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  ISBN: 978-0-323-02396-2

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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

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Printed in China

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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 diag-
nosis 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 malig-
nant 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 infor-
mation 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 intro-
duced multiple years into my practice, was full of enlight-
ening 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, necessi-
tated 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 opportu-
nity 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 phi-
losophy 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 muta-
tions 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 Gene-
Cards 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 Neurofibroma-
tosis 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 atten-
tion was given to provide the reader with new molecular
and genomic data that are relevant in the current diag-
nostic 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 revi-
sions 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 col-
laborations with William Schmitt and Amy Meros in the
revision process as well as with Ted Rodgers during the
final production of the book.
Preface vii
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 implementa-
tion of molecular data. I hope that Bone Tumors will con-
tribute to this mission.
Bogdan Czerniak
 Foreword
Since the publication of the first edition of this book in
1998, much new information has become available con-
cerning 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 reinter-
preted 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, specifi-
cally 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 exten-
sive reworking and updating of the remainder of the
existing text through the exhaustive efforts of my col-
league 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 collabora-
tors 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 profes-
sional 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 Pathol-
ogy 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 interrelation-
ships of bone tumors, a profound knowledge of these
tumors’ clinical features, follow-up data, radiographic
correlation using mainly plain radiographs and a primi-
tive form of tomography, hematoxylin, eosin slide mor-
phology, 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 oppor-
tunity 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 innova-
tion. 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 fore-
word to this book, what seemed initially to be a reason-
ably 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 evi-
dence 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 malig-
nant 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 surgi-
cal 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 data-
base 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,
and End Results program from 1973 to 1986 were ana-
lyzed and used as a representative sample of bone neo-
plasms occurring in the American population. In addition,
pathologic and clinical data on 4904 benign and primary
malignant bone tumors from patients treated and fol-
lowed 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 epidemio-
logic, 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:

Claus-Peter Adler, MD Timothy A. Jennings, MD Margaret Nuovo, MD

Seena C. Aisner, MD Sonny L. Johansson, MD Nelson G. Ordóñez, MD
Lennart Angervall, MD Craig P. Jones, MD H. Ostertag, MD
Norio Azumi, MD Gernot Jundt, MD Antonio Perez-Atayde, MD
Fidelis A. Barba, MD Leonard B. Kahn, MD A. Kevin Raymond, MD
Thomas Bauer, MD, PhD Bridget C. Kahntroff, MD Wolfgang Remagen, MD
Morgan Berthrong, MD Robert S. Katz, MD Jae Y. Ro, MD, PhD
Belur S. Bhagavan, MD Richard L. Kempson, MD Andrew E. Rosenberg, MD
Peter G. Bullough, MD Demetrios E. Kepas, MD Joel A. Roth, MD
Jane Chatten, MD Peter Klacsmann, MD John M. Rowland, MD, PhD
Janet B. Christman, MD Michael J. Klein, MD C. Peter Schwinn, MD
Robert W. Cihak, MD Carl T. Koenen, MD Marco Semiglia, MD
Karen R. Cleary, MD Harry Kozakewich, MD Hubert A. Sissons, MD
Robert A. Colyer, MD Donald A. Kristt, MD Richard Slavin, MD
Katrina A. Conard, MD Dhruv Kumar, MD Suzane Spanier, MD
Harry C. Cooper, MD Jack P. Lawson, MD German C. Steiner, MD
Jose Costa, MD Alan M. Levine, MD Masayuki Takagi, MD
F. Gonzalez Crussi, MD Mario Luna, MD Jerome B. Taxy, MD
Raffaele David, MD William Martel, MD Felix Tchang, MD
Elina Donskoy, MD Takeo Matsuno, MD Henry Tesluk, MD
Tadashi Hasegawa, MD James A. McAlister, MD Timothy J. Triche, MD
Jack Hasson, MD Edward F. McCarthy, MD Maria Tsokos, MD
K. P. Heidelberger, MD Maria J. Merino, MD Masazumi Tsuneyoshi, MD
William Hicken, MD Markku Miettinen, MD Bruce L. Webber, MD
A. R. Von Hochstetter, MD Sara Milchgrub, MD Sharon W. Weiss, MD
Herbert Ichinose, MD Mark L. Mitchell, MD Gary B. Witkin, MD
Tetsuo Imamura, MD Artemis Nash, MD Benjamin Wittels, MD
Tsuyoshi Ishida, MD Takayuki Nojima, MD Marianne Wolfe, MD
x

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 neo-
plasms. 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 signifi-
cantly 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 complemen-
tary cultural and professional interests, and our initial
interaction rapidly evolved into a professional partner-
ship 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 xi
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. Jacob-
son, MD.
Several of our colleagues reviewed the chapters per-
taining 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 Neurofibroma-
tosis Affecting Bone.” The presentation of ultrastructural
features of many bone tumors was made possible by
Bruce Mackay, MD, PhD, who provided generous unlim-
ited access to his enormous collection of electron micro-
scopic specimens.
Extensive use of digitized imaging and computer
graphics was accomplished with the creative techni-
cal 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 judg-
ment, 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

xii

General Considerations
CHAPTER OUTLINE
MORPHOLOGY OF NORMAL BONE
PROCESSING OF BONE SPECIMENS
STAGING, GRADING, AND REPORTING OF BONE
TUMORS
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 con-
sidered to be reactive in nature. Dramatic advancement in
our understanding of the biology of skeletal-forming cell
lineages such as osteoblastic, chondroblastic, and osteo-
clastic 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 histogen-
esis have undergone reassessment due to findings from
these techniques while the well-defined pathologic enti-
ties 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 correla-
tions is now coupled with new molecular approaches to
delineate this still mysterious group of tumors.
Introduction of newer techniques of immunohisto-
chemistry, molecular pathology, and cytogenetics has not
ERRNVPHGLFRVRUJ
C H A P T E R 1 
SPECIAL STAINS
ELECTRON MICROSCOPY
CYTOMETRY AND HISTOMORPHOMETRY
IMMUNOHISTOCHEMISTRY
CYTOGENETICS
changed the fact that histologic and cytologic character-
istics 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 cat-
egorized 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 diag-
nostic 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 dispa-
rate 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 spe-
cific reason, we attempt to describe individual neoplastic
lesions of bone with an approach that includes clinicora-
diographic, pathologic, and molecular correlations. The
description of most lesions is separated into paragraphs
including epidemiologic, radiographic, gross, and micro-
scopic data, and pertinent information on any special
techniques required for identification is also provided.
1
2 1  General Considerations

TABLE 1-1 WHO Classification of Tumors of Bone*

Tumor Code Tumor Code
Chondrogenic Tumors Osteofibrous dysplasia
Benign Chondromesenchymal hamartoma
Rosai-Dorfman disease
Osteochondroma 9210/0
Chondroma 9220/0 Fibrogenic Tumors
  Enchondroma 9220/0
  Periosteal chondroma 9221/0 Intermediate (locally aggressive)
Osteochondromyxoma 9211/0 Desmoplastic fibroma of bone 8823/1
Subungual exostosis 9213/0
Bizarre parosteal osteochondromatous proliferation 9212/0 Malignant
Synovial chondromatosis 9220/0 Fibrosarcoma of bone 8810/3

Intermediate (locally aggressive) Fibrohistiocytic Tumors

Chondromyxoid fibroma 9241/0 Benign
Atypical cartilaginous tumor Benign fibrous histiocytoma/non-ossifying fibroma 8830/0
  Chondrosarcoma grade 1 9222/1
Hematopoietic Neoplasms
Intermediate (rarely metastasizing) Malignant
Chondroblastoma 9230/1 Plasma cell myeloma 9732/3
Malignant Solitary plasmacytoma of bone 9731/3
Primary non-Hodgkin lymphoma of bone 9591/3
Chondrosarcoma
  Chondrosarcoma grade 2, grade 3 9220/3 Osteoclastic Giant Cell Rich Tumors
Dedifferentiated chondrosarcoma 9243/3
Benign
Mesenchymal chondrosarcoma 9240/3
Clear cell chondrosarcoma 9242/3 Giant cell lesion of the small bones

Osteogenic Tumors Intermediate (locally aggressive, rarely metastasizing)

Benign Giant cell tumor of bone 9250/1
Osteoma 9180/0 Malignant
Osteoid osteoma 9191/0 Malignant giant cell tumor of bone 9250/3
Intermediate (locally aggressive)
Notochordal Tumors
Osteoblastoma 9200/0
Benign
Malignant Benign notochordal tumor 9370/0
Low-grade central osteosarcoma 9187/3
Malignant
Conventional osteosarcoma 9180/3
  Chondroblastic osteosarcoma 9181/3 Chordoma 9370/3
  Fibroblastic osteosarcoma 9182/3
Vascular Tumors
  Osteoblastic osteosarcoma 9180/3
Telangiectatic osteosarcoma 9183/3 Benign
Small cell osteosarcoma 9185/3 Hemangioma 9120/0
Secondary osteosarcoma 9184/3
Parosteal osteosarcoma 9192/3 Intermediate (locally aggressive, rarely metastasizing)
Periosteal osteosarcoma 9193/3 Epithelioid hemangioma 9125/0
High-grade surface osteosarcoma 9194/3
Malignant
Myogenic Tumors Epithelioid hemangioendothelioma 9133/3
Benign Angiosarcoma 9120/3
Leiomyoma of bone 8890/3 Intermediate (locally aggressive)
Malignant Aneurysmal bone cyst 9260/0
Leiomyosarcoma of bone 8890/3 Langerhans cell histiocytosis
  Monostotic 9752/1
Lipogenic Tumors   Polystotic 9753/1
Benign Erdheim-Chester disease 9750/1
Lipoma of bone 8850/0 Miscellaneous Tumors
Malignant Ewing’s sarcoma 9364/3
Adamantinoma 9261/3
Liposarcoma of bone 8850/3 Undifferentiated high-grade pleomorphic sarcoma 8830/3
Tumors of Undefined Neoplastic Nature of bone
Benign
Simple bone cyst 8818/0
Fibrous dysplasia

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.

ERRNVPHGLFRVRUJ

Clinical Radiologic
presentation features
Diagnosis
Molecular Microscopic
data features
FIGURE 1-1  ■  Analytical approach to diagnosis of bone tumor.
Stepwise, analytic approach depicted as a diagnostic quadran-
gle 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 orig-
inally 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 integ-
rity of overall body structure and body movements.
ERRNVPHGLFRVRUJ
1  General Considerations 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, physi-
cal, 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 indi-
viduals 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 par-
ticular 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 matri-
ces.2,7,8,13,14,17,22,30,40 Dense fibrous connective tissue is
formed of well-oriented bundles of collagen, and its prin-
cipal 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
4 1  General Considerations
Axial
Craniofacial
Trunk
Appendicular
Axial
Acral
Acral
FIGURE 1-2  ■  Regional designations of skeleton. Major topo-
graphic regions of the skeleton frequently used in the descrip-
tion 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 inter-
trabecular spaces of the medullary cavity consist of
adipose tissue, fibrovascular structures, and hematopoi-
etic tissue. The trabecular bone with its high surface/
volume ratio is susceptible to rapid turnover, and hence
most sensitively reflects alterations in mineral homeosta-
sis.3,4,16,18 The trabecular bone contributes to skeletal sta-
bility 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
ERRNVPHGLFRVRUJ
types.34,43,45 In woven bone, the collagen fibers are hap-
hazardly 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 cir-
cumferential, concentric, and interstitial. The circumferen-
tial 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 con-
nected 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 spa-
tially organized to form fibrils composed of platelets of
minerals and intrafibrillary matrix.
Cartilage
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
 1  General Considerations 5

Cartilaginous epiphysis

Growth plate
Cartilaginous
epiphysis
Metaphysis

Primary spongiosa

Enchondral ossification
Diaphysis

Developing shaft
Metaphysis
Cartilaginous
epiphysis

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).

ERRNVPHGLFRVRUJ
6 1  General Considerations

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 epi-
physioid bones.

ERRNVPHGLFRVRUJ

Epiphyseal ossification
center
Primary
spongiosa
Secondary
spongiosa
FIGURE 1-5  ■  Topographic anatomy of a developing long bone. Growth plate or physis results from formation of a secondary ossi-
fication center in the cartilage mass at the end of the cartilage model. Increase in length results mainly from cartilage-cell prolifera-
tion and interstitial growth in the cartilaginous physis.
the skeleton, consist of several major basic components:
collagen, proteoglycans, and minerals.5,7,10,13 Metaboli-
cally 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 syn-
thesized on ribosomes and subsequently are assembled
into a triple helix. The cross-linking among these mol-
ecules 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
ERRNVPHGLFRVRUJ
1  General Considerations 7
Epiphysis
Metaphysis
Shaft
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 ossifica-
tions 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 consis-
tency of a stiff gel. The size and consistency of the
8 1  General Considerations
Epiphysis
Physis
Metaphysis
(anatomic)
Radiologic
(diagnostic)
metaphysis
Diaphysis
Radiologic
(diagnostic)
metaphysis
Metaphysis
(anatomic)
Physis
Epiphysis
FIGURE 1-6  ■  Topographic regions of long tubular bones. Ana-
tomically 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 hydroxyapa-
tite [Ca10 (PO4)6 (OH)2] that forms submicroscopic irreg-
ular 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.
ERRNVPHGLFRVRUJ
On its initial appearance in the skeleton, calcium phos-
phate 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
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 anatomi-
cally 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 car-
tilage.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
 1  General Considerations 9

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.)

ERRNVPHGLFRVRUJ
10 1  General Considerations

collagen matrix
mineral platelet
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 per-
mission 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 para-
thormone 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 immu-
nohistochemical hallmark of cartilaginous differentiation
that is expressed on all cells of cartilage lineage. Young
cartilage cells are relatively small compared with chon-
drocytes. They may have a flattened or irregular contour,
and the surface may show multiple projections or filopo-
dia. The nucleus usually contains a prominent nucleolus,
and it may show a prominent paranuclear Golgi zone.

ERRNVPHGLFRVRUJ
 1  General Considerations 11

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 magnifica-
tion 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 (bone-
resorbing cells) are the multinucleated giant cells shown in concavities (Howship’s lacunae). (A, B, and C, ×100; Insets, ×200.) (A to
C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
12 1  General Considerations
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 pro-
totype 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 epiphy-
seal plates of long bones, the cartilage cells are arranged
in long columns. During the skeletal growth phase, car-
tilage cells in the epiphyseal plates undergo transient
proliferative activity followed by deposition of a cartilagi-
nous matrix and programmed cell death (apoptosis). Pro-
liferation 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 pro-
liferating cartilage cells. The ultrastructure of chondro-
cytes 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 osteo-
blasts. In enchondral bone formation, a predeposited
cartilaginous matrix (cartilage model) serves as a scaffold
for the deposition of osteoid (Fig. 1-10). In the develop-
ing 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 differentia-
tion 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. Conse-
quently, 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
ERRNVPHGLFRVRUJ
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). Mem-
branous bones are directly formed from the mesenchy-
mal 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 evalu-
ation 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 speci-
mens 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 preop-
erative 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 spe-
cifically any questions regarding the therapeutic conse-
quences of the diagnosis.
Gross specimens submitted for frozen sections must
be carefully evaluated for the presence of heavily mineral-
ized 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 sec-
tions stained with hematoxylin-eosin. Occasionally, it
may be superseded by the evaluation of cytologic prepa-
rations. Cytologic preparations (touch smears, scrape,
 1  General Considerations 13

Apoptotic
cartilage cells

Columns
of cartilage
cells

Enchondral
ossification
(primary
spongiosa)

Calcified cartilage matrix

Osteoid

C
FIGURE 1-10  ■  Enchondral ossification: Microscopic features. A, Overall view of anatomy of growth plate and zone of primary spon-
giosa formation below. B, Zone of cartilage-cell hypertrophy at base of cartilage-cell columns where programmed cell death (apop-
tosis) 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.)

ERRNVPHGLFRVRUJ
14 1  General Considerations

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 diag-
nosis, which provides an opportunity to evaluate the mor-
phology 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 proce-
dure 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 diag-
nostic approach and, similar to closed biopsy techniques,
is frequently assisted by radiographic imaging techniques.
These techniques are recommended as the initial diag-
nostic 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 con-
tamination and inflammatory complication. Therefore it
is generally recommended that an open biopsy be per-
formed at a medical institution that can provide definitive

ERRNVPHGLFRVRUJ
 1  General Considerations 15

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

Biopsy/Curettings/Resection

Gross Examination

Processing with Processing without

demineralization demineralization

Microscopic Analysis

Special microscopic
techniques
(immunohistochemistry, etc)
Sterile material for
microbiological,
Diagnostic
tissue cultures, and
cytogenetics

Electron microscopic
Fresh tissue for
Immunohistochemistry
special techniques
on frozen tissue

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 contami-
nation 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 exami-
nation, 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 extracellu-
lar components. Demineralization of the entire mate-
rial may render the tissue unsuitable for some special
techniques. Nucleic acids, in particular, are degraded
by acid-based demineralization procedures. As a conse-
quence, 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 immunohisto-
chemical studies can be performed on decalcified tissue
with satisfactory results. For that reason, it is impor-
tant 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 diagnos-
tic 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 examina-
tion. 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 over-
night step through the use of Bouin’s solution. This fixa-
tive contains glacial acetic acid in addition to picric acid,
and sufficient demineralization is often achieved simulta-
neously with fixation.

ERRNVPHGLFRVRUJ
16 1  General Considerations
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 per-
formed 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 radio-
graphs are extremely helpful in planning the dissection
of resected or amputated specimens.48,50,51,65,68,75,93 There-
fore the preoperative radiographs (plain x-rays, comput-
erized tomograms, or magnetic resonance images) should
always be reviewed before dissection. These images may
be supplemented by specimen radiographs. The radio-
graphic data assist in localizing the tumor within the
specimen and identifying any areas of extension into soft
ERRNVPHGLFRVRUJ
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 particu-
lar importance. The potential closest margins are best
identified by reviewing the clinicopathologic data in con-
sultation 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 involve-
ment 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 radio-
graphs 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 reac-
tion. 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 resec-
tion specimens.55,56,66,67,81-84,87-89 Subsequent data indicates
that such an assessment may provide important prognos-
tic 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

Distance from
bone resection
margin
10
12
17
22
27
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 pro-
cessed 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 assess-
ment. 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 sec-
tions 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 che-
motherapy 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, compartmentaliza-
tion, 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
ERRNVPHGLFRVRUJ
1  General Considerations 17
2
4
5
11
6
13
14 15 16
18 19 20 21
7
23
24
25 26
28 8
29
30
9
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 intramed-
ullary tumors except immunohematopoietic malignan-
cies.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 histologi-
cally 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 compartmental-
ization 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
Text continued on p. 22
18 1  General Considerations

Epiphysis

Growth plate

Intramedullary
ivory-like
tumor

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.

ERRNVPHGLFRVRUJ
 1  General Considerations 19

Bone resection
margin

Soft tissue
extension

Soft tissue
extension

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 osteosar-
coma of distal femur shows extensive epiphyseal penetration distally and a large soft tissue mass that exceeds the size of intra-
medullary tumor. Blood-filled cystic spaces within the intramedullary tumor and in the extraosseous extension suggest telangiectatic
features.

ERRNVPHGLFRVRUJ
20 1  General Considerations

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 con-
tinuous medullary involvement was found.

ERRNVPHGLFRVRUJ
 1  General Considerations 21

Myxoid area

Intramedullary tumor

Cystic change

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 chondro-
sarcoma, 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.

ERRNVPHGLFRVRUJ
22 1  General Considerations

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 Primary tumor cannot be assessed
T0 No evidence of primary tumor TNM TWO-GRADE THREE-GRADE FOUR-GRADE
SYSTEM SYSTEMS SYSTEM
T1 Tumor 8 cm or less in greatest dimension Low grade Grade 1 Grade 1
T2 Tumor more than 8 cm in greatest dimension Grade 2
T3 Discontinuous tumors in the primary bone site High grade Grade 2 Grade 3
Grade 3 Grade 4
N—Regional Lymph Nodes Note: If grade cannot be assessed, Ewing’s sarcoma is classified
as high grade. If grade cannot be assessed, classify as low
grade.
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph-node metastasis Stage Grouping
N1 Regional lymph-node metastasis
Stage IA T1 N0 M0 Low grade
Stage IB T2-3 N0 M0 Low grade
M—Distant Metastasis Stage IIA T1 N0 M0 High grade
Stage IIB T2 N0 M0 High grade
Mx Distant metastasis cannot be assessed Stage III T3 N0 M0 High grade
M0 No distant metastasis Stage IVA Any T N0 M0 Any grade
M1 Distant metastasis Stage IVB Any T N1 Any M Any grade
M1a Lung Any T Any N M1b Any grade
M1b other distant sites Note: use N0 for Nx. For T1 and T2, use low grade if no grade is
stated.

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 TABLE 1-4 Musculoskeletal Tumor Society
the Musculoskeletal Tumor Society Staging System
Staging System
Stage Grade Site Metastasis
Intracompartmental (T1) Extracompartmental (T2) IA G1 T1 M0
Intraarticular Soft tissue extension IB G1 T2 M0
Superficial to deep fascia Deep fascial extension IIA G2 T1 M0
Paraosseous Intraosseous or extrafascial IIB G2 T2 M0
extension III G1 or G2 T1 or T2 M1
Intrafascial compartment Extrafascial compartment
Modified from Enneking WF, et al: A system for the surgical
Modified from Enneking WF, et al: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 153:106–
staging of musculoskeletal sarcoma. Clin Orthop 153:106– 120, 1980 and Peabody TD, et al: Evaluation and staging of
120, 1980 and Peabody TD, et al: Evaluation and staging of musculoskeletal neoplasms. J Bone Joint Surg 80:1204–
musculoskeletal neoplasms. J Bone Joint Surg 80:1204– 1218, 1998.
1218, 1998.

The designations of this parameter are G0, G1, and G2.
G0 is a benign neoplasm, and G1 is a locally aggres-
sive 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 des-
ignates 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 consid-
ered a single compartment. Hence, extension beyond the
cortex into adjacent soft tissue, joint, or another bone is
considered extracompartmental and this lesion is desig-
nated T2. With these parameters, lesions are separated
into three stages. Low-grade lesions are stage I. Stage II
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 extracom-
partmental lesions, respectively. A summary of Ennek-
ing’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 accord-
ing 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 eradi-
cate tumors by surgical excisions in these distinct ana-
tomic locations. This system uses a cutoff point of 5 cm
as an important factor to predict the prognosis. It has to

ERRNVPHGLFRVRUJ
 1  General Considerations 23

be understood that this discrimination is somewhat arbi-

TABLE 1-5 Definitions of Grading Parameters
trary, and the size of the tumor is rather a continuous,
for the FNCLCC System
incremental variable. The Enneking system adopted by
the American Joint Committee Task Force on Bone Parameter Criterion
Tumors (also referred to as the Musculoskeletal Tumor
Tumor Differentiation
Society Staging System) places the emphasis on compart-
Score 1 Sarcoma closely resembling normal adult
mentalization and is preferable, especially for lesions mesenchymal tissue (e.g., well-
affecting the extremities. Regardless which staging system differentiated liposarcoma)
is used, a multidisciplinary approach is needed to accu- Score 2 Sarcomas for which histologic typing is
rately stratify the tumors using the information generated certain (e.g., myxoid liposarcoma)
by different modalities (i.e., clinical presentation, radio- Score 3 Embryonal and undifferentiated sarcomas;
sarcoma of uncertain type
graphic imaging, and pathology).
Mitosis Count
Score 1 0-9/10 HPF
Grading Systems Score 2 10-19/10 HPF
Score 3 ≥20/10 HPF
Grading of bone sarcomas represents the evolution of
historical concepts of grading proposed almost a century Tumor Necrosis (Microscopic)
ago by Broders and originally designed for a fibrosar- Score 0 No necrosis
coma.95 Following this publication, numerous studies Score 1 ≤50% tumor necrosis
reaffirmed the importance of grading in a variety of Score 2 >50% tumor necrosis
tumors. In general, grading systems include the state Histologic Grade
of differentiation, the degree of atypia, and the mitotic Grade 1 Total score 2, 3
activity assessed based on the mitotic count in conven- Grade 2 Total score 4, 5
tional pathology preparations or with the assistance of Grade 3 Total score 6, 7, 8
proliferation markers.98,99,107,108,110-114,116-118,121,128 A proto- Modified from Coindre JM, et al: Reproducibility of a
typic large-scale study based on the analysis of stage and histolopathologic grading system for adult soft tissue
grade of 1000 sarcomas was published by Russell et al.124 sarcomas, Cancer 58:306–309, 1986.
The stratification of sarcomas in various systems is based FNCLCC, Federation Nationale de Centres de Lutte Contre le
on two-, three-, or four-tier concepts. None of these Cancer; HPF, high-power field.
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 TABLE 1-6 Grading of Bone Sarcoma
grade, which may behave as a fully malignant tumor
capable of metastasis or as a locally aggressive tumor only. Grade Sarcoma Type
The overall tendency is to classify the tumors into two Grade 1 Parosteal osteosarcoma
grades, designated as either a low-grade tumor, signifying Grade 1 chondrosarcoma
a locally aggressive tumor, or a high-grade tumor, signify- Clear cell chondrosarcoma
ing a lesion capable of metastasis. The problem with the Low-grade intramedullary osteosarcoma
Grade 2 Periosteal osteosarcoma
two-tier stratification is that it is not always possible to Grade 2 chondrosarcoma
classify the tumor as definitively low or high grade. Classic adamantinoma
The system that is gaining increased popularity was Chordoma
originally published by Trojani et al. in 1984126 and was Grade 3 Osteosarcoma (conventional, telangiectatic,
subsequently adopted by the French Federation of Cancer small cell, secondary, high-grade surface)
Undifferentiated high-grade pleomorphic
Centers Sarcoma Group.96,97,103,109 The system is based on sarcoma
multivariate analysis of microscopic features and utilizes Ewing’s sarcoma
a combination of tumor differentiation, mitotic rate, and Grade 3 chondrosarcoma
necrosis as parameters for grading.(Table 1-5) It is being Dedifferentiated chondrosarcoma
Mesenchymal chondrosarcoma
utilized with increasing popularity both in Europe and Dedifferentiated chordoma
the United States.120 It assigns a score to each parameter Malignancy in giant cell tumor of bone
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 grade. For example, Ewing’s sarcoma, mesenchymal
tumors in which the benign tissue or cell counterpart is chondrosarcoma, and conventional osteosarcomas are
not known or hypothetical, the differentiation score is highly aggressive tumors considered as high grade.115,127
not very reliable.120 Disregarding this, the system has On the other hand, specific subtypes of osteosarcoma
reasonably good interobserver reproducibility. such as parosteal osteosarcoma are defined as low-grade
The use of grading systems in general, including the tumors. In addition, chondrosarcomas are graded accord-
above listed French system, has never been validated for ing to their own system originally proposed by Evans
bone sarcomas.106 In bone sarcomas, similar to many soft et al., which is described in detail in Chapter 7.104 The
tissue sarcomas, the identification of a specific type deter- grade assignments proposed by the WHO Classification
mines the biologic behavior and by itself defines the System for tumors of bone are listed in Table 1-6.

ERRNVPHGLFRVRUJ
24 1  General Considerations

TABLE 1-7 Checklist for Standard Reporting of Bone Biopsy

Specimen Tumor Size Lymph-Vascular Invasion
Specify bone involved: ___________ Greatest dimension: ___ cm ___ Not identified
___ Not specified Additional dimensions: ___ × ___ cm ___ Present
___ Cannot be determined (see “Comment”) ___ Indeterminate
Procedure
___ Core needle biopsy Histologic Type (World Health Organization Additional Pathologic Findings
___ Curettage Classification) Specify: ___________
___ Excisional biopsy Specify: _____________
___ Other (specify): ____________ ___ Cannot be determined Ancillary Studies
___ Not specified Immunohistochemistry
Mitotic Rate Specify: __________
Tumor Site Specify: ___ /10 high-power fields (HPF) ___ Not performed
___ Epiphysis or apophysis (1 HPF × 400 = 0.1734 mm2; X40 objective; Cytogenetics
___ Metaphysis most proliferative area) Specify: __________
___ Diaphysis ___ Not performed
___ Cortex Necrosis Molecular Pathology
___ Medullary cavity ___ Not identified Specify: __________
___ Surface ___ Present ___ Not performed
___ Tumor involves joint Extent: ___%
___ Tumor extension into soft tissue ___ Cannot be determined Radiographic Findings
___ Cannot be determined Specify: __________
Histologic Grade ___ Not available
Specify: ___
___ 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.

