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DORFMAN and CZERNIAK’S

BONE TUMORS

ERRNVPHGLFRVRUJ

SECOND EDITION

DORFMAN and CZERNIAK’S

BONE TUMORS ERRNVPHGLFRVRUJ Bogdan Czerniak, MD, PhD Professor of Pathology Department of Pathology The University of Texas MD Anderson Cancer Center Houston, Texas

1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

DORFMAN AND CZERNIAK’S BONE TUMORS  Copyright © 2016 by Saunders, an imprint of Elsevier Inc.

ISBN: 978-0-323-02396-2

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. Library of Congress Cataloging-in-Publication Data Czerniak, Bogdan, author.   Dorfman and Czerniak’s bone tumors / Bogdan Czerniak. – 2nd edition.    p. ; cm.   Bone tumors   Preceded by Bone tumors / Howard D. Dorfman, Bogdan Czerniak. c1998.   Includes bibliographical references and index.   ISBN 978-0-323-02396-2 (hardcover : alk. paper)   I.  Dorfman, Howard D. Bone tumors. Preceded by (work):  II.  Title.  III.  Title: Bone tumors.   [DNLM: 1. Bone Neoplasms. WE 258]   RC645.7   616.99′441–dc23   2014038002

Senior Content Strategist: William Schmitt Content Development Specialist: Amy Meros Publishing Services Manager: Patricia Tannian Project Manager: Ted Rodgers Designer: Margaret Reid

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

To my wife Elzbieta with love

Portrait of Elzbieta Czerniak by Gretchen Van Atta Loro

Preface

More than a decade has passed since the advent of the first edition of Bone Tumors. During that time, we have witnessed the emergence of genomic medicine, which has significantly affected clinical practice, including the diagnosis and treatment of tumors that arise in the skeleton. The second edition attempts to address this change but does not neglect the continuation of nearly 50 years of combined experience for the authors of both editions in the conventional practice of skeletal pathology. Similar to the first edition, the second edition is based on large databases of bone tumors from several sources. Pathologic and clinical data on 11,500 benign and malignant bone tumors from patients treated and followed at the University of Texas MD Anderson Cancer Center in Houston, Texas, represent the core database for this edition. The data on 8,417 malignant bone tumors entered into the National Cancer Institute’s Surveillance, Epidemiology, and End Result (SEER) program (www. seer.cancer.gov) were analyzed and included in the text as reflecting malignant bone tumor epidemiology in the U.S. population. Most important, I was given free access to Dr. Howard Dorfman’s consultation files, comprising more than 9,500 cases, which were used extensively for the new edition. The resulting database totaling nearly 30,000 primary bone tumors and tumor-like lesions was used to provide the reader with the most complete information on the epidemiologic, clinical, pathologic, and molecular aspects of bone tumors, even those that are extremely rare. My route to skeletal pathology, to which I was introduced multiple years into my practice, was full of enlightening experiences and charismatic influences. I am fortunate and proud to include among my initial teachers Stanisław Woyke, Maria Dąbska, and Wenancjusz Domagała, from Poland, and Leopold Koss, Juan Rosai, and Alberto Ayala, in the United States. However, by far the most significant influence, specifically related to skeletal pathology, was that of Howard Dorfman. It was a fortunate moment when I walked into his office in Montefiore Medical Center in 1988 and expressed my interest in learning skeletal pathology. He immediately gave me a recent case sent in consultation, and my lessons began. During the following years, we reviewed together most of his extensive consultation files, which provided the foundation for the first edition of Bone Tumors. His full retirement, several years ago, necessitated the change of authorship for the second edition; it was decided that I would be the sole author but the book would be titled Dorfman and Czerniak’s Bone Tumors to honor his contributions. vi

Henry L. Jaffe is considered the conceptual founder of modern skeletal pathology. I did not have an opportunity to work with him, but his diagnostic philosophy was transmitted to me by Howard Dorfman and is evident in both editions of the book. My contribution to this philosophy is the extension of the diagnostic concepts to molecular techniques that, similar to other aspects of pathology, require in-depth knowledge and a critical approach and should be considered in synchrony with other clinical, radiographic, and pathological features of the lesion in question in order to be meaningful. All molecular and genetic annotations included in the book are from the University of California, Santa Cruz Genome Browser (http://genome.ucsc.edu/). The mutations in genes are annotated according to the Catalogue of Somatic Mutations in Cancer (COSMIC, http:// cancer.sanger.ac.uk/cancergenome/projects/cosmic/). The genetic locations and the information concerning the structure of the genes are according to the GeneCards Database of Human Genes (http://www.genecards. org/). The reader is encouraged to use these and other website-based tools in studying the molecular data included in this text for the most updated information, which is arriving at an exponential rate. The second edition is significant for the inclusion of four chapters written by five additional authors: Chapter 2, “Clinical Considerations and Imaging of Bone Tumors,” by Colleen M. Costelloe and John E. Madewell; Chapter 12, “Hematopoietic Tumors,” by April Ewton; Chapter 14, “Neurogenous Tumors and Neurofibromatosis Affecting Bone,” by Gregory N. Fuller; and Chapter 19, “Metastatic Tumors of Bone,” by John D. Reith. The remaining chapters were extensively reviewed to provide updated photographic documentation. I am particularly in debt to Colleen Costelloe, who spent endless hours assisting me in updating the radiographic imaging data for virtually every chapter in this text. Particular attention was given to provide the reader with new molecular and genomic data that are relevant in the current diagnostic workup. The extensive photographic documentation and molecular diagrams necessitated computer processing and were diligently performed by Kim-Anh T. Vu, a computer graphic designer in our department. Multiple molecular and epidemiologic diagrams for the second edition were prepared by Jolanta Bondaruk and Tadeusz Majeweski, researchers in my laboratory. Extensive revisions of the text were prepared by Stephanie Garza and Virginia Hurley. Ms. Hurley also served as an editor to the endless versions of the text.





I would also like to acknowledge the assistance of the editorial staff at Elsevier, who tolerated the long process of revision with limited complaints and provided every possible assistance to the author to fulfill the vexing mission of the multiple revisions with an attempt to bring the reader the most current information available. In particular, I would like to recognize the encouraging collaborations with William Schmitt and Amy Meros in the revision process as well as with Ted Rodgers during the final production of the book.

Preface

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Practicing pathology in the genomic era necessitates the education of a new generation of pathologists to be equally vested in clinical, radiographic, and microscopic details and who are also capable of critical implementation of molecular data. I hope that Bone Tumors will contribute to this mission. Bogdan Czerniak

Foreword Since the publication of the first edition of this book in 1998, much new information has become available concerning the neoplasms that affect the skeleton. It seems obvious that the greatest advance in our understanding of these perplexing tumors should have come about through the explosive expansion of knowledge in the fields of molecular and cellular biology of skeletal tissue and of the mechanisms of malignant transformation. These dramatic changes have occurred at such a dizzying pace that any textbook treatment of such a complex subject would be at risk of becoming obsolete in short order. The revision of this work has been carried out over the last several years largely through the efforts of my colleague Bogdan Czerniak, whose intellectual vigor and generosity of spirit know no bounds. I have offered suggestions as to changes in content and have provided some of the examples of newly recognized or reinterpreted entities derived from my ongoing consultation practice and the accumulated case material in my files. The updating and elaboration of new knowledge addressed in each of the twenty-four chapters has finally come to fruition, with the inclusion of some newly written chapters. These were produced by five authors, specifically chosen and invited to do so because of their special expertise in selected areas related to bone neoplasia. It is clear to me that their contributions, as well as the extensive reworking and updating of the remainder of the existing text through the exhaustive efforts of my colleague Dr. Czerniak, have substantially enhanced and updated the material covered in this new and more weighty volume. At this point, I would like to pause to reflect on the remarkable advances in our knowledge of this vast and complex discipline, the changes that have taken place in the field of surgical pathology of bone tumors and related disorders that I personally have encountered during the more than fifty years of my own practice. I am proud to include among my teachers and professional collaborators Paul Klemperer, Sadao Otani, Arthur Purdy Stout, Raffaele Lattes, and Lauren V. Ackerman. But by far, the most powerful influence upon my work and later professional life has been that of Henry Jaffe. I arrived at the Hospital for Joint Diseases where Dr. Jaffe was retiring after a 40-year career as Chief of Pathology and, though well trained but modestly experienced as a surgical pathologist, I was faced with the rather daunting task of attempting to follow in his footsteps. During his career he had succeeded in revolutionizing the understanding of bone tumors and had coined the names for many neoplasms. He and Dr. Lichtenstein became the world’s leading experts on the subject of bone viii

tumor classification and diagnosis. Dr. Henry L. Jaffe (1896-1979) and Dr. Louis Lichtenstein (1906-1977) based their groundbreaking contributions to bone tumors on their understanding of the nature and interrelationships of bone tumors, a profound knowledge of these tumors’ clinical features, follow-up data, radiographic correlation using mainly plain radiographs and a primitive form of tomography, hematoxylin, eosin slide morphology, and a rudimentary array of special stains. During the following years, electron microscopy was available but rarely used for diagnostic purposes, and cytogenetic or molecular biologic methods that could be readily applied to pathologic diagnosis, computed tomography, magnetic resonance imaging, and PET scanning were still far in the future. It is worth noting that as recently as the 1970s the only special staining method in wide use for the differential diagnosis of bone neoplasms was the PAS stain for demonstrating intracytoplasmic glycogen in the cells of Ewing’s sarcoma. The introduction of the greatly useful and dramatically informative methods of immunohistochemistry did not occur until the 1980s. The then-available cryostat for frozen section diagnosis was a rudimentary prototype model. Fortunately, my long career as a surgical pathologist dealing with bone neoplasms has afforded me the opportunity to witness profound changes for the better in almost every respect. Not only are we better equipped and informed about the diagnostic features and biologic potential of these rare tumors, but the five-year survival rates after precise diagnosis rise with each new innovation. The major turning points in treatment were the introduction of multidrug neoadjuvant chemotherapy and limb-salvage surgery. In modern times, these are complemented with the concepts of targeted therapy based on genomic profiles. The former edition of this book was based, in part, on my consultation files, and recently the entire collection, now totaling more than 9,500 case files, was donated to the Departments of Radiology and Orthopaedic Surgery, at Montefiore Medical Center, supervised by Dr. Nogah Haramati and Dr. David Geller. It is my fervent hope that this large database will be utilized for many research projects and studies supporting new publications in the fields of orthopaedic oncology, muculoskeletal radiology, and pathology. In approaching the assigned task of composing a foreword to this book, what seemed initially to be a reasonably routine one, has proved to be an emotionally challenging effort that was fraught with self-revelation. In looking backward over almost six decades of study of the entities described here, it became clear that one’s ever-changing, always-evolving view of a specific





neoplasm grows with the accretion of novel bits of evidence revealed by each new technological method that we apply to its examination. For me, to have participated in this process, even in a small way as an engaged observer and over such an extended span of time, has been a sometimes daunting but always fascinating experience. It is my fervent hope that the present volume will serve not only as a comprehensive reference source for that part of the medical community which is faced with the need for an in-depth treatment of the theoretical and

Foreword

ix

practical background knowledge for precise diagnosis of these relatively rare and difficult neoplasms, but also as a basis for appropriate and effective patient care. Howard D. Dorfman, MD Professor Emeritus of Pathology, Orthopedic Surgery and Radiology Albert Einstein College of Medicine of Yeshiva University New York, New York

Preface to the First Edition

This book represents the distillation of more than 30 years of experience in the diagnosis of benign and malignant bone lesions. It is an attempt to bring into focus the lessons learned through long exposure to vexing clinical and radiologic challenges. We have attempted to place this body of knowledge into the context of modern surgical pathology by the integration of clinicopathologic, immunohistochemical, ultrastructural, and molecular diagnostic techniques. The present volume is based on several large databases composed of personally analyzed cases. The core database was the consultation file consisting of 5872 cases from one of the authors. During the course of this project, two additional large case files became available to us. The data on 2627 malignant bone tumors entered into the National Cancer Institute’s Surveillance, Epidemiology,

Claus-Peter Adler, MD Seena C. Aisner, MD Lennart Angervall, MD Norio Azumi, MD Fidelis A. Barba, MD Thomas Bauer, MD, PhD Morgan Berthrong, MD Belur S. Bhagavan, MD Peter G. Bullough, MD Jane Chatten, MD Janet B. Christman, MD Robert W. Cihak, MD Karen R. Cleary, MD Robert A. Colyer, MD Katrina A. Conard, MD Harry C. Cooper, MD Jose Costa, MD F. Gonzalez Crussi, MD Raffaele David, MD Elina Donskoy, MD Tadashi Hasegawa, MD Jack Hasson, MD K. P. Heidelberger, MD William Hicken, MD A. R. Von Hochstetter, MD Herbert Ichinose, MD Tetsuo Imamura, MD Tsuyoshi Ishida, MD x

and End Results program from 1973 to 1986 were analyzed and used as a representative sample of bone neoplasms occurring in the American population. In addition, pathologic and clinical data on 4904 benign and primary malignant bone tumors from patients treated and followed at M.D. Anderson Cancer Center were extensively reviewed. (Cases seen only in consultation were not included.) The resulting compilation of data on 13,403 primary bone tumors and tumorlike lesions from several major sources has been drawn on to provide the reader with comprehensive information on various epidemiologic, clinical, and pathologic aspects of bone neoplasms, even those that are extremely rare. The acquisition of many of the cases on which the text and illustrations are based could not have been possible without the cooperation of the following colleagues:

Timothy A. Jennings, MD Sonny L. Johansson, MD Craig P. Jones, MD Gernot Jundt, MD Leonard B. Kahn, MD Bridget C. Kahntroff, MD Robert S. Katz, MD Richard L. Kempson, MD Demetrios E. Kepas, MD Peter Klacsmann, MD Michael J. Klein, MD Carl T. Koenen, MD Harry Kozakewich, MD Donald A. Kristt, MD Dhruv Kumar, MD Jack P. Lawson, MD Alan M. Levine, MD Mario Luna, MD William Martel, MD Takeo Matsuno, MD James A. McAlister, MD Edward F. McCarthy, MD Maria J. Merino, MD Markku Miettinen, MD Sara Milchgrub, MD Mark L. Mitchell, MD Artemis Nash, MD Takayuki Nojima, MD

Margaret Nuovo, MD Nelson G. Ordóñez, MD H. Ostertag, MD Antonio Perez-Atayde, MD A. Kevin Raymond, MD Wolfgang Remagen, MD Jae Y. Ro, MD, PhD Andrew E. Rosenberg, MD Joel A. Roth, MD John M. Rowland, MD, PhD C. Peter Schwinn, MD Marco Semiglia, MD Hubert A. Sissons, MD Richard Slavin, MD Suzane Spanier, MD German C. Steiner, MD Masayuki Takagi, MD Jerome B. Taxy, MD Felix Tchang, MD Henry Tesluk, MD Timothy J. Triche, MD Maria Tsokos, MD Masazumi Tsuneyoshi, MD Bruce L. Webber, MD Sharon W. Weiss, MD Gary B. Witkin, MD Benjamin Wittels, MD Marianne Wolfe, MD





The subspecialty of surgical pathology which is devoted to the study of bone tumors is a relatively recent development. It was not until the 1940s, a mere 50 years ago, that meaningful classification systems and precise terminology were applied to bone and cartilage neoplasms. The authors of this book were fortunate in having had the benefit of direct contact, as students, with some of the more celebrated figures in this field. It is often stated that a teacher’s role should be limited to clearly showing the pupil the goal that science sets for itself and to pointing out all possible means for reaching it. Our teachers have done this while leaving us free to move about in our own way to reach our goals. They have never acted as the promoters of absolute and immutable truth. Some of our concepts expressed in the following pages have aroused controversy, but we have been inspired by our mentors to push our ideas to their full development, provided that we are careful to test them by experiment and by experience. We would like to acknowledge the grace and magnanimity of our teachers. The senior author’s debt to his principal mentors, Henry L. Jaffe, MD; Arthur Purdy Stout, MD; Raffaele Lattes, MD; and Lauren V. Ackerman, MD; cannot be overstated, and it was with the persistent encouragement of the late Dr. Ackerman that this effort was undertaken. The junior author would like to thank Stanisław Woyke, MD; Leopold G. Koss, MD; and Juan Rosai, MD, who significantly contributed to his professional skills and inspired his academic interests. Dr. Koss’ role as a principal mentor and his inspirational role before and during the conduct of this project are acknowledged with particular pleasure. A fortunate concurrence of informal events brought the authors of this book together approximately 10 years ago. It quickly became evident that we have complementary cultural and professional interests, and our initial interaction rapidly evolved into a professional partnership and friendship. One hardly thanks a partner for partnership and a friend for friendship, but we wish to place on record our mutual sense of fulfillment in the completion of this project. This work was not carried out

Preface to the First Edition

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in solitude, and we would therefore like to express our appreciation to the following for their encouragement and support: Alberto G. Ayala, MD; John G. Batsakis, MD; Edward T. Habermann, MD; and Harold G. Jacobson, MD. Several of our colleagues reviewed the chapters pertaining to their fields of expertise. We would like to thank T.J. McDonnell, MD, PhD, and G. Karsenty, MD, PhD, for the review of Chapter 3, “Molecular Biology of Bone Tumors,” and John T. Manning, MD, for his comments on Chapter 12, “Immunohematopoietic Tumors.” Janet M. Bruner, MD, provided unlimited access to her collection of neuropathologic specimens and reviewed Chapter 14, “Neurogenous Tumors and Neurofibromatosis Affecting Bone.” The presentation of ultrastructural features of many bone tumors was made possible by Bruce Mackay, MD, PhD, who provided generous unlimited access to his enormous collection of electron microscopic specimens. Extensive use of digitized imaging and computer graphics was accomplished with the creative technical assistance of Vernon Durke II and Ian Suk. The monumental task of printing hundreds of radiologic and photomicrographic images was performed by Elsa Ramos and Lydia Shanks. Dianne Crawley-Paolillo and Donna Sprabary provided skillful secretarial assistance and patiently typed endless versions of the text. The difficult task of editing the manuscript and correcting many errors and inconsistencies was accomplished by Kimberly Herrick. Finally, Mosby’s representatives, Lynne Gery and Pat Joiner, guided us through tedious stages of book development and production, gracefully enduring consistent delays in completion of various chapters. The reader will be the ultimate judge of the quality of this work. The contributors of case material are relieved of all responsibility for any errors of fact, taste, or judgment, which are entirely our own. Howard D. Dorfman Bogdan Czerniak

Contributors Colleen M. Costelloe, MD

Associate Professor of Radiology Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

April Ewton, MD

Associate Professor of Pathology Associate Medical Director of Hematopathology Houston Methodist Hospital Department of Pathology and Genomic Medicine Weill Cornell Medical College of Cornell University Houston, Texas

Gregory N. Fuller, MD, PhD

Professor and Chief Neuropathologist Department of Pathology The University of Texas MD Anderson Cancer Center Houston, Texas

John E. Madewell, MD

Professor and Chief of Musculoskeletal Imaging Department of Diagnostic Radiology The University of Texas MD Anderson Cancer Center Houston, Texas

John D. Reith, MD

Professor of Pathology Departments of Pathology, Immunology, Laboratory Medicine and Orthopaedics and Rehabilitation Shands Hospital University of Florida College of Medicine Gainesville, Florida

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C H A P T E R 1 

General Considerations CHAPTER OUTLINE MORPHOLOGY OF NORMAL BONE

SPECIAL STAINS

PROCESSING OF BONE SPECIMENS

ELECTRON MICROSCOPY

STAGING, GRADING, AND REPORTING OF BONE TUMORS

CYTOMETRY AND HISTOMORPHOMETRY

GENERAL EPIDEMIOLOGY OF BONE TUMORS SPECIAL TECHNIQUES

INTRODUCTION The new edition of this book retains the conventional approach to the classification of bone tumors, dividing them into the categories of osteoblastic, chondroblastic, fibrous and fibroosseous, vascular and neurogenic, and others of mesenchymal tissue derivation. In general, the discussion of the lesions is similar but not identical to the World Health Organization’s classification of bone tumors (Table 1-1). The past decade has been marked by major advancements in our understanding of the molecular biology of sarcomas, and some of these new developments are of diagnostic as well as of potential therapeutic significance. The identification of recurrent chromosomal translocations in many sarcomas, and their application in the differential diagnosis of these tumors, is changing the paradigm of both pathologic and clinical practice. It is surprising and at the same time insightful that such clonal chromosomal translocations and their respective hybrid genes have been identified in several bone and soft tissue lesions that were traditionally considered to be reactive in nature. Dramatic advancement in our understanding of the biology of skeletal-forming cell lineages such as osteoblastic, chondroblastic, and osteoclastic has further expanded the armamentarium of genes and their encoded proteins that may be useful as potential biomarkers in the differential diagnosis of bone tumors. As a consequence, many tumors of uncertain histogenesis have undergone reassessment due to findings from these techniques while the well-defined pathologic entities are undergoing molecular sub-classifications. Ewing’s sarcoma and the family of small round cell malignancies represent a paradigm for the changing practice in skeletal pathology, in which the established diagnostic algorithm based on clinical, radiologic, and microscopic correlations is now coupled with new molecular approaches to delineate this still mysterious group of tumors. Introduction of newer techniques of immunohistochemistry, molecular pathology, and cytogenetics has not

IMMUNOHISTOCHEMISTRY CYTOGENETICS

changed the fact that histologic and cytologic characteristics are the basis for classifying bone tumors. Although radiologic features can provide valuable clues about predisposing conditions and mineralization or growth patterns, ultimately bone tumors are microscopically categorized on the basis of cell type and matrix production. The histogenesis of the tumor usually can be deduced from the cell morphology and whether collagen, osteoid, or cartilage matrix production can be identified. The need, originally stressed by Jaffe,1 to regard bone tumors as clinicopathologic entities whose behavior and biologic potential are affected by other clinical factors such as patient age, location in a particular bone or part of a bone, multicentricity, and association with other (underlying) conditions, is reaffirmed. The familiar diagnostic triangle recommended by Jaffe—the surgeon, radiologist, and pathologist sharing their points of view on a bone lesion to arrive at a rational diagnosis—is still valid. This approach, which avoids overemphasis on one aspect of a tumor’s presentation (often leading to disparate opinions), remains as a standard of practice in skeletal pathology. However, the advent of molecular diagnostic techniques has expanded this diagram into a diagnostic quadrangle, as shown in Figure 1-1. The approach of the so-called diagnostic quadrangle postulates a stepwise, analytic approach in which four distinctive data sets—clinical, radiographic, microscopic, and molecular—are considered to establish the diagnosis. Although an intuitive approach based on fragmentary data can occasionally be very impressive when used to arrive at a diagnosis, a stepwise, analytic approach is more likely to lead to consistency and accuracy. For that specific reason, we attempt to describe individual neoplastic lesions of bone with an approach that includes clinicoradiographic, pathologic, and molecular correlations. The description of most lesions is separated into paragraphs including epidemiologic, radiographic, gross, and microscopic data, and pertinent information on any special techniques required for identification is also provided.

