosis Syringoma must be distinguished from desmoplastic trichoepithelioma, which typically features numerous keratocysts. Although there is obvious histological overlap with eccrine epithelioma, the clinical features are quite different.2 Eccrine epithelioma, which is a much more extensive tumor that may involve the subcutaneous fat, is associated with a markedly desmoplastic stroma. Syringoma-like features are not usually extensive and infiltration of the perineural space is often observed. Mitoses are not a feature of syringoma.

Papillary eccrine adenoma Fig. 33.111 Eccrine porocarcinoma: pigmented variants due to melanocyte colonization are common in colored races. By courtesy of W. Grayson, MD, University of Witwatersrand, University of Johannesburg, South Africa.

Clinical features Papillary eccrine adenoma is a rare tumor that predominantly involves the extremities.1–12 It particularly affects blacks and shows a marked ­predilection

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Tumors of the sweat glands

A

A

B

B

Fig. 33.113 (A, B) Syringoma: note the typical periorbital distribution of these small papules. (A) By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK; (B) by courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features

C

Fig. 33.112 Eccrine porocarcinoma: (A) low-power view of a spindle cell variant. There is extensive tumor necrosis. (B) High-power view of spindled cells; (C) the tumor shows striking ductal differentiation on the right side of the field.

for females (4:1).1,6 The age at presentation is wide and children are occasionally affected.1 The tumor presents as an erythematous, yellow or brown nodule measuring 0.5–4.0 cm in diameter.1,6 Rarely, presentation as a cutaneous horn has been reported.13 Most tumors are slow growing and are ­usually asymptomatic. The lesion is entirely benign, recurrences being extremely rare.1

The tumor, which is most often situated in the mid and lower dermis, is well circumscribed although unencapsulated, and is composed of dilated branching ducts and cysts, which are usually dispersed in a dense, sometimes hyalinized, concentrically orientated stroma (Fig. 33.118).8 The epithelial lining consists of two or more layers of small eosinophilic cells with regular, round or oval nuclei containing small nucleoli (Fig. 33.119).1 Papillary projections are frequent, and occasionally a delicate cribriform pattern is evident. Foci of clear cell change due to cytoplasmic glycogen are sometimes present.8 The lumen contains diastase-resistant, PASand Alcian blue-positive material. Decapitation secretion, by definition, is absent. Nuclear pleomorphism is not a feature and mitoses are either absent or scanty (Fig. 33.120). Abnormal forms are not seen. Necrosis and perineural infiltration are not present. The tumor may be associated with a lymphocyte and plasma cell infiltrate, sometimes accompanied by lymphoid follicles.1,8 Immunohistochemically, the epithelium displays keratin (CK8 and CK14), EMA, and CEA expression.5–7,12,14–18 S-100 protein and SMA are also sometimes present.5,6,12,14,16,18 Expression of IKH-4, a marker of eccrine glandular differentiation, is also found.19 Histochemical studies have confirmed the ­presence of amylophosphorylase, and ultrastructural studies also suggest ­ductal differentiation.9,10

Aggressive digital papillary adenocarcinoma

Fig. 33.114 Syringoma: there is extensive involvement of the cheek. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK..

Fig. 33.116 Syringoma: note the epithelial strands and ductal differentiation.

Fig. 33.117 Syringoma: this field shows the characteristic tadpole appearance.

Fig. 33.115 Syringoma: characteristic epithelial strands and small cysts are present in the dermis. There is a dense, sclerotic fibrous stroma.

Differential diagnosis Papillary eccrine adenoma must be distinguished from aggressive digital papillary adenocarcinoma.20 The latter typically has a more infiltrative growth pattern and shows nuclear and cytoplasmic pleomorphism with conspicuous mitotic figures.

Aggressive digital papillary adenocarcinoma Clinical features Aggressive digital papillary adenoma and adenocarcinoma form a morphological spectrum of tumors with a high local recurrence rate and variable biological behavior; it is advisable to regard them all as potentially malignant tumors and the designation as adenocarcinoma should be the preferred term

Fig. 33.118 Papillary eccrine adenoma: the lesion is composed of dilated ducts and cysts dispersed in a fibrous stroma.

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Tumors of the sweat glands

Fig. 33.119 Papillary eccrine adenoma: the cysts are lined by a double layer of uniform cuboidal cells. Tiny papillary processes are present.

Fig. 33.120 Papillary eccrine adenoma: high-power view. There is no pleomorphism.

c­ ombined with careful evaluation of histological features and, when necessary, ­immunohistochemistry should, however, resolve the great majority of ­diagnostic dilemmas. The tumor, which is located in the deeper dermis, often involves the subcutaneous fat and may infiltrate skeletal muscle, tendon or bone. It is composed of multiple cystic epithelial nodules showing both glandular and papillary morphology separated by fairly dense fibrocollagenous stroma (Figs 33.121, 33.122).4 Tumors occasionally communicate with the overlying epidermis and may be predominantly solid.6 The glands are lined by one or two layers of cuboidal or columnar epithelium with eosinophilic cytoplasm and round or oval vesicular nuclei. The papillary component is variable and ranges from simple epithelial strands through to more structured elements composed of a connective tissue core covered by one or more layers of epithelium (Fig. 33.123). Squamous metaplasia, clear cell change, and spindled cell foci are commonly present.1,4,6 Decapitation (apocrine-type) secretion is sometimes a feature.6 Differentiation is variable, with some tumors showing more obvious nuclear pleomorphism, hyperchromatism, mitotic activity, and necrosis. Other findings include extensive and deep infiltration, and lymphovascular involvement. Immunohistochemically, the epithelium shows strong keratin, S-100 ­protein, and CEA expression.3–5 The last is particularly seen along the ­luminal border.

Fig. 33.121 Aggressive digital papillary adenocarcinoma: this example is partially cystic. Note the papillary processes covered by multiple layers of basophilic epithelium.

since histological features are not predictive of outcome.1–7 They are rare and most often present on the distal extremities, particularly the fingers and toes and adjacent skin of palms and soles.3,4,6–21 The single most common site is the volar aspect of the digit tip between the nail bed and distal interphalangeal joint.4,6 Lesions present in the adult (median: 52 years) as solitary, usually asymptomatic nodules measuring 2 cm or more in diameter. Adolescents are only rarely affected.18 The presenting symptom is a mass frequently accompanied by pain.6 The overall local recurrence rate is roughly 30% but is significantly lower (5%) after adequate surgical treatment with re-excision or amputation.6 Irrespective of treatment or the presence of local recurrence, the rate of distant metastasis is approximately 14%.6 Metastatic disease most commonly affects the lung and lymph nodes and death from disease has been documented.4,6,22,23 Sentinel lymph node biopsy in addition to local treatment has been performed in rare instances, but its value has not been assessed in larger prospective trials as yet.24,25 Males are more often affected than females (7:1).4

Pathogenesis and histological features Aggressive digital papillary adenocarcinoma is of particular ­importance because it may be mistaken for a metastasis of papillary adenocarcinoma of mammary, thyroid or colonic origin. Knowledge of the entity

Fig. 33.122 Aggressive digital papillary adenocarcinoma: the papillae have a fibrovascular core.

Hidradenoma

A

Fig. 33.124 Eccrine hidradenoma: this lesion presents as a solitary nodule most often on the head and neck or limbs. By courtesy of the Institute of Dermatology, London, UK.

B

Fig. 33.123 Aggressive digital papillary adenocarcinoma: (A) medium-power view showing papillary processes; (B) there are prominent nucleoli and multiple mitoses are present.

Hidradenoma

finding, it has been proposed that clear cell variants are of apocrine derivation whereas only a minority of tumors composed of poroid and cuticular cells are of true eccrine derivation/differentiation (poroid hidradenoma).5,14 A reproducible chromosomal translocation t(11;19)(q21;p13) involving the CRTC1 and the MAML2 genes has recently been reported in salivary gland tumors such as mucoepidermoid carcinoma and Warthin's tumor and has also been detected in approximately 50% of hidradenomas.15–18 This fusion appears to be particularly prevalent in tumors with clear cell features.18 At least a subset of the remaining tumors have been found to harbor the chromosomal translocation t(6;22) involving the EWS and the POU5F1 genes.19 The tumor is circumscribed, but unencapsulated, and is composed of lobulated, sometimes cystic masses of cells in the upper or mid dermis (Figs 33.125, 33.126). Some tumors are associated with follicular structures whereas others display connection to or even replace the overlying epidermis, reminiscent of eccrine poroma. On occasions the tumor may extend into the subcutaneous fat. The tumor has a biphasic cellular population: in some

Clinical features Hidradenoma (clear cell hidradenoma, solid–cystic hidradenoma, clear cell myoepithelioma, eccrine acrospiroma), which generally occurs on the head and neck or limbs (although any site may be affected), usually presents as a solitary, slowly growing, solid or cystic nodule (Fig. 33.124).1–6 The overlying skin may be flesh colored, erythematous or blue.1 Lesions typically measure about 1–2 cm in diameter and present most often in middle-aged adults or the elderly (range: 3–93 years), with a slight predominance in females.6 Giant variants measuring up to 12.0 cm in diameter have been documented.7,8 Exceptionally, children are affected.9–11 The tumors are sometimes symptomatic, with spontaneous oozing, hemorrhage, tenderness, pruritus, and burning.1 Recurrences are uncommon.3

Pathogenesis and histological features The histogenesis of this tumor is uncertain. In keeping with an eccrine derivation, the tumor has been shown to contain large quantities of succinic dehydrogenase, amylophosphorylase, and leucine aminopeptidase.2 Additionally, earlier reports showed that clear cell hidradenoma did not express markers of apocrine differentiation including GCDPF-15 and GCDFP-24.12,13 More recently, however, this has been contested and a small series of cases published in which GCDPF-15 was expressed.14 On the basis of follicular continuity, decapitation secretion, mucin production, and the latter ­immunohistochemical

Fig. 33.125 Eccrine hidradenoma: this example shows multiple, variably sized cysts in addition to a solid component (solid–cystic hidradenoma).

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Tumors of the sweat glands

Fig. 33.126

Fig. 33.128

Eccrine hidradenoma: low-power view of a circumscribed dermal tumor nodule.

Eccrine hidradenoma: in this field, the tumor consists of an admixture of cells with eosinophilic cytoplasm and glycogen-rich clear cell forms.

areas it is composed of round, fusiform or polygonal cells with eosinophilic cytoplasm and a round or oval vesicular nucleus showing nuclear grooves and conspicuous nucleolus, sometimes arranged in whorls; elsewhere it consists of cells with clear cytoplasm containing a small, dark, often eccentrically located, nucleus (clear cell hidradenoma) (Figs 33.127, 33.128).1,2,4,20,21 Transition between the two cell types is common. The proportions and overlap of the two cell types vary within an individual tumor. Glycogen may be demonstrated in most of the tumor cells, but is in greater abundance in the clear cell areas (Fig. 33.129). The tumors are usually mitotically inactive. Tumor lobules may be intimately associated with dermal sweat glands or ducts, and occasionally the latter may be seen to be continuous with islands of tumor cells.1 As mentioned above, focal apocrine decapitation secretion can be seen. Some tumors may show squamous differentiation, squamous eddy formation or keratinization.21,22 Mucin-rich goblet cells are an occasional finding and rarely mucinous change is extensive (mucinous hidradenoma) (Fig. 33.130).23 Sebaceous differentiation may also be a feature.14,24–26 Exceptionally, hidradenoma has been demonstrated in continuity with mucinous syringometaplasia.27 Ductlike structures are present in most tumors. These may appear as differentiated structures lined by a layer of cuboidal cells (Fig. 33.131). On other occasions the tumor contains variably sized cystic cavities, sometimes comprising the vast bulk of the lesion (solid–cystic hidradenoma). Such cysts

are lined by flattened cells and probably represent cystic degeneration. Ductal differentiation is also seen as foci of squamous cells surrounding irregular lumina complete with a diastase-resistant, PAS-positive cuticle resembling the acrosyringium (Fig. 33.132). The tumor lobules are surrounded by a definite stroma, which may be fibrovascular, collagenous or even hyalinized (Fig. 33.133). Some tumors appear highly vascular, resulting in perivascular pseudorosettes and, occasionally, hemangiopericytoma-like areas. Occasionally, tumors may appear pigmented due to increased melanin pigment and colonization by pigmented dendritic cells.28,29 The tumor cells express AE1/AE3, EMA, and CEA.12,15 The last two are of particular value in highlighting ductal differentiation.

Comment Occasionally, benign-appearing tumors show focal atypical features including nuclear pleomorphism and hyperchromatism, macronucleoli, giant cell forms, and prominent mitotic activity (two or more mitoses per 10 highpower fields) (Figs 33.134, 33.135).30 These appearances correlate with an increased risk of recurrence and possible malignant biological potential (atypical hidradenoma).31 Wide re-excision and careful follow-up are therefore advisable for these worrisome lesions. In addition, high MIB-1 proliferative index (> 11%) and phosphorylated histone H3 of > 0.7% have been proposed to be associated with malignant rather than atypical hidradenoma.32

Clear cell hidradenocarcinoma Clinical features

Fig. 33.127 Eccrine hidradenoma: high-power view showing uniform cells with eosinophilic cytoplasm.

Clear cell hidradenocarcinoma (malignant acrospiroma, malignant nodular hidradenoma, malignant clear cell hidradenoma) is a rare neoplasm, with fewer than 100 cases documented in the literature. These have mainly represented single case reports although there are a few small series.1–30 Little clinical information is available other than that they present as intradermal nodular tumors said to have a predilection for the face and extremities.2 The more recent literature, however, has described these tumors at a very diverse range of sites including the scalp, lip, neck, chest wall, breast, back, leg, toe, and vulva. There is no gender predilection and the age range is wide, extending from childhood through to the elderly, with a predilection for middleaged to elderly adults.30 Presentation at birth has also been documented.4,19 These tumors appear to be generally aggressive with a high recurrence rate (50–75%). It is difficult to determine precise figures from the more recent literature but in the few larger series both metastatic as well as mortality rates appear to be high.12,28 The lymph nodes, lungs, and bones are the sites most commonly affected and there may be a role for sentinel lymph node biopsy in addition to wide excision at time of diagnosis.1,4,25,31

Clear cell hidradenocarcinoma

A

Fig. 33.129

A

(A, B) Eccrine hidradenoma: clear cell variant. The cells have clear cytoplasm and small hyperchromatic nuclei. The cytoplasm is PAS positive, diastase sensitive.

B

Fig. 33.131 Eccrine hidradenoma: (A) ductal differentiation as shown in this field is usually evident; (B) the ducts can be highlighted with EMA or CEA immunohistochemistry (EMA).

B

Fig. 33.130 Eccrine hidradenoma: in this field there is mucinous metaplasia, which is an uncommon feature.

Fig. 33.132 Eccrine hidradenoma: note the intracytoplasmic lumen with eosinophilic cuticle.

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Tumors of the sweat glands

A

Fig. 33.133 Eccrine hidradenoma: in this field the stroma is markedly hyalinized.

B

Fig. 33.135

Fig. 33.134 Atypical eccrine hidradenoma: low-power view showing hemorrhage.

Pathogenesis and histological features A pre-existing benign hidradenoma may be identified in a subset of tumors and, analogous to hidradenoma, the chromosomal translocation t(11;19) involving the CRTC1- and the MAML2 genes has also been found in hidradenocarcinoma, albeit less frequently (Fig 33.136).30 No data regarding the prevalence of the t(6;22) involving the EWS and the POU5F1 genes are available in hidradenocarcinoma as yet. Nuclear staining for p53 may be identified in a subset of tumors although a p53 mutation is only rarely detected in these tumors.30 Clear cell hidradenocarcinoma can be distinguished from eccrine porocarcinoma (in particular the clear cell variant) by an absence of epidermal origin or involvement. The tumor is composed most often of lobules of epithelium, although occasionally a diffuse growth pattern may be observed. A cystic variant may also be infrequently encountered (Figs 33.137, 33.138). The epithelial cells, which show varying degrees of mitotic activity and nuclear pleomorphism, have characteristically vacuolated cytoplasm due to the presence of abundant glycogen (Figs 33.139–33.141). In some areas cells with eosinophilic cytoplasm may also be evident. Occasionally, the tumor is composed predominantly of basaloid cells with little or no vacuolation and basal cell carcinoma may therefore enter the differential diagnosis. Nuclear ­peripheral palisading and retraction artifact, however, are not features of this neoplasm. Spindled cell differentiation, mucin-rich goblet cells or signet ring cells are infrequently encountered. Necrosis is variable but in some tumors it can be extensive or else

Atypical eccrine hidradenoma: (A) focal nuclear pleomorphism is present. There is hyperchromatism and nucleoli are prominent. (B) Mitotic figures are easily found. A complete excision with careful follow-up is advisable for patients with this borderline variant.

it may present with comedo carcinoma-like features (Figs 33.142, 33.143). It has been argued that at least some if not all of the cases reported as ‘adnexal clear cell carcinoma with comedonecrosis’ represent hidradeoncarcinomas with extensive clear cell change and necrosis.30,32 A case showing sarcomatoid/ metaplastic features composed of pleomorphic spindled cells has also been reported.30 Exceptionally, in situ carcinoma affecting adjacent sweat glands and pagetoid spread within the overlying epidermis have been described.6,33 A characteristic finding is the presence of intracytoplasmic ductal differentiation, sometimes showing a well-formed cuticular border; occasionall, wellformed ducts are also evident (Fig. 33.144). In cases of doubt, the use of the diastase–PAS reaction and EMA or CEA immunohistochemistry are of value in highlighting these structures (Fig. 33.145). Although Her-2/neu amplification as demonstrated by FISH is rare despite its relatively frequent expression immunohistochemically.26,29,30

Differential diagnosis Clear cell hidradenocarcinoma can sometimes appear deceptively benign and yet be associated with metastatic disease. Clear cell hidradenoma may occasionally show mild focal cytological atypia and increased mitotic activity (atypical hidradenoma). However, any tumor that shows brisk mitotic activity (particularly abnormal forms), cytological atypia or an infiltrating growth pattern should be viewed with great caution. If it involves or is close to a ­margin, a wide excision is recommended.

Clear cell hidradenocarcinoma

A

B

Fig. 33.136 Hidradenocarcinoma: (A) low-power view showing hidradenoma flanked on one side by poorly differentiated carcinoma; (B) high-power view.

A

B

Fig. 33.137 (A, B) Hidradenocarcinoma: this is a cystic variant which presented on the forearm. It recurred four times despite apparently negative margins.

A

B

Fig. 33.138 (A, B) Hidradenocarcinoma: the tumor shows well-developed ducts. Mitoses are very conspicuous.

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Fig. 33.141 Clear cell hidradenocarcinoma: numerous mitoses are present.

Fig. 33.139 Clear cell hidradenocarcinoma: in this example the tumor is composed of broad trabeculae.

Fig. 33.142 Clear cell hidradenocarcinoma: the tumor shows extensive necrosis.

Fig. 33.140 Clear cell hidradenocarcinoma: the tumor cells have large vesicular nuclei and palestaining or clear cytoplasm.

It must also be distinguished from other tumors showing conspicuous cytoplasmic vacuolation including clear cell squamous carcinoma, trichilemmal carcinoma, and metastatic clear cell carcinoma from the kidney, bronchus, liver, and female genital tract. Rarely, clear cell melanoma may enter the differential diagnosis. Although on some occasions the diagnosis is not problematic, sometimes extensive clinical investigation and comprehensive immunohistochemistry are necessary before a diagnosis of a primary ­cutaneous tumor can be established.

Dermal cylindroma Clinical features Dermal cylindroma is one of the more common benign adnexal tumors.1 The vast majority (90%) occur on the head, neck, and scalp (60%) as slowly growing, sometimes painful, solitary pink or red dermal nodules averaging about

Fig. 33.143 Clear cell hidradenocarcinoma: in this example, central necrosis has resulted in a comedo carcinoma-like appearance.

Dermal cylindroma

A

Fig. 33.144 Clear cell hidradenocarcinoma: well-developed glandular differentiation is evident.

B

Fig. 33.146 Dermal cylindroma: (A) two dome-shaped nodules with associated telangiectasia are evident; (B) multiple lesions are present – turban tumor. By courtesy of the Institute of Dermatology, London, UK.

Fig. 33.145 Clear cell hidradenocarcinoma: numerous intracytoplasmic lumina are evident (EMA).

1 cm in diameter (Fig. 33.146).1 Involvement of orbit, ear canal, abdomen, and breast is unusual.2–8 There is a marked female preponderance (9:1). Familial cases have been described and are typically associated with multiple tumors. Multiple cylindromas may be associated with facial trichoepitheliomas and also eccrine spiradenomas and milia, a constellation known as the autosomal dominant Brooke-Spiegler syndrome (familial cylindromatosis or turban tumor syndrome).6–37 Penetrance in affected families is high but the clinical presentation is very variable and within the same family individual members may present with multiple dermal cylindromas or multiple trichoepitheliomas or a combination of both in addition to eccrine spiradenomas and milia. Tumors may also show hybrid features of cylindroma and spiradenoma, and additional trichoepitheliomatous, trichoblastic as well as sebaceous differentiation can be present.37,38 Furthermore, patients sometimes develop other benign skin adnexal tumors including trichoblastoma, cutaneous lymphadenoma, and syringoma.38,39 Onset of the skin lesions is usually in early adulthood and there is a predilection for females. Dermal cylindromas affect predominantly the scalp but on occasions lesions may also be seen on the trunk and the extremities. A linear arrangement has been documented.40 Scalp lesions can grow to a large size, and coalescence of numerous lesions is known as a ‘turban tumor’. Trichoepitheliomas show a predilection for the centrofacial area.

Unusual presentations of this syndrome include the development of membranous-type basal cell adenoma of the parotid, a salivary gland tumor morphologically and pathogenetically related to dermal cylindroma, as well as malignant transformation within both dermal cylindromas and the salivary gland tumors.12,41–50

Pathogenesis and histological features Insights into the molecular pathways involved in these tumors have recently been gained through genetic analysis of patients with the Brooke-Spiegler syndrome. Using linkage analysis, this syndrome has been mapped to chromosome 16q12-q13, and a novel gene (CYLD) has been identified and subsequently cloned. CYLD represents a tumor suppressor gene. There is loss of heterozygosity of the wild-type copy in tumors. Germline mutations have been reported in patients with the Brooke-Spiegler syndrome and somatic mutations are present in both solitary and familial tumors, resulting in inactivation of the CYLD gene.13,14,16,28–33,51 The function of CYLD is only partially understood at this time. It belongs to the family of deubiquinating proteins and interferes with the tumor necrosis alpha (TNF-α)/NF-κb pathway, typically involved in mediating inflammation. Lack of CYLD results in NF-κb pathway activation in addition to decreased apoptosis.52–55 How this NF-κb pathway activation is involved in tumorigenesis is currently unclear. Dermal cylindromas are remarkable for a prominent basement membranelike structure surrounding tumor lobules. This is composed of proteins found at the normal dermal–epidermal junction including collagen types IV and VII,

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Tumors of the sweat glands integrin α4β6 and laminin 5.56–59 Recent biochemical studies implicate improperly processed laminin5 and low expression of integrin α4β6 within the tumor, resulting in reduced numbers of hemidesmosomes and alterations in basement membrane structure.60 Dermal cylindroma, which is not encapsulated, is located in the upper dermis (Fig. 33.147). There is no connection with the overlying epidermis. Characteristically, the lesion is composed of multiple lobules arranged in a jigsaw or mosaic pattern (Fig. 33.148). Each lobule has an outer hyaline diastase-resistant, PAS-positive basement membrane (Fig. 33.149).56–59 Hyaline droplets are typically seen in the center of the lobules and sometimes almost replace entire lobules (Fig. 33.150). Two cell types may be identified. Usually, though not invariably, situated at the periphery of the lobule are small cells with scanty cytoplasm containing a hyperchromatic nucleus. These surround larger cells with pale cytoplasm and an oval vesicular nucleus. Ductal lumina are usually present (Fig. 33.151). Often there is morphological ­overlap

Fig. 33.149 Dermal cylindroma: each lobule consists of an outer layer of cells with small hyperchromatic nuclei and an inner zone of cells with oval vesicular nuclei. Each lobule is surrounded by a hyaline mantle.

Fig. 33.147 Dermal cylindroma: this scanning view shows the complex interrelationship of the tumor lobules.

Fig. 33.150 Dermal cylindroma: the lobules contain deposits of hyaline material.

Fig. 33.148

Fig. 33.151

Dermal cylindroma: the arrangement of the irregular lobules is reminiscent of pieces of a jigsaw.

Dermal cylindroma: ductal differentiation which is present at the edge of the field is an invariable feature.

Malignant cylindroma between cylindroma and spiradenoma.9,61,62 Such cases have been referred to as spiradenocylindroma.61 Additional trichoepitheliomatous, trichoblastic, and sebaceous differentiation has also been observed.37,38 Immunohistochemically, the ductal epithelium shows marked luminal CEA expression, but is HMFG negative.63 The epithelial cells express CK6 and CK19 as well as CK7 and EMA.64,65 Positive staining for SMA and S-100 protein is evidence of myoepithelial differentiation and staining with IKH-4 supports the eccrine nature of this neoplasm.64–67

Malignant cylindroma Clinical features Malignant cylindroma is extremely rare with only approximately 40 histologically confirmed documented cases.1–17 Diagnosis is dependent upon the recognition of pre-existent benign tumor. Lesions may arise within solitary cylindromas or complicate the autosomal dominant multiple tumor variant, but the latter is more common.10,11,16 Most malignant cylindromas have presented on the scalp, although the trunk, face, and extremities as well as the external auditory canal have occasionally been affected. There is a slight female predominance and most patients are in their seventh to ninth decades. Clinical features suggestive of malignant transformation include ulceration, rapid growth, and bleeding.7 This is a high-grade tumor with a recurrence rate of 36% and a metastasis rate of 46%, the lymph nodes, liver, and vertebral column being particularly affected.7,10

Fig. 33.153 Malignant cylindroma: scattered throughout the tumor are residual cylindromatous foci. Note the hyaline mantle.

Pathogenesis and histological features The etiology of malignant cylindroma in most instances is unknown. Several tumors, however, have developed following previous therapeutic radiation.3,9 Features suggesting possible malignant potential include an infiltrating growth pattern and loss of mosaic appearance, hyalin sheaths, and biphasic cellular distribution (Figs 33.152–33.155).7 Nuclear and cytoplasmic pleomorphism, prominent nucleoli, and frequent or abnormal mitoses are also worrying features. Lymphatic and vascular invasion or infiltration of the perineural sheath also signifies an aggressive biological potential. Although most malignant cylindromas have represented variably differentiated adenocarcinomas, occasional tumors have displayed squamous or spindled cell features, and metaplastic/sarcomatous differentiation has been documented.1,16 Immunohistochemically, the tumor cells express CAM 5.2, EMA, and CEA.1,4,7,10 S-100 protein and GCDFP-15 expression are variable.1,10

A

Fig. 33.152 Malignant cylindroma: low-power view showing tumor nodules with obvious ductal differentiation and cysts.

B

Fig. 33.154 Malignant cylindroma: (A) the dual cell population is lost and the tumor cells form expansile nodules and a sheetlike growth pattern; (B) higher-power view. Note the fibrous trabeculae.

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A

Fig. 33.156 Eccrine spiradenoma: this small nodule is typically tender or painful. By courtesy of D. McGibbon, MD, Institute of Dermatology, London, UK.

B

Fig. 33.155 Malignant cylindroma: (A) there is a centrally located mitotic figure. (B) This tumor showed perineural infiltration.

Eccrine spiradenoma Clinical features Eccrine spiradenoma is clinically rather distinct, as most examples are either tender or painful.1,2 It presents as a usually solitary, intradermal, circumscribed, round or oval, firm lesion (Fig. 33.156). Often the overlying skin is blue. Most tumors measure 0.3–5.0 cm in diameter, but occasionally giant variants are encountered.3–6 Approximately 80% are present on the ventral aspect of the skin, most often affecting the upper half of the body.1,2 Unusual anatomic sites include the ear and postauricular area, eyelid, lip, and hand.7–13 Although any age may be affected, most patients are in their second to fourth decades. Congenital onset or presentation in early infancy is unusual.14,15 Multiple lesions occasionally occur and a linear or zosteriform variant has been described.16–29 Multiple eccrine spiradenomas can be familial and are then inherited in an autosomal dominant pattern.21 They may be associated with multiple trichoepitheliomas and cylindromas as well as, less frequently, trichoblastoma and cutaneous lymphadenoma as part of the morphological spectrum of the Brooke-Spiegler syndrome.19,22,28–33

Pathogenesis and histological features Eccrine spiradenoma is characterized by the presence of one or more tumor lobules located in the dermis and sometimes extending into the subcutaneous fat (Fig. 33.157).1,2 The overlying epidermis is normal. Due to nuclear crowding, the lobules are intensely basophilic. The tumor is usually ­encapsulated

and is typically sharply circumscribed. Sometimes a retraction artifact ­separates the capsule from the surrounding tissues, and not infrequently a nerve trunk may be identified in close proximity to the tumor lobules. The latter contain two cell types. At the periphery of the lobule the cells are small with round hyperchromatic nuclei whereas centrally they are larger with oval vesicular nuclei, often containing a small eosinophilic nucleolus, and have pale-staining or eosinophilic cytoplasm (Figs 33.158–33.160). Ductal differentiation is usually present (Fig. 33.161). An unusual and rare finding is the focal presence of small closely packed glandular structures with round lumina and composed of palely eosinophilic staining cuboidal to columnar cells. Luminal cells are typically surrounded by an additional myoepithelial layer. This pattern has been referred to as ‘spiradenoma with an adenomatous component’.34 With limited follow-up, these tumors showed benign behavior.34 However, as this finding has also been found in association with severe cytological atypia and spiradenocarcinoma, its biological significance and potential are best regarded as uncertain at this time. Typically, eccrine spiradenoma does not contain glycogen. Mitoses are exceedingly rare. Some tumors may contain cystic cavities filled with diastase-resistant, PAS-positive finely granular eosinophilic material. The tumor lobules are supported by a delicate reticulin network, which demonstrates an alveolar pattern. Marked lymphedema may be present within the tumor lobules and also in the surrounding connective tissue sheath (Fig. 33.162).2 Eccrine spiradenoma is richly vascular and on occasions conspicuous, widely dilated vascular channels may result in a superficial resemblance to an angioma, hemangiopericytoma or glomus tumor (Fig. 33.163).4 Prominent infarction can be seen in some cases with very little viable tumor left making diagnosis difficult. Variably sized perivascular spaces around one or more centrally located blood vessels are frequently present and are demarcated peripherally by palisading tumor cells and basement membrane material.35 Rarely, hyaline droplets are present within the paler central component of the lobules. Occasionally, spiradenomas also show cylindromatous features (spiradenocylindroma), and less frequently trichoepitheliomatous as well as trichoblastomatous and s­ ebaceous differentiation may be observed.29,36–39 By immunohistochemistry, eccrine spiradenoma expresses IKH-4 in keeping with its eccrine differentiation.40 Tumor cells furthermore express CK7, CK8, and CK18 as well as EMA and CEA.41,42 Myoepithelial ­differentiation is documented by positive staining for SMA and S-100 protein.42–46 The ­immunohistochemical findings are similar to those of dermal cylindroma.

Eccrine spiradenoma

Fig. 33.157

Fig. 33.159

Eccrine spiradenoma: in this example, there are three discrete tumor lobules. The largest appears encapsulated.

Eccrine spiradenoma: close-up view of biphasic population.

A

Fig. 33.160 Eccrine spiradenoma: in this field, the tumor lobules are surrounded by a thick hyaline mantle composed of basement membrane material.

B

Fig. 33.158 (A, B) Eccrine spiradenoma: in this field, the biphasic cell population is evident. The outer layer cells have small hyperchromatic nuclei and minimal cytoplasm. These surround larger cells with round or oval vesicular nuclei and more conspicuous eosinophilic cytoplasm; the lobules are surrounded by a well-developed reticulin sheath.

Fig. 33.161 Eccrine spiradenoma: in this field, there is extensive ductal differentiation.

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Fig. 33.162 Eccrine spiradenoma: very marked edema has resulted in this ‘lymphangiectatic’ variant.

Fig. 33.164 Eccrine spiradenocarcinoma: this tumor had been present for many years. Note the necrosis and cystic degeneration. By courtesy of A.J. Blackshaw, MD, Bedford Hospital, Bedford, UK.

auditory canal and breast.10,29,40 Presenting features have included a change in character including size, color, bleeding, and ulceration (Fig. 33.164).4,20 Tumors are typically sporadic and solitary, but less frequently they may also present in the setting of Brooke Spiegler syndrome.44 It is said to be a high-grade tumor with a reported recurrence rate of approximately 30%, a metastasis rate of 30–40%, and a mortality of 20%.2,23,27,31,44 Preferred metastatic sites have been locoregional lymph nodes and lung followed by other visceral sites including brain, bone, liver, and kidney.6–8,11,18,26,27,36,37 Accurate prognostic data are, however, difficult to obtain in such a rare entity (particularly as many documented examples are single case reports). The overall rates of recurrence and metastasis, as well as mortality, may indeed be lower.20 This may particularly apply to morphologically ‘low-grade’ spiradenocarcinoma.44 Treatment consists of wide excision. The benefit of sentinel lymph node biopsy and additional chemotherapy is not established at this point and ­hormonal treatment such as tamoxifen could become a therapeutical option in estrogen receptor-positive tumors.15 Fig. 33.163 Eccrine spiradenoma: note the widely dilated and congested vascular channels. This tumor is sometimes mistaken for a hemangioma or glomangioma.

Differential diagnosis Eccrine spiradenoma usually poses few diagnostic problems. Occasionally, however, particularly with small lesions in which ductal differentiation may not be obvious, the tumor may be mistaken for a lymphoid aggregate. The immunocytochemical demonstration of duct formation by EMA or CEA expression should rapidly resolve any diagnostic difficulty.

Eccrine spiradenocarcinoma Clinical features Eccrine spiradenocarcinoma (malignant eccrine spiradenoma) is an extremely rare neoplasm and fewer than 100 examples having been documented in the English literature.1–45 The clinical appearance is not distinctive, diagnosis being dependent upon the recognition of a pre-existent benign counterpart.2,44 It is characterized by a long history, often in decades, and in one case amounting to 70 years.3,20,27,45 There is an equal sex incidence.20 Elderly adults with a median age around 60 years are predominantly affected but age at presentation is variable, ranging from 12 to 92 years.6,19,20,27 A wide range of anatomical sites may be affected including the extremities, the trunk, and (less frequently) the head and neck.20,27 Unusual locations are the external

Pathogenesis and histological features The diagnosis of malignant eccrine spiradenoma requires the recognition of an at least focal component of benign spiradenoma, which may be present to varying degrees (Figs 33.165–33.167).2,4–6,20,44 The malignant features are not specific and include an infiltrating border, tumor necrosis, hemorrhage, lymphovascular invasion and infiltration of the perineural sheath.20 Cytological changes include loss of the dual cell population, nuclear pleomorphism, prominent nucleoli, and marked mitotic activity, including atypical forms (Figs 33.168–33.170). Malignant transformation change in ­spiradenoma can show two morphologically distinct patterns:20 • One pattern is that of an abrupt transition from a benign-appearing spiradenoma to frankly carcinomatous or sarcomatous areas. Carcinomatous change may be noted in the form of adenocarcinoma but squamous differentiation may also be seen.20,25,44 Depending on the degree of differentiation of the carcinomatous component, these tumors have recently been classified into ‘salivary gland-type basal cell adenocarcinoma-like, high grade’ and ‘infiltrative adenocarcinoma, NOS’. Sarcomatous differentiation (carcinosarcoma) may be present in the form of a spindled cell, leiomyosarcomatous, osteosarcomatous, chondrosarcomatous, osteocartilagenous or rhabdomyoblastic component.7–9,15,18,19,26,28,29,33,44 Without identification of a benign component, these tumors would be difficult to classify. • A second morphological type of malignant spiradenoma is characterized by a histologically low-grade tumor in which the lobular architecture of spiradenoma is retained. Due to their close resemblance to

Eccrine spiradenocarcinoma

A

Fig. 33.167 Eccrine spiradenocarcinoma: high-power view showing multiple mitoses.

B

Fig. 33.165 Eccrine spiradenocarcinoma: (A) scanning view showing a nodule of carcinoma with adjacent benign eccrine spiradenoma; (B) high-power view of spiradenoma.

A

B

Fig. 33.166 Eccrine spiradenocarcinoma: the tumor is composed of broad trabeculae. Note the loss of the dual cell population.

Fig. 33.168 Eccrine spiradenocarcinoma: (A), precursor lesion; (B) note the biphasic population.

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A

salivary tumors, they have been termed ‘salivary gland-type basal cell adenocarcinoma-like, low-grade’. These tumors are difficult to recognize at scanning magnification, but are characterized by loss of the dual cell population and are composed of a single component of only mildly atypical basaloid cells showing increased mitotic activity upon closer inspection.11,20 A further clue is the absence of admixed intratumoral lymphocytes. Although metastasis and death from disease have been reported in a patient with ‘low-grade’ spiradenocarcinoma, the incidence may be lower compared with morphologically ‘high-grade’ tumors.11,44 Additional morphological findings include squamous metaplasia and clear cell change as well as mucinous metaplasia.44 An adenomatous component of small and densely packed, well-developed glands may also be present.44 Malignant change has also been documented in association with a preexisting benign tumor showing morphological overlap between dermal cylindroma and eccrine spiradenoma (spiradenocylindrocarcinoma) and malignant cylindroma, spiradenocarcinoma, and spiradenocylindrocarcinoma likely represent the morphological spectrum of the same disease.41,44 Immunohistochemistry may be of help in highlighting ductal differentiation, the latter expressing EMA and CEA. The background population of cells expresses S-100 protein and CAM 5.2 in addition to EMA.1 Overexpression of p53 is seen in the malignant component and tumor cells may express estrogen receptor.15,25,46 p53 mutations have recently been identified in malignant but not benign spiradenoma, implicating ultraviolet light in the pathogenesis and progression of these tumors.47

Syringoid eccrine carcinoma Syringoid eccrine carcinoma, microcystic adnexal carcinoma, and adenoid cystic carcinoma show overlap and are probably variations on a single theme. However, in keeping with the current literature, they are classified as separate lesions in this chapter.

Clinical features B

Fig. 33.169 (A, B) Eccrine spiradenocarcinoma: these fields come from the junction of the benign and malignant components. There is nuclear pleomorphism and nucleoli are prominent.

Syringoid eccrine carcinoma (eccrine epithelioma, basal cell tumor with eccrine differentiation) is rare and most commonly presents on the scalp although tumors have also arisen on the face, neck, leg, forearm, dorsum of hand, and palm.1–12 Clinical features are variable, ranging from a sometimes painful infiltrated plaque associated with alopecia through to a nonhealing ulcer reminiscent of basal cell carcinoma.10 Lesions generally measure from 0.5 to 7.0 cm in greatest dimension. The tumor is characterized by a female preponderance (3:1) and most often affects the middle aged (range: 42–74 years, mean: 55 years).10 It is frequently slowly growing and has often been present for many years, sometimes decades, before diagnosis. Syringoid eccrine carcinoma is therefore characterized by a protracted course, multiple recurrences, and aggressive behavior. Rarely, lymph node and pulmonary metastases have been documented and one patient died from systemic spread.6,13,14

Pathogenesis and histological features

Fig. 33.170 Eccrine spiradenocarcinoma: note the abnormal mitotic figure.

The tumor is characterized by an infiltrate of basaloid cells showing ­ductular differentiation and set in a dense, often hyalinized, fibrous stroma (Figs 33.171, 33.172). It is usually centered in the mid dermis and contact with or origin from the epidermis is uncommon. The tumor is typically deeply invasive and often extends to the subcutaneous fat, fascia or skeletal muscle. In some examples, the infiltrate is intimately associated with eccrine sweat glands and ducts. The epithelial cells are small with oval hyperchromatic nuclei, ill-defined pale cytoplasm, and indistinct cell membranes. They are arranged in narrow cords and, in addition to duct formation, are sometimes associated with the development of cysts (Figs 33.173, 33.174). Pleomorphism is not usually marked and mitotic activity is low. Intracytoplasmic glycogen is occasionally present. The lumen sometimes contains diastase-resistant, PAS-positive material. Rarely, the tumor epithelium may show striking vacuolation due to glycogen accumulation reminiscent of clear cell syringoma (Fig. 33.175).4,7,10,15 Tadpole-like forms are sometimes evident, but squamous differentiation and cribriform patterns are generally not present (Fig. 33.176). In addition,

Syringoid eccrine carcinoma

Fig. 33.171 Syringoid eccrine carcinoma: this is a tumor on the face. Note the darkly stained epithelium epithelial strands and cysts within the fibrosed dermis. The tumor extends to the skeletal muscle.

Fig. 33.173 Syringoid eccrine carcinoma: ductal differentiation, as shown in this field, is invariably present.

Fig. 33.174 Syringoid eccrine carcinoma: cysts are commonly seen.

Fig. 33.172 Syringoid eccrine carcinoma: there is superficial involvement of the muscle.

­ eratocysts and features of follicular differentiation are absent. Infiltration of k the perineural sheath is a common feature and undoubtedly contributes to the tumor's tendency to recurrence (Fig. 33.177). Histochemically, syringoid eccrine carcinoma shows abundant phosphorylase, acid phosphatase, and succinic dehydrogenase activity.2 Immunohistochemically, the tumor cells express high and low molecular weight keratin, EMA, CEA, and occasionally S-100 protein (Fig. 33.178).9,10,13,15–17 The ducts can be highlighted by EMA and/or CEA immunohistochemistry. In our experience, both of these antibodies should be included in the panel, as the staining characteristics of these tumors are quite variable.

Differential diagnosis Syringoid eccrine carcinoma can be distinguished from microcystic adnexal carcinoma and adenoid cystic carcinoma by the absence of keratocysts, follicular differentiation, and cribriform morphology. It should, however, be noted that distinction is not always clear-cut and that on occasions typical

Fig. 33.175 Syringoid eccrine carcinoma: occasionally abundant intracytoplasmic glycogen results in this clear cell variant.

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Tumors of the sweat glands ­sclerosing eccrine carcinoma may recur with focal cribriform features reminiscent of adenoid cystic carcinoma. It differs from basal cell carcinoma by the lack of retraction artifact and peripheral palisading and by the presence of EMA and CEA positivity. Basal cell carcinoma may rarely show ductal differentiation but in our experience this finding is limited to nodular variants where there is no diagnostic difficulty. In those tumors unassociated with evidence of origin, the possibility of metastasis may have to be excluded by clinical investigation. The lack of expression of CK20 and GCDFP-15 may be of diagnostic help.16,17

Microcystic adnexal carcinoma Clinical features

Fig. 33.176 Syringoid eccrine carcinoma: a ‘tadpole’ morphology reminiscent of syringoma is often seen.

Fig. 33.177

Microcystic adnexal carcinoma (sclerosing sweat duct (syringomatous) carcinoma, malignant syringoma, sweat gland carcinoma with syringomatous features, locally aggressive adnexal carcinoma, combined adnexal tumor) is a locally aggressive malignant adnexal tumor displaying sweat duct and follicular differentiation.1–7 It is rare and, due to a combination of lack of familiarity and inadequate small punch or shave biopsies, it is frequently initially misdiagnosed, with potential serious consequences for the patient. The tumor is characteristically very indolent with some examples having been present for decades before diagnosis.6 While there is a female preponderance in some series, overall the sexes are affected equally. The tumor presents in a wide age range (6–90 years) although the majority of patients are in their fifties or sixties.8–10 There are very occasional reports of lesions arising in children.11,12 The head (particularly the nasolabial and periorbital regions) is involved most often (Figs 33.179, 33.180).3,8,13 Lesions on the neck and scalp are uncommon and the trunk, axilla, and breast are only rarely affected.6,14–16 The left side of the face has been noted to be predominantly affected in two series, but this has not been confirmed in other reports.6,17 Tumors have also been rarely described on the buttock, palm, toe, and vulva.7,18 An orbital variant and an example arising in the tongue have recently been reported.19–21 The tumor presents as a slow-growing, flesh-colored, yellow or erythematous, firm or hard plaque or nodule, which may be associated with hyperkeratosis. Sometimes a central dell is evident. The margins are typically difficult to delineate. Indeed, the findings at surgery almost invariably disclose that the tumor extends several centimeters beyond the clinically visible lesion. Ulceration is unusual. Most tumors measure between 0.5 cm and 2.0 cm in diameter but occasionally very large examples are encountered, measuring up to 12 cm in greatest dimension.6,12 Although lesions are often asymptomatic,

Syringoid eccrine carcinoma: perineural infiltration is a common feature and in part accounts for the high recurrence rate.

Fig. 33.178 Syringoid eccrine carcinoma: in this example, the ductal epithelium shows CEA expression.

Fig. 33.179 Microcystic adnexal carcinoma: a scaly, erythematous swelling is present at the angle of the mouth. By courtesy of D. McGibbon, MD, Institute of Dermatology, London, UK.

Microcystic adnexal carcinoma

A

features (see below) – postulate dual follicular and sweat gland differentiation.1,8,42,43 The occasional finding of decapitation secretion and ­sebaceous differentiation has led some authors to propose derivation from the ­folliculosebaceous-apocrine unit.43 The tumor is poorly circumscribed, usually deeply infiltrating, and uncommonly shows an epidermal origin or connection with hair follicles. It expresses a constellation of features including numerous small to medium-sized keratocysts, usually superficially located and merging into smaller cysts, and solid strands of cells, many showing ductular lumina (Fig. 33.181).1,3,22 In some examples, a tadpole-like morphology as seen in syringoma is a feature.40 Very occasionally, the cyst contents are calcified. The deeper component consists of small solid strands with a highly infiltrative growth pattern (Fig. 33.182). Intracytoplasmic lumina are typically present and are a major diagnostic feature. A dense fibrous stroma surrounds all components and becomes more sclerotic in the infiltrative areas (Fig. 33.183). The subcutaneous fat and skeletal muscle are commonly affected. Invasion of bone has been documented in 13% of cases.9,44–46 Perineural invasion is frequently observed (Fig. 33.184). Cytological atypia is rare and mitoses are uncommon. Glycogen-rich clear cells suggestive of external root sheath differentiation may be a feature and occasionally large basaloid nodules with variable peripheral palisading reminiscent of trichoblastoma are present (Figs 33.185–33.187).1,3,14,40,47 Shadow cells have also been described.8 Sebaceous gland and duct (cuticular) differentiation has rarely been documented.8,47 Apocrine-type decapitation secretion has been occasionally reported.40 Ultrastructural studies confirm the presence of ductal differentiation.48

B

Fig. 33.180 (A, B) Microcystic adnexal carcinoma: there is a yellow ulcerated tumor on the lower eyelid near the inner canthus. By courtesy of J.M. Oliver, MD, Western Eye Hospital, London, UK.

patients sometimes have pain, burning or paresthesia due to perineural infiltration.9,22 While the tumor has been predominantly reported in Caucasians, there is a small number of case reports documenting presentation in blacks, and recently a large series of Japanese patients has been reported.7,23–25 Microcystic adnexal carcinoma is an aggressive neoplasm often associated with considerable tissue destruction. With inadequate excision, recurrences are common, occurring in 30–40% of cases.8,13 More recent series (particularly in patients following Mohs' surgery) have described low or even zero recurrence rates.12,26 There is a small number of cases with associated local lymph node metastases.27–31 Systemic spread and tumor-associated mortality is very exceptional.32,33

A

Pathogenesis and histological features In most cases the etiology is unknown, but a small number of tumors have followed therapeutic cutaneous irradiation.6,9,12,34–37 Other factors of possible importance include ultraviolet light and immunodeficiency.28,38 There is one report documenting familial incidence in two sisters.6 One or two tumors appear to have arisen within a pre-existent organoid nevus.39,40 While the majority of tumors arise on sun-exposed skin, unlike squamous cell carcinoma, there is little evidence to suggest that p53 mutation is of any pathogenetic importance.8,41 The histogenesis of microcystic adnexal carcinoma remains ­uncertain. Although some authors believe that it shows only eccrine differentiation, others – on the basis of keratin immunohistochemistry and ­morphological

B

Fig. 33.181 Microcystic adnexal carcinoma: (A) the dermis is widely infiltrated by a tumor characterized superficially by the presence of keratocysts; (B) the latter typically show epidermoid keratinization.

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A

Fig. 33.184 Microcystic adnexal carcinoma: the tumor has infiltrated a nerve fiber.

B

Fig. 33.182 (A, B) Microcystic adnexal carcinoma: the deeper component consists of narrow epithelial strands and small ductules.

Fig. 33.185 Microcystic adnexal carcinoma: there is marked cytoplasmic vacuolation due to glycogen accumulation. Pilar keratinization is evident.

With immunohistochemistry, the tumor cells express AE1/AE3 and EMA.40,42 The latter is valuable for highlighting ductal differentiation or intracytoplasmic lumen formation as is CEA (Fig. 33.188).35,40,42–44,48 In our experience, both of these antibodies should always be included in the panel, as the staining pattern is very variable. In addition, diastase–PAS may also be of value in this context. S-100 protein is negative. In support of follicular differentiation, the tumor expresses hard keratin (AE13 and AE14).8,42 LeuM1 is also positive and CK15 as well as Ber-EP4 expression is frequently observed.36,49 Microcystic adnexal carcinoma shows a low proliferation rate as determined by MIB-1 immunohistochemistry.8

Differential diagnosis

Fig. 33.183 Microcystic adnexal carcinoma: in this field, the stroma is hyalinized and has compressed the epithelial component. Note the ductal differentiation. This aspect of the tumor histology overlaps with eccrine epithelioma.

Microcystic adnexal carcinoma must be distinguished from desmoplastic trichoepithelioma, trichoadenoma, syringoma, morpheaform basal cell carcinoma, and desmoplastic squamous cell carcinoma.50 • Microcystic adnexal carcinoma differs from desmoplastic trichoepithelioma by its deep and infiltrative growth pattern, perineural infiltration, and presence of ductal differentiation. These same features exclude trichoadenoma. • Superficial biopsies may be difficult to distinguish from syringoma. The presence of keratocysts, mild nuclear atypia, and mitoses argues strongly against this diagnosis.

Primary adenoid cystic carcinoma

A

A

B

B

Fig. 33.186 Microcystic adnexal carcinoma: (A) in this field, the tumor shows typical features with conspicuous keratocysts; (B) elsewhere, there are discrete nodules of basaloid cells with peripheral palisading reminiscent of trichoblastoma.

Fig. 33.187 (A, B) Microcystic adnexal carcinoma: high-power views of Figure 29.186.

• Morpheaform basal cell carcinoma and desmoplastic squamous cell

carcinoma are excluded on the basis of ductal differentiation and intracytoplasmic lumen formation. Although basal cell carcinoma may rarely show evidence of ductal differentiation, in our experience this occurs in nodular variants, when the correct diagnosis should be obvious.

Primary adenoid cystic carcinoma Clinical features Primary adenoid cystic carcinoma is a rare primary tumor of skin, fewer than 70 cases having been described in the English literature.1–13 Much more commonly it is a tumor of the salivary glands and bronchus and may also arise within the breast, esophagus, cervix, prostate, vulva, and lacrimal and ceruminous glands.2 The tumor shows a slight preponderance in females (3:2), usually of middle age or older (mean age: 58 years) and presents as a slowly growing, 0.5–8.0 cm in diameter crusted plaque or nodule, often of long duration.6 Although a wide variety of sites may be affected, at least 40% have arisen on the scalp.2 The breasts, back, and abdomen are also more often affected.6 Perineal involvement is unusual.11 Primary adenoid cystic carcinoma of the skin is a much less aggressive tumor than its systemic counterpart. Although recurrence of the tumor is

Fig. 33.188 Microcystic adnexal carcinoma: the ducts and intracytoplasmic lumina can be outlined by EMA and CEA immunohistochemistry (EMA).

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Tumors of the sweat glands likely (57–70%), metastases to lymph nodes and the lung are relatively uncommon.6,12,14–21 This contrasts with the approximately 50% metastasis rate of the salivary gland variant.16 The high recurrence rate is a reflection of the frequent presence of infiltration of the perineural space. Long-term follow-up is essential as presentation of recurrent tumor may be delayed for many years or even decades. Cutaneous adenoid cystic carcinoma may also represent direct extension from an underlying salivary gland primary neoplasm.22 Metastasis from a more distant site has been documented exceptionally rarely.23–26

Pathogenesis and histological features The histogenesis of this tumor is uncertain, and while some authors have argued apocrine derivation, citing the example of ceruminous gland variants (the ceruminous gland is a modified apocrine gland), others (on the basis of enzyme histochemistry) have favored an eccrine derivation.15,18 Thus adenoid cystic carcinoma is positive for succinic dehydrogenase and phosphorylase and negative for acid phosphatase and β-glucuronidase.27 The tumor has a characteristic basophilic low-power appearance due to nuclear hyperchromatism and crowding. It typically occupies the mid and deep dermis and often extends into the subcutaneous fat (Fig. 33.189). There is no evidence of an epidermal origin. Adenoid cystic carcinoma is composed of variably sized islands of tumor cells dispersed in a loose fibrous and sometimes mucinous stroma (Fig. 33.190). The epithelium consists of fairly uniform cells with darkly staining nuclei, which sometimes contain conspicuous, small, solitary nucleoli. Cytoplasm is minimal. Nuclear palisading is not a feature. Mitotic activity is usually sparse (Fig. 33.191). A typical feature is the presence of excessive diastase-resistant, PASpositive eosinophilic hyaline basement membrane-like material both between tumor cells and also surrounding individual lobules (Figs 33.192, 33.193). Occasionally it lines the luminal surface of cystic spaces (pseudolumina). The latter, which contain Alcian blue (pH 2.5)-positive hyaluronic acid and sulfated acid mucin, are a common feature, giving rise to the pathognomonic cribriform appearance (Fig. 33.194). Less frequently, tubular and diffuse patterns are encountered.28 True ductal differentiation associated with mucin secretion is sometimes present. Adenoid cystic carcinoma typically shows an infiltrative border, and perineural spread is ­common (Fig. 33.195). Immunohistochemically, the tumor cells express low and high molecular weight keratin, S-100 protein, and variably CEA.6,11,22,23 The presence of ductal differentiation can be confirmed with EMA and CEA (Fig. 33.196).29,30 The basement membrane material is composed of an admixture of collagens IV and V and laminin (Fig. 33.197).27

Fig. 33.189 Primary cutaneous adenoid cystic carcinoma: the tumor is composed of basophilic epithelium forming cords and ductular structures.

Fig. 33.190 Primary cutaneous adenoid cystic carcinoma: in this field, there is ductal differentiation and a focal cribriform pattern.

Fig. 33.191 Primary cutaneous adenoid cystic carcinoma: high-power view.

Fig. 33.192 Primary cutaneous adenoid cystic carcinoma: the pseudolumina are lined by thickened hyaline membranes formed from basement membrane constituents, notably type IV collagen and laminin.

Primary adenoid cystic carcinoma

Fig. 33.193

Fig. 33.196

Primary cutaneous adenoid cystic carcinoma: the hyaline membranes are strongly PAS positive (diastase resistant).

Primary cutaneous adenoid cystic carcinoma: there is striking EMA expression along the luminal border.

Fig. 33.194 Primary cutaneous adenoid cystic carcinoma: the luminal contents are strongly Alcian blue (pH 2.5) positive.

A

B

Fig. 33.195

Fig. 33.197

Primary cutaneous adenoid cystic carcinoma: infiltration of the perineural space is a common manifestation.

Primary cutaneous adenoid cystic carcinoma: the hyaline membrane lining the pseudolumina is composed of (A) type IV collagen and (B) laminin.

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Differential diagnosis Cutaneous adenoid cystic carcinoma may be confused with adenoid basal cell carcinoma, particularly as both produce hyaluronic acid. However, an origin from the epidermis and stromal retraction are not seen in the former while the latter is typically EMA, CAM 5.2, S-100 protein, and CEA negative.16 As mentioned above, it must be stressed that direct extension from an underlying salivary gland tumor or metastasis should be excluded before accepting that a cutaneous lesion represents a primary tumor.

Primary mucinous carcinoma Clinical features Primary mucinous carcinoma (cutaneous adenocystic carcinoma) is a rare neoplasm showing a predilection for the head and neck, particularly the eyelids, but on occasions affecting other sites including the scalp, face, ear, axillae, thorax, abdomen, groin, foot, hand, and vulva.1–14 It presents as a slowly growing, flesh-colored, erythematous or blue nodule.1,5 Size at presentation is very variable, ranging from 0.5 to 8.0 cm in greatest dimension.14,15 A wide range of ages may be affected (8–89 years) but the tumor particularly develops in the elderly (median age: 62 years).4,14 Primary cutaneous mucinous carcinoma usually follows a rather indolent course. Although it is locally aggressive and commonly recurs (26%), distant metastases are rare and usually only involve the regional lymph nodes.3,6,7,12–14

A

Pathogenesis and histological features The tumor is situated in the dermis and often involves the subcutaneous fat. It is compartmentalized by delicate fibrous septa, which enclose a lake of palestaining mucin, in which are suspended islands of tumor cells (Figs 33.198, 33.199). The latter are cuboidal with pink-staining, sometimes vacuolated cytoplasm, and centrally located round or oval vesicular nuclei (Fig. 33.200). Light- and dark-cell forms are occasionally distinguishable.3 The tumor cells are cohesive. Signet ring forms are rarely a feature and mitoses are inconspicuous (Fig. 33.201) but decapitation secretion is a not infrequent finding. Rarely, a focal solid pattern is evident. Glandular differentiation is often present and sometimes a cribriform pattern is a feature.14 An in situ component reminiscent of ductal carcinoma in situ of the breast with cribriform, solid or micropapillary growth patterns may often be identified.14 A subset of tumors is characterized by the additional presence of an invasive adenocarcinoma showing a solid or cribriform architecture, and comedo necrosis may be present.14 Microcalcifications and psammoma body formation may be further features.14 Foci of hemorrhage are commonly evident, but necrosis is not usually seen. The mucin is diastase-resistant/PAS-positive, hyaluronidase-resistant/ Alcian blue-positive (pH 2.5) and also stains with mucicarmine and colloidal iron (Fig. 33.202).4 It is sensitive to sialidase, indicating the presence of nonsulfated sialomucin.4 It is negative with Alcian blue at pH 1 and 0.4.16 The tumor cells express AE1/AE3, EMA, and CEA (Fig. 33.203).8,9,16,17 In keeping with a derivation from the secretory lobule, CAM 5.2 is also often present and tumor cells are CK7 positive but CK20 negative (Fig. 33.204).18 S-100 protein expression is variable.8 p53 and c-erbB-2 are not expressed.16 The tumor shows a low proliferation index with Ki-67.16 Estrogen and progesterone receptors are positive (Fig. 33.205).16,18–20 A rim of myoepithelial cells may be a focal finding which can be confirmed by immunohistochemistry for p63, CK5/6, calponin, and SMA.14,18 Myoepithelial cells are preserved in areas of in situ carcinoma and the presence of basement membrane material can be highlighted by collage type IV staining.14 The identification of a myoepithelial component is useful in confirming the cutaneous origin of the tumor. Neuroendocrine differentiation demonstrated by a positive Grimelius reaction and neuron-specific enolase (NSE), chromogranin, and synaptophysin immunohistochemistry has been described in a small number of cases (Figs 33.206, 33.207).16,17,19,21 Ultrastructural studies have confirmed the presence of membrane-bound granules.17,21 Ultrastructurally, the tumor is composed of an admixture of pale and dark cells, the latter containing mucin droplets.2,5 Histochemistry supports an eccrine derivation, the tumor cells containing the oxidative enzymes

B

Fig. 33.198 (A, B) Primary cutaneous mucinous carcinoma: the epithelial component is widely dispersed in lakes of mucin.

Fig. 33.199 Primary cutaneous mucinous carcinoma: less often the tumor adopts a papillary configuration.

Primary mucinous carcinoma

A

Fig. 33.200 Primary cutaneous mucinous carcinoma: the tumor cells are regular and have eosinophilic cytoplasm and small vesicular nuclei.

B

Fig. 33.202 Primary cutaneous mucinous carcinoma: (A) the mucin is PAS positive; (B) it stains with Alcian blue at pH 2.5.

Fig. 33.201 Primary cutaneous mucinous carcinoma: mitotic figures, as seen in the center of the field, are typically sparse.

s­ uccinic dehydrogenase, lactic dehydrogenase, and isocitric dehydrogenase.2 Immunohistochemistry in a small number of cases has demonstrated expression of HMFG, GCDFP-15, GCDFP-24 and lysozyme in addition to focal decapitation secretion, suggesting that a subset may be derived from or ­differentiate towards the apocrine gland.15,22

Differential diagnosis Cutaneous mucinous carcinoma may be histologically indistinguishable from metastatic lesions, particularly of mammary derivation.23,24 Tumors from the gastrointestinal tract and ovary may also enter the differential diagnosis.25 The clinical information in most instances will resolve any diagnostic problem. A breast carcinoma is most unlikely to present as a cutaneous metastasis. On the basis of statistics, therefore, a mucinous carcinoma arising on the face (particularly the eyelid) is almost certainly a p ­ rimary lesion. Cutaneous mucinous carcinoma can be distinguished from gastrointestinal tumors on the basis of mucin histochemistry. In primary cutaneous tumors, the mucin contains abundant sialomucin (Alcian blue positive at pH 2.5) in contrast to gastrointestinal tumors, which produce sulfamucins (Alcian blue ­positive at pH 1.0 and 0.4).3,4 In addition, primary ­cutaneous variants are CK20 negative in contrast to gastrointestinal lesions which ­characteristically express

Fig. 33.203 Primary cutaneous mucinous carcinoma: there is prominent membranous labeling with EMA.

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Tumors of the sweat glands

A

Fig. 33.204 Primary cutaneous mucinous carcinoma: the tumor cells express CAM 5.2.

B

Fig. 33.206 (A, B) Primary cutaneous mucinous carcinoma: in this example, there is a predominant solid component.

A

this keratin.18 A further helpful clue is the ­identification of a ­myoepithelial layer in primary cutaneous mucinous carcinoma by ­immunohistochemistry for p63.18,26

Endocrine mucin-producing sweat gland carcinoma Clinical features Endocrine mucin-producing sweat gland carcinoma is a rare tumor with less than 20 reported cases in the literature.1–6 It is closely related to mucinous carcinoma and may represent part of a morphological continuum. There is strong predilection for the eyelid, and in particular the lower eyelid.1–6 The cheek may also be affected.2 It is a tumor of the elderly with an average age at presentation of 70 years (range: 48–84 years).1–6 Females are twice as frequently affected as males.2 Endocrine mucin-producing sweat gland carcinoma is regarded as a low-grade carcinoma with only rare recurrence but no reported metastasis as yet.2,4 B

Fig. 33.205 Primary cutaneous mucinous carcinoma: the nuclei are positive for (A) estrogen and (B) progesterone receptors.

Histological features Endocrine mucin-producing sweat gland carcinoma presents as a well­circumscribed uni- to multinodular tumor. Tumor lobules are solid and cystic with papillary areas composed of uniform, medium-sized, round to oval cells with abundant cytoplasm and stippled chromatin pattern.1,2 Decapitation

Eccrine ductal carcinoma presentations include location on the vulva and the nipple and mimicking Paget's disease.3,6 The prognosis is poor, the tumor being associated with a high recurrence (70%) and metastasis rate (57%), with an overall mortality of 70%.1

Pathogenesis and histological features

A

The tumor is situated in the lower dermis and often extends into the subcutaneous fat (Fig. 33.208). There is no evidence of epidermal origin and pagetoid spread is not a feature. Eccrine ductal carcinoma is characterized by nests and cords of cuboidal epithelium showing marked ductal differentiation (Figs 33.209, 33.210).1–3,6,7 Intracytoplasmic lumina are sometimes evident. Pleomorphism and mitotic activity are variable features, but are usually not marked. The tumor is associated with a dense, sometimes sclerotic, fibrous stroma. Perineural infiltration and lymphatic and/or vascular invasion are commonly present. By immunohistochemistry, the tumor cells are cytokeratin and CEA positive. They may also express estrogen and progesterone receptors, c-erbB-2, S-100, and GCDFP-15 to varying degrees.3,6,8,9

B

Fig. 33.207 Primary cutaneous mucinous carcinoma: the solid component expressed (A) chromogranin and (B) NSE.

Fig. 33.208 Eccrine ductal carcinoma: the reticular dermis is extensively infiltrated by moderately differentiated adenocarcinoma, which is histologically indistinguishable from a metastasis. Note the dense fibrous stroma.

secretion may be a focal finding and moderate cytological atypia as well as mitotic activity may be present. Intracellular mucin is seen within a subset of tumor cells as highlighted by mucicarmine staining. Small amounts of extracellular mucin may also be identified. Areas of in situ carcinoma are recognizable in some tumors and approximately 50% of cases are associated with small foci of conventional mucinous carcinoma.2 By immunohistochemistry, tumor cells express neuroendocrine markers such as chromogranin, synaptophysin, NSE, and CD57. They are cytokeratin and EMA positive and express CK7 but not CK20. All tumors tested also express estrogen and progesterone receptors. A myoepithelial cell layer, as highlighted with calponin, p63, and SMA, is preserved only in areas of in situ carcinoma.2

Eccrine ductal carcinoma Clinical features Eccrine ductal carcinoma is a rare malignancy of major importance because it shows striking similarities to infiltrating ductal carcinoma of the breast and can therefore readily be mistaken for a metastasis. It shows a predilection for the head, neck, and extremities, and presents most often in the middle aged and elderly as a hard, usually nonulcerated, cutaneous nodule.1–5 Unusual

Fig. 33.209 Eccrine ductal carcinoma: there is widespread ductal differentiation.

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Tumors of the sweat glands be observed in other adnexal tumors such as eccrine porocarcinoma. It is then more focal than and not as prominent as in squamoid eccrine ductal carcinoma.

Polymorphous sweat gland carcinoma Clinical features This recently described low-grade sweat gland carcinoma is not uncommonly mistaken for a cutaneous metastasis.1–3 Only a small number of cases have been documented. Patients present with a slowly growing, smooth dermal nodule with a predilection for the limbs.1,3 Many tumors have been present for 5 or even 10 years before presentation. Local recurrences are common but lymph node metastases occur in fewer than 10% of cases.1,3 There have been no tumor associated deaths.

Histological features Fig. 33.210 Eccrine ductal carcinoma: intracytoplasmic lumina are evident in the center of the field. The diagnosis of this very rare tumor is one of exclusion. A metastasis must always be excluded.

Differential diagnosis The histological features are indistinguishable from those of invasive ductal breast carcinoma, and immunohistochemistry is of little value.5,8 Before accepting such a tumor as being of primary sweat gland derivation, a careful clinical and radiological examination of the breasts is mandatory.1 Rarely, metastatic large bowel carcinoma may result in an identical appearance.

Squamoid eccrine ductal carcinoma Clinical features Squamoid eccrine ductal carcinoma is an exceedingly rare tumor. It occurs in elderly adults as a solitary nodule on the head and neck area or extremities.1,2,3 Tumor size measures up to 2  cm. No metastasis or death from disease has been reported but there may be local recurrence.1

Histological features Histologically, this tumor presents as a poorly demarcated and infiltrative neoplasm extending into deep dermis and subcutaneous tissue.1–5 Connection with the overlying epidermis or follicular structures may be evident and ulceration is sometimes a feature.1 The superficial aspect of the tumor shows prominent squamoid differentiation resembling squamous cell carcinoma and frequently connects with eccrine ducts at different levels.1,2 Squamous eddies, horn cysts, and epithelial structures reminiscent of syringoma may also be present.1 In the deeper reaches the tumor appears more infiltrative and ductal differentiation in the form of a cuticle-like luminal structure is identified in addition to intracytoplasmic vacuoles.1,2 Marked cytologic atypia may be present in both ductal and squamoid elements and mitotic figures are present. Perineural infiltration can be seen but lymphovascular invasion has only rarely been reported.1,4,5 Ductal differentiation is confirmed with immunohistochemical staining for CEA and EMA. No reactivity is seen against S-100 protein.1,2

Differential diagnosis Squamous cell carcinoma can be excluded by the presence of ductal differentiation and connection with eccrine ducts. Immunohistochemistry for CEA and EMA will provide additional support. Squamous differentiation can also

Histologically, polymorphous sweat gland carcinoma presents as a pseudoencapsulated deep dermal nodular growth associated with a wide range of histological patterns including solid, trabecular, tubular, pseudopapillary, and cylindroma-like patterns.1 Ductal differentiation is regularly present and PASand mucicarmine-positive mucin may be evident.1 The tumor cells are uniform with little cytoplasm and round to oval vesicular nuclei with prominent nucleoli. Mitoses are often conspicuous but abnormal forms are not a feature.3 Perineural infiltration may rarely be seen but there is no tumor necrosis.1 The stroma is often hyalinized and hemorrhage is common. The tumor cells express keratin, CEA, and to a lesser extent EMA.

Primary cutaneous signet ring cell carcinoma Clinical features Signet ring cell carcinoma (histiocytoid carcinoma) is a rarely reported primary tumor presenting almost exclusively in the eyelid. The axilla may rarely be affected.1–4 In the small number of cases published in the literature, it shows a striking predilection for males (5:1) and arises most often in the sixth decade (range: 47–87 years, mean: 63 years).1,5–14 It is often slowly growing and presents as a non-specific thickening of the eyelid or as a mass. The tumor is associated with an aggressive growth pattern commonly involving the orbit and with frequent recurrences. Lymph node spread has been described in 30% of cases.7,8,11 Thus far, disseminated metastases have not been reported.

Histological features The tumor presents with a diffuse or widely infiltrating growth pattern typically associated with a single cell, ‘stack of pennies’ appearance. The tumor cells are variably described as histiocytoid with abundant eosinophilic cytoplasm containing small vacuoles and signet ring with a large intracytoplasmic vacuole compressing the nucleus to the periphery of the cell.8,11 Nuclei may be hyperchromatic or vesicular and contain prominent nucleoli with variable mitotic activity. Mucin stains including D-PAS and Alcian blue are positive.8 With immunohistochemistry, the tumor cells express pancytokeratin, EMA, CEA, and variably estrogen receptor, progesterone receptor, lysozyme, GCDFP-15, and HMFG.8,9,11 Ultrastructural studies have confirmed the presence of intracytoplasmic lumina with microvilli and intracytoplasmic mucin.11

Differential diagnosis Although a signet ring cell carcinoma of the eyelid is likely to represent a primary tumor, the diagnosis should never be made until the patient has been thoroughly investigated to exclude a metastasis from an underlying visceral primary tumor, particularly arising in the breast or gastrointestinal tract.

Cutaneous cysts

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for references and additional material

Follicular cysts  1571

Dermoid cysts  1580 Cutaneous mature cystic teratoma  1580

Epidermoid cyst  1571 Proliferating epidermoid cyst  1574 Hybrid cyst  1574 Verrucous cyst  1575 Epidermoid cyst of the sole  1575 Comedonal cyst  1575 Milia  1576 Trichilemmal cyst  1577 Vellus hair cysts  1578

Glandular cysts  1580 Bronchogenic cysts  1580 Thyroglossal duct cyst  1581 Branchial cyst  1582 Cervical thymic cyst  1582 Cutaneous ciliated cyst  1582 Median raphe cyst  1583

Although a wide variety of cysts may present in the skin, usually these turn out to be epidermoid (infundibular), trichilemmal or glandular in nature (Table 34.1). It can sometimes be difficult to determine whether a structure is a true cyst, a sinus, a comedone or an obliquely sectioned dilated hair follicle. Usually the clinical information or further sections provide the answer, but the alternatives should always be borne in mind. The majority of cutaneous cysts are recognized as such clinically. However, a significant proportion of misdiagnoses do occur; therefore, it is advisable that all lesions are ­submitted for histological confirmation.1,2

Follicular cysts

Chapter

34

Cutaneous metaplastic synovial cyst  1584 Pilonidal sinus  1584 Dental sinus  1585 Mucinous syringometaplasia  1585 Umbilical polyp and granuloma  1586 Pseudocyst of the auricle  1587

Epidermoid cyst Clinical features Epidermoid (epidermal, infundibular) cysts, which occur particularly on the face, neck, and upper trunk, are believed to result from damage to the ­pilosebaceous units.1 The vulval labia majora and scrotum are also sites of predilection. Young and middle-aged adults are most often affected and the sexes are involved equally. Epidermoid cysts present as smooth dome-shaped swellings a few millimeters to a few centimeters across (Fig. 34.1). A ­punctum is usually present (Fig. 34.2).

Most cutaneous cysts are derived from the pilosebaceous unit. Thus epidermoid, pigmented follicular and vellus hair cysts and milia are each derived from the follicular infundibulum.1 Pilar (trichilemmal cysts) are believed to originate in the follicular isthmus of anagen hairs. Steatocystoma is a cyst of the sebaceous duct. Cystic pilomatrixoma is derived from hair matrix cells and hybrid cysts can originate from any of the above.1

Table 34.1 Classification of cutaneous cysts Keratinizing

Glandular

Epidermoid

Bronchogenic

Proliferating epidermoid

Thyroglossal duct

Hybrid cyst

Branchial

Verrucous

Cervical thymic

Epidermoid cyst of the sole

Ciliated

Comedonal

Median raphe

Milia Trichilemmal Vellus hair Steatocystoma Dermoid

Fig. 34.1 Epidermoid cyst: a typical dome-shaped swelling with two puncta. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

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Cutaneous cysts

A

Fig. 34.2 Epidermoid cyst: close-up view of a punctum. By courtesy of the Institute of Dermatology, London, UK.

The presence of multiple lesions may suggest the possibility of Gardner's syndrome, which includes polyposis coli, jaw osteomas, and intestinal fibromatoses in addition to cutaneous cysts.2,3 Less frequently, patients may manifest lipomas, pilomatrixomas (including epidermoid cysts with pilomatrical lining), and leiomyomas. Multiple and often large epidermoid cysts are sometimes seen as a complication of ciclosporin therapy in transplantation recipients.4,5 Multiple epidermoid cysts have also been described in association with imiquimod therapy.6 Epidermoid inclusion cysts may also complicate penetrating trauma to the skin, such as by a sewing needle, with resultant implantation of squamous epithelium into the dermis (Fig. 34.3).7,8 Lesions may rarely develop after genital mutilation,9 after vaccination (BCG),10 and after cosmetic surgical procedures including penile girth enhancement therapy11 and abdominoplasty.12

B

Fig. 34.4 (A, B) Epidermoid cyst: in this excision specimen, the punctum is clearly visible.

Pathogenesis and histological features Epidermoid cysts are unilocular, spherical, and are lined by an epidermislike epithelium including a granular cell layer (Figs 34.4–34.6).1 Exceptional multilocular lesions may occur.13 The cyst contents of laminated keratin are believed to represent follicular infundibular derivation (the ­nonimplantation

Fig. 34.5 Epidermoid cyst: a solitary lesion is present in the dermis.

Fig. 34.3 Epidermoid cyst: this implantation variant is at a characteristic site. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

variant). In older lesions the lining is often somewhat attenuated. Acute inflammation may result in the subsequent disruption of the cyst wall, with the development of an intense foreign body giant cell reaction (Fig. 34.7). Sometimes this may be so marked that it completely destroys the cyst and only focal dermal collections of keratin fragments remain (Fig. 34.8). It is

Follicular cysts

A

B

Fig. 34.6 Epidermoid cyst: (A) in this example, the punctum is present; (B) the cyst wall is composed of squamous epithelium and includes a granular cell layer. Note the laminated keratin.

Fig. 34.7 Epidermoid cyst: rupture is associated with a foreign body granulomatous response. In the center of the field, a giant cell contains a keratin fragment.

A

B

Fig. 34.8 Epidermoid cyst: (A) in this almost healed lesion, residual keratin lamellae, as seen in the center of the field, are all that is left of the ruptured cyst; (B) these may be highlighted by the Lendrum's phloxine tartrazine reaction.

not clear whether bacteria play an important role in the development of ­inflammation in epidermoid cysts. A study from Japan found an increased incidence of anaerobes in inflamed lesions as opposed to those without inflammation.14 It is not clear, however, whether this is the result of colonization or a true infection. Occasionally, the cyst lining may show epidermoid and focal trichilemmal keratinization. In the rare hybrid cyst there is epidermoid keratinization in the superficial half of the cyst and trichilemmal in the lower.15 Exceptionally, a pigmented variant containing multiple terminal hair shaft fragments may be encountered (pigmented follicular cyst).16,17 A case with numerous keratin spherules has been reported.18 In patients with Gardner's syndrome, the cyst lining occasionally shows focal basaloid cell proliferation with ghost cell change, as seen in pilomatrixoma (Fig. 34.9).19,20 These were once thought to be pathognomonic of Gardner's syndrome, but they have now been described outside of this context, including a case arising in a background of nevus sebaceous.21,22 Thus, while highly suggestive, these cannot be considered pathognomonic. Epidermoid cysts not uncommonly coexist with melanocytic nevi. This is of particular importance, as the resulting increase in size of the cyst may raise clinical suspicion of melanoma.23,24 Most nevi are banal and dermal but cysts associated with compound nevi, congenital nevi, dysplastic nevi, blue nevi, and spindle cell nevi of Reed have also been documented.24 Malignant tumors may rarely develop within the wall of an epidermoid cyst including basal cell carcinoma, squamous cell carcinoma, and squamous cell carcinoma in situ (Fig. 34.10).25–30 There are also single case

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Cutaneous cysts reports describing an epidermoid cyst in association with Paget's disease and cutaneous neuroendocrine carcinoma.31,32 There have been no cases reported of melanoma arising in cutaneous lesions, although in situ melanoma associated with an adjacent cutaneous melanoma has been reported to colonize an epidermoid cyst and there is a single report of it arising in a noncutaneous cerebellopontine angle epidermoid cyst.33,34 Pilomatrixoma (in the absence of Gardner's syndrome) in conjunction with an epidermoid cyst has also been documented.35 Because epidermoid cysts with malignant change cannot be clinically reliably distinguished from their extremely common benign counterpoints, histologic examination of all such cysts is recommended.36 Epidermoid cysts showing features of a range of cutaneous dermatoses have been described.37 These include psoriasis, lichen planus, and Darier's disease.38–40 Changes of epidermolytic hyperkeratosis and involvement by molluscum contagiosum have also been described.41,42 Human ­papillomavirus (HPV) associations are described below (see verrucous cyst). A

Proliferating epidermoid cyst Clinical features Proliferating epidermoid cyst is rare and poorly documented, the majority of cases, in fact, describing the pilar/trichilemmal variant.1,2 There are, however, very occasional reports of this entity, of which the comprehensive review from the Armed Forces Institute of Pathology is the most informative.3,4 The tumor shows a predilection for males (1.8:1) and although a wide variety of sites may be affected, the majority appear to present on the pelvic area, scalp, and trunk in descending order of frequency.4 Most patients are middle aged or elderly (range: 21–88 years, mean: 54 years). Occasional patients document the presence of a lesion for several decades, giving support to the concept that the resulting tumor has developed within a preexistent benign epidermoid cyst.4 In this series, proliferating epidermoid cyst was associated with a 20% recurrence rate but metastases were not encountered.4

B

Fig. 34.9 (A, B) Epidermoid cyst: the lower half of the cyst wall shows matrical differentiation.

Histological features By definition, focal cyst wall lined by stratified squamous epithelium and showing a granular cell layer with epidermoid/infundibular keratinization must be evident. The proliferating component is variable and ranges from well-differentiated squamous epithelium with conspicuous squamous eddies reminiscent of inverted follicular keratosis through to multicystic, keratotic, and verrucous lesions.4 Rarely, frank invasive carcinoma is encountered.

Hybrid cyst

Fig. 34.10 Epidermoid cyst: in this example, the epithelial wall shows the features of carcinoma in situ.

The term hybrid cyst was originally introduced to describe a cyst in which the upper half showed features of an epidermoid cyst whereas the lower ­portion comprised a trichilemmal cyst.1 There was a sharp distinction between the two linings. The spectrum was subsequently expanded to include cysts with a variety of dual linings including epidermoid cyst and pilomatrixoma, trichilemmal cyst and pilomatrixoma, epidermoid with both trichilemmal and pilomatrical features, and eruptive vellous hair cyst with trichilemmal cyst.2–4 There are also a number of reports of cysts combining the features of eruptive vellus hair cyst and steatocystoma.2,5–8 These are intriguing, given the potentially shared molecular pathogenic features of these processes likely involving keratin 17. Epidermoid cyst with apocrine hidrocystoma and pilomatrixoma with cystic trichilemmoma have also been described.9,10 Hybrid cysts with follicular and apocrine differentiation seem to be more common on the eyelid.11 Since all of these cysts are derived from various components of the hair follicle, their combination is not surprising. The characteristic cyst of Gardner's syndrome, in which ­epidermoid ­features merge with ­pilomatrixoma, can also be regarded as a type of hybrid cyst.12

Follicular cysts

Verrucous cyst

of particular interest as it has been shown to be associated with HPV ­infection in some cases.5 An exceptional giant lesion extending from the sole into the ­dorsum of the foot through the interosseous muscles has been described.8

Clinical features The verrucous cyst is a variant of epidermoid cyst associated with human papillomavirus (HPV) infection.1–5 Adults are affected and lesions may ­present at a wide variety of sites although the face, back, and (to a lesser extent) the arms and chest are most often involved.5 The sexes are affected equally. The cysts show no particular distinguishing clinical features.4

Pathogenesis and histological features Verrucous cysts are associated with HPV infection as determined by polymerase chain reaction.3,4 Thus far, HPV antigens have not been identified with immunohistochemistry. The subtype is unknown in most cases, but a single lesion with the HPV type 59 has recently been described.6 An unusual case of multiple verrucous cysts associated with epidermodysplasia verruciformis-associated HPVs (20, 24, alb-7, and 80) and epidermodysplasia verruciformis-like epidermal lesions in the setting of idiopathic CD4 lymphopenia (immunosuppression) has been described.7 Histologically, verrucous cyst shows focal features of a typical epidermoid cyst and rarely features of a trichilemmal cyst.8 The greater part of the cyst wall, however, is lined by papillomatous, acanthotic squamous epithelium with hyperkeratosis, parakeratosis, and conspicuous hypergranulosis. Keratohyaline granules are enlarged and irregular, and occasionally koilocytes are seen.2,3,5 In some lesions, the epithelium consists of an admixture of basaloid and squamous cells, and squamous eddies are prominent.3 A lymphohistiocytic infiltrate is sometimes present in the surrounding dermis.

Histological features Histologically, it is characterized by the presence of eosinophilic intracytoplasmic inclusions in the wall of the cyst and vacuolated cells in the keratin layer.2,5 Parakeratosis with absence of the granular cell layer is sometimes noted in the more superficial portion of the cyst.9 The cyst is filled with orthokeratotic keratin. Immunoperoxidase confirms the presence of viral antigen and inclusions have been identified ultrastructurally.2,5 HPV 60 has been demonstrated.10

Comedonal cyst Clinical features Acne, including chloracne (a condition characterized by the development of acneiform lesions in patients following exposure to the halogenated hydrocarbons), is the commonest cause of comedone formation. Comedones are follicular retention cysts.1 When they open directly onto the surface, a blackhead is visible clinically (Fig. 34.11). If the ostial canal is blocked, pigmented keratin is not visible and the medium-sized whitish papule is classed as a closed comedone or whitehead (Fig. 34.12).

Pathogenesis and histological features

Epidermoid cyst of the sole

Follicular dilatation and hyperkeratosis (follicular plugging) are common ­features of facial skin. The development of an acne microcomedone is a ­further extension of that process. The fully developed blackhead contains abundant laminated keratin and cellular debris (Fig. 34.13). A large sebaceous gland with a small hair may be attached to the widely distended but patent follicle. If the lesion persists, the sebaceous gland and hair commonly atrophy (Fig. 34.14). A histological section through a closed comedone will often miss the blocked connection with the epidermis and sometimes a blackhead may appear as an intradermal cyst.

Clinical features

Differential diagnosis

Epidermoid cyst of the sole has been described mainly in the Japanese.1–5 A single case report documents the lesion in a non-Japanese.6 Involvement of the palm has also been reported.4 The cyst likely represents an implantation variant.7 It is

Solar comedones (Favre-Racouchot disease) occur as a clinical triad of cysts, comedones, and elastosis around the orbit and malar areas of elderly patients, and are due to prolonged exposure to sunlight (Fig. 34.15).2 Rarely, a

Differential diagnosis Verrucous cyst differs from HPV-associated epidermoid cysts of the sole which predominantly affect the Japanese and in which the morphology of the wall of the cyst is that of a typical epidermoid cyst.9,10

Fig. 34.11

A

B

Acne vulgaris: (A) typical open comedones (blackheads); (B) close-up view. (A) By courtesy of R.A. Marsden, St George's Hospital, London, UK; (B) by courtesy of the Institute of Dermatology, London, UK.

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Cutaneous cysts

Fig. 34.12

Fig. 34.15

Acne: numerous closed comedones (whiteheads) are present on this patient's cheek and chin. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Solar comedones: note the presence of blackheads and multiple yellow cysts.

­plaquelike lesion may be seen.3 Large thin-walled open and closed comedones are present in the upper dermis, accompanied by marked solar elastosis.4 A small series of cases of what is regarded as a variant of Favre-Racouchot disease and including epidermoid cysts with vellus hairs and solar elastosis and presenting on the ears has been described.5 Open and closed comedones are also a feature of the congenital conditions familial comedones and familial dyskeratotic comedones. Both of these have an autosomal dominant mode of inheritance; the former is characterized by a greater number of lesions and an absence of dyskeratosis.6–8. Rarely, latestage follicular mucinosis and discoid lupus erythematosus may feature large thin-walled comedones as the dominant histological component.

Milia Clinical features

Fig. 34.13 Open comedone: the lesion consists of a cystically dilated hair follicle containing abundant keratin.

Fig. 34.14 Open comedone: the wall is composed of squamous epithelium. In addition to keratin, there are three pale-staining vellus hairs. Note the atrophic sebaceous gland.

Milia are common superficial keratinous cysts that present as white or yellow dome-shaped nodules measuring 1–3 mm in diameter.1,2 They may represent primary lesions when no cause can be identified or secondary variants usually following skin trauma or other injury. Primary milia are seen in up to 50% of newborns and present on the face, upper trunk, and extremities.3 These typically regress spontaneously. Children and adults can also be affected, when lesions are most often ­apparent on the face (forehead, eyelids, and cheeks) and the external genitalia (Fig. 34.16).3 Possible association of persistent infantile milia with steatocystoma multiplex and eruptive vellus hair cysts has also been suggested.4 Secondary milia may complicate a wide range of conditions including follicular mucinosis, folliculotropic mycosis fungoides, lichen sclerosus, radiotherapy, herpes zoster infection, leishmaniasis, severe burns, dermabrasion, chemical peeling, cutaneous local steroid therapy, adverse drug reactions (e.g., benoxaprofen), and contact dermatitis.3,5–15 Milia are also a feature of a number of subepidermal blistering disorders including dystrophic epidermolysis bullosa, epidermolysis bullosa acquisita, porphyria cutanea tarda, and pseudoporphyria. They may also be a feature of a variety of familial dermatoses including Rombo's syndrome (facial anetoderma vermiculatum, telangiectasia, milia, hypotrichosis, acral erythema, cyanosis and tendency to develop trichoepitheliomas and basal cell carcinomata), Bazex-DupréChristol syndrome (follicular atrophoderma, congenital hypotrichosis, basal cell carcinomas), and familial multiple cylindromas, trichoepitheliomas, milia and spiradenomas.16–18 Rarely, milia present as a localized plaque variant (milia en plaque).3,19–25 Such lesions are most often described around the ears. A small number of cases involving the eyelids have been documented and there is one supraclavicular example.20 One case that developed in a background of ­pseudoxanthoma elasticum has been described.21 A further example in association with

Follicular cysts

Fig. 34.16 Milia: numerous typical pale small spherical lesions are present. The cheek is a characteristic site. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 34.17 Milia: the cysts are lined by keratinizing stratified squamous epithelium. A granular cell layer is present.

lupus erythematosus has also been reported.26 In the small number of documented cases, the sex incidence is equal and a wide age range has been affected (12–62 years). There is no racial predilection.23 Patients present with an edematous, erythematous plaque studded with numerous milia. Very occasional examples of eruptive milia have been described including rare cases in children.4,27–29 Recently these have been classified into spontaneous and autosomal dominant familial variants.30 They may also represent a component of a genodermatosis.4

Pathogenesis and histological features Milia consist of miniature epidermoid cysts located in the superficial dermis just underneath the epithelium (Fig. 34.17). Attachment to a vellus hair follicle is often seen in the newborn variant. Secondary lesions may be related to hair follicles or an eccrine sweat duct. The latter are typically seen in milia associated with scarring blistering diseases. The etiology of milia en plaque is unknown although spectacles, earrings, and perfume have been suggested as possible causes.22–24 In this variant, a background dense T-cell lymphocytic infiltrate is typically present.22,23

Trichilemmal cyst The outer root sheath of the hair follicle at the level of the follicular isthmus is recapitulated in the wall of trichilemmal (pilar) cysts.1–3 It has been suggested that these cysts should be renamed as isthmic-catagen cysts. Their origin is unknown, but it has been suggested that they are produced by budding off from the external root sheath as a genetically determined structural aberration. Familial occurrence is seen in 75% of patients, in a pattern suggesting autosomal dominant inheritance.4

Clinical features Trichilemmal cysts are found on the scalp in 90% of cases; they are solitary in 30% and multiple in 70% (Fig. 34.18).4 Unusual sites such as the pulp of a finger have been reported.5 They present as smooth, yellowish, dome-shaped intradermal swellings and are more common in females (Fig. 34.19). In contrast to epidermoid cysts, they are characteristically devoid of a punctum. It should be noted that the term ‘sebaceous cyst’ favored by many clinicians

Fig. 34.18 Trichilemmal cyst: note the characteristic dome-shaped swelling on the scalp, a typical site. By courtesy of A. du Vivier, MD, King's College Hospital, London, UK.

is a misnomer because such lesions represent either epidermoid or trichilemmal cysts. Typically, the cyst is encapsulated and uncomplicated lesions readily ‘shell out’ at surgery.4 Acute inflammation is uncommon and when it does occur is usually of nonbacterial origin; its presence makes excision more difficult, with an increased likelihood of rupture. An exceptional case of a lesion presenting as an organoid nevus, following Blaschko's lines and showing multiple trichilemmal cysts on histologic examination, has been described as trichilemmal cyst nevus.6

Histological features The cyst is surrounded by a fibrous capsule against which rests a layer(s) of small dark-staining basal cells. These merge with characteristic squamous epithelium composed of pale keratinocytes, which increase in height as they mature and transform abruptly into solid eosinophilic-staining keratin without forming a granular cell layer (Figs 34.20–34.22). Occasionally, small foci of

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Cutaneous cysts

Fig. 34.19

Fig. 34.20

Trichilemmal cyst: there are yellowish circumscribed nodules on the upper eyelids. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Trichilemmal cyst: this shows the typical macroscopic appearance of cheesy lamellated contents.

epidermal keratinization (i.e., with a granular cell layer) may also be identified. Calcification occurs in 25% of lesions, regardless of the age or size of the cyst, and cholesterol clefts occur in up to 90% (Figs 34.23, 34.24).1,4 Secondary inflammation is manifest as an influx of inflammatory cells into the lumen of the cyst, in contrast to the granulomatous response that may surround an epidermoid cyst. In a small percentage of cases there is budding of tiny daughter cysts from the parent.7 Very rarely, sebaceous and apocrine differentiation are found in the cyst wall.8 Exceptional cases of other neoplasms such as Merkel cell carcinoma colonizing or arising in a trichilemmal cyst have been reported.9,10

f­ lesh-colored or reddish-brown papules, 1–5 mm across, particularly over the parasternal area, although the distribution may be quite widespread.4 A generalized ­distribution has recently been documented.5 An exceptional case mimicking a nevus of Ota has been described.6 Lesions may rarely be unilateral.7 Occasional lesions are umbilicated, and squeezing may express white caseous material. Further cases have expanded the condition to include an inherited (autosomal dominant) variant, which may or may not be manifest at birth and is more likely to occur over the extensor aspects of the limbs.3,8 A facial form and a patient presenting with a periorbital distribution have been described.9–11 Spontaneous involution is not uncommon.2,12 Vellus hair cysts have occasionally been associated with renal failure and a number of genodermatoses including pachyonychia congenita, anhidrotic ectodermal dysplasia, hidrotic ectodermal dysplasia and, rarely, Lowe syndrome (oculocerebrorenal syndrome characterized by Fanconi-type renal failure, mental retardation and ocular abnormalities).13–17 Occasionally, solitary lesions are encountered.

Vellus hair cysts Clinical features Vellus hair cysts were originally reported in children and young adults of both sexes.1–4 The sex distribution is equal and there is no racial ­predilection. Patients present with numerous asymptomatic, discrete, soft,

Fig. 34.21 A

B

(A, B) Trichilemmal cyst: these views show the homogeneous eosinophilic contents. Note the distinct basal cell layer.

Follicular cysts

Pathogenesis and histological features Eruptive vellus hair cysts most probably develop as a consequence of ­occlusion of the infundibulum of vellus hairs with resultant cystic dilatation and retention of keratinous debris and vellus hairs.2 The primary cause of the obstruction is unknown. It has also been proposed that they represent ­follicular hamartomas.8 Studies indicate that both eruptive vellus hair cysts and ­steatocystomas express keratin 17, with the latter also expressing ­keratin 10.18,19 This overlap in keratin expression may help explain the underlying ­similarities and perhaps overlapping features of these two lesions, but this opinion is not universal, their exact relationship remains to be elucidated.20–22 The characteristic histology is that of a mid-dermal cyst ­containing laminated keratin and many vellus hairs (Figs 34.25, 34.26).2,4,12 The ­epithelial lining consists of several layers of squamous epithelium, often with a granular cell layer. Sometimes the cyst is in continuity with the epidermis, an atrophic follicle or a pilomotor muscle.3,4,12 Vellus hair cysts are more likely to open onto the surface in the congenital variant. Occasionally the cyst ruptures and there is an associated foreign body giant cell reaction. Fig. 34.22

Differential diagnosis

Trichilemmal cyst: the cyst wall is composed of squamous epithelium and a granular cell layer is not present. The most superficial cells are larger, vertically orientated, and have abundant cytoplasm. Keratinization is abrupt.

Eruptive vellus hair cysts show very marked clinical overlap with steatocystoma multiplex and can only be distinguished by histological analysis.23 Steatocystoma is characterized by an epidermoid lining without a granular

Fig. 34.23

Fig. 34.25

Trichilemmal cyst: basophilic granular calcification is a frequent histological finding.

Fig. 34.24 Trichilemmal cyst: the empty spaces (cholesterol clefts) are a common feature of this lesion.

Vellus hair cyst: this thin-walled cyst is present in the mid dermis.

Fig. 34.26 Vellus hair cyst: on high power, the lumen contains numerous vellus hairs.

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Cutaneous cysts cell layer. The innermost aspect of the cyst wall is covered by an undulating eosinophilic cuticle. Sebaceous glands are present in the wall of the cyst or in the immediate vicinity. Sometimes, however, patients have both types of cyst simultaneously and occasionally there are overlapping histological features sometimes constituting a hybrid cyst.24,25 As noted above, differential keratin expression has been shown to distinguish the two cysts. Thus vellus hair cyst expresses K17 but not K10 whereas steatocystoma expresses K17 and K10.26 Interestingly, mutations in the KRT17 gene can cause both pachyonychia congenital type 2 and also a condition very similar or identical to steatocystoma multiplex.27,28 The relevance of these findings to steatocystoma simplex and vellus hair cysts, if any, remains to be determined.

Dermoid cyst Clinical features Dermoid cysts result from the sequestration of cutaneous tissues along embryonal lines of closure.1–5 The most common clinical appearance is that of a single nontender small subcutaneous nodule at birth on the lateral aspect of the upper eyelid (Fig. 34.27). Although slow enlargement is the rule, sometimes a sudden increase in size may occur, bringing the lesion to attention at a later age. Other potential sites of dermoid cysts include the midline of the neck, nasal root, nose, forehead, the mastoid area, anterior chest, and scalp.3,6,7 The last is a particularly important site as the lesion may very occasionally show intracranial extension (dumbbell dermoid).3,4 Midline occipital lesions are most often affected.3 Dermoid cysts may also present on mid chest, sacrum, perineum, and scrotum.5 Dermoid cysts are also encountered in deeper noncutaneous sites. Infection of a cranial dermoid cyst is a serious development as it may be complicated by central nervous system involvement.3 Squamous cell carcinoma very rarely develops in the wall of the cyst.8,9 There are occasional reports of familial dermoid cysts, including one ­family associated with midline cleft lip.10–12

Pathogenesis and histological features The unilocular cysts are usually subcutaneous and may be attached to the periosteum. They are lined by stratified squamous epithelium with associated hair follicles and sebaceous glands (Fig. 34.28). Eccrine sweat glands are present in 35% of cases and apocrine glands in 15%. Smooth muscle can be present but – in contrast to benign cystic teratoma – cartilage and bone are not described. Some authors propose an embryological origin for these cysts, particularly in the nasal form.13 Antenatal diagnosis has been reported.10

Fig. 34.28 Dermoid cyst: the cyst is lined by stratified squamous epithelium. Note the numerous sebaceous glands.

Differential diagnosis Dermoid cyst should be distinguished from congenital dermoid fistula, which presents at birth as a superficial fistula tract (Figs 34.29, 34.30).14–16

Cutaneous mature cystic teratoma Cutaneous mature cystic teratomas are exceptionally rare but lesions presenting on the face, neck, and back have been documented.1–3 To establish the diagnosis, representative elements from ectoderm, endoderm, and mesoderm should be identifiable.

Glandular cysts Bronchogenic cyst Clinical features Bronchogenic cysts presenting in the skin are very rare, with fewer than 70 cases reported.1–14 There is a marked predilection for males (4:1).13 Most are situated on the precordium or overlying the suprasternal notch and are usually present at birth.1–3 Occasionally, they are located about the shoulder, back, scapula, neck, abdomen or chin or present at a later age.4 Clinical presentation is variable and includes cutaneous cystic nodules, sinuses, and even a papillomatous growth.4,5 Occasionally, the cysts drain a mucinous fluid.1,8 Most are asymptomatic but some are tender or painful. Exceptionally, multiple lesions may be seen.15

Pathogenesis and histological features

Fig. 34.27 Dermoid cyst: note the swelling adjacent to the upper eyelid – the external angular dermoid cyst. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Bronchogenic cysts are believed to form from buds or diverticula that separate from the foregut during the development of the tracheobronchial tree; they may be intrapulmonary or peripheral. Cutaneous bronchogenic cysts may result from subsequent sequestration outside the chest cavity following fusion of the mesenchymal bars of the sternum or else from active migration prior to fusion.13,14 Lesions overlying the scapula likely arose before the scapula developed, at the sixth week of gestation.6 The cutaneous bronchogenic cyst is situated within the dermis or subcutaneous tissue and usually its lining is thrown into small folds. The epithelium is invariably pseudostratified cuboidal or columnar and ciliated, with mucus-secreting goblet cells in about 50% of cases.2,13 Nonciliated cuboidal, columnar, and stratified squamous epithelium may also be identified. Smooth muscle supports the mucosa in 8% of cases.1,12,13 Lymphoid follicles are found in only 25% of cases and then appear to be part of a secondary inflammatory response.1 Seromucinous glands are also sometimes present.2,5,12 Cartilage is

Glandular cysts

Fig. 34.29

A

Median nasal dermoid fistula: (A) on the dorsum of the nose is an erythematous crateriform depression; (B) the presence of protruding white hairs is characteristic. By courtesy of D. Shuttleworth, MD, Chichester, UK.

B

c­ ommonly found in the midline of the neck in the region of the hyoid bone as a fluctuant swelling up to 3 cm in diameter. It characteristically moves with swallowing.10 The development of an associated sinus is a not ­uncommon complication. Very occasional familial variants have been reported.11 Most of these have displayed an autosomal dominant mode of inheritance although recessive forms are also recognized.12–14 Although the number of documented families is small, there appears to be a predilection for females.11 Recurrence following surgery is low, varying from 2% to 6% of cases.11,15

Pathogenesis and histological features Thyroglossal duct cysts, which are variably lined by cuboidal, columnar or stratified squamous epithelium, are frequently accompanied by an epitheliallined tract.1 Ciliated epithelium is also often present. The adjacent tissues may show mucous glands, thyroid follicles, and a heavy lymphocytic infiltrate (Fig. 34.31). Occasionally, skin appendages (including hair follicles and

Fig. 34.30 Median nasal dermoid fistula: the fistula, which communicates with the surface epidermis, is lined by hair-bearing epithelium. By courtesy of D. Shuttleworth, MD, Chichester, UK.

evident in a minority of cases.4,6,10,13 Not all of these features are necessarily present in any one particular cyst and the diagnosis may then be in part dependent upon clinicopathological correlation.8,9 Cutaneous lung tissue heterotopia in which fully developed bronchioles and alveoli are present can be regarded as a variant.16 Immunohistochemistry has been only rarely documented. The lining ­epithelial cells express cytokeratin (AE1/AE3) but not carcinoembryonic antigen (CEA).13

Thyroglossal duct cyst Clinical features The thyroglossal duct cyst, which is a congenital anomaly representing a vestigial remnant of the tubular thyroid gland precursor, may present at any age including adulthood, but children are most often affected.1–9 It is

Fig. 34.31 Thyroglossal duct cyst: the cyst is lined by tall columnar epithelium. Note the colloid-containing thyroid follicles.

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Cutaneous cysts sebaceous and sweat glands) are additionally found, resulting in histological overlap with a dermoid cyst – the so-called mixed or hybrid cyst.2,6 Smooth muscle is not present. Occasionally, histological examination may reveal ectopic thyroid gland, thyroid adenoma and, in approximately 1% of cases, carcinoma.16–24 The last are most often papillary adenocarcinoma but follicular and squamous variants have also been described.10 They sometimes represent an incidental ­finding following excision.

Branchial cyst Clinical features The branchial (lymphoepithelial) cyst presents as a swelling near the angle of the jaw anterior to the sternomastoid muscle, most often at the junction of its upper one-third and lower two-thirds.1–4 The cyst is asymptomatic and does not move on swallowing.3 Patients are most commonly in their second or third decade. The sexes are affected equally.3 Occasionally, bilateral cysts are present and then a familial tendency is sometimes in play.5

Pathogenesis and histological features The origin of the cyst is uncertain although it is generally considered to represent a developmental anomaly of the branchial arches. Possibilities include incomplete obliteration of branchial mucosa, remnants of the precervical sinus or an origin from the thymopharyngeal duct.3,6 Cystic degeneration of cervical lymph nodes has also been suggested.6 It is lined by stratified squamous or pseudostratified ciliated columnar epithelium (Fig. 34.32). Its wall typically contains lymphoid tissue in which germinal centers are usually conspicuous.3 Occasionally, seromucinous glands may also be evident.2

Cervical thymic cyst Clinical features Cervical thymic cysts mostly affect children and present in the anterior triangle along a line from the angle of the mandible to the manubrium sternae.1–6 The left side of the neck is affected in 68% of cases, the right side in 25% of cases, and the midline in 7% of cases.3 Extension into the mediastinum is common.5 The cyst may enlarge on Valsalva maneuver.

Pathogenesis and histological features The cyst develops from remnants of the thymopharyngeal duct which persist as the thymic precursor descends into the mediastinum.3,4

Fig. 34.32 Branchial cyst: the wall is composed of stratified squamous epithelium. Note the intense lymphocytic infiltrate.

Cysts are unilocular or multilocular and contain clear, brown, red or gelatinous material.4,5,7 The lining epithelium is variably stratified squamous, cuboidal, columnar, pseudostratified or ciliated.1,3 Thymic remnants including Hassall's corpuscles and cholesterol granulomata are also present.1,3,8 The adjacent fibrous capsule often contains lymphocytic aggregates.2

Cutaneous ciliated cyst Clinical features The term cutaneous ciliated cyst (cutaneous müllerian cyst) most often refers to a solitary lesion which presents shortly after the menarche on the limb of young females (12–42 years).1–12 The thigh, buttock, calf, and foot are affected, in decreasing order of frequency. The cysts are located in the deep dermis or subcutaneous tissue and are usually asymptomatic.4 Occasionally, they become inflamed and painful and sometimes they rupture. Identical lesions have been described on the abdominal wall.13,14 Lesions have occasionally been described in males and at atypical sites including the back, shoulder, scalp, and cheek.15–22 These might better be ­classified as separate, distinct entities.

Pathogenesis and histological features Two theories have been proposed to explain the development of ciliated cysts. Those lesions which present on the limbs of young females are generally thought to be of müllerian (paramesonephric) derivation, their presence representing a migration abnormality of fetal development (heterotopia).2,3 In support of this hypothesis, authors have cited the close proximity of the paramesonephric duct to the developing limb bud, the striking predilection for females, the histological similarity between the lining epithelium and that of the fallopian cord and the absence of sweat glands in the near vicinity of the cyst wall.13 Cysts arising at other sites and in males may represent metaplasia of the lining of a pre-existent simple cyst of sweat duct derivation or else an entirely different histogenesis (see differential diagnosis).5 The cyst is unilocular or multilocular and has intraluminal papillary projections (Fig. 34.33). The lining, which is similar to that of normal fallopian tube, consists of cuboidal to columnar ciliated epithelium with frequent pseudostratified foci (Fig. 34.34).6 Intercalated dark cells are also occasionally evident.4 Squamous metaplasia is often a feature. Mucin-secreting cells have very exceptionally been described and there are one or two reports of apocrine-like features.2,8,11 Deep to the epithelium lie well-vascularized parallel bundles of collagen, but smooth muscle is not a feature.1 Ultrastructurally, the cilia have characteristic morphology with a central pair of microtubules, nine radially orientated pairs of microtubules, basal bodies, and cross-striated rootlets.7,8,13 Microvilli are sometimes evident.8,13

Fig. 34.33 Cutaneous ciliated cyst: note the papillary projections in the lower left of the field.

Glandular cysts the ventral aspect of the penis.1–10 The glans is the most commonly affected site.5 Lesions may also be seen along the ventral surface of the scrotum and on the perineum.11–16 The cyst does not communicate with the urethra. Recurrences are uncommon.1

Pathogenesis and histological features

Fig. 34.34 Cutaneous ciliated cyst: the wall is lined by tall columnar cells. Cilia are evident in the center of the field.

The cyst is generally believed to result from anomalous fusion of the genitourethral folds and urethral plate, with resultant misplaced nests of urethral epithelium in the ventral midline.11 Alternatively, some examples may result from misplaced periurethral glands (mucoid cyst) or aberrant urethral buds.2,5 Similar malfusion of the labial–scrotal folds results in scrotal and perineal variants.11 Histologically, the cyst lining is variable. In most reports it consists of pseudostratified columnar epithelium, 1–4 cells thick (Fig. 34.35).1,2,5 Uncommonly, diastase-resistant, periodic acid-Schiff (PAS) positive mucinous and stratified squamous epithelia are present (Fig. 34.36).1,8,12 Metaplastic ciliated variants and admixed goblet cells are very occasionally seen.9,10,12 Exceptionally, pigmented variants associated with intraepithelial dendritic melanocytes may be encountered.6 One publication described linear small epidermoid cysts extending along the median raphe of the scrotum to the anal verge of a male infant. These may have resulted from entrapped squamous epithelial rests during the development of the raphe scroti.11

The lining cells express keratin and epithelial membrane antigen (EMA) but not CEA or desmin and smooth muscle actin (SMA).8–10,13,14 One case, which presented on the cheek of a male and demonstrated an S-100 protein and SMA positive myoepithelial layer, would be better classified as a sweat gland hidrocystoma with cilia metaplasia.20 Desmin expression restricted to the apical aspect of the ciliated cells has been documented in one case.8 Estrogen and progesterone receptors may be positive and S-100 protein is occasionally present.8,11,13 Single case reports also document expression of amylase and dynein.3,10

Differential diagnosis Ciliated epithelial cells are also seen in bronchogenic, thyroglossal duct, branchial, and thymic cysts. They may also be present in mature cystic teratoma.

Median raphe cyst Clinical features Median raphe cysts (genitoperineal raphe cyst, parameatal cyst) are usually up to 1 cm across, contain clear fluid, and are most often noticed in the first three decades of life as an asymptomatic nodule, sometimes translucent, on

A

Fig. 34.35 Median raphe cyst: low-power view showing papillary processes covered by columnar epithelium.

B

Fig. 34.36 Median raphe cyst: (A) the cyst is focally lined by mucus-containing epithelium; (B) the latter is PAS-positive (diastase-resistant).

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Cutaneous cysts The epithelial cells are CK7 and CEA positive, and CK20 negative.7,8 Focal neuroendocrine differentiation characterized by chromogranin and synaptophysin expression has been documented in two cases.8

Differential diagnosis The midline site, the predominant pseudostratification, and the lack of both decapitation secretion and a myoepithelial layer distinguish median raphe cyst from apocrine cystadenoma. In addition, median raphe cysts do not express human milk fat globulin 1 (HMFG-1).7

Cutaneous metaplastic synovial cyst Clinical features First described by González and coworkers in 1987, cutaneous metaplastic synovial cyst is an uncommonly reported lesion which usually follows surgical or other trauma.1–12 Patients present with an often tender dermal nodule adjacent to a scar and clinically diagnosed as a suture granuloma.1 Lesions draining serosanguinous fluid sometimes communicate with the surface epithelium. Exceptionally, multiple lesions may be encountered.7 Occasional examples have arisen without a history of trauma, most often in patients with severe rheumatoid arthritis.7,9 Two cases have presented in patients with Ehlers-Danlos syndrome.6,13 Lesions can occur at any site and there is no sex or age predilection.7

A

Pathogenesis and histological features Seyle originally showed that a synovium-like membrane could develop in the connective tissue of rats following its disruption by the subcutaneous injection of air.14 The experiment was later repeated and similar observations have been reported following implantation of various prosthetic devices.15–19 Cutaneous metaplastic synovial cyst is not a true cyst since it lacks an epithelial lining. It is located in the dermis underneath a sometimes thickened epidermis with which it occasionally communicates through a fistulous tract (Fig. 34.37).1 It contains multiple villous processes of two types: some are composed of hyalinized connective tissue covered by fibrin, whereas others are highly cellular and are lined by multilayered epithelioid cells (Fig. 34.38).1,4 The core of the second type is composed of admixed spindled and epithelioid cells and a mixed inflammatory cell infiltrate in which multinucleate giant cells are sometimes conspicuous. The lining cells  are devoid of atypia but multiple (normal) mitoses are sometimes present. The cyst is surrounded by chronically inflamed granulation and scar tissue.3

B

Fig. 34.38 (A, B) Metaplastic synovial cyst: the villi are covered by a layer of fibrin and vertically orientated spindle cells.

The epithelioid cells regularly express vimentin and occasionally CD68, lysozyme, and α1-antichymotrypsin.1,2,9 They are consistently negative for keratins, CEA, EMA, S-100 protein, SMA, and desmin.2,4,6,9

Pilonidal sinus Clinical features Pilonidal sinus (jeep disease) is a fairly common condition which shows a predilection for males (3–4:1) and presents most often in the second two decades.1–4 Caucasians are predominantly affected.3 The disease is very uncommon in blacks and exceptionally rare in Asians.3 Although patients may very rarely be asymptomatic, the typical history is of a chronic painful draining sinus or multiple sinuses affecting the base of the spine or the intergluteal cleft.2 Similar lesions have been described on the ear, scalp, chest, umbilicus, penis, vulva, and anal canal.5–11 Similar interdigital variants may be encountered in barbers, sheep-shearers, cow-milkers and dog-groomers as a reaction to hair embedded in the dermis.12–18 A subungual form has also been documented.19 There are a small number of reports of malignancy supervening in chronic sacrococcygeal pilonidal sinus.20–22

Pathogenesis and histological features Fig. 34.37 Metaplastic synovial cyst: this example presented as a fistulous tract following abdominal surgery. Villous processes are evident.

The sacrococcygeal variant appears to develop as a consequence of the patient's own hair penetrating the skin directly or via dilated follicular ostia.2–4 Free hair in the gluteal cleft rubs against the adjacent skin and the ­friction from movement of the buttocks propels the shaft through the epithelium

Mucinous syringometaplasia into the dermis where a foreign body granulomatous reaction results. It also results in a nidus for secondary infection and abscess formation.3 Superficially, the sinus is often lined by stratified squamous epithelium but towards the deeper reaches the wall consists of granulation and scar tissue surrounding intensely inflamed dermis containing one or more hair shaft fragments (Figs 34.39, 34.40). Abscesses are commonly present and foreign body multinucleate giant cells are usually conspicuous. The rare malignancies are generally well-differentiated squamous cell carcinomas.23 Morbidity and mortality are significant with local recurrence and metastasis in around a third of cases.20 Immunosuppression can augment or complicate malignant degeneration.21 Verrucous carcinoma has also been noted.22 Very occasionally, basal cell carcinoma has been described and there is one example of adenocarcinoma.24,25

Dental sinus Clinical features

A

Dental sinus tracts (odontogenic sinus) develop as a result of a periapical root infection or abscess.1–7 Clinically, they present as papules, nodules, cysts, abscess, ulcers or frank sinuses, usually associated with scarring.4 In some patients, the dental abnormality is silent, which can result in delay in diagnosis or misdiagnosis.8 Lesions may appear at a variety of sites on the head and neck but the chin, submental region, and the cheek are most often affected (Fig. 34.41).1 The lesion typically heals when the dental infection is cured.

Histological features Biopsy findings are non-specific and include a mixed inflammatory cell infiltrate with abscess formation and scarring, sometimes associated with a foreign body granulomatous component.

Mucinous syringometaplasia Clinical features Mucinous syringometaplasia (acral mucinous syringometaplasia, mucinous metaplasia, muciparous epidermal tumor) is a rare condition which most commonly presents on the soles of the feet or palmar aspect of the fingers as a 0.5–1.5-cm verrucous nodule, often diagnosed clinically as a viral wart.1–8 Sometimes a central dell or sinus is present and occasionally a ­history of

B

Fig. 34.40 (A, B) Pilonidal cyst: multiple hair shaft fragments are evident.

Fig. 34.41 Fig. 34.39 Pilonidal sinus: the sinus is lined by stratified squamous epithelium. Note the surrounding scar tissue, chronic inflammation, and hemosiderin deposition.

Dental sinus: the chin is a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.

­drainage of clear fluid is given.7 Lesions occur less often at a variety of other sites including the neck, chin, chest, buttock, knee, and penis, when the appearance varies from a small plaque to a nodule.6–8 Males are affected more often than females. The age at presentation is very variable, ranging from 15 to 66 years.6 Duration of the lesion ranges from months to decades. The lesion is almost certainly reactive and does not recur following complete excision.5–7

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Cutaneous cysts

Pathogenesis and histological features When first described, mucinous syringometaplasia was thought to represent a benign tumor – muciparous epidermal tumor.1 Currently, however, it is generally believed to represent a metaplastic phenomenon principally affecting the superficial eccrine ducts. The etiology is unknown although chronic trauma, pressure, and inflammation have been suggested as possible causes.6,7 Histologically, it is usually characterized by an epidermal invagination which is continuous at its base with eccrine ducts lined by nonkeratinizing squamous and mucin-containing epithelium (Figs 34.42, 34.43).5–7 These latter are sometimes seen in the epidermis and goblet cells are often evident.6 There is no significant pleomorphism and mitoses are sparse or absent.6,8 The adjacent epidermis is hyperkeratotic, focally parakeratotic, and markedly acanthotic.7 The underlying dermis commonly contains a heavy chronic inflammatory cell infiltrate with conspicuous plasma cells; fibrosis is often present.6 In some cases, the ducts are continuous with the underlying ­dermal eccrine sweat ducts.5 In one case, the changes extended to the eccrine ­secretory coil.3 In other cases, no such continuity is demonstrable.1,7,8 The mucin-containing cells are positive for diastase–PAS, mucicarmine, colloidal iron (with and without hyaluronidase), and Alcian blue at pH 1 and 2.5.5,7 Immunohistochemically, the mucin-containing cells express pankeratin, CAM 5.2, CEA, and EMA.6–8 They are GCDPF-15 and S-100 protein negative.6,7

rather sticky or mucinous and there may be damage to the surrounding skin, caused by acid or enzymes.2,3 The umbilical granuloma represents a granulation tissue polyp which sometimes develops in the umbilicus soon after separation of the cord. It is likely to be related to infection and presents as a 1.0-cm diameter or greater red polypoid lesion.

Histological features The polyp is associated with abrupt transition from stratified squamous to glandular epithelium of gastric, small intestinal or colonic type (Figs 34.44, 34.45).9 Smooth muscle components of the bowel wall are sometimes present. Pancreas has also been identified.8 Urachal lesions are composed of ­transitional cell epithelium.

Umbilical polyp and granuloma The congenital umbilical polyp represents persistence of the distal-most segment of the vitelline (omphthalomesenteric) duct, which connects the small intestine of the early fetus to the yolk sac. It usually disappears by about the seventh week of gestation. The commonest manifestation of persistence is Meckel's diverticulum, and the most serious consequence is an intestinal– umbilical fistula.1 Cutaneous manifestations include polyps, sinuses, and cysts.2–5,6 Less often, an umbilical polyp may arise from urachal remnants (urachal sinus or cyst).7

Fig. 34.43 Mucinous syringometaplasia: the epithelial lining contains numerous mucin-secreting cells. By courtesy of J. Grant, MD, Worthing Hospital, Worthing, UK.

Clinical features The lesions are usually noticed at birth, but presentation of sinuses and cysts may be delayed for days or years. Exceptionally, the lesion may not appear until late adulthood.8 There is a marked predilection for males of 6:1. The patient commonly presents with a bright red, 1–4-cm diameter pyogenic granuloma-like polyp on the umbilicus; secretions sometimes cause it to feel

Fig. 34.42

Fig. 34.44

Mucinous syringometaplasia: this lesion comes from the palm of the hand. Within the center of the defect are two epithelial-lined papillae. By courtesy of J. Grant, MD, Worthing Hospital, Worthing, UK.

Congenital umbilical polyp: in this example, the surface of the polyp is covered by large intestinal mucosa. Note the tubular glands. The fascicles of smooth muscle deep to the epithelium represent muscularis mucosae.

Pseudocyst of the auricle The granuloma is composed of inflamed vascular granulation tissue.

Pseudocyst of the auricle Clinical features Pseudocyst of the auricle (endochondral pseudocyst) is uncommon and shows a predilection for males.1–6 It presents as an asymptomatic, unilateral 1–5-cm swelling of the pinna.5 The scaphoid or triangular fossa of the antihelix is predominantly affected.7 Very occasionally, bilateral involvement may occur and exceptionally the disease involves children.8–10 Although there is a predilection for the Chinese, other Asian races and Caucasians can be affected.11,12 If untreated, it may result in severe ­deformity of the ear.

Pathogenesis and histological features

Fig. 34.45 Congenital umbilical polyp: note the continuity between the columnar and squamous epithelium.

A

The etiology is unknown. Low-grade trauma, ischemia, embryological defect of cartilage development and autoimmunity have been suggested as possible causes.6,13 A recurrent case has been described in the setting of atopic dermatitis.14 Grossly, the pseudocyst may contain 1–2 cc of serous fluid, rich in lactate dehydrogenase-4 and -5.3,15 It is suggested that the presence of high lactate dehydrogenase levels results from trauma to the cartilage.6 Histologically, the lesion presents as an intracartilaginous cystic space lacking an epithelial lining (Fig. 34.46). Degeneration of the adjacent cartilage is often evident. There are no significant inflammatory changes.

B

Fig. 34.46 Pseudocyst of the auricle: (A) cystic space within the cartilage; (B) the cavity is occupied by granulation tissue.