Reporting of Bone Tumors Formulation of a pathology report is a complex task

A pathologist reporting on a bone tumor is confronted
with the task of categorizing them into three major sub-
types: 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 cat-
egory 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 interme-
diate 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 occa-
sionally 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 metasta-
sis. 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 corre-
spond to the histologic intermediate grade.
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 Pathol-
ogy 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 concern-
ing 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 regis-
tries 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 (1973-
2010) of the National Cancer Institute’s SEER Program.152
The SEER Program reports long term incidence, preva-
lence, 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

ERRNVPHGLFRVRUJ
 1  General Considerations 25

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 Number of Lymph Nodes Involved
Specify: ___ Specify: ___
___ Not applicable ___ Number cannot be determined
___ Cannot be determined (explain): ________
Margins Distant Metastasis (pM)
___ Cannot be assessed ___ Not applicable
___ Margins uninvolved by sarcoma ___ pM1a: Lung
  Distance of sarcoma from closest ___ pM1b: Metastasis involving distant
margin: ___ cm sites other than lung
  Specify margin (if known): ___________   +Specify site(s), if known:
___ Margin(s) involved by sarcoma _______________
  Specify margin(s) (if known): _________
Additional Pathologic Findings
Lymph-Vascular Invasion Specify: ___________
___ Not identified
Ancillary Studies (required only if
___ Present
applicable)
___ Indeterminate
Immunohistochemistry
Pathologic Staging (pTNM) Specify: ___________
TNM Descriptors (required only if ___ Not performed
applicable) (select all that apply) Cytogenetics
___ m (multiple) Specify: ___________
___ r (recurrent) ___ Not performed
___ y (posttreatment) Molecular Pathology
Primary Tumor (pT) Specify: ___________
___ pTx: Primary tumor cannot be ___ Not performed
assessed
Radiographic Findings (if available)
___ pT0: No evidence of primary tumor
___ pT1: Tumor ≤8 cm in greatest Specify: ___________
dimension ___ Not performed
___ pT2: Tumor >8 cm in greatest
Preresection Treatment
dimension
___ pT3: Discontinuous tumors in the ___ No therapy
primary bone site ___ Chemotherapy performed
Regional Lymph Nodes (pN) (Note K) ___ Radiation therapy performed
___ pNx: Regional lymph nodes cannot ___ Therapy performed, type not specified
be assessed ___ Unknown
___ pN0: No regional lymph node
Treatment Effect
metastasis
___ pN1: Regional lymph node metastasis ___ Not identified
___ No nodes submitted or found ___ Present
Number of Lymph Nodes Examined   +Specify percentage of necrotic tumor
Specify: ___ (compared with pretreatment biopsy, if
___ Number cannot be determined available): ___%
(explain): ________ ___ 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 Connecti-
cut, Iowa, New Mexico, Utah, and Hawaii, and the
metropolitan areas of Detroit (Michigan), San Francisco–
Oakland (California), Seattle–Puget Sound (Washing-
ton), 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 col-
lected 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 ethnic-
ity. 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 cov-
erage 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 coun-
terparts.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

ERRNVPHGLFRVRUJ
26 1  General Considerations

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 White Black
Histology Frequency % Frequency % Frequency %
Bones and Joints 8417 100.00 6930 100.00 825 100.00
  Sarcoma 8322 98.87 6854 98.90 815 98.79
   Malignant fibrous histiocytoma/high-grade 138 1.64 115 1.66 13 1.58
pleomorphic sarcoma (8830-8831)
   Fibrosarcoma (8810-8812) 67 0.80 54 0.78 8 0.97
   Osteosarcoma 3005 35.70 2281 32.91 468 56.73
   Osteosarcoma, NOS (9180) 2011 23.89 1529 22.06 304 36.85
   Specified osteosarcomas (9181-9185, 9190) 752 8.93 583 8.41 115 13.94
   Osteosarcoma in Paget’s disease of bone (9184) 32 0.38 25 0.36 5 0.61
   Other 210 2.49 144 2.08 44 5.33
   Chondrosarcoma, NOS (9220-9240) 2305 27.39 1987 28.67 165 20.00
   Ewing’s sarcoma (9260) 1142 13.57 1023 14.76 42 5.09
   Adamantinoma of long bones (9261) 46 0.55 34 0.49 5 0.61
   Hemangioasarcoma and malignant 116 1.38 96 1.39 2 0.24
hemangioendothelioma (9120-9134)
   Chordoma (9370) 650 7.72 570 8.23 18 2.18
   Other 853 10.13 694 10.01 94 11.39
Unspecified 95 1.13 76 1.10 10 1.21
Bones and Joints—in Situ 0 0.00 0 0.00 0 0.00

Bone Sarcomas
1.8 14

1.6
12
1.4
(cases/100,000 persons)

10

Age distribution (%)

1.2
Indcidence rate

1 8

0.8 6

0.6
4
0.4
2
0.2

0 0
0

9
4

+
9

4
5-
1-

-1

85
-1

-2

-2

-3

-3

-4

-4

-5

-5

-6

-6

-7

-7

-8
10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

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 diag-
nosed 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 histio-
cytoma 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 sur-
vival. 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

ERRNVPHGLFRVRUJ
 1  General Considerations 27

TABLE 1-10 Relative Frequencies of Bone Sarcomas by Histologic Type, Sex, and Race: SEER Data
1973-2010
Total Male Female White Black
No. % No. % No. % No. % No. %
Osteosarcoma 3005 35.70 1651 35.13 1354 36.43 2281 32.91 468 56.73
Chondrosarcoma 2305 27.38 1228 26.13 1077 28.98 1987 28.67 165 20.00
Ewing’s Sarcoma 1142 13.57 710 15.11 432 11.62 1023 14.76 42 5.09
Chordoma 650 7.72 386 8.21 264 7.10 570 8.23 18 2.18
Fibrosarcoma/Malignant Fibrous Histiocytoma 205 2.44 105 2.23 100 2.69 169 2.44 21 2.55
Angiosarcoma 116 1.38 72 1.53 44 1.18 96 1.39 2 0.24
Adamantinoma of Long Bones 46 0.55 24 0.51 22 0.59 34 0.49 5 0.61
Unspecified 95 1.13 53 1.13 42 1.13 76 1.10 10 1.21
Others (Sarcomas) 853 10.13 471 10.02 382 10.28 694 10.01 94 11.39
Total 8417 100 4700 100.00 3717 100.00 6930 100.00 825 100.00

TABLE 1-11 Incidence Rates of Bone Sarcomas by Histologic Type, Race, and Sex: SEER Data,
1973-2010
All Races White Black
Total Male Female Total Male Female Total Male Female
Osteosarcoma 0.31 0.35 0.28 0.3 0.34 0.26 0.39 0.42 0.37
Chondrosarcoma 0.25 0.27 0.23 0.26 0.28 0.25 0.14 0.17 0.11
Ewing’s Sarcoma 0.12 0.15 0.08 0.13 0.17 0.1 0.03 0.05 0.02
Chordoma 0.07 0.08 0.05 0.08 0.09 0.06 0.01 0.02 0.01
Malignant Fibrous Histiocytoma 0.01 0.02 0.01 0.02 0.01 0.02 0.01 0.01 0.01
Total 0.76 0.87 0.65 0.79 0.89 0.69 0.58 0.67 0.52

TABLE 1-12 Median Age at Diagnosis for Bone Sarcomas by Histologic Type, Race, and Sex:
SEER Data 1973-2010
All Races White Black
Total Male Female Total Male Female Total Male Female
Osteosarcoma, NOS 21 20 23 23 23 23 18.5 17 23
Osteosarcoma, Paget’s Disease 73 71.5 74 73.5 73 74 59.5 60 _
Chondrosarcoma 52 52 53 54 53 54 45 44 45
Ewing’s Sarcoma 17 17 16 17 17 16 19 20 16
Chordoma 57.5 57 57.5 58 57.5 59 42 45 36
Malignant Fibrous Histiocytoma 68.5 68.5 68 69 69 69 59 59 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, chon-
drosarcoma, chordoma, and malignant fibrous histiocy-
toma 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 par-
ticularly 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, environ-
mental factors, or industrial factors or are simply the
results of inaccuracies related to disease and population
monitoring. The most striking difference is in the inci-
dence 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

ERRNVPHGLFRVRUJ
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, 50.6 38.7 40.14 40.42 55.74 53.96 53.2 48.7 53.4 49.8 51.7
NOS
Osteosarcoma, 18.8 * * * * * * 15.6 21.5 20.3 *
Paget’s
Disease
Chondrosarcoma 79.3 73.3 70.42 67.02 79.24 82.92 80.65 76.4 82.2 79.4 77.1
Ewing’s 46.8 34.6 41.46 49.58 46.36 48.2 49.46 44.6 50.9 47.1 37.7
Sarcoma
Chordoma 73.1 63 52.04 73.26 67.16 75.02 77.55 72.5 73.9 73.5 71.7
Malignant 65.4 51.8 54.58 62.12 65.04 65.52 67.88 65.6 65.2 66.1 53.7
Fibrous
Histiocytoma

*<25 cases.

1.0

Osteosarcoma
Chondrosarcoma
0.8 Ewing's sarcoma
(cases/100,000 persons)

Chordoma
Malignant fibrous histiocytoma
Incidence rate

0.6

0.4

0.2

0.0
0

4
+
-1

-1

-2

-2

-3

-3

-4

-4

-5

-5

-6

-6

-7

-7

-8
1-

5-

85
10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

Age at diagnosis
FIGURE 1-20  ■  Bone sarcomas: Epidemiology. Age-specific incidence rates and frequency distribution, all races, both sexes, SEER
data, 1973-2010.

currently indicates improvement in 5-year survival rates
for osteosarcoma, Ewing’s sarcoma, chordoma, and
malignant fibrous histiocytoma. There has not been
improvement in survival rates for chondrosarcoma (Fig.
1-22). A detailed analysis of the epidemiologic features of
bone tumors is provided in addition to a description of
any specific tumors.
SPECIAL TECHNIQUES
Fundamental to the diagnosis of bone tumors is the
microscopic examination of formalin-fixed (calcified or
decalcified) tissue embedded in paraffin and stained
with hematoxylin-eosin, interpreted in conjunction with
clinical and radiographic data. Hematoxylin-eosin has
proved to be one of the most enduring and reliable stains
in the entire arsenal of techniques used in diagnostic
pathology, including the diagnosis of skeletal conditions.
The majority of bone tumors and tumorlike conditions
can be accurately diagnosed with the use of this simple
staining technique. Hematoxylin stains nuclei blue, and
subsequent counterstaining with eosin provides red stain-
ing of the cytoplasm and of various extracellular compo-
nents. In brief, hematoxylin must be oxidized with
formalin to a purple compound (hematin) and positively
charged with metallic salt (mordant). The second com-
ponent used in the technique (eosin) is an anionic

ERRNVPHGLFRVRUJ
 1  General Considerations 29

30

Osteosarcoma
Chondrosarcoma
25
Ewing's sarcoma
Chordoma
Age distribution (%)
20 Malignant fibrous histiocytoma

15

10

0
0

4
+
-1

-1

-2

-2

-3

-3

-4

-4

-5

-5

-6

-6

-7

-7

-8
1-

5-

85
10

15

20

25

30

35

40

45

50

55

60

65

70

75

80
Age at diagnosis
FIGURE 1-21  ■  Bone sarcomas: Epidemiology. Age-specific frequency distribution by histologic subtype, all races, both sexes, SEER
data, 1973-2010.

90

80
Five-years relative survival rate (%)

70

60

50

40

30 Osteosarcoma
Chondrosarcoma
20
Ewing's sarcoma
10
Chordoma
Malignant fibrous histiocytoma
0
1973-1977 1978-1982 1983-1987 1988-1992 1993-1997 1998-2005
FIGURE 1-22  ■  Bone sarcomas: Epidemiology. Disease specific, 5-year survival rates. Comparison of survival rates by histologic
subtype in all races and both sexes. SEER data, 1973-2010.

ERRNVPHGLFRVRUJ
30 1  General Considerations
dye that electrostatically binds various proteins. The
hematoxylin-eosin stain enables accurate microscopic
evaluation of a tissue’s architecture and cells. This tech-
nique is certainly not perfect and occasionally must be
supplemented with so-called special techniques. From
the very beginning of microscopic inspections of tissue
specimens for both investigative and diagnostic purposes
there was the necessity to identify specific components of
extracellular matrix as well as subcellular elements. The
original techniques were based on the combination of
organic dyes and chemicals intended to identify specific
tissue components. Collectively, this approach is referred
to as histochemistry or special stains, which identify various
components of tissue based on color reactions. Although
many of these reactions are nonspecific, the special stains
represent a valuable auxiliary diagnostic tool. The tech-
niques of histochemistry, especially the color detection
systems, were subsequently combined with immunologic
detection of individual molecules with the use of antibod-
ies; they now represent the mainstay of the differential
diagnostic workup widely used in pathology, including
skeletal pathology, referred to as immunohistochemistry.
Because microscopic inspections of both cellular features
and tissues architecture is subjective, the intention to
quantify the microscopic images has evolved into the
technology of cytometry and histomorphology, in which
individual cellular and extracellular components are
quantitatively measured by machines referred to as cyto-
photometers or image analyzers. The necessity to identify
and elaborate upon details of tissue architecture on a
higher resolution level has evolved into the technique
collectively referred to as electron microscopy. Various
machines using different electron-based beams were
developed and the so-called transmission electron microscopy
has significantly contributed to our understanding of
pathogenetic concepts of tumors and has some limited
applications in modern diagnostic pathology. Finally, the
investigations of the genetic origin of human cancer have
identified disease-specific aberrant chromosomes as well
as the hybrid genes, providing the foundations of the
discipline of cytogenetics. The concepts of special tech-
niques listed have evolved in parallel with the concepts
of both investigative and diagnostic pathology. In general,
these special techniques are used when specific diagnos-
tic, pathogenetic, or etiologic questions cannot be cate-
gorically or satisfactorily answered with the use of the
standard approach. In this section, we describe the fun-
damental principles of these special techniques, focusing
on their relevance for skeletal pathology.
SPECIAL STAINS
Numerous special stains are listed in histotechnology
textbooks, but relatively few provide specific diagnostic
information that cannot be obtained from hematoxylin-
eosin–stained sections. Many of these stains are nonspe-
cific, but historically they represent the first auxiliary
tools available to the pathologist to identify extracel-
lular and subcellular components as well as microor-
ganisms aiding in the diagnosis.165,168,176,186 The advent
of modern biomarkers detected with antibodies and
ERRNVPHGLFRVRUJ
immunohistochemistry has dramatically reduced the
applicability of these techniques in current diagnostic
pathologic routines. A family of small cell malignancies
is the prototype for which the use of special stains was
replaced with modern immunohistochemical biomark-
ers and molecular tests in their differential diagnosis.169
The special stains that are still of value and are at least
occasionally used in diagnostic skeletal pathology are
described here.
Periodic Acid-Schiff Stain
The principle of periodic acid-Schiff (PAS) stain is based
on the oxidizing reaction in the presence of periodic
acid and Schiff’s reagent.177 Molecules containing vicinal
glycol groups form in the presence of periodic acid dial-
dehydes that combine with Schiff’s reagent to produce a
reddish (magenta) substance. PAS stain is principally used
to demonstrate intracytoplasmic glycogen. The stain by
itself is nonspecific but with diastase digestion (reduction
or elimination of a substance positive for PAS after enzy-
matic treatment) it demonstrates the presence of glyco-
gen. In bone tumors, it is most often used to demonstrate
glycogen in Ewing’s sarcoma and clear cell chondrosar-
coma. In general, PAS stain can be used to demonstrate
the presence of neutral mucin to outline the basement
membrane and to visualize fungal and parasitic organisms.
Mucins
Stains for mucins are frequently used in the diagnosis
of adenocarcinoma. In bone, they are occasionally used
in the diagnosis of metastatic adenocarcinoma when the
tumor cells do not form conspicuous glandular struc-
tures. Alcian blue combined with PAS stain is used to
demonstrate neutral and slightly acidic types of muco-
substances.167,171,172 Mayer’s mucicarmine is probably
the stain used most frequently to demonstrate acidic
mucin.176,183,198 These stains are useful in demonstrating
both intracellular and extracellular mucins in chordoma.
Trichrome Stain
The trichrome stain is frequently used to demonstrate the
presence of extracellular substances such as collagen.175,179
It is sometimes used in research investigation of soft and
skeletal tissue, but it has minimal diagnostic applicabili-
ties. As the name implies, the technique uses three dyes
that stain nuclei, cytoplasm, and extracellular matrix, pri-
marily the collagen. This technique is rarely used in the
diagnosis of tumors, but it is frequently used for histomor-
phometric evaluation of mineralized versus nonmineral-
ized osteoid in metabolic bone diseases (Fig. 1-23).175
Stains for Microorganisms
Of a long list of stains used to visualize infectious organ-
isms, only a few are routinely used in diagnostic pathol-
ogy. Gram stain is used to classify bacteria into two major
categories: those that retain crystal violet-iodine dye
after alcohol and acetone treatment (gram positive)
and those that are decolorized by this technique (gram
 1  General Considerations 31

A B

C D
FIGURE 1-23  ■  Special stains. A, Modified trichrome (Goldner’s stain) of undecalcified bone documents mineralized (blue) and unmin-
eralized (red) bone. Note increased amount of mineralized osteoid (hyperosteoidosis). B, Trichrome stain shows thick rim of unmin-
eralized osteoid in area with increased osteoblastic activity. C, von Kossa’s stain on undecalcified bone demonstrates mineralized
osteoid as black substance. Increased resorptive (osteoclastic) activity is present and is due to secondary hyperparathyroidism.
D, von Kossa’s stain of undecalcified bone with hyperosteoidosis (increased amount of unmineralized osteoid) in tumorigenic
osteomalacia. (A, ×50; B, ×200.)

ERRNVPHGLFRVRUJ
32 1  General Considerations
negative).160,185 The acid-fast stain (Ziehl-Neelsen) is used
to document the presence of mycobacteria.157 The degree
of resistance to acid hydrolysis depends on the lipid
content in the wall of the bacteria. Bacteria with a high
content of complex lipids retain carbolfuchsin after
decolorization with acid alcohol. Other stains occasion-
ally used to document the presence of infectious organ-
isms are Grocott’s silver (fungi),180,191,194 PAS (fungi),
Dieterle’s (spirochetes),161,196 and Warthin-Starry (spiro-
chetes and rickettsiae).162,192
Argentaffin and Argyrophilic Stains
Before the advent of immunohistochemistry, argentaffin
and argyrophilic reactions were frequently used to dis-
close the neuroendocrine and neural differentiation of
cells.158,184,189,197 In skeletal pathology, these reactions
were used mainly in the diagnosis of metastatic tumors.
In modern diagnostic pathology, they have been replaced
by more specific immunohistochemical stains such as for
synaptophysin and chromogranin. The Fontana-Masson
modification of the argentaffin reaction is used as a stain
for melanin (see later section). In the argentaffin reaction,
the presence of the phenolic groups, mainly in catechol-
amines and indolamines, reduces the silver salt concen-
tration and generates an insoluble black precipitate. The
argyrophilic reaction requires an external reducing agent,
usually hydroquinone or formalin. For this reason, the
argyrophilic reaction produces the best results when
tissue is fixed in formalin-free fixative such as Bouin’s
solution.
Reticulin Stain
Reticulin fibers represent fine fibrillary material deposited
in the intercellular matrix throughout the body. The
major component of these fibers is type III collagen. The
histochemical stains used to identify reticulin fibers are
silver-based, such as Gomori’s, Wilder’s, or Gordon and
Sweet’s stains.174,178,190 These stains are nonspecific, and a
positive reaction is related to the presence of interstitial
proteoglycans. Therefore all elements rich in proteogly-
cans stain positive with these stains. Before the discovery
of cell markers and immunohistochemistry, reticulin
stains were used to disclose the patterns of reticulin fibers,
to distinguish epithelial and nonepithelial neoplasia, and
to subclassify some of the mesenchymal tumors. Epithelial
neoplasms are characterized by the presence of reticulin
fibers surrounding nests of tumor cells. In mesenchymal
tumors, reticulin fibers are sparsely distributed among
individual tumor cells. In addition, some of the mesenchy-
mal tumors have a distinct pattern of reticulin fibers (e.g.,
longitudinal parallel arrangement in tumors of Schwann
cells). In fibrosarcoma, reticulin fibers encircle individual
tumor cells. In the era of immunohistochemistry, reticulin
stains are seldom used for diagnostic purposes.
Amyloid Stain
Staining for amyloid is one of the most useful special
techniques.170,173 The Congo red stain and examination
with nonpolarized and polarized light are the most
ERRNVPHGLFRVRUJ
frequently used techniques. The dye binds the β-pleated
arrangement of amyloid and has no chemical specificity.
This is seen as a reddish deposit under nonpolarized
light. Green birefringence is present when the sections
are examined under polarized light. Excessive or pro-
longed exposure to Congo red can cause binding to the
tissue that is unrelated to the presence of amyloid.
Hemosiderin
The most frequently used stain for hemosiderin is an iron
stain. In this technique the acid hydrolysis separates the
iron from the protein.163 Potassium ferrocyanide is sub-
sequently used and forms an insoluble ferric ferrocyanide
also known as Prussian blue.
Melanin Stain
The most frequently used Fontana-Masson technique is
a silver stain without an external reducing substance
(argentaffin reaction). In this technique, metallic silver is
directly reduced by melanin.159,164,200
Calcium Stain
Goldner and von Kossa’s technique for calcium is another
variant of a silver stain.193 Calcified tissue such as mineral-
ized osteoid is identified by the substitution of calcium
with potassium and is reduced to an insoluble black silver
precipitate with the photographic developer (Fig. 1-23).
von Kossa’s technique is frequently used on nondecalci-
fied bone sections for histomorphometric assessment of
metabolic bone disorders.
Enzyme Histochemistry
Histochemical identification of enzymatic activity in
diagnostic pathology has been largely replaced by the
immunohistochemical identification of specific proteins.
Histochemical identification requires that the enzyme
retain its activity, and complex, largely nonspecific color
reactions are used to visualize the enzyme in ques-
tion.181,187 In skeletal and general pathology, a few histo-
chemical reactions are still being used. A good example
of the use of this technique is the identification of chlo-
roacetate esterase (Leder’s esterase) to document myeloid
or mast cell differentiation of tumor cells.166,182,188,199 In
bone tumors, acid phosphatase can be used as a marker
of osteoclastic cells. Both Leder’s esterase and acid phos-
phatase retain their activity after routine fixation and
paraffin embedding. The identification of tyrosinase by
the dihydroxyphenylalanine (DOPA) reaction was used
in the past to identify melanocytic differentiation.195
With the advent of immunohistochemistry, this reaction
is rarely used for diagnostic purposes.
ELECTRON MICROSCOPY
Examination of the ultrastructural features of cellular
and extracellular structures was and continues to be a
powerful investigative tool. The introduction of the

transmission electron microscope in the early decades of
the twentieth century dramatically expanded the investi-
gative capabilities to study the submicroscopic details of
diseased tissue, including bone tumors and tumorlike
conditions.201,202 Use of the transmission electron micro-
scope, in which the electron beam passes through a thin
section of tissue impregnated with electron-dense mate-
rial and embedded in plastic medium, provided new
understanding of the subcellular organization of cells and
extracellular matrixes. The scanning electron microscope
provides an opportunity to examine the cell surface and
intracytoplasmic membranous structures, as well as the
three-dimensional composition of extracellular compo-
nents. Transmission electron microscopy represented a
substantial diagnostic tool aiding the differential diagno-
sis of tumors including those in the skeleton. The
so-called scanning and analytical instruments had little
use in routine diagnosis. With the advent of modern
immunohistochemistry, coupled with the dramatic expan-
sion of biomarkers as well as the introduction of molecu-
lar diagnostic tests, even the most enthusiastic electron
microscopist must admit that as far as diagnostic pathol-
ogy is concerned, the era of electron microscopy is mainly
of historical interest.203,207 The emergence of immunohis-
tochemistry and molecular pathology has significantly
changed the approach to the diagnosis of bone tumors,
and many diagnostic questions that in the past required
ultrastructural studies are now addressed with the use of
antibodies and molecular tests. It is premature, however,
to close the diagnostic chapter of electron microscopy in
pathology; it is still being used and the good examples
represent its application to glomerular disorders of the
kidneys and myopathies.204,206,210 In this book, the descrip-
tion of certain ultrastructural features of bone tumors by
electron microscopy is retained because it provides the
ultrastructural basis for cellular and extracellular phe-
nomena observed on the light microscope level.
In bone tumors, as in general tumor pathology, ultra-
structural studies have provided valuable information
about tumor histogenesis and differentiation pathways,
complementing the immunohistochemical biomarker-
based observations. Such studies were essential to formu-
late novel pathogenetic concepts concerning the tissue
and cellular origin of many bone tumors. Unfortunately,
like other special techniques, ultrastructural studies are
not useful in distinguishing benign versus malignant
tumors and reactive conditions. In the past, the most
frequent applications of this technique in bone tumor
pathology were in the differential diagnosis of (1) spindle-
cell neoplasms, (2) small blue cell neoplasms, (3) vascular
versus nonvascular neoplasms, and (4) a wide range of
metastatic tumors of bone. These four main areas of
electron microscopy have numerous specific applications.
For educational purposes, we retained the sections
describing ultrastructural features that are of potential
diagnostic significance for individual bone tumors and
tumorlike conditions. Electron microscopy continues to
be used as a valuable investigative tool.205,208,209
Generally, tumors that cannot be diagnosed by light
microscopy and that also have an inconclusive biomarker-
based immunohistochemical profile very likely are not
diagnosable by electron microscopy.
ERRNVPHGLFRVRUJ
1  General Considerations 33
Ultrastructural studies conducted without a definite
list of differential diagnoses and specific questions are
likely to provide disappointing results. Such studies have
the best chance of being useful if conducted along with
light microscopy and other applicable special techniques,
with the formulation of specific questions that need to be
answered.
The major limitations of ultrastructural studies in the
diagnosis of bone tumors are similar to those listed in
general pathology textbooks:
1. Only a small proportion of tissue can be sampled
and examined. Relatively few ultrastructural fea-
tures are diagnostically specific; as with light
microscopy, the entire picture is more informative.
2. It is occasionally difficult to distinguish neoplastic
from nonneoplastic cells in ultrastructural studies.
Therefore the entrapment of normal elements with
specific ultrastructural features of cellular differen-
tiation can be misleading. This pitfall can be largely
eliminated by careful examination of the so-called
semithin section.
3. The consensus is that in the modern era of immu-
nohistochemistry and molecular pathology, elec-
tron microscopy has minimal application in the
routine diagnosis of bone tumors.
CYTOMETRY AND
HISTOMORPHOMETRY
The concept that quantitative analysis of cellular and
extracellular tissue components significantly expands the
investigative capabilities of cell biology and pathogenesis
of diseases is a very old one. The prototype of modern
quantitative instruments was the simple ocular microm-
eter. The idea that quantitative cytometry could be used
to diagnose tumors failed because of the lack of known
parameters that could be used to formulate measurable
criteria to distinguish malignant from benign tumors and
to delineate their different categories. Still, the tech-
niques of quantitative cytometry and histomorphometry
provide reliable information that can be used to study
tumor cells, and some of this information has prognostic
significance. Moreover, histomorphometry of bone is a
very useful tool for the diagnosis of metabolic diseases of
bone. In the past, flow cytometry and image analysis were
primarily used to assess the deoxyribonucleic acid (DNA)
ploidy and proliferation rates of the tumors, which were
shown to have some prognostic value. These applications
continue to be of some interest for practical value, but in
modern diagnostic pathology these techniques are more
often used as investigative rather than diagnostic tools.
The assessment of DNA ploidy and proliferation rates
have been largely replaced by more accurate techniques
such as SNP-based microarray and DNA sequencing.
For diagnostic purposes, the assessment of tumor prolif-
eration with the use of immunohistochemistry and pro-
liferation specific biomarkers is much simpler and cost
effective. Today, flow cytometry is mainly used for immu-
nophenotyping of cell populations in lymphohematopoi-
etic malignancies, and the description of such application
is beyond the scope of this book.
34 1  General Considerations

Cell suspension

Sheath fluid

Signal
Light scatter detector processors
Fluorescence
detectors

Integral
computer
Dichroic mirror

Obscuration bar

Remote computers

Laser

FIGURE 1-24  ■  Flow cytometry. Diagrammatic representation of flow cytometric measurements of cell fluorescence stained with fluo-
rochrome and excited by laser beam. Cell size is assessed by measurements of light scatter at low angles. Fluorescence signal is
separated by dichroic mineralization, and several (typically two) fluorescence signals at different wavelengths can be measured by
fluorescence detectors. Finally, data are stored and analyzed by computer.