ERRNVPHGLFRVRUJ

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2

1  General Considerations

TABLE 1-1 WHO Classification of Tumors of Bone* Tumor Chondrogenic Tumors Benign Osteochondroma Chondroma   Enchondroma   Periosteal chondroma Osteochondromyxoma Subungual exostosis Bizarre parosteal osteochondromatous proliferation Synovial chondromatosis Intermediate (locally aggressive) Chondromyxoid fibroma Atypical cartilaginous tumor   Chondrosarcoma grade 1

Code

9210/0 9220/0 9220/0 9221/0 9211/0 9213/0 9212/0 9220/0 9241/0 9222/1

Tumor Osteofibrous dysplasia Chondromesenchymal hamartoma Rosai-Dorfman disease Fibrogenic Tumors Intermediate (locally aggressive) Desmoplastic fibroma of bone

8823/1

Malignant Fibrosarcoma of bone

8810/3

Fibrohistiocytic Tumors Benign Benign fibrous histiocytoma/non-ossifying fibroma

8830/0

9732/3 9731/3 9591/3

Intermediate (rarely metastasizing) Chondroblastoma

9230/1

Malignant Chondrosarcoma   Chondrosarcoma grade 2, grade 3 Dedifferentiated chondrosarcoma Mesenchymal chondrosarcoma Clear cell chondrosarcoma

Hematopoietic Neoplasms Malignant Plasma cell myeloma Solitary plasmacytoma of bone Primary non-Hodgkin lymphoma of bone

9220/3 9243/3 9240/3 9242/3

Osteoclastic Giant Cell Rich Tumors Benign Giant cell lesion of the small bones Intermediate (locally aggressive, rarely metastasizing) Giant cell tumor of bone 9250/1

Osteogenic Tumors Benign Osteoma Osteoid osteoma

9180/0 9191/0

Intermediate (locally aggressive) Osteoblastoma

9200/0

Malignant Low-grade central osteosarcoma Conventional osteosarcoma   Chondroblastic osteosarcoma   Fibroblastic osteosarcoma   Osteoblastic osteosarcoma Telangiectatic osteosarcoma Small cell osteosarcoma Secondary osteosarcoma Parosteal osteosarcoma Periosteal osteosarcoma High-grade surface osteosarcoma

9187/3 9180/3 9181/3 9182/3 9180/3 9183/3 9185/3 9184/3 9192/3 9193/3 9194/3

Myogenic Tumors Benign Leiomyoma of bone

8890/3

Malignant Leiomyosarcoma of bone

8890/3

Lipogenic Tumors Benign Lipoma of bone

8850/0

Malignant Liposarcoma of bone

8850/3

Tumors of Undefined Neoplastic Nature Benign Simple bone cyst Fibrous dysplasia

Code

Malignant Malignant giant cell tumor of bone

9250/3

Notochordal Tumors Benign Benign notochordal tumor

9370/0

Malignant Chordoma

9370/3

Vascular Tumors Benign Hemangioma

9120/0

Intermediate (locally aggressive, rarely metastasizing) Epithelioid hemangioma 9125/0 Malignant Epithelioid hemangioendothelioma Angiosarcoma Intermediate (locally aggressive) Aneurysmal bone cyst Langerhans cell histiocytosis   Monostotic   Polystotic Erdheim-Chester disease Miscellaneous Tumors Ewing’s sarcoma Adamantinoma Undifferentiated high-grade pleomorphic sarcoma of bone

9133/3 9120/3 9260/0 9752/1 9753/1 9750/1 9364/3 9261/3 8830/3

8818/0

International Agency for Research on Cancer (IARC): WHO Classification of tumours of soft tissue and bone, ed 4, Lyon Cedex, France, 2013 (edited by Fletcher CDM, Bridge JA, Hogendoorn PCW, et al). *The morphology codes are from the International Classification of Diseases for Oncology (ICD-0) {916A}. Behavior is coded /0 for benign tumors, /1 for unspecified, borderline or uncertain behavior, /2 for carcinoma in situ and grade III intraepithelial neoplasia, and /3 for malignant tumors.

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1  General Considerations

Clinical presentation

Radiologic features

Diagnosis

Molecular data

Microscopic features

FIGURE 1-1  ■  Analytical approach to diagnosis of bone tumor. Stepwise, analytic approach depicted as a diagnostic quadrangle in which four distinct sets of data (clinical, radiographic, microscopic, and molecular) are taken into consideration in establishing a diagnosis.

The frequency distributions in skeletal areas represent approximate compilations based on findings from several major published series. Published data from the Mayo Clinic, Memorial Sloan-Kettering Cancer Center, and The University of Texas M.D. Anderson Cancer Center have been included in the analysis. In addition, national epidemiologic data are provided for the most common malignant bone tumors and are based on the most recent analysis of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. The description of most lesions is accompanied by a graphic presentation of the peak age incidence and their typical sites of skeletal involvement. This should help readers recognize the most typical clinicoradiographic patterns of most bone tumors and tumorlike lesions. The system of graphic depiction of skeletal distribution patterns originally designed by the Mayo Clinic Group is used with some modifications in this book. The intention is to provide a balanced view of current pathogenetic and diagnostic concepts on bone tumors and tumorlike lesions. In reference to several bone lesions the author’s concepts, which may differ from those of others, are presented. In such instances, the controversies are discussed in some detail. Personal opinions in the form of recommendations on the basis of experience as to how to address a particular diagnostic problem are expressed in interspersed paragraphs entitled “Personal Comments.”

MORPHOLOGY OF NORMAL BONE Discussion of the morphology of the skeletal system is restricted to some basic elements important to the pathologist and helpful in the understanding of basic gross, radiographic, and microscopic features of bone tumors and related conditions described in this text. For more comprehensive descriptions of the structure of the skeletal system, readers should refer to any of the major textbooks and monographs strictly dedicated to this subject. Bone and cartilage represent highly specialized tissues that perform several functions: mechanical, protective, and metabolic. Mechanically, they provide for the integrity of overall body structure and body movements.

3

The protective function of bone is demonstrated by the encasement of several vital organs (lungs, heart, and central nervous system) and of bone marrow, which is the source of blood cells. Metabolically, bone represents a reservoir for several ions, predominantly calcium and phosphorus. Living bone is a highly labile, dynamic tissue that is able to respond to a number of metabolic, physical, and endocrine stimuli. At the same time, its relative simplicity in terms of structural elements allows bone to restore itself to its normal function and architecture after injury.

Topographic Features Major topographic regions of the skeleton frequently used in the description of bone tumors are shown in Figure 1-2. The skeleton forming the central axis (skull, vertebral column, and sacrum) is referred to as the axial skeleton.The bones of the extremities (including the scapula and pelvis) are collectively called the appendicular skeleton. The term acral skeleton designates the bones of the hands and feet. In the axial skeleton lesions involving craniofacial bones form a distinct group separate from those of the vertebral column and sacrum. Similarly, in the discussion of neoplastic lesions arising in the scapula and pelvis, these sites are grouped with other bones of the trunk. On the basis of their gross appearance, bones are divided into two main groups: flat and tubular bones. In general, the bones of the trunk and craniofacial region, such as the skull, scapula, clavicle, pelvis, and sternum, are classified as flat. The bones of the extremities and the ribs are tubular. The tubular bones are further subdivided into the long bones (e.g., femur, tibia, humerus) and the short bones (e.g., phalanges, metatarsals, metacarpals) (Figs. 1-3 and 1-4). The carpal and tarsal bones, as well as the patella, are designated as epiphysioid bones, which are analogous to the epiphyses of long bones with regard to development and tumor predilection. The tubular bones have several regions or zones: 1. Epiphysis: The region between the growth plate and the end of bone in skeletally immature individuals or between the growth plate scar and the end of the bone in skeletally mature individuals 2. Metaphysis: The region adjacent to the growth plate opposite the epiphysis 3. Diaphysis or shaft: The region between metaphyses 4. Physis: The region of bone corresponding to the growth plate. Knowledge of these terms and their definitions is very useful because many tumors have a predilection for particular regions of bone (Figs. 1-5 and 1-6).

Bone Bone, cartilage, and fibrous connective tissue differ in their visible appearance and mechanical properties because of the various compositions of their matrices.2,7,8,13,14,17,22,30,40 Dense fibrous connective tissue is formed of well-oriented bundles of collagen, and its principal function is to resist tension. Bone and cartilage must also resist compression, torsion, and bending forces. Each bone has a peripheral compact layer known as the

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1  General Considerations Axial

Axial

Acral

Appendicular

Trunk

Craniofacial

types.34,43,45 In woven bone, the collagen fibers are haphazardly organized and form an irregular framework. In contrast, in lamellar bone the collagen fibrillary network has an orderly parallel organization. In general, woven bone is produced during rapid bone growth or repair, such as a fracture callus. It represents an immature form of bone in which osteoid is rapidly deposited and is gradually remodeled into a mature lamellar form. The mature lamellar bone, within the cortex, is organized into several distinct architectural patterns referred to as circumferential, concentric, and interstitial. The circumferential lamellar bone forms the outer and inner layer of the cortex. The concentric lamellar bone forms the bulk of the so-called haversian or osteon systems within the cortex. It contains the central canal with blood vessels surrounded by a cylindrical concentric lamellae of bone. The osteocytes within such systems are also somewhat concentrically arranged within the lacunae and are connected by dendritic processes extending outside of the main osteocytes’ bodies via the system of canaliculi that forms an interconnecting mesh within the mineralized matrix. Volkmann’s canals course through the cortex at more perpendicular angles with respect to the haversian systems and contain the connective tissue and feeding vessels that eventually branch into the vasculature of the haversian canals. The microarchitecture of the mineralized deposit and fibrular network is still poorly understood. The recently developed models postulate the tubular nature of basic structural units in which the mineralized plates of hydroxyapatite are connected by helical collagen fibers. (Fig. 1-8) The mineral material provides the structural stiffness of bone but it is the most brittle component that is protected by interfibrillary matrix of protein.19,28,42 The intrafibrillary matrix contains both collagen and non-collagen proteins. The mineralized plates are spatially organized to form fibrils composed of platelets of minerals and intrafibrillary matrix.

Cartilage

Acral FIGURE 1-2  ■  Regional designations of skeleton. Major topographic regions of the skeleton frequently used in the description of bone tumors.

cortex (Fig. 1-7). The interior of bone has a network of trabeculae called the cancellous (spongy) or trabecular bone (see Fig. 1-7). The space inside the bone delineated by the cortex is referred to as the medullary cavity. The intertrabecular spaces of the medullary cavity consist of adipose tissue, fibrovascular structures, and hematopoietic tissue. The trabecular bone with its high surface/ volume ratio is susceptible to rapid turnover, and hence most sensitively reflects alterations in mineral homeostasis.3,4,16,18 The trabecular bone contributes to skeletal stability by distributing compressive loads across a joint. On the other hand, the diaphyseal cortex resists bending and tension forces. Based on the overall organization of type I collagen fibers bone is categorized into woven and lamellar

Cartilage consists of specialized cells (chondrocytes) and an extracellular matrix composed of fibers embedded in an amorphous, eosinophilic, gel-like matrix.15,20,49 On the basis of the matrix composition, cartilage can be divided into three major subtypes: hyaline, fibrous, and elastic. Hyaline cartilage is present at the ends of ribs and covers the joint surfaces. It also is seen in tracheal rings and the larynx. It is composed of collagen fibers and a dense amorphous eosinophilic substance. Fibrocartilage is present at the insertion of tendons. The unique feature of this type of cartilage is its gradual transition to the dense connective tissue of tendons. Elastic cartilage is present in the external and auditory canal, eustachian tube, external ear, and cuneiform cartilage of the larynx. It is characterized by the presence of a rich network of elastic fibers.

Extracellular Matrix Elements of the extracellular matrix of the skeletal system, uniquely suited to perform the mechanical function of

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5

Cartilaginous epiphysis

Metaphysis

Cartilaginous epiphysis

Growth plate

Primary spongiosa

Developing shaft

Cartilaginous epiphysis

Metaphysis

Diaphysis

Enchondral ossification

FIGURE 1-3  ■  Development of bone. Development of primary ossification center in a long bone (tibia). Cartilaginous epiphyses at both ends are remnants of cartilage model. Center has been replaced by developing diaphysis with zones of enchondral ossification at both ends. At this stage primary spongiosa with active enchondral ossification occupies most of the bone length within the metaphyseal portions while the developing shaft is a relatively minor component of the length. Secondary ossification centers will develop in cartilage masses at bone ends, and continued ossification will lead to formation of growth plates (physis) (see Fig. 1-5).

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Epiphysis Short tubilar bones

Shaft

Base

Epiphysioid tarsal bones

FIGURE 1-4  ■  Development of bone. Whole-mount section of fetal foot shows basic topographic features of short tubular and epiphysioid bones.

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Epiphyseal ossification center

Epiphysis

Primary spongiosa

Metaphysis

Secondary spongiosa

Shaft

FIGURE 1-5  ■  Topographic anatomy of a developing long bone. Growth plate or physis results from formation of a secondary ossification center in the cartilage mass at the end of the cartilage model. Increase in length results mainly from cartilage-cell proliferation and interstitial growth in the cartilaginous physis.

the skeleton, consist of several major basic components: collagen, proteoglycans, and minerals.5,7,10,13 Metabolically they represent a major body reservoir of several ions, predominantly calcium and phosphorus. Collagen Collagen is the most abundant protein in the body and the major organic component of extracellular matrix in bone. The collagen molecule comprises three chains, each of which contains a repeating tripeptide sequence of glycine-x-y, in which x and y are frequently proline and hydroxyproline. These three chains are individually synthesized on ribosomes and subsequently are assembled into a triple helix. The cross-linking among these molecules is responsible for the formation of the fibrillar matrix. The architecture of collagen fibers reflects the integrity of bone and its level of maturation. In normal adults, virtually all bone collagen is deposited in parallel lamellar bundles as seen by polarizing microscopy, hence the term lamellar bone. When metabolism of the skeleton is accelerated and there is need for rapid formation of matrix collagen, its lamellar architecture is lost and

replaced by randomly arranged fibers of varying sizes known as woven bone. Woven bone (fiber bone) is formed at sites of early endochondral and membranous ossifications and in fracture callus, periosteal reactions, endosteal healing processes, and rapidly formed tumor bone. The recognition of woven bone and its distinction from mature lamellar bone are greatly facilitated by the use of polarization microscopy. Proteoglycans Proteoglycans are the major noncollagenous organic components of skeletal matrices.7,14,20,31,35 They are present in greatest concentrations in cartilage, resulting in its intense metachromasia. Proteoglycans consist of a core of hyaluronic acid with protein side chains lined by a variety of sulfated glycosaminoglycans. They are mainly assembled and sulfated in the Golgi apparatus after the protein moieties have been synthesized by the ribosomes. In the presence of water, the hydrophilic macromolecule of the protein polysaccharide inflates to form a body with a shape analogous to a test tube brush with the consistency of a stiff gel. The size and consistency of the

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Epiphysis Physis

Metaphysis (anatomic)

Radiologic (diagnostic) metaphysis

On its initial appearance in the skeleton, calcium phosphate exists in a relatively poorly crystallized form. In lamellar bone, it is deposited at the interface of osteoid and mineralized tissue. The lamellar maturation of bone is associated with conversion of the mineralized deposits into a hydroxyapatite with a more distinct crystalline pattern.

Cells The cells of the skeleton system include osteoblasts, osteocytes, osteoclasts, chondroblasts, and chondrocytes (Fig. 1-9). Osteoblasts

Diaphysis

Radiologic (diagnostic) metaphysis Physis

Metaphysis (anatomic)

Epiphysis

FIGURE 1-6  ■  Topographic regions of long tubular bones. Anatomically and developmentally, the metaphysis is defined as a narrow zone just adjacent to the cartilaginous growth plate (physis) in which primary spongiosa is first formed in the process of enchondral ossification. In radiologic terms, the metaphysis is more loosely defined as a broad region enclosed by the flare of cortex on the shaft side of the growth plate. This less precisely designated area is diagnostically useful because of the predilection of some bone tumors to develop there.

hydrated molecule are responsible for many of the mechanical and physicochemical properties of cartilage. Bone Mineral The bony skeleton is made rigid by the addition of mineral to the deposited extracellular organic matrix.2,8,10,13,31 The inorganic phase of mature bone mineral is a carbonate-containing analog of hydroxyapatite [Ca10 (PO4)6 (OH)2] that forms submicroscopic irregular crystals. The precise mechanism of mineral deposition in the skeleton is not clear, but there is evidence that the organic components of bone play a role in the process.

Osteoblasts are specialized cells that synthesize the bone matrix.6,25,41,44 They are cuboidal or columnar and are invariably found lining osteoid seams. They most likely arise from precursor cells present in the peritrabecular marrow. Osteoblasts have a prominent Golgi apparatus and are rich in rough endoplasmic reticulum, resulting in prominent basophilia. These features reflect their active participation in mineralization and in the process of organic matrix production. Osteoblasts contain large amounts of alkaline phosphatase. When engaged in the synthesis of lamellar bone, osteoblasts are polarized in relationship to the underlying osteoid seam. In woven bone, this orderly anatomic arrangement of osteoblasts is absent. Although there is no question that osteoblasts as just described actively synthesize bone, most bone surfaces are covered by flat, fusiform cells, variously called inactive osteoblasts or bone-lining cells. These cells are capable of skeletal synthesis at a slower rate than activated cuboidal or columnar osteoblasts. They also may act as a barrier that separates the bone fluid compartment both anatomically and functionally from the general extracellular fluid. Osteocytes Osteocytes represent specialized cells that have been incorporated into the bone matrix. They are involved in the maintenance and turnover of bone at a slow rate (i.e., slower than activated osteoblasts).9,24,27,29 They are the most numerous of bone cells and, with their cytoplasmic processes, which extend through canaliculi, constitute the major portion of the bone cell syncytium. Young osteocytes often resemble osteoblasts ultrastructurally. They are capable of perilacunar matrix synthesis and mineralization, which result in progressive diminution of lacunar size. Osteocytes that are older and hence deeper in the matrix may assume osteoclastic features and resorb bone. Osteoclasts Osteoclasts are large, multinucleated cells that are responsible for the resorption of bone and calcified cartilage.11,12,26,32,33,36,44 An abundance of enzymes that play a role in bone lytic activities, including acid phosphatase and various proteolytic enzymes such as collagenases, is

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A

B

C

FIGURE 1-7  ■  Compact bone versus cancellous or spongy bone: Microscopic features. A, Dense cortical compact bone shows haversian canals surrounded by concentric lamellae-forming units (osteons). Inset: Osteons with concentric lamellae under polarization microscopy. B, Cancellous bone consists of connecting plates of lamellar bone separated by mature adipose tissue. C, Higher magnification of A shows connecting and branching plates of lamellar bone. (A, B, and Inset ×50; C, ×160.) (A to C, hematoxylin-eosin.)

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mineral platelet

collagen matrix

10

A

B

C

FIGURE 1-8  ■  Architectural organization of collagen tissue fibers and mineralized deposits. A, The fibrils are made of organized mineral platelets bound by noncollagenous proteins. The helical structures of proteins absorb and dissipate energy during tensile strain. B, Scanning electron microscope image of a fractured surface of human bone shows filaments (arrows) connecting the neighboring fibrils. C, Atomic force microscope image of a fractured surface of human bone showing filaments (arrows) connecting the neighboring fibrils. (A, Reprinted with permission from Gupta HS, et al: PNAS 108:17741–17746, 2006. B and C, Reprinted with permission from Fantner GE, et al: Nature Materials 4:612–616, 2005.)

present in these cells. Osteoclasts are derived from the monocyte macrophage precursors and share some of their antigenic features. Osteoclasts have a convoluted cell membrane, or “ruffled border,” that is juxtaposed to the bone surface. The formation of the ruffled border and its adherence to the bone surface are stimulated by parathormone and inhibited by calcitonin. In addition, the activity of osteoclasts is mediated by several ubiquitous cytokines. Chondroblasts Chondroblasts represent immature cells of cartilage and are precursors of chondrocytes.15,20,25 They are

typically not seen in the adult normal skeleton. During fetal development, areas of cartilaginous differentiation occur within mesenchymal tissue. The earliest forms of chondroblastic differentiation are difficult to recognize microscopically because they do not differ significantly from fetal myxoid mesenchymal tissue. However, they are at least weakly positive for S-100 protein, an immunohistochemical hallmark of cartilaginous differentiation that is expressed on all cells of cartilage lineage. Young cartilage cells are relatively small compared with chondrocytes. They may have a flattened or irregular contour, and the surface may show multiple projections or filopodia. The nucleus usually contains a prominent nucleolus, and it may show a prominent paranuclear Golgi zone.