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Connective tissue tumors

Introduction  1589 Adipocytic tumors  1590 Benign adipocytic tumors  1590 Lipoma  1590 Angiolipoma  1592 Spindle cell lipoma  1593 Mammary-type myofibroblastoma of soft tissue  1594 Pleomorphic lipoma  1594 Chondroid lipoma  1594 Lipomatosis  1596 Adiposis dolorosa  1596 Nevus lipomatosus superficialis (Hoffman and Zurhelle)  1596 Piezogenic pedal papules  1597 Lipomatosis of nerve  1597 Lipoblastoma  1597 Hibernoma  1599 Fibrohistiocytic lipoma  1599 Lipofibromatosis  1599 Hemosiderotic fibrohistiocytic lipomatous lesion  1599

Malignant adipocytic tumors  1600 Liposarcoma  1600

Tumors of fibrous and myofibroblastic tissue  1604 Benign fibrous and myofibroblastic tumors  1604 Hypertrophic scar  1604 Keloid  1604 Nodular fasciitis  1606 Fibro-osseous pseudotumor of the digits  1609 Proliferative myositis  1609 Ischemic fasciitis  1610 Elastofibroma  1611 Fibroepithelial polyp  1612 Dermatomyofibroma  1613 Storiform collagenoma  1614 Nuchal fibroma  1615 Gardner fibroma  1615 Nuchal fibrocartilaginous pseudotumor  1615 Fibromatosis colli  1616 Calcifying fibrous tumor  1616 Myofibroma and myofibromatosis  1616 Fibroma of tendon sheath  1618 Desmoplastic fibroblastoma  1619 Superficial acral fibromyxoma  1620 Inclusion body fibromatosis  1620 Calcifying aponeurotic fibroma  1621 Ossifying plexiform tumor  1622

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for references and additional material

Knuckle pad  1622 Acquired digital fibrokeratoma  1623 Plaque-like CD34-positive dermal fibroma (medallion-like dermal dendrocyte hamartoma)  1623 Fibrous hamartoma of infancy  1624 Juvenile hyaline fibromatosis  1625

Locally aggressive fibrous lesions  1626 Palmar fibromatosis  1626 Plantar fibromatosis  1627 Penile fibromatosis  1627 Desmoid fibromatosis  1628

Low-grade malignant fibrous lesions  1629 Giant cell fibroblastoma  1629 Dermatofibrosarcoma protuberans  1630 Acral myxoinflammatory fibroblastic sarcoma  1635 Inflammatory myofibroblastic tumor  1636 Solitary fibrous tumor  1637 Giant cell angiofibroma  1639 Low-grade myofibroblastic sarcoma  1639

Malignant lesions  1640 Fibrosarcoma: adult variant  1640 Fibrosarcoma: infantile variant  1640 Sclerosing epithelioid fibrosarcoma  1640 Low-grade fibromyxoid sarcoma  1642

Fibrohistiocytic tumors  1643 Benign fibrohistiocytic tumors 1643 Fibrous papule  1643 Multinucleate cell angiohistiocytoma  1643 Dermatofibroma  1644 Deep benign fibrous histiocytoma  1654 Giant cell tumor of tendon sheath  1654

Low-grade malignant fibrohistiocytic lesions  1656 Giant cell tumor of soft tissues  1656 Angiomatoid fibrous histiocytoma  1656 Plexiform fibrous histiocytoma  1657 Atypical fibroxanthoma  1658

Malignant fibrous histiocytoma/ undifferentiated pleomorphic sarcoma  1662 Giant cell malignant fibrous histiocytoma  1662 Myxofibrosarcoma  1663 Inflammatory malignant fibrous histiocytoma  1664 Infiltrative subcutaneous malignant fibrous histiocytoma  1665

Neuroectodermal tumors  1665 Reactive lesions  1665 Traumatic neuroma  1665

Digital pacinian neuroma  1665 Morton's neuroma  1666

Hamartomas  1666 Mucosal neuroma  1666 Other hamartomas and choristomas  1666

Benign neoplasms  1667 Solitary circumscribed neuroma  1667 Epithelial sheath neuroma  1668 Schwannoma  1668 Schwannoma–perineurioma hybrid  1672 Neurofibroma  1672 Neurofibromatosis  1677 Granular cell tumor  1680 Gingival granular cell tumor of the newborn  1682 Nerve sheath myxoma (neurothekeoma)  1682 Cellular ‘neurothekeoma’  1684 Perineurioma  1685

Heterotopias  1687 Meningeal heterotopias  1687 Glial heterotopias  1689 Malignant peripheral nerve sheath tumor  1690 Peripheral primitive neuroectodermal tumor  1693 Clear cell sarcoma/melanoma of soft parts  1694

Smooth muscle tumors  1695 Hamartomas  1695 Congenital smooth muscle hamartoma  1695

Benign smooth muscle tumors  1696 Pilar leiomyoma  1696 Genital leiomyoma  1697 Angioleiomyoma  1698

Malignant smooth muscle tumors  1698 Leiomyosarcoma  1698

Striated muscle tumors  1701 Hamartomas  1701 Rhabdomyomatous mesenchymal hamartoma  1701

Benign striated muscle tumors  1701 Rhabdomyoma  1701

Malignant striated muscle tumors  1702 Rhabdomyosarcoma  1702

Tumors of vascular origin  1705 Benign tumors including reactive vascular proliferations and ectasias  1705 Intravascular papillary endothelial hyperplasia  1705 Reactive angioendotheliomatosis  1705 Glomeruloid hemangioma  1706

Introduction

Papillary hemangioma  1706 Nevus flammeus  1707 Cutis marmorata telangiectatica congenita  1708 Spider nevus  1708 Angioma serpiginosum  1708 Venous lake  1709 Hereditary hemorrhagic telangiectasia  1709 Generalized essential telangiectasia  1710 Cutaneous collagenous vasculopathy  1710 Angiokeratoma  1710

Congenital hemangiomas  1711 Rapidly involuting congenital hemangioma (RICH)  1711 Noninvoluting congenital hemangiomas (NICH)  1711

Capillary hemangioma and its variants  1711 Infantile hemangioma  1711 Infantile hemangioma with minimal or arrested growth (abortive hemangioma)  1712 Tufted angioma  1712 Verrucous hemangioma  1713 Cherry angioma  1714 Lobular capillary hemangioma  1714 Cavernous hemangioma  1716 Arteriovenous hemangioma  1718 Microvenular hemangioma  1718 Hobnail hemangioma  1718 Acquired elastotic hemangioma  1720 Cutaneous epithelioid angiomatous nodule  1720 Epithelioid hemangioma  1720 Spindle cell hemangioma (hemangioendothelioma)  1724 Angiomatosis  1725 Symplastic hemangioma  1725

Retiform hemangioendothelioma  1726 Papillary intralymphatic angioendothelioma  1727 Kaposiform hemangioendothelioma  1728 Kaposi's sarcoma  1729 Composite hemangioendothelioma  1734 Giant cell angioblastoma  1735 Epithelioid sarcoma-like hemangioendothelioma  1735

Malignant vascular tumors  1736

Malignant tumors of cartliage  1752 Extraskeletal myxoid chondrosarcoma  1752 Extraskeletal mesenchymal chondrosarcoma  1753

Miscellaneous benign lesions  1754 Synovial metaplasia  1754 Cutaneous myxoma  1754

Epithelioid hemangioendothelioma  1736 Angiosarcoma  1737 Epithelioid angiosarcoma  1742 Lymphangioma  1743 Multifocal lymphangiomatosis with thrombocytopenia (cutaneovisceral angiomatosis with thrombocytopenia)  1745 Atypical vascular proliferation after radiotherapy  1745 Lymphangiomatosis  1746

Massive localized lymphedema  1754

Tumors of perivascular cells  1746

Miscellaneous low-grade and malignant tumors  1759

Glomus tumor  1746 Myopericytoma  1749

Non-neural dermal granular cell tumor (primitive polypoid granular cell tumor)  1755 Superficial angiomyxoma  1756 Ossifying fibromyxoid tumor  1756 Phosphaturic mesenchymal tumor (mixed connective tissue variant)  1758

Myoepithelioma of soft tissue  1759

Tumors of bone and cartilageforming tissue  1751 Benign tumors of bone  1751

Perivascular epithelioid cell tumor  1759 Pleomorphic hyalinizing angiectatic tumor  1761

Osteoma cutis  1751

Epithelioid sarcoma  1761

Malignant tumors of bone  1751

Synovial sarcoma  1765

Extraskeletal osteosarcoma  1751

Alveolar soft part sarcoma  1766

Benign tumors of cartliage  1751

Extrarenal rhabdoid tumor  1767

Soft tissue chondroma  1751

Vascular tumors of low-grade or borderline malignancy  1726

Introduction Connective tissue tumors presenting primarily in the skin are relatively ­common. Because the majority of such lesions are benign and clinically nondistinctive they are sometimes neglected by clinicians. However, ­histologically they constitute a complex group of tumors showing various lines of differentiation and it is often difficult to classify a lesion as benign or malignant. Also, cutaneous or subcutaneous sarcomas, as well as various neoplasms of ­intermediate malignancy, are seen sufficiently frequently that some ­knowledge of their behavior and pathological appearances is mandatory for ­dermatologists and dermatopathologists alike. Many benign soft tissue lesions – lipoma and fibrous histiocytoma being the most common – are often slow growing and asymptomatic. As a result, they frequently remain untreated unless they are a cosmetic nuisance, and so an accurate estimation of their incidence (which is probably relatively high) is impossible. However, sarcomas are relatively rare at any site, accounting for less than 1% of all malignant neoplasms. In this chapter, emphasis is placed upon those lesions that commonly ­present in the skin; various nondermatological conditions are included for

the sake of completeness and because they may be seen, albeit very occasionally, in dermatopathological practice. When dealing with any soft tissue neoplasm, the single most important dictum to be strictly followed is that adequate tissue sampling, surgically and pathologically, is essential for accurate diagnosis. The range of diagnostic and non-specific histological appearances seen in these tumors is very wide, reflecting the multipotentiality of mesenchyme; only by obtaining an overall view of a given neoplasm can a reliable diagnosis be made. In this regard, punch and shave biopsies are almost guaranteed to give rise to diagnostic errors. A number of cutaneous mesenchymal tumors have genetic features that can be helpful diagnostically. In general, malignant soft tissue tumors fall into the class of complex karyotype sarcomas (for example, angiosarcoma and leiomyosarcoma) or simple genetic profile (for example, clear cell sarcoma or dermatofibrosarcoma) often associated with a chromosomal translocation or, less often, with mutation or loss of a specific gene. An exhaustive discussion of the molecular diagnostics of soft tissue tumors is beyond the scope of this chapter, but see Chapter 2 for additional discussion of relevant techniques. Most of the molecular features discussed in this present chapter can be used diagnostically when required, although some of the tests are available only in specialized centers.

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Connective tissue tumors

Adipocytic tumors Benign adipocytic tumors Lipoma Clinical features Lipomas are the most common connective tissue tumors.1–3 They appear to occur more frequently in the obese, usually in middle and late adult life, may be multiple and are purportedly more common in females. This, ­however, may only be a reflection of the greater tendency of women to request cosmetic attention for otherwise innocuous lesions. Lipomas are very uncommon in children and when present should raise the possibility of Bannayan-Riley-Ruvalcaba syndrome.4 Congenital lipomas are very rare.5 Multiple lesions may occur in a familial setting.6 A case of multiple lipomas after total body electron beam therapy for mycosis fungoides has been reported.7 Multiple lipomas have also been described in association with rosiglitazone, a ­peroxisome proliferator-activator receptor (PPAR) gamma agonist, in ­association with ­systemic ­chemotherapy for Hodgkin's ­lymphoma and in Cowden's disease.8–10 The lesions are found most often on the trunk, abdomen or neck, followed by the proximal extremities, and rarely on the face (particularly the forehead), scalp, hands or feet. Palmar lipomas are exceptional and may present with lesions ­simulating piezogenic pedal papules.11 Periungual and subungual lesions are exceptional.12,13 Trauma has been associated with induction of lipomas although it is not clear whether all of these lesions may represent pseudolipomas.14,15 The latter sometimes includes an intravascular lesion.16 Typically, they originate subcutaneously, are slow growing, mobile and ­painless; sometimes they are multiple. Size varies and some lesions are very large. Dermal examples are often clinically confused with fibroepithelial ­polyps. Although the lesions are usually well circumscribed, the less ­common deep variants, which may arise in muscle or in association with a tendon sheath or nerve, are generally ill defined and infiltrative. Subcutaneous lipomas are entirely benign and local excision is nearly always curative; recurrence is infrequent and progression to liposarcoma almost never occurs.

Fig. 35.1 Lipoma: low-power view showing a circumscribed encapsulated tumor composed of mature adipocytes.

Pathogenesis and histological features Lipomas at all locations show clonal karyotypic abnormalities in up to 75% of cases.17–20 The most common rearrangement in the 12q13~15 region and the HMGA2 gene most often with LLP at 3q27~28, though other loci are described.17–22 The tumors are usually encapsulated, lobulated and largely composed of univacuolated mature adipocytes, the nucleus and cytoplasm of which are compressed centrifugally (Fig. 35.1). The lobules are divided by delicate fibrous septa containing thin-walled vessels. Degenerative changes, often ­characterized by fibrosis, focal fat necrosis or myxoid change, are not ­uncommon, ­particularly in long-standing or frequently traumatized cases (Figs 35.2–35.7). Prominent myxoid change and high vascularity are sometime present.23 Foci of other fully differentiated mesenchymal elements, including bone or cartilage, may also be seen. Although nuclear pleomorphism, hyperchromasia and mitotic ­activity do not occur in lipomas, in any benign fatty lesion (or even in normal ­adipose ­tissue) occasional vacuolated nuclei known as lochkern may be seen (Fig. 35.8). These must not be confused with lipoblasts, the most important ­diagnostic feature of liposarcoma, which are characterized by multiple intracytoplasmic lipid vacuoles associated with scalloping of peripherally located hyperchromatic or bizarre nuclei. In some lesions there are septa of collagen between adipose tissue lobules and they are referred to as fibrolipomas. A variant of lipoma with predilection for acral sites (fingers, wrists, toes) and characterized by prominent collagenous or myxocollagenous stroma, bland stellate or spindle-shaped cells and scattered adipocytes has been described as sclerotic (fibroma-like) lipoma.24 A further variant known as ­fibrohistiocytic lipoma has been reported and this is described

Fig. 35.2 Lipoma: post-traumatic fat necrosis.

Fig. 35.3 Lipoma: note the lipid laden xanthoma cells.

Benign adipocytic tumors

Fig. 35.4

Fig. 35.7

Fibrolipoma: this term is sometimes applied to a lipoma with a prominent fibrous component.

Myxofibrolipoma: note the abundant mucinous matrix and spindled cells admixed with adipocytes.

Fig. 35.5 Fibrolipoma: high-power view of Figure 35.4.

Fig. 35.8 Lipoma: intranuclear lipid ‘inclusions’ (lochkern) should not be mistaken for lipoblasts.

below.25 Rare lipomas may contain bone.26 Those containing sweat glands do not represent an adenolipoma but rather entrapment of normal glands by the tumor.27–29 Lesions containing smooth muscle are rare; they have been described as myolipomas and tend to be deep seated.30 Focal areas of fat necrosis with foamy histiocytes are often seen and some cases show membranous fat necrosis.31 Dermal lipomas are less well circumscribed and consist of scattered groups of mature adipocytes between collagen bundles (Figs. 35.9, 35.10).

Differential diagnosis

Fig. 35.6 Myxofibrolipoma: this variant of lipoma is characterized by fibrosis and foci of myxoid change. It is of no clinical significance.

The diagnosis of a lipoma is usually straightforward. Distinction from an atypical lipomatous tumor is based on the presence of adipocytes varying in size and shape and with hyperchromatic nuclei in the latter. Dermal ­lipomas may be confused with pseudolipomatosis cutis. The latter is an artifactual incidental finding distinguished from a dermal lipoma by the ­presence of empty, round spaces simulating adipocytes but lacking nuclei and of ­variable size.32

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Connective tissue tumors are more often multiple than solitary and treatment can be problematic. Multiple lesions have exceptionally been documented in association with ­diabetes ­mellitus and as a complication of antiretroviral therapy (particularly with indinavir and saquinavir) in acquired immunodeficiency syndrome (AIDS).9–12 A case of intravascular lymphomatosis presenting in an angiolipoma has been documented.13 Metastatic melanoma within an angiolipoma has also been described.14

Pathogenesis and histological features Cytogenetic studies in angiolipoma have consistently shown a normal karyotype. This is in contrast with other benign lipomatous tumors (including ordinary lipoma) which show characteristic cytogenetic abnormalities.15 This suggests that angiolipomas may have a completely different pathogenesis from that of lipomas. The tumor, almost always encapsulated, is composed of mature ­adipocytes and varying proportions of irregular, anastomosing small blood vessels ­without endothelial atypia (Fig. 35.11). Luminal microthrombi are invariably present (Fig. 35.12). Although the blood vessels are usually seen in the periphery of the tumor, they may constitute most of the lesion. Such examples are known as cellular angiolipomas (Figs 35.13, 35.14).16,17 Fig. 35.9 Dermal lipoma: the dermal variant is often less well circumscribed and tends to dissect between the collagen fibers.

Fig. 35.11 Angiolipoma: admixed with the adipocytes are aggregates of small vessels.

Fig. 35.10 Dermal lipoma: it is often separated from the epidermis by a grenz zone.

Angiolipoma Clinical features Angiolipomas are benign lesions which, in contrast to simple lipomas, are seen most often in young adults and have a predilection for the subcutis of the upper limbs, particularly the forearm and less commonly the trunk.1–3 Oral, intra-articular, extradural, breast and bronchial lesions are exceptional.4–8 Familial cases are rarely seen. The lesions are typically tender or painful, less than 2 cm in diameter and may impart a reddish or bluish discoloration to the overlying skin. They

Fig. 35.12 Angiolipoma: vascular thromboses are an invariable feature. They are often found at the periphery of the tumor.

Benign adipocytic tumors tissue, a lesion closely related to spindle cell lipoma.17 They usually occur as a ­well-circumscribed, slowly growing, solitary, subcutaneous or (rarely, in up to 13% of cases) dermal lesion, less than 5 cm in diameter.18–20 The last appear most commonly on the face and are more common in females. Intramuscular presentation is very rare.21–24, A case has been reported at the site of an infantile fibrosarcoma treated with chemotherapy.25 Spindle cell lipoma is an entirely benign, nonrecurring lesion.

Pathogenesis and histological features

Fig. 35.13 Cellular angiolipoma: in this variant, bland spindled cells (possibly pericytes) predominate. The presence of adipocytes and capillary microthrombi confirms the diagnosis.

Fig. 35.14 Cellular angiolipoma: the vessels can be outlined with CD31.

A number of chromosomal abnormalities have been found in spindle cell lipoma, identical to those found in pleomorphic lipoma. Monosomy or partial loss of chromosomes 13 and 16 are the most common alterations also seen in pleomorphic lipoma, strongly suggesting that these two lesions exist as a morphologic continuum.26–29 Interestingly, similar loss of 13q has been found in mammary-type myofibroblastoma and cellular angiofibroma, suggesting a close link between these tumors.18,30,31 Subcutaneous lesions tend to be well circumscribed and dermal tumors are ill defined.20 In addition to mature univacuolated adipocytes, irregular collections of slender spindled cells are seen with pale eosinophilic cytoplasm, ­uniform nuclei and rare mitoses (Fig. 35.15). Hyaline bundles of collagen and occasional giant cells may also be present, but lipoblasts are rarely identified. Mast cells are often numerous (Fig. 35.16). The relative proportions

Fig. 35.15 Spindle cell lipoma: the tumor consists of an admixture of mature adipocytes and delicate spindle cells, often associated with broad bundles of hyalinized collagen.

Differential diagnosis Cellular angiolipoma can be confused with a vascular tumor, especially immature capillary hemangioma and kaposiform hemangioendothelioma.16 The presence of mature adipocytes and capillaries with microthrombi allows distinction from immature capillary hemangioma. Kaposiform hemangioendothelioma may have capillaries with microthrombi in the periphery of tumor lobules, but mature adipocytes are absent.

Spindle cell lipoma Clinical features Spindle cell lipoma is a comparatively uncommon variant and may be a source of histological concern to the unwary.1–3 Found predominantly in males, they arise mainly in the posterior portion of the neck, shoulder or upper back, and are characteristically seen in the sixth or seventh decade. Multiple lesions are rare and some are familial.4,5 Rare cases can occur at other locations including the foot, oral cavity (including the tongue), larynx, orbit, soft tissues of the perianal area, aortic valve, mediastinum and breast.6–16 The last may ­represent an example of mammary-type myofibroblastoma of soft

Fig. 35.16 Spindle cell lipoma: high-power view. Note the conspicuous mast cells.

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Mammary-type myofibroblastoma of soft tissue Clinical features This is a rare tumor identical to myofibroblastoma that occurs in the breast.1 As with the latter tumor, it is most common in adult males and presents as an asymptomatic slowly growing subcutaneous mass with predilection for the groin/inguinal area. Size varies but tends to be less than 2 cm. Lesions can also rarely occur on the trunk, vaginal wall, paratesticular area, vulva, perianal area and lower limb.1–5 There seems to be a predilection for tumors to occur along the milk line. Simple excision is the treatment of choice and there is no tendency for local recurrence.

Pathogenesis and histological features

Fig. 35.17 Spindle cell lipoma: in some examples, the spindled cells predominate such that the lesion is easily mistaken for another connective tissue tumor.

of ­adipose tissue to spindled cells vary between individual cases (Fig. 35.17). Some cases contain few or, rarely, no adipocytes at all.32 Vascularity also ­varies and focal hemangiopericytoma-like areas are sometimes seen. Extensive myxoid change can lead to striking degenerative features with a pseudovascular pattern in which papillary structures project into empty spaces (Fig. 35.18).33 However, it has been shown that at least in some examples showing this change, the spaces are truly lined by endothelial cells, and these should be named angiomatous spindle cell lipoma.34 The spindled cells are positive for CD34 but negative for S-100. Only mature adipocytes are positive for S-100. Ultrastructural studies show cells with features of mature adipocytes and spindled cells representing undifferentiated mesenchymal cells.33

Differential diagnosis Although the clinical history may be sufficiently characteristic to aid the ­diagnosis, distinction from liposarcoma is made by the absence of either adipocytic atypia or variation in adipocyte size. Histologically comparable lesions in deeper tissue should be classified as atypical lipoma, reflecting their much greater tendency to recur.

Mammary-type myofibroblastoma appears to be part of a morphologic spectrum that includes cellular angiofibroma and spindle cell lipoma. It has been suggested that the histological variations probably depend on anatomic location.6 Tumors are well-circumscribed and composed of a mixture of bland spindled cells and variable, sometimes prominent, amounts of mature adipose tissue.1 The spindled cells are arranged in fascicles and display a myofibroblast-like appearance with tapering nuclei and amphophilic cytoplasm with an indistinct cytoplasmic membrane. Cytologic atypia is rare and mitotic figures are exceptional. Epithelioid cells may rarely be seen and sometimes scattered multinucleate cells can be identified. Blood vessels are small and tend to be inconspicuous. The stroma is often myxoid, mast cells are common and hyalinized collagen bundles are intermixed with tumor cells. Immunohistochemistry shows positivity for CD34 and desmin and focal positivity for actin and calponin in a number of cases.1 Cytogenetic analysis has shown partial monosomy of chromosomes 13q and 16q, further emphasizing the relationship with spindle cell lipoma, a tumor with similar cytogenetic abnormalities.7

Pleomorphic lipoma Clinical features Pleomorphic lipoma represents a variant of spindled cell lipoma, from which it is clinically and cytogenetically indistinguishable; it is entirely benign.1–5

Pathogenesis and histological features Cytogenetic abnormalities are the same in pleomorphic lipoma and ­spindle cell lipoma, confirming that they are part of the same spectrum (see above).4,5 In addition to the histological features of spindle cell lipoma, pleomorphic lipoma is characterized by numerous hyperchromatic and irregular ­multinucleated giant cells, with nuclei often arranged in a concentric floret pattern (floret giant cells) (Figs 35.19–35.21). Floret-like cells may also be seen in prolapsed orbital fat as a result of a degenerative process.6 Mitotic figures may rarely be evident and occasional multivacuolated lipoblasts are sometimes present (Fig. 35.22). Lesions that show few or no adipocytes may pose a diagnostic challenge.7

Chondroid lipoma Clinical features

Fig. 35.18 Spindle cell lipoma: rarely, massive myxoid degeneration results in the formation of pseudovascular spaces (the so-called lymphangiomatous variant).

Chondroid lipoma is a distinctive tumor that presents predominantly in adult females, with a predilection for the proximal extremities and limb girdles.1 Tumors in children are very rare.2 Lesions are usually small and arise mainly in deeper soft tissues and (less commonly) in the subcutis. Rare examples present in the oral cavity, nasopharynx and pelvis.3–5 Clinical features are not distinctive. Tumors are benign and there is no tendency for recurrence after simple excision.

Benign adipocytic tumors

Fig. 35.19 Pleomorphic lipoma: this view shows adipocytes, thick collagen bundles and spindled cells.

Fig. 35.22 Pleomorphic lipoma: high-power view.

Pathogenesis and histological features This tumor is characterized by t(11;16)(q13;p13) fusing C11orf95 and MLK2.6,7 The lesion is well circumscribed, lobular and often encapsulated. It ­consists of an admixture of mature adipocytes, uni- or multivacuolated ­lipoblasts and hibernoma-like cells with granular eosinophilic cytoplasm in a myxoid and chondroid matrix, which can show hyalinization (Figs 35.23, 35.24). Fibrosis and hemorrhage are often seen. The matrix is composed of ­chondroitin sulfate.8 Some tumor cells contain glycogen in the cytoplasm. Ossification is exceptional.9 By immunohistochemistry, mature adipocytes are strongly positive for S-100 protein; lipoblasts are only weakly positive for this marker.8 Cytokeratin is very rarely focally positive.8 Electron microscopy confirms the presence of lipoblasts and mature fat cells. There is no evidence of true cartilaginous differentiation.10

Differential diagnosis

Pleomorphic lipoma: multiple hyperchromatic giant cells are seen.

Myxoid liposarcoma usually lacks the presence of a ‘chondroid-like’ matrix and has a characteristic vascular pattern. In myxoid chondrosarcoma there are no mature adipocytes, although some cells may occasionally focally resemble lipoblasts.

Fig. 35.21

Fig. 35.23

Pleomorphic lipoma: conspicuous floret giant cells are present.

Chondroid lipoma: in the center of this otherwise typical lipoma were several chondroid foci showing marked hyalinization.

Fig. 35.20

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Connective tissue tumors lower limbs and abdomen, particularly in juxta-articular areas. Localized ­disease is very rare and the breasts may be involved.4,5 The condition is much more common in females, especially after the menopause, and patients often have associated obesity and psychological problems.1–3 Occasional cases are inherited in an autosomal dominant manner.6,7 A case associated with the use of corticosteroids and a further patient with hypercholesterolemia and severe atherosclerosis have been documented.8,9 Pain occurs mainly as the result of palpation but may also occur spontaneously or as a result of movement.

Histological features Biopsy reveals mature adipose tissue with focal areas of fat necrosis and, exceptionally, granulomatous inflammation.

Nevus lipomatosus superficialis (Hoffman and Zurhelle) Clinical features Fig. 35.24 Chondroid lipoma: high-power view.

Lipomatosis Clinical features Lipomatosis is extremely rare and may present in several forms, two of which affect the superficial subcutaneous tissue:1–4 • Multiple symmetric lipomatosis (Launois-Bensaude) represents the commonest form and can be diffuse or localized.1–3,5 In the diffuse variant, there is usually symmetrical involvement of the trunk or proximal limbs and occasionally the abdominal cavity;4 it is seen most often in children (particularly males). Some cases show an autosomal dominant inheritance, others are associated with myoclonic epilepsy with ragged red fibers (MERRF), and a number may be associated with diabetes mellitus.6–9 The localized variant is characteristically seen in the cervical region, usually in middle-aged males, and is known as Madelung's disease. In the latter, inspiratory dyspnea or obstructive sleep apnea may exceptionally occur.10,11 The axillae and groins may also be affected. There is a strong association with alcohol abuse and liver disease.12 A variant of localized symmetrical lipomatosis restricted to the hands or the feet has been reported.13,14 • Asymmetric lipomatosis can present at any site and usually has no association with other diseases.15 Single reports of associations with familial hyperlipidemia and tuberous sclerosis have been documented.16,17 A localized form of lipomatosis of the scalp has been reported as ­encephalocraniocutaneous lipomatosis and is associated with alopecia and ocular and cranial abnormalities.18,19 Congenital facial infiltrating lipomatosis refers to a disorder associated with hypertrophy of bones and soft tissues, macrodontia and premature ­dental eruption.20,21 In both forms of lipomatosis, only radical surgery can prevent local ­recurrence. The disadvantages of recommending such treatment must be weighed against the possible functional impairment that the condition may induce.

Nevus lipomatosus superficialis is an uncommon form of connective tissue nevus, manifest principally by the deposition of fatty tissue in the dermis.1–4 In its classical form, it is characterized by multiple papular, polypoid or plaquelike lesions, up to 2 cm in diameter, which almost always arise unilaterally on the posterior surfaces of the buttocks, upper thighs or lower back. More extensive and diffuse involvement may occur and patients present with prominent folds in what has been described as the Michelin tire appearance.5–7 Typically, the lesions present in early childhood or adolescence. Unusual associations include co-occurrence with lipedematous scalp, folliculosebaceous cystic hamartoma, dermoid cysts and angiokeratoma of Fordyce.8–11 A solitary form, usually seen in adults, shows a predilection for the same sites or occurs elsewhere and is more likely to represent a variant of fibroepithelial polyp or skin tag (Figs 35.25, 35.26). Such lesions have been described as pedunculated lipofibroma.12 In all types of nevus lipomatosus the sex incidence is equal. The papules or plaques, varying from skin-colored to yellow, are characteristically broad based and may show superficial comedone formation.

Pathogenesis and histological features The pathogenesis is unknown. In a single case, a 2p24 deletion has been described.13 Although alterations are seen in all the connective tissue elements in the dermis, the predominant feature is deposition of lobules of mature fat in ­variable quantities in the superficial dermis (Fig. 35.27).3,14 These fatty ­lobules are located particularly around small blood vessels, the numbers of

Histological features Histologically, all forms are characterized by unencapsulated overgrowth of mature adipose tissue.

Adiposis dolorosa Clinical features Adiposis dolorosa (Dercum's disease) is a rare disease characterized by ­painful, circumscribed areas with increased fat in a plaque-like distribution.1–3 Usually, multiple body sites are involved but there is predilection for the buttocks,

Fig. 35.25 Nevus lipomatosus superficialis: solitary lesions are often polypoid and have a soft consistency. By courtesy of the Institute of Dermatology, London, UK.

Benign adipocytic tumors

Fig. 35.26 Nevus lipomatosus superficialis: in this patient there are multiple papules and nodules. Secondary changes due to trauma are present. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.28 Piezogenic pedal papules: note the multiple flesh-colored papules on the heel and lateral border of the foot. From the collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

e­ licited when the patient is standing. Lesions become more noticeable when the patient stands up as a result of pressure. Piezogenic pedal papules are ­common in patients with Ehlers-Danlos syndrome.4 They have been described in athletes, including a marathon runner, and in association with Prader-Willi syndrome.5–7 Rare familial cases have been described.8

Pathogenesis and histological features It is likely that trauma plays a role in the pathogenesis of the lesions.5,6 A  biopsy from a papule shows normal adipose tissue herniating into the ­dermis. This may mimic an intradermal lipoma but the clinical setting allows a diagnosis to be made.

Lipomatosis of nerve Clinical features

Fig. 35.27 Nevus lipomatosus superficialis: this specimen came from the lower back of a teenage male. There is widespread infiltration of the dermis by mature adipocytes.

which are also increased. Areas of loose fibrous tissue, diminished ­elastic fibers and reduced numbers of epidermal appendages may also be a feature. As mentioned previously, it has been argued that the solitary form represents a pedunculated, fat-containing skin tag or a lipofibroma. Although the distribution of fat in the superficial dermis makes this suggestion unlikely, the argument is semantic and of no practical value. Nevus lipomatosus superficialis is also histologically indistinguishable from the cutaneous nodules of focal dermal hypoplasia.

Lipomatosis of nerve (fibrolipomatous hamartoma of nerve, perineural fibrolipoma, perineural lipoma, intraneural lipoma) is a very rare hamartomatous condition usually occurring in children or young adults of either sex, around the wrists and hands, particularly along the distribution of the median nerve followed by the ulnar nerve and (less frequently) others including the ­brachial plexus and cranial nerves.1–5 Presentation at birth is sometimes seen. It can be associated with macrodactyly of the fingers innervated by the involved nerve in up to one-third of cases.1,6 Patients typically present with a slowly growing mass, which is either asymptomatic or associated with neurological ­symptoms including pain, paresthesia, loss of sensation or motor deficit. Carpal tunnel syndrome may develop when the median nerve is involved.7,8 Although the lesion is benign, treatment is difficult, as surgical excision often results in permanent neurological deficit.

Histological features The lesion is characterized by proliferation of mature fatty and fibrous ­tissue within the epineurium of a major nerve accompanied by prominent ­concentric perineural fibrosis (Fig. 35.29). Rarely, bone formation has been described.9

Piezogenic pedal papules

Lipoblastoma

Clinical features

Clinical features

Piezogenic pedal papules characteristically present as multiple skin-colored papules on the heels (Fig. 35.28).1–3 They show predilection for the ­internal aspect of the heels and are usually asymptomatic although pain may be

Lipoblastoma is the circumscribed subcutaneous counterpart of lipoma seen in infancy and childhood.1–6 Its diffuse form, lipoblastomatosis, is infiltrative and typically involves deeper structures, including muscle.

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Fig. 35.29 Fibrolipomatous hamartoma of nerve: note the extensive epineural fat deposition.

Fig. 35.30 Lipoblastoma: at low power, the tumor is lobulated and composed of mature fat cells and numerous multivacuolated lipoblasts.

In either form, this condition most often presents in the first 9 years of life (exceptionally at birth, and 10% between the ages of 10 and 16), affects males rather more than females, and is typified by a slowly growing, usually subcutaneous mass with size ranging from 1 to 15 cm.1–7 Most tumors involve the trunk and extremities, followed by the head and neck.7,8 Presentation in the retroperitoneum, mediastinum and a number of internal organs including the kidney occurs rarely.9–14 Intrascrotal tumors and association with accessory scrota have also been documented.15–17 In the infiltrative type, local recurrence can occur following incomplete excision in up to 19% of cases.3 Familial cases may be seen.7 In about 17% of patients central nervous system anomalies are noted including macrocephaly, developmental delay, autism, Sturge-Weber syndrome and seizures.7 Unusual associations include a patient with glomuvenous malformations, epidermal nevus, temporal ­alopecia and ­heterochromia in addition to a lipoblastoma.18 A small series of adipose tumors closely resembling lipoblastoma and presenting in the vulva of young to middle-aged patients has been described as lipoblastoma-like tumor of the vulva.19 One or more recurrences may occur in up to 46% of cases.7

Pathogenesis and histological features It has been shown that lipoblastoma has a consistent rearrangement of 8q11~q13, resulting in overexpression of the PLAG1 oncogene.20–29 Rarely chromosomal numerical abnormalities may be found.7,17,27,28 Lipoblastoma recapitulates developing fat and therefore contains varying proportions of mature adipocytes, lipoblasts and prelipoblasts arranged in a lobulated pattern and separated by loose fibrous connective tissue septa (Figs 35.30, 35.31). The stroma is often myxoid with numerous small capillaries giving a ‘crow's feet’ appearance (Fig. 35.32) and may contain very primitive stellate or spindled tumor cells. Hibernoma-like tumors may be seen.30 Mitotic figures are uncommon; some cases show areas of extramedullary hematopoiesis.2 Positivity for S-100 protein and CD34 is seen.7 The degree of adipocytic differentiation does not predict risk of recurrence.7 Ultrastructural studies show adipocytes in different stages of development.31

Fig. 35.31 Lipoblastoma: this field shows an admixture of adipocytes and multivacuolated lipoblasts.

Differential diagnosis Distinction from myxoid liposarcoma, which is extremely rare in children, is made possible by the presence of prominent lobulation and the absence of nuclear hyperchromasia in lipoblastoma. Cytogenetics is very useful in allowing distinction between these tumors, as myxoid liposarcoma lacks rearrangement of 8q11~q13 and instead shows a consistent t(12;16)(q13;p11). Cytogenetics is also very useful in tumors mimicking ordinary lipoma and hibernoma.30 Human insulin injection may induce lipoatrophy with focal lipoblastoma-like changes.32

Fig. 35.32 Lipoblastoma: the adipocytes are of varying size. In the center of the field is a thinwalled, branched ‘crow's foot’ type of blood vessel.

Benign adipocytic tumors

Hibernoma

Lipofibromatosis

Clinical features

Clinical features

Hibernoma is a rare, invariably benign tumor resembling normal brown fat, which typically occurs in young adults with a slight female predominance. The tumor most often presents in the interscapular region and thigh followed by the axillae or chest wall.1–5 It is a slowly growing, highly vascular lesion that may attain a considerable size and is typified macroscopically by tannishbrown fatty tissue. The large majority of tumors are subcutaneous but about 10% of cases are intramuscular.1 Lesions are benign and there is no tendency for local recurrence.

Lipofibromatosis is a recently described neoplasm that presents in children as a subcutaneous mass measuring from 1 to 7 cm and involving mainly the upper and lower limbs, with predilection for the hand.1–3 Rare cases may present in the head and neck and back.4–6 The rate of local recurrence or ­persistence is reported as being 72%.1–3

Pathogenesis and histological features In cytogenetic studies, hibernomas have shown consistent rearrangement at 11q13.1,6,7 Hibernomas are classified histologically into four categories: typical (82% of cases), lipoma-like (7%), myxoid (9%) and spindled cell (2%).1,3,8,9 Typical hibernoma is characterized by an admixture of multivacuolated large adipocytes with central nuclei, large cells with granular eosinophilic cytoplasm and mature univacuolated adipocytes (Fig. 35.33). They are usually encapsulated and lobulated, being subdivided by fine fibrous septa containing numerous small capillaries. Some cases have focal myxoid stroma and very few resemble spindle cell lipoma.1,9 Tumor cells show variable staining for S-100 protein; in the spindle cell variant, the spindled cells are CD34+.1

Differential diagnosis Distinction from a granular cell tumor is easy, as in the latter the cells are not vacuolated and there are no mature adipocytes.

Fibrohistiocytic lipoma

Pathogenesis and histological features In a single case a three-way translocation (4;9;6) has been described.7 Histology reveals large amounts of mature adipose tissue combined with a focal spindled fibroblastic element that tends to be localized mainly in the septa of the fat or within the neighboring skeletal muscle.1–3 Cytological ­atypia and mitotic figures are rare and univacuolated cells may be seen in the interface between the mature adipose tissue and the fibroblastic fascicles. A single case has been published with pigment and Melan-A and S-100 ­positive cells.6 Beta-catenin expression is not seen.8

Hemosiderotic fibrohistiocytic lipomatous lesion Clinical features Hemosiderotic fibrohistiocytic lipomatous lesion (HFHL) develops almost exclusively on the foot, particularly the ankle, with predilection for females.1–3 Most patients are adults but children may rarely be affected. It grows slowly and is asymptomatic. Simple excision is the treatment of choice. Local recurrence may occur. An alternative name of hemosiderotic fibrolipomatous tumor has been proposed.2

Pathogenesis and histological features

Tumors are well circumscribed and consist of lobules of mature adipocytes containing focal areas with plump spindled cells arranged in a fascicular or focal storiform pattern.

Hemosiderotic fibrohistiocytic lipomatous lesion is likely to arise as the result of trauma. It has also been suggested that the lesion may develop as a result of stasis.4 An alternative proposal is that it represents a neoplastic process.5,6 This is based on the observation that the so-called early pleomorphic hyalinizing angiectatic tumor, a lesion regarded as precursor of pleomorphic hyalinizing angiectatic tumor (PHAT), is identical histologically to HFHL.5 This view is, however, controversial.7 Histology shows a fairly well-circumscribed mass composed of abundant mature adipose tissue admixed with focal bundles of plump spindle-shaped cells with vesicular nuclei and a small inconspicuous nucleolus. Cytological atypia is mild and mitotic figures are very rare. A striking feature is the ­presence of prominent hemosiderin deposition, particularly in the spindle cell areas (Figs 35.34, 35.35).

Fig. 35.33

Fig. 35.34

Hibernoma: the admixture of mature adipocytes and large cells with eosinophilic granular cytoplasm is characteristic.

Hemosiderotic fibrohistiocytic lipomatous lesion: there are lobules of mature adipocytes containing scattered areas of spindled cells and histiocytes.

Clinical features Fibrohistiocytic lipoma is a previously undescribed variant of lipoma delineated in a series of 12 cases.1 Tumors typically present in the subcutis of the trunk and have predilection for young men. Most lesions are small and asymptomatic.

Histological features

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Connective tissue tumors ­ articularly the thigh. All tumors, without exception, tend to local ­recurrence, p and metastases occur in approximately one-third of cases depending on the percentage of round cell component (see below).11,12 The presence of a round cell component, necrosis and p53 overexpression has been found to be associated with poor prognosis.14

Pleomorphic liposarcoma Pleomorphic liposarcoma is the least common variant of liposarcoma. There is no sex predilection, patients are elderly and tumors are deep seated, ­presenting mainly on the limbs.15,16 Only exceptional tumors occur in the dermis or subcutis.1,15,16 Tumors grow rapidly and there is a high tendency for local recurrence and metastasis.15,16

Pathogenesis and histological features

Fig. 35.35 Hemosiderotic fibrohistiocytic lipomatous lesions: there are bland spindle-shaped cells and prominent hemosiderin.

By immunohistochemistry, the spindled cells are positive for vimentin, ­calponin and CD34, and focally positive for KP1.

Malignant adipocytic tumors Liposarcoma Clinical features In spite of being one of the most common soft tissue sarcomas, liposarcoma presents infrequently as a primary subcutaneous lesion and only exceptionally as a primary dermal tumor.1 Liposarcoma may be divided into three subtypes: • atypical lipomatous tumor (atypical lipoma, well-differentiated liposarcoma), which includes the dedifferentiated variant2,–6 • myxoid, which includes the round cell variant,2,4,7,8 • pleomorphic.2,4,7,8 For practical purposes only the first two histological subtypes present as subcutaneous tumors.

Atypical lipomatous tumor Atypical lipomatous tumors are usually deep seated and may occur in the subcutaneous tissue, within skeletal muscle, the retroperitoneum, the mediastinum and the spermatic cord.2–6 Visceral tumors are very rare. Subcutaneous tumors have a predilection for the legs (particularly the thighs) and the trunk.2–6 Patients are more often male and usually present in their sixth and seventh decades, complaining of a slowly growing, painless mass measuring several centimeters. Deep-seated tumors, particularly those arising in the retroperitoneum, are usually very large by the time they are discovered. Prognosis in atypical lipomatous tumors is closely related to site. Peripheral tumors are prognostically more favorable than their retroperitoneal counterparts: the smaller the tumor, the better the outlook. Subcutaneous tumors have a tendency for local recurrence due to incomplete excision but behavior is not aggressive and they do not metastasize unless they become dedifferentiated. Dedifferentiation refers to a biphasic tumor containing an atypical lipomatous tumor and a sarcomatous undifferentiated component. Dedifferentiation tends to occur mainly in deep-seated tumors (particularly those occurring in the retroperitoneum) and is exceptional in subcutaneous lesions.9,10

From the cytogenetic point of view, ring or giant marker chromosomes with ­integration of variable portions of the 12q13~15 interval characterize welldifferentiated lesions.17,18 MDM2 at 12q15 is virtually universally amplified.19,20 Myxoid and round cell liposarcomas show a specific t(12;16)(q13;p11) fusing DDIT3 and FUS.17,18,21 In a small subset of cases a t(12;22)(q13;q12) has been found where EWSR1 substitutes for FUS.17,18,21 These translocations are seen in virtually all cases.22 No consistent cytogenetic abnormality has been demonstrated in pleomorphic liposarcoma, which often shows complex cytogenetic abnormalities.17,23 Atypical lipomatous tumor (usually referred to as well-differentiated ­liposarcoma in deep, surgically complex sites such as the retroperitoneum) occurs in three forms: the adipocytic, the sclerosing and the spindle cell.2–6,24,25 The last, although uncommon, usually favors subcutaneous tissue. It has recently been suggested, however, that well-differentiated spindle cell liposarcoma is not a morphologic variant of atypical lipomatous tumor but an ­atypical/low-grade variant of spindle cell lipoma.26 This is based on a small series of cases in which although rare cells display nuclear positivity for MDM2, none of the cases showed amplification of MDM2/CDK4, but instead deletion of the Rb-1 gene was found. • Microscopically, the adipocytic lipoma-like type is characterized by an appearance very similar to mature adipose tissue, but with scattered moderate nuclear pleomorphism, which is most prominent in the fibrous stroma, along with variation in adipocyte size and a few lipoblasts (Figs 35.36–35.38). Purely dermal lesions are occasionally seen.1,27 • The sclerosing type is always deep seated and consists of variably fibrillary or sclerotic collagenous tissue containing bizarre, often multinucleated cells and rare lipoblasts (Fig. 35.39). Both types show minimal, if any, mitotic activity. Atypical hyperchromatic cells are frequently seen in a perivascular location. Rare cases display a prominent mononuclear inflammatory cell infiltrate, often in a patchy distribution.28 Metaplastic elements including cartilage, bone and smooth muscle are sometimes a feature.29

Myxoid liposarcoma Myxoid liposarcoma occurs in adults, with a peak incidence between the fourth and fifth decades of life, and has no sex predilection.8,11,12 Although rare in children and adolescents, it is the most common type of liposarcoma in this age group.13 The majority of tumors arise in deep soft tissues, subcutaneous tumors being very rare. The most common site is the lower limb,

Fig. 35.36 Atypical lipomatous tumor/well-differentiated liposarcoma: lipoma-like variant. Note the characteristic variation in adipocyte size and the scattered hyperchromatic cells.

Malignant adipocytic tumors

• In the spindle cell variant, short fascicles or whorls of pale eosinophilic

Atypical lipomatous tumor/well-differentiated liposarcoma: lipoma-like variant. Irregular hyperchromatic stromal cells are typically present, often in proximity to the septa.

spindled cells with mild to moderate atypia predominate and the adipocytic component can be overlooked (Figs 35.40–35.43). Often this lesion is misdiagnosed as a neural tumor or dermatofibrosarcoma protuberans. Dedifferentiated liposarcoma is defined as a well-differentiated liposarcoma showing abrupt transition to a high-grade nonlipogenic sarcoma.9,10 Focal lipoblastic differentiation may be seen within the dedifferentiated areas.30 This change can occur in a primary tumor and less often in a recurrence. Although in most cases the dedifferentiated component is pleomorphic, there are often focal less atypical areas that may mimic other tumors such as dermatofibrosarcoma protuberans. Meningothelial-like whorls have also been documented.31,32 Heterologous differentiation is rarely seen.33 Myxoid liposarcoma is composed of fairly uniform stellate or spindled cells with small vacuoles set in a myxoid matrix composed of acid mucopolysaccharide (Figs 35.44–35.47).2,4,11,12 Mucin pooling, producing a lymphangioma-like pattern, is common. Emphasis should be placed on the presence of a ­complex plexiform network of small thin-walled capillaries in a pattern resembling chicken-wire or ‘crow's feet’. Mitoses are sparse. Lipoblasts are most easily identified at the periphery of the tumor. Occasionally, ­extramedullary hematopoiesis may be seen. The presence of more cellular areas composed of uniform ovalto-round larger cells with hyperchromatic nuclei and ­inconspicuous cytoplasm

Fig. 35.38

Fig. 35.40

Fig. 35.37

Atypical lipomatous tumor/well-differentiated liposarcoma: lipoma-like variant. A multivacuolated lipoblast shown in high power.

Atypical lipomatous tumor/well-differentiated liposarcoma: spindled cell variant. In this example, the tumor consists predominantly of spindled cells with hyperchromatic nuclei. Only one or two adipocytes are present.

Fig. 35.39

Fig. 35.41

Atypical lipomatous tumor/well-differentiated liposarcoma: sclerosing variant. This field shows sclerotic collagenous tissue, adipocytes and hyperchromatic cells.

Atypical lipomatous tumor/well-differentiated liposarcoma: spindle cell variant. ­Highpower view of atypical spindle cells with hyperchromatic nuclei.

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Fig. 35.42 Atypical lipomatous tumor/well-differentiated liposarcoma: spindled cell variant. High-power view showing signet-ring cell lipoblasts.

Fig. 35.43 Atypical lipomatous tumor/well-differentiated liposarcoma: spindled cell variant. The lipoblasts can be highlighted with S100-protein immunohistochemistry.

Fig. 35.45 Myxoid liposarcoma: medium-power view showing multiple signet-ring cell lipoblasts and conspicuous capillaries.

Fig. 35.46 Myxoid liposarcoma: this field shows a typical ‘crow's-foot’ type of blood vessel.

Fig. 35.44

Fig. 35.47

Myxoid liposarcoma: low-power view showing spindled cells in a myxoid stroma and conspicuous delicate vessels.

Myxoid liposarcoma: multiple lipoblasts are present.

Malignant adipocytic tumors indicates round cell change. This is associated with more aggressive behavior and such lesions are known either as combined myxoid and round cell liposarcoma or high-grade myxoid ­liposarcoma (Figs 35.48, 35.49).4,5 The round cell component may predominate. Pure round cell ­liposarcomas are extremely rare in the subcutis, but mixed tumors are occasionally seen. Dedifferentiation in myxoid liposarcoma is exceptional.34 Pleomorphic liposarcoma consists of highly pleomorphic spindle cells, lipoblasts and numerous multinucleated multivacuolated giant cells (Fig. 35.50).15,16,35 Identification of lipoblasts is vital in distinguishing this variant from other pleomorphic sarcomas. The most important feature required to make the diagnosis of liposarcoma is the presence of lipoblasts. Typically, these cells are highly variable in size, contain more than one well-defined or punched-out lipid vacuole and have irregular, hyperchromatic (and sometimes multiple) nuclei, the margins of which are scalloped by the fat droplets. The very rare dermal liposarcomas may have histological features of an atypical lipomatous tumor, a myxoid liposarcoma or a pleomorphic liposarcoma. Immunohistochemistry has usually been of limited value in the diagnosis of liposarcoma, especially the poorly differentiated variants. S-100 protein is positive in adipocytes and some lipoblasts, the round cell component of myxoid liposarcoma and can be focally positive in spindled cells. CD34 is sometimes positive in spindled cells. Immunohistochemistry for MDM2 and CDK4, however, is useful in the distinction between atypical lipomatous

A

B

Fig. 35.50 Pleomorphic liposarcoma: recognition of this variant is dependent upon identification of lipoblasts amongst the highly pleomorphic cellular background.

Fig. 35.48 Myxoid liposarcoma: round cell differentiation. In this field, the tumor is much more cellular. The background vasculature is still visible.

tumor/well-differentiated liposarcoma (ALT-WDLPS) and dedifferentiated liposarcoma (DDLPS) from other benign lipomatous tumors and from poorly differentiated sarcomas. MDM2 and CDK4 are positive in the majority of the former and negative in most of the latter.36 FISH and real-time PCR are more sensitive techniques and these should complement immunohistochemistry in difficult cases.37 p16 has also been advocated as useful in the distinction between ALT-WDLPS and lipoma as the latter do not express this marker.38

Differential diagnosis

Fig. 35.49 Myxoid liposarcoma: round cell differentiation. The nuclei are hyperchromatic and pleomorphic.

Atypical lipomatous tumor (ALT) is distinguished from a lipoma by the variation in the size of the adipocytes and the presence of cells with hyperchromatic nuclei in the former condition. The changes seen in massive localized lymphedema associated with morbid obesity may mimic an atypical lipomatous tumor but the former lacks adipocytes with atypia and consists of large lobules of mature adipocytes with edema, thick septa and vascular proliferation within the septa.39,40 Subconjunctival herniated orbital fat may be confused with an ALT, as the former often contains multinucleate floret-like giant cells (a mimic of pleomorphic lipoma), fibrous tracts and Lockhern cells. However, atypical cells within fibrous septae are absent in subconjuctival herniated fat.41 Myxoid liposarcoma is distinguished from myxofibrosarcoma (myxoid malignant fibrous histiocytoma) by the lack of lipoblasts and the presence of more variable pleomorphism in the latter. Distinction from lipoblastoma may be very difficult or impossible. However, liposarcoma is very rare in children and, in difficult cases, cytogenetic studies may be helpful (see lipoblastoma). The diagnosis of pleomorphic liposarcoma is based on the identification of lipoblasts in the background of a pleomorphic sarcoma.

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Connective tissue tumors

Tumors of fibrous and myofibroblastic tissue Benign fibrous and myofibroblastic tumors Hypertrophic scar Clinical features Hypertrophic scars occur most frequently on the head and neck, chest, knees and shoulders and show no racial predilection.1–3 Clinically, they may be distinguished from keloids by being less raised and not extending beyond the boundaries of the initiating injury. Unlike keloids, hypertrophic scars are far less prone to recur after treatment, but, in fact, precise distinction between these two lesions is not always possible and they represent a continuous spectrum.4

Pathogenesis and histological features Hypertrophic scar appears to be induced by overactivation of dermal wound healing pathways, in some ways similar to that of keloids below.5–8 Transforming growth factor beta 1 has been associated with the induction of both hypertrophic scars and keloids by inducing production of collagen by fibroblasts particularly in early stages.9 The appearances are typified by a somewhat non-specific dermal ­fibroblastic proliferation, which is often associated with epidermal atrophy (Figs 35.51–35.53). They tend to be more cellular than keloids, and hyalinized collagen fibers are far less prominent. A nodular growth pattern is common. Evidence of a foreign body granulomatous reaction may ­sometimes be present.

Fig. 35.52 Hypertrophic scar: the lesion is composed of banal fibroblasts with a variably collagenous stroma.

Keloid Clinical features A keloid is a common reactive lesion that represents exuberant scar ­formation. It typically extends beyond the site of original injury.1–5 Although keloids occasionally appear to arise spontaneously, it is believed that most develop as a direct result of local trauma, even if minor or unnoticed (Figs 35.54–35.56).1–5 Keloids also develop as a result of inflammation in ­conditions such as acne vulgaris. The use of isotretinoin has also been linked to the development of keloids.6 Although these lesions may arise at any age, they are most common in adolescents and young adults; they occur at least four times more frequently in patients of African descent and show a slight predilection for females. A positive family history is not uncommon and probably reflects a genetic predisposition to keloid formation.

Fig. 35.51 Hypertrophic scar: within the dermis is a nodular fibrous lesion.

Fig. 35.53 Hypertrophic scar: note the spindled cells and collagenous stroma.

Fig. 35.54 Prominent keloid developing at the side of a tattoo. By courtesy of Dr J. Dayrit, Manila, The Philippines.

Benign fibrous and myofibroblastic tumors activating the synthesis of collagen by fibroblasts.11,12 The Wnt/β-catenin pathway associated with fibrosis and normal wound healing is strongly ­up-regulated and epigenetic changes affecting multiple profibrotic ­pathways are noted.13–15 The interaction between keratinocytes and fibroblasts appears to play an important role in the formation of keloids.16 It has been demonstrated that when keloid fibroblasts are co-cultured with keloid keratinocytes there is increased production of soluble and insoluble collagen and procollagen III mRNA up-regulation.17 The histological appearances are typified by a nodular fibroblastic ­proliferation and the presence of hypocellular, ‘glassy’, eosinophilic, hyalinized collagen fibers in the dermis (Figs 35.57, 35.58). Early lesions may show a slight vascularity and foci of myxoid ground substance. Normal mitoses may occasionally be seen.

Fig. 35.55 Keloid: lesions commonly follow trauma and are a frequent complication of piercing. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.57 Keloid: this lesion is distinguished from a hypertrophic scar by the presence of broad bundles of eosinophilic, hyalinized collagen.

Fig. 35.56 Keloid: extensive keloid formation can be very disfiguring. By courtesy of the Institute of Dermatology, London, UK.

Keloids usually occur on the head and neck (especially the ear), upper chest and arms, but may be seen at almost any cutaneous site although areas such as the hands and feet and the genitalia are very rarely affected.7 Characteristically, they present as raised, well-circumscribed, rather smooth lesions, becoming progressively more indurated as time passes. They are occasionally itchy or tender and may be multiple, again reflecting individual susceptibility to their development. Irrespective of the treatment used, local recurrence is very common.

Pathogenesis and histological features The pathogenesis of keloids is not clear but seems to be multifactorial.8 Genetic predisposition and local tissue tension play an important role. Collagen synthesis is increased in keloids and the quality of the collagen produced is also different from that in normal skin. Apoptosis is reduced in fibroblasts in keloids.9 There is an increased production of collagen I and III as demonstrated by an increase in levels of mRNA.10 Transforming growth factor beta (TGF-β) seems to play an important role in wound healing and its increased production has been linked to the pathogenesis of keloids by

Fig. 35.58 Keloid: high-power view: note the swollen hyalinized collagen bundles admixed with bland spindled cells.

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Connective tissue tumors

Nodular fasciitis Clinical features Nodular fasciitis is uncommon and represents a florid proliferative reactive process of unknown etiology.1–7 It is most often seen in young or middleaged adults of either sex, particularly on the limbs (especially the forearms) or trunk. Cases in children are rare and tend to favor the head and neck area (including the external auditory canal and oral cavity).8,9 The lesion ­presents as a rapidly growing, subcutaneous nodule rarely exceeding 4–5 cm in diameter, and is typically painful or tender. The tumor develops with such speed that most patients present within 3 months of first becoming aware of a mass. Local recurrence may be a feature, but is sufficiently infrequent that its occurrence should raise the possibility of misdiagnosis. Recurrence seems to be more common in lesions of the head and neck mainly in children and in lesions presenting in the auricle.10–12 Spontaneous regression may occur.13 Intraneural and intra-articular lesions are very rare.14,15

Pathogenesis and histological features A few cases of nodular fasciitis have shown evidence of clonality, suggesting that the lesion is neoplastic.16–19 DNA ploidy studies of nodular fasciitis have revealed a diploid pattern.16 Nodular fasciitis is typified by a relatively well-circumscribed but ­unencapsulated mass composed of plump spindled cells set in a loose myxoid and collagenous stroma with a typically feathery, microcystic appearance (Figs 35.59–35.62). Numerous thin-walled blood vessels, often lined by rather prominent endothelial cells, ramify through the lesion, usually in a radial arrangement. Foci of hemorrhage and a sparse chronic inflammatory infiltrate composed largely of lymphocytes are usually present, and occasional cases contain foamy histiocytes and multinucleate osteoclast-type giant cells. The plump spindled cells (Figs 35.63–35.65) are mitotically active, but the mitoses are never atypical. The degree of cellularity and relative amounts of collagenous tissue and loose edematous stroma vary between lesions, probably reflecting the duration of the process. Extension into skeletal muscle is rare and mainly seen in lesions of the head and neck.10 Immunohistochemistry shows diffuse positivity for muscle actin and calponin, but desmin and h-caldesmon are usually negative, in keeping with myofibroblastic differentiation (Fig. 35.66).20

Fig. 35.60 Nodular fasciitis: this view highlights the circumscription.

Fig. 35.61 Nodular fasciitis: in this lesion, there is a much more irregular border.

Fig. 35.59 Nodular fasciitis: low-power view showing a wellcircumscribed example.

Fig. 35.62 Nodular fasciitis: the stroma is characteristically myxoid, which results in this feathery appearance.

Benign fibrous and myofibroblastic tumors

Fig. 35.63

Fig. 35.66

Nodular fasciitis: foci of hemorrhage are commonly present.

Nodular fasciitis: the spindled cells show strong SMA expression.

Fig. 35.64

Fig. 35.67

Nodular fasciitis: small numbers of lymphocytes are usually evident.

Nodular fasciitis: ultrastructurally, the spindled cells show features of myofibroblasts. Note the conspicuous rough endoplasmic reticulum and filaments with dense bodies.

Ultrastructurally, the tumor cells have abundant rough endoplasmic r­ eticulum and contain aggregates of filaments with dense bodies deep to the plasma membrane (Fig. 35.67).

Variants • Intradermal fasciitis refers to a very rare variant of fasciitis that primarily

•

•

• Fig. 35.65 Nodular fasciitis: in this example multiple giant cells are seen.

arises in the dermis with only focal extension into the subcutaneous tissue.21–25 A polypoid architecture is exceptional.26 Histological features are identical to those of the classic variant (Figs 35.68–35.70). Fasciitis ossificans describes the small proportion of cases of nodular fasciitis that show metaplastic formation of osteoid, mature bone or even cartilage.5,27 A zoning pattern of maturation, as seen in myositis ossificans, is usually absent. In some cases, osteoid formation is only focal and calcification may be absent. Fibro-osseous pseudotumor of the digits is described below. Periosteal fasciitis arises from the periosteum and most often presents on the head of children (usually under the age of 2 years and with predilection for males). It is then known as cranial fasciitis when there is significant erosion of bone.28 Proliferative fasciitis tends to occur in rather older adults and quite often affects the lower limbs, but is otherwise clinically similar to typical nodular fasciitis.29–31 Regression, sometimes rapid, may occur.32 Intradermal lesions

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Connective tissue tumors are exceptional.33 Histologically, in addition to the features described above, this subset of cases is characterized by the presence of numerous basophilic, ganglion-like giant cells, which are often multinucleated and may be mitotically active (Figs 35.71, 35.72). Distinction from pleomorphic rhabdomyoblasts is afforded by the cytoplasmic basophilia, short history and usually superficial nature of proliferative fasciitis. • Intravascular fasciitis is a very rare lesion seen most often in young adults. Although histologically very similar to typical nodular fasciitis, it involves the full thickness and lumen of a peripheral blood vessel (usually a vein), and therefore simulates vascular invasion.7,34–36 To avoid a diagnosis of malignancy, careful attention should be paid to the bland histological features. Ultrastructural studies show cells with features of fibroblasts and myofibroblasts.

Differential diagnosis Fig. 35.68 Dermal fasciitis: low-power view showing a myxoid dermal spindled cell proliferation.

Fig. 35.69

Features that should raise the possibility of malignancy in diagnostically ­difficult lesions include abnormal mitotic figures, nuclear hyperchromasia or pleomorphism and necrosis. The dermal variant of nodular fasciitis can be distinguished from benign fibrous histiocytoma because the latter is more polymorphic and actin tends to be only focally positive or negative.

Fig. 35.71

Dermal fasciitis: the spindled cells have uniform vesicular nuclei with small nucleoli.

Proliferative fasciitis: the fascia is thickened, edematous and infiltrated by large numbers of ganglion-like giant cells.

Fig. 35.70

Fig. 35.72

Dermal fasciitis: normal mitoses are often present.

Proliferative fasciitis: the ganglion-like cells have abundant eosinophilic cytoplasm and large vesicular nuclei containing prominent nucleoli.

Benign fibrous and myofibroblastic tumors

Fibro-osseous pseudotumor of the digits Clinical features This is a reactive myofibroblastic proliferation with bone formation, which occurs almost exclusively on the digits (Fig. 35.73).1–3 It presents predominantly in young adults, with predilection for females. The fingers are more commonly affected than the toes. A single identical lesion occurred on the forehead.3 The lesion grows rapidly and it is not attached to bone. There is no tendency for local recurrence.

Pathogenesis and histological features The tumor is ill-defined and similar to nodular fasciitis, except for the fact that there is formation of osteoid and mature bone (Figs 35.74–35.76). Edematous stroma, vascular proliferation and bundles of spindle-shaped myofibroblast-like cells are seen intermixed with osteoid and mature bone. Mitotic figures are present and their number depends on the age of the lesion. Proliferating cells are positive for smooth muscle actin and calponin.

Proliferative myositis

Fig. 35.74

Clinical features

Fibro-osseous pseudotumor of the digits: scanning view showing osteoid, foci of calcification and a myxoid spindle cell tumor.

Proliferative myositis is closely allied to nodular fasciitis. It is a deep ­intramuscular lesion, which represents the deep counterpart of proliferative fasciitis; it is therefore rarely encountered in dermatology.1–3 It is regarded as

Fig. 35.75 Fibro-osseous pseudotumor of the digits: medium-power view showing calcified osteoid and spindled cells within a myxoid matrix.

Fig. 35.73 Fibro-osseous pseudotumor of the digits: this lesion presented as a rapidly growing nodule. Note the prominent calcification. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.76 Fibro-osseous pseudotumor of the digits: high-power view of tumor myofibroblasts.

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Connective tissue tumors a reactive condition of rapid onset and is entirely benign. It usually occurs in the fifth and sixth decades, and most often affects the trunk or proximal upper limbs. Presentation in children is rare.1 Most tumors are only a few centimeters in diameter. Simple excision is curative.

Pathogenesis and histological features Cytogenetic studies have been reported in two cases of proliferative myositis. Both have demonstrated the presence of trisomy 2 and, in one, a t(6;14) (q23;q32) was identified.4,5 Histologically, proliferative myositis is characterized by proliferating spindled cells and large basophilic ganglion-like cells distributed within the fibrous tissue septa surrounding and dividing striated muscle fibers. These fibers are displaced rather than destroyed by the tumor and lesional cells alternating with skeletal muscle fibers produce a typical ‘checkerboard’ pattern (Figs 35.77, 35.78). Normal mitotic figures are commonly found. Bone and cartilage may occasionally be seen.6 Lesions in children tend to be more circumscribed, are more cellular and may show necrosis.1 The spindle-shaped proliferating cells are positive for actin but negative for desmin, whereas the ganglion-like cells may be negative for actin and are negative for neural markers.6 Electron microscopy studies indicate that these cells have features of fibroblasts.7,8 The flow cytometry profile of these lesions is diploid.9

Differential diagnosis Distinction from a sarcoma may be difficult in small lesions, especially if close clinicopathological correlation is lacking. Most sarcomas have a larger size and although a ‘checkerboard’ appearance may be present in sarcomas or metastatic carcinomas, this is usually only focal and there is more tendency towards destruction of the surrounding muscle. A desmoid tumor lacks ganglion-like cells and usually replaces the muscle completely.

Ischemic fasciitis Clinical features Ischemic fasciitis (also known as atypical decubital fibroplasia) is a relatively rare pseudosarcomatous fibroblastic/myofibroblastic condition that occurs over bony prominences.1–3 The great majority of patients are elderly (between the sixth and ninth decades of life) and immobilized. Lesions consist of an asymptomatic, subcutaneous, ill-defined mass only occasionally associated with ulceration. The majority of lesions arise in the deep subcutaneous tissue but involvement of the dermis and deeper soft tissues including skeletal muscle and tendons may also be seen.4 Exclusive involvement of skeletal muscle is very rare.4 Most tumors are less than 4 cm in diameter but larger lesions also occur. The usual sites are the shoulders, thighs, buttocks, sacral area and chest wall. Local excision is generally curative and recurrences are only seen in patients where the predisposing factor persists. A case of ischemic fasciitis associated with bizarre parosteal osteochondromatous proliferation has been documented.5

Pathogenesis and histological features

Proliferative myositis: the muscle fibers are separated by a cellular infiltrate, giving a ‘checkerboard’ appearance.

The proliferation is thought to be due to ischemia induced by pressure resulting from prolonged immobilization. However, a recent study has not ­consistently found immobility or debilitation.4 Some cases are triggered by trauma.4 Histologically, lesions are multilobular and characterized by ­replacement of the subcutaneous tissue by areas of fibrinoid necrosis and granulation ­tissue (Figs 35.79, 35.80). Myxoid change, hemorrhage and edema are ­usually prominent. In the areas of necrosis there is marked fibrinoid change and ghosts of necrotic adipocytes are seen. At the periphery there is vascular proliferation accompanied by variable numbers of spindle-shaped and more round cells with irregular hyperchromatic nuclei and a single ­prominent ­basophilic nucleolus. Ganglion-like cells similar to those present in proliferative ­fasciitis are also found and in these the nuclei contain smudged chromatin (Fig. 35.81). Mitotic figures may be found but atypical forms are generally not seen. Thrombosis of blood vessels is also a feature. Immunohistochemistry shows that the cells in the proliferation are ­variably positive for smooth muscle actin (SMA), calponin and desmin.4

Fig. 35.78

Fig. 35.79

Proliferative myositis: the giant cells have abundant cytoplasm and contain large vesicular nuclei with prominent intensely eosinophilic nucleoli.

Ischemic fasciitis: scanning view showing massive fibrin deposition with adjacent granulation tissue.

Fig. 35.77

Benign fibrous and myofibroblastic tumors ­ resentation has been described in up to 30% of cases.5,15 Tumors are usually p asymptomatic and may reach a large size. Simple excision is the treatment of choice but asymptomatic lesions do not necessarily need to be removed.16,17 Recurrence is extremely uncommon.

Pathogenesis and histological features

Fig. 35.80 Ischemic fasciitis: this field shows an atypical cellular population.

It is a commonly held belief that elastofibroma arises as a consequence of chronic frictional trauma between the scapula and underlying connective tissues, but a relationship with heavy manual labor is unsubstantiated. The theory that the process is a result of degeneration is given support by the finding of changes similar to those of elastofibroma in tissue taken in autopsies of elderly patients with no discernible mass.18,19 Cytogenetic studies have shown clonal and nonclonal structural changes, particularly aberrations of the short arm of chromosome 1.20–22 Elastofibroma is typically an ill-defined unencapsulated mass merging with adjacent connective tissue and composed of fairly acellular collagenous and adipose tissue containing numerous elastic fibers (Figs 35.82, 35.83). These fibers, ideally demonstrated by an appropriate histochemical stain, tend to be coarse, thick or globular, and are sometimes distributed as irregular masses (Fig. 35.84). It has been shown that the fibers represent true elastin and not elastotic collagen.23,24 The cells in the background tend to be positive for CD34 but negative for myofibroblastic markers.25

Fig. 35.81

Fig. 35.82

Ischemic fasciitis: there are atypical spindled cells and histiocyte-like cells, some with a ganglion-like appearance.

Elastofibroma: there is an admixture of collagen bundles and thickened, irregular, eosinophilic elastic fibers.

Differential diagnosis As already discussed, this lesion closely resembles proliferative fasciitis and is probably best regarded as a variant of nodular fasciitis. Distinction between ischemic fasciitis and a sarcoma is based on the relatively low mitotic count, the absence of atypical mitotic figures and the low cellularity in the former lesion.

Elastofibroma Clinical features Elastofibroma is an uncommon, deep-seated pseudotumor that is thought to represent a degenerative and reactive change in elastic fibrous tissue.1–5 It almost always arises in the infrascapular region, most often in the elderly, and is usually unilateral. Rare cases have been reported in the hip, hand, olecranon, upper arm, eye and oral cavity.6–8 Elastofibromatous changes are ­present in a number of samples obtained from patients operated for spinal canal ­compression.9 Infrequently, lesions are bilateral and multiple;10–12 Often, the second lesion is subclinical and can only be detected ­radiologically.13 A ­visceral location is very rare but includes the trachea and gastrointestinal tract.14 Females are predominantly affected and, although tumor size varies, fixation to the periosteum of the underlying ribs is invariable. Familial

Fig. 35.83 Elastofibroma: the elastic fibers are fragmented and appear beaded.

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Connective tissue tumors catheter use.12 It has been suggested that fibroepithelial polyps should not be submitted for histological examination since malignant tumors only very exceptionally show similar clinical features.13 This is, however, controversial and, in our view, all should be carefully evaluated. Melanoma, for example, may very rarely grossly mimic a fibroepithelial polyp. Fibroepithelial ­polyps in children are very rare and their occurrence has been reported as a ­presenting sign of the nevoid basal cell carcinoma syndrome.14 Lesions ­identical to fibroepithelial polyps have been described in the tongue of ­immunosuppressed patients and may also occur in the skin.15,16 In these patients, the polypoid lesions show features of basal cell carcinoma. Fibroepithelial polyps can be associated with the rare Birt-Hogg-Dubé syndrome.

Histological features Fibroepithelial polyps show a normal or hyperplastic epidermis surrounding a core of fibrovascular tissue with loose or dense collagen fibers (Figs 35.86, 35.87). Fat cells can be present and, if abundant, the lesion shows overlap with nevus lipomatosus superficialis. Focal pagetoid dyskeratosis may be an incidental finding in keratinocytes.17 Fig. 35.84 Elastofibroma: the serrated edge so characteristic of this condition is seen in this elastic–van Gieson stained section.

Differential diagnosis Identification of the distinctive changes in the elastic fibers allows for easy recognition of the condition. Nuchal fibroma is distinguished from elastofibroma by the absence of altered elastic fibers and the presence of fairly thick collagen bundles in the former condition.

Fibroepithelial polyp Clinical features Fibroepithelial polyps (acrochordon, skin tag, soft fibroma) are very common lesions that typically present in adults, especially obese females, with a predilection for the neck, axillae and groin.1,2 Perianal lesions are also frequently encountered. Rare lesions have been documented in the umbilicus.3 These polyps are often multiple and can be associated with pregnancy. Contrary to what was proposed in the past, they do not appear to be a marker for colonic polyps.4,5 An association with diabetes mellitus has been ­suggested.6,7 Lesions are usually less than 1 cm in diameter and can be papular, filiform or pedunculated (Fig. 35.85). Rarely, tumors such as squamous cell carcinoma, keratoacanthoma and basal cell carcinoma may develop within a ­fibroepithelial polyp.8–11 Lymphedematous fibroepithelial polyps have been documented in the glans penis and prepuce as a result of chronic condom and

Fig. 35.85 Acrochordon: also known as a skin tag or fibroepithelial polyp, this soft polyp is exceedingly common. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.86 Acrochordon: histologically, it consists of connective tissue covered by squamous epithelium.

Fig. 35.87 Acrochordon: this unusually sectioned example shows the features to advantage.

Benign fibrous and myofibroblastic tumors

Histological features Histology is distinctive and shows a plaque-like proliferation of fascicles of bland spindled cells with pale eosinophilic cytoplasm and elongated vesicular nuclei with one or two nucleoli (Figs 35.90–35.92). These fascicles tend to be parallel to the epidermis. The papillary dermis is usually spared and there is entrapment, but no destruction of adnexal structures by the tumor. Focal extension into the subcutaneous tissue is sometimes seen and occurs mainly along the septa in a perpendicular fashion. Rare cases display prominent hemorrhage.13 Myofibroblastic differentiation is suggested immunocytochemically by actin and calponin expression (Fig. 35.93). However, expression of actin and calponin is variable and may be focal or negative.6 CD34 may be focally positive.6 H-caldesmon and desmin are negative. Electron microscopy shows cells with features of fibroblasts and myofibroblasts.14

Differential diagnosis Pleomorphic fibroma: this lesion is characterized by the presence of scattered mononuclear and multinucleated giant cells.

Dermatomyofibroma should be distinguished from plaque-stage dermatofibrosarcoma protuberans, in which the tumor cells are more basophilic and infiltrative. In addition, tumor cells in dermatofibrosarcoma protuberans are actin negative, and are usually diffusely positive for CD34.

Fig. 35.89

Fig. 35.90

Fig. 35.88

Pleomorphic fibroma: note the fusiform and stellate cells with hyperchromatic irregular nuclei.

Dermatomyofibroma: low-power view showing fascicles of spindled cells orientated parallel to the surface epithelium.

Pleomorphic fibroma refers to a small proportion of cases of acrochordons that show cells with bizarre hyperchromatic and pleomorphic nuclei (Figs 35.88, 35.89).18 Multinucleation is also a feature, but mitotic figures are very few and never atypical. These cells are actin positive and the changes are likely to be the result of degeneration, as seen in other tumors such as pleomorphic lipoma and ancient schwannoma. Similar lesions have been described under the name cutaneous pseudosarcomatous polyp.19,20 Changes similar to pleomorphic fibroma may also be seen in ‘regressed’ or hyalinized examples of solitary myofibroma or dermatomyofibroma.

Dermatomyofibroma Clinical features Dermatomyofibroma is a rare tumor that presents as a solitary, slowly growing, asymptomatic, skin-colored or hypopigmented plaque.1–6 It ­usually ­presents on the upper trunk or neck of young adults, with a predilection for females. Most lesions are less than 4 cm in diameter. Tumors may resemble a plaque lesion of dermatofibrosarcoma protuberans or a keloid. An exceptional case presenting in a linear distribution and one with an annular ­configuration have been documented.7,8 Rare cases occur in children.9–11 Multiple tumors are very rare.12 Local recurrence is exceptional.

Fig. 35.91 Dermatomyofibroma: the fascicles grow between the dermal collagen bundles.

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Connective tissue tumors

Histological features Microscopically, storiform collagenoma is a well-circumscribed dermal ­nodule composed of hypocellular hyalinized collagen bundles separated by clefts and arranged in a storiform pattern (Figs 35.94–35.96). Rare ­spindle-shaped cells are occasionally seen. Occasional lesions display more cellularity and ­scattered pleomorphic cells as seen in pleomorphic fibroma; hence, a link has been suggested between both entities.11,12 Tumor cells are positive for CD34 and CD99.12 Giant cell collagenoma appears to be a variant of storiform collagenoma with scattered multinucleate giant cells, some of which have a bizarre appearance.13,14 On electron microscopy the lesional cells are seen to be separated from blood vessels by laminated concentric collagen resulting in a plywood-like pattern.15

Differential diagnosis

Fig. 35.92 Dermatomyofibroma: the tumor cells have eosinophilic cytoplasm and regular elongated nuclei.

Areas simulating storiform collagenoma are sometimes seen in a variety of tumors, including fibroma of tendon sheath (which is never dermal), sclerotic fibrous histiocytomas, neurofibroma and even solitary myofibromas.16,17 However, the distinctive histological features of these latter conditions are usually apparent in neighboring fields. Dermal lipomas with prominent

Fig. 35.93

Fig. 35.94

Dermatomyofibroma: the tumor cells express smooth muscle actin.

Storiform collagenoma: the storiform arrangement of these eosinophilic collagen bundles is characteristic.

Dermatomyofibroma may also be confused with diffuse neurofibroma. The latter, however, is paler, lacks parallel orientation of tumor cells to the epidermis, and is S-100 protein and CD34 positive. Rare hemorrhagic cases may be confused with nodular stage Kaposi's sarcoma. However, in the latter condition, tumor cells are arranged in nodules, and are accompanied by numerous cleft-like spaces containing red blood cells. Inflammatory cells including plasma cells are always present, eosinophilic globules are prominent and all cases show nuclear reactivity with immunohistochemistry for human herpesvirus.8

Storiform collagenoma Clinical features Storiform collagenoma (also known as sclerotic fibroma) is a solitary skincolored nodule, usually less than 1 cm in diameter.1,2 It presents in adults of either sex and has a wide anatomical distribution. Simple excision is ­curative. Multiple lesions with identical histological features are seen in Cowden's ­disease (multiple hamartoma and neoplasia syndrome) and it has been suggested that they represent a marker for this condition.3–6 In this setting, and also sporadically, such lesions have also been described in the oral cavity.7–9 An exceptional case has been documented in the nail.10

Fig. 35.95 Storiform collagenoma: high-power view.

Benign fibrous and myofibroblastic tumors

Fig. 35.96

Fig. 35.97

Storiform collagenoma: the features are highlighted with Masson's trichrome stain.

Nuchal fibroma: the tumor consists of hypocellular collagen with a keloid-like appearance.

s­ clerosis may simulate a storiform collagenoma but mature adipocytes are always demonstrated in the former lesion.18 Focal changes simulating ­sclerotic fibroma may also be seen in inflammatory conditions such as ­erythema ­elevatum diutinum and folliculitis.19

Nuchal fibroma Clinical features Nuchal fibroma (also known as collagenosis nuchae) is a distinctive dermal and subcutaneous tumor that tends to present mainly in the posterior neck of men between the third and fifth decades of life.1–5 Despite the name, up to a third of lesions can occur in other locations including the shoulder, back and even the face and limbs (including a lesion on an ankle).2–7 It has been proposed that lesions occurring in extranuchal sites should be described as nuchal-type fibroma. An association with diabetes has been documented.5,8 Identical tumors – when multiple and presenting in children – are usually seen in Gardner's syndrome (see below).9,10 Tumors are asymptomatic and measure less than 3 cm in diameter. Local recurrence occurs in a small number of cases but this is not destructive. A case associated with dermatofibrosarcoma protuberans has been documented.11

Histological features Tumors are poorly circumscribed and composed of thick collagen bundles with a lobular architecture and few scattered fibroblasts (Figs 35.97, 35.98). Entrapped fat and traumatic neuroma-like changes are often seen. Occasionally, there is focal infiltration of skeletal muscle. Mononuclear inflammatory cells are rare. By immunohistochemistry, tumor cells are positive for CD34 and CD99 but negative for desmin and actin.12

Differential diagnosis Desmoid fibromatosis may show focal areas resembling a nuchal fibroma but, in most areas, tumors are more cellular and show prominent infiltration of surrounding tissues.13

Gardner fibroma Clinical features Gardner fibroma is a benign soft tissue tumor identical to nuchal fibroma, presenting in patients with Gardner's syndrome (colonic adenomatous ­polyposis, epidermoid cysts), a familial adenosis poliposis (FAP) variant also associated with germline inactivating mutations in APC.1 The tumor may be the first manifestation of the disease and lesions tend to be ­multiple,

Fig. 35.98 Nuchal fibroma: high-power view.

a­ rising in children and at different sites including the neck, head, trunk and ­extremities.2–4 Desmoid fibromatosis may develop at the sites of Gardner fibromas and the relationship of these two lesions is unclear. Lesions are poorly ­circumscribed, slow growing and range in size from 2 to 10 cm. Local recurrence is possible.

Pathogenesis and histological features These tumors are driven by overaction of the Wnt/β-catenin pathway ­secondary to inactivation of the APC gene.1,5,6 Tumors are identical to nuchal fibroma (see above) but some lesions are more cellular and lack a lobular growth pattern.7 Immunohistochemistry to examine for nuclear ­accumulation of beta-catenin may be helpful, but is not entirely specific.8

Nuchal fibrocartilaginous pseudotumor Clinical features Nuchal fibrocartilaginous pseudotumor is a rare distinctive proliferation described in adults and rarely in children.1–4 Patients usually (but not always) have a previous history of neck injury and present with an asymptomatic mass on the posterior aspect of the neck at the junction of the nuchal ­ligament and the deep cervical fascia.1,3 Tumors are only a few centimeters in diameter.

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Connective tissue tumors

Histological features Histology shows a poorly circumscribed tumor consisting of moderately ­cellular fibrocartilaginous tissue within the nuchal ligament. Mitotic figures are rare and cytological atypia is absent. Tumor cells are positive for vimentin and CD34 and scattered chondroid cells stain for S-100 protein.5 Actin, desmin and keratin are negative. Ultrastructural studies show cells with features of fibroblasts and ­chondroblasts. No myofibroblasts are identified.5

Fibromatosis colli Clinical features Fibromatosis colli is a rare condition seen only in infants and children. Most of the cases present within the first few weeks of life, with no sex ­predilection.1–3 Typically, a mass involving the distal sternocleidomastoid muscle and ­measuring less than 3 cm in diameter is seen. The mass results in ­rotation of the head and torticollis. Lytic clavicular lesions have been reported.4 Treatment is surgical but in some cases there is slow spontaneous resolution.

Pathogenesis and histological features

Fig. 35.99 Calcifying fibrous tumor: this example shows a relatively hypocellular tumor. Note the focal calcification.

Fibromatosis colli appears to be related to trauma, as often there is a history of intrauterine positional abnormalities or complicated deliveries.1–3 Other musculoskeletal abnormalities may also be seen. Histology shows partial replacement of skeletal muscle by collagenous ­tissue with poor cellularity. Degenerate muscle fibers are commonly seen.

Differential diagnosis Distinction from infantile fibromatosis is based on the typical clinical presentation and the presence of a predominantly collagenous hypocellular mass in fibromatosis colli.

Calcifying fibrous tumor Clinical features Calcifying fibrous tumor (calcifying fibrous pseudotumor, childhood fibrous tumor with psammoma bodies) is rare and presents mainly in children and young adults with no sex predilection.1–3 Most tumors occur in subcutaneous and deeper soft tissues and exceptional oral, visceral (including the stomach, small intestine, adrenal gland, heart, lung and gallbladder), mediastinal and pleural examples have been documented.4–11 Multiple lesions are very rare and appear to be mainly pleural.12 Familial cases are uncommon.13 Soft tissue lesions favor the extremities and trunk. Associations with Castleman's disease and inflammatory myofibroblastic tumor have been reported.14,15 Size varies from 1 to 15 cm. Local ­recurrences may occur.16

Pathogenesis and histological features The pathogenesis is unknown and although a close relationship with inflammatory myofibroblastic tumor was proposed in the past, this is not likely.3 Histology shows a well-circumscribed mass consisting of sclerotic hypocellular collagen with scattered mononuclear inflammatory cells consisting of lymphocytes and plasma cells (Figs 35.99, 35.100). The latter may form focal aggregates. A striking feature is the presence of focal calcification with formation of psammoma bodies.1,2 Tumor cells are diffusely positive for CD34 and rare cells may be positive for actin and desmin.3 ALK-1 is negative.3

Differential diagnosis The presence of a tumor combining sclerotic collagen, inflammation and calcification is distinctive and allows differential diagnosis from other tumors such as desmoplastic fibroblastoma.

Fig. 35.100 Calcifying fibrous tumor: note the inflammatory cell infiltrate, which is often a feature of this tumor.

Myofibroma and myofibromatosis Clinical features Solitary and multicentric myofibromas are relatively rare tumors with marked predilection for children.1–8 Myofibroma forms part of the spectrum of myopericytoma.9,10 The majority of tumors present before the age of 2 years and many of these are congenital. It appears as a usually solitary dermal, ­subcutaneous, intramuscular nodule or rarely intraosseous tumor, and is more frequently seen in males.11,12 In the solitary form, the head and neck (including the oral cavity and rarely the pharynx) are most often involved, followed by the trunk and extremities.1–8,13–15 A lesion involving the sclera has been documented.16 Individual lesions are firm or rubbery, somewhat nodular and rarely exceed 3–4 cm in diameter. Although most tumors are single, multiple lesions may occur in children and occasionally in adults. Multicentric tumors in children have also been referred to as congenital generalized fibromatosis and infantile myofibromatosis (Fig. 35.101).4–8,17 In these cases, patients are more often female and are found to have multiple soft tissue lesions with associated bony, oral or (rarely) visceral tumors of a similar nature.18 Organs involved include the kidney, lung, pancreas, gastrointestinal tract, liver and rarely the central nervous system.1,19–23

Benign fibrous and myofibroblastic tumors

Fig. 35.101

Fig. 35.102

Infantile myofibromatosis: multiple large tumor nodules are present. By courtesy of the Institute of Dermatology, London, UK.

Infantile myofibromatosis: scanning view of a circumscribed tumor showing a hemangiopericytomatous central component.

A few cases appear to be inherited, most often in an autosomal dominant pattern.5,24–26 A single case associated with porencephaly, hemiatrophy and cutis marmorata telangiectatica congenita has been documented.27 A case associated with thrombocytopenia has been reported.28 Myofibroma in adults is almost always solitary and superficial, only exceptionally presenting as multiple lesions. A patient with multiple acral lesions had generalized morphea.29 Usually, they affect the skin or oral mucosa, and no familial cases have been reported. Most patients are young to middle-aged adults of either sex who present with a firm superficial nodule up to 3 cm in diameter.1–3 Lesions may be painful. Local recurrence is very rare.30 Solitary soft tissue or associated bony lesions may recur locally if excised; however, if these lesions are left untreated, spontaneous regression is very common. In contrast, if there is visceral involvement the course is often fatal, being associated with progressive impairment of respiratory or ­gastrointestinal function.

Histological features Lesions tend to be reasonably well circumscribed, but unencapsulated. A ­distinctive biphasic pattern is commonly produced by the presence of ­varying proportions of two populations of cells. These comprise: • fascicles of bland eosinophilic myofibroblasts with tapering or vesicular nuclei, • more primitive, smaller, round and spindle-shaped cells with scanty cytoplasm and round or oval nuclei (Figs 35.102–35.105). The latter cells tend to be arranged around branching blood vessels in a hemangiopericytomatous pattern (Fig. 35.106). Small foci of necrosis and vascular invasion are often present. Mitotic figures may be readily found, but are never abnormal. Tumor cells in both components are usually focally smooth muscle actin positive.6 Calponin tends to be more diffusely positive and h-caldesmon is focally positive.31 In some cases, especially those with multicentric disease, the primitive areas with a hemangiopericytoma-like pattern predominate. These lesions are almost identical clinically and histologically to tumors classified in the past as infantile hemangiopericytoma and it has been proposed that the latter belong to the spectrum of infantile myofibromatosis.32 The histological features of myofibroma are identical to those of infantile myofibromatosis, but the more primitive hemangiopericytomatous component is often not prominent and can be almost absent (Figs 35.107, 35.108). The myofibroblastic nodules may undergo hyalinization with a pseudochondroid appearance. Some tumor nodules appear to be in intravascular ­locations but this mainly represents subendothelial growth. This is seen in up to 30% of cases.1 Tumor cells are positive for muscle actin.

Fig. 35.103 Infantile myofibromatosis: high-power view showing primitive cells with basophilic vesicular nuclei.

Fig. 35.104 Infantile myofibromatosis: this field highlights the myofibroblastic component.

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Connective tissue tumors

Fig. 35.105

Fig. 35.108

Infantile myofibromatosis: the tumor cells express smooth muscle actin.

Myofibroma: high-power view.

Differential diagnosis The presence of a biphasic pattern allows distinction from cutaneous smooth muscle tumors, which are also consistently actin and desmin positive, and from fibrous histiocytoma, which is more polymorphic and less well circumscribed.

Fibroma of tendon sheath Clinical features Fibroma of tendon sheath is a relatively common tumor and is usually seen in the third to fifth decades. It predominates in males and is virtually confined to the extremities, especially the fingers, hands, wrists and more rarely the knees.1–8 The lesion presents as a solitary, usually painless, subcutaneous nodule attached to a tendon or tendon sheath, particularly on the flexor aspect. It rarely exceeds 2 cm in diameter and is of variable duration. Exceptionally, bone erosion has been documented.9 It may occur in an intra-articular location.10–12 An association with carpal tunnel syndrome is occasionally seen.13 Local recurrence may be seen in up to 24% of cases, almost always as a result of marginal or incomplete excision.2 Fig. 35.106 Infantile myofibromatosis: high-power view of the center of the lesion shown in Figure 35.102, highlighting the hemangiopericytomatous vascular network.

Histological features Fibroma of tendon sheath is a well-circumscribed encapsulated tumor with a lobulated appearance. It shows marked variation in cellularity and is ­composed of an admixture of dense, relatively acellular, fibrous tissue containing scattered uniform spindled cells and foci of myxoid change. Collagenous hyalinization and areas of increased cellularity, sometimes resembling nodular fasciitis, are commonly present (Figs 35.109, 35.110). In uniformly cellular lesions the spindled cells are more often arranged in fascicles. These are composed of closely packed fibroblasts showing infrequent normal mitotic figures. A cardinal feature of this lesion, irrespective of the degree of collagenization, is the presence of numerous, usually slit-like, vascular spaces lined by normal endothelium (Fig. 35.111). A scattered chronic inflammatory infiltrate is not uncommon and some cases show rare, osteoclast-like giant cells and foamy macrophages, suggesting a histological spectrum with giant cell tumor of tendon sheath.14 Cytogenetic studies in a single case have found a t(2;11)(q31-32;q12).15 The same cytogenetic abnormality has been found in collagenous fibroma ­(desmoplastic fibroblastoma) suggesting a genetic link between both entities.16

Differential diagnosis Fig. 35.107 Myofibroma: low-power view of a dermal nodule. Even at this magnification, the biphasic nature of the tumor is apparent.

The encapsulation and presence of a distinctive vascular pattern separate fibroma of tendon sheath from nodular fasciitis and fibromatosis. Dermal lesions composed of hypocellular eosinophilic concentric collagen, and ­considered in the past to be examples of fibroma of tendon sheath, ­represent examples of storiform collagenoma.

Benign fibrous and myofibroblastic tumors

Desmoplastic fibroblastoma Clinical features Desmoplastic fibroblastoma (collagenous fibroma) is a distinctive, benign soft tissue tumor that mainly presents in a subcutaneous, fascial or intramuscular location.1–4 Presentation in the dermis is very rare and in one of the reported cases, the patient had a long-standing history of pemphigus.5–8 Lesions are asymptomatic and present as a slowly growing mass, most commonly located on the arm, shoulder, thigh, forearm, back and hands and feet.4 Size varies from 1 to 20 cm but the majority of tumors measure less than 4 cm. Unusual tumors presenting on the neck mimicking a goiter, on the face mimicking a parotid tumor, in the oral cavity (including the tongue), in a lacrimal gland and within a joint have been documented.9–15 Most patients are middle-aged to elderly males but cases in younger patients and in children may rarely occur.4,16 The clinical behavior is entirely benign with no local recurrences reported in the literature to date. Fig. 35.109 Fibroma of tendon sheath: scanning view of a densely hyalinized nodule.

Pathogenesis and histological features Cytogenetic studies in multiple cases have shown clonal abnormalities involving 11q12.17–20 This locus is identical to that found in a single case of fibroma of tendon sheath.21 Tumors are fairly well circumscribed, round or oval and sometimes appear lobulated (Figs 35.112, 35.113). Low-power examination reveals a lesion with very focal infiltration of surrounding tissues, poor cellularity and a prominent collagenous stroma.1–4 Tumor cells are elongated or stellate, with vesicular nuclei, a small nucleolus and pale cytoplasm. Mitotic figures are not seen. In some cases there is focal myxoid change. Vascularity is not prominent and consists of small blood vessels with thin walls. Immunohistochemistry shows diffuse positivity for vimentin, focal positivity for α-SMA and occasional positivity for keratin.4 There is negative staining for other markers including S-100 protein, CD34 and desmin. Ultrastructural studies suggest that the cells in the lesion are fibroblasts or myofibroblasts.7,22

Differential diagnosis

Fibroma of tendon sheath: high-power view showing scattered myofibroblasts.

The main differential diagnosis is fibromatosis. The latter tumor has an infiltrative growth pattern, is cellular, tumor cells have an elongated appearance and there is a prominent vascular network. An old lesion of nodular ­fasciitis is usually more hyalinized, with focal inflammation and degenerative changes. Fibroma of tendon sheath almost always occurs in acral sites and has a ­prominent lobular architecture with a conspicuous vascularity.

Fig. 35.111

Fig. 35.112

Fibroma of tendon sheath: bland fibroblasts are evident in this field. Note the slitlike vessel.

Desmoplastic fibroblastoma: a low-power view showing a paucicellular tumor with abundant collagen.

Fig. 35.110

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Connective tissue tumors

Fig. 35.113 Desmoplastic fibroblastoma: the tumor cells are fusiform or stellate. Mitotic figures are absent.

Superficial acral fibromyxoma Clinical features Superficial acral fibromyxoma is a distinctive, relatively rare benign tumor with predilection for the fingers and toes, followed by the palm.1–5 Identical lesions have been described under the rubric cellular digital fibroma.6,7 Involvement of the nail region is very common. Lesions on the heel are rare.5 Patients are usually young to middle-aged adults and there is predilection for males. Tumors are small, slowly growing and asymptomatic. Local recurrence after excision is rare.8

Histological features Histology shows a fairly circumscribed dermal and/or subcutaneous tumor composed of bland, spindle-shaped or stellate cells with a focal storiform or fascicular pattern in a myxoid or collagenous stroma (Fig. 35.114). Lesions contain scattered small vascular channels. Some tumors are more cellular than others and in these, myxoid change tends to be very focal (Fig. 35.115).3 An adipocytic component is exceptional.9

Fig. 35.115 Superficial acral fibromyxoma: high-power view of bland spindled cells in a myxoid stroma.

Mitotic figures are rare and cytological atypia is mild or absent. Mast cells are often present. By immunohistochemistry, tumor cells are positive for CD34 and are commonly also positive for epithelial membrane antigen (EMA), CD99 and CD10.1–5 Ultrastructurally, tumor cells show cytoplasmic intermediate filaments and rough endoplasmic reticulum, indicating fibroblastic differentiation.10

Differential diagnosis The differential diagnosis includes neurofibroma, onychomatricoma, dermatofibrosarcoma protuberans and minute synovial sarcoma. Neurofibroma is rare in acral sites and, although tumor cells may be focally positive for CD34, they are also positive for S-100 protein. The stromal component in onychomatricoma may be identical to that seen in superficial acral ­fibromyxoma with CD34-positive cells. Distinction is based in the ­presence of distinctive epithelial changes in onychomatricoma.11 A focal storiform pattern may mimic dermatofibrosarcoma protuberans. However, the ­latter is vanishingly rare in the distal extremities, infiltrates the subcutaneous ­tissue diffusely and is positive for apolipoprotein D.12 Minute synovial sarcoma of the hands and feet can have similar appearances to superficial acral fibromyxoma with myxoid stroma and bland spindle-shaped cells.13 However, in the former there are focal areas of calcification, tumor cells are at least focally positive for keratin and cytogenetic analysis shows an tX;18 translocation.

Inclusion body fibromatosis Clinical features

Fig. 35.114 Superficial acral fibromyxoma: low-power view of a vascular spindle cell tumor with a myxoid stroma.

Inclusion body fibromatosis is a rare benign neoplasm initially described as infantile digital fibromatosis. The latter term derives from the fact that almost all cases arise on the fingers or toes of infants less than 3 years of age, and onethird of the cases are congenital.1–7 However, rare cases have been reported in older children and in adults and at other sites, and a more accurate designation is that of inclusion body fibromatosis.8–12 Typically, it presents as a small (usually less than 1 cm diameter), rapidly growing, dermal or subcutaneous nodule on the dorsal or lateral aspect of one of the digits; multiple lesions arising synchronously or separately on more than one digit (fingers and toes) are not uncommon. Lesions may also be seen elsewhere on the hands and feet.7 Inclusion digital fibromatosis shows a marked tendency towards local recurrence after excision (up to 50%), but has no capacity to metastasize. Spontaneous regression is usually seen in most cases and ­therefore treatment should only be symptomatic.

Benign fibrous and myofibroblastic tumors

Histological features The lesion is composed predominantly of an irregular mass of proliferating myofibroblasts, showing occasional normal mitoses, but no atypia, embedded in a dense collagenous stroma, which extends deeply from the dermis and may be attached to underlying osteoarticular structures (Fig. 35.116). The diagnostic sine qua non and characteristic feature is the presence of brightly eosinophilic intracytoplasmic inclusions in a variable number of the myofibroblasts (Figs 35.117, 35.118). Tumor cells are usually positive for alpha smooth-muscle actin, calponin and desmin.7 Occasionally, they may be positive for h-caldesmon and beta-catenin (nuclear staining).7 These inclusions are actin positive, especially in alcohol-fixed tissue, and the presence of these filaments has been demonstrated by immunoelectron microscopy.13,14 Positivity for actin may also be demonstrated if sections are pretreated with KOH.15 The inclusions are composed of intermediate filaments measuring 5–7 nm. It is not clear why these inclusions are formed. It is very likely that they are the result of a defect in actin metabolism.16 Other myofibroblastic lesions (including myofibrosarcoma), the stromal cells of phyllodes tumor, fibroadenoma and some leiomyomas can rarely show similar actin-positive intracytoplasmic inclusions.16–21

Fig. 35.118 Inclusion body fibromatosis: in this example, there are numerous inclusions.

Differential diagnosis The presence of eosinophilic inclusions and the clinical history allow no differential diagnosis. Identical lesions may occur in the digits of patients with a syndrome consisting of terminal osseous dysplasia and pigmentary defects.22,23 However, in these patients, inclusions are not seen.

Calcifying aponeurotic fibroma Clinical features Calcifying aponeurotic fibroma (also known as juvenile aponeurotic fibroma) is a very rare lesion seen predominantly in the first two decades of life, with a predilection for males.1–3 It presents as a single small nodular or infiltrative mass, most often on the feet or hands, especially the palms. Involvement of other sites such as the head and neck, back, abdominal wall, legs and arms is very rare.4,5 Multiple lesions are exceptional.6 Bone involvement is extremely rare.7 Local recurrence, particularly in younger patients, is common and occurs in up to 50% of cases. Fig. 35.116 Inclusion body fibromatosis: the tumor is composed of bland spindled cells with a collagenous stroma.

Histological features Calcifying aponeurotic fibroma characteristically forms an irregular mass of dense, fairly cellular, fibrous tissue invading subcutaneous and muscular structures widely (Fig. 35.119). Myofibroblasts tend to be plump with

Fig. 35.117

Fig. 35.119

Inclusion body fibromatosis: the spindled cells have uniform vesicular nuclei with small nucleoli.

Calcifying aponeurotic fibroma: an irregular infiltrative mass of fibroblastic tissue is present in the subcutaneous fat.

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Connective tissue tumors

Fig. 35.120

Fig. 35.121

Calcifying aponeurotic fibroma: in this section, there is chondroid metaplasia and there is focal basophilic calcification.

Ossifying plexiform tumor: scanning view showing polypoid mass with multiple foci of osteoid.

­ rominent nuclei. Usually, these cells have a linear or palisaded arrangement p and comprise the bulk of the tumor. As the lesion matures, the calcified areas undergo chondroid metaplasia (Fig. 35.120). Extramedullary hematopoiesis may occasionally be seen.8

Differential diagnosis The differential diagnosis includes palmar fibromatosis, which is rare in young people and tends to be fairly circumscribed, and soft tissue chondroma, which lacks the dense myofibroblastic component and is composed solely of cartilaginous tissue, which is often rather cellular.

Ossifiying plexiform tumor Only three cases of this lesion with distinctive histogical features have been described.

Clinical features All cases have presented as a firm nodule on a digit of adult females.1,2 Behavior is benign with no tendency for local recurrence.

Fig. 35.122 Ossifying plexiform tumor: higher-power view showing focally calcified osteoid.

Pathogenesis and histological features It has been suggested that this tumor may represent a variant of ­cellular ­neurothekeoma. Histologically, there is a well-defined dermal lobular tumor consisting of bland epithelioid and spindle-shaped cells in a myxoid matrix. Tumor lobules are separated by fibrous bands and in the center of each ­lobule there is abundant mature bone often surrounded by a rim of ­osteoblasts (Figs 35.121, 35.122).

Knuckle pad Clinical features Knuckle pads are not uncommon, rather banal lesions that rarely come to the attention of either clinicians or pathologists. They present as fairly ­ill-defined foci of fibrous thickening over the metacarpophalangeal or proximal ­interphalangeal joints, most often in the middle aged (Fig. 35.123).1–3 They may be familial, associated with Dupuytren's contracture or ­plantar ­fibromatosis, secondary to repeated trauma or idiopathic. They are almost always asymptomatic. Knuckle pad-like lesions occur in ­epidermolytic ­palmoplantar keratoderma.4,5 A case of knuckle pads with ­leukonychia and deafness has been documented.6 An exceptional association with ­pseudoxanthoma e­ lasticum is probably coincidental.7

Fig. 35.123 Knuckle pad: typical thickened plaques are present over the interphalangeal joints and second metacarpophalangeal joint. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.

Benign fibrous and myofibroblastic tumors

Pathogenesis and histological features

Histological features

The etiology of knuckle pads is unknown but it has been suggested that they may be induced by knuckle cracking.8 A case induced by trauma from playing video games has been reported.9 A knuckle pad is manifest as an area of non-specific fibrous proliferation in the dermis, often associated with overlying hyperkeratosis (Fig. 35.124).

Microscopically, fibrokeratomas are pedunculated lesions covered by variably acanthotic and hyperkeratotic skin (Figs 35.126, 35.127). The core is composed of an admixture of dense collagen fibers containing a variable number of mature fibroblasts, small blood vessels and elastic tissue, all merging with the adjacent normal dermis. Within fibrokeratomas, small peripheral nerves or tactile corpuscles are inconspicuous in contrast to their prominence in accessory digits. The clinical history allows their distinction from an accessory digit, periungual fibroma or knuckle pad. Local excision is curative.

Acquired digital fibrokeratoma Clinical features Acquired digital fibrokeratoma is of no clinical significance and arises most often in adult life, affecting males more often than females.1–3 It presents as a slowly growing firm nodule or excrescence, usually less than 1 cm in size, on the fingers or toes; as such, it may clinically resemble a supernumerary digit (Fig. 35.125). A similar lesion has been documented on the heel.4 Some regard these lesions as traumatic, although with little supporting evidence. Acquired digital fibrokeratoma may be similar to the periungual fibroma that occurs in tuberous sclerosis but the latter tends to be multiple and has ­minimal or no epidermal component.5

Fig. 35.124

Plaque-like CD34-positive dermal fibroma (medallion-like dermal dendrocyte hamartoma) Clinical features This distinctive lesion was originally described as medallion-like dermal ­dendrocyte hamartoma to highlight the typical clinical appearance and also to suggest a possible line of differentiation towards dermal dendrocytes.1

Knuckle pad: in this section there is massive hyperkeratosis and acanthosis. The appearances are non-specific.

Fig. 35.126

Fig. 35.125

Fig. 35.127

Acquired digital fibrokeratoma: the resemblance to a supernumerary digit is striking. By courtesy of J.C. Pascual, MD, Alicante, Spain.

Acquired digital fibrokeratoma: the core of the lesion consists of mature collagen bundles, fibroblasts and small blood vessels.

Acquired digital fibrokeratoma: low-power view showing the hyperkeratotic acanthotic surface epithelium.

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Connective tissue tumors Since then, isolated case reports have been described and a small series was recently published challenging the theory regarding the line of differentiation and proposing the term plaque-like CD34-positive dermal fibroma.2–5 Lesions usually present in young children, may be congenital, are rarely seen in adults and have predilection for the proximal limbs, neck and upper trunk. Females are more often affected than males. Tumors usually measure several centimeters, are red or brown in color and have a medallion-like appearance.

Histological features Tumors are characterized by a band-like proliferation of fibroblast-like bland cells usually occupying the upper part of the dermis. Extension into the subcutaneous tissue is rare. Scattered small dilated vascular channels are present and tumor cells are interspersed with collagen bundles with decrease in elastic fibers. Superficial tumor cells have a vertical orientation to the epidermis and deeper cells usually have a horizontal orientation with regards to the epidermis. CD34 is positive in tumor cells and there is minimal focal staining for smooth-muscle actin and few factor XIIIa-positive cells.

Differential diagnosis The main differential diagnosis is with early plaque-stage dermatofibrosarcoma protuberans. This is discussed under the latter condition.

Fig. 35.128 Fibrous hamartoma of infancy: the tumor comprises mature fat, fibrous tissue, myofibroblastic elements and circumscribed aggregates of undifferentiated mesenchymal cells.

Fibrous hamartoma of infancy Clinical features Fibrous hamartoma of infancy is a rare benign tumor of childhood, which although occasionally manifest at birth, usually presents in the first 2 years of life as a solitary, dermal and subcutaneous mass; boys are predominantly affected.1–8 It occurs most often in the shoulder region, proximal upper limb, groin, back or forearm. Tumors rarely occur on the hands, feet, scrotum and scalp.9–11 It typically presents as an asymptomatic, firm but mobile lesion up to 10 cm in diameter. Multicentric tumors are rare.12,13 There is no family history. A likely coincidental association has been reported in a case of Williams syndrome and in a case of tuberous sclerosis.14,15 Overlying hypertrichosis has been reported in one case.16 Rarely, there may be local recurrence after inadequate excision.

Histological features Fibrous hamartoma of infancy is an ill-defined lesion that merges with ­adjacent normal tissue and involves predominantly the deep dermis and subcutaneous fat. It is characterized by varying proportions of four components:1–4 • disorderly fibrous tissue (coarse bundles of collagenous fibrous tissue with blood vessels and inflammatory cells), • orderly fascicles of eosinophilic myofibroblasts with wavy nuclei, which are actin positive (Figs 35.128, 35.129), • mature adipose tissue, • primitive myxoid foci containing plump, undifferentiated mesenchymal cells arranged in whorls (Fig. 35.130). The combination of these components produces an organoid pattern. Occasional normal mitotic figures may be seen. Numerous thin-walled ­capillaries are also present. This distinctive appearance makes this tumor readily distinguishable from any other. The myofibroblasts in the lesion stain positively for SMA and calponin. S-100 and desmin are usually negative.5,17–19 The more primitive cells stain only for vimentin. Changes in the overlying eccrine glands have been described ­including hyperplasia with papillary projections, dilatation and squamous syringometaplasia.20 Ultrastructurally, cells within the more mature areas show features of ­fibroblasts and myofibroblasts. The cells in more undifferentiated myxoid areas show no specific features except for slender cytoplasmic processes.5,17–20 Cytogenetics in a single case revealed t(2;3)(q31;q21); desmoplastic ­fibroblastoma and fibroma of tendon sheath have also shown involvement of 2q31 in a few cases.21–23 Two further cases have shown complex chromosomal translocations.24,25

Fig. 35.129 Fibrous hamartoma of infancy: note the fascicles of myofibroblasts.

Fig. 35.130 Fibrous hamartoma of infancy: the primitive foci are composed of myxoid tissue containing small cells with round or oval vesicular nuclei.

Benign fibrous and myofibroblastic tumors

Differential diagnosis The clinical presentation and histological features usually allow a ­diagnosis to be made. In small biopsies, the spindle-shaped component in a ­myxoid stroma may be confused with a neurofibroma but this is only a focal change and cells are negative for S-100 protein. Distinction from a myofibroma is based on the presence of a distinctive biphasic pattern in the ­latter tumor.

Juvenile hyaline fibromatosis Clinical features Juvenile hyaline fibromatosis is an exceedingly rare autosomal recessive disfiguring condition of younger children and usually presents as cutaneous papules and nodules, multiple soft tissue masses of variable size that particularly affect the head and neck, and gingival hyperplasia (Fig. 35.131).1–7 The back and flexures of the lower limbs may also be involved, resulting in flexion contractures. Often, joint contractures and gingival hypertrophy precede the cutaneous manifestations of the disease.8 Other associations include mental retardation and osteolytic bone lesions. A more localized and limited form of the disease has been documented.9 In a single case, a squamous cell carcinoma developed in association with oral lesions.10 The only treatment is surgical excision of each lesion, but new tumors may continue to develop into adult life. Infantile systemic hyalinosis is considered to be an allelic disorder with ­similar but more severe involvement, hyaline deposits in many organs, ­recurrent infections and death early in life, usually within the first 2 years.11–15

anthrax toxin.23 Infantile systemic hyalinosis has similar ­disease manifestations and ANTXR2 mutations and likely represents a ­disease spectrum with juvenile hyaline fibromatosis.21,23–26 The tumors are largely composed of irregular poorly circumscribed masses of deeply eosinophilic, hyalinized, collagen-like material within which are embedded a variable (though usually small) number of fairly plump spindled cells (Figs 35.132–35.134). Hyalinization is rarely not prominent.27 Scattered macrophages and multinucleated giant cells may also be seen.17 Basophilic calcospherules have been documented.28 Electron microscopy shows mesenchymal cells with dilated rough endoplasmic reticulum, prominent Golgi complexes and vesicles with abundant fibrillogranular material.29

Differential diagnosis The presence of multiple lesions arising in childhood and the characteristic histological features narrow down the differential diagnosis. Infantile myofibromatosis presents with multiple lesions but the histological features are quite different from those of juvenile hyaline fibromatosis. Nuchal fibroma presents as a single lesion and is characterized by abundant collagen lacking masses of amorphous eosinophilic material.

Pathogenesis and histological features Juvenile hyaline fibromatosis, thought to be due to a genetic abnormality of collagen production, may be seen in siblings, particularly of consanguineous parents.2,16 Ultrastructural studies and skin fibroblasts from cultures have suggested defective synthesis of collagen within fibroblasts.17–19 The disease results from an abnormal assembly of basement membrane material and ­collagen deposition is also abnormal.13,14,20 The gene for the disease has been mapped to chromosome 4q21.21 Multiple different mutations have been identified in this gene, which encodes capillary morphogenesis protein 2 (CMG2), also termed anthrax toxin receptor 2 (ANTXR2).22 ANTXR2 is a transmembrane protein induced during capillary morphogenesis.13,14 The protein binds laminin and collagen type IV and alterations in the protein result in abnormalities in the assembly of basement membrane material with the typical manifestations of the disease. Interestingly, ANTXR2 also serves as a ­receptor for

Fig. 35.132 Juvenile hyaline fibromatosis: this field is largely acellular and composed of intensely eosinophilic, hyalinized material. By courtesy of J. Sciubba, DDS, Baltimore, USA.

Fig. 35.131

Fig. 35.133

Juvenile hyaline fibromatosis: there is a large circumscribed ulcerating mass. A smaller lesion is also present behind the left ear. By courtesy of Y. Kitano, MD, Osaka University School of Medicine, Japan.

Juvenile hyaline fibromatosis: other areas may be more cellular. By courtesy of J. Sciubba, DDS, Baltimore, USA.

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Connective tissue tumors be related to risk of recurrence.30 Periostin, an extracellular matrix protein, may have a role in the pathogenesis of the disease by inducing proliferation, ­contraction and apoptosis of fibroblasts.31 The microscopic appearances of palmar fibromatosis depend, to some extent, upon the duration of the lesion. In the early stages, cellular nodules composed of uniformly plump, proliferating myofibroblasts develop in the palmar aponeurosis, and may show mitotic activity but without ­atypia (Figs 35.135, 35.136). This proliferative process, which has very little ­collagenous stroma, gradually extends as an infiltrative mass into adjacent subcutaneous tissues. With the passage of time, maturation of the fibrous tissue leads to late lesions characterized by large amounts of hypocellular, hyalinized collagen (Fig. 35.137). Scattered chronic inflammatory cells may be present at the periphery of the tumor, but there is no evidence of an active inflammatory process. Hemosiderin is uniformly absent, militating against a traumatic etiology. The degree of cellularity appears to correlate with the risk of local recurrence.32

Fig. 35.134 Juvenile hyaline fibromatosis: the spindle cells are bland with hyperchromatic nuclei. By courtesy of J. Sciubba, DDS, Baltimore, USA.

Locally aggressive fibrous lesions Locally aggressive fibrous lesions are defined as infiltrative neoplasms that are prone to local recurrence. They may be destructive, but never metastasize.

Palmar fibromatosis Clinical features Palmar fibromatosis (Dupuytren's contracture) is a common condition that is largely confined to adults; its incidence increases with age.1–6 Presentation in children is rare and occasional congenital cases may occur.7,8 Males are affected more often than females and up to 4% of the adult male population, particularly the elderly, are thought to develop this lesion.9 People of northern European descent are predominantly affected and women usually develop the disease much later in life than men.10,11 The disease is much less common in Oriental Jews.12 In contrast to keloid, Dupuytren's ­contracture is comparatively uncommon in the dark-skinned races, but the ­incidence is increased in patients with plantar fibromatosis and knuckle pads. An association with diabetes and with Peyronie's disease has also been ­documented.13,14 Traditionally, the disease has been associated with alcoholism and epilepsy but this has not been substantiated in recent studies.13,15 Bilateral involvement is common, but is usually asynchronous. There is an increased familial incidence, but no evidence of any relationship to either occupation or trauma.16 Typically, palmar fibromatosis begins as firm nodules in the distal palmar aponeurosis and culminates in disabling flexion at the metacarpophalangeal joints, especially in the ring finger, giving rise to a claw-like deformity and puckering of the palmar skin. Involvement of the wrist and of the interphalangeal joints is very rare.17,18 Local recurrence is very common unless radical excision of the palmar fascia is performed.9

Fig. 35.135 Palmar fibromatosis: scanning view showing multiple nodules of hypercellular tissue with admixed hyalinized collagen.

Pathogenesis and histological features The etiology is unknown. Although trauma has been suggested as an important factor, this has not been substantiated in a large study.19 Array comparative genomic hybridization has shown no gene copy number changes.20 Indinavir treatment in human immunodeficiency virus (HIV)-positive patients has been linked to the development of Dupuytren's contracture.21 TGF-β1, a multifunctional cytokine that plays a central role in wound healing, fibrosis and collagen deposition, is implicated in the pathogenesis of the disease.22 While β-catenin is overexpressed, mutations in the encoding gene CTNNB1 which are common in desmoid fibromatosis are not seen in palmar fibromatosis.23–29 Overexpression in β-catenin does not seem to

Fig. 35.136 Palmar fibromatosis: the lesion is composed of spindled cells with elongated vesicular nuclei containing small central nucleoli. Occasional normal mitotic figures are typical in early lesions.

Locally aggressive fibrous lesions

Fig. 35.137

Fig. 35.138

Palmar fibromatosis: older lesions are characteristically hypocellular and consist largely of broad bundles of hyalinized collagen.

Plantar fibromatosis: this example is strikingly cellular and shows focal osseous metaplasia.

Differential diagnosis

form of fibromatosis it appears more likely to represent an unusual fibrotic reaction developing in response to chronic inflammation, veno-occlusive ­dysfunction or trauma.4,5 Veno-occlusive dysfunction has been demonstrated by Doppler studies.4 The prevalence of the disease is higher in diabetic patients and in those with low testosterone levels.4,6 Hypertension and serum lipid abnormalities appear to have an impact in the severity of the symptoms and outcome.7 A case was reported in association with methotrexate therapy.8 Peyronie's disease usually presents as either solitary or multiple fibrous plaques adjacent to the corpora cavernosa, most often on the dorsal ­surface of the shaft. The peak incidence is in the fifth and sixth decades and there is no predilection for any particular racial group. The plaques rarely exceed 2 cm in diameter. The alleged rapidity of onset in many patients probably reflects the severe psychological problems that frequently develop. Spontaneous ­resolution is rare.

The only lesion that requires exclusion in the differential diagnosis is desmoid fibromatosis, which rarely occurs in the hand, is more uniformly cellular and tends to be deeper.

Plantar fibromatosis Clinical features Plantar fibromatosis (Ledderhose's disease) is essentially the equivalent of palmar fibromatosis affecting the foot (although flexion deformity only rarely develops). The condition may be bilateral, usually arising asynchronously.1,2 Although the overall age and sex distribution is similar to palmar fibromatosis, a significant proportion of cases occur in children or adolescents.3 Familial cases including occurrence in twins are rare.4,5 It is much less common than Dupuytren's contracture and may be associated with it and with diabetes.6 Characteristically, it presents as single or multiple nodules on the medial aspect of the sole, usually just distal to the pedal arch. A variant of plantar fibromatosis presenting in children and characterized by nodules on the anteromedial aspect of the sole has been documented.7 Involvement of the plantar aspect of the heel in children is also seen.8 Although most cases are asymptomatic, patients may complain of discomfort or a burning sensation, particularly after walking. Neurological symptoms due to entrapment of nerves are exceptionally encountered.9 Contracture of the toes is extremely rare.10 Local recurrence is very common.3,11 Plantar hyperkeratosis is a rare association.12

Histological features The microscopic appearances vary according to the duration of the condition. Early lesions are typified by a vasculitic and chronic inflammatory ­process in the loose connective tissue between the corpora cavernosa and penile ­fascia. This leads to an irregular reparative fibrotic process, culminating in the ­development of dense masses of hyalinized collagen with occasional foci of chronic inflammation (Fig. 35.139). Occasionally, metaplastic ossification may occur. There is no differential diagnosis.

Pathogenesis and histological features Cytogenetic studies have revealed trisomy 8 and trisomy 14.13 Superficial fibromatoses are genetically distinct from deep fibromatoses in their lack of mutations in CTNNB1, the gene encoding β-catenin.14–16 The histological features are very similar to those of palmar fibromatosis; however, evidence of chronic inflammation or previous hemorrhage (both of which are probably secondary in nature) is more frequently present in plantar fibromatosis. Lesions also tend to be more consistently cellular and show much less tendency to hyalinize with time (Fig. 35.138). Scattered multinucleated giant cells may be seen.17 Osseous metaplasia is exceptional.18

Penile fibromatosis Clinical features Penile fibromatosis (Peyronie's disease) is an uncommon fibromatous lesion of the penis that results in pain or curvature on erection.1–3 The etiology is entirely unknown and although it has traditionally been considered to be a

Fig. 35.139 Penile fibromatosis: biopsy from end-stage disease showing dense collagen without any significant inflammation. Despite its name, the condition most probably represents a reactive process.