Flow Cytometry To circumvent these problems, methods have been devel-

Flow cytometers are machines constructed to measure
and record fluorescence on particles (cells) stained with
fluorochrome and flowing in suspension past an excita-
tion source (typically a laser beam) (Fig. 1-24). The fluo-
rescence levels of the individual cells are captured by a
photomultiplier tube, converted into an electric pulse,
and stored and analyzed by a computer. The cells can also
be stained with multiple fluorochromes and can be excited
by two different laser beams. This technique, known as
multiparameter flow cytometry, helps analyze several cel-
lular components and their relationships. In addition to
specific cellular components, some other cellular fea-
tures, such as light scattering at small angles, pulse width,
or electrical conductivity, related to some extent to cell
size, can also be measured.
A major limitation of flow cytometry is that it does not
permit morphologic corroboration of the identity of the
measured objects. A second limiting factor is the need to
prepare cell suspensions from solid tumors for analysis.
Cells that normally lack intercellular junctions (e.g.,
peripheral blood cells, bone marrow cells) are ideal for
this technique. Single-cell suspensions can also be pre-
pared from cultured cells. On the other hand, the prepa-
ration of single-cell suspensions from most solid tumors
cannot be done without significant damage to cell mem-
branes. Therefore, the measurement of cytoplasmic com-
ponents of solid tumors is more difficult and less accurate.
oped for the isolation of intact nuclei that permit flow
cytometric analysis of nuclear components such as DNA.
The techniques of nuclear isolation from formalin-fixed,
paraffin-embedded tissue are widely used for retrospec-
tive studies.
Analyses of the cell cycle and of DNA ploidy distribu-
tion patterns are the most common applications of this
technique in diagnostic pathology. For investigative pur-
poses, any cellular component that can be specifically
bound with the use of free fluorochromes or in conjunc-
tion with an antibody can be measured and analyzed with
this approach.219,224,236,237
Flow cytometric analysis of DNA content can be
accomplished with several fluorochromes. Propidium
iodide, ethidium bromide, and diamidine phenylindole
(DAPI) are normally used. Acridine orange, which binds
differentially to DNA and ribonucleic acid (RNA), can
be used for the simultaneous analysis of both compo-
nents. The results of single-parameter measurements are
displayed as frequency histograms (Fig. 1-25). With
simultaneous measurement of several parameters (usually
two), the results are presented as scattergraphs or contour
maps that show the relationship between the measured
parameters. In immunofluorescence studies, the proper-
ties of cells binding a given fluorescent antibody are dis-
played as a percentage of the cell population screened. In
reference to DNA, its content is usually calculated as an
expression of ploidy by comparison with the known

ERRNVPHGLFRVRUJ
 1  General Considerations 35

ploidy strands (e.g., 2C = diploid, 4C = tetraploid). The

DNA index is a formula used to express the position of
2C 4C histogram peaks (DNA index 1 = diploid content of
G1 = 60.73%
G1 DNA). The principle of total DNA content analysis is
G2 M S = 19.42%

Time (h)
S G2 + M = 19.84% based on the fact that normal nondividing cells have a
Relative cell number

diploid DNA content. The growing or proliferating cells

G2/G1 = 2.01
G1 can be divided into the three basic cell-cycle compart-
ments: G1, S, and G2 + M. The DNA content of normal
DNA content and nondividing cells (G1) or quiescent (G0) cells is
G2 + M
diploid. During the S phase (synthesis), a duplication of
DNA occurs. During the G2 + M phase, DNA duplica-
S
tion is completed and corresponds to 4C or a tetraploid
value (Fig. 1-25).
DNA content In contrast to normal tissues, neoplastic lesions often
A
undergo chromosomal aberrations that result in the
appearance of aneuploid clones. From a practical point
of view, human tumors can be divided into two major
Aneuploid
groups: diploid and aneuploid. If the main peak of the
(DNA index = 1.32)
DNA histogram centers on the 2C region, the DNA
80 Diploid distribution pattern is similar to that of normal somatic
70 (DNA index = 1.0) cells. Tumors with such a normal or near-normal DNA
60 histogram are classified as diploid or, better, near-diploid.
50 Many tumors exhibit an abnormal position of one or
Number

40 several cell populations that corresponds to the abnormal

30
chromosome complement of their cell populations. Such
tumors are classified as aneuploid. The presence of a
20 diploid or nondiploid DNA histogram, however, is not
10 synonymous with a normal diploid chromosomal com-
0 plement by karyotyping standards. Many of the so-called
10 30 50 70 90 110 140 170 200 230 diploid tumors may in fact exhibit structural chromo-
B DNA somal alterations or can even have an increased number
of chromosomal copies that are too small to be identified
by measurements of total DNA content.
40 p = 0.00002 In addition to DNA ploidy, cell proliferation can also
Diploid
be analyzed. Cell-cycle analysis based on DNA histo-
Aneuploid
grams is not always easy or possible, especially in aneu-
30 ploid tumors, in which several overlapping abnormal cell
populations may be present. The DNA ploidy and cell-
Cases (%)

20 cycle analyses have been repeatedly proven to provide

10
0 ence to some soft tissue and bone tumors are less
1 2
Histologic grade
C most frequently occurring primary bone sarcomas—
FIGURE 1-25  ■  Flow cytometry. A, Changes of DNA content in
individual cells traversing the cell cycle and calculation of pro-
portion of cells in different components of the cell cycle is
shown. B, Aneuploid DNA histogram in high-grade osteosar-
coma. Note presence of prominent cell population with diploid
DNA content (DNA index = 1) that accompanies population of
cells with abnormal DNA content (DNA index = 1.32). C, DNA
distribution patterns in chondrosarcoma of bone in relation
to histologic grade. Virtually all grade 1 chondrosarcomas
are diploid, and majority of grade 3 tumors are aneuploid.
(A, B, Courtesy Dr. A.K. El-Naggar, Houston.)
reliable prognostic information in many tumors of differ-
ent organs, including some bone tumors. The most reli-
able data are available in reference to several common
epithelial malignancies such as carcinomas of the breast,
urinary bladder, prostate, and colon. The data in refer-
3
convincing, but it seems that in at least two of the
osteosarcoma and chondrosarcoma—DNA ploidy pro-
vides prognostically valuable information.214,223,229,231,233
Preliminary data indicate that the assessment of DNA
ploidy is also a prognostic factor for small cell malignan-
cies, including Ewing’s sarcoma.232,238
Generally, tumors with modal patterns close to diploid
have a more favorable prognosis compared with tumors
that have an aneuploid DNA distribution.226,227 Normal
or near-normal total DNA content correlates with a high
degree of histologic differentiation. In bone tumors,
most high-grade conventional osteosarcomas are aneu-
ploid. On the other hand, well-differentiated low-grade
osteosarcomas, such as low-grade intramedullary or par-
osteal osteosarcomas, are diploid or near-diploid. Dedif-
ferentiation of low-grade precursor conditions with the

ERRNVPHGLFRVRUJ
36 1  General Considerations

30 30

24 24

18 18

12 12

6 6

0 0

Cell count
Cell count

2c 4c 8c 2c 4c 8c

20 20

16 16

12 12

8 8

4 4

0 0
2c 4c 8c 2c 4c 8c
DNA ploidy DNA ploidy
A B
FIGURE 1-26  ■  Image analysis. A, DNA histograms in two components of dedifferentiated chondrosarcoma. Diploid DNA histogram
of low-grade cartilaginous component of tumor(top panel). Aneuploid DNA histogram of high-grade sarcomatous component of
tumor (bottom panel). B, Image analysis of DNA content in cartilage lesions. Diploid histogram in enchondroma (top panel). Aneu-
ploid DNA histogram in grade 3 chondrosarcoma (bottom panel).

development of high-grade sarcomatous phenotypes is
typically associated with the development of pronounced
aneuploidy (typically, several abnormal cell populations
are present).217,235 Virtually all conventional high-grade
osteosarcomas are aneuploid.239 Conventional osteosar-
comas that have a prominent near-diploid cell popula-
tion, in addition to abnormal (aneuploid) cell clones,
are less aggressive than those without prominent near-
diploid cell populations (Fig. 1-25 and Fig. 1-26).217,229,230
In chondrosarcoma, most grade 1 tumors are diploid,
and nearly all grade 3 chondrosarcomas are aneuploid
(Fig. 1-26).212,213,240 Approximately 30% to 40% of grade
2 chondrosarcomas are aneuploid. In chondrosarcoma of
bone, the presence of a diploid DNA distribution pattern
correlates with lower recurrence and metastasis rates as
well as longer disease-free and overall survival rates com-
pared with aneuploid tumors.218,222,223,228 The correlation
of DNA ploidy with clinical behavior in other primary
bone tumors is less clear and has not been proven to
represent a strong prognostic factor.
Image Analysis
Cytophotometry, or image analysis, is conceptually
similar to flow cytometry but requires a different prepara-
tion of cells for the measurements.217,227,232 The principle
of this technique is the measurement of the optical density
of cells in histologic sections or, even better, of whole
cells spread on the glass. Compared with flow cytometry,
the technique is much slower and fewer objects can be
measured. The main advantage of this approach is the
ability to identify a measured object microscopically and
to perform the measurements separately on different cell
populations and tissue components. The technique is
uniquely suited for the measurements of distinct (micro-
scopically recognizable) tumor cell populations (e.g., dif-
ferent components of dedifferentiated chondrosarcoma)
(Fig. 1-26). Originally, only the smears and cytologic
preparations of whole cells could be measured, but recent
developments in computerized tissue-reconstruction pro-
grams have made it possible to perform the quantitations
on histologic sections. The information provided is some-
what similar to data gained by flow cytometry. In pathol-
ogy, including that of bone tumors, this technique is most
frequently used to generate DNA ploidy distribution pat-
terns and to perform cell-cycle analysis (Fig. 1-26). For
this type of analysis, the cells are typically stained with
the Feulgen reaction. As with flow cytometry, any cellular
component that can be visualized directly by an appropri-
ate color reaction or with the use of antibodies can be
quantitated for investigative purposes. In addition, several
other parameters, such as nuclear size, shape, volume, and
chromatin texture, can be measured. In summary, the
main advantage of this technique is its ability to verify

ERRNVPHGLFRVRUJ

the measured objects microscopically in standard cyto-
logic and histologic preparations.
Histomorphometry
Histomorphometry is similar to image analysis and rep-
resents a microscopic planimetry or stereology. In skel-
etal pathology, it is used to study homeostasis of the
skeleton, mainly in metabolic disorders of bone.211,215,216,221
The application of histomorphometry to the diagnosis of
bone tumors is minimal. In bone tumors, the technique
is occasionally used to evaluate the skeletal status and
treatment effect in rickets and osteomalacia associated
with tumors (see Chapter 22).
For histomorphometry, undecalcified bone sections
stained with techniques that enable the visualization of
calcified and uncalcified osteoid, such as von Kossa’s or
Goldner’s (modified trichrome) stains, are used.220,225
Another frequently used technique is tetracycline-pulse
labeling for epifluorescence.234 Two short cycles (3 days)
of tetracycline approximately 2 weeks apart allow two
separate mineralization fronts to be visualized as epifluo-
rescence lines outlining the bone trabeculae of cancellous
medullary and endosteal cortical bone. This is due to the
ability of tetracyclines to incorporate at the border of
osteoid, which is actively mineralized. The width between
the two lines of fluorescence (pulse labels) reflects the
rate of mineralization.
A number of parameters can be assessed by histomor-
phometry of bone. They can be separated into three
major categories: (1) measurements that assess the struc-
tural integrity of the skeleton, (2) parameters that measure
bone formation and mineralization, and (3) measure-
ments that reflect the bone’s resorptive activity.
The most important and frequently measured
parameters that reflect the structural integrity of the
skeleton (i.e., the amount of mineralized bone) are as
follows:
1. Total bone volume; the content of mineralized and
nonmineralized bone calculated as the percentage
of the total area of tissue examined
2. Cancellous bone volume; mineralized and nonmin-
eralized cancellous bone calculated as the percent-
age of the total area of tissue examined or as the
percentage of the area of the medullary cavity
3. Trabecular osteoid volume; nonmineralized cancel-
lous bone calculated as a percentage of total cancel-
lous bone.
The parameters indicative of osteoblastic activity
consist of measurements of bone formation and
mineralization:
1. Trabecular osteoid surface; the percent of cancel-
lous bone surface covered by osteoid
2. Mineralizing surface; the proportion of trabecular
osteoid surface that exhibits tetracycline labeling
3. Mineral apposition value; the distance (in microns)
between two tetracycline-pulse labels per day
4. Bone formation value; the mineralized bone pro-
duced in 1 year
5. Mineralization lag time; the time (delay) of miner-
alization of the matrix after its deposition by
osteoblasts.
ERRNVPHGLFRVRUJ
1  General Considerations 37
The parameters indicative of bone resorptive activity
are as follows:
1. Trabecular resorptive surface; the percent of bone
surface that shows current or prior osteoclastic
activity
2. Cortical resorptive surface; the percent of the corti-
cal surface that shows current or prior osteoclastic
activity
3. Periosteal resorptive surface; the percent of perios-
teal surface with osteoclastic activity
4. Trabecular osteoclast count; the number of osteo-
clasts per area (millimeters squared) of medullary
cavity or the number of osteoclasts per length (in
centimeters) of the trabecular bone
5. Osteoclastic index; the number of osteoclasts per
length of the trabecular surface with evidence of
present or prior resorptive activity
6. Cortical porosity; the percentage of the cortex that
contains pores without osteocytic cells.
Accurate measurements of bone resorption usually
require specimens taken from two consecutive biopsies.
A description of specific features of metabolic disorders
that can be assessed by this technique is beyond the scope
of this textbook.
IMMUNOHISTOCHEMISTRY
The immunohistochemical detection of various extra-
cellular and intracellular markers with antibodies has
become a generally accepted and widely used auxiliary
method of diagnostic pathology, including the pathol-
ogy of bone tumors and tumorlike lesions. This method
has emerged as a diagnostically useful technique because
of the development of highly specific antibodies and
the invention of sensitive immune and enzymatic detec-
tion systems. The fluorescence detection methods are
more often used in investigative studies and are rarely
used in diagnostic pathology. During the past decade,
the discipline of immunohistochemistry has developed
novel, more efficient detection systems complemented
by an exponentially increasing roster of biomarkers
that can be used to assess various aspects of differen-
tial diagnosis and biologic assessment of the lesion in
question.
The immunohistochemical method is based on the
binding of a specific cellular or extracellular substance by
the antibody, with subsequent visualization of the bound
antibody by a color-based detection system. Subsequent
use of a counterstain such as hematoxylin or toluidine
blue enables the precise microscopic localization of a
positive reaction in various components of the tissue.
Historically, the first identification of the antigen in tissue
visualized with a fluorescent antibody was reported in
1942; the horseradish peroxidase detection system was
developed in the mid-1960s.336 It subsequently evolved
into the immunoperoxidase bridge method and the per-
oxidase antiperoxidase method. The next generation
detection methods emerged in the early 1980s with the
development of the avidin-biotin complex (ABC) detec-
tion system, which is still in use today. In this system,
secondary antibodies are conjugated to biotin and act as
38 1  General Considerations

Avidin-biotin
enzyme complex
Enzyme

Secondary Biotinylated
Label antibody secondary
antibody

Primary Primary
antibody antibody
Tissue
antigen
Tissue
antigen

Direct staining Indirect staining B

A

Dextran backbone
Streptavidin
enzyme complex
HRP enzyme

Biotinylated
secondary antibody, Secondary antibody,
mouse/rabbit mouse/rabbit

Primary Primary
antibody antibody
Tissue Tissue
antigen antigen

C D
FIGURE 1-27  ■  Immunohistochemistry: Visualization of bound antibodies with different reactions. A, Direct and indirect staining
methods using primary and secondary antibodies. B, Avidin-biotin complex (ABC) method, in which preformed complex reacts with
the secondary antibody. C, Labeled streptavicin-biotin (LSAB) method, in which biotinylated secondary antibody links a primary
antibody with a streptavidin-peroxidase conjugate. D, Two-step polymer method. The visualization system contains a dextran
polymer backbone to which enzyme molecules are attached. It also contains secondary antibodies with anti-mouse immunoglobulin
and anti-rabbit immunoglobulin specificity facilitating universal application as a detection reagent. (Modified and reprinted with per-
mission from Taylor CR and Rudbeck L, eds, Education Guide: Immunohistochemical Staining Methods, 6th ed, Carpinteria, California, 2013,
Dako.)

a link between tissue-bound primary antibodies and an
avidin-biotin-peroxidase compound. A closely related
system utilizes the labeled streptavidin-biotin (LSAB)
complex and utilizes a biotin-related secondary antibody
as a link between the primary antibody and a streptavidin-
peroxidase complex. The modern detection systems are
polymer based and contain a dextran backbone attached
with multiple enzyme molecules. It also contains second-
ary antibodies with anti-mouse and anti-rabbit immuno-
globulin specificities. Such a universal polymer-based
reagent can be used to detect any primary antibody that
is of mouse or rabbit origin. This system is currently  recognize the most frequent artifactual (nonspecific)
used in the immunohistochemical laboratory in the
Department of Pathology at the University of Texas MD
Anderson Cancer Center. The principles of immunohis-
tochemical visualization of the tissue-bound primary
antibodies using various detection systems are graphically
depicted in Fig. 1-27.
In formalin-fixed, paraffin-embedded tissue, the
so-called antigen retrieval techniques are important steps
in increasing the sensitivity of the test.336 The goal of this
step is to expose the epitopes of the studied antigen and
to facilitate antigen-antibody binding. The antigen
retrieval techniques are simple and typically include
limited digestion with proteolytic enzymes, microwave
treatment, or both. At the level of current advancement,
immunohistochemistry provides consistent results with
most fixatives. Satisfactory results can be obtained in
decalcified tissue or even on decolorized, previously
stained microscopic sections. It can also be used in most
cytologic preparations.
There are many pitfalls in immunohistochemistry that
to some extent can be avoided by continuous use of
quality-control methods in the laboratory. The patholo-
gist should be familiar with typical patterns of staining
that are diagnostically helpful and should also be able to
staining patterns. Constant daily comparison of the
immunohistochemical results with external and internal
positive and negative controls helps prevent misinterpre-
tation of ambiguous results. The pitfalls of immunohis-
tochemistry are in general caused by false-negative or
false-positive results.270,336 The major causes of false-
negative results are as follows:
1. The epitopes of antigens in the tissue are lost
because of inadequate fixation. The amount of
antigen is reduced by degradation and cannot be
detected by immunohistochemistry.
2. The antigens are misplaced from the specific tissue
or cellular location because of diffusion. This is

ERRNVPHGLFRVRUJ

most frequently observed in reference to endothe-
lial antigens such as factor VIII–related antigen.
3. The antibody is inappropriately used (too low a
concentration) or destroyed, or its affinity for the
antigen is inadequate.
4. The components of the detection system are inad-
equate or are inappropriately used.
The major causes of false-positive results are as
follows:
1. Cross-reactivity (lack of specificity) of the antibody
with other antigens or its nonspecific binding to the
tissue
2. Nonspecific color reaction caused by the presence
of unblocked endogenous peroxidase
3. Nonspecific binding of detection system compo-
nents, such as the avidin-biotin complex, to the
tissue (typically caused by excessive use of detection
system components)
4. Positive reaction on normal tissue entrapped among
the tumor cells and interpreted as an integral com-
ponent of the tumor
5. Misplacement of the antigen from normal tissue
that is subsequently absorbed or phagocytized by
tumor cells.
False-positive results are in fact more misleading
than false-negative results and probably occur more
frequently.
Immunohistochemistry is a powerful tool used to
provide diagnostically valuable information on the histo-
genesis and differentiation of cells. Similar to other auxil-
liary techniques, the immunophenotypic profiles of cells
are not used to distinguish among benign, malignant, and
reactive conditions.
The number of antibodies with potential diagnostic
applications is huge, and new antibodies are constantly
being developed. The immunophenotypic markers of
hematopoietic lesions of bone and their diagnostic appli-
cations are discussed and tabulated in Chapter 12. The
specific applications of immunohistochemical stains and
the so-called immunophenotypic features of bone tumors
are provided in the sections on special techniques that
accompany the discussion of each specific bone tumor.
The markers most frequently used in the diagnosis of
bone tumors are described in the sections that follow.
Intermediate Filaments
Intermediate filaments are ubiquitous cytoplasmic struc-
tures that are 10 nm thick (i.e., they are between 6-nm
microfilaments and 25-nm thick microtubular struc-
tures). Ultrastructurally, they have a uniform appearance
and represent a nonbranching, fine filamentous, cytoplas-
mic material.259,332 They were originally described nearly
half a century ago in a muscle cell. On the basis of their
chemical composition and presumptive biologic function,
they can be separated into five major groups (Fig. 1-28).
The five groups of intermediate filaments comprise kera-
tins, (types I and II); vimentin, desmin, glial fibrillary
acidic protein (GFaP), peripherin, and syncoilin (type
III); and neurofilaments L, M, and H (NF-L, NF-M, and
NF-H), α-internexin, synemin, and nestin (type IV); and
lamins A, B, and C (type V). An additional subgroup VI
ERRNVPHGLFRVRUJ
1  General Considerations 39
designated as orphan comprises filensin and phakinin. All
intermediate filaments have a propensity for self-assembly
into ~10-nm wide filaments as heteropolymers with con-
served tripartite domain consisting of a central α-helical
rod forming heptad repeats that is flanked by highly vari-
able end domains comprising their N- and C-termini.
This structural uniformity is coupled with pronounced
heterogeneity of their N- and C-termini, resulting in
highly variable mass ranging from 40 kDa (type I keratin
19) to 240 kDa (type IV nestin). Another signature
feature of intermediate filaments is their tissue type and
the differentiation program-dependence that is in part
retained in the neoplastic process. Although there is a
considerable degree of homology among the various
groups of intermediate filaments, the differences are suf-
ficient for distinct antigenicity. Therefore the major
groups of intermediate filaments and even their various
subcategories can be identified by their respective anti-
bodies. These two features (i.e., tissue specific expression-
dependence and specific antigenicity) make them model
markers widely used in the differential diagnosis of
tumors including bone cancers. Out of the diverse group
of intermediate filaments the keratins, vimentin, desmin,
and GFaP are widely used in the differential diagnosis of
tumors.
Keratins. The keratins are prototypic intermediate
filaments of epithelial cells that show a high degree of
molecular diversity.306 They frequently form heteropoly-
mers by pairing type I and II keratins. In humans, over
50 keratin genes exist, and they are expressed in a highly
specific manner in various types of epithelial cells and in
relation to their stage of differentiation. The recent con-
sensus nomenclature for mammalian keratin genes and
proteins has been established by the Keratin Nomencla-
ture Committee and is summarized in Table 1-14.326 In
the human genome, the keratin genes cluster in two chro-
mosomal sites: chromosome 17q21.2 for type I keratins
and chromosome 12q13.13 for type II keratins. In some
epithelial cells, they form bundles of structures referred
to as tonofilaments. In a typical epithelial cell, they form a
network inside the cytoplasm that braids the nucleus and
spans through the cytoplasm (Fig. 1-29). These filaments
are attached to the cytoplasmic plaques at the areas of
cell-to-cell junctions such as desmosomes and hemides-
mosomes. In general, they play a major functional role in
preserving cell structural integrity and mechanical stabil-
ity. They are also important components of cell-to-cell
and cell-to-stroma interactions. Different epithelia (i.e.,
stratified and simple) have different keratin profiles.
Moreover, epithelia in different organs have different
compositions of their keratin, and their expression is
retained to some extent in neoplasms derived from these
organs.306,319 Therefore knowledge of the so-called organ-
specific keratin profile can be helpful in the differential
diagnosis of neoplasms. In general, keratins are markers
of epithelial differentiation.274 However, the presence of
keratin is not absolute proof of epithelial phenotype and
is occasionally observed in tumors of mesenchymal
origin.319 In reference to bone tumors, it is important to
bear in mind that tumors such as chordoma and, to some
extent, chondrosarcoma (predominantly those located in
the central axis) express keratins. The use of highly
40 1  General Considerations

Subgrouping Proteins Cell type specificity

Type I Keratins Soft complex epithelia (skin, oral mucosa, etc.)
Type II Soft simple epithelia (liver, gut, kidney, etc.)
Hard epithelia (hair, nail, oral papillae)
Type III Vimentin, Desmin Various (fibroblasts, leukocytes, edothelium
GFAP, Peripherin muscle, astrocytes, glia, peripheral nerves)
syncoilin
Type IV NF-L, NF-M, NF-H CNS & neurons
a-internexin CNS & neurons
synemin, nestin Muscle, neural stem cells
Type V Lamins A, B & C Nucleus
Orphan Filensin, Phakinin Lens
A

Head Rod Tail

1A 1B 2A 2B

N C
L1 L12 L2
B
C
FIGURE 1-28  ■  Intermediate filaments. A, Classification of intermediate filaments according to sequence homology and cell-type
specificity of their expression patterns. B, Schematic representation of the common tripartite domain structure for all intermediate
filaments. A central rod-domain is comprised of heptad repeat-containing α-helical coils 1A, 1B and 2A, 2B. They are separated by
nonheptad repeat-containing linkers L1, L12, and L2. The central rod domain is flanked by head and tail domains of variable length
and structure at their N- and C-termini. C, Assembled 10-nm wide intermediate filament structures reconstituted from recombinant
protein visualized by negative staining and transmission electron microscopy. Bar = 100 nm. GFaP, Glial fibrillary acidic protein; NF,
neurofilament. (Reprinted with permission from Chung G-M, et al: Curr Opin Cell Biol 25:600–612, 2013.)

sensitive reverse transcriptase polymerase chain reaction
(RT-PCR) techniques has shown that low levels of mes-
senger RNA that code for keratins (predominantly kera-
tins 8 and 18) are expressed in a wide range of mesenchymal
cells and tumors of mesenchymal origin. Fortunately,
these low levels of keratins cannot be detected by tech-
niques routinely used in diagnostic immunohistochemis-
try. Examples of positivity for keratin have been described
for virtually every nonepithelial tumor, including many
bone tumors. Still, for practical purposes, a strong,
uniform positivity of tumor cells for keratin typically is
seen in epithelial tumors.
For diagnostic purposes, several antibodies reacting
with keratin are often mixed (AE1/AE3). In skeletal
pathology, keratins are used in the diagnosis of adaman-
tinoma, chordoma, chondrosarcoma, epithelioid heman-
gioendothelioma, and sarcomatoid carcinoma and in the
differential diagnosis of metastatic neoplasms (Fig. 1-30).
Vimentin is a 57-kDa filamentous protein universally
expressed in mesenchymal cells and in some epithelial
cells and their neoplasms.325 In epithelial cells, it is typi-
cally coexpressed with other epithelial markers, such as
keratins. For these two reasons, the specific diagnostic
applicability of vimentin in the differential diagnosis of
tumors is minimal. It is most often used to verify the
antigenicity of cells in question when other markers are
negative. More recent evidence indicates that it is not
only performing a function of the mesenchymal cell
cytoskeleton, but it is also involved in the progression
of several common human malignancies and plays an
important role in phenotypic plasticity of tumor cells,
being a signature marker of epithelial to mesenchymal
transition.290
Desmin is a 55-kDa filamentous molecule expressed
in smooth, skeletal, and cardiac muscle fibers.248 In skel-
etal muscle fibers, it is located in a Z band and acts as an
adhesion molecule for contractile filaments.248,292,320 In
smooth muscle fibers, it is located in dense bodies and
submembranous dense plaques. In general, desmin is a
marker of muscle differentiation, but it is also present in
other cells that have contractile properties, such as myo-
fibroblasts (Fig. 1-31). Desmin is also expressed in some
fetal cells, such as embryonal mesothelium, stromal cells
of fetal kidney, and chorionic villi. It belongs to the cat-
egory of type III intermediate filaments. In mammalian
skeletal muscle, including in humans, desmin is one
of the earliest proteins expressed in muscle lineage dif-
ferentiation and can be detected in somites and early
myoblasts. During skeletal muscle differentiation, the
expression of desmin precedes the expression of other

ERRNVPHGLFRVRUJ
 1  General Considerations 41

differ in their molecular weight: NF-H (200 kDa), NF-M

TABLE 1-14 The Human Keratin Nomenclature
(160 kDa), and NF-L (68 kDa). Typically, all three poly-
Type I Type II peptides are expressed, but some neuronal cells may lack
all or some of the neurofilament proteins. In general
New Former New Former
Keratin Types Name Name Name Name
pathology, neurofilaments are used as markers of neural
differentiation.305
Epithelial Keratins K9 K9 K1 K1 With reference to bone tumors, neurofilament pro-
K10 K10 K2 K2
K12 K12 K3 K3 teins are used in the differential diagnosis of primary and
K13 K13 K4 K4 metastatic small cell tumors (e.g., neuroblastoma). Poorly
K14 K14 K5 K5 differentiated tumor cells may express undetectable levels
K15 K15 K6a K6a of neurofilament protein. Moreover, fixation and paraffin
K16 K16 K6b K6b
K17 K17 K6c K6e/h
embedding significantly reduce the stainability of cells
K18 K18 K7 K7 for this marker.
K19 K19 K8 K8
K20 K20 K76 K2p
K23 K23 K77 K1b Epithelial Markers
K24 K24 K78 K5b
K79 K6l Keratins are the markers most frequently used in the
K80 Kb20 identification of epithelial phenotypes (see the section on
Hair Follicle-Specific K25 K25irs1 K71 K6irs1 intermediate filaments).
Epithelial Keratins K26 K25irs2 K72 K6irs2 Epithelial membrane antigen (EMA) represents a
(Root Sheath) K27 K25irs3 K73 K6irs3
membrane glycoprotein that was originally identified in
K28 K25irs4 K74 K6irs4
K75 K6hf milk fat globule membranes and is most likely similar or
Hair Keratins K31 Ha1 K81 Hb1 identical to the casein fraction of human milk.278,331 It is
K32 Ha2 K82 Hb2 expressed by virtually all epithelial cells and neoplasms of
K33a Ha3-I K83 Hb3 epithelial origin. However, it is also expressed on a wide
K33b Ha3-II K84 Hb4
K34 Ha4 K85 Hb5
range of tumors of mesenchymal and neural origin and
K35 Ha5 K86 Hb6 even on some lymphomas.276,302
K36 Ha6
K37 Ha7
K38 Ha8 Muscle Markers
K39 Ka35
K40 Ka36 In addition to desmin (described in the section on inter-
mediate filaments), actin and myoglobin are the most
From Moll R et al. Histochem Cell Biology 129:705-733, 2008 frequently used markers of muscle differentiation.
based on new consensus nomenclature from Schweizer J Actin is a major component of the cytoskeleton that
et al. J Cell Biol 174:169-174, 2006.
The respective gene names (“KRT”) by the human genome is ubiquitously present within the cells involved in practi-
consortium utilize the same numbers, e.g. “KRT20”. cally all biologic activities, especially those related to cell
motility. It is an indispensable component of cell integ-
rity, shape, and movement in all eukaryotic cells.251,324
The basic subunit of actin is a monomeric globular
protein (G-actin) that contains an adenosine triphosphate
muscle-specific markers, including the transcriptional (ATP) or adenosine diphosphate (ADP) molecule. Its
regulators of the MyoD family. This expression pattern function depends on the ability to polymerize and form
makes desmin one of the most useful markers of muscle filamentous F-actin. F-actin is composed of two strands
differentiation. In pathology, desmin is used as a marker forming a left-handed double helix. The F-actin is a
for the diagnosis of tumors that exhibit muscle, predomi- unique polar structure that contains a fast-expanding
nantly skeletal, differentiation.243,323 In bone tumors, it is polymerizing plus-end and a minus-end in which depo-
typically used in the differential diagnosis of primary lymerization (referred to as treadmilling) occurs. Actin
and metastatic spindle-cell neoplasms and in the docu- binds numerous partners that participate in various bio-
mentation of rhabdomyoblastic differentiation in dedif- logic functions involved in cell motility and signal trans-
ferentiated chondrosarcoma. It is also frequently used in ductions. Actins are divided into three major subgroups
the differential diagnosis of small cell tumors (Fig. 1-31). of similar molecular weight, 42-kDa: α, β, and γ. The
Glial fibrillary acidic protein is an intermediate fila- three forms of α actin are organ or tissue specific and are
ment expressed in the cytoplasm of glial cells.289 It is designated as α-skeletal, α-cardiac, and α−smooth
useful in the differential diagnosis of cranial and spinal muscle. The two forms of γ actin are γ–smooth muscle
lesions (i.e., glial versus nonglial tumors). It is also used and γ-cytoplasmic. There is only one form of β actin, and
in the diagnosis of malignant and benign peripheral nerve it is designated as β-cytoplasmic. β- and γ-cytoplasmic
sheath tumors.289 The applicability of this marker in the actins are ubiquitous and are expressed in virtually all
diagnosis of bone tumors is minimal. It is rarely used in cells. On the other hand, the expressions of α actins
lesions of the axial skeleton in the differential diagnosis (skeletal, cardiac, and smooth muscle) as well as γ–smooth
of meningeal versus ependymal or glial lesions. muscle actin are tissue specific. The antibody HHF-35 is
Neurofilament protein is expressed in most neuronal most frequently used and reacts with α− and γ–smooth
cells. It is subdivided into three distinct polypeptides that muscle actins. Therefore it is frequently used as a marker

ERRNVPHGLFRVRUJ
42 1  General Considerations

A B

C D

FIGURE 1-29  ■  Cytoskeleton of epithelial cells. A, Immunofluorescence staining of keratin K18 (red, nuclei stained in blue by DAPI)
in PLC (liver carcinoma) cells in vitro. B, Keratin filaments (in red) and the desmosomal component desmoplakin (in green) are
labeled in cultured keratinocytes of line HaCaT. C, Electron microscopic image of tonofilament (keratin) bundles (arrowhead) of
HaCaT keratinocytes. D, Keratin intermediate filaments (black arrowhead) insert at desmosomes (white arrowhead) at cell–cell
contact sites of keratinocytes of the epidermal stratum spinosum (electron microscopy). (Reprinted with permission from Moll R, et al:
Histochem Cell Biology 129:705–733, 2008.)

ERRNVPHGLFRVRUJ
 1  General Considerations 43

A B

C D
FIGURE 1-30  ■  Immunohistochemistry. A, Expression of S-100 protein in normal metaphyseal chondrocytes. B, Expression of S-100
protein in chordoma. C, Positivity of endothelial cells for factor VIII–related antigen in hemangioma of bone. D, Strong positivity for
cytokeratins in adamantinoma of bone. (A, ×400; B and D, ×200; C, ×50.)

ERRNVPHGLFRVRUJ
44 1  General Considerations

A B

C D
FIGURE 1-31  ■  Immunohistochemistry. A, Expression of desmin in normal skeletal muscle. B, Expression of smooth muscle actin in
normal smooth muscle of small intestine. C, Expression of desmin in dedifferentiated component of chondrosarcoma. D, Expression
of desmin in metastatic round-cell rhabdomyosarcoma in bone. (A-D, ×200.)