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A

B

C FIGURE 1-9  ■  Histology of cartilage and bone. A, Hyaline cartilage from articular end of a long bone. Individual chondrocytes are seen within lacunae surrounded by a zone of basophilic chondroid matrix that is rich in glycosaminoglycan. Inset, Higher magnification of A. B, Osteoblasts that actively synthesize bone matrix are seen bordering trabeculae of newly formed (woven) bone. These mononuclear cells are cuboidal and have basophilic cytoplasm with a paranuclear clear zone (Golgi center). Osteoid matrix produced by these cells is deposited in a seam just inside the rim of osteoblasts. Inset, Higher magnification of B. C, Osteoclasts (boneresorbing cells) are the multinucleated giant cells shown in concavities (Howship’s lacunae). (A, B, and C, ×100; Insets, ×200.) (A to C, hematoxylin-eosin.)

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A pericellular lacuna is usually absent or indistinct, and the amount of intercellular matrix is less abundant than that associated with chondrocytes. In general, immature cartilage is highly cellular. The morphology of immature cartilage cells is best studied in lesions that recapitulate embryonal stages of cartilaginous differentiation, such as chondromyxoid fibroma, chondroblastoma, clear cell chondrosarcoma, and myxoid chondrosarcoma. A prototype chondroblast is a cell typically seen in a benign cartilage tumor designated as chondroblastoma. It has a dense eosinophilic cytoplasm with an oval nucleus that has a prominent longitudinal groove, often seen under light microscopic examination. Chondrocytes Chondrocytes represent mature cartilage cells that are derived from mesenchymal precursor cells.15,20,46 They are located in lacunae surrounded by the cartilaginous matrix. Chondrocytes tend to be clustered in small, loose groups that are isogenous or monoclonal because they represent progeny of a single chondrocyte. In the epiphyseal plates of long bones, the cartilage cells are arranged in long columns. During the skeletal growth phase, cartilage cells in the epiphyseal plates undergo transient proliferative activity followed by deposition of a cartilaginous matrix and programmed cell death (apoptosis). Proliferation of cartilage cells followed by apoptosis is the most important mechanism governing skeletal growth. Mature chondrocytes have small, dense nuclei. Open nuclear chromatin with small nucleoli is present in proliferating cartilage cells. The ultrastructure of chondrocytes is characterized by numerous branched cytoplasmic processes, a well-developed endoplasmic reticulum, and a Golgi center.

Development of Bone Fetal bone formation and postnatal growth occur in one of two ways. In intramembranous ossification, clusters of fetal mesenchymal cells differentiate directly into osteoblasts. In enchondral bone formation, a predeposited cartilaginous matrix (cartilage model) serves as a scaffold for the deposition of osteoid (Fig. 1-10). In the developing epiphyseal centers, this cartilage model undergoes focal calcification, followed by vascular invasion and the appearance of bone-synthesizing osteoblasts.21,23,38,39 Thus the cartilaginous matrix is replaced by bone, except at the growth plate and articular surfaces.37-39 At the mesenchymal-vascular junction of the epiphyseal growth plate and metaphyseal bone, invasion of continuously growing cartilage is followed by osteoblastic differentiation and deposition of osteoid. The devitalized, calcified cartilage serves as a scaffolding for the deposition of bone matrix and is resorbed by osteoblasts at the same rate at which the growth plate is internally expanded. Consequently, long bone growth occurs while the thickness of the epiphyseal plate remains constant. The cessation of interstitial expansion of the epiphyseal plate results in its gradual obliteration and the termination of growth. Cartilage serves as the mediator of long bone growth because it is capable of interstitial matrix deposition and

surface apposition. Intramembranous bone formation first appears as many separate centers of ossification that enlarge and fuse to form a single plate (Fig. 1-11). Membranous bones are directly formed from the mesenchymal tissue without a preexisting cartilage model. Growth in the diameter of a bone continues principally by the deposition of osteoid on the outer convex surface of the shaft through membranous ossification in the cambium layer of the periosteum. Tubulation and remodeling are achieved by osteoclastic activity resorption on the inner concave surface.

PROCESSING OF BONE SPECIMENS The nature of bone specimens sent for pathologic evaluation requires some special procedures that are usually not required for other specimens.48-50,53,75,91,92 For the purpose of this description, the bone specimens are divided into several major categories: 1. Intraoperative diagnostic procedures 2. Diagnostic or therapeutic biopsies and curettings 3. Resection specimens. We will discuss the processing of orthopedic specimens relevant for tumor-containing specimens, focusing on some practical handling aspects of general interest. The basic steps in handling diagnostic bone specimens are shown in Fig. 1-12.

Intraoperative Diagnostic Procedures The pathologist is requested to comment on the nature of biopsy specimens intraoperatively for two reasons: to establish the preliminary diagnosis and to evaluate the adequacy of the specimen for future diagnosis to be established on permanent sections. The ideal recommended approach begins with preoperative consultation between the surgeon and pathologist to understand the clinical setting and to establish the optimal diagnostic and therapeutic plan. Moreover, it reduces miscommunication at the time of surgery. Most important, it enables the pathologist to answer more specifically any questions regarding the therapeutic consequences of the diagnosis. Gross specimens submitted for frozen sections must be carefully evaluated for the presence of heavily mineralized tissue, such as fragments of cortical bone. These fragments must be removed from the specimen because they cannot be submitted for sectioning without prior decalcification. Heavily mineralized specimens are unsuitable for frozen sections. Conversely, most bone tumors can be sectioned without prior decalcification despite matrix mineralization. When the intraoperative frozen sections are planned, use of a less mineralized (softer) portion of the lesion for the biopsy specimen is recommended. It is also important to remember that some heavily mineralized lesions may be unsuitable for frozen sections. Intraoperative diagnosis is usually based on frozen sections stained with hematoxylin-eosin. Occasionally, it may be superseded by the evaluation of cytologic preparations. Cytologic preparations (touch smears, scrape,

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13

Apoptotic cartilage cells

Columns of cartilage cells

B

Enchondral ossification (primary spongiosa)

A

Calcified cartilage matrix

Osteoid

C FIGURE 1-10  ■  Enchondral ossification: Microscopic features. A, Overall view of anatomy of growth plate and zone of primary spongiosa formation below. B, Zone of cartilage-cell hypertrophy at base of cartilage-cell columns where programmed cell death (apoptosis) supervenes. C, High-power view of metaphyseal side of growth plate shows osteoid deposition on surface of calcified chondroid by rimming osteoblasts. (A, ×25; B and C, ×100.) (A to C, hematoxylin-eosin.)

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B

A FIGURE 1-11  ■  Intramembranous ossification: Microscopic features. A, Low-power photomicrograph of fetal calvarial bone formation by direct osteoblastic differentiation from primitive mesenchymal cells. B, Medium-power photomicrograph shows formation of woven bone trabeculae with osteoblastic rimming without cartilage stage. (A, ×13; B, ×25.) (A and B, hematoxylin-eosin.)

aspirations) can be made from the surface of material that is too heavily mineralized for frozen section. More often, cytology is used as a supplement for frozen-section diagnosis, which provides an opportunity to evaluate the morphology of individual cells without freezing artifacts.

Biopsy and Curettage The specimen for diagnosis can be obtained by various transcutaneous closed biopsy instruments. The use of “closed” biopsy techniques has increased, and the procedure is often assisted by various radiographic imaging techniques.47,52,54,59,60,62-64,70,73,74,76-79,90 In many institutions, aspiration cytology often is used as a preliminary diagnostic approach and, similar to closed biopsy techniques, is frequently assisted by radiographic imaging techniques.

These techniques are recommended as the initial diagnostic approaches, but in many cases they yield adequate material to establish the final diagnosis. However, some lesions are extremely difficult or even impossible to diagnose on the basis of a small amount of material obtained by closed biopsy techniques. In such instances, open biopsy must be performed. Planning the open biopsy approach is a complex process that must take into account the clinical presentation, the imaging context, and the technical aspects of subsequent definitive surgery.51,65,69,71,80 For example, an inappropriately placed open biopsy incision may put an optimal limb-sparing procedure at risk because of problems such as tissue contamination and inflammatory complication. Therefore it is generally recommended that an open biopsy be performed at a medical institution that can provide definitive

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15

Preoperative Analysis of Clinical and Radiographic Data (Diagnostic/Therapeutic Plan)

Biopsy/Curettings/Resection

Gross Examination Processing with demineralization

Processing without demineralization

Microscopic Analysis

Sterile material for microbiological, tissue cultures, and cytogenetics

Special microscopic techniques (immunohistochemistry, etc) Diagnostic

Electron microscopic Immunohistochemistry on frozen tissue

Fresh tissue for special techniques

Frozen tissue for nonmicroscopic special techniques (DNA, RNA, protein, etc.) FIGURE 1-12  ■  Algorithm for diagnostic plan after clinical and radiographic identification of a suspected bone tumor. Systematic approach with procurement of adequate samples will lead to a complete workup and more precise diagnosis.

treatment. In general, the incision site and the biopsy track should be carefully selected so that if the lesion proves to be malignant, it can be excised en bloc with the segment of affected bone. This prevents tissue contamination and is of particular importance for limited local excision in limb-salvage procedures (Fig. 1-13). Not every lesion requires microscopic verification before treatment and in some instances imaging techniques are used to guide the placement of therapeutic devices such as a radiofrequency electrode for ablation of osteoid osteoma.86 Open biopsy specimens are submitted in their entirety for histologic examination. At the time of gross examination, a decision must be made as to whether the specimen requires decalcification or can be processed without demineralization. Routine demineralization of all bone biopsy specimens is inappropriate because this procedure destroys some cellular and extracellular components. Demineralization of the entire material may render the tissue unsuitable for some special techniques. Nucleic acids, in particular, are degraded by acid-based demineralization procedures. As a consequence, the demineralized tissue cannot subsequently be used for certain molecular genetic procedures such as in

situ hybridization or polymerase chain reaction–based genetic testing. In general, most routine immunohistochemical studies can be performed on decalcified tissue with satisfactory results. For that reason, it is important to divide the specimen into several sections and to process the softer sections without demineralization. Demineralization also can destroy some diagnostically important structures (e.g., chicken wire–type calcification in chondroblastoma). Occasionally, a one-step diagnostic and therapeutic procedure is chosen on the basis of the clinicoradiologic data. In such instances, the material consists of curettings of the entire lesion. A portion of the specimen is typically submitted for microscopic examination. All tissue fragments that appear different should be submitted for microscopic examination because they may contain diagnostically important and histologically distinct components. Small biopsy fragments containing only cancellous bone spicules or tumor tissue containing small amounts of bone often can be decalcified and fixed in one overnight step through the use of Bouin’s solution. This fixative contains glacial acetic acid in addition to picric acid, and sufficient demineralization is often achieved simultaneously with fixation.

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Proposed incision for definitive surgery

Biopsy incision

Proposed incision for definitive surgery

FIGURE 1-13  ■  Example of incision site for biopsy of distal femoral tumor. Planning of incision site so that tumor can be excised en bloc with the segment of affected bone and biopsy tract without contaminating remaining tissue.

Resection and Amputation Specimens Resection (limb-sparing procedure) or amputation is performed after the malignant or locally aggressive nature of the lesion has been confirmed by biopsy. Dissection of a bone resection or amputation specimen should facilitate the following objectives:51,57,58,61,68,72,85,93 1. Assessment of the margins of excision 2. Confirmation of the preoperative diagnosis or its modification on the basis of new information 3. Extent of involvement of bone and adjacent structures 4. Assessment of therapeutic effect. The preoperative radiographs or specimen radiographs are extremely helpful in planning the dissection of resected or amputated specimens.48,50,51,65,68,75,93 Therefore the preoperative radiographs (plain x-rays, computerized tomograms, or magnetic resonance images) should always be reviewed before dissection. These images may be supplemented by specimen radiographs. The radiographic data assist in localizing the tumor within the specimen and identifying any areas of extension into soft

tissue. They also help in the selection of the optimal plane of bone dissection and may identify special areas of interest, such as skip metastases, involvement of other structures such as a neurovascular bundle, and closest margin of resection. The best approach is to have the radiographic documentation available for review during dissection. To accomplish the goals of gross examination, it is important to perform the dissection in an organized manner: 1. Review the clinical and specimen radiographs. 2. Examine the external surface of the specimen. 3. Check the margins of excision (e.g., bone, soft tissue, synovium, biopsy tract). 4. Expose the involved bone. 5. Expose and examine the tumor. The specimen’s external surface should be examined before dissection. Any attached soft tissue or skin should be inspected for induration, soft tissue masses, and other changes. Areas of previous incisions and biopsies should be identified. Margins should be identified and sampled on the basis of gross examination and radiographic data. Areas of the closest soft tissue margin of excision, bone resection margin, and synovial articular resection margin should be sampled. In limb-sparing procedures, the soft tissue resection margins around the tumor are of particular importance. The potential closest margins are best identified by reviewing the clinicopathologic data in consultation with the surgeon. The bone resection margins are routinely sampled. In long bone resection specimens, an en face proximal bone margin of excision is sufficient. Occasionally multiple sections from large and complex margins are necessary (e.g., pelvic resection specimens). Prior biopsy tracks should be left attached to bone and appropriately sampled to verify their margins and involvement by the tumor. Figure 1-14 shows a sampling plan for osteosarcoma in a distal femoral resection specimen. After examination and sampling, the attached soft tissue is dissected down to the periosteum and is removed. Areas of extension into soft tissue identified on radiographs or during dissection should be left attached to the bone in continuity with the main tumor mass. Bisected specimens expose the tumor cut surface, and their gross examination can reveal features such as epiphyseal involvement, intramedullary invasion and extension into soft tissue, areas of disrupted cortex, and periosteal reaction. The basic features of the two most frequent primary bone tumors—osteosarcoma and chondrosarcoma—seen in typical major resection or amputation specimens are shown in Figures 1-15 to 1-18. Pathologic assessment of the chemotherapy effect in postoperative specimens is an integral element of the multi-model approach to the management of bone tumors, and it was originally designed and clinically validated for osteosarcoma resection specimens.55,56,66,67,81-84,87-89 Subsequent data indicates that such an assessment may provide important prognostic and management information for other malignant bone tumors, including Ewing’s sarcoma.94 The current standards of practice indicate that so-called histologic mapping of bone resection specimens provides important insights for prognosis and management for virtually all malignant tumors of bone. Therefore, virtually all

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17

1

2

Distance from bone resection margin

4

12

13

17

18

5 6

11

3

10

28

19

20

24 29

25

16 21 26 8

27

23

15

7

22

14

30 9

FIGURE 1-14  ■  Gross evaluation of bone tumors. Sampling plan for mapping procedure of central slab to provide precise histologic information on margins of resection and extent of tumor necrosis after chemotherapy (also see Chapter 5).

resection specimens for primary bone tumors are processed for mapping. Theoretically the assessment of chemotherapy-related necrosis requires submission of the entire tumor for microscopic evaluation, but such an approach is impractical and dramatically increases both the workload and the technical cost of pathologic assessment. For practical purposes, it is performed from the central slice of the tumor which is subjected to specimen radiography and is subsequently divided into smaller sections submitted in individual cassettes typically averaging approximately 2.0 cm2. The general sampling plan for such mapping can be found in Figure 1-14. A detailed description of pathologic assessment of preoperative chemotherapy effect is provided in Chapter 5.

STAGING, GRADING, AND REPORTING OF BONE TUMORS Staging Systems Several staging and grading systems have been developed with the overall idea to stratify tumors according to prognostic factors such as tumor size, compartmentalization, histologic grade, and the presence or absence of metastasis. Two staging systems are currently used to assess the clinicopathologic parameters of bone tumors. The first is the common tumor, node, metastasis (TNM) staging system designed by the American Joint Committee on Cancer.100,105 It was adopted by the International Union Against Cancer in 1987. A second system was proposed

by Enneking et al.101,102 in 1986 and adopted by the American Joint Committee Task Force on Bone Tumors. The TNM system can be used to assess any intramedullary tumors except immunohematopoietic malignancies.100,125 The surface bone and soft tissue lesions do not fit well into this system. Stages I and II represent local disease. Stage IV designates disseminated disease with local or distant metastases. Stage III identifies lesions that cannot be defined by the system. Assessment of the tumor is based on three parameters: T (tumor), N (node), and M (metastasis). The tumor is designated as Tx if it cannot be assessed. T1 represents a tumor confined within the cortex, and T2 extends beyond the cortex. Nx designates the lymph nodes that cannot be assessed, N0 indicates no detectable lymph node metastases, and N1 designates the presence of metastases. Mx indicates an unknown status of metastases, M0 indicates the absence of detectable distant metastases, and M1 designates the presence of distant metastases. In addition, the tumors are histologically classified into two major categories according to their histologic grade: low (grades 1 and 2) and high (grades 3 and 4). A high-grade tumor places the lesion at least in stage II. A summary of the TNM staging system is provided in Table 1-2. The Enneking system may be applied to both bone and soft tissue tumors. It is based on the assessment of two basic parameters: biologic aggressiveness and local extent of the disease based on the compartmentalization concept of bone and soft tissue(Table 1-3). The biologic and clinical aggressiveness is a combination of histologic grading and specific histologic types.100-102,122

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1  General Considerations

Epiphysis

Growth plate

Intramedullary ivory-like tumor

A

Disrupted cortex

Elevated periosteum (Codman's triangle)

B FIGURE 1-15  ■  Description of gross findings in resected specimens of osteosarcoma. A, Coronally cut specimen of proximal end of tibia shows intramedullary lesion delimited by the cartilaginous growth plate in a skeletally immature patient. There is total sparing of the epiphysis. B, Cortical breakthrough by an intramedullary osteosarcoma with elevation of the periosteum and formation of Codman’s triangle. This specimen shows crossing of the epiphyseal scar by the tumor and invasion of the epiphysis. Measurements of the tumor size, the depth of extraosseous penetration, and its distance from the margin of the resection should be obtained.

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19

Bone resection margin

Soft tissue extension

Soft tissue extension

A

Epiphyseal extension

B FIGURE 1-16  ■  Gross examination of resected specimens of bone tumor. A, Femoral osteosarcoma confined distally by cartilaginous growth plate but with extensive invasion into soft tissue. Measurements of tumor size, length of resection margin, and extent of penetration into soft tissue can be determined. Foci of cartilage differentiation can be discerned grossly. B, Specimen of osteosarcoma of distal femur shows extensive epiphyseal penetration distally and a large soft tissue mass that exceeds the size of intramedullary tumor. Blood-filled cystic spaces within the intramedullary tumor and in the extraosseous extension suggest telangiectatic features.

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Intramedullary extension

A

B Soft tissue extension Epiphyseal extension

FIGURE 1-17  ■  Gross examination of resected specimens of bone tumor. A, Overall view of coronally cut femur containing a very large osteosarcoma arising in the distal shaft and extending proximally the full length of the medullary cavity of the diaphysis. Distally the cortex is breached, as is the cartilaginous growth plate. There is circumferential extension into soft tissue. B, Close-up view of intramedullary growth in the diaphysis. The tumor appears to be discontinuous grossly, but microscopic evidence of continuous medullary involvement was found.

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21

Myxoid area

Intramedullary tumor

A

Cystic change

B Soft tissue extension FIGURE 1-18  ■  Gross examination of resected specimens of bone tumors. A, Chondrosarcoma involving the pelvis (hemipelvectomy specimen) that was cut coronally through the iliac wing and acetabulum. Note extensive intramedullary involvement with hyaline cartilage tumor nodules and extracortical extension. Tumor breakdown with cyst formation, a common finding in large chondrosarcoma, is seen in the supraacetabular region. B, Proximal femoral resected specimen shows extensive intramedullary growth of a chondrosarcoma that extruded from the bone on the medial aspect of the shaft to form a large extraosseous tumor mass. There is gross evidence of bone formation (enchondral ossification) in tumor cartilage, as well as cystic degeneration.

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TABLE 1-2  TNM Classification of Bone Sarcomas T—Primary Tumor

G—Histopathologic Grading Translation table for three- and four-grade systems to a two-grade (low grade vs high grade) system

Tx T0

Primary tumor cannot be assessed No evidence of primary tumor

T1 T2 T3

Tumor 8 cm or less in greatest dimension Tumor more than 8 cm in greatest dimension Discontinuous tumors in the primary bone site

N—Regional Lymph Nodes Nx N0 N1

Regional lymph nodes cannot be assessed No regional lymph-node metastasis Regional lymph-node metastasis

THREE-GRADE SYSTEMS Grade 1

FOUR-GRADE SYSTEM Grade 1 Grade 2 High grade Grade 2 Grade 3 Grade 3 Grade 4 Note: If grade cannot be assessed, Ewing’s sarcoma is classified as high grade. If grade cannot be assessed, classify as low grade. Stage Grouping Stage Stage Stage Stage Stage Stage Stage

T1 N0 M0 Low grade T2-3 N0 M0 Low grade T1 N0 M0 High grade T2 N0 M0 High grade T3 N0 M0 High grade Any T N0 M0 Any grade Any T N1 Any M Any grade Any T Any N M1b Any grade Note: use N0 for Nx. For T1 and T2, use low grade if no grade is stated.