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Connective tissue tumors

Desmoid fibromatosis Clinical features Desmoid fibromatosis represents a group of deep-seated fibrous neoplasms which can present in a variety of clinical settings.1–5 Although most cases are sporadic and solitary, some can be familial or associated with familial adenomatous polyposis (FAP, Gardner's syndrome) and rare examples can be multicentric.6,7 A further subgroup presents in children.8 According to their anatomical distribution, desmoid tumors are classified into: • extra-abdominal (around 60% of cases), • abdominal (20–25%), • intra-abdominal (15%). All of these anatomical subsets typically occur between the second and fourth decades of life with a predilection for females. Extra-abdominal fibromatoses are often sporadic and solitary.1,2 Most patients are young adults presenting with a slowly growing mass that may occasionally be painful. Tumors arise most often around the shoulder girdle or on the proximal lower limbs and rarely in the head and neck area, the latter group being commonest in children.8 Subcutaneous involvement is an occasional feature. A small ­proportion of tumors arise in association with a previous scar or post ­radiotherapy. Desmoid tumors arising in the anterior abdominal wall are ­particularly ­common in females, especially during or after pregnancy.3,5 Often, those arising after pregnancy appear at the site of the scar from a cesarean section. Many cases associated with FAP are intraabdominal. Local recurrence is common even when excision is believed complete.9,10 Desmoid fibromatosis occurring in children less than 10 years of age is referred to as infantile fibromatosis.11 Most patients with this form of fibromatosis present before the age of 5 and there is predilection for the head and neck, shoulder girdle or thigh.8,12–14 Infiltration of neighboring tissues may be prominent.

Fig. 35.140 Desmoid fibromatosis: low-power view showing cellular bundles with focal collagen deposition.

Pathogenesis and histological features Familial adenomatous polyposis patients have germline inactivation of the adenosis polyposis coli gene (APC) which helps mediate the destruction of β-catenin.15–17 The location and type of mutation in FAP appear to affect likelihood of desmoid development.18,19 The tumors develop with loss of heterozygosity at the wild-type allele. Mutations in CTNNB1, the gene encoding β-catenin, are seen in approximately 85 % of sporadic desmoids.20–23 Somatic mutations in APC can also be seen in sporadic cases.24–26 All of these genetic deficits allow unregulated accumulation of β-catenin in the nucleus. Cytogenetic anomalies include trisomies of chromosomes 8 and/or 20 and loss of Y and 5q where APC is located.27–30 Overactivation of the Wnt/APC/β-catenin pathway contributes to desmoid development by constitutive ­activation of pathways in common with fibrosis and scarring.22,31,32 Although etiologically there is clear evidence to suggest a genetic predisposition, this is probably secondarily influenced by trauma or sex hormones.33 It has been shown that high levels of estrogens can promote, but do not initiate, growth of desmoid tumors. Histological features are very similar in all subsets of desmoid tumor. Typical cases show a variegated appearance characterized by an admixture of plump spindled cells with rounded or tapering nuclei showing occasional mitotic figures embedded in a variably hyalinized or myxoid collagenous stroma (Figs 35.140–35.142). At the periphery of the lesion, skeletal muscle fibers, subcutaneous fat and fascia are irregularly infiltrated, resulting in bizarre atrophic, degenerative or reactive muscle cell forms. Peripheral collections of chronic inflammatory cells, particularly lymphocytes, are common. In children, tumors may show a pattern typical of extra-abdominal fibromatosis or else may show a pattern consisting of more immature round cells in a myxoid background. Immunohistochemical studies show variable positivity of tumor cells for actin and only rarely and focally for desmin. Demonstration of nuclear accumulation of β-catenin can be helpful, but is not entirely specific (Fig. 35.143).21,34–36 Ultrastructural studies show cells with features of myofibroblasts and fibroblasts.

Fig. 35.141 Desmoid fibromatosis: the tumor is composed of spindled cells with a variable admixture of collagen.

Fig. 35.142 Desmoid fibromatosis: the spindled cells have vesicular nuclei with small nucleoli. Mitoses are commonly present.

Low-grade malignant fibrous lesions

Fig. 35.143

Fig. 35.144

Desmoid fibromatosis: the spindled cells are beta-catenin positive.

Giant cell fibroblastoma: the admixture of dilated vessel-like spaces and mixed spindled and giant cells in a myxoid stroma is characteristic.

Differential diagnosis The most important differential diagnosis is fibrosarcoma, which shows greater cellularity, nuclear atypia, prominent abnormal mitotic activity, a much lower collagen content and, typically, a herring-bone pattern. Scarring or reactive fibrosis can show virtually identical findings and here history is helpful. CTNNB1 genotyping can be helpful in challenging sporadic-type desmoid cases.20,21,34 Distinction from myofibroblastic tumors including myofibroma is based on the fact that ­desmoid tumor is deep seated and infiltrative and shows β-catenin nuclear ­staining. Myofibroblastic tumors tend to be negative for the latter marker.

Low-grade malignant fibrous lesions Low-grade malignant lesions are defined as neoplasms with a high recurrence rate and very low metastatic potential.

Giant cell fibroblastoma Clinical features Giant cell fibroblastoma is a rare dermal or subcutaneous tumor that ­presents as a slowly growing mass up to 6 cm in diameter.1–7 It commonly affects children under 10 years of age (almost two-thirds of cases), especially males, but lesions may also occur in young, middle-aged and elderly adults.7 Exceptionally, a tumor may be congenital.8 It has a wide anatomical distribution with predilection for the trunk (back, chest and abdomen) and (less commonly) the proximal extremities.1–4 A tumor in the vulva and one in the penis have been reported.9,10 Local recurrence is seen in up to 50% of cases after incomplete excision.1–4 Some cases recur as dermatofibrosarcoma protuberans (see below) and this tumor can be considered a pediatric form of this disease.

Fig. 35.145 Giant cell fibroblastoma: medium-power view showing blood vessel-like space lined by tumor cells.

Pathogenesis and histological features Giant cell fibroblastoma shares the same chromosomal abnormalities as those of dermatofibrosarcoma protuberans (see below). There is a t(17;22)(q22;q13) resulting in fusion of the platelet-derived growth factor B-chain (PDGFB) and the collagen gene COL1A1. Ring chromosomes resulting from the t(17;22) are also seen.11–14 Microscopically, giant cell fibroblastoma is a poorly circumscribed dermal and superficial subcutaneous lesion composed of bland to moderately pleomorphic spindle and multinucleated giant cells (frequently floret-like) in a conspicuous loose myxoid stroma, which is sometimes focally hyalinized and typically contains irregular gaping sinusoidal spaces simulating vascular lumina (Figs 35.144, 35.145). The latter, however, are only lined discontinuously by hyperchromatic mononuclear or multinucleated giant cells, which do not stain for vascular markers (Fig. 35.146). Mitotic figures are only rarely seen. Focal hemorrhage and ­perivascular lymphocytes in an onion-skin pattern are common.7 Exceptional tumors are purely dermal and rarely there is focal involvement of skeletal muscle.7 Tumor cells are positive for CD34 and also for CD99.15

Fig. 35.146 Giant cell fibroblastoma: the sinusoid-like spaces are lined by multinucleate giant cells.

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Connective tissue tumors Ultrastructurally, and by immunohistochemistry, the tumor cells display fibroblastic features. Giant cell fibroblastoma is closely related histogenetically to dermatofibrosarcoma protuberans, as demonstrated by the fact that some cases present combined histological features, tumor cells in both lesions are CD34 positive and, more importantly, both tumors share the same cytogenetic abnormalities (see below) (Figs. 35.147, 35.148).11–13,16,17 Cases of giant cell fibroblastoma may recur as dermatofibrosarcoma protuberans and vice versa.18,19 Bednár tumor (pigmented dermatofibrosarcoma protuberans) may also present primarily or recur with areas of giant cell fibroblastoma.20,21 Mixed tumors may have fibrosarcomatous areas and myoid nodules.7

Differential diagnosis Distinction from other myxoid tumors is readily made based on the biphasic appearance of solid and angiectoid areas with giant cells. Fibrous hamartoma of infancy may rarely show areas resembling giant cell fibroblastoma and in these areas tumor cells are also positive for CD34.22 The diagnosis is ­usually established by the presence of the distinctive components seen in fibrous hamartoma of infancy.

Dermatofibrosarcoma protuberans Clinical features Dermatofibrosarcoma protuberans typically presents in the third and fourth decades, shows a slight male predominance and is uncommon in the elderly.1–5 However, many patients have a long preoperative history (often 10–20 years), probably corresponding to the plaque phase. In these patients a patch develops and may have features resembling morphea, atrophoderma or an angioma.6 Lesions can occur in children and some of these are congenital (Fig. 35.149).1,4,7–11 Clinical diagnosis in this age group is difficult, as tumors often resemble a vascular birthmark.6 Occurrence at sites of previous trauma (including scars, vaccination, an arteriovenous fistula, a decorative tattoo and leishmaniasis) has been documented.12–17 Familial cases are exceptional and an association with HIV infection is probably coincidental.18,19 Accelerated growth during pregnancy has been reported in a case.20 Rare (probably coincidental) associations include multiple spindle cell lipomas and a nuchal fibroma.21,22 The tumor usually develops as a multinodular cutaneous mass, several centimeters in diameter that is slowly growing and appears to evolve from a dermal fibrous plaque stage. The overlying skin frequently shows a reddishblue discoloration (Figs 35.150–35.152). Presentation as an atrophic plaque

Fig. 35.147

Fig. 35.149

Giant cell fibroblastoma: this lesion merges imperceptibly with typical dermato­ fibrosarcoma protuberans on the right side of the field.

Dermatofibrosarcoma protuberans: congenital lesions as shown here are exceedingly rare. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.148

Fig. 35.150

Giant cell fibroblastoma: higher-power view of the left side of the field showing typical features.

Dermatofibrosarcoma protuberans: a typical multinodular reddish-blue plaque is present on the lower abdomen of a middle-aged female. By courtesy of M.H.A. Rustin, MD, Royal Free Hospital, London, UK.

Low-grade malignant fibrous lesions

Fig. 35.151 Dermatofibrosarcoma protuberans: close up view. By courtesy of M.H.A. Rustin, MD, Royal Free Hospital, London, UK.

Fig. 35.153 Dermatofibrosarcoma protuberans: presentation as an atrophic plaque is rare. By courtesy of the Institute of Dermatology, London, UK.

and the rate of metastasis is up to 20% of cases in some series.44,45,49 However, in a more recent series, the rate of local recurrence (20%) and metastatic rate (10%) is much less than that reported in the past.50 Aggressive behavior appears to be related to mitotic activity, pleomorphism and necrosis.35,44,45,50

Pathogenesis and histological features

Fig. 35.152 Dermatofibrosarcoma protuberans: this example shows a combination of a plaque and nodules. By courtesy of the Institute of Dermatology, London, UK.

is seen in some cases (Fig. 35.153).23,24 Polypoid tumors are exceptionally seen.25 There is a marked predilection for the trunk (especially the abdominal wall and chest) and lower limbs (particularly the thighs). Involvement of hands and feet is very uncommon.26,27 Rare tumors occur in the vulva and an exceptional case has been reported in the oral cavity.28–30 Simultaneous occurrence of two tumors at different sites has been documented.31 Local recurrence is frequent and varies in different series from 20% to 50% of cases.1,5,32–34 However, in cases treated by wide excision or in those treated by Mohs' micrographic surgery the rate of local recurrence is lower.35–40 A frequent subject of debate is how wide the excision has to be to reduce the rate of local recurrence. Although the tendency in the past was to advocate several excisions with margins of several centimeters, more recent studies suggest that smaller excision margins of 2 cm achieve good local control in many cases.41 Treatment with Mohs' micrographic surgery using paraffin ­sections appears to be an excellent choice of treatment, allowing tissue conservation.42 Intracranial invasion may occur in scalp lesions mainly after multiple recurrences.43 Metastasis is exceedingly rare, less than 0.3% in our experience; many of the cases reported to have metastasized are supported by inadequate or even incorrect histological evidence. Metastasis usually occurs after repeated recurrences, often with fibrosarcomatous transformation.1–3,44–48 Fibrosarcomatous dermatofibrosarcoma protuberans recurs locally in 75%

The genetic abnormalities found in dermatofibrosarcoma protuberans and giant cell fibroblastoma are identical, further indicating that they represent a spectrum.51–53 As expected, other histological variants of dermatofibrosarcoma protuberans – including Bednár tumor, dermatofibrosarcoma protuberans with granular cell change and fibrosarcomatous dermatofibrosarcoma protuberans – show the same cytogenetic abnormalities.54–57 Ring chromosomes derived from chromosome 22 containing low-level amplified sequences from 17q22-qter and 22q10-q13.1 or t(17;22) are the most frequent ­finding.53 In both the rings and linear der(22) a specific fusion of COL1A1 and PDGFB is found. Ring chromosomes are mainly observed in adults, whereas translocations are present in all pediatric cases.53 The breakpoint localization in PDGFB is remarkably constant, placing exon 2 under control of the COL1A1 promoter. In contrast, the COL1A1 breakpoint is variably located within the exons of the α-helical coding region (exons 6–49).53,58–60 Evidence of the COL1A1-PDGFB fusion is present in most but not all cases.53,58–60 Negative results may be due to limitations in the technique used, but other fusion genes could also be involved.60,61 PDGFB appears to act as a mitogen in tumor cells of dermatofibrosarcoma protuberans by autocrine stimulation of the PDGF receptor. Interestingly, imatinib mesylate (an antagonist of the PDGF receptor α tyrosine kinase) has been found to have an inhibitory effect in vivo and has been used with variable success in multiple cases of dermatofibrosarcoma protuberans (mainly in patients with unresectable or recurrent tumors and those with metastatic disease) including clinical trials.53,62–65 The rate of response has been estimated to be up to 50%.66 The microscopic appearances vary little from case to case. The tumor is located in the dermis, but invariably shows diffuse irregular infiltration of the subcutaneous fat in a typical lace-like pattern or bundles of cells which ramify parallel to the epidermis (Figs 35.154, 35.155). Rare cases may be mainly or exclusively subcutaneous.67 Epidermal hyperplasia is rare but does occur and the degree of hyperplasia seems to be inversely related to the distance of the tumor from the epidermis.68 The lesion is composed almost entirely of fairly uniform spindled cells with elongated nuclei showing little or no pleomorphism and scanty pale cytoplasm. The cells are characteristically arranged in a storiform or ‘rush mat’ pattern typified by numerous whorls of cells, sometimes centered around small blood vessels (Figs 35.156–35.158).

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Connective tissue tumors

Fig. 35.154

Fig. 35.156

Dermatofibrosarcoma protuberans: the lower dermis is replaced by a dense cellular infiltrate. In contrast to fibrous histiocytoma, the epidermis appears normal.

Dermatofibrosarcoma protuberans: this field shows the characteristic storiform (L. storia, a rush mat) pattern.

Fig. 35.157 Fig. 35.155 Dermatofibrosarcoma protuberans: involvement of the subcutaneous fat is usual and typically results in a lace-like appearance.

Mitotic activity, rarely abnormal in appearance, is scanty, not ­usually exceeding five mitoses per 10 high-power fields. Peripheral collections of chronic inflammatory cells are sometimes present, as are foci of myxoid degeneration, but necrosis is rarely a feature and is always minimal (Fig. 35.159). Cytological polymorphism is not a feature except in those infrequent cases showing overlap with giant cell fibroblastoma. However, in some cases, occasional nonpleomorphic giant cells are present. Focal histological variation may be seen and includes areas of sclerosis, palisading, formation of Verocaylike bodies, granular cell change and meningothelial-like whorls.69–74 In a case treated with imatinib mesylate prominent hyalinized collagen was seen.75 Immunohistochemically, tumor cells are usually diffusely positive for CD34 and negative for other markers including factor XIIIa, S-100 protein, desmin, actin and CD117 (Fig. 35.160).76–78 Staining for EMA has been reported and, based on this finding, a perineural line of differentiation has been suggested although this marker is not specific.79 CD99 is also positive in a number of cases.80 Stromelysin, cathepsin K and D2–40 have been reported

Dermatofibrosarcoma protuberans: the storiform pattern comprises a central, almost syncytial, arrangement of cells with vesicular nuclei from which radiate the more delicate spindle cells with elongated darkly staining nuclei. Taken in context, this appearance is pathognomonic. Note the mitotic figure.

Fig. 35.158 Dermatofibrosarcoma protuberans: adnexal sparing is typically seen.

Low-grade malignant fibrous lesions

Fig. 35.159

Fig. 35.161

Dermatofibrosarcoma protuberans: a diffuse lymphocytic infiltrate is present in this field.

Dermatofibrosarcoma protuberans: the tumor consists of a uniform population of fibroblasts typified by elongated nuclei and abundant rough endoplasmic reticulum.

Fig. 35.160

Fig. 35.162

Dermatofibrosarcoma protuberans: the tumor cells characteristically express CD34.

Dermatofibrosarcoma protuberans: myofibroblastic differentiation is not a feature of this tumor.

as ­useful ­markers in the differential diagnosis between dermatofibroma and ­dermatofibrosarcoma protuberans, as they tend to be positive in the former and negative in the latter.81–83 Cthrc1 (collagen triple helix repeat containing-1) and Apo D, on the other hand, tend to be positive in ­dermatofibrosarcoma protuberans and ­negative in dermatofibroma.84,85 Other markers that have been reported as ­useful in ­dermatofibrosarcoma protuberans include lowaffinity nerve growth ­factor receptor (p75) and tenascin.86 Tumor cells in dermatofibroma and ­dermatofibrosarcoma protuberans show positive staining with tenascin but ­staining of the dermoepidermal junction overlying the tumor is only seen in dermatofibroma.87 Although the line of differentiation in dermatofibrosarcoma protuberans has been controversial for many years, it is increasingly being accepted as a fibroblastic tumor (Figs 35.161, 35.162).88,89

Fibrosarcomatous dermatofibrosarcoma Fibrosarcomatous dermatofibrosarcoma is a variant in which a focal fascicular or ‘herring-bone’ pattern is present.40–46 Fibrosarcomatous transformation may occur either de novo or in the recurrence of a typical dermatofibrosarcoma protuberans. These areas are more cellular, show more nuclear atypia and the mean mitotic count is higher than in typical dermatofibrosarcoma (Figs 35.163, 35.164). Focal loss or less intense staining with CD34 is seen in the fibrosarcomatous areas.50 Fibrosarcomatous dermatofibrosarcoma

Fig. 35.163 Dermatofibrosarcoma protuberans: this is an example of fibrosarcomatous change. Note the characteristic herringbone pattern.

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Connective tissue tumors

Fig. 35.164 Dermatofibrosarcoma protuberans: high-power view.

combined with Bednár may occur.90 A case with formation of giant rosettes has been documented.91 Progression in dermatofibrosarcoma protuberans to the fibrosarcomatous variant appears to be related to microsatellite instability and mutations in p53 as early and late events respectively.92 In rare cases, areas of a high-grade sarcoma may be found within an otherwise ordinary dermatofibrosarcoma protuberans.93–95 These areas can mimic a myxofibrosarcoma or a pleomorphic malignant fibrous histiocytoma. It is not clear what the prognosis of these tumors is, as the occurrence of this phenomenon is very rare. Interestingly COL1A1-PDGFB fusion transcripts can also be detected in sarcomatous areas of the tumor.96

Fig. 35.166 Bednár tumor: the melanin pigment is contained within dendritic cells.

Myxoid dermatofibrosarcoma Myxoid dermatofibrosarcoma is a term used to describe rare cases in which the more typical features may be only focally identifiable because of extensive myxoid degeneration (Figs 35.167–35.169).101–103 Macroscopically, tumors are gelatinous. Thin-walled blood vessels are prominent. Myxoid change may occur in association with any variant of the tumor.104

Dermatofibrosarcoma with areas of giant cell fibroblastoma Dermatofibrosarcoma with areas of giant cell fibroblastoma has already been discussed.

Pigmented dermatofibrosarcoma

Dermatofibrosarcoma with myoid nodules

Pigmented dermatofibrosarcoma (also known as the Bednár tumor or formerly as pigmented storiform neurofibroma) contains dendritic melanocytes and small deposits of melanin pigment within an otherwise typical tumor (Figs 35.165, 35.166).97–99 The presence of melanocytes within the tumor is puzzling and is probably secondary to colonization. An alternative view proposes neuroectodermal multidirectional differentiation to explain this phenomenon.100

Dermatofibrosarcoma with myoid nodules refers to cases showing areas composed of bundles of eosinophilic SMA-positive spindle cells indicating myofibroblastic differentiation (Figs 35.170, 35.171).105,106 Most cases of dermatofibrosarcoma protuberans with myoid nodules have fibrosarcomatous areas.105,106 Small biopsies can cause confusion with myofibroblastic lesions, such as adult myofibroma, but other typical features of dermatofibrosarcoma are usually evident. It has been suggested that the myoid nodules do

Fig. 35.165

Fig. 35.167

Bednár tumor: except for the foci of pigmented cells, the appearances are identical to those of dermatofibrosarcoma protuberans.

Myxoid dermatofibrosarcoma protuberans: myxoid areas, as seen here, are nondiagnostic and therefore may cause confusion. A careful search should be made for more typical foci.

Low-grade malignant fibrous lesions

Fig. 35.168

Fig. 35.171

Myxoid dermatofibrosarcoma protuberans: high-power view.

Dermatofibrosarcoma protuberans: high-power view of Figure 35.170.

not ­represent true myofibroblastic differentiation but rather residual smooth muscle originating from blood vessels destroyed by the tumor.107 However, the bundles of myoid cells are usually positive for actin and negative for desmin, suggesting myofibroblastic rather than smooth muscle origin/differentiation. Flow cytometry studies in dermatofibrosarcoma protuberans often show aneuploidy.108

Differential diagnosis

Fig. 35.169 Myxoid dermatofibrosarcoma protuberans: high-power view from a different case showing complete loss of the storiform growth pattern.

The differential diagnosis includes fibrous histiocytoma, especially its cellular variant, dermatomyofibroma, perineurioma, plaque-like CD34-positive dermal fibroma (medallion-like dermal dendrocyte hamartoma) and neurofibroma (mainly in the superficial part of the tumor). Fibrous histiocytoma tends to be CD34 negative, shows cytological polymorphism, only a focal storiform pattern and limited superficial infiltration of the subcutis, usually in a radial pattern.109 Epidermal changes (especially hyperplasia) are much more commonly associated with fibrous histiocytoma than with dermatofibrosarcoma protuberans. Cellular fibrous histiocytoma may show positivity for CD34 but this is often in the periphery of the tumor and associated with ­variable staining for factor XIIIa and focal staining for SMA. Plaque-like CD34-positive dermal fibroma (medallion-like dermal dendrocyte hamartoma) has to be distinguished from the plaque stage of dermatofibrosarcoma protuberans.110,111 The former occurs predominantly but not exclusively in children, is a ­neoplasm of the reticular dermis that tends not to extend to the subcutaneous tissue and consists of CD34-positive fibroblast-like cells with superficial cells oriented perpendicular to the epidermis and deep cells oriented parallel to the epidermis. The superficial part of a dermatofibrosarcoma protuberans may mimic neurofibroma, as the storiform pattern is usually lacking, and this is a particular problem in superficial samples.112 Immunohistochemistry for CD34 and S-100 is crucial as the latter is positive for both markers and the former positive for CD34. It has been suggested that there is a small subgroup of indeterminate fibrohistiocytic tumors of the skin in which it is not possible to distinguish accurately between dermatofibrosarcoma protuberans and fibrous histiocytoma because of histological and immunohistochemical overlap; however, these tumors lack the COL1A1-PDGFB fusion transcript.113,114 Distinction between neurofibroma and the myxoid variant of dermatofibrosarcoma is based on the storiform growth pattern, CD34 expression and S-100 protein negative cells in the latter condition.

Acral myxoinflammatory fibroblastic sarcoma Clinical features Fig. 35.170 Dermatofibrosarcoma protuberans: some tumors, particularly the fibrosarcomatous variant, contain nodules and bundles of myofibroblasts (the myoid variant).

Acral myxoinflammatory fibroblastic sarcoma (inflammatory myxohyaline tumor) is a distinctive, rare, low-grade tumor with marked predilection for the hands and feet.1–4 The ankles and wrists may also be affected and,

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Connective tissue tumors rarely, tumors have been described on the forearm, upper arm and thigh.5 Most patients are middle-aged adults who present with a slowly growing, ill-defined, dermal and subcutaneous (usually asymptomatic) mass measuring between 1 and 6 cm, and there is no sex predilection.1 Larger tumors may also be seen.4 Pain is an occasional symptom. The clinical diagnosis is either a ganglion cyst or a giant cell tumor of tendon sheath. A case occurred in a renal transplant patient.6 Local recurrences are seen in from 22% to 67% of cases and may occur many years after the primary tumor has been excised. Regional lymph node metastasis has been reported in rare cases and distant metastases are exceptional, with only one patient dying of disease.6,7

Pathogenesis and histological features Cytogenetic studies in a single case have shown a reciprocal t(1;10)(p22;q24) and loss of chromosomes 3 and 13.8 Histology shows a multinodular and poorly circumscribed tumor with prominent myxoid change and focal areas of hyalinization (Figs 35.172–35.174). In the background, there are neutrophils, eosinophils, lymphocytes, plasma cells and variable numbers of pleomorphic mono- or multinucleated large cells with vesicular or hyperchromatic nuclei. These cells often have a prominent inclusion-like nucleolus. They may mimic ganglion cells, ­Reed-Sternberg

Fig. 35.174 Acral myxoinflammatory fibroblastic sarcoma: high-power view showing tumor cells with admixed lymphocytes and conspicuous eosinophils.

cells or lipoblasts, and are sometimes masked by the intense inflammatory cell infiltrate. Hemosiderin deposition can be prominent. Mitotic figures, although present, are not conspicuous. Tumor cells are positive for CD68, CD163 and CD34.4 They may be focally positive for EMA and positivity for EGFR has been reported.4

Differential diagnosis Acral myxoinflammatory fibroblastic sarcoma is most likely to be mistaken for an inflammatory condition but the presence of bizarre tumor cells should alert the pathologist to the correct diagnosis. Distinction from myxofibrosarcoma is based on the absence of prominent inflammation in the latter condition and also the knowledge that myxofibrosarcoma is very rare on the hands and feet. Epithelioid sarcoma may enter the differential diagnosis. It often has areas of necrosis, tumor cells are epithelioid or short and spindled, and keratin is consistently positive. Fig. 35.172 Acral myxoinflammatory fibroblastic sarcoma: within the dermis is a multinodular tumor with striking myxoid change.

Inflammatory myofibroblastic tumor Clinical features Inflammatory myofibroblastic tumor (inflammatory fibrosarcoma, inflammatory pseudotumor) is a term that includes a heterogeneous group of lesions characterized by proliferation of fibroblasts and myofibroblasts in a background of numerous inflammatory cells.1–3 Most cases occur in children, usually in visceral organs (particularly the lung but also in the liver, heart, gastrointestinal tract, pancreas and urinary bladder), mesentery, omentum and (less commonly) the soft tissues (limbs and head and neck).1–5 Oral, laryngeal, bone and lymph node lesions may also occur.6–9 The tumor presents less frequently in young adults but is exceptional after the age of 30. Comparable examples in the skin have only exceptionally been reported.4,10,11 Systemic symptoms including high erythrocyte sedimentation rate (ESR), anemia, fever and weight loss occur in up to 30% of cases. Rare associations include obliterative phlebitis and dermatomyositis.12,13 Intestinal obstruction may be the cause of presentation in intra-abdominal tumors. Rare tumors have been described at the site of a tooth extraction and at the location of a pace maker.14,15 The prognosis is good in most cases but local recurrences and exceptional metastasis occur.16

Histological features Fig. 35.173 Acral myxoinflammatory fibroblastic sarcoma: this lesion consists of stellate and histiocyte-like cells with scattered mononuclear inflammatory cells dispersed within the myxoid stroma.

Histologically, the tumors are well circumscribed and those presenting in the skin are located in the deep dermis or subcutis. The proportion of fibroblasts/ myofibroblasts varies among tumors. Lesions have prominent or moderate cellularity with a myxoid background or appear fairly hypocellular with areas of sclerosis and hyalinization often simulating a scar (Fig. 35.175). Focally, tumor

Low-grade malignant fibrous lesions

Fig. 35.175

Fig. 35.177

Inflammatory myofibroblastic tumor: low-power view showing tumor, a heavy lymphocytic infiltrate and background scar tissue.

Inflammatory myofibroblastic tumor: the tumor cells are admixed with lymphocytes, eosinophils and plasma cells.

cells have a histiocyte-like or Reed-Sternberg appearance and may resemble ganglion cells. In most tumors there is a variable mixed inflammatory cell infiltrate composed of numerous plasma cells, lymphocytes, ­histiocytes, neutrophils, eosinophils and occasional giant cells (Figs 35.176, 35.177). Rare lesions do not display prominent inflammation. Germinal centers and proliferation of high endothelial venules may be a feature and, on low-power examination, lesions sometimes vaguely resemble a lymph node. Tumor cells are usually positive for smooth muscle actin, muscle specific actin and calponin.17 Focal desmin and cytokeratin positivity has also been reported and in up to 50% of cases there is positivity for anaplastic lymphoma kinase (ALK) which correlates with rearrangements at chromosome 2p23 with a variety of partners that change the cellular compartment localization of the constitutively active fusion kinase.17–21 Some of these translocations are also seen in anaplastic large cell lymphoma.22

Differential diagnosis The main differential diagnosis is with other myofibroblastic tumors, mainly low-grade myofibroblastic sarcoma. The latter usually lacks inflammation, is more monomorphic and infiltrative and is not associated with positivity for ALK-1 or cytokeratin.11

Solitary fibrous tumor Clinical features Solitary fibrous tumor is a distinctive lesion with fibroblastic and myofibroblastic differentiation that presents mainly in the pleura but has increasingly been reported at numerous sites including solid organs, soft tissues (mainly limbs and head and neck) and (more rarely) the skin where a small number of cases have been documented.1–10 Lesions also occur in the oral cavity and orbit.11–13 Multiple tumors are very rare.14 Most tumors present as a fairly circumscribed, slowly growing, asymptomatic mass in middle-aged to elderly patients, with no sex predilection. Rare cases, mainly in the pleura, are associated with hypoglycemia (Doege-Potter syndrome) and finger clubbing (PierreMarie-Bamberg syndrome).15 Hypoglycemia can be due to the secretion of insulin-like growth factor 2 by tumor cells. The majority of cases behave in a benign fashion, but a small percentage may recur locally or even metastasize to internal organs.1–8 Aggressive behavior does not strictly correlate with morphology, as a number of tumors with no apparent histological features suggestive of malignancy have metastasized. Soft tissue tumors metastasize less frequently than those presenting at internal sites such as the mediastinum or retroperitoneum. Although cutaneous lesions may rarely recur, aggressive behavior has not been reported thus far in such lesions.

Pathogenesis and histological features

Fig. 35.176 Inflammatory myofibroblastic tumor: medium-power view with conspicuous myofibroblasts.

No characteristic clonal cytogenetic abnormalities have been noted.16 The features are those of a usually well-circumscribed tumor, typically described as having a patternless architecture (Figs 35.178–35.180). Hypo- and hypercellular areas alternate throughout the lesion and in the background there is prominent hyalinized collagen with a focal keloidal appearance and a prominent vascular network with a hemangiopericytomatous pattern and perivascular hyalinization (Figs 35.181, 35.182). Tumor cells are round to short and spindled, with vesicular nuclei and little or no cytological atypia. Mitotic activity is usually low. Myxoid change may be prominent and has been highlighted in a cutaneous example.17,18 Mature adipocytes are sometimes a feature and can be prominent. Such tumors have been described as lipomatous hemangiopericytoma and are part of the spectrum of solitary fibrous tumor.19 Rare lesions may show histological features of malignancy including cytological atypia, increased mitotic activity, high cellularity and necrosis.3 Giant cell angiofibroma is probably a variant of solitary fibrous tumor and is described below. Exceptional cases display abrupt transition to a high-grade sarcoma with loss of CD34 expression. This feature has been regarded as dedifferentiation and is associated with aggressive behavior and mortality.20 No such cases, however, have been documented in the skin. By immunohistochemistry, tumor cells are diffusely positive for CD34 and also for bcl-2 and CD99 (Fig. 35.183).21 Insulin-like growth factor 2 is highly expressed in tumor cells.22

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Connective tissue tumors

Fig. 35.178

Fig. 35.181

Solitary fibrous tumor: low-power view of a spindle cell tumor with focal hyalinization. Note the prominent blood vessels.

Solitary fibrous tumor: foci of keloid formation are a characteristic feature.

Fig. 35.179

Fig. 35.182

Solitary fibrous tumor: medium power view displaying alternating hyper- and hypocellular foci.

Solitary fibrous tumor: hemangiopericytomatous vessels are often seen.

Fig. 35.180

Fig. 35.183

Solitary fibrous tumor: tumor cells have eosinophilic or clear cytoplasm and oval to spindled basophilic nuclei.

Solitary fibrous tumor: the tumor cells show strong CD34 expression.

Low-grade malignant fibrous lesions

Differential diagnosis Distinction from a fibrous histiocytoma is based on the relative lack of ­circumscription, the polymorphism and the negative or only very focal ­positive staining for CD34 in the latter condition. Dermatofibrosarcoma ­protuberans is diffusely positive for CD34 but is widely infiltrative and ­consists of ­monotonous cells arranged in a storiform pattern.

Giant cell angiofibroma Clinical features Giant cell angiofibroma is a distinctive benign tumor occurring mainly in the orbit but also presenting elsewhere in the head and neck (including the oral cavity and pharynx), trunk, groin, vulva and perianal area.1–7 An ­exceptional case in the mediastinum has also been described.8 Patients are usually ­middle-aged adults and although orbital lesions have predilection for males, extraorbital lesions affect mainly females.1–5 Tumors are asymptomatic, subcutaneous, slowly growing and measure only a few centimeters in diameter. Local recurrence is rare. It has been ­suggested that giant cell angiofibroma represents a giant cell-rich variant of solitary fibrous tumor.5,9 Aggressive behavior, however, has not been ­documented in any cases.

Fig. 35.185 Giant cell angiofibroma: high-power view.

Pathogenesis and histological features Cytogenetic studies in a one case showed abnormalities of chromosome 6q, while another showed t(12;17)(q15;q23).10,11 Histology shows a well-circumscribed mass with variable cellularity ­composed of small or medium-sized vascular channels with thick walls, ­pseudovascular spaces, a combination of round and short spindle-shaped cells and a variable number of multinucleated giant cells (Figs 35.184–35.186). The latter often seem to be lining the pseudovascular spaces. Mitotic figures are rare. The stroma is myxoid or sclerotic.

Low-grade myofibroblastic sarcoma Clinical features Low-grade myofibroblastic sarcoma is a rare distinctive tumor that presents as a deep-seated mass in the limbs and head and neck of adults, with a slight male predilection.1–3 Tumors may rarely occur in bone, the oral cavity, heart, abdomen and vulva.4–9 A single cutaneous tumor has been described.10 A

Fig. 35.186 Giant cell angiofibroma: note the tumor giant cells.

case in association with a desmoplastic melanoma has been reported.11 Local recurrence is common and metastatic disease is rare.1

Histological features

Fig. 35.184 Giant cell angiofibroma: low-power view showing prominent blood vessels and tumor cells dispersed in a myxoid stroma.

Histology shows an infiltrative tumor composed of fascicles of cells with indistinct cytoplasmic margins, pale pink cytoplasm and elongated, vesicular nuclei. In some lesions there is variable cellularity. Cytological atypia is not prominent but is always present. Mitotic activity tends to be low. In a single case intracytoplasmic hyaline inclusions have been reported.12 Tumor cells are positive for smooth muscle actin, muscle specific actin and calponin.13,14 There may be focal positivity for desmin but h-caldesmon is negative.13 ALK-1 and keratin are also negative a feature that allows distinction from inflammatory myofibroblastic tumor.13 Beta-catenin shows no nuclear staining, a feature that allows distinction from desmoid fibromatosis. Ultrastructural examination reveals subplasmalemmal bundles of ­myo­filaments and fibronexus.15

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Malignant lesions Fibrosarcoma: adult variant Clinical features Contrary to age-old teaching, adult fibrosarcoma is now regarded as ­distinctly uncommon. With the aid of improved diagnostic techniques, many previous cases of fibrosarcoma would now be reclassified, most often as monophasic synovial sarcoma, solitary fibrous tumor or malignant peripheral nerve sheath tumor. True fibrosarcoma accounted for less than 1% of sarcomas among 100 000 adult sarcoma patients studied.1 Adult fibrosarcoma usually arises in the fifth and sixth decades, and shows a slight male predominance. It occurs most often in the lower limbs, ­followed by the upper limbs and trunk.1–4 Tumors presenting in children are classified separately (see below). Fibrosarcoma is most often deep seated and ­asymptomatic. Only very occasional tumors are subcutaneous. There is a ­tendency for local recurrence and metastasis, with a 5-year survival of about 50%.

Pathogenesis and histological features A small proportion of adult tumors have been reported to be radiation induced but it is not clear whether all of these tumors represent true fibrosarcomas.5 Cytogenetic studies in a small number of fibrosarcomas have shown complex chromosomal abnormalities.6,7 In two cases, tri- or tetrasomy of 2q has been described.7 Adult fibrosarcoma tends to be well circumscribed and is composed of relatively uniform spindled cells with little cytoplasm, typically arranged in a herring-bone pattern (Figs 35.187, 35.188). There is usually minimal collagen production, mild pleomorphism can be present and the mitotic count varies. It is important to remember that tumors such as dermatofibrosarcoma protuberans and dedifferentiated liposarcoma may have areas identical to fibrosarcoma. Immunohistochemistry shows that tumor cells are positive for vimentin and are occasionally focally positive for actin. Other markers including CD34, S-100, EMA and desmin are negative. Ultrastructural studies show cells with features of fibroblasts and myofibroblasts.8

Differential diagnosis All cases should be assessed for S-100 protein, pankeratin and EMA expression to exclude malignant schwannoma and monophasic ­synovial sarcoma since the diagnosis of fibrosarcoma is one of exclusion. Leiomyosarcoma is composed of plumper spindle-shaped cells with ­abundant ­eosinophilic

Fig. 35.188 Fibrosarcoma: the spindle cell borders are indistinct and their nuclei are elongated with thin tapered ends, unlike those in leiomyosarcoma and neurofibrosarcoma.

cytoplasm and cigar-shaped nuclei. Tumor cells are usually ­positive for desmin and staining for actin is more widespread than that seen in fibrosarcoma.

Fibrosarcoma: infantile variant Clinical features Infantile fibrosarcoma presents before the age of 10 years. The great majority of patients are less than 2 years of age and tumors are often congenital with a predilection for males.1–5 It frequently presents as a subcutaneous tumor with predilection for the limbs, but not uncommonly arises on the head and neck. The clinical course is much less aggressive than that of its adult counterpart and the 5-year survival is higher than 80%.1–5 Local recurrence is seen in up to 25% of cases. Metastases are rare but may occur even before birth.6 A case associated with coagulopathy, one with fetal anemia and a further with urticaria pigmentosa have been described.7–9

Pathogenesis and histological features Cytogenetic studies of infantile fibrosarcoma have shown a t(12;15)(p13;q26) resulting in activation of the NTRK3 receptor tyrosine kinase gene, although in our experience this cannot be demonstrated in all cases.10–12 This same translocation can also be associated with congenital mesoblastic nephroma and secretory breast carcinoma.13,14 Microscopic appearances are very similar to those of the adult variant (Figs 35.189–35.191). However, some cases show more primitive rounded cells and/or a hemangiopericytoma-like pattern. Tumor cells are positive for vimentin and sometimes focally positive for actin. Ultrastructural studies show cells with features of fibroblasts.15

Differential diagnosis Infantile myofibroma may contain focal areas resembling infantile fibrosarcoma. Careful attention should be paid in such cases to identify areas typical of myofibromatosis. Cytogenetic analysis may also be of help.16

Sclerosing epithelioid fibrosarcoma Clinical features Fig. 35.187 Fibrosarcoma: marked basophilia and a herring-bone pattern of spindle cells are typical features of this lesion.

Sclerosing epithelioid fibrosarcoma is a very rare distinctive variant of fibrosarcoma. It involves deep soft tissues of the lower limbs/limb girdles followed by the trunk and upper limbs and rarely the head and neck (including the salivary gland and mouth) and bone.1–5 Rare tumors can occur in the liver, colon and pituitary gland.6–8 One tumor developed after radiotherapy.7 Patients are

Malignant lesions middle-aged adults and present with a variably painful mass. There is no sex predilection. There is a high recurrence rate of up to 50% and metastatic ­disease occurs in up to 40% of cases.1–3

Pathogenesis and histological features Recently, this tumor has been described in combination with low-grade fibromyxoid sarcoma (see below) with demonstration of the characteristic t(7;16)(q33;p11) in these mixed cases.9,10 However, in our experience, FUS re­arrangements are uncommon in pure epithelioid fibrosarcoma, casting some doubt on the pathogenetic relationship between these two tumors in their pure, unmixed forms.11 The tumor is characterized by prominent hyalinization and relatively ­uniform, small, round or ovoid epithelioid cells with sparse and often clear cytoplasm arranged in cords and nests (Figs 35.192, 35.193). Focal calcification and bone formation are features that are sometimes present. Tumor cells are generally positive for vimentin only, although some show focal positivity for EMA, S-100 protein and more infrequently for neuronspecific enolase (NSE).1,3 Rare tumors focally express keratin.1 Fig. 35.189 Infantile fibrosarcoma: the tumor is densely cellular and an ill-defined herring-bone pattern is evident.

Fig. 35.190

Fig. 35.192

Infantile fibrosarcoma: the tumor cells are basophilic and have regular elongated nuclei.

Sclerosing epithelioid fibrosarcoma: low-power view showing a paucicellular infiltrate within a densely hyalinized stroma.

Fig. 35.191

Fig. 35.193

Infantile fibrosarcoma: in this field the tumor cells are more epithelioid and show striking mitotic activity.

Sclerosing epithelioid fibrosarcoma: the tumor cells characteristically show a singlefile distribution.

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Low-grade fibromyxoid sarcoma Clinical features Low-grade fibromyxoid sarcoma is a rare distinctive tumor which belongs within the spectrum of hyalinizing spindle cell tumor with giant rosettes.1–9 It presents mainly in young adults or less commonly younger patients as a slowly growing, asymptomatic large mass with a predilection for the limbs.1–7 Most lesions are deep seated, may be intramuscular and some tumors are subcutaneous. Superficial lesions tend to be more common in children.10 Unusual sites include intracranial, intrathoracic, mesenteric, omental, the ovary, the lung, the colon and the falciform ligament.11–18 Although the rates of local recurrence, metastasis and death were high in the first published series, a subsequent large series reported the rates of local recurrence, metastasis and death as 9%, 6% and 2%, respectively.3,4,6 Local recurrence and metastases may occur many years after excision of the primary tumor.1,3,6,19 A case ­associated with radiotherapy has been reported.20

Pathogenesis and histological features

Fig. 35.195

The vast majority of cases are associated with t(7;16)(q33;p11) fusing CREB3L2 and FUS; the former can be substituted by CREB3L1 (11p11) in a small subset of cases.5,21–27 In some examples the fusion results in a ­supernumerary ring and these tumors appear to recur more frequently.28 Histology shows an infiltrative tumor with characteristic alternating myxoid and collagenous areas (Figs 35.194, 35.195). Cellularity is not prominent and tumor cells tend to predominate in the myxoid areas. Bundles of bland, elongated spindle-shaped cells with focal whorling are seen. Small blood vessels with surrounding fibrosis are often present and tumor cells may concentrate around vascular channels. Cytological atypia is minimal and mitotic figures are very rare. In some cases, there is transition to areas with tumor cells that are focally epithelioid ­surrounding ­prominently hyalinized collagen with formation of giant rosettes (Figs 35.196, 35.197). The latter neoplasm was previously considered a distinct entity termed hyalinizing ­spindle cell tumor with giant rosettes.8,9,29 Rare cases contain focal areas resembling an ordinary fibrosarcoma or sclerosing ­epithelioid fibrosarcoma (see above).4–6,30 Immunohistochemistry shows staining for vimentin and very focal ­positivity for SMA and EMA. Claudin 1 is also often positive and this, coupled with positivity for EMA, may lead to a misdiagnosis of ­perineurioma.31 However, Glut-1 tends to be positive in perineurioma and negative in ­low-grade ­fibromyxoid sarcoma.32 Ultrastructural studies show cells with features of fibroblasts.

Low-grade fibromyxoid sarcoma: high-power view.

Fig. 35.194

Fig. 35.197

Low-grade fibromyxoid sarcoma: this field shows cellular foci and adjacent myxoid regions.

Hyalinizing spindle cell tumor with giant rosettes: transition between bundles of bland elongated spindled cells and a giant rosette.

Fig. 35.196 Hyalinizing spindle cell tumor with giant rosettes: note the presence of giant rosettes containing abundant hyalinized collagen in the center.

Benign fibrohistiocytic tumors

Differential diagnosis Distinction from myxofibrosarcoma is based on the presence of curvilinear blood vessels and at least focal prominent cytological atypia with mitotic activity in the latter tumor.33 Tumor cells in neurofibroma are more wavy and myxoid, and collagenous areas do not alternate, but focal collagen deposition is seen between tumor cells. Furthermore, tumor cells in neurofibroma are S-100 protein positive.

Fibrohistiocytic tumors Benign fibrohistiocytic tumors A group of heterogeneous soft tissue tumors, many of which probably have little in common, is traditionally included under this heading. The term ‘­fibrohistiocytic’ is essentially descriptive and refers to a light microscopic morphological resemblance of tumor cells to fibroblasts and histiocytes; it does not appear to have any relationship to line of differentiation or histogenesis. However, the term is retained in this chapter due to its widespread general use and because most tumors in this category are of uncertain histogenesis.

Fibrous papule Clinical features Fibrous papule is a very common lesion that presents on the face of middle­aged adults, with predilection for the nose.1–3 It is usually skin-colored, asymptomatic and measures a few millimeters. Lesions with similar features occur in the tongue and are referred to as solitary oral fibromas.4

Pathogenesis and histological features Although in the past it was suggested that fibrous papule represents an old fibrosed nevus, several studies have demonstrated that this is not the case.5,6 Histologically, the lesion is slightly raised, well circumscribed and located in the superficial dermis. It is composed of a collagenous stroma with increased vascular channels and scattered cells varying from spindle shaped to ­multinucleated (Figs 35.198, 35.199). Mitotic figures are exceptional and some of the cells may show hyperchromatism. Variants with granular cell change, clear cell change and epithelioid cells have been described.7–11 Focal pigmentation and inflammation may be seen.12 Lesions with scattered ­pleomorphic cells overlap with pleomorphic fibroma. The overlying ­epidermis appears normal or slightly flattened.

Fig. 35.198 Fibrous papule: shave biopsy from a lesion on the bridge of the nose. The dermis shows dense collagenous tissue.

Fig. 35.199 Fibrous papule: high-power view of scattered dendritic cells.

By immunohistochemistry, the cells in the lesion are positive for factor XIIIa and may also be positive for CD34.13–16 S-100 protein is negative. Lesions with clear cells are positive for NKI/C3.17 Ultrastructurally, the cells have features of fibroblasts.18,19

Multinucleate cell angiohistiocytoma Clinical features Multinucleate cell angiohistiocytoma is a distinctive condition characterized by multiple, localized, angiomatous papules with predilection for the upper and lower limbs of middle-aged women (Figs 35.200–35.202).1–6 The thigh and dorsum of the hands are frequent sites of involvement. Generalized lesions are very rare.7 The lesions are asymptomatic and do not tend to regress spontaneously. A case has been reported in the oral cavity and a further lesion occurred in association with an iatrogenic arteriovenous fistula.8,9

Pathogenesis and histological features The pathogenesis is unknown but the lesions are much more common in females and the tumor cells express estrogen receptor alpha, suggesting a ­possible hormonal etiologic role.10 The epidermis appears unremarkable. In the superficial and mid ­dermis there is a proliferation of small, thin-walled vascular channels, each of which

Fig. 35.200 Multinucleate cell angiohistiocytoma: multiple papules are present.

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Fig. 35.201

Fig. 35.203

Multinucleate cell angiohistiocytoma: the hand is a characteristic site. By courtesy of the Institute of Dermatology, London, UK.

Multinucleate cell angiohistiocytoma: within the dermis is a vascular and collagenous proliferative lesion with conspicuous multinucleate giant cells.

Fig. 35.202 Multinucleate cell angiohistiocytoma: in this example, the papules appear hemorrhagic. By courtesy of the Institute of Dermatology, London, UK.

is ­surrounded by a layer of pericytes (Fig. 35.203). The surrounding dermis ­contains scattered multinucleate cells with angulated cytoplasm and a background of somewhat hyalinized collagen bundles (Figs 35.204, 35.205). Occasional ­lymphocytes are also seen. Hemosiderin deposition may be present. The multinucleate cells are positive for CD68.

Differential diagnosis An atrophic dermatofibroma can look remarkably similar to ­multinucleate angiohistiocytoma; however, the former presents as a single lesion. Distinction from Kaposi's sarcoma is based on the presence of irregular, ­jagged, ­thin-walled ­vascular channels, absence of multinucleate giant cells and presence of plasma cells. Multinucleate angiohistiocytoma lacks HHV8 on immunohistochemistry.11

Dermatofibroma Dermatofibroma (fibrous histiocytoma, sclerosing hemangioma, histiocytoma cutis, nodular subepidermal fibrosis) represents one of the most common benign cutaneous soft tissue tumors.1–5 Over the years a number of variants have been described, and although they essentially highlight specific histological features that can cause diagnostic confusion, some of them also correlate with characteristic clinical findings and behavior6,7 (see below). However, it must be emphasized that the histological features of several v­ ariants can coexist in the same lesion.8

Fig. 35.204 Multinucleate cell angiohistiocytoma: medium-power view showing vessels with giant cells and pericytes.

Clinical features Dermatofibroma occurs most often in the middle aged and shows a slight female predominance. The majority of lesions are located on the limbs or (to a lesser degree) the trunk, and present as small, raised, hyperkeratotic ­cutaneous nodules usually less than 1 cm in diameter with a reddish-brown surface (Figs 35.206, 35.207). Giant variants including a plaque-like variant are very rare.9–11 A significant proportion of cases are associated with previous minor local trauma, especially insect bites. They are slow growing and painless, and may sometimes be multiple. Eruptive lesions have been documented in the context of immunosuppression, HIV infection and highly active antiretroviral therapy (HAART).12–18 Simple excision is usually curative and local recurrence is exceptional except for some of the variants (see below) and in lesions occurring on the face, where the reported rate of local recurrence is 20%.19 In some variants (e.g., atypical and cellular fibrous histiocytoma) rare metastases have been reported.20–24 A small subgroup of these lesions originates in subcutaneous fat or in deeper structures.25

Benign fibrohistiocytic tumors

Pathogenesis and histological features

Multinucleate cell angiohistiocytoma: high-power view of giant cell.

It is controversial whether dermatofibroma is a reactive or a ­neoplastic ­process. An association with insect bites and even trauma such as ­body-piercing has been reported.26 A neoplastic process, however, is favored, as lesions do not tend to regress spontaneously, there is variable potential for local recurrence in some of the variants, and a few cases have metastasized.27 Furthermore, clonality has been demonstrated in some examples of cellular fibrous histiocytoma.28,29 The common variant is an ill-defined dermal lesion that may extend into superficial subcutaneous fat (Figs 35.208–35.212). It is largely ­composed of interlacing fascicles of slender spindled cells, sometimes in a focal ­storiform arrangement, set within a loose collagenous or (less often) myxoid stroma. Scattered between the spindled cells are foamy histiocytes, multinucleated giant cells and thin-walled blood vessels (Figs 35.213–35.216). Foci of chronic inflammatory cells, including lymphocytes and plasma cells, and hemosiderin deposition are frequently seen. A typical feature is the ­presence of individual hyaline collagen bundles surrounded by tumor cells in the periphery of the lesions. Long-standing lesions show progressive hyalinization and decreased ­cellularity and are usually referred to as sclerosing or atrophic dermatofibroma.

Fig. 35.206

Fig. 35.208

Fig. 35.205

Dermatofibroma: this tumor most often presents as an erythematous raised lesion. Surface scaling is not uncommon. From the collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Fig. 35.207 Dermatofibroma: dark brown (due to hemosiderin deposition) lesions are sometimes mistaken for melanocytic tumors, including melanoma. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Dermatofibroma: scanning section showing the characteristic architecture. The lateral borders of the lesion interdigitate with the adjacent dermis. There is hyperkeratosis and acanthosis of the overlying epidermis.

Fig. 35.209 Dermatofibroma: the tumor extends into the adjacent normal dermis.

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Fig. 35.210

Fig. 35.213

Dermatofibroma: high-power view showing storiform growth pattern.

Dermatofibroma: scattered multinucleated giant cells are a not infrequent feature of this lesion. Note the hemosiderin pigment.

Fig. 35.211

Fig. 35.214

Dermatofibroma: the tumor is composed of uniform, interlacing spindle cells in a vaguely curlicue pattern embedded in a hyaline collagenous stroma.

Dermatofibroma: lipid-laden histiocytes are commonly present.

Fig. 35.212

Fig. 35.215

Dermatofibroma: occasional normal mitotic figures may be seen.

Dermatofibroma: high-power view.

Benign fibrohistiocytic tumors

Fig. 35.216

Fig. 35.218

Dermatofibroma: when the lipid-laden histiocytes are numerous, this lesion is sometimes called histiocytoma cutis.

Dermatofibroma: the tumor is often separated from the epidermis by a grenz zone.

All of these tumors, including the variants, may be associated with a­ canthosis or even pseudoepitheliomatous hyperplasia of the overlying ­epidermis and hyperpigmentation of the basal cell layer (Figs 35.217, 35.218). It has been suggested that epidermal growth factor may play a role in the pathogenesis of the epidermal hyperplasia.30 A grenz zone of papillary dermal sparing is usually present (Fig. 35.219). Changes simulating seborrheic keratosis are common, followed by proliferation of clear cells mimicking a clear cell acanthoma, and proliferation of immature hair follicle-like structures closely resembling a trichoblastoma, and induction of sebaceous glands sometimes in a reticulate pattern (Fig. 35.220).31 Mature hair follicles are rarely induced and more unusual epidermal changes including, epidermolytic hyperkeratosis, focal acantholysis and even Bowen's disease, have also been described.32,33 Most cases of basal cell carcinoma overlying dermatofibroma represent induction of immature follicular structures. A proportion of tumors, especially the cellular variant, stain focally for α-SMA and calponin, suggesting myofibroblastic differentiation (Fig. 35.221). It has been proposed that this lesion arises from a fixed dermal connective tissue cell, the dermal dendrocyte, which stains positively for factor XIIIa.34 Although a number of cells within fibrous histiocytomas react with this marker, especially towards the edges of the lesion, these appear to be reactive cells and not true tumor cells. In contrast to dermatofibrosarcoma, CD34 expression is not usually a feature except in the cellular variant of fibrous

Fig. 35.219 Dermatofibroma: in this example, there is an extensive grenz zone.

histiocytoma where focal positivity for this marker may be seen (see below). D2–40 is diffusely positive in dermatofibromas and only very focally positive or negative in dermatofibrosarcoma protuberans.35 Common dermatofibroma is usually easy to diagnose and problems with differential diagnosis generally only arise with its variants.36 Variants of dermatofibroma include: • cellular fibrous histiocytoma, • aneurysmal fibrous histiocytoma, • epithelioid fibrous histiocytoma, • atypical (pseudosarcomatous) fibrous histiocytoma, • lipidized (‘ankle-type’) fibrous histiocytoma, • clear cell fibrous histiocytoma, • palisading cutaneous fibrous histiocytoma, • atrophic dermatofibroma.

Cellular fibrous histiocytoma

Fig. 35.217 Dermatofibroma: the epithelium overlying the tumor is often acanthotic.

Cellular benign fibrous histiocytoma accounts for almost 5% of cutaneous fibrous histiocytomas.37–39 It is most common in young adults, especially males, and has a predilection for the limbs and head and neck area (Figs 35.222, 35.223). These lesions are larger than common fibrous histiocytoma and have a high recurrence rate of up to 26%. Metastasis to regional lymph nodes and lungs has been reported in a handful of cases.36,40 In a

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Fig. 35.222 Cellular fibrous histiocytoma: tumors may be large and sometimes present at unusual sites, as in this example. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.220 Dermatofibroma: proliferation of basaloid cells reminiscent of trichoblastoma.

Fig. 35.223 Cellular fibrous histiocytoma: children may rarely be affected. Ulceration is sometimes a feature. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.221 Dermatofibroma: this example shows strong smooth muscle actin expression.

f­ urther case, erosion of the phalanx occurred.41 Histological features do not allow ­prediction of those cases that will metastasize. Histologically, lesions are highly cellular with a more prominent fascicular growth pattern (Figs 35.224–35.227). Frequently there is involvement of the superficial subcutis. Tumor cells tend to have more abundant eosinophilic cytoplasm, and normal mitotic figures are common (Fig. 35.228). Central necrosis is seen in some cases. Immunohistochemistry shows variable (usually focal) staining for SMA and calponin and negative or only focal staining for CD34 (Fig. 35.229). When the last is present, expression is limited to peripheral parts of the tumor. Exceptionally, very focal desmin positivity may be seen. Distinction from leiomyosarcoma is possible by the presence in the ­latter of cells with cigar-shaped nuclei, at least focal cytological atypia, a ­uniform fascicular growth pattern and diffuse positivity for SMA and desmin. Dermatofibrosarcoma protuberans has a monotonous, storiform growth ­pattern, monomorphous cells and diffuse positivity for CD34.

Fig. 35.224 Cellular fibrous histiocytoma: this variant of dermatofibroma is often a source of diagnostic confusion. It is larger than the conventional form and appears more cellular and mitotically active.

Benign fibrohistiocytic tumors

Fig. 35.227 Cellular fibrous histiocytoma: high-power view of Figure 35.226

Fig. 35.225 Cellular fibrous histiocytoma: scanning view showing extension into the deep reticular dermis.

Fig. 35.228 Cellular fibrous histiocytoma: note the mitotic activity.

Fig. 35.226 Cellular fibrous histiocytoma: this example shows striking cellularity.

Aneurysmal fibrous histiocytoma Aneurysmal benign fibrous histiocytoma represents less than 2% of fibrous histiocytomas and presents as a blue–brown nodule on the limbs of middleaged adults, especially females (Fig. 35.230).42–45 Rapid growth can be seen due to extensive hemorrhage, and clinical confusion with a melanocytic or vascular tumor is common. The rate of recurrence is around 19%. A single case presented with involvement of a regional lymph node. The tumor, however, was on the neck, and this phenomenon may have represented direct extension rather than true metastasis.43 Histologically, the most striking feature is the presence (especially towards the center of the lesion) of hemorrhagic irregular cleft-like and cystic spaces mimicking cavernous vascular channels, but without endothelial lining (Figs 35.231, 35.232). Adjacent solid areas show the usual features of benign fibrous histiocytoma, but are often very cellular. Multifocal interstitial hemorrhage and intra- and extracellular hemosiderin deposition are prominent and normal mitotic figures are common (Figs 35.233–35.235). Due to

Fig. 35.229 Cellular fibrous histiocytoma: the tumor cells at the edge of the lesion often express CD34.

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Fig. 35.232 Fig. 35.230 Aneurysmal fibrous histiocytoma: this lesion presents as a hemorrhagic nodule. By courtesy of the Institute of Dermatology, London, UK.

Aneurysmal fibrous histiocytoma: the hemorrhagic spaces are devoid of an endothelial lining.

Fig. 35.233 Hemosiderotic fibrous histiocytoma: the marked vascularity and heavy hemosiderin content sometimes seen in this lesion gives a dark bluish-brown coloration, which clinically may cause confusion with melanoma.

Fig. 35.231 Aneurysmal fibrous histiocytoma: a densely cellular infiltrate is present in the deeper dermis. Blood-filled cystic spaces are evident.

the extensive secondary changes this lesion is frequently diagnosed as a vascular tumor, but typical features of fibrous histiocytoma are always present and endothelial markers are only positive in normal blood vessels. In a single case, a translocation t(12;19)(p12;q13) was reported.46 Aneurysmal fibrous histiocytoma should not be confused with angiomatoid fibrous histiocytoma. The latter is usually subcutaneous and is composed of monomorphic spindle-to-ovoid eosinophilic cells, which are usually desmin positive. A prominent lymphoplasmacytic infiltrate is commonly present. Some patients with the latter condition have striking systemic symptoms. Hemosiderotic fibrous histiocytoma probably represents a stage in the development of aneurysmal fibrous histiocytoma.

Epithelioid fibrous histiocytoma Epithelioid fibrous histiocytoma is rare, has a wide age and anatomical distribution (with predilection for the proximal lower limb), and often ­presents as a polypoid red nodule, which is usually confused with a pyogenic ­granuloma (Fig. 35.236).47–50 Multiple lesions are exceptional and a lesion has been

Fig. 35.234 Hemosiderotic fibrous histiocytoma: this variant is also sometimes known as sclerosing hemangioma.

Benign fibrohistiocytic tumors

Fig. 35.235 Hemosiderotic fibrous histiocytoma: a Perl stain highlights the hemosiderin.

Fig. 35.236 Epithelioid benign fibrous histiocytoma: this variant typically presents as an erythematous polypoid lesion. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.237 Epithelioid benign fibrous histiocytoma: this low-power view shows a superficial tumor nodule with an associated epidermal collarette.

Fig. 35.238 Epithelioid benign fibrous histiocytoma: the tumor is composed of large cells with abundant eosinophilic cytoplasm. The infiltrate is uniform, in contrast to the more typical variant. Often, conventional features are identifiable elsewhere in the specimen.

reported in the tongue.51,52 Histologically, most tumors are superficial, but rare examples extend into the superficial subcutis. An epidermal collarette is often present and tumor cells are rounded with abundant eosinophilic cytoplasm and a vesicular nucleus with small eosinophilic nucleoli (Figs 35.237– 35.240). Binucleate or multinucleate cells are common. Rarely, cells may have granular cell change.53 Occasional normal mitotic figures may be evident. Some lesions are more myxoid and vascular. Immunohistochemistry reveals a population of CD34 positive cells and a population of factor XIIIapositive dendritic cells (Fig. 35.241).54 Distinction from Spitz nevus is facilitated by the absence of a junctional component or nesting of tumor cells and negativity for S-100 protein (see Fig. 35.191). Distinction from a cutaneous perineurioma with epithelioid cell change is made by the presence of diffuse EMA and claudin-1 positivity in the latter tumor.

Atypical (pseudosarcomatous) fibrous histiocytoma Atypical (pseudosarcomatous) fibrous histiocytoma is also known as dermatofibroma with monster cells.20,55–58 Clinically, it has a predilection for the limbs with some tumors occurring on the trunk and head and neck. Lesions are usually papular or nodular but may be polypoid, and rare tumors measure up to several centimeters.20

Fig. 35.239 Epithelioid benign fibrous histiocytoma: high-power view.

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Fig. 35.240 Epithelioid benign fibrous histiocytoma: occasional normal mitotic figures may be present.

Fig. 35.242 Atypical benign fibrous histiocytoma: this cellular lesion extends into the subcutaneous fat.

Fig. 35.241 Epithelioid benign fibrous histiocytoma: the tumor cells express factor XIIIA but are negative for S-100 protein.

Histologically, the lesion is mainly dermal but extends into the superficial subcutis in one-third of cases. In some areas, the tumor shows the features of a more typical fibrous histiocytoma (Fig. 35.242). However, a variable proportion of cells in the tumor have irregular, large and pleomorphic nuclei with prominent nucleoli (Fig. 35.243). Pleomorphism may be marked. The mitotic rate varies and may be high in some cases. Atypical mitotic figures are sometimes seen. An unusual feature is that of focal necrosis.20 There is local recurrence in a minority of cases, and in the largest series reported to date two patients developed metastasis and one died as a result of systemic spread.20 Atypical fibrous histiocytoma should not be confused with atypical fibro­ xanthoma. The latter occurs in a completely different clinical setting (see below) and shows diffuse pleomorphism, cytological atypia and numerous mitoses throughout.

Lipidized (‘ankle-type’) fibrous histiocytoma Lipidized (‘ankle-type’) fibrous histiocytoma presents as a polypoid yellow lesion on the lower leg.59 Histologically, there is a predominance of foamy ­histiocytes surrounded by abundant, almost keloidal, hyalinized collagen bundles (Figs 35.244–35.246).

Fig. 35.243 Atypical benign fibrous histiocytoma: there is striking nuclear pleomorphism. Note the mitotic figure.

Clear cell fibrous histiocytoma This is a very rare variant with no distinctive clinical features and with ­massive clear cell change throughout the lesion.60–62 The overall architecture and morphological features are not usually typical of a fibrous histiocytoma and thus may represent an altogether unrelated tumor. It is likely that tumors previously described as clear cell fibrous histiocytoma represent the entity more recently reported as dermal clear cell mesenchymal neoplasm.62a Only a handful of cases of the latter entity have been described in adults with predilection for the lower limbs. Tumors consist of sheets of clear cells with vesicular nuclei that occupy the reticular dermis and may extend into the subcutaneous tissue. Cytological atypia and mitotic figures are rare. Tumor cells are negative for most markers except NKI-C3 and sometimes CD68. Behaviour is benign.

Palisading cutaneous fibrous histiocytoma Palisading cutaneous fibrous histiocytoma refers to lesions which histologically show prominent nuclear palisading (Figs 35.247, 35.248).63,64 They

Benign fibrohistiocytic tumors

Fig. 35.244

Fig. 35.247

Lipidized (‘ankle-type’) fibrous histiocytoma: this is a distinctive morphological subset characterized by a predominance of xanthoma cells associated with marked stromal hyalinization. By courtesy of R. Carr MD, Warwick Hospital, UK.

Palisading fibrous histiocytoma: occasionally, palisading mimicking Verocay bodies may be a feature.

Fig. 35.245

Fig. 35.248

Lipidized (‘ankle-type’) fibrous histiocytoma: high-power view of foamy histiocytes. By courtesy of R. Carr MD, Warwick Hospital, UK.

Palisading fibrous histiocytoma: high-power view.

appear to present most often on acral sites. Focally, there is a resemblance to schwannoma as the palisading mimics Verocay bodies. However, lesions are not encapsulated and tumor cells are S-100 negative.

Atrophic dermatofibroma Atrophic dermatofibroma probably represents the end stage of many dermatofibromas and is characterized clinically by an area of depression or retraction, often resembling a scar or even anetoderma.65–67 Histologically, lesions are hypocellular and show prominent hyalinization of collagen (Figs 35.249, 35.250). The changes may resemble those seen in multinucleate angiohistiocytoma but the latter usually presents with multiple clinical lesions.

Rare variants

Fig. 35.246 Lipidized (‘ankle-type’) fibrous histiocytoma: this field shows densely hyalinized collagen reminiscent of amyloid. By courtesy of R. Carr MD, Warwick Hospital, UK.

Very occasionally, tumors can show prominent osteoclast-like giant cells (occasionally with ossification), granular cell change, cholesterol deposition, focal smooth muscle proliferation, marked myxoid change, keloidal change, balloon cell change and signet-ring change.68–83 Tumors may also present with a lichenoid pattern and in a single case intracytoplasmic eosinophilic globules were described.84,85 Two cases of a tumor with scattered ­pigmented ­melanocytes, with CD34 positivity and overlapping histological features between Bednar's tumor and dermatofibroma have been reported. Unfortunately, no cytogenetic studies were performed in these cases.86 A ­further case of a melanoma

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Connective tissue tumors Histologically, tumors are very similar to those occurring in the dermis. They are well-circumscribed and polymorphic, with a mixture of histiocyte-like cells, spindle-shaped cells and frequently multinucleated giant cells and foamy cells. A sprinkling of lymphocytes is common. More monomorphic tumors very similar to cellular fibrous histiocytoma are common. Atypical variants of the tumor are rarely seen and are also identical to more superficial tumors.4 Deep tumors have a more prominent storiform appearance. Up to 42% of cases display a hemangiopericytoma-like pattern and stromal hyalinization is present in 39% of cases.2 Necrosis and lymphovascular invasion are exceptional. Immunohistochemically, tumor cells are often positive for CD34 and smooth muscle actin in about two-thirds of cases and very rarely for desmin.2 Cytogenetic studies of a single case demonstrated a t(16;17)(p13.3;q21.3).5 However, this change appears to be very rare as it was not demonstrated in a further six cases studied.

Differential diagnosis Fig. 35.249 Atrophic fibrous histiocytoma: this variant appears hypocellular and orientated parallel to the surface epithelium.

The main differential diagnosis is with solitary fibrous tumor and dermatofibrosarcoma protuberans. The former is less monomorphic and displays ­­hypoand hypercellular areas lacking a storiform pattern and the latter is infiltrative with replacement of the subcutaneous tissue with a lace-like ­pattern. CD34 is of limited help as is tends to be positive in deep benign fibrous histiocytoma and in the latter tumors.

Giant cell tumor of tendon sheath Clinical features

Fig. 35.250 Atrophic fibrous histiocytoma: the tumor cells are compressed by the collagenous component.

Giant cell tumor of tendon sheath is a frequently encountered tumor that occurs most often in the third to fifth decades and has a slight predilection for females.1–6 Lesions in children are rare.7 It occurs almost exclusively on the hands and feet, especially the fingers and less commonly the toes (Fig. 35.251).1–6 It presents as a slowly growing, usually painless nodule and is most often less than 2 cm in diameter. Multiple or bilateral lesions are uncommon.8,9 This lesion has no malignant potential, but may recur locally in up to 30% of cases, usually as a consequence of incomplete excision.1–7,10 It appears that there is increased risk of local recurrence in lesions involving the flexor and extensor tendons and the joint capsules.11 Invasion of the underlying bone has been reported in up to 11% of cases.12 The diffuse tenosynovial giant cell tumor is a rare variant which tends to involve the distal limbs, the larger joints of the limb girdles (especially the hip) and more rarely the vertebral column.13–16 It is locally aggressive and there is quite often infiltration of extra-articular soft tissues and occasionally bone. Recurrence in up to a third of cases is common following incomplete ­surgical

­ verlying a dermatofibroma has been reported.87 Although inflammatory cells o are a feature of most fibrous histiocytomas, formation of germinal centers is rare.88

Deep benign fibrous histiocytoma Clinical features Deep benign fibrous histiocytoma is a rare tumor that presents most often between the fourth and fifth decades of life in the subcutis or deep soft tissues, with a predilection for males. It occurs mainly on the limbs followed by the head and neck and trunk. Rare cases present in the mediastinum, ­retroperitoneum and pelvis.1–3 Tumors are usually a few centimeters in diameter but larger tumors also occur. There is local recurrence in up to 22% of cases and two cases of metastatic lesions that resulted in death have been recorded.2 These tumors did not look histologically different from non­ metastasizing lesions.

Pathogenesis and histological features The pathogenesis is unknown but these tumors are the deep counterpart of dermal fibrous histiocytoma (dermatofibroma).

Fig. 35.251 Giant cell tumor of tendon sheath: this lesion presents as a firm nodule that most often affects the finger. By courtesy of H. du P. Menagé, MD, Institute of Dermatology, London, UK.

Benign fibrohistiocytic tumors excision.16 Exceptional tumors with benign histology may metastasize to regional lymph nodes, and tumors with sarcomatous change may develop distant metastases.16

Pathogenesis and histological features The nature of giant cell tumor of tendon sheath, whether reactive or neoplastic, has been disputed for years, but is now resolved.17,18 The most common cytogenetic abnormality is t(1;2)(p13;q37) placing colony-stimulating factor (CSF) under the COL6A3 promoter.18–21 Substitution of COL6A3 by other promoters is likely.17 Each of these result in overexpression of CSF-1, but only in a small subset of cells. These express CSF-1, with the majority of apparently nonclonal cells, particularly macrophages, expressing CSF-1 receptor, a situation described as ‘tumor landscaping effect’.19 This may explain why some studies fail to demonstrate clonality.22 Treatments inhibiting the CSF-1 receptor may have efficacy.23 The tumors are usually lobulated and well defined, often with a fibrous pseudocapsule (Fig. 35.252). They are composed of mononuclear cells with eosinophilic cytoplasm and vesicular nuclei, xanthomatous cells, siderophages, osteoclast-like multinucleated giant cells and mononuclear inflammatory cells (Figs 35.253–35.255).24 The cells are typically set in a variably prominent collagenous stroma within which cholesterol clefts or evidence of previous hemorrhage in the form of stromal hemosiderin may be apparent. Normal mitotic figures are commonly seen and may be numerous. Old lesions can show prominent hyalinization. Immunohistochemically, some of the mononuclear cells and most of the osteoclastic giant cells are CD68 positives. Actin may be focally positive in the mononuclear cells. Other markers are generally uninformative. Histological appearances of diffuse giant cell tumor are similar to those of the localized variant, except that cellularity is often higher, osteoclastic cells tend to be fewer and intralesional cleft-like spaces are common. An additional feature seen in most cases is the presence of a subpopulation of large, desmin-positive, dendritic histiocyte-like cells.16 These have abundant eosinophilic cytoplasm, large vesicular nuclei, paranuclear eosinophilic inclusions and rare intranuclear inclusions.16

Fig. 35.253 Giant cell tumor of tendon sheath: higher-power view showing xanthoma cells and giant cells.

Differential diagnosis Fibroma of tendon sheath may be distinguished by its more uniform spindled cell appearance, its greater tendency for stromal hyalinization and the presence of characteristic slit-like vascular spaces. However, as mentioned

Fig. 35.254 Giant cell tumor of tendon sheath: there is conspicuous hemosiderin deposition.

Fig. 35.252 Giant cell tumor of tendon sheath: low-power view showing a sharply circumscribed pseudoencapsulated tumor.

Fig. 35.255 Giant cell tumor of tendon sheath: osteoclast-like multinucleate giant cells are present.

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Connective tissue tumors under fibroma of tendon sheath, some cases show overlapping features.25 Granulomatous inflammatory lesions are not usually circumscribed, show greater infiltration by chronic inflammatory cells and usually contain welldeveloped epithelioid granulomata. Diffuse-type lesions can be distinguished from synovial sarcoma by the absence of an epithelial lining in the clefts and negativity for epithelial markers.

Low-grade malignant fibrohistiocytic lesions Giant cell tumor of soft tissues Clinical features Giant cell tumor of soft tissues (also known as soft tissue giant cell tumor of low malignant potential) represents the soft tissue counterpart of giant cell tumor of bone.1–7 It is rare and presents mainly in adults, with no sex predilection. The great majority of lesions occur in the limbs followed by the trunk and only exceptionally in the head and neck.8 Most tumors are well circumscribed and subcutaneous but dermal (exceptionally polypoid) and deeper lesions may occur.6,9,10 The size ranges from less than 1 cm to up to 10 cm. In a single documented case, the tumor had been present for 46 years.11 Local recurrence is seen in up to 10% of cases and metastases are exceptional.1–3,12

Fig. 35.257 Giant cell tumor of soft tissue: high-power view of osteoclast-like giant cells.

The pathogenesis is unknown but rare associations with trauma, surgical scars and Paget's disease of bone have been reported.2,13,14 Histology shows a welldefined tumor which is often multinodular and has focal areas of hemorrhage (Fig. 35.256). A peripheral shell of bone is seen in some cases. Focal areas of bone formation may also be present elsewhere in the tumor. Hemorrhage, aneurysmal bone cyst-like areas and sclerotic changes are additional features. Vascular invasion is found in up to one-third of the cases.2,3 Tumor cells ­consist of a mixture of osteoclast-like giant cells and mononuclear cells (Fig. 35.257). The osteoclast-like giant cells often form nodular aggregates. Both the osteoclast-like giant cells and the mononuclear cells are positive for CD68. Positive staining for actin may be focally present in mononuclear cells but not in the giant cells.3 Exceptional focal positivity for keratin and S-100 protein can be seen.2

trunk in children or young adults of either sex.1–7 Presentation in the head and neck is exceptional.8 Unusual sites include the lung, brain and mediastinum.9–12 Lesions arising in deeper soft tissues are less common. A congenital example has been documented.13 A case arising in the background of chronic radiodermatitis, a tumor developing in an HIV-positive child and one in a child with neuroblastoma have also been reported.14–16 Most tumors are slow growing and less than 2 cm in diameter. Patients sometimes present with ­systemic symptoms including fever, weight loss, anemia and ­paraproteinemia. Systemic symptoms usually disappear after removal of the tumor. There is local recurrence in 2–12% of cases.2 Recurrences appear to be associated with deep-seated lesions, those with an infiltrative margin and lesions located in the head and neck.2 Metastases to local lymph nodes occur in up to 1% of cases but behavior is usually benign with only very exceptional cases presenting with distant metastases and death. No histological features allow prediction of which tumors will recur or metastasize.

Angiomatoid fibrous histiocytoma

Pathogenesis and histological features

Pathogenesis and histological features

Clinical features Angiomatoid fibrous histiocytoma (previously known as angiomatoid malignant fibrous histiocytoma) is a rare tumor. It usually arises in the subcutaneous tissues and only exceptionally in the dermis of the extremities or

The most common chromosomal translocation involves FUS (16p11) and CREB1 (2q33) though these can be substituted by EWSR1 (22q12) and ATF1 (12q13), respectively, in a small subset of cases.17–23 Identical fusion events are seen in clear cell sarcoma, though EWSR1-ATF1 is most common. 24–26 Angiomatoid fibrous histiocytoma is characterized by well-circumscribed nodules composed of relatively uniform, pale, round or short spindle-shaped eosinophilic cells with ovoid vesicular nuclei, interspersed with blood-filled sinusoidal spaces and foci of hemorrhage (Figs 35.258–35.260). Mitotic figures are usually not prominent. Typically, there is a dense lymphoplasmacytic mantle around and within the tumor, which thereby often simulates a lymph node. Cytological atypia (which may be prominent) and mitotic activity may sometimes be more prominent but this does not correlate with behavior.2,27 Few giant cells are seen. Immunohistochemically, tumor cells are positive in about 50% of cases for desmin and for muscle actin (HHF-35), but not for smooth muscle actin (see Fig. 35.203).4 Positivity for EMA, CD68 and CD99 is seen in up to 50% of cases.5,6 Tumor cells are negative for S-100 protein, keratins and vascular markers. It is possible, combining morphology with immunophenotype, that these lesions show myoid (probably myofibroblastic) differentiation, although the combination of EMA and desmin is unusual.4 Ultrastructural studies show a variety of cells including fibroblastic, ­myofibroblastic, histiocyte-like or undifferentiated forms.3,13,19

Differential diagnosis Fig. 35.256 Giant cell tumor of soft tissue: low-power view of the edge of a lesion.

Distinction from aneurysmal fibrous histiocytoma is discussed under the ­latter entity.

Low-grade malignant fibrohistiocytic lesions

Plexiform fibrous histiocytoma Clinical features Plexiform fibrous histiocytoma (plexiform fibrohistiocytic tumor) is a rare but distinctive neoplasm that most commonly presents on the limbs of children and young adults (more than 50% of patients are younger than 20 years) and has a slight predilection for females.1–9 A single congenital case has been documented.10 About 60% of the cases occur on the upper limbs (particularly the forearms, hands and wrists) followed by the lower limbs (about one-third of cases). Involvement of the trunk and face and neck is very rare.1–3 Lesions present as an ill-defined nodule or plaque that predominantly involves the subcutaneous tissue but may extend into the dermis. Dermal variants of the tumor may occur.7,11 There is a tendency for local recurrence varying from 12% to 37.5% of cases. Local lymph node metastasis has been reported in three cases and in one of these spread to the lungs was also seen.1,2,12

Pathogenesis and histological features Fig. 35.258 Angiomatoid fibrous histiocytoma: viewed at low power, this condition sometimes resembles a lymph node. Note the multiple tumor nodules and foci of hemorrhage.

Fig. 35.259 Angiomatoid fibrous histiocytoma: the tumor cells are fairly uniform and have round or oval vesicular nuclei.

Cytogenetic studies have been performed in two cases with differing clonal chromosomal abnormalities.13,14 Recently, it has been suggested that plexiform fibrous histiocytoma and cellular neurothekeoma are part of the same spectrum, based on morphologic and phenotypic similarities.7,15 Tumors are infiltrative and most are located mainly at the junction between the dermis and subcutaneous tissue, and occasionally there is involvement of underlying skeletal muscle (Figs 35.261–35.264). About one-third of cases are predominantly dermal.7 Microscopic appearances vary according to the proportion of two main components, one of which may predominate:1–3 • fascicles of fibroblast/myofibroblast-like cells, which usually predominate (fibroblastic), • nodules of histiocyte-like cells (histiocytic). Varying numbers of osteoclast-like giant cells are also present, mainly in the histiocytic variant. Areas of hemorrhage with hemosiderin deposition can be seen in and around the nodules, which may also show peripheral hyalinization. Often, the fibroblastic fascicles appear to radiate from a more solid central area. Entrapment of fat with the presence of microfat cells and myxoid change is occasionally observed. A focal lymphocytic inflammatory cell ­infiltrate is seen in most cases and it tends to be more prominent in the fibroblastic variant.7 Perineural and peripacinian extension is rarely seen and in a few cases there is cytological atypia and increased mitotic ­activity.7 Occasionally, vascular invasion is present (Fig. 35.265). Bone formation has also exceptionally been documented. Dermal tumors spare ­adnexal ­structures. A variant of plexiform fibrous histiocytoma with prominent granular cell change has been described.16 There are no histological findings that allow prediction of tumors that will recur or metastasize.

Fig. 35.260

Fig. 35.261

Angiomatoid fibrous histiocytoma: medium-power view highlighting the lymphocytic infiltrate and hemosiderin deposition.

Plexiform fibrous histiocytoma: the prototypical case consists of fibroblastic spindle cell areas in which there are nodules of histiocyte-like cells.

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Fig. 35.262 Plexiform fibrous histiocytoma: there are prominent osteoclast-like giant cells.

Fig. 35.263 Plexiform fibrous histiocytoma: high-power view of a histiocytic nodule.

Fig. 35.265 Plexiform fibrous histiocytoma: vascular invasion as seen in this field is an occasional feature. It does not appear to be of prognostic significance.

Fig. 35.266 Plexiform fibrous histiocytoma: note the fascicles of myofibroblasts infiltrating the subcutaneous tissue.

By immunohistochemistry, most of the giant cells and some of the mononuclear cells within the nodules express CD68, while the spindle-shaped cells outside the nodules label for SMA and calponin.2,3,6 Some of the mononuclear cells within the nodules are focally positive for SMA.2,3 Myofibroblastic ­differentiation of the latter cells is also suggested by ultrastructural studies.3,17

Differential diagnosis Cases with a prominent fibroblastic component may be confused with ­dermatomyofibroma and fibromatosis (Fig. 35.266). The former, however, is mainly dermal and the latter is deep seated. Both lack a plexiform growth pattern. Fibrous hamartoma of infancy has a typical organoid growth pattern and lacks histiocytic nodules with osteoclast-like giant cells. Dermal and deep benign fibrous histiocytomas usually have a more cohesive growth pattern and polymorphism is seen throughout the lesion.

Atypical fibroxanthoma Clinical features Fig. 35.264 Plexiform fibrous histiocytoma: the histiocyte-like nodules also contain multinucleate (usually osteoclast-like) cells and tend to show stromal hemorrhage.

Atypical fibroxanthoma almost always presents on the sun-exposed actinically damaged areas of the head and neck of individuals in the seventh or eighth decade of life.1–4 Incidence figures depend on local climate and skin

Low-grade malignant fibrohistiocytic lesions pigmentation. The lesion presents as a firm solitary cutaneous nodule, which is often ulcerated, rarely exceeds 3 cm in diameter and has typically been present for less than 1 year (Figs 35.267, 35.268). Tumors may arise in the setting of xeroderma pigmentosum and solid organ transplantation.5–10 Although the latter patients generally do not seem to be at increased risk of developing the tumor, multiple lesions developed in a heart transplant patient.11 A case in an African-American woman, one following hair transplantation, another in the palpebral conjunctiva, one arising in the background of a nevus sebaceous and one at the site of a thermal burn have been reported.12–16 Excision may be followed by local recurrence in up to 5% of patients, but metastasis is exceptional.17–21 Metastatic lesions have been reported in lymph nodes, lungs and peritoneum.17–21 The rate of local recurrence appears to be less in patients treated with Mohs' micrographic surgery.22 Most of the cases with metastasis reported in the older literature before immunohistochemistry was available are likely to represent examples of other pleomorphic malignancies and therefore most probably represent misdiagnoses.

Pathogenesis and histological features Etiologically, almost all cases are associated with solar or therapeutic irradiation damage. Support for the pathogenetic role of ultraviolet light in the genesis of this tumor is given by the recent demonstration of classical p53 UV-induced mutations (C–T and C–G transitions).23 Further support comes from the demonstration of immunoexpression of UV photoproducts of cyclobutane pyrimidine dimers in atypical fibroxanthoma.24 In a small ­percentage of cases, Merkel cell polyomavirus DNA has been detected but the significance of this finding is not clear.25 Atypical fibroxanthomas are characteristically reasonably well-defined, predominantly dermal lesions, which may show extremely superficial invasion of subcutaneous fat in a small proportion of cases; they usually abut on the basal layer of the epidermis and ulceration is common (Figs 35.269–35.271). Most lesions are polypoid and often have an epidermal collarette. The deep margin is generally pushing rather than infiltrative. The appearances comprise an admixture of spindle-shaped cells, histiocyte-like cells, xanthomatous cells and multinucleated giant cells, any or all of which may show marked pleomorphism, hyperchromasia and prominent mitotic activity (Figs 35.272–35.275). Abnormal forms are also common. In some tumors, epithelioid cells may be prominent.26 From a purely cytological point of view, therefore, atypical fibroxanthoma appears malignant.

Fig. 35.267 Atypical fibroxanthoma: the tumor presents as an exophytic nodule, usually on sun-damaged skin of the elderly. The ear is a characteristic site. By courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK.

Fig. 35.269 Atypical fibroxanthoma: this low magnification shows an obviously pleomorphic intradermal spindle cell tumor which has eroded the epidermis. Note the lateral collarette.

Fig. 35.268

Fig. 35.270

Atypical fibroxanthoma: the scalp is another common site. This example is extensively ulcerated. By courtesy of R. Barlow, MD, Institute of Dermatology, London, UK.

Atypical fibroxanthoma: medium-power view showing a highly cellular and pleomorphic tumor cell infiltrate.

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Fig. 35.273 Atypical fibroxanthoma: occasional osteoclast-like giant cells are present.

Fig. 35.271 Atypical fibroxanthoma: the adjacent dermis shows gross solar elastosis. There is no epidermal involvement.

Fig. 35.274 Atypical fibroxanthoma: mitotic figures, often abnormal, are frequently present.

Fig. 35.272 Atypical fibroxanthoma: the tumor is composed of pleomorphic spindled and epithelioid cells with bizarre nuclei.

A chronic inflammatory infiltrate may be seen, particularly at the periphery of the tumor. The adjacent dermis shows marked solar elastosis. Histological variants of atypical fibroxanthoma include tumors with ­pigment, clear cell change, granular cell change, with osteoclast-like giant cells, myxoid change, and with keloidal change in the collagen.26–42 Hemorrhage may be prominent and tumors may mimic a vascular lesion (Figs 35.276, 35.277). Occasional cases display prominent sclerosis and even regression (focal or extensive).43,44 Osteoid is exceptional.45 Spindle cell atypical fibroxanthoma is a relatively monomorphic variant which is composed predominantly of spindle-shaped cells with mild to moderate pleomorphism (Figs 35.278–35.280).46 By immunohistochemistry (Figs 35.281, 35.282), the spindle cells are focally positive for SMA and calponin and the mononuclear and multinucleated cells are variably positive for CD68.47–51 Focal positivity for EMA may also be seen. Other markers that are positive in tumor cells include CD99 and procollagen I.52,53 CD163 is focally positive in some cases.54 CD10 has been regarded as a useful marker, as most tumors show strong diffuse positivity

Fig. 35.275 Atypical fibroxanthoma: xanthomatized cells are commonly present. Note the conspicuous eosinophilic nucleoli.

Low-grade malignant fibrohistiocytic lesions

Fig. 35.276

Fig. 35.279

Atypical fibroxanthoma: this is an example of an osteoclast-rich variant.

Spindle cell atypical fibroxanthoma: cytologically, this lesion is easily confused with spindle cell melanoma or leiomyosarcoma.

Fig. 35.277

Fig. 35.280

Atypical fibroxanthoma: high-power view of a clear cell variant.

Spindle cell atypical fibroxanthoma: there is brisk mitotic activity.

Fig. 35.278

Fig. 35.281

Spindle cell atypical fibroxanthoma: the monomorphic appearance of the spindle cell variant differs considerably from conventional atypical fibroxanthoma.

Spindle cell atypical fibroxanthoma: the tumor cells express CD10.

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Fig. 35.282 Spindle cell atypical fibroxanthoma: note the diffuse expression of smooth muscle actin.

for this marker.55,56 However, any tumor with spindle cell morphology may show positivity for CD10, including sarcomas such as myxofibrosarcoma.57 CD31 may be focally positive and this may lead to an erroneous ­diagnosis of angiosarcoma, especially in cases associated with hemorrhage.16,26 In one case, focal positivity was reported for HMB-45 and melanoma antigen recognized by T cells 1 (MART-1) but only in the neoplastic giant cells.58 In a further tumor with clear cell change, HMB-45 was expressed.59 Tumor cells are negative for S-100 protein, other melanocytic markers, keratin, desmin, h-­caldesmon and CD117.50,60,61 An important pitfall is that a number of tumors contain a prominent number of reactive, dendritic S-100 protein-positive cells in the background, and this may be interpreted as positivity of tumor cells. Features that are unacceptable in the diagnosis of atypical fibroxanthoma include areas of necrosis and vascular or perineural invasion. If present, they indicate an alternative diagnosis such as spindle cell squamous cell carcinoma, melanoma or a superficial pleomorphic sarcoma. Perineural invasion, however, has exceptionally been reported in the context of atypical fibroxanthoma.62 Flow cytometry studies in atypical fibroxanthoma often show evidence of aneuploidy.63

Differential diagnosis Atypical fibroxanthoma is a diagnosis of exclusion.64,65 Distinction from spindle cell variants of squamous carcinoma or melanoma is helped by adequate tissue sampling to detect an epithelial origin, a junctional component or more obviously differentiated areas, but this is not often found. Immunocytochemical stains for S-100 protein, keratin and desmin expression should always be undertaken to exclude melanoma, spindle cell squamous cell carcinoma, an unusual metastasis or a leiomyosarcoma. P63 is a useful marker as it is diffusely positive in sarcomatoid squamous cell carcinoma and usually negative in atypical fibroxanthoma.66 It is important to highlight that sarcomatoid squamous cell carcinomas of the skin are often negative for CAM 5.2. Merkel cell carcinoma, which recurred with features mimicking atypical fibroxanthoma, has been described as has a ‘collision tumor’ of these two types. 67,68 A collision with basal cell carcinoma and one with invasive melanoma have also been documented and this may represent a source of error in small samples.69,70 Tumors reported in the past as atypical fibroxanthoma occurring in ­nonsun-exposed skin of young patients represent examples of atypical fibrous histiocytoma.

Malignant fibrous histiocytoma/ undifferentiated pleomorphic sarcoma Traditionally, malignant fibrous histiocytoma has been regarded as the most common soft tissue sarcoma and five distinctive variants were originally described including pleomorphic, myxoid, angiomatoid, giant cell and

inflammatory.1–3 In recent years, however, it has become apparent that not only is true histiocytic differentiation in these tumors unlikely, but also that these variants appear to have very little in common. The angiomatoid variant has recently been reclassified as angiomatoid fibrous histiocytoma. Moreover, the existence of a pleomorphic subtype (by far the most common tumor in the group) as an independent entity has been challenged.4 Pleomorphic malignant fibrous histiocytoma as classically described is characterized histologically by prominent cytological pleomorphism, bizarre multinucleated giant cells, often a storiform pattern, and a ­mononuclear inflammatory cell infiltrate with foamy macrophages.1–3 However, these features are non-specific and pleomorphic malignant fibrous histiocytoma represents a waste basket for pleomorphic neoplasms, which, if studied by appropriate techniques such as electron microscopy and immunohistochemistry, demonstrate a specific line of differentiation in the vast majority of cases.4,5 Although most prove to be sarcomas (pleomorphic variants of ­leiomyosarcoma, rhabdomyosarcoma, liposarcoma), a small proportion represent melanomas or epithelial or even lymphoid neoplasms, and around 10% defy further classification.4,6 Excluding atypical fibroxanthoma, ­pleomorphic sarcomas are very rare in the skin and it is important to remember that the majority of ‘sarcomatoid’ cutaneous lesions are not true sarcomas but spindle cell variants of melanoma and carcinoma. Most true pleomorphic sarcomas in the skin represent extension from tumors arising in deeper soft tissues.

Giant cell malignant fibrous histiocytoma Giant cell malignant fibrous histiocytoma (Fig. 35.283) is another heterogeneous group of tumors, which have in common a multinodular growth pattern and the presence of multiple osteoclast-like multinucleated giant cells.6 They tend to occur in older individuals and show a predilection for the limbs. More than 50% of cases show neoplastic osteoid or bone ­formation and they are better classified as soft tissue osteosarcomas (see Fig. 35.268). A smaller proportion of tumors represent leiomyosarcomas rich in osteoclast-like giant cells and a further group of lesions is indistinguishable from giant cell tumor of bone.7,8 The last has a benign histology and behavior is generally benign; as such it has been reclassified as giant cell tumor of soft tissue or soft tissue giant cell tumor of low-grade malignant potential.9–11 Only tumors with histological malignant features in which a specific line of differentiation has not been established should be classified as giant cell malignant fibrous histiocytoma.9–11 It should be remembered that a variety of other lesions with a different phenotype can be rich in osteoclast-like giant cells and that immunohistochemistry is an important aid in differential diagnosis.

Fig. 35.283 Giant cell malignant fibrous histiocytoma (soft tissue osteogenic sarcoma): numerous osteoclast-type giant cells are present. Osteoid is present in the center of the field.

Malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma

Myxofibrosarcoma Clinical features Myxofibrosarcoma (myxoid malignant fibrous histiocytoma) commonly ­presents in the limbs of the elderly and shows a slight predilection for males.12–14 Up to 60% of cases arise in the subcutis and secondary involvement of the skin is common (Fig. 35.284). 15–17 Prognosis is related to histological grading, but behavior tends to be indolent with a high tendency for local recurrence, occasional metastasis to regional lymph nodes and a 5-year survival of up to 70%.14 Metastases are seen more commonly in deep-seated lesions and those with a high histological grade.14 Local recurrences appear to be associated with higher histologic grade and more complex cytogenetic abnormalities.18 Mortality is associated with tumor necrosis, large size and decrease in myxoid areas.19 Gains at chromosome 7 have been described in the tumor and more recently overexpression of MET (chromosome 7q31) has been reported in myxofibrosarcoma and this feature is associated with deeper, higher-grade tumors in more advanced stages.20,21 MET is a transmembrane receptor tyrosine kinase representing the only high-affinity receptor of hepatocyte growth factor (HGF). Ezrin, as protein associated with cell adhesion-mediated signaling, is over-expressed in myxofibrosarcoma and the expression correlates with poor prognostic factors including necrosis, high mitotic activity, high histologic grade and advanced stage.22

Fig. 35.285 Myxofibrosarcoma: low-grade lesions are relatively hypocellular and contain distinctive curvilinear vessels.

Histological features Histologically, appearances vary from low-grade, markedly myxoid, hypocellular lesions, to highly cellular, pleomorphic tumors with focal myxoid change. Tumor cells range from stellate to spindle shaped with variable pleomorphism. All tumors share a multinodular growth pattern, curvilinear thin-walled blood vessels, and a minimum of 10–20% of myxoid stroma with hyperchromatic stellate or spindle-shaped cells ( Figs 35.285–35.290 ). Epithelioid cell change can be prominent, particularly in high-grade tumors. 23 Tumor cells have ultrastructural features of fibroblasts and myofibroblasts and stain with vimentin and are only rarely focally for actin.14,24,25 Distinction from superficial angiomyxoma is easy because the latter lacks cytological atypia, is less cellular, is predominantly dermal and commonly has an epithelial component. Rare tumors can show focal changes mimicking a pleomorphic hyalinizing angiectatic tumor and sampling is very important to avoid a misdiagnosis.26 In low-grade fibromyxoidsarcoma, there is no pleomorphism, mitotic figures are rare and curvilinear blood vessels are usually absent.27

Fig. 35.284 Low-grade myxofibrosarcoma: note the multilobularity and prominent myxoid change. By courtesy of C.D.M. Fletcher, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Fig. 35.286 Myxofibrosarcoma: the curvilinear vessels are characteristic.

Fig. 35.287 Myxofibrosarcoma: note the pleomorphic tumor cells scattered in the myxoid matrix.

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Inflammatory malignant fibrous histiocytoma Clinical features Inflammatory malignant fibrous histiocytoma is a variant of so-called ­malignant fibrous histiocytoma and is only mentioned briefly for the sake of completeness because it mainly involves the retroperitoneum and other ­visceral soft tissues and not the skin.28,29 The behavior of this group of tumors is very aggressive with a high mortality.

Histological features

Fig. 35.288

Histologically, the tumors are composed of prominent bland or atypical ­xanthomatous cells and, to a lesser extent, of pleomorphic and multinucleated cells admixed with numerous neutrophil polymorphs (Figs 35.291, 35.292). Spindled cells with a focal storiform pattern can also be seen. In our experience, using immunohistochemistry, at least a proportion of cases with the features described correspond to lymphoreticular malignancies including T-cell lymphomas.

Myxofibrosarcoma: the tumor stains strongly with Alcian blue at pH 2.5, indicating the presence of hyaluronic acid.

Fig. 35.289

Fig. 35.291

Myxofibrosarcoma: in this field, the multinodularity is emphasized.

Inflammatory malignant fibrous histiocytoma: scattered tumor cells are present within a histiocyte-rich inflammatory cell infiltrate.

Fig. 35.290

Fig. 35.292

Myxofibrosarcoma: there is marked nuclear pleomorphism.

Inflammatory malignant fibrous histiocytoma: there is marked nuclear pleomorphism. The cell in the center resembles a Reed-Sternberg cell.

Reactive lesions

Infiltrative subcutaneous malignant fibrous histiocytoma This form of malignant fibrous histiocytoma is extremely infiltrative and associated with extensive involvement of fibrous septae by atypical spindled and pleomorphic cells in the subcutis and sometimes muscle. 30 This may be more of an architectural pattern than a distinct entity or subtype, but is important to recognize, as it is one of the types often seen in the superficial subcutis and sometimes involving the dermis proper. It can usually be distinguished from atypical lipomatous tumor/well-differentiated liposarcoma by the lack of scattered atypical cells involving the lobules in contrast to the septa of the subcutaneous fat.

Neuroectodermal tumors Reactive lesions Traumatic neuroma Clinical features Traumatic neuroma is not a true neoplasm but instead represents a proliferative hyperplastic response to peripheral nerve injury.1,2 It may occur at any age or site, but is most often seen in young people after severe accidental trauma or in older individuals following limb amputation (usually undertaken because of peripheral vascular disease). However, trauma is not always severe and, in rare cases, a history of trauma cannot be elicited.3,4 Associations with an arteriovenous aneurysm, a human bite and multiple lesions after deep burns have been documented.5–7 Genital lesions, sometimes multiple, may be seen and are not always associated with known trauma.8 Clinically, it presents as a small firm mass, which is often painful, but is sometimes associated with local anesthesia. Multiple recurrences of cutaneous carcinoma as a result of local tumor spread along the nerves of a traumatic neuroma have been reported.9

Histological features A traumatic neuroma is characterized by a variably well-defined, but unencapsulated, mass of numerous axons and Schwann cells embedded in scar tissue adjacent to the cut end of a damaged nerve (Figs 35.293, 35.294). The newly formed neural tissue, failing to achieve continuity with the distal portion of the affected nerve, is arranged completely haphazardly. Nuclear pleomorphism and mitotic activity are not present. Dystrophic calcification is exceptionally seen.10 Granular cell change can rarely occur in traumatic

Fig. 35.294 Traumatic neuroma: high-power view.

­ euroma.11,12 A rare oral lesion associated with intraepithelial proliferation n of axons has been documented.13 Accessory digits often show the features of a traumatic neuroma and this may be the result of partial intrauterine amputation.14

Differential diagnosis The clinical history, together with the typical histological appearances, is usually sufficient to make a diagnosis. The presence of numerous axons as well as Schwann cells and fibroblasts allows ready distinction from a neurofibroma.

Digital pacinian neuroma Clinical features Digital pacinian neuroma (pacinian corpuscle hyperplasia) is a rare but distinctive type of neuroma that usually presents as a result of trauma to the fingers of adults.1–3 Lesions are small and very painful.4,5 A case has been associated with a Morton's metatarsalgia.5 Erosive bone changes have been documented in one patient.6

Histological features Histologically, there are numerous pacinian corpuscles intermixed with small nerve fibers and surrounded by fibrous tissue (Figs 35.295, 35.296).

Fig. 35.293

Fig. 35.295

Traumatic neuroma: arising from the cut end of this peripheral nerve is a proliferative spindle cell lesion.

Pacinian neuroma: this field shows an admixture of pacinian corpuscles, fibrous tissue and conspicuous nerve fibers.

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Fig. 35.296

Fig. 35.298

Pacinian neuroma: high-power view showing the characteristic lamellated structure.

Morton's neuroma: high-power view showing numerous fibroblasts.

Morton's neuroma Clinical features Morton's neuroma (metatarsalgia) is also not a true neoplasm, but represents a degenerative response to chronic low-grade tissue damage.1,2 It most often presents in adults, who complain of pain in the distal sole of the foot, usually when walking. Females are affected more often than males. Close examination reveals that the pain is often localized between (or over) the metatarsal heads, but a nodule or mass is not usually palpable. Bilateral involvement is rare. If excision is undertaken, a localized, rather fusiform, expansion of one of the plantar digital nerves is seen.

Histological features Traditionally, histology has been described as revealing marked fibrosis of the endo-, epi- and perineurium associated with edematous change, marked degeneration and loss of nerve fibers (Figs 35.297, 35.298). Fibrotic changes are often seen in the adjacent subcutaneous tissues and around blood vessels. However, a recent study comparing the histology of nerves excised from patients with Morton's metatarsalgia with that of nerves from the same area excised from autopsy patients found no differences between both groups except for slightly thicker nerves in patients with the disease.3 The authors concluded that histology has no role in confirming the diagnosis.

Fig. 35.297 Morton's neuroma: the nerve trunk is markedly distorted by intense concentric fibrosis.

Hamartomas Mucosal neuroma Clinical features Mucosal neuromas are always multiple and have predilection for the mouth.1–3 They may present as part of the multiple endocrine neoplasia syndrome type IIB (MEN IIB, Sipple), an autosomal dominant disease characterized by a marfanoid body habitus, dysmorphic facies, medullary carcinoma of thyroid and pheochromocytoma.1–5 Rare examples may present in the mouth and even the larynx in patients without MEN IIB.6–8 Laryngeal lesions may rarely also present in multiple endocrine neoplasia syndrome type IIB.9

Histological features Histologically, lesions are poorly circumscribed and consist of hyperplastic nerves in a haphazard and disorganized arrangement. An incomplete capsule surrounded by a layer of EMA-positive perineural cells is sometimes present.

Other hamartomas and choristomas These include a group of miscellaneous acquired or congenital lesions with very few or only single case reports in the literature. • Cutaneous ganglion cell choristoma or cutaneous ganglioneuroma presents as a solitary papule, usually on the trunk of adults.1–7 A congenital case and one with multiple facial lesions have been documented.8,9 Histologically, there is a dermal proliferation of mature ganglion cells admixed with Schwann cells and nonmyelinated axons. Ganglion cells are positive for glial fibrillary acid protein and Schwann cells are positive for S-100 protein. Unusual examples include a case associated with a seborrheic keratosis, a lesion with a desmoplastic stroma and two with prominent overlying hyperkeratosis.10–13 • Congenital neurovascular hamartoma (NVH) of the skin is characterized by a proliferation of capillaries in a background of spindle cells that stain with NSE.14 The two patients described with this lesion subsequently developed rhabdoid tumors and NVH has been proposed as a marker for this tumor. • In other lesions – variably called congenital neural hamartoma, cutaneous nerve hamartoma and linear cutaneous neuroma – there is a proliferation of Schwann cells or nerves.15–17 • Congenital lesions containing hyperplastic pacinian corpuscles in the lower back with spina bifida occulta have been termed sacrococcygeal paciniomas while similar lesions on the buttock without underlying neural tube defects are described as multiple hairy pacinian neurofibromas.18,19 • A single case of an intraneural benign lesion displaying dual neural and melanocytic differentiation has been described under the rubric melanocytoneuroma.20

Benign neoplasms

Benign neoplasms It is controversial whether some of the lesions included under this heading are true neoplasms or, rather, represent hamartomas. However, they are included in this section because they have traditionally been considered neoplastic.

Solitary circumscribed neuroma Clinical features Solitary circumscribed neuroma (palisaded encapsulated neuroma) is a common but often unrecognized tumor that presents as a solitary, asymptomatic, skin-colored papule on the face (especially nose, nasolabial folds and cheeks) of middle-aged to elderly adults.1–4 Lesions also seem to be relatively common in the oral cavity, particularly in the masticatory mucosa.5 Rarely, acral lesions exceptionally multiple and bilateral may occur.6 Other rare sites include the eyelid and penis.7,8 There is no sex predilection and most lesions are less than 1 cm in diameter. Occasional cases present at other sites including the oral mucosa, nose and penis, and rarely multiple lesions have been described.9–13 There is no known association with ­neurofibromatosis or MEN IIB.

Fig. 35.300 Solitary circumscribed neuroma: medium-power view showing multinodularity.

Histological features Typically, low-power examination reveals a well-circumscribed dermal nodule (Figs 35.299–35.302). However, the growth pattern in some lesions is multinodular or even plexiform.5,10 Encapsulation is incomplete and the superficial part of the tumor often appears to merge with the surrounding dermis. Tumor cells are arranged in short fascicles separated by artifactual clefting and have wavy hyperchromatic nuclei and ill-defined pale eosinophilic cytoplasm. Palisading of nuclei is not as common as its original name might suggest. Occasional cases show degenerative nuclear changes or focal epithelioid morphology.14 The epidermis is usually normal, but mild to prominent hyperplasia is sometimes a feature.15 Commonly, a normal nerve is identified near the base of the lesion, often entering (or fusing with) the lesional capsule. Prominent vascularity is occasionally present.16 By immunohistochemistry, most of the cells are S-100 protein positive, in keeping with Schwann cells (Fig. 35.303). GFAP is negative.5 Numerous axons can be identified with neurofilament protein and the cells in the capsule stain for EMA, as expected in normal perineurial cells (Fig. 35.304).17,18 As the capsule tends to be partial and EMA can be weak, additional stains that help identifying the perineural cells include claudin 1 and glut-1.5

Fig. 35.299 Solitary circumscribed neuroma: the lesion is a well-circumscribed intradermal nodule.

Fig. 35.301 Solitary circumscribed neuroma: note that the tumor merges imperceptibly into the papillary dermis.

Fig. 35.302 Solitary circumscribed neuroma: the tumor is composed of pale-staining spindled cells with uniform elongated darkly staining nuclei.

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Fig. 35.303 Solitary circumscribed neuroma: the tumor cells express S-100 protein.

Fig. 35.305 Epithelial sheath neuroma: prominent nerves are present in the superficial reticular dermis encased by nests of bland squamous epithelium. By courtesy of L. Requena, MD, Madrid, Spain.

Fig. 35.304 Solitary circumscribed neuroma: the tumor contains numerous nerve fibers (neurofilament immunocytochemistry).

Fig. 35.306 Epithelial sheath neuroma: high-power view. By courtesy of L. Requena, MD, Madrid, Spain.

Differential diagnosis Distinction from neurofibroma and schwannoma is easy if attention is paid to the characteristic architecture and the presence of numerous intralesional axons.

Schwannoma

Epithelial sheath neuroma

Schwannomas (neurilemmomas) are common benign lesions, occurring most often in the fourth and fifth decades with an equal sex incidence and arising most frequently on the limbs (mainly the upper limbs) followed by the head and neck (including the oral cavity, orbit and salivary glands) (Fig. 35.307).1–5 Lesions in children are very rare and exceptionally congenital.6,7 They present most often as a solitary painless subcutaneous mass of variable size (exceptionally very large), but very occasionally they may be multiple and in this context are rarely associated with von Recklinghausen's neurofibromatosis.8,9 Prominent cystic change is occasionally seen. Purely dermal tumors are rare.10,11 Cutaneous lesions exceptionally have an agminate pattern and one was associated with overlying anetoderma.12,13 Tumors in the penis and vulva are exceedingly rare.14,15 Some tumors occur in other locations including bone, gastrointestinal tract, pancreas, liver, retroperitoneum, mediastinum, trachea, nasopharynx, larynx, thyroid, adrenal gland and lymph node.16–26 Neurological symptoms including pain and paresthesias are uncommon except in large deep-seated lesions; malignant change is ­exceedingly rare

Clinical features Epithelial sheath neuroma is a very rare distinctive lesion combining nerves and squamous epithelium.1–3 The handful of cases reported so far have presented in adults as asymptomatic solitary lesions mainly on the back.

Histological features Histology characteristically shows fairly prominent nerves in the superficial dermis encased by cytologically bland squamous epithelium (Figs 35.305, 35.306). There is no evidence of a connection to the overlying epidermis or neighboring adnexal structures. Similar appearances may be seen in keratoacanthoma but in the latter there is evidence of inflammation and fibrosis accompanying the overlying tumor. In addition, the perineural invasion is usually deeply seated.

Clinical features

Benign neoplasms

Fig. 35.307 Neurilemmoma: this tumor presents as a non-specific dermal nodule. By courtesy of the Institute of Dermatology, London, UK.

(see neurofibroma).5,27,28 Exceptional cases include a cutaneous example that may have been associated with foreign material.29 Recurrence after simple excision is very infrequent. Neurofibromatosis type II is characterized by acoustic schwannomas, cutaneous tumors and other central nervous system lesions including meningioma, cataract and retinal hamartoma.30,31 About 59% of patients have skin tumors, the majority of which represent schwannomas.31 Only rarely do patients develop neurofibromas or hybrid lesions. Café-au-lait spots may be present in up to 33% of patients but these tend to be fewer than in patients with neurofibromatosis type I.31 The development of neurofibromas in neurofibromatosis type II may be due to interaction between neurofibromin and merlin, the NF2 gene product, in regulating the ras proto-oncogene.32,33 Cutaneous schwannomas are only rarely associated with neurofibromatosis type II.34 The presence of multiple cutaneous schwannomas with or without similar lesions in spinal and other nerves has been termed schwannomatosis. Whether this represents a distinct entity or merely a variant of neurofibromatosis type II is uncertain.31,35–40 Most cases appear to be sporadic but in a few an autosomal dominant pattern of inheritance has been described. A case associated with multiple meningiomas and a family with predisposition to malignant rhabdoid tumors have been described.41,42 Germline aberrations in INI1 / SMARCB1 (22q11) may be involved.43,44 Recently, a new hereditary syndrome consisting of multiple schwannomas, multiple nevi and multiple vaginal leiomyomas has been described.45 The nevi are congenital but the schwannomas and vaginal leiomyomas develop in adult life.

Fig. 35.308 Neurilemmoma: scanning view of spindle cell tumor with prominent blood vessels. A capsule is seen on the right side.

Fig. 35.309 Neurilemmoma: palisading is a characteristic feature.

Pathogenesis and histological features Cytogenetic studies in schwannomas have shown either loss of 22q material or monosomy 22, probably corresponding to the NF2 gene (22q12.2) encoding the neurofibromin 2 or merlin protein.33,34,46,47 Neurilemmomas are usually rounded and invariably encapsulated, and are typically found in the subcutaneous or deeper tissues; primary intradermal origin is unusual. Purely intraneural tumors are exceptional.48 Microscopically, they are characterized by a classical biphasic pattern of Antoni A and Antoni B areas. • Antoni A areas form the more cellular component of the lesion and are composed of fairly closely packed spindled cells with tapering, elongated, rather wavy nuclei; nuclear palisading is a prominent feature, producing the distinctive Verocay bodies (Figs 35.308–35.310).These are sometimes the predominant feature.49 Verocay-like bodies may be seen in a number of other tumors including dermatofibroma and leiomyoma.50 Degenerative nuclear pleomorphism and mitotic activity are occasionally seen, but tend to be spatially unrelated. Hyalinization of stromal collagen and focal dystrophic calcification are sometimes present.

Fig. 35.310 Neurilemmoma: the Verocay body, typical of the Antoni A areas, is characterized by two parallel rows of nuclei separated by Schwann cell processes.

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Variants61 • Plexiform schwannoma is an uncommon tumor only very rarely associated

• Fig. 35.311 Neurilemmoma: myxoid degeneration gives rise to Antoni B areas.

with neurofibromatosis (mainly NF2) and tending to arise mainly on the head and neck or trunk of children or young adults.62–68 These lesions represent about 4.3% of all schwannomas and around 15% of cutaneous schwannoma.68 It is usually a small intradermal or subcutaneous lesion characterized by multiple encapsulated nodules composed predominantly of Antoni A tissue (Fig. 35.313). Any histological type of schwannoma may be represented in plexiform tumors particularly the cellular variant. A subgroup of plexiform and multinodular schwannomas affects major peripheral nerves.69 Deep-seated tumors also occur.68 Nuclear pleomorphism (mild to moderate), limited mitotic activity and focal necrosis (the latter in deep-seated examples) may be present, but recurrence is not a feature and there is no malignant potential.70 Distinction from plexiform neurofibroma is vital to avoid an inappropriate clinical diagnosis of von Recklinghausen's disease. Rarely, tumors are associated with neurofibromatosis type 2 and schwannomatosis.68 Ancient schwannoma, which is usually a more deeply located, longstanding lesion, is characterized by pronounced degenerative changes manifest as nuclear pleomorphism associated with extensive cyst formation, calcification, hyalinization or hemorrhage (Figs 35.314, 35.315).71 Mitoses, however, are rare.

Fig. 35.312 Neurilemmoma: there is marked hyalinization of the blood vessel walls in Antoni B.

• Antoni B areas are typified by irregularly scattered spindled or stellate

cells set in an abundant loose myxoid stroma (Fig. 35.311). Within these areas, scattered chronic inflammatory cells and small blood vessels, often with hyalinized walls, are a prominent feature (Fig. 35.312). Focal degenerative changes, including microcystic change and hemosiderin deposition, are not uncommon. A schwannoma with collagenous spherulosis has been documented and in one case meningothelial-like whorls were present.51,52 The very rare finding of apparent glandular differentiation in benign schwannomas represents proliferation of entrapped normal adnexal structures.53,54 Very rarely, tumors may have a hybrid appearance of schwannoma and neurofibroma. These can be seen in patients with neurofibromatosis and often the neurofibroma is of the plexiform variant.55 The schwannomas seen in neurofibromatosis type II have been shown to contain axons.56 Malignant transformation often shows pleomorphic epithelioid cells and rarely there is divergent differentiation such as the presence of epithelioid angiosarcoma.57–59 Ultrastructurally, schwannomas are composed predominantly of Schwann cells and this is reflected immunohistochemically by S-100 protein positivity in the majority of tumor cells. The capsule contains a layer of EMA-positive perineurial fibroblasts. Tumor cells express PDGFR-alpha, PDGFR-beta and c-kit, and it has been shown that imatinib mesylate inhibits a schwannoma cell line.60

Fig. 35.313 Plexiform schwannoma: this small tumor is composed of multiple discrete nodules of schwannomatous tissue. Nuclear palisading and Verocay bodies are evident.

Fig. 35.314 Ancient schwannoma: degenerative changes have resulted in marked myxoid features with fibrosis and conspicuous vascularity.

Benign neoplasms

Fig. 35.315 Ancient schwannoma: focal nuclear pleomorphism should not be taken as having sinister implication. Mitotic activity is not present in these tumors.

Fig. 35.317 Cellular schwannoma: scattered mitoses are commonly present.

• Cellular schwannoma only rarely presents subcutaneously as a large and

•

encapsulated mass.72–74 Microscopically, there is a marked increase in cellularity which, combined with a mainly fascicular architecture, may simulate a smooth muscle tumor (Figs 35.316, 35.317). Verocay bodies are generally not seen. Xanthomatous cells and a lymphocytic infiltrate may be prominent (Fig. 35.318). Normal mitoses may number up to 10 per 10 high-power fields, but neither necrosis nor significant nuclear pleomorphism is a feature. Distinction from smooth muscle tumors is readily afforded by S-100 positivity (Fig. 35.319). Melanotic schwannoma is a rare lesion which, in addition to the features of a neurilemmoma, contains pigmented cells (Fig. 35.320).75 Nuclei are often distinctively grooved. It arises most frequently around the spinal nerve roots and cutaneous presentation is very rare, with only 20 cases reported so far arising in the dermis or subcutaneous tissue, two of which have developed metastasis, and one patient died of disseminated disease.76,77 Two cases arising in association with nevus of Ota have been documented.78 A proportion of cases are malignant, and prediction of behavior based on histological features is not always easy. Psammomatous melanotic schwannoma is a variant with numerous psammoma bodies and is usually seen in association with Carney's

Fig. 35.316 Cellular schwannoma: typically, lesions are highly cellular, superficially resembling leiomyosarcoma.

Fig. 35.318 Cellular schwannoma: although xanthomatous histiocytes may be seen in any type of schwannoma, they are particularly common in this variant.

Fig. 35.319 Cellular schwannoma: the spindled cells are S-100 positive.

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Schwannoma–perineurioma hybrid Clinical features This is a recently described tumor that usually presents as an asymptomatic small subcutaneous, dermal or rarely deeper nodule, with an equal sex ­incidence.1,2 Lesions most commonly involve the lower limb followed by the upper limbs, with rare tumors occurring in the head and neck and trunk. It is not associated with neurofibromatosis and there is little tendency for local recurrence. Simple excision is the treatment of choice.

Histological features

Fig. 35.320 Melanotic schwannoma: this is usually a deep-seated lesion showing extensive melanin pigmentation. The nuclei are often grooved, resembling coffee beans.

Tumors are well circumscribed but lack a capsule and are composed of bland spindled cells with ill-defined pale cytoplasm and elongated nuclei with tapering ends. The distribution pattern of tumor cells is storiform, lamellar or whorled. Myxoid change can be present as can focal cytological atypia that appears to be degenerative in nature. Antoni A and Antoni B areas are not a feature. Mitotic figures are rare. An infiltrative growth pattern and plexiform architecture are exceptional. By double staining, it has been demonstrated that tumor cells are either Schwann cells or perineural cells, with predominance of the former and no antigen coexpression. Tumor cells are very often positive for CD34, GFAP and claudin 1. Axons are rarely highlighted by neurofilament.

Neurofibroma Clinical features

Fig. 35.321 Psammomatous melanotic schwannoma: this variant is commonly seen in Carney's complex.

•

•

complex (myxomas, spotty pigmentation and endocrine overactivity) (Fig. 35.321).79,80 Lesions associated with the latter may also present with metastatic disease.81 Tumor cells stain for S-100 protein and other melanocytic markers. CD34 may also be positive.82 Pacinian schwannoma is a very rare tumor that presents as a solitary nodule, most often in the distal extremities. It is characterized histologically by an encapsulated mass composed of round or ovoid concentrically lamellated corpuscles (somewhat resembling pacinian corpuscles) set in a collagenous spindled cell stroma.83 Although regarded in the past as pacinian neurofibroma, the histological features are more in keeping with a schwannoma. Epithelioid schwannoma (neuroblastoma-like schwannoma) is a rare variant of schwannoma presenting mainly in the subcutis or dermis of adults. It is characterized histologically by an encapsulated tumor composed of focal nests of epithelioid cells in cords and nests surrounded by areas with features of classic schwannoma.84–86 The capsule contains EMA-positive cells.87 In some cases, the epithelioid areas may mimic neuroblastoma and contain rosette-like structures with fibrillary collagenous centers.88 Other areas of the tumor, however, are typical of a schwannoma. Tumors may rarely be plexiform.89 A single case with prominent collagen deposition has been documented.90

Neurofibroma is perhaps the commonest tumor of nerve sheath origin.1–3 In the majority of cases it is solitary and unassociated with any other systemic features; however, multiple lesions are not rare and form the cardinal feature of neurofibromatosis type I (von Recklinghausen's disease). The tumor presents in a somewhat younger age group than schwannoma, as a polypoid or nodular soft lesion; in contrast to the latter it is frequently cutaneous and may arise anywhere in the integument (Figs 35.322, 35.323). A case of multiple lesions induced by radiotherapy has been reported.4 It is essential that any patient found to have a neurofibroma, even if seemingly in isolation, should be carefully examined for other stigmata of neurofibromatosis. Neurofibromas, particularly the plexiform ­variant in ­neurofibromatosis type I, have an undoubted, albeit uncommon, tendency to undergo malignant change, but this only exceptionally occurs in the more ­typical cutaneous neurofibromas. Local recurrence of truly benign lesions is very infrequent.