ERRNVPHGLFRVRUJ

of muscle differentiation (smooth and skeletal). As with
desmin, actin is expressed on various cells that perform
contractile functions such as myofibroblasts, myoepithe-
lial cells, and pericytes. In bone tumors, antibodies against
actin are frequently used in the differential diagnosis of
primary and metastatic spindle- and round-cell tumors.
Myoglobin is the heme metalloprotein that binds
oxygen and is expressed in skeletal muscle fibers. In con-
trast to other muscle markers, it is not expressed in
smooth muscle cells. Therefore it serves as a marker of
skeletal muscle differentiation and is used in the diagnosis
of rhabdomyosarcoma.252,272,287 However, its expression is
restricted to tumor cells with more differentiation, and
most poorly differentiated tumors do not express suffi-
cient amounts of this protein to be identified in paraffin-
embedded, formalin-fixed tissue.307
MyoD is a member of a family of four myogenic
transcriptional regulator factors (MyoD, Myf5, Mrf4,
and Myogenin) that control the formation of skeletal
muscle. They belong to a family of basic-helix-loop-
helix factors that, when overexpressed in undifferentiated
mesenchymal cells, will activate the myogenic differen-
tiation program. MyoD and Myogenin are expressed
relatively early in skeletal muscle differentiation and
can be used as markers in the differential diagnosis of
rhabdomyosarcoma.252,253,329
Vascular Markers
A group of heterogeneous proteins with diverse functions
commonly expressed in endothelial cells are used as vas-
cular markers to facilitate the differential diagnosis of
tumors of putative endothelial origin. The most fre-
quently used endothelial markers are described below.
Factor VIII–associated antigen, or von Willebrand
factor, is a protein expressed by endothelial cells, most
likely in areas corresponding to Weibel-Palade bodies.280,322
The factor can be demonstrated in all normal endothelial
cells and is expressed by virtually all benign vascular
lesions. However, there is great variability of its expres-
sion in malignant vascular lesions.273 High-grade angio-
sarcoma may show only focal positive staining. In skeletal
pathology, it is most often used to disclose the endothelial
nature of tumor cells in vascular lesions such as heman-
gioendothelioma. It is also used in the differential diag-
nosis of spindle-cell proliferations with a presumed
vascular origin.
False-positive staining of nonendothelial cells as a
result of diffusion of the antigen from nontumor endo-
thelial cells is a frequent pitfall in the diagnostic applica-
tion of factor VIII–associated antigen. Nonspecific
staining as a result of leakage of the antigen can be sus-
pected if diffuse extracellular and cellular staining is
observed.
Platelet-endothelial adhesion molecule (CD31) is
a member of the immunoglobulin family and represents
a transmembrane protein of endothelial cells.262,286,322 It is
also expressed by megakaryocytes and platelets and can
be detected in some plasma cells. Like CD34, it is
expressed by virtually all benign vascular tumors and by
a high percentage of malignant vascular lesions (approxi-
mately 80%).317
ERRNVPHGLFRVRUJ
1  General Considerations 45
Human progenitor cell antigen (CD34) is a member
of a large, superfamily of lymphoid markers. It is expressed
early in lymphoid differentiation and also by normal and
neoplastic (benign and malignant) endothelial cells.312,322
The expression of CD34 is not restricted to endothelial
cells. Unfortunately, it is also present in a wide range of
spindle cells and peripheral nerve sheath tumors.317
Therefore the applicability of CD34 in the differential
diagnosis of vascular lesions is limited.
ERG, an ETS-family transcription factor, is a less
frequent partner of EWSR1 translocations in Ewing’s
sarcoma and is a common translocation partner for
TMPRSS2-ERG fusions in prostatic carcinoma.335 Immu-
nohistochemical evidence of ERG overexpression in
Ewing’s sarcoma and prostatic adenocarcinoma is indica-
tive of translocations. In contrast it is constitutively
expressed in endothelial cells, and its nuclear expression
can be used as a marker of endothelial differentia-
tion.263,304,313 It is also commonly overexpressed in epithe-
lioid sarcoma.303,334
Neural Markers
Several proteins expressed in neural tissues are used in
the differential diagnosis of tumors with putative neural
origin. The most frequently used neural markers are
described below.
S-100 protein is an acidic nuclear protein that binds
calcium and is composed of two (α and β) subunits. It was
originally identified in glial and Schwann cells but is also
expressed by melanocytes, fat cells, myoepithelial and
Langerhans cells, and cartilage cells.309 In general pathol-
ogy, S-100 protein is often used in the differential diag-
nosis of tumors of neural origin and melanoma.310
In bone tumors, S-100 protein is more frequently used
as a marker of cartilaginous differentiation. It is expressed
early during cartilage lineage differentiation and can be
identified in tumors exhibiting relatively primitive
cartilaginous differentiation such as in chondromyxoid
fibroma, chondroblastoma, and mesenchymal chondro-
sarcoma. S-100 protein is expressed by chordal tissue,
and its expression is retained in chordomas. Therefore
together with epithelial markers (keratins and epithelial
membrane antigen), it is frequently used in the differen-
tial diagnosis of chordoma, chondrosarcoma, and the
so-called chondroid chordoma. It is also frequently used
in the differential diagnosis of Langerhans cell histiocy-
tosis because it is expressed by antigen-presenting cells.
Myelin basic protein is a major polypeptide compo-
nent of the myelin. Hence, it is expressed in tumors
derived from the Schwann cells, both benign and
malignant.
Leu-7 was identified as a marker of natural killer cells,
but it is also present in the nerve sheath and neuroendo-
crine cells.283 It is typically used in the differential diag-
nosis of spindle-cell neoplasm with a presumed nerve
sheath origin.284 Leu-7 is also expressed in tumors such
as leiomyosarcoma, synovial sarcoma, and occasionally in
rhabdomyosarcoma. It is also used in the differential
diagnosis of small blue-cell neoplasms.
Synaptophysin is expressed in neural cells and is
found in the presynaptic vesicles. It is also expressed in
46 1  General Considerations
neuroendocrine cells. Synaptophysin is generally used as
a sensitive marker to document neural or neuroendocrine
differentiation.264,271,305 In bone tumors, it is most often
used in the differential diagnosis of metastatic lesions
such as neuroblastoma, paraganglioma, and other neuro-
endocrine tumors.
Chromogranin A is an acidic protein belonging to a
granin family that is expressed by several normal and
neoplastic cells of neuroendocrine origin. It is encoded
by a gene located on 14q32. In physiologic conditions,
chromogranin A is stored and released with catechol-
amines from storage granules in the adrenal medulla
or with the parathyroid hormone in response to hypocal-
cemia from the parathyroid glands.260 In diagnostic
pathology it is used as a marker of neuroendocrine
differentiation.264,283
Oligodendrocyte lineage transcription factor 2
(Olig2) is a 32 kD transcription factor that contains a
basic helix-loop-helix DNA binding domain and serves a
critical role in the developing nervous system by deter-
mining lineage development, particularly of motor
neurons and oligodendrocytes.296 It is highly expressed in
diffuse gliomas and is involved in a translocation found
in T-cell acute lymphoblastic leukemia.296
Feminizing locus, Fox-3, or hexaribonucleotide
binding protein-3 on X3 was originally discovered as a
marker for neurons that strongly labeled their nuclei
(NeuN, “Neuronal Nuclei”) and was later shown to
correspond to Fox-3. NeuN/Fox-3 is involved in RNA
splicing.291 Within the nervous system, NeuN expression
is confined to neurons and labels the vast majority of
neuron subpopulations, with a few notable exceptions
such as cerebellar Purkinje neurons.308 NeuN is com-
monly used in oncologic neuropathology to identify
neuronal differentiation in neuronal and glioneuronal
tumors.
Miscellaneous Antigens
Multiple additional markers related to different aspects
of cell biology, including proliferation and differentia-
tion programs, are frequently used in the differential
diagnosis of various tumors. The most frequently used
markers assessing cell proliferation and differentiation,
as well as markers overexpressed in a transformed cel-
lular state, referred to as tumor-associated antigens, are
described below.
MIC2 gene product is located in the Xp22.32-pter
region, which corresponds to the p11.2- pter of chromo-
some X.244,267,268 The product of this gene is a glycopro-
tein of approximately 30 kDa molecular weight (p30/32)
that serves as an adhesion molecule of the T cell. The
MIC2 gene is expressed by a majority of Ewing’s sarcomas
and primitive neuroectodermal tumors.267,268,298 It is also
expressed by some pediatric lymphomas, leukemias, and
rarely rhabdomyosarcomas. The MIC2 gene product is
the most significant immunohistochemical marker in the
differential diagnosis of Ewing’s sarcoma and related
tumors, as well as other small round-cell malignancies of
bone and soft tissue.
Bone morphogenetic proteins represent a class of
heterogeneous polypeptides that are potent inducers of
ERRNVPHGLFRVRUJ
ectopic bone formation.242,246,255 They play an important
role as molecular mediators of bone and cartilage forma-
tion in skeletal development as well as in the morpho-
genesis of other organs.315 Preliminary studies have
shown that, in addition to osteosarcomas, they are
expressed in several other soft tissue and bone neoplasms.
Their applicability in the differential diagnosis of bone
tumors is unclear at this time.
Proliferating cell nuclear antigen (PCNA) belongs
to the cyclin family of nuclear proteins and plays an aux-
iliary role for DNA polymerase-δ.258,261,265,321 It appears in
the late G1 phase of the cell cycle.300 In pathology, it is
frequently used for the immunohistochemical identifica-
tion of proliferating cells.
Ki-67 is similar to PCNA and is expressed in all phases
of the cell cycle. Ki-67, together with PCNA, is fre-
quently used to assess the proliferative fraction of tumor
cells.257,269,339 Because mitotic count is included in several
grading systems for sarcomas assessment of proliferation
rate Ki-67 is frequently used as a prognostic marker in
sarcomas including bone tumors.245,258,277,281,285,311,327,333
Lectins are plant proteins that have an affinity for
carbohydrate substances on the cell surface.328,337 The two
most frequently used lectins are concanavalin A and the
lectin of Ulex europaeus. Concanavalin A has an affinity
for lymphoid cells.337 The Ulex europaeus lectin binds
the H antigen of the blood O complex. It binds to the
endothelial cells of all individuals regardless of blood
group.279
Lineage-Specific Transcription Factors
A large number of transcription factors have been identi-
fied during the past decade that activate a cascade of
genes that control various important cell functions
ranging from proliferation to differentiation. Some of
these factors are involved in lineage-specific differentia-
tion and organogenesis. Their expression is retained in
the neoplasms derived from their specific tissues and
organs. Hence, they represent useful markers in the dif-
ferential diagnosis of various tumors, including those that
affect the skeleton.314 Here we describe two groups of
such factors that belong to the SOX and PAX families as
well as RUNX2 and Osterix, focusing on their relevance
in differential diagnosis of skeletal neoplasms.247
The SOX genes arise from the founding member Sry,
the mammalian testis-determining factor. More than 20
SOX proteins are known; they are defined by the pres-
ence of the similar HMG (high mobility group) box
domain.256,282 These genes play important roles in embry-
onic development of many tissues and organs and are
frequently used as lineage differentiation markers.288,301
Of major relevance for skeletal pathology is SOX9, a
marker of osteoprogenitor cells expressed in mesenchy-
mal chondrosarcoma with retention of expression in all
benign and malignant skeletal neoplasms exhibiting car-
tilage differentiation.241,249,266,316,338,342 Its expression in
osteosarcoma, primarily in the chondroblastic compo-
nent, adversely affects the prognosis.344 It is also involved
in the development of testis, and its expression is retained
in some of the germ cell tumors.282 The expression of
SOX9 is also present in a wide range of carcinomas as a

part of the phenomenon referred to as epithelial to mesen-
chymal transition.288 SOX9 is also expressed in some soft
tissue sarcomas; most importantly it is consistently
expressed in synovial sarcoma.254 In contrast, SOX10
plays a role in neural differentiation and is also expressed
in melanomas.275
The PAX genes play an important role in body pat-
terning and organogenesis and, similar to SOX genes,
their expression is retained in neoplasms derived from the
specific tissues and organs where they originate.250,295
Consequently, similar to SOX genes they are frequently
used in differential diagnosis of various tumors. There
are nine PAX genes referred to as PAX1/9.318 PAX2 and
PAX8 are expressed in the genitourinary tract, and PAX5
is expressed in lymphoid tissue of B cell lineage. PAX
genes are also partners in chromosomal rearrangements.
PAX3 is a partner of FOXO1 chromosomal rearrange-
ment in alveolar rhabdomyosarcoma; PAX8 undergoes
rearrangement with PPARγ in thyroid carcinomas. In
skeletal pathology, PAX genes and their encoded proteins
are used as biomarkers in the differential diagnosis of
metastatic lesions.
Multiple transcription factors involved in regulation
of cell lineages participating in skeletal development have
been identified. Some of these factors are being explored
as potential biomarkers in differential diagnosis of bone
tumors. In addition to SOX9 described above, such tran-
scriptional factors as RUNX2 and Osterix, involved in
osteoblastic lineage differentiation, are of potential inter-
est as biomarkers in skeletal pathology.
RUNX2, also referred to as Cbfa1 (anti-core-binding
factor α1), regulates the recruitment of preosteoblastic
cells from multipotent mesenchymal cells.293,294,297 Its
expression is retained in all benign and malignant bone-
forming neoplasms. (Fig. 1-32) In general, in skeletal
pathology it can be used as a marker of osteoblastic
lineage differentiation. It has been shown that in osteo-
sarcoma RUNX2 modulates the proliferation rate.299,340,341
Similar to other transcription factors, it can be upregu-
lated in a wide range of nonskeletal neoplasms as a part
of epithelial to mesenchymal transition.
Osterix is a transcription factor essential for osteo-
blastic differentiation.343 Its expression is controlled by
RUNX2, which binds to the promoter of the Osterix
gene and upregulates its expression.330 The expression
pattern of Osterix is similar to that for RUNX2, and
in skeletal pathology it can be used as a marker of osteo-
blastic lineage differentiation (Fig. 1-32). Similar to
RUNX2 it can also be aberrantly expressed in nonskeletal
neoplasms.
CYTOGENETICS
The fundamental observations made at the turn of the
20th century by von Hansemann and Boveri, that chro-
mosomes are asymmetrically distributed during the divi-
sion of cancer cells and that cancer cells behave abnormally
because they have an improper chromosomal comple-
ment, have initiated a quest to unravel the mechanisms
of the genetic origin of cancer.347,357,373 They also pro-
vided the foundation for the discipline referred to today
ERRNVPHGLFRVRUJ
1  General Considerations 47
as clinical cytogenetics. The first specific abnormal chro-
mosome was identified a half century later by Nowell; it
was originally called a minute chromosome in chronic
granulocytic leukemia but was later renamed as the Phila-
delphia chromosome.365-367 The discovery by Rowley a
decade later that this abnormality represented in fact
a unique translocation (9;22)(q34;q11.2) has provided a
new paradigm for the function of chromosomal abnor-
malities in human cancer.366,371 The subsequent cloning
of the breakpoint and the identification of the BRD/ABL
hybrid gene opened a new era in cancer genetics.355 Simi-
larly, the identification of t(11;22)(q24;q12) in Ewing’s
sarcoma in 1983 represented a prototypic specific chro-
mosomal abnormality for sarcomas.346,372 The parallel
cloning of the Ewing’s sarcoma breakpoint and the iden-
tification of the EWSR1/FLI1 hybrid gene facilitated the
application of this finding to differential diagnosis of
small cell malignancies.353 The advent of genome sequenc-
ing technologies and high throughput mapping platforms
in the 21st century has dramatically increased the effi-
ciency of identification of chromosomal translocations
and specific DNA abnormalities in human cancer includ-
ing skeletal neoplasms.345,350,352,363,374 The number of such
abnormalities identified during the last decade has entered
an exponential phase, and their application to differential
diagnosis of sarcomas, including those that affect the
skeleton, have changed the standards of pathology prac-
tice.345,349,354,356,361,370 In this section, we briefly outline the
techniques of cytogenetics; their details are described in
Chapter 3. In addition, the specific molecular tests are
discussed together with the description of individual
tumors throughout the book.
The conventional cytogenetic studies based on cultur-
ing of tumor cells are still being used and are comple-
mented with several newly developed techniques.351,356,358
Technical advances such as more efficient short-term cul-
tures and techniques of tumor cell dissociation have made
solid tumor genetics more applicable to diagnosis.
However, the overgrowth of tumor cells by normal tissue
and the frequent inability to grow tumor cells are still
major limitations of this technique for everyday diagno-
sis. For example, only approximately 50% of Ewing’s
sarcoma samples can be successfully cultured for diagnos-
tic purposes. The conventional cytogenetic analysis based
on karyotyping of metaphase chromosomes after their
staining with Giemsa (G-banding) is the mainstay of this
still valid approach.364 It is efficient for the identification
of gross chromosomal translocations and other chromo-
somal abnormalities. The analysis of karyograms for
translocations is efficient in a background of clean
karyotype. However, when specific chromosomal trans-
locations are associated with complex chromosomal aber-
rations, their identification by this approach may be
difficult. In such instances, fluorescent techniques with
chromosome painting probes or the so-called spectral
karyotyping (SKY) can be used.359,362
Because of technical difficulties and the time-
consuming nature of the cytogenetic studies based on
culturing of tumor cells, other techniques that are capable
of interrogating chromosomes and their genes in nondi-
viding cells have been developed. These techniques are
collectively designated as interphase genetics. The use of
48 1  General Considerations

SOX9 SOX9high
RUNX2low

SOX9 Chondrocyte

SOX9
Mesenchymal Skeletal RUNX2high
Cells Progenitor
RUNX2

A Preosteoblast
Osx
B

C D SOX9
E RUNX2
F Osterix
Chondromyxoid fibroma Chondroblastoma Osteoid osteoma Osteoblastoma
SOX9
RUNX2
Osterix

G
FIGURE 1-32  ■  Immunohistochemistry: expression of master regulatory genes as chondroblast and osteoblast lineage markers.
A, Schematic diagram depicting the role of SOX9, RUNX2, and Osterix in osteoblastic and chondroblastic differentiated pathways.
B, Representative cores of tissue microarray corresponding to (1 through 4) chondromyxoid fibroma, chondroblastoma, osteoid
osteoma, and osteoblastoma, respectively. C, Whole-mount section of mouse embryo (embryonic day 15 stained with hematoxylin-
eosin). D, Expression of SOX9 in proliferating chondrocytes of the skeletal developmental center. E and F, Expression of RUNX2
and Osterix, respectively, primarily in the perichondrium of the skeletal developmental center. G, Expression of SOX9, Osterix, and
RUNX2 in benign cartilage and bone forming tumors. Strong nuclear expression of SOX9 is evident in chondromyxoid fibroma and
chondroblastoma. Osteoid osteoma and osteoblastoma show strong nuclear expression of RUNX2 and Osterix (DAB and hematoxy-
lin, ×300). (Modified and reprinted with permission from Dancer JY, et al: Hum Pathol 41:1788–1793, 2010.)

ERRNVPHGLFRVRUJ

fluorescence in situ hybridization (FISH) with specific
DNA probes to identify chromosomal abnormalities and
specific breakpoints of genes involved in translocation is
among the most frequent molecular tests used in differ-
ential diagnosis of sarcomas.348,349,354,362 An alternative
approach is based on extracted RNA from tumor cells,
which is amplified with specific probes using RT-PCR to
detect specific fusion transcripts of translocated genes.
This approach can be combined with PCR-based
sequencing to identify the specific sequences of fusion
partners. In addition, the PCR-based amplifications of
both coding exons and expressed RNA can be performed
on a genomic scale and after combining with the next
generation sequencing can provide more complete infor-
mation on both translocations and mutations.360,368,369
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Clinical Considerations and
Imaging of Bone Tumors
Colleen M. Costelloe, MD  •  John E. Madewell, MD
CHAPTER OUTLINE
CLINICAL CONSIDERATIONS
Age
Location
INITIAL STAGING
Diagnostic Principles
Imaging Modalities
Imaging Characterization of Primary
Bone Tumors
INTRODUCTION
Bone lesions lend themselves to radiographic assessment
because of the fact that bone has a built-in contrast agent,
the calcium hydroxyapatite crystal. Much information
about bone destruction, bone production, matrix calcifi-
cation and ossification, and the reactive response of the
surrounding bone and periosteum is available from plain
radiographs. Although other imaging techniques play a
role in the diagnostic process, the plain film is still the
method of choice and should never be bypassed. Imaging
is an important tool for diagnosis, staging, therapeutic
response evaluation, and oncologic surveillance of bone
tumors and can be used to augment histopathologic find-
ings. Imaging modalities such as radiography, computed
tomography (CT), and magnetic resonance imaging
(MRI) have major roles in the initial characterization and
identification of bone lesions through the assessment of
characteristics such as margin, bone expansion, periosteal
reaction, soft tissue extension, and matrix mineralization.
Additional imaging modalities such as bone scan, single-
photon emission computed tomography with fused CT
(SPECT/CT), 18F-fluorodeoxyglucose positron emission
tomography with fused CT (FDG PET/CT), and whole-
body MRI can be used to stage patients for distant metas-
tases. These modalities, in addition to ultrasonography,
can also be used for restaging and oncologic surveillance.
In this chapter, we discuss the general imaging and diag-
nostic features of bone tumors, assessment of therapeutic
responses, and staging of both primary and metastatic
bone tumors. Specific imaging features of individual bone
tumors and radiographic-pathologic correlations are dis-
cussed in their respective chapters.
In general, at least 95% of bone tumors can be diag-
nosed with precision when the clinician, radiologist, and
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C H A P T E R 2 
RESPONSE TO THERAPY
Primary Bone Tumors
Bone Metastases
RESTAGING AND ONCOLOGIC SURVEILLANCE
Local Recurrence
Distant Metastases
pathologist work in concert and share their information.
The clinical history, age of the patient, location of the
lesion, and radiographic appearance provide a foundation
for the analytic approach to the diagnosis of bone tumors.
It is important to state that the identification of a bone
abnormality per se does not definitively indicate that a
biopsy or indeed any surgical intervention is required.
Easily recognizable fibrous cortical defects, small osteo-
chondromas, phalangeal enchondromas, and common
traumatic and avulsion lesions can be treated by observa-
tion alone. Often these are incidental findings observed
on radiographs taken for other reasons. Lesions that
cannot be confidently assigned to a benign radiologic
category or that have aggressive or malignant appear-
ances require biopsy.
CLINICAL CONSIDERATIONS
The analytic approach begins with an appreciation that
tumors of bone have different predilections for certain age
groups, anatomic locations, and even specific sites within
a bone.42,72-81,83,84 Some lesions are painless, and some
present with specific pain patterns. Thus a small, painful
lesion in the neck of the femur in an adolescent is far more
likely to be an osteoid osteoma than a chondroblastoma.
A large lytic lesion in the end of a long bone of an adult
is likely to be a giant cell tumor and not a nonossifying
fibroma. Computerized radiographic techniques, such as
CT and MRI, facilitate analysis of bone lesions in greater
detail and are indispensable techniques in planning
therapy. They also provide reliable clues for the patholo-
gist.71,78,82 The clinical, radiographic, and pathologic rec-
ognition patterns of the most common bone tumors and
tumorlike lesions are summarized in Table 2-1.
57
58 2  Clinical Considerations and Imaging of Bone Tumors

TABLE 2-1 Summary of Clinicopathologic Recognition Patterns of Most Common Bone Tumor and
Tumorlike Lesions
Peak Age
Incidence
Type of Tumor (years) Most Frequent Sites Radiographic Features Microscopic Features
Malignant osteosarcoma 10-20 Metaphyseal parts of Destructive lytic or blastic Highly atypical sarcomatoid
long bones (knee, lesion with cloudlike cells exhibiting tumor
proximal humerus) opacities bone formation
Chondrosarcoma >50 Pelvis, proximal femur Destructive lesion with Exclusively cartilaginous
punctate calcifications, tumor with atypical
cortical scalloping, or cartilage cells
disruption
Ewing’s sarcoma 10-20 Shafts of long bones Permeative, lytic pattern of Small cell tumor
bone destruction
Malignant fibrous >50 Pelvis, long bones, Lytic moth-eaten or Highly atypical spindle or
histiocytoma predominantly lower permeative bone pleomorphic cell sarcoma
extremity (femur, destruction with cortical (no tumor bone
tibia) disruption production)
Adamantinoma of long >20 Predominantly tibia Lytic lesion with Nests of epithelioid cells in
bone with synchronous predominant fibrous stroma
involvement of involvement of
fibula anterolateral cortex
Borderline giant cell 20-40 Ends of long tubular Eccentric epiphyseal lytic Multiple osteoclast-like giant
tumor bones (knee regions, lesion cells with mononuclear
distal radius) stromal cells
Epithelioid >30 Lower extremity, Multifocal, sharply Vascular neoplasm with
hemangioendothelioma multifocal demarcated lytic lesions epithelioid endothelial
involving bones of one cells
extremity (predominantly
lower extremity)
Benign osteoid osteoma 10-30 Long bones of lower Well-demarcated Interlacing network of bone
extremity (femoral intracortical lytic lesion trabeculae in vascular
neck) with sclerosis of adjacent stroma
cortex
Osteoblastoma 5-45 Posterior neural arch Similar to osteoid osteoma Same as osteoid osteoma
of vertebral column (radius >1.5 cm), less
and craniofacial sclerosis
bones
Enchondroma Wide- Small bones of hands Radiolucent defect with Mature cartilage (low
range and feet, long punctate or stippled cellularity)
tubular bones calcifications (<2 cm)
Chondroblastoma 10-20 Epiphyses of long Sharply demarcated Tumor composed of
tubular bones in epiphyseal defect chondroblasts with focal
skeletally immature immature cartilage
patients formation (chicken wire
calcifications)
Chondromyxoid fibroma 10-30 Metaphyses of long Eccentric cortical-based Myxoid tissue with septa
tubular bones lytic defect with containing chondroblasts
scalloped margin and giant cells
Hemangioma >40 Craniofacial bones and Lytic defect with prominent Vascular lesion with
vertebral bodies striations; honeycomb capillary or cavernous
appearance vessels
Nonneoplastic fibrous 0-20 Craniofacial bones, Central, lytic defect with Woven bone trabeculae in
dysplasia ribs, femur ground-glass appearance fibrous stoma
Nonossifying fibroma 0-20 Metaphyses of long Eccentric cortex-based lytic Fibrohistiocytic lesion with
tubular bones defect with sharp giant cells
(femur, tibia) scalloped margins
Aneurysmal bone cyst 10-25 Metaphyses of long Expansile lytic defect Cystic lesion with
tubular bones hemorrhage; septa
containing histiocytic and
giant cells
Synovial chondromatosis >40 Major joints of lower Punctate or stippled Island of atypical cartilage in
extremity calcifications in synovial membrane
periarticular soft tissue
Pigmented villonodular >40 Periarticular synovial Ill-defined, multinodular Histiocytic cells, giant cells,
tenosynovitis tissue and tendons periarticular mass hemosiderin deposits
Osteofibrous dysplasia 0-15 Tibia, fibula Multilocular lytic defects of Fibroosseous lesion with
anterolateral tibial cortex zonal architecture
associated with sclerosis
and tibial bowing;
synchronous fibular
lesions

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 2  Clinical Considerations and Imaging of Bone Tumors 59
TABLE 2-1 Summary of Clinicopathologic Recognition Patterns of Most Common Bone Tumor and
Tumorlike Lesions  (Continued)
Peak Age
Incidence
Type of Tumor (years) Most Frequent Sites
Giant cell reparative Craniofacial bones,
granuloma acral skeleton
Myositis ossificans >20 Parosteal or periosteal
soft tissue
Florid reactive periostitis 20-40 Acral skeleton
Avulsion/stress fracture 20-40 Attachment of major
tendons, long
bones, and pelvis
Pubic osteolysis Females Pubic bones
>50
Age
Most benign tumors and tumorlike lesions, including
osteoid osteoma, chondroblastoma, chondromyxoid
fibroma, solitary bone cysts, aneurysmal bone cysts, and
nonossifying fibromas, occur in adolescents and young
adults (second and third decades of life). Giant cell tumor
is a lesion that almost exclusively occurs in skeletally
mature patients (i.e., those with growth plates fused)
between ages 20 and 50 years. Of the malignant bone
tumors, osteosarcoma and Ewing’s sarcoma are tumors of
children and young adults. On the other hand, chondro-
sarcoma, malignant fibrous histiocytoma, plasma cell
myeloma, metastatic tumors to the skeleton, and second-
ary malignancies in Paget’s disease of bone, after radia-
tion injury, and adjacent to bone infarcts usually develop
during the sixth through the eighth decades of life.
In this text the age distribution of various tumors and
tumorlike lesions is discussed under the separate diagnos-
tic headings, and the peak incidence for most is presented
graphically. Although exceptional cases of individual
bone tumors occur at unusual ages (e.g., chondrosarco-
mas in children or Ewing’s sarcoma in middle-aged
patients), it is best to be circumspect with regard to these
statistical guidelines.
Location
The fact that tumors of bone have predilections for
certain bones and even for characteristic locations in an
individual bone provides an additional clue about the
nature of the lesion. Figure 2-1 shows the sites of predi-
lection of the more common benign bone tumors. In
some instances, the location alone strongly suggests the
diagnosis, as in a heavily ossified tumor on the posterior
surface of the distal femur. That will most likely prove to
be a parosteal osteosarcoma. Adamantinoma and osteofi-
brous dysplasia almost exclusively involve the tibia or
fibula. Chondroblastoma is most often seen in the epiph-
yses of long bones in children or in tarsal or carpal
ERRNVPHGLFRVRUJ
Radiographic Features Microscopic Features
Central lytic defect Giant cell lesion with
fibrohistiocytic cells and
reactive bone
Zonal maturation, Histiocytic cells; reactive
peripheral shell of bone bone formation maturing
toward periphery
Ill-defined bone surface Metaplastic cartilage;
lesion reactive bone and giant
cells
Ill-defined surface bone Reactive process with
lesion; presence of metaplastic cartilage and
fracture line reactive bone
Lytic lesion with florid Reparative process with
periosteal reaction prominent metaplastic
cartilage and reactive
bone
(epiphysioid) bones. Periosteal chondroma has a strong
predilection for the surface of the proximal humeral
metaphysis. Solitary bone cysts in childhood are almost
always found in the proximal humeral shaft or upper end
of the femur. Nonossifying fibromas in childhood are
lesions that favor the metaphyses of long bones of the
lower extremities.
Similar generalizations can be made for bone sarco-
mas. Chondrosarcomas have a predilection for the femur,
pelvis, ribs, and sternum and are almost never found in
the spine or short tubular bones. Osteosarcomas arise
most often in the distal femoral shaft or proximal tibial
shaft before closure of the growth plates, and they seldom
penetrate the cartilaginous physis to involve the epiphy-
sis. Ewing’s sarcoma tends to have a diaphyseal point of
origin, although it may also involve the metaphysis.
Ewing’s sarcoma seldom affects the epiphyseal ends of
bones. Figure 2-1 shows the growth patterns of the most
frequent primary malignant bone tumors, osteosarcoma,
chondrosarcoma, and Ewing’s sarcoma.
INITIAL STAGING
Diagnostic Principles
Bone lesions come to clinical attention due to symptoms
such as swelling and local pain with or without pathologic
fracture, or they can be incidentally discovered on
imaging studies performed for other reasons. Bone
lesions can be divided into benign and malignant catego-
ries. Benign lesions occur more frequently than malig-
nant tumors, and the initial diagnostic maneuvers should
include obtaining a complete medical history and per-
forming both physical examination and radiography.1
The radiographic appearance of a tumor often suggests
benignity or malignancy. When the radiographic analysis
is coupled with clinical information, decisions can be
made concerning the need for additional imaging studies
and procedures. Radiologic imaging reflects the gross
60 2  Clinical Considerations and Imaging of Bone Tumors