M—Distant Metastasis Mx M0 M1

TNM TWO-GRADE SYSTEM Low grade

Distant metastasis cannot be assessed No distant metastasis Distant metastasis M1a Lung M1b other distant sites

IA IB IIA IIB III IVA IVB

Adapted from American Joint Committee on Cancer (AJCC) cancer staging manual, ed 7, New York, 2010, Springer (edited by Edge SB, Byrd DR, Compton CC, et al),and International Union against Cancer (UICC): TNM classification of malignant tumors, ed 7, Oxford, 2010, Wiley-Blackwell (edited by Sobin LH, Gospodarowicz MK, Wittekind CH, et al).

TABLE 1-3 Definitions of Anatomic Extent in the Musculoskeletal Tumor Society Staging System

TABLE 1-4 Musculoskeletal Tumor Society Staging System Stage

Grade

Site

Metastasis

Intracompartmental (T1)

Extracompartmental (T2)

Intraarticular Superficial to deep fascia Paraosseous

Soft tissue extension Deep fascial extension Intraosseous or extrafascial extension Extrafascial compartment

IA IB IIA IIB III

G1 G1 G2 G2 G1 or G2

T1 T2 T1 T2 T1 or T2

M0 M0 M0 M0 M1

Intrafascial compartment

Modified from Enneking WF, et al: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 153:106– 120, 1980 and Peabody TD, et al: Evaluation and staging of musculoskeletal neoplasms. J Bone Joint Surg 80:1204– 1218, 1998.

The designations of this parameter are G0, G1, and G2. G0 is a benign neoplasm, and G1 is a locally aggressive tumor with a low probability of metastases. The examples of tumors in the G1 category include giant cell tumor, low-grade intraosseous osteosarcoma, parosteal osteosarcoma, or grade 1 or 2 chondrosarcoma. G2 designates aggressive tumors with high metastatic potential, such as high-grade conventional osteosarcoma, Ewing’s sarcoma, grade 3 chondrosarcoma, or malignant fibrous histiocytoma. T1 tumors involve only one compartment. An individual bone with its medullary cavity is considered a single compartment. Hence, extension beyond the cortex into adjacent soft tissue, joint, or another bone is considered extracompartmental and this lesion is designated T2. With these parameters, lesions are separated into three stages. Low-grade lesions are stage I. Stage II

Modified from Enneking WF, et al: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 153:106– 120, 1980 and Peabody TD, et al: Evaluation and staging of musculoskeletal neoplasms. J Bone Joint Surg 80:1204– 1218, 1998.

lesions are of high histologic grade. Stage III disease is any kind of tumor with metastases. The suffixes A and B in this system indicate intracompartmental or extracompartmental lesions, respectively. A summary of Enneking’s staging system is provided in Table 1-4. These two systems provide valuable guides to therapy and help to stratify tumors of the same categories according to clinically validated prognostic information. The American Joint Commission on Cancer system can be used for staging of tumors at any anatomic site, but it is difficult to compare the lesions, especially those involving the extremities as compared with those that affect the axial skeleton given the differences in the ability to eradicate tumors by surgical excisions in these distinct anatomic locations. This system uses a cutoff point of 5 cm as an important factor to predict the prognosis. It has to

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be understood that this discrimination is somewhat arbitrary, and the size of the tumor is rather a continuous, incremental variable. The Enneking system adopted by the American Joint Committee Task Force on Bone Tumors (also referred to as the Musculoskeletal Tumor Society Staging System) places the emphasis on compartmentalization and is preferable, especially for lesions affecting the extremities. Regardless which staging system is used, a multidisciplinary approach is needed to accurately stratify the tumors using the information generated by different modalities (i.e., clinical presentation, radiographic imaging, and pathology). Grading Systems Grading of bone sarcomas represents the evolution of historical concepts of grading proposed almost a century ago by Broders and originally designed for a fibrosarcoma.95 Following this publication, numerous studies reaffirmed the importance of grading in a variety of tumors. In general, grading systems include the state of differentiation, the degree of atypia, and the mitotic activity assessed based on the mitotic count in conventional pathology preparations or with the assistance of proliferation markers.98,99,107,108,110-114,116-118,121,128 A prototypic large-scale study based on the analysis of stage and grade of 1000 sarcomas was published by Russell et al.124 The stratification of sarcomas in various systems is based on two-, three-, or four-tier concepts. None of these systems are precise. The four-tier system usually shows minimal differences between the two lowest grades. The three-tier system has a problem with the intermediate grade, which may behave as a fully malignant tumor capable of metastasis or as a locally aggressive tumor only. The overall tendency is to classify the tumors into two grades, designated as either a low-grade tumor, signifying a locally aggressive tumor, or a high-grade tumor, signifying a lesion capable of metastasis. The problem with the two-tier stratification is that it is not always possible to classify the tumor as definitively low or high grade. The system that is gaining increased popularity was originally published by Trojani et al. in 1984126 and was subsequently adopted by the French Federation of Cancer Centers Sarcoma Group.96,97,103,109 The system is based on multivariate analysis of microscopic features and utilizes a combination of tumor differentiation, mitotic rate, and necrosis as parameters for grading.(Table 1-5) It is being utilized with increasing popularity both in Europe and the United States.120 It assigns a score to each parameter and then the scores are added to define a combined grade. The principal weakness of the system is based in the assignment of the differentiation score, in which the tumor is compared with its benign tissue origin. In those tumors in which the benign tissue or cell counterpart is not known or hypothetical, the differentiation score is not very reliable.120 Disregarding this, the system has reasonably good interobserver reproducibility. The use of grading systems in general, including the above listed French system, has never been validated for bone sarcomas.106 In bone sarcomas, similar to many soft tissue sarcomas, the identification of a specific type determines the biologic behavior and by itself defines the

23

TABLE 1-5 Definitions of Grading Parameters for the FNCLCC System Parameter

Criterion

Tumor Differentiation Score 1 Sarcoma closely resembling normal adult mesenchymal tissue (e.g., welldifferentiated liposarcoma) Score 2 Sarcomas for which histologic typing is certain (e.g., myxoid liposarcoma) Score 3 Embryonal and undifferentiated sarcomas; sarcoma of uncertain type Mitosis Count Score 1 Score 2 Score 3

0-9/10 HPF 10-19/10 HPF ≥20/10 HPF

Tumor Necrosis Score 0 Score 1 Score 2

(Microscopic) No necrosis ≤50% tumor necrosis >50% tumor necrosis

Histologic Grade Grade 1 Total score 2, 3 Grade 2 Total score 4, 5 Grade 3 Total score 6, 7, 8 Modified from Coindre JM, et al: Reproducibility of a histolopathologic grading system for adult soft tissue sarcomas, Cancer 58:306–309, 1986. FNCLCC, Federation Nationale de Centres de Lutte Contre le Cancer; HPF, high-power field.

TABLE 1-6 Grading of Bone Sarcoma Grade

Sarcoma Type

Grade 1

Parosteal osteosarcoma Grade 1 chondrosarcoma Clear cell chondrosarcoma Low-grade intramedullary osteosarcoma Periosteal osteosarcoma Grade 2 chondrosarcoma Classic adamantinoma Chordoma Osteosarcoma (conventional, telangiectatic, small cell, secondary, high-grade surface) Undifferentiated high-grade pleomorphic sarcoma Ewing’s sarcoma Grade 3 chondrosarcoma Dedifferentiated chondrosarcoma Mesenchymal chondrosarcoma Dedifferentiated chordoma Malignancy in giant cell tumor of bone

Grade 2

Grade 3

grade. For example, Ewing’s sarcoma, mesenchymal chondrosarcoma, and conventional osteosarcomas are highly aggressive tumors considered as high grade.115,127 On the other hand, specific subtypes of osteosarcoma such as parosteal osteosarcoma are defined as low-grade tumors. In addition, chondrosarcomas are graded according to their own system originally proposed by Evans et al., which is described in detail in Chapter 7.104 The grade assignments proposed by the WHO Classification System for tumors of bone are listed in Table 1-6.

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TABLE 1-7 Checklist for Standard Reporting of Bone Biopsy Specimen Specify bone involved: ___________ ___ Not specified Procedure ___ Core needle biopsy ___ Curettage ___ Excisional biopsy ___ Other (specify): ____________ ___ Not specified Tumor Site ___ Epiphysis or apophysis ___ Metaphysis ___ Diaphysis ___ Cortex ___ Medullary cavity ___ Surface ___ Tumor involves joint ___ Tumor extension into soft tissue ___ Cannot be determined

Tumor Size Greatest dimension: ___ cm Additional dimensions: ___ × ___ cm ___ Cannot be determined (see “Comment”)

Lymph-Vascular Invasion ___ Not identified ___ Present ___ Indeterminate

Histologic Type (World Health Organization Classification) Specify: _____________ ___ Cannot be determined

Additional Pathologic Findings Specify: ___________

Mitotic Rate Specify: ___ /10 high-power fields (HPF) (1 HPF × 400 = 0.1734 mm2; X40 objective; most proliferative area) Necrosis ___ Not identified ___ Present Extent: ___% ___ Cannot be determined Histologic Grade Specify: ___ ___ Cannot be determined

Ancillary Studies Immunohistochemistry Specify: __________ ___ Not performed Cytogenetics Specify: __________ ___ Not performed Molecular Pathology Specify: __________ ___ Not performed Radiographic Findings Specify: __________ ___ Not available

Rubin BP, et al: Protocol for the examination of specimens from patients with tumors of bone, College of American Pathology, Based on AJCC/UICC TNM, ed 7, 2013.

Reporting of Bone Tumors A pathologist reporting on a bone tumor is confronted with the task of categorizing them into three major subtypes: benign, locally aggressive, and malignant. Benign tumors are defined as having a limited growth potential. Although they may recur, the recurrence is typically nondestructive and can be cured by complete reexcision or curettage. Examples of tumors in this category include osteoid osteoma and chondroblastoma. Intermediate, locally aggressive tumors are subdivided into two groups. The first are those tumors that often recur in an infiltrative, locally destructive manner but do not have any evident potential to metastasize. Such lesions require wide, complete excision to accomplish local control. The exemplary lesion in this category is grade 1 chondrosarcoma. The second group of intermediate tumors, in addition to having locally aggressive recurrence, has the capacity for distant metastasis although the risk for such metastasis is minimal, typically less than 5%. The prototypic tumor of this category is a conventional giant cell tumor of bone, which may occasionally metastasize, typically to the lung. Malignant tumors are defined by their ability to grow locally in a destructive pattern, as well as to have a high propensity for both local recurrence and distant metastasis. Many of the tumors in this category have a risk for distant metastasis exceeding 20%; in some of them the metastasis develops in virtually every instance without therapeutic intervention. The recommended grouping of bone tumors into these three categories does not correspond to histologic grading. Specifically, it is important to mention that the intermediate category in this grouping does not correspond to the histologic intermediate grade.

Formulation of a pathology report is a complex task that requires the integration of data from various resources, including clinical, imaging, molecular, gross, and microscopic. The current recommendations for the formulation of pathology reports of bone biopsies and resection specimens by the College of American Pathology are summarized in Table 1-7 and Table 1-8.123

GENERAL EPIDEMIOLOGY OF BONE TUMORS Primary bone tumors are comparatively uncommon among the wide array of human neoplasms. This has contributed to a paucity of meaningful data concerning the relative frequency and incidence rates of the various subtypes of bone tumors, as well as only a rudimentary understanding of risk factors. In previous studies, some regional cancer centers and cancer registries have provided information on the epidemiology of bone tumors and some predisposing conditions, which include relative frequency of occurrences by age and sex in addition to skeletal localization.129-134,136,142,146,150,156 Such reports have also provided potentially important pathogenetic information concerning age and gender, as well as ethnic and racial predispositions for bone sarcomas.135,137,139,140-142,144,150,155 The data presented here are from 37 years (19732010) of the National Cancer Institute’s SEER Program.152 The SEER Program reports long term incidence, prevalence, and survival data provided by medically oriented, nonprofit organizations, such as universities and state health departments, to obtain epidemiologic data on all cancers diagnosed in residents of selected geographic areas of the United States referred to as the Centers for

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TABLE 1-8 Checklist for Standard Reporting of Bone Sarcoma Resection Specimens Specimen Specify bone involved (if known): _______ ___ Not specified Procedure ___ Intralesional resection ___ Marginal resection ___ Segmental/wide resection ___ Radical resection ___ Other (specify): ________ ___ Not specified Tumor Site ___ Epiphysis or apophysis ___ Metaphysis ___ Diaphysis ___ Cortex ___ Medullary cavity ___ Surface ___ Tumor involves joint ___ Tumor extension into soft tissue ___ Cannot be determined Tumor Size Greatest dimension: ___ cm Additional dimensions: ___ × ___ cm ___ Cannot be determined ___ Multifocal tumor/discontinuous tumor at primary site (skip metastasis) Histologic Type (World Health Organization Classification) Specify: ____________ ___ Cannot be determined Mitotic Rate Specify: ___ /10 high-power fields (1 HPF × 400 = 0.1734 mm2; X40 objective; most proliferative area) Necrosis (macroscopic or microscopic) ___ Not identified ___ Present   Extent: ____%

Histologic Grade Specify: ___ ___ Not applicable ___ Cannot be determined Margins ___ Cannot be assessed ___ Margins uninvolved by sarcoma   Distance of sarcoma from closest margin: ___ cm   Specify margin (if known): ___________ ___ Margin(s) involved by sarcoma   Specify margin(s) (if known): _________ Lymph-Vascular Invasion ___ Not identified ___ Present ___ Indeterminate Pathologic Staging (pTNM) TNM Descriptors (required only if applicable) (select all that apply) ___ m (multiple) ___ r (recurrent) ___ y (posttreatment) Primary Tumor (pT) ___ pTx: Primary tumor cannot be assessed ___ pT0: No evidence of primary tumor ___ pT1: Tumor ≤8 cm in greatest dimension ___ pT2: Tumor >8 cm in greatest dimension ___ pT3: Discontinuous tumors in the primary bone site Regional Lymph Nodes (pN) (Note K) ___ pNx: Regional lymph nodes cannot be assessed ___ pN0: No regional lymph node metastasis ___ pN1: Regional lymph node metastasis ___ No nodes submitted or found Number of Lymph Nodes Examined Specify: ___ ___ Number cannot be determined (explain): ________

Number of Lymph Nodes Involved Specify: ___ ___ Number cannot be determined (explain): ________ Distant Metastasis (pM) ___ Not applicable ___ pM1a: Lung ___ pM1b: Metastasis involving distant sites other than lung   +Specify site(s), if known: _______________ Additional Pathologic Findings Specify: ___________ Ancillary Studies (required only if applicable) Immunohistochemistry Specify: ___________ ___ Not performed Cytogenetics Specify: ___________ ___ Not performed Molecular Pathology Specify: ___________ ___ Not performed Radiographic Findings (if available) Specify: ___________ ___ Not performed Preresection Treatment ___ No therapy ___ Chemotherapy performed ___ Radiation therapy performed ___ Therapy performed, type not specified ___ Unknown Treatment Effect ___ Not identified ___ Present   +Specify percentage of necrotic tumor (compared with pretreatment biopsy, if available): ___% ___ Cannot be determined

Rubin BP, et al: Protocol for the examination of specimens from patients with tumors of bone, College of American Pathology, Based on AJCC/UICC TNM, ed 7, 2013.

Disease Control and Prevention’s National Program of Cancer Registries. The long term incidence and survival trends are available for 1975 to 2010 and are based on the data collected from the nine original geographic SEER areas that comprised the entire states of Connecticut, Iowa, New Mexico, Utah, and Hawaii, and the metropolitan areas of Detroit (Michigan), San Francisco– Oakland (California), Seattle–Puget Sound (Washington), and Atlanta (Georgia). The Seattle and Atlanta areas joined the program in 1974 and 1975, respectively. These areas represent approximately 10% of the population in the United States. As of 1992, SEER data has been collected from four additional populations (Alaska Natives, Los Angeles County, San Jose–Monterey, and rural Georgia) that increase the representation of minority groups and allow better stratification by race and ethnicity. The data from all 13 SEER registries are the source of incidence and survival rates from 1992 to 2010. The

SEER program added five additional areas beginning in 2000; these include greater California, greater Georgia, Kentucky, Louisiana, and New Jersey, bringing the coverage to 28% of the population in the United States. Unfortunately this program does not register the data on benign tumors, including those that arise in the skeleton, which are considered to be more frequent than bone sarcomas and are as mysterious as their malignant counterparts.138 For the purpose of SEER data analysis, bone tumors were classified according to the International Classification of Diseases (ICD) as shown in Table 1-9. The total number of bone sarcomas diagnosed among residents of SEER areas from 1973 to 2010 was 8417. Bone sarcomas are rare when compared with other cancers, constituting only 0.2% of all tumors for which data were obtained by the SEER Program during the 1973 to 2010 period. Comparison of the incidence of bone sarcomas with that of the closely related group of

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TABLE 1-9 Bones and Joints (T-170.0-170.9): Frequency and Percent Distribution by Histology and Race, Both Sexes, Microscopically Confirmed Cases, SEER Data 1973-2010 All Races Histology

White

Black

Frequency

%

Frequency

%

Frequency

%

8417 8322 138

100.00 98.87 1.64

6930 6854 115

100.00 98.90 1.66

825 815 13

100.00 98.79 1.58

67 3005 2011 752 32 210 2305 1142 46 116

0.80 35.70 23.89 8.93 0.38 2.49 27.39 13.57 0.55 1.38

54 2281 1529 583 25 144 1987 1023 34 96

0.78 32.91 22.06 8.41 0.36 2.08 28.67 14.76 0.49 1.39

8 468 304 115 5 44 165 42 5 2

0.97 56.73 36.85 13.94 0.61 5.33 20.00 5.09 0.61 0.24

650 853 95 0

7.72 10.13 1.13 0.00

570 694 76 0

8.23 10.01 1.10 0.00

18 94 10 0

2.18 11.39 1.21 0.00

Bones and Joints   Sarcoma    Malignant fibrous histiocytoma/high-grade pleomorphic sarcoma (8830-8831)    Fibrosarcoma (8810-8812)    Osteosarcoma    Osteosarcoma, NOS (9180)    Specified osteosarcomas (9181-9185, 9190)    Osteosarcoma in Paget’s disease of bone (9184)    Other    Chondrosarcoma, NOS (9220-9240)    Ewing’s sarcoma (9260)    Adamantinoma of long bones (9261)    Hemangioasarcoma and malignant hemangioendothelioma (9120-9134)    Chordoma (9370)    Other Unspecified Bones and Joints—in Situ

Bone Sarcomas 14

1.8

12

1.4 10 1.2 1

8

0.8

6

0.6

4

0.4

Age distribution (%)

Indcidence rate (cases/100,000 persons)

1.6

2

0.2 0

+ 85

-8 4

-7 9

80

-7 4

75

-6 9

70

4 -6

65

9 -5

60

-5 4

55

9 -4

50

45

-4 4

40

-3 9

35

9

-3 4

30

4

-2 25

-2

20

-1 9

-1 4

15

9 5-

10

14

0

0

Age at diagnosis FIGURE 1-19  ■  Bone and soft tissue sarcomas: Epidemiology. Comparison of age-specific incidence rates of bone and soft tissue sarcomas, all races, both sexes, SEER data, 1973-2010.

soft tissue sarcomas indicates that bone sarcomas occur at a rate that is approximately one tenth that of soft tissue sarcomas.154 The incidence rate of bone sarcomas diagnosed between 1973 and 2010 fluctuated around 0.8/100,000 and showed no tendency to increase or decrease. Osteosarcoma was the most frequently diagnosed primary sarcoma of bone (35.7%), followed by chondrosarcoma (27.3%), Ewing’s sarcoma (13.5%), and chordoma (7.7%) (Table 1-9). Malignant fibrous histiocytoma and fibrosarcoma formed another distinct group of lesions and when combined constituted 4.0% of all bone sarcomas. Angiosarcomas of bone were extremely rare and constituted 1.3% of cases. Unspecified primary

malignant neoplasms of bone constituted 1.1% of all cases. The number of cases in five major groups of bone sarcomas—osteosarcoma (3005), chondrosarcoma (2305), Ewing’s sarcoma (1142), chordoma (650), and malignant fibrous histiocytoma combined with fibrosarcoma (205), was sufficient to analyze incidence rates and patient survival. The age-specific frequencies and incidence rates of bone sarcomas as a group are clearly bimodal (Fig. 1-19). The first well-defined peak occurs during the second decade of life. The second peak occurs in patients older than 60 years. The risk of development of bone sarcomas during the second decade of life is close to that seen in the population older than 60 years, but there are more

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TABLE 1-10 Relative Frequencies of Bone Sarcomas by Histologic Type, Sex, and Race: SEER Data 1973-2010 Total

Osteosarcoma Chondrosarcoma Ewing’s Sarcoma Chordoma Fibrosarcoma/Malignant Fibrous Histiocytoma Angiosarcoma Adamantinoma of Long Bones Unspecified Others (Sarcomas) Total

Male

Female

White

Black

No.

%

No.

%

No.

%

No.

%

No.