Fig. 35.322 Neurofibroma: erythematous nodule with surrounding simple lentigines. From the collection of the late N.P. Smith, MD, Institute of Dermatology, London, UK.

Benign neoplasms

Fig. 35.323

Fig. 35.325

Neurofibroma: this example presented as a circumscribed firm exophytic nodule. By courtesy of J. Dayrit, MD, Manila, The Philippines.

Neurofibroma: a large nerve trunk is present in the center of the field.

Pathogenesis and histological features The microscopic features of neurofibroma are readily recognizable. Typically, it is a reasonably well-defined but unencapsulated dermal or subcutaneous lesion. In contrast to a schwannoma, it contains numerous small nerve fibers. It consists of loosely arranged spindled cells with scanty pale ­cytoplasm and elongated wavy nuclei set in a fibrillar, collagenous and sometimes ­myxoid stroma (Figs 35.324–35.326). Multinucleated floret-like giant cells can be present, and in a small number of tumors are numerous.5 These multinucleated giant cells are S-100 protein negative and CD34 positive and they are not a clue to the diagnosis of neurofibromatosis, as has previously been suggested.6–8 Scattered inflammatory cells, particularly mast cells, are a ­prominent feature (Fig. 35.327). The relative amounts of stromal collagen and mucin vary both within and between lesions; hyalinization of collagen may sometimes occur (Fig. 35.328). However, no recognizable biphasic appearance is seen (see ­schwannoma). Prominent sclerosis is present in some lesions. Fig. 35.326 Neurofibroma: the nuclei of the spindled cells are characteristically elongated and wavy.

Fig. 35.324 Neurofibroma: the tumor is composed of small spindled cells with indistinct cell borders.

Fig. 35.327 Neurofibroma: mast cells with granular eosinophilic cytoplasm are frequently seen in these tumors.

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Fig. 35.328

Fig. 35.330

Neurofibroma: the collagen content is highly variable, but may be prominent, as in this example.

Atypical neurofibroma: high-power view showing pleomorphic nuclei.

Degenerative nuclear pleomorphism and hyperchromasia are rare features (compare with ancient schwannoma) and occasionally sporadic neurofibroma is associated with very low mitotic activity (see below) (Figs 35.329–35.331). Such pleomorphism in a lesion from a patient with neurofibromatosis type I, however, should prompt a very thorough search for mitoses. The presence of the latter in the setting of neurofibromatosis type I is regarded as evidence of malignancy. Positive staining for S-100 protein is seen in only 30–50% of cells. Variable CD34 and in some cases EMA positivity is also seen. Ultrastructurally, a neurofibroma is composed of an admixture of Schwann cells, fibroblasts and perineurial cells.9 Clonality has been demonstrated in neurofibromas, favoring a neoplastic process.9,10 Although chromosomal imbalances are most frequently found in neurofibromas, in neurofibromatosis type I they have also been identified in sporadic neurofibromas.11 Loss of chromosomes is the most frequent event, particularly chromosomes 17 where the NF1 gene is located and 19p.11,12 Loss-of-function mutations in NF1 are also common and seen in multiple neurofibroma cell types.13 More recently, mast cells, while not having NF1 mutations, have been shown to be a required component of neurofibromas in mouse models of neurofibromastosis.14–18

Variants • Myxoid neurofibroma is a histological variant not necessarily

Fig. 35.331 Atypical neurofibroma: very occasionally, single mitoses may be identified.

associated with neurofibromatosis type I, and represents a conventional neurofibroma with extensive deposition of stromal

•

•

Fig. 35.329 Atypical neurofibroma: even at this magnification, hyperchromatic and enlarged nuclei are evident.

mucin. As a consequence, the lesion may appear markedly hypocellular (Fig. 35.332).1–3 Plexiform neurofibroma, which is considered pathognomonic of neurofibromatosis type I, most often presents in children of either sex.1–-3 Its anatomical distribution varies, but the most common site is the head and neck area. Commonly, the skin overlying the lesion shows large and redundant folds with variable hyperpigmentation; the underlying bone may be hypertrophic. The macroscopic appearance is that of a mass of nerve fibers in complex and tortuous arrangement reminiscent of a bag of worms. The histological features consist of large thick nerves or nerve fibers often showing extensive myxoid change within a background of more typical neurofibroma (Figs 35.333, 35.334). The surrounding tissue, however, may sometimes show changes of a diffuse neurofibroma. Small cutaneous lesions showing a microscopic plexiform pattern are not necessarily associated with neurofibromatosis type I. Diffuse neurofibroma, which is associated with neurofibromatosis type I in up to 20–30% of cases, is most often seen in young patients and generally occurs on the head, neck or trunk.1–3 It presents as an ill-defined area of subcutaneous thickening. Histologically, it is characterized by neurofibromatous tissue with a diffuse infiltrative growth pattern in which the stroma tends to be uniformly collagenous rather than myxoid (Figs 35.335, 35.336). Meissnerian differentiation is often a prominent feature (Figs 35.337, 35.338).

Benign neoplasms

Fig. 35.332

Fig. 35.335

Myxoid neurofibroma: in this variant, there is marked stromal mucin.

Diffuse neurofibroma: both the papillary and the reticular dermis are extensively infiltrated by neurofibromatous tissue.

Fig. 35.333

Fig. 35.336

Plexiform neurofibroma: thickened, haphazardly distributed nerve trunks are present in the reticular dermis.

Diffuse neurofibroma: high-power view.

Fig. 35.334

Fig. 35.337

Plexiform neurofibroma: hypertrophied nerves are seen embedded in a matrix of fibroblasts and Schwann cells.

Diffuse neurofibroma: there is marked organoid differentiation.

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Fig. 35.338

Fig. 35.340

Diffuse neurofibroma: in the center of the field there is differentiation towards a Meissner's corpuscle.

Neurofibroma with pseudorosettes: low-power view showing conspicuous pseudorosettes.

Fig. 35.339

Fig. 35.341

Pigmented neurofibroma: note the pigmented dendritic cells. By courtesy of H. Diwan, MD, Houston, Texas, USA.

Neurofibroma with pseudorosettes: there is a single central large pale cell surrounded by a mantle of small lymphocyte-like cells.

• Pigmented neurofibroma is characterized by whorled structures similar

• • •

•

to Meissner corpuscles with scattered pigmented cells that are positive for melanocytic markers (Fig. 35.339).19–21 In one patient, an association with hypertrichosis was documented.22 Granular cell neurofibroma is focally composed of tumor cells with abundant periodic acid-Schiff-positive diastase-resistant granular cytoplasm.3 Diagnosis is often dependent on identifying areas with more typical morphology. Epithelioid neurofibroma is focally composed of epithelioid cells with pink cytoplasm in a background of an otherwise typical neurofibroma. Dendritic cell neurofibroma with pseudorosettes is a distinctive variant of neurofibroma with a nodular growth pattern and two cell types.23 Small round, dark, lymphocyte-like dark cells surround larger cells with vesicular nuclei, frequent intranuclear inclusions and abundant pale cytoplasm, resulting in a distinctive pseudorosette appearance (Figs 35.340, 35.341). Both cell types are positive for S-100 protein and CD57. An intraneural example of this variant has recently been documented.24 Similar lesions may be seen in neurofibromatosis type I.25 Cellular neurofibroma with atypia (atypical neurofibroma) refers to a sporadic neurofibroma with increased cellularity, focal atypia and very low mitotic activity.26,27 These lesions appear to have a benign behavior. Similar lesions, however, in the context of neurofibromatosis type I and in the presence of any mitotic activity, should be regarded as evidence of malignancy.

• Pacinian neurofibroma is best considered as a variant of schwannoma •

• •

(see above). Examples of nerve sheath myxomas were formerly described as pacinian neurofibromas. Lipomatous neurofibroma refers to the presence of collections of mature fat cells within a neurofibroma.28–30 It seems to be more common in the head and neck.31 Distinction from a neurotized nevus with fatty metaplasia may be impossible (see differential diagnosis). Hybrid tumors show features of both neurofibroma and schwannoma.32 Perineurial differentiation has also been documented.33 A single case with clear cell change, one with balloon cell change and one with prominent sclerosis mimicking sclerotic fibroma have been reported.34–36

Differential diagnosis Small biopsies of plaque-stage dermatofibrosarcoma protuberans may be ­difficult to distinguish from a neurofibroma. The former, however, has a ­distinctive lace-like pattern of infiltration of the fat, the dermal bundles tend to be parallel to the epidermis and tumor cells are negative for S-100 and ­positive for CD34. Old neurotized nevi are often indistinguishable from neurofibroma if no residual nevus cells or epidermal component are present. S-100 protein will be positive in both lesions, but neurotized nevi tend to be symmetrical and are also more often NSE positive.

Benign neoplasms

Neurofibromatosis Clinical features Traditionally neurofibromatosis is classified into: • the classic peripheral cutaneous variant or type I neurofibromatosis (NF1, von Recklinghausen's disease), • the central or acoustic form or type II neurofibromatosis (NF2). A third variant, segmental neurofibromatosis, has also been described. This occurs as a result of mosaicism in either NF1 or NF2, more commonly the former. Other variants of neurofibromatosis have been documented and include hereditary spinal neurofibromatosis, schwannomatosis, familial intestinal neurofibromatosis, autosomal dominant ‘café-au-lait spots alone’, autosomal dominant ‘neurofibromas alone’, Watson syndrome, Noonan/neurofibromatosis syndrome and multiple nevi, multiple schwannomas and multiple vaginal leiomyomas.1,2 Neurofibromatosis type I is an important congenital neurocutaneous disorder with an autosomal dominant mode of inheritance, affecting about 1/3000 live births; a number of cases also arise as a result of spontaneous germline mutation.3–12 It encompasses a constellation of signs and symptoms and may involve most systems of the body. The gene for NF1 has been cloned to chromosome 17q11.2.13–16 The encoded protein is called neurofibromin, which helps control Ras activity in cells.17–19 Tumors are generated with loss of heterozygosity at the NF1 wild type allele. Chromosomal imbalances are more common in NF1-associated neurofibromas than in sporadic neurofibromas.20 Other chromosomal imbalances described in NF1 include losses in chromosomes 19 and 22q.20 See also the neurofibroma section above. Patients with NF1 and no evidence of cutaneous neurofibromas have a 3-bp inframe deletion in exon 17 of the NF1 gene.21 Recently, a neurofibromatosis type 1-like autosomal dominant syndrome lacking NF1 mutations but associated with germline inactivating mutations in SPRED1 (sprout-related EVH1 domain-containing protein 1) has been described.22 In this syndrome, patients present with café-au-lait macules, axillary freckling and macrocephaly.

Fig. 35.342 Type I neurofibromatosis: the presence of typical café-au-lait macules is characteristic. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

The National Institutes of Health (NIH) criteria for the diagnosis of NFI include two or more of the following:23 • six or more café-au-lait macules with a diameter of > 5.0 mm in children less than 6 years of age and > 15 mm in older individuals, • two or more neurofibromas of any type or one plexiform neurofibroma, • freckling in the axillary or inguinal regions, • an optic nerve glioma, • two or more Lisch nodules (iris hamartomas), • a distinctive osseous lesion, such as dysplasia of the sphenoid bone or thinning of the cortex of long bones, with or without pseudoarthrosis, • a first-degree relative with NF1. Neurofibromatosis type I shows very wide clinical variability. A large study has demonstrated an association between several pairs of features in affected probands: • intertriginous freckling and Lisch nodules, • discrete neurofibromas and plexiform neurofibromas, • discrete neurofibromas and Lisch nodules, • plexiform neurofibromas and scoliosis, • learning disability or mental retardation and seizures.24 Café-au-lait macules are flat, light-brown lesions which may be distributed anywhere on the integument, but are found predominantly on unexposed surfaces of the body (Fig. 35.342). Up to 10% of the population may have solitary lesions from birth. Patients may also exhibit more darkly colored macules overlying cutaneous plexiform neurofibromas (Fig. 35.343). It has been suggested that dermal fibroblast-derived stem cell factor and hepatocyte growth factor may play a role in the development of the hyperpigmentation.25 Neurofibromas presenting at birth are often plexiform and are located particularly around the eyes and neck; some are generalized.26 By late childhood or adolescence, large numbers of cutaneous tumors have developed, which may be nodular, sessile or pedunculated (Figs 35.344–35.348). Neurofibromas in NFI have increased vascularity and this may result in prominent bleeding, particularly during surgical excision of large plexiform variants. The increased vascularity may result from elevated tumor cell expression of basic fibroblast and endothelial growth factors.27

Fig. 35.343 Type I neurofibromatosis: this heavily pigmented raised lesion overlies a cutaneous plexiform neurofibroma. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 35.344 Type I neurofibromatosis: widespread cutaneous neurofibromata are a prominent feature of the classical variant. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

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Connective tissue tumors

Fig. 35.348

Fig. 35.345

Fig. 35.346

Type 1 neurofibromatosis: lesions are often soft and appear as polypoid or sessile papules and plaques. By courtesy of the Institute of Dermatology, London, UK.

Type I neurofibromatosis: this disease can be extremely disfiguring. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.347 Type 1 neurofibromatosis: close-up view. By courtesy of the Institute of Dermatology, London, UK.

The diffuse neurofibroma which is generally found on the head, neck and back in a proportion of cases is also associated with neurofibromatosis; ­however, in ­contrast to the plexiform type, it does not appear to be associated with an increased risk of malignant transformation except in rare cases (Figs 35.349, 35.350). Interestingly, biopsies from normal skin in patients with NF1 show an increase in the number of S-100 protein-positive cells.28 Occasionally, large plexiform neurofibromas may be associated with excessive redundant skin folds, giving rise to the so-called elephantiasiform neurofibroma (Fig. 35.351).

Type 1 neurofibromatosis: there is marked facial disfigurement. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.349 Type I neurofibromatosis: there is extensive replacement of dermis and subcutaneous fat by a homogeneous pale yellow tumor – a diffuse neurofibroma.

Lisch nodules are pigmented hamartomas of the iris and are pathognomonic of NF1 (Fig. 35.352).12 However, they are never found in the acoustic or segmental variants. Patients with neurofibromatosis may develop tumors at any site in the body, including internal nerve trunks and viscera (Figs 35.353, 35.354). As this is a progressive disorder, increasing age is associated with the acquisition of further nodules; ultimately the patient may exhibit sometimes grotesque features with accompanying psychological and social problems. Neurofibromatosis may also be associated with a diverse range of other manifestations including

Benign neoplasms

Fig. 35.350

Fig. 35.352

Type 1 neurofibromatosis: the skin overlying the tumor has a wrinkled, unevenly elevated appearance.

Type I neurofibromatosis: multiple Lisch nodules (iris nevi) are a pathognomonic feature. By courtesy of D. Spalton, MD, St Thomas' Hospital, London, UK.

Fig. 35.353 Fig. 35.351 Type I neurofibromatosis: the elephantiasiform variant. By courtesy of D. Allen, MD, St Thomas' Hospital, London, UK.

short stature, pheochromocytoma, gastrointestinal neoplasms (including adenocarcinoma, carcinoid, somatostatinoma and gastrointestinal stromal tumor), mental retardation and a variety of central nervous system tumors (mainly low-grade gliomas but also high-grade tumors including medulloblastoma).11,12,29–33 An association with juvenile xanthogranuloma and leukemia in children is also known.34 A few cases of achondroplasia and NF1 have been documented.35 A number of other associations have been recorded but they are likely to be coincidental. These include cutaneous T-cell lymphoma, epidermodysplasia verruciformis, urticaria pigmentosa, piebaldism, eccrine angiomatous hamartoma, segmental unilateral lentiginosis and multiple glomus tumors.36–43 Multiple glomus tumors of the digits, however, have been identified as an important association of NF1.44,45 An association with Noonan's syndrome is also common and both conditions are pathogenetically related.46,47 Factors found in a recent study to be associated independently with mortality in NF1 include the presence of subcutaneous neurofibromas, the absence of cutaneous neurofibromas and facial asymmetry.48 Independent cutaneous predictor

Type I neurofibromatosis: this massive plexiform neurofibroma arose from the spermatic cord in a young man. By courtesy of H. Pambakian, MD (retired), St Thomas' Hospital Medical School, London, UK.

factors associated with internal neurofibromas include the presence of at least two subcutaneous neurofibromas, age = or less than 30, absence of cutaneous neurofibromas and fewer than six café-au-lait spots.49,50 Based on the latter, a scoring system has been proposed to calculate the risk of internal neurofibromas. Blue–red macules and pseudoatrophic macules in patients with NF1 have been shown to indicate the presence of neurofibromas.51 Plexiform neurofibromas in NF1 may increase in size during pregnancy but tumors do not appear to express progesterone receptors.52,53 As mentioned earlier, patients with NF1 have an increased risk of developing malignant peripheral nerve sheath tumors, with a lifetime incidence of between 8% and 13%.54–59 Patients with NF1 tend to present earlier in life than those with sporadic malignancy.59 They also tend to present with recurrences and metastatic spread at shorter intervals than patients with sporadic tumors.60 Pain and enlargement are the most frequent signs suggesting malignant transformation. Most lesions occur in the limbs; these are highly aggressive tumors and patients have a mean survival of 18 months. Tumor volume and expression of p53 have been found to be independent factors predictive of poor behavior.61,62 By the use of murine models, it has been demonstrated that loss of the tumor suppressor PTEN (phosphatase and tensin homolog) combined with overexpression of the K-ras oncogene is crucial in the development of malignant transformation.63,64

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Connective tissue tumors NKI-C3 (a putative melanoma marker) and often a variety of immunoreagents may be necessary to establish the specific differentiation pattern.4,8 The following description emphasizes the more common neuroectodermal type of granular cell tumor.

Clinical features

Fig. 35.354 Type I neurofibromatosis: a typical acoustic neuroma of the left eighth cranial nerve is visible in the cerebellopontine angle.

Melanocytic differentiation has exceptionally been documented.65 Acoustic neurofibromatosis (NF2) comprises a syndrome of acoustic ­neuroma (schwannoma; see Fig. 35.277), which is often bilateral, and ­intracranial and intraspinal neoplasms, including astrocytomas, meningiomas and ependymomas. An exceptional association with a soft tissue perineurioma has been reported.66 The gene for NF2 has been cloned to chromosome 22.67,68 Segmental neurofibromatosis can occur in both NF1 and NF2 as a result of somatic mosaicism.69–74 Segmental neurofibromatosis may occur in a patient with classic NF1 or, more commonly, in patients with no signs of neurofibromatosis other than café-au-lait spots. Most cases of segmental neurofibromatosis have no positive family history. Involvement is usually unilateral but may be bilateral.74

Granular cell tumor is a comparatively common lesion, arising most often in adults of 30–60 years of age, and showing a predilection for females.9 Although it may be found at almost any cutaneous, subcutaneous or visceral site (see below), it occurs most frequently on the tongue, trunk or limbs, particularly the arms.10,11 Less frequently, lesions may present on the feet, perianal region and genitalia including the penis, scrotum, vulva (labia and clitoris) and breast.12–22 Tumors have also been reported in the thyroid, parotid gland, esophagus, trachea, larynx, lung, mediastinum, rectum, duodenum, pancreas, biliary tract, ureter, bladder, nerve and within the cranium.23–39 Up to 10% of patients have multiple tumors (which may be cutaneous, oral or visceral, particularly in the gastrointestinal tract).40–44 Exceptional cases are familial. Lesions are slow growing, usually less than 2 cm in diameter, sometimes ­painful, and often have a verrucous appearance (Fig. 35.355). Giant tumors are rarely seen. Local recurrence is very uncommon except in the infrequent infiltrative examples. A very uncommon association with neurofibromatosis has been documented.36,45 The malignant counterpart is exceedingly rare in the skin and is more usually deeply seated.46–57 A rare malignant tumor has been described in association with a nerve and a single case report of a tumor associated with polymyositis documented.56,57 One patient presented with a granular cell tumor, a schwannoma and vitiligo, another with LEOPARD syndrome, yet another with Noonan's syndrome, and in a further case there was associated congenital deaf-mutism.58–61 Cytogenetic analysis in a single malignant case showed a 46,XX,+X,dic(5;15).62

Histological features Granular cell tumor is an ill-defined lesion composed of nests or trabeculae of large, round or oval cells with brightly eosinophilic granular cytoplasm, which in a proportion of cases stains with periodic acid-Schiff (PAS) after diastase digestion (Figs 35.356, 35.357). The cell borders are indistinct, resulting in a rather syncytial appearance. Nuclei are uniformly small, round and usually centrally situated. Mitotic activity is variable. Pustulo-ovoid bodies of Milian, representing large granules surrounded by a clear halo are ­common.63 Clear cell change is rare but can be prominent.64 Uncommonly, cases with a prominent plexiform growth pattern have been reported ­including an intraneural

Histological features The histological appearances of the skin and subcutaneous tumors seen in neurofibromatosis have been described under previous headings. Hypertrophy of pacinian corpuscles has been reported in a patient with NF1.75 Increased cellularity and cytological atypia is found in about one-fifth of cases and may represent an indicator of increased risk of malignant transformation.76 Although it has been reported that floret-like giant cells are associated with tumors in neurofibromatosis type 1, they can also be identified in sporadic neurofibromas.77,78 Malignant peripheral nerve sheath tumors tend to be more cellular but less pleomorphic than sporadic tumors.60 The café-au-lait macules show increased numbers of functionally active melanocytes with giant melanosomes.

Granular cell tumor This has been a controversial entity for many years, particularly with respect to its histogenesis.1–4 With the introduction of immunohistochemistry, it has become clear that most granular cell tumors represent neuroectodermal lesions.4,5 However, it must be emphasized that the presence of granular cell change is due to an increased number of secondary lysosomes and that it can occur focally or extensively in a variety of tumors, not only in other ­mesenchymal neoplasms such as smooth muscle tumors, but also in epithelial tumors including basal cell carcinoma.6,7 Additionally, a subset of granular cell tumors presenting mainly in the dermis is characterized by having a ‘null’ immunophenotype (see below).8 It is important to note that all granular cell tumors, regardless of their line of differentiation, are positive for

Fig. 35.355 Granular cell tumor: clinically, these tumors are not distinctive and present as slowly growing papules or nodules. By courtesy of D. Munroe, MD, St Bartholomew's Hospital, London, UK.

Benign neoplasms lesion.65–67 Colorectal tumors may present calcification and hyalinization.32,68 Intravenous invasion has rarely been reported in otherwise histologically benign tumors.69 A distinctive and quite common finding is the presence of pseudoepitheliomatous hyperplasia of the overlying squamous epithelium in tumors of the dermis or tongue. This finding may lead the unwary to make a diagnosis of squamous cell carcinoma ( Fig. 35.358 ). Epidermal growth factor and transforming growth factor do not appear to play a role in the induction of pseudoepitheliomatous hyperplasia. 70 Prominent perineural spread may be a feature in some lesions ( Fig. 35.359 ). Rarely, prominent fibrosis is present around the tumor and in one case there was ossification. 71,72 Pagetoid spread has been documented in a single case with malignant features. 73 Tumor cells are positive for NKI-C3, NSE, CD68 and S-100

Fig. 35.358 Granular cell tumor: the overlying squamous epithelium often shows striking pseudoepitheliomatous hyperplasia, which should not be mistaken for an invasive tumor.

Fig. 35.356 Granular cell tumor: the lesion consists of large cells with eosinophilic granular cytoplasm.

Fig. 35.359 Granular cell tumor: occasionally infiltration of the perineural space is a feature. This does not appear to be of clinical significance.

protein ( Fig. 35.360 ). 4,12 Tumor cells may also express calretinin, the alpha unit of inhibin, PGP 9.5, nestin and low-affinity nerve growth factor receptor. 15,74–77 With regard to other melanocytic markers, Melan-A may be focally positive and microphthalmia transcription factor is often diffusely positive but HMB-45 seems to be consistently negative. 78 Histological criteria for the diagnosis of malignancy are poorly defined, since cases with only mild atypia have metastasized.46–-57 However, ­features that should raise the possibility include large size (> 5 cm), rapid growth, vascular invasion, necrosis, high mitotic rate and increased pleomorphism.46–48,51–54 Electron microscopy shows that tumor cells contain numerous lysosomes.

Differential diagnosis Fig. 35.357 Granular cell tumor: high-power view.

The differential diagnosis is usually not problematic. Occasional cases may have to be distinguished from adult rhabdomyoma, which is desmin and myoglobin positive, and granular cell histiocytic reactions, which usually contain other inflammatory cells.

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Fig. 35.360

Fig. 35.361

Granular cell tumor: the tumor cells express S-100 protein.

Neurothekeoma: the tumor is composed of discrete lobules separated by fibrous septa.

Gingival granular cell tumor of the newborn Clinical features Gingival granular cell tumor of the newborn (congenital epulis) is very rare and presents as a congenital polypoid lesion, most often on the lateral alveolar ridge of the maxilla.1–3 Most cases are seen in females, and occasional patients have multiple lesions.4–6 In the latter setting, obstructive symptoms can occur.7 Tumors do not increase in size after birth and spontaneous regression is common, even after incomplete excision.8 These features suggest a reactive pathogenesis.

Histological features Histologically, the features are almost identical to those of the common neuroectodermal variant, but vascularity is more prominent and there is sometimes a sparse inflammatory infiltrate composed of lymphocytes and histiocytes. There may be entrapped islands of odontogenic epithelium. Immunohistochemically, tumor cells are negative for S-100 protein and p75/NGFR and positive for PGP 9.5 and, as expected from the granular cell change, for NKI/C3.9 Ultrastructural studies suggest an origin from undifferentiated mesenchymal cells.

Fig. 35.362 Neurothekeoma: the lobules are composed of delicate spindled cells dispersed in a myxoid stroma.

Nerve sheath myxoma (neurothekeoma) Clinical features Nerve sheath myxoma (neurothekeoma) arises most often on the extremities, mainly the hand/fingers, knee/pretibial region and ankle/foot, in the fourth decade of life and shows a predilection for males.1–7 A much smaller percentage of cases presents in the head and neck including the oral cavity.8–10 A single subungual case has been reported.11 There is no association with neurofibromatosis and typically the tumor presents as a solitary, long-standing, asymptomatic, raised, skin-colored nodule of variable duration measuring less than 3 cm in diameter.1–-7 Local recurrences, sometimes multiple, may be seen in up to 47% of patients. This tumor has no evident malignant potential.7

Histological features The appearances are distinctive; it is a well-defined, multinodular or multilobular unencapsulated mass situated predominantly in the dermis and subcutis (Figs 35.361–35.363).

Fig. 35.363 Neurothekeoma: high-power view showing fusiform and stellate tumor cells.

Benign neoplasms The tumor lobules are of variable size, separated from one another by thin fibrovascular septa, and are composed of epithelioid, stellate, spindle or ringlike cells with pale indistinct cytoplasm set in an abundant myxoid matrix (Fig. 35.364). Tumor cells are arranged in cords, small nests or sometimes in a syncytial pattern.7 Within some lobules are larger, more rounded cells with plump, rather hyperchromatic nuclei and eosinophilic cytoplasm (Fig. 35.365). Occasionally, bland multinucleate giant cells may be seen. Sparse mitotic activity is a common finding, but abnormal mitoses are not a feature (Fig. 35.366). Scattered within and around the tumor are chronic inflammatory cells and mast cells. Careful examination of the small adjacent peripheral nerves may reveal tumor-like myxoid changes within them; however, nerve fibers are not identifiable within the tumor itself. Tumor cells are usually positive for S-100 protein and low-affinity nerve growth factor receptor (Fig. 35.367).7,12,13 They are also usually variably positive for glial fibrillary acidic protein (GFAP) and CD57.7,13 All these findings support nerve sheath differentiation. Individual lobules of tumor cells are sometimes surrounded by a layer of EMA-positive cells (Fig. 35.368). Typical nerve sheath myxomas in which there is a transition to more cellular lobules were described in 1986 by Rosati and coworkers as ‘cellular neurothekeoma’.14 These tumors, however, are quite different from those described by Barnhill and Mihm in 1990 under the same heading.15 Although

Fig. 35.366 Neurothekeoma: note the multinucleate giant cell.

Fig. 35.364

Fig. 35.367

Neurothekeoma: note the myxoid stroma.

Neurothekeoma: the tumor cells are S-100 protein positive.

Fig. 35.365

Fig. 35.368

Neurothekeoma: in this section, the cells are epithelioid with abundant cytoplasm and conspicuous vesicular nuclei.

Neurothekeoma: the perineurium is highlighted with EMA immunohistochemistry.

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Connective tissue tumors the latter have different histological features and immunohistochemistry that do not support a nerve sheath origin (see below), they are nevertheless still known as cellular ‘neurothekeoma’.

Differential diagnosis Distinction from superficial angiomyxoma is based on the lack of circumscription, inconspicuous blood vessels, presence of scattered inflammatory cells and the common occurrence of epithelial elements in the latter tumor. Myxoid neurofibroma is poorly circumscribed and lacks a lobular architecture. Dermal myxomas are hypocellular and show few blood vessels and abundant stromal mucin. Distinction from circumscribed palisaded neuroma may be very difficult when the latter has prominent myxoid change.16

Cellular ‘neurothekeoma’ Clinical features Cellular ‘neurothekeoma’, as described by Barnhill and Mihm in 1990, usually presents on the head, neck and upper limbs followed by the trunk of children and young adults and shows predilection for females.1–8 Tumors in elderly patients are rare.9 Unusual sites of presentation include the maxilla, the bulbar conjunctiva, the oral cavity, hypopharynx, the ear and the vulva.10–16 Lesions are long-standing skin-colored papules, which usually measure less than 1 cm and in most cases less than 2 cm in diameter. Multiple lesions are exceptional.8,17 Local recurrence is rare and the figure of around 7% reported in large series likely reflects a referral bias.7,8,18 Recurrent tumors are more common on the face.7,18 Some cases present with atypical features (see below), raising the possibility of malignancy.19,20 However, the behavior of these tumors is benign.

Fig. 35.370 Cellular neurothekeoma: the cells have abundant cytoplasm and vesicular nuclei.

Histological features Lesions are poorly circumscribed and located in the reticular dermis with frequent focal extension into the subcutis. Atypical variants (see below) extend deeper into the subcutaneous tissue and an exceptional example with purely subcutaneous presentation has been documented.21 Facial tumors can focally involve the skeletal muscle. The tumor has a lobular growth pattern and consists of small nests and fascicles of epithelioid and short spindled cells with pale eosinophilic cytoplasm, vesicular nuclei and mild or no cytologic atypia (Figs 35.369–35.371). More prominent cytologic atypia can be seen in up to 25% of cases.7 Normal mitotic figures are fairly common and in some cases are prominent, and in exceptional instances atypical mitotic figures are found.8 Multinucleated giant cells including osteoclast-like giant cells can be seen. The collagen around the tumor cells sometimes appears somewhat sclerotic. In some cases the ­latter,

Fig. 35.369 Cellular neurothekeoma: the tumor consists of nests and fascicles of eosinophilic cells.

Fig. 35.371 Cellular neurothekeoma: mitoses are sometimes present.

change is prominent and these lesions are regarded as desmoplastic.22 A predominantly plexiform pattern is very rare and in occasional cases larger lobules are identified.7,23 Myxoid change is frequently observed and tends to be focal or more rarely predominant.7,24 Two rare tumors containing melanin have been documented.25 Atypical cellular neurothekeoma is characterized by larger size, deep involvement, infiltrative growth pattern, vascular invasion, high mitotic rate and marked cytological atypia (Figs 35.372, 35.373).7,19 The histogenesis of this tumor remains enigmatic.2–5 It has been suggested that the line of differentiation is fibroblastic/myofibroblastic and that it may represent part of the spectrum of plexiform fibrous histiocytoma.7,26,27 Immunohistochemistry is quite distinctive, as cases are consistently S-100 protein negative and NSE, NKI-C3 (described originally as a melanoma marker and a very non-specific marker) and CD10 positive (Fig. 35.374).7,8,28 Although it has been reported that NKI-C3 tends to be negative in tumors in which spindle cells predominate this is not our personal experience.29 Although S-100 protein is negative, S100A6 is positive in all reported cases.30 A proportion of cases are focally positive for SMA.2 PGP 9.5, microphthalmia transcription factor 1 (MITF-1) and podoplanin (D2–40) have also been reported as useful markers of cellular neurothekeoma.29,31,32 A single case was positive for desmin.7

Benign neoplasms

Differential diagnosis Although the overall growth pattern with nesting somewhat resembles a melanocytic lesion, there is no epidermal component and lesions are S-100 protein, HMB-45 and Melan-A negative. Nerve sheath myxoma is a predominantly acral tumor lacking cellular areas and composed of myxoid lobules of stellate cells which are positive for S-100 protein.

Perineurioma Clinical features

Fig. 35.372 Atypical cellular neurothekeoma: tumor cells show variation in size and there is cytological atypia.

Perineurioma is a neoplasm that was originally described as presenting in the subcutaneous tissue as soft tissue perineurioma or storiform perineural fibroma.1–4 However, the spectrum of perineurioma is wide and includes other variants such as cutaneous perineurioma, intraneural perineurioma (localized hypertrophic neuropathy) and sclerosing perineurioma.5–12 • Cutaneous perineurioma is relatively common and presents as a small papular lesion, mainly on the lower limbs of middle-aged adults, with predilection for females.5–8 Behavior is benign with no tendency for local recurrence. • Soft tissue perineurioma has very similar clinical features to those of cutaneous variants but lesions are subcutaneous and tend to be larger (up to 5 cm).1–4 • Malignant soft tissue perineuriomas are exceptional.13–16 Local recurrence has been reported but metastatic spread is rare and thus far no mortality has been documented. • Intraneural perineurioma generally presents in young adults, and patients develop localized neurological symptoms as a result of intraneural growth.9,10 • Sclerosing perineurioma presents in young adults, with marked predilection for the fingers and palm. Extra-acral lesions are very rare.17 An exceptional case with bilateral lesions, and a patient with numerous tumors, have been documented.18,19 Behavior is benign.11,12

Histological features

Fig. 35.373 Atypical cellular neurothekeoma: at higher power, note the marked nuclear pleomorphism.

Histologically, cutaneous perineurioma is a well-circumscribed, often dumbbell-shaped tumor composed of bland, short, spindle-shaped cells arranged in fascicles, with a focal whorling and a storiform pattern (Figs 35.375– 35.377). Tumor cells may have epithelioid morphology and this can be prominent (Figs 35.378, 35.379). Variable hyalinization of the collagen is present and some cases show scattered, mononuclear inflammatory cells. Exceptional lesions with ossification, granular cell change and adipocytes have been

Fig. 35.374

Fig. 35.375

Cellular neurothekeoma: the tumor cells express NKI-C3 but are S-100 protein negative.

Perineurioma: this tumor may closely resemble dermatofibrosarcoma protuberans but is generally better circumscribed.

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Connective tissue tumors

Fig. 35.376

Fig. 35.379

Perineurioma: there is a whorled growth pattern.

Epithelioid perineurioma: high-power view showing nuclear detail. Note the intranuclear pseudoinclusions. This tumor can easily be mistaken for a melanocytic lesion or epithelioid fibrous histiocytoma.

Perineurioma: often, the tumor cells are arranged in a typical storiform growth pattern.

described.20–22 In a patient with multiple tumors, the lesions showed hybrid features of perineurioma and granular cell tumor.23 In a further case, granular cell change was documented.24 Soft tissue perineuriomas are very similar to those seen in the skin. Tumors are well circumscribed and generally cellular, being composed of monotonous bipolar cells with slender small nuclei in a fascicular, whorled or storiform growth pattern. Some cases are less cellular with a myxocollagenous stroma. Mitotic figures are rare and pleomorphism is absent. A reticular variant of soft tissue perineurioma has been documented (Fig. 35.380).25,26 In this variant, a lace-like or reticular growth pattern composed of anastomosing cords of spindle-shaped cells with pale pink cytoplasm and bipolar cytoplasmic processes is seen. In intraneural perineurioma, perineurial cells proliferate around individual axons with a characteristic onion ring appearance. A reticular pattern has been documented in one case.27 Sclerosing perineurioma is characterized by prominent hyalinized collagen around the tumor cells, which are arranged in cords, bundles and whorls (Figs 35.381, 35.382). Cytological atypia is absent and mitotic figures are exceptional. A single case contained mature adipocytes.28

Fig. 35.378

Fig. 35.380

Epithelioid perineurioma: in this obliquely cut example, a collarette has completely enclosed the tumor.

Reticular perineurioma: note the lace-like growth pattern.

Fig. 35.377

Heterotopias

Fig. 35.383 Perineurioma: the tumor cells express epithelial membrane antigen.

Fig. 35.381 Sclerosing perineurioma: this variant is characterized by a dense fibrous stroma.

Fig. 35.384 Perineurioma: there is cytoplasmic CD34 expression.

Heterotopias Fig. 35.382 Sclerosing perineurioma: residual nodules are scattered throughout the lesion.

A plexiform pattern is very rare.26 In all perineuriomas, tumor cells are diffusely positive for EMA, but ­negative for other neural markers (including S-100 protein), in keeping with perineurial differentiation (Fig. 35.383).3,4 Focal and sometimes diffuse positivity for CD34 is seen in a small number of cases (Fig. 35.384). In soft tissue perineurioma and sclerosing perineurioma, rare focal positivity for keratin has been described.11 Abnormalities of chromosome 22 and specifically deletion of NF2 have been reported in a few cases.10,29

Differential diagnosis Distinction from dermatofibrosarcoma protuberans is afforded by the latter's diffuse CD34 positivity and infiltrative growth pattern. Other neural tumors usually lack a storiform pattern and are generally S-100 protein positive.

Meningeal heterotopias Meningeal lesions presenting in the skin are usually known as ‘cutaneous meningiomas’. The use of this term tends to imply a neoplastic origin and since most lesions in this group are probably hamartomatous or the result of developmental defect, we prefer the designation meningeal heterotopias. It is convenient to classify cutaneous meningeal lesions into three types.1 However, there is a great degree of overlap, especially histologically, between type I and type II lesions and they probably represent variants of a similar hamartomatous process.

Clinical features Type I lesions have also been described as ectopic meningothelial hamartoma and sequestrated or rudimentary meningocele.2–6 Although they are ­congenital, they are sometimes only recognized during childhood and adolescence. There is an equal sex incidence and presentation is that of a nondescript cutaneous or subcutaneous nodule or plaque on the scalp (especially the occipital area) or less commonly on the back along the midline (Fig. 35.385). Often, they are diagnosed clinically as cysts. There is no underlying bone abnormality.

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Fig. 35.385 Ectopic meningothelial hamartoma: the scalp is a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.387 Ectopic meningothelial hamartoma: high-power view showing meningothelial cells lining the cystic spaces.

Type II lesions present mainly in adulthood on the head and neck but may rarely occur in children.7,8 A case associated with pregnancy and one with a sinus pericranii have been documented.9,10 Their behavior is entirely benign and it appears that they also represent hamartomas. Type III lesions represent local invasion or true metastasis from a primary intracranial meningioma.11 The scalp is the most common site and growth through bony surgical defects is well recognized. A case of meningioma was reported after trauma due to the entrapment of meningothelial tissue in the skin.12

Histological features Type I lesions are located in the deep dermis and subcutis and show irregular, elongated, anastomosing and dilated spaces resembling vascular channels ­dissecting between somewhat thickened collagen bundles (Figs 35.386–35.388). The spaces are filled or lined by small, round eosinophilic epithelioid meningothelial cells with minimal or no atypia and showing no mitotic activity. They are consistently positive for EMA (Fig. 35.389). Focally, cells wrap around

Fig. 35.388 Ectopic meningothelial hamartoma: the pseudovascular spaces are associated with dense fibrous tissue.

Fig. 35.386 Ectopic meningothelial hamartoma: this lesion is composed of pseudovascular clefts lined by meningothelial cells.

Fig. 35.389 Ectopic meningothelial hamartoma: the tumor cells express epithelial membrane antigen.

Heterotopias

Fig. 35.390

Fig. 35.392

Ectopic meningothelial hamartoma: the tumor cells characteristically entrap collagen.

Cutaneous ‘metastatic’ meningioma: the dermis is diffusely infiltrated by a spindle cell tumor.

Fig. 35.391

Fig. 35.393

Ectopic meningothelial hamartoma: psammoma bodies are sometimes a feature. Note the conspicuous meningothelial proliferation.

Cutaneous ‘metastatic’ meningioma: in this example well-developed basophilic psammoma bodies are evident.

hyalinized collagen bundles with calcification or psammoma body formation (Figs 35.390, 35.391). Occasional multinucleated cells may be a feature. Throughout the tumor there is an increase in the number of normal blood vessels, and fatty tissue may be evident within the dermis. Type II lesions are characterized by the presence of small numbers of more discrete and larger solid nests of meningothelial cells. A case of meningioma apparently developing from a rudimentary meningocele has been documented.13 Type III lesions show the features of an intracranial meningioma. They are composed of spindle-shaped and ovoid meningothelial cells, with a variable fibrocollagenous stroma (Figs 35.392, 35.393). A whorled or storiform pattern is common and sometimes the tumor cells are arranged in lobules or packets. Not infrequently, the larger ovoid cells, which have indistinct cell borders, are distributed in sheets, giving rise to a syncytial appearance. Psammoma bodies are often present (see Fig. 35.306).

Differential diagnosis Due to the pseudovascular appearance, type I lesions may be confused with angiosarcoma. The latter, however, generally occurs in older patients and typically shows cytological atypia, multilayering, mitotic figures and positive expression for vascular markers, but not for EMA.

Metastatic carcinoma can be distinguished from type I and type II lesions by a short history and the presence of cytological atypia, mitosis and keratin positivity.

Glial heterotopias Clinical features Glial heterotopias are rare developmental congenital anomalies that are typically detected in infancy although very occasional cases are first noticed in adult life.1–5 In the latter setting, a case was detected because of visual loss.6 The majority are subcutaneous and present as a firm mass adjacent to the bridge of the nose, often with associated hypertelorism (Fig. 35.394). Up to one-third of cases are solely intranasal and a small proportion show both components. As most cases occur in or around the nose they are known as nasal gliomas. Lesions present as a nodule or polyp, and intranasal lesions often are accompanied by obstruction.7 However, rare examples can arise on the lip, pharynx, oral cavity, scalp and even the midline of the back and the sphenoid sinus.8–11 Multiple lesions are rare and a heterotopia and an encephalocele may occur simultaneously.12 A case associated with agenesis of the corpus callosum has been documented.13 A further case associated with

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Fig. 35.394

Fig. 35.395

Fig. 35.396

Nasal glioma: the nose is the most commonly affected site. By courtesy of the Institute of Dermatology, London, UK.

Nasal glioma: this section from the bridge of the nose of a 2-year-old girl shows an ill-defined tumor mass deep to the compressed subcutaneous fat.

Nasal glioma: the lesion consists of circumscribed nodules of cellular tissue dispersed within a loose glial, fibrillary stroma.

PHACE syndrome (posterior fossa anomalies, hemangiomas of the face and scalp, arterial abnormalities, cardiac defects and eye anomalies) has also been reported.14 Although excision is curative, it is mandatory to preoperatively exclude the presence of a persistent communication with the frontal lobes.15,16 Such a communication is present in about 20% of cases and although it most often manifests as a fibrous cord, it may sometimes represent a true meningocele or encephalocele.1 Clinical and histological features do not allow ­distinction between ­heterotopia and encephalocele, and neuroimaging studies are mandatory.12,17 CT and MRI scans (particularly the latter) are the preferred radiological studies but distinction from a hemangioma may be difficult. In such cases ultrasound or Doppler flow studies may afford the distinction.18 Prenatal diagnosis may be made by ultrasound.19,20 Incautious treatment of such patients sometimes results in leakage of cerebrospinal fluid, meningitis and cerebral abscess.

Histological features The microscopic appearances are characteristic, being typified by well-circumscribed nodules composed largely of well-differentiated astrocytes in a loose neurofibrillar stroma situated in the subcutaneous tissues (Figs 35.395, 35.396). Oligodendrocytes may be focally identified and, in rare cases, there may be a demonstrable neuronal component (Fig. 35.397). Histological distinction from an encephalocele is not possible since even heterotopias may show laminated cerebral cortex with neurons and ependymal canals (Fig. 35.398).12 Focal calcifications and mild inflammation are sometimes seen.5 Proliferation of associated eccrine sweat ducts has been described in a case.21 In older patients, lesions may be almost completely replaced by ­fibrosis, ­making recognition very difficult.12 Diagnosis can be confirmed by the ­expression of GFAP and S-100 protein.3,5

Malignant peripheral nerve sheath tumor Malignant peripheral nerve sheath tumor is synonymous with the terms ‘neurofibrosarcoma’ and ‘malignant schwannoma’ and is the preferred name, since the precise histogenesis of a given tumor – be it Schwann

Fig. 35.397 Nasal glioma: the nodules are composed predominantly of astrocytes with round vesicular nuclei. The cells with small hyperchromatic nuclei are oligodendrocytes.

cell, perineurial cell or fibroblast – is rarely certain. Malignant peripheral nerve sheath tumors showing perineural differentiation are discussed under perineurioma.

Clinical features Malignant peripheral nerve sheath tumor occurring in the skin is very rare and usually results from malignant change in a neurofibroma, mainly in patients with neurofibromatosis type I (50% of cases), as a complication of ­radiotherapy (10% of cases) or secondary to extension from a tumor ­arising in deeper soft tissues.1–12 Tumors arising from a neurofibroma in patients without neurofibromatosis are exceptional.13,14 Additionally, the rare epithelioid variant (which is associated with a better prognosis) has a predilection

Heterotopias

Fig. 35.398 Encephalocele: this cystic cavity is lined by ependymal cells and communicated with an intracranial component.

for the deep dermis and subcutis.15,16 The latter tumor is more common in the upper extremities of adults, with no sex predilection.15–17 Malignant peripheral nerve sheath tumor most often presents in adults although its age range is wide. Tumors in children are rare and may be ­sporadic or associated with NF1.18 A distinctive variant – plexiform ­malignant peripheral nerve sheath tumor – has been reported in children.19 This tumor tends to have a better prognosis than ordinary malignant peripheral nerve sheath tumors, with a high rate of local recurrence but low metastatic potential. Sporadic cases show an equal sex incidence and tend to cluster in the fifth decade of life. By contrast, tumors associated with NF1 are more common in males with a peak in the fourth decade. Anatomical distribution is wide with most lesions presenting on the limbs followed by the trunk and (less ­frequently) the head and neck region. These tumors affect only 2–3% of patients with NF1.1 They occur in either sex and most often present in the third and fourth decades; a rapid ­alteration in the size or symptomatology of a pre-existent neurofibroma is suggestive of malignant change. The 5-year survival for patients with NF1 and ­irradiation-induced tumors is around 20%, which is much lower than that for other NF1 patients.1,8 The literature varies as to whether NF1associated malignant nerve sheath tumors are more aggresive.20–23 This ­question may be complicated by the difficulty in diagnosis of this tumor ­outside the context of NF1.

Fig. 35.399 Malignant peripheral nerve sheath tumor: this shows an infiltrate of small cells with ill-defined eosinophilic cytoplasm and focal palisading.

Fig. 35.400 Malignant peripheral nerve sheath tumor: nuclear palisading as seen in this field is only rarely a feature.

Pathogenesis and histological features Many malignant peripheral nerve sheath tumors arise in the context of NF1 (see syndrome discussion above) and thus are associated with loss of neurofibromin, as are their neurofibroma precursors. Somatic NF1 loss also appears to be common in sporadic tumors.24,25 Malignant progression often proceeds with P16 or P53 abrogation though other genes are also involved.26–28 Tumors often show gains in chromosomes 8q, 17q and 7p and losses in chromosomes 9p, 11q and 17p. Neoplasms with gains in chromosome 16p or losses in chromosomes 10q or Xq are associated with poor prognosis.29 Irrespective of the clinical context, the histological features are fairly consistent, comprising alternating myxoid and cellular areas containing irregular interlacing bundles of spindled cells with scanty pale cytoplasm and wavy, usually hyperchromatic, variably pleomorphic nuclei (Figs 35.399, 35.400). Myxoid change can be prominent. The degree of pleomorphism and mitotic activity varies among cases, but correlates with the grade of the tumor (Fig. 35.401). Perivascular whorling by tumor cells is also a typical feature, as are hyaline nodules if present (Figs 35.402, 35.403). Tumor cells quite often appear to infiltrate small vessel walls. Nuclear palisading is rare. Pigmentation and melanocytic differentiation are very rare features.30

Fig. 35.401 Malignant peripheral nerve sheath tumor: note the presence of conspicuous mitotic figures.

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Fig. 35.402 Malignant peripheral nerve sheath tumor: the presence of focal areas of perivascular cuffing is a typical feature.

Fig. 35.403 Malignant peripheral nerve sheath tumor: hyalinized nodules, often with a peripheral ring of nuclei, are rare but characteristic.

It should be noted that only 50% of malignant peripheral nerve sheath tumors are S-100 protein positive, probably reflecting the heterogeneity of the tumor cell population.31–33 Lack of S-100 protein reactivity may confer a worse prognosis. Heterologous differentiation is seen in up to 15% of cases, most often as foci of malignant bone or cartilage. A rhabdomyoblastic element may sometimes be apparent (malignant Triton tumor) (Figs 35.404, 35.405).34,35 Very rarely, gland formation is evident.36–38 Angiosarcoma may also develop within a malignant peripheral nerve sheath tumor.39,40 Epithelioid malignant nerve sheath tumor comprises the small proportion of neoplasms containing, in addition to the more conventional features, variably sized areas consisting of plump, round or oval cells with eosinophilic cytoplasm, sometimes arranged in a packeted or trabecular pattern (Figs 35.406, 35.407).15,16 These cells have an epithelioid appearance not dissimilar to amelanotic melanoma cells. The positivity rate for S-100 protein is higher than in conventional malignant peripheral nerve sheath tumor and the staining tends to be more diffuse and intense. In subcutaneous lesions, tumor cells tend to be smaller, bluer and more nevoid. Plexiform malignant peripheral nerve sheath tumor is a dermal and subcutaneous lesion. It has well-defined or infiltrative margins and plexiform

Fig. 35.404 Malignant Triton tumor: this field shows a highly cellular spindle cell tumor with nuclear pleomorphism.

Fig. 35.405 Malignant Triton tumor: there are scattered rhabdomyoblasts with intensely eosinophilic cytoplasm within this poorly differentiated malignant nerve sheath tumor.

Fig. 35.406 Epithelioid malignant peripheral nerve sheath tumor: low-power view of an intensely cellular tumor.

Heterotopias

Fig. 35.407 Epithelioid malignant nerve sheath tumor: the marked nuclear and cytoplasmic pleomorphism and conspicuous eosinophilic nucleoli are reminiscent of epithelioid malignant melanoma or poorly differentiated carcinoma.

Histologically, most tumors are cellular and show a lobular or (less often) trabecular growth pattern with numerous small blood vessels and little or no stroma between cells (Figs 35.408–35.410). Confluent areas of necrosis are common. Differences between cases reflect a spectrum of neuroectodermal differentiation. • At the less differentiated end of the spectrum (Ewing's sarcoma), tumor cells have scanty cytoplasm, round nuclei with finely distributed chromatin, and very rare or no rosettes. • At the other end of the spectrum (neuroepithelioma), tumor cells have more abundant eosinophilic cytoplasm, nuclei have coarser chromatin with more conspicuous nucleoli, and rosettes and perivascular pseudorosettes are often seen. Cytoplasmic glycogen detected by the PAS stain is more common in Ewing's sarcoma. By immunohistochemistry, tumor cell cytoplasmic membrane stains for an antibody against the MIC-2 protein (CD99) (Fig. 35.411).17 This antibody is less specific than was previously thought and may be positive in tumors entering the differential diagnosis including lymphoblastic lymphoma. A panel of antibodies, however, usually allows accurate distinction. Other markers that may be positive in tumor cells include NSE, synaptophysin, CD57, S-100 protein, chromogranin and CAM 5.2.6 Staining for an antibody against FLI-1 protein

appearance, resembling entangled hypercellular nerve trunks.19 Tumor cells are elongated with wavy vesicular nuclei, and mitotic activity is variable. Necrosis and vascular invasion are not seen. Melanotic schwannoma is discussed under Carney complex.

Differential diagnosis Conventional malignant peripheral nerve sheath tumor must be distinguished from monophasic synovial sarcoma and fibrosarcoma: the former tends to be at least focally positive for EMA or pankeratin and negative for S-100 ­protein; the latter shows a typical herring-bone pattern and is S-100 ­protein ­negative. The epithelioid variant of malignant peripheral nerve sheath tumor is ­separated from metastatic melanoma by the negativity of the former for the melanoma ­markers HMB-45 and Melan-A. It is distinguished from ­metastatic ­carcinoma by epithelial markers.

Peripheral primitive neuroectodermal tumor Clinical features Peripheral primitive neuroectodermal tumor (extraosseous Ewing's sarcoma, Askin's tumor, peripheral neuroepithelioma) is exceptionally rare in the skin, but may occur either as a primary or, somewhat more often, as a result of secondary spread.1–12 Most cases arise in the deep soft tissues of the trunk or limbs in children and young adults, with an equal sex incidence, although the overall age range is wide. Primary cutaneous and subcutaneous lesions have a predilection for the trunk followed by the lower and upper limbs and head and neck.6–8,13 Most patients are children or young adults but lesions have been reported in older individuals. Prognosis is generally poor although tumors occurring primarily in the skin and subcutaneous tissue appear to have relatively indolent behavior. Although the series of primary cutaneous tumors reported so far are small and with relatively limited follow-up, recurrences and metastases have been rare.6–8,13

Fig. 35.408 Peripheral primitive neuroectodermal tumor: low-power view of a small blue cell tumor.

Pathogenesis and histological features All the tumors in this group share a t(11;22), the fusion product of which has been cloned and used for diagnostic purposes.14–16 The fusion resulting from the translocation is between Ewing's sarcoma and FLI1 genes and this results in overexpression of FLI-1 protein.17 While this is the most common fusion event seen in greater than 90 % of cases, more than six substitutes, all members of the ETS superfamily of transcription factors, have been described for FLI1, with ERG being the most common at around 5%.18–20 The others are exceedingly rare.21 Molecular confirmation of this diagnosis is becoming routine.22–25

Fig. 35.409 Peripheral primitive neuroectodermal tumor: the tumor cells have hyperchromatic nuclei with ill-defined and minimal cytoplasm.

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Connective tissue tumors Presentation in ­children is rare.8 Tumors have also been rarely described in bone, gastrointestinal tract and kidney.9–11 Soft tissue melanoma presents as a slowly growing, rather deep-seated, nodular mass, often associated with an underlying tendon or aponeurosis. Clear cell sarcoma confined to the dermis has been described, but probably requires molecular confirmation for diagnosis.12 This tumor is particularly prone to local recurrence and widespread metastases, commonly many years after the diagnosis of the primary tumor, resulting eventually in death in up to 75% of patients.1,5,6,13 The rate of local recurrence is around 60%. Soft tissue melanoma associated with calciphylaxis has been documented.14

Pathogenesis and histological features

Fig. 35.410 Peripheral primitive neuroectodermal tumor: high-power view showing classical rosettes.

Cytogenetic studies in soft tissue melanoma have shown a specific t(12;22) (q13–14;q12-13).15–17 As a result of this translocation, there is fusion of the Ewing's sarcoma (EWSR1) oncogene and the activating transcription factor 1 (ATF1). Expression of the melanocyte-inducing factor – microphthalmia transcription factor (MITF) – is directly induced by the EWSR1/ATF1 fusion protein.18–20 CREB1 (2q12) can substitute for ATF1 in a small subset of cases.21,22 Fusions of EWSR1 and CREB1 may be more common in the gastrointestinal form of clear cell sarcoma and might be less efficient in promoting melanocytic differentiation.23 Identical gene fusions are seen in angiomatoid fibrous histiocytoma, but MITF transcription is not induced.24,25 Gene expression profiles confirm strong melanocytic differentiation in clear cell sarcoma.26,27 The tumor is typically a well-circumscribed mass composed of nests, fascicles or trabeculae of uniformly fusiform or (less commonly) rounded cells with eosinophilic to clear cytoplasm (Figs 35.412, 35.413). The nuclei are usually vesicular, centrally located and have prominent nucleoli. They are relatively uniform, but otherwise appear identical to those of cutaneous melanoma. Mitotic activity is generally inconspicuous and the nests tend to be separated by delicate fibrous septa, which may impart a spurious alveolar pattern. Frequently scattered throughout the tumor are bland multinucleated giant cells with a wreath-like nuclear arrangement (Fig. 35.414). About 60% of cases contain variable amounts of melanin pigment, which can be highlighted by special stains (Fig. 35.415). Tumor cells are positive for S-100 protein, HMB-45, Melan-A and NSE.4–6 Ultrastructurally, tumor cells show typical features of melanocytic ­differentiation with melanosomes.4

Fig. 35.411 Peripheral primitive neuroectodermal tumor: a variety of CD99 antibodies, notably O13 and MIC-2, have increased diagnostic sensitivity for this tumor. They are, however, by no means specific.

is also present in a large number of tumors but is not specific and may be seen in lymphoblastic lymphoma.17 Variable keratin reactivity is seen in a ­significant subset of cases and can cause diagnostic confusion for the unwary. 22

Differential diagnosis Metastatic neuroblastoma is an important differential diagnosis, especially in children. However, this is CD99 negative. Lymphoblastic lymphoma may on occasions be CD99 positive and leukocyte common antigen (LCA) negative. In such cases the distinction is dependent upon lymphocyte immunophenotyping.16 A minority of cells in rhabdomyosarcoma (especially the ­alveolar ­variant) may be CD99 positive, but the tumor cells also express muscle ­antigens, and rhabdomyoblasts can usually be identified.

Clear cell sarcoma/melanoma of soft parts Clinical features Clear cell sarcoma (melanoma of soft parts) is a rare tumor that usually arises in young adults, shows a predilection for females and occurs most often in the distal extremities, particularly the feet and hands.1–7

Fig. 35.412 Clear cell sarcoma: the tumor consists of nests of clear cells separated by fibrous septa.

Hamartomas

Fig. 35.413

Fig. 35.415

Clear cell sarcoma: the tumor cells have clear cytoplasm and round vesicular nuclei with prominent eosinophilic nucleoli.

Clear cell sarcoma: this section shows focal melanin pigmentation.

Differential diagnosis Occasional cases may bear a striking resemblance to a primary or metastatic melanoma and epithelioid malignant schwannoma (see above). Distinction from the former can be difficult as both tumors share the same immunohistochemical phenotype. However, cutaneous melanomas are usually more superficially located, pleomorphism is more marked and junctional activity is present. Usually metastatic melanoma also shows more mitoses, pleomorphism and necrosis, but in some patients only a careful clinical assessment will allow distinction. Epithelioid malignant schwannoma is HMB-45 and Melan-A negative and does not contain melanin pigment. Molecular confirmation of clear cell sarcoma is extremely helpful in ­challenging cases, as distinction from melanoma can have staging and treatment implications.

Fig. 35.414 Clear cell sarcoma: paraseptal irregular multinucleate cells are a common feature.

Smooth muscle tumors Hamartomas Congenital smooth muscle hamartoma Clinical features Congenital smooth muscle hamartoma is a rare lesion that presents in infants as an indurated, often hyperpigmented macule or plaque with perifollicular papules or coarse hairs.1–5 There is a slight male predominance and the prevalence has been estimated as 1:2600 live births.5 Occasional cases have been reported presenting after birth.6,7 The most frequent location is the ­lumbosacral area and there is also predilection for the proximal limbs, with rare cases occurring elsewhere including the oral cavity.8 Unusual presentations include a linear and atrophic plaque, marked folding of the skin, a Michelin tire ­syndrome-like appearance and diffuse involvement with hypertrichosis lanuginosa.9–12 In one case, the presenting sign was myokymia (pseudo-Darier's sign).13 In other cases, a pseudo-Darier's sign can rarely be elicited.14 Unusual sites of presentation include the conjunctival fornix.15

Occasional patients have multiple lesions and more extensive, ­generalized involvement.16,17 Familial cases may occur.18 Acquired cases are exceptional.19,20 Examples of acquired smooth muscle hamartoma of the genitalia may represent hyperplasia of smooth muscle as a result of chronic scrotal lymphedema.21,22 Focal changes simulating smooth muscle hamartoma have been documented in a case of port-wine stain.23

Histological features Histologically, there are numerous haphazardly oriented intradermal bundles of mature smooth muscle (Figs 35.416, 35.417). Hair follicles are ­normal in number and there is sometimes mild hyperkeratosis, acanthosis and ­hyperpigmentation of the basal cell layer. A rare association within the same lesion of a congenital melanocytic nevus and a smooth muscle hamartoma has been documented.24 Immunohistochemistry shows diffuse staining for SMA, desmin and h-caldesmon.25 A close relationship with Becker's nevus has been suggested, but the latter is an acquired lesion that appears later in life and shows hypertrichosis, hyperpigmentation and usually only a mild increase in the amount of smooth muscle.2,26

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Fig. 35.416 Congenital smooth muscle hamartoma: irregular bundles of smooth muscle are present in the deeper dermis and subcutaneous fat.

Fig. 35.418 Pilar leiomyoma: multiple erythematous papules are present. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.417 Congenital smooth muscle hamartoma: high-power view.

Benign smooth muscle tumors Pilar leiomyoma Clinical features Pilar leiomyoma usually presents in young adults, most often on the limbs or trunk (Figs 35.418, 35.419).1–5 Congenital lesions are probably variants of smooth muscle hamartoma.6 Lesions are multiple (rarely hundreds of lesions are seen), small, slowly growing papules generally less than 1 cm in diameter, and typically painful or tender, particularly when compressed or exposed to a cold environment. In the limbs, pilar leiomyomas tend to favor the extensor surfaces. Patients may present with plaque-like variants or tumors in a zosteriform distribution.7 Multiple leiomyomas have been described in association with HIV infection, chronic lymphocytic leukemia and erythrocytosis.8–10 Recurrence is uncommon after excision, but new lesions may continue to develop over the years. In a small proportion of cases with multiple lesions, there is a positive family history, with an autosomal dominant inheritance (Fig. 35.420).11,12 A case in identical twins has been documented.13 A segmental distribution may be seen in familial cases.14–17 For many years it has been recognized that multiple cutaneous leiomyomas are associated with uterine leiomyomas.18–21

Fig. 35.419 Pilar leiomyoma: close-up view of an erythematous nodule. By courtesy of the Institute of Dermatology, London, UK.

More recently, a further association with papillary or collecting duct renal cell cancer has been identified and the syndrome is now termed hereditary leiomyomatosis and renal cell cancer (HLRCC).21–23 Loss of function in the gene responsible for this syndrome, FH (1q42.3~q43), results in fumarate hydratase deficiency.24–31 Fumarate hydratase, a component of the tricarboxylic acid cycle, acts as a tumor suppressor gene and may be involved in DNA damage response.32 Although most patients with the syndrome have cutaneous and uterine leiomyomas, renal cancer is only seen in a minority of patients. Interestingly, similar mutations are very rare in sporadic variants.33,34 Solitary pilar leiomyomas are less commonly seen and tend to be larger. There is a slight male predominance, with predilection for the limbs.

Histological features Pilar leiomyomas, which are ill defined and intradermal, usually merge imperceptibly with the surrounding connective tissue (Figs 35.421, 35.422). Only occasional lesions are more nodular. The epidermis is typically ­unaffected. Each

Benign smooth muscle tumors

Fig. 35.420 Familial pilar leiomyomas: sometimes, hundreds of lesions may be present. By courtesy of the Institute of Dermatology, London, UK.

tumor is composed of uniform interlacing bundles or irregular collections of elongated cells with brightly eosinophilic cytoplasm and blunt-ended or cigarshaped nuclei (see Fig. 35.328). Mitotic figures are only very rarely seen.5 Focal cytological atypia due to degeneration may be a feature, similar to that seen in symplastic leiomyomas of the uterus (pilar symplastic or atypical leiomyoma).35–39 Adequate sampling of these lesions is ­necessary as changes of otherwise typical leiomyosarcoma may be focally found.40 Exceptionally, palisading mimicking Verocay bodies, and granular cell change may be evident.41,42 Tumor cells are usually uniformly positive for SMA, calponin, desmin and h-caldesmon.

Differential diagnosis The clinical history, particularly in cases with multiple lesions, often makes the diagnosis straightforward. Distinction from dermatofibroma is afforded by the leiomyoma's uniform cell content and configuration in addition to desmin and SMA positivity. Cellular neurofibroma is S-100 protein positive and lacks the eosinophilic cytoplasm, myofibrils and blunt-ended nuclei of leiomyoma. Differentiation from cutaneous leiomyosarcoma is based on the presence of mitoses and the usually greater nuclear pleomorphism in the ­latter tumor.

Fig. 35.422 Pilar leiomyoma: the tumor cell nuclei are characteristically cigar shaped.

Genital leiomyoma Clinical features Genital leiomyoma originates from the superficial smooth muscle of the ­scrotum, vulva or nipple.1,2 Traditionally, such cases have been classified as variants of pilar leiomyoma. This is appropriate for nipple lesions, but ­scrotal and vulval tumors show different pathological features. They are uncommon, tend to be larger and are better circumscribed. They usually present in m ­ iddle-aged adults. A pericentric inversion (12)(p12q13–14) has been described in a single case of vulval leiomyoma.3

Histological features Nipple leiomyoma is histologically identical to lesions arising elsewhere on the integument (Fig. 35.423). Scrotal leiomyomas, however, which arise from the dartos muscle, tend to be quite cellular and often show a focal ­mononuclear inflammatory cell infiltrate (Fig. 35.424). Cytological atypia as ­present in symplastic leiomyoma may be seen but mitotic ­figures

Fig. 35.421

Fig. 35.423

Pilar leiomyoma: within the reticular dermis is an ill-defined tumor composed of broad interlacing fascicles of eosinophilic spindle cells.

Nipple leiomyoma: as with the pilar variant, the tumor is composed of a poorly circumscribed proliferation of mature smooth muscle cell infiltrate.

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Fig. 35.424 Scrotal leiomyoma: note the circumscription and multinodularity.

Fig. 35.425

are exceptional (bizarre leiomyoma).4,5 Vulval leiomyomas arise in the labia majora and commonly display myxoid change and hyalinization.6 Epithelioid cell change may also be a feature.6 Scrotal leiomyomas express androgen receptor.7

Angioleiomyoma: lesions are very rarely superficial, as in this example which presented as a vascular papule. By courtesy of the Institute of Dermatology, London, UK.

Angioleiomyoma Clinical features Angioleiomyomas are common, deep dermal or subcutaneous, benign, smooth muscle tumors that originate from vascular smooth muscle. They arise most often in adults between 30 and 60 years of age, particularly on the limbs (especially the lower legs).1–3 Two cases of digital angioleiomyoma have been documented, one with bone destruction.4,5 Involvement of the palm is exceptional.6 Females are affected at least twice as often as males, except in the head and neck regions where the ratio is reversed. Lesions can rarely occur in the oral cavity.7 Tumors are typically solitary, slowly growing lesions less than 2 cm in diameter, and may be painful or tender when compressed (Fig. 35.425). Recurrence after simple excision is very rare and malignant change has never been convincingly documented. An association with multiple pilar leiomyomas is extremely rare.8 In an HIV-positive patient, multiple lesions developed and EBV was demonstrated by in situ hybridization within the nuclei of the tumor cells.9

Pathogenesis and histological features Cytogenetic studies vary and have revealed chromosomal imbalances and a few nonrecurring translocations, with the most consistent loss being found in chromosome 22.10–12 Histologically, in contrast to pilar leiomyoma, these are rounded, encapsulated lesions. They are composed of interlacing bundles of uniform smooth muscle cells, distributed around numerous small vessels with walls of variable thickness (Figs 35.426, 35.427). Hyaline or myxoid degeneration, thrombosis and dystrophic calcification are frequently encountered.13 Calcification can be very prominent and seems to be more common in acral lesions.14 Some cases contain collections of mature adipocytes (angiomyolipoma, angiolipoleiomyoma) and, although they probably represent metaplastic change, it has been proposed that such variants are hamartomatous.15–18 Such tumors are negative for HMB-45 and are not associated with tuberous sclerosis.19 In a small proportion of cases, the vascular spaces may show marked, almost sinusoidal, dilatation. Occasionally, scattered cells with enlarged hyperchromatic nuclei are seen.20–23 This change is not associated with increased mitotic ­activity, does not indicate malignancy and is probably secondary to ­degeneration. Unusual findings in angioleiomyoma include epithelioid cell change, clear cell change and prominent palisading mimicking Verocay bodies.24–26 A case reported as intravascular angioleiomyoma probably represents a myopericytoma.27 Some reports regard the latter as part of the spectrum of angioleiomyoma, although tumor cells in myopericytoma are positive for actin and usually negative

Fig. 35.426 Angioleiomyoma: the tumor is well circumscribed and shows an admixture of bundles of smooth muscle cells surrounding thick-walled blood vessels.

for desmin. Notwithstanding this, however, there is morphological overlap between both tumors and they are likely to be related.28 Immunohistochemical findings are identical to those for pilar leiomyoma and consist of diffuse staining of tumor cells for SMA, calponin, desmin and h-caldesmon.29

Malignant smooth muscle tumors Leiomyosarcoma Clinical features Leiomyosarcoma accounts for a significant proportion of superficial soft tissue sarcomas, although it is more common in a deep location, being most prevalent in the abdomen or retroperitoneum.1–5 The superficial tumors can be divided into two clinical groups: • cutaneous leiomyosarcoma, which includes leiomyosarcoma of the nipple, • subcutaneous leiomyosarcoma, which includes vulval and scrotal variants.6

Malignant smooth muscle tumors

Fig. 35.427 Angioleiomyoma: high-power view.

Cutaneous lesions are usually derived from the arrector pili muscle and arise most often in young adults, with a predilection for males.2–4,7–12 The limbs, especially the lower leg, are often affected and the tumor can be painful. Local recurrence is commonly seen, but metastasis is very rare.13–15 Subcutaneous leiomyosarcomas are very closely related to deeper leiomyosarcomas of soft tissues.2,3,7,16 They arise most often in the fifth to seventh decades, usually in the limbs (especially the thigh) and are larger than dermal lesions. Occasional cases arise from a vein wall. There is a slight predilection for males. Local recurrence is common, and in the long term around 50% of tumors metastasize, with a mortality rate of between 30% and 50%.10 The subcutaneous location and size are associated with ­aggressiveness.17 Tumor size greater than 5 cm is associated with a poor prognosis.10 Vulval and scrotal tumors appear to have a better prognosis than lesions arising at other sites.6 Exceptionally, leiomyosarcoma has been documented at the site of radiation dermatitis, in a pacemaker pocket, in a tattoo, in a scrofuloderma scar, in a nevus sebaceous and in association with a chronic venous ulcer.18–23 Cutaneous leiomyosarcoma in childhood is very rare.24 Metastatic leiomyosarcoma to the skin is very rare and usually presents as a rapidly growing mass with predilection for the scalp and with most cases arising from the genitourinary tract.25 In a single case, the patient presented with hemorrhagic bullae.26

Fig. 35.428 Leiomyosarcoma: extending up to the papillary dermis is a spindled cell tumor.

Histological features Cutaneous leiomyosarcoma tends to present as an ill-defined diffuse lesion in contrast to the well-circumscribed, more nodular subcutaneous variant. Both, however, are locally infiltrative tumors composed of interlacing bundles of smooth muscle cells with eosinophilic cytoplasm and blunt-ended, cigar-shaped, often vesicular nuclei (Figs 35.428, 35.429). Nuclear palisading and tandem alignment are not uncommon. Significant cytological pleomorphism (even to the point of mimicking so-called pleomorphic malignant fibrous ­histiocytoma, MFH) is more common in subcutaneous than cutaneous variants (Fig. 35.430). Prominent pleomorphism in dermal tumors is generally a feature of metastatic lesions, particularly from the uterus.27–29 Primary cutaneous lesions with prominent pleomorphism can be more aggressive as those that extend into the subcutis even if the extension is minimal.30 Most cases are usually diffusely or more uncommonly focally positive for SMA, calponin, desmin and h-caldesmon (Fig. 35.431).7,31,32 Very focal keratin positivity has also been documented.33 Periodic acid-Schiff staining may demonstrate perinuclear glycogen vacuoles. Cutaneous and subcutaneous leiomyosarcomas can rarely be predominantly epithelioid or show granular cell change (Figs 35.432, 35.433).34–37 Prominent desmoplasia has also been documented in rare cases.38–42 In ­addition, ­subcutaneous variants sometimes display myxoid change, hyalinization, admixed osteoclastic giant cells and an inflammatory cell infiltrate.43

Fig. 35.429 Leiomyosarcoma: as with its benign counterpart, the spindled cells exhibit marked eosinophilia.

Although leiomyosarcoma may bear a close resemblance to benign l­eiomyoma, the former usually shows variable pleomorphism and mitotic activity. Necrosis and hemorrhage are more common in subcutaneous ­variants and are also suggestive of malignancy. The tumor cells may be ­identified ultrastructurally by the presence of actin filaments with focal ­densities (Figs 35.434, 35.435).

Differential diagnosis Differential diagnosis is usually not problematic. Spindle cell melanoma can look remarkably similar to leiomyosarcoma, especially in an acral location, but the growth pattern in the former is more infiltrative, pleomorphism is usually more prominent and S-100 protein is positive whereas muscle

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Fig. 35.430

Fig. 35.433

Leiomyosarcoma: note the presence of marked mitotic activity.

Epithelioid leiomyosarcoma: the tumor cells express desmin.

Fig. 35.431

Fig. 35.434

Leiomyosarcoma: the tumor cells show strong h-caldesmon expression.

Leiomyosarcoma: note the presence of abundant actin filaments.

Fig. 35.432

Fig. 35.435

Epithelioid leiomyosarcoma: in this variant, the tumor cells are epithelioid with abundant eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli.

Leiomyosarcoma: high-power view showing focal densities characteristic of smooth muscle differentiation.

Benign striated muscle tumors

Fig. 35.436

Fig. 35.437

Metastatic leiomyosarcoma: metastatic deposits are characteristically nodular and well circumscribed.

Metastatic leiomyosarcoma: note the nuclear pleomorphism and abnormal mitosis.

­ arkers are negative. Similarly, epithelioid variants of leiomyosarcoma can m be distinguished from melanoma and carcinoma by immunohistochemistry. Distinction from the cellular variant of fibrous histiocytoma and cellular schwannoma has already been discussed in the representative sections.

Metastatic leiomyosarcoma also enters the differential diagnosis. This typically presents as a distinct nodule showing nuclear pleomorphism and mitotic activity (Figs 35.436, 35.437). Clinicopathological correlation is essential to establish the correct diagnosis.

Striated muscle tumors Hamartomas

Benign striated muscle tumors

Rhabdomyomatous mesenchymal hamartoma

Rhabdomyoma

Clinical features

Rhabdomyomas are very uncommon, usually deep-seated lesions and ­therefore rarely present to the dermatologist.1–3 Leaving aside genital ­rhabdomyoma (which occurs mainly in the vagina or cervix), those ­presenting occasionally in superficial subcutaneous tissues may be divided into either adult or fetal types. • The adult type typically arises in the head and neck region of males in the middle aged or elderly.2 A case of multiple cutaneous lesions on the trunk of a child has been documented.4 • The fetal type presents in infants, with male predilection.3 The great majority occur on the face and neck, with particular predilection for preauricular or retroauricular and periorbital regions. Involvement of the upper respiratory tract may also occur. Most tumors involve children less than 1 year of age and some are congenital. A single cutaneous case have been described.5

Rhabdomyomatous mesenchymal hamartoma (also known as striated muscle hamartoma) is a very rare congenital lesion.1–8 It presents in neonates and infants as one or more polypoid lesions simulating skin tags in the head and neck region (including intraoral lesions), especially on the central face.9,10 Exceptional cases have been described in the vagina, sternoclavicular area and on a digit.11–13 Unusual clinical presentations include a case resembling morphea ‘en coup de sabre’, one mimicking a basal cell carcinoma and another presenting as a plaque.14–16 Occasional cases have been associated with other congenital abnormalities including cleft lip, preauricular sinuses, sclerocorneas, low-set ears, thyroglossal sinus, colobomata, dermoid cysts, microphthalmia and meningocele.7,8,17,18 It appears that some of the lesions seen in Delleman's syndrome (oculocerebrocutaneous syndrome) represent rhabdomyomatous mesenchymal hamartomas.17 In a single case, spontaneous regression has been documented.19

Histological features The lesions are characterized by multiple bundles of mature striated ­muscle admixed with variable amounts of fat and fibrous tissue in the reticular dermis.

Differential diagnosis Distinction from accessory tragus can be made by the usual acral clinical location, histological absence of striated muscle and the presence of cartilage in the latter condition.

Clinical features

Histological features Adult type The adult type is composed almost entirely of large, round, polygonal or strap-shaped cells with plentiful eosinophilic cytoplasm (rhabdomyoblasts)2 (Fig. 35.438). Cross-striations are readily identifiable and rod-like inclusions are commonly present (Fig. 35.439). Immunohistochemistry shows positivity for muscle-specific actin, ­myoglobin and desmin.2 Very focal positivity for S-100 protein and SMA may also be seen.2

Fetal type The fetal type is composed almost entirely of immature round to spindleshaped rhabdomyoblasts in a myxoid stroma, showing progressive ­maturation towards more eosinophilic cells (which often show cross-striations) peripherally (Figs 35.440, 35.441).

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Fig. 35.438

Fig. 35.441

Rhabdomyoma: the adult-type lesion is composed of large polygonal cells with copious eosinophilic cytoplasm and peripherally located nuclei without pleomorphism.

Fetal rhabdomyoma: typical cross-striations are evident (phosphotungstic acid–hematoxylin).

Immunohistochemistry shows positivity of tumor cells for muscle-specific actin, myoglobin and desmin.3 Focal positivity for SMA, GFAP and S-100 protein may be evident.3

Differential diagnosis Distinction of any of these lesions from rhabdomyosarcoma is made possible by their lack of mitotic activity, nuclear pleomorphism or infiltrative growth pattern.

Malignant striated muscle tumors Rhabdomyosarcoma Rhabdomyosarcoma very rarely presents to the dermatologist, first because the tumor itself is rare, and second because it seldom arises in the dermis, albeit that occasional cutaneous metastases do occur.1–6 There are three ­subtypes: embryonal (including the botryoid variant), alveolar and ­pleomorphic, of which the first two are the most common.7–9 Fig. 35.439 Rhabdomyoma: in the center of the field are pathognomonic ‘jack straw’ intracytoplasmic inclusions.

Clinical features Rhabdomyosarcoma presenting in the skin either as a primary tumor or as a metastasis is extremely rare, accounting for only 0.7% of all rhabdomyosarcomas (Fig. 35.442).1–3 In the documented cutaneous cases there is a male predominance, a predilection for the face, very young age at presentation and alveolar histological subtype. The last feature is unusual, not only because at most other sites embryonal cases outnumber alveolar, but also because alveolar rhabdomyosarcomas arising elsewhere present in older children. Information about the prognosis of cutaneous lesions is extremely limited.

Pathogenesis and histological features At the molecular genetic level, the alveolar type is characterized by a t(2;13)(q35;q14) and less frequently a t(1;13) (p36;q14) fusing PAX3 or PAX7, ­respectively, with FOXO1A.9–13 More recently, NCOA1 (2p23) and AFX/FOXO4 (Xq13.1) have been shown to substitute for FOXO1A and pair with PAX3 on rare occasion.14,15 Embryonal lesions usually have 11p ­deletions amongst other cytogenetic aberrations.7 Pleomorphic ­rhabdomyosarcoma shows a complex karyotype.16,17

Embryonal type Fig. 35.440 Fetal rhabdomyoma: this example of the fetal myxoid type is composed of obvious elongated strap cells set in a loose myxoid stroma.

The embryonal type is composed largely of small round or spindle-shaped undifferentiated cells, often arranged loosely in a myxoid stroma.7 Obvious rhabdomyoblasts are variably prominent and show eosinophilic cytoplasm with a ‘strap’ or ‘tadpole’ shape (Figs 35.443–35.445). Variants of rhabdomyosarcoma include botryoid, spindle cell and anaplastic.

Malignant striated muscle tumors

Fig. 35.442 Cutaneous rhabdomyosarcoma: presentation in the skin is exceptional and occurs in children. This was an embryonal variant. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.443 Embryonal rhabdomyosarcoma: an example of undifferentiated rhabdomyosarcoma. The tumor cells are small and contain basophilic nuclei. Diagnosis depends upon immunocytochemistry or identifying more typical rhabdomyoblasts elsewhere in the specimen.

Fig. 35.444 Embryonal rhabdomyosarcoma: beneath the epithelium is an infiltrate of small basophilic cells, and there are also occasional primitive rhabdomyoblasts with more obvious eosinophilic cytoplasm.

Fig. 35.445 Embryonal rhabdomyosarcoma: in the center of the field is a typical ‘tadpole’ rhabdomyoblast with a tapering eosinophilic, cytoplasmic process.

Alveolar type The alveolar variant is typified by tumor cells arranged in discrete nests separated by fibrous septa and with an alveolar pattern of cellular dissociation at the center of the cellular aggregates (Figs 35.446, 35.447).7 Some cases, however, have an almost entirely solid growth pattern (Fig. 35.448). The tumor cells tend to be relatively large and rounded or readily recognizable as rhabdomyoblasts, and may be arranged as delicate papillae, solid clumps or lying free within each cell nest. Nuclei are larger and more hyperchromatic than in the embryonal type. Multinucleated (wreath-like) giant cells are a common feature (Fig. 35.449). Epidermotropism has been documented in a case of primary alveolar rhabdomyosarcoma.6 Alveolar-type histology can be seen in cases lacking characteristic fusion genes. Whether these cases are more similar to embryonal or fusion-positive alveolar cases genetically and clinically is currently debated in the literature.18–20

Pleomorphic type The pleomorphic type is a heterogeneous tumor characterized by bizarre spindled cells admixed with readily recognizable polygonal rhabdomyoblasts, often in large numbers (Fig. 35.450).7 This variant is largely confined to adults and is almost unknown in the skin. 21

Fig. 35.446 Alveolar rhabdomyosarcoma: this is a very rare example showing epidermotropism. The features mimic neuroendocrine (Merkel cell) carcinoma.

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Fig. 35.447

Fig. 35.450

Alveolar rhabdomyosarcoma: high-power view.

Pleomorphic rhabdomyosarcoma: the rhabdomyoblasts are extremely pleomorphic.

Fig. 35.448

Fig. 35.451

Alveolar rhabdomyosarcoma: the tumor cells have pleomorphic nuclei and multiple mitoses are present. There is no evidence of skeletal muscle differentiation in this example. Diagnosis depends upon immunohistochemistry.

Alveolar rhabdomyosarcoma: in this example, the tumor cells strongly express desmin.

Immunohistochemistry is very useful in the diagnosis of rhabdomyosarcoma because tumor cells tend to be at least focally positive for desmin, muscle-specific actin (HHF-35), and the more diagnostically specific myogenin and MyoD1 (Fig. 35.451).7,8

Spindle cell type Although embryonal rhabdomyosarcoma includes a spindle cell variant, a distinctive variant of spindle cell rhabdomyosarcoma has been described in adults. In these lesions there are atypical spindle-shaped cells intermixed with rhabdomyoblasts.22 In all variants of rhabdomyosarcoma tumor cells are variably positive for desmin, myogenin (myf-4) and MyoD-1.

Differential diagnosis

Fig. 35.449 Alveolar rhabdomyosarcoma: wreath-like giant cells are a characteristic feature.

Rhabdomyosarcomas should be distinguished from other small round cell neoplasms: • neuroblastoma contains neurofibrils and shows rosette formation, • primitive neuroectodermal tumor often has a packeted appearance, shows variable intracytoplasmic PAS positivity, lacks cells resembling rhabdomyoblasts and is diffusely CD99 positive, • malignant lymphomas are most often (but not always) PAS negative and stain positively for LCA. The pleomorphic type should be differentiated from other pleomorphic tumors by immunohistochemistry and identification of rhabdomyoblasts.

Benign tumors including reactive vascular proliferations and ectasias

Tumors of vascular origin Benign tumors including reactive vascular proliferations and ectasias Intravascular papillary endothelial hyperplasia Clinical features Intravascular papillary endothelial hyperplasia (Masson's tumor) is a relatively common lesion that represents a distinctive pattern of organizing thrombus.1–4 It can present as a primary phenomenon in a thrombosed normal blood vessel (usually a vein) or as an incidental finding (secondary form) in other vascular tumors, especially cavernous hemangiomas. Very rare cases are seen in an extravascular location in relation to a hematoma.5,6 The primary form arises most often in young adults and shows a slight predilection for females. It occurs most frequently in the head and neck region (including the oral cavity) or on the extremities (particularly the hand), presenting as a slowly growing, elevated, rather cystic nodule that usually measures less than 2 cm in diameter. Large lesions, sometimes in unusual locations, can mimic a soft tissue sarcoma.7 Presentation in the breast has also been described.8 Rare cases are multiple and, in this setting, an association with treatment with interferon beta has been documented.9,10 The behavior is entirely benign.

Fig. 35.453 Intravascular papillary endothelial hyperplasia: numerous small papillae are present within the lumen.

Histological features The lesion is typically well circumscribed and lies within a vessel or angioma in the dermis or subcutis. The appearances are of numerous small papillary structures covered by a single layer of flattened endothelium lying within a clearly demonstrable pre-existent vascular lumen (Figs 35.452, 35.453). The papillary endothelium shows neither atypia nor mitotic activity and the core is composed of hypocellular collagen, sometimes containing tiny capillaries (Fig. 35.454). The papillae may be seen attached to the internal surface of the vessel wall or apparently lying free in the lumen. Adjacent associated thrombus, showing a varying degree of organization, is commonly evident.

Differential diagnosis The principal lesion from which Masson's tumor should be distinguished is angiosarcoma, from which it differs by its invariable intravascular confinement, its lack of pleomorphism, mitotic activity or endothelial multilayering, and the absence of necrosis. Fig. 35.454 Intravascular papillary endothelial hyperplasia: the papillae are composed of eosinophilic hyaline material covered by flattened endothelial cells. There is an absence of atypia, multilayering and mitotic activity.

Reactive angioendotheliomatosis Clinical features

Fig. 35.452 Intravascular papillary endothelial hyperplasia: low-power view of a thrombosed hemangioma.

For many years, angioendotheliomatosis was divided into benign and malignant variants, which were difficult to separate on clinical and histological grounds.1 With the advent of immunohistochemistry, it became apparent that the malignant type is not endothelial in nature, but is an aggressive form of systemic angiotropic lymphoma. The benign variant of reactive angioendotheliomatosis is uncommon, purely cutaneous and self-limited. It presents as erythematous macules, papules or plaques, which can occasionally be purpuric (Fig. 35.455).1,2 A livedo-like pattern is rarely seen. Anatomical distribution and age range are wide and there is no sex predilection. Presentation in children is very rare.3 Some cases are related to systemic infections, especially bacterial endocarditis, but this association is not as strong as was previously believed. Associations with cryoglobulinemia, paraproteinemia, renal disease,

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Connective tissue tumors vessel lumina are obliterated by plump endothelial cells. Cases related to cryoglobulinemia show capillaries occluded by hyaline eosinophilic thrombi. In diffuse dermal angiomatosis there is proliferation of poorly canalized ­capillaries and endothelial cells. It has been suggested that intralymphatic histiocytosis and reactive angioendotheliomatosis are part of the same spectrum.21,22 The former, however, is mainly seen in patients with rheumatoid arthritis, can be an incidental finding in skin biopsies of patients with various pathologies and is characterized by dilated lymphatics containing numerous histiocytes.23,24

Glomeruloid hemangioma Clinical features

Fig. 35.455 Reactive angioendotheliomatosis: note the purpuric macular and papular lesions. By courtesy of the Institute of Dermatology, London, UK.

a­ myloidosis, antiphospholipid syndrome, rheumatoid arthritis, cirrhosis, polymyalgia rheumatica, myelodysplastic syndrome and a well-differentiated angiosarcoma have also been documented.2,4–12 A case of reactive angioendotheliomatosis associated with myelodysplastic syndrome presented with a cellulitis-like plaque and localized lesions were described in a patient with high antiocardiolipin antibodies and subclavian stenosis.10,13 An exceptional case localized to the intestine has been reported.14 Simultaneous occurrence of reactive angioendotheliomatosis and leukocytoclastic vasculitis have been documented.15,16 A number of cases are idiopathic. Localized forms of the disease are sometimes seen and include a variant associated with peripheral vascular atherosclerotic disease and iatrogenic arteriovenous fistulas described as diffuse dermal angiomatosis.17–20 The latter has also been reported in the breast of two female patients with large ­pendulous breasts, one of whom had IgM antiocardiolipin antibodies.21

Histological features

Glomeruloid hemangioma is a distinctive reactive vascular proliferation that has been described almost exclusively in patients with multicentric Castleman's disease and POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome (Crow-Fukase syndrome).1–5 Patients present with numerous vascular papules on the trunk and limbs and this may be the initial presentation of the disease.6 In one patient, intracranial ­hemangiomas were also seen.7 Exceptionally, one or multiple lesions have been described in patients with no evidence of POEMS syndrome.8–10

Histological features Histologically, appearances vary from small capillary hemangiomas (identical to cherry angiomas) to those of glomeruloid hemangioma or even a mixture of both. In the latter, there are dilated vascular spaces in the dermis, containing in their lumina clusters of capillaries surrounded by pericytes and strikingly resembling renal glomeruli (Figs 35.457, 35.458). Occasional larger cells with vacuolated cytoplasm and PAS-positive hyaline globules (representing immunoglobulin) are sometimes seen. By electron microscopy, the inclusions appear to represent enlarged secondary lysosomes (thanatosomes).11 Two types of endothelial cell with different immunophenotype have been described in glomeruloid hemangioma.12 The endothelial cells express endothelial growth factor and its receptor.13 Human herpesvirus 8 (HHV-8) is not present in the lesions of glomeruloid hemangioma.14

Papillary hemangioma Clinical features

Lesions are located mainly in the dermis with occasional extension into the subcutis. They consist of a multifocal, variably lobular proliferation of closely packed capillaries lined by plump endothelial cells and surrounded by pericytes (Fig. 35.456). Cytological atypia is absent or mild and frequently the

Papillary hemangioma is a recently described cutaneous vascular lesion.1 It presents as a small, long-standing papule on the head and neck with ­predilection for adult males. Only one of the 11 reported lesions recurred.

Fig. 35.456

Fig. 35.457

Reactive angioendotheliomatosis: the dermis is extensively infiltrated by welldefined capillary lobules.

Glomeruloid hemangioma: there is striking intraluminal capillary proliferation.

Benign tumors including reactive vascular proliferations and ectasias

Fig. 35.458 Glomeruloid hemangioma: high-power view.

Fig. 35.459

Histological features The lesion is characterized by dilated vascular spaces within the dermis. These spaces display papillary projections lined by plump endothelial cells with no cytologic atypia and containing cytoplasmic hyaline globules. The latter have been shown to represent giant lysosomes, as demonstrated by electron microscopy. These lysosomes contain cellular debris and fat vacuoles (thanatosomes). It has been suggested that glomeruloid hemangioma and papillary hemangioma are part of the same spectrum.2 The latter, however, is not associated with POEMS syndrome, lacks a glomeruloid architecture and is characterized by thick basement membrane-like material and pericytes within the cores of the papillary projections.3 Whether papillary hemangioma represents a solitary variant of glomeruloid hemangioma not associated with POEMS syndrome has not been clearly established.

Port-wine stain: this large red–purple lesion was present at birth and, in contrast to the strawberry nevus, shows no tendency to regress. From the collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

or with hypertrophy of a limb and partial venous agenesis with varicosities (Klippel-Trenaunay syndrome)16,17 (Figs 35.460–35.462). In Cobb's ­syndrome, there is a port-wine stain overlying an underlying spinal cord ­vascular malformation in the midline of the back.18,19 The cutaneous vascular lesion may also represent a verrucous hemangioma.19 Other vascular lesions, particularly pyogenic granuloma, vascular malformations, a combination of the latter two and even tufted angioma, may occur within a port-wine stain.20–25 Pyogenic granuloma-like lesions can occur after laser treatment.26 Basal cell carcinoma may occasionally develop within a port-wine stain.27,28

Nevus flammeus Clinical features The old term nevus flammeus encompasses both the salmon patch and the port-wine stain.1–3

Salmon patch Salmon patch is a congenital lesion that usually presents on the head and neck (forehead and nape of neck) as a reddish-purple macule and tends towards spontaneous involution. It can be seen in up to one-third of neonates.4 In a study of cutaneous findings in hospitalized neonates, a salmon patch was found in 91.2% of patients.5 In a further study in 500 newborns, a salmon patch was found in 28% of full-term infants and in 25.8% of pre-term infants.6 A salmon patch on the nape of the neck seems to be more commonly associated with a mother greater than 35 years of age.7

Port-wine stain Port-wine stain is a lateralized dark lesion that tends towards continued growth and only very rarely involutes (Fig. 35.459).1–3,8 A similar lesion characterized by light-red or pale-pink color has been described as nevus roseus.9 It is the most common vascular malformation and is seen in 0.3% of live births. Rare acquired cases of port-wine stain may also be seen, often in association with trauma.10,11 The familial combination of port-wine stain and arteriovenous malformation appears to be related to mutations in RASA1 (5q13.3) encoding a regulator of the Ras protein.12–15 Port-wine stain may be associated with ipsilateral cerebral or meningeal vascular lesions and vascular eye abnormalities (Sturge-Weber syndrome)

Fig. 35.460 Sturge-Weber syndrome: this 12-year-old girl presented with fits, mental retardation and a port-wine vascular nevus affecting much of the right side of her face. CT scanning showed meningeal angiomatosis. By courtesy of D. Atherton, MD, Institute of Dermatology and Children's Hospital at Great Ormond Street, London, UK.

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Fig. 35.461 Sturge-Weber syndrome: the intracranial moiety is often calcified, as in this radiograph. By courtesy of I. Moseley, MD, National Hospital for Nervous Diseases, London, UK.

Fig. 35.462 Klippel-Trenaunay syndrome: this 2-year-old boy has a port-wine vascular nevus, affecting much of the skin of the left leg, associated with increased soft tissue growth in the leg and a slight increase in its length. By courtesy of D. Atherton, MD, Institute of Dermatology and Children's Hospital at Great Ormond Street, London, UK.

Histological features

Spider nevus

Both salmon patch and port-wine stain are characterized solely by ectatic vessels of variable caliber in the dermis; designation as a true hemangioma, therefore, is probably inappropriate (Fig. 35.463).

Clinical features

Fig. 35.463 Port-wine stain: the malformation is characterized by numerous dilated blood-filled capillaries.

Cutis marmorata telangiectatica congenita

Spider nevi are extremely common lesions of little pathological significance.1,2 Although they may arise at any age, they are typically a cutaneous manifestation of chronic liver disease or thyrotoxicosis and may also be seen in pregnancy. The lesions manifest as pinhead-sized, deep red puncta from which tiny tortuous vessels radiate (Fig. 35.464).

Clinical features

Histological features

Cutis marmorata telangiectatica congenita is a rare condition that presents at birth and shows an equal sex incidence.1,2 It is characterized by cutis marmorata, telangiectasia, phlebectasia, occasional ulceration and atrophy. Lesions are more often unilateral, localized and with predilection for the limbs.1,2 They consist of a reticulated, blue–violet vascular network. The disease is sporadic and tends to improve with age. Only rare cases persist.3 In two-thirds of cases, associated abnormalities – including nevus flammeus, macrocephaly, syndactyly, hydrocephalus, body asymmetry, anal atresia, hearing loss, cardiovascular abnormalities, strabismus, ­hypothyroidism, nevus anemicus, café-au-lait spots, lipoma and hypospadias – may be seen.1,2,4,5 A distinctive syndrome combining the skin features with macrocephaly has been described.5 In the Adams-Oliver syndrome, aplasia cutis congenita and transverse limb defects are associated with other malformations in addition to cutis marmorata ­telangiectatica congenita.6,7

Histological features Biopsy shows dilatation of capillaries and venules in the superficial dermis. Occasionally, vascular proliferation may be seen.8

A typical lesion consists solely of a dilated dermal arteriole that communicates with a network of ectatic superficial capillaries.

Angioma serpiginosum Clinical features Angioma serpiginosum is rare, usually arises in childhood, and occurs particularly on the extremities.1–3 It is characterized by multiple tiny punctate red or purple lesions about the size of a pinhead, typically arranged in a gyrate or serpiginous pattern (Figs 35.465, 35.466).1–3 New papules tend to form gradually, thereby expanding the lesion. Sometimes the condition may simulate purpura.4 A linear arrangement may rarely be seen.5,6 Ocular and nervous system involvement has occasionally been documented.7,8 Although most cases are localized, extensive involvement rarely occurs.9 Occasional cases are familial.10

Pathogenesis and histological features It has been suggested that the disease is caused by deletions or mutations on chromosome Xp11 encoding for the PORCN gene.11,12 However, this view has been challenged with the suggestion that the patients reported in these papers had focal dermal hypoplasia.13

Benign tumors including reactive vascular proliferations and ectasias

Fig. 35.466

Fig. 35.464 Spider nevus: note the central macule with radiating vessels. From the collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Fig. 35.465 Angioma serpiginosum: the distribution of these tiny red macules is characteristic. From the collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Angioma serpiginosum: close-up view. From the collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.

Fig. 35.468 Fig. 35.467 Angioma serpiginosum: histologically, it is composed of a localized cluster of thickwalled and dilated capillaries, usually in the superficial dermis.

Venous lake: there is a typical blister-like vascular lesion. By courtesy of the Institute of Dermatology, London, UK.

Pathogenesis and histological features Each lesion is composed of a localized collection of relatively thick-walled, dilated capillaries in the superficial or mid dermis (Fig. 35.467).

Histology shows a dilated and congested vein in the superficial dermis. There is no evidence of vascular proliferation (Fig. 35.469). The pathogenesis is possibly related to defective stromal support.

Venous lake

Hereditary hemorrhagic telangiectasia

Clinical features

Clinical features

Venous lake is a fairly common vascular ectasia that presents on the sun-damaged skin of elderly people and show a predilection for the lip (Fig. 35.468).1–3 Lesions are sometimes multiple and can measure up to 1 cm in diameter.

Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome) is an autosomal dominant disease. It is characterized by numerous telangiectasias involving the skin, mucosae and internal organs, especially the

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• Angiokeratoma of Fordyce: this develops mainly on the scrotum of

Fig. 35.469 Venous lake: there is striking venous ectasia.

gastrointestinal tract and lungs.1 The upper respiratory tract is often involved and epistaxis is a frequent finding. Lesions become more evident in early adulthood. Internal organs are often involved by vascular arteriovenous malformations and pulmonary hypertension is a frequent finding.2,3

Pathogenesis and histological features Pathogenic mutations have been found in genes at 9q33~q34.1 and 12q11~q14 encoding endoglin (ENG) and activin-like receptor type II-like 1 (ACVRL1 or ALK1 – which is distinct from ALK the anaplastic lymphoma kinase gene), respectively.4–9 Both are related to the TGF-β receptors present on endothelial cells. A reported group of patients has combined juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia with mutations in the MADH4 on chromosome 18.10,11 Histology shows dilated small vascular channels in the affected organs.

Generalized essential telangiectasia Clinical features Generalized essential telangiectasia is a rare condition characterized by ­multiple tiny telangiectasias arising on the limbs and trunk and shows a ­predilection for females.1–3 Presentation is usually in childhood. In one case, lesions were more prominent in a surgical scar, one patient developed lesions in association with Graves disease and in a further report involvement of the conjunctiva was described.4–6

elderly men as single or multiple, blue or red papules.2 Involvement of the penis may also be seen and is sometimes prominent.3 Similar lesions can occur on the vulva of young women.4 Unilateral lesions are very rare.5 • Angiokeratoma of Mibelli: this presents as warty papules on the distal limbs (especially fingers and toes) of children and adolescents, showing a predilection for females.6 • Angiokeratoma circumscriptum: this is very rare and presents as grouped papules or a plaque with predilection for the upper and lower limbs of children, with a predilection for females.7 A case associated with injury and one in a systematized band-like pattern suggesting mosaicism have been documented.8,9 • Angiokeratoma corporis diffusum: this is characterized by widespread clusters of red papules in a symmetrical distribution, especially in the ‘bathing-trunk’ area.1,10 Exceptionally, lesions are seen on the palms and soles.11 It is usually, but not exclusively, associated with AndersonFabry's disease, an X-linked genetic disorder that results from a deficiency of the lysosomal enzyme α-galactosidase A. Treatment with the enzyme can induce regression of the angiokeratomas.12 Patients with other enzymatic deficiencies including L-fucosidase, β-mannosidase, α-N-acetylgalactosaminidase, neuraminidase and β-galactosidase deficiency and even individuals with no detectable abnormalities, exceptionally in a familial setting, can show identical lesions.13–21 Multiple hemangiomas without angiokeratomas in a female carrier of Fabry's disease have been documented.22 • Solitary and multiple angiokeratomas: these have a wide age range and anatomical distribution and preferentially affect the lower limbs.1 Most lesions are solitary. Multiple lesions have been reported in a zosteriform distribution.23 Distribution along Blaschko's lines can be seen.24 Lesions can develop as a consequence of radiotherapy and angiokeratoma-like lesions can be seen in lichen sclerosus.25–27 Injection of etanercept induced angiokeratomas in a single patient.28 Associations with epidermal nevus, vascular malformations, nevus lipomatosus superficialis have also been documented.29–32 Oral angiokeratomas are seen either as an isolated phenomenon or in association with other types of angiokeratomas including Fabry's disease.33,34

Histological features The histological features in all variants are similar and consist of numerous dilated and congested capillaries in the papillary dermis with overlaying acanthosis and hyperkeratosis (Fig. 35.470). In Anderson- Fabry's disease, intracytoplasmic lipid vacuoles have been described in endothelial cells, pericytes and fibroblasts.35

Histological features Histology shows dilated small vascular channels in the papillary dermis.

Cutaneous collagenous vasculopathy This is an exceptionally rare condition characterized by generalized telangiectasia mimicking generalized essential telangiectasia with histological evidence of collagen deposition around the basal lamina of blood vessel walls.1–4

Angiokeratoma Clinical features Angiokeratoma represents ectasia of superficial blood vessels associated with secondary epidermal changes, especially acanthosis and hyperkeratosis.1 Five variants have been described.

Fig. 35.470 Angiokeratoma: the lesion consists of small dilated vessels that often appear to be within the epidermis.

Capillary hemangioma and its variants

Differential diagnosis

Differential diagnosis

Identical features can be seen in the superficial portion of a verrucous hemangioma, which always, however, has a deep dermal and subcutaneous component.

Infantile hemangioma is the main differential diagnosis. Infantile hemangioma typically develops shortly after birth, grows rapidly during the first year of life and tends to involute over a period of several years. The vascular lobules of RICH and infantile hemangioma are often identical and it has been proposed that distinction between both is mainly based in the presence of bands of fibrosis around tumor lobules and lack of GLUT-1 positivity in the former. In practice, however, and especially in small biopsies, distinction may be very difficult or impossible. Clinicopathological correlation is paramount. Distinction between infantile hemangioma and NICH is easier, as the latter tends to display more variability in the size of vascular channels, GLUT-1 staining is usually negative and arteriovenous fistulae are identified. The main problem with NICH, RICH and infantile hemangioma is that there is some degree of overlap between the three entities as demonstrated by the fact that infantile hemangioma may coexist with either RICH or NICH. The problem is further compounded by the fact that some cases of RICH fail to involute completely and behave more like NICH, and in such cases the histological appearances overlap with those of RICH and NICH. At present, the pathogenetic relation between these groups of lesions remains obscure.

Congenital hemangiomas The term congenital hemangioma is used to describe a group of hemangiomas that develop in-utero and are fully developed at birth.1–5 These lesions were classified in the past as infantile hemangiomas, vascular malformations and cavernous hemangiomas. There is overlap with the latter entities and the ­concept of congenital hemangiomas is still evolving. Congenital hemangiomas have been divided into rapidly involuting ­congenital hemangioma (RICH) and noninvoluting congenital hemangioma (NICH).2,3 Although they seem to represent distinctive ­clinicopathologic ­entities, there is some degree of overlap not only between RICH and NICH but also between RICH and infantile hemangioma and they may be part of the same spectrum. This means that accurate diagnosis usually relies on close ­clinicopathological correlation. It is likely that these lesions are ­pathogenetically interconnected.

Capillary hemangioma and its variants

Rapidly involuting congenital hemangioma (RICH)

Infantile hemangioma

Clinical features

Clinical features

Rapidly involuting congenital hemangioma develops fully before birth, tends to regress during the first year of life, affects males and females equally and has a wide anatomical distribution with some predilection for the head and limbs.2

Infantile hemangioma (juvenile hemangioma, strawberry nevus) is a relatively common benign vascular tumor.1–4 It occurs most often as a congenital lesion (overlapping with the so-called congenital hemangioma, see above) affecting as many as 1/100 births) or infantile lesion arising at any cutaneous region, although the head and neck are by far the most commonly involved (Figs 35.471, 35.472). Females are affected more often than males. The flat red or purple lesions, frequently less than 5 cm in diameter, gradually enlarge and develop a raised surface. Usually they are discrete but (less often) can be large, diffuse and disfiguring. Over a period of months or years, the vast majority involute spontaneously.

Histological features Rapidly involuting congenital hemangioma is characterized by involvement of the subcutaneous tissue and dermis. The epidermis and adnexal structures can be atrophic.The architecture is lobular, and between tumor lobules there are often bands of fibrosis with focal inflammation, dystrophic calcification and hemosiderin deposition. Lobules are composed of variably congested, sometimes slightly dilated, capillaries, each of which is surrounded by a layer of pericytes. Larger vascular channels may be found in the fibrotic areas. Individual lobules may show variable fibrosis. Extramedullary hematopoiesis is rare and perineural extension is absent. GLUT-1 staining is usually negative or very focally positive in tumor lobules.

Histological features Capillary hemangiomas have a fairly uniform microscopic appearance characterized by an intradermal or subcutaneous multilobular proliferation of numerous small vascular spaces lined by plump endothelial cells, which may

Noninvoluting congenital hemangioma (NICH) Clinical features Noninvoluting congenital hemangioma is fully developed at birth but does not regress; rather it tends to progress over time. Males and females are equally affected. Anatomical distribution is wide, but there is predilection for the head and limbs.3

Histological features Noninvoluting congenital hemangioma is characterized by vascular ­lobules of variable size and often composed of capillaries and larger, sometimes thicker, blood vessels. Draining larger blood vessels are present in tumor ­lobules. Surrounding the latter, there are areas of fibrosis containing large blood ­vessels with features of veins and arteries. Arteriovenous fistulae are common and this closely mimics an arteriovenous malformation. Histological distinction can be very difficult and close clinicopathological correlation is often necessary. As opposed to vascular malformations, NICH does not tend to recur. GLUT-1 staining is usually negative.

Fig. 35.471 Infantile hemangioma: multiple raised erythematous nodules are present around this child's ear and neck. By courtesy of J. Dayrit, MD, Manila, The Philippines.

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Fig. 35.472 Infantile hemangioendothelioma: two raised nodules are present on the forehead of this female infant. By courtesy of M.M. Black, MD., The Institute of Dermatology, London, UK.

Fig. 35.474 Infantile hemangioendothelioma: the blood vessels are lined by plump endothelial cells. Note the multiple mitoses.

this marker is a valuable aid in differential diagnosis, particularly in the setting of vascular malformations.11 Endothelial cells in proliferating lesions coexpress LYVE-1 and CD34 and are negative for Prox-1, while LYVE-1 is negative in involuting lesions, suggesting that endothelial cells in proliferating infantile hemangiomas are arrested early in the developmental stage of vascular differentiation.12

Differential diagnosis The differential diagnosis with congenital hemangiomas is discussed under the latter.

Infantile hemangiomas with minimal or arrested growth (abortive hemangiomas) Clinical features

Fig. 35.473 Infantile hemangioendothelioma: this is an evolving lesion composed of lobulated aggregates of poorly canalized blood vessels.

be mitotically active (Figs 35.473, 35.474). In the early stages, vascular lumina tend to be inconspicuous and the vascular nature of the tumor might not be immediately apparent. However, a reticulin stain highlights the presence of numerous poorly canalized vascular channels. With maturation, the vessels enlarge and dilate and the endothelium appears more flattened and mature. At the deep margin of the lesion a large feeding arteriole is often apparent. An occasional entirely benign feature is the presence of perineural invasion.5,6 Older lesions become progressively more fibrotic, showing a gradual disappearance of the vascular elements, and histological diagnosis of largely regressed examples can be difficult. By immunohistochemistry and electron microscopy it has been demonstrated that the tumor cell population is heterogeneous and composed not only of endothelial cells but also of fibroblasts and pericytes.7,8 This favors a hamartomatous process rather than a true neoplasm. It has a unique immunophenotype shared with placental microvessels expressing GLUT-1 and LeY. GLUT-1, the erythrocyte-type glucose transporter protein, is expressed by these hemangiomas at all stages of their evolution.9,10 Since GLUT-1 is not expressed in other vascular tumors which occur in children, the presence of

These recently described lesions are characterized by telangiectatic patches with peripheral papules and predilection for the lower body.1–3 They are defined as vascular lesions with a proliferative component equal to or less than 25% of the total surface of the lesion.1 Slightly less than 50% of patients have typical infantile hemangiomas elsewhere.1 Lesions tend to persist.

Histological features A biopsy from the telangiectatic patch shows scattered dilated vascular channels in the superficial dermis. In the deep dermis, lobules of capillaries may be seen. A biopsy from a papule shows features of a capillary hemangioma. Endothelial cells are positive for GLUT-1. This feature, and the coexistence with typical infantile hemangiomas, confirms that they are closely related.

Tufted angioma Clinical features Tufted angioma (angioblastoma of Nakagawa) is a distinctive variant of capillary hemangioma which was described in the Japanese literature in 1949 as angioblastoma.1–4 It presents most commonly in infants or children, showing an equal sex incidence and a predilection for the neck, upper trunk and limbs (Fig. 35.475).1–8 Lesions tend to be acquired mainly during the first year of life, but congenital tumors occur in about 25% of patients.8,9 Isolated cases occur in adults.10,11 Familial tumors are exceptional.12 Unusual locations of the tumor include the oral cavity, the perianal area and the palm.13–15 The lesion grows slowly over a period of years as an erythematous macule or

Capillary hemangioma and its variants

Fig. 35.475 Tufted angioblastoma: lesions commonly present on the neck and upper trunk. Note the presence of extensive macules and plaque-like lesions. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.477 Tufted angioma: the nodules are composed of tightly knit capillaries. Note the conspicuous lymphatic vessel.

plaque, or as a cluster of papules attaining a size of up to 10 cm or more. An annular configuration can also be seen and multifocal lesions are rare.16–18 In some cases hyperhidrosis and hypertrichosis are seen.8 Kasabach-Merritt syndrome is an important complication in a very small number of cases and more rarely low-grade coagulopathy is seen.8,19–21 An exceptional case associated with a complex vascular malformation and one occurring at the site of herpes zoster have been documented.22,23 Surgical excision is difficult due to the size and extension of the tumor beyond the evident clinical margins. Spontaneous regression does occur and seems more common than previously thought.24–27 Regression may even be seen in congenital tumors.28

Histological features At low power, the distinctive feature is the presence in the dermis and superficial subcutis of scattered, rounded, oval or elongated lobules of closely packed capillaries in a typical ‘cannonball’ distribution (Fig. 35.476). Each lobule is composed of poorly canalized capillaries lined by bland endothelial cells and surrounded by pericytes, and closely resembling the early stages of a strawberry nevus. A distinctive feature is the presence in the periphery of the lobules of dilated crescent-shaped or semilunar lymphatic channels (Fig. 35.477). Focal crystalline inclusions in the endothelial cell cytoplasm

Fig. 35.478 Tufted angioma: note the eosinophilic inclusions.

can be seen in some cases (Fig. 35.478).29 Unusual histological features include an intravenous location and proliferation of sweat glands.30,31 Areas of tufted hemangioma may occur in kaposiform hemangioendothelioma and it has been suggested that both tumors are part of the same spectrum.32,33

Differential diagnosis Strawberry nevus has a more diffuse, confluent and extensive involvement of the dermis and subcutis, and lacks the dilated crescent-shaped lymphatic channels at the periphery of the lobules. Distinction from nodular Kaposi's sarcoma is easy because the latter lacks the ‘cannonball’ pattern and is composed of a uniform population of spindle-shaped cells and pseudovascular clefts. Furthermore, cutaneous involvement by Kaposi's sarcoma in immunocompetent children is exceedingly rare.

Verrucous hemangioma Clinical features Fig. 35.476 Tufted angioma: this is a typical low-power appearance of sharply circumscribed vascular nodules in the reticular dermis.

Verrucous hemangioma typically presents as a warty dark-blue nodule mainly on the extremities, especially the lower limbs, of children.1–4 Linear lesions are very rare.5,6 A similar cutaneous lesion on the midline of the back associated with a spinal cord vascular malformation is known as Cobb's syndrome.7

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Pathogenesis and histological features It is likely that verrucous hemangioma represents a form of lymphovascular malformation and the name hemangioma is therefore a misnomer.8,9 Histologically, there are numerous dilated and congested capillaries and occasional cavernous vascular spaces involving mainly the papillary dermis, with extension into the deep dermis and subcutis. The overlying epidermis shows marked acanthosis, hyperkeratosis and papillomatosis. As the depth of the involvement is frequently overlooked, recurrences are common.

Differential diagnosis Resemblance to angiokeratoma can be striking, but angiokeratoma lacks a deep component.

Cherry angioma Clinical features Cherry angiomas (senile angiomas, Campbell de Morgan spots) are very common and present as multiple tiny red papules on the trunk and upper limbs of the middle aged and elderly.1

Fig. 35.480 Lobular capillary hemangioma: a typical raised red nodule on the face of a young female patient. By courtesy of M.M. Black, MD, St Thomas' Hospital, London, UK.

Pathogenesis and histological features The pathogenesis is unknown. A case of eruptive lesions associated with topical nitrogen mustard therapy, another associated with exposure to bromides, a familial nevus flammeus with early-onset cherry angiomas and a case associated with familial cerebral cavernous malformations have been documented.2–5 Histology shows a small polypoid lesion with an epidermal collarette and multiple lobules of dilated and congested capillaries in the papillary dermis (Fig. 35.479). In a single case, lesions of cherry angioma were colonized by intravascular large B-cell lymphoma.6

Lobular capillary hemangioma (pyogenic granuloma) is a very common benign vascular lesion that was regarded for many years as a reactive or infective process.1 This assumption was based on the extensive secondary changes that are almost invariably present in these lesions. However, the underlying process is that of a lobular proliferation of capillaries, which is much more likely to be neoplastic, and therefore it has been redesignated lobular capillary hemangioma.2 It may arise at any age in either sex and shows a

predilection for the head and neck (especially the mucous membranes) and limbs (particularly the arms and hands) (Fig. 35.480). Oral lesions are more common in females.3,4 Pyogenic granuloma also occurs in the gastrointestinal tract and other organs. Typically, the lesion evolves rapidly, reaching its maximum size (usually less than 2 cm in diameter) within a matter of months. It presents as a pedunculated red or bluish nodule, which is prone to ulceration or bleeding (Fig. 35.481).5 Complete spontaneous regression does not occur and rare patients present with multiple lesions, either disseminated or localized.6–10 Eruptive lesions have been described following a drug hypersensitivity reaction, a landmine injury, burns and associated with an acquired arteriovenous malformation.11–13 Congenital lesions are exceptional and one case presented with disseminated lesions.14–17 Lobular capillary hemangioma may occur within a port-wine stain and more rarely in association with unilateral dermatomal superficial telangiectasia.18–21 Multiple pyogenic granulomalike lesions have been documented in association with capecitabine, topical tretinoin, isotretinoin, gefitinib, 5-fluorouracil and in one case an association

Fig. 35.479

Fig. 35.481

Cherry angioma: there are widely dilated, congested vessels in the superficial dermis.

Lobular capillary hemangioma: these lesions are characteristically ulcerated. By courtesy of the Institute of Dermatology, London, UK.

Lobular capillary hemangioma Clinical features

Capillary hemangioma and its variants with erythropoietin was suggested.22–29 Subungual lesions may occur not only in association with drugs and trauma but also after peripheral nerve injury.30 Lobular capillary hemangiomas have also been documented as a complication of pulse dye laser used to treat port-wine stains and following orbital hydroxyapatite implants.31,32 Local recurrence after excision is relatively frequent and in a small proportion of cases there is a recurrence with multiple satellite lesions that may be clinically worrying (Fig. 35.482).33,34 This latter phenomenon tends to occur in younger individuals who very often have primary lesions on the trunk. • Granuloma gravidarum is a variant that presents on the gingivae of pregnant women and involutes after delivery. Pregnancy may also induce lesions elsewhere.35,36 • Subcutaneous or deep dermal pyogenic granuloma has a predilection for the upper limb.37,38 Since it never becomes ulcerated, it is not associated with secondary inflammatory changes. • Intravenous pyogenic granuloma is uncommon, but tends to occur on the neck and upper extremity of young adults.39–41

Histological features Pyogenic granuloma consists of a usually exophytic, lobulated, dermal mass made up of numerous small capillaries, often radiating from larger, more central vessels set in a loose edematous collagenous matrix (Figs 35.483, 35.484). Endothelial cells have variably bland to plump nuclei and may be focally epithelioid, especially in mucosal tumors.42 Mitoses are commonly present and may be numerous (Fig. 35.485). Focal cytological atypia as a result of degeneration may be seen (Figs 35.486, 35.487). Metaplastic ossification is sometimes seen and extramedullary hematopoiesis has exceptionally been documented.43,44 Superficial infiltration by acute and chronic inflammatory cells in large numbers is a common finding, but this is seen only in ulcerated lesions. In such instances, the adjacent epidermis is often acanthotic and tends to form a well-defined collarette. When inflammation is marked, the overall features show a close resemblance to granulation tissue, except for the presence of capillary lobules in the deeper dermis at the base of the lesion. Those cases developing satellite lesions often show extension into the subcutaneous fat. Intravenous pyogenic granuloma is histologically similar to the more conventional lesion except that it lacks a significant inflammatory component (Figs 35.488, 35.489).

Fig. 35.483 Lobular capillary hemangioma: this scanning section shows the polypoid structure of the lesion and the well-formed collarette.

Fig. 35.484 Lobular capillary hemangioma: note the well-developed lobular architecture.

Fig. 35.482 Lobular capillary hemangioma (satellitosis): characteristic appearance of multiple satellite lesions on the trunk. By courtesy of E. Wilson Jones, MD, Institute of Dermatology, London, UK.

Fig. 35.485 Lobular capillary hemangioma: conspicuous mitotic activity is often present, particularly in evolving lesions.

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Fig. 35.486 Lobular capillary hemangioma with atypia: scanning view showing multiple lobules with an associated fibrous stroma.

Fig. 35.489 Intravascular lobular capillary hemangioma: higher-power view showing the vascular lobules.

Differential diagnosis The most important differential diagnosis is bacillary angiomatosis, an infectious vascular proliferation caused by a rickettsial organism Rochalimaea henselae.45–47 The latter occurs mainly in patients with AIDS and rarely in other immunosuppressed hosts or exceptionally in normal individuals. Although both lesions are architecturally very similar, bacillary angiomatosis is composed of pale eosinophilic endothelial cells and shows polymorphs throughout the lesion, accentuated in the vicinity of basophilic granular aggregates. The latter, when stained with Giemsa or Warthin-Starry, show clumps of short bacilli. Pyogenic granuloma may sometimes need to be distinguished clinically from other types of capillary hemangioma. Mucosal lesions with very plump endothelial cells and a high mitotic rate may be readily distinguished from angiosarcoma by their lobular architecture.

Cavernous hemangioma Fig. 35.487 Lobular capillary hemangioma with atypia: there is nuclear pleomorphism and an atypical mitosis is present.