Fibrous dysplasia

Enchondroma

Giant cell
tumor
Nonossifying fibroma
Chondromyxoid fibroma

Chondroblastoma
OSTEOSARCOMA

A B

CHONDROSARCOMA EWING’S SARCOMA

C D
FIGURE 2-1  ■  Sites of predilection and growth pattern of the most common bone tumors. A, Diagrammatic representation of sites
of predilection in a long bone for more common benign bone tumors. B, Osteosarcoma tends to provoke little or no intraosseous
or cortical bone sclerosis and shows early breakthrough into soft tissue. Periosteal reactions tend to be linear and interrupted either
parallel or perpendicular. C, Chondrosarcoma tends to grow within the medullary cavity until very late in its course and provokes
irregular cortical thickening, sometimes with concave scalloping on the inner surface of thickened cortex. Periosteal reactions tend
to be solid and incorporated into cortex, indicating slow growth. D, Ewing’s sarcoma grows permeatively and shows breakthrough
in cortex that provokes multilayered periosteal reactions. Tumor mass shows no evidence of matrix mineralization.

anatomy and pathology of the tumor. Although the final
diagnosis of the tumor ultimately resides with the pathol-
ogist, the overall process is best performed as a multidis-
ciplinary correlation of clinical, imaging, and pathologic
factors.
Benign primary bone tumors are common but not
typically troublesome. Because these lesions are often
incidentally found on imaging studies performed for
other purposes, their true incidence is unknown. Common
benign bone tumors include bone islands (enostoses),
enchondromas, osteochondromas, fibroxanthomas (non-
ossifying fibromas), and fibrous dysplasia. The growth of
most of these tumors is indolent, allowing bony remodel-
ing that limits the loss of structural integrity of the bone.
Although some benign bone lesions can grow rapidly
(e.g., aneurysmal bone cyst), they rarely if ever metasta-
size. One of the most common benign bone tumors that
can (rarely) produce distant metastases is giant cell tumor
of bone.2,3 These lesions rarely cause death.4 Conse-
quently, it is hypothesized that the metastases occur due

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 2  Clinical Considerations and Imaging of Bone Tumors 61

A B

C
FIGURE 2-2  ■  Meniscal tear and incidental enchondroma. A, Lateral radiograph of a 61-year-old female with knee pain demonstrates
an intramedullary lesion of the distal femoral metaphysis with stippled and arc-and-ring matrix mineralization, characteristic of
cartilaginous tumors (arrow). No aggressive imaging features are detected, but pain may indicate chondrosarcoma. B, Sagittal fat-
saturated (FS) T2-weighted magnetic resonance image shows a round lesion that is heterogeneously high in signal intensity. C, A
complex tear of the posterior horn of the medial meniscus was responsible for the knee pain, which resolved after meniscal surgery
(arrow, postoperative image). The lesion was an incidental enchondroma that was stable after 2 years of follow-up imaging.

to the passive venous embolism of tumor cells.5,6 This is
in contradistinction to secondary sarcomas that develop
at the site of treated giant cell tumors, actively metasta-
size, and carry a poor prognosis.7-9 Benign bone tumors
are a rare cause of patient demise, but they can cause
morbidity through mass effect (e.g., osteochondromas
abrading adjacent tendons, muscles, or neurovascular
bundles), by predisposing to pathologic fracture due to
cortical thinning, or by mimicking malignancy when they
arise in a location that is in close proximity to an undi-
agnosed source of pain (e.g., distal femoral enchondroma
in a patient with a meniscal tear of the knee in Figure
2-2). In the case of an enchondroma, the lack of aggres-
sive imaging features such as osteolysis, periosteal reac-
tion, or cortical breakthrough may aid the pathologist in
rendering a benign interpretation of the sample, particu-
larly when advanced imaging demonstrates an alternative
source of pain. Pathologists and radiologists must be
familiar with the strengths and weaknesses of both spe-
cialties for both disciplines to augment each other and
increase the likelihood of correct patient diagnosis and
treatment.
Malignant primary bone tumors are not common but
are of critical importance due to their high likelihood of
metastasizing and causing death in the absence of proper
treatment. The five most common primary bone sarco-
mas account for the majority of these lesions and include
osteosarcoma, chondrosarcoma, Ewing’s sarcoma, fibro-
sarcoma, and malignant fibrous histiocytoma. Neverthe-
less, bone metastasis and multiple myeloma are much
more common. The age of the patient and the location
of the tumor are two of the most important demographic
features in diagnosing bone tumors. The typical age
range for Ewing’s sarcoma and osteosarcoma is in child-
hood or adolescence10,11 with a second peak of osteosar-
coma in adults.12 Chondrosarcoma, fibrosarcoma, and
malignant fibrous histiocytoma most commonly occur in
middle age or older age groups.13-15
Bone sarcomas occur in predictable locations within
the bone. Primary chondrosarcomas and osteosarcomas
typically occur in the metaphysis, whereas Ewing’s
sarcoma most commonly arises in the diaphysis of long
bones. Fibrosarcoma and malignant fibrous histiocytoma
can occur in many sites but are preferentially found in
the metaphysis or metaphyseal/diaphyseal junction. The
dominant anatomic sites of many of these tumors have
been described by Johnson et al.16,17 The locations in
which these bone tumors arise tend to be areas of current
or previous rapid skeletal growth (Fig. 2-3), and tumor
development may be related to the high rate of cell divi-
sion. The distal femur and proximal tibia are most com-
monly involved. However, bone sarcomas may arise in
other areas and any bone may be involved. Most benign
bone tumors also arise in or near the metaphysis of
long bones. Some lesions, such as osteochondromas or
nonossifying fibromas/fibroxanthomas, may arise in the
metaphysis and “migrate” away with skeletal growth.
Due to lack of symptoms they may be incidentally dis-
covered in the diaphysis of older patients.
Biopsy is an integral part of the diagnostic process and
is indicated in tumors that are suspicious for malignancy.
Percutaneous core biopsy is less invasive, less costly, and

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62 2  Clinical Considerations and Imaging of Bone Tumors

A C
FIGURE 2-3  ■  Cellular activity of the epiphyseal growth plate. A, Frontal radiograph of the distal femur in 9-year-old male with
osteosarcoma that involves the epiphysis, growth plate, and metadiaphysis with osteoid mineralization in all three sites. Tumor
breakout is shown laterally with moth-eaten osteolysis, layered Codman’s triangle, and spiculated periosteal reaction. B, The high
degree of normal cellular activity in the epiphyseal growth plate of skeletally immature individuals may predispose to later tumor
development at the ends of the long bones, such as in the metaphyses. C, Higher power photomicrograph demonstrating that active
enchondral bone formation is most prominent near the metaphysis and that tumor extends into the growth plate. (B, ×10; C, ×25)
(B and C, hematoxylin-eosin.)

typically more convenient for patients than open surgical
biopsy. Contrast-enhanced MRI is commonly used to
guide selection of the biopsy site. Enhancing portions of
the tumor are viable and preferable for sampling, as
opposed to nonenhancing areas, which are likely cystic
or necrotic.18,19 Because the biopsy track must be excised
for complete resection of malignancies, the biopsy must
be performed in such a way as to minimize contamination
of the anatomic compartments, neurovascular structures,
or tissues that may be necessary for surgical reconstruc-
tion.20 This advanced surgical planning can be greatly
facilitated by the excellent soft tissue contrast resolution
provided by MRI.21,22 All intervention must be planned
in light of the surgical options. Therefore, the diagnosis
of bone tumors cannot be separated from treatment. A
multidisciplinary approach is critical in evaluation and
treatment planning for bone sarcomas.
Imaging Modalities
Radiography is essential for the initial staging of primary
bone tumors and is the least expensive and most readily
available of the imaging modalities.23 Radiographic
images are produced by bombarding anatomic structures
with x-rays. The x-rays that pass through the body are
responsible for forming the image by exposing/darkening
the film or other receiving device.24 Dense anatomic
structures such as bone impede the course of the x-rays,
leaving the corresponding areas unexposed. Bone is
therefore white in appearance on conventional radio-
graphs. Unlike CT, which provides anatomic cross-
sections (see the discussion of CT below), radiographs
are a “summation” of the density of all points in the plane
(frontal, lateral, or oblique). This quality portrays the
tumors in a unique fashion that is often essential for
properly assessing the appearance of key diagnostic attri-
butes of the tumors such as margins, periosteal reactions,
and matrix mineralization. Radiography is recommended
for all bone tumors because it provides well-established,
reliable information on which to build further analyses,
such as the cross-sectional and multiplanar imaging
studies discussed below.
CT is a useful adjunct to radiography for staging
primary bone tumors. Unlike radiography, in which a
single x-ray source strikes a film or detector, most CT
scanners utilize multiple x-ray sources that strike multiple
detectors positioned opposite their respective sources on
a circular frame. This hardware is located in a circular
gantry through which the patient table moves during the
scan. The majority of CT scanners utilize this design to

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 2  Clinical Considerations and Imaging of Bone Tumors 63
either rotate source/detector pairs around the patient or
to rotate an x-ray source within a ring of stationary detec-
tors embedded in the gantry. These source/detector com-
binations allow the imaging of “slices” of anatomy per
revolution. Most modern scanners are operated in helical
mode, allowing rapid scanning while the patient table
moves continuously through the gantry.25 CT scanning
eliminates the effect of overlapping structures and can
provide sharp delineation of the anatomy. CT is the most
efficacious imaging modality for evaluating mineralized
structures, such as tumor matrix.21,26 For example, CT
can be used to detect small areas of mineralized matrix
that are not evident on radiography. Nevertheless, the
indistinct quality of aggressive bone tumor margins can
be underestimated with CT; it is not recommended that
CT be substituted for radiography during the initial
evaluation of bone tumors.
Skeletal scintigraphy, commonly known as bone scan, is
a whole-body method of surveying the entire skeleton in
a single imaging session and is often used to detect metas-
tases to bone. Bone scan typically plays a limited role in
the initial staging of bone tumors unless the disease is
metastatic to bone or multifocal at presentation. Uptake
of technetium-based tracers such as technium-99m meth-
ylene diphosphonate (MDP) is dependent on a combina-
tion of factors such as blood flow and the binding of the
diphosphonate molecules to hydroxyapatite found in
areas of new bone formation.27,28 Diphosphonate uptake
is nonspecific and can be seen with benign and malignant
primary bone tumors, as well as with metastases. For
example, uptake in benign cartilaginous lesions, such as
enchondromas, can be problematic because similar uptake
can also found in chondrosarcomas.29 Enchondromas
may also be difficult to differentiate from low-grade
chondrosarcomas on radiographs, other imaging modali-
ties,30 and even on histopathologic analysis.31 Although
radiography, CT, and MRI can each be limited regarding
the diagnosis of enchondromas versus low-grade cartilage
tumors, the combined information provided by multiple
imaging studies can be valuable in management decisions
and can often aid the diagnostic process.
Bone scan can be used for initial staging for skip
metastases. Skip metastases occur in the same bone as the
primary malignancy but in a noncontiguous location or
across the adjacent joint32 and are associated most com-
monly with osteosarcoma33 and Ewing’s sarcoma.34 The
ability to survey large anatomic regions makes bone scan
a useful imaging modality for this purpose.
MRI is capable of producing greater soft tissue resolu-
tion than other imaging modalities and is commonly used
to assess the extent of disease prior to the surgical treat-
ment of bone tumors. MRI scanners manipulate free
protons. Protons precess, or spin, randomly. When
placed in a strong magnetic field, the majority of protons
align with the field. Radiofrequency pulses or magnetic
gradients are used to reorient proton spins.35 As the spins
return to normal, radio waves are released and interact
with a receiver coil. An electric current is generated, from
which computer-generated images are derived.36
High soft tissue resolution makes MRI the optimal
imaging modality for evaluating the extent of tumors
inside the medullary cavity of bone as well as the extent
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of soft tissue masses.21,22 MRI can allow unparalleled pre-
surgical evaluation of the relationship of the tumor to
vital structures such as nerves and blood vessels. Most
untreated bone tumors demonstrate T1 signal that is
similar (isointense) to muscle, as well as heterogeneously
high T2 signal, and enhance on administration of a
gadolinium-based intravenous contrast medium. The
entire length of the bone can be imaged in detail; MRI
is also considered the imaging method of choice for eval-
uating for skip metastases.37 Heavily mineralized struc-
tures such as cortex and matrix mineralization do not
typically contain a sufficient number of free protons to
produce a magnetic resonance signal. Therefore, bone
cortex appears as a black signal void on MRI (Fig. 2-4),
and fine cortical detail is not well discerned. MRI is
therefore best used in combination with radiography or
CT with which cortical detail and other mineralized fea-
tures can be more fully evaluated. The combined strengths
of each imaging modality permit excellent evaluation of
the many and varied features of bone tumors.
Imaging Characterization of Primary
Bone Tumors
The initial diagnosis of bone tumors on imaging studies
begins by dividing lesions into “aggressive” or “nonag-
gressive” categories on the basis of characteristics such as
lesion margin, expansion of the bone, periosteal reaction,
and soft tissue extension. Aggressive lesions often cor-
respond to malignancy with a small number of notable
exceptions, such as giant cell tumors of bone, that are
often aggressively destructive but rarely result in patient
demise. Conversely, nonaggressive lesions are typically
benign with the exception of indolent malignancies such
as low-grade chondrosarcomas. Further refinements to
the differential diagnosis are made through features such
as the presence or absence of mineralized matrix and the
appearance of the periosteal reaction.
The most important factor in determining the aggres-
sive or nonaggressive nature of a lesion is the appearance
of its margin, which is a product of the osteoclastic activ-
ity of the host bone in response to the tumor and of
reparative, osteoblastic activity. The radiographic appear-
ance of the margin is an indicator of the growth rate of
the lesion.38,39 Three main types of lesion margins have
been identified on radiographs. Greater tumor aggres-
sion is found with progression up the scale (Fig. 2-5).17
Type I margins are geographic (round or ovoid) and have
been divided into three subcategories. Type IA margins
are well defined and have a narrow zone of transition,
which is defined by the presence of normal cortical bone
in close proximity to the lesion. A sclerotic rim is present,
indicative of a successful reparative response by the host
bone. Type IA margins are commonly seen with tumors
such as fibrous dysplasia, chondroblastoma, enchon-
droma, and fibroxanthoma/nonossifying fibroma (Fig.
2-6). Type IB margins are well defined but have no scle-
rotic rim and are therefore of indeterminate biologic
potential (Fig. 2-7). The tumor may be aggressive and
growing only slightly faster than the bone’s ability to
produce a reparative response. Alternatively, the tumor
may produce factors that inhibit osteoblastic activity,
64 2  Clinical Considerations and Imaging of Bone Tumors

A B
FIGURE 2-4  ■  Magnetic resonance image of a skip metastasis. A, Lateral radiograph of the ankle in a 10-year-old male with primary
osteosarcoma of the calcaneus. Dense osteoid formation gives the calcaneus the appearance of an “ivory” bone. B, Coronal fat-
saturated T1-weighted magnetic resonance image of the ankle reveals an enhancing soft tissue mass extending from the primary
tumor. The tumor has not broken through the inferior calcaneal cortex, and the intact cortex is represented as a black signal void
(arrow). A skip metastasis to the distal fibular diaphysis is also demonstrated. The skip metastasis (arrowheads on A and B) is dif-
ficult to see on radiography but is well visualized on MRI, which is a highly sensitive method for evaluating local extent of disease.

IA Sclerotic IB Non-Sclerotic IC Ill-Defined

ll-Moth-Eaten lIl Permeative

FIGURE 2-5  ■  Classification of bone tumor margins.

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 2  Clinical Considerations and Imaging of Bone Tumors 65
A B
FIGURE 2-6  ■  Type IA margin (geographic, sclerotic rim). A, Frontal radiograph of the proximal lower leg in a 16-year-old female
with an incidental nonossifying fibroma (fibroxanthoma). B, A sclerotic rim encircles the nonaggressive lesion on coronal computed
tomography reformation.
such as in myelomatous lesions.40 Type IB margins are
commonly seen with tumors such as aneurysmal bone
cyst, giant cell tumor, chondromyxoid fibroma, low-
grade chondrosarcoma, myeloma, and early metastasis.
Type IC margins are typically seen with aggressive bone
tumors. While retaining a geographic round or ovoid
shape, the margin is ill-defined and indistinct, demon-
strating a wide zone of transition with no sharp margin-
ation (Fig. 2-8). Type IC margins are commonly seen
with lesions such as chondrosarcoma, osteosarcoma,
fibrosarcoma/MFH, metastasis/myeloma, and giant cell
tumors (Fig. 2-9).
Type II and III margins are frankly aggressive, repre-
sent disorganized areas of osteolysis, and are typical of
high-grade sarcomas such as osteosarcoma and Ewing’s
sarcoma. Type II is described as moth-eaten; either the
periphery or the entire lesion is composed of lucent areas
of varying size and shape, representing nonuniform oste-
olysis. MRI will typically demonstrate complete or near-
complete invasion of the marrow cavity (see Figs. 2-10
and 2-11). The type III margin corresponds to the most
highly aggressive bone tumors and is described as perme-
ative. This radiographic appearance is primarily caused
by tumor-stimulated osteoclastic cutting cones that
tunnel rapidly through the bone, producing lesions with
wide zones of transition and a more uniform pattern of
cortical lysis than does the moth-eaten margin (Fig.
2-12). The margin classification system is most appropri-
ately applied to radiographs because CT can produce a
“smoothing” effect that can underestimate the aggres-
siveness of the margin of geographic lesions, and MRI
does not directly image calcified structures.
Continuous cortical expansion is a feature that is more
commonly seen with benign than with malignant tumors.
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Mild expansion is commonly seen with benign fibrous
lesions such as fibrous dysplasia, fibrous cortical defects,
or enchondromas (Fig. 2-13). Greater degrees of cortical
expansion can be seen with other benign lesions such as
nonossifying fibromas/fibroxanthomas and desmoplastic
fibromas. Gross expansion of the cortex with thinning
beyond radiographic visibility can be seen with benign
tumors such as aneurysmal bone cyst, giant cell tumor of
bone, and chondromxyoid fibroma (Fig. 2-14). Malignant
lesions will often precipitously destroy cortex and are
more likely to extend directly into the soft tissues than to
expand the bone. The cortex surrounding a large, malig-
nant soft tissue mass may appear expanded but is typically
noncontinuous and fragmented, with numerous areas of
frank cortical destruction. A notable exception to the
benign nature of continuous cortical expansion can be
seen in low-grade chondrosarcomas. These lesions are
indolent and slowly expand the circumference of the
bone, producing a generally thickened cortex with vari-
able areas of thinning (Fig. 2-15). Nevertheless, the
majority of tumors that continuously expand cortex are
benign.
Extension of tumor into the soft tissues is typically an
aggressive feature that is most commonly seen with
malignancy. Primary bone malignancies are often distin-
guished from metastatic lesions by the presence of a large
soft tissue mass extending from a solitary bone tumor,
and they most commonly demonstrate a type IC, II, or
III margin. On tumor extension into the soft tissues, MRI
can be used to evaluate for abutment or encasement of
adjacent structures such as other bones, nerves, blood
vessels, and visceral organs, as well as extension across
fascial planes (Fig. 2-16).21,22,26
Text continued on p. 75
66 2  Clinical Considerations and Imaging of Bone Tumors

A B

C
FIGURE 2-7  ■  Type IA/IB margin (geographic, well-defined). Enchondroma of the fourth metacarpal head in a 22-year-old female.
A, Mild expansion of the circumference of the bone is demonstrated with minimal sclerotic rim. B, Photomicrograph of the lesion
with close-up (C) shows a thin rim of continuous sclerotic bone around the distal margin with thicker (arrows) and thinner (arrow-
head) areas, some of which may not be radiographically apparent. The cortex is thinned but expanded and intact, reflecting endosteal
erosion that is balanced with periosteal reaction. Incidentally noted are small foci of enchondral bone formation within the enchon-
droma. (B, C, hematoxylin-eosin.)

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 2  Clinical Considerations and Imaging of Bone Tumors 67

FIGURE 2-8  ■  Type IB and IC margins. Frontal radiograph of the left proximal femur in a 53-year-old male with multiple myeloma
demonstrates a lytic lesion involving the proximal femoral neck, the greater trochanter, and intertrochanteric region. The distal
aspect of the lesion is sharply marginated and well-defined but no sclerotic rim is present (IB margin, arrow). The proximal margin
is ill-defined, though the lesion retains an oval, geographic shape (IC margin, arrowheads). The malignant lesion was internally fixed
due to the high risk of pathologic fracture.

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68 2  Clinical Considerations and Imaging of Bone Tumors

B
FIGURE 2-9  ■  Type IC margin (geographic, ill-defined). A, Photomicrograph of the proximal margin of a tibial malignant fibrous
histiocytoma in a 50-year-old female. The aggressive lesion demonstrates an infiltrating rim with tumor encasing the partially
destroyed trabeculae with a central area of necrosis and cyst formation. B, Specimen radiograph shows infiltrating bony destruction
with transition from complete trabecular osteolysis on the inner edges through a progressive partial trabecular osteolytic zone to
normal trabecular bone at the lesion margin. These zones blend radiographically to form the perception of an ill-defined border.
(A, hematoxylin-eosin.)

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 2  Clinical Considerations and Imaging of Bone Tumors 69

A B
FIGURE 2-10  ■  Type II margin. A, Frontal radiograph of the lower leg in a 53-year-old male with osteosarcoma of the proximal tibial
diaphysis. Areas of osteolysis vary in size and shape, indicating a moth-eaten, or type II margin. The aggressive tumor has under-
mined the structural integrity of the bone and an incomplete pathologic fracture has occurred in the medial tibial cortex (arrow).
B, Cortical erosions that correspond to the moth-eaten radiographic pattern are seen in greater detail on coronal computed tomog-
raphy reformation. Inset, Axial fat-saturated T1-weighted magnetic resonance imaging after the administration of intravenous
contrast shows a centrally necrotic medullary tumor, with varying depth of cortical invasion (arrowheads).

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70 2  Clinical Considerations and Imaging of Bone Tumors

FIGURE 2-11  ■  Type II margin (moth-eaten). A, Specimen radiograph of a calcaneal fibrosarcoma. Patchy foci of moth-eaten osteolysis
are present with sparing of areas of normal bone. B, Macroscopic photomicrograph demonstrates bone invasion with areas of
marrow infiltrated by small islands of tumor corresponding to the moth-eaten osteolytic foci in the radiograph. A central area of
coalescent osteolysis corresponds to a more cohesive focus of tumor and uniform radiographic lucency. (B, hematoxylin-eosin.)

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 2  Clinical Considerations and Imaging of Bone Tumors 71

A B
FIGURE 2-12  ■  Type III margin (permeative). A and B, Frontal and lateral radiographs of the knee in a 63-year-old female with a
chondrosarcoma of the distal femoral metaphysis. The proximal margin is permeative (arrows), the most aggressive margin type.
Marked osteolysis with soft tissue extension is seen at the level of the metaphysis, resulting in abnormal angulation of the distal
femur.

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72 2  Clinical Considerations and Imaging of Bone Tumors

A B

FIGURE 2-13  ■  Cortical expansion in a nonaggressive benign lesion. A, Well-corticated expansion of the proximal fibular metadiaphy-
sis with areas of focal calcification are demonstrated on a frontal radiograph of the lower leg in a 44-year-old male with an intraos-
seous lipoma. B, The expanded cortex is contiguous and intact on the macroscopic photomicrograph. Inset, Background fatty tissue
(lipoma) on higher power photomicrograph with central ossification and ischemic bone correspond to the mineralization seen on
the radiograph. (B and inset, hematoxylin-eosin.)

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 2  Clinical Considerations and Imaging of Bone Tumors 73

FIGURE 2-14  ■  Cortical expansion in an aggressive benign lesion. Frontal radiograph of the pelvis in a 19-year-old female with a giant
cell tumor of bone. A lytic, expansile lesion is centered at the level of the acetabulum. The expanded cortex is well demonstrated
laterally. The cortex is thinned nearly beyond radiographic detection superiorly and is less severely thinned inferiorly (arrows). A
type IB margin is seen proximally (arrowhead). Giant cell tumors can demonstrate an unusual combination of locally aggressive
yet overall benign behavior.

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74 2  Clinical Considerations and Imaging of Bone Tumors

FIGURE 2-15  ■  Low-grade chondrosarcoma. Frontal radiograph of the proximal humerus in a 68-year-old male with a lytic lesion that
has mildly expanded the bone and produced variable cortical thickening and thinning. The thickened cortex is the bone’s attempt
to contain the slowly and relentlessly growing tumor. The lesion is a secondary chondrosarcoma that has arisen from an enchon-
droma. The cartilaginous matrix mineralization of the enchondroma can be seen in the nonexpansile, proximal portion of the tumor
(arrow). No sclerotic margin is seen.

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 2  Clinical Considerations and Imaging of Bone Tumors 75

FIGURE 2-16  ■  MRI of local disease extent: neural involvement. Axial fat-saturated T1-weighted magnetic resonance image of the
pelvis in a 21-year-old male with mesenchymal chondrosarcoma of the sacrum demonstrates a large tumor arising from the sacrum.
The greatest bulk of the lesion extends anteriorly into the pelvis. A smaller component invades the sacral spinal canal and encases
the left S2 nerve root (arrow). Also observe that the enhancement of the tumor is more heterogeneous anteriorly, corresponding
to a greater degree of central necrosis in the larger portion of the tumor (arrowheads).

Periosteal reaction is another indicator of the aggres-
sive or nonaggressive nature of tumors.41 During devel-
opment, the circumference of the bone enlarges through
the mechanism of periosteal bone formation; this mecha-
nism plays a major role in the healing of fractures that
experience small degrees of motion at the fracture site.42,43
The periosteum is more active in children than adults,
and the appearance of adult periosteal reactions typically
parallels that of those reactions in children but are lesser
in magnitude. Rapidly aggressive tumors often result in
multilaminar or interrupted periosteal reactions. The
mass effect of the tumor can lift the periosteum from the
cortex, producing a triangular interface that is termed a
Codman’s triangle (Fig. 2-17). The periosteal reaction of
Ewing’s sarcoma is commonly parallel to the long axis of
the bone and resembles an onion skin (Fig. 2-18), though
osteosarcoma can produce a similar appearance (Fig.
2-19). The periosteal reaction of osteosarcomas often
extends perpendicularly from the long axis of the bone,
giving a spiculated, “hair-on-end” or “sunburst” appear-
ance (Fig. 2-20). Indolent processes often produce a
thicker, more solid, or unilaminar appearance. Knowl-
edge of the medical history is important because the
periosteal reactions of treated malignant primary bone
tumors or metastases can thicken or solidify with success-
ful therapy and can mimic a benign feature.
Matrix is an acellular substance located in the extracel-
lular space between tumor cells; the presence of mineral-
ized matrix can aid in the identification of bone tumors.44
Characteristic patterns of matrix mineralization can be
seen with osteoid, cartilaginous, or fibrous tumors. The
mineralization that occasionally occurs in myxoid matrix
is indistinguishable from dystrophic calcification, is non-
specific, and is not helpful for the diagnosis of bone
tumors on imaging studies.
The presence or absence of mineralized matrix is not
an indicator of benign or malignant behavior. Osteoid
matrix can be seen in bone islands/endosteomas, osteoid
osteomas, osteoblastomas, or osteosarcomas and is most
commonly described as “fluffy” or “cloudlike” on radio-
graphs and CT although dense, ivorylike osteoid can also
be produced (Fig. 2-21). Cartilaginous matrix is the result
of enchondral bone formation and is often “stippled” or
demonstrates a curvilinear “arc-and-ring” quality that
conforms to the rounded contour of cartilage lobules
(Fig. 2-22). The lobular growth of cartilaginous tumors
is often reflected in a lobulated pattern of endosteal scal-
loping on radiographs and a septal enhancement pattern
on MRI (Fig. 2-23) that is common but not exclusive to
cartilaginous tumors. Distinguishing between benign and
malignant cartilaginous tumors by means of imaging or
histopathology can be difficult. Not all chondrosarcomas
demonstrate frankly aggressive imaging findings such as
a type II or III margin. A comparative imaging study of
92 enchondromas and 95 chondrosarcomas45 found that
chondrosarcomas were typically larger than the enchon-
dromas (>5-6 cm in length), produced deeper endosteal
scalloping (scalloping of at least two-thirds the thickness
of the cortex over at least two-thirds the length of the
Text continued on p. 82

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76 2  Clinical Considerations and Imaging of Bone Tumors

A B

FIGURE 2-17  ■  Codman’s triangle. A, Radiograph with aggressive, multilaminar periosteal reaction caused by a fibrosarcoma lifting
the periosteum from the anterior tibial diaphysis in a 56-year-old female. B and Inset, Photomicrograph and close-up of the tumor
show the elevated periosteum, its osteoid product beneath it, and the extracortical but still subperiosteal tumor arising from deep
within the femur (arrow). The periosteum is intact, but detectable mineralization is only seen at the peripherial edge where it has
formed and mineralized bone. (B, Inset, hematoxylin-eosin.)

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 2  Clinical Considerations and Imaging of Bone Tumors 77

FIGURE 2-18  ■  “Onionskin” periosteal reaction: Ewing’s sarcoma. Frontal radiograph of a 12-year-old male with Ewing’s sarcoma of
the humerus. An aggressive, multilaminar periosteal reaction (arrow) is associated with the aggressive tumor, which produces
moth-eaten and permeative osteolysis of the distal metaphysis of the elbow.