%

3005 2305 1142 650 205 116 46 95 853 8417

35.70 27.38 13.57 7.72 2.44 1.38 0.55 1.13 10.13 100

1651 1228 710 386 105 72 24 53 471 4700

35.13 26.13 15.11 8.21 2.23 1.53 0.51 1.13 10.02 100.00

1354 1077 432 264 100 44 22 42 382 3717

36.43 28.98 11.62 7.10 2.69 1.18 0.59 1.13 10.28 100.00

2281 1987 1023 570 169 96 34 76 694 6930

32.91 28.67 14.76 8.23 2.44 1.39 0.49 1.10 10.01 100.00

468 165 42 18 21 2 5 10 94 825

56.73 20.00 5.09 2.18 2.55 0.24 0.61 1.21 11.39 100.00

TABLE 1-11 Incidence Rates of Bone Sarcomas by Histologic Type, Race, and Sex: SEER Data, 1973-2010 All Races

Osteosarcoma Chondrosarcoma Ewing’s Sarcoma Chordoma Malignant Fibrous Histiocytoma Total

White

Black

Total

Male

Female

Total

Male

Female

Total

Male

Female

0.31 0.25 0.12 0.07 0.01 0.76

0.35 0.27 0.15 0.08 0.02 0.87

0.28 0.23 0.08 0.05 0.01 0.65

0.3 0.26 0.13 0.08 0.02 0.79

0.34 0.28 0.17 0.09 0.01 0.89

0.26 0.25 0.1 0.06 0.02 0.69

0.39 0.14 0.03 0.01 0.01 0.58

0.42 0.17 0.05 0.02 0.01 0.67

0.37 0.11 0.02 0.01 0.01 0.52

TABLE 1-12 Median Age at Diagnosis for Bone Sarcomas by Histologic Type, Race, and Sex: SEER Data 1973-2010 All Races

Osteosarcoma, NOS Osteosarcoma, Paget’s Disease Chondrosarcoma Ewing’s Sarcoma Chordoma Malignant Fibrous Histiocytoma

White

Black

Total

Male

Female

Total

Male

Female

Total

Male

Female

21 73 52 17 57.5 68.5

20 71.5 52 17 57 68.5

23 74 53 16 57.5 68

23 73.5 54 17 58 69

23 73 53 17 57.5 69

23 74 54 16 59 69

18.5 59.5 45 19 42 59

17 60 44 20 45 59

23 _ 45 16 36 58

cases in the second decade. The bimodal age-specific incidence rate pattern of bone sarcomas is clearly different from that of soft tissue sarcomas, which shows a gradual increase of incidence with age. General epidemiologic data on relative frequencies, incidence, and survival rates as well as the mean age at diagnosis by histologic type, sex, and race are summarized in Table 1-9 to Table 1-13. Age-related incidence rates and frequency distribution patterns for four major groups of primary bone sarcomas—osteosarcoma, chondrosarcoma, Ewing’s sarcoma, and chordoma—are shown in Figures 1-20 and 1-21. The overall incidence rates of osteosarcoma, chondrosarcoma, chordoma, and malignant fibrous histiocytoma for the white and black populations are similar. The incidence rates for the black population, especially for males, are somewhat higher for osteosarcoma but the difference is relatively small.145-147,151,153 In general, the incidence rates for major groups of bone sarcomas reported in North America and Europe are similar.131,148,149

However, there are several populations that appear to have increased incidence rates of bone sarcomas particularly evident for osteosarcoma, including parts of Brazil and Italy, as well as Argentina, Finland, and Israel.131,148,149 It is uncertain whether these differences reflect increased ethnically based predisposition, environmental factors, or industrial factors or are simply the results of inaccuracies related to disease and population monitoring. The most striking difference is in the incidence of Ewing’s sarcoma, which shows a tenfold higher incidence in the white population compared with the black population. This difference has been repeatedly shown in SEER data and regional analyses in the United States.134,143-145,150 The paucity of reports for Ewing’s sarcoma from Africa, although the exact population data is not available for this continent, confirms the extreme rarity of Ewing’s sarcoma in the black population. The comparison of survival rates for major groups of bone sarcoma at the beginning of the SEER program and

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28

1  General Considerations

TABLE 1-13 Five-year Relative Survival Rates (%) for Bone Sarcomas by Histologic Type, Sex, and Race: SEER Data 1973-2010 Calendar Period

Sex

Race

Total 1973-1977 1978-1982 1983-1987 1988-1992 1993-1997 1998-2005 Male Female White Black Osteosarcoma, NOS Osteosarcoma, Paget’s Disease Chondrosarcoma Ewing’s Sarcoma Chordoma Malignant Fibrous Histiocytoma

50.6

38.7

40.14

40.42

55.74

53.96

53.2

48.7

53.4

49.8

51.7

18.8

*

*

*

*

*

*

15.6

21.5

20.3

*

79.3 46.8

73.3 34.6

70.42 41.46

67.02 49.58

79.24 46.36

82.92 48.2

80.65 49.46

76.4 44.6

82.2 50.9

79.4 47.1

77.1 37.7

73.1 65.4

63 51.8

52.04 54.58

73.26 62.12

67.16 65.04

75.02 65.52

77.55 67.88

72.5 65.6

73.9 65.2

73.5 66.1

71.7 53.7

*T mutation in a black African family. Genet Couns 19:183–192, 2008. 197. Larsson T, Davis SI, Garringer HJ, et al: Fibroblast growth factor-23 mutants causing familial tumoral calcinosis are differentially processed. Endocrinology 146:3883–3891, 2005. 198. Lufkin EG, Wilson DM, Smith LH, et al: Phosphorus excretion in tumoral calcinosis: response to parathyroid hormone and acetazolamide. J Clin Endocrinol Metab 50:648–653, 1980. 199. Lyles KW, Burkes EJ, Ellis GJ, et al: Genetic transmission of tumoral calcinosis: autosomal dominant with variable clinical expressivity. J Clin Endocrinol Metab 60:1093–1096, 1985. 200. Lyles KW, Halsey DL, Friedman NE, et al: Correlation of serum concentrations of 1,25-dihydroxy vitamin D, phosphorus, and parathyroid hormone in tumoral calcinosis. J Clin Endocrinol Metab 67:88–92, 1988. 201. Maathuis JB, Koten JW: Kikuyu-bursa and tumoral calcinosis. Trop Geogr Med 21:389–396, 1969. 202. McClatchie S, Bremner AD: Tumoral calcinosis: an unrecognized disease. Br Med J 1:153–155, 1969. 203. Meltzer CC, Fishman EK, Scott WW, Jr: Tumoral calcinosis causing bone erosion in a renal dialysis patient. Clin Imaging 16:49–51, 1992. 204. Mozaffarian G, Lafferty FW, Pearson OH: Treatment of tumoral calcinosis with phosphorus deprivation. Ann Intern Med 77:741– 745, 1972. 205. Murthy DP: Tumoral calcinosis: a study of cases from Papua, New Guinea. J Trop Med Hyg 93:403–407, 1990. 206. Noyez JF, Murphree SM, Chen K: Tumoral calcinosis, a clinical report of 11 cases. Acta Orthop Belg 59:249–254, 1993. 207. Prince MJ, Schaeffer PC, Goldsmith RS, et al: Hyperphosphatemic tumoral calcinosis: association with elevation of serum 1,25-dihydroxycholecalciferol concentrations. Ann Intern Med 96:586–591, 1982. 208. Slavin RE, Wen J, Kumar D, et al: Familial tumoral calcinosis: a clinical, histopathological, and ultrastructural study with an analysis of its calcifying process and pathogenesis. Am J Surg Pathol 17:788–802, 1993. 209. Sledz K, Ortiz O, Wax M, et al: Tumoral calcinosis of the temporomandibular joint: CT and MR findings. Am J Neuroradiol 16:782–785, 1995. 210. Steinbach LS, Johnston JO, Tepper EF, et al: Tumoral calcinosis: radiologic-pathologic correlation. Skeletal Radiol 24:573–578, 1995. 211. Steinherz R, Chesney RW, Eisenstein B, et al: Elevated serum calcitriol concentrations do not fall in response to hyperphosphatemia in familial tumoral calcinosis. Am J Dis Child 139:816–819, 1985. 212. Tezelman S, Siperstein AE, Duh QY, et al: Tumoral calcinosis: controversies in the etiology and alternatives in the treatment. Arch Surg 128:737–744, 1993. 213. Topaz O, Indelman M, Chefetz I, et al: A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis. Am J Hum Genet 79:759–764, 2006. 214. Vasudev KS, Tapp L, Harris M, et al: Tumoral calcinosis in Britain. Br Med J 1:767, 1973.

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215. Veress B, Malik MO, El Hassan AM: Tumoural lipocalcinosis: a clinicopathological study of 20 cases. J Pathol 119:113–118, 1976. 216. Wilber JF, Slatopolsky E: Hyperphosphatemia and tumoral calcinosis. Ann Intern Med 68:1043–1049, 1968. 217. Yaghmai I, Mirbod P: Tumoral calcinosis. Am J Roentgenol Radium Ther Nucl Med 111:573–578, 1971. 218. Yu X, White KE: FGF23 and disorders of phosphate homeostasis. Cytokine Growth Factor Rev 16:221–232, 2005. Tophaceous Pseudogout 219. Fam AG: Calcium pyrophosphate crystal deposition disease and other crystal deposition diseases. Curr Opin Rheumatol 4:574–582, 1992. 220. Hamilton EB: Diseases associated with CPPD deposition disease. Arthritis Rheum 19:353–357, 1976. 221. Ishida T, Dorfman HD, Bullough PG: Tophaceous pseudogout (tumoral calcium pyrophosphate dihydrate crystal deposition disease). Hum Pathol 26:587–593, 1995. 222. Jensen PS, Putman CE: Current concepts with respect to chondrocalcinosis and the pseudogout syndrome. AJR Am J Roentgenol Radium Ther Nucl Med 123:531–539, 1975. 223. Markel SF, Hart WR: Arthropathy in calcium pyrophosphate dihydrate crystal deposition disease. Arch Pathol Lab Med 106:529– 533, 1982. 224. Martel W, McCarter D, Solsky MA, et al: Further observations on the arthropathy of calcium pyrophosphate crystal deposition disease. Radiology 141:1–15, 1981. 225. McAllister CM, Dorfman HD: Crystal deposition disease in bone: a review. Einstein Q J Biol Med 7:122–130, 1989. 226. McCarty DJ, Kohn NN, Faires JS: The significance of calcium phosphate crystals in the synovial fluid of arthritic patients: the “pseudogout syndrome.” I. Clinical aspects. Ann Intern Med 56:711–737, 1962. 227. Resnick CS, Resnick D: Crystal deposition disease. Semin Arthritis Rheum 12:390–403, 1983. 228. Richards AJ, Hamilton BB: Destructive arthropathy in chondrocalcinosis articularis. Ann Rheum Dis 33:196–203, 1974. 229. Shaffrey CI, Munoz EL, Sutton CL, et al: Tumoral calcium pyrophosphate dihydrate deposition disease mimicking a cervical spine neoplasm: case report. Neurosurgery 37:335–339, 1995. 230. Yu SL, Li RZ, Bian ZH: Tumoral calcium pyrophosphate dihydrate deposition disease: report of a case with review of the literature. Chin Med J 105:780–784, 1992. Tophaceous Gout 231. Bloch C, Hermann G, Yu TF: A radiologic reevaluation of gout: a study of 2,000 patients. AJR Am J Roentgenol 134:781–787, 1980. 232. Keith MP, Gilliland WR: Updates in the management of gout. Am J Med 120:221–224, 2007. 233. Kelley WN, Fox IH: Gout and related disorders of purine metabolism. In Kelley WN, Harris ED, Jr, Ruddy S, et al, editors: Textbook of rheumatology, ed 4, 2 vols, Philadelphia, 1993, WB Saunders. 234. Monu JU, Pope TL, Jr: Gout: a clinical and radiologic review. Radiol Clin North Am 42:169–184, 2004. 235. Peh WC: Tophaceous gout. Am J Orthop 30:665, 2001. 236. Pennes DR, Martel W: Hyperuricemia and gout. Semin Roentgenol 21:245–255, 1986. 237. Resnick D, Broderick TW: Intraosseous calcifications in tophaceous gout. AJR Am J Roentgenol 137:1157–1161, 1981. 238. Resnick D, Niwayama G: Gouty arthritis. In Resnick D, editor: Diagnosis of bone and joint disorders, ed 3, Philadelphia, 1994, WB Saunders. Chronic Recurrent Multifocal Osteomyelitis 239. Bergdahl K, Bjorksten B, Gustavson K-H, et al: Pustulosis palmoplantaris and its relation to chronic recurrent multifocal osteomyelitis. Dermatologica 159:37–45, 1979. 240. Bjorksten B, Gustavson K-H, Eriksson B, et al: Chronic recurrent multifocal osteomyelitis and pustulosis palmoplantaris. J Pediatr 93:227–231, 1978. 241. Bjorksten B, Boquist L: Histopathological aspects of chronic recurrent multifocal osteomyelitis. J Bone Joint Surg Br 62:376– 380, 1980.

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242. Catalano-Pons C, Comte A, Wipff J, et al: Clinical outcome in children with chronic recurrent multifocal osteomyelitis. Rheumatology (Oxford) 47:1397–1399, 2008. 243. Cyrlak D, Pais MJ: Chronic recurrent multifocal osteomyelitis. Skeletal Radiol 15:32–39, 1986. 244. El-Shanti HI, Ferguson PJ: Chronic recurrent multifocal osteomyelitis: a concise review and genetic update. Clin Orthop Relat Res 462:11–19, 2007. 245. Giedion A, Holthusen W, Masel LF, et al: Subacute and chronic “symmetrical” osteomyelitis. Ann Radiol (Paris) 15:329–342, 1972. 246. Girardet JP, Sambucy F, Douillet P, et al: Osteomyelite symetrique subaigue. Arch Fr Pediatr 36:418–422, 1979. 247. Girschick HJ, Zimmer C, Klaus G, et al: Chronic recurrent multifocal osteomyelitis: what is it and how should it be treated? Nat Clin Pract Rheumatol 3:733–738, 2007. 248. Golla A, Jansson A, Ramser J, et al: Chronic recurrent multifocal osteomyelitis (CRMO): evidence for a susceptibility gene located on chromosome 18q21.3-18q22. Eur J Hum Genet 10:217–221, 2002. 249. Gustavson KH, Wilbrand HF: Chronic symmetric osteomyelitis. Acta Radiol 15:551–557, 1974. 250. Hoffmann T, Finger D: Chronic recurrent multifocal osteomyelitis. J Rheumatol 34:2499–2500, 2007. 251. Jansson A, Renner ED, Ramser J, et al: Classification of nonbacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology (Oxford) 46:154– 160, 2007. 252. Kawakami T, Toyoshima R, Furuse K, et al: So-called sternocosto-clavicular hyperostosis: its etiology and manifestations. Rinsho Seikei Geka 15:650, 1980. 253. Kozlowski K, Masel J, Harbison S, et al: Multifocal chronic osteomyelitis of unknown etiology. Pediatr Radiol 13:130–136, 1983. 254. Machiels F, Seynaeve P, Lagey C, et al: Chronic recurrent multifocal osteomyelitis with MR correlation: a case report. Pediatr Radiol 22:535–536, 1992. 255. Murray SD, Kehl DK: Chronic recurrent multifocal osteomyelitis: a case report. J Bone Joint Surg 66A:1110–1112, 1984. 256. Probst FP: Chronic multifocal cleido-metaphyseal osteomyelitis of childhood. Acta Radiol Diagn (Stockholm) 17:531–537, 1976. 257. Probst FP, Bjorksten B, Gustavson KH: Radiological aspects of chronic recurrent multifocal osteomyelitis. Ann Radiol (Paris) 21:115–125, 1978. 258. Ravelli A, Marseglia GL, Viola S, et al: Chronic recurrent multifocal osteomyelitis with unusual features. Acta Paediatr 84:222– 225, 1995. 259. Segev E, Hayek S, Lokiec F, et al: Primary chronic sclerosing (Garré’s) osteomyelitis in children. J Pediatr Orthop B 10:360–364, 2001. 260. Solheim LF, Paus B, Liverud K, et al: Chronic recurrent multifocal osteomyelitis: a new clinical-radiological syndrome. Acta Orthop Scand 51:37–41, 1980. 261. Stanton RP, Lopez-Sosa FH, Doidge R: Chronic recurrent multifocal osteomyelitis. Orthop Rev 22:229–233, 1993. 262. Tlougan BE, Podjasek JO, O’Haver J, et al: Chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome with associated neutrophilic dermatoses: a report of seven cases and review of the literature. Pediatr Dermatol 26:497–505, 2009. Amyloidosis of Bone 263. Casey TT, Stone WJ, DiRaimondo CR, et al: Tumoral amyloidosis of bone of beta 2-microglobulin origin in association with long-term hemodialysis: a new type of amyloid disease. Hum Pathol 17:731–738, 1986. 264. Cloft HJ, Quint DJ, Markert JM, et al: Primary osseous amyloidoma causing spinal cord compression. Am J Neuroradiol 16:1152–1154, 1995. 265. Cohen AS: Proteins of the systemic amyloidoses. Curr Opin Rheum 6:55–67, 1994. 266. Cornwell GG, III, Johnson KH, Westermark P: The age related amyloids: a growing family of unique biochemical substances. J Clin Pathol 48:984–989, 1995. 267. Davidson GS, Montanera WJ, Fleming JF, et al: Amyloid destructive spondyloarthropathy causing cord compression: related to chronic renal failure and dialysis. Neurosurgery 33:519–522, 1993.

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268. Dickman CA, Sonntag VK, Johnson P, et al: Amyloidoma of the cervical spine: a case report. Neurosurgery 22:419–422, 1988. 269. Drueke T, Touam M, Zingraff J: Dialysis-associated amyloidosis. Adv Renal Replace Ther 2:24–39, 1995. 270. Ferreiro JA, Bhuta S, Nieberg RK, et al: Amyloidoma of the skull base. Arch Pathol Lab Med 114:974–976, 1990. 271. Fierens J, Mees U, Vanbockrijck M, et al: Amyloidoma of the chest wall: a rare entity. Interact Cardiovasc Thorac Surg 7:1194– 1195, 2008. 272. Griffin M, Parai M, Fernandez D, et al: Amyloid tumor of the sacrum: a case report. Acta Cytol 39:503–506, 1995. 273. Isaacs M, Bansal M, Flombaum CD, et al: Case report 772: stress fracture of the hip secondary to renal osteodystrophy and erosion of ischium due to amyloid deposition. Skeletal Radiol 22:129–133, 1993. 274. Kisilevsky R: Amyloid and amyloidosis: differences, common themes, and practical considerations. Mod Pathol 4:514–518, 1991. 275. Krishnan J, Chu WS, Elrod JP, et al: Tumoral presentation of amyloidosis (amyloidomas) in soft tissue: a report of 14 cases. Am J Clin Pathol 100:135–144, 1993. 276. Lai KN, Chan KW, Siu DL, et al: Pathologic hip fractures secondary to amyloidoma: case report and review of the literature. Am J Med 77:937–943, 1984. 277. Lipper S, Kahn LB: Amyloid tumor: a clinicopathologic study of four cases. Am J Surg Pathol 2:141–145, 1978.

278. Naito M, Ogata K, Shiota E, et al: Amyloid bone cysts of the femoral neck: impending fractures treated by curettage and bone grafting. J Bone Joint Surg Br 76:922–925, 1994. 279. Onishi S, Andress DL, Maloney NA, et al: Beta 2-microglobulin deposition in bone in chronic renal failure. Kidney Int 39:990–995, 1991. 280. Pasternak S, Wright BA, Walsh N: Soft tissue amyloidoma of the extremities: report of a case and review of the literature. Am J Dermatopathol 29:152–155, 2007. 281. Sipe JD: Amyloidosis. Crit Rev Clin Lab Sci 31:325–354, 1994. 282. Sprague SM, Popovtzer MM: Is beta-2-microglobulin a mediator of bone disease? Kidney Int 47:1–6, 1995. 283. Tan SY, Pepys MB: Amyloidosis. Histopathology 25:403–414, 1994. 284. Tateishi H, Maeda M, Yoh K, et al: Pathologic fracture associated with amyloid deposition in the bone of a chronic hemodialysis patient: a case report. Clin Orthop 274:300–304, 1992. 285. Unal F, Hepgul K, Bayindir C, et al: Skull base amyloidoma: case report. J Neurosurg 76:303–306, 1992. 286. Urban BA, Fishman EK, Humphrey RL: Primary amyloidosis of the sternum: imaging findings. Clin Imaging 18:75–78, 1994. 287. Villarejo F, Perez Diaz C, Perla C, et al: Spinal cord compression by amyloid deposits. Spine 19:1178–1181, 1994. 288. Weiss SW: Tumoral amyloidosis of soft tissue (amyloidoma): new approaches to an old problem. Am J Clin Pathol 100:91, 1993.