Clinical features The age, sex and anatomical distribution of cavernous hemangioma are much the same as for capillary hemangioma.1–3 However, cavernous hemangioma differs principally in its tendency to be larger and more diffuse, showing little, if any, propensity to involute (Fig. 35.490). These lesions are very likely to be part of the spectrum of lesions described under the rubric noninvoluting congenital hemangioma (RICH, see above). Some of them are also likely to represent vascular malformations. The overlying skin tends towards a rather more bluish-red coloration, reflecting the increased blood content of these lesions. Cavernous hemangioma may rarely be associated clinically with multiple enchondromas (Maffucci's syndrome), hemangiomas in the alimentary tract (blue rubber bleb nevus syndrome) or with a consumption coagulopathy due to sequestration of platelets within the lesion (Kasabach-Merritt syndrome).4–7 Sinusoidal hemangioma is a relatively uncommon variant of cavernous hemangioma.8 It presents as a bluish, solitary deep dermal or subcutaneous nodule on the trunk (particularly in the subcutaneous tissue of the breast) or limbs of middle-aged adults, showing a predilection for females. Rare cases in males are associated with gynecomastia. There is no tendency to local recurrence.

Histological features Fig. 35.488 Intravascular lobular capillary hemangioma: this is a rare lesion. Note the thin vessel wall and prominent lobularity.

In contrast to capillary hemangiomas, cavernous lesions are composed of a nonlobular, poorly demarcated proliferation of numerous dilated vessels with flattened endothelium (Figs 35.491, 35.492). Vessel wall thickness is variable. Moderate stromal chronic inflammation is often a feature.

Capillary hemangioma and its variants

Fig. 35.490 Cavernous hemangioma: this massive lesion is distorting the nose and cheek of this female infant. Cavernous hemangiomas often involve the deeper tissues, with resultant pressure necrosis. By courtesy of M.M. Black, MD, St Thomas' Hospital, London, UK.

Fig. 35.492 Cavernous hemangioma: higher-power view.

Fig. 35.493 Sinusoidal hemangioma: the back-to-back appearance is characteristic. By courtesy of C.D.M. Fletcher, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Fig. 35.491 Cavernous hemangioma: the vessels are dilated and rather thin walled.

The sinusoidal hemangioma is usually lobular and focally ill defined. It is composed of gaping, markedly dilated, intercommunicating, back-to-back, congested vascular channels with very thin walls, giving rise to a typical sieve-like or sinusoidal pattern (Figs 35.493, 35.494). Cross-sectioning artifact may produce a pseudopapillary appearance reminiscent of Masson's tumor. Focal thrombosis, areas of infarction, hyalinization and even calcification or ossification can be present, especially in long-standing lesions. Endothelial cells are monolayered and flat, but occasionally mild pleomorphism is a feature. Each vessel is surrounded by an attenuated layer of ­actin-positive pericytes.

Differential diagnosis The diagnosis of sinusoidal hemangioma is usually straightforward, but breast lesions can sometimes be confused with angiosarcoma. The latter, however, is intraparenchymal rather than subcutaneous and shows an infiltrative growth pattern with at least focal endothelial atypia, multilayering and mitoses.

Fig. 35.494 Sinusoidal hemangioma: the presence in some cases of mild nuclear atypia combined with the thin-walled architecture may cause confusion with angiosarcoma. By courtesy of C.D.M. Fletcher, MD, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

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Arteriovenous hemangioma Clinical features Arteriovenous hemangiomas (cirsoid aneurysms) present as small (less than 1 cm in diameter) reddish-blue papules, most often on the head and neck (especially the lip) or extremities.1–4 Adults in their fifth and sixth decades are most frequently affected and there is an equal sex incidence. The papules are prone to intermittent bleeding and may sometimes be tender. Local recurrence is not a feature. Histologically comparable lesions in deep soft tissues tend to affect younger patients, may sometimes be associated with hemodynamic complications, and occasionally recur. There is an association with chronic liver disease.5 A distinctive variant occurring in the digits has been documented.6

Histological features Arteriovenous hemangiomas are composed of a well-circumscribed intradermal, submucosal or subcutaneous mass of numerous, fairly thick-walled vessels lined with plump endothelium (Figs 35.495, 35.496). The vessels characteristically have muscular walls with variable elastic laminae and, in some cases, arteriovenous anastomoses are apparent. Luminal microthrombi are not uncommon and dystrophic calcification is occasionally seen. Frequently, it is difficult to identify the arterial component despite serial sectioning. These latter lesions are probably pure venous hemangiomas.

Fig. 35.496 Arteriovenous hemangioma: higherpower view showing admixture of arteries and veins.

Microvenular hemangioma Clinical features Microvenular hemangioma is an asymptomatic lesion that commonly presents on the limbs of young adults as a red–bluish papule.1,2 Multiple, sometimes numerous, lesions have been documented in a few patients.3,4 Presentation in children is rare.5,6 A case positive for human herpesvirus-8 has been documented in the context of POEMS syndrome.7 Recurrence is exceptional.

Histological features Histologically, it consists of irregular, branching, thin-walled venules lined by bland endothelial cells containing plump nuclei (Fig. 35.497). The tumor extends widely throughout the dermis, dissecting between ­somewhat

Fig. 35.497 Microvenular hemangioma: the manner in which the vessels irregularly infiltrate the dermis is sometimes mistaken for Kaposi's sarcoma.

hyalinized collagen bundles (Fig. 35.498). Infiltration of arrector pili ­muscles by vascular channels is a frequent finding. The endothelial cells are positive for CD31, CD34 and von Willebrand factor but are negative for podoplanin.8

Hobnail hemangioma Clinical features Fig. 35.495 Arteriovenous hemangioma: within the dermis is a collection of thick-walled blood vessels comprising both arteries and veins.

Hobnail hemangioma (targetoid hemosiderotic hemangioma) usually presents on the limbs (particularly the thigh) and trunk of young or middle-aged adults and shows a male predilection.1–4 Occasional tumors occur in the oral cavity including the tongue and gingivae.5,6 The lesion is asymptomatic, usually less than 2 cm in diameter and increases in size very slowly. Patients sometimes describe cyclic changes.7 In women, lesions often become larger and darker prior to menstruation and become lighter and smaller after the menstrual period.8–11 In pregnancy, they increase in size probably due to estrogen, and

Capillary hemangioma and its variants

Fig. 35.498 Microvenular hemangioma: the ramifying vessels are lined by a plump endothelial monolayer and an outer layer of more spindled pericytes.

Fig. 35.500 Hobnail hemangioma: thin-walled vascular channels are present in the superficial dermis. The growth pattern is wedge shaped.

Fig. 35.499 Hobnail hemangioma: this example shows the characteristic targetoid appearance. A

in one case two lesions developed at the same time as the ­secondary sexual changes.9 Multiple lesions are exceptional. The original clinical description comprised a central red papule or macule, surrounded by successive clear and ecchymotic haloes (Fig. 35.499). Most often, however, the clinical presentation is nondistinctive and the differential diagnosis includes hemangioma, nevus or fibrous histiocytoma. There appears to be little or no tendency for recurrence.

Histological features The most striking low-power feature is the presence of a wedge-shaped vascular proliferation with the base towards the epidermis. The vascular channels are irregular, thin-walled, dilated and lined by endothelial cells with bland protruding nuclei and scanty cytoplasm (hobnail cells) (Figs 35.500, 35.501). Focal papillary projections are a characteristic feature. As the lesion descends into the deep dermis, the vascular channels become less conspicuous, appear to dissect between collagen bundles, and are lined by more flattened endothelial cells. Extravasation of red blood cells and hemosiderin deposition can be prominent but this depends on the stage of the lesion. Inflammation is not usually a feature but scattered lymphocytes and plasma cells may sometimes be seen. It is likely that this tumor represents the benign end of the spectrum of a group of lesions characterized by hobnail endothelial cells, including ­papillary

B

Fig. 35.501 Hobnail hemangioma: (A) the endothelial cells are prominent and protrude into the lumen. Note the papillary processes; (B) there is abundant hemosiderin pigment.

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Connective tissue tumors intralymphatic angioendothelioma (PILA, Dabska's tumor) and retiform hemangioendothelioma.12 Trauma may induce secondary changes similar to those seen in hobnail hemangioma.13 The endothelial cells in hobnail hemangioma stain diffusely for vascular markers including CD31 and von Willebrand factor. CD34 is usually negative or only very focally positive. A layer of alpha-SMA-positive pericytes surrounds some of the vascular channels. Despite the changes associated with the menstrual cycle, endothelial cells are negative for estrogen and progesterone receptors.9 The positive staining for vascular endothelial growth factor receptor 3 (VEGFR-3) in some cases has led to the suggestion that hobnail hemangioma displays lymphatic differentiation.4,14 VEGFR-3 is, however, not entirely specific for lymphatic endothelium. Staining for HHV-8 is consistently negative.15

Differential diagnosis The differential diagnosis includes retiform hemangioendothelioma and patchstage Kaposi's sarcoma: the former is diffusely infiltrative and extends into the subcutaneous tissue; the latter lacks a wedge-shaped architecture, does not display hobnail endothelial cells lining the proliferating vascular channels and plasma cells are conspicuous. Furthermore, the endothelial cells lining the vascular channels in Kaposi's sarcoma are invariably positive for HHV-8.

A

Acquired elastotic hemangioma Clinical features Acquired elastotic hemangioma is a rare lesion arising in sun-exposed skin of the forearms and neck, with predilection for middle-aged and elderly women. It presents as a small, solitary, asymptomatic ­erythematous plaque.1,2

Histological features A band-like superficial dermal proliferation of capillaries, which are often parallel to the epidermis, is seen (Fig. 35.502). In the surrounding, dermis there is solar elastosis.

Cutaneous epithelioid angiomatous nodule Clinical features Cutaneous epithelioid angiomatous nodule is very rare and occurs as a papule or nodule in adults, with predilection for the trunk followed by the limbs and face.1–3 In one case the lesion was intranasal.4 Multiple lesions are exceptional.1,2

B

Fig. 35.502 Acquired elastotic hemangioma: (A) there is a superficial plaque-like proliferation of small blood vessels; (B) note the background solar elastosis.

Histological features Histology shows a single small nodule composed of plump, pink, epithelioid cells with intracytoplasmic lumina and very focal formation of vascular channels (Figs 35.503, 35.504). In the background there may be mild fibrosis, hemosiderin deposition and scattered inflammatory cells. Mitotic figures are usually not numerous but can be prominent in some cases. A single case examined showed no evidence of microsatellite instability.5

Differential diagnosis Distinction from epithelioid hemangioma is based on the different clinical presentation and the presence of a single lobule of epithelioid endothelial cells with very focal formation of vascular spaces other than intracytoplasmic lumina and a usually mild inflammatory cell infiltrate in cutaneous epithelioid angiomatous nodule. However, it seems likely that both lesions are related.1–3,6 Epithelioid angiosarcoma is not usually circumscribed or superficial, and cytological atypia is always seen.

Epithelioid hemangioma Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) is the preferred term for a group of benign vascular tumors characterized by the presence of endothelial cells with abundant eosinophilic, sometimes vacuolated, cytoplasm that resemble epithelial cells.1–4 An alternative name, histiocytoid hemangioma, although accurate, has been abandoned because it originally included a clinically broader group of tumors.5,6 Other names used

Fig. 35.503 Epithelioid angiomatous nodule: the lesion presented as a solitary nodule. It is superficially located and well circumscribed.

Capillary hemangioma and its variants

Fig. 35.504

A

Epithelioid angiomatous nodule: (A) there is a diffuse proliferation of epithelioid endothelial cells. Vascular channels may be focal or absent; (B) the epithelioid endothelial cells have abundant eosinophilic cytoplasm and vesicular nuclei. Note the intracytoplasmic lumina, some of which contain erythrocytes.

B

Fig. 35.505 Epithelioid hemangioma: the ear is commonly involved. There are multiple confluent lesions. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

a giant skin lesion.20,21 Intravascular origin is a frequent microscopic finding but the tumor may originate from larger blood vessels including arteries.22,23 A single case involving a nerve has been documented.24 Tumors can present at other sites including the deep soft tissues, bone, lymph node, oral mucosa, tongue, breast, testis, ovary and colon.2,25–35 An exceptional case presented as a giant axillary artery aneurysm.36 Blood eosinophilia is present in up to 10–15% of cases. An association with pregnancy is probably coincidental.37 Simple excision is often followed by recurrence, but metastasis does not occur. Spontaneous regression is exceptional.38,39 Transient angiolymphoid hyperplasia and Kaposi's sarcoma have been documented after primary infection with HHV-8 in a patient with HIV infection.40 However, HHV-8 is not found in lesions of isolated epithelioid hemangioma.41 Lesions with features similar to those seen in epithelioid hemangioma have been documented in association with arteriovenous malformations.42,43

Histological features to describe this entity include atypical pyogenic granuloma, pseudopyogenic granuloma, inflammatory angiomatous nodule, papular angioplasia and intravenous atypical vascular proliferation.7–9 The previously described overlap with Kimura's disease was erroneous, since the latter is a morphologically quite separate immunologically mediated disorder.10,11 There is no absolute consensus about whether epithelioid hemangioma is neoplastic or is a reactive process associated with trauma.12,13 In some cases, there is a history of previous trauma including a burn.14 It represents the benign end of the spectrum of a family of vascular tumors which includes epithelioid hemangioendothelioma and epithelioid angiosarcoma.

Clinical features Epithelioid hemangioma typically arises in the third and fourth decades, shows a slight predilection for males (although purely cutaneous lesions are more common in females) and occurs most often as painless, dull red, single or multiple nodules in the head and neck region (Fig. 35.505).1–4 Presentation elsewhere in the skin is rare but distribution is wide and includes the upper extremities including the palm, nail bed, the penis and the scrotum.15–19 Lesions tend to be sessile or plaque-like and are prone to secondary ulceration and/or bleeding. Rare lesions present as a large soft tissue tumor or as

Tumors are predominantly intradermal although occasionally subcutaneous variants are encountered. They present as an ill-defined, lobulated mass composed of numerous vascular spaces (Fig. 35.506). The latter, of varying luminal diameter, are lined by large rounded endothelial cells with copious, rather eosinophilic cytoplasm and oval vesicular nuclei (Fig. 35.507). Some show cytoplasmic vacuoles, representing primitive lumina (Fig. 35.508). Solid cords of cells may also be present. Although the endothelial cells are prominent, they do not show pleomorphism or mitotic activity. A significant proportion of cases are partially or totally intravascular, most often arising within a vein. Surrounding these small vessels is a variably prominent inflammatory cell infiltrate composed largely of lymphocytes, numerous eosinophils and histiocytes (Fig. 35.509). Increased lymphatic channels have been highlighted by immunohistochemistry for podoplanin.44 Lymphoid follicles may be present in some cases (Fig. 35.510). Long-standing lesions show stromal sclerosis. Unusual findings include multinucleated giant cells, a granulomatous ­reaction and follicular mucinosis.45–47 Immunohistochemically, the tumor cells are variably positive for endothelial markers but, in contrast to epithelioid hemangiomas in other ­locations such as bone, cutaneous lesions are cytokeratin negative.23 HHV-8 is negative.48 A T-cell clone has been rarely reported.18,49 The significance of this finding is uncertain.

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Connective tissue tumors

Fig. 35.506

Fig. 35.509

Epithelioid hemangioma: scanning view of a vascular nodule with lymphoid aggregates at the periphery.

Epithelioid hemangioma: eosinophils are conspicuous.

Fig. 35.507

Fig. 35.510

Epithelioid hemangioma: the vessels are lined by large endothelial cells with markedly histiocytoid appearances.

Epithelioid hemangioma: lymphoid follicles are sometimes present

Differential diagnosis

Fig. 35.508 Epithelioid hemangioma: endothelial cell intracytoplasmic lumina are a characteristic feature.

Kimura's disease, with which epithelioid hemangioma is frequently confused, tends to occur more commonly in Orientals in their first and second decades. It also presents on the trunk or limbs and the lesions are frequently tender (Figs 35.511, 35.512).10,11,50 The majority of cases show a histologically distinctive lymphadenopathy, a circulating eosinophilia and raised IgE levels; some patients have associated renal disease and juvenile temporal arteritis.51 Only one patient with epithelioid hemangioma has had associated nephrotic syndrome.52 Histologically, Kimura's disease has a prominent inflammatory cell infiltrate with numerous lymphoid follicles, eosinophil microabscesses, infiltration of germinal centers by eosinophils, proliferation of high endothelial venules (not lined by epithelioid endothelial cells) and large areas of stromal sclerosis (Figs 35.513–35.516). Rare cases of epithelioid hemangioma and Kimura's disease presenting in the same patient have been reported.53 Cutaneous involvement by lymphoma lacks the distinctive vascular ­proliferation, while a persistent insect-bite reaction shows a greater number of small capillaries lined by normal flattened endothelium. In injection-site granuloma, epithelioid endothelial cells are not a feature and histiocytes with bluish granular cytoplasmic material representing aluminum are found.54,55 In bacillary angiomatosis, the epithelioid cells are pale and there are abundant neutrophils with nuclear dust and basophilic clumps of bacteria.

Fig. 35.512

Fig. 35.511

Kimura's disease: there is soft tissue and nodal involvement. By courtesy of the Institute of Dermatology, London, UK.

Kimura's disease: this patient presented with striking swelling of the neck. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.513

Fig. 35.514

Kimura's disease: low-power view showing an intense cellular infiltrate.

Kimura's disease: the infiltrate consists of lymphocytes and numerous eosinophils.

Fig. 35.515

Fig. 35.516

Kimura's disease: there is a background proliferation of high capillary venules.

Kimura's disease: the endothelial cells are prominent but do not contain intracytoplasmic lumina.

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Connective tissue tumors

Spindle cell hemangioma (hemangioendothelioma) Clinical features Spindle cell hemangioendothelioma was first described as a variant of lowgrade angiosarcoma in 1986.1,2 This proposal was based on the fact that one of the patients in the series developed a metastasis. However, it is almost certain that this metastasis originated from a radiation-induced sarcoma and not from the original lesion. More recent evidence strongly supports the notion that this condition is probably a vascular malformation or a benign process superimposed upon a malformation (spindle cell hemangioma).3–6 It most commonly affects the dermis or subcutis of the distal extremities and presents as single or (in 50% of cases) multiple red–blue nodules, which are quite often painful (Fig. 35.517). Rare lesions develop in the head and neck including the oral cavity.7,8 When multiple, lesions develop slowly over years and the clinical course is indolent. Most patients are in their first three decades and there is an equal sex incidence. Some cases are associated with early-onset varicose veins, congenital lymphedema, Klippel-Trenaunay ­syndrome or Maffucci's syndrome.9

Fig. 35.518 Spindle cell hemangioma: low-power view showing conspicuous dilated vascular channels

Histological features Lesions are poorly circumscribed and consist of thin-walled, congested cavernous vascular spaces intermixed with varying proportions of bland spindled to epithelioid cells with vesicular nuclei (Figs 35.518–35.521). Intracytoplasmic lumina are often present and are a helpful diagnostic feature (Fig. 35.522). The vascular spaces are lined by a single layer of bland endothelial cells, which can rarely show degenerative nuclear pleomorphism. Thrombosis and papillary projections resembling those seen in Masson's tumor are common features. Bundles of smooth muscle are quite often present around the blood vessels and in the spindled cell areas. In the periphery of many lesions, there are thick-walled, irregular blood vessels resembling a localized arteriovenous shunt. Rare cases can be associated with epithelioid hemangioendothelioma. Immunohistochemically, vascular markers label mainly the endothelium of the blood vessels and the more epithelioid cells in the stroma. Admixed with the latter are actin-positive pericytes.3 Reticulin staining in the solid areas reveals a vasoformative architecture. Fig. 35.519 Spindle cell hemangioma: there is an intravascular component.

Fig. 35.517

Fig. 35.520

Spindle cell hemangioma: multiple nodules are present at a characteristic site.

Spindle cell hemangioma: the tumor is composed of an admixture of spindle cells and, often, cavernous vascular channels.

Capillary hemangioma and its variants

Histological features Histologically, two patterns have been described:2 • The more common variant consists of a mixture of veins, capillaries and cavernous vascular spaces (Figs 35.523, 35.524). • The second variant consists almost exclusively of capillaries, often with a focal lobular pattern. In both types there is an abundant admixture of mature fat. Perineural invasion is sometimes a feature. Osseous metaplasia has been reported in one case.5

Symplastic hemangioma Symplastic hemangioma is defined as extensive degenerative changes in a pre-existing hemangioma closely mimicking malignancy.1–3 Only a handful of cases have been reported. The variant of pre-existing hemangioma is often not clearly identifiable. Fig. 35.521 Spindle cell hemangioma: the spindle cells are bland and have fairly regular oval or elongated nuclei.

Fig. 35.523 Angiomatosis: this example consists of variably sized congested cavernous vessels.

Fig. 35.522 Spindle cell hemangioma: intracytoplasmic lumina are an important diagnostic feature.

Differential diagnosis In nodular Kaposi's sarcoma there are usually no cavernous vascular spaces or vacuolated epithelioid cells, and hyaline globules are often present in the spindled cells. The latter cells in Kaposi's sarcoma are consistently CD34 positive.

Angiomatosis Clinical features Angiomatosis is a rare condition that presents in children and adolescents.1,2 A single case involving the left forearm of an adult has been documented.3 It is characterized by a diffuse proliferation of blood vessels affecting a large contiguous area of the body (usually a limb).1,2 Presentation in the head and neck is rarely seen.4 Involvement of the skin, underlying soft tissues and bone is common, and this is associated with hypertrophy of the affected limb. Lesions within parenchymal organs and the central nervous system are sometimes a feature. Due to extensive involvement, surgical treatment is often difficult.

Fig. 35.524 Angiomatosis: high-power view showing dilated vessels with admixed adipocytes.

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Connective tissue tumors

Clinical features It usually presents in the limbs of an adult, as a long-standing lesion that starts changing.

Pathogenesis and histological features The histological appearances are likely to reflect degenerative changes within a hemangioma (Figs 35.525, 35.526).Tumors are often polypoid, dermal and well circumscribed. The typical histological picture consists of dilated and congested thin to thick-walled vascular spaces surrounded by a variable cellular stroma with frequent myxoid change and hemorrhage. Stromal cells and smooth muscle cells within the vessel walls show variable cytological atypia consisting of nuclear enlargement and hyperchromatism (Fig. 35.527). Often cells have a bizarre appearance, and multinucleated cells are common. The endothelial cells lining the vascular spaces may be plump but do not display cytological atypia, multilayering or mitotic activity, allowing distinction from an angiosarcoma. Mitotic figures may be found in the stromal component but tend to be rare (Fig. 35.528). Very occasional atypical mitotic figures can be a feature.

Fig. 35.527 Symplastic hemangioma: there is marked nuclear pleomorphism and hyperchromatism.

Fig. 35.525 Symplastic hemangioma: low-power view showing dilated vessels, and a cellular stroma containing conspicuous atypical cells.

Fig. 35.528 Symplastic hemangioma: note the mitotic figures.

Vascular tumors of low-grade or borderline malignancy Retiform hemangioendothelioma Clinical features

Fig. 35.526 Symplastic hemangioma: higher-power view of dilated vessels and atypical stromal cells.

Retiform hemangioendothelioma is a variant of low-grade angiosarcoma that is closely related to (and more common than) papillary intralymphatic angioendothelioma (Dabska's tumor) (see below).1–4 It usually presents in young adults as a slowly growing, asymptomatic tumor and shows a predilection for the distal extremities, especially the lower leg. Sex incidence is equal. Very rarely, cases occur in association with radiation therapy or chronic lymphedema. A patient with multiple lesions has been documented.5 Local, often repeated, recurrences are common, but so far only two cases have metastasized to regional lymph nodes and a further case metastasized to soft tissues close to the primary tumor.1,6,7 No distant spread or tumor-related death has been reported.

Vascular tumors of low-grade or borderline malignancy

Histological features Lesions are ill defined and involve the dermis and/or subcutis. A striking ­feature is the histological resemblance of the tumor to normal rete testis. This appearance is conferred by the presence of long, arborizing, branching blood vessels, which are lined by monomorphic bland endothelial cells with prominent apical nuclei and scanty cytoplasm (Fig. 35.529). These cells protrude prominently into the vascular lumina, with a typical hobnail appearance (Figs 35.530, 35.531). A common but not invariable feature is the presence of numerous lymphocytes both within and adjacent to the vessels and in close relation to the endothelial cells (Fig. 35.532). Focally, intravascular papillae with collagenous cores are present. Most tumors show solid areas composed of spindled and rare epithelioid cells. Immunohistochemically, the cells stain for vascular markers including CD31 and CD34. Staining for lymphatic markers including D2-40 and the less specific VEGFR-3 has yielded contradictory results.8,9

Differential diagnosis Retiform hemangioendothelioma has similar clinical and histological features to papillary intralymphatic angioendothelioma (PILA) and it has been ­proposed that the former is an adult variant of the latter. However, in PILA,

Fig. 35.531

Fig. 35.529

Fig. 35.532

Retiform hemangioendothelioma: low-power view showing the conspicuous vascularity.

Retiform hemangioendothelioma: intraluminal papillae are commonly present.

Retiform hemangioendothelioma: aggregates of lymphocytes are frequently seen.

there is no retiform architecture, cavernous lymphangioma-like vascular spaces predominate and intravascular papillae with collagenous cores are prominent. Targetoid hemosiderotic hemangioma (hobnail hemangioma) is always more superficial and more localized, and hobnail endothelial cells are only focally present. Angiosarcoma usually presents in a different ­clinical setting and is characterized histologically by at least focal pleomorphism, ­mitosis, absence of hobnail endothelial cells and multilayering.

Papillary intralymphatic angioendothelioma

Fig. 35.530 Retiform hemangioendothelioma: protuberant (hobnail) endothelial cell nuclei are a characteristic feature.

Papillary intralymphatic angioendothelioma (PILA) is a very rare tumor, first described by Dabska in 1969 as malignant endolymphatic angioendothelioma (Dabska's tumor).1 Since then, only very few additional cases had been reported in the literature, and there has been no consensus regarding its specific histological features. A recent series has delineated the histological features of this tumor more accurately and the alternative name of PILA has been proposed.2 Tumors present mainly in infants and children but around 25% of patients are adults.1–3 Males and females are equally affected and tumors have predilection for the limbs. Clinical presentation is that of a slowly growing, solitary, asymptomatic nodule or plaque. Classification as a tumor with low-grade malignant potential is based on reports of local recurrence and rare regional lymph node metastasis in the original series.1 However, follow-up in 8 of the 12 cases recently reported

1727

1728

Connective tissue tumors showed no evidence of either local recurrence or distant spread.2 This ­finding raises the possibility that this tumor is benign but confirmation of these ­findings is required in larger series with longer follow-up. Until this happens, complete excision of these tumors is advised.

Pathogenesis and histological features Based on the close interaction between lymphocytes and endothelial cells in Dabska's tumor, it has been proposed that the hobnail endothelial cells differentiate towards high endothelial cells, which are normally responsible for the selective homing of lymphocytes in lymphoid organs.4 A similar theory can be proposed for retiform hemangioendothelioma, which shares some of the histological features of PILA. The strong expression of VEGFR-3 by tumor cells has led to suggestions that these tumors display lymphatic differentiation.2 The specificity of this marker as an indicator of lymphatic ­differentiation is, however, doubtful. Histology shows a dermal and often subcutaneous tumor composed of markedly dilated, thin-walled vascular channels resembling a cavernous lymphangioma. These vascular channels are lined by bland hobnail endothelial cells with protruding nuclei and very scanty cytoplasm. A prominent intra- and extravascular lymphocytic inflammatory cell infiltrate is often present, and intravascular papillae with collagenous cores are a frequent finding (Figs 35.533–35.535). Commonly, the lymphocytes appear to be in close apposition to the endothelial cells. Tumor cells stain for vascular markers including CD31, CD34 and von Willebrand factor.

Fig. 35.534 Papillary intralymphatic angioendothelioma (Dabska's tumor): high-power view showing hobnail endothelial cells.

Differential diagnosis The differential diagnosis is the same as that for retiform hemangioendo­ thelioma.

Kaposiform hemangioendothelioma Clinical features Kaposiform hemangioendothelioma is a relatively rare vascular tumor that was originally described as occurring most often in the retroperitoneum or deep soft tissues of infants.1–4 Tumors exceptionally occur in the choledocus, kidney, maxillary sinus, ethmoid sinus, mediastinum, larynx, internal auditory canal, oropharynx and thymus.5–14 Lesions involving the skin and superficial soft tissues also occur and adults may also be affected.4,15,16 A case associated with trauma has been documented.17 Cutaneous and soft tissue tumors have predilection for the limbs and head and neck. Multifocal lesions are exceptional.18,19 Kaposiform hemangioendothelioma is characterized by locally aggressive and destructive growth. In one case, concurrent skin and

Fig. 35.535 Papillary intralymphatic angioendothelioma (Dabska's tumor): hobnail endothelial cells and intraluminal papillae.

concomitant pleural involvement was reported and a tumor led to fetal death due to nonimmune fetal hydrops.20,21 An association with Kasabach-Merritt syndrome is seen in more than 50% of cases and this is an important cause of mortality.1,3,16 Regional perinodal involvement is uncommonly seen but metastatic disease has not been reported.16 Rarely, there is association with lymphangiomatosis.3,22,23 It has been suggested that there is a close relationship between kaposiform hemangioendothelioma and tufted angioma.24–26 This is based on clinical and histologic overlap and the fact that both proliferations may induce Kasabach-Merritt syndrome. This is also substantiated by both tumors sharing an identical immunophenotype with expression of PROX-1, a lymphatic endothelial nuclear transcription factor.27 Overexpression of the latter has been shown to be associated with promotion of invasion in two murine models of kaposiform hemangioendothelioma.28

Histological features

Fig. 35.533 Papillary intralymphatic angioendothelioma (Dabska's tumor): tumors have dilated, thin-walled vascular spaces mimicking a cavernous lymphangioma. Note the lymphoid aggregates.

Histologically, tumors are lobular, infiltrative and composed of fascicles of bland endothelial cells, congested capillaries, slit-like vascular spaces and occasional pale epithelioid endothelial cells (Fig. 35.536). Different areas resemble either Kaposi's sarcoma or capillary hemangioma (Fig. 35.537). Focally, the capillaries may show thrombosis, especially at the periphery of tumor lobules. Areas resembling lymphangioma are often seen.6 Biopsies of lesions after Kasabach-Merritt syndrome tend to show histologic features

Vascular tumors of low-grade or borderline malignancy neoplastic process, but other studies have not confirmed this.4–6 Although occasional cases of Kaposi's sarcoma may have an aggressive behavior, at present most evidence suggests that the process is probably reactive.7 This is further supported by the discovery of DNA sequences from a distinctive new type of human herpesvirus (HHV-8, KS-associated herpesvirus) in all types of Kaposi's sarcoma.8–11 A study of multicentric advanced lesions of Kaposi's sarcoma has shown that although some tumors are clonal most advanced cases represent oligoclonal proliferations, suggesting that the process is reactive rather than neoplastic.12 Serological evidence of infection by the virus is found before patients develop the tumor.13,14 HHV-8 is also associated with multicentric Castleman's disease and primary effusion lymphoma.15

Clinical features Kaposi's sarcoma may be divided into four distinct clinical groups:16–20 • Classic (endemic) Kaposi's sarcoma most often arises in elderly males and shows a predilection for the distal extremities (Figs 35.538, 35.539).16–18

Fig. 35.536 Kaposiform hemangioendothelioma: nodular proliferation with lobular, vascular and spindle cell areas.

Fig. 35.538 Classic Kaposi's sarcoma: the distal extremities are typically involved. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 35.537 Kaposiform hemangioendothelioma: in this field, the features are reminiscent of Kaposi's sarcoma.

that resemble tufted angioma.24 In one case, prominent telangiectasia and amianthoid-like fibrosis were described.29 Endothelial cells in the tumor are positive for CD31, CD34 and FLI-1 but negative for GLUT-1 and LeY (juvenile hemangioma-associated antigens).16 Von Willebrand factor is only very focally positive. Podoplanin is positive in the bulk of tumor lobules but negative in the dilated blood vessels.30 Focal actin positivity is seen in areas with epithelioid morphology. HHV-8 has not been demonstrated.

Differential diagnosis Nodular Kaposi's sarcoma in children usually involves the lymph nodes, has a prominent inflammatory cell infiltrate, lacks a lobular growth pattern and contains eosinophilic globules.

Kaposi's sarcoma The histogenesis of Kaposi's sarcoma has been a source of debate for many years; currently, it appears most likely that it is derived from endothelial cells, particularly lymphatic endothelium.1–3 However, recent studies have demonstrated a mixed cell population. Although we include Kaposi's sarcoma in the group of low-grade malignant vascular tumors, in keeping with ­present convention, the issue about whether it is a reactive or neoplastic process remains controversial. Clonality has occasionally been found, supporting a

Fig. 35.539 Classic Kaposi's sarcoma: numerous tumor nodules are present. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

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Connective tissue tumors

Fig. 35.540 AIDS-related Kaposi's sarcoma: darkly pigmented plaques are widely distributed on this young man's chest and abdomen. From the collection of the late N.P. Smith, MD, Institute of Dermatology, London, UK.

•

•

•

Mediterranean and Jewish populations are most often affected. Familial cases are exceptional and presentation in children is very uncommon.19,20 Lesions have been reported in children born to consanguineous parents, suggesting an autosomal recessive predisposition that facilitates induction of the tumor by HHV-8.21 Internal lesions are distinctly uncommon and mucosal lesions are rare.22 Disseminated disease is very rare.23 The condition generally tends to pursue a prolonged indolent and only very rarely fatal course, but such patients have a higher incidence of lymphoreticular neoplasms, especially non-Hodgkin's lymphoma.24,25 Aggressive behavior has only exceptionally been documented.26 AIDS-related Kaposi's sarcoma commonly presents in young adults, mostly males, many of whom either are homosexual or abuse drugs (Figs 35.540, 35.541).27–29 Lesions are much less common in women and children.30 The tumor often disseminates widely and rapidly and may prove fatal. However, with the advent of highly active antiretroviral therapy, the incidence of Kaposi's sarcoma has decreased dramatically, and when lesions develop they tend to be limited. The skin (especially of the trunk and limbs) and mucosae are usually extensively involved. Lesions may occur as a result of the immune reconstitution inflammatory syndrome.31,32 The condition can also develop in association with chronic lymphedema in HIV-positive patients.33 Immunosuppression-associated Kaposi's sarcoma is rare and presents in patients receiving immunosuppressive therapy, especially after kidney transplantation.34–36 Although the course of the disease tends to be indolent, it can occasionally be aggressive. Regression of the lesions sometimes occurs after immunosuppression is stopped or reduced. Kaposi's sarcoma in this setting may be induced by local immunosuppression, for example after infiltration of steroids or the use of topical tacrolimus.37,38 Chronic use of systemic steroids, leflunomide and other immunosuppressive drugs outside the setting of transplantation can also induce lesions.39,40 A case associated with a hypothalamic adrenocorticotropic hormone-secreting adenoma has been documented.41 Interestingly, although immunosuppressive drugs such as sirolimus may induce recurrence of Kaposi's sarcoma, in several instances complete regression has been noted after the introduction of the drug.42–44 Kaposi's sarcoma has been described in a patient with idiopathic low CD4 counts.45 African Kaposi's sarcoma includes those cases arising largely in subSaharan Central Africa.17,18,46,47 In this region, Kaposi's sarcoma has long

Fig. 35.541 AIDS-related Kaposi's sarcoma: infraorbital and nasal purple plaques are present. From the collection of the late N.P. Smith, MD, Institute of Dermatology, London, UK.

been endemic and accounts for up to 10% of all cases of ‘malignant’ disease. Within this category there are two clinical subgroups: those arising predominantly on the limbs of middle-aged men and tending to be fairly indolent; those arising in young children who typically present with visceral or lymph node involvement and in whom the disease is usually fatal. In addition, there are a large number of AIDS-related cases in young African adults of either sex (see above). Clinically, the cutaneous lesions present similarly in all the subtypes. They commence as small, reddish-blue macules or flat plaques, which are often ­multiple and gradually enlarge. They may become nodular, and sometimes coalesce to form larger lesions (Fig. 35.542). Some may regress as new lesions continually form and others ulcerate and fungate. The rate of spread or enlargement is usually related to the clinical subgroup into which the patient falls. Regression may occur in a number of settings, particularly after immunosuppression is stopped or reduced. Anecdotal examples of regression have been reported with imatinib and sorafenib.48,49

Fig. 35.542 Kaposi's sarcoma: a tumor nodule is present on the upper eyelid. From the collection of the late N.P. Smith, MD, Institute of Dermatology, London, UK.

Vascular tumors of low-grade or borderline malignancy

Histological features The microscopic appearances of Kaposi's sarcoma go through three phases, apparently related to the duration of the lesion.27–29,50 There is morphological overlap between patch and plaque phases, but nodular lesions appear distinct. Lesions usually involve the dermis and may extend to the subcutaneous tissue. Purely subcutaneous tumors are rare.51 • The early patch stage is characterized by a mild increase in the number of dermal vessels showing minimal endothelial atypia and characteristically surrounded by an admixture of lymphocytes and plasma cells associated with hemosiderin deposition and red cell extravasation (Figs 35.543–35.547). These vessels are arranged mainly parallel to the epidermis, may dissect between collagen bundles and surround adnexal structures and vessels (the promontory sign). This stage of Kaposi's sarcoma is the most difficult to recognize as it bears a superficial resemblance to granulation tissue. • The plaque stage is typified by more obvious and extensive dermal vascular proliferation, the lumina of which vary considerably in caliber (Figs 35.548–35.552). Endothelial cells may appear plump, but remain single layered. Noticeable at this stage is the appearance of eosinophilic spindled cells in the dermis around these vessels. These cells have tapering, somewhat hyperchromatic nuclei. The margins of the lesion are ill defined

Fig. 35.543 Kaposi's sarcoma (patch stage): there is increased vascularity, spindled cells and a light chronic inflammatory cell infiltrate.

Fig. 35.545 Kaposi's sarcoma (patch stage): the infiltrate consists of an admixture of lymphocytes and plasma cells.

Fig. 35.546 Kaposi's sarcoma (patch stage): focal hemosiderin deposition is present.

Fig. 35.544

Fig. 35.547

Kaposi's sarcoma (patch stage): the vessels are lined by swollen, focally hyperchromatic endothelial cells.

Kaposi's sarcoma (patch stage): this field shows extensive dissection of collagen (a characteristic feature).

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Connective tissue tumors

Fig. 35.548

Fig. 35.551

Kaposi's sarcoma (plaque stage): the changes affect the full thickness of the dermis.

Kaposi's sarcoma (plaque stage): increased numbers of spindle cells are present. Dissection of collagen is marked.

Fig. 35.549

Fig. 35.552

Kaposi's sarcoma (plaque stage): there is very extensive vascular proliferation.

Kaposi's sarcoma (plaque stage): the spindle cells have pale eosinophilic cytoplasm with oval or elongated nuclei.

Fig. 35.550 Kaposi's sarcoma: newly formed vessels sometimes ensheath pre-existent ones – the promontory sign.

and primitive vascular clefts may be apparent within the spindle cell mass. Chronic inflammatory cells remain a prominent feature. • The nodular stage is manifest predominantly as a relatively wellcircumscribed dermal mass of variably eosinophilic spindle cells (Fig. 35.553). Scattered between these cells are numerous irregular, slit-like, vascular spaces, which lack an endothelial lining, but often contain extravasated red cells. In cross-section these spaces resemble a sieve (Figs 35.554–35.557). Readily identifiable ectatic vessels may, however, still be apparent at the periphery of the nodule. Normal mitotic activity is most prominent at this stage. A chronic inflammatory infiltrate including histiocytes is variably conspicuous. The spindle cells are consistently CD34 positive and also CD31 positive (Fig. 35.558). Focal positivity for actin is also seen. Rarely, nodular Kaposi's sarcoma is entirely or partially intravascular.52 The vascular spaces in Kaposi's sarcoma are positive for D2–40, suggesting a lymphatic lineage (Fig. 35.559).53,54 Also noted in all forms of Kaposi's sarcoma, but especially in the nodular variant, is the presence of amorphous eosinophilic hyaline globules lying free between spindle cells or intracellularly. These probably represent degenerate red blood cells.55 They are diastase resistant and PAS positive, and stain bright red with Masson's trichrome.

Vascular tumors of low-grade or borderline malignancy

Fig. 35.553

Fig. 35.556

Kaposi's sarcoma (nodular stage): the dermis is diffusely infiltrated by a spindle cell tumor.

Kaposi's sarcoma (nodular stage): multiple mitoses are present.

Fig. 35.554

Fig. 35.557

Kaposi's sarcoma: the spindled cells have eosinophilic cytoplasm. Hemorrhage is conspicuous.

Kaposi's sarcoma: numerous mitoses are present in this predominantly spindled cell high-grade population.

Fig. 35.555

Fig. 35.558

Kaposi's sarcoma (nodular stage): this sieve-like appearance is diagnostic.

Kaposi's sarcoma: the presence of hyaline inclusions is a useful diagnostic marker.

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Connective tissue tumors

Fig. 35.559

Fig. 35.561

Kaposi's sarcoma: the spindled cells express CD34.

Kaposi's sarcoma: HHV-8 is regularly present.

It is important to remember that in patients with HIV/AIDS more than one pathology can be found in a single biopsy. Kaposi's sarcoma has been reported in association with cryptococcosis and tuberculosis and cryptococcosis and Mycobacterium avium intracellulare in the same sample.63–65 After the discovery of HHV-8, demonstration of virus in skin biopsies from patients with Kaposi's sarcoma was done by in situ hybridization. A monoclonal antibody against the latent nuclear antigen-1 of HHV-8 is ­available for use in paraffin-embedded biopsies.66,67 This represents an invaluable tool in the histological diagnosis of Kaposi's sarcoma and its differential diagnosis as other vascular tumors are only exceptionally positive for HHV-8 (Fig. 35.561).

Differential diagnosis

Fig. 35.560 Kaposi's sarcoma: rarely, marked lymphatic dilatation gives rise to the lymphangiomatous variant.

Lymphangiomatous Kaposi's sarcoma is a variant of the patch–plaque stage in which moderately dilated vascular channels, resembling lymphatics, are prominent (Fig. 35.560).56,57 It may be mistaken for progressive lymphangioma. In HIV patients with chronic lymphedema, additional histologic features include fibrosis, pools of lymph fluid and fibroma-like nodules.33 The latter may include Kaposi's sarcoma spindle-shaped cells. Anaplastic Kaposi's sarcoma is very rare and characterized by cytologic atypia and variable mitotic activity.58 Epithelioid morphology can rarely be seen.59 Distinction from angiosarcoma is often very difficult and a helpful clue is the finding of areas typical of Kaposi's sarcoma in the same sample. Many of the cases of anaplastic disease described before the advent of immunohistochemistry are probably examples of other sarcomas. Unusual histological variants of Kaposi's sarcoma may be encountered including glomeruloid KS, pigmented KS, KS with myoid nodules, telangiectatic KS and ecchymotic KS.60 In HIV-positive patients with Kaposi's sarcoma, treatment with paclitaxel or the angiogenesis inhibitor Col-3 induces partial or complete regression of lesions.61 Histologically, in partial regression, there is reduction in spindled cells and fibrosis. In complete regression, there is fibrosis, lymphocytic inflammation and hemosiderin deposition. In patients on HAART, lesions can also change, becoming more circumscribed, less cellular and surrounded by a thick band of fibrosis.62

The differential diagnosis is wide and includes acroangiodermatitis, aneurysmal benign fibrous histiocytoma, progressive lymphangioma, tufted angioma, targetoid hemosiderotic hemangioma, spindle cell hemangioma, kaposiform hemangioendothelioma and angiosarcoma.27,68 In acroangiodermatitis, which most often affects the lower legs and complicates severe chronic venous stasis, there is proliferation of small normal ­capillaries in the superficial dermis associated with fibrosis, hemosiderin ­deposition and few inflammatory cells.69 Aneurysmal benign fibrous histiocytoma is a more polymorphic, focally storiform lesion in which foamy histiocytes and multinucleated cells are prominent. In angiosarcoma, endothelial cytological atypia is more prominent and endothelial multilayering is present.

Composite hemangioendothelioma Clinical features Composite hemangioendothelioma is a low-grade malignant vascular tumor with a tendency for local recurrence but very low metastatic potential. It is defined as a neoplasm containing a mixture of histological patterns including benign, intermediate and/or malignant.1 It is a very rare tumor, presenting mainly in adults and only exceptionally in children.1–5 Two congenital cases and a patient with associated Maffucci's syndrome have been reported.3 There is no sex predilection and most tumors occur in the extremities, with a predilection for the hands and feet. A tumor arising in the mediastinum and two in the oral cavity have been documented.6,7 In 25% of patients, tumors arise in association with lymphedema and present as long-standing red–blue nodules or plaques. The rate of local recurrence is around 50% and this may occur years after excision of the primary tumor. Only three cases have been reported to metastasize to a regional lymph nodes.1,8,9 One of these cases was associated with satellitosis.9

Vascular tumors of low-grade or borderline malignancy The prognosis is likely to depend on the component with the highest histological grade (see below) but this should be confirmed in larger series of cases with adequate follow-up.

Histological features Composite hemangioendothelioma is a poorly circumscribed dermal and subcutaneous tumor, with an infiltrative growth pattern. The different components vary from lesion to lesion and may include retiform hemangioendothelioma, epithelioid hemangioendothelioma, spindle cell hemangioma, conventional angiosarcoma (low and even high grade), lymphangioma circumscriptum and areas simulating an arteriovenous malformation (Figs 35.562–35.565).1,3 Immunohistochemistry displays positive staining for vascular markers including CD31, CD34 and von Willebrand factor.

Giant cell angioblastoma It is unclear whether this is a true vascular tumor but it is briefly described here until further reports clarify the line of differentiation. Only four cases have been reported, all presenting in the lower limbs of children. Tumors are large and present with progressive growth.1,2

Fig. 35.564 Composite hemangioendothelioma: the appearances resemble papillary intralymphatic angioendothelioma.

Fig. 35.562 Composite hemangioendothelioma: this lesion is characterized by various vascular patterns.

Fig. 35.565 Composite hemangioendothelioma: there is marked dissection of collagen suggestive of angiosarcoma.

Histology shows aggregates of histiocyte-like cells in nodules distributed around vascular channels.

Epithelioid sarcoma-like hemangioendothelioma Clinical features Epithelioid sarcoma-like hemangioendothelioma has only been reported in a small series of cases and isolated case reports.1–3 Tumors occur in adults with predilection for the limbs and tend to be deep seated. There may be local recurrence but metastatic spread has not been documented.1

Histological features Fig. 35.563 Composite hemangioendothelioma: in this field, the features are reminiscent of spindle cell hemangioma.

Tumors are infiltrative and characterized by nodules of epithelioid cells surrounded by a desmoplastic stroma. Tumor cells display atypia, mitotic activity and intracytoplasmic lumina. Formation of vascular channels is not usually seen. There is positive staining of tumor cells for keratin and vascular markers.

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Connective tissue tumors

Malignant vascular tumors Epithelioid hemangioendothelioma Clinical features Epithelioid hemangioendothelioma was originally described in 1982 as a distinctive low-grade malignancy in soft tissues.1,2 However, this tumor is now classified as fully malignant in view of its behavior with potential for metastatic spread and mortality (see below). Identical cases involving other organs (mainly lung, liver and bone) have been described in the past under different names. Most cases present in adults and only rarely in children.3–5 Tumors can arise in any organ, as up to 50% of cases develop from a blood vessel, most often a vein. Pain is often a symptom. Multicentric disease is common, especially in the lungs, liver and bones. Involvement of the skin, which is relatively rare, may be associated with an underlying bone or soft tissue lesion and is occasionally multicentric. Only a few cases of epithelioid hemangioendothelioma of the skin with wide anatomical distribution and no distinctive clinical features have been described.6–13 Although no internal organ involvement has been described in cutaneous lesions, a cutaneous tumor with lymph node metastasis in a child, one with multifocal recurrent penile tumors and two internal tumors with metastasis to the skin have been documented.14–17 Intraoral lesions are very rare.18,19 An adult patient with a hepatic tumor presented with Kasabach-Merritt syndrome and in a further patient the tumor presented after radiotherapy for a congenital hemangioma.20,21 Metastasis and mortality rates vary according to the organ involved, but it is generally believed that no more than 30% metastasize.

Fig. 35.567 Epithelioid hemangioendothelioma: the tumor cells have eosinophilic cytoplasm and large vesicular nuclei.

Pathogenesis and histological features Cytogenetic studies in a few cases of epithelioid hemangioendothelioma have shown a t(1;3)(p36.3;q25) and in a further case a t(10;14)(p13;q24) involving the placental growth factor gene was demonstrated.22,23 Microscopically, most tumors are ill defined, infiltrative and composed of rounded, polygonal or short spindle-shaped cells with pink cytoplasm and vesicular nuclei. They are arranged in short cords or nests and are surrounded by abundant myxoid or hyaline stroma (often with a somewhat chondroid appearance and rich in sulfated acid mucopolysaccharides) (Figs 35.566, 35.567). Intracytoplasmic lumina with occasional erythrocytes are often prominent and resemble primitive vascular channels (Figs 35.568–35.570). Fig. 35.568 Epithelioid hemangioendothelioma: intracytoplasmic lumina are a characteristic feature.

Fig. 35.566 Epithelioid hemangioendothelioma: this is the edge of an ulcerated lesion. Tumor is present superficially and is bordered by a heavy lymphoid infiltrate.

Fig. 35.569 Epithelioid hemangioendothelioma: careful scrutiny often reveals erythrocytes within the intracytoplasmic lumina.

Malignant vascular tumors

Fig. 35.570 Epithelioid hemangioendothelioma: the intracytoplasmic lumina may sometimes be highlighted with immunohistochemistry (CD31).

Fig. 35.572 Epithelioid hemangioendothelioma: high-power view.

Fig. 35.571

Fig. 35.573

Epithelioid hemangioendothelioma: this example is much more cellular. Intracytoplasmic lumina are still conspicuous.

Epithelioid hemangioendothelioma: note the mitotic figures.

Well-formed vessels, however, are not a feature of most cases or are infrequent. Calcification, ossification and (less commonly) osteoclast-like giant cells can be present.24,25 Rare cases show significant cytological atypia and a high mitotic rate, demonstrating a continuum with epithelioid angiosarcoma (Figs 35.571–35.573). Tumors of larger size and increased mitotic activity are associated with higher mortality. Bad prognosis is associated with tumors larger than 3 cm and more than three mitotic figures per 50 high-power fields. Necrosis, tumor site, cytological atypia and spindling of tumor cells do not seem to be affect prognosis.26 Immunohistochemically, the tumor cells label for vascular markers including CD31, CD34, podoplanin and FLI-1.27–29 CD10 is usually positive and keratin expression is seen in up to 25% of cases.30,31 Actin positivity may also be present.

Angiosarcoma

Differential diagnosis In epithelioid hemangioma, there is prominent inflammation, and well-formed blood vessels predominate. Metastatic adenocarcinoma usually shows more pleomorphism and is positive for epithelial markers including EMA and negative for vascular markers. Mucin stains are often positive in the tumor cell cytoplasm. Myxoid chondrosarcoma has a lobular architecture; the tumor cells are S-100 protein positive and lack intracytoplasmic lumina.

The term angiosarcoma is synonymous with hemangiosarcoma, malignant hemangioendothelioma, ‘hemangioblastoma’ and lymphangiosarcoma.

Clinical features Cutaneous angiosarcoma predominantly occurs in one of three clinical settings: • idiopathic angiosarcoma of the head and neck, • lymphedema-associated angiosarcoma, • postirradiation angiosarcoma.1–9 Sporadic cases in the limbs (unassociated with lymphedema) may occur at any age. Very rare cases have been reported in association with vinyl chloride exposure, xeroderma pigmentosum, epidermolysis bullosa, stasis ulceration, a gouty tophus, as a complication of morbid obesity and in association with arthroplasty.10–17 A patient with Klippel-Trenaunay-Weber syndrome developed an angiosarcoma and a malignant peripheral nerve sheath tumor in the same involved limb.18 Development of angiosarcoma in a teratoma and a congenital example have also been documented.19,20 Angiosarcoma arising in other organs may metastasize to the skin.21,22 Rare cases in association with chronic immunosuppression in renal transplant patients and in HIV

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Connective tissue tumors have been reported.23–26 Angiosarcoma in children is exceptional and tends to occur mainly in the soft tissues and internal organs, particularly the head and neck and mediastinum.27–31 The tumor may occasionally occur within a blood vessel, a hemangioma, nerve and in benign or malignant nerve sheath tumors.32–36 A case of multiple cutaneous and visceral vascular malformations associated with hepatic disseminated angiosarcoma has been reported.37

Idiopathic angiosarcoma of the head and neck Idiopathic angiosarcoma of the head and neck is predominantly a tumor of late adulthood, with an equal sex incidence and a predilection for the scalp and central face.1,2,8,9 Involvement confined to the eyelid has been documented.38 It presents as single or multiple raised reddish or purple plaques, papules or nodules which may show a variable growth rate. High-grade lesions tend to ulcerate and bleed readily (Figs 35.574–35.579). The tumor is typically much more extensive than is clinically apparent. Spontaneous ­regression

e­ xceptionally occurs.39,40 Rare cases may mimic other diseases including ­rosacea and rhinophyma.41,42 Thrombocytopenia may rarely occur, probably as a result of platelet consumption and destruction within the tumor.43,44 Alopecia is an uncommon manifestation.45

Lymphedema-associated angiosarcoma Lymphedema-associated angiosarcoma (traditionally known as lymphangiosarcoma) classically arises on the arms of elderly females who have undergone mastectomy with axillary lymph node dissection or radiotherapy many years previously (Stewart-Treves syndrome) (Fig. 35.580).46–49 It may also develop in other forms of iatrogenic lymphedema, congenital lymphedema, very rarely in a lymphangiomatous malformation, in association with elephantiasis and even in an area of lymphedema secondary to morbid obesity.50,51 A case developing in an area of lipodermatosclerosis in a lower limb with changes of stasis has been reported.52 Lesions typically present as numerous purplish nodules or vesicles, often distributed over a wide area.

Fig. 35.574

Fig. 35.576

Angiosarcoma: there is a purplish bruise-like discoloration of the face with an infraorbital nodule. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Angiosarcoma: note this diffuse crusted and ulcerated lesion. The face and scalp are sites of predilection. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 35.575 Angiosarcoma: ulcerated and hemorrhagic plaque on the frontal scalp. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 35.577 Angiosarcoma: patients often present with a bruise-like lesion. By courtesy of the Institute of Dermatology, London, UK.

Malignant vascular tumors

Postirradiation angiosarcoma

Fig. 35.578 Angiosarcoma: the scalp, particularly in bald individuals, is a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.

Postirradiation angiosarcoma is the rarest of the three variants and can develop many years after radiotherapy for benign (hemangiomas, tinea capitis) or malignant conditions.53–58 Most cases are associated with radiotherapy from breast and gynecological cancer.59 In cutaneous postirradiation angiosarcoma of the breast there is usually no associated lymphedema and the latency period is shorter than that in Stewart-Treves syndrome.60 Some cases of postirradiation angiosarcoma of the breast may be associated with chronic lymphedema and this may contribute to the development of the disease.61 A case following treatment of metastatic melanoma has been reported.62 All postirradiation angiosarcomas show high-level amplification of MYC, reflecting gains in chromosome 8q24 and this is regarded as an early necessary alteration in the development of the tumor.63 In about 25% of these cases there is co-amplification of FLT4, which encodes VEGFR3. Interestingly, these alterations are not found in atypical vascular proliferations associated with radiotherapy. All forms of angiosarcoma carry a very poor prognosis, with repeated local recurrences, rapid dissemination and death in up to 80% of cases, often within a fairly short time.64–68 A recent retrospective study of angiosarcoma of the scalp and face found an improved 43% 5-year survival attributed to combined modality therapy.69 A further study including all sporadic cutaneous angiosarcomas, including those from the scalp and face and those with pure epithelioid morphology, found poor prognosis to be associated with necrosis, epithelioid morphology and old age (over 70 years).70 Local recurrence was associated with tumor depth. This study confirms findings of a previous study in which adverse prognosis correlated with size of the tumor, depth of invasion and mitotic rate.71 We regard pure cutaneous epithelioid angiosarcomas occurring outside the usual three clinical settings of angiosarcoma as a ­distinctive category of neoplasms with very poor prognosis (see below). Younger patients appear to have a better prognosis and radiation therapy appears to improve survival.72,73 Among metastatic sites, lymph nodes and lungs are the commonest. Interestingly, complete remission of a radioresistant, an inoperable and a metastatic angiosarcoma after treatment with ­liposomal doxorubicin, paclitaxel or a combination of the latter and ­sorefenib, ­respectively, have been reported.74–76

Pathogenesis and histological features

Fig. 35.579 Angiosarcoma: oral lesions in a patient with minimal cutaneous involvement highlighting the multifocality of the process. By courtesy of the Institute of Dermatology, London, UK.

Fig. 35.580 Lymphedema-associated angiosarcoma (StewartTreves tumor): very marked lymphedema has complicated radical mastectomy in this elderly female patient. There is diffuse involvement of the arm by tumor.

Cytogenetic analysis in a small number of superficial and deep ­angiosarcomas has shown complex chromosomal abnormalities mainly involving chromosomes 5, 7, 8, 13, 15, 20, 22 and Y.77 Activating mutations in KDR and other genes which may be amenable to therapeutic targeting have been documented.78 Microscopically, all clinical variants are largely indistinguishable other than by the presence of coexistent lymphedema and are therefore considered together. The appearances are of an ill-defined infiltrative intradermal mass of numerous anastomosing vascular channels of varying caliber (Figs 35.581–35.584). The endothelium, which may be single or multilayered, is typically plump, ­pleomorphic and mitotically active (abnormal mitoses being quite common), and may form papillae or solid nests within vascular lumina. The vascular proliferation tends to ramify through the dermis, ‘dissecting’ the collagen bundles (Figs 35.585, 35.586). Focal epithelioid change is not uncommon and can be prominent in some instances. In some cases, the tumor adopts (focally or diffusely) a solid, undifferentiated, spindled cell appearance, which is not easily recognizable as vascular in ­origin (Figs 35.587–35.589). A small number of cases appear to demonstrate true lymphatic differentiation, mainly those located on the scalp and face.79 These tumors are characterized by interconnecting irregular channels devoid of red blood cells lined by atypical hobnail endothelial cells, have stromal lymphoid aggregates and stain for lymphatic markers including D2-40, prox-1 and VEGFR-3. A small subset of angiosarcomas simulate Kaposi's sarcoma, a feature also suggestive of lymphatic differentiation.80,81 A useful means of identifying the vascular nature of this tumor is by reticulin staining, which will demonstrate that in the better differentiated areas the tumor cells lie within a perivascular reticulin sheath; single cells are not surrounded by the reticulin framework (Fig. 35.590). Chronic ­inflammatory

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Fig. 35.581

Fig. 35.584

Angiosarcoma: this low-power view shows extensive infiltration of the dermis by a vascular tumor.

Angiosarcoma: in this example, intraluminal papillae are present.

Fig. 35.582

Fig. 35.585

Angiosarcoma: the endothelial cells are pleomorphic and hyperchromatic.

Angiosarcoma: note the spindled cell population with vesicular nuclei and prominent nucleoli.

Fig. 35.583

Fig. 35.586

Angiosarcoma: high-power view.

Angiosarcoma: there is conspicuous dissection of collagen.

Malignant vascular tumors

Fig. 35.587

Fig. 35.590

Angiosarcoma (spindle cell variant): the dermis is extensively infiltrated by a spindled cell tumor.

Angiosarcoma: the tumor cells are enclosed within a reticulin sheath.

Fig. 35.588 Angiosarcoma (spindle cell variant): the spindle cells have eosinophilic cytoplasm and pleomorphic, vesicular nuclei. Intracytoplasmic lumina are apparent.

cells scattered throughout the tumor are often a prominent feature. In ­exceptional cases the infiltrate simulates a lymphoma and obscure the real tumor.82 Rare cases of angiosarcoma are mainly composed of cells with granular cytoplasm.83,84 A variant composed of foamy cells mimicking histiocytes has also been reported.85 In postirradiation tumors, capillary lobules may be present, and although this has been traditionally regarded as a feature indicative of a benign proliferation, in this setting it should raise the alarm about the presence of angiosarcoma.86,87 In poorly differentiated cases, it is useful to assess a panel of endothelial markers because individual antibodies or lectins tend to be variably positive in different tumors. These include von Willebrand factor (factor VIII-related antigen), CD31, CD34 and FLI-1, of which CD31 and probably FLI-1 are by far the most sensitive and also very specific (Fig. 35.591). Tumors lacking epithelioid morphology are usually not positive for keratin and epithelial membrane antigen.88 It is important to remember that no antibody is entirely specific, and staining of histiocytes by CD31 may be a confounding feature in hemorrhagic atypical fibroxanthomas and may lead to a misdiagnosis of angiosarcoma.89 Angiosarcomas are usually negative for HHV-8 except in tumors ­occurring in patients with AIDS.25

Fig. 35.589

Fig. 35.591

Angiosarcoma (spindle cell variant): note the mitotic activity.

Angiosarcoma: the tumor cells express CD31.

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Differential diagnosis The presence of endothelial cell atypia, multilayering and mitotic activity allows ready distinction from a benign hemangioma (or lymphangioma) and Masson's tumor. Occasional cases may need to be distinguished from spindle cell melanoma or carcinoma, in which circumstances immunohistochemistry is most helpful. Ultrastructurally, the presence of Weibel-Palade bodies confirms the vascular nature of the tumor (Fig. 35.592).

Epithelioid angiosarcoma Clinical features

as melanocytic or epithelial neoplasms. Lesions have a wide anatomical distribution and usually present in adults, with no sex predilection (Fig. 35.593). Tumors are single or less commonly multiple.4 Tumors in the skin, soft tissues and other organs have a dismal prognosis. Early metastasis and high mortality of up to 55% is seen in primary cutaneous epithelioid angiosarcoma.4 Occasional cases have been associated with a foreign body, radiotherapy and an arteriovenous fistula.1,6–9 One case developed at a peristomal site.10 Exceptional cutaneous metastasis from cardiac, mediastinal, bone and intravascular epithelioid angiosarcomas has been documented.4,11,12

Histological features

Epithelioid angiosarcoma represents the malignant end of the spectrum of epithelioid vascular neoplasms.1–5 The term is reserved for tumors composed almost exclusively of epithelioid cells, as conventional angiosarcomas are quite often focally epithelioid. We reserve this term to tumors with epithelioid morphology occurring outside the conventional settings of cutaneous angiosarcoma described earlier. Although involvement of the skin by this tumor is rare, it appears to occur more often than was previously thought. It is likely that before it was delineated as a distinctive entity, cases were misdiagnosed

Lesions are infiltrative and composed of sheets of large oval or round cells with abundant eosinophilic or amphophilic cytoplasm and vesicular nuclei with prominent eosinophilic nucleoli (Figs 35.594–35.596). Although cytological atypia is present, the tumor cells are relatively monomorphic. Mitosis, necrosis and hemorrhage are common findings. Focally, a few cells show intracytoplasmic lumina containing occasional red blood cells (Fig. 35.597). Blood vessel formation can also be a feature. A reticulin stain is useful to highlight the vasoformative architecture. Immunohistochemically, the tumor cells are consistently positive for CD31,

Fig. 35.592

Fig. 35.594

Angiosarcoma: in spindle cell variants, the diagnosis is sometimes confirmed ultrastructurally by the identification of Weibel-Palade bodies.

Epithelioid angiosarcoma: there is a diffuse epithelioid cell infiltrate with multiple foci of hemorrhage.

Fig. 35.593

Fig. 35.595

Epithelioid angiosarcoma: presentation on the scalp is not uncommon. The lesion is less obviously vascular when compared with more typical angiosarcoma. By courtesy of the Institute of Dermatology, London, UK.

Epithelioid angiosarcoma: the tumor cells have abundant eosinophilic cytoplasm and pleomorphic vesicular nuclei.

Malignant vascular tumors

Fig. 35.596

Fig. 35.599

Epithelioid angiosarcoma: note the mitoses.

Epithelioid angiosarcoma: this example also expressed keratin (MNF -118).

FLI-1 or von Willebrand factor (Fig. 35.598). Cytokeratin is also positive in up to 50–60% of cases and EMA is focally positive in about 25% of cases (Fig. 35.599).1,4 INI is often focally or diffusely positive in tumor cells.4 Exceptional focal positivity for Melan-A and smooth muscle actin can be seen.4 A case of pure epithelioid angiosarcoma arising in the setting of radiotherapy for breast cancer was positive for CD30.13 These important findings need to be borne in mind when considering the differential diagnosis from a carcinoma (especially metastatic) or epithelioid sarcoma.

Differential diagnosis The differential diagnosis includes metastatic carcinoma, melanoma, epithelioid sarcoma and epithelioid malignant schwannoma, all of which are negative for endothelial markers and lack focal blood vessel formation and intracytoplasmic lumina.

Lymphangioma

Fig. 35.597 Epithelioid angiosarcoma: intracytoplasmic lumina are present in the center of the field.

Lymphangiomas take four principal forms: • cavernous lymphangioma, • cystic hygroma, • lymphangioma circumscriptum, • acquired progressive lymphangioma (benign lymphangioendothelioma). The existence of a true capillary lymphangioma is highly questionable.

Clinical features Cavernous lymphangioma Cavernous lymphangioma is a congenital or infantile lesion of equal sex incidence that arises most often in the head and neck region (particularly the tongue) and extremities.1–5 It presents as a large diffuse, rather doughy mass and is very prone to local recurrence after simple excision. Rare cases present for the first time in adults. Coexistence with a lymphangioma circumscriptum is very rare.6

Cystic hygroma Cystic hygroma is also a lesion of infancy, and presents as a large cystic mass, most often in the neck, axillae or inguinal region.1,2,5 Scrotal lesions have also been reported.7 Intra-abdominal and intrathoracic lesions also occur.8,9 It is also prone to local recurrence unless widely excised, although this tendency is much less marked than with cavernous tumors. Coexistence with a port-wine stain is exceptional.10 Lesions have been reported in adults.11

Lymphangioma circumscriptum Fig. 35.598 Epithelioid angiosarcoma: the tumor cells express CD31.

Lymphangioma circumscriptum also presents most often in infancy, but may arise at any age and shows an equal sex distribution.3–5 Although it develops at any cutaneous site, the proximal portions of the limbs and limb girdles

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Connective tissue tumors

Fig. 35.600 Lymphangioma circumscriptum: the lesion presents as variable numbers of superficial fluid-filled blebs. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 35.601 Cavernous lymphangioma: widely dilated lymph-filled channels are characteristic.

are usually affected. The lesion occurs as a localized collection of numerous small vesicles or blebs which may sometimes form larger confluent masses, filled with clear fluid or blood (Fig. 35.600). Occasionally, solitary lesions are present. They are typically asymptomatic unless irritated by the patient. Although the majority of these tumors probably represent developmental malformations, a small proportion are acquired, usually following block dissection of regional lymph nodes or radiotherapy.12 Similarly, a small number of cases are associated with an underlying cavernous or cystic lymphangioma. Vulval lesions are idiopathic or have been associated with Crohn's disease and radiation therapy.13 Rare vulvar lesions associated with malignancy and hidradenitis suppurativa have been described.14 Recurrence after excision is quite common.

Acquired progressive lymphangioma Acquired progressive lymphangioma is a rare tumor that was originally described as more frequently seen in children.15–21 However, the more recent literature suggests that it is more common in adults.21 It has an equal sex incidence and particularly involves the extremities, especially the upper limbs, although the anatomical distribution is wide. It presents as a solitary, well-defined erythematous macule or plaque that gradually increases in size. Simple excision is usually curative, with only exceptional local recurrences.21 Occasional partial spontaneous regression is rarely seen. A case has been ­documented after radiotherapy, a further case developed following femoral arteriography and one has been reported in an HIV-positive patient.22–24

Fig. 35.602 Lymphangioma circumscriptum: thin-walled lymphatic channels are present in both the reticular and papillary dermis.

Histological features Cavernous lymphangioma is typically an ill-defined lesion in the dermis or subcutaneous fat, composed of numerous dilated lymphatic channels without endothelial atypia (Fig. 35.601). The surrounding stroma may be inconspicuous or composed of prominent adventitial-type reticulin fibers with a chronic inflammatory cell infiltrate. Cystic hygroma is histologically almost indistinguishable from the cavernous lesions except that its thin-walled lymphatic spaces show gross cystic dilatation. As well as a lymphocytic infiltrate, scattered lymphoid follicles are common. In both lesions, the vascular lumina often contain proteinaceous, pale, eosinophilic lymph, and the vessel walls may contain an incomplete layer of smooth muscle. Lymphangioma circumscriptum is usually situated in the superficial ­dermis. It is composed of multiple dilated lymphatic channels which often have fairly thick walls and commonly appear to extend into the overlying ­epidermis (Fig. 35.602). The latter is frequently acanthotic and a stromal lymphocytic infiltrate is sometimes evident. Cavernous spaces may be seen in the deeper dermis and occasionally a muscular lymphatic channel (often regarded as the feeding vessel) is present (Fig. 35.603).

Fig. 35.603 Lymphangioma circumscriptum: within the subcutaneous fat is a large muscular ‘feeder’ lymphatic trunk. If this is not ligated at surgery, there is a high risk of recurrence.

Malignant vascular tumors

Fig. 35.604 Progressive lymphangioma: despite the architectural resemblance to angiosarcoma, there is a complete absence of endothelial multilayering or nuclear atypia.

In progressive lymphangioma, involvement of the superficial dermis is usually prominent, but extension into the deep dermis and superficial subcutis is not uncommon (Fig. 35.604). Horizontal, irregular, thin-walled vascular channels lined by a single layer of flat attenuated endothelial cells are seen dissecting the collagen bundles (Fig. 35.605). The channels appear empty but occasionally proteinaceous material or red blood cells are seen. Focal papillary projections are sometimes present. Some vascular spaces may have a layer of smooth muscle. Stromal inflammation is not a feature.

Differential diagnosis Progressive lymphangioma may mimic low-grade angiosarcoma and patch-stage Kaposi's sarcoma. The former has at least focal cytological atypia and multilayering and the clinical setting is different. In the latter there are usually multiple lesions and histologically there is hemosiderin deposition with extravasated erythrocytes and adjacent inflammatory cells, including plasma cells. Distinction from lymphangiomatosis is afforded mainly by the clinical extent of the lesion.

Multifocal lymphangiomatosis with thrombocytopenia (cutaneovisceral angiomatosis with thrombocytopenia) Clinical features This condition is also known as cutaneovisceral angiomatosis with thrombocytopenia or infantile hemorrhagic angiodysplasia, and is characterized by multiple red–brown to blue discrete papules, macules, plaques and nodules ranging in size from millimeters to several centimeters, predominantly affecting the trunk and extremities.1–4 Many lesions are congenital but new ones continue to develop throughout childhood. Other sites involved include the gastrointestinal tract, lung, bone, liver, spleen, muscle and synovium. Thrombocytopenia is an associated phenomenon. Death from gastrointestinal bleeding and sepsis may occur.

Fig. 35.605 Progressive lymphangioma: some cases show more dissection of dermal structures by the dilated lymphatic spaces.

Differential diagnosis Benign lymphangioendothelioma, Dabska's tumor and hobnail hemangioma can show similar histological features to multifocal lymphangiomatosis with thrombocytopenia. However, the former are usually solitary lesions lacking visceral involvement or thrombocytopenia.

Atypical vascular proliferation after radiotherapy Clinical features Lymphangiomatous lesions rarely occur in the field of radiotherapy.1–3 They sometimes have identical features to other lymphangiomas such as lymphangioma circumscriptum or benign progressive lymphangioma with typical histology.2,3 However, most frequently their clinical and ­histological appearances do not fit with any other vascular tumor and sometimes display a­typical features, raising the possibility of a postirradiation angiosarcoma. Lesions usually develop a few months or years after radiotherapy for breast cancer.1–4 Similar lesions can occur at the site of radiotherapy elsewhere, mainly in relation to genital cancer, but these are rare.3–5 The time elapsed between radiotherapy and development of the lesions is usually shorter (around 3 years) than that seen in angiosarcomas (around 6 years).4 The former lesions tend to be smaller than angiosarcomas associated with radiotherapy. The clinical presentation is not distinctive and varies from skin colored to red, usually multiple, macules and papules. The relationship between these lesions and postirradiation angiosarcomas is controversial and it is not clear whether the former are precursors of the latter or whether they all represent a benign process.4–9 Although most lesions appear histologically benign, there is a wide histological spectrum. In a few instances, overlap or even progression to angiosarcoma is seen. Therefore treatment of these lesions should be by complete excision with close follow-up.

Histological features

Histological features

Microscopically, irregular dilated vascular channels involve the reticular dermis and subcutis and are lined by bland endothelial cells with hobnail morphology and focal intraluminal papillary projections.

Most lesions are characterized by irregular lymphatic-like vascular channels lined by a single layer of endothelial cells in the superficial and/or deep dermis (Figs 35.606–35.608). An infiltrative growth pattern is lacking and lesions

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Connective tissue tumors are usually fairly circumscribed. The cells lining the channels often have a hobnail appearance and are usually bland although some hyperchromatism may be present. Papillary projections may occasionally be seen. Multilayering or mitotic figures are not usually found. In some cases, overlap with angiosarcoma is clearly seen. A recent study separated these lesions into lymphatic type and vascular type and concluded that the risk of angiosarcoma is higher in patients with the vascular type.6 In the latter, a lymphatic component is minimal and the proliferation consists of congested capillary-like vascular channels surrounded by a layer of pericytes.

Differential diagnosis

Fig. 35.606 Atypical vascular proliferation after radiotherapy: dilated vessels are evident in the superficial dermis. Nuclear atypia is minimal.

The differential diagnosis includes a well-differentiated angiosarcoma, hobnail hemangioma and Kaposi's sarcoma. As opposed to hobnail hemangioma, the lesion is asymmetrical, and the vascular channels do not have a predominant superficial dermal location. The clinical setting, the absence of inflammation and the presence of hobnail endothelial cells with focal ­papillary projections should allow distinction from Kaposi's sarcoma. Careful examination of multiple sections is recommended to make sure that there are no mitotic figures and cytological atypia to distinguish it from a well-differentiated angiosarcoma. This distinction can be very difficult, especially in small biopsies. In some cases, immunohistochemistry for MIB1 can be useful as this marker tends to be negative or minimally positive in benign lesions and more prominently positive in angiosarcoma.

Lymphangiomatosis Clinical features

Fig. 35.607 Atypical vascular proliferation after radiotherapy: high-power view.

Lymphangiomatosis is a congenital abnormality characterized by diffuse involvement of soft tissues, skin, bone and (often) parenchymal organs.1,2 The disease can be localized to the thorax or abdomen, with predilection for some organs including the kidney and spleen.3–7 Involvement of the colon can result in protein-losing enteropathy.8 Multifocal lymphangiomatosis has been described in association with protein-losing enteropathy in patients after palliation of complex congenital heart disease with total cavopulmonary connection.9 An exceptional association with disseminated intravascular ­coagulation has been reported.10 Extensive involvement may be associated with ­mortality.11 Most cases present in children and there is no sex ­predilection. In rare cases, the disease affects only a limb, with or without concomitant bone involvement.2,12 Coexistence with a cystic hygroma is exceptional.13 Overlap with angiomatosis can occur and accurate diagnosis requires lymphangiography. Rare cases are associated with kaposiform hemangioendothelioma.14 Gorham-Stout syndrome refers to the proliferation of lymphatic and vascular channels associated with prominent osteolytic lesions.15 It has been suggested that this disease is mediated by monocytes that secrete cytokines, inducing angiogenesis and proliferation of osteoclasts.16

Histological features Histologically, lesions resemble a benign lymphangioendothelioma except that there is very extensive diffuse dissection of dermal structures (the ‘hairdryer effect’) (Figs 35.609, 35.610).2 Long-standing lesions may show stromal sclerosis, and extramedullary hemopoiesis is evident in some cases. The endothelial cells lining the vascular channels in lymphangiomatosis ­display increased expression of epidermal growth-factor receptor suggesting that this may be used therapeutically.17

Tumors of perivascular cells Glomus tumor

Fig. 35.608 Atypical vascular proliferation after radiotherapy: the extent of the lesion can be highlighted by immunohistochemistry (CD31).

Glomus tumor arises from the glomus body, which is a specialized arteriovenous anastomosis found most often in the fingers and palms and characterized by the Sucquet-Hoyer canal. They are thought to serve as thermoregulatory receptors. The precise cell of origin is probably a modified smooth muscle cell – the glomus cell – found scattered within the muscle coat of the Sucquet-Hoyer canal.

Tumors of perivascular cells

Fig. 35.611

Fig. 35.609

Glomus tumor: multiple, typically small, reddishblue papules are present on the forearm of a young male. By courtesy of the late M. Beare, MD, Royal Victoria Hospital, Belfast, UK.

Lymphangiomatosis: this condition shows massive dissection of the dermal collagen and is always clinically extensive.

Fig. 35.610 Lymphangiomatosis: high-power view.

Clinical features Glomus tumors are relatively common lesions and arise most often in the third and fourth decades, with an equal sex incidence.1–3 They may occur at almost any cutaneous site, but are predominantly seen on the hands, particularly the fingers, and especially the subungual region. Lesions can, however, occur with a wide anatomic distribution, not only in the skin but also rarely in mucosae (including oral cavity) and internal organs.4 The latter include the esophagus, stomach, lung, trachea, bone, small bowel, pterygoid fossa, mediastinum, liver, pancreas, ovary and kidney.5–16 A glomus tumor arising in an ovarian teratoma has been documented.17 Typically, the tumors are small (less than 1 cm in diameter), reddish-blue nodules and classically ­present with paroxysmal severe pain, which is often precipitated by cold, pressure or dependency. Pain appears to be more frequent in histologically solid tumors in contrast to the more common glomangiomas. In a small proportion of cases, the tumors are multiple and may be segmental in distribution.18,19 Multiple lesions are usually seen in children (an otherwise unusual age group) and have an autosomal dominant inheritance (Figs 35.611, 35.612).20–22 Congenital lesions may also occur and in one there was associated hypertrichosis.23–25 Familial glomangiomas, also known as glomuvenous malformations, are associated with inactivating mutations in GLMN (1p21-22), encoding glomulin which is normally expressed on

Fig. 35.612 Glomus tumor: close-up view. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

vascular smooth muscle cells.26–33 Local and systemic expression of basic fibroblast growth factor has been found in occasional patients with multiple glomangiomas, suggesting that this cytokine may play a role in their pathogenesis.34,35 Multiple or solitary glomus tumors have been described in neurofibromatosis type I.36–38 Tumors tend to occur on the fingers and toes and they are now regarded as part of the spectrum of NF1.39 Glomus tumors in this ­setting appear to be related to hyperactivation of RAS mitogen-activated protein kinase, resulting from the lack of inhibition by neurofibromin.39 Local recurrence, which is uncommon, only follows inadequate excision and is therefore more frequent in those rare cases (usually deep seated) with infiltrative margins.40 Digital glomus tumors that are skin-colored or those that arise in the nail matrix appear to have a higher risk of local recurrence.41 Rare lesions originate within a blood vessel or a nerve.42–45

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Connective tissue tumors

Histological features The vast majority of glomus tumors are well circumscribed and composed of small vessels with normal endothelium surrounded by a dense, rather organoid, mantle of uniformly round glomus cells with pale eosinophilic cytoplasm, clearly defined cell margins and central nuclei (Figs 35.613, 35.614). Lesional vessels have no demonstrable elastic laminae, and the glomus cells may extend to abut the endothelium or be separated from it by a thin layer of smooth muscle cells. These predominantly solid glomus tumors (the ‘classic’ type) are in fact less common than glomangiomas (see below). Mitotic figures, which are always normal, are only rarely seen and pleomorphism is not a feature. Small nerve fibers may occasionally be demonstrated ramifying through the tumor. Rare cases may show extensive oncocytic change.46 Prominent epithelioid cell change has been documented (Figs 35.615, 35.616) and in a single case there was prominent sclerosis.47,48 Calcification is exceptional.49 The tumor cells are positive for SMA, muscle-specific actin and, depending on the antibody, myosin; they are only rarely focally positive for desmin.50 CD34 may also be positive.51 In glomangioma, the most common variant of glomus tumor (up to 60% of cases), the vascular component is more prominent and the lumina tend to be somewhat dilated or cavernous (Figs 35.617, 35.618). Glomus cells may be distributed as an attenuated monolayer or bilayer in the vessel wall. These

Fig. 35.613 Glomus tumor: the tumor consists of uniform small cells with eosinophilic cytoplasm associated with a conspicuous vasculature.

Fig. 35.615 Epithelioid glomus tumor: this field shows the transition between typical small round glomus cells and larger epithelioid variants with abundant pale pink cytoplasm.

Fig. 35.616 Epithelioid glomus tumor: high-power view.

Fig. 35.614

Fig. 35.617

Glomus tumor: the glomus cells have round regular small nuclei. Small numbers are present in this blood vessel wall.

Glomangioma: in this variant, the blood vessels predominate.

Tumors of perivascular cells

Fig. 35.618

Fig. 35.620

Glomangioma: high-power view.

Glomangiomyoma: high-power view.

cases often exhibit hyalinization of the vessel walls and may show thrombosis with the formation of phleboliths. • Symplastic glomus tumor is defined as a tumor with high nuclear grade in the absence of any other malignant feature.52–54 • Glomangiomyoma, the rarest subtype (15% of cases), is characterized by a larger and more obvious number of smooth muscle cells, most often distributed adjacent to or around the vascular spaces. These muscle cells merge imperceptibly with the surrounding solid collection of glomus cells (Figs. 35.619, 35.620). • Glomangiomatosis is defined as a tumor with features of angiomatosis and excess glomus cells.52,55 • Infiltrating glomus tumor is a very rare variant that usually presents in deeper soft tissues.40,56 It is characterized by an infiltrative growth pattern and a high recurrence rate. • Malignant glomus tumors are rare.40,52,57–61 A single superficial case was associated with pregnancy.62 The histological diagnosis is difficult and only recently have refined criteria been proposed to define malignant lesions.52 These include: • deep location and a size of more than 2 cm, or • atypical mitotic figures, or • moderate to high nuclear grade diagnosis and five or more mitotic figures per 50 high-power fields (HPF).52 Glomus tumors of uncertain malignant potential are defined as lesions that lack criteria for the diagnosis of malignant glomus tumor or symplastic

glomus tumor but have high mitotic activity and superficial location, or large size only, or deep location only.52 Some 38% of cases fulfilling criteria for malignancy metastasize.52

Differential diagnosis The classical clinical history combined with the distinctive histological features usually prevents diagnostic confusion. Eccrine spiradenoma can be distinguished by the presence in the latter of two populations of cells, positivity for epithelial markers and focal ductal differentiation.

Myopericytoma Traditionally, tumors thought to differentiate towards perivascular myoid cells or pericytes have been divided into two main groups: infantile hemangiopericytoma and adult hemangiopericytoma.1,2 Both variants, however, appear to have very little in common except for the histological presence of a pericytomatous vascular pattern. Moreover, with the combination of immunohistochemistry and electron microscopy, most tumors classified as adult hemangiopericytoma on light microscopy show other lines of differentiation including synovial sarcoma, mesenchymal chondrosarcoma and solitary fibrous tumor.3 The handful of cases in which the line of differentiation remains obscure are the ‘true’ adult hemangiopericytomas, but it is likely that they arise from an undifferentiated mesenchymal cell. These rare examples of ‘true’ adult hemangiopericytomas do not usually occur in the skin and will not be discussed further in this chapter. In recent years, the concept of myopericytoma has been introduced to describe a spectrum of tumors composed of short oval to spindle-shaped cells with a myoid appearance and a distinctive concentric perivascular growth.4 These tumors tend to occur mainly in the deep dermis and subcutaneous tissue and include lesions classified in the past as glomangiopericytoma, myopericytoma, myofibroma and myofibromatosis in adults. Infantile hemangiopericytoma and infantile myofibromatosis also represent part of the spectrum of tumors with true pericytic differentiation.5–8

Clinical features

Fig. 35.619 Glomangiomyoma: in this variant, bundles of smooth muscle are present.

Myopericytoma most commonly occurs in middle-aged adults (mainly in the fifth decade) with a predilection for the limbs, particularly the distal lower limb followed by the head and neck (including the oral cavity).9 Exceptional tumors may occur in the kidney, the lung, the parotid gland, within the cranium or in the thoracic spine.10–14 Males are more frequently affected than females. Lesions are small (less than 2 cm in diameter), long-standing, usually asymptomatic and may be single or (less frequently) multiple. Rarely,tumors are painful. Recurrence is rare and frequently represents either persistence or the development of a new tumor. Very rare malignant examples of myopericytoma have been described; these appear to have an aggressive clinical behavior.8,15

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Connective tissue tumors An association with HIV/AIDS has been reported and in this setting tumor tend to occur at sites other than soft tissue and skin (including bronchus, larynx, tongue, liver and brain), are often multiple and are associated with EpsteinBarr virus.16,17 Two exceptional cases of glomangiopericytoma associated with oncogenic osteomalacia have been documented.18,19 In two cases, trauma was suggested as a possible factor in the development of the tumors.20

Histological features Tumors are dermal, dermal and subcutaneous, or purely subcutaneous and rarely arise in deeper soft tissues.8 The histological spectrum of myopericytoma is very wide and varies from lesions that are very similar to myofibromatosis to those that closely resemble glomus tumors and even an angioleiomyoma (Figs 35.621, 35.622). They are well circumscribed and are composed of a ­mixture of solid cellular areas intermixed with variable numbers of vascular channels. The latter are often elongated and display prominent branching, resulting in a stag-horn appearance (hemangiopericytoma-like). The cells in the solid areas are round or short and spindle-shaped with eosinophilic or amphophilic cytoplasm and vesicular nuclei. Cytological atypia is not usually a feature and mitotic figures are very rare. A common and striking feature is the presence of concentric layers of tumor cells around vascular channels, resulting in a typical ‘onion-ring’ appearance (Fig. 35.623). Myxoid change may be focally prominent. Occasional findings include hyalinization/­sclerosis, cystic

Fig. 35.623 Myopericytoma: this perivascular distribution of tumor cells in an onion ring-like appearance is characteristic.

degeneration and bone formation. Rare examples are entirely intravascular (within a vein or an artery).8,21–25 In some cases, tumor cells closely resemble glomus cells and are characterized by round, punched-out central nuclei and pale eosinophilic cytoplasm. These cases are referred to as glomangiopericytomas. Tumors regarded as malignant display cytologic atypia and increased mitotic activity.8,15 Myopericytoma cells stain diffusely for SMA and calponin, are often ­positive for h-caldesmon and only very rarely focally positive for desmin (Fig. 35.624).8 Focal staining for CD34 may also be seen.

Differential diagnosis Some authors regard angioleiomyoma as part of the spectrum of myopericytoma.26 The coexistence of both tumors in the same patient and a number of morphological features support this theory. Angioleiomyoma, however, is composed of uniform smooth muscle cells, which stain diffusely for both SMA and desmin. Furthermore, concentric arrangement of tumor cells around ­vascular channels is less prominent than that seen in myopericytoma.

Fig. 35.621 Myopericytoma: low-power view showing dilated vessels and abundant smooth muscle.

Fig. 35.624 Fig. 35.622 Myopericytoma: high-power view.

Myopericytoma: the tumor cells express smooth muscle actin.

Benign tumors of cartliage

Tumors of bone and cartilage-forming tissue The vast majority of tumors in the skin that show ossification do so as a s­econdary degenerative or metaplastic phenomenon. The most common tumors showing this feature are melanocytic nevi and the calcifying epithelioma of Malherbe (pilomatrixoma). Primary bone-forming lesions arising in the skin are extremely rare. Fasciitis ossificans has already been described under fasciitis.

Benign tumors of bone Osteoma cutis Clinical features Osteoma cutis is a rare benign lesion of the dermis that may be seen at any age in either sex.1–3 Lesions are occasionally multiple and, in some cases, may be inherited or associated with diaphyseal aclasis. Microscopic osteoma cutis is not uncommonly found as a result of dystrophic ossification in association with inflammatory conditions including acne and folliculitis.4 The latter is often seen in association with intradermal nevi, as the latter obstruct the hair follicle and lead to inflammation. Multiple miliary osteoma cutis may occur on the face of middle-aged patients with marked predilection for females.5 The lesions are tiny and the etiology is unknown, although slightly more than half of patients have a history of acne vulgaris. Osteoma cutis is associated with Albright hereditary osteodystrophy and this is discussed further in the chapter on disorders of pigmentation. A case of pigmented osteoma cutis resulting from long-term tetracycline treatment has been described.6 A distinctive plaque-like variant of osteoma cutis can occur and it is rarely congenital.7 It may be multiple and is exceptionally associated with transepidermal elimination.8

Histological features Histologically, osteoma cutis is composed of a well-circumscribed nodule of mature lamellar bone, often containing marrow spaces, within the dermis (Fig. 35.625).

Malignant tumors of bone Extraskeletal osteosarcoma Clinical features Extraskeletal osteosarcoma is a rare lesion that most often arises in older adults and shows an equal sex incidence.1–6 It typically occurs in the deep soft tissues of the limbs, particularly the legs, but subcutaneous cases are well recognized and exceptional cases are dermal in location. A case of extraskeletal osteosarcoma arising in the mediastinum metastasized to the skin.7 Up to 10% of lesions are associated with previous radiation to the affected site.5,8 These tumors tend towards rapid local recurrence and widespread systemic dissemination. The mortality rate is as high as 75%.

Histological features The tumor is typically ill defined and characterized by a variable admixture of pleomorphic or spindle-shaped cells associated with the production, at least focally, of an osteoid or chondroid matrix (Figs 35.626–35.628). Bizarre multinucleated giant cells are common. The diagnostic sine qua non is the presence of hyperchromatic osteoblasts within the newly formed osteoid matrix. Cases with numerous osteoclastic giant cells were often formerly labeled as so-called giant cell ‘MFH’; such examples not infrequently are ­subcutaneous. Immunohistochemical demonstration of osteocalcin may be useful in tumors with poor osteoid formation.9

Benign tumors of cartliage Soft tissue chondroma Clinical features

Osteoma cutis should not be confused with a benign cartilaginous exostosis. The latter condition, also known as osteochondroma, most often presents under the nail as a solitary, often painful, hard tumor nodule. Histologically, it is composed of mature cartilage overlying a layer of lamellar bone. It arises from the underlying phalanx.

Soft tissue chondromas are uncommon tumors that arise most often in ­middle-aged adults, showing a slight male predominance and typically occurring on the hands or feet.1–4 Rare cases develop on the face and neck and exceptional familial cases have been described.5 Lesions, which present as a slowly growing mass usually less than 3 cm in diameter, sometimes show calcification on radiological examination. Up to 10% of cases recur locally after excision, but malignant change has never been reported. A case

Fig. 35.625

Fig. 35.626

Osteoma cutis: note the osteoid rimmed by osteoblasts and the scarred medullary cavity.

Extraskeletal osteosarcoma: low-power view showing an osteoclast-rich cellular infiltrate with focal osteoid production in the center of the field.

Differential diagnosis

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Connective tissue tumors

Fig. 35.627

Fig. 35.629

Extraskeletal osteosarcoma: high-power view showing nuclear pleomorphism.

Soft tissue chondroma: the tumor is encapsulated and composed of well-defined lobules of mature cartilage.

Fig. 35.628

Fig. 35.630

Extraskeletal osteosarcoma: the osteoid is rimmed by malignant osteoblasts.

Soft tissue chondroma: the nuclei are typically irregular. In many areas, multiple chondrocytes occupy individual lacunae.

of ­bilateral ­chondromas occurring in association with chronic renal failure has been reported.6

Distinction from a benign mixed tumor of adnexal origin is easy because the latter always shows epithelial elements.

Histological features The tumor, which may be intradermal or subcutaneous, is composed of a well-circumscribed, lobulated mass of mature hyaline cartilage (Figs 35.629, 35.630). Dystrophic or degenerative features – such as myxoid change, hemorrhage, calcification or ossification – are commonly seen, particularly at the periphery of the tumor lobules. These features may be associated with a histiocytic and osteoclastic giant cell reaction. A typical feature, often of diagnostic concern, is the hypercellularity of the lesional cartilage, often with binucleated nuclei and focal nuclear atypia. In the context of a bone tumor, such features would be suggestive of malignancy. Some cases are composed of small, rounded, more primitive chondroblasts, often in a myxoid stroma. If the presence of a primary lesion in bone has been carefully excluded, the diagnosis of a benign chondroma is assured, despite the worrying features described above. The basis of this assumption is that there is no convincing evidence that a lesion such as an extraskeletal well-differentiated chondrosarcoma exists.

Malignant tumors of cartliage Extraskeletal myxoid chondrosarcoma Clinical features Extraskeletal myxoid chondrosarcoma is an uncommon tumor that usually arises in adulthood, shows a slight predilection for males, and occurs most often in the limbs (particularly the legs).1–4 Although frequently of deep origin, up to 20% of cases arise subcutaneously. It presents as a slowly growing, usually painless, large mass. Although it was formerly believed that only 10–15% of cases recur or metastasize, it appears that most patients die of metastatic disease after long follow-up of 10–20 years.3,4 However, in a recent study the overall 5-, 10- and 15-year survival was 82%, 65% and 58%, respectively, after combined treatment with surgery and chemotherapy.5

Malignant tumors of cartliage

Pathogenesis and histological features In recent years, it has become clear that this tumor does not have chondrosarcomatous lineage as previously believed and it is more likely to represent a tumor of primitive mesenchymal cells.6 Extraskeletal myxoid chondrosarcoma is characterized in most cases by a ­specific t(9;22)(q22;q12) fusing NR4A3 and EWSR1.7–10 EWSR1 can be substituted by at least three additional homologous genes in a small subset of cases.11–15 These tumors have a characteristic microscopic appearance consisting of irregular but well-defined lobules with peripheral closely packed undifferentiated small cells with little cytoplasm (Figs 35.631, 35.632). The more central portion of each tumor lobule comprises a loose myxoid stroma within which are ovoid to spindle-shaped cells arranged in interlacing cords and strands (Fig. 35.633). Occasional cases show obvious chondroblastic differentiation. Mitotic figures tend to be sparse. Infrequently, there are foci of metaplastic bone formation, most often at the periphery of the lesion, and rare cases exhibit intracytoplasmic eosinophilic (­rhabdoid) inclusions. Fig. 35.633 Extraskeletal myxoid chondrosarcoma: the tumor cells are pleomorphic and hyperchromatic.

Tumor cells usually have abundant intracytoplasmic glycogen, and up to 20% of cases are positive for S-100 protein.16,17 Rarely, there may be focal positivity for EMA and keratin.17

Differential diagnosis The most important differential diagnosis includes myxoid liposarcoma and malignant mixed tumors. The former has a distinctive branching vascular pattern and lipoblasts are evident, whereas the latter tumor shows epithelial elements with ductal differentiation and, often, more differentiated cartilage. In addition, it expresses keratin and actin. Fig. 35.631 Extraskeletal myxoid chondrosarcoma: the tumor is lobulated and shows a biphasic population. Small hyperchromatic cells at the periphery merge with a central myxoid component.

Extraskeletal mesenchymal chondrosarcoma Clinical features Extraskeletal mesenchymal chondrosarcoma is a very rare, deep-seated tumor that tends to occur more often in younger adults than the myxoid type.1–3 It is more common in females and appears frequently in the head and neck region and upper trunk, and less often in the limbs. The prognosis appears to be worse than that for the myxoid variants.

Histological features

Fig. 35.632 Extraskeletal myxoid chondrosarcoma: medium-power view.

Extraskeletal mesenchymal chondrosarcoma has a distinctive biphasic histological appearance characterized by undifferentiated round or ­spindle-shaped mesenchymal cells and variably prominent foci of generally mature, well-differentiated cartilage (Figs 35.634, 35.635). Mitotic activity is usually prominent. Often, the undifferentiated cells are arranged around numerous slit-like vessels in a hemangiopericytoma-like pattern. Cartilaginous areas may show dystrophic calcification and sometimes ossification. Tumor cells are positive for CD99.4 The cartilaginous areas are S-100 protein positive. Nuclear Sox9, a chondrogenic transcription factor, can be detected.5–7

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Connective tissue tumors

Fig. 35.634

Fig. 35.635

Extraskeletal mesenchymal chondrosarcoma: low-power view showing an intensely cellular tumor.

Extraskeletal mesenchymal chondrosarcoma: malignant cartilage is present on the right of the field.

Miscellaneous benign lesions Synovial metaplasia Clinical features Synovial metaplasia is a rare phenomenon that has no distinctive clinical features. It usually presents as an incidental histological finding in biopsies performed at sites of previous trauma, particularly surgery.1–5 Synovial metaplasia is not uncommon in the setting of silicone implants.3 It may also be seen in association with the use of tissue expansors. Synovial metaplasia-like changes have also been described in oral mucoceles under the rubric papillary synovial metaplasia-like changes or myxoglobulinosis.6–9 A single recurrent lesion has been described and a case was documented in a patient with Ehlers-Danlos syndrome.10,11

Pathogenesis and histological features It has been suggested that, at least in cases associated with foreign material, the phenomenon probably represents a specialized form of tissue repair.12 Histology shows a cystic cavity with a lining identical to that seen in hyperplastic synovial tissue and composed of histiocyte-like cells which are ­variably positive for CD68 (Figs 35.636, 35.637).

Cutaneous myxoma Clinical features Cutaneous myxomas (also known as cutaneous myxoid cysts) are rare and are characterized by a solitary small painful lesion that occurs most often on the hand (especially the fingers) of adults and shows a marked predilection for females.1 Local recurrence is common. Multiple lesions are exceptional and in one reported case there was transepidermal elimination of myxoid material.2 A case presenting on the knee joint has been documented.3

Histological features Histological features consist of a poorly circumscribed dermal lesion composed of plump stellate and spindle-shaped cells with no atypia ­surrounded by an abundant myxoid matrix. Lesional cells are negative

Fig. 35.636 Synovial metaplasia: low-power view of cyst lined by cells with intensely eosinophilic cytoplasm.

for S-100 ­protein and actin. Whether these swellings are related to focal ­cutaneous mucinosis is uncertain.

Massive localized lymphedema Clinical features Massive localized lymphedema is a distinctive soft tissue lesion that arises as a complication of morbid obesity and can be confused with a neoplasm, mainly a well-differentiated liposarcoma.1–7 Patients are grossly obese, predominantly women in the fifth decade of life and present with a unilateral, or rarely bilateral, large mass with predilection for the inner aspect of the proximal limbs. Involvement of other areas in the limbs, scrotum and suprapubic area has also been reported. Lesions are long-standing, asymptomatic,

Non-neural dermal granular cell tumor

Fig. 35.637 Synovial metaplasia: high-power view.

Fig. 35.638 Non-neural dermal granular cell tumor: these lesions are generally superficial and polypoid with an epidermal collarette.

i­ll-defined, can weight more than 7 kilograms and may be recurrent. The overlying skin can show a cobblestone appearance.2 The clinical diagnosis is usually that of a lipoma or recurrent cellulitis.

Pathogenesis and histological features The lesion develops as a result of localized chronic lymphedema secondary to gross obesity. The latter is complicated in some patients by other causes of chronic lymphedema including surgery and trauma. An association with hypothyroidism has been reported.3 Histologically, fat lobules are separated by thick fibrous and edematous septa with elongated fibroblasts. Groups of capillaries are identified at the interface between adipose tissue and the septa.

Differential diagnosis The main differential diagnosis is with sclerosing atypical lipomatous tumor. In the latter, there is cytological atypia of adipocytes, and clusters of capillaries in the interface between adipose tissue and sclerosed septa are not usually present.

Fig. 35.639 Non-neural dermal granular cell tumor: the tumor cells have eosinophilic granular cytoplasm, similar to other granular cell tumors.

Non-neural dermal granular cell tumor (primitive polypoid granular cell tumor) Clinical features Primitive polypoid granular cell tumor is a rare variant of granular cell tumor which usually presents as an exophytic cutaneous lesion with a wide anatomical distribution, broad age range and no sex predilection.1–4 Oral lesions are exceptional.5 Not all tumors are polypoid. Clinical behavior appears to be benign with only rare local recurrences.1–4 In two cases, regional lymph node metastases have been documented.4,6

Histological features Histologically, lesions are often but not always polypoid, intradermal and well-circumscribed. An infiltrative growth pattern is exceptional.7 Focal extension into the subcutaneous tissue is sometimes seen. Tumor cells are rounded or spindle-shaped cells with prominent granular cell change (Figs 35.638–35.640). Nuclear pleomorphism varies and tends to be focal. However, in some lesions, cytologic atypia may be prominent throughout. Mitotic figures may be conspicuous. Multinucleated cells are sometimes

Fig. 35.640 Non-neural dermal granular cell tumor: in this example, the tumor cells are spindled and there is conspicuous mitotic activity.

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Connective tissue tumors present. There is diffuse positivity for NKI-C3 (a non-specific marker for lysosomes) and focal positivity for CD68. Positivity for PGP 9.5 has been documented in two cases.8 Tumor cells do not express keratin, EMA, actin or S-100 protein.1–4

Superficial angiomyxoma Clinical features Superficial angiomyxoma comprises a relatively uncommon group of lesions which present on the head, neck or trunk of adults as slowly growing, solitary, asymptomatic nodules or polyps ranging in size from 1 to 5 cm.1–3 Larger lesions rarely occur.4 Tumors also appear to be relatively common in the genital region and are very rare in the oral cavity and pharynx.5–8 Three cases associated with pilomatricomas have been documented.9 Local recurrence is common and occurs in up to 25% of cases. The myxomas described in the Carney complex are very similar, if not identical, to superficial angiomyxomas.2,3,7–10 This complex, described in 1985, is an autosomal dominant disorder associated with inactivating mutations in PRKAR1A which encodes a regulatory subunit of protein kinase A,11–14 consisting of myxomas, spotty pigmentation (lentigines on the face, especially the lips) and endocrine overactivity (Cushing's syndrome, pituitary adenoma and testicular tumors).11,15,16 Additional features of the complex include blue nevi and psammomatous melanotic schwannoma. The myxomas can present in the skin, breast and heart. Their recognition in the skin is important because they can be the first manifestation of the syndrome. They are usually multiple, present in young adults, and have a wide anatomical distribution, with a special preference for the eyelids, ears and nipples.17

Histological features Histologically, the lesions are dermal and subcutaneous, consisting of multiple, poorly circumscribed myxoid lobules containing bland spindle-shaped or stellate cells and abundant small blood vessels (Figs 35.641, 35.642). Often, a sparse inflammatory cell infiltrate containing lymphocytes and neutrophils is also present. In about 30% of cases – either in the primary lesion or its recurrence – there is an epithelial component. The latter consists of epithelial strands, keratin cysts or nests of basaloid cells.1,2,18 It may mimic a follicular tumor such as a trichofolliculoma.19 In a single case of a vulvar tumor, necrotizing vasculitis was found within the lesion.20

Fig. 35.642 Superficial angiomyxoma: the myxoid deposits contain stellate cells and thin-walled vessels.

Immunohistochemistry shows positivity of tumor cells for vimentin and variable focal positivity for factor XIIIa, CD34 and (less frequently) actin.

Differential diagnosis Nerve sheath myxoma is composed of discrete, well-defined nodules which contain S-100 protein-positive cells. Low-grade myxofibrosarcoma is also a multilobular tumor but it is more deeply located and contains pleomorphic cells with mitotic activity. Superficial angiomyxoma hardly ever occurs in the fingers, and this, together with the presence of a more prominent vascular proliferation and a focal inflammatory cell infiltrate, allows distinction from a myxoid cyst.

Ossifying fibromyxoid tumor Clinical features Ossifying fibromyxoid tumor is a distinctive neoplasm that presents mainly as a small asymptomatic subcutaneous nodule usually less than 3 cm, on the trunk or proximal limbs of middle-aged adults and shows a predilection for males.1–7 However, the anatomical distribution and age range are wide and tumors can present in the head and neck including the oral cavity and mediastinum.8,9 Recurrence occurs in 20–30% of cases after incomplete excision, although the latter was not found to be of relevance in a large recent study.3,7,8 Primary cutaneous lesions are very rare and include a malignant example.10,11 Rare examples of atypical and malignant variants of this tumor have been described and they have metastatic potential (see below).3,12 Even rarer tumors with no atypical histological features may occasionally have an aggressive behavior. Based on this, ossifying fibromyxoid tumor should be considered as a tumor of intermediate malignancy.3

Histological features

Fig. 35.641 Superficial angiomyxoma: there is massive myxoid change in the dermis associated with numerous small vessels.

The tumors are well circumscribed and lobular and consist of rounded or polygonal cells with pale or eosinophilic cytoplasm and vesicular nuclei, arranged in cords or nests, in a myxoid or hyaline richly vascular matrix (Figs 35.643, 35.644). Tumor lobules are separated by fibrous septa. In up to two-thirds of cases, metaplastic bone is present within the capsule and in the fibrous septa. Nonossifying tumors may also occur. Unusual findings include microcysts, microcalcifications, satellite micronodules, epidermoid cysts and atypical chondroid differentiation.13,14 Rare cases with otherwise typical histological features are more cellular, display cytological atypia, have an increased mitotic rate, and the bone clearly originates from

Ossifying fibromyxoid tumor

Fig. 35.643

Fig. 35.645

Ossifying fibromyxoid tumor: around 60% of lesions have a distinctive outer shell of lamellar bone. Note the characteristic lobulation.

Malignant ossifying fibromyxoid tumor: the lesion appears pseudo-encapsulated and there is a peripheral rim of osteoid. Myxoid change is present on the right side.

Fig. 35.644

Fig. 35.646

Ossifying fibromyxoid tumor: the tumor cells are rounded and uniform with pale staining cytoplasm.

Malignant ossifying fibromyxoid tumor: the tumor cells show nuclear pleomorphism and have pale-staining or clear cytoplasm.

tumor cells (Figs 35.645–35.647). Necrosis (in up to 10% of cases) and vascular invasion are additional findings.7 Histologically malignant cases have a high recurrence rate and pulmonary metastases and death have been reported.3,12 It has been suggested that lesions with high nuclear grade or high cellularity and mitotic activity of more than two mitotic figures per 50 high-power fields (HPFs) should be regarded as sarcomas.3 Tumors with an infiltrative growth pattern are associated with an increased recurrence rate.3 In a more recent and larger study of 104 patients, no metastasis were noted and only a mitotic count of more than two per 50 HPFs was associated with increased risk of local recurrence.7 Necrosis, tumor size, satellite nodules and incomplete excision were not associated with increased risk of local recurrence.7 The tumor cells are positive for S-100 protein (in up to 94%% of cases) and desmin (up to 13% of cases).3,4,6,7,13 Focal positivity for glial fibrillary acid protein, SMA, cytokeratin and collagen II may also be seen.3,7 CD56 and CD99 positivity has been reported in one case.14 Proposed lines of differentiation for this tumor include neural, myoid, chondroid and myoepithelial. In one case in which ultrastructural studies were performed, ribosome–lamella complexes were identified.15

Fig. 35.647 Malignant ossifying fibromyxoid tumor: malignant cartilage is maturing into osteoid.

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Connective tissue tumors Cytogenetic studies have shown complex clonal chromosomal abnormalities; however, no repetitive events have been identified.16–18

Differential diagnosis The differential diagnosis includes myxoid chondrosarcoma, which is usually negative for desmin and SMA, and chondroid syringoma, which in most cases shows an obvious epithelial component.

Phosphaturic mesenchymal tumor (mixed connective tissue variant) Clinical features Phosphaturic mesenchymal tumor (mixed connective tissue variant) is a ­distinctive neoplasm that induces oncogenic osteomalacia, a paraneoplastic syndrome resulting from phosphate wasting. Occasional identical tumors not associated with oncogenic osteomalacia are seen.1 Lesions vary in size and arise in deep soft tissues and bone and rarely in the subcutaneous tissue.2 Most patients are adults but the age range is wide and there is predilection for females.1 At the time of diagnosis, patients have often had long-standing osteomalacia. In one patient, symptoms of osteomalacia only appeared 1 year after resection of the tumor.3 Occasional malignant tumors occur and exceptionally ­metastases are seen.1,4

Fig. 35.649 Phosphaturic mesenchymal tumor: the tumor cells have eosinophilic cytoplasm and hyperchromatic spindled nuclei. Microcysts are present.

Histological features Tumors appear to produce fibroblast growth factor-23 and this seems to be important pathogenetically, as the protein induces loss of phosphate in the renal tubules.5 Lesions are ill-defined and hypocellular with areas of myxoid change, bland spindle-shaped cells, hemorrhage, microcystic spaces, proliferation of blood vessels often in a hemangiopericytomatous pattern, ­osteoclasts and a calcified matrix (Figs 35.648–35.651). Focal ­ossification can also be identified. A small number of tumors display other histological patterns including hemangiopericytoma, giant cell tumor and osteosarcoma.1 Tumor cells are usually positive for fibroblast growth factor-23, and this is a very useful diagnostic test. Vascular channels in the tumor are positive for LYVE-1 and podoplanin, indicating lymphatic lineage.6 Fig. 35.650 Phosphaturic mesenchymal tumor: higher-power view showing tumor cells and blood vessels.

Fig. 35.648

Fig. 35.651

Phosphaturic mesenchymal tumor: scanning view showing cysts, blood vessels, focal hemorrhage and a myxoid stroma.

Phosphaturic mesenchymal tumor: high-power view of spindled cells showing a vaguely fascicular growth pattern.

Perivascular epithelioid cell tumor

Miscellaneous low-grade and malignant tumors Myoepithelioma of soft tissue Clinical features Myoepithelioma of soft tissue is a rare tumor that presents mainly in middleaged adults, with no sex predilection, as a subcutaneous or deep-seated, fairly well-circumscribed mass.1,2 Lesions frequently occur in the limbs and limb girdles, followed by the head and neck and trunk. There is local recurrence in up to 20% of cases and a number of tumors with malignant histology may metastasize. It is controversial as to whether myoepithelioma represents the same tumor as parachordoma.3,4

Pathogenesis and histological features Recently, t(19;22)(q13;q12) fusing EWSR1 and ZNF444 has been described in this neoplasm.5 PBX1 (1q23) can also pair with EWSR1.6 A recent larger study demonstrated EWSR1 rearrangements in 59% of cases and identified POU5F1 (6p21.31) as an additional partner.7 Other studies have described very heterogeneous genetic alterations in these tumors.8 Histology shows a lobulated circumscribed tumor that may have a focal infiltrative margin. Tumor cells are epithelioid, ovoid or short and spindleshaped and are arranged in cords and nests in a variably myxoid, chondroid, hyalinized or fibrotic stroma (Figs 35.652, 35.653). Solid areas may ­predominate and some cells may have a plasmacytoid appearance. Ductal ­differentiation and bone and cartilage formation are additional features. Tumors classified as malignant have prominent atypia and variable mitotic activity. Malignant bone or cartilage may be seen. Immunohistochemistry shows that in most cases tumor cells are positive for keratin, calponin and sometimes S-100 protein (Figs 35.654, 35.655).2 Frequent staining for EMA, GFAP and SMA is also seen, and rare cases are positive for desmin (Fig. 35.656).2

Fig. 35.653 Myoepithelioma of soft tissue: the tumor cells have eosinophilic cytoplasm and uniform round nuclei.

Perivascular epithelioid cell tumor Perivascular epithelioid cell tumor (‘PEComa’) is part of the spectrum of neoplasms that includes clear cell ‘sugar’ tumor of the lung, angiomyolipoma, lymphangioleiomyomatosis and clear cell myomelanocytic tumor of the falciform ligament.1 The first three neoplasms are often associated with tuberous sclerosis. Occurrence of similar tumors in the skin and soft tissue is rare but increasingly reported and these are not associated with tuberous sclerosis.2–7 Cutaneous lesions are more common in middle-aged females and

Fig. 35.654 Myoepithelioma of soft tissue: the tumor cells express pankeratin.

Fig. 35.652

Fig. 35.655

Myoepithelioma of soft tissue: scanning view of a multilobulated tumor with conspicuous pools of mucin.

Myoepithelioma of soft tissue: S-100 protein is also expressed.

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Connective tissue tumors

Fig. 35.656

Fig. 35.658

Myoepithelioma of soft tissue: desmin is positive.

Perivascular epithelioid cell tumor: the tumor cells are surrounded by a vascular network.

have ­predilection for the limbs where they present as a slowly growing, small asymptomatic nodule. A single case of malignant cutaneous perivascular ­epithelioid cell tumor with lymph node metastasis has been reported.8

Histological features Histology shows an ill-defined dermal tumor that may extend into the subcutaneous tissue and is composed of bland epithelioid cells typically arranged radially around thin-walled vascular channels (Figs 35.657, 35.658). A smaller population of spindled cells is often seen. Tumor cells have clear, granular or pale pink cytoplasm and vesicular nuclei (Fig. 35.659). Rare multinucleated cells may be seen. Mitotic figures are often found but are not prominent, and very focal cytologic atypia can be seen (Fig. 35.660). A hyalinizing variant has been described in the retroperitoneum.9 The immunophenotype is distinctive, as tumor cells stain for ­melanocytic markers including HMB-45, MITF-1, Melan-A and tyrosinase and for ­muscular markers including desmin, SMA and, less frequently, calponin. NKIC3 is also positive. It is important to highlight that HMB-45 may only be focally positive. Cells are negative for S-100 protein, h-caldesmon, epithelial ­membrane antigen and keratin. Recently, nuclear TFE3 expression has been documented in a subset of cases (see alveolar soft part sarcoma).10–12 The ­significance of this finding is unclear.

Fig. 35.659 Perivascular epithelioid cell tumor: high-power view showing clear cytoplasm and uniform vesicular nuclei with eosinophilic nucleoli.

Fig. 35.657

Fig. 35.660

Perivascular epithelioid cell tumor: low-power view of a clear cell tumor. Note that the appendages are spared.

Perivascular epithelioid cell tumor: note the mitotic figures.

Epithelioid sarcoma

Differential diagnosis Distinction from melanocytic lesions with balloon cell change is based on the presence of a junctional component and the frequent diffuse positivity for S-100 in the latter. The so-called dermal clear cell neoplasm has very ­similar histologic features to those of perivascular epithelioid cell tumor but the ­former is negative for melanocytic markers. Clear cells may be focally or ­diffusely present in dermatofibroma but the latter is associated with ­epidermal hyperplasia and is negative for melanocytic markers and variably positive for factor XIIIa. In metastatic renal cell carcinoma, the blood vessels are dilated and congested, there is more cytological atypia and more prominent clear cell change and tumor cells are positive for keratins and EMA.

Pleomorphic hyalinizing angiectatic tumor Clinical features Pleomorphic hyalinizing angiectatic tumor is a distinctive, rare, low-grade malignancy of uncertain line of differentiation. In the few cases reported so far, the tumor has presented in the subcutaneous tissue of adults, with the same sex incidence and predilection for the lower limbs.1–6 There is local recurrence but metastases have not so far been documented. A single case recurred with a high-grade myxofibrosarcoma component.7

Fig. 35.662 Pleomorphic hyalinizing angiectatic tumor of soft parts: surrounding the vessels are pleomorphic spindled cells with irregular, hyperchromatic nuclei.

Histological features Tumors are poorly circumscribed and consist of congested, angiectatic blood vessels surrounded by spindle-shaped pleomorphic cells in a myxoid background (Figs 35.661–35.663). Hemorrhage, hemosiderin deposition and perivascular hyalinization with fibrin and collagen deposition are additional features. Mitotic activity is very low. Tumor cells are focally positive for CD34, CD99, vascular endothelial growth factor and factor XIIIa.8,9 Early lesions of the tumor consist of spindle-shaped cells arranged in short fascicles infiltrating the fat, associated with cytoplasmic hemosiderin and with damaged blood vessels in the background.10 There are always scattered pleomorphic cells, some of which contain intranuclear inclusions. Lipoblast-like cells are exceptional.11 This precursor lesion has been considered as identical to hemosiderotic fibrohistiocytic lipomatous lesion, a view not shared by all authors.11–14 The change may reflect impaired blood circulation as a result of venous insufficiency in the vicinity of the tumor.14

Differential diagnosis The differential diagnosis is mainly with an ancient schwannoma. Distinction is based on the presence of a capsule, less cytologic atypia and diffuse S-100 protein positivity in the latter.

Fig. 35.663 Pleomorphic hyalinizing angiectatic tumor of soft parts: high-power view showing marked nuclear pleomorphism.

Epithelioid sarcoma Clinical features

Fig. 35.661 Pleomorphic hyalinizing angiectatic tumor of soft parts: there are numerous thinwalled angiectatic blood vessels surrounded by a cellular stroma.

Epithelioid sarcoma is a comparatively rare tumor arising most often on the distal extremities (particularly the hand and wrist) of young adults, especially males.1–5 Occurrence in children is uncommon.6 The overall age range and the anatomical distribution are wide. Rare cases present in the head and even in the oral cavity and parotid gland (Figs 35.664, 35.665).7–10 It is predominantly a dermal or subcutaneous tumor that presents as a slowly ­growing, ­elevated, often tender nodule(s) measuring less than 5 cm in diameter. Ulceration is a common feature. Due to the distinctive tendency for extensive spread of the tumor along blood vessels, nerves and fascia, the presence of satellite ­nodules at a distance from the main tumor is common. The tumor may mimic other diseases including perforating granuloma annulare and Dupuytren's disease.11,12 Indolent and repeated locoregional recurrence is common. Metastasis to the lymph nodes, an unusual feature in other sarcomas, is quite common, ­followed by metastasis to the lungs. Although the overall 5-year survival is about 70%, the 20-year survival is no more than 20–25%.2,3 Improved ­prognosis appears to be related to smaller tumor size.3 A group of epithelioid sarcomas arising in pelvi-perineal locations (including the vulva) have a very aggressive clinical course, more so than the ordinary

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Fig. 35.664 Epithelioid sarcoma: the hand is a commonly affected site. By courtesy of Dr. Yi-Guo Feng, Xian, China.

Fig. 35.665 Epithelioid sarcoma: spread along the neurovascular bundles and fascial planes commonly results in more proximal tumor deposits as seen in this patient. By courtesy of Dr. Yi-Guo Feng, Xian, China.

Fig. 35.666 Epithelioid sarcoma: the upper dermis is diffusely infiltrated by an ulcerated tumor.

Fig. 35.667 Epithelioid sarcoma: in this field the tumor cells are epithelioid with abundant eosinophilic cytoplasm and large vesicular nuclei.

variant, and have been described as proximal-type epithelioid sarcoma.13–17 Similar cases exceptionally occur in other locations.18 Independent indicators of worse biological behavior are early metastases and large tumor size.19

Pathogenesis and histological features The most consistent cytogenetic abnormality in the few cases studied so far has been loss of heterozygosity of chromosome 22q.20–22 Loss of INI1 (BAF47) nuclear expression encoded by SMARCB1 (INI1) at 22q11.23 is characteristic and likely critical for the pathogenesis.23,24 Other abnormalities have been found in 8q and monosomy 21 has also been documented.21 Abnormalities of chromosomes 8 and 22 have also been found to be involved in the proximaltype of epithelioid sarcoma.25 An N-ras oncogene mutation has been described in a case of metastatic epithelioid sarcoma.26 The microscopic appearances are distinctive (Figs 35.666–35.668). The tumor is composed of multiple nodules of polygonal, epithelioid or spindle-shaped cells with eosinophilic cytoplasm which show variable pleomorphism. Mitoses are often scanty. Giant cell forms are occasionally seen. At the ­center of these nodules, focal necrosis is a prominent feature in around 50% of cases, producing an appearance reminiscent of a granulomatous ­process (Fig. 35.669). Other cases show a vague fibrinoid or myxoid pattern of degeneration. The latter may predominate in rare cases. At the periphery

Fig. 35.668 Epithelioid sarcoma: elsewhere the tumor cells have a spindled morphology.

Epithelioid sarcoma

Fig. 35.669

Fig. 35.671

Epithelioid sarcoma: geographical necrosis seen at low-power examination may result in diagnostic confusion with a granulomatous process.

Epithelioid sarcoma: the tumor cells characteristically express keratin, as shown in this field.