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78 2  Clinical Considerations and Imaging of Bone Tumors

A B
FIGURE 2-19  ■  “Onionskin” periosteal reaction: osteosarcoma. A, Multilaminar, “onionskin” periosteal reaction is seen on a specimen
radiograph of the proximal humeral diaphysis (arrow) of a 20-year-old male with osteosarcoma. A combination of moth-eaten
osteolysis and mineralized osteoid is seen within the humerus, while foci of mineralized tumor osteoid are seen within the layered
periosteal reaction. B, Macroscopic photomicrograph closely parallels the radiographic image, showing both mineralized tumor
osteoid and nonmineralized tumor and osteoid in the osteolytic areas. These same features are demonstrated in the periosteum
and the layered periosteal reaction. (B, hematoxylin-eosin.)

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 2  Clinical Considerations and Imaging of Bone Tumors 79

A B
FIGURE 2-20  ■  “Hair-on-end” periosteal reaction: osteosarcoma. A, The periosteal reaction extends perpendicularly from the cortex
on a specimen radiograph of a 14-year-old male with osteosarcoma of the distal femoral metaphysis. The distal growth plate is
involved, with extension of mineralized tumor into the epiphysis. The proximal periosteal reaction is more contiguous and mineral-
ized, corresponding to less biologic growth at this site. B, Macroscopic photomicrograph demonstrates inhomogeneous but diffuse
mineralized tumor osteoid throughout the metadiaphysis and extending through the growth plate into the epiphysis. Foci of unmin-
eralized osteoid in the intraosseous and extraosseous tumor contribute to the inhomogeneous appearance. The hair-on-end min-
eralization shows varying lengths and widths of spicule formation. (B, hematoxylin-eosin.)

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80 2  Clinical Considerations and Imaging of Bone Tumors

FIGURE 2-21  ■  Osteoid matrix. Frontal radiograph of the shoulder in a 15-year-old male with osteosarcoma. The tumor produces
aggressive bone destruction and a large soft tissue mass with osteoid matrix that is “fluffy” or “cloudlike” in appearance (arrow).

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 2  Clinical Considerations and Imaging of Bone Tumors 81

A B
FIGURE 2-22  ■  Chondroid matrix. A, Radiograph of the scapula in a 22-year-old male with chondrosarcoma of the scapular body.
Cartilaginous matrix mineralization is characteristically curvilinear with an “arc-and-ring,” or stippled appearance. Also note the
stalk at the base of the tumor, indicating that it is a secondary chondrosarcoma that has arisen from an osteochondroma. B, These
characteristics are seen in better detail on the axial computed tomography image of the tumor.

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A B

C
FIGURE 2-23  ■  Septal enhancement of chondrosarcoma. A, Axial T1-weighted, B, fat-saturated T2-weighted, and C, fat-saturated
T1-weighted postcontrast MRI of the same chondrosarcoma as in FIGURE 2-22. A, T1 signal is lower than muscle. B, T2 signal is
predominately high and the lesion is lobulated. C, Enhancement is seen predominately at the periphery of the lesion in the “septae”
extending about the cartilaginous lobules. The matrix does not enhance. This unusual pattern of tumor enhancement is commonly
seen in cartilage tumors and can be contrasted with the more solidly enhancing tumor in FIGURE 2-16.

lesion), and were more likely to be painful. Other studies
have found malignant cartilaginous tumors to be more
intensely FDG avid than benign cartilage lesions on PET
imaging,46,47 implying that malignant tumors are more
metabolically active than benign ones. FDG PET is
further described below in the section on response to
therapy.
Matrix mineralization can exhibit a spectrum of
appearances. Fibrous dysplasia may be lucent or may
demonstrate ground-glass or dense mineralization
depending on the amount of woven bone formed by the
lesion (Fig. 2-24). An increase in lesion mineralization
can occur over time in nonossifying fibromas, fibrous
dysplasia, osteochondromas, Langerhans cell histiocyto-
sis, bone islands, and osteoid osteomas (Fig. 2-25).48 The
cartilaginous matrix of benign tumors can also increase
in density over time, in a process termed maturation. Suc-
cessful treatment of malignant tumors will often result in
increased tumor mineralization. The “fluffy” or “cloud-
like” matrix that is found in untreated osteosarcoma
coarsens and becomes more solid after treatment, and the
posttherapeutic appearance can mimic chondroid matrix
(Fig. 2-26). These potentially confusing changes in the
imaging appearance of treated tumors serve to emphasize
the importance of the medical history in the proper inter-
pretation of diagnostic images. Multiple lesion character-
istics identified on imaging studies can combine to aid
the appropriate diagnosis of bone tumors.
RESPONSE TO THERAPY
Primary Bone Tumors
The treatment for bone tumors is closely related to their
likelihood of recurrence. Benign, symptomatic bone
tumors with a high likelihood of local recurrence (giant
cell tumor, aneurysmal bone cyst) are treated with curet-
tage, which involves tumor removal while leaving the
surrounding bone intact. A high-speed burr is used on all
surfaces of the curetted cavity. Numerous adjunctive
techniques can be used to destroy remaining tumor cells,

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 2  Clinical Considerations and Imaging of Bone Tumors 83

A B
FIGURE 2-24  ■  Variation in matrix mineralization. Frontal radiographs of the proximal femora in two patients with fibrous dysplasia.
A, The mildly expansile lesion demonstrates ground-glass matrix that is similar in density to the normal trabeculae. Two cannulated
screws span a healed, pathologic fracture of the femoral neck. B, The lesion in the second patient demonstrates denser matrix with
more maturation (ossification) and sclerosis about the periphery. This lesion also weakened the structure of the bone, resulting in
an abnormal curvature termed the shepherd’s crook deformity.

such as the application of liquid nitrogen, hydrogen per-
oxide, phenol,49 or an argon laser.50 The cavity is then
packed with autologous bone graft, cadaveric bone graft,
or polymethylmethacrylate cement.
Benign bone tumors that do not typically recur can be
treated with lesion destruction rather than removal.
Osteoid osteoma can be treated through radiofrequency
ablation, which is a percutaneous technique that utilizes
heat necrosis to destroy the painful tumor nidus in a
minimally invasive fashion.51,52 Because systemic therapy
is typically not available or necessary for benign bone
tumors, imaging plays no role in evaluating response to
therapy. Posttherapeutic imaging of benign lesions is per-
formed for the purpose of detecting local recurrence or
complications such as fractures or infections. This
imaging strategy also applies to bone malignancies for
which no standard extrasurgical therapy has been devel-
oped, such as chondrosarcoma.
Systemic therapy is available for some malignant
primary bone tumors, such as osteosarcoma and Ewing’s
sarcoma, and the resultant changes that are observed on
imaging studies have been correlated with either a posi-
tive response or progression of disease. Many tumors,
such as osteosarcomas and plasmacytomas, typically
become more densely mineralized on radiographs53 and
CT54 with successful systemic or radiation therapy. The
MRI appearance of a positive therapeutic response
typically results in decreased enhancement following
gadolinium-based intravenous contrast administration
and a decrease in T2 signal intensity. T1 signal may also
diminish. These changes correspond to increased miner-
alization, diminished vascular perfusion, and decreased
lesional water content. Central necrosis is identified as
peripheral enhancement in the absence of central
enhancement. Central necrosis in a pretherapeutic or
recurrent lesion is an aggressive feature, implying that
the tumor has outgrown its blood supply (Fig. 2-27). The
posttherapeutic development of central necrosis, or
increase in central necrosis, typically indicates a positive
response, reflecting therapy-induced cell death. In the
past, bone scan played an important role in evaluating
therapeutic response in bone tumors. Primary bone
tumors have been shown to increase or decrease in tracer
uptake on bone scan with negative or positive response,
respectively. Nevertheless, bone scan has largely been
supplanted by MRI and CT for primary bone tumor
staging. Skeletal scintigraphy continues to play a large
role in staging for skeletal metastases.

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84 2  Clinical Considerations and Imaging of Bone Tumors

A B
FIGURE 2-25  ■  Healing nonossifying fibroma (fibroxanthoma). Frontal radiographs in an 8-year-old female with a nonossifying
fibroma of the distal femur. A, The lesion demonstrates a combination of internal lucency and mature mineralization with a sclerotic
type IA, nonaggressive margin. B, One year later, the lucent areas have partially mineralized, indicating interval maturation and
ossification within the lesion. The lesion appears to have “migrated” proximally with growth of the bone distally.

A B
FIGURE 2-26  ■  Posttherapeutic osteoid mimicking chondroid matrix. Axial computed tomography images of the humerus in a
15-year-old male with osteosarcoma. A, “Fluffy” osteoid matrix is evident in the large soft tissue mass extending from the humeral
diaphysis (arrow). B, After chemotherapy, the osteoid has coarsened, simulating the stipples and arcs and rings of chondroid matrix
in some portions of the tumor (arrowheads). The lesion has also decreased in size, corresponding to a positive response to therapy.

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 2  Clinical Considerations and Imaging of Bone Tumors 85

A B
FIGURE 2-27  ■  Central necrosis in progressing, recurrent disease. A, Axial fat-saturated T1-weighted magnetic resonance image of
a 19-year-old female with recurrent spinal Ewing’s sarcoma following intravenous contrast demonstrates a solidly enhancing recur-
rent tumor mass. B, Two months later, the lesion enhances less uniformly but has enlarged (arrowheads), indicating central necrosis
in a progressing lesion that now also involves the adjacent right L4-5 foramen (arrow).

Tumor response criteria have been developed to
provide a standardized, uniform methodology for deter-
mining response in patients undergoing therapy in dif-
ferent clinical trials and at different institutions. Response
criteria define the minimal allowable tumor change that
constitutes a response and delineate the methods by
which change can be measured. The most commonly
used response criteria, exemplified by the Response Eval-
uation Criteria in Solid Tumors (RECIST), rely primar-
ily on anatomic change in tumor size.55 Osteosarcoma
typically demonstrates an initial decrease in size that cor-
relates with a positive outcome, whereas an increase in
size during therapy correlates with a poor prognosis.56
Nevertheless, the tumor may not continue to diminish in
size or may diminish only slightly (not meeting minimal
change in size for a “measurable” response as per the
criteria), despite continued positive histologic response.
Lack of size correlation with successful chemotherapy is
a potential pitfall in determining treatment response in
primary bone tumors on conventional, anatomic imaging.
FDG PET/CT is a form of functional imaging that
demonstrates cellular uptake of the glucose analog FDG.
The FDG molecule is transported into cells using GLUT
transporters located in cell membranes.57,58 FDG is a
phosphorylated molecule that cannot be metabolized by
the cell and is broken down slowly. The majority of
malignancies demonstrate a high rate of glucose metabo-
lism. Therefore, the resultant intracellular accumulation
of FDG in tumor cells permits functional, metabolic
imaging. As a reflection of tumor metabolism that dimin-
ishes with cell death, FDG has been shown to effectively
anticipate therapeutic response in primary bone sarcomas
such as osteosarcoma,59-64 Ewing’s sarcoma,65 and chon-
drosarcoma.66 The change in FDG uptake, when mea-
sured before and after chemotherapy, may also have
prognostic value, as has been shown in studies of osteo-
sarcoma (Fig. 2-28).59,61,63,64 Change in FDG uptake can
occur independently of change in tumor size; FDG PET
scanning can provide an alternative method of measuring
tumor response. Currently, lack of standardization in
PET scan acquisition in different institutions has limited
its inclusion into major response criteria.
The soft tissue component of Ewing’s sarcoma and
plasmacytomas predictably undergoes a marked decrease
in size with successful therapy. Nevertheless, some soft
tissue sarcomas, such as gastrointestinal stromal tumors,
have a tendency to increase in size with successful therapy
due to loss of structural integrity.67 This is a rare phe-
nomenon in bone tumors, in which an increase in size on
any imaging modality after therapy is usually a sign of
disease progression. The determination between positive
or negative response can be difficult when the lesion
increases in central necrosis because this could either be
caused by outgrowth of blood supply in a progressing
tumor or desired cell death after effective therapy. Typi-
cally, the progressing, centrally necrotic lesion will dem-
onstrate stable or increasing soft tissue nodularity along
the enhancing rim. Rim nodularity in a responding lesion
will often diminish.
Imaging has become an essential tool for evaluating
therapeutic response in primary bone tumors. Therapy
can be modified based on imaging results, potentially
allowing the patient to be changed from ineffective to
effective therapeutic agents before surgical resection and
histopathologic analysis of the specimen.
Bone Metastases
Bone sarcomas metastasize most commonly to the lungs
but demonstrate a predilection for metastasizing to other
bones.68,69 Muliple foci of osteosarcoma may be found
only in the skeleton, raising the possibility of multicentric
primary disease in the absence of a dominant lesion.70,71
Bone metastases can be osteolytic and lucent, osteoblastic
and sclerotic, or they can be mixed lytic and sclerotic
(Fig. 2-29). Many parallels can be seen in the imaging

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86 2  Clinical Considerations and Imaging of Bone Tumors

A C

B D
FIGURE 2-28  ■  Response to therapy on FDG PET/CT. A, Axial computed tomography (CT) portion of a positron emission tomography
(PET)/CT scan in a 17-year-old male demonstrates an osteoid-containing mass extending from the left iliac bone that was biopsy-
proven osteosarcoma. B, The maximum standardized uptake value (SUVmax) of the lesion on the fused PET/CT image was 8.5 before
therapy. C, After chemotherapy, the lesion increased in mineralization but only slightly decreased in size. D, The posttherapeutic
PET/CT image shows a marked decrease in fluorodeoxyglucose uptake, with an SUVmax of 2.5. The functional imaging reflected the
histologic response, which included 99% necrosis in the resected specimen.

A B
FIGURE 2-29  ■  Types of metastases. A, Axial computed tomography (CT) scan of the L2 vertebra in a 53-year-old female with breast
cancer. The blastic/sclerotic metastasis is dense on CT (arrow) and radiography (not shown). B, The lytic metastasis to the T9 ver-
tebra is lucent (arrowheads). Additional metastases on both images are mixed.

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A C E

B D F
FIGURE 2-30  ■  Flare phenomenon. A and B, Computed tomography (CT) of the pelvis before and after therapy demonstrates the
interval appearance of a sclerotic lesion in the right sacral ala (arrow) in a 38-year-old female with metastatic breast cancer. C and
D, Technetium-99m methylene diphosphonate (MDP) bone scans contemporaneous with A and B show an interval development of
tracer uptake in the area of interest (arrowhead). The CT and bone scans appear to indicate disease progression. E and F, Neverthe-
less, contemporaneous fused positron emission tomography/CT images show a marked reduction in fluorodeoxyglucose uptake on
the latter examination, indicating that the sclerotic lesion seen on CT and the associated MDP uptake were a deceptive flare phe-
nomenon caused by healing sclerosis within the lesion that was initially occult on CT and bone scan.

appearance of therapeutic response in bone metastases as
compared to primary bone tumors.
Different imaging modalities demonstrate different
physical characteristics of the neoplastic process. Radio-
graphs, CT, and nuclear medicine bone scans primarily
image the secondary response of the host bone to the
tumor rather than the lesion itself. On radiographs and
CT, lytic lesions frequently heal with peripheral (rim) or
internal sclerosis irrespective of the histology of the
primary tumor, with the exception of nonexpansile
myelomatous lesions, which typically remain lucent.
Nevertheless, expansile plasmacytomas will develop
peripheral mineralization after successful therapy.72
Enlarging lucencies caused by tumor osteolysis indicate
progression.73,74 Stability of size typically comprises a
positive response in sclerotic metastases, whereas an
increase in size is seen with progression. Healing sclerotic
lesions may increase in density but rarely fade. Tracer
uptake on bone scan will typically decrease or increase
with healing or progression, respectively.75 A pitfall asso-
ciated with positive therapeutic response can occur on
bone scan. Increasing sclerosis within effectively treated
lesions can cause a spurious increase in tracer uptake
within the first 3 months of therapy.76,77 This potential
diagnostic conundrum is designated the flare phenomenon,
and it can be diagnosed by observing a healing response
on other imaging modalities (Fig. 2-30).
The majority of bone metastases arise in the medullary
cavity, with a small minority arising in the cortex.78 As
with primary bone tumors, MRI can directly image the
metastatic tumor mass inside the medullary cavity. After
successful therapy, T2 signal, T1 signal, and enhance-
ment often diminish while the size of the lesion may or
may not diminish. MRI can detect metastases earlier than
radiography or CT79 because MRI does not depend on a
secondary host bone response such as the development
of the reparative new bone that is dense on x-ray based
imaging modalities and “hot” on bone scan. PET scan-
ning reflects metabolic uptake of FDG in the tumors,
which is another direct method of evaluating response in
FDG-avid lesions. Studies have shown FDG PET to be
efficacious in determining the response of the bone
metastases of breast cancer.80-82 Although not primarily
investigated at the time of this writing, FDG uptake was
seen to decrease with therapy in seven bone metastases
from three Ewing’s sarcoma patients in a study that evalu-
ated the response of the primary tumors.61
The most commonly used response criteria, such as
RECIST, are often applied to soft tissue metastases such
as lymph nodes or lung nodules and, as mentioned

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88 2  Clinical Considerations and Imaging of Bone Tumors

TABLE 2-2 MD Anderson (MDA) Criteria*

Response Category Criteria
Complete response Complete sclerotic fill-in of lytic lesions on XR or CT
Normalization of bone density on XR or CT
Normalization of signal intensity on MRI
Normalization of tracer uptake on SS
Partial response Development of a sclerotic rim or partial sclerotic fill-in of lytic lesions on XR or CT
Sclerotic flare: Interval visualization of lesions with sclerotic rims or new sclerotic lesions in the setting
of other signs of partial response and absence of progressive bony disease
≥50% decrease in measurable lesions on XR, CT, or MRI
≥50% subjective decrease in the size of ill-defined lesions on XR, CT, or MRI
≥50% subjective decrease in tracer uptake on SS
Progressive disease ≥25% increase in size of measurable lesions on XR, CT, or MRI
≥25% subjective increase in the size of ill-defined lesions on XR, CT, or MRI
≥25% subjective increase in tracer uptake on SS
New bone metastases
Stable disease No change
<25% increase or <50% decrease in size of measurable lesions
<25% subjective increase or <50% subjective decrease in size of ill-defined lesions
No new bone metastases

*Measurements are based on the sum of a perpendicular, bidimensional measurement of the greatest diameters of each individual
lesion. Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; SS, skeletal scintigraphy; XR, radiography.
Table modified from Hamaoka T, et al. and published with permission from J Cancer 1:80–92, 2010.

previously, are primarily based on change in size. The
successful therapy of bone metastases rarely results in a
decrease in size on radiography or CT. A measurable
decrease in the size of positively responding bone metas-
tases is more likely to be demonstrated on MRI but does
not occur in a consistent fashion. Additionally, the irregu-
lar shape of many bones and the inability to ensure that
the lesions will be imaged at consistent obliquity renders
most bone lesions “unmeasurable” according to RECIST.
Patients who have undergone resection of their primary
tumor and have metastases only to bone could be denied
enrollment into clinical trials due to the absence of mea-
surable disease by which to gauge the efficacy of the
therapeutic agents. To address this need, bone-specific
response criteria have been developed at the University
of Texas MD Anderson Cancer Center (MDA Criteria;
Table 2-2, Fig. 2-31).23 The MDA criteria incorporate
the changes in imaging appearance of bone metastases on
radiographs, CT, bone scan, and MRI into a system that
has been used to successfully predict progression-free
survival in breast cancer patients with bone-only metas-
tases.83 This retrospective study included 41 breast cancer
patients who received standardized, systemic therapeutic
regimens. Medical records and patient images were
analyzed at 2 to 6 months or 11 to 13 months after the
initiation of therapy. Two musculoskeletal radiologists
analyzed the response of bone metastases on each imaging
modality for each patient at each time point using the
MDA, World Health Organization (WHO), and Union
for International Cancer Control (UICC) response cri-
teria. The UICC criteria provide response guidelines
only for radiography and were excluded due to low
numbers of radiographs. The WHO criteria include radi-
ography and bone scan but not CT or MRI. The study
found that using the MDA criteria, patients who
responded to therapy could be differentiated from those
who did not (progression-free survival) at 5.5 months.
Response was not identified with the WHO criteria until
23.5 months (P = 0.025). Early response identification
can allow timely modification of therapeutic regimens,
implying that the behavior of bone metastases can be
used to guide therapy in these patients.
RESTAGING AND
ONCOLOGIC SURVEILLANCE
Local Recurrence
The restaging and surveillance of patients with bone
tumors can be divided into two main categories, includ-
ing local recurrence and distant metastases. The most
common imaging modality used to evaluate for local
recurrence is radiography. Serial radiographs are used to
restage malignancies and benign tumors with a tendency
to recur, such as aneurysmal bone cyst or giant cell tumor
of bone (10%-20% recurrence rates with modern
therapeutic techniques).84,85,86,87 Radiographs of recurrent
tumor may show interval development of osteolysis (Fig.
2-32), matrix mineralization in the soft tissues, periosteal
reaction, or expansion of cortex.88 Suspicious radio-
graphic findings are often further investigated with MRI
to assess disease extent and corroborate the diagnosis of
recurrence. Most recurrent primary bone tumors have
T1 signal that is isointense to muscle, T2 signal that
is high or heterogeneous, and demonstrate internal
enhancement after the administration of intravenous
contrast.88 Most small recurrent nodules show solid or
predominantly solid enhancement. Even tumors that are
characteristically cystic or hemorrhagic, such as giant
cell tumors, will typically demonstrate foci of nodular
enhancement. An exception is aneurysmal bone cyst,
which is entirely cystic and enhancement is seen only in
the rim. The cystic appearance of recurrent aneurysmal

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 2  Clinical Considerations and Imaging of Bone Tumors 89

A: 12.7mm

B: 11.7mm

A B

B: 26.4mm

A: 26.4mm

C D
FIGURE 2-31  ■  MDA bone response criteria for metastatic disease. Axial computed tomography images of a 24-year-old female with
a primary osteosarcoma of the left humerus. A, A blastic metastasis is observed in the L3 vertebral body. B, The lesion initially
measured 12 mm × 13 mm (25 mm sum of diameters). C and D, Four months later, the lesion enlarged to 26 mm × 26 mm (52 mm
sum of diameters), having undergone a 108% change. This meets the minimum MD Anderson (MDA) size criteria of ≥25% increase
in the sum of the diameters needed for disease progression. The most commonly used response criteria, such as RECIST, would
not have categorized this bone metastasis as measurable disease. The MDA response criteria can be used to quantify response to
therapy in bone metastasis.

bone cysts is corroborated by the clinical context. Con-
trast enhanced MRI scans can be helpful in distinguishing
between simple, postoperative cysts (thin, uniform rim
enhancement) and other types of recurrent tumors (solid
or nodular internal enhancement), both of which can
demonstrate similar low T1 and homogeneous, high T2
signal intensity.89 Ultrasonography is useful for oncologic
surveillance of superficial or soft tissue resection sites and
can be used to guide biopsy of superficial or palpable
masses. Ultrasound waves cannot penetrate cortex, and
MRI is the most sensitive modality for evaluating recur-
rent tumor in the marrow cavity.
The local restaging of high-risk sarcoma patients is
often performed with a combination of radiography and
MRI or ultrasonography. Clinic visits, which may or may
not include imaging, are typically performed every 6
months for 3 to 5 years for lower grade lesions. For high-
grade sarcomas, the patients are followed every 3 months
for 2 years, every 4 months for the third year, every 4 to
6 months for the fourth year, and every 6 months for the
fifth year. Sarcoma patients are then followed at least once
per year for a total of 10 years.90 This surveillance regimen
is designed to facilitate early detection of recurrent tumor
with the cost-effective distribution of imaging studies and
clinic visits in the years immediately after the surgery.
The risk of recurrence diminishes with time; the clinical
emphasis of later visits shifts to the integrity of the ortho-
pedic reconstruction.
Distant Metastases
Malignant bone tumors typically metastasize in a predict-
able fashion, and various imaging studies are used to
evaluate the anatomic locations in which metastatic
lesions are most likely to occur. Most primary malignant
bone tumors are sarcomas and metastasize preferentially
to the lungs. Chest CT is more sensitive for detecting
pulmonary nodules than is radiography and can be used
to monitor high-risk patients, whereas lower risk patients
can be followed with posteroanterior (PA) and lateral

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90 2  Clinical Considerations and Imaging of Bone Tumors

A B

C
FIGURE 2-32  ■  Local recurrence. A, Frontal radiograph of the proximal humerus in a 7-year-old male with pain in the proximal upper
arm demonstrates a unicameral bone cyst (UBC) with an undisplaced pathologic fracture (arrowheads). B, The lesion was curetted
and ablated with hydrogen peroxide, and the cavity was packed with bone graft. C, Four months later, a rounded lucency indicates
recurrent UBC (arrows). The interventional procedure was repeated and no further recurrence occurred.

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 2  Clinical Considerations and Imaging of Bone Tumors 91

A B
FIGURE 2-33  ■  Radiography for indeterminate bone scan. A, Frontal planar technetium-99m MDP bone scan of a 15-year-old male
who underwent resection of an osteosarcoma of the distal right femur. A globular area of tracer uptake at the medial aspect of the
distal right femur is indeterminate and could be potentially related to the resection arthroplasty. B, Knee radiography was then
obtained, and a small focus of osteoid at the area of the area of interest (arrowhead) was indicative of recurrent osteosarcoma.
(Images courtesy of Hubert H. Chuang, MD, PhD, University of Texas MD Anderson Cancer Center.)

chest radiography. Visceral and lymph node metastases
may occur later in the course of the disease and are most
commonly evaluated with CT of the abdomen and pelvis.
These CT examinations are optimized by use of oral,
rectal, and intravenous contrast agents.
The majority of bone metastases occur in the axial
skeleton, although metastases to the extremities are not
uncommon.91,92 Therefore, whole-body imaging modali-
ties are necessary to properly evaluate the entire skeleton
of patients at risk for bone metastases. Imaging of the
entire skeleton can also aid in the diagnosis of metastases
because multiplicity of lesions is common. Bone scan is
the most commonly used imaging modality for this indi-
cation and is sensitive but not specific for the detection
of bony metastases.73 Nonmalignant processes such as
arthritis, degenerative joint disease, and posttraumatic
findings, such as fractures, can induce tracer uptake.93-95
This lack of tracer uptake specificity is exacerbated by a
relative lack of anatomic resolution that further limits
differentiation between benign and malignant processes.
Radiographs are specific but not sensitive and can be used
to augment planar bone scans for further evaluation of
indeterminate areas of tracer uptake73 (Fig. 2-33). Con-
versely, radiography is the initial imaging modality of
choice to evaluate a specific area of bone pain in cancer
patients at risk for osseous metastases. This can be
followed by planar bone scan to stage the remainder of
the skeleton.96 Direct imaging of the marrow cavity with
MRI allows early detection of bony metastases,79 but
MRI is more expensive than the combination of radio-
graphs and bone scan.23 If the radiographs are inconclu-
sive and bone scan is not definitive for bone metastases,
MRI is recommended in sarcoma patients as in patients
with breast cancer.96
Another option for evaluating indeterminate areas of
tracer uptake on planar bone scan is SPECT/CT. A
SPECT scan is essentially a cross-sectional bone scan.
Tracer uptake from degenerative change is more easily
identified on SPECT than on a planar bone scan.97 For
example, SPECT can more readily differentiate an
abnormality in the pedicle of a vertebra, which is often
metastatic, from one in a facet joint, which is usually
degenerative.98 Modern SPECT scanners are hybrid
devices that also perform a CT to create fused SPECT/
CT images. The CT further increases the specificity
of the scan by providing anatomic information that
can allow even more precise identification of affected
structures (Fig. 2-34).99
PET/CT is an imaging modality that can also provide
whole-body coverage. Advantages over bone scan include
increased anatomic resolution and multiorgan system
evaluation. PET/CT has become standard of care for the

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92 2  Clinical Considerations and Imaging of Bone Tumors

A B
FIGURE 2-34  ■  SPECT/CT for indeterminate bone scan. A, Bone scan in a 58-year-old breast cancer patient with tracer uptake in the
left distal femoral diaphysis that is suspicious for a bone metastasis (arrow). B, Coronal fused single-photon emission computed
tomography/computed tomography (SPECT/CT) of the area of interest, obtained in the same imaging session as the planar scan,
demonstrates an intramedullary lesion with characteristic arc-and-ring cartilaginous matrix mineralization. No aggressive features
were seen on the CT, and the diagnosis was an incidental enchondroma. Fused CT adds specificity to functional examinations such
as bone scan and positron emission tomography. Osteoarthritic changes are incidentally seen at the medial compartment of both
knees (arrowheads).

staging of many types of lymphoma.100 As with SPECT/
CT, modern PET scanners are hybrid devices that acquire
PET and CT scans in the same imaging session, allowing
the fusion of functional and anatomic data sets. PET by
itself has limited anatomic resolution, and the addition of
the fused CT data set has been shown to facilitate the
identification of bony metastases with high sensitivity and
specificity101 and has also been found useful in detecting
extraskeletal metastases, such as to the mediastinum and
liver in patients with Ewing’s sarcoma.102 FDG PET/CT
has been approved for the initial staging of sarcoma
patients by the US Centers for Medicare and Medicaid
Services (CMS) at the time of this writing, and its use in
the care of patients with bone sarcoma is expected to
increase in the United States.
Conventional MRI is most commonly obtained as a
regional rather than whole-body examination due to the
effect of image-distorting artifacts that increase as the
size of the area to be scanned enlarges and due to exces-
sive scan times. Technologic developments have permit-
ted diagnostic MR scanning of the entire body in
approximately 1 hour.103 Whole-body MRI has been
shown to be more sensitive than bone scan for detecting
osseous metastases in numerous malignancies.91,104-109 In
addition to the skeleton, whole-body MRI has been
shown capable of evaluating organs, such as liver, brain,
and lymph nodes.91
Numerous imaging modalities are available to evaluate
patients for local recurrence and distant metastases. The
unique strengths of specific imaging modalities are used