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C H A P T E R 2 4 

Precancerous Conditions CHAPTER OUTLINE PAGET’S DISEASE OF BONE

OSTEOGENESIS IMPERFECTA

OSTEOMYELITIS

SYNDROMES PREDISPOSING TO MALIGNANCY IN BONE

BONE INFARCTS

Rothmund-Thomson Syndrome Li-Fraumeni Syndrome

METALLIC IMPLANTS RADIATION INJURY

The presence of a neoplasm in bone is manifested in a variety of ways. Pain and localized swelling or pathologic fracture are the most frequent presenting complaints, but rarely is a bone tumor discovered as an incidental finding on radiographic images made for other reasons (e.g., after trauma). Occasionally, the appearance of new symptoms or a changing clinical picture in the presence of a known skeletal disorder may signal the onset of malignant transformation in a benign precursor lesion. Early diagnosis of bone neoplasms is complicated by the fact that except for osteoid osteoma and the extremely uncommon intraosseous glomus tumor, small bone tumors are usually asymptomatic. Primary malignant tumors of bone generally reach substantial dimensions before they produce symptoms (predominantly pain or pathologic fracture). Although the majority of primary bone malignancies arise de novo, it is increasingly apparent that some develop in association with recognizable precursors. The likelihood of discovering these associated lesions can be facilitated by attention to clinicopathologic correlation of all available data before arriving at a diagnosis. In bone, the inclusion of radiographic imaging data in the diagnostic process offers a unique opportunity to discover clues to causal relationships that may not be reflected in histologic patterns or in other laboratory data. This is especially true when serial radiographs are available for review. Paget’s disease, radiation injury, and some of the more common benign cartilaginous dysplasias are the most clearly established precancerous conditions. The relative rarity of malignant transformation in fibrous dysplasia, osteomyelitis, bone cysts, osteogenesis imperfecta, and bone infarction places these conditions in a separate category. The possible relationship of secondary malignancy to metallic implants and joint prostheses is a subject of increasing concern, although its statistical validity is still in doubt. Additional neoplastic and nonneoplastic lesions that may be precursors of malignancy in bone

are listed in Table 24-1. In this chapter the discussion of precancerous lesions is limited to those conditions that play a major role in increasing the risk for bone malignancy.

PAGET’S DISEASE OF BONE Definition Osteitis deformans, as described by Sir James Paget, represents a prototype skeletal disorder that predisposes to the development of sarcoma in bone.12,13 A comprehensive description of this unique disease is beyond the scope of this book; thus the discussion of Paget’s disease is restricted to the basic clinicopathologic features of osteitis deformans that are relevant for its recognition when it is associated with sarcoma of bone. From the pathogenetic point of view, the disease can be explained by increased transient but progressive and multifocal osteoclastic activity, with bone resorption followed by new bone formation, and ultimately bone sclerosis. Ultrastructural and immunohistochemical analyses have demonstrated cytoplasmic and nuclear inclusions in the osteoclasts of pagetic bone that are similar to those seen in paramyxovirus infection.4,8,10 As a result of these observations, some authors support the hypothesis that Paget’s disease may be induced by a slow viral infection.8,17 When there is a high rate of bone turnover with rapid bone growth, cell proliferation, and osteoclastic activity, it is conceivable that somatic mutations and genomic deletions will occur with a high frequency and thus provide a molecular basis for malignant transformation. Other authors have alluded to the possibility that an infectious etiology is a cofactor in the development of malignancy in Paget’s disease.10 However, more recent attempts to identify paramyxovirus coding sequences by the use of polymerase chain reactions have failed to demonstrate the presence of a paramyxoviral genome in

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24  Precancerous Conditions

TABLE 24-1 Neoplastic and Nonneoplastic Precursors of Malignancy in Bone Nonneoplastic Conditions Paget’s disease* Chronic osteomyelitis* Bone infarct* Metallic implants* Radiation, osteitis* Osteogenesis imperfecta* Fibrous dysplasia (see Chapter 8) Bone cysts (see Chapter 15) Synoval chondromatosis (see Chapter 20)

Benign Tumors Osteochondroma (see Chapter 6) Enchondroma (see Chapter 6) Ollier’s disease and Maffucci’s syndrome (see Chapter 6) Chondromyxoid fibroma (see Chapter 6) Giant cell tumor (see Chapter 10) Metaphyseal fibrous defect (see Chapter 8) Osteoblastoma (see Chapter 4) Osteofibrous dysplasia and adamantinoma of long bones (see Chapters 8 and 17)

*These conditions are described in this chapter. For a description of the other lesions and their roles as precursors of malignancy in bone, refer to the appropriate chapters.

Paget’s disease. Modern concepts postulate that the etiology of Paget’s disease is heterogeneous and involves both genetic and environmental components (Fig. 24-1).1,4,15 The gene with mutations in the coding region associated with Paget’s disease is sequestosome 1 (SQSTM1) encoding the p62 protein.5 All mutations involving p62 identified in Paget’s patients cause the loss of function of the C-terminal ubiquitin-associated (UBA) domain. These mutations result in elevation of NFκB in pagetic osteoclastic cells but are insufficient to induce full pagetic phenotype, and additional genetic as well as environmental factors are needed for full expression of the pagetic phenotype. The scaffold p62 protein has specific interactions that mediate activations of RANKL, a key regulator of osteoclast function. The most common mutation, SQSTM1C1215T, causes amino acid substitution and is found in approximately 10% of sporadic and 30% of familial Paget’s disease. Recently, SQSTM1 mutations have been identified in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration, neurodegenerative disorders in which there is previously unrecognized coexistence with Paget’s disease of bone.16 The mutations in these disorders can overlap with those identified in Paget’s disease, but some of them appear to be specific for the neurodegenerative disease. These findings provide an unexpected link between amyotrophic lateral sclerosis/frontotemporal lobar degeneration and Paget’s disease of bone. The genetic linkage studies have identified seven predisposing loci that involve 1p12.3 (macrophage colony stimulating factor [M-CSF; CSF1]), 18q21.33 (RANK [TNFRSF11A]), 8q22.3 (dendritic-cell-specific transmembrane protein [DCSTAMP]), 10p13(optineurin [OPTN]), 7q33 (nucleoporin 205κDa [NUP205]), 14q32 (Ras and Rab interactor 3 [RIN3]), 15q24 (promyelocytic leukemia [PML] and golgin A6 family, member

A [GOLGA6A]).4,15 The environmental factors that are suggested as possible contributors for Paget’s disease include dietary deficiencies (calcium and vitamin D), chronic infection with measles virus, canine distemper virus, and respiratory syncytial virus.4,18 The potential contribution of chronic infections with measles virus has been the most extensively studied. In animal models, the expression of measles virus nucleocapsid gene (MVNP) in osteoclasts induces pagetic lesions. The overexpression of MVNP in osteoclastic cells activates NFκB and results in increased levels of IL-6 and ephrinB2. This, in turn, elevates ephrinB4 in osteoblastic cells, leading to the increased bone formation implicated in the development of pagetoid sclerosis. These new molecular developments provide interesting clues to the pathobiology of Paget’s disease, but full understanding of this complex and still mysterious disorder is far from complete. Incidence and Location Paget’s disease is widespread in many countries. Autopsy data indicate that it can be found in 3% to 4% of unselected patients older than age 45 years who died of various causes.2,17 The rate of radiographically diagnosed Paget’s disease varies from 1 in 500 to 1 in 12,000 hospital admissions.1 It appears that male and female patients are almost equally affected by the disease, but in many series, the incidence is slightly higher in men. Paget’s disease is common in Europe. The incidence is highest in the United Kingdom, France, and Germany. It is less frequent in Scandinavia, Spain, Italy, Central Europe, and Russia. The incidence in Australia and New Zealand is similar to that in Great Britain. Families with several generations affected by Paget’s disease have been described. The rate of familial variants is unclear, and most authors report that less than 10% of cases have a familial pattern. A mendelian-dominant pattern of transmission has been documented in some families. The onset of Paget’s disease is insidious, and the disease can be asymptomatic for many years. The full clinical picture with characteristic bone deformities appears after 20 to 30 years. Cases with widespread involvement of the skeleton and characteristic deformities are rare. It is estimated that there is 1 such case per every 100 patients with indolent asymptomatic disease. The disease is rarely diagnosed in people younger than age 40 years. The disease in its fully developed clinical picture is typically seen in patients in the sixth through eighth decades of life. Clinical Symptoms The typical skeletal deformities of fully developed Paget’s disease consist of an enlarged head, outward bowed femora, forward bowed tibiae, and bowed back. The long bones appear to be thickened on external examination. A single bowed and enlarged long bone, such as the tibia or femur, may be the only clinical sign. In most such cases, a radiographic examination documents the involvement of additional bones. Clinically silent Paget’s disease is most frequently identified on radiographs of the pelvis, sacrum, and lumbar spine. In general, the spine, pelvis,

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13.1 13.3

14 13.2 12 11.1 12 13.2

SQSTM1

14 15

1

21 22 23.2 31.1 31.3 33.1 33.3

A

35.1 35.3

PB1 ZZ LIR KIR UBA

Exon 9

Exon 7 Exon 8

cds

Exon 6

Exon 4 Exon 5

Exon 3

15.2

P392L

13.3 13.1 11 11.2

Exon 1

15.3 15.1

Exon 2

SQSTM1

Chr 5

440 aa 3

23.1 23.3

B

PB1

102 122

ZZ

LIR KIR

167

387

UBA 436

31.2 32 33.2 34 35.2 SQSTM1

Phox/Bem1p domain Zinc finger type domain LC3-interacting region Keap1-interacting region Ubiquitin associated domain

Synonymous substitution Missense substitution Substitution - coding silent Deletion frameshift

C

p65 NF-κB Activation & IL-6 gene expression

D

1,25-(OH)2D3 signaling

NF-κB activation

E

FIGURE 24-1  ■  Molecular mechanisms of Paget’s disease. A, Chromosomal location and exon-intron structure of the sequestosome 1 (SQSTM1) gene. B, Linear diagram of the p62 protein showing specific domains and motifs with the position of mutations. The mutations involved in Paget’s disease of bone cluster in the ubiquitin-associated domain (UBA). C, The structural diagrams of the p62 protein showing domains and motifs with selected mutations identified in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and Paget’s disease of bone. The diagram shows domain specific peptides: Phox and Bem1p domain (PB1), LC3-interacting region (LIR), Keap1-interaction region (KIR), and UBA bound to their respective recognition proteins with the highlighted mutations. Mutation sites common to both ALS/FTLD and PDB with (A390X, P392L, G411S, G425R) or very close (P387L) to the UBA domain are highlighted. D, Molecular mechanisms activated by overexpression of MVNP in pagetic osteoclastic cells, which increases TBK1, resulting in activation of NFκB, leads to nuclear translocation. MVNP also decreases Sirt1 deacetylation of NFκB, leading to increased NFκB activity. In addition, TBK1 cooperates with MVNP to increase TAF12 and phosphoATF7, causing hypersensitivity of VDR to 1,25(OH)2D3. E, Activation of TNFα and RANKL in Paget’s disease of bone is mediated by mutant p62. Binding of TNFα activates RIP1 and TRAF6 by inducing K63-linked ubiquitination. The scaffold protein p62 interacts with RIP1 and TRAF6, leading to downstream activation of NFκB with complementary biologic effects to MVNP. Mutant p62 has faulty interactions with intermediary Cyld protein and does not associate with RIP1 and TRAF6, leading to decreased signal attenuation resulting in hyperactive NFκB. Both MVNP and mutant p62 hyperactivation of NFκB in pagetic osteoclastic cells increase IL-6 and ephrinB2 in osteoclasts and cause ephrinB4 dependent hyperactivation of osteoblasts resulting in increased bone formation. (C, Modified and reprinted with permission from Rea SL, Majcher V, Searle MS, et al: Exp Cell Res 325:27–37, 2014. D and E, modified and reprinted with permission from Galson DL, Roodman GD: J Bone Metab 21:85–98, 2014.)

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24  Precancerous Conditions

28 Peak age incidence of Paget's sarcoma

31

11

1

Incidence

76

14

Peak age incidence of Paget's disease

1

2

3

31

4

5

6

7

8

Age in decades

14

2 FIGURE 24-2  ■  Paget’s disease and sarcomatoid transformation. Skeletal sites most frequently involved by Paget’s disease are indicated by shaded areas. Numbers show skeletal distribution of 208 published cases of Paget’s sarcoma. Note that sarcomatous transformation predominantly occurs in sites frequently affected by Paget’s disease.

skull, and femur are considered the most frequently affected parts of the skeleton (Fig. 24-2). The tibia and the humerus are less frequently affected.

Bowing deformities and pathologic fractures are typically seen in weight-bearing sites. Microscopic Findings

Radiographic Imaging Radiographically, the lesions present as areas of irregular increased density with a cotton wool–like appearance interspersed by radiolucent areas1,11 (Fig. 24-3). More consolidated and larger areas of sclerosis can also be present. The bones are usually enlarged, and their normal shape or contour is altered by the development of prominent bony deformities (Fig. 24-4). In the long bones, the disease typically starts within the end portion and progresses toward the shaft (Fig. 24-5). When the disease is confined to the epiphyses of long bones, it can be confused on radiographs with other conditions such as giant cell tumor. Radiolucent areas represent younger, active foci. Patchy sclerosis is the intermediate phase. More consolidated larger areas of sclerosis represent the final stages of the process. Early lesions of the skull represent well-demarcated circular lytic areas, referred to as osteoporosis circumscripta (Figs. 24-6 and 24-8). Characteristically, in areas with paired bones such as the forearm or leg, only one bone is altered (Fig. 24-7). The other bone either is intact or shows only minimal involvement.

Microscopically, the initial early phase of the disease shows increased osteoclastic activity with fibrosis and prominent vascularization of the intertrabecular spaces. The fully developed, active phase of Paget’s disease is a mixture of osteoclastic activity that may lead to the formation of large clusters adjacent to Howship’s lacunae (Fig. 24-9). In addition, prominent osteoblastic activity results in the production of new osteoid. Bone in Paget’s disease represents irregular trabeculae with scalloped contours and irregular lines of mineralization that mimic a mosaic pattern. The end of the last phase is dominated by large areas of bone sclerosis in which multiple irregular lines of mineralization are present. Typically, different phases of the disease are present in different areas of the affected bone (Figs. 24-9 to 24-11). Malignant Transformation The development of bone sarcoma in this condition is the most serious complication and, although uncommon,

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B FIGURE 24-3  ■  Paget’s disease of skull: radiographic features. A and B, Advanced Paget’s disease of skull presenting as large, illdefined lytic area with cotton wool–like opacities.

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B

A FIGURE 24-4  ■  Paget’s disease of bone: radiographic features. A and B, Lateral radiographs of two examples of Paget’s disease involving tibia. Note anterior bowing deformity and coarse trabecular pattern with obscured corticomedullary demarcation in both radiographs. Incomplete transverse fracture is seen in proximal tibial shaft in B.

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B FIGURE 24-5  ■  Paget’s disease of humerus: radiographic features. A and B, Lytic lesion involving proximal end of humerus. Note sharp demarcation of advancing edge. Lesion is associated with pathologic fracture and was considered to represent giant cell tumor.

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A

*

B FIGURE 24-6  ■  Paget’s disease of skull: radiographic features. A, Early phase of Paget’s disease in skull presents as well-delineated lytic area referred to as osteitis circumscripta (arrows). B, Progression of lesion. Note large advancing lytic edge at periphery (arrows) and development of bony opacities in central, older areas of lesion (asterisk).

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FIGURE 24-7  ■  Paget’s disease of long bones: radiographic features. A, Early localized phase of Paget’s disease of radius with pathologic fracture (arrows). B, Early predominantly lytic phase of Paget’s disease of radius. Note involvement of only one bone of pair and bony deformity of affected bone. C and D, Fully developed phase of Paget’s disease with prominent osteoclastic activity and irregular scalloped trabeculae of bone. Osteoblastic activity is prominent focally. Note that osteoclasts are markedly enlarged and occur in clusters. (C and D, ×100) (C and D, hematoxylin-eosin.)

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FIGURE 24-8  ■  Paget’s disease: gross, radiographic, and microscopic features. A, Autopsy specimen showing advanced Paget’s disease of skull. B, Early phase of Paget’s disease in skull presents as lytic area refered to as osteitis circumscripta. C, Sclerotic phase of Paget’s disease shows cement (reversal) lines in mosaic pattern. D, Specimen radiograph of slice of parietal bone with marked thickening and multiple cotton wool opacities that form larger sclerotic areas. Note the obliteration of corticomedullary borders. (C, ×50) (C, hematoxylin-eosin.)

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FIGURE 24-9  ■  Paget’s disease: microscopic features. A, Active “hot” phase with extensive osteoclastic bone resorption and fibrous replacement of marrow. B, At higher magnification, osteoclast can be seen resorbing bone; this is early phase of Paget’s disease. Note fibrovascular stroma. C, Mosaic pattern in thickened bone trabeculae of late-stage Paget’s disease. D, Higher magnification shows complex pattern of cement (reversal) lines in mosaic pattern. (A and C, ×50; B, ×200; D, ×100) (A-D, hematoxylin-eosin.)

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FIGURE 24-10  ■  Paget’s disease of bone: microscopic features. A and B, Microscopic features of Paget’s disease in region of active “hot” phase include scalloped bone trabeculae, increased osteoclastic activity, and intertrabecular fibrosis. C, Higher magnification reveals osteoclasts in Howship’s lacunae. D, Sclerotic phase of Paget’s disease is characterized by thickened bone trabeculae and irregular mosaic lines of mineralization. (A, B, and D, ×50; C, ×200.) (A-D, hematoxylin-eosin.)

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FIGURE 24-11  ■  Paget’s disease of bone: radiographic and microscopic features. A, Specimen radiograph of slice of parietal bone shows marked thickening with multiple cotton-wool opacities that fuse and form larger sclerotic areas. Note indistinct corticomedullary border. B, Microscopic features of Paget’s disease in region of active “hot” phase include scalloped bone trabeculae, increased osteoclastic activity, and intertrabecular fibrosis. C, Higher magnification reveals osteoclasts in Howship’s lacunae. D, Sclerotic phase of Paget’s disease is characterized by thickened bone trabeculae and irregular mosaic lines of mineralization. (B and D, ×50; C, ×200) (B-D, hematoxylin-eosin.)

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accounts for 20% of the bone sarcomas occuring in patients older than age 40 years.21 The incidence of Paget’s sarcoma increases steadily with age until the seventh decade of life,14 and the rate of sarcomatous transformation ranges between 1% and 10% depending on the extent and severity of the disease. Data from the Surveillance, Epidemiology, and End Results program confirm this epidemiologic pattern of incidence and show that the overall incidence rate of Paget’s sarcoma is approximately 0.1 to 0.2 per 100,000.3 In patients older than age 50 years, it is significantly higher and varies from 0.4 to 0.7 per 100,000. Because so many cases of Paget’s disease are asymptomatic, the interval between onset and the development of a sarcoma is uncertain. Sarcoma complicating Paget’s disease is typically diagnosed in patients older than age 50 years.3 Clinically, the most common presenting symptoms are a progressive increase of localized pain and a palpable mass; less often, a pathologic fracture is the first symptom. Serum levels of alkaline phosphatase can be increased compared with previous levels. The sites most frequently involved by sarcomatous changes are the pelvis, humerus, and femur. Overall the distribution of sarcomatous changes parallels the distribution of skeletal sites involved by the disease (i.e., the bones frequently altered by Paget’s disease are likely to develop sarcomatous transformation) (Fig. 24-2). Typically the bone involved by sarcoma also exhibits both the radiographic and gross features that are characteristic of Paget’s disease (Figs. 24-8 and 24-12). Radiographically, the predominant tumor pattern is osteolytic.9,19 Mixed and osteoblastic patterns occur less frequently. Cortical breakthrough without periosteal reaction and bulky extension into soft tissue are other signs of malignancy (Figs. 24-13 and 24-14). Computed tomography and magnetic resonance imaging may be more sensitive for the early detection of sarcomatous degeneration. The most common histologic type of Paget’s sarcoma is osteosarcoma (Figs. 24-15 and 24-16), although fibrosarcoma, chondrosarcoma (Fig. 24-17), malignant giant cell tumor, and malignant fibrous histiocytoma can also occur.6,7,9 Because of the variability in histologic patterns, some authors designate these tumors only as Paget’s sarcomas. The prognosis is poor for the majority of patients. The 5-year survival rate for osteosarcoma is 8% compared with the current 50% to 65% 5-year survival rate for de novo osteosarcoma. In addition to the higher grade of the tumors, the fact that these patients are in an older age group that is typified by decreased immunity, poor general health, and low tolerance for conventional chemotherapy and radiotherapy may account for this discrepancy.21 In addition, the unusual anatomic location of the tumors, such as the axial skeleton and craniofacial bones, accounts for the difficulty in treatment by complete resection. The most frequent cause of death is distant metastasis. Multicentric Paget’s sarcoma has been described and interpreted by some as metastases; others believe that each site is a separate primary tumor. Benign giant cell tumors have also been described in association with Paget’s disease (see Chapter 10). The most common locations for these tumors are the skull

and facial bones, and although benign, such tumors can be locally destructive and extend into soft tissues. The tumors may have the histologic appearance of giant cell tumors of bone, but some authors have emphasized the resemblance to giant cell reparative granuloma.11 Many patients with these types of tumors have a common ancestry from Avellino, Italy.20 It is still not clear whether genetic factors, environmental factors, or both play a role in the link between patients and the development of this unusual neoplasm.