Fig. 35.670

Fig. 35.672

Epithelioid sarcoma: the tumor commonly extends along nerve trunks, in part accounting for its high recurrence rate.

Epithelioid sarcoma: epithelial membrane antigen positivity is usually evident.

of the nodules, the tumor cells tend to be more spindle shaped, and in rare cases this feature can be prominent (see below).18,27 Vascular and perineural invasion is often present (Fig. 35.670). In a small number of cases, spindleshaped cells predominate, they are arranged in bundles and necrosis is minimal or absent. This variant is known as fibroma-like.27,28 In a few cases, an angiomatoid pattern is seen.28 Heterotopic bone formation is exceptional.29 Immunohistochemically, more than 90% of cases are positive for vimentin, cytokeratin and EMA (Figs 35.671, 35.672) and up to 60% are positive for CD34.30–33 SMA is also often focally positive. The combination of vimentin, CD34 and keratin positivity is very useful in the diagnosis of epithelioid sarcoma. The immunohistochemical profile of proximal-type epithelioid sarcoma is similar to that of classic epithelioid sarcoma. Both forms show loss of nuclear INI1 expression in greater than 90 % of cases, a relatively specific finding within the reasonable differential diagnoses.34–36 GLUT-1 is not a useful marker in the diagnosis of epithelioid sarcoma.37 CA125 has been reportedly often positive in epithelioid sarcoma and negative in reactive and neoplastic conditions that can mimic this tumor.38 Proximal epithelioid sarcoma is characterized by a diffuse growth pattern (Figs 35.673, 35.674). Tumor cells are mainly epithelioid and mitotic activity is often brisk (Fig. 35.675). Focal or extensive rhabdoid change is often present (Figs 35.676– 35.678).17 Necrosis seems to be less common than in the ordinary variant.

Fig. 35.673 Proximal epithelioid sarcoma: the tumor is characterized by a diffuse cellular infiltrate with widespread necrosis.

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Fig. 35.674 Proximal epithelioid sarcoma: the tumor cells are epithelioid with eosinophilic cytoplasm and round vesicular nuclei containing conspicuous nucleoli.

Fig. 35.677 Proximal epithelioid sarcoma: the tumor cells are positive for keratin (AE1/AE3).

Fig. 35.675

Fig. 35.678

Proximal epithelioid sarcoma: in this example, there is marked mitotic activity.

Proximal epithelioid sarcoma: CD34 is also expressed in this example.

Ultrastructural studies show that the epithelioid tumor cells contain wellformed desmosome-like junctions and aggregates of intermediate filaments, often in a paranuclear location.32 In a case of proximal-type epithelioid sarcoma immunoelectron microscopy demonstrated keratin filaments but not vimentin, suggesting a closer relation to epithelial cells than to mesenchymal cells.39

Differential diagnosis

Fig. 35.676 Proximal epithelioid sarcoma: rhabdoid inclusions, as seen in the center of the field, are often present.

The distinctive histological features in an appropriate clinical setting usually prevent diagnostic confusion. Lack of awareness of this entity may lead to the mistaken diagnosis of necrotic metastatic carcinoma or a granulomatous inflammatory lesion. Distinction from epithelioid hemangioendothelioma or angiosarcoma can be difficult because often in epithelioid sarcoma there are pseudovascular clefts and focal cytoplasmic vacuolation. However, cells in the former tend to grow in cords, at least focally, and are often larger; they stain positively for endothelial markers and are frequently keratin positive. Malignant rhabdoid tumor shows many cells with intracytoplasmic inclusions, and although immunohistochemically the tumor cells are positive for epithelial markers, they also usually show positivity for other markers, indicating divergent differentiation. Furthermore, rhabdoid

Synovial sarcoma tumors have distinctive vesicular nuclei with macronucleoli. Deep granuloma annulare and rheumatoid nodule can mimic epithelioid sarcoma, particularly on low-power examination.40 However, the former entities show neither cytological atypia nor mitotic activity, there is absence of necrosis and presence of necrobiosis with either fibrin or mucin deposition, and histiocytes are positive for CD68 and negative for keratin and CD34.41

Synovial sarcoma Clinical features Synovial sarcoma is a relatively common, deep-seated tumor that characteristically arises in the limbs (particularly the legs) of young adults and shows a predilection for males.1–3 Overall age and anatomical distribution is wide, including truncal and head and neck lesions. The dermis is only exceptionally involved by deep-seated tumors. Primary cutaneous synovial sarcoma is vanishingly rare.4 A subset of more superficial, minute synovial sarcomas measuring less than 1 cm and with predilection for the hands and feet has been described.5 Histologic features are similar to those of ordinary synovial sarcoma. They seem to have a better prognosis than deep-seated lesions.5 Most cases show no evidence of a tenosynovial origin. In general, the prognosis is poor, with eventual metastatic spread and death in at least 50% of patients. The tumor tends to metastasize late, and long follow-up is therefore necessary.6

Fig. 35.680 Synovial sarcoma: the glandular spaces contain eosinophilic material.

Pathogenesis and histological features Most cases of synovial sarcoma including monophasic and biphasic variants show a balanced t(X;18)(p11;q11) which fuses either SSX1, SSX2 or much less commonly SSX4, situated together on the X chromosome, with SYT.7–9 Involvement of SSX1 is more common in biphasic tumors while any of the three can be involved in the monophasic form. 10 The prognostic value of the different fusion types is debated, but is likely small, if present. 11–14 When biphasic, these tumors usually have a distinctive appearance typified by an undifferentiated spindled cell component with tapering nuclei admixed with well-formed glandular spaces lined by tall columnar PASpositive, mucin-secreting epithelium (Figs 35.679–35.681). The glandular component very rarely shows apocrine differentiation, and in superficial tumors, this may lead to a diagnosis of carcinosarcoma. The relative proportions of the spindled cell and glandular components vary from tumor to tumor and most cases have a monophasic spindle cell appearance (Figs 35.682–35.684). A hemangiopericytoma-like vascular pattern and calcification are common findings, as is the presence of wiry stromal collagen and mast cells.

Fig. 35.681 Synovial sarcoma: the secretion is diastase–PAS positive.

Fig. 35.679

Fig. 35.682

Synovial sarcoma: this field shows the characteristic biphasic population of spindle cells and glandular spaces.

Synovial sarcoma: low-power view of a monophasic example showing the characteristic hemangiopericytomatous blood vessels.

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Fig. 35.683 Synovial sarcoma: high-power view showing hyperchromatic tumor cells with indistinct cytoplasm.

Fig. 35.685 Synovial sarcoma: the glandular component expresses keratin.

Pathogenesis and histological features

Fig. 35.684

Alveolar soft part sarcoma is associated with t(X;17)(p11;q25) which fuses TFE3 and ASPL ASPSCR1 (ASPL) in virtually all cases.5,9 This same translocation is present in a subset of pediatric renal tumors, though TFE3 is more often substituted by another gene.10,11 Characteristically situated within skeletal muscle, this tumor is composed of large round or oval cells with eosinophilic granular cytoplasm and ­hyperchromatic nuclei arranged in a distinctive alveolar pattern (Figs 35.686, 35.687). Some cases have an organoid pattern reminiscent of paraganglioma. Vascular invasion is common. The morphologic diagnostic sine qua non is the presence of ­intracytoplasmic PAS-positive, diastase-resistant crystals (Fig. 35.688) shown to be ­composed of monocarboxylate transporter 1 and CD147.12 These can sometimes be difficult to demonstrate.4 Although it has been suggested that the line of ­differentiation is muscular, results from different studies are not consistent. Tumors are sometimes positive for desmin and MyoD1 (often cytoplasmic and thus not meaningful) but are negative for myogenin (Fig. 35.689).13–16 Immunohistochemistry demonstrating nuclear TFE3 expression is ­diagnostically helpful.17 Intriguing for a mesenchymal malignancy, ­vimentin expression is absent in the great majority of cases.18

Synovial sarcoma: this example highlights the vascular pattern.

The glandular spaces and some of the adjacent spindled cells stain positively for epithelial markers, including keratin and EMA (Fig. 35.685).15,16 The markers, especially EMA, are also usually positive, albeit focally, in the monophasic variant. These findings usually allow distinction from malignant schwannoma and fibrosarcoma, the latter now being regarded as extremely rare. Focal positivity for S-100 protein and CD99 may also be seen.17,18 Nuclear expression of the new immunohistochemical marker TLE1 identified in a synovial sarcoma gene expression study appears to be specific and can be helpful.19–21

Alveolar soft part sarcoma Clinical features Alveolar soft part sarcoma is an extremely rare neoplasm that invariably arises in deep soft tissues and is therefore very infrequently encountered in dermatological practice.1–3 Cutaneous metastases are, however, occasionally seen.4–6 It presents in young adults, shows a slight predilection for females and arises most often in the extremities. The disease course can be relatively indolent, but the long-term prognosis is very poor.3,5,7,8

Fig. 35.686 Alveolar soft part sarcoma: this is a very rare example of a cutaneous metastasis.

Extrarenal rhabdoid tumor

Fig. 35.687

Fig. 35.689

Alveolar soft part sarcoma: the tumor cells have abundant eosinophilic cytoplasm and vesicular nuclei with large eosinophilic nucleoli. Rhabdoid forms are present.

Alveolar soft part sarcoma: there is strong nuclear expression of TFE3.

Fig. 35.688

Fig. 35.690

Alveolar soft part sarcoma: periodic acid-Schiff-positive, diastase-resistant intracytoplasmic needle-shaped crystalline inclusions are a distinctive feature.

The crystals usually obviate the necessity of any differential diagnosis when they can be unequivocally demonstrated, but occasional cases may need to be distinguished from metastatic renal cell carcinoma or granular cell tumor (Fig. 35.690).

Extrarenal rhabdoid tumor Clinical features Extrarenal rhabdoid tumor represents a group of heterogeneous lesions that presents in almost any organ including the skin.1–3 Most cases arise almost exclusively in infants and children, with a wide anatomical distribution (mainly the neck and paraspinal region), and the clinical course is almost invariably fatal. The best chance of longer survival is in patients with localized disease.4 Tumors may develop in the fetus and some familial cases have been documented.5–9

Alveolar soft part sarcoma: characteristic partially lamellated inclusions are seen on electron microscopy. By courtesy of Nelson Ordonez MD, UT-MD Anderson Cancer Centre, Houston, Texas.

Pathogenesis and histological features Cytogenetic analysis has demonstrated mutations in the hSNF5/INI1 (SMARCB1) gene located in chromosome 22q11.2.10–12 Histologically, the tumors share the presence of globular hyaline cytoplasmic inclusions, vesicular nuclei and prominent nucleoli (Figs 35.691, 35.692). Although the tumor cells are usually epithelioid, they vary in size and shape. The growth pattern of different tumors is not consistent and in some lesions small round blue cells may be prominent. Immunohistochemically, the tumor cells are usually positive for cytokeratin and EMA, but positivity for a variety of other markers indicating divergent differentiation is common.1 The relationship to their renal counterparts is uncertain as loss of nuclear INI1 expression is seen in both and can be helpful diagnostically.13–15 Loss of INI1 is also seen in epithelioid sarcoma .16

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Fig. 35.691

Fig. 35.692

Extrarenal rhabdoid tumor: this tumor, showing striking rhabdoid inclusions, proved to be a metastatic melanoma.

Rhabdoid melanoma: the tumor cells were positive for S-100 protein and HMB-45.

Index Note: ‘vs’ indicates differential diagnosis. Abbreviations: EB, epidermolysis bullosa. Illustrations are comprehensively referred to from the text. Therefore, significant material in illustrations and tables have only been given a page reference in the absence of their concomitant mention in the text referring to that figure

A

AA3 (monoclonal antibody), epidermolysis bullosa, 112 ABCA12 and harlequin fetus, 54 ABCC6 mutations and pseudoxanthoma elasticum, 952 ABCDE(F) rule, subungual melanoma, 1064 abdominal tumors, cutaneous metastases, 1423–1424 abscess, subcutaneous candidal, 862 metastatic tuberculous (=tuberculous gumma), 814, 815t, 817 acanthamebiasis, 848, 849 acantholysis, pseudovascular squamous carcinoma, 1128, 1129 acantholytic dermatitis herpetiformis (pemphigus herpetiformis), 162 acantholytic dermatoses/disorders (in general), 151–179 with dyskeratosis see dyskeratosis acantholytic EB, lethal, 104 acantholytic squamous carcinoma, 1128 acantholytic squamous cell carcinoma (adenoid/ pseudoglandular squamous cell carcinoma) conjunctival, 1277 oral, 429 penile, 508 acanthoma acantholytic, 178 acantholytic dyskeratotic, 179 clear cell (Degos), 1086–1087 epidermolytic, 59–60 granular parakeratotic, 1086 large cell, 1082–1085 pilar sheath, 1449 reticulated, superficial epithelioma with sebaceous differentiation vs, 1500 acanthosis nigricans, 583–585 acanthotic seborrheic keratosis, 1081 ‘acetowhite’ penile lesions, flat, 498 acid glycosaminoglycans (mucin), 571 see also mucinosis acinic cell carcinoma, 419 acne apocrine (acne inversa; hidradenitis suppurativa), 458–459, 655–657 halogen, 1044–1045 Mallorcan, 1045 papular, scars, 956 penile, 457–458 see also PAPA syndrome acne aestivalis, 1045 acne agminata (acnitis; papular tuberculid), 310, 818, 1049 acne agminita, 1049 acne conglobata and hidradenitis suppurativa, 656 acne cosmetica, 1043 acne fulminans, 1045 acne keloidalis nuchae (folliculitis keloidalis nuchae), 959, 1029–1031 differential diagnosis, 1030 dissecting cellulitis, 1028 acne necrotica (varioliformis), 1030 acne vermoulante, 69 acne vulgaris, 1041–1043 comedones, 1041–1043, 1575–1576 differential diagnosis, 1043 rosacea, 1048 acoustic neurofibromatosis see neurofibromatosis, type II acoustic schwannomas of NF2, 1669, 1680 acquired brachial cutaneous dyschromatosis, 933–934 acquired cutis laxa, 949 acquired elastotic hemangioma, 1720 acquired epithelial cysts of conjunctiva, 1273 acquired ichthyosiform conditions see ichthyosiform conditions acquired immune deficiency syndrome see HIV disease acquired immune response (adaptive response), 9 acquired inflammatory skin eruption, Blaschko linear, 232–233

acquired lipodystrophy, 354, 355–356 acquired melanosis, conjunctival primary (PAM), 1281–1283, 1284, 1285 acquired nevus of Ota, 1208 acquired palmoplantar keratoderma and internal malignancy, 91–97 acquired progressive kinking of hair, 1041 acquired progressive lymphangioma, 1744, 1745 acquired relapsing self-healing Blaschko dermatitis, 233–234 acquired reticulated lentigo, 1155 acral dominant dystrophic EB, 108–109 acral dysplastic nevus vs atypical acral nevus, 1171 acral fibromyxoma, superficial, 1071, 1072–1073, 1620–1621 acral hyperkeratosis, 82 acral keratoderma, 80 acral lentiginous melanoma, 1223–1224, 1228–1229 clinical features, 1223–1224 histology, 1228–1229 nail apparatus, 1065 see also acral melanoma acral lentigo, 1152–1153 acral melanoma DNA copy number changes, 42f UV exposure levels and, 1264–1265 see also acral lentiginous melanoma acral mucinous syringometaplasia, 1585–1586 acral myxoinflammatory fibroblastic sarcoma, 1635–1636 acral nevi, atypical, 1170–1171 acral persistent papular mucinosis, 578–579 acral pseudolymphomatous angiokeratoma, 1360 acroangiodermatitis (pseudo-Kaposi's sarcoma), 192–193, 1734 acrochordon see fibroepithelial polyp acrochordons, anogenital, 443 acrodermatitis, infantile papular, 195–196 acrodermatitis chronica atrophicans, 807, 808 acrodermatitis continua of Hallopeau, 204, 1057 acrodermatitis enteropathica, 586 morphea vs, 748 acrokeratoderma, marginal papular, 82 acrokeratoelastoidosis, 82 acrokeratosis paraneoplastica, 215 acrokeratosis verruciformis of Hopf, 91–92 acropigmentation, reticulate see reticulate acropigmentation acropustulosis of Hallopeau, 204 infantile, 217–218 acrospiroma see clear cell hidradenocarcinoma; clear cell hidradenoma acrosyringeal acantholytic disease, sudoriferous, 175, 176 acrosyringeal nevus, 1528 actin see smooth muscle actin actinic comedonal plaque, 962 actinic damage, lentigo maligna at sites of actinic damage, 1226–1227 actinic dermatitis, chronic (actinic reticuloid; photosensitivity dermatitis), 269 HIV-associated, 899, 1362–1364 actinic folliculitis, 1045 actinic granuloma (O'Brien), 302–304 differential diagnosis, 295t, 304 actinic keratosis (senile/solar keratosis), 1106–1109, 1274 chemotherapeutic drug-related, 622 conjunctival, 1274 in vitiligo, 913 actinic lentigo (solar/senile lentigo; liver spot), 1154–1155 clinical features, 1154 histology, 1154–1155 large cell acanthoma vs, 1085 see also reticulated black solar lentigo actinic lichen nitidus, 229 actinic lichen planus, 221, 226–227 actinic porokeratosis, disseminated superficial, 92, 94 actinic prurigo, 194

actinic reticuloid, 269 actinomycetic mycetoma, 878, 878t actinomycosis, 837–838 active sweating, 19 acute adult T-cell leukemia/lymphoma, 1351 acute febrile neutrophilic dermatosis see Sweet's syndrome acute generalized exanthematous pustulosis, 611 acute hemorrhagic edema of childhood, 461, 665–666 acute infectious id panniculitis, 352 acute intermittent porphyria, 550t acute myelogenous leukemia in Sweet's syndrome, 637 acute myeloid leukemia (AML), 1413 adalimumab, 626 lymphoproliferative disorders, 1384 adamantinoid lymphadenoma, 1469, 1475, 1482 Adamson's fringe, 976 ADAMTS13 deficiency, 707 adaptive immune response, 9 adenoacanthoma, 429 adenocarcinoma, 1430–1434 aggressive digital papillary, 1543–1544 anogenital mammary-like gland, 1515 ceruminous, 1518 cutaneous metastases, 1430–1434 mucous-secreting, vs myxoid melanoma, 1247 adenocystic carcinoma see mucinous carcinoma adenoid basal cell carcinoma vs adenoid cystic carcinoma, 1566 adenoid cystic carcinoma, 1558, 1563–1566 differential diagnosis (of cutaneous forms), 1566 syringoid eccrine carcinoma, 1559–1560 primary vs secondary, 1434–1435 salivary gland, 419, 1095 basaloid squamous cell carcinoma vs, 419 adenoid melanoma, 1247 adenoid seborrheic keratosis, vs Dowling-Degos disease, 926 adenoid squamous cell carcinoma see acantholytic squamous cell carcinoma adenoma aggressive digital papillary, 1543–1544 anogenital mammary-like glands, 510–511, 1515 apocrine see apocrine adenoma nipple see nipple oxyphil cell, lacrimal gland, 1273 papillary eccrine, 1514, 1541–1543 salivary gland canalicular, 418 pleomorphic, 417, 419 sebaceous see sebaceous adenoma sebocrine, 1507, 1515–1516 vulval, 510–511, 512 see also cystadenoma; dacryoadenoma; hidradenoma; lymphadenoma; spiradenoma; syringocystadenoma papilliferum; syringofibroadenoma; trichoadenoma adenoma sebaceum see angiofibroma adenomatoid hyperplasia of salivary glands, 417 adenomatosis of nipple, erosive, 1515 adenomatous polyposis, familial see Gardner's syndrome adenosquamous carcinoma see mucoepidermoid (adenosquamous) carcinoma adherens junctions, 14 adhesion, cell, abnormality in Hailey-Hailey disease, 168 adipocytes, 30–31 adipocytic (lipomatous/lipoma-like) tumors, 1590 atypical massive localized lymphedema vs, 1755 oral, 369–370 conjunctival, 1270, 1291 adipose tissue see fat adiposis dolorosa, 1596 adnexal carcinoma (primary cutaneous) metastatic adenocarcinoma vs, 1433, 1434 microcystic/aggressive, 1558, 1559–1563 adnexal polyp, neonatal, 1528

1770

Index adnexal structures, basal cell carcinoma with differentiation towards, 1098 adolescents, mycosis fungoides, 1326 adult generalized acquired cutis laxa, 949 adult T-cell leukemia/lymphoma (ATLL), 1351–1353 advanced sclerosis lupus nephritis, 733 adverse drug reactions see druginduced disorders and reactions AF-1/AF-2 (monoclonal antibodies), epidermolysis bullosa, 112 African Kaposi's sarcoma, 1730 agammaglobulinemia, granulomata, 314 agglomerate keratoacanthoma, 1135 aggressive adnexal carcinoma, locally aggressive (microcystic adnexal carcinoma), 1558, 1559–1563 aggressive digital papillary adenoma and adenocarcinoma, 1543–1544 aggressive fibrous lesions, locally, 1626–1629 aging effects chronological (intrinsic), 961–962 extrinsic (photoaging), 961–962 see also progeria agranular CD4+ CD56+ hematodermic neoplasm/tumor, 1414 agranular CD4+ NK-cell leukemia, 1414 AIDS see HIV disease alanine:glyoxylate aminotransferase deficiency, 343 albinism, oculocutaneous, 916–918 partial of Chédiak–Higashi syndrome, 918 of Hermansky–Pudlak syndrome, 918 piebaldism formerly known as, 919 UV/sun exposure and, 917, 1118 Albright's disease, 923 Albright's hereditary osteodystrophy, 568 alcian blue, 33 Aleppo boil, 844 algal infections, 850 Alibert (classical form) mycosis fungoides, 1313 ALK+ primary cutaneous anaplastic large cell lymphoma, 1344–1345 pleomorphic sarcoma see fibrous histiocytoma, malignant alkaline phosphatase-antialkaline phosphatase (APAAP) techniques, 34 alkaptonuria, 564–565 allelic imbalance, 39–40 allergic contact dermatitis, 184–185 allergic contact urticaria, 647 allergic granulomatosis with angiitis see Churg–Strauss syndrome allergic reactions (in general) see hypersensitivity reactions; id reaction allergic vasculitis see leukocytoclastic vasculitis allysines, 25–26 alopecia (hair loss and baldness), 982–1009 drug-induced, 606–607 chemotherapeutic, 621 follicular ichthyosis with photophobia and, 66 nonscarring/noncicatricial, 982–1009 in porphyria cutanea tarda, 554, 558–559 scarring/cicatricial see scarring alopecia in systemic lupus erythematosus, 719 alopecia areata, 987–995 differential diagnosis, 993–995 androgenetic alopecia, 986, 995 loose anagen hair syndrome, 1007 syphilitic alopecia, 993–994, 1008 trichotillomania, 993–994, 1000 alopecia mucinosa see follicular mucinosis alopecia syphilitica (syphilitic alopecia), 1007–1008 differential diagnosis, 1008 alopecia areata, 993–994, 1008 Alstrom syndrome, 584 alterniosis, 881 aluminium granuloma, 315 alveolar rhabdomyosarcoma, 1702, 1703 alveolar ridge benign keratosis, 374–375 lymphangioma, 371 alveolar soft part sarcoma, 1766–1767 amalgam tattoo, 431–432, 626 amebae, free-living, 848–849 amebiasis cutis, 478, 848 amelanotic blue nevus, 1211 amelanotic lentigo maligna and lentigo maligna melanoma, 1227 amelanotic melanoma clear cell, vs squamous carcinoma, 1125 conjunctival, 1284 metastatic, 1438–1439 nail apparatus, 1064 spindle cell, differential diagnosis, 1237 ameloblastoma, peripheral, 394 American Joint Committee on Cancer (AJCC) staging system, melanoma, 1232–1233, 1236

American leishmaniasis, 844, 845 American Rheumatology Association diagnostic guidelines, systemic lupus erythematosus, 718t amino acid metabolism, abnormalities/disturbances Hartnup disease, 565 necrolytic migratory erythema, 588 aminolevulinic acid (ALA) dehydratase deficiency, 550t amiodarone pigmentation, 602, 603 amyloid, in basal cell carcinoma, 1094 amyloid elastosis, 537 amyloid-K, 539–540 amyloidosis, 532–543 classification, 533t macular see macular amyloidosis primary, 534–536 secondary, 536 amyloidosis cutis dyschromica, 541 anagen, 979, 980 hair bulb examination, 969 hair follicle, in alopecia areata, 992 loose hair see loose anagen hair syndrome terminal hair in, 969, 973f, 974f, 976f, 977f, 978, 978f, 979f, 980f anagen effluvium, 1006 chemotherapeutic drug effects, 621 drug-induced, 606 anal skin see anogenital skin; anosacral amyloidosis anaphylaxis, drug-associated, 591, 594 anaplastic (undifferentiated) tumors Kaposi's sarcoma, 1734 large cell lymphoma (primary cutaneous), 1343–1348 squamous carcinoma, 1122–1123 anatomy of skin, 1–31 anchoring fibrils, 21, 22 anchoring filaments, 21–22 ancient schwannoma, 1670, 1761 Anderson–Fabry's disease (angiokeratoma corporis diffusum), 530–532, 1710 androgen(s), role acne vulgaris, 1043 androgenetic alopecia, 983 androgen receptor and Paget's disease, 1443 androgenetic alopecia, 982–986 differential diagnosis, 986 alopecia areata, 986, 995 central centrifugal cicatricial alopecia, 1025 senescent alopecia, 1002 telogen effluvium, 986, 1005 anetoderma, 954–956 anetoderma-like scars, 956 aneurysm, cirsoid, 1718 aneurysmal fibrous histiocytoma, 1649–1650, 1734 angiectatic tumor, pleomorphic hyalinizing (PHAT), 1599, 1761 angiitis see vasculitis angioblastoma giant cell, 1735 of Nakagawa, 1712–1713 angiocentric lymphoma/immunoproliferative lesion see lymphomatoid granulomatosis angiodermatitis arteriovenous malformation with (acroangiodermatatis), 192–193, 1734 pruriginous, 273 angiodysplasia, infantile hemorrhagic, 1745 angioedema, 1705–1706 drug-associated, 594 urticarial, 647 angioendothelioma, papillary intralymphatic (Dabska's tumor), 1726, 1727–1728 angioendotheliomatosis, reactive vs intravascular histiocytosis, 1392 vs intravascular large B-cell lymphoma, 1381 angiofibroma (adenoma sebaceum), 941–944 cellular, 516–517 giant cell, 1639 angiogenesis, melanoma, prognostic importance, 1236 angiohistiocytoma, multinucleate cell, 1643–1644 angioimmunoblastic T-cell lymphoma (angioimmunoblastic lymphadenopathy with dysproteinemia), 1350 angiokeratoma, 1710–1711 diffuse (angiokeratoma corporis diffusum), 530–532, 1710 pseudolymphomatous (APACHE), 1360, 1362 other forms/variants, 532, 1710 angioleiomyoma, 1698 myopericytoma vs/or relationship between, 1750 angiolipoma, 1592-1593 angiolymphoid hyperplasia with eosinophilia (epithelioid hemangioma), 382, 1720–1722 plasma cell granuloma-like lesions vs, 1391 with high endothelial venules (APA-HEL), 1362

angiolymphoid proliferation with epithelioid features in adults and children, papular (PALEFACE), 1362 angioma cherry/senile, 1714 tufted, 1712–1713 see also hemangioma angioma serpiginosum, 1708–1709 angiomatoid fibrous histiocytoma, 1650, 1656 angiomatoid melanoma, 1250 angiomatoid polypoid pseudolymphoma, T-cell rich, 1360–1362 angiomatosis, 1725 bacillary see bacillary angiomatosis cutaneovisceral, with thrombocytopenia, 1745 angiomatous hamartomas, eccrine, 1529–1530 angiomatous nodule, epithelioid, 1720 angiomyofibroblastoma, anogenital, 515, 517 angiomyolipoma, renal, tuberous sclerosis, 943 angiomyxoma anogenital, aggressive, 515, 516 superficial (benign), 1756 focal mucinoses vs, 583 myxofibrosarcoma vs, 1663 angiopathy, congenital dysplastic (acroangiodermatatis), 192–193, 1734 angiosarcoma (hemangiosarcoma; malignant hemangioendothelioma; ‘hemangioblastoma’; lymphangiosarcoma), 1737–1742 differential diagnosis, 1742, 1743 atypical vascular proliferation after radiotherapy, 1746 epithelioid sarcoma, 1764–1765 Kaposi sarcoma, 1734 meningeal heterotopia, 1689 progressive lymphangioma, 1745 retiform hemangioendothelioma, 1727 sinusoidal hemangioma (breast), 1717 epithelioid, 1742–1743 angiotropic large cell lymphoma, 1380–1381, 1392 angiotropic melanoma, 1250 angular cheilitis, candidal, 861f anhidrotic ectodermal dysplasia, X-linked, 1489 see also OL-EDA-ID syndrome animal-type melanoma see pigment-synthesizing melanoma ankle, nevi, 1170 ankle-type fibrous histiocytoma, 1652 annular dermatitis superimposed upon acquired benign melanocytic nevus (=Meyerson's nevus), 1177–1178 annular elastolytic giant cell granuloma, 302 annular granuloma see granuloma annulare annular lichen planus, 219–220, 221, 226 annular lipodystrophy, 356 annular psoriasis, 201 annular variant of congenital bullous ichthyosiform erythroderma, 56 annulus migrans, 375–377 anogenital skin, 438–519 embryology (genitalia), 440–441 female anatomy/histology, 438–439 lesions/involvement, 438–519 acantholytic dermatosis, 169, 457 Behçet's syndrome, 686 Bowen's disease, 1111, 1114–1115 female anatomy, 438–439 herpes simplex, 771 HPV and see human papillomavirus infectious diseases, 461–479 inflammatory lesions, 444–460 leiomyoma, 517–518, 1697–1698 lentiginosis, 1152 lichen planus, 219–220, 449–451 mucous membrane pemphigoid, 134 Paget's disease, 1441–1442 pigmented lesions, 481–485 schistosomiasis, 476–477, 893 in systemic diseases, 460–461 verrucous carcinoma, 493, 499–500, 506–507, 1132–1133 male anatomy/histology, 439 mammary-like glands see mammary-like glands normal variant, 443–444 anosacral amyloidosis, 538 anthrax, cutaneous, 801–802 anthrax toxin receptor 2 gene (ANTXR2) mutations and juvenile hyaline fibromatosis, 1625 antibiotics EBV-associated eruptions with, 1392 serum-sickness-like reactions, 594 antibody see autoantibodies; immune complex-associated reactions; immunoglobulin; monoclonal antibodies anticonvulsant hypersensitivity syndrome, 597–598 antifungal drugs, adverse reactions, 620 antigen-presenting cell, epidermal see Langerhans cell

Index antigenic stimulation (in pathogenesis) B-cutaneous lymphoid hyperplasia, 1386–1387 mycosis fungoides, 1317 antimalarial pigmentation, 602–603 antimony sulfur colloid, lymph node mapping, 1298 antiphospholipid (lupus anticoagulant) syndrome, 705–706, 723–724 anetoderma and, 955 diagnostic criteria, 723t lupus erythematosus and, 723–724 α1-antitrypsin deficiency-associated panniculitis, 333 Antoni A areas, 1669 Antoni B areas, 1670 ANTXR2 mutations and juvenile hyaline fibromatosis, 1625 anus see anogenital skin aphthe/aphthous ulceration mouth (stomatitis), recurrent, 380–381 penis/scrotum, 459 aplasia cutis congenita, 938–939 see also SCALP syndrome apocrine acne (hidradenitis suppurativa), 458–459, 655–657 apocrine adenoma ceruminous, 1518 sebaceous and, 1515–1516 tubular, 1513–1514 apocrine carcinoma, 1516–1518 metastatic mammary ductal, 1518 papillary, 1529 apocrine chondroid syringoma, 1520 apocrine cyst, hybrid epidermoid and, 1510 apocrine cystadenoma, 1508–1510 apocrine glands, 19–20 anogenital, 441 hair follicles and, 981 see also sweat glands apocrine hidrocystadenoma, 1508–1510 apocrine miliaria, 200 apocrine nevus, 1508 apocrine poroma, 1507, 1515–1516 apo-eccrine gland, 20 apolipoproteins see apoproteins aponeurotic fibroma, calcifying/juvenile, 1621–1622 apopilosebaceous unit, 15 apoproteins (apolipoproteins), 520 Apo E and amyloidosis, 539–540 apoptosis amyloidogenesis and, 540–541 in erythema multiforme, keratinocytes, 240 juvenile colloid milium and, 543, 544 mycosis fungoides and apoptosis-related genes, 1317 appendageal neoplasms, immunohistochemical diagnosis, 35t aquagenic urticaria, 646 arachnid bites, reactions, 641–643 areca nut and submucous fibrosis, 424, 425 arenaviridae, 789 areoles Montgomery's tubercles, 1488 skin histology, 4f argyria, 619 armadillo family of nuclear and junctional proteins, 13–14 arrector pili muscle, 972, 974–976, 980–981 arrhythmogenic cardiomyopathy, keratosis palmoplantaris with (Naxos disease), 87, 1032t, 1040 ARS (component B) gene encoding SLURP-1, 80 arsenic, 614–615 keratosis, 1115 arteries in systemic sclerosis, 739 arterioles, 27 in systemic sclerosis, 739 arteriovenous anastomoses, 27 arteriovenous hemangioma, 1718 arteriovenous malformation with angiodermatitis (acroangiodermatatis), 192–193 arteritis, giant cell see giant cell arteritis; Takayasu's disease arthritis degenerative (osteoarthritis), in alkaptonuria, 564 gouty, 562 juvenile rheumatoid (systemic juvenile idiopathic), 644–645 Lyme disease, 807 in polyarteritis nodosa, 668 psoriatic, 204–206 reactive see Reiter's syndrome rheumatoid see rheumatoid arthritis See also BADAS syndrome; joint involvement; lipoid dermatoarthritis; PAPA syndrome arthrochalasia, Ehlers–Danlos syndrome type VIIA/B, 936t, 937 arthropods bite reactions, 641–643 papular urticaria, 649 infections borne by, viral hemorrhagic fevers, 788 infestations, 888

Asboe–Hansen sign, 152 ascorbic acid (vitamin C) deficiency and scurvy, 566 ashy dermatosis, 236 Askin's tumor see peripheral primitive neuroectodermal tumor aspergillosis, 863, 864 asteatotic dermatitis, 186–188 asteroid bodies sarcoidosis, 287–288 sporotrichosis, 884–885 asthma, Churg–Strauss syndrome, 677, 678 asymmetric lipomatosis, 1596 athlete's foot, 856–857 atopic dermatitis, 180–182 ATP-binding cassette transporter family see ABCA12; ABCC6 ATP receptors and Hailey-Hailey disease, 168 ATP2A2 mutations acrokeratosis verruciformis of Hopf, 92 Darier's disease, 168, 171–172, 366 Hailey-Hailey disease, 168 ATP2C1 gene mutations, Hailey–Hailey disease, 169 atrial myxoma see myxoma atrophic benign EB, generalized, 107 atrophic candidiasis, chronic, 861 atrophic connective tissue panniculitis, 356–357 atrophic dermatofibroma, 1653 vs multinucleate cell angiohistiocytoma, 1644 atrophic lichen planus, 221 atrophic papulosis, malignant, 696–698 atrophic-type squamous cell carcinoma in situ, 1112 atrophie blanche (segmental hyalinizing vasculitis; livedo vasculitis), 698–700 morphea vs, 748 atrophoderma follicular, 1105 of Moulin, linear, 744 of Pasini and Pierini, 748–749 atrophoderma vermiculata, 69 atypia (cytological) conjunctival primary acquired melanosis with, 1282–1283, 1284 conjunctival primary acquired melanosis without, 1282, 1283, 1285 dysplastic nevi, 1197 neurofibroma with, 1676 pigmented lentiginous nevus with, 1167 aural features see ear auricle (pinna) chondritis, 757 pseudocyst, 1587 see also oculoauricularvertebral dysplasia Auspitz's sign, 201 autoantibodies (to autoantigens) alopecia areata, 991 antiphospholipid syndrome, 705–706, 706t bullous pemphigoid, 123–125 bullous SLE, 143–144 Churg–Strauss syndrome, 678 dermatitis herpetiformis, 146 EB acquisita, 139, 141–142 linear IgA disease, 149, 149–150 to lipoprotein components, 521t lupus erythematosus, 721–724 subacute cutaneous, 717–718 verrucous (hypertrophic) discoid, 712–713 microscopic polyangiitis, 670 mixed connective tissue disease, 757 morphea (localized scleroderma), 746–747 mucous membrane pemphigoid, 137, 410 necrobiosis lipoidica, 297 pemphigoid gestationis, 130 pemphigus, 151, 151t endemic pemphigus foliaceous, 161 IgA pemphigus, 166 paraneoplastic pemphigus, 164 pemphigus foliaceous, 159 pemphigus herpetiformis, 162, 163 pemphigus vegitans, 157 pemphigus vulgaris, 99, 100, 153, 154 to phospholipids see antiphospholipid syndrome polyarteritis nodosa, 669, 671 polymyositis/dermatomyositis, 754 relapsing polychondritis, 758–759 systemic sclerosis, 740–741 temporal arteritis, 690 urticaria, 648 Wegener's granulomatosis, 412, 674 autoimmune bullous diseases, 117–127 HIV-associated, 904 autoimmune diseases alopecia areata as, 991, 992 anetoderma associated with, 955 blistering see autoimmune bullous diseases

blistering, anogenital, 457 lipodystrophy associated with acquired generalized, 355 acquired partial, 356 of oral mucosa, 409 polymyositis/dermatomyositis and, 754 psoriasis coexisting with, 210 sarcoidosis associated with, 286 systemic sclerosis associated with, 735–737 vitiligo and, 913–914, 915 autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome, 862 autosensitization (Id) reaction, 184 axillae chronic itching papular eruption of the pubic region and, 200 hidradenitis suppurativa, 655 skin histology, 4f

B

B-(cell) chronic lymphocytic leukemia see chronic lymphocytic leukemia B-(cell) lymphoblastic leukemia/lymphoma, 1415 B-(cell) lymphoid hyperplasia, cutaneous (B-CLH), 1386–1389 differential diagnosis, 1388–1389 follicle center lymphoma, 1371 marginal zone lymphoma, 1368, 1388–1389 B-cell lymphomas (non-Hodgkin), 1313t, 1344–1348 benign cutaneous infiltrates mistaken for, 1327 conjunctival, 1292 primary cutaneous, 1344–1348 Ig gene rearrangements, 45 primary, 1364 secondary cutaneous involvement, 1373 B-cell lymphomatoid drug reactions, 612, 613 B-cell lymphoproliferative disorders, post-transplant, 1327 B-cell pseudolymphomas, 1327 B-cell tumor, Hodgkin lymphoma as, 1383 baboon syndrome, 619–620 vitiligo and, 913–914 bacillary angiomatosis, 771 epithelioid hemangioma vs, 1722 HIV-associated, 907 pyogenic granuloma (lobular capillary hemangioma) vs, 1716 Bacille Calmette–Guérin vaccination, 819–820 Bacillus anthracis and cutaneous anthrax, 801–802 back, skin histology, 3f bacterial arteritis, 693–694 bacterial infections, 790 mycetoma in, 878 bacterial superantigens and Kawasaki syndrome, 681 bacterid, panniculitic, 352 BADAS (bowel-associated dermatosis–arthritis) syndrome, 639 Bahgdad boil, 844 Balamuthia mandrillaris, 848, 849 balanitis, 444 candidal, 862 circinate, 447 pseudoepitheliomatous micaceous and keratotic, 489–490 Zoon's, 456–457 balanoposthitis, 444 non-specific, 444 baldness see alopecia balloon cell melanoma, 1245–1246 balloon cell nevus vs, 1175, 1246 sebaceous carcinoma vs, 1505 balloon cell nevus, 1175 balloon cell melanoma vs, 1175, 1246 conjunctival, 1278 bamboo hair (trichorrhexis invaginata), 62, 1034–1035 banal melanocytic nevus see melanocytic nevi Bannayan–Riley–Ruvalcaba (Bannayan–Zonana) syndrome, 584, 928 Barber, palmoplantar pustular psoriasis of, 204, 209 barbiturates, 621 Barraquer–Simon syndrome (acquired partial lipodystrophy), 355–356, 355t barrier function, 1, 8–9 Bart syndrome in aplasia cutis, 939 Bartholin's duct cyst, 487 Bartholin's gland benign tumors, 511–512 carcinoma, 512 Bartonella, 803 B. bacilliformis and bartonellosis, 804 B. henselae and bacillary angiomatosis, 804–805, 907 and cat scratch disease, 803 B. quintana and bacillary angiomatosis, 804–805, 907 and trench fever, 803–804

1771

1772

Index basal cell(s), 1 development, 6–7 in lichen planus, 224, 225 in pilomatrixoma, 1461–1462 basal cell carcinoma (BCC), 1088–1100 basaloid follicular hamartoma vs, 1448 clinical features, 1088–1100 differential diagnosis actinic keratosis, 1109 adenoid cystic carcinoma, 1566 desmoplastic trichoepithelioma, 1475 melanocytic matricoma, 1466 microcystic adnexal carcinoma, 1563 sebaceoma, 1498 squamous carcinoma, 1125 trichoblastoma, 1479 trichoepithelioma, 1472–1473 nail unit, 1068 nevus sebaceus associated with, 1491–1492 pathogenesis and histology, 1086 with sebaceous differentiation, 1491 seborrheic keratosis (malignant change to BCC within), 1081 variants, 1089–1090, 1091–1100 rare, 1097–1100 see also nevoid basal cell carcinoma syndrome basal cell tumor with eccrine differentiation (syringoid eccrine carcinoma; eccrine epithelioma), 1541, 1558–1560 basal EB, 104–106 classification, 102t basaloid cells, sebaceoma, 1498 basaloid follicular hamartoma, 1446–1448 basaloid intraepithelial neoplasia, penile, 496 basaloid squamous cell carcinoma oral, 428 penile, 503 unusual morphological features, 504 basement membrane (and basement membrane zone; BMZ), 21, 22 antibodies to bullous pemphigoid, 123–125, 126–127 bullous SLE, 143 EB acquisita, 139 mucous membrane pemphigoid, 137 in EB, 37f, 38–39 thickened, basal cell carcinoma with, 1100 basidiobolomycosis, 874 basomelanocytic tumor, 1260–1261 basosquamous basal cell carcinoma, 1097 ‘bathing trunk’ nevus, giant hairy, 1204–1205 BAX and basal cell carcinoma, 1094 Bazex–Dupré–Christol syndrome, 1105 Bazex syndrome, 215, 819 Bazin's disease (erythema induratum), 346–349, 819, 1625 BCG (Bacille Calmette–Guérin vaccination), 819–820 Bcl-2, 1238–1239 melanoma, 1238–1239 Spitz nevus, 1184 beaded hair (monilethrix), 1032t, 1039 beard area, pseudofolliculitis, 960–961, 1050 Beare-type pili torti, late-onset, 1040 Becker's nevus/melanosis, 1156, 1695 Bednár tumor, 1634 Behçet's syndrome, 686–688 erythema nodosum-like lesions, 332 benign alveolar ridge keratosis, 374–375 benign cephalic histiocytosis, 1400–1401 benign familial acanthosis nigricans, 585 benign familial pemphigus see Hailey-Hailey disease benign intraepithelial dyskeratosis, hereditary, 364–365 benign lichenoid keratosis, 231–232 benign migratory glossitis, 375–377 benign mucinous metaplasia see mucinous metaplasia benign tumors see tumors and specific tumors Berardinelli–Seip syndrome (congenital generalized lipodystrophy), 354, 355t Berlin classification of Ehlers–Danlos syndrome, 935, 936t beryllium disease, 312–313 β-hemolytic streptococci erysipelas, 853–854 impetigo, 790 necrotizing fasciitis, 796 BIDS (brittle sulfur-deficient hair, intellectual impairment, decreased fertility and short stature), 1034 bilharziasis, 476–477 bilharziasis see schistosomiasis biliary disease, neutrophilic dermatoses associated with, 639–640 bioAlcamid, 629 biopsy lymph node see lymph nodes; sentinel lymph node biopsy nail, 1052 pemphigus herpetiformis, 162

scalp, 969–971 cicatricial alopecia, 1010–1012 report, 971 Birbeck granules in Langerhans cell histiocytosis, 1396 Birt–Hogg–Dubé syndrome, 1484, 1485–1486 bismuth, 620 bites arthropod see arthropods intraoral injury due fibroma of, 385 misdiagnosed as hairy leukoplakia, 400 spider, reactions due to, 641–643 see also fibroepithelial polyp Björnstad's syndrome, 1040 B-K mole (familial atypical multiple mole melanoma syndrome), 1192 black fever, 845 black people hair counts, 972t hypopigmented lesions in sarcoidosis, 283–284 black piedra, 854, 879 black widow spider, 641 blackflies see Simulidae BLAISE (Blaschko linear acquired inflammatory skin eruption), 232–233 Blaschkitis, adult, 233–234 Blaschko line(s), 233 Blaschko linear acquired inflammatory skin eruption, 232–233 blastic lymphomas, 1414 plasmablastic lymphoma vs other types, 1382 blastic plasmacytoid dendritic cell neoplasm, 1414–1415 blastoid mantle cell lymphoma, 1373 blastomycosis North American, 865–868, 869 South American, 868–869 Blau's syndrome vs infantile sarcoidosis, 281 bleomycin and scleroderma-like lesions, 738 blister (and blistering) amyloidosis, 534, 536 chronic lymphocytic leukemia, 1375–1376 coma, 621 definition, 99 drug-induced, 607–609 mechanisms of development, 99 see also bullae blistering (bullous) disorders, subepidermal, 99–150 anogenital, 457 autoimmune see autoimmune bullous diseases desmosomal, 14 inherited, 101–117 diagnosis, 37–39 Bloch–Sulzberger syndrome see incontinentia pigmenti blood flow and thermoregulation, 27 blood vessels see microangiopathy; vasculature Bloom's syndrome, 247–248 blue dye, lymph node mapping, 1298 blue nevus, 1063 in Carney complex, 929, 930 cellular see cellular blue nevi common, 1208, 1279 hypopigmented, 1211 compound, 1210–1211 conjunctival, 1279 desmoplastic/sclerosing, 1211 epithelioid see epithelioid blue nevus malignant see blue nevus-like melanoma patch-like, 1209 plaque-like, 1210 target, 1209–1210 see also Mongolian spot blue nevus-like melanoma (malignant blue nevus), 1247–1249 cellular nevus vs, 1214, 1248–1249 blue nevus-like metastatic melanoma, 1252 blue rubber bleb nevus syndrome, 1716 Bockart's impetigo, 797 boil, 798 Baghdad/Aleppo boil, 844 bone involvement see skeletal involvement bone tumors, 1751 nail apparatus, 1072–1075 Borrelia B. burdorferi (and Lyme disease), 806 B-cutaneous lymphoid hyperplasia and, 1386–1387, 1389 eosinophilic fasciitis and, 749 pseudopélade of Brocq and, 1022 granuloma annulare and, 291, 294 necrobiosis lipoidica and, 297 necrobiotic xanthogranuloma, 307 Borst–Jadassohn epithelioma, 1086, 1114

botryoid pseudosarcoma, female genitalia, 513–514 botryoid sarcoma vs fibroepithelial stromal polyp, 514 botryomycosis, 835–836 Bourneville's disease, 941–944 bovine collagen for esthetic microimplantation, 628, 629 bowel (intestine), involvement Behçet's syndrome, 687 Henoch–Schönlein purpura, 665 malignant atrophic papulosis, 697, 698 Peutz–Jeghers syndrome, 927, 928 bowel-associated dermatosis-arthritis (BADAS) syndrome, 639 Bowen disease see squamous cell carcinoma in situ bowenoid actinic keratosis, 1109 bowenoid papulosis (koilocytosis with intraepithelial neoplasia), 769 oral, 424 penile, 498 bowenoid plaques, verrucous hyperkeratotic, 1112 bowenoid porocarcinoma, 1536–1537 BP antigens see bullous pemphigoid 180-kD antigen; bullous pemphigoid 230-kD antigen brachial cutaneous dyschromatosis, acquired, 933–934 BRAF mutations and melanocytic nevi, 967, 1012, 1014 lentigo simplex, 1151 and melanoma, 1262–1263 and UV-exposed skin, 1263–1264 and UV-protected skin, 1265 brain tissue, heterotopic in mouth, 368 see also neurological involvement branchial cyst, 1582 Brazil, endemic pemphigus vulgaris, 155 Brazilian pemphigus foliaceus, 160–162 breast cancer/carcinoma, cutaneous metastases, 1422f, 1425–1426, 1429, 1431–1432, 1518, 1569, 1570 Montgomery's tubercles on areola of, 1488 nevi, 1169 Paget disease see Paget disease sinusoidal hemangioma vs angiosarcoma, 1717 see also areoles; nipples Breslow thickness (with melanoma), 1232–1233 nail apparatus, 1065 prognostic importance, 1232–1233 Brocq bullous ichthyosiform erythroderma of (epidermolytic hyperkeratosis), 55–58 pseudopélade of see pseudopélade of Brocq Broder's system of squamous carcinoma differentiation, 1120–1121 bromoderma, 615–616 bronchial carcinoma metastases, 1422f, 1423–1424, 1437 vs primary neuroendocrine carcinoma, 1147 bronchiolitis in diffuse systemic sclerosis, 737 bronchogenic cyst, 1580–1581 Brooke, epithelioma adenoides cysticum of, 1469–1470 Brooke–Spiegler syndrome, 1470, 1471, 1551 brown fat/adipose tissue, 30–31 brown recluse spider, 641 brucellosis, 802 Brünauer–Fuchs–Siemens syndrome, 80 Brunsting–Perry pemphigoid, 119, 134, 136, 137 Brunsting–Perry pemphigoid-like variant of EB acquisita, 139 bubble hair, 1039 bubonic plague, 800 Buerger's disease, 688–689 bulla(e) (bullous lesions) chronic lymphocytic leukemia, 1375–1376 definition, 99 lichen planus, 228 lipoid proteinosis, 547 pyoderma gangrenosum, 632 see also blister; immunobullous diseases; immunobullous lesions; vesiculobullous mycosis fungoides bullous… see blistering disorders; bulla and entries below bullous dermatosis/lesions (in general) autoimmune see autoimmune bullous diseases of childhood, chronic, 147, 148 drug-induced, 607–609 of hemodialysis see pseudoporphyria in solar elastosis, 962 bullous dermolysis of the newborn, transient, 116 bullous diabeticorum, 589 bullous epidermolysis see epidermolysis bullosa bullous erythema multiforme, 237 bullous ichthyosis (ichthyosis bullosa), congenital of Brocq (bullous ichthyosiform erythroderma), 55–58 of Siemens, 58 bullous impetigo, 790, 791, 791f, 792f, 793f, 794

Index bullous lichen planus, 237, 410 bullous morphea, 747 bullous pemphigoid, 117–127, 608–609 clinical features, 117–120 differential diagnosis, 127 mycosis fungoides, 1327 drug-induced, 608–609 HIV-associated, 904 orf lesions resembling, 785 pathogenesis and histology, 121–127 pustular psoriasis and, 210f bullous pemphigoid 180-kD antigen (BP180/BBAG2/ COL17A1) in bullous pemphigoid, 125, 126 in epidermolysis bullosa, 112 mutations in junctional EB (non-Herlitz), 115 linear IgA disease, 149–150 in mucous membrane pemphigoid, 135, 137 NC16A domain of BP180, 123, 125, 126, 130, 132, 149–150 in pemphigoid gestationis, 130 bullous pemphigoid 230-kD antigen (BP230; BPAG1) in bullous pemphigoid, 125, 126 in linear IgA disease, 149–150 bullous pemphigoid-like lesions EB acquisita, 138 scabies, 890 bullous systemic lupus erythematosus, 142–144 differential diagnosis, 104t, 144 bunyaviridae, 788 Burkitt's lymphoma vs plasmablastic lymphoma, 1383 Buruli ulcer (of M. ulcerans), 821, 824–825 Buschke–Fischer–Brauer disease (punctate palmoplantar keratoderma), 75t, 81 Buschke–Löwenstein tumor, 463–464, 509, 948, 1131 Buschke–Ollendorf syndrome, 947, 959–960, 961 papular elastorrhexis and, 961 busulfan, 623

C

C1-esterase inhibitor deficiency, 647 cadherins, 13–14 P-cadherin mutations, 14 pemphigus foliaceous, 159 pemphigus vulgaris, 154 CADSIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy), 37 café-au-lait macules/spots, 1677, 1680 calcifying aponeurotic fibroma, 1621–1622 calcifying epithelioma of Malherbe (pilomatircoma), 1460–1463, 1465 calcifying fibrous epulis (calcifying fibroblastic granuloma), 391–392 calcifying fibrous (pseudo)tumor, 1616 calcifying odontogenic tumor, peripheral, 395 calcinosis cutaneous (calcinosis cutis), 566–570 in systemic sclerosis, 737 idiopathic genital, 480 see also CREST syndrome calcinosis universalis, 568 calciphylaxis, 344–345, 569 calcium disturbances see hypercalcemia calcium oxalate crystal deposition, 343, 344 calculus, salivary gland, 414 callus (callosities), 91 hereditary painful, 80–81 calretinin, primary vs secondary cutaneous tumors, 1434 Calymmatobacterium granulomatis and granuloma inguinale, 472–473 CAM 5.2 apocrine glands, 20 eccrine glands, 18–19 Merkel cells, 12f Camisa variant form of Vohwinkel syndrome (ichthyotic variant of VS), 73, 83, 84 Campbell de Morgan spots, 1714 canal of Nuck, cyst, 488 canalicular adenoma, 418 cancer (cutaneous and mucosal), 1221–1267 arsenic-related, 615 chemotherapeutic drugs see chemotherapy conjunctival epithelial, 1270 melanocytic, 1270 epidermoid cyst and risk of, 1573–1574 genital skin, 490–509, 512, 518 melanocytic see melanoma in Hailey-Hailey disease, 168 HIV-associated, 904 in leishmaniasis, 845 in necrobiosis lipoidica, 296

oral melanocytic, 434–435 oral non-melanocytic, 425 lichen planus and transformation risk, 402 in Sweet's syndrome, 637 penile, 498 proliferating pilar, 1458–1459 PUVA therapy (in psoriasis) and risk of, 209–210 in recessive dystrophic EB, 109–111, 115 in relapsing polychondritis, 758 salivary gland, 418–419, 1501–1502 vs oral basaloid squamous carcinoma, 428 schwannoma and transformation risk, 1670 seborrheic keratosis (malignant change within), 1081 see also metastases; premalignant lesions, specific histologic types and chapters 24-35 cancer (internal/non-cutaneous/underlying/occult) acanthosis nigricans and, 585 acquired palmoplantar keratoderma and, 91–97 arsenic-related, 615 Bowen's disease and, 1112 eosinophilic cellulitis and, 650 erythema gyratum repens and, 263 esophageal, autosomal dominant focal nonepidermolytic palmoplantar keratoderma with, 90–91 hematological see hematological malignancy HIV-associated, 904 paraneoplastic syndromes see paraneoplastic syndromes in polymyositis/dermatomyositis, 753 systemic sclerosis and, 738 urticarial vasculitis and, 279, 667 candidiasis, 861–863 Canon white sponge nevus, 364 capillaritis, chronic see pigmented purpuric dermatoses capillary (capillaries), 27 dermatomyositis (childhood), 756 capillary hemangioma (and variants), 1711–1726 lobular see pyogenic granuloma capillary morphogenesis protein 2 gene (CMG2) mutations and juvenile hyaline fibromatosis, 1625 capillary hemangioma, conjunctival, 1287 capsular nevus cells, sentinel node immunohistochemistry, 1300–1301 carbohydrate stains, 34t carbon particles, lymph node mapping, 1298 carbuncle, 798 carcinoembryonic antigen (CEA) apocrine glands, 20 eccrine glands, 18–19 carcinoid tumor, 1438 carcinoma, 1115–1124 adenoid cystic see adenoid cystic carcinoma adnexal see adnexal carcinoma apocrine see apocrine carcinoma colorectal see colorectal carcinoma conjunctival metastases, 1294 cutaneous metastases, 1421, 1422, 1425–1426 children, 1423 meningeal heterotopia vs, 1689 cutaneous primaries actinic keratosis transforming into, 1107 in Hailey-Hailey disease, 168 PUVA therapy (in psoriasis) and risk of, 209–210 in recessive dystrophic EB, 109–111, 115 eccrine see eccrine carcinoma esophageal, autosomal dominant focal nonepidermolytic palmoplantar keratoderma with, 90–91 genital, 490–509, 512 lymphoepithelioma-like see lymphoepithelioma-like carcinoma nail unit, 1068 oral cavity, 425–428, 429–430 in Sweet's syndrome, 637 pilomatrix/matrical, 1463, 1465 salivary gland, 418–419 vs basaloid squamous carcinoma, 428 vs mucopapillary retention cyst, 414 vs sialolithiasis, 415 seborrheic keratosis (malignant change to BCC within), 1081 sweat gland endocrine mucin-producing, 1558 polymorphous, 1570 syringoid eccrine, 1558–1560 trichoblastic, 1480–1482 see also specific histological types carcinoma cuniculatum, penis, 506–507 carcinoma in situ conjunctival, 1276 nail apparatus, 1068–1069 squamous cell see squamous cell carcinoma in situ vulval (differentiated vulval intraepithelial neoplasia), 490, 491, 492

carcinosarcoma (carcinoma with heterologous differentiation; carcinosarcoma; metaplastic squamous cell carcinoma) eccrine spiradenocarcinoma with sarcomatous differentiation, 1556 oral, 427–428 penis, 505 sarcomatoid carcinoma; spindle cell carcinoma), 1139–1140 trichoblastic, 1480–1482 cardiolipin, autoantibodies to antiphospholipid syndrome, 705–706, 706t temporal arteritis, 690 cardiomyopathy arrhythmogenic, keratosis palmoplantaris with (Naxos disease), 87, 1032t, 1040 dilated, in Carvajal–Huerta syndrome, 89–90 cardiovascular involvement alkaptonuria, 564 angiokeratoma corporis diffusum, 530–531 Carvajal–Huerta syndrome, 89–90 Churg–Strauss syndrome, 677 Kawasaki syndrome, 680 lupus erythematosus neonatal, 721 systemic, 720, 733 Lyme disease, 807 Naxos disease, 87, 1040 polyarteritis nodosa, 669 pseudoxanthoma elasticum, 952, 953 relapsing polychondritis, 758 sarcoidosis, 285 systemic sclerosis (diffuse), 737–738 tuberous sclerosis, 942, 943 woolly hair, 1040 Carney's complex, 482, 929–930 epithelioid blue nevus in, 929, 930, 1211–1212 myxomas, 1756 protein kinase A (and subunits) and, 929–930, 1267 Carney's syndrome (unilateral basal cell nevus), 1105 Carrión's disease, 804 cartilage in relapsing polychondritis, autoantibodies, 759 tumors derived from, 1751 cartilaginous choristoma, 367 cartilaginous exostosis, benign, 1751 caruncular tumors, 1270, 1295 Carvajal (Carvajal–Huerta) syndrome, 89–90, 1040 Castleman's disease (giant lymph node hyperplasia), 1390 follicular dendritic cell sarcoma associated with, 1410 multicentric, 1389, 1390 cat scratch disease, 803 catagen, 979, 980 catarrhal phase of rhinoscleroma, 833–834 β-catenin, 14 and basal cell carcinoma, 1093 and desmoid fibromatosis, 1628 and Gardner fibroma, 1615 and hair follicle calcifying epithelioma of Malherbe, 1460–1463 follicular development, 972 and keloid, 1605 and melanocytic matricoma, 1482–1484 and melanoma, 1264 and nuchal fibroma, 1615 and palmar fibromatosis, 1626 and pilomatrix carcinoma, 1463 and sebaceous adenoma, 1495 caterpillar bodies, variegate porphyria, 557–558 cathepsin C gene and Papillon–Lefèvre syndrome, 87 Caucasian (white) people, hair counts, 972t cavernous hemangioma, 1716–1717 conjunctival, 1287 cavernous lymphangioma, 1743, 1744 CD antigens (in general) adult T-cell leukemia/lymphoma, 1353 angioimmunoblastic T-cell lymphoma, 1351 angiosarcoma, 1741 B-cutaneous lymphoid hyperplasia, 1387–1388 chronic lymphocytic leukemia, 1376 dendritic cell sarcoma follicular, 1411 interdigitating, 1411 extranodal marginal zone lymphoma, 1366–1368 extranodal NK/T cell lymphoma, 1357 follicle center lymphoma, 1369–1370 histiocytic sarcoma, 1411 Hodgkin lymphoma, 1384 hydroa vacciniforme-like lymphoma, 1359 indeterminate dendritic cell tumor, 1399 intravascular large B-cell lymphoma, 1380–1381 Langerhans cell histiocytosis, 1396–1397 lymphoblastic leukemia/lymphoma, 1415 lymphomatoid granulomatosis, 1377–1378

1773

1774

Index CD antigens (in general) (Continued) lymphomatoid papulosis, 1343 mantle cell lymphoma (secondary cutaneous), 1374 mast cell sarcoma, 1419–1420 mycosis fungoides, 1322–1323 in large cell transformation, 1325 pediatric patients, 1326 myeloid sarcoma, 1414 pagetoid reticulosis, 1336 plasma cell tumors, 1378 plasmablastic lymphoma, 1382 Sézary syndrome, 1340 CD4+ CD56+ hematodermic neoplasm/tumor, agranular, 1414 CD4+ NK-cell leukemia, agranular, 1414 CD4+ small/medium T-cell lymphoma , primary cutaneous, 1348–1349 CD4+ T cells (helper T cells) chronic superficial dermatitis, 259 exanthamatous drug eruptions and, 593 granuloma annulare, 291 lymphoproliferative disorders mycosis fungoides, 1322–1323 primary cutaneous anaplastic large cell lymphoma, 1345–1348 sarcoidosis, 286 systemic lupus erythematosus, 731 CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, 1357, 1360 clinical features, 1357 differential diagnosis, 1357 epidermotropic CD8+ variant of lymphomatoid papulosis, 1343 mycosis fungoides, 1325 pagetoid reticulosis, 1337 histology, 1357 CD8+ lymphoid proliferation of ear, indolent, 1349–1350 CD8+ lymphomatoid papulosis, epidermotropic, 1343 CD8+ T cells (cytotoxic/suppressor T cells) drug reactions involving, 592 fixed, 600 leprosy and, 829 CD23, Paget's disease, 1443 CD30+ T-cell lymphoproliferative disorders, primary cutaneous, 1340–1348, 1431–1432 CD34+ dermal fibroma, plaque-like, 1623–1624 CD40, Spitz nevus, 1184 CD44, Spitz nevus, 1184 CD99 (and MIC-2 antibody) peripheral primitive neuroectodermal tumor, 1693–1694 Spitz nevus, 1184 CD117 see kit CD207 and Langerhans cell histiocytosis, 1396–1397 Cdc7, Spitz nevus, 1184 CDK see cyclin-dependent kinase CEA see carcinoembryonic antigen celiac disease (gluten-sensitive enteropathy) dermatitis herpetiformis and, 144–145 erythema elevatum diutinum and, 684 linear IgA disease and, 148–149 cell(s) adhesion abnormality in Hailey-Hailey disease, 168 junctions between, 13–15 cell cycle inhibitors and melanocytic nevi, 1013 cellular angiofibroma, 516–517 cellular angiolipoma, 1592, 1593 cellular blue nevi, 1213–1214 atypical, 1216–1217 conjunctival, 1279 differential diagnosis, 1214 deep penetrating nevus, 1192 malignant blue nevus, 1214, 1248–1249 locally-invasive, 1214–1216 cellular fibrous histiocytoma, 1647–1648 cellular ‘neurothekeoma’, 1684–1685 cellular schwannoma, 1671 cellulitis, 794–795 dissecting, central centrifugal cicatricial alopecia vs, 1025 eosinophilic, 649–651 central centrifugal cicatricial alopecia, 1023, 1030 central nervous system involvement see neurological involvement centriole autoantibodies, lupus erythematosus, 741 centripetal (recessive) dystrophic EB, 111 centrocytic lymphoma see mantle cell lymphoma centrofacial lentiginosis, 1153–1154 centrofacial malignant granuloma, 430–431 centromere autoantibodies, lupus erythematosus, 741 cephalic histiocytosis, benign, 1400–1401 cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADSIL), 37 cerebral Gaucher syndrome, infantile, 66

cerebral lesions (in general) see neurological involvement cerebriform lymphocytes (Sézary cell), 1339, 1340 cerebrotendinous xanthomatosis, 521–522 ceruminous gland tumors (ceruminoma), 1518 cervical thymic cyst, 1582 cervicofacial actinomycosis, 837 cestodes, 894 chancre syphilitic, 465, 470, 815–816 tuberculous, 811–812, 815t chancroid, 474–475 Chédiak–Higashi syndrome, 918 cheilitis candidal, 861 granulomatous see orofacial granulomatosis cheilitis glandularis, 416 chemical carcinogens, squamous cell carcinoma, 1119t, 1120 chemical-induced scleroderma-like syndromes, 738 chemotherapy (cytotoxic drugs) adverse reactions, 621–623 induction or augmentation, reaction to lymphocyte recovery after, 626 cherry angioma, 1714 cheveux incoiffables trianguli, 1035–1037 chewing gum, lesions associated with, 406 chickenpox, 776 Chiclero's ulcer, 844 chilblain(s) (perniosis), 270–272 chilblain lupus erythematosus (lupus pernio), 272, 337, 714 clinical features, 714 pathogenesis and histology, 729 in sarcoidosis, 283 CHILD nevus and CHILD syndrome, 1078 children calcifying fibrous tumor, 1616 cold panniculitis, 337 congenital nevus, 1203–1206 dermatomyositis, 756 disabling pansclerotic morphea, 746, 747 EB acquisita, 139 eosinophilic pustular folliculitis, 218 hemorrhagic edema, 461, 665–666 Henoch–Schönlein purpura, prognosis, 665 Hutchinson–Gilford syndrome presentation, 963 lichen planus, 222 linear IgA disease, 147, 148 lipophagic panniculitis, 357 melanoma, 1257–1259 melanoma in situ vs lentigo, 1063 mercury-associated lesions, 620 metastases in skin, 1423 mycosis fungoides, 1326 myofibromatosis, 1616 neutrophilic eccrine hidradenitis, 624 papular acrodermatitis, 195–196 papular angiolymphoid proliferation with epithelioid features in children in adults and (PALEFACE), 1362 pemphigoid, 119 polyarteritis nodosa, 669 polymyositis or dermatomyositis, 753, 756 psoriatic arthritis, 206 purpura fulminans, 701, 702 sarcoidosis, 281 scleredema, 580 sebaceous hyperplasia, 1488–1489 squamous papilloma of conjunctiva, 1271 vulval fibroma, 515 see also adolescents; infants; neonates and entries under congenital; juvenile Chlamydia trachomatis lymphogranuloma venereum and L1-L3 strains of, 476 Reiter's syndrome and, 447 chloracne, 1044–1045 chloroquine pigmentation, 602–603 chlorpromazine pigmentation, 603, 604 cholestasis, plane xanthomata, 528 cholesterol, xanthomatoses related to abnormal levels, 521t cholesterol clefts, necrobiotic xanthogranuloma, 307–308 cholesterol crystal embolism, 700–701 cholinergic urticaria, 647 chondritis, auricular, 757 chondrodermatitis nodularis chronica helicis, 324–325, 759 chondrodysplasia punctata, 65 chondroid (cartilaginous) choristoma, 367 chondroid lipoma, 1594–1595 chondroid syringoma, 1519–1522 malignant, 1522–1526 ossifying fibromyxoid tumor vs, 1758 chondroma periosteal, vs subungual exostosis, 1075 soft tissue, 1751–1752 chondromyxoid tumor, ectomesenchymal, 436

chondrosarcoma (extraskeletal) mesenchymal, 1753 myxoid, 1752–1753 vs ossifying fibromyxoid tumor, 1758 vs pleomorphic lipoma, 1595 choriocarcinoma, cutaneous metastases, 1423, 1435–1436 choristomas, 1666 conjunctival, 1270, 1292–1294 oral, 366–368 sebaceous see sebaceous adenoma chromoblastomycosis (chromomycosis), 876–877 phaeohyphomycosis vs, 880 chromogens false positives in immunohistochemistry, 35 as in situ hybridization probes (CISH), 41–42 chromomycosis see chromoblastomycosis chromosomal (karyotypic/cytogenetic) abnormalities, 39 actinic keratosis, 1107 adipocytic tumors angiolipoma, 1592 lipoblastoma, 1598 lipoma, 1590 liposarcoma, 1600 mammary-type myofibroblastoma of soft tissue, 1594 spindle cell lipoma, 1593 alveolar soft part sarcoma, 1766 analysis for, 39–43 angioimmunoblastic T-cell lymphoma, 1350 angioleiomyoma, 1698 angiosarcoma, 1676 chronic lymphocytic leukemia, 1375–1376 clear cell sarcoma, 1694 diffuse large B-cell lymphoma, 1372 epithelioid hemangioendothelioma, 1736 epithelioid sarcoma, 1762 extranodal marginal zone lymphoma, 1365 fibrous/myofibroblastic tumors angiomatoid fibrous histiocytoma, 1656 dermatofibrosarcoma protuberans, 1631 desmoplastic fibroma, 1618, 1619 fibroma of tendon sheath, 1618 fibrosarcoma (adult variant), 1640 fibrosarcoma (infantile variant), 1640 fibrous hamartoma of infancy, 1624 giant cell fibroblastoma, 1627 giant cell tumor of tendon sheath, 1655 myxofibrosarcoma, 1663 neurofibromatosis type I, 1677, 1691 proliferative myositis, 1610 granular cell tumor (malignant), 1680–1681 hidradenocarcinoma, 1548 hidradenoma, 1545 keratoacanthoma, 1136 mantle cell lymphoma (secondary cutaneous), 1373, 1374 melanocytic nevi, 1015 hypomelanosis of Ito, 922 pagetoid Spitz nevus, 1186 melanoma and UV-exposed skin, 1263–1264 and UV-protected skin, 1265 myoepithelioma (malignant), 1527 neuroendocrine carcinoma, 1142 see also molecular pathology; translocations chronic actinic dermatitis see actinic dermatitis, chronic chronic adult T-cell leukemia/lymphoma, 1351 chronic atrophic candidiasis, 861 chronic bullous dermatosis of childhood, 147, 148 chronic discoid lupus erythematosus vs lichen planus, 229, 406 chronic erythema nodosum, 328, 332 chronic fibrosing vasculitis, 684, 685–686 chronic granulomatous disease and discoid lupus erythematosus, 715–716 chronic inflammation or infection, squamous carcinoma and, 1120 chronic itching papular eruption of the axillae and pubic region, 200 chronic lymphocytic leukemia (small lymphocytic lymphoma; small lymphocytic leukemia), 1375–1376 differential diagnosis, 1376 marginal zone B-cell lymphoma, 1368 squamous carcinoma with, 1140 chronic mucocutaneous candidiasis, 862 chronic superficial dermatitis, 259–260 chronic ulcerative stomatitis, 405–406 chronological aging, effects, 961–962 chrysiasis, 618–619 Churg–Strauss syndrome (allergic granulomatosis with angiitis), 659t clinical features, 677–679 differential diagnosis, 678–679 Wegener's granulomatosis, 675–676 pathogenesis and histology, 678

Index chylomicrons, 521 raised, 521t and raised VLDL, 521t cicatricial alopecia see scarring alopecia cicatricial pemphigoid see mucosal pemphigoid ciclosporin (cyclosporin)-induced gingival hyperplasia, 396, 397 ciliated cyst, 1582–1583 cinnamaldehyde-associated contact stomatitis, 405 circinate balanitis, 447 circinate erythema, 375–377 circled hair, 1041 circumcision, 443 circumscribed lymphangioma, 1743–1744 circumscribed neurodermatitis see lichen simplex chronicus circumscribed neuroma, solitary, 1667–1668 circumscribed nevi of conjunctiva, 1277 circumscribed palmar or plantar hypokeratosis, 96–97 circumscribed palmoplantar keratoderma, 75t with associated symptoms, 75t circumscribed pityriasis rubra pilaris, 212 cirsoid aneurysms, 1718 Civatte, poikiloderma of, 245 Civatte bodies, lichen planus, 225 CLA T cells see cutaneous lymphocyte antigen T cells Clark levels (with melanoma), 1233 nail apparatus, 1065 prognostic importance, 1233 claudins, 15 Paget's disease, 1443 clavus, 91 clear cell acanthoma, 1086–1087 clear cell actinic keratosis, 1109 clear cell atypical fibroxanthoma vs squamous carcinoma, 1125 clear cell basal cell carcinoma, 1097 clear cell squamous carcinoma vs, 1125 clear cell carcinoma, cutaneous metastases, 1125, 1436 see also clear cell hidradenocarcinoma; clear cell porocarcinoma; clear cell squamous cell carcinoma clear cell eccrine porocarcinoma, 1570 clear cell fibrous histiocytoma, 1652 clear cell hidradenocarcinoma (malignant acrospiroma; malignant nodular hidradenoma; malignant clear cell hidradenoma), 1546–1550 clear cell squamous carcinoma vs, 1125 sebaceous carcinoma vs, 1505 trichilemmal carcinoma vs, 1455 clear cell hidradenoma/myoepithelioma (eccrine acrospiroma; solid–cystic hidradenoma), 1545–1546 malignant see clear cell hidradenocarcinoma clear cell melanoma, 1245–1246 amelanotic, vs squamous carcinoma, 1125 of soft parts see clear cell sarcoma clear cell papulosis vs Paget's disease, 1444 clear cell porocarcinoma vs clear cell squamous carcinoma, 1125 vs trichilemmal carcinoma, 1455 clear cell sarcoma (melanoma of soft parts), 1694–1695 molecular diagnostics, 40–41, 43 clear cell squamous cell carcinoma, 1124–1125, 1124t differential diagnosis, 1124–1125 sebaceous carcinoma, 1125, 1505 trichilemmal carcinoma, 1125, 1455 penis, 507 clear cell squamous cell carcinoma in situ, 1112 clear cell trichoblastoma, 1477 clear cell tumors metastases vs squamous carcinoma, 1125 climacteric keratoderma, 91 clitoris glans, histology, 439 granuloma inguinale, 474f prepuce, histology, 439 cloacogenic carcinoma, 509–510 clonal nevus, 1163–1164 clonality/monoclonality, B-cell cutaneous infiltrates, 45 B-cutaneous lymphoid hyperplasia, 1388 follicle center lymphoma, 1371 Sézary syndrome, 1340 Clouston's syndrome, 71t, 84–85 CMG2 mutations and juvenile hyaline fibromatosis, 1625 CMV see cytomegalovirus coagulation, disseminated intravascular, 701–703 Cobb's syndrome, 1707 coccidioidomycosis, 869–871 Cockarde nevus, 1172 Cockayne syndrome, 248 Cockayne–Touraine disease, 108 coelenterate stings, 643–644 Cohen's syndrome, 585 cold panniculitis, 337 horseriders (cold equestrian panniculitis), 270, 337

cold urticaria, 646–647 familial, 537, 646–647 collagen classification by fibre architecture in tissues, 22–23 dermal, 22–24 dermal–epidermal junction, 22 for esthetic microimplantation, 629 bovine, 628, 629 lipoid proteinosis and, 548 relapsing polychondritis, 758–759 systemic sclerosis, 740 autoantibodies, 741 type I, 23–24 fusion of COL1A1 to PDGFB, dermatofibrosarcoma protuberans, 1631 type III, 24 type IV, 22 dystrophic EB, 38–39 type V, 24 type VII, 22 dystrophic EB, 38–39, 116 EB acquisita, 141–142 type XV111 antigen see bullous pemphigoid 180-kD antigen collagen disorders, 935 generalized, 935–939, 940–947 localized, 947–948 collagen vascular diseases see connective tissue diseases collagenoma, 947–948 eruptive, 947–948, 961 storiform, 1614–1615 tuberous sclerosis, 942 collagenosis, reactive perforating, 316–317, 318t, 322 collagenosis nuchae see nuchal fibroma collagenous fibroma, 1618, 1619 collagenous vasculopathy, cutaneous, 1710 collodion baby, 51–52, 53, 55, 66 colloid bodies, lichen planus, 225 colloid milium, 543–546, 962 colloidal iron, 34 Colombia (El Bagre in), endemic pemphigus foliaceous, 161, 162 colony-stimulating factors (CSFs) adverse reactions, 625 in giant cell tumor of tendon sheath pathogenesis, 1655 colorectal carcinoma hereditary non-polyposis, 1505–1506 in Muir–Torre syndrome, 1505 colorectal polyposis, familial see Gardner's syndrome coma blisters, 621 combined immune deficiency, granulomata, 314 combined nevus (melanocytic nevus with phenotypic heterogeneity), 1173 combined Spitz nevus, 1181–1183 conjunctival, 1278, 1279 element of blue nevus, 1279 comedonal plaque, actinic, 962 comedone(s) acne vulgaris, 1041–1043, 1575–1576 familial dyskeratotic, 177–178 comedone nevus, 1446 Comèl–Netherton's syndrome see Netherton's syndrome comparative genomic hybridization, 42–43 melanocytic nevi, 1014, 1015 melanomas in UV-protected sites, 1264–1265 complement pathway (anomalies) acquired partial lipodystrophy, 355–356 bullous pemphigoid, 125 EB acquisita, 142 systemic lupus erythematosus, 720–721 urticarial vasculitis, 278, 647 complex choristoma, conjunctival, 1294 complexion-associated conjunctival pigmentation, 1280–1281 composite hemangioendothelioma, 1734–1735 compound nevi, 1158, 1159 blue, 1210–1211 dysplastic, 1196–1197 pediatric, 1203 condyloma acuminatum genital (genital warts), 463–464, 767–768 giant (Buschke–Löwenstein tumor), 463–464, 509, 948, 1131 oral cavity, 383, 398 condyloma lata, 466–467 condylomatous carcinoma, 500–501 congenital absence of skin see aplasia cutis congenita; SCALP syndrome congenital cutaneous candidiasis, 861 congenital dermoid fistula, 1469, 1580 congenital dyskeratosis see dyskeratosis congenital dysplastic angiopathy (acroangiodermatatis), 192–193, 1734 congenital epithelial cysts of conjunctiva, 1273 congenital erythropoietic porphyria, 550–551

congenital facial infiltrating lipomatosis, 1596 congenital generalized lipodystrophy, 354, 355t congenital generalized myofibromatosis, 1616 congenital gingival leiomyomatous polyp/hamartoma, 371 congenital granular cell tumor, 370–371, 1682 congenital hemangioma see hemangioma congenital ichthyosis, 46–69 congenital immunodeficiency syndromes see immunodeficiency syndromes congenital linear nevoid variant of basaloid follicular hamartoma, 1446 congenital melanosis oculi, 1281 congenital myxoma, conjunctival, 1290 congenital neurovascular hamartoma, 1666 congenital nevus, 1201–1203 giant, 1204–1205 neonates/young children, 1203–1206 proliferation nodule within, 1205–1206 congenital nevus sebaceus, 1489–1492 congenital ocular melanocytosis, 1281 congenital pachyonychia see pachyonychia congenita congenital poikiloderma, 246–247 congenital protein S deficiency and warfarin reactions, 616 congenital self-healing reticulohistiocytosis, 1392–1393, 1397–1398 congenital smooth muscle hamartomas, 1695 congenital syphilis, 472 congenital telangiectatic erythema with dwarfism, 247–248 congenital triangular alopecia see triangular temporal alopecia congenital vellus hamartoma, 1445 conidiobolomycosis, 874 conjunctiva, 1268–1295 classification, 1269 differential diagnosis, 1269–1271 mucous membrane pemphigoid, 136 tumors, 1268–1295 examination, 1269 junctional nevi see junctional nevi conjunctivitis ligneous, gingival involvement, 396, 398 mucopurulent, in Reiter's syndrome, 447 connective tissue, stains, 34 connective tissue (collagen vascular) diseases, 711–759 elastosis perforans serpiginosa associated with, 320 erythema gyratum repens in, 263 idiopathic, 711–759 leukocytoclastic vasculitis in, 659 mixed, 756–757 connective tissue panniculitis, 357–358 atrophic, 356–357 connective tissue tumors see soft tissue tumors connexins, 14, 72 mutations, 15, 71t, 74, 84 erythrokeratoderma variabilis, 72 hidrotic ectodermal dysplasia, 85 connexons, 14 Conradi–Hünermann–Happle syndrome, 65 consumptive coagulopathy, disseminated intravascular coagulation as a, 701 contact dermatitis, 184–185 granulomatous, 313–314 irritant see irritant contact dermatitis lymphomatoid drug-related, 612, 613 contact lichenoid hypersensitivity, 405 contact pemphigus, 167 contact urticaria, 647, 648 contagious pustular dermatosis, 783–785 coproporphyria, hereditary, 549–559 corn(s), 91 cornea dystrophy, keratosis palmoplantaris with, 89 lesions (in general) Darier's disease, 171, 173 mucous membrane pemphigoid, 133, 136f opacities, X-linked ichthyosis, 49 tumors histological examination, 1269 melanoma, 1285 cornified cell envelope, 8 cornu cutaneum see horn coronary artery bypass, vein graft site dermatitis, 195 corpuscular sensory endings, 28–29 cortex, hair shaft, 977–978 corticosteroids see steroids Corynebacterium diphtheriae, 841 Corynebacterium minutissimum see erythrasma Corynebacterium tenuis and trichimycosis, 840 Corynebacterium ulcerans, 841 cosmetic microimplants see esthetic microimplants cosmetic preparations and acne vulgaris, 1043 Costello syndrome, 584 coumadin, 616–617

1775

1776

Index Cowden's syndrome/disease, 1078, 1450–1453 multiple trichilemmomas, 1450–1453 cowpox, 781 coxsackievirus A16 and hand, foot and mouth disease, 787 Crandall's syndrome, 1040 CREB1 and cell sarcoma, 1694 CREST (calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, telangiectasis) syndrome, 734, 735–737, 743 cribriform adenoid cystic carcinoma, 419 CrmB, variola virus, 782 Crohn's disease (cutaneous/metastatic), 309–310, 408–409, 460 anogenital, 460 differential diagnosis, 309 granulomatous cheilitis, 309, 408 sarcoidosis, 288, 309 erythema elevatum diutinum and, 684 neutrophilic dermatoses, 639 pyoderma gangrenosum, 632, 634 oral, 309, 408–409 Cronkhite–Canada syndrome, 928–929 Crouzon syndrome, 584 Crow–Fukase syndrome, 1706 CRTC1, and hidradenoma, 1545 cryoglobulinemia (and associated vasculitis), 659t, 703–705 cryptococcosis, 871–872 paracoccidioidomycosis vs, 869 Cryptococcus neoformans, stains, 34 crystal-storing histiocytosis, 346 crystalline folliculitis, necrotizing infundibular, 323 CSFs see colony-stimulating factors Curth–Macklin-type ichthyosis hystrix, 60–61 cutaneous lymphocyte antigen (CLA) T cells allergic contact dermatitis, 184–185 atopic eczema, 182 cutaneovisceral angiomatosis with thrombocytopenia, 1745 cuticle, hair shaft, 977–978 cutis laxa, 948–950 cutis marmorata telangiectatica congenita, 1708 cutis rhomboidalis nuchae, 962 cutis verticis gyrata vs lipedematous alopecia, 1009 cyclin D1, 1239 mantle cell lymphoma (secondary cutaneous), 1373, 1374 melanoma, 1239 and UV-protected skin, 1265 Spitz nevus, 1184 cyclin-dependent kinase (CDK) genes, melanoma and familial cutaneous, 1196 UV-protected skin and, 1265 cyclosporin-induced hyperplasia gingival, 396, 397 non-gingival, 397 CYLD, 1551 Brooke–Spiegler syndrome, 1471, 1551 epithelioma adenoides cysticum, 1470 cylindroma (dermal), 1550–1553 malignant, 1553 cylindromatosis, familial (Brooke–Spiegler syndrome), 1470, 1471, 1551 cyst(s), 1571–1587 anogenital, 392, 393–395, 396–398 digital mucous, 19 echinococcal, 894, 895 epidermoid see epidermoid cysts epidermoid and apocrine, hybrid, 1510 epithelial, conjunctiva, 1273 eruptive vellus hair see vellus hair cysts eyelid, of Schöpf–Schulz–Passarge syndrome, 91 follicular, 1571–1580 glandular, 1580–1584 jaw, in nevoid basal cell carcinoma syndrome, 1103, 1104 Moll's gland, 1508, 1509 myxoid, 582, 1754 oral cavity, 368, 369 gingiva (adults), 395 rhinosporidial, 887 salivary duct, 412, 413 cystadenocarcinoma, papillary, 419 cystadenoma apocrine, 1508–1510 papillary (salivary gland), 414 cystic fat necrosis, nodular, 335 cystic hamartoma, folliculosebaceous, 1467–1469 cystic hygroma, 1743, 1744 cystic teratoma, mature, 1580 cysticercosis, 894 cytogenetics see chromosomal abnormalities; molecular pathology cytoid bodies, lichen planus, 225

cytokeratins (CKs) metastases to skin adenocarcinoma vs primary adnexal tumor, 1434 carcinoma (in general), 1429 gastrointestinal cancer, 1429–1430 lung cancer, 1426 squamous carcinoma, 1430 neuroendocrine carcinoma, 1146 Paget's disease, 1442–1443 trichilemmoma, 1472–1473 trichoblastoma, 1479 cytokines adverse reactions to therapeutic use, 625–626 hemophagocytic lymphohistiocytosis and role of, 1410 receptors, mycosis fungoides cells expressing, 1317 systemic sclerosis and role of, 739–740, 741 cytomegalovirus (CMV), 779–780 HIV-associated, 779, 908 cytophagic histiocytic panniculitis, 337–339 cytoplasmic ribonuclear protein autoantibodies, lupus erythematosus, 722t cytoskeleton, keratinocyte, 5–6 cytotoxic drugs see chemotherapy cytotoxic T cells see CD8+ T cells

D

Dabska's tumor (papillary intralymphatic angioendothelioma), 1726, 1727–1728 dacryoadenoma, 1272 daily hair shedding count, 968 Darier's disease (Darier–White disease; keratosis follicularis; morbus Darier), 169–173, 1060 ATP2A2 mutations, 168, 171–172, 366 differential diagnosis, 156t, 169, 366, 1060 endemic pemphigus vulgaris, 156 Grover's disease, 175–176 Hailey-Hailey disease and, 168, 169 linear, 173–174 nail involvement, 170, 1060 oral involvement, 170, 366 Davis–Colley disease (punctate palmoplantar keratoderma), 75t, 81 De Barsy's-type cutis laxa, 948 de novo intraepidermal epithelioid melanocytic dysplasia, 1185 deafness Cockayne syndrome, 248 of keratitis–ichthyosis–deafness syndrome, 73 Debre-type cutis laxa, 948 decubitus fibroplasia, atypical, 1610–1611 dedifferentiated liposarcoma, 1601 deep benign fibrous histiocytoma, 1654 deep dermal pyogenic granuloma, 1715 deep granuloma annulare (subcutaneous granuloma annulare), 290, 295t deep penetrating nevus, 1189–1192 deep perivascular inflammatory dermatoses, 259–280 degenerative diseases, 520–589 Degos' acanthoma, 1086–1087 Degos' disease, 696–698 19-DEJ-1 (monoclonal antibody), epidermolysis bullosa, 112 delayed hypersensitivity (type 4) reactions to drugs, 592 delayed pressure urticaria, 647 demodic(id)osis, 311 anogenital, 478–479 rosacea and, 1046–1047, 1049 dendritic cell(s) blue nevus-like melanoma, 1249 sentinel node immunohistochemistry, 1300–1301 dendritic cell neurofibroma, 1676 dendritic cell sarcoma, 1410–1411 dendritic cell tumor/neoplasm blastic plasmacytoid, 1414–1415 indeterminate, 1398–1399 dendritic melanocytes, prominent intraepidermal, superficial blue nevus with, 1210–1211 dental amalgam tattoo, 431–432, 626 dental sinus, 1585 dentition (tooth/teeth) dental lamina cysts in newborns, 395 in focal dermal hypoplasia syndrome, 940 in incontinentia pigmenti, 653 plaque, 389 structure, 363 denture-associated fibrous hyperplasia, 387–389 Derbyshire neck, 245 Dercum's disease, 1596 dermal cylindroma see cylindroma dermal dendrocyte hamartoma, medallion-like, 1623–1624 dermal duct nevus, porokeratotic eccrine ostial and, 1530 dermal duct tumor, 1534–1535 dermal–epidermal junction, 21–22 in EB, 37–39

dermal fibroma Cowden's disease, 1451, 1452 plaque-like CD34-positive, 1623–1624 dermal fibrous histiocytosis see dermatofibroma dermal granular cell tumor, non-neural, 1755–1756 dermal hypermelanotic melanoma see pigment-synthesizing melanoma dermal liposarcomas, 1603 dermal melanocytoses, 1206–1217 dermal melanoma, primary, 1261–1262 dermal nevus (intradermal nevus), 1159, 1160–1161 differential diagnosis, 1162 pediatric, 1203 dermal nodular fasciitis (intradermal fasciitis), 1607, 1608 dermal pyogenic granuloma, deep, 1715 dermal sclerosis in morphea, 747 dermal squamomelanocytic tumor, 1259–1260 dermal tumors, unusual, high index of suspicion with, 1421 dermatitis atopic, 180–182 chronic actinic, HIV-associated, 899 chronic superficial, 259–260 contact see contact dermatitis eczematous see eczema exfoliative see erythroderm(i)a granulomatous see granulomatous dermatitis interface see interface dermatoses lichenoid see lichenoid dermatitis neutrophilic see neutrophilic dermatoses papuloerosive, of Jacquet and Sevestre, 445 perioral, 310–311, 1049 radiation see radiotherapy seborrheic see seborrheic dermatitis spongiotic see spongiotic dermatitis dermatitis artefacta dermatitis herpetiformis (Duhring–Brocq disease), 144–147, 411 acantholytic (pemphigus herpetiformis), 162 differential diagnosis, 104t, 147 bullous SLE, 143 oral mucosal lesions, 411 overlap with IgA pemphigus, 162 dermatoarthritis, lipoid, 1408–1409 dermatofibroma (dermal fibrous histiocytosis; sclerosing hemangioma; histiocytoma cutis; nodular subepidermal fibrosis), 1644–1654 atrophic see atrophic dermatofibroma deep counterpart, 1654 plexiform fibrous histiocytoma vs, 1658 dermatofibrosarcoma protuberans, 1630–1635 clinical features, 1630–1631 dermatomyofibroma and, histogenetic relationship between, 1613–1614 differential diagnosis, 1592 cellular fibrous histiocytoma, 1648 deep benign fibrous histiocytoma, 1654 giant cell fibroblastoma, 1630 superficial acral fibromyxoma, 1620 pathogenesis and histology, 1631–1635 plaque-stage, 1630–1631, 1635, 1676 dermatofibrosarcoma with monster cells, 1651–1652 dermatomycosis see candidiasis; tinea versicolor dermatomyofibroma, 1613–1614 dermatomyositis, 751–756 presenting with panniculitis, 353 dermatoneuro syndrome, 575–576 dermatopathia pigmentosa reticularis, 927 dermatopathic lymphadenopathy mycosis fungoides, 1323–1324 Sézary syndrome, 1340 Dermatophilus congolensis, 840 dermatophytosis see tinea dermatosis cenicienta, 236 dermatosis papulosa nigra, 1082 dermatosparaxis, Ehlers–Danlos syndrome type VIIC, 936t, 937–938 dermis, 1 collagen, 22–24 elastic tissue see elastic tissue fibroblasts, 27 focal dermal hypoplasia syndrome, 940–941 in mycosis fungoides infiltration, 1321 mucin deposits, 1331 nail matrix and nail bed, normal histology, 1053 papillary see papillary dermis dermoid (dermoid tumor) conjunctiva, 1293 oral cavity, 368–369 see also SCALP syndrome

Index dermoid cyst, 1580 differential diagnosis, 1580 sebaceous trichofolliculoma, 1469 oral cavity, 368 dermoid fistula, congenital (median nasal), 1469, 1580 dermolipoma, 1270 dermolysis of the newborn, transient bullous, 116 dermolytic EB see dystrophic EB dermolytic pemphigoid see epidermolysis bullosa acquisita dermoscopy/dermatoscopy androgenetic alopecia, 983 subungual melanoma, 1064 desipramine pigmentation, 603, 604 desmocollins, 13–14 desmogleins (Dsgs), 13–14 autoantibodies in pemphigus, 151t endemic pemphigus foliaceous, 161 endemic pemphigus vulgaris, 155 IgA pemphigus, 166 paraneoplastic pemphigus, 164 pemphigus foliaceous, 159 pemphigus herpetiformis, 162 pemphigus vulgaris, 154 mutations, 80 desmoid fibromatosis, 1628–1629 in Gardner's syndrome, 1615 desmoplakin mutations Carvajal–Huerta syndrome, 90 keratosis palmoplantaris areata et striata, 80 desmoplastic blue nevus, 1211 desmoplastic fibroblastoma, 1618, 1619 desmoplastic hairless hypopigmented nevus, 1205 desmoplastic melanoma, 1252–1257 differential diagnosis, 1257 desmoplastic Spitz nevus, 1188 desmoplastic seborrheic keratosis, 1081 desmoplastic Spitz nevus (juvenile melanoma; spindle and epithelioid nevus), 1181, 1186–1188 desmoplastic squamous carcinoma, 1127–1128, 1563 desmoplastic trichilemmoma, 1453–1454 desmoplastic trichoepithelioma, 1473–1475, 1541, 1562 desmosines, 25–26 desmosomes, 8, 13–14 cadherins see cadherins immunobullous diseases, 14 see also hemidesmosomes desquamative gingivitis, 409 in mucosal pemphigoid, 120, 133 diabetes insipidus, xanthoma disseminatum, 1402 diabetes mellitus bullous eruption, 589 necrobiosis lipoidica, 296–297 scleredema in late-onset disease, 580 dialysis see hemodialysis differentiated intraepithelial neoplasia penile, 494, 496 mixed with undifferentiated form, 498 vulval, 490, 491, 492 differentiation of squamous carcinoma, 1120–1123 diffuse alopecia areata, differential diagnosis, 995, 1005 diffuse angiokeratoma (angiokeratoma corporis diffusum), 530–532, 1710 diffuse basal cell carcinoma, 1090 diffuse cutaneous leishmaniasis, 845, 846 diffuse cutaneous mastocytoma, 1418 diffuse granuloma annulare, 292 diffuse large B-cell lymphoma of leg, 1319 other, 1373 diffuse lupus nephritis in systemic lupus erythematosus, 732–733 diffuse mucinoses, 571t diffuse necrobiosis lipoidica, 299 diffuse neurofibroma, 1674, 1678 diffuse palmoplantar keratoderma, 75t with associated symptoms, 75t diffuse non-epidermolytic palmoplantar keratoderma, 77–78 diffuse systemic sclerosis, 734, 737–738, 739t digits fibrokeratoma see fibrokeratoma fibromatosis, 1620–1621 fibro-osseous pseudotumor, 1609 mucous cyst, 1073 pacinian neuroma see Pacinian corpuscle see also subungual lesions dilated cardiomyopathy in Carvajal–Huerta syndrome, 89–90 dilated pore (of Winer), 1448–1449 diphtheria, cutaneous, 841 direct immunofluorescence, 36–37 disabling pansclerotic morphea of children, 746, 747 discoid dermatitis, 183 see also distinctive exudative discoid and lichenoid chronic dermatosis

discoid lupus erythematosus (chronic cutaneous erythematosus), 711–713, 726–730, 1012–1014 alopecia areata vs, 994–995 chronic, lichen planus vs, 229, 406 chronic granulomatous disease and, 715–716 clinical features, 711–712, 1012–1013 Jessner's lymphocytic infiltrate of the skin coexisting with, 264 Jessner's lymphocytic infiltrate of the skin vs, 264–265 pathogenesis and histology, 726–730, 1013 scarring alopecia of, 1012–1014 central centrifugal cicatricial alopecia vs, 1025 lichen planopilaris vs, 1017 pseudopélade of Brocq vs, 1023 verrucous/hypertrophic, 712–713 dissecting cellulitis/folliculitis of scalp (perifolliculitis capitis abscendens et suffodiens), 1027 differential diagnosis, 1028 central centrifugal cicatricial alopecia, 1025 folliculitis decalvens, 1027 hidradenitis suppurativa and, 656 dissecting folliculitis see dissecting cellulitis disseminated epidermolytic acanthoma, 59–60 disseminated fungal infections candidiasis, 862, 863 histoplasmosis, 865–866 disseminated intravascular coagulation, 701–703 disseminated superficial porokeratosis, 92, 94 distinctive exudative discoid and lichenoid chronic dermatosis, 195 DKC1 mutation, dyskeratosis congenita, 249 DNA copy changes, detection see comparative genomic hybridization damage melanocytic nevi and senescence related to, 1014 repair see mismatch repair genes; nucleotide excision– repair defects see also mitochondrial DNA syndrome-associated poikiloderma DNA autoantibodies lupus erythematosus, 723 verrucous (hypertrophic) discoid, 712–713 morphea, 746–747 DNA exonuclease TREX1 and chilblain lupus erythematosus, 272 Dohi, reticulate acropigmentation of, 927 donovanosis, 390 Dorfman–Chanarin syndrome, 66 Dowling–Degos disease, 924–926 Dowling–Meara EB simplex (EB simplex herpetiformis), 104 clinicopathological consequences of mutations, 7f electron microscopy, 38f, 39 pathogenesis and histological features, 113, 114, 115f drug (medication)-induced disorders and reactions, 590–630 bullous, 607–609 clinical manifestations, 592 diagnostic difficulties, 590 acne vulgaris, 1043 erythema multiforme, 238–240, 601 gingival hyperplasia, 396, 397 granulomatous, 605–606 ichthyosis-like conditions, 70t, 612 lichenoid, 598–599, 627 anogenital, 451 lichen planus vs, 229 oral, 403 lupus erythematosus, 607, 718 systemic, 607, 721 lymphomatoid, 1362 mycosis fungoides vs, 1314 panniculitis, 335, 626 papulosquamous, psoriasis vs, 211 pemphigoid, 134 pemphigus, 167, 609 pemphigus foliaceous, 159 pigmentation (hypo- and hyperpigmentation), 601–604, 621, 623 oral, 435 pityriasiform, 198, 610 pseudoporphyria, 559, 609 psoriasiform, 609–610, 626 purpuric, 605 pustular, 611–612 pyoderma gangrenosum, 632 specific drugs, 614–621 telogen effluvium, 606–607, 1002–1003 toxic epidermal necrolysis/Stevens–Johnson syndrome, 243, 601 type A reactions, 591 type B reactions, 591 type C reactions, 591–592 urticaria, 594, 647

drug (medication)-induced disorders and reactions (Continued) vasculitic, 604, 659 vitiligo, 914 see also specific drugs ductal apocrine carcinoma (mammary duct), metastatic, 1518 ductal carcinoma breast, 1569, 1570 eccrine see eccrine carcinoma ductal cysts (arising from accessory lacrimal gland), 1273 ductal hidrocystoma, 1509–1510 Duhring–Brocq disease see dermatitis herpetiformis Dunnigan-variant familial partial lipodystrophy, 354, 355t Dutch staging systems for lymph nodes in mycosis fungoides, 1323–1324, 1324t dwarfism, congenital telangiectatic erythema with, 247–248 dysbetalipoproteinema, familial, 528 dyschromatosis, acquired brachial cutaneous, 933–934 dyschromatosis symmetrica hereditaria, 927 dyshidrosiform pemphigoid, 119 dyskeratoma, warty see warty dyskeratoma dyskeratosis acantholytic, 169 anogenital, 169, 457 congenital, 248–249, 366 oral involvement, 366 hereditary benign intraepithelial see hereditary benign intraepithelial dyskeratosis pagetoid, 1444 dyslipidemias see hyperlipidemias dysplasia ectodermal see ectodermal dysplasia epithelial in actinic keratosis, 1108 conjunctival, 1276 genital, complicating lichen sclerosus, 453–454 oral, 421–424 familial white folded, of mouth, 364 lichenoid, 405 oculoauricularvertebral, 1293 polyostotic fibrous, 923 dysplastic angiopathy, congenital (acroangiodermatatis), 192–193, 1734 dysplastic keratosis, PUVA therapy (in psoriasis) and risk of, 209–210 dysplastic nevus, 1192–1201 acral, 1171 classification, 1193–1194, 1195t clinical features, 1194–1201 differential diagnosis, 1200–1201 atypical acral nevus, 1171 banal nevi, 1162–1163 lower leg/ankle nevi, 1170 genital, 483 lentiginous see lentiginous dysplastic nevus pathogenesis and histology, 1196–1200 dysplastic nevus syndrome, 1192–1201 dysproteinemia, angioimmunoblastic lymphadenopathy with, 1350 dystrophic calcinosis cutis, 566–568, 570 dystrophic EB (dermolytic EB), 102, 104, 108–111 classification, 102t diagnosis, 38–39 dominant, 102t, 108–109 pathogenesis and histology, 115–116 recessive, 102t, 109–111 dystrophic EB inversa, recessive, 111

E

ears (aural tissue) auricle of see auricle chondrodermatitis nodularis chronica helicis, 324–325, 759 elastotic nodules, 962 in focal dermal hypoplasia syndrome, 940 indolent CD8+ lymphoid proliferation of, 1349–1350 juvenile spring eruption, 268, 269 in keratitis–ichthyosis–deafness syndrome, 74 lambing, 268 nevi in/around, 1167–1169 skin histology, 5f Eberhartinger-variant bullous pemphigoid, 119 Ebola virus, 789 eburneous metastases see sclerodermatous metastases EBV see Epstein–Barr virus eccrine acrospiroma see clear cell hidradenoma eccrine adenoma, papillary, 1514, 1541–1543 eccrine angiomatous hamartomas, 1529–1530 eccrine carcinoma ductal, 1569–1570 squamoid, 1570 syringoid (eccrine epithelioma), 1541, 1558–1560 eccrine-centred nevus, 1164–1165 eccrine epithelioma (syringoid eccrine carcinoma), 1541, 1558–1560

1777

1778

Index eccrine glands (incl. ducts), 17–19 anogenital, 441 chemotherapy-associated reactions, 623–625 HIV-associated mucinosis involving, 905 transient acantholytic dermatosis involving, 200 see also sweat glands eccrine hidrocystoma, 1509–1510 eccrine nevus, 1527–1528 eccrine ostial and dermal duct nevus, porokeratotic, 1530 eccrine porocarcinoma, 1535–1538 differential diagnosis, 1538 hidradenocarcinoma, 1548 squamous carcinoma, 1123, 1538 eccrine poroma, 1533–1534 malignant see eccrine porocarcinoma eccrine spiradenocarcinoma, 1556–1558 eccrine spiradenoma, 1554–1556, 1749 eccrine syringofibroadenoma, 1528 echinococcosis, 894–895 ECM1 mutation and lipoid proteinosis, 546 ectasias, vascular, 1705–1711 ecthyma, 790, 791 ecthyma contagiosum, 783–785 ecthyma gangrenosum, 790–791 ectodermal dysplasia anhidrotic see anhidrotic ectodermal dysplasia hidrotic (Clouston syndrome), 71t, 84–85 hypohidrotic, skin fragility with, 87–88 multiple eccrine syringofibroadenoma associated with, 1528 palmoplantar see palmoplantar ectodermal dysplasia ectodysplasin (EDA) and ectopic sebaceous glands, 1489 and hair follicle development, 972 ectomesenchymal chondromyxoid tumor, 436 ectopic tissue see heterotopic tissue eczema (eczematous dermatitis), 180 acute and subacute, pityriasis rosea vs, 198 annular, superimposed upon acquired benign melanocytic nevus (=Meyerson's nevus), 1177–1178 anogenital, 445 endogenous, 180–184 exogenous, 184–200 general considerations, 185 hands (pompholyx), 180, 183–184 eczema herpeticum, 773 EDA see ectodysplasin edema, hemorrhagic, of childhood, 461, 665–666 EGFR inhibitors see epidermal growth factor receptor inhibitors Ehlers–Danlos syndrome, 935–938 El Bagre (Colombia), endemic pemphigus foliaceous, 161, 162 elastic tissue, 24–26 disorders, 948 elastin, 25–26 gene (ELN) mutations and cutis laxa, 949 elastin-associated microfibrils, 24–25, 26 elastofibroma, 1611–1612 elastolysis generalized, 948–950 mid-dermal, 957–958 perifollicular, 956 postinflammatory, 949, 950 elastolytic granulomata, 302–306 elastoma (elastic nevus), 959–961 juvenile, 959, 961 elastorrhexis, papular, 961 elastosis late-onset focal dermal, 954 linear focal, 958 solar see solar elastosis elastosis perforans serpiginosa, 318t, 319–321, 322 elastotic hemangioma, acquired, 1720 elastotic material, actinic granuloma, 303–304 elastotic nodules, ear, 962 elderly (skin) atypical dysplastic lentiginous nevus, 1167 pilomatrixoma, 1462–1463 pseudoxanthoma elasticum-like papillary dermal elastolysis vs, 957 electron microscopy (ultrastructure), 37 EB, 38f, 39 metastases, 1430 see also immunoelectron microscopy Elejalde syndrome, 919 ELN mutations and cutis laxa, 949 EMA see epithelial membrane antigen embedding for light microscopy, 32 embolism from atrial myxoma, 700–701 cholesterol crystal, 700–701 embryology genitalia, 440–441 hair follicle, 972 see also fetus

embryonal rhabdomyosarcoma, 1702 EMLA cream, 630 encephalocraniocutaneous lipomatosis, 1596 enchondral pseudocyst (auricle), 1587 enchondroma, nail apparatus, vs exostosis, 1075 enchondromas, multiple (of Maffucci's syndrome), 1716 endarteritis in lichen sclerosus, 456 endemic Kaposi sarcoma, 1729–1730 endemic pemphigus foliaceous, 160–162 endemic pemphigus vulgaris, 155 endemic syphilis, 808 endemic typhus, 842 endocrine mucin-producing sweat gland carcinoma, 1558 endometriosis, 486 endophytic component, verrucous carcinoma, 1133 endosalpingiosis, 486 endospores, coccidioidal, 870–871 endothelin-3 gene mutations and Waardenburg's syndrome, 920 endothelium cells, 27 intravascular papillary hyperplasia, 1705 systemic sclerosis, 739 endothrix infections, 853 engraftment syndrome, 254 Enhanced Polymer One Step (EPOS), 35 Entamoeba histolytica and amebiasis cutis, 478, 848 enterovirus 17 and hand, foot and mouth disease, 787 entomophthoromycosis, 874 envenomation see venom EORTC see European Organization of Research and Treatment of Cancer eosinophil(s), granuloma annulare, 292 eosinophilia angiolymphoid hyperplasia with see angiolymphoid hyperplasia stromal, traumatic ulcerative granuloma with, 381–382 eosinophilia–myalgia syndromes, L-tryptophan-related, 750 eosinophilic, polymorphic and pruritic eruption associated with radiotherapy, 280 eosinophilic dermatoses (in general), 631–657 eosinophilic fasciitis, 749–751 eosinophilic folliculitis HIV-associated, 902 mycosis fungoides vs, 1334 eosinophilic granuloma, 1392–1393, 1394 eosinophilic panniculitis, 350 eosinophilic pustular folliculitis (Ofuji's disease), 651–652 childhood, 218 HIV-associated, 652, 902 mycosis fungoides vs, 1334 eosinophilic spongiosis, 194 eosinophilic ulcer/granuloma of the tongue, 381–382 eotaxin and incontinentia pigmenti, 654 ephelides see freckles epidermal cysts see epidermoid cysts epidermal growth factor receptor (EGFR) inhibitors, 622, 623 radiation combined with, 965 epidermal necrolysis, toxic see toxic epidermal necrolysis epidermal neoplasms, immunohistochemical diagnosis, 35t epidermal nevus, 1076–1079 acantholytic dyskeratotic, 173–174 Hailey-Hailey-like, 169 inflammatory linear verrucous (ILVEN), 214–215 linear epidermolytic, 59 pigmented hairy, 1156 epidermal tumor, muciparous see mucinous metaplasia/ syringometaplasia epidermis, 1 barrier function, 8 histology, 1–2 stem cells, 6–8 see also dermal–epidermal junction epidermodysplasia verruciformis, 940, 1119 epidermoid carcinoma, nail, 1068–1069 epidermoid (epidermal/infundibular) cysts, 1571–1574 hybrid apocrine and, 1510 miniature, milia consisting of, 1577 oral cavity, 368 proliferating, 1574 sole of foot, 1575 subungual, 1066 verrucous variant, 1575 epidermolysis bullosa, 101–117 in aplasia cutis, 939 classification, 101–102 clinical features, 104–117 diagnosis, 37–39 differential diagnosis, 117 dystrophic see dystrophic EB junctional see junctional EB with muscular dystrophy, 103–104, 105, 114 pathogenesis and histology, 112–116

epidermolysis bullosa acquisita (EBA; dermolytic pemphigoid), 137–142, 411 differential diagnosis, 104t, 142 drug-induced, 609 oral lesions, 411 epidermolysis bullosa atrophicans generalisata (Herlitz-type junctional EB), 107, 114–115 epidermolysis bullosa atrophicans generalisata mitis, 107 epidermolysis bullosa gravis (Hallopeau–Siemens syndrome), 109–111, 116f epidermolysis bullosa hereditaria letalis (Herlitz-type junctional EB), 107, 114–115 epidermolysis bullosa simplex (EBS; EB variant), 102–103, 104–106 classification, 102t clinical features, 104–106 Dowling–Meara see Dowling–Meara EB simplex herpetiform see Dowling–Meara EB simplex localized (Weber–Cockayne syndrome), 104, 114 pathogenesis and histology, 112–114 superficial, 104 epidermolytic acanthoma, 59–60 epidermolytic epidermal nevus, linear, 59 epidermolytic hyperkeratosis, 48t congenital bullous ichthyosiform erythroderma also known as, 55–58 focal, 60 with polycyclic psoriasiform plaques, 77 epidermolytic palmoplantar keratoderma, 76 epidermolytic toxins (S. aureus), 794 epidermotropism apocrine carcinoma, 1516 CD8+ aggressive cytotoxic T-cell lymphoma see CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma CD8+ variant of lymphomatoid papulosis, 1343 metastatic melanoma, 1251 mycosis fungoides, 1318, 1320–1321, 1325 pagetoid reticulosis, 1335, 1336f Sézary cells, 1340 epignathus, 368–369 epiloia, 941–944 epithelial cysts, conjunctival, 1273 epithelial dysplasia see dysplasia epithelial hamartoma, sclerosing (desmoplastic trichoepithelioma), 1473–1475, 1541, 1562 epithelial hyperplasia focal, oral, 384, 400–401 reactive see pseudoepitheliomatous hyperplasia epithelial membrane antigen (EMA) eccrine glands, 18–19 sebaceous cells, 16–17, 17f epithelial sheath neuroma, 1668 epithelial tumors, 1076–1149 conjunctival benign, 1270, 1271–1274 maligant, 1270 nail apparatus, 1066–1070 epithelioid angiomatous nodule, 1720 epithelioid angiosarcoma, 1742–1743 epithelioid blue nevus, 1211–1212 in Carney complex, 929, 930, 1211–1212 differential diagnosis, 1212 pigmented epithelioid cell nevus, 1185 epithelioid cell tumor, perivascular, 1759–1761 epithelioid features in adults and children, papular angiolymphoid proliferation with (PALEFACE), 1362 epithelioid fibrosarcoma, sclerosing, 1640–1641 epithelioid fibrous histiocytoma, 1650–1651 desmoplastic Spitz nevus vs, 1187 epithelioid hemangioendothelioma, 1736–1737, 1764–1765 epithelioid hemangioma see angiolymphoid hyperplasia epithelioid histiocytoma, solitary see reticulohistiocytoma epithelioid leiomyosarcoma, 1699–1701 epithelioid malignant nerve sheath tumor (epithelioid malignant schwannoma), 1692, 1693 clear cell sarcoma vs, 1695 epithelioid melanocytic dysplasia, de novo intraepidermal, 1185 epithelioid melanoma, 1230 epithelioid neurofibroma, 1676 epithelioid nevus, pigmented, 1185 epithelioid sarcoma, 1761–1765 differential diagnosis, 1761–1762 acral myxoinflammatory fibroblastic sarcoma, 1636 granuloma annulare, 295, 1764–1765 rheumatoid nodules, 302, 1764–1765 epithelioid sarcoma-like hemangioendothelioma, 1735 epithelioid schwannoma, 1672

Index epithelioma (epitheliomata) Borst–Jadassohn, 1086, 1114 calcifying, of Malherbe (=pilomatricoma), 1460–1463, 1465 eccrine, 1541, 1558–1560 familial primary self-healing (of skin), 1136 sebaceous, 1496 superficial, with sebaceous differentiation, 1489 epithelioma adenoides cysticum of Brooke, 1469–1470 epithelium follicular, mycosis fungoides involving, 1320, 1333 genital lesions, benign, 486–490 melanocytic tumors unassociated with epithelial structures, 1266–1267 nail matrix, 1053 Epstein–Barr virus and antibiotic eruptions, 1392 and extranodal NK/T cell lymphoma, 1339 and Hodgkin lymphoma, 1383 and hydroa vacciniforme-like lymphoma, 1358, 1359 and lymphoepithelioma-like carcinoma, 1148 and lymphomatoid granulomatosis, 1376–1377 and plasmablastic lymphoma, 1381 and post-transplant lymphoproliferative disorders, 1385–1386 epulis calcifying fibrous, 391–392 congenital (granular cell of newborn), 370–371, 1682 definition, 389 epulis fissuratum, 387–389 equestrian cold panniculitis, 270, 337 equine-type melanoma see pigment-synthesizing melanoma ERCC genes and xeroderma pigmentosum, 1140 Erdheim–Chester disease, 1399 erosive adenomatosis of nipple, 1515 erosive lichen planus anogenital, 449 oral, 402 eruptive blue nevi, 1210 eruptive collagenoma, 947–948, 961 eruptive histiocytosis, generalized, 1401 eruptive keratoacanthoma, 1136 eruptive milia, 1577 eruptive pseudoangiomatosis, 780–781 eruptive psoriasis see guttate psoriasis eruptive pustular dermatosis, 1030 eruptive syringoma, 1540 eruptive vellus hair cysts see vellus hair cysts, eruptive eruptive xanthoma(ta), 522–523 Rosai–Dorfman disease vs, 1407 erysipelas, 794–795 erythema annular see erythema annulare congenital telangiectatic, with dwarfism, 247–248 necrolytic migratory, 587–589 toxic see toxic erythema UV-induced, 965 erythema annulare (annular erythema), 261 erythema annulare centrifugum, 261–262 tumid lupus erythematosus vs, 270 erythema areata migrans, 375–377 erythema chronicum migrans, 806, 807 erythema circinata, 375–377 erythema dyschromicum perstans, 236 erythema elevatum diutinum, 684–686 HIV-associated, 902–903 erythema gyratum (gyrate erythema), 261 erythema gyratum repens, 263–264 erythema gyratum repens-like lesions, erythrokeratoderma variabilis with, 71t, 72 erythema induratum, 346–349, 819 erythema marginatum rheumaticum, 644 erythema migrans, 806, 807 erythema multiforme, 237, 238–241, 601 bullous, 237 drug-associated, 238–240, 601 Stevens–Johnson syndrome and toxic epidermal necrolysis and differential diagnosis, 244–245 overlap between, 241 see also lupus erythematosus-erythema multiforme-like syndrome erythema multiforme major, 238 erythema necroticans (Lucio's phenomenon), 828, 829, 830–831 erythema nodosum, 327–332 Behçet's syndrome lesions resembling, 332 erythema nodosum leprosum (ENL), 827–828, 829, 831 erythema nodosum-like panniculitis syndrome in systemic sclerosis, 737 erythematotelangiectatic rosacea, 1046, 1046t, 1047 erythematous lesions mycosis fungoides, 1313 pagetoid reticulosis, 1335

erythematous mucinosis, reticular see reticular erythematous mucinosis erythematous oral lichen planus, 402 erythokeratoderma, progressive symmetrical, 73, 84 erythrasma (C. minutissimum infection), 839 anogenital/flexural, 461 erythroderm(i)a (incorrectly called exfoliative dermatitis), 194–195 ichthyosiform see ichthyosiform erythroderma progressive palmoplantar, 73 psoriatic, 203–204, 209 in Sézary syndrome, 1338 erythrodermic bullous pemphigoid, 117–118 erythrokeratoderma, 71–75 erythrokeratoderma variabilis, 71–73 erythrokeratolysis hiemalis, 78–79 erythroleukoplakia, oral, 402 erythronychia, longitudinal, 1070 erythroplakia, 421–424 erythropoietic porphyria, congenital, 550–551 erythropoietic protoporphyria, 550t, 551–552 esophagus lichen planus involving, 219, 228 polymyositis involving, 752 squamous carcinoma, autosomal dominant focal nonepidermolytic palmoplantar keratoderma with, 90–91 see also CREST syndrome essential mixed cryoglobulinemia, 703 essential telangiectasia, generalized, 1710 esthetic microimplants, 627–629 foreign body granulomata, 313, 628 etanercept, 626 lymphoproliferative disorders, 1384 ethics regarding research use of sentinel node samples, 1298–1299 ethnicity see race etoposide, 623 eumelanin, 11 European Organization of Research and Treatment of Cancer (EORTC) lymphoma classification, 1312 sentinel node sampling guidelines, 1300 see also International Society for Cutaneous Lymphomas– EORTC; World Health Organization–EORTC classification EVER1 and EVER2, 770 Ewing's sarcoma see EWS; EWSR1; peripheral primitive neuroectodermal tumor EWS and peripheral primitive neuroectodermal tumor, 1693 EWSR1 (Ewing sarcoma breakpoint region 1), 40–41 clear cell sarcoma and, 1694 extraskeletal myxoid chondrosarcoma and, 1753 myoepithelioma of soft tissue and, 1759 exacerbation of conditions by drugs, 591 examination (physical) conjunctival tumors, 1269 hair disorders, 968 exanthemata and exanthamatous eruptions drug-associated, 592–594 mercury, 619–620 viral infection, 280 exanthem subitum, 780 HIV, 905–906 see also acute generalized exanthematous pustulosis excision–repair defects see nucleotide excision–repair defects exfoliative cytology, ocular surface squamous neoplasia, 1276 exfoliative dermatitis see erythroderm(i)a exfoliative toxins (S. aureus), 794 exogen, 979 Exophiala jeanselmei, 879, 880 Exophiala werneckii, 861 exophytic component, verrucous carcinoma, 1133 exostosis benign cartilaginous, 1751 subungual, 1074–1075 extracellular matrix see matrix extramedullary hematopoiesis, 1416 extramedullary plasmacytoma, 1378 extranodal marginal zone lymphoma see marginal zone B-cell lymphoma extranodal NK/T cell lymphoma, nasal type, 1355–1357, 1378 extraosseous Ewing's sarcoma, 1693–1694 extraosseous plasmacytoma, 1378 extraskeletal myxoid chondrosarcoma see chondrosarcoma extraskeletal osteosarcoma, 1751 extravasation of chemotherapeutic drugs, 623 extremities see leg; limb eye see ocular features eyelid cysts of Schöpf–Schulz–Passarge syndrome, 91 Moll's gland cyst, 1508, 1509 sebaceous carcinoma, 1492, 1502, 1503–1505 signet ring cell carcinoma, 1570 ezrin and myxofibrosarcoma, 1663