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 2  Clinical Considerations and Imaging of Bone Tumors 93
to perform oncologic staging in the most therapeutically
and cost effectively optimal manner.
CONCLUSION
Imaging studies provide important information regard-
ing the biologic activity and unique characteristics of
bone tumors that often aids in the initial diagnosis of the
lesions. Initial staging and local restaging is performed
with techniques such as radiography, CT, and conven-
tional MRI. The entire skeleton can be evaluated for
metastases with bone scan. Modalities such as PET/CT
and whole-body MRI permit evaluation of multiple organ
systems for distant metastases in a single imaging session.
Oncologic imaging can greatly aid the pathologist and
other specialists in the care of cancer patients.
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 C H A P T E R 3 
Molecular Biology of Bone Tumors
CHAPTER OUTLINE
MOLECULAR TECHNIQUES
MOLECULAR BIOLOGY OF BONE FORMATION
MECHANISMS OF MALIGNANT
TRANSFORMATION
During the past two decades, our knowledge of the
molecular events that are responsible for the develop-
ment and progression of many human neoplasms, includ-
ing those that affect the skeleton, has dramatically
improved. This has been made possible by numerous
technologic developments that have contributed to the
understanding of cellular biology and that shed light on
some molecular aspects of the malignant transformation
of cells. The past decade is defined as the postgenomic
era, in which many diseases, including bone tumors, are
beginning to be understood in the context of genome
changes rather than only in relation to individual genes
and their respective pathways. This is due to the comple-
tion of the sequencing of the human genome released to
the public as the so-called reference human genome sequence
in 2004.9,10,23 This accomplishment has altered the land-
scape of biomedical science including medicine and has
changed the environment in which health care is pro-
vided.7,3,20,23,27 It also has accelerated improvements in our
understanding of skeletal physiology as a complex body-
supporting organ and has provided new insights into the
biology of bone tumors.
In this chapter, we focus on some of the most promis-
ing areas of molecular research related to the understand-
ing of the molecular pathogenesis of bone tumors and
that are relevant to their diagnosis, as well as representing
novel, still to be fully explored, therapeutic targets.
The pathogenesis of neoplasia cannot be understood
without basic knowledge of the biology of the cells
involved in the process of transformation. Therefore the
description of the molecular biology of bone tumors is
preceded by a section describing some fundamental tech-
niques used to investigate the function of cells and on the
molecular biology of physiologic bone formation. The
description of both skeletal physiology and the biology
of bone tumors is restricted to a few fundamental aspects
of cell function in physiology and disease. An interested
reader is referred to comprehensive textbooks concern-
ing the biology of the skeleton as well as the biology of
cancer. The two recommended highly respected and
periodically reviewed texts are by JP Bilezikian, et al,
Principles of Bone Biology, and by RA Weinberg, The Biology
of Cancer.
96
ERRNVPHGLFRVRUJ
CELL-CYCLE AND MITOTIC REGULATION
MOLECULAR CONCEPTS OF BONE NEOPLASIA
MOLECULAR TECHNIQUES
The most frequently used techniques to elucidate the
genetic abnormalities discussed here are based on the
extraction and analysis of deoxyribonucleic acid (DNA),
ribonucleic acid (RNA), or proteins. To facilitate the
separation and identification of the genetic material, long
strands of DNA are usually cut with specific restriction
enzymes (endonucleases). Restriction endonucleases are
a unique class of enzymes that recognize specific nucleo-
tide sequences and cut double-stranded DNA at specific
points. These enzymes are used in nearly all gene recon-
struction and gene transfection (gene transfer) experi-
ments, collectively known as DNA recombinant technology
or genetic engineering. The many techniques used to iden-
tify normal or altered components of a genome are
assembled into strategies capable of identifying both the
structural and functional aspects of the genetic element
under the study.
The techniques of modern molecular genetics can
be divided into three main groups: DNA hybridization
techniques, technologies that involve polymerase chain
reaction (PCR), and genomic sequencing with high
throughput genomic profiling. Commonly used terms
and techniques are described in the following paragraphs.
Hybridization Techniques
Hybridization techniques were originally designed to
identify individual components of our genetic material
such as genes and expressed species of RNA such as
mRNA or proteins.11,25 In general, the material is first
separated by gel electrophoresis and transferred to a
membrane; then the specific DNA, RNA, or proteins are
identified with a detection probe. These techniques
involve Southern blotting, in which specific components
of DNA are identified, Northern blotting, in which spe-
cific species of RNA are analyzed, and finally Western
blotting for the identification of specific proteins. These
techniques are described here for historical purposes.
However, today Southern blotting is rarely used, most
often in the identification of the ablated regions of the
genome in the development of genetically engineered
 3  Molecular Biology of Bone Tumors 97

animals. Northern blotting has almost been completely
eliminated from the modern armamentarium of molecu-
lar techniques and has been replaced by more effective
techniques such as PCR and quantitative PCR. On the
other hand, Western blotting remains the most popular
technique used in molecular biology and pathology for
diagnostic clinical workups.
Southern Blotting
Southern blotting is used to identify particular sequences
within genomic DNA. Traditionally, DNA is digested
with restriction endonucleases, and the resulting DNA
fragments are separated by size using electrophoresis
through agarose gels. After in situ denaturation of the
fragments by an alkaline solution or heat, the DNA is
transferred from the gel onto a solid support (nylon mem-
branes, nitrocellulose filters). The relative positions of the
fragments are preserved during this transfer. Subsequently,
the DNA blotted to the solid support is hybridized with
a known, specific DNA or RNA probe with a radioactive
label and is visualized by autoradiography to identify posi-
tions of bands that are complementary to the probe.
Northern Blotting
Northern blotting is used to determine the size and
amount of specific messenger RNA (mRNA). As in South-
ern blotting, the RNA is separated by electrophoresis on
the basis of size using denaturing agarose gels and is
transferred to a solid support (nylon membranes, nitrocel-
lulose filters). The RNA of interest is located by hybrid-
ization with an appropriately labeled DNA or RNA probe.
Western Blotting
Western blotting is used for the immunologic identification
of proteins extracted from tissues or cells. For this proce-
dure, protein extracts are separated by electrophoresis and
then transferred to a solid support and identified with
labeled or unlabeled antibodies that recognize the antigenic
epitopes displayed by the target protein (Fig. 3-1). When

Sample Preparation

Well
Samples
Electrode −

Larger fragments Buffer

Smaller fragments
Gel

Electrode +

Plastic frame

Electrophoresis
A B Transfer

Detection signal
(colorimetric or chemiluminescent)

Enzyme substrate cathode (−)

Enzyme covalenty
attached to 2nd antibody filter papers
Secondary antibody
against primary polyacrylamide gel
Anti-target protein antibody
antibody (IgG) membrane
(primary antiobody)
Target protein
filter papers
anode (+)
Membrane blo
t Membrane Staining
C
Fluorescent Detection
D
FIGURE 3-1  ■  Identification of individual proteins by Western blotting. A, Separation of protein lysates by electrophoresis. B, Western
blotting machine facilitating electrophoresis and membrane transfer. C, Transfer of proteins from polyacrylamide gel to nitrocellulose
membrane. D, Identification of proteins with primary antibodies and colorimetric or chemiluminescent secondary detection antibodies.

ERRNVPHGLFRVRUJ
98 3  Molecular Biology of Bone Tumors

unlabeled antibodies are used, the identification of the
bands is done with a labeled secondary antibody to the
immunoglobulin class of the animal species in which the
first antibody was raised. In general, the Western blotting
procedure depends on three key steps: (1) the separation
of proteins by size using gel electrophoresis, (2) the trans-
fer of separated proteins to a membrane, and (3) the
detection of a target protein by specific antibodies. Typi-
cally, the antibodies used in Western blotting recognize
a short specific linear sequence of amino acids within the
target protein. The target protein is visualized as a band
on a blotting membrane using radiography or an imaging
system with secondary antibodies labeled with chemilu-
minescence or fluoroluminescence. The thickness of the
band or, in general, the staining intensity corresponds to
the amount of the target protein. Western blotting is one
of the most efficient and popular techniques, utilizing
simple equipment and inexpensive reagents.
Polymerase Chain Reaction
PCR is an in vitro technique used to amplify a DNA
segment lying between two regions of known sequences
by using two oligonucleotide primers.5,8 The primers are
complementary to the sequences on the opposite strands
of the target template DNA and flank the DNA segment
being amplified. The reaction mixture contains the four
nucleotides required for DNA synthesis in the presence
of a heat-stable DNA polymerase. The procedure com-
prises three basic steps: heat denaturation of the DNA,
cooling and annealing of the primers to their target
sequences, and extension by a heat-stable DNA poly-
merase (Fig. 3-2). Because the product generated in the
first PCR round serves as the template for subsequent
rounds, an exponential amplification of the DNA segment
of interest may be obtained by repeating the cycles. The
usual amplification level is on the order of 106 after 25 to
30 cycles. Greater amplification (109 to 1011) of DNA
copies may be achieved by repeating the cycles with the
product generated in the first run used as a template
and fresh DNA polymerase. PCR can also be used to
generate amplified DNA from mRNA after initial reverse
transcription.
Real-time reverse transcription polymerase chain
reaction (RT PCR), or quantitative polymerase chain
reaction (qPCR), is based on the concept of standard
PCR and facilitates the quantitative assessment of a tem-
plate DNA (Fig. 3-3). It utilizes fluorescent dyes tagged
to a probe, which anneal to the amplified product; the
signal intensity is proportional to the amount of DNA

A 5’ 3’ B
3’ 5’

Denaturation

p53 exon 9
5’ 3’ 3’ 5’

Size marker
Annealing
5’ 3’ 3’ 5’
Extending
5’ 3’
3’ 5’
Elongation
5’ 3’
x30 3’ 5’

etc

C
T

mutation: CAG TAG (Gln330STOP)

C
FIGURE 3-2  ■  Polymerase chain reaction. A, Schematic drawing showing the design of polymerase chain reaction and exponential
amplification of DNA in each thermal cycle comprising denaturation, annealing, and elongation repeated 30 times with the use of
forward and reverse primers, depicted as forward and reverse arrows. B, Amplified DNA fragments shown on fluorescent electro-
phoresis gel. C, DNA sequence of the PCR fragment shown in B with C-T mutation results in STOP codon.

ERRNVPHGLFRVRUJ
 3  Molecular Biology of Bone Tumors 99

TaqMan being amplified.1,14,29 RT PCR utilizes the standard PCR

Fluorophore Probe Quencher sequence, specific forward and reverse primers, and a
5’ fluorescently labeled probe that provides quantitative
3’
assessment of the template DNA. In general, the inten-
reverse PCR primer sity of the fluorescence emitted during the amplification
cycle correlates with the amount of the DNA that is
amplification assay
Polymerization amplified. Fluorescence intensity increases proportion-
ally to the amplification cycles; after a few initial cycles
5’
3’ it surpasses a threshold level set above the background
and starts to increase exponentially. The Cq value (quan-
Fluorescence Probe displacement tification cycle), which represents the number of PCR
and cleavage
cycles that pass before the threshold is reached, is a
measure of the original template DNA. By comparing the
5’
3’ results of samples of unknown concentration with a series
of standards, the amount of template DNA in the mea-
Result sured sample with unknown concentration can be deter-
Fluorescence mined. RT PCR has wide applications in gene expression
analysis, pathogen detection, and genetic testing. It can
also be performed in a multiplex form, assessing the
PCR Cleavage expression level of many genes.
A products products

Genomic Sequencing
0.3
Exponential phase With the completion of the Human Genome Project, the
Non-
exponential release of the first draft of the human genome sequence
Fluorescence

plateau in 2001, and the final publication of a reference human

0.2 phase genome sequence in 2004, genomics became a main-
stream discipline of biomedical research.9,10 The rapid
Cq value advances in genomic sequencing technologies facilitated
0.1 the ability to sequence the genome of an individual
Threshold line human being in 2008, offering genomic profiling of
tumor samples and their paired germ line DNA to cancer
0
patients.12,16,19,21,24,28 This approach has provided new
0 10 20 30 40
insights into the biology of many diseases, including
B Cycle
cancer, potentially improving human health. Technologic
4,000
development is the driving force of genomics and is
Target responsible for the invention of new methods, reagents,
Relavive Fluorescence

input and instruments.23,24,30 It also inspires the improvement

3,000
2,000
1,000 Baseline Fluorescence
0 NTC
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
C Cycle
FIGURE 3-3  ■  Quantitative polymerase chain reaction. A, Ampli-
fication cycles of the quantitative polymerase chain reaction
(PCR), which utilize the standard forward and reverse primers
and the third fluorescently labeled primers that are used to
quantitate the amplified template DNA. B, The fluorescence
intensity curve during amplification of template DNA. The
number of PCR cycles that pass before the threshold fluores-
cence level is reached (Cq value) reflects the amount of the
original template DNA. C, Fluorescence intensity curves after
titration of the template DNA. The Cq values for each titration
are indicated by the arrows.
108 of efficiency and output, with consistently decreasing
107 costs making genomic profiling possible for individual
106
105 patients (Fig. 3-4). The novel genome sequencing tech-
104 nologies collectively referred to as next-generation sequenc-
103 ing enable assessment of mutations in several hundreds
102 of potential therapeutically targetable genes and are also
101
capable of applying total genome sequencing to indi-
vidual patients. It is predicted that during the next decade
we will witness an unprecedented genomic characteriza-
tion of many human cancers. This will be accomplished
in parallel with a more in-depth understanding of the
biology of our genome and how it functions in a disor-
dered state in cancer development and progression.
Genomic approaches are also anticipated to open novel
avenues for the improvement of cancer therapy and the
overall effectiveness of cancer patient outcomes. The
most advanced genome sequencing technologies are
capable of analyzing the entire human genome sequence
within a few days at reasonable cost (Fig. 3-5). Such
technologies offer the detection of a full spectrum of
genomic abnormalities that include point mutations,
copy number alterations including homozygous and
hemizygous deletions, copy gain, translocation break-
points, and pathogen identification.

ERRNVPHGLFRVRUJ
100 3  Molecular Biology of Bone Tumors

ps
gr of
ou
e e
tiv ag
io se

g
ec av
er

llin
ns a
n
te e b
rim

o t le
g

ca
pr C
in
ex ngl
.p

ag

se
q

Si

Im

Ba
Se
T
G
C
T G
G A
C A
G T
A T
A
T
T

A B
Reference sequence Non-human
Chr 1 Chr 5 sequence
A
c
c
c
c
c
c
c
c
c
c
c
c
c
c
c

Homozygous Hemizygous Translocation

Point mutation Indel deletion deletion Gain breakpoint Pathogen

Copy number alterations

C
FIGURE 3-4  ■  Principles of DNA sequencing using next-generation technologies. A, Illumina 2000 Hi-Seq DNA Sequencer. B, DNA
sequencing with fluorescent chain elongation used in modern next-generation sequencing strategies. The base calling is accom-
plished on the addition of the fluorescently labeled nucleotide pairing the template DNA attached to solid support. C, Types of
genomic alterations that can be analyzed on a total genome scale using genome profiling platforms. (Reprinted with permission from
Meyerson M, et al: Nat Rev Genet 11:685–696, 2010.)

High Throughput Genomic Profiling
The completion of the Human Genome Project and the
knowledge of the complete sequence of our genome
enabled the development of a full roster of high through-
put genomic platforms that facilitate the analysis of
various structural and functional aspects of our genome
both in physiology and disease. They include the single
nucleotide polymorphism-based, high density microar-
rays with which we can assess precisely the copy number
change of specific genomic regions and analyze it on a
global genomic scale.6,15,27 The expression patterns of
genes can be investigated by testing the levels of mRNA
using the cDNA microarray.4,15 Similarly, the expression
levels of various regulatory RNA species such as
microRNA can also be assessed on a total genome scale.22
Finally, the epigenetic modifications of the genome,
including methylation and histone acetylation, can be
analyzed with specific strategies and microarrays.18 The
genomic high throughput platforms are complemented
with proteomic and metabolomic technologies that are
capable of analyzing the expression profiles and status of
metabolic activities in the entire cellular proteome.2,13,17,26
All of these platforms are capable of generating tsunami
waves of data that represent a major analytical challenge
to the health care system in our time.

ERRNVPHGLFRVRUJ
 3  Molecular Biology of Bone Tumors 101

NRAS
FAM46C
FAF1
CDKN2C ANP32E
CKS1B

40

40
120

80

120
0
0

160
DTNB

80
y

200
40
IGL@ 1 DNMT3A

240
x

0
40

0
IGK@

40
0
22

40
MAFB

80
21

0
12
40
2 16
0
40
0 20
0
20
0 0
19 24 ULK4
0
40
TRAK1
Translocation Partner 40
18
800 80
Deleted
3
40 Mutated 120
TP53 17
WWOX 0 Deleted and Mutated 160
80
FGFR3
MAF MMSET
Gained 0
CYLD 40 16
Inherited 40
0
80
80 4
15 120
40
160
IGH@ 0
TRAF3 80 0
14
40
40 DNAH5
0
5 80

120
DIS3 80 13
16
0
40
RBQ1 0
0
0 40
12 6
12 80 CCND3
80
12
40 0
KRAS
0

16
11

0
0
0

CCND2 7
12

40
80

BIRC2 80 DNAH11
40

BIRC3 10 8 CDCA7L
120
0
120

9
0
80

40

BRAF
40

80

CCND1
0

120
120

0
80

40

MYC
FIGURE 3-5  ■  Example of genome sequencing data in multiple myeloma. Circos diagram summarizing the sequencing and copy
number variation data in multiple myeloma. The chromosomes are aligned in a clockwise circle and the key mutations are depicted.
The inner circle shows the copy number change. Solid lines designate the positions and partners for chromosomal translocation.
(Reprinted with permission from Morgan GJ, et al: Nat Rev Cancer 12:335–348, 2012.)

template undergo stepwise differentiation into hyper-

MOLECULAR BIOLOGY tropic chondrocytes.70,73 This maturation process requires
OF BONE FORMATION cessation of proliferation. Hypertropic chondrocytes,
after exiting the cell cycle, die by apoptosis and their
The human skeleton is a complex body-supporting organ cartilage matrix is used as a template for bone formation.
with more than 200 bones adapted to bipedal locomo- This process requires precise zonal orchestration of two
tion. The majority of the human skeleton is formed main cell lineages involved in skeletal development—
by endochondral ossification, which is responsible for chondroblasts and osteoblasts—which are mediated in
growth and patterning of the long bones of the limbs and this process through Indian hedgehog (IHH) signal-
elements of the axial skeleton (Fig. 3-6).60,84 Fewer bones, ing.52,53 In intramembranous ossification, flat bones
predominantly the flat bones and the clavicle, are formed develop directly from mesenchymal condensation and no
by intramembranous ossification.60,84,112 Endochondral interaction with a preformed cartilage template is needed
ossification starts as condensations of mesenchymal cells for bone development. During the past decade, there has
that form cartilaginous templates subsequently remod- been a dramatic development of our understanding of the
eled into bone. The condensation centers have peculiar molecular mechanisms that orchestrate these processes.
zonal patterns of differentiation in which the central The genes and their respective proteins that play a role
component differentiates into cartilage while the periph- in skeletal development can be, in part, used as biomark-
eral cells form perichondrium, which differentiates into ers for differential diagnosis of bone tumors and can
osteoblastic precursors and in the mature phase forms provide new insights, not only into the physiology of
the periosteum. The central components of the cartilage bone, but also on the pathogenesis of bone tumors.

ERRNVPHGLFRVRUJ
102 3  Molecular Biology of Bone Tumors

da

B li
B

li

da

C da

li
D

cm

oc oc

cm cm
ob

A F
FIGURE 3-6  ■  Morphology of tissue undergoing endochondral ossification. A, Light micrograph of the growth plate of an equine
fetus. Labels B-D indicate the regions corresponding to electron micrographs of chondrocytes shown in parts B-D of this figure. The
invading ossification front is seen in the lower part of the image and includes blood vessels (arrowheads) and multinucleated
osteoclasts (oc); arrows indicate the bone matrix being deposited on remnants of cartilage matrix (cm) by a row of osteoblasts.
B-F, Electron micrographs of different cell types seen in part A. Light (li) and dark (da) chondrocytes are seen in the late zone of
proliferation (B), the middle zone of hypertrophy (C), and the last few lacunae before the ossification front, where the cells are dying
(D). E, An osteoclast adherent to a remnant of cartilage matrix, adjacent to an erythrocyte (arrowhead) in a blood capillary. F, Two
osteoblasts (ob) depositing bone matrix (arrows) on a remnant of cartilage matrix. (Bar in A = 50  µm. The magnification for parts
B-D is the same, and the magnification for parts E and F is the same; bar = 10  µm.) (Reprinted with permission from Mackie EJ, et al:
IJBCB 40:46–62, 2008.)

ERRNVPHGLFRVRUJ

Three distinct cell lineages of mesenchymal origin
participate in the formation of the skeleton: osteoblastic,
chondroblastic, and osteoclastic.74,85 These cells cooper-
ate and influence one another in the formation and
remodeling of the skeleton. For example, osteoblasts
produce factors that affect the function of osteoclasts. In
the enchondral ossification model, the formation of car-
tilage matrix is a prerequisite event for osteoid deposition
in the primary spongiosa. Subsequent resorption of the
primary spongiosa by osteoclastic cells is an important
step in bone remodeling and formation of the secondary
spongiosa. Other factors that regulate bone-forming and
bone-remodeling functions of cells are produced in
response to extracellular growth factors and hormonal
stimulation. It is speculated that the osteoblastic cells
participating in intramembranous and enchondral bone
formation may be phenotypically distinct or may even
originate from another sublineage differentiation
pathway.42,64,65,103,107,108 In general, bone development and
its maintenance are regulated by conserved pathways
linked to the interactive network of growth factors, regu-
lated by hormones, their respective receptors, and vita-
mins.36,65 The major hormones and their receptors
involved in regulating bone development include para-
thyroid hormone, parathyroid hormone-like peptide,
thyroid hormones, and steroid hormones as well as
vitamin D.109 In addition to contributing to the develop-
ment of the skeleton, these factors also control bone mass
and bone maintenance during adult life.90,91,100,108,112
The unique capacity of bone for complete structural
and functional renewal depends on the presence of stem
cells that can proliferate rapidly and differentiate into
different bone-forming cell lineages. It is postulated that
the unique ability for renewal is in the bone itself.104,105 A
unique class of matrix polypeptides, collectively desig-
nated as bone morphogenetic proteins (BMPs), is implicated
as potent early inducers of bone formation and cartilage
development, as well as of bone reconstitution after
injury.41,44,46-49,66,77,82,87 BMPs also seem to play a ubiqui-
tous role in skeletal patterning, limb development, and
organogenesis of some nonskeletal structures.55,58,71,72
They show a significant sequence homology to the beta
family of transforming growth factors (TGFs).45-49,51,67
Osteoblastic Lineage
Osteoblastic lineage cells, as they participate in bone
production, are separated into several distinctive sub-
groups on the basis of their gene expression patterns,
ability to produce extracellular matrix, and their relation-
ship to bone (Fig. 3-7). The development of osteoblastic
lineage cells and bone production are regulated by
a complex cascade of growth factors, which are graphi-
cally depicted in Figure 3-8.37,38,53,60,61,63,68,69,100,112 Skeletal
progenitor cells that co-express SOX9 and RUNX2
are not fully committed to osteoblastic lineage.56,83 It
appears that the osteoblastic lineage fate in the early
phases of lineage commitment is controlled by the tran-
scription factor Osterix/SP7.54,81,107,110 It belongs to a
super family of Kruppel-like zinc-finger transcription
factors and is expressed at high levels in osteoblasts. Low
levels of Osterix/SP7 are also found in prehypertrophic
ERRNVPHGLFRVRUJ
3  Molecular Biology of Bone Tumors 103
chondrocytes. The expression level of Osterix is con-
trolled by RUNX2 and is stimulated by interaction with
the nuclear factor of activated T-cells (NFAT). RUNX2
is required in early phases of osteoblastic progenitor cells
and is downregulated in mature osteoblasts. The activity
of RUNX2 is enhanced by multiple factors such as
SATB2, ATF/CREB family members, and is reduced by
DLX3 and MSX2. The transcription factors SP3 and
ATF4 play a role in the late phases of osteoblastic dif-
ferentiation. ATF4 is expressed at high levels in osteo-
blasts because of its inhibited proteasomal degradation.
The activation of osteoblasts is also modified by phos-
phorylation of ATF4 by the kinase RSK2 and interaction
with SATB2. Finally, the matrix production of osteoblasts
is likely controlled by FRA1. Osteocalcin gene upregula-
tion is a feature of late osteoblastic and osteocytic dif-
ferentiation. Similar patterns of expression in association
with later stages of osteoblastic differentiation are seen
in reference to osteopontin, galectin-3, and CD44. The
production of collagen type I starts with the onset of dif-
ferentiation and increases with the cell’s progression to a
mature osteocytic state.
In summary, there is a reciprocal relationship between
two distinct groups of genes that predominantly act on
one another in a proliferative and postmitotic differenti-
ated stage. The high levels of histone proteins and other
genes related to the proliferative stage gradually approach
residual constituent levels or are completely suppressed
with the onset of osteoblastic differentiation (see the
section in this chapter on cell-cycle regulation). One of
the earliest events that signifies the onset of osteoblastic
maturation is the upregulation of collagen type I genes,
followed by the upregulation of alkaline phosphatase and
matrix GLA protein. High levels of osteopontin, osteo-
calcin, and collagenase are characteristic of the mineral-
ized phase of osteoblastic differentiation.
Chondroblastic Lineage
A number of ubiquitous growth factors have been
shown to mediate early phases of skeletal development.68,84
Their role in the regulation of skeletal growth and
cartilage formation is graphically depicted in Figure
3-8.61,69,73,76,78,80,82,99 One of the transcription factors that
acts very early and is responsible for rescuing of pluripo-
tential mesenchymal cells into skeletal progenitor cells is
SOX9.83,107 SOX9 is a member of the SOX gene family
of transcription factors characterized by high-mobility-
group box DNA binding motif showing homology with
sex determining factor SRY. Skeletal progenitor cells
with upregulated SOX9 and RUNX2, a Runt domain
transcription factor, are capable of bimodal differentia-
tion into chondrocytes and osteoblasts. The chondro-
blastic fate of the skeletal progenitor cells is ensured by
direct interaction of SOX9 transcriptionally inhibiting
RUNX2 and indirectly by the repression of NKX3.2/
BAPX1. Collective in vitro and in vivo evidence indi-
cate that SOX9 activity is required for chondrocyte dif-
ferentiation, but it requires cooperation with additional
transcription factors such as PAX1 and PAX9, paired-box
family members, and NKX3-2 and NKX3-1, homebox
family members. In addition, such transcription factors as
104 3  Molecular Biology of Bone Tumors

Multipotential
stem cell
Progenitors
Unlimited of other
renewal mesenchymal
cells

Limited
Osteoprogenitor
renewal
cells

Limited
proliferation Preosteoblasts

Mature osteoblasts
Bone-lining cells

Osteoblasts

Osteoid

Osteocyte
Limited
proliferation

FIGURE 3-7  ■  Differentiation of osteoblastic cells. Stages of differentiation and their location imply phenotypically recognizable
phases of osteoblastic lineage cells that originate from multipotential mesenchymal stem cells and, through osteoprogenitor and
osteoblastic cells, result in formation of mature osteocytic or bone-lining cells.

RUNX1, DLX5, and DLX6 as well as BARX2 have been
implicated in chondrocyte differentiation. SOX9 has been
shown to control expression of important cartilage matrix
proteins, including COL2A1, COL9A1, COL27A1,
and matrilins. Cooperation with additional SOX family
members such as SOX5 and SOX6 are required to dif-
ferentiate chondroblasts into early chondrocytes. The
development of fully matured cartilage requires matu-
ration of chondroblastic/early chondrocytic cells into
prehypertrophic and hypertrophic chondrocytes. This
process is again mediated by SOX genes, which further
signifies their central role in cartilage development. Mat-
uration into hypertrophic chondrocytes is accomplished
through NKX3-2 mediated downregulation of RUNX2
and the β-catenin/TCF complex. Downregulation of
RUNX2, IHH, and FGFR3 plays a role in the timing of
the chondrocyte hypertrophic stage. Multiple regulatory
loops control the sequential suppression of these factors
via the helix-loop-helix transcription factor, TWIST1,
and other cofactors, such as GRG5, HDAC4, DLX5,

ERRNVPHGLFRVRUJ
 3  Molecular Biology of Bone Tumors 105

Resting Proliferating Hypertrophic

chondrocyte chondrocyte chondrocyte Chondroclast Woven bone Blood vessel Periosteum
Lamellar
Cartilaginous Calcified bone
matrix cartilage Osteoblast Osteoclast

MMP9

VEGF

ANG1

PTC SMO PTHR PTHR

FGFR3 FGFR2
IHH LRP5

PTHrP FGF18 PTH PTHrP FGF18

WNT

RANK
OPG
RANKL

Primary spongiosa Secondary spongiosa

A
ATF4 FIAT

Sox8 HDAC3,7
SATB2

Osterix Runx2 Fra1 ATF4 Runx2 Sp3

Sox8 TWIST HDAC3,7

Dlx5
Runx2
Msx2 osteoprogenitor committed immature mature
osteoprogenitor osteoblast Msx2 osteoblast
osteocyte
MSX2nc Sox9 Sox9+
Runx2+

skeletal
precursor Sox9 GRG5 HDAC4
mesenchymal SOX9 Sox5/6
Pax1 Sox9
cell Runx3
Pax9 L-Sox5
Nkx3.1 Sox6 Atf2 -CATENIN Runx2 Runx2c Mef2 cMaf
Runx2 Fra2
Nkx3.2 Dlx5/6
Dlx
D 5/6
Nkx3.2

Sox9 chondroblast chondrocyte prehypertrophic Fgf18

F hypertrophic mineralized
Msx2 chondrocyte chondrocyte hypertrophic
p chondrocyte
Sox5, Sox6 Runx2
B
TWIST
FIGURE 3-8  ■  Molecular regulation of endochondral bone formation. A, Selected molecular regulations and their zonal effects stimu-
lating bone growth through endochondral bone formation. (A, Reprinted with permission from Goltzman D: Nat Rev Drug Discov
1:784–796, 2002.) B, Schematic summary of the activities of the most important transcriptional factors involved in differentiation
and maturation of the osteoblastic and chondroblastic cell lineages. Positive influences are indicated by green arrows and positive
factors are labeled in green. Negative influences are indicated by blunted red lines and negative acting factors are labeled in red.
(B, Reprinted with permission from Hartmann C: Curr Opin Genet Dev 19:437–443, 2009.)