OSTEOMYELITIS Long-standing inflammation with intermittent sinus tract formation in chronic osteomyelitis and reactive hyperplasia of the squamous epithelium provides the setting for malignant transformation in approximately 0.5% of patients affected by this condition. Therefore the risk of malignant transformation in chronic osteomyelitis is relatively small. The tibia is most frequently affected by chronic osteomyelitis and consequently is the typical site of secondary malignancy in this setting (Fig. 24-18). A tumor mass or an ulceration with indurated borders typically develops within the sinus tract and may extend down into the bone (Figs. 24-19 and 24-20). Less frequently, squamous cell carcinoma develops in the epithelialized lining of the bone defect.24 Atypical pseudoepitheliomatous hyperplasia heralds the transformation into squamous cell carcinoma. Sometimes it is difficult to separate the two conditions in the limited, small, and superficial biopsy material. Differential diagnosis between florid pseudoepitheliomatous proliferation and well-differentiated squamous cell carcinoma is the common problem in evaluating sinus tract biopsy specimens from patients with chronic osteomyelitis (Figs. 24-21 and 24-22). Some authors advocate amputation as an appropriate treatment for both conditions; it is followed by evaluation of large tissue sections from postoperative material to distinguish between the two conditions with certainty. Regional lymph nodes are often enlarged as a reaction to the inflammatory process, but metastasis occurs in only 10% to 20% of cases. However, this rate is high enough to require that the surgical approach must include lymph node biopsies.23 Tumor histology and regional lymph node involvement are related to survival. Pulmonary and visceral metastases are exceedingly rare in this form of secondary malignancy. Squamous cell carcinoma is the most common type of malignant tumor that evolves at the site of chronic osteomyelitis, and the latency period is between 20 and 50 years. The lower extremities, in particular the tibial region, are most commonly affected.24 Clinical signs that should arouse suspicion about malignant transformation include increased pain with foul or bloody discharge from the sinus, a progressively enlarging mass in and around the sinus tract opening, and progressive bone destruction.27 Multiple biopsies are advisable for adequate assessment of the affected tissues. The histologic features of malignancy include cellular atypia, abnormal mitosis,

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FIGURE 24-12  ■  Paget’s sarcoma: gross features. A, Destructive tumor mass of proximal humerus with pathologic fracture. B, Tanwhite tumor with matrix mineralization (histologically osteosarcoma) of distal femoral end with circumferential extension into soft tissue. Note thickened sclerotic bone proximally. C, Resected femoral head with pathologic fracture. Note intramedullary tan-gray tumor mass. D, Destructive tumor mass with pathologic fracture of femoral shaft. Note diffuse sclerotic change in femoral shaft, feature consistent with Paget’s disease.

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A

B FIGURE 24-13  ■  Paget’s sarcoma of skull: radiographic features. A, Magnetic resonance image of skull shows destructive mass in right frontal area. Note thickened sclerotic bone of skull. B, Computed tomogram shows bone destruction with extension into soft tissue of right frontal area. Note thick sclerotic bones of skull and multiple coalesced opacities.

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D FIGURE 24-14  ■  Paget’s sarcoma: radiographic, gross, and microscopic features. A, Advanced Paget’s disease of tibia with bowing deformity. Note absence of involvement of fibula. Destructive process of proximal tibial end extends into soft tissue, and cloudy opacities within tumor mass extend into popliteal soft tissue (arrows). Histologically, this tumor was high-grade osteosarcoma. B, Extensive involvement of tibia by Paget’s disease. Note large mass that extends into soft tissue at proximal end; this is consistent with sarcomatous transformation. C, Sagittal section of amputated specimen shows abnormal sclerotic tibia with destructive mineralized mass at its proximal end. D, Microscopically the tumor is high-grade osteosarcoma (D, ×200) (D, hematoxylin-eosin).

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FIGURE 24-15  ■  Paget’s disease with secondary osteosarcoma. A, Low power photomicrograph of osteosarcoma associated with Paget’s disease. B, Low power photomicrograph of sclerotic tumor with a solid area of osteoid showing different level of mineralization juxtaposed on the preexisting host bone. C, Higher magnification showing atypical osteoblastic cells and tumor osteoid deposition. (A, ×50; B, ×100; C, ×400) (A-C, hematoxylin-eosin.)

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FIGURE 24-16  ■  Paget’s disease with secondary osteosarcoma. A, Lateral radiograph of an 85-year-old man with long-standing Paget’s disease of humerus and osteosarcoma destroying distal end of bone; soft tissue involvement is apparent. B, Sclerotic bone with irregular mosaic lines of mineralization consistent with sclerotic phase of Paget’s disease adjacent to tumor. C and D, Photomicrographs of high-grade osteoblastic osteosarcoma shown in A. Note lacelike osteoid pattern and nuclear anaplasia. (B, ×50; C and D, ×100.) (B-D, hematoxylin-eosin.)

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FIGURE 24-17  ■  Chondrosarcoma, grade ii secondary to Paget’s disease of femur. A, Lateral radiograph of knee of a 66-year-old man with Paget’s disease of distal femur and tibia who had secondary chondrosarcoma in femur. B, Amputation was performed after biopsy revealed presence of malignant cartilage tumor that broke out of bone and invaded soft tissue and synovium of knee joint. C, Close-up view of B. Note that tumor extends across joint to invade tibia, which is also affected by Paget’s disease. D, Photomicrograph of tumor shown in C reveals grade 2 myxoid chondrosarcoma. (D, ×400) (D, hematoxylin-eosin.)

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B A FIGURE 24-18  ■  Chronic osteomyelitis: radiographic features. A, Anteroposterior radiograph shows sclerotic changes of tibial shaft and lateral bowing deformity. B, Lateral radiograph shows sclerosis of tibial shaft and anterior cortical deformity corresponding to draining fistula.

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FIGURE 24-19  ■  Squamous cell carcinoma associated with chronic osteomyelitis. A, Clinical photograph of draining fistulas of tibia. B, Bisected tibia with several bone defects and draining tracts. C, Higher magnification of B shows two fistulas connected to tibial bone defects. D, Histologic section of bone in vicinity of larger bone defect shows infiltrating well-differentiated squamous cell carcinoma. (D ×100, hematoxylin-eosin)

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B FIGURE 24-20  ■  Squamous cell carcinoma in association with chronic osteomyelitis. A, Coronally bisected specimen from below-knee amputation. B, Higher magnification of A shows area of fistulous tract with destructive cheesy mass consistent with keratinized squamous cell carcinoma.

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B FIGURE 24-21  ■  Chronic osteomyelitis: microscopic features of pseudoepitheliomatous hyperplasia. A, Low power magnification of hyperplastic squamous epithelium lining fistulous tract. B, Higher magnification of A. Note preserved maturation pattern of squamous epithelium and absence of nuclear atypia. Tongues of hyperplastic epithelium have smooth regular borders and gradually merge with overlapping epithelium. (A ×50; B ×100) (A and B, hematoxylin-eosin.)

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B FIGURE 24-22  ■  Pseudoepitheliomatous hyperplasia versus well-differentiated squamous cell carcinoma: microscopic features. A, Pseudoinfiltration pattern of stroma in hyperplastic epithelium. Note smooth outlines of epithelial nests and their orderly interconnecting arrangement. B, Well-differentiated squamous cell carcinoma. Note irregular outlines of disorderly arranged tumor cell nests and presence of keratinized pearls within tumor cell nests. (A and B, ×100) (A and B, hematoxylin-eosin.)

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lymphatic permeation, and invasion into blood vessels. Abnormal maturation patterns that show formation of squamous pearls deep within the infiltration tongues of squamous epithelium help distinguish squamous carcinoma from pseudoepitheliomatous hyperplasia (Fig. 24-23). The diagnostic difficulties are amplified by the irregular shapes of the fistulous tracts, which cause the squamous lining to be cut tangentially on histologic sections. Moreover, squamous cell carcinomas that develop in sites of chronic osteomyelitis frequently tend to be moderately to well-differentiated lesions that on small biopsy samples can easily be confused with benign squamous epithelium proliferation. In addition to squamous cell carcinoma, other tumors have been described in association with osteomyelitis. These include basal cell carcinoma, adenocarcinoma, myeloma, fibroblastic osteosarcoma, angiosarcoma, rhabdomyosarcoma, and lymphoma.22,24-26 Because the sarcomas metastasize in 56% of cases, they have a worse prognosis than that for secondary carcinoma.23

BONE INFARCTS Definition Bone infarction is a relatively common lesion that typically occurs in the metaphyseal region of the long bones, often around the knee. The terms aseptic and avascular necrosis are generally applied to areas of epiphyseal or subarticular involvement, as commonly seen in the femoral head. A variety of conditions predispose to bone infarction, including alcoholism; corticosteroid therapy; renal dialysis; exposure to compressed air, such as occurs in caisson workers and divers; Legg-Calvé-Perthes disease; hemoglobinopathies, especially sickle cell disease and trait; Gaucher’s disease; chronic pancreatitis; gout; pregnancy; exposure to radiation; and collagen or vascular disorders. Although the majority of the reported cases of infarctrelated sarcomas have been associated with idiopathic bone infarcts, those found in 37% of our patients stemmed from some prior medical or occupational cause, such as exposure to compressed air or rapid decompression,33,42-44 sickle cell disease or trait,34,45 alcohol abuse,34,40 or previous steroid therapy.46 One patient had development of an angiosarcoma in a bone infarct; this patient had a history of Hodgkin’s disease and had undergone chemotherapy.29 Arnold30 described a family with hereditary bone infarcts, and two family members had associated fibrosarcomas. It is difficult to assess the real risk of malignant transformation associated with bone necrosis because many bone infarcts are asymptomatic. Based on the relatively low number of published cases, overall risk of development of sarcoma in these settings appears to be low.32,38 Clinical Findings We have seen 22 cases of bone sarcomas associated with infarcts. The ages of our patients ranged from 28 to 82 years (average age, 51.5 years). The highest incidence was

in the fourth and fifth decades of life (5 cases each), followed by the sixth and seventh decades (4 cases each). There were 13 men and 9 women. Except for 1 patient whose race was unknown, 11 were white patients and 10 were black patients. The duration of symptoms of our 22 cases ranged from 1 month to 2 years (average, 6 months). The most frequent presenting symptom was local pain or tenderness, in 15 of 19 patients in whom symptoms were recorded; pain was unassociated with other symptoms in 7 patients, whereas 5 reported associated swelling. Seven patients had pathologic fracture, in 4 of whom it was the presenting symptom. Fifteen (68%) of the patients had no medical condition or work history associated with bone infarction; 7 had such a condition or history, with 3 having sickle cell disease or trait, 2 with decompression bone disease (caisson disease), 1 with alcoholism, and 1 with Gaucher’s disease. In the 2 cases of caisson disease, the interval between the last exposure to decompression and the clinical manifestation of the sarcoma was 17 and 25 years, respectively. Skeletal distribution of bone sarcomas associated with infarcts in our 22 cases is shown in Figure 24-24. The area around the knee was the site of tumor in 13 (59%) of the patients; the distal femur was involved in 6 patients and the proximal tibia in 7. Most lesions were located in the metaphysis; one each occurred in the diaphysis of the humerus and the femur. Radiographic Imaging On radiographs, chronic bone infarcts typically appear as irregular but sharply demarcated intramedullary densities in the metaphyseal or metadiaphyseal region (Figs. 24-25 to 24-28). Serpiginous or wavy rims and coils of calcific density are characteristic of bone infarcts. Oval shadows outlined by a thin radiopaque zone of margination can be present in some cases. Thirteen (59%) patients in our series had radiographic evidence of infarcts that affected multiple bones; 9 (41%) had a single infarct only. Of patients with multiple infarcts, 7 had symmetric infarcts in the opposite bone without associated tumor. Secondary sarcoma appears as irregular areas of destruction of the medullary and cortical bones and has a permeative margin within or at the edge of the infarct that is usually accompanied by a soft tissue mass, with or without pathologic fracture (Figs. 24-25 to 24-28). An associated periosteal reaction can be present. Poorly defined mineralization can be seen in matrix-producing lesions such as osteosarcoma. The computed tomographic scans available in two of our cases showed both a well-defined endosteal calcific shell and focal disruption of the cortex with a soft tissue mass. Bone scans reveal increased uptake of isotope in the regions corresponding prominently to the tumor and, to a lesser degree, the bone infarct. Specimen radiographs disclose ill-defined, irregular, lytic lesions of the metaphysis with focal areas of calcification at the periphery, which correspond to bone infarct.

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C FIGURE 24-23  ■  Squamous cell carcinoma developing within fistulous tract of chronic osteomyelitis. A, Invasive squamous cell carcinoma in fistulous tract. B, Higher magnification of A shows well-differentiated squamous cell carcinoma mimicking pattern seen in pseudoepitheliomatous hyperplasia. C, Higher magnification of B shows abnormal maturation pattern with keratinized pearls in deeper invasive portion of the lesion. (A, ×5; B, ×15; C, ×100) (A-C, hematoxylin-eosin.)

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2 6

Females

Incidence

5

1

13

Males

TOTAL

9 22

4 2 3 1 6

2

7 1

0 1

2

3

4

5

6

7

8

9

3

Age in decades FIGURE 24-24  ■  Sarcomas associated with bone infarcts. Age-specific and skeletal distribution patterns of 22 sarcomas associated with bone infarcts.

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FIGURE 24-25  ■  Sarcoma associated with bone infarcts: radiographic features. A and B, Anteroposterior and oblique views on plain radiographs of knee show extensive bone infarct. Note lytic, ill-defined area involving lateral condyle. Biopsy material from this region shows high-grade malignant fibrous histiocytoma. C, Bone scintigram shows increased uptake, predominantly in distal femoral metaphysis. D, Microscopically tumor is malignant fibrous histiocytoma (D, ×100) (C, hematoxylin-eosin.)

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B

A

C FIGURE 24-26  ■  Sarcoma associated with bone infarcts: radiographic and microscopic features. A and B, Plain radiographs show extensive multifocal infarcts of femur and tibia. Note destructive lesion with cortical disruption in proximal tibial metaphysis (better seen in B [arrows]). C, Biopsy material shows high-grade malignant fibrous histiocytoma (C, ×100) (C, hematoxylin-eosin.)

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FIGURE 24-27  ■  Sarcoma associated with bone infarcts: radiographic features. A, Specimen radiograph shows fracture through distal femoral metaphysis with geographic mineralization pattern consistent with infarct. B, Coronally bisected amputation specimen shows pathologic fracture through destructive tumor mass. Fibrous and mineralized pattern in distal fragment corresponds to infarct. C, Multiple symmetric bone infarcts of femur and tibia were present in contralateral lower extremity of same patient. D, Microscopically, tumor represents malignant fibrous histiocytoma (D, ×100) (D, hematoxylin-eosin.)

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A

C

FIGURE 24-28  ■  Sarcoma associated with bone infarct: radiographic and microscopic features. A, Specimen radiograph of distal femur with geographic mineralization pattern consistent with infarct and a large destructive intramedullary mass penetrating the cortex and extending to the soft tissue. Inset, Specimen radiograph of the tibia from the same amputation specimen with geographic mineralization pattern consistent with infarct. B, Low power photomicrograph showing interface between bone infarct and associated with high-grade sarcomatoid neoplasm. C, Microsocopically, tumor represents malignant fibrous histiocytoma. (B, ×25; C, ×100) (B and C, hematoxylin-eosin.)

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Gross Findings Bone infarcts appear as sharply demarcated, irregular, yellow-white zones in medullary bone and are sometimes accompanied by fibrous-walled, cystlike structures and areas of cystic fat necrosis. Infarct-associated tumors range in size from 2 to 13 cm (mean, 6.7 cm). The tumors generally have ill-defined, gray-tan, firm, and rather gritty appearances that blend into the surrounding medullary tissue and often erode or destroy the cortex while infiltrating into the adjoining muscle and fascia. Hemorrhage and necrosis are usually obvious. Microscopic Findings Histologic examination of the bone infarcts shows irregular fragments of necrotic bone trabeculae and intervening hyalinized fibrous tissue and fat necrosis with a variable amount of dystrophic calcification (Fig. 24-29). Cysts lined by loose fibrous tissue, old focal hemorrhage, and calcified debris are also observed. Abnormal cells provide a clue to the predisposing factor, such as foamy histiocytes in Gaucher’s disease (Fig. 24-30) or sickled erythrocytes in patients with sickle cell disease. The peripheral areas of bone infarction in the transition zone adjacent to frank sarcoma contain focal resorption of dead bone trabeculae; layering of new viable bone on the dead trabecular surfaces; and formation of granulation tissue composed of scattered infiltrates of chronic inflammatory cells, proliferation of small vessels, and cellular fibrous tissue with occasional atypical spindle cells. Atypical spindle cells, whose nuclei are somewhat larger and hyperchromatic, are present in these areas. The cellularity of reparative tissue ranges from isolated cells to relatively hypercellular with interlacing spindle-cell fascicles. The fascicles of these cells are sometimes arranged in a storiform pattern with desmoplastic collagen. Farther from the infarct, atypical spindle cells merge into a high-grade, spindle-cell sarcomatous component. Infarct-associated sarcomas show the typical microscopic features of malignant fibrous histiocytoma, low-grade osteosarcoma, and conventional high-grade osteosarcoma.18,36,39,40,44 Low-grade osteosarcomas associated with bone infarcts are mostly composed of interlacing bundles of spindle cells interspersed with strands of osteoid or mineralized woven bone and a small number of associated osteoclast-like giant cells. The tumor cells have uniform nuclei with only slight atypia and rare mitotic figures. Malignant fibrous histiocytoma and osteosarcoma associated with bone infarcts do not differ microscopically from their conventional de novo counterparts. Treatment and Behavior Among 12 of the 22 patients whose follow-up data were available, 9 (75%) died of metastases from 2 months to 5 years after diagnosis (mean, 19 months), and 3 (25%) were alive and well from 9 to 19 years (mean, 15.5 years) after treatment. As is the case with tumors secondary to other underlying conditions, sarcoma arising in bone

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infarcts seems to have a poorer prognosis and to affect older patients. Personal Comments Men seem to be more affected by bone infarcts associated with sarcomas than women. This difference can be attributed to the fact that many conditions that predispose to bone infarction are predominantly related to maleoriented occupations or propensities, such as tunnel workers, divers, and heavy alcohol abusers. Black patients account for a large proportion (48%) of cases, partly because of the association between infarcts and sickle cell disease and trait. The ages of previously reported patients ranged from 18 to 82 years (mean, 53.7 years). Malignant fibrous histiocytoma is the most frequent infarct-related sarcoma in our series, as well as in previously reported cases.28,31,34-37,40-45 As in individuals who have malignant fibrous histiocytomas that develop in bones affected by preexisting conditions (low-grade chondrosarcoma, Paget’s disease, or previous irradiation), patients with sarcoma secondary to bone infarct are generally older than those in whom sarcomas develop de novo with no underlying condition. The increased radiographic density of chronic bone infarcts is probably due to a combination of heavy calcium deposition in necrotic marrow and an increased amount of reactive bone surrounding the necrotic component. Such a radiographic appearance may sometimes mimic that of calcified enchondroma. However, the foci of calcified matrix in enchondroma are discrete and scattered diffusely throughout the lesion and have punctate to popcornlike densities; the margin of the lesion is not so clearly outlined as that of an infarct. Approximately 75% of the patients with infarct-associated sarcomas have multiple infarcts, usually in the bone symmetrically opposite the tumor-bearing bone. The proposition that infarct-associated sarcoma arises as a result of prolonged excessive activity or a high degree of chronic proliferative activity of reparative tissue adjacent to the infarct has been questioned by some authors.48 It has been suggested that large infarcts are not totally replaced because of the eventual cessation of the reparative process. No studies have documented excessive or persistent repair adjacent to metaphyseal or diaphyseal infarcts. On the other hand, scintigraphy shows intense isotope uptake not only in the sarcomatous areas, but also to a lesser degree in the infarcted lesions. We have observed cases of multiple bone infarcts that were not associated with secondary sarcomas in which “hot” lesions (those with increased uptake) corresponded to chronic bone infarcts. The reparative process surrounding bone infarction has been described in association with revascularization and increased accumulation of the radioisotope.47 On the basis of the microscopic evidence from our studies with proliferative markers (i.e., proliferating cell nuclear antigen) and scintigraphic evidence, the active repair process adjacent to bone infarcts appears likely to continue in some instances, although the cause of its persistence is unclear. The exact reason for the preponderance of malignant fibrous histiocytoma as the tumor most commonly

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B

C

D

FIGURE 24-29  ■  Sarcoma associated with bone infarct: microscopic features. A and B, Periphery of infarct shows regenerative granulation tissue adjacent to hyalinized tissue that has dystrophic calcification. High-grade sarcomatoid neoplasm is seen in the upper half of the photomicrograph. C, Example of malignant fibrous low-grade fibroblastic osteosarcoma associated with bone infarct. D, High-grade pleomorphic variant of malignant fibrous histiocytoma associated with bone infarct infiltrating fatty bone marrow. (A and B, ×50; C, ×100; D, ×200.) (A-D, hematoxylin-eosin.)

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B FIGURE 24-30  ■  Malignant fibrous histiocytoma associated with Gaucher’s disease: radiographic and microscopic features. A, Lowpower magnification of spindle-cell neoplasm is consistent with malignant fibrous histiocytoma. B, Higher-power magnification of A shows spindle tumor cells with prominent atypia. Insets, Anteroposterior and oblique views on plain radiographs show lytic mass of proximal tibial shaft. Note increased mineralization pattern of bone adjacent to lytic area corresponding to bone infarcts. Gaucher’s disease was diagnosed in early childhood. (A, ×100; B, ×200) (A and B, hematoxylin-eosin.)

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associated with bone infarcts and the relative infrequency of osteosarcoma and angiosarcoma is unknown. The tumors expected to develop, however, would reflect the cell types involved in such a reparative process (i.e., fibroblasts, osteoblasts, and endothelial cells). Thus it seems clear that a close pathogenetic relationship exists between bone infarcts and the associated sarcomas. The reparative, predominantly fibroblastic tissue, which has a relatively high degree of proliferative activity in the border zone, could be the presumptive origin of this malignancy.