F

FAB system, leukocyte precursor cell neoplasms, 1413 Fabry's (Anderson–Fabry's) disease (angiokeratoma corporis diffusum), 530–532, 1710 face acquired dermal melanocytosis of, and extremities, 1208 angiofibromas in tuberous sclerosis, 941 Cowden's disease-related lesions, 1451 hair counts, 972t keratosis lichenoides chronica, 235 keratosis pilaris atrophicans, 68 necrobiosis lipoidica (atypical), 304 see also centrofacial lentiginosis; cervicofacial actinomycosis; congenital facial infiltrating lipomatosis; granuloma faciale; lupus miliaris disseminatus faciei; periorificial dermatitis; pyoderma faciale FACE-1 (ZMPSTE24) mutation and restrictive dermopathy, 947 factitious disorders dermatitis artefacta, 480 oral mucosa see morsicatio mucosae oris panniculitis, 334–336 factor V (Leiden) mutation, 708 factor XIIIa and verrucous xanthoma, 530 FALDH (microsomal fatty aldehyde dehydrogenase) mutations, 64 familial acanthosis nigricans, benign, 585 familial adenomatous polyposis see Gardner's syndrome familial amyloidotic polyneuropathy, 537 familial atypical multiple mole melanoma syndrome, 1192–1201 familial basaloid follicular hamartoma, 1447 familial cold inflammatory syndrome (familial cold urticaria), 537, 646–647 familial continuing peeling skin, 60 familial cutaneous collagenoma, 947 familial cutaneous mucinosis, self-healing infantile, 583 familial cutis laxa variants, 948–949 familial cylindromatosis (Brooke–Spiegler syndrome), 1470, 1471, 1551 familial dysbetalipoproteinema, 528 familial dyskeratotic comedones, 177–178 familial glomangiomas, 1747 familial hemophagocytic lymphohistiocytosis, 1409 familial lipodystrophy, 354–355 familial Mediterranean fever, 537 familial melanoma, 1222 familial pemphigus, benign see Hailey-Hailey disease familial porphyria cutanea tarda, 553 homozygous form, 555 familial primary cutaneous amyloidosis, 541 familial primary self-healing squamous epitheliomata of the skin, 1136 familial thrombotic thrombocytopenic purpura, 707 familial thyroglossal duct cyst, 1581 familial trichoepithlioma, multiple, 1469–1470 familial white folded dysplasia of mouth, 364 familiar Hibernian fever, 280 family history-taking, hair disorders, 968 fasciitis eosinophilic, 749–751 ischemic, 1610–1611 necrotizing see necrotizing fasciitis nodular see nodular fasciitis fasciitis ossificans, 1607 fat (adipose tissue), subcutaneous, 30–31 inflammatory diseases, 326–361 necrosis see necrosis fatty aldehyde dehydrogenase (FALDH) mutations, 64 Favre–Racouchot syndrome/disease (solar comedones), 962, 1575–1576 favus, 853–854 FBLN5 mutations and cutis laxa, 949 febrile neutrophilic dermatosis, acute see Sweet's syndrome febrile nodular nonsuppurative panniculitis, relapsing, 332–333 febrile ulceronecrotic Mucha–Haberman disease, 255, 256, 258 feet see foot female(s) (women) androgenetic alopecia, 983 genitalia, anatomy, 438–439 postmenopausal, telogen effluvium, 1003–1004 sex hormones see sex hormones ‘female pattern’ (Ludwig) hair loss, 983 lichen planopilaris vs, 1019–1020 Fergusson–Smith syndrome, 1136 ferrochelatase gene mutation, 555 fetal rhabdomyoma, 1701–1702 fetus harlequin, 54 in pemphigoid gestationis, complications, 128–129, 129f skin development, 6f see also embryology FGFR2 mutation, comedone nevus, 1446

1779

1780

Index fibrillin, 26 systemic sclerosis and, 740 fibroblast(s), 26–27 keloids and, 1605 systemic sclerosis, 740 fibroblast growth factor receptor 2 gene mutation, comedone nevus, 1446 fibroblastic granuloma, calcifying, 391–392 fibroblastic sarcoma, acral myxoinflammatory, 1635–1636 fibroblastoma desmoplastic, 1618, 1619 giant cell see giant cell fibroblastoma fibrocartilaginous pseudotumor, nuchal, 1615–1616 fibroepithelial polyp (acrochordon; fibrovascular polyp; skin tag; soft fibroma incl. bite/irritation fibroma), 1612–1613 anogenital, 443 lymphedamatous (of penis), 514–515 oral, 385 fibroepithelial stromal polyp, female genitalia, 513–514 fibroepithelial tumors, nail matrix, 1070–1072 fibroepithelioma of Pinkus, 1105–1106 fibrofolliculoma, 1484 see also Birt–Hogg–Dubé syndrome fibrohistiocytic lipoma, 1599 fibrohistiocytic lipomatous lesion, hemosiderotic, 1599–1600 fibrokeratoma, acquired digital, 1623 ungual, 1071–1072 onychomatricoma vs, 1071 fibroma bite/irritation/soft see fibroepithelial polyp calcifying aponeurotic, 1621–1622 collagenous, 1618, 1619 conjunctival, 1288 dermal see dermal fibroma Gardner's, 1615 giant cell, 386–387, 389 gingival, 389 nuchal see nuchal fibroma perifollicular, 1484 peripheral odontogenic, 393–395 peripheral ossifying, 391–392 pleomorphic subungual, 1072 sclerotic, 1614–1615 tendon sheath, 1618, 1619 ungual, 1071–1072 vulval prepubertal, 515 fibromatosis desmoid see desmoid fibromatosis desmoplastic fibroblastoma vs, 1619 gingival, 371 inclusion body, 1620–1621 juvenile hyaline see juvenile hyaline fibromatosis palmar, 1626–1627 penile, 1627 plantar, 1627 plexiform fibrous histiocytoma vs, 1658 fibromatosis colli, 1616 fibromyxoid sarcoma, low-grade, 1641, 1642–1643 fibromyxoid tumor, ossifying, 1756–1758 fibromyxoma, superficial acral, 1071, 1072–1073, 1620–1621 fibro-osseous pseudotumor of digits, 1609 fibroplasia, atypical decubitus, 1610–1611 fibrosarcoma adult variant, 1640 infantile variant, 1640 inflammatory see inflammatory myofibroblastic tumor malignant peripheral nerve sheath tumor vs, 1693 sclerosing epithelioid, 1640–1641 see also dermatofibrosarcoma; myxofibrosarcoma; nerve sheath tumor, peripheral malignant fibrosarcomatous dermatofibrosarcoma, 1633–1634 fibrosing alopecia, frontal, 1018 fibrosing vasculitis, chronic, 684, 685–686 fibrosis nephrogenic systemic see nephrogenic systemic fibrosis nodular subepidermal see dermatofibroma submucous, 424–425 fibrous dysplasia, polyostotic, 923 fibrous epulis, calcifying, 391–392 fibrous hamartoma of infancy, 1624–1625 fibrous histiocytoma aneurysmal, 1649–1650, 1734 angiomatoid, 1650, 1656 atypical pseudosarcomatous, 1651–1652 cellular benign, 1647–1648 clear cell, 1652 conjunctival, benign and malignant, 1288 deep benign, 1654 dermal see dermatofibroma dermatofibrosarcoma protuberans vs, 1635 epithelioid see epithelioid fibrous histiocytoma hemosiderotic, 1650, 1650f, 1651f

lipidized (ankle-type), 1652 lipidized, 526 malignant (undifferentiated pleomorphic sarcoma), 1662–1665 giant cell, 1662 infiltrative subcutaneous, 1665 inflammatory, 1664 myxoid (myxofibrosarcoma), 1643, 1663 palisading cutaneous, 1652–1653 plexiform, 1657–1658 fibrous hyperplasia, denture-associated, 387–389 fibrous-long spacing collages, 24 fibrous papule, 1643 fibrous papulosis, white, 947 fibrous tumors, 1604 benign, 1604–1625 calcifying, 1616 conjunctival, 1270, 1288–1289 locally aggressive lesions, 1626–1629 malignant, 1640–1643 low-grade, 1629–1639 solitary, 1637–1639, 1654 fibrovascular polyp see fibroepithelial polyp fibroxanthoma, atypical, 1658–1662 clear cell, 1125 conjunctival, 1288 differential diagnosis, 1662 atypical fibrous histiocytoma, 1652 squamous carcinoma, 1125, 1662 fibulin-5 gene (FBLN5) mutations and cutis laxa, 949 filaggrin (FLG), 8–9 mutations, 8–9 ichthyosis vulgaris, 47 irritant contact dermatitis, 185 filgrastim (G-CSF), adverse reactions, 625 fillers (cosmetic), 628 filoviridae, 789 fine needle aspiration cytology, metastases, 1430 FISH (fluorescence in situ hybridization), 40–42 fish tank granuloma, 820–821 fistula, dermoid (congenital), 1469, 1580 fixation electron microscopy, 37 light microscopy, 32 fixed drug eruptions, 599–600 fixed-form sporotrichosis, 884 fixed solar urticaria, 646 flaviviridae, 788 flea, sand/jigger (Tunga penetrans), 890 Flegel's disease, 95–96, 178 flexures atopic dermatitis, 180–182 nevi, 1169–1170 psoriasis, 202 anogenital, 446 reticulate pigmented anomaly of, 924–926 FLG see filaggrin FLI1 and peripheral primitive neuroectodermal tumor, 1693 florid papillomatosis of nipple, 1515 flukes see trematode infestations fluorescence in situ hybridization (FISH), 40–42 fluorochromes for immunofluorescence, 35–37 focal acantholytic dyskeratosis, 179 focal acral hyperkeratosis, 82 focal dermal elastosis, late-onset, 954 focal dermal hypoplasia syndrome, 940–941 focal elastosis, linear, 958 focal epidermolytic hyperkeratosis, 60 focal epithelial hyperplasia, 384, 400–401 focal lupus nephritis in systemic lupus erythematosus, 732 focal mucinoses, 571t, 582–583 focal nonepidermolytic palmoplantar keratoderma autosomal dominant, 90–91 with oral hyperkeratosis, 88 fogo selvagem, 160–162 follicle(s) (hair), 972–978, 1445–1487 anagen, in alopecia areata, 992 anatomy, 972–978 bulge stem cells lichen planopilaris and, 1016 pseudopélade of Brocq, 1022 scarring alopecia and, 1010 chemotherapeutic drug effects, 621 Demodex and, 311 embryology, 972 epithelial involvement in mycosis fungoides, 1320, 1333 immune privilege, 982 infundibulum see infundibulum stellae, in androgenetic alopecia, 985 stem cells, 7–8 tumors, 1445–1487 see also perifollicular skin

follicle(s) (lymphoid), in B-cutaneous lymphoid hyperplasia, 1387–1388 follicle center lymphoma, primary cutaneous (PCFCL), 1317 differential diagnosis, 1371 B-cutaneous lymphoid hyperplasia, 1388–1389 diffuse large B-cell lymphoma of leg, 1372 marginal zone lymphoma, 1368 follicular atrophoderma, 1105 follicular cysts, 1571–1580 follicular dendritic cell sarcoma, 1410–1411 follicular dermatoses (in general), 1041–1050 follicular differentiation, chondroid syringoma, 1521 follicular hamartoma, basaloid, 1446–1448 follicular hyperkeratosis, 48t see also Kyrle's disease follicular ichthyosis, 66 with alopecia and photophobia, 66 follicular keratosis see Darier's disease follicular lichen planus (lichen planopilaris), 221, 226 follicular lymphoma, 1373 cutaneous follicle center lymphoma vs, 1383 nodal see nodal follicular lymphoma follicular lymphomatoid papulosis vs mycosis fungoides, 1334 follicular mucinosis (alopecia mucinosa), 1025, 1334–1335 HIV-associated, 905 mycosis fungoides or Sézary syndrome associated with, 1334–1335 follicular occlusion triad/syndrome, 1028 folliculitis actinic, 1045 dissecting see dissecting cellulitis eosinophilic see eosinophilic folliculitis; eosinophilic pustular folliculitis infective/bacterial, 797–799 folliculitis decalvens vs, 1027 Gram-negative, 1050 HIV-associated, 907 Malassezia, 859–860 necrotizing infundibular crystalline, 323 necrotizing lymphocytic, 1030 perforating, 318t pseudolymphomatous see pseudolymphomatous folliculitis pustular see pustular folliculitis; perifolliculitis folliculitis decalvans, 798, 1026 folliculitis keloidalis nuchae see acne keloidalis nuchae folliculitis ulerythema reticulata, 69 folliculosebaceous cystic hamartoma, 1467–1469 folliculotropic mycosis fungoides, 1331–1334 Fonsecaea compacta, 876 foot (feet) Cowden's disease lesions, 1451 EB simplex of hand and (Weber–Cockayne syndrome), 104, 114 skin histology, 3f tinea (athlete's foot), 856–857 see also hand, foot and mouth disease; hand–foot reaction; plantar surfaces and entries under palmoplantar Fordyce, angiokeratoma of, 1710 forearm, Raimer's solar elastotic bands, 962 foreign body gingivitis, 379 foreign body granulomata, 311–313, 628 foreskin see prepuce formalin fixation, 32 Fournier's gangrene, 479, 796 Fox–Fordyce disease, 200 fragility (skin) with hypohidrotic ectodermal dysplasia, 87–88 Francisella tularensis and tularemia, 842 freckles (ephelides), 1150 Hutchinson's melanotic see melanoma in situ senile see actinic lentigo French–American–British (FAB) system, leukocyte precursor cell neoplasms, 1413 fringed hair, 1039 frontal fibrosing alopecia, 1018 frontoparietal linear morphea, 745 functional properties of skin, 1–31 fungal infections, 851–852 dermatophytic see tinea groin, 461–479, 857 nail (onychomycosis), 1054 vasculitis associated with, 694 see also yeasts furanocoumarin-associated photodermatitis, 596 furuncle, 798 Fusarium, 861, 863–864

G

G-protein alpha subunit (GNA…) blue nevus-like melanoma, 1249 McCune–Albright syndrome, 923 melanocytic nevi, 967, 1012 melanocytic tumors unassociated with epithelial structures, 1266–1267

Index α-galactosidase A deficiency, 530, 1710 Galli–Galli disease, 926 gamma-delta T-cell lymphoma, primary cutaneous, 1359–1360 vs subcutaneous panniculitis-like T-cell lymphoma, 1354–1355, 1360 ganglion cell choristoma (ganglioneuroma), 1666 gangrene, Fournier's, 479, 796 gangrenous ecthyma, 790–791 gangrenous fasciitis see necrotizing fasciitis gap junctions, 14 Gardner's syndrome (familial adenomatous/colorectal polyposis; FAP), 1573, 1574, 1628 fibroma, 1615 gastrointestinal disorders/conditions in choristoma, 367 in Churg–Strauss syndrome, 677 in Ehlers–Danlos syndrome, 936 in Henoch–Schönlein purpura, 665 in ichthyosis-like conditions, 70t in Kawasaki syndrome, 680 neutrophilic dermatoses associated with, 639–640 in Peutz–Jeghers syndrome, 927, 928 in polyarteritis nodosa, 669 in pseudoxanthoma elasticum, 952 in systemic lupus erythematosus, 720 in systemic sclerosis, 738, 743 gastrointestinal metastases to skin, 1429–1430, 1434 mucinous carcinoma vs, 1567–1568 Gaucher syndrome type II, 66 GB3 (monoclonal antibody), epidermolysis bullosa, 112 GCDFPs (gross cystic disease fluid proteins) hidradenoma, 1545 metastatic breast cancer, 1429 gene(s) amplifications, melanoma, 1264–1265, 1266 expression patterns, basal cell carcinoma, 1094 polymorphisms, melanoma, 1262 see also molecular pathology generalized acquired cutis laxa, adult, 949 generalized basaloid follicular hamartoma, 1446–1447 generalized collagen disorders, 935–939, 940–947 generalized cutaneous pemphigoid, 117–118 generalized dystrophic EB dominant, 108 other/non-Herlitz, 111, 114–115 severe (Hallopeau–Siemens syndrome), 109–111, 116f generalized elastolysis, 948–950 generalized eruptive histiocytosis/histiocytoma, 1401 generalized essential telangiectasia, 1710 generalized exanthematous pustulosis, acute, 611 generalized gingival hyperplasia, 371, 396–398 generalized granuloma annulare, 289–290 generalized lipodystrophy acquired, 355, 355t congenital, 327t, 354 generalized melanosis associated with metastatic melanoma, 934 generalized morphea, 361, 746, 747 generalized myofibromatosis, congenital, 1616 generalized myxedema, 572–573 generalized non-Herlitz junctional EB, 107 generalized pustular psoriasis, 202–203, 208 genetic abnormalities see molecular pathology genetic (inherited) disorders, 37–39 acanthosis nigricans in, 583–584 adherens junction proteins, 14 amyloidosis in, 537 blistering see blistering disorders connexin see connexin desmosomal components, 14, 14f diagnosis, 37–39 fibrillin, 26 filaggrin, 8–9 hair growth, 1032t keratin see keratin oral mucosa, 364–366 porphyrin metabolism, 549–559 tight junction proteins, 15 see also specific disorders and genes and entries under familial genetic (inherited) predisposition or factors alopecia areata, 992 atopic dermatitis, 181–182 basal cell carcinoma, 1093, 1094 mycosis fungoides, 1317 psoriasis, 206 systemic lupus erythematosus, 724–725 genetics, molecular see molecular pathology genitalia see anogenital skin genitocrural area, acantholytic dermatosis, 176 genitoperineal (median raphe) raphe, 486–487, 1583–1584 genomic hybridization, comparative see comparative genomic hybridization

geographic tongue, 375–377 gestational disorders see pregnancy ghost cells odontogenic tumor, 395 pancreatic panniculitis, 340 pilomatrixoma, 1460, 1461–1462, 1463 Gianotti–Crosti syndrome, 195–196 giant basal cell carcinoma, 1091–1093 giant cell(s) multinucleate see multinucleate cells necrobiotic xanthogranuloma, 307–308 pyoderma gangrenosum in Crohn's disease, 634 giant cell angioblastoma, 1735 giant cell angiofibroma, 1639 giant cell arteritis (=Takayasu's arteritis) see Takayasu's disease giant cell arteritis (=temporal arteritis), 659t, 689–692 giant cell basal cell carcinoma, 1097 giant cell fibroblastoma, 1629–1630 dermatofibrosarcoma with areas of, 1634 giant cell fibroma, 386–387, 389 giant cell granuloma annular elastolytic, 302 peripheral, 392 giant cell malignant fibrous histiocytoma, 1662 giant cell reticulohistiocytosis, 1408–1409 giant cell tumor of soft tissues, 1656 of tendon sheath, 1654–1656 giant condyloma acuminatum (Buschke–Löwenstein tumor), 463–464, 509, 948, 1131 giant hairy ‘bathing trunk’ nevus, 1204–1205 giant keratoacanthoma, 1135 giant lymph node hyperplasia see Castleman's disease giant rosettes, hyalinizing spindle cell tumors with, 1642 gingiva (gums) congenital gingival leiomyomatous polyp/hamartoma, 371 congenital granular cell tumor (epulis), 370–371, 1612 cysts (adults), 395 fibroma, 389 fibromatosis, 371 generalized hyperplasia, 371, 396–398 nodules, 389 parulis (gum-boil), 393, 413 pyogenic granuloma, 390 see also vulvovaginal–gingival syndrome gingivitis desquamative see desquamative gingivitis foreign body, 379 gingivostomatitis, plasma cell, 406–407 GJA mutations, 71t GJB mutations, 71t, 72 Gla protein, matrix, and pseudoxanthoma elasticum, 952 glandular cheilitis, 416 glandular cysts, 1580–1584 glandular stomatitis (stomatitis glandularis), 416 glans clitoris, histology, 439 glans penis erosive lichen planus, 449f granuloma inguinale, 473f histology, 439 inflammation see balanitis lymphedamatous fibroepithelial polyp, 514–515 myointimoma, 518–519 see also balanitis glatiramer acetate-induced panniculitis, 336 gli-1 (glioma-associated oncogene homologue-1) granuloma annulare, 291 necrobiosis lipoidica, 297 sarcoidosis, 288 trichoepithelioma, 1471 gli-2 (glioma-associated oncogene homologue-2) and basal cell carcinoma, 1093 gliadin autoantibodies in dermatitis herpetiformis, 146 glioma, nasal (glial heterotopias), 1689–1690 glioma-associated oncogene homologues see gli-1; gli-2 glomangiomas, 1747, 1748–1749 familial, 1747 glomangiomatosis, 1749 glomangiomyoma, 1749 glomeruloid hemangioma, 1706 glomerulonephritis lupus membranous, 733 mesangiocapillary, associated with acquired partial lipodystrophy, 355–356 glomus bodies, 27 glomus tumor, 1746–1749 nail apparatus, 1074 glomuvenous malformation (glomangioma), 1747 glossitis benign migratory, 375–377 median rhomboid, 376–377 glucagonma syndrome, 587

glucose transporter, human erythrocytes (glut-1), and necrobiosis lipoidica, 297 glut-1 and necrobiosis lipoidica, 297 glutathione transferases and vitiligo, 914 gluteal granuloma, infantile, 445 gluten-sensitive enteropathy see celiac disease l-glyceric aciduria, 343 glycoconjugate stains, 34t glycosaminoglycans acid, 26 see also mucinosis systemic sclerosis, 740 glycosphingolipid metabolism and angiokeratoma corporis diffusum, 530 gold, 618–619 Goldenhar's syndrome, 1293 Golgi-Mazzoni corpuscle, 29 Goltz syndrome, 940–941 gonorrhea, 800 Gore-Tex (polytetrafluoroethylene), 628, 629 Gorham–Stout syndrome, 1746 Gorlin–Goltz (nevoid basal cell carcinoma) syndrome, 1101–1105, 1131 Gottron's papules, 751–752, 755 Gottron's syndrome, 73 Gougerot and Blum, pigmented purpuric lichenoid dermatitis of, 273 gout, 562 gouty panniculitis, 346 graft-versus-host disease, 249–254 acute, 250, 252–253, 254 chronic, 250–251, 252, 253–254 differential diagnosis, 254 erythema multiforme, 241 exanthematous adverse drug reactions, 593–594 morphea, 747–748 in toxic epidermal necrolysis, evolution of, 243 Graham–Little syndrome, 1020 Gram-negative folliculitis, 1050 granular basal cell carcinoma, 1098 granular cell layer see stratum granulosum granular cell neurofibroma, 1676 granular cell tumor, 1680–1681 conjunctival, 1289–1290 hibernoma vs, 1599 malignant, 1680, 1681 non-neural dermal/primitive polypoid, 1755–1756 oral, 435–436 congenital/neonatal (of gingiva), 370–371, 1612 differential diagnosis, 371, 436, 530 granular parakeratosis, 96 granular parakeratotic acanthoma, 1086 granules, mycetoma, 878–879 granulocyte colony-stimulating factors, adverse reactions, 625 granulocyte macrophage colony-stimulating factor, adverse reactions, 625 granuloma calcifying fibroblastic, 391–392 eosinophilic, 1392–1393, 1394 fish tank/swimming pool, 820–821 giant cell see giant cell granuloma histiocytic see histiocytic granuloma infantile gluteal, 445 injection site, vs epithelioid hemangioma, 1722 Majocchi's, 858 mercury, 619–620 midline lethal, 430–431 plasma cell see plasma cell granuloma pyogenic see pyogenic granuloma traumatic ulcerative, 381–382 umbilical, 1586–1587 granuloma annulare, 288–295 clinical features, 288–290, 900 differential diagnosis, 295 epithelioid sarcoma, 295, 1764–1765 interstitial granulomatous drug reactions, 606 xanthomata, 523 generalized, 289–290 HIV-associated, 900 linear, 290 localized, 288–289 papular, 290 pathogenesis and histology, 290–294, 900 penis, 457 perforating, 290, 295t subcutaneous/deep, 290, 295t granuloma faciale, 681–684 differential diagnosis, 683–684 erythema elevatum diutinum, 685–686 Sweet's syndrome, 638 granuloma gravidarum, 390, 1715 granuloma inguinale, 472–473

1781

1782

Index granuloma multiforme, 304–306 differential diagnosis, 295t, 306 granulomatosis allergic, with angiitis see Churg–Strauss syndrome Langerhans cell see Langerhans cell histiocytosis lymphomatoid see lymphomatoid granulomatosis orofacial, 407–408 pathergic, 674 Wegener's see Wegener's granulomatosis granulomatous cheilitis see orofacial granulomatosis granulomatous dermatitis lichenoid and, 236–237 palisaded neutrophilic and see palisaded neutrophilic and granulomatous dermatitis granulomatous dermatoses (in general), 281–288 drug-associated, 605–606, 626–627 chemotherapeutic, 622, 623 esthetic implant materials, 628, 629 granulomatous disease, chronic, and discoid lupus erythematosus, 715–716 granulomatous inflammation in lymphomas other than granulomatous mycosis fungoides, 1330 granulomatous mycosis fungoides, 1329–1330 granulomatous slack skin vs, 1330, 1338 granulomatous perifolliculitis, nodular, 858 granulomatous phlebitis of skin, nodular, 819 granulomatous pyoderma, superficial, 633, 634 granulomatous rosacea, 1046, 1050 granulomatous slack skin, 1337–1338 granulomatous mycosis fungoides vs, 1330, 1338 granulomatous variant of scleromyxedema, 576 granulomatous vasculitis of CNS, infections associated with, 694t drug-associated, 604 Graves' dermopathy (pretibial myxedema), 573 gravis variant dystrophic EB (Hallopeau–Siemens syndrome), 109–111, 116f junctional EB (Herlitz-type junctional EB), 107, 114–115 Greither syndrome, 78 Grenz ray effects, 965 grenz zone granuloma faciale, 682–684 indolent CD8+ lymphoid proliferation of ear, 1349–1350 primary cutaneous marginal zone B-cell lymphoma, 1365–1366 T -cell rich angiomatoid polypoid pseudolymphoma, 1360 Griscelli syndrome, 918–919 groin fungal infections, 461–479, 848 dermatophyte, 461–463, 857 Grönblad–Strandberg syndrome see pseudoxanthoma elasticum gross cystic disease fluid proteins see GCDFPs ground substance, 26 Grover's disease (transient/persistent acantholytic dermatosis), 174–176 differential diagnosis, 176 pemphigus vulgaris, 156, 175–176 with eccrine ductal involvement, 200 sudoriferous (sudoriferous acrosyringeal acantholytic disease), 175, 176 growth phase of melanoma, prognostic significance, 1232 Grzybowski's syndrome, 1136 Guarnieri bodies, 782 gum-boil, 393, 413 see also gingiva gum-chewing, lesions associated with, 406 gumma(ta) syphilitic, 469, 472 tuberculous, 814, 815t, 817 Gunther's disease, 550–551 guttate hypomelanosis, 916 differential diagnosis, 916 vitiligo, 915 guttate morphea, 745, 748 guttate psoriasis (eruptive psoriasis), 201 histology, 208 pityriasis rosea vs, 198 gyrate erythema see erythema gyratum

H

Haber's syndrome vs Dowling-Degos disease, 926 Haemophilus ducreyi and chancroid, 474–475 Hailey-Hailey disease (benign familial pemphigus), 167–169 differential diagnosis, 156t endemic pemphigus vulgaris, 156, 176 Grover's disease, 173, 176 Hailey-Hailey-like epidermal nevus, 169

hair (hair fiber), 15, 967–1050 bamboo (trichorrhexis invaginata), 62, 1034–1035 counts by ethnicity, 972t diseases, 967–1050 diagnosis/history/laboratory tests, 968–969 growth, 15, 974 cycle see hair cycle mutations affecting, 1032t loss see alopecia lupus, 1013 pubic, 441 HAIR-AN syndrome, 585 hair bulb examination, 969 hair casts, 1041 hair cycle, 974, 979–982 telogen effluvium-associated disturbances, 1004 hair discs (Iggo discs; touch spots/domes/corpuscles), 12, 28 hair follicles see entries under follichair-growth window technique, 968 trichotillomania, 997 hair matrix, differentiation towards see matric(i)al differentiation hair nevus, 1445 woolly, 1445–1446 hair-pluck test see trichogram hair-pull test, 968 telogen effluvium, 1003 hair-pulling, compulsive see trichotillomania hair shaft anatomy, 977–978 diseases, 1031 shaft coiling and twisting, 1032, 1039–1041 shaft fractures, 1032, 1033–1035 shaft irregularities, 1032, 1035–1039 extraneous matter on, 1041 microscopic examination, 968–969 hairless hypopigmented nevus, desmoplastic, 1205 hairy ‘bathing trunk’ nevus, giant, 1204–1205 hairy cell leukemia, leukocytoclastic vasculitis, 661 hairy epidermal nevus, pigmented, 1156 hairy epidermal nevus syndrome, pigmented, 1077 hairy leukoplakia, oral, 374, 399–400 HIV-associated, 910 Hallopeau, acrodermatitis continua of, 204, 1057 Hallopeau–Siemens syndrome, 109–111 Hallopeau-variant pemphigus vegetans see pyoderma vegetans halo nevus (leukoderma acquisitum centrifugum; Sutton's nevus), 912, 1175–1176 Spitz nevus with features of, 1181–1183 halogen acne, 1044–1045 hamartomas, 1666, 1695 congenital gingival leiomyomatous, 371 congenital smooth muscle, 1695 congenital vellus, 1445 conjunctival, 1270 dermal melanocytic, 1208 eccrine angiomatous, 1529–1530 follicular basaloid follicular hamartoma, 1446–1448 folliculosebaceous cystic hamartoma, 1467–1469 neurofollicular hamartoma, 1486–1487 sclerosing epithelial hamartoma (desmoplastic trichoepithelioma), 1473–1475, 1541, 1562 other types, 1466, 1469, 1484, 1485 infantile fibrous, 1624–1625 medallion-like dermal dendrocyte, 1623–1624 neurocristic, 1212–1213 rhabdomyomatous mesenchymal, 1701 sudiferous, 1527–1528 Hamilton-Norwood ‘male pattern’ hair loss, 983 hand(s) Cowden's disease lesions, 1451 Darier's disease, 170 EB simplex of feet and (Weber–Cockayne syndrome), 104, 114 eczema (pompholyx), 180, 183–184 keratoelastoidosis marginalis, 82 multicentric reticulohistiocytosis, 1408 occupational dermatitis, 185 see also digits; knuckle pad; nail; palmar surfaces; tripe palms and entries under palmoplantar hand, foot and mouth disease, 952–953 hand–foot reaction with multikinase inhibitors, 622, 623 Hand–Schüller–Christian disease, 1392–1394 harderoporphyria, 568 harlequin ichthyosis, 54 Hartnup disease, 565 Hashimoto–Pritzker disease, 1392–1393, 1397–1398 Haxthausen's disease, 91 head and neck angiosarcoma, idiopathic, 1738 poikiloderma of, 245

Headington technique, 970 heart conditions involving see cardiovascular involvement myxoma see myxoma see also myocardial involvement heavy metal pigmentation, 603 Heck's disease (focal epithelial hyperplasia), 384, 400–401 helix of ear chondrodermatitis nodularis chronica helicis, 324–325, 759 juvenile spring eruption, 268 helminths (worms), 476–477, 891–895 helper T cells see CD4+ T cells ‘hemangioblastoma’ see angiosarcoma hemangioendothelioma composite, 1734–1735 epithelioid, 1736–1737, 1764–1765 epithelioid sarcoma-like, 1735 kaposiform, 1728–1729 malignant see angiosarcoma retiform, 1716–1717 spindled cell, 1724–1725 hemangioma arteriovenous, 1718 capillary, and variants see capillary hemangioma; pyogenic granuloma cavernous see cavernous hemangioma congenital, 1711 non-involuting, 1711 rapidly involuting, 1711 conjunctival, 1287–1288 elastotic, acquired, 1720 epithelioid see angiolymphoid hyperplasia glomeruloid, 1706 hobnail (targetoid hemosiderotic), 781, 1718–1720, 1727, 1746 infantile/juvenile (strawberry nevus), 1711–1712, 1713 abortive/minimal or arrested growth, 1712 microvenular, 1718 papillary, 1706–1707 sclerosing see dermatofibroma sinusoidal, 1716, 1717 spindled cell, 1724–1725 symplastic, 1725–1726 verrucous, 1713–1714 see also angioma hemangiopericytoma, 1749–1750 hemangiopericytoma-like pattern, myofibroma and myofibromatosis, 1617 hemangiosarcoma see angiosarcoma hematodermic neoplasm/tumor, agranular CD4+ CD56+, 1414 hematogenous spread (vascular invasion and) M. tuberculosis, 813 metastases, 1424 hematological malignancy erythropoietic protoporphyria and, 552 relapsing polychondritis and, 758 vasculitis and, 695 hematoma, subungual, 1062 hematopoiesis, extramedullary, 1416 hematoxylin and eosin (H&E), 33 heme synthase gene mutation, 555 hemidesmosomal EB, 102, 106, 107 hemidesmosomes, 21–22 hemodialysis amyloidoses associated with, 536–537 bullous dermatosis of see pseudoporphyria hemolytic conditions, inherited, and pseudoxanthoma elasticum, 954 hemolytic–uremic syndrome, 706–707 hemophagocytic syndrome/lymphohistiocytosis, 1409–1410 panniculitis associated with, 337–339 hemorrhage, amyloidosis, 534 hemorrhagic angiodysplasia, infantile, 1745 hemorrhagic cellulitis, 795 hemorrhagic cutaneous nodules, 1425 hemorrhagic edema of childhood, 461, 665–666 hemorrhagic fevers, viral, 788–789 hemorrhagic telangiectasia, hereditary, 1709–1710 hemosiderotic fibrohistiocytic lipomatous lesion, 1599 hemosiderotic fibrous histiocytoma, 1650, 1650f, 1651f hemosiderotic hemangioma, targetoid, 781, 1718–1720, 1727, 1746 Henoch–Schönlein purpura, 659t, 664–665 differential diagnosis, 665 infantile hemorrhagic edema, 666 solid tumors and, 665, 695 heparin, adverse effects, 617 hepatic disease see liver disease hepatitis B cryoglobulinemia, 704 vasculitis and, 694 polyarteritis nodosa, 670–671

Index hepatitis C porphyria cutanea tarda and, 553–554 vasculitis and, 694 polyarteritis nodosa, 671 hepatoerythropoietic porphyria, 550t, 555 Her-2 (neu) and Paget's disease, 1443 herald patch of pityriasis rosea, 196 hereditary… see genetic disorders and disorders below hereditary benign intraepithelial dyskeratosis conjunctival, 1272 oral, 364–365 hereditary hemorrhagic telangiectasia, 1709–1710 hereditary leiomyomatosis and renal cell cancer (HLRCC), 1696 hereditary motor and sensory neuropathy type 4, 50–51 hereditary non-polyposis colorectal carcinoma, 1505–1506 hereditary painful callosities, 80–81 Herlitz-type junctional EB, 107, 114–115 Hermansky–Pudlak syndrome, 918 herpes gestationis (pemphigoid gestationis), 127–130 herpes simplex virus (HSV), 771–775 erythema multiforme and, 238–240 herpes varicella virus, 776–779 herpes virus 6, human (HHV-6), 947 herpes virus 8, human (HHV-8/KS-associated herpesvirus), 1729–1734 and angiolymphoid hyperplasia, 1721 and Castleman's disease Castleman's disease, 1355–1356, 1390 and Kaposi sarcoma, 1729–1734 and mycosis fungoides, 1317 and plasmablastic lymphoma, 1382 herpes zoster, 777 herpetiform lesions see dermatitis herpetiformis; pemphigus herpetiformis heterologous differentiation carcinoma see carcinosarcoma malignant peripheral nerve sheath tumors, 1692 melanoma, 1250 heterotopic (ectopic) tissue, 1687–1695 in mouth from brain, 368 from sebaceous glands, 1488 from thyroid, 370 from sebaceous glands, 1488, 1489 HHVs see herpes virus Hibernian fever, familial, 280 hibernoma, 1599 hidradenitis idiopathic plantar, 624 neutrophilic eccrine see neutrophilic eccrine hidradenitis suppurative, 458–459, 655–657 hidradenocarcinoma, clear cell see clear cell hidradenocarcinoma hidradenoma clear cell/solid–cystic, 1545–1546 tubulopapillary, 1513–1514 hidradenoma papilliferum (papillary hidradenoma), 1512–1513 vulva, 510–511 hidroacanthoma simplex, 1531–1532 hidrocystoma apocrine, 1508–1510 eccrine, 1509–1510 hidrotic ectodermal dysplasia (Clouston syndrome), 71t, 84–85 high density (alpha) lipoproteins, 521 high endothelial venules, angiolymphoid hyperplasia with (APA-HEL), 1362 high iron diamine, 34 high-mobility-group protein family member (HMGA2) and aggressive angiomyxoma, 515, 516 hilar lymphadenopathy, sarcoidosis, 284 histidine-rich transmembrane protein (hZIP4) and acrodermatitis enteropathica, 586 histiocytic disorders (incl. tumors), 1391 conjunctival, 1270, 1290 histiocytic granuloma(ta) atypical see pseudolymphoma syphilis, 472 histiocytic panniculitis, cytophagic, 337–339 histiocytic sarcoma/lymphoma, 1411–1412 histiocytoid carcinoma see signet ring cell carcinoma histiocytoma fibrous see fibrous histiocytoma generalized eruptive, 1401 solitary epithelioid see reticulohistiocytoma histiocytoma cutis see dermatofibroma histiocytosis benign cephalic, 1400–1401 crystal-storing, 346 generalized eruptive, 1401 intralymphatic/intravascular, 1392, 1706 Langerhans cell see Langerhans cell histiocytosis malignant, 1411–1412 progressive nodular, 1339 sinus, with massive lymphadenopathy, 1404–1407

histiocytosis X see Langerhans cell histiocytosis histocompatibility antigen see HLA histoid leprosy, 831 histology (non-pathological aspects) epidermal (normal), 1–2 female genitalia, 438–439 male genitalia, 439 specimen fixation/grossing/put-through/processing/ embedding/sectioning, 32 histone autoantibodies, lupus erythematosus, 723 histoplasmosis, 881–883 Whipple's disease vs, 839 history-taking, hair disorders, 968–969 HIV disease/AIDS, 896–911 botryomycosis, 836 bowenoid papulosis, 769 candidiasis, 862 Castleman's disease, 1390 CMV infection, 779, 908 eosinophilic pustular folliculitis, 652, 902 general aspects (epidemiology/biology etc.), 896 Kaposi's sarcoma, 1730, 1734 conjunctiva, 1288 lymphoproliferative disorders (atypical cutaneous), 1362 molluscum contagiosum, 785 mucinosis and, 904–905 reticular erythematous, 266, 904, 905 mucous membrane pemphigoid, 135, 904 Mycobacterium avium-intracellulare infection and, 822, 909 Mycobacterium leprae infection and, 828 Mycobacterium tuberculosis infections and, 811, 909 myopericytoma, 1750 ocular surface squamous neoplasia, 1276 papulosquamous dermatoses, 896–899 paracoccidioidomycosis, 868 plasmablastic lymphoma, 1381 pneumocystosis, 886, 909 porphyria cutanea tarda and, 553–554, 900 protothecosis, 850 syphilis and, 465, 468 toxic epidermal necrolysis and, 243 vasculitis and, 902–904 Kawasaki syndrome, 681 leukocytoclastic, 661 VZV infection, 778 warts (common), 763 HLA (human leukocyte/major histocompatibility antigens/ MHC) benign migratory glossitis, 375 dermatitis herpetiformis, 145 endemic pemphigus foliaceous, 161 erythema multiforme, 240 graft-versus-host disease, 249, 251 Henoch–Schönlein purpura, 665 juvenile rheumatoid arthritis, 645 lichen planus, 224 oral, 404 lichen sclerosus, 454 linear IgA disease, 148 lupus erythematosus, subacute cutaneous, 717 lupus erythematosus, systemic, 724–725 bullous, 143 mycosis fungoides, 1317 paraneoplastic pemphigus, 164 pemphigoid gestationis, 130 pemphigus vulgaris, 154 psoriasis, 206 HIV-associated, 897 Reiter's syndrome, 370 squamous carcinoma, 1120 systemic sclerosis, 741 HMB-45 conjunctival primary acquired melanosis, 1283 melanoma, 1237 desmoplastic, 1256–1257 prognostic value, 1236 subungual, 1066 in sentinel node samples, 1301–1303 Spitz nevus, 1183 HMGA2 and aggressive angiomyxoma, 515, 516 hMLH1 and Muir–Torre syndrome, 1505–1507 hMSH2 and Muir–Torre syndrome, 1505–1507 hobnail hemangioma, 781, 1718–1720, 1727, 1746 hobo spider, 642 Hodgkin cells and Hodgkin–Reed–Sternberg (HRS) cells, 1383–1384 Hodgkin lymphoma, 1383–1384 Hoffman and Zurhelle, nevus lipomatosus superficialis of, 1596–1597 homogentisate 1, 2-dioxygenase deficiency, 564 honeycomb atrophy, 69 Hopf, acrokeratosis verruciformis of, 91–92

Hori's nevus, 1208 horn (cornu cutaneum), 1079 penile, 489 pilomatricomal pilomatrixoma, 1463 Hornstein-Knickenberg syndrome, 1469 horseriders, cold panniculitis, 270, 337 Hortaea werneckii, 861 Howell–Evans syndrome, 90–91 HPV see human papillomavirus HRAS mutations and melanocytic nevi, 967, 1012 HSV (herpes simplex virus) and erythema multiforme, 238–240 HTLV1 see human T-cell leukemia virus type 1 human herpes viruses see herpes virus, human human immunodeficiency virus see HIV disease human leukocyte antigens see HLA human papillomavirus (HPV), 463–464, 935–939, 940–941 anogenital lesions, 463–464 flat ‘acetowhite’ lesions, 498 hidradenoma papilliferum, 1513 lichen sclerosus, 454–455 melanoma, 485 squamous cell carcinoma, 492, 493, 499t, 500–501 vulval intraepithelial neoplasia, 491 Bowen's disease, 1112 keratoacanthoma, 1136 ocular surface squamous neoplasia, 1276 oral lesions bowenoid papulosis, 424, 769 focal epithelial hyperplasia, 384, 401 squamous cell carcinoma, 425, 426 squamous papilloma, 383–384 periocular sebaceous carcinoma, 1502 periungual lesions, 1057 seborrheic keratosis, 1082 squamous cell carcinoma, 1119t, 1120 anogenital lesions and, 492, 493, 499t, 500–501 common warts and, 763 variants (types), and associated conditions, 762t verruciform epidermodysplasia, 769–771, 949 verrucous cyst, 1575 verrucous xanthoma, 529 warts see warts human T-cell leukemia (lymphotropic) virus type 1 (HTLV-1) and adult T-cell leukemia/lymphoma, 1351, 1352 and dermatitis, 186 Huriez syndrome, 82–83 Hutchinson's sign, 1064 Hutchinson–Gilford syndrome, 963 hyaline cells, chondroid syringoma (mixed tumor), 1522 hyaline fibromatosis, juvenile see juvenile hyaline fibromatosis hyalinizing angiectatic tumor, pleomorphic (PHAT), 1599, 1761 hyalinizing spindle cell tumor with giant rosettes, 1642 hyalinizing spindle and epithelioid nevus (desmoplastic Spitz nevus), 1155, 1181 hyalinizing vasculitis, segmental see atrophie blanche hyalinosis, infantile systemic, 1625 hyalinosis cutis et mucosae, 546–548 hyaluronic acid (esthetic microimplants), 628 with polyhydroxyethylmethacrylate/ethylmethacrylate, 629 hybrid anogenital verrucous carcinoma, 500 hybrid cysts, 1574 hybrid epidermoid and apocrine cyst, 1510 hybrid schwannoma–neurofibroma, 1676 hybrid schwannoma–perineurioma hybrid, 1672 hydatid disease (echinococcosis), 894–895 hydroa vacciniforme-like lymphoma, 1358–1359 hydroxychloroquine pigmentation, 602–603 hygroma, cystic, 1743, 1744 hyperandrogenism and insulin resistance and acanthosis nigricans, syndrome with, 585 hypercalcemia pancreatic panniculitis, 340–341 sarcoidosis, 285 hypereosinophilic syndrome, 649 hyperextensible skin, Ehlers–Danlos syndrome types I/AA, 936, 936t hypergammaglobulinemia purpura, 708–709 hyperimmunoglobulinemia D syndrome, 709 hyperkeratosis acral, 82 epidermolytic see epidermolytic hyperkeratosis follicular see follicular hyperkeratosis; Kyrle's disease ichthyoses with, 48t oral, focal nonepidermolytic palmoplantar keratoderma with, 88 hyperkeratosis lenticularis perstans (Flegel's disease), 95–96, 178 hyperkeratotic actinic keratosis, 1108–1109 hyperkeratotic bowenoid plaques, verrucous, 1112 hyperkeratotic mycosis fungoides (verrucous MF), 1321, 1328 hyperlipidemias, 520–530 classification, 523t hyperliproteinemias, primary and secondary, 521t

1783

1784

Index hypermelanosis, postinflammatory, 433, 932–933 hypermelanotic dermal melanoma see pigment-synthesizing melanoma hypermobility-type Ehlers–Danlos syndrome (=type III), 936–937, 936t isolated collagenoma, 948 hyperpigmentation, 923 drug-associated see drug-induced disorders and reactions postinflammatory, 433, 931–932 systemic sclerosis, 737 hyperpigmented mycosis fungoides, 1326–1327 hyperplasia adenomatoid, of salivary glands, 417 angiolymphoid see angiolymphoid hyperplasia epithelial see epithelial hyperplasia fibrous, denture-associated, 387–389 generalized gingival, 371, 396–398 giant lymph node see Castleman's disease intravascular papillary endothelial, 1705 lymphoid, B-cutaneous, 1327 Merkel cell, 12–13 Pacinian corpuscle see Pacinian corpuscle pseudoepitheliomatous/pseudocarcinomatous see pseudoepitheliomatous hyperplasia sebaceous gland, 1488–1489 genitalia, 443–444 oral, 367, 1489 squamous, vs penile intraepithelial neoplasia, 496 Toker cell, 1442–1443, 1444 verrucous, 423 hypersensitivity (allergic) reactions drug-related, 591–592, 597–598 chemotherapeutic, 622, 623 lymphomatoid, 1362 oral, 402 urticaria, 648 hypersensitivity vasculitis see leukocytoclastic vasculitis hypertension, pulmonary see pulmonary hypertension hyperthyroidism, pretibial myxedema, 573 hypertrophic discoid lupus erythematosus, 712–713 hypertrophic lichen planus, 222, 227 hypertrophic scars, 1604 hypoaminoacidemia and necrolytic migratory erythema, 588 hypocomplementemia (complement deficiency) acquired partial lipodystrophy and, 355–356 systemic lupus erythematosus, 720–721 urticarial vasculitis and, 278, 647 hypodermatitis sclerodermaformis, 352–353 hypodontia of Schöpf–Schulz–Passarge syndrome, 91 hypohidrotic ectodermal dysplasia, skin fragility with, 87–88 hypokeratosis, circumscribed palmar or plantar, 96–97 hypomelanosis guttate see guttate hypomelanosis of Ito, 921–922 progressive macular, 921 see also hypopigmentation hypopigmentation (and hypopigmented lesions), 912 black patients, in sarcoidosis, 283–284 chemotherapeutic drug-related, 621 postinflammatory, 922 systemic sclerosis, 737 tinea versicolor, 859 see also hypomelanosis hypopigmented common blue nevus, 1211 hypopigmented mycosis fungoides, 1326–1327 hypopigmented nevus, desmoplastic hairless, 1205 hypotrichosis of Schöpf–Schulz–Passarge syndrome, 91 hystrix ichthyosis see ichthyosis hystrix hZIP4 and acrodermatitis enteropathica, 586

I

iatrogenic disorders/causes calcinosis cutis, 568 immunosuppression see immunosuppressed persons lymphoproliferative disorders, 1384 pseudominolethrix, 1039 IBIDS (ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature) syndrome, 66, 1034 ichthyosiform (ichthyosis-like) conditions (acquired), 69–70 drug-induced, 70t, 612 ichthyosiform erythroderma, congenital bullous, 55–58 non-bullous, 52, 53–54 reticular, 61 ichthyosis, 46–69 bullous see bullous ichthyosis erythema gyratum repens accompanied by, 263 mycosis fungoides and, 1327 Vohwinkel keratoderma with (Camisa variant form of Vohwinkel syndrome), 73, 83, 84 see also IBIDS; PIBIDS ichthyosis follicularis see follicular ichthyosis

ichthyosis hystrix, 1076 Curth–Macklin-type, 60–61 syndrome of deafness with hystrix-like ichthyosis, 74–75 ichthyosis-like conditions, acquired see ichthyosiform conditions ichthyosis linearis circumflexa see Netherton's syndrome ichthyosis vulgaris, 46–48 id reaction, 184 acute infectious id panniculitis, 352 idiopathic angiosarcoma of head and neck, 1738 idiopathic arthritis, systemic juvenile, 644–645 idiopathic calcinosis cutis, 567t, 568–570 idiopathic genital calcinosis, 480 idiopathic plantar hidradenitis, 624 idiopathic thrombocytopenic purpura, 707–708 idiosyncratic drug reactions, 591 Iggo discs (hair discs; touch spots/domes/corpuscles), 12, 28 imatinib, 622 imipramine pigmentation, 603, 604 immune complex (antibody–antigen)-associated (type 3) reactions to drugs, 592 erythema elevatum diutinum, 684–685 leukocytoclastic vasculitis, 662 polyarteritis nodosa and, 671 relapsing polychondritis, 759 systemic lupus erythematosus, 724 urticaria, 648 immune system abnormalities/involvement allergic contact dermatitis, 184–185 atopic eczema, 182 infection-associated abnormalities, 694t lichen planus (genital), 449 neutrophilic-associated primary scarring alopecias, 1026–1027 polymyositis/dermatomyositis and, 754 psoriasis, 130, 131 relapsing polychondritis, 759 rheumatoid nodules, 301 Rosai–Dorfman disease, 1406 sarcoidosis, 285–286 squamous carcinoma, 1119 see also autoantibodies; autoimmune disease cryptococcosis and, 872 drug reactions mediated by, 591–592 fixed, 600 hair follicles and immune privilege, 982 failure in alopecia areata, 992 mycosis fungoides cell evasion of, 1317–1318 normal function, 9–10 tuberculids and, 818, 819 immune thrombocytopenic purpura, 707–708 immunoblastic lymphadenopathy with dysproteinemia, 1350 immunobullous diseases, desmosomal, 14 immunobullous lesions, orf, 785 immunocompromised persons see immunosuppressed persons immunocytochemistry see immunolabelling immunocytoma, 1365, 1366 immunodeficiency syndromes acquired see HIV disease/AIDS congenital granulomata, 314 mucocutaneous candidiasis, 862 lymphomatoid granulomatosis associated with, 1377 immunoelectron microscopy bullous pemphigoid, 125 bullous SLE, 143–144 EB acquisita, 139–141 immunofluorescence, 35–37 epidermolysis bullosa, 112 split skin, 100 immunoglobulin (antibody) gene rearrangements in cutaneous lymphoproliferations, 45 angioimmunoblastic T-cell lymphoma, 1351 B-cutaneous lymphoid hyperplasia, 1368 lymphoblastic leukemia/lymphoma, 1415 pseudolymphomatous folliculitis, 1362 in immunodetection/immunohistochemistry (incl. monoclonals), 34–35 epidermolysis bullosa, 112 metastases, 1427–1429 immunoglobulin A deposits dermatitis herpetiformis, 145–146 Henoch–Schönlein purpura, 665 linear IgA disease, 149 immunoglobulin A disease, linear see linear IgA disease immunoglobulin A pemphigus, 165–166 overlap with dermatitis herptiformis, 162 immunoglobulin E-mediated allergic reactions drug-related, 591–592 urticaria, 648

immunoglobulin G, elevated levels of hyperimmunoglobulinemia D syndrome, 709 immunoglobulin G4-related sclerosing disease, 1389–1390 immunoglobulin M monoclonal gammopathy and urticarial vasculitis, 278, 647, 666 immunohistochemistry see immunolabelling immunolabelling (incl. immunohistochemistry/ immunocytochemistry), 34–35 Merkel cells, 12 sebaceous glands, 16–17 sentinel node samples, 1300–1307 sweat glands apocrine, 20 eccrine, 18–19 troubleshooting, 34–35 see also various specific disorders/lesions and specific antigens immunoperoxidase antigen mapping, 101 immunosuppressed/immunocompromised persons (incl. iatrogenic causes such as immunosuppressive drug use) actinic keratosis, 1107–1108 aspergillosis, 863 candidiasis, 862 CMV infection, 779 common warts, 763 Kaposi's sarcoma, 1730 molluscum contagiosum, 785 neuroendocrine carcinoma, 1142 nocardiosis, 835 pneumocystosis, 886 protothecosis, 850 squamous cell carcinoma, 1119t, 1120 squamous cell carcinoma in situ, 1111 tuberculosis, 811 VZV reactivation, 777–778 see also HIV disease/AIDS impetigo, 790–791 Bockart's, 797 bullous, 790, 791, 791f, 792f, 793f, 794 implantation cyst (nail), subungual epidermoid, 1066 impression cytology, ocular surface squamous neoplasia, 1276 in situ hybridization chromogenic (CISH), 41–42 fluorescence (FISH), 40–42 in situ neoplastic lesions see carcinoma in situ; melanoma in situ inclusion body (bodies) epidermoid, 1572 intranuclear, CMV, 779–780 sarcoidosis, 287–288 inclusion body fibromatosis, 1620–1621 inclusion cyst (nail), subungual epidermoid, 1066 incontinentia pigmenti (Bloch–Sulzberger syndrome), 652–655 neonatal toxic erythema vs, 655 incontinentia pigmenti achromians, 921–922 indeterminate dendritic cell tumors, 1398–1399 indeterminate hairs, 974 indirect immunofluorescence, 36–37 indolent CD8+ lymphoid proliferation of ear, 1349–1350 infants (and infantile diseases/syndromes) acropustulosis, 217–218 atopic dermatitis, 180–182 cerebral Gaucher syndrome, 66 cold panniculitis, 337 eosinophilic pustular folliculitis, 218 exanthem subitum, 780 fibromatosis, 1628 digital, 1620–1621 fibrosarcoma, 1640 fibrous hamartoma, 1624–1625 gluteal granuloma, 445 hemangioma see hemangioma hemangiopericytoma, 1749 hemorrhagic angiodysplasia, 1745 hemorrhagic edema, 461, 665–666 lipoid proteinosis presenting in, 546 mucinosis papular, 579 self-healing familial cutaneous, 583 myofibromatosis, 1616, 1617 napkin dermatitis, 369 papular acrodermatitis, 195–196 polyarteritis nodosa, 669 restrictive dermopathy, 946–947 rhabdomyoma (fetal-type), 1701–1702 sarcoidosis sarcoidosis, 281 syphilis, 472 systemic hyalinosis, 1625 see also neonates and entries under congenital

Index infections, 761–895 anogenital, 461–479 chronic, squamous carcinoma risk, 1120 esthetic microimplants and risk of, 628 fungal see fungal infections giant cell arteritis, 690–691 granulomatous, 311 hair, laboratory tests, 968 see also folliculitis, infective Henoch–Schönlein purpura and, 664 ichthyosis-like conditions, 70t in mycosis fungoides in etiology, 1317 predisposition to, 1316 nail, 798, 1054 oral mucosa, 399 panniculitis associated with, 350–351 erythema nodosum, 329 polymyositis/dermatomyositis pathogenesis, 754 psoriasis predisposition with, 206 pyoderma gangrenosum vs, 635 stains for various organisms, 34t vasculitis associated with, 693–694 hemorrhagic edema of childhood, 665–666 Kawasaki syndrome, 681, 694t polyarteritis nodosa, 670–671, 694t vasculitis-associated, leukocytoclastic, 659, 660t viral see viral infections infective dermatitis, 186 infiltrating glomus tumor, 1749 infiltrative basal cell carcinoma, 1095–1097 infiltrative subcutaneous malignant fibrous histiocytoma, 1665 inflamed juvenile conjunctival nevus, 1279–1280 inflammation chronic, and squamous carcinoma, 1120 granulomatous, in lymphomas other than granulomatous mycosis fungoides, 1330 inflammatory bowel disease erythema elevatum diutinum and, 684 pyoderma gangrenosum and, 632 see also Crohn's disease; ulcerative colitis inflammatory carcinoma, cutaneous metastases, 1431–1432 inflammatory cells granuloma annulare, 292 primary cutaneous anaplastic large cell lymphoma, 1345 inflammatory cutaneous metastases, 1425–1426 inflammatory dermatoses anogenital, 444–460 perivascular, 259–280 inflammatory diseases nail, 1057 subcutaneous fat, 326–361 inflammatory fibrous (denture-associated) hyperplasia, 387–389 inflammatory linear verrucous epidermal nevus (ILVEN), 214–215 inflammatory malignant fibrous histiocytoma, 1664 inflammatory myofibroblastic tumor (inflammatory pseudotumor; inflammatory fibrosarcoma), 1390–1391, 1636–1637 cutaneous plasmacytosis vs, 1389 inflammatory papillary (denture-associated) hyperplasia, 387–389 inflammatory primary scarring alopecia, mixed, 1029–1031 inflammatory pseudotumor see inflammatory myofibroblastic tumor inflammatory response, oncogene-induced, melanocytic nevi, 1014 inflammatory skin eruption, Blaschko linear acquired, 232–233 inflammatory-variant EB acquisita, 138, 139, 140f, 142 infliximab, 626 lymphoproliferative disorders, 1384 infundibular crystalline folliculitis, necrotizing, 323 infundibulocystic basal cell carcinoma, 1098–1099 infundibulum, follicular, 974–976 tumor (infundibuloma), 1450 superficial epithelioma with sebaceous differentiation vs, 1500 inherited disorders and predisposition see entries under genetic injection site granuloma vs epithelioid hemangioma, 1722 injection site reaction, TNF-α inhibitors, 626, 627 injury see bites; traumatic lesions ink spot lentigenes, 1155 innate (natural; non-specific) immunity, 9 psoriasis and, 207 innervation, 28–30 inoculation, infection by actinomycosis, 838 coccidioidomycosis, 870 mycetoma, 877 tuberculosis, 811–812 insect bite reactions, 641, 642 papular urticaria, 649 insensible perspiration, 19

insulin resistance and hyperandrogenism and acanthosis nigricans, syndrome with, 585 integrin, mucous membrane pemphigoid, 137 interactions, drug–drug, 591 intercellular junctions, 13–15 interdigitating dendritic cell sarcoma, 1410–1411 interface dermatoses, 220b, 237–258 drug-associated, 598–599 chemotherapeutic, 622–623 HIV-associated, 907 interferon-α, adverse reactions, 625, 626 interferon-β, adverse reactions, 625, 626 panniculitis, 336, 626 interferon-γ adverse reactions, 625 juvenile rheumatoid arthritis and, 645 interleukin-2 adverse reactions, 625, 626 juvenile rheumatoid arthritis and, 645 interleukin-4 adverse reactions, 625, 626 interleukin-23 receptor, psoriasis, 206 intermediate density (pre-beta) lipoproteins, 521 raised, 521t intermediate-variant neuroendocrine carcinoma, 1143–1145 intermittent porphyria, acute, 550t International Cowden consortium, 1451, 1452b International Society for Cutaneous Lymphomas (ISCL)– EORTC, staging and classification of mycosis fungoides and Sézary syndrome, 1314–1315, 1323–1324 interphalangeal joints, multicentric reticulohistiocytosis, 1408 interstitial granulomatous reactions, drug-induced, 605, 606 chemotherapeutic, 622, 623 intertriginous xanthomata, 528 intertrigo, 444 intestinocutaneous syndrome, lethal, 696–698 see also bowel intracranial involvement see neurological involvement intracranial meningioma, metastases from, 1688, 1689 intradermal lesions see entries under dermal intraepidermal dendritic melanocytes, intraepidermal, superficial blue nevus with, 1210–1211 intraepidermal epithelioid melanocytic dysplasia, de novo, 1185 intraepidermal epithelioma of Borst–Jadassohn, 1086, 1114 intraepidermal neutrophilic (IEN) IgA dermatosis variant, 165, 166 intraepithelial dyskeratosis, hereditary benign see hereditary benign intraepithelial dyskeratosis intraepithelial neoplasia (squamous) conjunctival (OSSN), 1274–1277 koilocytosis with see bowenoid papulosis penile, 494–498 upper aerodigestive tract, 422 vulval, 398, 399 intralymphatic angioendothelioma, papillary (Dabska's tumor), 1726, 1727–1728 intralymphatic histiocytosis, 1392, 1706 intraneural perineurioma, 1685, 1686 intranuclear inclusions, CMV, 779–780 intraoperative sentinel node evaluation, 1299 intravascular fasciitis, 1608 intravascular histiocytosis (intralymphatic histiocytosis), 1392, 1706 intravascular large B-cell lymphoma (intravascular lymphoma/ lymphomatosis), 1380–1381, 1392 intravascular papillary endothelial hyperplasia, 1705 intravenous pyogenic granuloma, 1715 invasion by melanoma, depth/level see Clark levels by squamous carcinoma, 1119 depth/level, 1123 inverse form dystrophic EB (recessive), 111 junctional EB, 107 psoriasis, 202 inverted papilloma conjunctiva, 1271–1272 salivary duct, 416 inverted type A nevus, 1163–1164 ‘invisible’ mycosis fungoides, 1329 involutional alopecia, 1001 iododerma, 615 iron-based stains colloidal iron, 34 high iron diamine, 34 iron deficiency and telogen effluvium, 1003 irregular-variant Bowen disease, 1113 irritant contact dermatitis, 185 with EMLA cream, 630 irritant contact urticaria, 647, 648 irritation fibroma, oral, 385 ischemia, systemic sclerosis features relating to, 739 ischemic fasciitis, 1610–1611 isolated collagenoma, 948

isthmus, follicular, 974–976 itching see pruritus Ito's hypomelanosis, 921–922 Ito's nevus, 1208 Ixodes tick and Lyme disease, 807

J

Jackson–Lawler (Jackson–Sertoli) syndrome, 88–89 Jacquet and Sevestre, papuloerosive dermatitis of, 445 Jadassohn effect, seborrheic keratosis exhibiting, hidroacanthoma simplex vs, 1532 Jadassohn–Lewandowsky syndrome, 88 Jadassohn nevus, 1489–1492 Jadassohn–Pellizzari anetoderma, 954 jaw cysts in nevoid basal cell carcinoma syndrome, 1103, 1104 jeep disease (pilonidal sinus), 480–481, 1584 jejunal biopsy, dermatitis herpetiformis, 147 jellyfish stings, 643–644 Jessner's lymphocytic infiltration of the skin see lymphocytic infiltrate of the skin jigger flea (Tunga penetrans), 890 joint hypermobility, Ehlers–Danlos syndrome see hypermobilitytype Ehlers–Danlos syndrome joint involvement, 687 multicentric reticulohistiocytosis, 1408 polyarteritis nodosa, 668 polymyositis/dermatomyositis, 753 systemic lupus erythematosus, 733 Wegener's granulomatosis, 673 see also arthritis; osteoarticular involvement junctional EB, 102, 104, 107–108, 114–115 classification, 102t pathogenesis and histology, 114–115 with pyloric atresia, 107, 114 junctional EB inversa, 107 junctional EB mitis, 107 junctional nevi, 1157f, 1158, 1159 conjunctival, 1157f, 1278, 1283 conjunctival primary acquired melanosis vs, 1283 dysplastic, 1196–1197 lentiginous see lentiginous junctional nevus pediatric, 1203 juvenile aponeurotic fibroma, 1621–1622 juvenile colloid milium, 543–544 juvenile conjunctival nevus, inflammed, 1279–1280 juvenile cutaneous mucinosis, self-healing, 579–580 juvenile dermatomyositis, 753, 755 juvenile elastoma, 959, 961 juvenile hemangioma see hemangioma juvenile hyaline fibromatosis, 1625 oral, 372 juvenile melanoma see Spitz nevus juvenile pityriasis rubra pilaris atypical, 212 classical, 211–212 juvenile plantar dermatosis, 199 juvenile rheumatoid arthritis (systemic juvenile idiopathic arthritis), 644–645 juvenile spring eruption (of ears), 268, 269 juvenile xanthogranuloma (JXG; nevoxanthoendothelioma; xanthoma multiplex), 1400 conjunctival, 1290 genital, 513 solitary epithelioid histiocytoma vs, 1409 juvenile xanthogranuloma family, 1391, 1399–1404

K

kala-azar, 845 Kamino bodies, Spitz nevus, 1181 Kaposi disease (lichen planus/lichen ruber pemphigoides), 131–132, 222 Kaposi sarcoma, 1643 AIDS-related see HIV disease/AIDS conjunctival, 1288 differential diagnosis, 1643 bacillary angiomatosis, 856–857 dermatomyofibroma, 1613–1614 progressive lymphangioma, 1745 pseudo-Kaposi sarcoma, 193 spindle cell hemangioma, 1725 tufted angioma, 1713 nodular see nodular Kaposi's sarcoma Kaposi varicelliform eruption, 773 kaposiform hemangioendothelioma, 1728–1729 karyotyping, 39 see also chromosomal abnormalities Kasabach–Merritt syndrome, 1716 Katayama disease, 893 Kawasaki syndrome (mucocutaneous lymph node) syndrome, 659t, 679–681 HIV-associated illness resembling, 903–904 infections associated with, 681, 694t

1785

1786

Index keloid, 1604–1605 penis, 513 see also acne keloidalis nuchae keloidal basal cell carcinoma, 1099 kenogen, 979 keratin(s) expression (and mutations affecting), 6, 15 bullous ichthyosiform erythroderma of Brocq, 56–57 chondroid syringoma (mixed tumor), 1522 EB simplex, 114 eruptive vellus hair cysts and steatocystoma, 1580 ichthyosis bullosa of Siemens, 59 keratosis palmoplantaris areata et striata, 80 keratosis palmoplantaris diffusa Vörner–Unna–Thost, 76 loose anagen hair syndrome, 1006 reticulate acropigmentation of Kitamura, 926 steatocystoma simplex, 1492–1493 hair, 15 keratinocyte, 5–6, 8–9 see also cytokeratins keratin casts, peripilar, 1041 keratin layer (stratum corneum), 2, 8 keratinization disorders, 46–98 keratinized sites in oral mucosa, 363 keratinizing cysts, 1571t keratinocytes, 5–6, 8–9 apoptosis, in erythema multiforme, 240 binucleated, 48t HSV infection, 774 keloids and, 1605 melanin transfer to, 11–12 verruciform epidermodysplasia, 771 verrucous xanthoma and, 530 keratitis–ichthyosis–deafness syndrome, 73–74 keratoacanthoma (molluscum sebaceum), 1134–1139, 1272 clinical features, 1134–1136, 1272 conjunctival, 1272 differential diagnosis, 1134, 1138–1139 histology, 1136–1138, 1272 intraoral (so-called), 427 pathogenesis, 1136–1138 subungual (distal digital), 1066–1068, 1136, 1138 squamous cell carcinoma vs, 1069 verrucous carcinoma vs, 1134 keratoacanthoma centrifugum marginatum, 1136 keratocysts, odontogenic (jaw), in nevoid basal cell carcinoma syndrome, 1103, 1104 keratoderma palmoplantar, 75–91 Vohwinkel see Vohwinkel keratoderma keratoderma climactericum, 91 keratoderma hereditarium dissipatum palmare et plantare (punctate palmoplantar keratoderma), 75t, 81 keratoderma hereditarium mutilans see Vohwinkel syndrome keratoelastoidosis marginalis, 962 keratoelastoidosis marginalis of hands, 82 keratolysis exfoliativa, 60 keratolysis plantare sulcatum (pitted keratolysis), 840–841 keratolytic winter erythema, 78–79 keratosis actinic, chemotherapeutic drug-related, 622 arsenical, 1115 benign alveolar ridge, 374–375 dysplastic, PUVA therapy (in psoriasis) and risk of, 209–210 factitial see morsicatio mucosae oris lichenoid, 231–232 psoriasiform, 1086 PUVA, 1115 seborrheic see seborrheic keratosis smokeless tobacco see smokeless tobacco keratosis stucco, 1085–1086 keratosis follicularis spinulosa decalvans vs Graham–Little syndrome, 1021 keratosis lichenoides chronica, 234–235 keratosis palmoplantaris areata et striata, 80 keratosis palmoplantaris diffusa transgrediens et progrediens, 78 keratosis palmoplantaris diffusa Vörner–Unna–Thost, 76–77 keratosis palmoplantaris diffusa with sclerodactyly, 82–83 keratosis palmoplantaris mutilans see Vohwinkel syndrome keratosis palmoplantaris nummularis, 80–81 keratosis palmoplantaris with arrhythmogenic cardiomyopathy (Naxos disease), 87, 1032t, 1040 keratosis palmoplantaris with corneal dystrophy, 89 keratosis pilaris, 67–68 virus-associated trichodysplasia spinulosa vs, 789 keratosis pilaris atrophicans, 68–69 keratosis punctata of palmar creases, 81 keratosis punctata palmaris et plantaris (punctate palmoplantar keratoderma), 75t, 81 keratotic balanitis, pseudoepitheliomatous micaceous and, 489–490 keratotic basal cell carcinoma, 1097 trichoepithelioma vs, 1472–1473

keratotic plaque, conjunctiva, 1274 kerion (kerion celsi), 852–853 dissecting cellulitis vs, 1028 KF-1 (monoclonal antibody), epidermolysis bullosa, 112 Ki-67 (and MIB-1 - monoclonal antibody to Ki-67) benign melanocytic nevi, 1238 Spitz nevus, 1184 conjunctival primary acquired melanosis, 1283 melanoma, 1238 KID (keratitis–ichthyosis–deafness) syndrome, 73–74 kidney see entries under renal Kikuchi–Fujimoto's disease, 1392 Kimura's disease epithelioid hemangioma vs, 1722 plasma cell granuloma-like lesions vs, 1391 Kindler syndrome, 102, 102t, 112 kinking of hair, acquired progressive, 1041 kinky hair syndrome (Menkes' disease), 1032t, 1040 kit (and c-kit/CD117) mast cell sarcoma, 1418 melanoma and UV-exposed skin, 1263–1264 and UV-protected skin, 1265, 1266 piebaldism and mutations in gene for, 919 Spitz nevus, 1184 Kitamura, reticulate acropigmentation of, 926 Klebsiella rhinoscleroma infection, 831–834 KLF7 and atopic eczema, 181–182 Klippel–Trenaunay syndrome, 1707 knotted hair, 1041 knuckle pad, 1622–1623 Köbberling-variant familial partial lipodystrophy, 354 Koebner phenomenon and koebnerization inverse, in alopecia areata, 988 psoriasis, 203f vitiligo, 912 Koebner-variant EB simplex, 104–105, 114f, 115f Koenen tumors, 1072 koilocytosis anogenital squamous cell carcinoma, 499t with intraepithelial neoplasia see bowenoid papulosis Koreans, hair counts, 972t Kveim test, 286 kyphoscoliosis, Ehlers–Danlos syndrome type VI, 936t, 937 Kyrle's disease (hyperkeratosis follicularis et parafollicularis in cutem penetrans), 321–322 clinical features, 321 differential diagnosis, 319, 322 familial dyskeratotic comedones, 178 Flegel's disease, 95–96 perforating folliculitis, 319 pathogenesis and histology, 321–322 Kytococcus sedentarius, 840

L

labia majora, histology, 438 labia minora, histology, 439 labial (lip) lesions see lip laboratory tests/management hair disorders, 968–969 sentinel nodes, 1297–1298 Lacazia loboi, 885 lacrimal caruncular tumors, 1270, 1295 lacrimal gland accessory, ductal cysts arising from, 1273 choristoma, 1294 oncocytoma, 1273 LAMB syndrome (former name for Carney complex), 482, 929–930 lambing ears (aural tissue), 268 lamellar granules, 8 lamellar ichthyosis autosomal dominant, 55 autosomal recessive, 51–54 lamin A and restrictive dermopathy, 947 lamina densa, 21–22 lamina lucida, 21–22 laminins, 22 mucous membrane pemphigoid and antibodies to, 135, 137 mutations, laryngo-onycho-cutaneous syndrome, 108 Langerhans cell (epidermal antigen-presenting cells), 9 in Langerhans cell histiocytosis, 1396 large sheets/clusters, 1394 in Rosai–Dorfman disease, 1406 Langerhans cell histiocytosis/granulomatosis (histiocytosis X), 1391, 1392–1397 congenital self-healing histiocytosis and, differentiation and overlap, 1392–1393, 1398 differential diagnosis, 1397, 1398 Paget's disease of nipple, 1444 Rosai–Dorfman disease, 1407 genital, 513 oral, 382

Langerhans cell sarcoma, 1397 langerin and Langerhans cell histiocytosis, 1396–1397 large B-cell lymphoma (LCL) B-cutaneous lymphoid hyperplasia vs, 1389 intravascular, 1380–1381, 1392 primary cutaneous diffuse see diffuse large B-cell lymphoma large cell acanthoma, 1082–1085 large cell lymphoma (LCL) angiotropic, 1380–1381, 1392 mycosis fungoides transforming to, 1325–1326 primary cutaneous anaplastic LCL, 1343–1348 large vessel vasculitis, types, 659t larva migrans, cutaneous, 893 laryngo-onycho-cutaneous syndrome, 108 Latrodectus mactans, 641 Laugier–Hunziker syndrome, 482, 923, 1151 Launois–Bensaude syndrome, 1596 Lawrence syndrome (acquired generalized lipodystrophy), 355, 355t LEF1 mutations, sebaceous adenoma, 1495 leg diffuse large cell lymphoma, 1319 lower, nevi, 1170 see also limb leiomyoma genital, 517–518, 1697–1698 pilar, 1696–1697 see also angioleiomyoma leiomyomatosis, vulval, 518 leiomyosarcoma, 1698–1701 cellular fibrous histiocytoma vs, 1648 leishmaniasis, 844–848 Leishman–Donovan bodies, 847 LEKT1 see SPINK5 Lelis syndrome, 584 LEMD5 mutations and Buschke–Ollendorff syndrome, 960 lentiginosis centrofacial, 1153–1154 genital, 1152 lentiginous dysplastic nevus, 1200 atypical/pigmented, of elderly, 1201 lentiginous junctional nevus atypical (dysplastic) lentiginous nevus of the elderly vs, 1201 lentiginous dysplastic nevus vs, 1200 lentiginous melanoma, 1261 lentiginous nevus, speckled, 1171–1172 lentigo/lentigenes (nail), 1062–1063 differential diagnosis, 1063 melanocytic activation, 1062 in situ melanoma, 1063, 1066 lentigo/lentigenes (skin) acral, 1152–1153 actinic see actinic lentigo ink spot, 1155 PUVA and sunbed, 1155 lentigo maligna see melanoma in situ lentigo maligna melanoma, 1222, 1226–1227 banal melanocytic nevi and, 1157–1158 clinical features, 1222 histology, 1226–1227 lentigo simplex, 1151 LEOPARD syndrome, 930–931, 1151 lepra reactions, 827–828 lepromatous leprosy (LL), 826, 830 leprosy, 825–831 borderline (BL), 820–825, 830 differential diagnosis, sarcoidosis, 288 indeterminate, 828, 830 lepromatous (LL), 826, 830 tuberculoid see tuberculoid leprosy vasculitis and, 694 Leser–Trélat sign, 1080, 1082 lethal acantholytic EB, 104 lethal intestinocutaneous syndrome, 696–698 Letterer–Siwe disease, 1392–1394 leukemia chronic lymphocytic see chronic lymphocytic leukemia extramedullary hematopoiesis vs, 1416 hairy cell, leukocytoclastic vasculitis, 661 infiltrates, 1413 anogenital, 513 conjunctival, 1292 in Sweet's syndrome, 637 see also adult T-cell leukemia/lymphoma leukocytes, precursor cell neoplasms, 1413 leukocytoclastic (allergic/hypersensitivity) vasculitis, 658–664 HIV-associated, 902–903 infections associated with, 694t urticarial vasculitis vs other forms of, 279, 667 leukoderma acquisitum centrifugum see halo nevus leukoedema, 372–373 leukoedema exfoliativum mucosae oris, 364

Index leukoencephalopathy, progressive sudanophilic, 353 leukoplakia, 421–424 hairy see hairy leukoplakia see also erythroleukoplakia LH7:2 (monoclonal antibody), epidermolysis bullosa, 112, 116 lichen amyloidoses, 537–541 lichen aureus, 275 lichen myxedematosus, 574–578 HIV-associated, 904 lichen nitidus, 229–231 anogenital, 452 lichen planopilaris, 221, 226, 1014–1021 differential diagnosis, 1017–1018 alopecia areata, 994–995 central centrifugal cicatricial alopecia, 1025 mycosis fungoides, 1334 pseudopélade of Brocq, 1023 scarring alopecia, 1014 lichen planus, 219–229, 402–406, 449–451 anogenital, 219–220, 449–451 bullous, 237, 410 differential diagnosis, 229, 406 erythema dyschromicum perstans, 236 lichenoid keratosis, 232 lupus erythematosus, 733 lichen nitidus coexisting with or predating, 230–231 oral, 402–406, 410 solitary, 231–232 lichen planus actinicus (or subtropicus), 221, 226–227 lichen planus pemphigoides, 131–132, 222 lichen planus pigmentosa, 219, 227 lichen purpuricus, 275 lichen ruber pemphigoides (lichen planus pemphigoides), 131–132, 222 lichen ruber verrucosus et reticularis, 234–235 lichen sclerosus genital, 452–456 neoplasia risk, 453–454, 496 morphea vs, 747–748 oral, 425 lichen scrofulosorum, 818, 819 lichen simplex chronicus (circumscribed neurodermatitis), 188–190, 374–375 anogenital, 445 oral, 374–375 psoriasis vs, 211 lichen spinulosus, 66–67 virus-associated trichodysplasia spinulosa vs, 789 lichen striatus, 232–233, 1060 adult Blaschkitis vs, 234 nail, 1060 lichenification in eczema, 180 pebbly, 189 lichenoid and granulomatous dermatitis, 236–237 lichenoid dermatitis, 219–237 drug-induced see drug-induced disorders pigmented purpuric, of Gougerot and Blum, 273 lichenoid dysplasia, 424 lichenoid lesions/reactions (in general) HIV-associated, 906–907 oral, 402 see also distinctive exudative discoid and lichenoid chronic dermatosis lichenoid photoeruptions, HIV-associated, 899 light see ultraviolet light and entries under photoligneous gingival hyperplasia, 396, 398 limb(s) (extremities) acquired dermal melanocytosis of face and, 1208 metastases to, 1424 spindle cell hemangioma, 1724 see also leg limb girdle muscle weakness in polymyositis, 752 limbic area, ocular surface squamous neoplasia, 1276 limited cutaneous systemic sclerosis, 734–737, 739t limited peripheral cutaneous sclerosis, 734 linear acantholytic dermatosis, relapsing, 169 linear acquired inflammatory skin eruption, Blaschko, 232–233 linear atrophoderma of Moulin, 744 linear basal cell carcinoma, 1091 linear Darier's disease, 173–174 linear eccrine syringofibroadenoma, nonfamilial unilateral, 1528 linear epidermolytic epidermal nevus, 59 linear focal elastosis, 958 linear granuloma annulare, 290 linear IgA disease (LAD), 147–150, 411, 607–608 differential diagnosis, 104t, 379 drug-induced, 607–608 oral mucosal lesions, 411 linear IgA disease-like variant of EB acquisita, 139 linear morphea, 743–745 linear nevoid variant of basaloid follicular hamartoma, 1446 linear prokeratosis, 92–93

linear psoriasis, 201 inflammatory linear verrucous epidermal nevus vs, 215 linear verrucous epidermal nevus, inflammatory (ILVEN), 214–215 lingual thyroid, 370 see also tongue lip (oral labium) HSV infection (herpes labialis), 949 melanotic macule see macule skin histology, 4f see also cheilitis lipedematous alopecia and lipedematous scalp, 1009 lipid(s), plasma, 520 abnormalities see hyperlipidemias lipidized fibrous histiocytoma, 526, 1652 lipoatrophy, localized (=localized lipodystrophy), 354, 356–361 lipodermatosclerosis (lipomembranous change in chronic panniculitis), 352–353 lipodystrophy, 354 acquired, 354, 355–356 classification and clinical features, 354 diagnostic criteria, 355t familial, 354–355 HIV-positive patients, 910–911 localized (=localized lipoatrophy), 354, 356–361 lipofibromatosis, 1599 lipogranuloma, sclerosing see paraffinoma lipoid dermatoarthritis, 1408–1409 lipoid proteinosis, 546–548 lipoma, 1590–1600 chondroid, 1594–1595 conjunctival, 1291 fibrohistiocytic, 1599 oral, 369–370 pleomorphic, 1594 scalp, lipedematous alopecia vs, 1009 spindle cell, 1593–1594 see also angiolipoma; angiomyolipoma; dermolipoma lipomatosis, 1596 lipomatous lesion, hemosiderotic fibrohistiocytic, 1599 lipomatous neurofibroma, 1676 lipomatous tumors see adipocytic tumors lipomembranous change in chronic panniculitis, 352–353 lipophagic panniculitis of childhood, 357 lipoproteins antibodies to lipoprotein components, 521t classes, 520 disorders of altered content and structure, 521t elevated levels (hyperliproteinemias), primary and secondary causes, 521t liposarcoma, 1600–1603 atypical, 1600 conjunctival, 1291 differential diagnosis, 1603 lipoblastoma, 1598 myxoid chondrosarcoma, 1753 pleomorphic lipoma, 1595 myxoid see myxoid liposarcoma pleomorphic, 1600, 1603 Lipschutz ulcer, 459 Lisch nodules, 1678 lithium-induced reactions, 620 psoriasis, 610 livedo reticularis in systemic lupus erythematosus, 719–720 livedo vasculitis see atrophie blanche liver disease/disorders acquired generalized lipodystrophy, 355 erythropoietic protoporphyria, 552 lichen planus and, 224 neutrophilic dermatoses associated with, 639–640 porphyria cutanea tarda, 559 see also hepatitis C; hepatoerythropoietic porphyria liver spot see actinic lentigo lobomycosis, 885–886 lobular capillary hemangioma see pyogenic granuloma lobular neutrophilic panniculitis recently described variant, 352 rheumatoid arthritis-associated, 349–350 local microenvironment, Langerhans cell histiocytosis, 1394 localized amyloidosis, classification, 533t localized basaloid follicular hamartoma, 1446 localized collagen disorders, 947–948 localized cutaneous amyloidosis primary, 537–541 secondary, 541 localized cutaneous pemphigoid, 119–120 localized cutis laxa, 949 localized dystrophic calcinosis, 567, 570 localized EB simplex, 104 localized granuloma annulare, 288–289 localized lipodystrophy (=localized lipoatrophy), 354, 356–361 localized lymphedema, massive, 1754–1755

localized mucinosis secondary to venous insufficiency, 583 localized myxedema, 573–574 localized non-Herlitz junctional EB, 107 localized pustular psoriasis, 204 localized scleroderma see morphea localized sporotrichosis, 884 localized symmetric lipomatosis, 1596 locally aggressive adnexal carcinoma (microcystic adnexal carcinoma), 1558, 1559–1563 locally aggressive fibrous lesions, 1626–1629 longitudinal erythronychia, 1070 longitudinal melanonychia see melanonychia loose anagen hair syndrome, 968–969, 1006–1007 differential diagnosis, 1007 telogen effluvium, 1005, 1007 loricrin, 8 genetic disorders related to, 73, 84 loss of heterozygosity (LOH), 39–40 basal cell carcinoma, 1093 melanocytic nevi, 1015 low density (beta) lipoproteins, 521 raised, 521t and raised VLDL, 521t Loxosceles reclusa, 641 Lucio's phenomenon, 828, 829, 830–831 Ludwig pattern hair loss see ‘female pattern’ hair loss lung cancer, cutaneous metastases, 1422f, 1423–1424, 1430 see also bronchial carcinoma lung involvement (pulmonary/lower airway involvement) Behçet's syndrome, 687, 688 Churg–Strauss syndrome, 677, 678 histoplasmosis, 868 polymyositis/dermatomyositis, 753 relapsing polychondritis, 758 sarcoidosis, 284 sporotrichosis, 884 systemic lupus erythematosus, 720, 733 systemic sclerosis, 743 diffuse, 737 Wegener's granulomatosis, 673 limited pulmonary granulomatosis, 674 see also bronchial carcinoma lupoid form of cutaneous leishmaniasis, 844, 847 lupus, warty, 812, 815t, 816 lupus anticoagulant syndrome see antiphospholipid syndrome lupus band test, 725 lupus erythematosus, 411–412, 711–733 alopecia in, 1012–1014 chronic cutaneous see discoid lupus erythematosus classification/subtypes, 711t clinical features, 711–712 oral involvement, 411–412, 712 differential diagnosis, 733 Kikuchi–Fujimoto's disease, 1392 polymorphic light eruption, 269, 270, 733 reticular erythematous mucinosis, 267 discoid see discoid lupus erythematosus drug-induced see drug-induced disorders neonatal see neonates pathogenesis and histological features, 721–733 polymorphic light eruption associated with, 268, 269 subacute cutaneous, 717–718, 725–726, 730–731 systemic see systemic lupus erythematosus lupus erythematosus-erythema multiforme-like syndrome, 714–715 lupus erythematosus panniculitis (LEP), 715, 1354 lupus erythematosus profundus, 358–360, 715 clinical features, 358–360, 715 pathogenesis and histology, 358–360 lupus erythematosus tumidus (tumid LE), 269–270 clinical features, 713 lupus hair, 1013 lupus miliaris disseminatus faciei (papular tuberculid), 310, 818, 1049 lupus pernio see chilblain lupus erythematosus lupus vulgaris, 813, 814, 815t, 816 Lutzner cell (Sézary cell), 1339, 1340 Lyell's disease see staphylococcal scalded skin syndrome Lyme disease see Borrelia lymph nodes biopsy (for metastases), 1296–1310 nonsentinel, 1309 sentinel see sentinel lymph node biopsy dissection (lymphadenectomy) completion, 1296–1297 elective/prophylactic, 1296 partial, 1298 therapeutic, 1296f hyperplasia, giant see Castleman's disease involvement angioimmunoblastic T-cell lymphoma, 1350 cat scratch disease, 803 Langerhans cell histiocytosis, 1396

1787

1788

Index lymph nodes (Continued) Sézary syndrome, 1323–1324, 1340 sporotrichosis, 884 systemic lupus erythematosus, 720 see also lymphadenopathy mapping (lymphatic mapping), 1296 agents used, 1298 non-melanocytic neoplasms, 1309 reporting, 1309 see also nodal follicular lymphoma lymphadenitis, histiocytic necrotizing, 1392 lymphadenoma (lymphoepithelial tumor of the skin), 1465 lymphoepithelioma-like carcinoma vs, 1149, 1484 trichoblastoma and, relationship between, 1475 lymphadenopathy angioimmunoblastic, with dysproteinemia, 1350 in cat scratch disease, 803 dermatopathic (in lymphoproliferative disease) see dermatopathic lymphadenopathy massive, sinus histiocytosis with, 1404–1407 in sarcoidosis hilar, 284 peripheral, 285 in systemic lupus erythematosus, 733 see also lymph nodes, involvement lymphangiectasia, conjunctival, 1288 lymphangiogenesis, 27 lymphangioma, 1743–1745 alveolar ridge, 371 conjunctival, 1288 lymphangiomatosis, 1746 multifocal, with thrombocytopenia, 1745 lymphangiomatous Kaposi's sarcoma, 1734 lymphangiosarcoma see angiosarcoma; lymphedema-associated angiosarcoma lymphangitis, sclerosing see sclerosing lymphangitis lymphatic/lymphovascular system (involvement or invasion of/ spread to), 28 eccrine porocarcinoma, 1536 melanoma, prognostic importance, 1235–1236 Spitz nevus, 1181 see also entries under intralymphatic lymphedamatous fibroepithelial polyp, penile, 514–515 lymphedema angiosarcoma (lymphangiosarcoma) associated with, 1738 massive localized, 1754–1755 lymphoblastic leukemia/lymphomas (precursor), 1415–1416 peripheral primitive neuroectodermal tumor vs, 1694 lymphocutaneous sporotrichosis, 884 lymphocytes cerebriform (Sézary cell), 1339 recovery after induction or augmentation chemotherapy, reaction to, 626 tumor-infiltrating (melanoma), prognostic importance, 1234 see also B-cell; T-cell lymphocytic folliculitis, necrotizing, 1030 lymphocytic infiltrate of the skin (Jessner), 264–265 differential diagnosis, 264–265 polymorphous light eruption, 269 reticular erythematous mucinosis, 267 tumid lupus erythematosus, 270 lymphocytic leukemia, chronic see chronic lymphocytic leukemia lymphocytic lymphoma of intermediate grade see mantle cell lymphoma lymphocytic primary scarring alopecias, 1012–1026 lymphocytic vasculitis, 696 lymphocytoma cutis (borrelial lymphocytoma), 807, 808 lymphoepithelial cyst, oral, 369 lymphoepithelial Kazal type Inhibitor see SPINK5 lymphoepithelial tumor of the skin see lymphadenoma lymphoepithelioma-like carcinoma, 1147–1149 lymphadenoma vs, 1149, 1484 lymphogranuloma venereum, 475–476 lymphogranuloma X, 1350 lymphohistiocytosis, hemophagocytic see hemophagocytic syndrome lymphoid hyperplasia, B-cutaneous, 1386–1389 lymphoma, Hodgkin, 1383–1384 lymphoma, non-Hodgkin, 1312 anogenital infiltrates, 513 classification, 1312 conjunctival, 1291, 1292 cutaneous drug-induced pseudolymphoma vs, 614 epithelioid hemangioma vs, 1722 molecular diagnostics, 43–45 peripheral primitive neuroectodermal tumor vs, 1694 in pityriasis lichenoides, 256–257 histiocytic, 1411–1412 midline destructive disease and, 430–431 neuroendocrine carcinoma vs deposits from, 1147 rhabdomyosarcoma vs, 1704 subcutaneous panniculitic, 338–339

lymphomatoid drug eruption, 612–614, 1362 lymphomatoid granulomatosis (angiocentric lymphoma; angiocentric immunoproliferative lesion), 1376–1378 clinical features, 1376 differential diagnosis, 1378 extranodal NK/T cell lymphoma, 1357, 1378 grading, 1378 pathogenesis and histology, 1376–1378 lymphomatoid papulosis, 1340–1343 differential diagnosis, 1343 Hodgkin lymphoma, 1384 mycosis fungoides, 1334 primary cutaneous anaplastic large cell lymphoma Hodgkin lymphoma, 1344, 1345–1348 pityriasis lichenoides and, 258 lymphomatosis, intravascular malignant, 1380–1381, 1392 lymphomatous adult T-cell leukemia/lymphoma, 1351 lymphoproliferative disorders, 1312–1420 conjunctival, 1270, 1291–1292 cutaneous, 1312–1420 atypical, HIV infection, 1362 iatrogenic, 1384 lymphoscintigraphy, 1296–1297 antimony sulfur colloid use, 1298 lymphovascular spread/invasion see lymphatic/lymphovascular system Lynch syndrome, 1505–1506 lysosomes, lipoid proteinosis, 547–548

M

McCune–Albright syndrome, 923 McGrath syndrome, 87–88 macroglobulinosis, cutaneous, 548–549 macromelanosomes, 11–12 macrophages and verrucous xanthoma, 530 macrovascular (large vessel) vasculitis, types, 659t macular amyloidosis, 537–541 notalgia paresthetica vs, 934 macular hypomelanosis, progressive, 921 macular lesions of oral mucosa, 364–366 macules (macular lesions) café-au-lait, 1677, 1680 of interface dermatitis, 237 oral/labial melanotic, 432–435 mucosal, 433 reticulated, 1155 white, in tuberous sclerosis, 941 maculopapular eruption chemotherapeutic drug-related, 621 sarcoidosis, 282–283 maculopapular mastocytoma, 1417–1418 Madelung's disease, 1596 maduromycotic mycetoma, 878, 878t Maffucci's syndrome, 1716 Majocchi's disease, 273 Majocchi's granuloma, 858 major histocompatibility complex see HLA mal del Meleda, 79–80 malakoplakia (malacoplakia), 479, 836–837 Malassezia, 858–860 folliculitis, 859–860 seborrheic dermatitis and, 182–183 male(s) androgenetic alopecia, 982–983 melanoma preponderance, 1222 ‘male pattern’ (Hamilton-Norwood) hair loss, 983 Malherbe's calcifying epithelioma (pilomatricoma), 1460– 1463, 1465 malignant atrophic papulosis, 696–698 ‘malignant’ pyoderma, 633 malignant tumors see cancer Mallorcan acne, 1045 MALT lymphoma see marginal zone B-cell lymphoma MAML2 and hidradenocarcinoma, 1548 and hidradenoma, 1545 mammary ductal apocrine carcinoma, metastatic, 1518 mammary-like glands, anogenital, 441 adenocarcinoma, 1515 adenoma, 510–511, 1515 see also hidradenoma papilliferum mammary Paget's disease see Paget disease mammary-type myofibroblastoma of soft tissue, 1594 MAN1 mutations and Buschke–Ollendorff syndrome, 960 mandibuloacral dysplasia, familial partial lipodystrophy with, 355 mantle cell lymphoma (centrocytic lymphoma; lymphocytic lymphoma of intermediate grade) primary cutaneous follicle center lymphoma vs, 1371 marginal zone lymphoma vs, 1368 secondary cutaneous, 1373–1375

mantleoma, 1507 Marburg virus, 789 Marfan syndrome, 26 marginal papular acrokeratoderma, 82 marginal zone B-cell lymphoma (extranodal/primary cutaneous), 1365–1368, 1388–1389 differential diagnosis, 1368 B-cutaneous lymphoid hyperplasia, 1388–1389 plasmacytosis, 1389 Marshall's syndrome (postinflammatory cutis laxa), 949, 950 MART-1 (Melan-A), melanoma, 1237–1238 desmoplastic, 1256–1257 prognostic value, 1236 sentinel node samples, 1301–1303 MASH-1, 1429 massive localized lymphedema, 1754–1755 massive lymphadenopathy, sinus histiocytosis with, 1404–1407 Masson's tumor, 1705 Masson–Fontana silver stain, 34 mast cell sarcoma, 1418–1420 mastocytoma, cutaneous diffuse, 1418 maculopapular, 1417–1418 solitary, 1417 mastocytosis, 1416–1420 MATP mutations and type IV oculocutaneous albinism, 918 matric(i)al carcinoma, 1463 matric(i)al differentiation basal cell carcinoma, 1099 pilomatrixoma, 1461–1462 matricoma, melanocytic, 1463–1466 matrilin-1, relapsing polychondritis, 759 matrix (nail) see nail matrix matrix Gla protein and pseudoxanthoma elasticum, 952 matrix metalloproteinases (MMPs), 24 squamous carcinoma invasion and, 1119 tissue inhibitors of (TIMPs), 24 matrix protein 1 mutation and lipoid proteinosis, 546 mechanical barrier function, 1, 8–9 mechanobullous variant of EB acquisita, 139, 142 medallion-like dermal dendrocyte hamartoma, 1623–1624 median nasal dermoid fistula, 1469, 1581f median raphe cyst, 486–487, 1583–1584 median rhomboid glossitis, 376–377 medication-induced disorders see drug-induced disorders Mediterranean fever, familial, 537 medulla, hair shaft, 977–978 Meischer's (granulomatous) cheilitis vs Crohn's disease, 309 Meissner's corpuscles, 29–30 Melan-A see MART-1 melanin, 10–12 melanoacanthosis, 433–434 α-melanocyte-stimulating hormone analogues, 629 melanocytes, 10–12 in nail unit, 1061 melanocytic activation, 1062 melanocytic dysplasia, de novo intraepidermal epithelioid, 1185 melanocytic hamartoma, dermal, 1208 melanocytic lesions, 432–435 nail apparatus, 1061 of uncertain metastatic potential in sentinel node biopsy, 1308 melanocytic matricoma, 1463–1466 melanocytic nevi, 1150–1202 banal/benign, 1156–1163 clinical features, 1158–1163 differential diagnosis, 1161–1163, 1240 histology, 1159–1161 congenital see congenital nevus dermal nevi as ‘end stage’ of, 1160 epidermoid cyst coexisting with, 1573 molecular pathology and diagnostics, 1045–1046 with phenotypic heterogeneity see combined nevus at special sites, 1165–1170 transformation risk see premalignant lesions melanocytic proliferations of unknown significance, superficial atypical, 1044–1045 melanocytic tumors conjunctival, 1270 benign, 1270, 1277–1287 immunohistochemical diagnosis, 35t unassociated with epithelial structures, 1266–1267 of uncertain malignant potential (MELTUMP), 1046–1048 melanocytoma, pigmented dermal, in Carney complex, 930 melanocytoses congenital ocular, 1281 dermal, 1208

Index melanoma, 1064–1066, 1221–1267 acral see acral lentiginous melanoma; acral melanoma biologically distinct subtypes, 1263 cell types, 1230 clinical features, 1240, 1257–1259 subungual, 1064–1066 conjunctival, 1283–1287 primary acquired melanosis with atypia progressing to, 1282, 1284 desmoplastic see desmoplastic melanoma differential diagnosis, 1066, 1237, 1259 atypical fibroxanthoma, 1662 balloon cell nevus, 1175 banal nevus, 1161–1162 combined nevus, 1173 deep penetrating nevus, 1190, 1192 desmoplastic Spitz nevus, 1188 halo nevus, 1176 leiomyosarcoma, 1699–1701 proliferation nodule, 1206 sebaceous carcinoma, 1505 Spitz nevus, 1181–1185 subungual, 1066 epidemiology, 1221, 1262 familial, 1222 dysplastic nevi and (familial atypical multiple mole melanoma syndrome), 1192 genital, 484–485 in areas of melanosis, 482 histology, 1225–1229, 1258–1259 subungual, 1064–1066 variants, 1239–1252, 1256–1257 immunohistochemistry/immunocytochemistry, 1237–1239 sentinel nodes, 1300–1307 subungual, 1066 of variants, 1240, 1242–1243, 1244, 1245, 1246 invasive, 1065–1066 juvenile see Spitz nevus lentigo maligna, banal melanocytic nevi and, 1157–1158 management/treatment principles, 1296 metastatic see metastases molecular classification, 1262–1267 molecular diagnostics, 1045–1046 nodular see nodular melanoma non-cutaneous primary, 1224–1225 ocular see conjunctival; uveal (subheadings above/below) oral, 434–435 pagetoid/superficial spreading see superficial spreading melanoma pathogenesis, subungual, 1064–1066 pediatric, 1257–1259 pigment-synthesizing see pigment-synthesizing melanoma prognosis children, 1258 indicators of, 1231–1237, 1238 rhabdoid, 1244–1245, 1767, 1768f sentinel node biopsy see sentinel lymph node biopsy small cell see small cell melanoma spindle cell see spindle cell melanoma spitzoid, 1178–1185, 1241–1243 transformation to see premalignant lesions uveal, 1266 melanoma antigen recognized by T cells 1 see MART-1 melanoma in situ (lentigo maligna; Hutchinson's melanotic freckle), 1222, 1226–1227 differential diagnosis, 1201 actinic keratosis, 1109 lentiginous dysplastic nevus, 1200 lentigo, 1063, 1066 early/evolving, 1201 histology, 1226–1227 melanoma arising within pre-existing see lentigo maligna melanoma melanonychia, longitudinal, 1061–1062 melanoma and, 1064 melanosis Becker's, 1156, 1695 conjunctival primary acquired (PAM), 1281–1283, 1284, 1285 generalized, with metastatic melanoma, 934 genital, 481–482 oculodermal see Ota's nevus Riehl's, 934 transient neonatal pustular, 218 see also congenital melanosis oculi; hypermelanosis; hypomelanosis; pigmentation melanosomes, 10–11 melanotan I and II (α-melanocyte-stimulating hormone analogues), 629 melanotic freckle, Hutchinson's see melanoma in situ melanotic macule, oral see macule melanotic schwannoma, 1671–1672 psammomatous, Carney complex, 929, 930 melasma, 923

Meleda disease (mal del Meleda), 79–80 Melkersson–Rosenthal syndrome, 407 Meltzer's triad, 703 membrane-associated transporter protein gene (MATP) mutations and type IV oculocutaneous albinism, 918 membrane-coating granules, 8 membranoproliferative glomerulonephritis associated with acquired partial lipodystrophy, 355–356 membranous fat necrosis, 353 membranous glomerulonephritis, lupus, 733 memory cells and fixed drug eruptions, 600 men see males meningeal heterotopias (cutaneous meningioma), 1687 meningococcal septicemia, 799–800 Menkes' disease, 1032t, 1040 mepacrine pigmentation, 602–603, 604 mercury, 619–620 Merkel cell, 12–13 hyperplasia, 12–13 ultrastructural of Merkel cell tumor cells resembling, 1146–1147 Merkel cell carcinoma see neuroendocrine carcinoma Merkel cell polyomavirus, 1142–1143 merlin (NF2 product), 1669 mesangial proliferative lupus nephritis in systemic lupus erythematosus, 732 mesangiocapillary glomerulonephritis associated with acquired partial lipodystrophy, 355–356 mesenchymal tumors see soft tissue tumors mesodermal stromal polyp, female genitalia, 513–514 Mesomycetozoea, 887 mesonephric cyst, 488 mesothelial cyst, 488 mesothelioma, 1437–1439 MET and myxofibrosarcoma, 1663 metabolic diseases, 520–589 metal(s), granulomatous reactions, 313 see also heavy metal pigmentation metalloproteinases see matrix metalloproteinases metaplasia mucinous see mucinous metaplasia myeloid, 1416 synovial (metaplastic synovial cyst), 1584, 1754 syringosquamous, 624–625 metaplastic basal cell carcinoma, 1099 metaplastic melanoma, 1250 metaplastic synovial cyst (synovial metaplasia), 1584, 1754 metastases/secondary tumors, 1270 anogenital skin, 513 clinical features (incidence/primary sites/chronology of presentation), 1421–1430 histological features, 1427–1430 immunohistochemistry/electron microscopy/fine needle aspiration cytology, 1427–1430 of individual/specific cutaneous (and related tissue) tumors, 1430–1439 clear cell carcinoma, 1125, 1436 conjunctival melanoma, 1285 eccrine porocarcinoma, 1537 leiomyosarcoma, 1699–1701 lymphoepithelioma-like carcinoma, 1149 melanoma see subheading below metaplastic carcinoma, 1140 myeloma see subheading below pilomatrix carcinoma, 1463 squamous carcinoma. see subheading below of intracranial meningioma, 1688, 1689 of melanoma (to cutaneous sites), 1251, 1252, 1438–1439 clear cell sarcoma vs, 1695 generalized melanosis associated with, 934 malignant peripheral nerve sheath tumor vs, 1693 origin of metastases, 1422 mucinous carcinoma vs, 1567 of myeloma, 1378 microscopic examination of sentinel nodes for, 1305–1307 plasma cell granuloma-like lesions vs, 1391 separation of nevus cells in sentinel node samples, 1307–1308 neuroendocrine carcinoma (primary) vs, 1147 to non-cutaneous sites aggressive digital papillary adenocarcinoma, 1543–1544 basal cell carcinoma, 1092–1093 to conjunctiva, 1270, 1294–1295 dermatofibrosarcoma protuberans, 1631 to lymph nodes, biopsy see lymph nodes neuroendocrine carcinoma, 1141–1142 squamous cell carcinoma, 1123 prognosis, 1427 rare tumors, 1426–1427 source (tissue of origin) breast, 1422f, 1425–1426, 1429, 1431–1432, 1518 determination, 1427 melanoma, 1422

squamous carcinoma conjunctival, 1275 skin, 1125, 1430–1437 see also TNM classification metastatic calcinosis cutis, 567t, 568 ‘metastatic’ Crohn's disease see Crohn's disease ‘metastatic’ silicone granulomata, 313 metastatic tuberculous subcutaneous abscess (gumma), 814, 815t, 817 metatarsalgia, 1666 metatypical basal cell carcinoma, 1097 methotrexate, 622, 623 lymphoproliferative disorders associated with, 1326 methyl bromide exposure, 615–616 Meyerson's nevus, 1177–1178 MIB-1 see Ki-67 Mibelli angiokeratoma of, 1710 porokeratosis of, 92, 94 MIC-2 antibody see CD99 Michaelis–Gutmann bodies, 837 microabscess Monro, 207 neutrophilic, dermatitis herpetiformis, 146 microangiopathic vasculitis see small vessel vasculitis microangiopathy, diabetic, and necrobiosis lipoidica, 297 Micrococcus sedentarius, 840 microcystic adnexal carcinoma, 1530, 1558, 1559–1563 microenvironment (local), Langerhans cell histiocytosis, 1394 microfilaria, onchocercal, 891, 892, 893 micronodular basal cell carcinoma, 1095 micropapular lichen planus, 226 microphthalmia transcription factor (MITF) melanoma, 1238 sun-exposed skin, 1264 Waardenburg's syndrome and, 920 microsatellite instability (DNA) and Muir–Torre syndrome, 1505–1507 microsatellite lesions with melanoma, prognostic importance, 1234–1235 microscopic examination hair, 968–969 sentinel nodes for metastatic melanoma, (for melanoma), 1305–1307 microscopic polyangiitis/polyarteritis, 659t, 667–673 HIV-associated illness resembling, 903 microscopic satellites with melanoma, prognostic importance, 1234–1235 microsomal fatty aldehyde dehydrogenase (FALDH) mutations, 64 Microsporum audouinii, 852 Microsporum canis, 852 microvenular hemangioma, 1718 mid-dermal elastolysis, 957–958 midline destructive disease, 430–431 migratory circinate EB simplex, 106 migratory erythema, necrolytic, 587–589 migratory glossitis, benign, 375–377 migratory panniculitis (erythema nodosum migrans), 328, 329, 332 milia (milium), 1576–1577 colloid, 543–546, 962 dystrophic EB, 116 EB acquisita, 138 primary vs secondary, 1576 milia-like idiopathic calcinosis cutis, 569, 570 milia-like syringoma, 1541 miliaria, 199–200 apocrine, 200 miliaria crystalline, 199 miliaria rubra, 199–200 profunda, 200 miliary tuberculosis, 814, 815t, 816 milker's nodule, 783 miniatuarized (vellus-like) hair, 974 minimal deviation melanoma, 1239–1240 minimal mesangial lupus nephritis in systemic lupus erythematosus, 732 minocycline pigmentation, 602, 603 minute synovial sarcoma, 1620, 1765 mismatch repair genes and Muir–Torre syndrome, 1505–1507 mites, demodectic see demodic(id)osis MITF see microphthalmia transcription factor mitochondrial DNA syndrome-associated poikiloderma, 246 mitotic rate in melanoma, prognostic importance, 1234–1235 Mitsuda (lepromin) reaction, 827, 828 mixed connective tissue disease, 756–757 mixed connective tissue variant of phosphaturic mesenchymal tumor, 1758 mixed cryoglobulinemia, 703–704 mixed inflammatory primary scarring alopecia, 1029–1031

1789

1790

Index mixed (localized) pustular psoriasis, 204 mixed tumor of skin see chondroid syringoma MMR (mismatch repair) genes and Muir–Torre syndrome, 1505–1507 moderately differentiated squamous carcinoma, 1122 molecular pathology/diagnostics/classification (incl. genetic abnormalities), 39–43 actinic keratosis, 1107 dermatofibrosarcoma protuberans, 1631 dysplastic nevus syndrome, 1196 Langerhans cell histiocytosis, 1394 lymphomas, 43–45 melanocytic nevi, 1045–1046 melanoma, 1262–1267 sentinel node assessment, 1308 UV-exposed skin, 1263–1264 UV-protected skin, 1264–1266 mycosis fungoides, 1317 rhabdomyosarcoma, 1702 trichoepithelioma, 1471 see also chromosomal abnormalities and specific genes Moll gland cyst, 1508, 1509 Mollifex Gurr, 1052 molluscoid pseudotumors, 936 molluscum contagiosum, 785–787 molluscum sebaceum see keratoacanthoma Mondor's disease see sclerosing lymphangitis Mongolian spot, 1206–1207 monilethrix, 1032t, 1039 monkeypox, 781–782 monoclonal antibodies/immunoglobulin (man-made) in immunodetection/immunohistochemistry (incl. monoclonals), epidermolysis bullosa, 112 in immunodetection/immunohistochemistry, 34–35 serum-sickness-like reactions, 594 monoclonal cryoglobulinemia, 703, 704 monoclonal gammopathy IgA pemphigus and, 166 IgM, urticarial vasculitis and, 278, 647, 666 monoclonality see clonality Monro microabscess, 207 monster cells, dermatofibrosarcoma with, 1651–1652 Montenegro skin test, 844, 845, 847 Montgomery's tubercles, 1488 morbus Darier see Darier's disease morphea (limited scleroderma), 734, 743–748 atrophoderma of Pasini and Pierini as variant of, 749 generalized, 361, 746, 747 systemic sclerosis and co-existing, 746 distinction, 742 relationship between, 743 morpheaform basal cell carcinoma, 1090, 1097 desmoplastic trichoepithelioma vs, 1475 microcystic adnexal carcinoma vs, 1563 morsicatio mucosae oris (factitial keratosis), differential diagnosis, 373, 374 Morton's neuroma, 1666 mosaic acral hyperkeratosis, 82 motor and sensory neuropathy, hereditary, type 4, 50–51 mottled pigmentation, EB simplex with, 105 Moulin, linear atrophoderma of, 744 mouth see hand, foot and mouth disease and entries under oral Mucha–Haberman disease, 255 febrile ulceronecrotic, 255, 256, 258 mucicarmine, 33 mucin dermal, mycosis fungoides with, 1331 Paget's disease, 1443 primary cutaneous mucinous carcinoma vs cutaneous metastases of gastrointestinal primary, 1434 mucin-producing sweat gland carcinoma, endocrine, 1558 mucinosis, 571–583 follicular see follicular mucinosis HIV and see HIV disease reticular erythematous, 265–267 secondary, 583 mucinous carcinoma (adenocystic carcinoma), 1566–1568 metastatic, 1434 mucinous cyst, 487–488 mucinous metaplasia/syringometaplasia (muciparous epidermal tumor) acral, 1585–1586 anogenital, 486 muciparous epidermal tumor see mucinous metaplasia/ syringometaplasia Muckle–Wells syndrome, 537, 646–647 mucocele (mucous escape phenomenon), 369–370, 412–414 mucocutaneous candidiasis, 861 chronic, 862 mucocutaneous leishmaniasis, 845, 846 mucocutaneous lymph node syndrome see Kawasaki syndrome

mucoepidermoid (adenosquamous) carcinoma, 418–419, 1131 acantholytic squamous carcinoma vs, 1128 conjunctival, 1277 cutaneous, 1131 oral, 429–430 distinction of adenosquamous and mucoepidermoid forms, 429 mucopapillary retention cyst vs, 414 sialolithiasis vs, 415 penile, 507–508 mucoid capsule, cryptococcosis, 872 mucopapillary cyst, salivary, 413, 414 mucormycosis, 874 mucosa see mucous membrane mucosa-associated lymphoid tissue lymphoma see marginal zone B-cell lymphoma mucosal pemphigoid (mucosal membrane/cicatricial pemphigoid), 133–137 clinical features, 133–135 anogenital lesions, 457 oral lesions, 120, 133, 409–410 EB acquisita variant resembling, 139 HIV-associated, 652, 904 mucositis, plasma cell orificial, 406, 407 mucous cells, eccrine glands, 19 mucous cyst, digital, 1073 mucous membrane(s) (mucosa), lesions/disorders in Darier's disease, 170 in leishmaniasis, 845, 846 in lichen nitidus, 229f melanoma, 1224–1225 in multicentric reticulohistiocytosis, 1408 neuroma, 1666 oral see oral mucosa see also hyalinosis cutis et mucosae mucous-secreting adenocarcinoma vs myxoid melanoma, 1247 Muir–Torre syndrome, 1505–1507 sebaceous adenoma, 1495, 1505 sebomatricoma, 1500 superficial epithelioma with sebaceous differentiation, 1499 müllerian cyst, 1582–1583 multicentric Castleman's disease, 1389, 1390 multicentric myofibromas, 1616 multicentric reticulohistiocytosis, 1408–1409 multidrug resistance-associated protein-6 mutations and pseudoxanthoma elasticum, 952 multifocal Langerhans cell histiocytosis, 1393 multifocal lymphangiomatosis with thrombocytopenia, 1745 multifocal papillomavirus epithelial hyperplasia (Heck's disease), 384, 400–401 multikinase inhibitors, 622 multinodular keratoacanthoma, 1136 multinucleate cell angiohistiocytoma, 1643–1644 multinucleate cells, HSV, 774, 775 multiple angiokeratoma, 1710 multiple eccrine syringofibroadenoma, 1528 multiple enchondromas (of Maffucci's syndrome), 1716 multiple familial trichoepithlioma, 1469–1470 multiple glomus tumors, 1747 multiple lipomas, 1590 multiple sulfatase deficiency, 50 multiple symmetric lipomatosis, 1596 muscle (skeletal or in general) inflammatory disorders see dermatomyositis; myositis; polymyositis sarcoidosis, 285 see also myocardial involvement muscle-derived tumors, immunohistochemical stains, 35t muscular arteries, 27 muscular dystrophy, EB with, 103–104, 105, 114 musculosketal involvement see joint involvement; osteoarticular involvement mutilating palmoplantar keratoderma see Vohwinkel syndrome mycetoma, 877–879 mycobacterial infections (in general) nontuberculous/environmental/atypical, 820–825 panniculitis and, 351 sarcoidosis and, 286 Mycobacterium avium-intracellulare (M. avium complex), 822, 825 HIV-associated, 822, 909 Whipple's disease vs, 839 Mycobacterium bovis attenuated form in BCG vaccine, 818 Mycobacterium fortuitum chelonae (M. fortuitum complex), 821, 823 Mycobacterium haemophilum, 823, 825 Mycobacterium kansasii, 821, 824 Mycobacterium leprae see leprosy Mycobacterium marinum, 785, 820–821 granuloma annulare vs, 295 Mycobacterium tuberculosis complex see tuberculosis Mycobacterium ulcerans, 821–822, 824–825

mycolactone, 822 mycosis cell (Sézary cell), 1339, 1340 mycosis fungoides, 1313–1325 clinical features/manifestations, 1313–1325 unusual, in classic form, 1326–1329 differential diagnosis, 1313–1314, 1324–1325, 1327, 1328, 1330, 1334 adult T-cell leukemia/lymphoma, 1353 chronic superficial dermatitis, 259, 260 granuloma annulare, 295 granulomatous slack skin, 1330, 1338 pagetoid reticulosis, 1337 distinct variants, 1331–1338 molecular diagnostics, 45 pathogenesis and histology, 1316–1324 pediatric, 1326 in pityriasis lichenoides, 256 transformation, 1325–1326 myelodysplastic syndrome, relapsing polychondritis associated with, 758 myelogenous leukemia in Sweet's syndrome, 637 myeloid leukemia, acute (AML), 1413 myeloid metaplasia, 1416 myeloid sarcoma, 1413–1414 myeloma (multiple myeloma; plasma cell myeloma), 1378–1379 amyloidosis, 534–536 differential diagnosis, 1379 plasma cell granuloma-like lesions, 1391 plasmablastic lymphoma, 1379, 1382 plasmacytosis, 1389 metastatic see metastases plane xanthoma and, 528 MYO5a mutations and Griscelli syndrome type 1, 919 myocardial involvement polymyositis/dermatomyositis, 753 systemic sclerosis, 743 myoepithelial cells apocrine gland, 19–20 apocrine hidrocystoma, 1509 chondroid syringoma, 1521–1522 eccrine gland, 17–19 myoepithelioma, 1526–1527 clear cell see clear cell hidradenoma malignant, 1526–1527 oral/salivary gland, 417 ectomesenchymal chondromyxoid tumor vs, 436 of soft tissue, 1759 myofibroblast(s), 26 myofibroblastic differentiation, immunohistochemical stains, 35t myofibroblastic sarcoma, low-grade, 1639 myofibroblastic tumors, 1604 benign, 1604–1625 inflammatory see inflammatory myofibroblastic tumor myofibroblastoma of soft tissue, mammary-type, 1594 myofibroma and myofibromatosis, 1616–1618 myogenic differentiation, immunohistochemical stains, 35t myogenic tumors, conjunctival, 1290–1291 myoid nodules, dermatofibrosarcoma with, 1634 myointimoma, 518–519 myopericytoma, 1749–1750 myosin-Va gene mutations and Griscelli syndrome type 1, 919 myositis, proliferative, 1609–1610 see also dermatomyositis; polymyositis myxedema, generalized, 572–573 see also scleromyxedema myxofibrosarcoma, 1643, 1663 myxohyaline tumor, 1635–1636 myxoid chondrosarcoma see also chondrosarcoma myxoid cyst, 582, 1754 myxoid dermatofibrosarcoma, 1634 myxoid liposarcoma, 1600, 1601–1603 lipoblastoma vs, 1598 myxoid chondrosarcoma, 1753 pleomorphic lipoma vs, 1595 myxoid malignant fibrous histiocytoma (myxofibrosarcoma), 1643, 1663 myxoid malignant nerve sheath tumor vs myxoid melanoma, 1247 myxoid melanoma, 1246–1247 myxoid neurofibroma, 1674 myxoid pseudocyst, nail apparatus, 1073 myxoid tumors, malignant, superficial acral fibromyxoma vs, 1073 myxoinflammatory fibroblastic sarcoma, acral, 1635–1636 myxoma atrial/cardiac in Carney complex, 929, 930 embolism from, 700–701 congenital conjunctival, 1290 cutaneous (incl. oral), in Carney complex, 929, 930 nerve sheath see neurothekeoma see also angiomyxoma; fibromyxoma

Index N

Naegeli–Francheschetti–Jadassohn syndrome, 926–927 Naegleria fowleri, 848 nail(s) anatomy and physiology, 1051–1052 biopsy, 1052 disorders and involvement of in alopecia areata, 990 chemotherapeutic drug-associated changes, 621 in Darier's disease, 170, 1060 drug-associated pigmentation, 602 in incontinentia pigmenti, 653 in lichen striatus, 233 in pemphigus vulgaris, 153, 1061 in psoriasis, 204, 1057–1058 histology (normal ), 1052–1054 thick see pachyonychia see also laryngo-onycho-cutaneous syndrome nail bed, normal histology, 1052–1053 nail fold histology, 1052–1053 suppurative infection see paronychia nail matrix biopsy, 1052 normal histology, 1052–1053 nail plate histology, 1054 Nakagawa, angioblastoma of, 1712–1713 NAME syndrome (former name for Carney complex), 482, 929–930 napkin dermatitis, 369 nasal conjunctiva, pinguecula, 1271 nasal dermoid fistula, median, 1469, 1581f nasal glial heterotopia, 1689–1690 nasal NK/T cell lymphoma, 1355–1357, 1378 nasal skin histology, 3f sebaceous glands, 16f Nasu–Halola's disease, 353 National Cancer Institute (NCI) and VA staging systems for lymph nodes in mycosis fungoides, 1323–1324, 1324t natural immunity see innate immunity natural killer (NK) cell, hemophagocytic lymphohistiocytosis, 1410 natural killer (NK) cell leukemia/lymphoma agranular CD4+, 1414 blastic, 1414 natural killer (NK) cell lymphoma, blastic, 1414 natural killer (NK) cell/T cell lymphoma, nasal extranodal, 1355–1357, 1378 Naxos disease, 87, 1032t, 1040 nC16A domain of BP180, 123, 125, 126, 130, 132, 149–150 neck see head and neck necrobiosis granuloma annulare, 291–292 granuloma multiforme, 305–306 necrobiotic xanthogranuloma, 307–308 necrobiosis lipoidica, 295–299 atypical, 295t, 296 atypical facial, 304 differential diagnosis, 295t, 299 necrobiotic xanthogranuloma, 306–308 necrolysis, toxic epidermal see toxic epidermal necrolysis necrolytic migratory erythema, 587–589 necrosis cutaneous (in general) heparin-induced, 617 warfarin-associated, 616 penile, 459–460 subcutaneous fat membranous, 353 in nodular vasculitis, 348 in pancreatic disease, 339–340 scrotal, 460 traumatic, 335–336 necrotizing erythema (erythema necroticans; Lucio's phenomenon), 828, 829, 830–831 necrotizing fasciitis/necrotizing gangrenous fasciitis, 796–797 differential diagnosis, 796–797 pyoderma gangrenosum, 635, 797 necrotizing granuloma, 314f necrotizing infundibular crystalline folliculitis, 323 necrotizing lymphadenitis, histiocytic, 1392 necrotizing lymphocytic folliculitis, 1030 necrotizing sialadenitis, subacute, 415 necrotizing sialometaplasia, 414–415 necrotizing vasculitides genital, 461 Sweet's syndrome vs, 638 Neisseria gonorrhoea, 800 Neisseria meningitidis (meningococcus) septicemia, 799–800 Nekam's disease, 234–235 nematode infestations, 891

NEMO see nuclear factor κB gene modulator mutations neonates (newborns) adnexal polyp, 1528 bullous dermolysis, transient, 116 bullous epidermolysis dominant, 109 recessive, 111 CMV infection, 779 collodion baby, 51–52, 53, 55, 66 congenital nevus, 1203–1206 dental lamina cysts, 395 gingival granular cell tumor (congenital epulis), 370–371, 1612 lupus erythematosus, 721, 733 clinical features, 721 pathogenesis and histology, 733 Ro autoantibodies, 724 neuroblastoma, cutaneous metastases, 1426 oral candidiasis, 861 premature, ichthyosis, 65 proliferation nodule vs melanoma, 1206 pustular melanosis, transient, 218 sclerema, 343 staphylococcal scalded skin syndrome (Ritter's disease), 216, 793 subcutaneous fat necrosis, 340–343 toxic erythema, 217, 655 neoplasms see tumors neovascularization, 27 nephritis, systemic lupus erythematosus, 732, 733 nephrogenic systemic fibrosis, 568, 570, 944–946 differential diagnosis, 946 scleromyxoedema, 578, 946 nerve sheath myxoma see neurothekeoma nerve sheath tumor, peripheral malignant (neurofibrosarcoma; malignant schwannoma), 1690–1693 epithelioid see epithelioid malignant nerve sheath tumor myxoid, vs myxoid melanoma, 1247 in neurofibromatosis type I, 1679, 1691 nervous system, 28–30 involvement see neurological involvement see also sensory nerves Netherton's syndrome (ichthyosis linearis circumflexa), 61–63, 1032t, 1035 differential diagnosis, 1035 neu (Her-2) and Paget's disease, 1443 Neumann-variant pemphigus vegetans, 156 neural tumors conjunctival, 1270, 1289–1290 immunohistochemical diagnosis, 35t neurilemmoma see schwannoma neuritis, CMV, 779–780 neuroblastoma, cutaneous metastases, 1423 neonatal, 1426 peripheral primitive neuroectodermal tumor vs, 1694 rhabdomyosarcoma vs, 1704 neuroblastoma-like schwannoma, 1672 neurocristic hamartoma, 1212–1213 neurodermatitis, circumscribed see lichen simplex chronicus neuroectodermal melanolysosomal syndrome, 919 neuroectodermal tumors, 1665–1666 immunohistochemical diagnosis, 35t peripheral primitive see peripheral primitive neuroectodermal tumor neuroendocrine (Merkel cell/small cell/trabecular) carcinoma, 1141–1147, 1436–1437 clinical features, 1141–1147 differential diagnosis, 1147 atypical fibroxanthoma, 1662 basaloid squamous cell carcinoma, 419 pathogenesis and histology, 1142–1147 secondary cutaneous (and distinction from primary forms), 1429, 1436–1437 neuroendocrine differentiation melanoma with, 1247 mucinous carcinoma with, 1566 neuroepithelioma, peripheral see peripheral primitive neuroectodermal tumor neurofibroma, 1672–1676 cellular/atypical, 1676 conjunctival, 1289 dendritic cell, 1676 diffuse, 1674, 1678 epithelioid, 1676 granular cell, 1676 lipomatous, 1676 myxoid, 1674 Pacinian, 1676 pigmented, 1676 pigmented storiform, 1634 plexiform, 1674, 1677, 1678 superficial acral fibromyxoma vs, 1620

neurofibromatosis, 1677–1680 segmental, 1680 type I (NF1; von Recklinghausen's disease), 1677, 1678–1679, 1680 malignant peripheral nerve sheath tumor, 1679, 1691 neurofibromas, 1672, 1674 type II (NF2; acoustic neurofibromatosis), 1669, 1680 glomus tumor, 1747 schwannoma, 1669, 1680 neurofibrosarcoma see nerve sheath tumor, peripheral malignant neurofollicular hamartoma, 1486–1487 neurogenic hypothesis, vitiligo, 914 neuroid-type nuclear palisading, basal cell carcinoma with, 1100 neurological involvement (intracranial/CNS/cerebral/brain disease) aplasia cutis, 939 Behçet's syndrome, 687, 688 Churg–Strauss syndrome, 677 Cockayne syndrome, 248 congenital nevus sebaceus, 1490 granulomatous vasculitis, associated infections, 694t Henoch–Schönlein purpura, 665 hyalinosis cutis et mucosae, 546 Kawasaki syndrome, 680–681 lichen myxedematosus, 575–576 locally-invasive cellular blue nevi, 1216 Lyme disease, 807, 808 malignant atrophic papulosis, 697 nevoid basal cell carcinoma syndrome, 1104 pellagra, 566 polyarteritis nodosa, 668–669 relapsing polychondritis, 757 sarcoidosis, 285 systemic lupus erythematosus, 720 tuberous sclerosis, 942, 943 Wegener's granulomatosis, 673 xeroderma pigmentosum, 1141 neuroma digital pacinian see Pacinian corpuscle epithelial sheath, 1668 Morton's, 1666 mucosal, 1666 solitary circumscribed (palisaded encapsulated), 1667–1668 traumatic, 1665 neuropathia mucinosa cutanea, 583 neuropathy (peripheral) hereditary motor and sensory, type 4, 50–51 in malignant atrophic papulosis, 697 in polyarteritis nodosa, 668–669 in systemic sclerosis, 738 see also polyneuropathy neurothekeoma (nerve sheath myxoma), 1682–1684, 1756 cellular (so-called), 1684–1685 neurotized nevus, 1676 neurotrophins, alopecia areata, 992 neurotropic melanoma, 1252–1257 neurovascular hamartoma, congenital, 1666 neutrophil(s), granuloma annulare, 292 antibodies to cytoplasmic components (ANCA) Churg–Strauss syndrome, 678 microscopic polyangiitis, 670 polyarteritis nodosa, 669, 670–671 Wegener's granulomatosis, 412, 674 see also palisaded neutrophilic and granulomatous dermatitis neutrophilic dermatoses, 631–657 associated with gastrointestinal and hepatobiliary disease, 639–640 neutrophilic eccrine hidradenitis chemotherapy-related, 623–624 children, 624 neutrophilic lobular panniculitis see lobular neutrophilic panniculitis neutrophilic microabscess, dermatitis herpetiformis, 146 neutrophilic primary scarring alopecias, 1026–1028 nevoid basal cell carcinoma syndrome, 1101–1105, 1131 nevoid melanoma, 1240 small cell melanoma vs, 1241 nevoid variant of basaloid follicular hamartoma, linear, 1446 of congenital bullous ichthyosiform erythroderma, 55 nevoxanthoendothelioma see juvenile xanthogranuloma

1791

1792

Index nevus (nevi), 1062–1063, 1150–1202 acrosyringeal, 1528 apocrine, 1508 balloon cell see balloon cell nevus Becker's, 1156, 1695 blue see blue nevus in Carney complex, 929, 930 clonal, 1163–1164 Cockarde, 1172 combined see combined nevus comedo(ne), 1446 congenital see congenital nevus conjunctival, 1277–1278, 1279–1280 deep penetrating, 1189–1192 desmoplastic hairless hypopigmented, 1205 dysplastic see dysplastic nevus eccrine, 1527–1528 eccrine-centred, 1164–1165 elastic tissue see elastoma epidermal see epidermal nevus genital atypical, 484 melanocytic, 482–483 giant hairy ‘bathing trunk’, 1204–1205 hair see hair nevus hair follicle, 1445 halo see halo nevus Hori's, 1208 Ito's, 1208 junctional see junctional nevi lentiginous see lentiginous nevus melanocytic see melanocytic nevi metastases to benign nevi, 1425 Meyerson's, 1177–1178 mucinous, 583 nail, 1062–1063 neurotized, 1676 oral melanocytic nevus, 434 white sponge nevus, 364 organoid/Jadassohn, 1489–1492 Ota's see Ota's nevus pigmented epithelioid cell, 1185 porokeratotic eccrine ostial and dermal duct, 1530 recurrent see recurrent nevus sclerosing, 1174 spider, 1708 spindle cell, vs pigmented spindle cell tumor of Reed, 1189 Spitz see Spitz nevus strawberry see hemangioma Sun's, 1208 see also blue rubber bleb nevus syndrome nevus achromicus, 920–921 nevus anemicus, 920 nevus cells in sentinel node samples immunohistochemistry, 1300–1301 separation from metastatic melanoma, 1307–1308 nevus comedonicus syndrome, 1077 nevus depigmentosus, 920–921 nevus flammeus, 1707–1708 nevus fuscoceruleus ophthalmomaxillaris see Ota's nevus nevus fuscoceruleus zygomaticus, 1208 nevus lipomatosus superficialis of Hoffman and Zurhelle, 1596–1597 nevus sebaceus, 1489–1492 nevus sebaceus syndrome (Schimmelpenning syndrome), 1077, 1490 nevus spilus, 1171–1172 nevus sudiferous, 1527–1528 nevus unius lateris, 1076 nevus verrucosus, 1076 New World (American) leishmaniasis, 844, 845 newborns see neonates NF1 gene mutations, 1677, 1691 NF2 (merlin), 1669 NHP2 mutation, dyskeratosis congenita, 249 niacin deficiency and pellagra, 565–566 nicotinic acid deficiency (and pellagra), 565–566 nicotinic stomatitis, 415–416 Niebauer-variant bullous pemphigoid, 119 neonatal, 340–343 nifedipine-induced gingival hyperplasia, 396 Nikolsky sign, 152, 166, 167 19-DEJ-1 (monoclonal antibody), epidermolysis bullosa, 112 nipples adenoma, 1515 syringomatous, 1515 leiomyoma, 1697–1698 nevi in/around, 1169 Paget disease see Paget disease NK cell see natural killer cell nocardiosis, 834–835

nodal follicular lymphoma, 1373 differential diagnosis cutaneous mantle cell lymphoma, 1374–1375 secondary cutaneous follicle center lymphoma, 1383 nodular amyloidosis, 541–543 nodular basal cell carcinoma (incl. nodulocystic), 1089–1090, 1094 trichoblastoma vs, 1479 see also micronodular basal cell carcinoma nodular chondrodermatitis (chondrodermatitis nodularis), 324–325, 759 nodular cutaneous mucinosis in systemic lupus erythematosus, 581–582 nodular cystic fat necrosis, 335 nodular erythema (erythema nodosum), 327–332 nodular fasciitis, 1606–1608 conjunctival, 1289 nodular granulomatous perifolliculitis, 858 nodular granulomatous phlebitis of skin, 819 nodular hidradenoma, malignant see clear cell hidradenocarcinoma nodular histiocytosis, progressive, 1339 nodular Kaposi's sarcoma nail apparatus, 1073–1074 spindle cell hemangioma vs, 1725 tufted angioma vs, 1713 nodular mantle cell lymphoma, 1373 nodular melanoma, 1224, 1229 clinical features, 1224 histology, 1229 nail apparatus, 1065 nodular migratory panniculitis, subacute (erythema nodosum migrans), 328, 329, 332 nodular nonsuppurative panniculitis, relapsing febrile, 332–333 nodular pemphigoid (pemphigoid nodularis), 119, 123, 124f nodular prurigo, 191–192 nodular-stage Kaposi's sarcoma, 1732 nodular subepidermal fibrosis see dermatofibroma nodular syphilis, 472 nodular trichoblastoma, 1477 nodular tuberculid, 819 nodular vasculitis, 346–349 in tuberculosis (Bazin's disease/erythema induratum), 347, 819 nodules (and nodular lesions) elastotic, ear, 962 epithelioid angiomatous, 1720 esthetic microimplant materials (incl. silicone), 628–629 gingival, 389 Lisch, 1678 metastatic, 1424 hemorrhagic, 1425 Sister Mary Joseph's nodule, 1423–1424 milker's, 783 myoid, dermatofibrosarcoma with, 1634 proliferation nodule within congenital nevus, 1205–1206 rheumatic fever, 301, 306 rheumatoid see rheumatoid nodule scabies, 890 spindle cell, postoperative, 519 subcutaneous, in sarcoidosis, 283–284 nodulocystic (nodular) basal cell carcinoma, 1089–1090, 1094 non-bullous congenital ichthyosiform erythroderma, 52, 53–54 non-epidermolytic palmoplantar keratoderma diffuse, 77–78 focal see focal nonepidermolytic palmoplantar keratoderma non-Hallopeau–Siemens-type recessive dystrophic EB, 111 non-Herlitz junctional EB, generalized, 107, 114–115 non-Hodgkin lymphoma see lymphoma non-involuting congenital hemangioma, 1711 non-keratinized sites in oral mucosa, 363 non-neural dermal granular cell tumor, 1755–1756 non-specific immunity see innate immunity Noonan's disease, 68–69 NOP10 mutation, dyskeratosis congenita, 249 North American blastomycosis, 865–868, 869 North American Hair Research Society (NAHRS) classification of scarring alopecia, 1012 nose see entries under nasal notalgia paresthetica, 539, 934 NPM-ALK fusion protein, primary cutaneous anaplastic large cell lymphoma, 1344 NRAS mutations melanocytic nevi, 967, 1012 melanoma, 1262–1263 sun-exposed skin, 1263–1264 nuchal fibrocartilaginous pseudotumor, 1615–1616 nuchal fibroma (collagenosis nuchae), 1612, 1615 Gardner's fibroma identical to, 1615 Nuck's canal, cyst, 488 nuclear autoantibodies lupus erythematosus, 722t systemic sclerosis, 740–741

nuclear factor κB gene modulator mutations (NEMO) incontinentia pigmenti, 654 trichoepithelioma, 1471 nuclear inclusions, CMV, 779–780 nuclear palisading neuroid-type, basal cell carcinoma with, 1100 trichilemmoma, 1452 nucleotide excision–repair defects trichothiodystrophy with photosensitivity and, 1034 xeroderma pigmentosum and, 1034, 1118, 1140, 1141 nummular eczema, 183 nummular palmoplantar keratosis, 80–81

O

obesity, acanthosis nigricans, 585 O'Brien granuloma see actinic granuloma obstetric patients see pregnancy OCA2 mutations and oculocutaneous albinism, 917 occipital horn syndrome, 948–949 occupational dermatitis of hands, 185 ochronosis, 564–565 ocular features/lesions Behçet's syndrome, 686 Cockayne syndrome, 248 Darier's disease, 171, 173 Ehlers–Danlos syndrome, 936 focal dermal hypoplasia syndrome, 940 keratitis–ichthyosis–deafness, 74 lichen planus, 219 melanoma, 1266 mucous membrane pemphigoid, 133, 136 polyarteritis nodosa, 668–669 pseudoxanthoma elasticum, 951 Reiter's syndrome, 370 rosacea, 1046, 1046t sarcoidosis, 284–285 Wegener's granulomatosis, 673 X-linked ichthyosis, 49 xeroderma pigmentosum, 1141 see also periocular sebaceous carcinoma ocular melanocytosis, congenital, 1281 ocular surface squamous neoplasia (OSSN), 1274–1277 oculoauricularvertebral dysplasia, 1293 oculocutaneous albinism see albinism, oculocutaneous oculodental dysplasia, 71t oculodermal melanosis, 1207, 1281 Odland bodies, 8 odontogenic fibroma, peripheral, 393–395 odontogenic keratocysts of jaw in nevoid basal cell carcinoma syndrome, 1103, 1104 odontogenic sinus, 1585 odontogenic tumors, peripheral (other than fibroma), 394, 395 Ofuji's disease see eosinophilic pustular folliculitis Ogna-type EB simplex, 106 Old World leishmaniasis, 844 OL-EDA-ID (osteopetrosis lymphedema, anhidrotic ectodermal dysplasia, immunodeficiency) syndrome, 654 Olmsted syndrome, 64 onchocerciasis, 891–893 oncocytoma, lacrimal gland, 1273 oncogenes and proto-oncogenes melanocytic nevi, 1012, 1013 and senescence, 1013, 1014 melanoma, 1262–1263 squamous carcinoma and UV exposure and, 1118–1119 xeroderma pigmentosum-related skin tumors and, 1141 oncostatin M receptor beta and familial primary cutaneous amyloidosis, 541 ONMR (onychotrichodysplasia, chronic neutropenia and mental retardation), 1034 onycholemmal tumor, malignant subungual, 1069 onychomatricoma, 1070–1072 superficial acral fibromyxoma vs, 1620 onychomycosis, 1054–1055 psoriasis (of nail) vs, 1058 onychopapilloma, 1070 ophiasis inversus, alopecia areata, 987, 1019 ophthalmological features see ocular features oral cavity, 363–436 lesions/involvement, 363–436 in acanthosis nigricans, 584 angiokeratoma, 1710 Behçet's syndrome, 686 bullous pemphigoid (generalized), 118f candidiasis, 861 Cowden's disease, 1451 Darier's disease, 170, 366 ectopic tissue see heterotopic tissue erythema multiforme, 238 hairy leukoplakia see hairy leukoplakia hypersensitivity-related, 402

Index in incontinentia pigmenti, 653 lichen planus, 219, 227–228 lichenoid, 402 in lupus erythematosus, 411–412, 712 mucosal see oral mucosa pityriasis rosea, 196 relapsing polychondritis, 757 sebaceous hyperplasia, 367, 1489 normal mucosa, 363 see also entries under orificial oral hyperkeratosis, focal nonepidermolytic palmoplantar keratoderma with, 88 oral mucosa, 363–436 anatomy, 363 lesions/conditions, 363–436 autoimmune, 409 hereditary, 364 infections, 399 melanotic macule see macule papillary, 383 premalignant, 421, 1217 reactive, 372 tumor-like, 366–369, 385 ulcerative see ulcerative oral mucosal lesions orchitis Henoch–Schönlein purpura, 665 polyarteritis nodosa, 669 orf, 783–785 organoid nevus, 1489–1492 organoid nevus phakomatosis (Schimmelpenning syndrome), 1077, 1490 oriental sore, 844 Orientia tsutsugamushi and scrub typhus, 842 orificial mucositis, plasma cell, 406, 407 orificial tuberculous lesions/ulcers, 812, 815t, 816 orofacial granulomatosis (granulomatous cheilitis), 407–408 differential diagnosis, 408 Crohn's disease, 309, 408 orthohyperkeratosis, ichthyoses with, 48t orthopox viruses, 781–782 Osler–Weber–Rendu syndrome, 1709–1710 OSMR mutation and familial primary cutaneous amyloidosis, 541 osseous choristoma conjunctiva, 1293–1294 oral, 366 ossifying fasciitis (fasciitis ossificans), 1607 ossifying fibroma, peripheral, 391–392 ossifying fibromyxoid tumor, 1756–1758 ossifying plexiform tumor, 1622 osteoarthritis, alkaptonuria, 564 osteoarticular involvement, systemic sclerosis, 738 see also joint involvement; skeletal involvement osteochondroma, 1751 osteochondroma, subungual, vs exostosis, 1075 osteodystrophy, Albright's hereditary, 568 osteoma cutis, 1751 osteopoikilosis, elastoma, 959–960 osteosarcoma, extraskeletal, 1751 ostium, follicular, 974–976 Ota's nevus (oculodermal melanocytosis; nevus fuscoceruleus ophthalmomaxillaris), 1207 acquired, 1208 conjunctival, 1281 uveal melanoma and, 1266 Oudtshoorn disease, 78–79 oxalosis, cutaneous, 343–344 oxyphil cell adenoma, lacrimal gland, 1273

P

P-cadherin mutations, 14 P2RY5 mutation and woolly hair, 1040 p16 (and melanocytic nevi), 1013, 1239 melanoma, 1239 Spitz nevus, 1184 desmoplastic, vs desmoplastic melanoma, 1188 p21, Spitz nevus, 1184 p53 basal cell carcinoma, 1093 eccrine spiradenocarcinoma, 1558 melanoma, 1239 Paget's disease, 1443 Spitz nevus, 1184 p63 pagetoid Bowen's disease vs Paget's disease, 1443–1444 primary adnexal tumor vs metastatic adenocarcinoma, 1434 p200 pemphigoid antigen, 126–127 p450 pemphigoid antigen, 127 pachyonychia congenita, 365–366 eruptive vellus hair cysts associated with, 1493 oral lesions, 365–366 type I, 88 type II, 88–89

Pacinian corpuscle, 29 hyperplasia (digital pacinian neuroma), 1665 congenital lesions containing, 1666 Pacinian neurofibroma, 1676 Pacinian schwannoma, 1672 Paget disease (of breast/nipple and extramammary), 1439–1444 clinical features, 1439–1444 differential diagnosis, 1443–1444 Bowen's disease, 1114, 1441, 1443–1444 pathogenesis and histology, 1440–1443 pagetoid Bowen's disease vs Paget's disease, 1443–1444 pagetoid dyskeratosis, 1444 pagetoid melanoma see superficial spreading melanoma pagetoid reticulosis, 1335–1337 pagetoid Spitz nevus, 1185–1186 pain, vulval, 479 palisaded encapsulated neuroma, 1667–1668 palisaded neutrophilic and granulomatous dermatitis, 308–309, 640–641, 695–696 differential diagnosis, 640–641, 696 palisading, nuclear see nuclear palisading palisading cutaneous fibrous histiocytoma, 1652–1653 palisading granuloma granuloma annulare, 291–292 necrobiosis lipoidica, 297–298 rheumatoid arthritis, 301 palmar surfaces circumscribed hypokeratosis, 96–97 Cowden's disease lesions, 1451 fibromatosis, 1626–1627 keratosis punctata of creases, 81 pits in nevoid basal cell carcinoma syndrome, 1104 palmoplantar ectodermal dysplasia type II, 88–89 type IV, 86–87 type VII see Vohwinkel syndrome type X (Clouston syndrome), 71t, 84–85 type XVI, 73–74 palmoplantar erythrodermia, progressive, 73 palmoplantar hidradenitis, idiopathic recurrent, 624 palmoplantar keratoderma, 75–91 palmoplantar keratoderma with eyelid cysts, hypodontia and hypotrichosis, 91 palmoplantar mercury-related peeling in children, 620 palmoplantar mycosis fungoides, 1328, 1337 palmoplantar nevi, 1170–1171 palmoplantar porokeratosis, 92 palmoplantar porokeratosis punctata, 93 palmoplantar pustular psoriasis of Barber, 204, 209 pancreatic panniculitis, 339–340 panfolliculoma, 1477 panniculitis, 326–361 classification, 327t cold see cold panniculitis interferon-β-induced, 336, 626 lupus erythematosus (LEP), 715, 1354 see also erythema nodosum-like panniculitis syndrome panniculitis-like T-cell lymphoma, subcutaneous see subcutaneous panniculitis-like T-cell lymphoma PAPA (pyogenic sterile arthritis, pyoderma gangrenosum and acne) syndrome, 632 papillary adenoma and adenocarcinoma, aggressive digital, 1543–1544 papillary adenomatosis of nipple, superficial, 1515 papillary apocrine carcinoma, 1529 papillary carcinoma, NOS, 502 papillary cystadenocarcinoma, 419 papillary cystadenoma, 414 papillary dermis, 1, 24–25, 27, 29 elastolysis, pseudoxanthoma elasticum-like see pseudoxanthoma elasticum-like papillary dermal elastolysis papillary ductal lesions (salivary ducts), 420 papillary eccrine adenoma, 1514, 1541–1543 papillary endothelial hyperplasia, intravascular, 1705 papillary hemangioma, 1706–1707 papillary hidradenoma see hidradenoma papilliferum papillary hyperplasia, inflammatory (denture-associated), 387–389 papillary intralymphatic angioendothelioma (Dabska's tumor), 1726, 1727–1728 papillary lesions of oral mucosa, 383 papillary metastases, 1432–1433 papillary squamous cell carcinoma, 1123 oral, 426 verrucous carcinoma vs, 430 papillary syringocystadenocarcinoma, 1512 papillary syringocystadenoma see syringocystadenoma papilliferum papillary tubular adenoma, 1513–1514 papillated Bowen disease, 1113

papilloma intraductal, 416 inverted see inverted papilloma squamous see squamous cell papilloma papillomatosis of nipple, florid, 1515 vestibular, 366 papillomatous seborrheic keratosis, 1080 Papillon–Lefèvre syndrome, 86–87 papular acantholytic dermatosis, genital, 176, 457 papular acne scars, 956 papular acrokeratoderma, marginal, 82 papular amyloidosis, 537–538, 539 papular angiolymphoid proliferation with epithelioid features in adults and children (PALEFACE), 1362 papular elastorrhexis, 961 papular granuloma annulare, 290 papular mucinosis acral persistent, 578–579 HIV-associated, 904, 905 in systemic lupus erythematosus, 581–582 variant in infancy, 579 papular oral lichen planus, 402, 404–405 papular plaque-type blue nevi, 1210 papular tuberculid (lupus miliaris disseminatus faciei), 310, 818, 882 papular urticaria, 649 papular xanthoma, 1402 papule and papular eruptions (in general) of axillae and pubic region, chronic itching, 200 fibrous, 1643 lichen planus, 224, 225 pearly penile papules, 443 pruritic (PPE), HIV-associated, 901–902 scabies, 890 see also maculopapular eruption; micropapular lichen planus papuloerosive dermatitis of Jacquet and Sevestre, 445 papulonecrotic tuberculid, 818, 819 papulopustular rosacea, 1046, 1046t papulosis bowenoid see bowenoid papulosis clear cell, vs Paget's disease, 1444 lymphomatoid see lymphomatoid papulosis malignant atrophic, 696–698 white fibrous, 947, 957 papulosquamous dermatoses drug-related, psoriasis vs, 211 HIV-related, 896–899 Paracoccidioides loboi (former name for Lacazia loboi), 885 paracoccidioidomycosis, 868–869 paraffinoma (sclerosing lipogranuloma), 335 anogenital, 480 parakeratosis in actinic keratosis, 1108–1109 granular, 96 ichthyoses with, 48t parakeratosis pustulosa, 1057 parakeratotic acanthoma, granular, 1086 parameatal (median raphe) cyst, 486–487, 1583–1584 paraneoplastic syndromes acrokeratosis, 215 ichthyosis-like conditions, 70t pemphigoid, 409 pemphigus, 163–164, 245, 411 vasculitis and, 695 paraproteinemia necrobiotic xanthogranuloma with, 306–308 scleromyxedema with, 576 xanthoma with, 528 paravaccinia, 783 paravestibular tumor, 512 paronychia (suppurative nailfold infection) acute, 798 proximal subungual onychomycosis with, 1055t parotid sebaceous carcinoma, 1501–1502 partial lipodystrophy acquired, 355–356, 355t familial, 354, 355, 355t parulis, 393, 413 Pasini and Pierini, atrophoderma of, 748–749 Pasini-variant dominant dystrophic EB, 108 patch-like blue nevus, 1209 patch-stage Kaposi's sarcoma, 1731–1732 progressive lymphangioma vs, 1745 patch-stage mycosis fungoides, 1313, 1314, 1318–1319 pathergic granulomatosis, 674 pauciarticular juvenile rheumatoid arthritis, 644 PAX-3 mutations and Waardenburg's syndrome, 920 PDGFB and dermatofibrosarcoma protuberans, 1631 pearly papules, penile, 443 pebbly lichenification, 189 PEComa (perivascular epithelioid cell tumor), 1759–1761

1793

1794

Index peeling skin syndrome, 60 pegylated interferon-α, adverse reactions, 625, 626 pellagra, 565–566 pemphigoid bullous see bullous pemphigoid dermolytic see epidermolysis bullosa acquisita drug-induced see drug-induced disorders impetigo vs superficial varian t of, 791 mucous membrane see mucosal pemphigoid prebullous, 101f pemphigoid gestationis, 127–130 pemphigoid lichen planus, 131–132, 222 pemphigoid nodularis, 104–105, 119, 123, 124f pemphigoid vegatans, 119, 123 pemphigus, 151–167, 411 anogenital lesions, 457 Grover's disease vs, 175–176 oral, 411 paraneoplastic, 163–164, 245, 411 superficial, differential diagnosis, 160t, 163 pemphigus erythematosus, 162–163 pemphigus foliaceous, 157–160 endemic, 160–162 Grover's disease vs, 175–176 pemphigus herpetiformis, 162 pemphigus vegetans, 156–157 anogenital lesions, 457 differential diagnosis, 157 pyostomatitis vegetans, 379 Hallopeau-variant see pyoderma vegetans pemphigus foliaceous during or after episode of, 159 pemphigus vulgaris, 152–156 differential diagnosis, 156 Grover's disease, 156, 175–176 pyostomatitis vegetans, 379 endemic, 155 HIV-associated, 904 nail changes, 153, 1061 penicillamine, 617–618 elastic tissue lesions associated with with, 320, 953–954 penicilliosis, 883 differential diagnosis, 883 histoplasmosis, 883 penis anatomy, 439 aphthous ulceration, 459 bowenoid papulosis, 498 Bowen's disease, 1111 chancre, 465, 470f circumcision, 443 fibromatosis, 1627 flat ‘acetowhite’ lesions, 498 glans of see glans penis granuloma annulare, 457 horn, 489 intraepithelial neoplasia, 494–498 keloid, 513 leiomyoma, 517 leukemic infiltration, 513 lichen nitidus, 229f lichen planus, 450f lymphedamatous fibroepithelial polyp, 514–515 lymphoma, 513 melanoma, 485 metastases, 513 mucinous cyst, 487 necrosis, 459–460 pearly papules, 443 psoriasis, 201 sclerosing lymphangitis, 459 squamous cell carcinoma see squamous cell carcinoma tinea, 462–463 pentazocine abuse, panniculitis, 335 perforating disorders (in general), 316–323 perforating granuloma annulare, 290, 295t perforating necrobiosis lipoidica, 299 perforating pseudoxanthoma elasticum, 322–323, 954 perifollicular skin elastolysis, 956 fibroma, 1484 in vitiligo, repigmentation, 912 perifolliculitis, nodular granulomatous, 858 perifolliculitis capitis abscendens et suffodiens see dissecting cellulitis perineurioma, 1685–1687 perineurioma–schwannoma hybrid, 1672 perinuclear vacuoles, 48t periocular sebaceous carcinoma, 1492, 1502, 1503–1505 periodic acid-Schiff (PAS) technique, 33 periodic syndrome, TNF receptor-associated, 280 periodontal disease vs plasma cell gingivostomatitis, 406 periodontopathia, palmoplantar keratoderma with, 86–87

periorificial (perioral) dermatitis, 310–311, 1049 periosteal chondroma vs subungual exostosis, 1075 periosteal fasciitis, 1607 peripheral calcifying odontogenic tumor, 395 peripheral giant cell granuloma, 392 peripheral nerve sheath tumor, malignant see nerve sheath tumor peripheral odontogenic fibroma, 393–395 peripheral odontogenic tumors (other than fibroma), 394, 395 peripheral ossifying fibroma, 391–392 peripheral primitive neuroectodermal tumor (Askin's tumor; extraosseous Ewing's sarcoma; peripheral neuroepithelioma), 1693–1694 differential diagnosis, 1694 rhabdomyosarcoma, 1704 peripheral T-cell lymphoma, not otherwise specified, 1360 peripilar keratin casts, 1041 periumbilical pseudoxanthoma elasticum, 954 periungual pigmentation (Hutchinson's sign), 1064 periungual warts, 1056–1057 periurethral cyst, 488–489 perivascular cell tumors, 1746–1750 perivascular epithelioid cell tumor, 1759–1761 perivascular inflammatory dermatoses, 259–280 perniosis see chilblain; chilblain lupus erythematosus peroxidase-antiperoxidase (PAP) technique, 34 see also immunoperoxidase antigen mapping peroxisomes, Refsum syndrome, 51 persistent acantholytic dermatosis see Grover's disease perspiration, 19 Peutz–Jeghers syndrome, 927–928, 1151 Peyronie's disease, 1627 Phaeoannelomyces werneckii, 861 phaeohyphomycosis, 879–880 phakomatosis, organoid nevus (Schimmelpenning syndrome), 1077, 1490 phakomatosis pigmentokeratotica, 1078 pharmacology, drug reactions relating to, 591 phenotypic heterogeneity, melanocytic nevi with see combined nevus p-phenylenediamine, lichenoid reaction, 599 pheomelanin, 11 phlebitis (of skin), nodular granulomatous, 819 phosphatase and tensin homolog gene see PTEN phosphaturic mesenchymal tumor (mixed connective tissue variant), 1758 photoaging (with UV exposure), 961–962 photoallergic reactions, 595–597 photochromogenic atypical mycobacteria, 820 photodynamic drug reactions, 596 photophobia, follicular ichthyosis with alopecia and, 66 photosensensitivity drug reactions with, 595–597 HIV-associated, 899, 1362–1364 in subacute cutaneous lupus erythematosus, 717 trichothiodystrophy with, 1034 xeroderma pigmentosum, 1141 see also PIBIDS and entries under actinic; solar phototoxic dermatosis, pseudoporphyria as, 560 phototoxic drug reactions, 595–597 phrynoderma, 67 phycomycosis, 874 phymatous rosacea, 1046, 1046t physical examination see examination physical urticaria, 646–647 physiological (functional) properties of skin, 1–31 phytanic acid deficiency, 50–51 phytanol-CoA hydroxylase, peroxisomal, Refsum syndrome, 51 phytophotodermatitis, 596 PIBIDS (photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility and short stature) syndrome, 66, 1034 picker's nodule, 190–192 piebaldism, 919–920 piedra black, 854, 879 white see trichosporosis pigment casts, trichotillomania, 999 pigment-synthesizing (animal/equine-type/hypermelanotic dermal) melanoma, 1212, 1250–1251 clinical features, 1250–1251 differential diagnosis, 1212 pigmented epithelioid cell nevus, 1185 epithelioid blue nevus and, as part of clinical and pathological spectrum, 1212 histology, 1251 pigmentation anogenital, normal variations, 443 complexion-associated conjunctival, 1280–1281 disorders, 912–934 drug-associated see drug-induced disorders and reactions EB simplex, 105 in incontinentia pigmenti, 653

ochronotic pigmentation, 564–565 systemic sclerosis, 737 disorders tinea, in versicolor, 859 periungual (Hutchinson's sign), 1064 see also hyperpigmentation; hypopigmentation; melanosis pigmented actinic keratosis, 1109 pigmented basal cell carcinoma, 1090, 1097 pigmented Bowen's disease of nail, 1062 pigmented conjunctival tumors, conditions simulating, 1271 pigmented dermal melanocytoma, Carney complex, 930 pigmented dermatofibrosarcoma, 1634 pigmented epithelioid cell nevus, 1185 pigmented hairy epidermal nevus, 1156 pigmented hairy epidermal nevus syndrome, 1077 pigmented lentiginous nevus with atypia, 1167 pigmented lesions (in general) anogenital, 481–485 conjunctival conjunctival primary acquired melanosis vs other forms of, 1283 melanoma vs other forms of, 1287 oral, 431 see also melanocytic lesions pigmented lichen planus, 219, 227 pigmented neurofibroma, 1676 pigmented nevus, spotted group, 1164–1165 see also SCALP syndrome pigmented Paget's disease, 1443 pigmented pilomatricoma, 1465 pigmented porocarcinoma, 1536–1537 pigmented purpuric dermatoses (chronic capillaritis; purpura simplex), 273–275 mycosis fungoides simulating, 1328 pigmented spindle cell tumor of Reed, 1188–1189 pigmented storiform neurofibroma, 1634 pilar cyst see trichilemmal cyst pilar keratosis see keratosis pilaris pilar leiomyoma, 1696–1697 pilar neurocristic hamartoma, 1212–1213 pilar sheath acanthoma, 1449 pili annulati, 1039 pili bifurcati, 1037 pili canaliculi et trianguli, 1035–1037 pili incarniti (pseudofolliculitis), 960–961, 1050 pili multigemini, 1037 pili torti, 1039–1041 pilomatrixoma (pilomatricoma) benign, 1460–1463, 1465 malignant (pilomatrix carcinoma), 1463, 1465 pilonidal sinus, 480–481, 1584 pilosebaceous unit, 15–17 see also follicle; sebaceous gland pinguecula, 1271 pink disease, 620 Pinkus' fibroepithelioma, 1105–1106 pinna see auricle pinta, 811 pipe smoking, nicotinic stomatitis, 415–416 pitted keratolysis, 840–841 pityriasiform drug reactions, 198, 610 pityriasis alba, 193, 922 pityriasis lichenoides, 255–258 Kikuchi–Fujimoto's disease vs, 1392 pityriasis rosea, 196–199 pityriasis rotunda, 70 pityriasis rubra pilaris, 211–214 HIV-associated, 898 psoriasis vs, 210, 214 pityriasis versicolor, 858–859 pityrosporum folliculitis, 859–860 plague, 800–801 plakins, 8, 13–14 plakoglobin mutations, 14 Naxos disease, 87 plakophylin mutations, McGrath disease, 88 planar xanthomata, 527–528 plant furanocoumarin-associated photodermatitis, 596 plantar fibromatosis, 1627 plantar surfaces (sole) Cowden's disease lesions, 1451 dermatosis, juvenile, 199 epidermoid cyst, 1575 hidradenitis, idiopathic, 624 hypokeratosis, circumscribed, 96–97 nevi, 1170–1171 pits in nevoid basal cell carcinoma syndrome, 1104 pitted keratolysis, 840–841 verrucous carcinoma, 1132 warts, 763–766

Index plaque(s) (cutaneous) actinic comedonal, 962 keratotic, conjunctiva, 1274 polycyclic psoriasiform, epidermolytic hyperkeratosis with, 77 pruritic urticarial papules and, of pregnancy (PUPPP), 127, 130, 276–277 soft (malakoplakia), 479, 836–837 verrucous hyperkeratotic bowenoid, 1112 plaque(s) (dental), 389 plaque-like blue nevus, 1210 plaque-like CD34+ dermal fibroma, 1623–1624 plaque psoriasis, 130, 131, 201, 207, 209–210 plaque-stage dermatofibrosarcoma protuberans, 1630–1631, 1635, 1676 plaque-stage Kaposi's sarcoma, 1731–1732 plaque-stage mycosis fungoides, 1314, 1320–1321 plaque-type lesions/plaque forms morphea, 743–745 oral lichen planus, 402 plaque variant of milia, 1576–1577 plasma cell(s), leprosy, 830 plasma cell balanitis, Zoon's, 456–457 plasma cell gingivostomatitis, 406–407 plasma cell granuloma inflammatory pseudotumor with features of, 1390, 1391 oral, 407 plasma cell orificial mucositis, 406, 407 plasma cell tumors see myeloma; plasmacytoma plasma cell variant of multicentric Castleman's disease, 1389, 1390 plasmablastic lymphoma, 1373, 1381–1382 differential diagnosis, 1382 plasma cell tumor, 1379, 1382 plasmacytoid dendritic cell neoplasm, blastic, 1414–1415 plasmacytoma, primary cutaneous, 1378–1379 plasma cell granuloma-like lesions vs, 1391 plasmacytosis vs, 1389 plasmacytosis, cutaneous, 1328 platelet-derived growth factor B-chain gene (PDGFB) and dermatofibrosarcoma protuberans, 1631 plectin mutation and EB simplex, 114 with muscular dystrophy, 103–104, 105, 114 pleomorphic adenoma, 417, 419 pleomorphic basal cell carcinoma, 1097 pleomorphic hyalinizing angiectatic tumor (PHAT), 1599, 1761 pleomorphic lipoma, 1594 pleomorphic liposarcoma, 1600, 1603 pleomorphic mantle cell lymphoma, 1373 pleomorphic melanoma, 1230 pleomorphic rhabdomyosarcoma, 1702, 1703–1704 pleomorphic sarcoma, undifferentiated see fibrous histiocytoma, malignant plexiform fibrous histiocytoma, 1657–1658 plexiform malignant peripheral nerve sheath tumor, 1692–1693 plexiform neurofibroma, 1674, 1677, 1678, 1679 plexiform schwannoma, 1670 plexiform tumor, ossifying, 1622 PMMA (polymethyl methacrylate) microspheres, 629 pneumocystosis (caused by P. jiroveci - formerly P. carinii), 886–887 HIV-associated, 886, 909 pneumonic plague, primary, 800 podoplanin, primary vs secondary cutaneous tumors, 1434 POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome, 1706 poikiloderma, 245 of Civatte, 245 lichen planus vs, 229 lupus erythematosus vs, 733 mitochondrial DNA syndrome-associated, 246 mycosis fungoides, 1314 poikiloderma congenita, 246–247 poikiloderma-like/poikilodermatous lesions cutaneous amyloidosis, 539 mycosis fungoides, 1314, 1320–1321 polymyositis/dermatomyositis, 755 polyalkylimide gel, 629 polyangiitis, microscopic see microscopic polyangiitis polyarteritis, microscopic see microscopic polyangiitis polyarteritis nodosa, 667–673 classical, 659t, 667–669 cutaneous, 670 HIV-associated illness resembling, 903 infections associated with, 670–671, 694t polyarticular juvenile rheumatoid arthritis, 644 polychondritis, relapsing, 757–759 polycyclic psoriasiform plaques, epidermolytic hyperkeratosis with, 77 polydysplastic EB (Hallopeau–Siemens syndrome), 109–111, 116f polyhedral cells, chondroid syringoma (mixed tumor), 1522

poly-l-lactic acid, 627 polymer detection systems, 35 polymerase chain reaction (PCR), 43 lymphoma diagnosis, 43–45 see also reverse transcriptase-PCR polymethyl methacrylate (PMAA) microspheres, 629 polymorphic eruption of pregnancy (pruritic urticarial papules and plaques of pregnancy; PUPPP), 127, 130, 276–277 polymorphic light eruption see polymorphous light eruption polymorphic low-grade adenocarcinoma, 419 polymorphic pemphigoid, 119, 123 polymorphic reticulosis, 430–431 polymorphisms, melanoma, 1262 polymorphous light eruption, 267–269 differential diagnosis, 269 lupus erythematosus, 269, 270, 733 reticular erythematous mucinosis, 267 polymorphous sweat gland carcinoma, 1570 polymyositis, 751–756 polyneuropathy, familial amyloidotic, 537 polyostotic fibrous dysplasia, 923 polyp(s) adnexal, neonatal, 1528 congenital gingival leiomyomatous, 371 fibroepithelial see fibroepithelial polyp; fibroepithelial stromal polyp gastrointestinal, Peutz–Jeghers syndrome, 927, 928 umbilical, 1586–1587 polyphenol oxidase and alkaptonuria, 564 polypoid basal cell carcinoma, 1091 polypoid granular cell tumor, primitive, 436, 1755–1756 polypoid pseudolymphoma, T-cell rich angiomatoid, 1360–1362 polyposis, familial adenomatous, familial see Gardner's syndrome polytetrafluoroethylene (Gore-Tex), 628, 629 pompholyx, 180, 183–184 poorly differentiated squamous carcinoma, 1122, 1123 PORCN mutations and focal dermal hypoplasia syndrome, 940 pore, dilated (of Winer), 1448–1449 pork tapeworm (cysticercosis), 894 porocarcinoma clear cell see clear cell porocarcinoma clear cell, vs trichilemmal carcinoma, 1455 eccrine see eccrine porocarcinoma porokeratoma, 1086 porokeratosis, 92–95 porokeratotic eccrine ostial and dermal duct nevus, 1530 poroma apocrine, 1507, 1515–1516 eccrine see eccrine poroma porphyria, 549–559 morphea vs, 747–748 porphyria cutanea tarda, 550t, 553–555 alopecia, 554, 558–559 familial see familial porphyria cutanea tarda HIV-associated, 900 port-wine stain, 1707, 1708 postcapillary venules, 27 posthitis see balanoposthitis postinflammatory elastolysis (cutis laxa), 949, 950 postinflammatory hyperpigmentation/hypermelanosis, 433, 931–932 postinflammatory hypopigmentation, 922 postirradiation conditions see radiotherapy post-kala-azar dermal leishmaniasis, 845, 847 postmenopausal women, telogen effluvium, 1003–1004 postoperative spindle cell nodule, 519 poststeroid panniculitis syndrome, 342–343 post-transplant complications see transplantation potassium iodide exposure, 615 povidone panniculitis, 335 prebullous pemphigoid, 101f prebullous pemphigoid gestationis, 128f precancerous lesions see premalignant lesions precursor cells in extramammary Paget's disease, 1441 leukocytic, neoplasms of, 1413 pregnancy antiphospholipid syndrome, 662 dermatoses, 127–130 pemphigus, 127–130 prurigo see prurigo pruritic urticarial papules and plaques of pregnancy (PUPPP), 127, 130, 276–277 granuloma gravidarum, 390, 1715 HSV infection, 773 pseudoxanthoma elasticum, 952 varicella, 776

premalignant lesions (and risk of transformation) actinic keratosis as, 1107 conjunctiva epithelial lesions, 1270, 1274–1277 melanocytic lesions, 1270, 1282 melanocytic nevi (transforming to melanoma), 1045–1049 desmoplastic hairless hypopigmented nevus, 1205 nevus of Ota, 1207 oral, 421, 1217 premature neonates, ichthyosis, 65 prepubertal vulval fibroma, 515 prepuce clitoral, histology, 439 penile (foreskin) circumcision, 443 histology, 439 inflammation (posthitis), 444 lymphedamatous fibroepithelial polyp, 514–515 see also balanoposthitis pressure (of immobilization), atypical decubitus fibroplasia due to, 1610 pressure alopecia, 1000 pressure urticaria, delayed, 647 pretibial bullous pemphigoid, 123 pretibial dystrophic EB dominant, 109 recessive, 111 pretibial myxedema, 573–574 prickle cell layer (stratum spinosum), 2, 8 prickly heat, 199–200 prilocaine–lidocaine, eutectic mixture (EMLA cream), 630 primary cutaneous tumors sees specific tumor types primitive neuroectodermal tumor, peripheral see peripheral primitive neuroectodermal tumor primitive polypoid granular cell tumor, 436, 1755–1756 PRKAR1A mutations and Carney complex, 929–930, 1267, 1756 profillagrin deficiency, 47 profound lupus erythematosus see lupus erythematosus profundus progeria adult form (Werner's syndrome), 963 childhood form (Hutchinson-Gilford syndrome), 963 progressive junctional EB, 107 progressive lymphangioma, acquired, 1744, 1745 progressive macular hypomelanosis, 921 progressive nodular histiocytosis, 1339 progressive palmoplantar erythrodermia, 73 progressive palmoplantar keratoderma, 78 progressive sudanophilic leukoencephalopathy, 353 progressive symmetrical erythrokeratoderma, 73, 84 progressive systemic sclerosis, 734–743 proliferating epidermoid cyst, 1574 proliferating trichilemmal (pilar) cyst, 1457–1459 proliferation nodule within congenital nevus, 1205–1206 proliferative fasciitis, 1607–1608 proliferative myositis, 1609–1610 Propionibacterium acnes acne vulgaris and, 1042–1043 progressive macular hypomelanosis and, 921 sarcoidosis and, 286 protein C activated, resistance to, 708 congenital deficiency, warfarin reactions and, 616 protein kinase A (and subunit), 1267 and Carney complex, 929–930, 1267, 1756 protein S deficiency, warfarin reactions and, 616 proteinosis, lipoid, 546–548 proteoglycans, 26 Proteus syndrome, 966, 1077–1078 protomyofibroblast, 26 proto-oncogenes see oncogenes protoporphyria, erythropoietic, 550t, 551–552 protoporphyrin oxidase gene mutations, 555 protothecosis, 850–851 protozoal infections, 844 pruriginous angiodermatitis, 273 pruriginous dystrophic EB dominant, 109 recessive, 111 prurigo actinic (prurigo aestivalis), 194 of pregnancy (prurigo gravidarum; prurigo gestationis), 127, 130, 277 late onset (pruritic urticarial papules and plaques of pregnancy), 127, 130, 276–277 prurigo mitis, 649 prurigo nodularis and prurigo nodule, 191–192 prurigo pigmentosa, 931–932 pruritic papular eruptions (PPE), HIV-associated, 901–902 pruritic purpura, 273 pruritic urticarial papules and plaques of pregnancy (PUPPP), 127, 130, 276–277

1795

1796

Index pruritus (itching) in pregnancy, 127 pemphigoid gestationis, 128 see also chronic itching papular eruption of the axillae and pubic region; eosinophilic, polymorphic and pruritic eruption associated with radiotherapy psammoma bodies, childhood fibrous tumor with, 1616 psammomatous melanotic schwannoma, Carney complex, 929, 930 Pseudallescheria boydii, 861, 864 pseudoallergic drug reactions, 591 pseudoangiomatosis, eruptive, 780–781 pseudoangiosarcomatous squamous carcinoma, 1128–1130 pseudocarcinomatous hyperplasia see pseudoepitheliomatous hyperplasia pseudocyst auricular, 1587 myxoid, nail apparatus, 1073 pseudoepitheliomatous (pseudocarcinomatous; reactive epithelial) hyperplasia, 1087–1088 conjunctiva, 1272 granular cell tumor, 1681 pseudoepitheliomatous micaceous and keratotic balanitis, 489–490 pseudofolliculitis (barbae), 960–961, 1050 pseudoglandular squamous cell carcinoma see acantholytic squamous cell carcinoma pseudoglucagonoma syndrome, 587 pseudohyperplastic carcinoma of penis, 506 pseudojunctional EB (EB simplex with muscular dystrophy), 103–104, 105, 114 pseudo-Kaposi's sarcoma (acroangiodermatatis), 192–193, 1734 pseudolepromatous leishmaniasis (diffuse cutaneous leishmaniasis), 845, 846 pseudolymphoma (atypical histiocytic granuloma), 382, 1360 B-cell, 1327 drug-induced, 612–614 T-cell, 1360 vs primary cutaneous CD4+ small/medium T-cell lymphoma, 1348–1349 pseudolymphomas, B-cell, 1327 pseudolymphomatous angiokeratoma (APACHE), 1360, 1362 pseudolymphomatous folliculitis, 1362 mycosis fungoides vs, 1334 pseudomalakoplakia, 837 pseudomelanoma see recurrent nevus Pseudomonas aeruginosa and folliculitis, 797 pseudomonilethrix, 1039 pseudomycosis, bacterial, 835–836 pseudo-nits, 1041 pseudo-ocular mucous membrane pemphigoid, 134 pseudopapillary melanoma, 1247 pseudopélade of Brocq, 1021 differential diagnosis, 1023 central centrifugal cicatricial alopecia, 1025 dissecting cellulitis, 1028 lichen planopilaris, 1018 scarring alopecia, 1014 pseudoporphyria (bullous dermatosis of hemodialysis), 559–561 drug-induced, 559, 609 pseudosarcoma botryoides, female genitalia, 513–514 pseudosarcomatous fibrous histiocytoma, atypical, 1651–1652 pseudosclerodermatous panniculitis, postirradiation, 361 pseudo-Sézary syndrome, 1362 pseudotumors fibro-osseous, of digits, 1609 inflammatory see inflammatory myofibroblastic tumor molluscoid, 936 nuchal fibrocartilaginous, 1615–1616 pseudovascular melanoma, 1250 pseudovascular squamous carcinoma, 1128–1130 pseudoxanthoma elasticum (Grönblad–Strandberg syndrome), 950–954 inherited hemolytic conditions and other syndromes and, 954 perforating, 322–323, 954 periumbilical, 954 pseudoxanthoma elasticum-like papillary dermal elastolysis, 956–957 differential diagnosis, 957 white fibrous papulosis, 947, 957 psoriasiform (psoriasis-like) dermatoses, 201 psoriasiform (psoriasis-like) features/reactions drug-related, 609–610, 626 epidermolytic hyperkeratosis with polycyclic psoriasiform plaques, 77 ichthyoses with, 48t pagetoid reticulosis, 1336 squamous cell carcinoma in situ, 1112 psoriasiform (psoriasis-like) keratosis, 1086

psoriasis, 201–211 anogenital, 446 benign migratory glossitis and, 375 clinical features, 201–211 differential diagnosis, 210–211 erythema annulare centrifugum, 262 inflammatory linear verrucous epidermal nevus, 215 pityriasis rubra pilaris, 210, 214 drug-induced, 609–610 TNF-α inhibitors, 626, 627 guttate see guttate psoriasis HIV-associated, 897 linear see linear psoriasis nail involvement, 204, 1057–1058 pathogenesis and histological features, 206–210 plaque, 130, 131, 201, 207, 209–210 psoriasis inversa, 202 PTCH1 mutations and basal cell carcinoma, 1131 in nevoid basal cell carcinoma syndrome, 1101–1103, 1131 and nevus sebaceus, 1491 and xeroderma pigmentosum, 1140 PTEN (phosphatase and tensin homolog gene) Cowden's disease and, 1451 melanoma and, 1263–1264 Proteus syndrome and, 966, 1077 pterygium, 1271 PTPN11 (tyrosine phosphatase SHP2 gene) mutations and LEOPARD disease, 931 pubic hair, 441 pubic region, chronic itching papular eruption of the axillae and, 200 pulmonary hypertension, systemic sclerosis, 743 diffuse, 737 pulmonary non-vascular involvement see lung punctate palmoplantar keratoderma, 75t, 81 punctate palmoplantar keratoderma with associated symptoms, 75t punctate prokeratosis, 93 purine metabolism and gout, 562 purinoceptors (P2X and P2Y) and Hailey-Hailey disease, 168 purpura drug-associated, 605 Henoch–Schönlein see Henoch–Schönlein purpura hypergammaglobulinemia, 708–709 itching, 273 pigmented see pigmented purpuric dermatoses senile, 710 thrombotic thrombocytopenic, 706–707 see also lichen purpuricus purpura fulminans in children, 701, 702 pustular dermatosis (non-psoriatic), 215 contagious, 783–785 drug-induced, 611–612 erosive, 1030 pustular folliculitis EGFR inhibitor-induced, 623 eosinophilic see eosinophilic pustular folliculitis pustular mycosis fungoides, 1328 pustular panniculitis, 349–350 pustular parakeratosis (parakeratosis pustulosa), 1057 pustular psoriasis bullous pemphigoid and, 210f generalized, 202–203, 208 localized (mixed), 204 nails (acrodermatitis continua of Hallopeau), 204, 1057 palmoplantar, of Barber, 204, 209 pustule, spongiform, in psoriasis, 207, 208 pustuloderma, toxic, 611 PUVA phototherapy keratosis associated with, 1115 lentigenes associated with, 1155 patch-stage mycosis fungoides masked with, 1319 in psoriasis, malignancy risk, 209–210 pyloric atresia EB simplex with, 105–106, 114 junctional EB with, 107, 114 pyoderma ‘malignant’, 633 superficial granulomatous, 633, 634 pyoderma faciale, 1049 pyoderma gangrenosum, 631–635 differential diagnosis, 635 bowel-associated dermatosis–arthritis syndrome, 639 necrotizing fasciitis, 635, 797 rheumatoid neutrophilic dermatitis, 640 genital, 459 pyoderma vegetans (pyodermite vegetante; Hallopeau-variant pemphigus vegetans), 156 oral counterpart, 379

pyogenic granuloma (lobular capillary hemangioma), 1714–1716 bacillary angiomatosis vs, 807 conjunctival, 1287 nail apparatus, 1073–1074 oral, 390 pyostomatitis vegetans, 379

Q

quinacrine pigmentation, 602–603, 604

R

RAB27A mutations and Griscelli syndrome type 2, 919 race/ethnicity hair counts, 972t melanosis related to (conjunctiva), 1280–1281 racemose hemangioma, 1287–1288 radiation and squamous carcinoma, 1118–1119 see also Grenz ray effects; radiotherapy; ultraviolet light radiotherapy and X-ray exposure (conditions associated with/ following) angiosarcoma, 1739 atypical vascular proliferation, 1745–1746 chemotherapeutic agents interaction with radiation therapy, 621, 623 dermatitis, 963–966 morphea vs, 748 eosinophilic polymorphic and pruritic eruption, 280 pseudosclerodermatous panniculitis, 361 squamous carcinoma, 1119 RAF1 mutations, LEOPARD disease, 931 Raimer's bands, 962 ranulas, 413 rapidly involuting congenital hemangioma, 1711 Raynaud's syndrome in limited cutaneous systemic sclerosis, 735 RCAS1, Paget's disease, 1443 RCC-Ma (renal cell carcinoma marker) metastatic, 1436 reactive angioendotheliomatosis, see also angioendotheliomatosis reactive arthritis see Reiter's syndrome reactive conditions/lesions (in general), 1665–1666 oral mucosa, 372 salivary gland, 412 reactive eccrine syringofibroadenoma, 1528 reactive epithelial hyperplasia see pseudoepitheliomatous hyperplasia reactive perforating collagenosis, 316–317, 318t, 322 reactive vascular proliferations, 1705–1711 REAL (revised European and American lymphoma) classification of lymphomas, 1312 RecQ DNA helicase family mutation Bloom's syndrome, 247 Rothmund–Thomson syndrome, 247 rectal carcinoma see colorectal carcinoma recurrent aphthous stomatitis, 380–381 recurrent erythema multiforme, 238, 240 recurrent melanoma, differential diagnosis, 1241 recurrent nevus (pseudomelanoma), 1152 Spitz nevus, 1183 5α-reductase acne vulgaris and, 1043 androgenetic alopecia and type-2 isozyme of, 983 Reed, pigmented spindle cell tumor of, 1188–1189 Reed–Sternberg cells, 1383–1384 Refsum syndrome, 50–51 regression of melanoma, prognostic importance, 1234 Reiter's syndrome (reactive arthritis), 211 anogenital, 446–449 relapsing febrile nodular nonsuppurative panniculitis, 332–333 relapsing linear acantholytic dermatosis, 169 relapsing polychondritis, 757–759 relapsing self-healing Blaschko dermatitis, acquired, 233–234 renal cell carcinoma/cancer metastatic, 1436 pilar leiomyoma associated with, 1696 renal failure angiokeratoma corporis diffusum, 530 bullous dermatosis in end-stage see pseudoporphyria see also nephrogenic systemic fibrosis renal problems/involvement Behçet's syndrome, 688 Churg–Strauss syndrome, 677 Henoch–Schönlein purpura, 665 microscopic polyangiitis, 672 polyarteritis nodosa, 669 systemic lupus erythematosus, 720, 732 systemic sclerosis, 738 tuberous sclerosis, 943 Wegener's granulomatosis, 673 renal transplant patients, immunosuppressed, squamous carcinoma, 1120

Index Renbök phenomenon in alopecia areata, 988 resorbable material for esthetic microimplants, 628t respiratory tract lower see lung relapsing polychondritis, 758 upper infections, and Henoch–Schönlein purpura, 664 involvement in Churg–Strauss syndrome, 677 restrictive dermopathy, 946–947 RET mutation and familial primary cutaneous amyloidosis, 541 retention cyst, oral, 369–370, 414 salivary gland (mucocele), 369–370, 412–414 reticular dermis, 1, 24–25, 27 reticular erythematous mucinosis, 265–267 HIV disease and, 266, 904, 905 reticular ichthyosiform erythroderma, congenital, 61 reticular livedo in systemic lupus erythematosus, 719–720 reticular oral lichen planus, 402, 404–405 reticular perineuroma of soft tissue, 1686 reticulate acropigmentation of Dohi, 927 of Kitamura, 926 reticulate pigmented anomaly of flexures, 924–926 reticulated acanthoma vs superficial epithelioma with sebaceous differentiation, 1500 reticulated black solar lentigo, 1155 reticulated pigmentation in incontinentia pigmenti, bizarre, 653 reticulohistiocytoma (solitary epithelioid histiocytoma), 1408–1409 conjunctival, 1290 reticulohistiocytosis congenital self-healing, 1392–1393, 1397–1398 multicentric/giant cell, 1408–1409 Rosai–Dorfman disease vs, 1407 reticuloid, actinic see actinic dermatitis, chronic reticuloid, actinic, 269 reticulosis pagetoid, 1335–1337 polymorphic, 430–431 retiform hemangioendothelioma, 1716–1717 retinoblastoma and periocular sebaceous carcinoma, 1501 reverse transcriptase-PCR (RT-PCR), 43 sentinel node samples, 1308 revised European and American lymphoma (REAL) classification of lymphomas, 1312 rhabdoid melanoma, 1244–1245, 1767, 1768f rhabdoid tumor (extrarenal malignant), vs epithelioid sarcoma, 1764–1765 rhabdomyoblastic element, malignant nerve sheath tumor, 1692 rhabdomyoma, 1701–1702 rhabdomyomatous mesenchymal hamartoma, 1701 rhabdomyosarcoma, 1702–1704 conjunctival, 1290–1291 cutaneous metastases, 1423 peripheral primitive neuroectodermal tumor vs, 1694 rheumatic fever erythema marginatum rheumaticum, 644 nodule, 301, 306 rheumatoid arthritis juvenile (systemic juvenile idiopathic arthritis), 644–645 neutrophilic dermatosis associated with, 640–641 neutrophilic lobular panniculitis associated with, 349–350 nodule in see rheumatoid nodule rheumatoid nodule, 300–302 clinical features, 300–301 differential diagnosis, 295t epithelioid sarcoma, 302, 1764–1765 rheumatic fever nodule, 301, 306 pathogenesis and histology, 301 rhinophyma, 1046, 1048 rhinoscleroma, 831–834 rhinosporidiosis, 887 rhomboid glossitis, median, 376–377 ribonuclear protein (ribonucleoprotein; RNP) autoantibodies lupus erythematosus, 722t, 723 systemic, 723 mixed connective tissue disease, 757 polymyositis/dermatomyositis, 754 systemic sclerosis, 740–741 Richner–Hanhart syndrome, 89 rickettsial infections, 842–843 vascular involvement, 694, 843 Riehl's melanosis, 934 Riga–Fede disease, 381–382 Riley–Smith syndrome, 584, 928 ring chromosomes dermatofibrosarcoma protuberans, 1631 giant cell fibroblastoma, 1627 ringworm see tinea Ritter's disease (neonatal staphylococcal scalded skin syndrome), 216, 793

river blindness, 891–893 Ro autoantibodies, lupus erythematosus, 724 Rocky Mountain spotted fever, 842, 843 rodent ulcer (ulcerative basal cell carcinoma), 1089, 1097 rolled hair, 1041 Rombo syndrome, 1105, 1471 Ronchese-type pili torti, 1039 rosacea, 1045–1049 rosacea fulminans, 1049 Rosai–Dorfman disease, 1404–1407 rose-coloured scale, 196–199 roseola infantum, 780 Rothmund–Thomson syndrome, 246–247 rough nail see trachyonychia roundworm (nematode) infestations, 891 Rowell's syndrome, 714–715 Ruffini organs/corpuscles, 12, 29–30 rufous albinism, 917 Ruvacalba–Myhre–Smith, 584, 928

S

S-100 protein apocrine glands, 20 Langerhans cells, 10f lymphadenoma, 1483–1484 malignant peripheral nerve sheath tumors, 1692 melanoma, 1237 desmoplastic, 1256–1257 sentinel node samples, 1300–1301 subungual, 1066 Spitz nevus, 1183 sacrococcygeal paciniomas, congenital lesions containing, 1666 sacrococcygeal pilonidal sinus, 480–481, 1584–1585 sago palm disease, 841–842 salivary ducts cyst, 412, 413 papillary lesions, 420 salivary gland disease, 412 malignant see cancer salmon patch, 1707, 1708 sample (specimen) fixation/grossing/put-through/processing/ embedding/sectioning, 32 sand flea (Tunga penetrans), 890 sandflies and leishmaniasis, 844 sanguinaria-induced leukoplakia, 424 saphenous vein donor site dermatitis, 195 sarcoidal-type necrobiosis lipoidica, 299 sarcoidosis, 281–288, 349 clinical features, 281–286, 349 differential diagnosis, 288, 349 Crohn's disease, 288, 309 discoid lupus erythematosus, 1014 nodular vasculitis, 349 tuberculosis, 817–818 pathogenesis and histology, 286–288, 349 subcutaneous, 349 TNF-α inhibitor-associated, 627 sarcoma acral myxoinflammatory fibroblastic, 1635–1636 alveolar soft part, 1766–1767 clear cell see clear cell sarcoma dendritic cell, 1410–1411 epithelioid see epithelioid sarcoma Ewing's see EWS; EWSr1; peripheral primitive neuroectodermal tumor fibromyxoid, low-grade, 1641, 1642–1643 genital, 518 histiocytic, 1411–1412 ischemic fasciitis vs, 1611 Kaposi's see Kaposi sarcoma Langerhans cell, 1397 mast cell, 1418–1420 metastases to skin, 1427 myeloid, 1413–1414 myofibroblastic, low-grade, 1639 proliferative myositis vs, 1610 synovial see synovial sarcoma trichoblastic, 1480–1482 undifferentiated pleomorphic see fibrous histiocytoma, malignant; angiosarcoma; carcinosarcoma; chondrosarcoma; liposarcoma; myxofibrosarcoma; neurofibrosarcoma; osteosarcoma; rhabdomyosarcoma sarcoma botryoides vs fibroepithelial stromal polyp, 514 sarcomatoid carcinoma see carcinosarcoma Sarcoptes scabiei, 888–890 scabies, 888–890 scalded skin syndrome, staphylococcal see staphylococcal scalded skin syndrome scalloped cell xanthogranuloma, 1402

scalp aplasia cutis, 939 biopsy see biopsy dermatophyte infection see tinea dissecting cellulitis/folliculitis see dissecting cellulitis hair loss see alopecia keratosis lichenoides chronica, 235 lipedematous, 1009 lipomatosis, 1596 metastases involving, 1424 nevi, 1165–1167 pilar tumor, 1457–1459 skin histology, 3f SCALP syndrome (nevus sebaceus, central nervous system malformations, aplasia cutis congenita, limbal dermoid and pigmented nevus), 1490 scarlatiniform variant of staphylococcal scalded skin syndrome (staphylococcal scarlet fever), 794 scarring (scar tissue) anetoderma-like, 956 desmoplastic melanoma vs, 1257 hypertrophic, 1604 keloid see keloid papular acne, 956 sarcoidosis, 283 systemic sclerosis, 740 scarring alopecia (cicatricial alopecia), 798, 982, 1009–1031 classification, 1012 mixed inflammatory, 1029–1031 non-specific, 1031 pathogenesis, 1010–1012 scalp biopsies, 1010–1012 Scedosporium apiospermum (asexual form of Pseudallescheria boydii), 864, 865 Schamberg's disease, 273 Schaumann bodies mycobacterial infections, 817–818 sarcoidosis, 287–288, 349 Schimmelpenning (–Fuerestein–Mims) syndrome, 1077, 1490 schistosomiasis (bilharziasis), 476–477, 893–894 anogenital lesions, 476–477, 893 Mycobacterium ulcerans and prevalence of, 822 Schnitzler's syndrome, 278, 647, 666 Schöpf–Schulz–Passarge syndrome, 91 Schulman's syndrome, 749–751 schwannoma (neurilemmoma), 1668–1672 ancient, 1670, 1761 Carney complex, 929, 930 conjunctival, 1289 malignant see nerve sheath tumor, peripheral malignant schwannoma–neurofibroma, hybrid, 1676 schwannoma–perineurioma, hybrid, 1672 Schweninger–Buzzi anetoderma, 954 Scl-70 antibody, 741 scleredema, 580–581 sclerema neonatorum, 343 sclerodactyly, keratosis palmoplantaris diffusa with, 82–83 see also CREST syndrome scleroderma limited/localized see morphea polymyositis overlap with, 753 scleredema vs, 581 scleroderma panniculitis, 361 sclerodermatomyositis, 753 sclerodermatous lesions (scleroderma-like lesions) chemical-induced, 738 necrobiosis lipoidica, 296 variegate porphyria, 558 sclerodermatous metastases (eburneous metastases), 1426 breast, 1431f, 1432f scleromyxedema, 574–578 differential diagnosis, 966 granuloma annulare, 295 nephrogenic systemic fibrosis, 578, 946 sclerosing atypical lipomatous tumor vs massive localized lymphedema vs, 1755 sclerosing basal cell carcinoma (morpheaform BCC), 1090, 1097 sclerosing blue nevus, 1211 sclerosing disease, IgG4-related, 1389–1390 sclerosing epithelial hamartoma (desmoplastic trichoepithelioma), 1473–1475, 1522, 1541 sclerosing epithelioid fibrosarcoma, 1640–1641 sclerosing hemangioma see dermatofibroma sclerosing lipogranuloma see paraffinoma sclerosing liposarcoma, 1600 sclerosing lymphangitis (Mondor's disease), 709–710 penis, 459 sclerosing nevus, 1174 sclerosing panniculitis, 352–353 sclerosing perineurioma, 1685, 1686

1797

1798

Index sclerosing sweat gland carcinoma (microcystic adnexal carcinoma), 1558, 1559–1563 sclerotic fibroma, 1614–1615 scotochromogenic atypical mycobacteria, 820 scrofuloderma, 812–813, 815t, 817 scrotum calcinosis, 569, 570 fat necrosis, 460 leiomyoma, 517, 1697–1698 leiomyosarcoma, 518 tinea, 462–463 ulceration aphthous, 459 spontaneous, 460 scrub typhus, 842 scurvy, 566 seabather's eruption, 643–644 sebaceoma, 1496–1499, 1500 sebaceous adenoma/choristoma, 1494–1496 in Muir–Torre syndrome, 1495, 1505 oral, 367 sebaceoma vs, 1498 sebaceous epithelioma as variant of, 1496 sebaceous and apocrine adenoma, 1515–1516 sebaceous carcinoma, 1491–1492 differential diagnosis, 1505 clear cell squamous carcinoma, 1125, 1505 sebaceoma, 1498 sebaceous differentiation basal cell carcinoma with, 1491 chondroid syringoma, 1521 superficial epithelioma with, 1489 other tumors, 1507 sebaceous duct, 16 sebaceous epithelioma, 1496 sebaceous glands, 15–17 ectopic, 1488, 1489 hyperplasia see hyperplasia scarring alopecia, loss, 1010–1011 tumors and related lesions, 1488–1507 sebaceous nevus syndrome (Schimmelpenning syndrome), 1077, 1490 sebaceous trichoblastoma, 1507 sebaceoma vs, 1499 sebaceous trichofolliculoma, 1469 differential diagnosis, 1469 folliculosebaceous cystic hamartoma, 1468–1469 sebocrine adenoma, 1507, 1515–1516 sebocystomatosis, 1492–1494 sebomatricoma, 1496, 1499, 1500 seborrheic dermatitis, 182–183, 187 anogenital, 445 psoriasis vs, 211 seborrheic keratosis, 1079–1082 acantholytic, 178 adenoid see adenoid seborrheic keratosis apocrine poroma vs, 1516 chemotherapeutic drug-related, 622 hidroacanthoma simplex vs, 1532 superficial epithelioma with sebaceous differentiation, 1500 seborrheic pemphigoid, 119 sebum, 17 sectioning for light microscopy, 32 sections, hair, 969, 970–971 segmental Darier's disease, 173–174 segmental hyalinizing vasculitis see atrophie blanche segmental neurofibromatosis, 1680 Seip–Lawrence syndrome, 584 self-destruction theory, vitiligo, 914 self-healing infantile familial cutaneous mucinosis, 583 self-healing juvenile cutaneous mucinosis, 579–580 self-healing reticulohistiocytosis, congenital, 1392–1393, 1397–1398 self-healing squamous epitheliomata of skin, familial primary, 1136 semicircular lipoatrophy, 356 Senear–Usher syndrome, 162–163 senescence mechanisms and melanocytic nevi, 1013, 1014 senile alopecia, 1001 senile angioma, 1714 senile keratosis see actinic keratosis senile lentigo see actinic lentigo senile purpura, 710 sensorineural deafness, Cockayne syndrome, 248 sensory and motor neuropathy, hereditary, type 4, 50–51 sensory nerve endings, 28–29 sensory nerves, HSV infection, 774 sentinel lymph node biopsy (for melanoma), 1296–1310 confirmation of sentinel status, 1298 errors (false-positives and negatives), 1303–1305 ethics regarding research use of samples, 1298–1299 immunohistochemistry, 1300–1307

intraoperative, 1299 laboratory management and gross evaluation of nodes, 1297–1298 melanocytic lesions of uncertain metastatic potential, 1308 microscopic evaluation for metastatic melanoma, 1305–1307 molecular biology techniques, 1308 multiple level evaluation, 1299–1300 nevus cells in see nevus cells prognostic value/outcome prediction, 1236, 1237, 1308–1309 Spitz nevus, 1184–1185 septal panniculitis, erythema nodosum as prototype of, 327–328, 329 septicemia, meningococcal, 799–800 septicemic plague, primary, 800 SERCA and Darier's disease, 171–172 serous cells, eccrine glands, 19 serpiginous angioma, 1708–1709 serpiginous elastosis, perforating, 318t, 319–321, 322 serum sickness and serum-sickness-like drug reactions, 594–595 severe generalized dystrophic EB (Hallopeau–Siemens syndrome), 109–111, 116f sex hormones (female) melasma and, 923 systemic lupus erythematosus and, 724 sex-linked conditions see X-linked conditions sexual transmission chancroid, 474 granuloma inguinale, 472–473 Reiter's syndrome and, 447 syphilis, 465 Sézary cell, 1339, 1340 Sézary syndrome, 1338–1340 adult T-cell leukemia/lymphoma vs, 1353 clinical features, 1338–1340 follicular mucinosis associated with, 1334–1335 pathogenesis and histology, 1341–1343 staging and classification, 1314–1315 shadow cell basal cell carcinoma with, 1099 shagreen patch, 941, 942 shaving bumps (pseudofolliculitis), 960–961, 1050 shingles, 777 sialadenitis, subacute necrotizing, 415 sialadenoma papilliferum, 420 sialocyst (salivary duct cyst), 412, 413 sialolithiasis, 414 sialometaplasia, necrotizing, 414–415 side-effects of drugs, 591 see also drug (medication)-induced disorders Siemens, ichthyosis bullosa of, 58 signet ring cell(s), apocrine carcinoma, 1517 signet ring cell basal cell carcinoma, 1098 signet ring cell carcinoma (histiocytoid carcinoma), 1570 metastasis to skin, 1434 signet ring cell melanoma, 1243–1244 signet ring cell squamous cell carcinoma, 1124–1125 silicone (for esthetic microimplants), 628–629 granulomata, 313 silver, adverse reactions, 619 silver stains, 34 Simulidae (blackfly) bites and endemic pemphigus foliaceous, 160 and onchocerciasis, 891 Sindbis fever, 789 sinus (tract) dental/odontogenic, 1585 pilonidal, 480–481, 1584–1585 sinus histiocytosis with massive lymphadenopathy, 1404–1407 sinusoidal hemangioma, 1716, 1717 ‘sisaipho’ pattern, alopecia areata, 987, 1019 Sister Mary Joseph's nodule, 1423–1424 β-sitosterolemia, 522 sixth disease (exanthem subitum), 780 Sjögren's syndrome limited cutaneous systemic sclerosis, 735–737 subacute cutaneous lupus erythematosus, 718 Sjögren–Larsson syndrome, 63–64 skeletal (bone) involvement focal dermal hypoplasia syndrome, 940 Hutchinson–Gilford syndrome, 963 nevoid basal cell carcinoma syndrome, 1104 sarcoidosis, 285 see also osteoarticular involvement skeletal (striated) muscle tumors, 1701 skin tag see fibroepithelial polyp SLC24A5 gene, 11–12 SLUG mutations and piebaldism, 919 SLURP-1, 80 SM5-1 (monoclonal antibody), melanoma, 1238 SMA see smooth muscle actin

small B-cell lymphomas (in general) chronic lymphocytic leukemia vs other types, 1376 mantle cell lymphoma vs other types of, 1374–1375 small cell carcinoma see neuroendocrine carcinoma small cell carcinoma metastases vs neuroendocrine carcinoma, 1147 small cell melanoma, 1240–1241 banal nevus vs, 1162 neuroendocrine carcinoma vs, 1147 small cell neuroendocrine carcinoma, 1145 small lymphocytic lymphoma see chronic lymphocytic leukemia small/medium T-cell lymphoma, CD4+ primary cutaneous, 1348 small round cell tumors, rhabdomyosarcoma vs other types of, 1704 small vessel vasculitis infections and, 694 types, 659t smallpox (variola), 781, 782 smokeless tobacco keratosis, 377–378 differential diagnosis, 378 leukoedema, 373 morsicatio mucosae oris, 374 submucosal fibrosis, 425 smoldering adult T-cell leukemia/lymphoma, 1351 smooth muscle actin (SMA) apocrine glands, 20 melanoma, 1238 smooth muscle tumors, 1695 Sneddon's syndrome, 705, 724 Sneddon–Wilkinson disease, 215–217 soft fibroma see fibroepithelial polyp soft plaque (malakoplakia), 479, 836–837 soft tissue (connective tissue/mesenchymal) tumors, 1589–1768 anogenital, 513–519 augmentation, 628 involvement in focal dermal hypoplasia syndrome, 940 nail apparatus, 1072–1075 solar comedones (Favre–Racouchot disease/syndrome), 962, 1575–1576 solar elastosis, 962 bullous lesions, 962 forearm (Raimer's) bands, 962 solar keratosis see actinic keratosis solar lentigo see actinic lentigo; reticulated black solar lentigo solar urticaria, 646 sole see entries under plantar solid–cystic hidradenoma see clear cell hidradenoma solitary (unilesional) forms angiokeratoma, 1710 basaloid follicular hamartoma, 1446 circumscribed neuroma, 1667–1668 collagenoma, 948 eccrine syringofibroadenoma, 1528 epithelioid histiocytoma see reticulohistiocytoma fibroma of conjunctiva, 1288 fibrous tumor, 1637–1639, 1654 glomus tumor, 1747 keratoacanthoma, 1135 lichen planus, 231–232 mastocytoma, 1417 mycosis fungoides, 1329 myofibromas, 1616, 1617 pilar leiomyoma, 1696 spindle cell xanthogranuloma, 1402–1404 trichilemmoma, 1452 trichoepithelioma, 1471 sonic hedgehog genes and basal cell carcinoma, 1093 and basaloid follicular hamartoma, 1447 sorafenib, 622, 623 South American blastomycosis, 868–869 SOX10 melanoma marker, 1238 desmoplastic, 1256–1257 Waardenburg's syndrome and mutations in gene for, 920 specific (adaptive) immune response, 9 specimen fixation/grossing/put-through/processing/embedding/ sectioning, 32 speckled lentiginous nevus, 1171–1172 spherules, coccidioidal, 870–871 spider bites, reactions, 641–643 spider nevus, 1708 spinal cord involvement, aplasia cutis, 939 spindle and epithelioid nevus see Spitz nevus spindle cell(s), chondroid syringoma (mixed tumor), 1522 spindle cell carcinoma see carcinosarcoma spindle cell hemangioma, 1724–1725 spindle cell lipoma, 1593–1594 spindle cell liposarcoma, 1600, 1601

Index spindle cell melanoma, 1230 differential diagnosis, 1237 atypical fibroxanthoma, 1658–1662 leiomyosarcoma, 1699–1701 spindle cell morphology, neuroendocrine carcinoma, 1145 spindle cell nevus conjunctival, 1278 pigmented spindle cell tumor of Reed vs, 1189 spindle cell nodule, postoperative, 519 spindle cell rhabdomyosarcoma, 1704 spindle cell squamous carcinoma, 1124t, 1125–1127 atypical fibroxanthoma vs, 1662 conjunctival, 1277 spindle cell tumors hyalinizing, with giant rosettes, 1642 malignant desmoplastic melanoma characterized as, 1253 superficial acral fibromyxoma vs, 1073 pigmented, of Reed, 1188–1189 spindle cell xanthogranuloma, 1402–1404 spindle cell-predominant trichodiscoma, 1486–1487 SPINK5 (LEKT1; lympho-epithelial Kazal type Inhibitor) mutation atopic eczema, 181–182 Netherton syndrome, 62–63, 1035 spiny keratoderma, 93 spiradenocarcinoma, eccrine, 1556–1558 spiradenoma, eccrine, 1554–1556, 1749 Spitz nevus (juvenile melanoma; spindle and epithelioid nevus), 1178–1185, 1241–1243 clinical features, 1178–1185, 1279 conjunctival, 1279 desmoplastic/hyalinizing, 1155, 1181 differential diagnosis, 1183–1185, 1241–1243 histology, 1179–1183, 1279 pagetoid, 1185–1186 spitzoid melanoma, 1178–1185, 1241–1243 Splendore–Hoeppli phenomenon entomophthoromycosis, 874 mycetoma, 878–879 sporotrichosis, 884–885 splenomegaly, sarcoidosis, 285 split skin immunofluorescence, 100 spongiform pustules in psoriasis, 207, 208 spongiosis differential diagnosis, 188 eosinophilic, 194 spongiotic dermatitis, 186 chemotherapeutic drug-related, 623 classification, 187 differential diagnosis, 188 spongiotic trachyonychia, 1060 sporotrichosis, 883–885 spotted fever group Rickettsia, 842 spotted group pigmented nevus, 1164–1165 spun glass hair, 1035–1037 squamoid eccrine ductal carcinoma, 1570 squamomelanocytic tumor, dermal, 1259–1260 squamous basal carcinoma, nail unit, 1068 squamous cell carcinoma (invasive), 1115–1124 clear cell see clear cell squamous cell carcinoma conjunctival, 1276–1277 metastatic, 1275 variants, 1277 cutaneous, 1115–1124 actinic keratosis transforming into, 1107 actinic keratosis vs, 1109 clinical features, 1115–1124 differential diagnosis, 1109, 1123–1124, 1563, 1662 in Hailey-Hailey disease, 168 in necrobiosis lipoidica, 296–299 pathogenesis and histology, 1118–1123 PUVA therapy (in psoriasis) and risk of, 209–210 in recessive dystrophic EB, 109–111, 115 secondary (metastatic), 1125, 1430–1437 variants, 1124–1140 in verruciform epidermodysplasia, 771 in verrucous discoid lupus erythematosus, 713 in vitiligo patients, 913 eccrine porocarcinoma vs, 1123, 1538 esophageal, autosomal dominant focal nonepidermolytic palmoplantar keratoderma with, 90–91 genital, 490–509 lichen sclerosus and risk of, 453–454, 496 penis see subheading below vulva see vulva HPV and see human papillomavirus nail, 1068–1069 oral, 425–428, 429 papillary see papillary squamous cell carcinoma in Sweet's syndrome, 637 penile, 453–454, 494–498

horn arising from, 489 invasive, 498 lichen sclerosus and, 453–454, 496 subtypes, 499–509 usual, 498 proliferating trichilemmal cyst vs, 1459 salivary gland, vs sialolithiasis, 415 squamous cell carcinoma in situ (Bowen's disease), 1110–1115 actinic keratosis and, 1109 anogenital, 1111, 1114–1115 clinical features, 1110–1115 differential diagnosis, 1114–1115 hidroacanthoma simplex, 1531–1532 Paget's disease, 1114, 1441, 1443–1444 nail apparatus, 1068–1069 pigmented, 1062 pathogenesis and histology, 1112–1114 squamous cell papilloma conjunctival, 1271 oral, 383–384 squamous epitheliomata of skin, familial primary self-healing, 1136 squamous hyperplasia vs penile intraepithelial neoplasia, 496 squamous intraepithelial neoplasia see intraepithelial neoplasia squamous neoplasia, ocular surface (OSSN), 1274–1277 squamous syringometaplasia, eccrine, 624–625 staging melanoma, 1232–1233, 1236 mycosis fungoides, 1314–1315 of lymph node involvement, 1323–1324 staining, 33–34 immunological see immunofluorescence; immunolabelling staphylococcal scalded skin syndrome (Lyell's disease), 791–794 clinical features, 791–794 differential diagnosis, 794 Stevens–Johnson syndrome, 244 subcorneal pustular dermatosis, 216 toxic epidermal necrolysis, 244, 794 neonatal (Ritter's disease), 216, 793 pathogenesis and histology, 794 Staphylococcus aureus folliculitis, 797 impetigo, 790 stasis change, histology, 5f, 6f stasis dermatitis, 192–193 steatocystoma, 1492–1494 eruptive vellus hair cysts and, overlap between, 1574, 1579–1580 stellae, follicular, in androgenetic alopecia, 985 stem cells epidermal, 6–8 follicular bulge see follicles sternocleidomastoid muscle, fibromatosis colli, 1616 steroid(s) (corticosteroid; glucocorticoid) use atrophy associated with, 962 panniculitis associated with, 342–343 patch-stage mycosis fungoides masked by, 1319 rosacea-like dermatitis, 1050 tinea incognito associated with, 461–462 steroid sulfatase deficiency, 49, 50 8–7 sterol isomerase, 65 Stevens–Johnson syndrome, 237, 238, 241–245 drug-associated, 243, 601 overlap with erythema multiforme, 241 with toxic epidermal necrolysis, 238, 241 Stewart–Treves syndrome, 1738 Still's disease, 644–645 stings, coelenterate, 643–644 stomatitis aphthous, recurrent, 380–381 chemotherapeutic drug-related, 621 chronic ulcerative, 405–406 geographic, 375–377 lichenoid, 404–405 nicotinic, 415–416 see also gingivostomatitis; pyostomatitis vegetans stomatitis glandularis, 416 stone, salivary gland, 414 storiform collagenoma, 1614–1615 storiform neurofibroma, pigmented, 1634 stratum corneum (keratin layer), 2, 8 stratum granulosum (granular cell layer), 8 reduced or absent, ichthyoses with, 48t stratum spinosum, 2, 8 strawberry nevus see hemangioma streptavidin-biotin labeling system, 34 streptococci, necrotizing fasciitis, 796 Streptococcus pyogenes cellulitis, 795 erysipelas, 794, 795 impetigo, 790

stress in alopecia areata pathogenesis, 992 stretch marks see striae distensae striae elastotic, 958 Wickham's see Wickham's striae striae distensae (stretch marks), 958–959 focal elastosis and, co-existing, 958 striate lichen see lichen striatus striate palmoplantar keratoderma, 80 striated muscle tumors, 1701 stromal cells, chondroid syringoma (mixed tumor), 1522 stromal eosinophilia, traumatic ulcerative granuloma with, 381–382 stromal polyp, fibroepithelial, female genitalia, 513–514 stromal tumors of conjunctiva, 1270, 1287 structure of skin, 1–31 stucco keratosis, 1085–1086 Sturge–Weber syndrome, 1707 subacute cutaneous lupus erythematosus (SCLE), 717–718, 725–726, 730–731 subacute necrotizing sialadenitis, 415 subacute nodular migratory panniculitis (erythema nodosum migrans), 328, 329, 332 subcorneal pustular dermatosis (SPD) variant of IgA pemphigus, 165, 166 subcorneal pustular dermatosis, 215–217 subcutaneous abscess see abscess subcutaneous fat see fat subcutaneous granuloma annulare, 290, 295t subcutaneous leiomyosarcoma, 1698, 1699 subcutaneous malignant fibrous histiocytoma, infiltrative, 1665 subcutaneous morphea, 746 subcutaneous nodules, sarcoidosis, 283–284 subcutaneous panniculitis-like T-cell lymphoma, 1353–1355 differential diagnosis, 1354–1355 gamma/delta T-cell lymphoma, 1354–1355, 1360 lymphomatoid granulomatosis, 1378 subcutaneous pyogenic granuloma, 1715 subcutaneous zygomycosis, 874 subepidermal blistering disorders see blistering disorders subepidermal fibrosis, nodular see dermatofibroma subepithelial conjunctival nevus, 1278 submucous fibrosis, 424–425 subungual, exostosis, 1074–1075 subungual lesions epidermoid cysts, 1066 exostosis, 1074–1075 glomus tumor, 1074 hematoma, 1062 keratoacanthoma see keratoacanthoma melanoma see melanoma onycholemmal tumor (malignant), 1069 onychomycosis, 1055, 1055t Sucquet–Hoyer canal, glomus tumor, 1746 sudanophilic leukoencephalopathy, progressive, 353 sud(or)iferous acrosyringeal acantholytic disease, 175, 176 sud(or)iferous hamartoma, 1527–1528 Sulzberger–Garbe syndrome, 195 summertime actinic lichenoid eruption (actinic lichen planus), 221, 226–227 sunbed lentigenes, 1155 sunitinib, 622, 623 sunlight see ultraviolet light exposure and entries under actinic; photo-; solar Sun's nevus, 1208 superantigens atopic eczema and, 182 Kawasaki syndrome and, 681 superficial acral fibromyxoma, 1071, 1072–1073, 1620–1621 superficial actinic porokeratosis, disseminated, 92, 94 superficial angiomyxoma see angiomyxoma superficial atypical melanocytic proliferations of unknown significance, 1044–1045 superficial basal cell carcinoma, 1090, 1097 actinic keratosis vs, 1109 superficial blue nevus with prominent intraepidermal dendritic melanocytes, 1210–1211 superficial dermatitis, chronic, 259–260 superficial EB simplex, 104, 114 superficial epithelioma with sebaceous differentiation, 1489 superficial granulomatous pyoderma, 633, 634 superficial papillary adenomatosis of nipple, 1515 superficial pemphigus, differential diagnosis, 160t, 163 superficial perivascular inflammatory dermatoses, 259–280 superficial spreading (pagetoid) melanoma clinical features, 1223 histology, 1228 Paget's disease vs, 1443–1444 superficial thrombophlebitic tuberculid, 819 superficial thrombophlebitis, 709 superficial white onychomycosis, 1055t suppurative folliculitis, 798–799

1799

1800

Index suppurative hidradenitis, 458–459, 655–657 suppurative nailfold infection see paronychia suprabasal EB simplex, 102t, 104 surgery, sentinel node evaluation during, 1299 Sutton's nevus see halo nevus sweat glands, 17–20 anogenital, 441 apo-eccrine, 20 chemotherapy-associated reactions, 623–625 tumors, 1508–19 see also apocrine glands; eccrine glands sweating, 19 Sweet's syndrome (acute febrile neutrophilic dermatosis), 636–638 differential diagnosis, 638 bowel-associated dermatosis–arthritis syndrome, 639 leukocytoclastic vasculitis, 664 necrotizing fasciitis, 797 pyoderma gangrenosum, 635 rheumatoid neutrophilic dermatitis, 640 swimmer's itch, 476, 893 swimming pool granuloma, 820–821 sycosis barbae (pseudofolliculitis), 960–961, 1050 symmetric lipomatosis, 1596 symmetrical dyschromatosis of extremities, 927 symmetrical erythokeratoderma, progressive, 73, 84 symplastic glomus tumor, 1749 symplastic hemangioma, 1725–1726 syndromes with ichthyoses congenital, 47t non-congenital, 47t synovial biopsy features, systemic sclerosis, 743–744 synovial cyst malignant peripheral nerve sheath tumor vs, 1693 metaplastic (synovial metaplasia), 1584, 1754 ‘so-called’ (=myxoid cyst), 582, 1754 synovial sarcoma, 1765–1766 minute, 1620, 1765 syphilis alopecia see alopecia syphilitica endemic, 808 venereal, 465–472 syringocystadenocarcinoma papilliferum, 1512 syringocystadenoma papilliferum (papillary syringocystadenoma), 1510–1512 mucosal counterpart (sialadenoma papilliferum), 420 tubular apocrine adenoma associated with, 1514 syringofibroadenoma, eccrine, 1528 syringoid eccrine carcinoma (eccrine epithelioma), 1541, 1558–1560 syringoma, 1538–1541, 1562 chondroid see chondroid syringoma malignant (microcystic adnexal carcinoma), 1558, 1559–1563 syringomatous adenoma of nipple, 1515 syringomatous carcinoma (microcystic adnexal carcinoma), 1558, 1559–1563 syringometaplasia eccrine squamous, 624–625 mucinous see mucinous metaplasia syringotropic mycosis fungoides, 1330–1331 systemic amyloidosis, 533t primary, 534–536 systemic disease anogenital lesions, 460–461 in Cowden's disease, 1451 in EB acquisita, 139 in epithelioma adenoides cysticum, 1469–1470 granuloma annulare in, 295 in sarcoidosis, 286 in Stevens–Johnson syndrome and toxic epidermal necrolysis, 242 in urticarial vasculitis, 667 in xanthoma disseminatum, 1402 see also visceral disease and specific systems systemic fibrosis, nephrogenic see nephrogenic systemic fibrosis systemic hyalinosis, infantile, 1625 systemic juvenile idiopathic arthritis, 644–645 systemic lupus erythematosus, 718–721 bullous see bullous systemic lupus erythematosus calcinosis associated with, 567–568 clinical features, 718–721 diagnostic guidelines (American Rheumatology Association), 718t drug-induced, 607, 721 mucinosis associated with (papular and nodular), 581–582 pathogenesis and histology, 721–733 scalp involvement (lupus hair), 1013 systemic mastocytosis, 1414, 1416–1417 systemic plasmacytosis, 1328

systemic sclerosis, 734–743 classification, 739t clinical features, 734–743 panniculitis, 361 pathogenesis and histology, 738–743 progressive, 734–743 see also morphea systemic vasculitis in sarcoidosis, 284

T

T cell(s), 9–10 allergic contact dermatitis, 184–185 atopic eczema, 182 chronic superficial dermatitis, 259 cytotoxic/suppressor see CD8+ T cells drug reactions, 592 exanthamatous, 593 graft-versus-host disease, 251 granuloma annulare, 291 helper see CD4+ T cells lymphomatoid drug reactions, 612 pemphigus vulgaris, 154 psoriasis, 130, 131 pyoderma gangrenosum, 634 receptor gene rearrangements in cutaneous lymphoproliferations, 44–45 angioimmunoblastic T-cell lymphoma, 1351 extranodal NK/T cell lymphoma, 1357 hydroa vacciniforme-like lymphoma, 1359 lymphoblastic leukemia/lymphoma, 1415 lymphomatoid papulosis, 1343, 1384 mycosis fungoides, 1315, 1316, 1323 pseudolymphomatous folliculitis, 1362 sarcoidosis, 286 systemic lupus erythematosus, 731 systemic sclerosis, 741 T-(cell) lymphoblastic leukemia/lymphoma, 1415 T-cell lymphoid dyscrasia, cutaneous, 45 T-cell lymphomas cutaneous, 1313 benign infiltrates mistaken for see pseudolymphoma, T-cell molecular diagnostics, 44–45 in pityriasis lichenoides, 256–257 midline destructive disease and, 430–431 subcutaneous panniculitic, 338–339 T-cell pseudolymphoma see pseudolymphoma T-cell rich angiomatoid polypoid pseudolymphoma, 1360–1362 Taenia solium (cysticercosis), 894 tag, skin see fibroepithelial polyp Takayasu's disease/arteritis (pulseless disease; also referred to as giant cell arteritis), 659t differential diagnosis, 693 giant cell arteritis, 692 tapered fracture of hair, 1035 tapeworms, 894 target blue nevus, 1209–1210 targetoid hemosiderotic hemangioma, 781, 1718–1720, 1727, 1746 tattoo amalgam, 431–432, 626 pseudolymphoma, 613–614 sarcoidosis in, 283–284 Tay syndrome, 66, 1034 teeth see dentition Tegenaria agrestis, 642 telangiectasia generalized essential, 1710 hereditary hemorrhagic, 1709–1710 see also congenital telangiectatic erythema with dwarfism; CREST syndrome; cutis marmorata telangiectatica congenita telangiectatic erythema with dwarfism, congenital, 247–248 telogen, 979, 980–981 hair bulb examination, 969 telogen effluvium differential diagnosis, 1004–1006 alopecia areata, 995 androgenetic alopecia, 986, 1005 loose anagen hair syndrome, 1005, 1007 syphilitic alopecia, 1008 drug-induced, 606–607, 1002–1003 senescent alopecia vs, 1002 telomeres dyskeratosis congenita and, 249 melanocytic nevi and telomere-induced senescence, 1014 temperature regulation, 27 temporal arteritis, 659t, 689–692 temporal triangular alopecia see triangular temporal alopecia tenascin X mutations, Ehlers–Danlos syndrome, 938 tendinous xanthomata, 522, 523–525 see also cerebrotendinous xanthomatosis

tendon sheath fibroma, 1618, 1619 giant cell tumor, 1654–1656 teratoma cutaneous mature cystic, 1580 oral cavity, 368–369 TERC mutation, dyskeratosis congenita, 249 terminal hair, 974 in anagen, 969, 973f, 974f, 976f, 977f, 978, 978f, 979f, 980f follicles, 972–974, 978 TERT mutation, dyskeratosis congenita, 249 testicles choriocarcinoma metastases, 1435 inflammation see orchitis tetracyclines (incl. minocycline) pigmentation, 602, 603 TGF-β see transforming growth factor beta thermoregulation, 27 thioredoxin domain containing 5 (TXNDC5) and vitiligo, 914 thioTEPA-induced pigmentation, 623 thromboangiitis obliterans, 688–689 thrombocytopenia heparin-induced, 617 multifocal lymphangiomatosis (cutaneovisceral angiomatosis), 1745 thrombocytopenic purpura immune/idiopathic, 707–708 thrombotic, 706–707 thrombophlebitic tuberculid, superficial, 819 thrombophlebitis, superficial, 709 thrombosis, antiphospholipid syndrome, 706, 724 thrombotic thrombocytopenic purpura, 706–707 thymic cyst, cervical, 1582 thyroglossal duct cyst, 1581–1582 thyroid, lingual, 370 thyroid dermopathy (pretibial myxedema), 573 thyroid transcription factor 1 (TTF-1), neuroendocrine carcinoma, 1146 primary vs secondary forms, 1429 ticks, Lyme disease, 807 tight junctions, 15 tinea (ringworm; dermatophytosis), 851–853, 853–857 body (tinea corporis), 855–856 foot (tinea pedis), 856–857 groin (tinea cruris), 461–463, 857 nail (unguium), 1054 obscure (tinea incognito), 461–462 scalp (tinea capitis), 852, 853–854 alopecia areata vs, 994–995 dissecting cellulitis vs, 1028 tinea nigra, 861 tinea versicolor, 858–859 tissue autolysis with bacterial overgrowth mimicking necrotizing fasciitis, 797 tissue inhibitors of metalloproteinases (TIMPs), 24 tissue microscopy see histology TNF see tumor necrosis factor TNM classification, melanoma, 1233t TNXB mutations, Ehlers–Danlos syndrome, 938 toad skin (phrynoderma), 67 tobacco, see also nicotinic stomatitis; smokeless tobacco keratosis Toker cells, 1–2 extramammary Paget's disease, 1441, 1442–1443 hyperplasia, 1442–1443, 1444 tongue eosinophilic ulcer/granuloma of, 381–382 geographic, 375–377 lichen planus, 221f thyroid tissue, 370 see also glossitis tooth see dentition tophi, gouty, 562 touch spots/domes/corpuscles (hair discs; Iggo discs), 12, 28 Touton-type giant cells, necrobiotic xanthogranuloma, 307–308 Townes–Brocks syndrome, 1293 toxic epidermal necrolysis, 237, 238, 241–245 drug-associated, 243, 601 graft-vs-host disease (acute) resembling, 250, 253 overlap with erythema multiforme, 241 with Stevens–Johnson syndrome, 238, 241 staphylococcal scalded skin syndrome vs, 244, 794 toxic erythema, 261–264 neonatal, 217, 655 of pregnancy (pruritic urticarial papules and plaques of pregnancy), 127, 130, 276–277 toxic oil syndrome, 750 toxic pustuloderma, 611 toxic shock syndrome, Kawasaki syndrome vs, 681 toxic shock syndrome toxin, 794 toxicity, drug, 591 see also drug (medication)-induced disorders

Index toxin animal see venom staphylococcal scalded skin syndrome, 794 toxoplasmosis, 849–850 trabecular carcinoma see neuroendocrine carcinoma trabecular nevus cells, sentinel node immunohistochemistry, 1300–1301 trachyonychia (rough nail), 1059–1060 in alopecia areata, 990, 993 traction alopecia, 1001 central centrifugal cicatricial alopecia vs, 1025 transforming growth factor beta (TGF-β) keloids and, 1605 palmar fibromatosis and, 1626 transglutaminase mutations, 53 transient acantholytic dermatosis see Grover's disease transient bullous dermolysis of the newborn, 116 transient neonatal pustular melanosis, 218 translocations, chromosomal (t), 39 alveolar soft part sarcoma, 1766 chronic lymphocytic leukemia, 1375 diffuse large B-cell lymphoma, 1372 epithelioid hemangioendothelioma, 1736 extranodal marginal zone lymphoma, 1365 FISH, 40–42 giant cell fibroblastoma, 1627 hidradenocarcinoma, 1548 hidradenoma, 1545 mantle cell lymphoma (secondary cutaneous), 1373, 1374 transmission electron microscopy, 37 Dowling-Meara EB simplex, 38f transplantation engraftment syndrome following, 254 lymphoproliferative disorders following, 1385–1386 see also graft-versus-host disease; vein graft site dermatitis transverse sections of scalp and hair, 969, 970–971, 971t traumatic lesions elastofibroma, 1611 fibroma see fibroepithelial polyp hair alopecia, 995–1001 pili torti, 1040 neuroma, 1665 panniculitis, 334–336 ulcerative granuloma, 381–382 see also bites traumatized Spitz nevus, 1181 trematode (fluke) infestations, 887 anogenital lesions, 476–477 trench fever, 803–804 Treponema pallidum subsp. carateum and pinta, 811 subsp. endemicum and endemic syphilis, 808 subsp. pertenue and yaws, 809 venereal syphilis, 465–472 treponematosis, endemic (non-venereal), 808 TREX1 and chilblain lupus erythematosus, 272 triangular temporal alopecia (congenital triangular alopecia), 986–987 differential diagnosis, 987 alopecia areata, 993–994 trichilemmal carcinoma, 1454–1455 differential diagnosis, 1455 clear cell squamous carcinoma, 1125, 1455 trichilemmal cyst (pilar cyst), 1577–1578 proliferating, 1457–1459 trichilemmoma, 1450–1453 desmoplastic, 1453–1454 trichimycosis, 840 trichoadenoma, 1450, 1562 trichoblastoma benign, 1475–1479 sebaceoma vs, 1499 trichoepithelioma overlap with or differentiation from, 1473, 1479 malignant, 1480–1482 trichoclasis, 1034 trichodiscoma, 1485–1486 spindle cell-predominant, 1486–1487 trichodysplasia spinulosa, virus-associated, 789 trichoepithelioma, 1469–1473 desmoplastic, 1473–1475, 1541, 1562 differential diagnosis, 1472–1473 basaloid follicular hamartoma, 1448 trichoblastoma (or overlap with), 1479 trichoepithelium, immunohistochemical profile, 1473t trichofolliculoma, 1466–1467 folliculosebaceous cystic hamartoma vs, 1468–1469 sebaceous see sebaceous trichofolliculoma trichogerminoma, 1477 trichogram (hair-pluck test), 968 telogen effluvium, 1003

trichomalacia in alopecia areata, 993 in trichotillomania, 986, 999 trichonodosis, 1041 Trichophyton and nodular granulomatous perifolliculitis, 858 T. mentagrophytes, 852 T. rubrum, 858 T. schoenleinii, 854 T. tonsurans, 853 T. violaceum, 853 trichoptilosis, 1040 trichorrhexis invaginata, 62, 1034–1035 trichorrhexis nodosa, 1033 trichoscan, 969 trichoschisis, 1034 trichosctasis spinulosa, 1038 trichosporosis (white piedra; Trichosporon beigelii), 854–855 anogenital, 463 trichoteiromania vs trichotillomania, 1000 trichothiodystrophy, 66, 1033–1034 trichotillomania, 996 differential diagnosis, 1000 alopecia areata, 993–994, 1000 androgenetic alopecia, 986 telogen effluvium, 1006 trichrome stain, 34 trichrome vitiligo, 912 triglycerides, xanthomatoses related to abnormal levels, 521t tripe palms, 584, 585 Triton tumor, 1692 trophozoites Acanthamoeba, 849 E. histolytica, 848 Trophyrema whippelii see Whipple's disease tropoelastin, 25–26 TRP1 mutation and type III oculocutaneous albinism, 917 trunk, melanomas, 1263 tryptophan deficiency in Hartnup disease, 565 pellagra due to, 565–566 L-tryptophan-related eosinophilia–myalgia syndromes, 750 TSC1/TSC2 mutations, 942 TTF-1 see thyroid transcription factor 1 tubercles, Montgomery's, 1488 tuberculids, 818–819 papular (lupus miliaris disseminatus faciei), 310, 818, 1049 tuberculoid granulomata, 314 tuberculoid leprosy (TL/TT), 825–826, 829 sarcoidosis vs, 288 tuberculosis (M. tuberculosis infection), 811–818 clinical features, 779 differential diagnosis, 780 HIV-associated, 811, 909 pathogenesis and histology, 814–817 tuberculosis verrucosa cutis, 812 tuberous sclerosis (Bourneville's disease; epiloia), 941–944 ungual fibromas (Koenen tumors), 1072 tuberous xanthomata, 522, 525–526 tubular apocrine adenoma, 1513–1514 tufted angioma, 1712–1713 tularemia, 842 tumid lupus erythematosus see lupus erythematosus tumidus tumor(s) (neoplasms) anogenital skin, 490–509 arsenic-related, 615 chromosomal abnormalities, 39 conjunctival see conjunctiva hair follicle, 1445–1487 HIV-associated, 911 immunohistochemical diagnosis, 35t invasion see invasion malignant see cancer nail, 1064–1066 non-melanocytic, 1066 oral, 425, 435 salivary gland, 416–420 sebaceous gland, 1488–1507 solid (non-cutaneous), Sweet's syndrome, 637 solid (non-cutaneous), vasculitis and, 695 Henoch–Schönlein purpura, 665, 695 sweat gland, 1508–19 see also specific histologic types and chapters 24-35 tumor-like lesions, oral mucosa, 366–369, 385 tumor necrosis factor-alpha granuloma annulare (and use of TNF-alpha blockers), 291 granuloma annulare and, 291 subacute cutaneous lupus erythematosus and, 725

tumor necrosis factor-alpha inhibitors adverse reactions, 626–627 lupus, 607 lymphoproliferative disorders, 1384 psoriasiform lesions, 610, 626 therapeutic use, granuloma annulare, 291 therapeutic use pyoderma gangrenosum, 634 tumor necrosis factor receptor (TNFr)-associated periodic syndrome, 280 tumor necrosis factor receptor homologue, variola virus, 782 tumor suppressor genes basal cell carcinoma and, 1093 melanoma and sun-exposed skin and, 1263–1264 mycosis fungoides, 1317 tumoral calcinosis, 569, 570 tungiasis, 890 turban tumor (Brooke–Spiegler) syndrome, 1470, 1471, 1551 twenty nail dystrophy (trachyonychia) in alopecia areata, 990, 993 TXNDC5 and vitiligo, 914 typhus group Rickettsia, 842 tyrosinase gene mutations and oculocutaneous albinism, 917 as melanoma marker, 1238 tyrosinase-related protein 1 (TRP1) mutation and type III oculocutaneous albinism, 917 tyrosine kinase inhibitors, 622 tyrosine phosphatase SHP2 gene mutations and LEOPARD disease, 931 tyrosinemia type II, 89 Tzanck test/smear HSV, 763 toxic epidermal necrolysis vs staphylococcal scalded skin syndrome, 794 VZV, 778–779

U

UCLA techniques and guideline for lymphatic mapping and sentinel node biopsy, 1296, 1300f ulcer(s) Buruli (of M. ulcerans), 821, 824–825 Chiclero's, 844 diphtherial, 841 Lipschutz, 459 orificial tuberculous, 812, 815t, 816 rodent (ulcerative basal cell carcinoma), 1089, 1097 ulceration aphthous see aphthe melanoma, prognostic importance, 1234 scrotal, spontaneous, 460 ulcerative basal cell carcinoma, 1089, 1097 ulcerative colitis erythema elevatum diutinum and, 684 pyoderma gangrenosum and, 632 ulcerative lichen planus, 222 ulcerative oral mucosal lesions, 380 chronic ulcerative stomatitis, 405–406 lichen planus, 402 ulceroglandular tularemia, 842 ulceronecrotic Mucha–Haberman disease, febrile, 255, 256, 258 ulerythema acneiforme, 69 ulerythema ophryogenes (keratosis pilaris atrophicans facei), 68 ultrastructure see electron microscopy ultraviolet light (incl. sunlight) exposure, 965 actinic keratosis and, 1106, 1107 basal cell carcinoma and, 1093 p53 and UV signature, 1093 conjunctival primary acquired melanosis, 1282 damaging effects with chronic exposure, 961–962 fibroxanthoma (atypical), 1659 lentigo maligna at sites of actinic damage, 1226–1227 melanoma, 1221–1222, 1262–1263 on UV-exposed skin, 1263–1264 on UV-protected sites, 1264–1266 neuroendocrine carcinoma, 1142 ocular surface squamous neoplasia, 1276 oculocutaneous albinism and, 917, 1118 polymorphic light eruption see polymorphous light eruption pseudoporphyria as UVA-related phototoxic dermatosis, 560 squamous carcinoma and, 1116, 1118–1119 subacute cutaneous lupus erythematosus and, 725 see also PUVA phototherapy; sunbed lentigenes and entries under actinic; photo-; solar umbilicus metastases, 1423–1424 pemphigoid gestationis, 128–129, 129f polyp and granuloma, 1586–1587 pseudoxanthoma elasticum in region around, 954 uncombable hair syndrome, 1035–1037 undifferentiated intraepithelial neoplasia penile, 494, 496 mixed with differentiated form, 498 vulva, usual or classic type, 490, 491–492

1801

1802

Index undifferentiated tumors see anaplastic tumors ungual lesions see nail unifocal Langerhans cell histiocytosis, 1393 unilateral Darier's disease, 173–174 unilesional forms of disease see solitary forms University of California, Los Angeles (UCLA) techniques and guideline for lymphatic mapping and sentinel node biopsy, 1296, 1300f Unna–Thost disease, 76–77 Urbach–Wiethe disease, 546–548 urethral meatus, cyst lateral to, 488–489 urethroid (median raphe) cyst, 486–487, 1583–1584 uric acid crystal deposition, 562 uroporphyrinogen decarboxylase deficiency, 553, 555 uroporphyrinogen III synthase deficiency, 550, 551 urticaria, 645–649 cold see cold urticaria drug-induced, 594, 647 urticaria pigmentosa, 1417–1418 urticarial bullous pemphigoid, 119 urticarial papules and plaques of pregnancy, pruritic (PUPPP), 127, 130, 276–277 urticarial vasculitis, 278–279, 647, 649, 666–667 clinical features, 278–279, 666–667 differential diagnosis, 279, 667 histology, 279, 667 UVA-related phototoxic dermatosis, pseudoporphyria as, 560 uveal melanoma, 1266 uveoencephalitis, 915–916

V

vaccinia, 781 vacuoles, perinuclear, 48t vagina fibroepithelial stromal polyp, 513 lichen planus, 219–220 vestibule see vestibule; vulvovaginal–gingival syndrome varicella, 776 varicella-zoster virus, 776–779 varicelliform eruption, Kaposi's, 773 variegate porphyria, 550t, 555–559 variola, 781, 782 varix conjunctival, 1287–1288 oral, 398 see also venous lakes vascular ectasias, 1705–1711 vascular proliferations atypical post-irradiation, 1745–1746 immunohistochemical diagnosis, 35t reactive, 1705–1711 vascular tumors, 1705 conjunctiva, 1270, 1287–1288 low-grade, 1726–1735 malignant, 1736–1746 borderline, 1726–1735 vasculature, 27–28 calcification (in calciphylaxis), 344, 345 diseases, 658–17 general aspects, 658 in Ehlers–Danlos syndrome type IV, involvement, 936t, 937 invasion see hematogenous spread in necrobiosis lipoidica, 298–299 in systemic sclerosis, involvement and in pathogenesis, 739 see also arteries; capillary; cardiovascular involvement; microangiopathy; vein graft site dermatitis and entries under intravascular; venous vasculitis (angiitis), 658–17 allergic granulomatosis with see Churg–Strauss syndrome chronic fibrosing, 684, 685–686 drug-induced, 604, 659 in erythema nodosum, 329 general aspects, 658 HIV-associated see HIV disease leukocytoclastic see leukocytoclastic vasculitis livedo/segmental hyalinizing see atrophie blanche lymphocytic, 696 necrotizing see necrotizing vasculitides nodular see nodular vasculitis in polymyositis/dermatomyositis, children, 753, 756 in pyoderma gangrenosum, 635 rickettsial, 694, 843 systemic, in sarcoidosis, 284 in systemic lupus erythematosus, 719–720 urticarial see urticarial vasculitis see also endarteritis veil cells, 27 vein graft site dermatitis, 195 vellus (hair), 15–16, 972–974 vellus (hair) cysts, 1578–1580 eruptive, 1493, 1579–1580 steatocystoma and, overlap between, 1574, 1579–1580

vellus (hair) hamartoma, congenital, 1445 vellus-like hair, 974 venom/toxin, reactions to arthropod and spider bites, 641–643 coelenterate stings, 643–644 venous insufficiency, localized mucinosis secondary to, 583 venous lakes, 1709 oral, 398 see also varix venules, postcapillary, 27 Verocay and Verocay-like bodies, 1669 verrucae see warts verruciform epidermodysplasia, 940, 1119 verruciform xanthoma, 384–385, 528–530 verrucous carcinoma (carcinoma cuniculatum) anogenital, 493, 499–500, 506–507, 1132–1133 cutaneous, 1131–1134 verruciform xanthoma vs, 530 nail, 1069 oral, 397 verrucous cyst, 1575 verrucous discoid lupus erythematosus, 712–713 verrucous epidermal nevus, inflammatory linear (ILVEN), 214–215 verrucous hemangioma, 1713–1714 verrucous hyperkeratotic bowenoid plaques, 1112 verrucous hyperplasia, 423 verrucous leukoplakia, 421–422, 423 verrucous mycosis fungoides, 1321, 1328 verrucous nevoid melanoma, 1240 vertical sections of scalp and hair, 970–971, 971t very low density (pre-beta) lipoproteins, 521 raised, 521t raised chylomicrons and, 521t raised LDL and, 521t vesicle (and vesicular lesions) definition, 99 lichen planus, 228 vesicular dermatitis of hands (pompholyx), 180, 183–184 vesicular pemphigoid, 119, 123, 124f vesiculobullous mycosis fungoides, 1327 vestibular glands, minor, adenoma, 512 vestibule (vagina) histology, 439 papillomatosis, 443 vestibulodynia, 479 Villefanche classification of Ehlers–Danlos syndrome, 935, 936t viral hemorrhagic fevers, 788–789 viral infections exanthemata, 280 polymyositis/dermatomyositis pathogenesis, 754 subacute cutaneous lupus erythematosus and, 725 visceral disease, juvenile xanthogranuloma, 1400 see also systemic disease and specific viscera visceral leishmaniasis, 845 vitamin B3 deficiency (and pellagra), 565–566 vitamin C deficiency and scurvy, 566 vitiliginous amyloidosis, 541 vitiligo, 912–915 vocalized idiopathic dermal calcinosis, 569 Vogt–Koyanagi–Harada disease, 915–916 Vohwinkel keratoderma, 71t with ichthyosis (Camisa variant form of Vohwinkel syndrome), 73, 83, 84 Vohwinkel syndrome (keratoderma hereditarium mutilans; keratosis palmoplantaris mutilans; mutilating palmoplantar keratoderma; palmoplantar ectodermal dysplasia type VII), 83–84 Camisa variant form (ichthyotic variant of Vohwinkel keratoderma), 73, 83, 84 von Recklinghausen's disease see neurofibromatosis, type I von Willebrand factor-cleaving metalloprotease (ADAMTS13), deficiency, 707 von Zumbusch (generalized pustular) psoriasis, 202–203, 208 voriconazole, adverse reactions, 620 Vörner–Unna–Thost disease, 76–77 vulva adenomas, 510–511, 512 cloacogenic carcinoma, 509–510 Crohn's disease, 460 endometriosis, 486 fibroma, prepubertal, 515 intraepithelial neoplasia, 398, 399 leiomyoma, 517, 1697–1698 leiomyomatosis, 518 leiomyosarcoma, 518 lichen planus, 219–220, 449 lichen sclerosus, 453 Lipschutz ulcer, 459 mammary-like gland adenoma, 510–511 melanoma, 484–485

melanosis, 481 mesonephric cyst, 488 metastases, 513 mucinous cyst, 487 Reiter's syndrome, 447 schistosomiasis, 477f skin histology, 5f sebaceous glands, 16f squamous cell carcinoma, 492–493 verrucous carcinoma, 493 vulvitis, Zoon's, 457 vulvocrural area, acantholytic dermatosis, 176 vulvodynia, 479 vulvovaginal–gingival syndrome, 449 vulvovaginitis, candidal, 861 VZV (varicella-zoster virus), 776–779

W

Waardenburg's syndrome, 920 Waldenström's hypergammaglobulinemic purpura, 708–709 Waldenström's macroglobulinemia., cutaneous lesions, 548–549 warfarin, 616–617 wart(s), viral (verrucae) common (verruca vulgaris), 761–763 genital, 463–464, 767–768 oral cavity, 383 periungual, 1056–1057 plane (verrucae plana), 766 plantar, 763–766 verruciform xanthoma vs, 530 verrucous carcinoma vs, 1133–1134 Warthin's tumor, 414 warty carcinoma, 500–501 warty dyskeratoma, 176–177, 366 oral, 366 warty lupus, 812, 815t, 816 warty penile intraepithelial neoplasia, 496 water exposure, urticaria, 646 Weber–Christian disease, 332–333 Weber–Cockayne syndrome, 104, 114 Wegener's granulomatosis, 412, 659t, 673–676 differential diagnosis, 412 Churg–Strauss syndrome, 677, 679 lymphomatoid granulomatosis, 1378 microscopic polyangiitis, 676 Weibel-Palade bodies, 27 Weil-Felix test, 843 well-differentiated squamous carcinoma, 1121 Well's syndrome, 649–651 Werner's syndrome, 963 Whipple's disease, 838–839 subcutaneous, 339 white fibrous papulosis, 947, 957 white macular lesions in tuberous sclerosis, 941 white onychomycosis, superficial, 1055t white people, hair counts, 972t white piedra see trichosporosis white sponge nevus, 364 WHO see World Health Organization Wickham's striae, 219 anogenital, 449 oral, 402 widow spiders, 641 ‘wild fire’ (endemic pemphigus foliaceous), 160–162 Winer, dilated pore of, 1448–1449 Witten and Zak syndrome, 1136 Wnt signalling and basal cell carcinoma, 1093 and desmoid fibromatosis, 1628 and focal dermal hypoplasia syndrome, 940 and Gardner fibroma, 1615 and keloid, 1605 and Peutz–Jeghers syndrome, 928 and pilomatrix carcinoma, 1463 and pilomatrixoma, 1460 and sebaceous adenoma, 1495 Wolbachia endobacteria, 893 women see females woolly hair, 1040 woolly hair nevus, 1445–1446 World Health Organization classification conjunctival tumors, 1269–1271 leukocyte precursor cell neoplasms, 1413 World Health Organization–EORTC classification of lymphomas, 1312, 1313t CD4+ small/medium T-cell lymphoma, 1348 follicle center lymphoma, 1368–1369 Sézary syndrome, 1338 subcutaneous panniculitis-like T-cell lymphoma, 1353 worms (helminths), 476–477, 891–895

Index X

X-linked conditions anhidrotic ectodermal dysplasia, 1489 CHILD syndrome, 1078 chronic granulomatous disease, discoid lupus erythematosuslike dermatosis, 715–716 cutis laxa, 948–949 focal dermal hypoplasia syndrome, 940–941 ichthyosis, 49–50 X-rays see radiotherapy xanthogranuloma juvenile see juvenile xanthogranuloma necrobiotic, 306–308 scalloped cell, 1402 spindle cell, 1402–1404

xanthoma(ta), 520–530 conjunctival, 1290 eruptive see eruptive xanthoma(ta) oral verruciform, 384–385, 528–530 papular, 1402 xanthoma cells, lipoma, 1590f xanthoma disseminatum, 1399, 1401–1402 xanthoma multiplex see juvenile xanthogranuloma xeroderma pigmentosum (XP), 1034, 1140–1141 nucleotide excision–repair defects, 1034, 1118, 1140, 1141 xerosis, HIV-associated, 899

Y

yaws, 809 yeasts and seborrheic dermatitis, 184

Yellow River fever, 893 Yersinia pestis and plague, 800–801

Z

zinc malabsorption in acrodermatitis enteropathica, 586 zinc metalloprotease and restrictive dermopathy, 947 zirconium disease, 312–313 ZMPSTE24 mutation and restrictive dermopathy, 947 Zoon's balanitis, 456–457 Zoon's vulvitis, 457 zosteriform Darier's disease, 173–174 zosteriform metastases, 1425 zygomycosis, 874

1803