METALLIC IMPLANTS Malignant tumors reported to arise at the site of metallic implants are exceedingly rare, with only 12 cases recorded up to 1990.49,51,53-55,60 Some authors believe that the association is coincidental and that the risk of inducing neoplasia is minimal.52 Osteosarcoma, Ewing’s sarcoma, hemangioendothelioma, malignant fibrous histiocytoma, lymphoma, and synovial sarcoma have been associated with metallic implants.53-56,60 Experimental investigations support the carcinogenic effect of heavy metals such as cobalt, cadmium, and nickel in a possible cause-andeffect relationship for neoplastic induction by orthopedic devices composed of metals.56-58 These observations are of concern when considering the long-term effect of metallic implants. The interaction between the body’s saline environment and the implanted metal sets the background for potential production of corrosive products. The rate of corrosion varies according to particle size; metal solubility; environmental pH; and concentrations of the metal, negative ions, and oxygen. The continuous exposure of tissue to metallic corrosion products is considered to be an initiating factor.50,59 Radiographically, these tumors present as destructive masses in the vicinity of metallic implants (Figs. 24-31 and 24-32).

RADIATION INJURY The bone damage produced by ionizing radiation from either internal or external sources is often referred to as radiation osteitis. The necrotic bone in this condition leads to reparative changes characterized by a highly cellular proliferation of fibroblastic tissue and reactive new bone formation. Unlike the reparative tissue adjacent to simple bone infarcts, atypical mesenchymal cells with pleomorphic and hyperchromatic nuclei are present. It is from this substrate that sarcomas may develop after exposure to radiation.61,63,66 The likelihood of sarcomatous change is directly related to the number of irradiation courses and the absorbed dose of radiation in bone. With the dose range used in modern radiotherapy (4000 to 7000 rads), the risk for sarcomatous transformation is low.67 The histologic types of induced sarcoma include osteosarcoma, chondrosarcoma, and malignant fibrous histiocytoma. The latter tumor is emerging as an important sequel to therapeutic irradiation. It also appears that radiation therapy can induce the transformation of a low-grade, barely aggressive lesion into a high-grade

metastatic sarcomatous malignancy.62,65 Radiographically and microscopically, these tumors do not differ from their conventional de novo counterparts (Figs. 24-33 and 24-34). A recent report of 20 examples of malignant fibrous histiocytomas developing as induced sarcomas in bone noted that a median dose of 5700 rads was given for either nonosseous conditions or preexisting skeletal lesions.64 A latency period of 2.75 to 13 years separated the irradiation from the appearance of a malignant tumor in one series,68 but some authors have recorded delays of up to 30 years. In a series of 91 bone sarcomas that developed in patients treated with radiotherapy with other modalities for previous malignancies and in patients who had genetic predispositions, the latency period was shortened by the use of adjuvant chemotherapy.68 Typically postradiation sarcoma develops 5 to 10 years after exposure (Figs. 24-33 and 24-34). Internal deposits of radioactive elements of radium and mesothorium from industrial exposure have been found in painters of watch dials, chemists, and technicians. Internal deposits of radium salts and thorium have been found in some individuals who use them in medical work. Once in the body, these substances behave like calcium, depositing in areas of active bone turnover. Their deposition predisposes the bone to the development of osteosarcoma and other malignancies. Bone damage, including osteopenia, necrosis, spontaneous fractures, and osteosarcoma, results from many decades of constant irradiation of bone cells and matrix and mineral formation affected by the α-rays emitted from these deposits.61 The anatomic sites of the induced tumors are evenly distributed and frequently are in the skull, pelvis, and short tubular bones. Multiple neoplasms may occur.

OSTEOGENESIS IMPERFECTA Osteogenesis imperfecta is an inherited disorder of connective tissue in which deficient osteoid formation leads to multiple fractures. It has a complex genetic background with 17 genetic causes transmitted in autosomal dominant or recessive patterns.78 Osteogenesis imperfecta patients are classified in four distinctive syndromes with different clinical characteristics and inheritance patterns. Mutations of collagen 1A (COL1A2) genes encoding collagen alpha-1 chains play a major role in the development of this disorder. In radiographic and microscopic diagnosis of bone tumors, the paradoxical predisposition to form exuberant fracture callus that may be mistaken for osteosarcoma is of major importance.69,71,72,76,79,80 Few case reports have dealt with the association of osteogenesis imperfecta and osteosarcoma.70,73-75,77 Most authors stress the importance of distinguishing between exuberant fracture callus and osteosarcoma (see Chapter 23). In addition to the clinical evaluation, laboratory and radiographic studies and adequate biopsy material are needed to make a correct diagnosis. The characteristic

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FIGURE 24-31  ■  Sarcoma of bone associated with metallic implant. A, Radiograph of resection specimen shows femoral head prosthesis and lytic area of proximal femur. B, Gross photograph of same specimen shows hemorrhagic destructive mass surrounding femoral head of metallic implant; hemorrhagic mass extends into soft tissue (arrows). C and D, Malignant fibrous histiocytoma associated with metallic implant (same case as shown in A and B). (C and D, ×100) (C and D, hematoxylin-eosin.)

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unique genetic predisposition. The risk of developing sarcoma in bone because of genetic predisposition has not yet been estimated. In general, familial syndromes that may predispose to cancer should be clinically suspected when (1) clusters of cancer occur in one family, regardless of whether the tumors are the same or different types that originate in the same or different organs; (2) cancer occurs in an unusual age, typically in younger patients; and (3) multiple independent primary tumors affect a single individual.

Rothmund-Thomson Syndrome

FIGURE 24-32  ■  Sarcoma of bone associated with metallic implant. Large destructive mass with patchy matrix mineralized in area of metallic implant (hip prosthesis).

malignant changes of osteosarcoma—pleomorphism, hyperchromatism, and bizarre mitoses—are absent in the hyperplastic callus.

SYNDROMES PREDISPOSING TO MALIGNANCY IN BONE There is increased awareness that hereditary etiologies with mendelian inheritance in addition to congenital syndromes without clear inheritance patterns are responsible for the development of bone and soft tissue tumors. During the past decade, there has been an exponential increase in the identification of germline mutations that predispose individuals to the development of bone tumors in these syndromes. Therefore, a detailed family history is an important component of prevention and surveillance, facilitating early detections in affected families. The list of hereditary disorders that are associated with the development of various skeletal and soft tissue tumors in which bone and cartilage forming tumors may develop is provided in Table 24-2. Their detailed description is beyond the scope of this book. Two familial syndromes, Rothmund-Thomson and Li-Fraumeni, that predispose individuals to the development of sarcoma in bone are described in this section. As in the case of retinoblastomaassociated osteosarcoma (see Chapters 3 and 5), both may have a unique inherited molecular mechanism. They are extremely rare, but it is estimated that up to 10% of common cancers in humans may develop because of a

This extremely rare syndrome is an autosomal recessive disorder that consists of skin lesions (atrophy, hyperpigmentation, subepidermal fibrosis, and telangiectasias referred to as poikiloderma), cataracts, and skeletal abnormalities such as dysostoses and dysplasias that result in abnormally shaped bones (Figs. 24-35 and 2436).91,92,107,112,116,119,120 Abnormal developmental anomalies of the skeleton are frequently associated with short stature and facial deformities. The skeletal anomalies can be settled and focal or may be widespread, resulting in major disfiguring deformities. The clinical features of the syndrome usually manifest in childhood. Abnormal skin pigmentation is typically the presenting sign. Benign skin adnexal lesions are the most frequent neoplasms seen in this condition. An increased incidence of osteosarcoma is the most serious complication of Rothmund-Thomson syndrome. The analysis of large clinical data indicates that 30% of patients with clinical manifestations of the syndrome develop osteosarcoma.84,89,122 Osteosarcomas in this syndrome have a tendency to develop in unusual sites, and some are multifocal. These osteosarcomas develop in patients who are younger than those who have conventional osteosarcomas. Mutations of the RECQL4 gene encoding a RCO DNA helicase are present in a large proportion of patients affected by the RothmundThomson syndrome (Fig. 24-37).85,93,105,109,121 In contrast, mutations of RECQL4 are infrequent in sporadic osteosarcoma.93,100 A more detailed description of the role of helicases in the biology of tumors and their associated clinical syndrome is provided in Chapter 3. The RECQ family of DNA helicases plays a role in DNA repair, replication, and recombination pathways.98 In humans, mutations of these enzymes encoded by the BLM, WRN, and RECQL4 genes are associated with Bloom’s, Werner’s and Rothmund-Thomson syndromes, respectively.98,99 In general, these disorders are characterized by premature aging and predisposition to cancer. Increased numbers of chromosomal breaks in somatic cells and sensitivity to ultraviolet light, consistent with a defect in DNA repair, are downstream effects of malfunctioning DNA helicases in these syndromes.103,104,110,123

Li-Fraumeni Syndrome In 1988, Li and Fraumeni described 24 kindreds affected by a wide range of cancer types. The most frequent cancer types were breast carcinoma and soft tissue sarcomas. The members of these families were less frequently

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D FIGURE 24-33  ■  Postradiation sarcoma: radiographic features. A, Plain radiograph shows destruction of C2 bone in a 30-year-old woman in whom this lesion developed 5 years after exposure to radiation from nuclear plant accident. Microscopically, tumor was malignant fibrous histiocytoma. B, Computed tomogram shows destructive lesion involving C2 body and posterior elements, protruding into spinal cord and extending into soft tissue. C and D, Coronal and sagittal magnetic resonance images show destructive low-signal mass encircling spinal cord. Mass has destroyed C2 bone elements and has extended into soft tissue.

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B FIGURE 24-34  ■  Postradiation sarcoma: radiographic features. A and B, Anteroposterior and oblique views of postradiation sarcoma of scapula 8 years after radiation therapy for breast carcinoma. Note lytic destructive mass of scapula (arrow) and patchy lytic areas of radionecrosis in proximal humerus.

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TABLE 24-2 Hereditary Disorders Associated with Tumors of Soft Tissue and Bone, Ordered by Genes Known to be Involved Gene

Locus

Inherited Syndrome

Inheritance

Associated Tumors

ACP5 ACVR1

19p13 2q24

Spondyloenchondrodysplasia Fibrodysplasia ossificans progressiva

AR Sporadic/AD

ANTXR2 APC

4q21 5q21

AR AD AD

BRAF BUB1B

7q34 15q15

TP53

17p13

Fibromatosis, juvenile hyaline Desmoid disease, hereditary Familial adenomatous polyposis 1 (Gardner’s syndrome included) Cardiofaciocutaneous syndrome Mosaic variegated aneuploidy syndrome 1 Li-Fraumeni syndrome 1

Enchondromas Progressive heterotopic ossification (myositis ossificans progressiva), proximal tibial osteochondromas Fibromatosis Desmoid tumors Craniofacial osteomas, desmoid tumors, Gardner fibromas Giant cell lesions of small bones (central) Embryonal rhabdomyosarcomas

CHEK2

22q12

Li-Fraumeni syndrome 2

AD

EXT1

8q24

Multiple osteochondromas

AD Sporadic

11p11

Trichorhinophalangeal syndrome type 2 Multiple osteochondromas Potocki-Shaffer syndrome

Sporadic

Glomovenous malformations Pseudohypoparathyroidism, type 1A McCune-Albright syndrome, incl. Mazabraud syndrome

AD AD Sporadic

Osseous heteroplasia, progressive Pseudopseudohypoparathyroidism Enchondromatosis (Ollier’s disease and Maffucci’s syndrome) Buschke-Ollendorff (osteopoikilosis isolated incl.) Opitz GBBB syndrome, X-linked Focal dermal hypoplasia Carney complex, type 1

AD AD Sporadic

LEOPARD syndrome 1 Metachondromatosis

AD AD

Noonan syndrome 1

AD

Retinoblastoma Baller-Gerold syndrome RAPADILINO syndrome Rothmund-Thomson syndrome Werner syndrome Bloom syndrome Cherubism Chordoma, familial Paget’s disease of bone Polyostotic osteolytic dysplasia, hereditary expansile

AD AR AR AR AR AR AD AD AD AD

EXT2

GLMN GNAS

1p22 20q13

IDH1 IDH2 PTH1R LEMD3

2q34 15q26 3p21 12q14

MID1 PORCN PRKAR1A

Xp22 Xp11 17q24

PTPN11

12q24

RB1 RECQL4

13q14 8q24

WRN BLM SH3BP2 T TNFRSF11A

8p12 15q26 4p16 6q27 18q22

AD AR AD

AD

AD XR XD AD

Osteosarcomas, rhabdomyosarcomas, and other soft tissue sarcomas Osteosarcomas, rhabdomyosarcomas, and other soft tissue sarcomas Osteochondromas, secondary peripheral chondrosarcomas Osteochondromas, secondary peripheral chondrosarcomas Osteochondromas, secondary peripheral chondrosarcomas Osteochondromas, secondary peripheral chondrosarcomas Glomus tumors Cutaneous osteomas Polyostotic fibrous dysplasia, osteosarcomas (Mazabraud syndrome: intramuscular myxomas) Cutaneous osteomas Cutaneous osteomas Enchondromas, chondrosarcomas (Maffucci’s syndrome: hemangiomas, angiosarcomas) Enostoses Cranial osteomas Giant cell tumors of bone Osteochondromyxomas, cardiac and other myxomas, melanocytic schwannomas Granular cell tumors Enchondromas, osteochondroma-like lesions Granular cell tumors, giant cell lesions of small bones (central) Osteosarcomas, soft tissue sarcomas Osteosarcomas Osteosarcomas Osteosarcomas Bone and soft tissue sarcomas Osteosarcomas Giant cell lesions Chordomas Osteosarcomas Osteosarcomas

AD, Autosomal dominant; AR, Autosomal recessive; GIST, Gastrointestinal stromal tumor; XD, X-linked dominant; XR, X-linked recessive. Modified from Bridge JA, Mertens F: Tumour syndromes: introduction. In Fletcher CDM, Bridge JA, Hogendoorn PCW, Mertens F, editors: WHO classification of tumours of soft tissue and bone, ed 4. Lyon, 2013, IARC.

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B

D

C

FIGURE 24-35  ■  Rothmund-Thomson syndrome: clinical and radiographic features. A, Anteroposterior view of pelvis. Note abnormally shaped iliac bones and multiple lytic defects with scalloped sclerotic margins. B and C, Clinical photographs showing deformities of both lower extremities. Note abnormal skin pigmentation and bulging mass corresponding to left proximal fibular region. D, Radiograph of right lower extremity with deformity and sclerosis of tibia.

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B

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C

FIGURE 24-36  ■  Osteosarcoma in Rothmund-Thomson syndrome: radiographic and gross features. A and B, Anteroposterior and lateral views of osteoblastic mass of left proximal fibula. Note deformity and sclerosis of tibia. C, Gross photograph of amputation specimen shows calcified mass of proximal fibular end and severe bowing deformity of tibia (same case as Fig. 24-35).

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21.3 22.2 23 24.2

RECQL4

22.1 22.3 1

1208 aa

Missense substitution Frameshift mutation Nonsense mutation

Zinc finger CCHC-type domain P-loop containing nucleoside triphosphate hydrolase domains Helicase superfamily 1/2 ATP-binding domain Helicase C-terminal domain

24.3 RECQL4

A

Exon 21

Exon 20

Exon 19

Exon 18

Exon 17

Exon 16

Exon 15

Exon 14

Exon 13

Exon 12

Exon 11

cds Exon 10

Exon 9

Splicing mutation Intronic deletion

21.2

24.1

Exon 8

Exon 7

Exon 6

Helicase region

5

21.1

22 21.2 12 11.1 11.21 11.23 13

6

11.2 11.1 11.22 12

RECQL4

23.2 Exon 5

21.3 21.1

Chr 8 Exon 4

23.3 23.1

Exon 1 Exon 2 Exon 3

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B N-End Rule Pathway

Base Excision Repair

UBR1/2

PARP1

RECQL4 Rad51

Cut5

RECQL4-interacting Partners Repair of DSBs

DNA Replication

Proposed Cellular Pathway

C FIGURE 24-37  ■  Molecular alterations in Rothmund-Thomson syndrome. A, Location of the RECQL4 gene on the long arm of chromosome 8 is shown. B, Mutations of the RECQL4 gene frequently present in patients with Rothmund-Thomson syndrome. The positions of mutations involving the non-coding sequence are shown on the upper diagram depicting the exon-intron structure of the RECQL4 gene. The positions of mutations involving the coding sequences are shown on the lower diagram depicting the structure of the RECQL4 protein. C, Interacting partners of the RCO DNA helicase and putative pathways controlled by this enzyme responsible for clinical manifestations in the Rothmund-Thomson syndrome. Modified from Wang LL, Gannavarapu A, Kozinetz CA, et al: JNCI 95:669– 674, 2003 and Dietschy T, Shevelev I, Stagljar I: Cell Mol Life Sci 64:796–802, 2007.

affected by other cancers, including osteosarcoma of bone.81,82,96,97 The syndrome is unique in the sense that it predisposes the affected family to a wide range of malignant neoplasms in different organs. In contrast, other well-known familial cancer syndromes, such as hereditary colon and breast cancers as well as rare examples of familial osteosarcomas, predispose to a limited range of cancers (see Chapter 5). It has been shown that families with Li-Fraumeni syndrome carry germline mutations of the TP53 gene.87,88,94,95,106,113,114,117,118,124 Therefore, Li-Fraumeni syndrome is the prototype clinical condition that links genetic predisposition to a wide range of cancers with the malfunction of a single tumor-suppressor gene.90,101,102 However, the syndrome may not have a uniform TP53-related pathogenesis because mutations of the TP53 gene were not identified in some affected families. In addition to TP53 mutations, fibroblastic cells of patients with Li-Fraumeni syndrome show an increased rate of replicative errors (genetic instability) and abnor-

mal control of the cell cycle.81,85,87,92,101 Alterations of other genes such as MDM2 and CHEK2, as well as shorter telomere length, have been postulated in the development of Li-Fraumeni syndrome, but linkage between the alterations in these genes and the development of sarcoma in the absence of TP53 mutations is uncertain at the time of this writing.83,86,108,111,115 REFERENCES Paget’s Disease of Bone 1. Bertoldi I, Cantarini L, Filippou G, et al: Paget’s disease. Reumatismo 66:171–183, 2014. 2. Collins DH: Paget’s disease of bone: incidence and subclinical forms. Lancet 2:51, 1956. 3. Dorfman HD, Czerniak B: Bone cancers. Cancer 75:203–210, 1994. 4. Galson DL, Roodman GD: Pathobiology of Paget’s disease of bone. J Bone Metab 21:85–98, 2014. 5. Guay-Belanger S, Picard S, Gagnon E, et al: Detection of SQSTM1/P392L post-zygotic mutations in Paget’s disease of bone. Hum Genet 134:53–65, 2015.

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6. Hadjipavlou A, Lander P, Srolovitz H, et al: Malignant transformation in Paget’s disease of bone. Cancer 70:2802–2808, 1992. 7. Haibach H, Farrell C, Dittrich FJ: Neoplasms arising in Paget’s disease of bone: a study of 82 cases. J Clin Pathol 83:594–600, 1985. 8. Harvey L: Viral aetiology of Paget’s disease of bone: a review. J R Soc Med 77:943–948, 1984. 9. Huvos AG, Butler A, Bretsky SS: Osteogenic sarcoma associated with Paget’s disease of bone: a clinicopathologic study of 65 patients. Cancer 52:1489–1495, 1983. 10. Mills BG, Singer FR: Nuclear inclusions in Paget’s disease of bone. Science 194:201–202, 1976. 11. Mirra JM, Brien EW, Tehranzadeh J: Paget’s disease of bone: review with emphasis on radiologic features. Part II. Skeletal Radiol 24:173–184, 1995. 12. Paget J: On a form of chronic inflammation of bones (osteitis deformans). Med Chir Trans 60:37, 1877. 13. Paget J: Additional cases of osteitis deformans. Med Chir Trans 65:225, 1882. 14. Price CH, Goldie W: Paget’s sarcoma of bone: a study of eighty cases from the Briston and the Leeds bone tumour registries. J Bone Joint Surg Br 51:205–224, 1969. 15. Ralston SH, Albagha OM: Genetics of Paget’s disease of bone. Curr Osteoporos Rep 12:263–271, 2014. 16. Rea SL, Majcher V, Searle MS, et al: SQSTM1 mutations— bridging Paget disease of bone and ALS/FTLD. Exp Cell Res 325:27–37, 2014. 17. Rebel A, Basle M, Pouplard A, et al: Viral antigens in osteoclasts from Paget’s disease of bone contained viral antigenic material: ultrastructural and immunological studies suggested that measles or measles-related virus was the agent involved. Lancet 16:344– 346, 1980. 18. Singer FR: Paget’s disease of bone: possible viral basis. Trends Endocrinol Metab 7:258–261, 1996. 19. Smith J, Botet JF, Yeh SD: Bone sarcomas in Paget disease: a study of 85 patients. Radiology 152:583–590, 1984. 20. Upchurch KS, Simon LS, Schiller AL, et al: Giant cell reparative granuloma of Paget’s disease of bone: a unique clinical entity. Ann Intern Med 98:35–40, 1983. 21. Wick MR, Siegal GP, Unni KK, et al: Sarcomas of bone complicating osteitis deformans (Paget’s disease). Am J Surg Pathol 5:47–59, 1981.

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