ERRNVPHGLFRVRUJ
106 3  Molecular Biology of Bone Tumors
and DLX6. Additional factors such as MSX2, MEF2C,
MEF2D, and FRA2 are likely involved in the regulation
of the chondrocyte hypertrophic phase. Terminal matu-
ration and progression to apoptosis is not fully under-
stood at this time but appears to be regulated by the
leucine zipper protein c-Maf. Chondrocytic cells express
the genes such as collagen type II (COL2A1) that are
responsible for the formation of the cartilage matrix and
the genes that contribute to the formation of the primary
proteoglycans in the matrix, which are aggrecan, decorin,
biglycan, and fibromodulin.50,52,57,98 These glycoproteins
are responsible for the osmotic properties of the matrix
and its interaction with collagen II fibers, and provide
the matrix with structural integrity.43,62,76,79,88 Extracellular
matrix synthesis is in part regulated by C-type natriuretic
peptide (CNP) and the MAPK pathway of fibroblast
growth factor (FGF) signaling.64,111
Osteoclastic Lineage
Orchestration of skeletal development requires not only
bone production, but also resorption of mineralized
matrix to achieve functionally optimal patterning of indi-
vidual bones.40,86,87 The cells in bone that perform this
function and are capable of resorbing mineralized matrix
are multinucleated osteoclasts (Fig. 3-9). It is generally
accepted that osteoclasts develop by means of a differen-
tiation pathway distinct from that of osteoprogenitor and
cartilage progenitor cells. Numerous experimental data
indicate that osteoclasts are derived from hematopoietic
precursor cells present in the bone marrow, spleen, and
peripheral blood.91-93,102 They have a common differentia-
tion pathway with macrophages and develop distinct phe-
notypic features in the final steps of their maturation.
These cells, in response to chemotactic stimulation,
migrate to areas of exposed matrix where the bone lining
cells have retracted and form sealing zones on the matrix
by interactions of αvβ3-integrins with matrix proteins.
Three of these receptors—, αvβ3 (fibronectin receptor),
α2β1 (collagen receptor), and αvβ1—are essential for
adherence and subsequent bone resorption. Osteoclasts
secrete acid to the sealed pockets on the surface of bone
to dissolve the mineralized matrix and protein degrading
enzymes to disintegrate exposed matrix proteins. These
functions are performed in a specialized apical cell mem-
brane surface referred to as a ruffled border. Only a few
biochemical reactions can solubilize mineralized deposits
of the bone matrix (i.e., hydroxyapatite), and for these
reactions to proceed, the environment must be acidic
(low pH).60,106 In fact, sealed bone lacunae are acidic and
reach this state by a V-type proton pump that uses ade-
nosine triphosphatases (ATPases) that operate in the
ruffled border of osteoclasts. The levels of these enzymes
are extremely high in activated osteoclasts. It can be envi-
sioned that without the sealing of the resorptive lacunae,
the proton pump is very unlikely to be effective in
lowering the pH; thus solubilization of the mineral
cannot be accomplished. After solubilization of the inor-
ganic component, the remaining protein material is
degraded with the use of multiple proteolytic enzymes
such as collagenases, lysosomal proteinases, and cathep-
sins. There is evidence that osteoclasts can go through
ERRNVPHGLFRVRUJ
several activation-resorption cycles. It is speculated that
cessation of bone resorptive activities must be accom-
plished by programmed cell death (apoptosis).
Surprisingly, receptors that mediate osteoclastic for-
mation are present on osteoblastic cells.39,75,86,90-96,101
It appears that interaction with mesenchymal cells is
important for early deposition for osteoclast progenitor
cells.97 Three major signal transduction pathways,
involving cyclic adenosine monophosphate, gp130, and
1,25-dihydroxyvitamin D3 [1,25(OH)2D3], are present
in the plasma membrane of osteoblasts and mediate
the formation of osteoclastic cells.75,86,106 These major
transduction pathways mediate the formation of osteo-
clasts in response to various extracellular factors (Fig.
3-9).31-35,59,89,90,94-96 Therefore the destruction of bone can
proceed only in the presence of bone-forming cells (i.e.,
matrix lysis occurs only when restoration or remodeling
of the structures is securely under way).
Osteoclasts are derived from mononuclear precursors
that are of monocyte or macrophage hematogenous
origin.40,60,91-93,106 These cells can proliferate and fuse to
form multinucleated osteoclasts. The transcription factor
PU.1 is essential for macrophage and osteoclast precur-
sor commitment to osteoclastic lineage. In addition, such
transcription factors as c-Fos, NFκB, and microphthalmia-
associated transcription factor are essential for the matu-
ration of osteoclasts. The cell-bound cytokine RANKL
plays an essential role in activating the osteoclastic
lineage. RANKL is a member of the tumor necrosis
factor family and interacts with its receptor RANK. Che-
motactic stimulation of bone resorption is mediated via
osteoblastic stromal cells, which can enhance RANKL
expression. On the other hand, interferon-γ primarily
produced by T-lymphocytes inhibits RANKL by causing
degradation of the RANK-adapter protein TRAF6
resulting in activation of NFκB and the kinase JNK.
MECHANISMS OF MALIGNANT
TRANSFORMATION
Among the more than 100 transforming and tumor sup-
pressor genes that have been identified, only a few have
been shown to play a significant role in the biology of
human neoplasia, including that of bone cancers.165,197,226
The process of tumorigenesis is initiated by mutations
that affect the so-called gatekeeping pathways, which
provide growth advantage.238 This process may represent
a single event or an acquisition of multiple alterations in
a sequence. Many of these initiating events were identi-
fied by studies that examined families with unique pre-
dispositions for certain tumor types. In many solid human
tumors such initiating events are still unknown. In this
section, we discuss the biologic significance of a few
tumor suppressors and oncogenes that play a potential
role in the development of bone cancers. Thus the RAS
family of genes, TP53 genes, genes of the so-called
p53regulatory pathway, and the retinoblastoma (RB) gene
seem to play roles in the biology of many human neo-
plasms. In addition, in this section we describe the role
of helicases in several bone cancer predisposing syn-
dromes, as well as the molecular biology of chromosomal
 3  Molecular Biology of Bone Tumors 107

PTH IL-6 + sIL-6R

PGE2 IL-11
1α,25(OH)2D3 IL-1 (PGE2) OSM
LIF

Cell membrane
of osteoblasts

Adenylate
cyclase

gp130
1α,25(OH)2D3 receptor cAMP ATP
(VDR)

Osteoclastic
differentiation
factors

Osteoclasticc
precursor

Osteo lasts
Osteoblasts
Integrins’
Osteoclast
A receptor
N
N

N CO2 + H2O
Golgi
ATP
CAll*
ADP
Secretory Primary
vesicle lysosome H+ + HCO3-
Cl- Ruffled
*αγβ3-integrins* border

Cl-
Metallo-
proteinases Cysteine
proteinases H+
(cathepsin K)*,
phosphatases

Matrix proteins and hydroxyapatite

Bone

B
FIGURE 3-9  ■  Osteoclast differentiation and action. A, Three major signal transduction pathways that mediate formation of osteo-
blastic cells are present in cell membrane of osteoblastic cells. These pathways involve vitamin D receptor (1α,25[OH]2D3 receptor)
adenylate cyclase and cyclic adenosine monophosphate pathway and the gp130 protein. Pathways respond to variety of extracel-
lular signals that include 1α,25(OH)2D3; parathormone (PTH); prostaglandins (PGE2); IL-1, IL-6, and IL-11; and oncostatin M (OSM)
and leukemia inhibitory factor (LIF) factors. Bone lysis is mediated by integrin type receptors that seal bone resorptive lacunae. Bone
mineral is solubilized by V-type proton pump operating in ruffled border of osteoclastic cells. (A, Adapted from Suda T, et al: Cells
of bone: osteoblast generations. In Bilezikian JP, Raisz LG, Rodan GA, editors: Principles of bone biology, San Diego, 1996, Academic.)
B, Multinucleated osteoclasts (N) adhere to bone through αvβ3-integrins. Carbonic anhydrase II (CAII) can generate H+ and HCO−3.
HCO−3 is extruded in exchange for Cl− at the basolateral membrane. H− can be secreted through an H+-ATPase on the apical mem-
brane (ruffled border) into the resorption space and Cl− is secreted through a Cl− channel. HCl will dissolve matrix mineral. Phos-
phatases and cysteine proteinases—notably cathepsin K—will be released from lysosomes and degrade matrix proteins.
Metalloproteinases that are released from secretory vesicles will also degrade matrix proteins. Asterisks (*) indicate potential sites
for the inhibition of osteoclast action. (B, Adapted and reprinted with permission from Goltzman D: Nat Rev Drug Discov 1:784–796, 2002.)

ERRNVPHGLFRVRUJ
108 3  Molecular Biology of Bone Tumors
translocations that play an important role in the develop-
ment of many sarcomas. Finally, we address the possible
role of a novel mechanism of cancer development referred
to as chromothripsis that may play a role in the develop-
ment of a significant proportion of such important bone
tumors as osteosarcoma and chordoma. Several lines of
evidence indicate that fully developed malignant pheno-
types result from the disruption of distinct regulatory
circuits. These acquired capabilities of cancerous cells are
signified by the following key functional characteristics:
(1) self-sufficiency in growth signals, (2) insensitivity to
antigrowth signals, (3) tissue invasion and metastases, (4)
limitless replicative potential, (5) sustained angiogenesis,
and (6) evasion of apoptosis.156,157
RAS Genes
The human RAS gene family (Ha-ras, Ki-ras, and N-ras)
has served as a prototype of cellular genes whose muta-
tions, overexpression, or both, can lead to malignant
transformation (Fig. 3-10). These genes encode a group
of closely related 21 kDa proteins (p21) that belong to a
super family of proteins that bind guanine nucleotides
with high affinity and have guanosine triphosphatase
(GTPase) activity.116 The genes encoding these proteins
map to chromosomes 11, 12, and 1, respectively. The
proteins encoded by these genes have a high degree of
homology and differ primarily in their hypervariable
anchoring region. These proteins are bound to the cyto-
plasmic surface of the cell membrane and serve as trans-
ducer molecules for signals that affect cell proliferation
and differentiation. Two mechanisms have been proposed
for RAS genes to transform cells. One involves a single
nucleotide mutation in the coding sequence that occurs
most frequently at codon 12, 13, 59, or 61.120,141,149,213,233
This alteration results in an amino acid substitution of
the gene product p21 that affects the GTP binding
domain and reduces its GTPase activity. The second pos-
sible mechanism involves overexpression of the normal
RAS gene product. There is evidence that overexpression
of an altered RAS gene product may play a role in the
biology of some human tumors.
It has been shown that introns play a regulatory role
in the function of RAS genes. The DNA sequence around
nucleotide 2719 within intron D functions as an alterna-
tive splicing site.126,127,130 It suppresses gene expression by
destabilizing the transcript and causing it to enter a non-
productive pathway. From the functional point of view,
the intron D splicing-recognition sequence acts as a neg-
ative regulatory element by suppressing gene expression
and presumably protecting the cell from the eventual
transforming activity of the mutated (altered) gene
product. As a result of the alternative splicing pathway, a
minimal amount of a different gene product, 19 kDa
(p19), may be produced. It is possible that this protein
acts as an antioncogene and protects the cell from the
effects of the oncogene. Hence Ha-ras appears to repre-
sent a gene capable of encoding two antagonistic prod-
ucts: one with transforming capability and the other
with antioncogenic (tumor suppressor gene) activity. A
mutation at position 2719 of intron D (A–T point muta-
tion) abolishes the alternative splicing pathway and its
ERRNVPHGLFRVRUJ
regulatory role, causing overexpression of p21 and sig-
nificantly increasing transforming efficiency. Thus a
mutation at position 2719 of the Ha-ras gene intron is
analogous in function to that of a strong promoter-
enhancer in that it causes overexpression of the gene
product. Although point mutations at coding sequences
alone are not essential for transformative activity, their
presence enhances the transforming efficiency of overex-
pressed RAS gene products.
Ras proteins bind GDP molecules in their inactive
state and release the bound GDP molecules after being
stimulated by the upstream regulatory partners and
absorb GTP molecules.243 The GTP bound state is
an activated configuration, and the molecule emits a
signal activating its downstream regulatory partners. The
active GTP binding state is transient and the protein
cleaves the bound GTP using its intrinsic GTPase func-
tion and returns to an inactive nonsignal emitting state
(Fig. 3-11).
The mutant Ras proteins were found to have lost the
GTPase activity, abolishing its ability to return to the
inactive state. In such conditions, the proteins can be
pushed to their signal emitting active states by the
upstream regulatory partners, hyperactivating the down-
stream pathways.
It is evident that Ras-regulated signaling pathways are
cascades of kinases that represent three important down-
stream signaling pathways (Fig. 3-11).243 The main and
originally discovered pathway is the Ras-Raf-MAP kinase
pathway. It represents a signature kinase signaling cascade
referred to as the mitogen-activated protein kinase (MAPK)
pathway. The activation of this pathway upregulates the
so-called immediate early genes encoding such transcrip-
tion factors as Fos and Jun. Together, these proteins form
the AP1 transcription factor, which is activated in many
human tumors.
The second Ras-regulated pathway governs inositol
lipids and Akt/PKB kinase. In this instance, the Ras pro-
teins activate phosphatidylinositol 3-kinase (PI3K) result-
ing in downstream activation of Akt and Rho guanine
nucleotide exchange factor (RhoGEF), which results in
the stimulation of several important downstream path-
ways that affect cell proliferation and apoptosis, including
mTOR.
The third Ras-regulated downstream pathway involves
RalGEF, which includes the distant cousins of Ras pro-
teins referred to as Ral-A and Ral-B. Similar to the pro-
totypic Ras proteins, activation of Ral proteins involves
the GDP-GTP switch. The activated Ral-A and Ral-B
upregulate multiple downstream partners, including
Sec5 and Exo84, which promote anchorage-independent
growth.
Activation of RAS genes by point mutation occurs in
approximately 15% to 20% of some common epithelial
malignancies.116,118,149 Rearrangement of RAS genes has
been sporadically identified in some soft tissue sarcomas.
In general, activation of the RAS gene by point mutation
occurs relatively infrequently in human cancers and espe-
cially in bone sarcomas, but it plays a major role in the
development of gastrointestinal malignancies, especially
colon cancer.141,211 Experimental transfection of the RAS
gene suggests that activated RAS genes can alter the
 3  Molecular Biology of Bone Tumors 109

Chr 12
13.3 13.2
KRAS
13.1

Exon1

Exon2

Exon3
Exon4

Exon5

Exon6
12.3

cds
12.2 12.1
11.2 KRAS
11 11.1
12
13.1
13.3 13.2

11
14
15 KRAS

18
21.1

6
21.2
21.3

6
24.902

132
22

6
4.365
23

497

133
25

24

28

15
12
24.1
6

4
5

5
5

5
24.2
24.31 24.32
24.33
188/9 aa
A 1

Chr 11
15.5
HRAS
15.4
HRAS
15.3
Exon1

Exon2

Exon3

Exon4

Exon5

Exon6
15.1 15.2

cds
14
13
12
11.2
11.11 11.12
11
12
13.1
13.2
13.4 13.3
13.5
HRAS
237
423

402

14.1
26

4
14.2
14.3
5

21
22.1 22.2
22.3
23.1
23.2
23.3 1 188/9 aa
24
25

NRAS
Chr 1
Exon1

Exon2

Exon3

Exon4

Exon5
Exon6

Exon7
cds

36.3
36.2
36.1
35
34.3
34.2
34.1
33
32.3
4

32.2
NRAS
4
4

32.1
31.3
2287

31.2
877
424

13

31.1
5
9

5
5

22.3
22.2
22.1
21 1 188/9 aa
13.3
13.2
13.1
11
NRAS Small GTP binding protein domain 1-159
12
11 P-loop containing nucleoside triphosphate hydrolase domain 3-164 Linker
12 Ancor
Hypervariable region 165-188/9
21.1
21.2
21.3 Missense substitution
22
23
Nonsense substitution - Stop K-ras KKKKKKSKTK
KKKKKKS CVIM
24 Insertion inframe H-ras GCMSCK
C C CVLS
25 Deletion inframe
Insertion frameshift N-ras GCMGLP
C CVVM
31 Deletion frameshift
Complex - deletion inframe CAAX
32.1
32.2
Unknown motif
32.3 Substitution - coding silent
41
42.1
Complex - frameshift
42.2
43
42.3 Complex - compound substitution
44 Complex
C
FIGURE 3-10  ■  Chromosomal location, exonal structure and functional domains of the RAS genes. A, Chromosomal location and
exonal structure of the K-ras gene. The functional domains of the encoded protein and the distribution of mutations are shown.
B, Chromosomal location and exonal structure of the H-ras gene. The functional domains of the encoded protein and the distribu-
tion of mutations are shown. C, Chromosomal location and exonal structure of the N-ras gene. The functional domains of the
encoded protein and the distribution of mutations are shown.

ERRNVPHGLFRVRUJ
110 3  Molecular Biology of Bone Tumors

upstream stimulatory
INACTIVE signal and Ras activation
GTP triggered by GEF
hydrolysis Ras
Switch I and Ras Pi
inactivation
induced GDP GEF
by GAP

GAP GTP

GDP

Switch II
blockage
caused by Ras
oncogenic
mutation GTP downstream
A B C signaling
ACTIVE

Ras

GTP

PI3K Raf (MAPKKK) Ral-GEFs

PIP3
MEK (MAPKK) RalA RalB

Akt/PKB Rho-GEFs
Erk1 or 2 (MAPK)
Sec5 Exo84 RalB

Cdc42 Rac
Bad mTOR GSK-3β FOXO Msk1 RSK Mnk1 Ets Elk-1 SAP-1
inhibition
of apoptosis stimulation stimulation cell-cycle chromatin
of protein of cell progression; remodeling (transcription) filopodia lamellipodia
synthesis proliferation inhibition of
(cell growth) apoptosis elF4E
(protein synthesis)
D
FIGURE 3-11  ■  The structure and biologic effects of the Ras protein. A, The ribbon diagram of the structure of a Ras protein as
determined by x-ray crystallography as it interacts with the guanosine 5′-triphosphate (GTP) molecule. The α-helical part is in red
and β-pleated polypeptide is in green. The GTP molecule is shown as a stick figure and the two amino acid residues that are often
mutated (glycine 12 and glutamine 61) are highlighted. B, The substitution of GDP by GTP resulting in the activation of RAS signal-
ing causes a conformational shift in the two regions of the Ras protein that interact with the GDP-GTP molecules. The conformational
shift activating the protein is indicated by the magenta arrows. The shift facilitates the interaction with the downstream effectors
activating the pathways. (A and B, Courtesy of A. Wittinghofer.) C, The Ras signaling cycle shows that the Ras proteins operate as
switches binding GDP (inactive state) and GTP (active state) in which they emit signals activating the downstream effectors. The
inactive GTP binding protein is stimulated by GEF (guanine nucleotide exchange factor) and they release the GDP in exchange for
a GTP. The active state is very transient and the signaling is halted by the GTPase activity intrinsic to the Ras protein, which hydro-
lyzes GTP to GDP. The GTPase activity is stimulated by GTPase activating proteins (GAP). D, The signaling pathways activated by
the Ras protein. The Ras-Raf-MAP kinase pathway, depicted in pink, represents the main signaling cascade activated by the Ras
proteins. In addition, the two alternative kinase pathways, referred to as the PI3 and Ral pathways, depicted in lavender and blue,
respectively, are shown. (C and D, Modified and reprinted with permission from Weinberg RA: The biology of cancer, 2d ed, New York,
2014, Garland Science.)

tumorigenicity of osteosarcoma cells.119,121 The increased TP53 Gene

tumorigenicity of Ras-transformed osteosarcoma cells
may be related to the activation of metalloproteinases.
Analysis of a larger series of human osteosarcoma, chon-
drosarcoma, and Ewing’s sarcoma indicates that the acti-
vation of RAS genes by point mutation does not play a
major role in the pathogenesis of these tumors.114 On the
other hand, upregulation of Ras regulatory pathways is a
common event in many human tumors, including bone
cancers.
The TP53 gene, located on the short arm of chromosome
17, has been a constant source of fascination since its
discovery more than two decades ago (Fig. 3-12).186,193
The gene product was originally identified as a 53 kDa
nuclear phosphoprotein in cells transformed by simian
virus 40 (SV40).186 The protein formed a complex with
the large T antigen of SV40, suggesting that this interac-
tion was important for transformation. The insights

ERRNVPHGLFRVRUJ
 3  Molecular Biology of Bone Tumors 111

TP53
Chr 17

Exon 10

Exon 11
Exon 1

Exon 2
Exon 3
Exon 4

Exon 5
Exon 6

Exon 7
Exon 8
Exon 9

cds
13 TP53
12
11.2
11.1 11.1
11.2
12
21.2 21.1
21.3 P53
22
1 393 aa
23
24
6 29 94 297 318 359
25 p53 transactivation domain
p53/RUNT-type transcription factor, DNA-binding domain
A p53, tetramerisation domain

C termini
Checkpoint kinases

ATP ADP
Mdm2 P
P
p53 p53
Tetramerization domain
Degradation
P P
P P

Flexible linker region p53 p53

Core domains DNA

Cdk p21 Puma

inhibitor
Inhibits

Cdk
Bcl-2
Cyclin
N termini (TAD) Cannot Cannot
with bound Taz2 phosphorylate inhibit
Rb protein apoptosis

B
CELL CYCLE APOPTOSIS
(arrest) (cell death)

C
FIGURE 3-12  ■  The structure and biologic effects of the TP53 gene and its encoded protein. A, Chromosomal location, exonal struc-
ture, and functional domains of the encoded protein of the TP53 gene. B, Model of a full length p53 protein forming the ternary
complex with cognate DNA. The p53 DNA-binding domains are shown in blue and green, and the tetramerization domain is shown
in red. (B, Modified and printed with permission from Joerger AC, et al: Cold Spring Harb Perspect Biol 1–20, 2010.) C, p53 DNA-binding
motif. (C, Modified and printed with permission from Smeenk L, et al: Nucleic Acids Res 36:3639–3654, 2008.) D, p53 regulatory pathway.

concerning the function of p53 in cellular physiology and
malignant transformations were provided by two main
lines of investigation. The first group of studies involved
the biologic effects of altered (mutant) TP53 gene in
model organisms and tumor cells grown in culture. The
second group of studies concerned biochemical and
structural analyses of the p53 protein. It was shown that
the transforming activity of TP53 is related to gene point
mutations and that the mutated protein has a much
longer half-life than the wild-type gene product. More-
over, it was established that the wild-type protein
acts more like a tumor suppressor gene, negatively regu-
lating the cell cycle by loss of function, gain of a new
function, or both capacities to perform its transforming
activity.143,188 Because of the gain of a new function, the
gene can act in the heterozygous state and does not
require allelic deletion for its transforming activity. p53
is a DNA-binding protein and a transcription activator
factor capable of inducing so-called p53-dependent genes.186
Biochemical and structural analyses of the p53 protein
showed that it functions as a transcription factor that
exists in normal cells as a homotetramer (Fig. 3-12).170
Chromatin precipitation studies have revealed that it
binds to a specialized DNA sequence. It appears that
there are more than 1500 p53 binding sites in the human
genome, confirming that p53 in both cell physiologic
and malignant stages can control the expression of a
vast of genes capable of significantly modifying cell

ERRNVPHGLFRVRUJ
112 3  Molecular Biology of Bone Tumors
behavior.191,224 Because a mutant p53 protein frequently
acts in a heterozygotic state, it is very likely that tetra-
meric complexes contain a mixture of mutant and wild-
type polypeptide subunits.
It is evident that, under normal conditions, the p53
protein is unstable and cells have to continuously synthe-
size new molecules at a high rate and degrade them with
the same efficiency. The system permits a rapid increase
of p53 by simply blocking its degradation. In normal
cells, the p53 protein level is controlled by a complex
system in which MDM2 plays an essential role. The p53-
MDM2 complex triggers the degradation of p53 by ubiq-
uitination. This identifies an alternative mechanism of
p53 loss of function by hyperactivated MDM2, which is
frequently amplified and overexpressed in sarcomas.
Another mechanism that affects MDM2 has been identi-
fied by the discovery of a gene that is antagonistic to
MDM2 termed p16INK4A.139,222 The upstream promotor
and alternative splicing program of the p16INK4A produces
a different protein referred to as p19ARF and in humans
p14ARF, which acts as a strong inhibitor of MDM2. Over-
expression of ARF by inhibiting MDM2 increases p53
levels. Conversely, the mutations involving the p16INK4A
locus, observed in many human tumors, represent another
mechanism contributing to the p53 loss of function.
Phosphorylation of the MDM2 binding domain is yet
another mechanism controlling the p53 protein levels
which is mediated by a number of kinases including the
family of Aurora kinases. These mechanisms position the
p53 protein and its function centrally in controlling cell
survival, proliferation, genetic stability, and differentia-
tion signifying its key role in malignant transformation.
The mutations that change the properties of TP53 are
usually missense substitutions.163,239 They are clustered in
one particular region of the gene product located between
amino acids 130 and 290 and mainly in the residue of
amino acids 117 through 142, 171 through 181, 239
through 258, and 270 through 286.186 These regions are
highly conserved among species and are most likely
important to the normal function of TP53. The human
TP53 gene is located on chromosome 17p13.1, and muta-
tions have been documented in a wide range of tumors.
Loss of heterozygosity of the TP53 locus has been found
in many human cancers. Therefore TP53 most likely
contributes to human carcinogenesis when its normal
allele is deleted or inactivated. The transforming activity
in the heterozygous state can be the result of the forma-
tion of an oligomeric complex between mutant and wild-
type TP53. It has been shown that in cells transformed
with the mutant TP53 gene, the altered protein com-
plexes with endogenous TP53, and the complex remains
in the cytoplasm.192 In general, mutations affecting dif-
ferent portions of the gene may result in the formation
of the gene product with distinct biologic activity.155
Mutated TP53 genes can cooperate with RAS genes to
transform primary cultured fibroblasts in the presence of
endogenous wild-type p53 protein. Because deletions of
chromosome 17 loci may occur simultaneously with
other chromosomal abnormalities in certain human
tumors, it has been suggested that the TP53 mutation is
a late event during carcinogenesis. Germline transmis-
sion of TP53 mutations has been described in certain
ERRNVPHGLFRVRUJ
cancer-prone families, especially those with Li-Fraumeni
syndrome. The functional domains of TP53 and the dis-
tribution of mutation sites in human tumors are shown
in Figure 3-12.
The TP53 gene is one of the most frequently altered
genes in various human cancers.201 In various common
epithelial malignancies, its overexpression being associ-
ated with an altered gene can be documented in up to
50% of cases. It is typically associated with a more aggres-
sive variant of the tumor. The altered gene, overexpressed
p53 protein, or both are frequent findings in osteosar-
coma and chondrosarcoma.122,135,136,211,237,245 Mutations of
the TP53 gene are infrequently present in Ewing’s
sarcoma, and its role in the pathogenesis of this tumor
and its clinical significance are not well established.176,178
Overexpression or alterations of p53 can be documented
in approximately 30% of high-grade conventional osteo-
sarcomas. As in epithelial malignancies, altered TP53 is
associated with highly aggressive variants of osteosar-
coma.212 In a small percentage of cases, alterations of
TP53 are associated with the amplification of the MDM2
gene.189,198 The amplification of the MDM2 gene is more
frequent in metastatic osteosarcoma.180,198
Alteration of the TP53 gene and overexpression of
p53 protein can be documented in approximately 30%
of conventional chondrosarcomas of bone. It is pre­
dominantly present in high-grade, clinically aggressive
tumors.136 It can be identified in a majority of grade 3
tumors and in approximately half of grade 2 tumors. In
chondrosarcomas, the presence of altered TP53 or over-
expression of its protein is accompanied by allelic dele-
tions in the TP53 locus. In chondrosarcoma, the presence
of altered TP53 correlates with an aggressive clinical
variant (high propensity for metastases as well as shorter
disease-free and overall survival times). The presence of
p53 overexpression in virtually all cases of dedifferenti-
ated chondrosarcoma studied, and in which it is restricted
to the high-grade sarcomatous component of the tumor,
suggests a critical role of this gene in the development of
high-grade secondary malignancies of bone.
RB Gene
The RB gene was originally identified as a gene of reti-
noblastoma, a rare intraocular malignant neoplasm of
early childhood. It was the first human tumor suppres-
sor gene (i.e., a gene whose loss of function leads to the
development of malignant neoplasms) discovered.153,248 In
humans, germ line alterations of the RB1 gene represent
the prototypic genetic predisposition to cancer. The main
tumor associated with this predisposition is retinoblas-
toma. The tumor is composed of poorly differentiated
cells that form rosettes and are referred to as retino-
blasts. The survivors of childhood retinoblastoma carry
an increased lifetime risk of secondary cancers, which
include osteosarcoma, fibrosarcoma, chondrosarcoma,
Ewing’s sarcoma, melanoma, leukemia and lymphoma,
brain tumors, and a long list of common epithelial
solid malignancies such as bladder cancer. The RB gene
codes for a 105 kDa protein that belongs to a family of
three proteins, including RBL2/p130 and RBL1/p107
(Fig. 3-13).166,218 These proteins are structurally and
 3  Molecular Biology of Bone Tumors 113

RB1

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
Exon 17

Exon 18
Exon 19
Exon 20
Exon 21
Exon 22
Exon 23

Exon 24
Exon 25
Exon 26
Exon 27
Chr 13

Exon 1
Exon 2

Exon 3
Exon 4
Exon 5
Exon 6

Exon 7
Exon 8
Exon 9

cds
13
12
11.2
11 11.1
12.1
12.2
12.3
13 14.1
14.2 RB1
21.1 14.3 RB1
21.3
21.2 638 786
1 928 aa
22
31
111 228 373 576 768 927
32
33 Retinoblastoma-associated protein, N-terminal domain
34
Cyclin-like – Retinoblastoma-associated protein, A-box domain
Cyclin-like – Retinoblastoma-associated protein, B-box domain
Retinoblastoma-associated protein, C-terminal
A

Growth factor

Ras pathway
P
Rb
P

Rb Cdk
Cyclin
E2F E2F

Genes needed ATP ADP

for S phase are
not transcribed Gene transcription

mRNA translation

Enzymes and other

proteins required
for S phase
D

B
FIGURE 3-13  ■  The structure and biologic effects of the RB1 gene and its encoded protein. A, Chromosomal location, exonal structure,
and the functional domains of the encoded protein of the RB1 gene. B, The model of a full length RB1 protein forming the complex
with cognate DNA. C, The RB1 DNA-binding motif. D, RB1 regulatory pathway. (B, Modified and printed with permission from Rubin
SM, et al: Cell 123:1093–1106, 2005 and Hassler M, et al: Molecular Cell 28:371–385, 2007. C, Based on Marinescu VD, et al: Nucleic Acids
Research 33:91–97, 2005, and Marinescu VD, et al: BMC Bioinformatics 6:1–20, 2005.)

functionally very similar to RB1/p105 and control the
same pathways but may show distinctive functions in
specific tissue environments.133,160 The most studied and,
likely, the most significant biologic effect of Rb proteins
is their regulation of cell cycle and inhibition of G1-S
phase transition.132,137,230 They interact with transcription
factors such as E2F1, E2F2, and F2F3a, which are the acti-
vators of transcriptions inhibited by RB1/p105.191,218,219 In
contrast, E2F4 and E2F5 are repressors of transcriptions
transported to the nucleus by interaction with RBL1/
p107 and RBL2/p130. Similar to p53, the function of all
Rb proteins are modulated by phosphorylation mediated
by cyclin-dependent kinase-cyclin complexes. Hyper-
phosphorylation of Rb proteins inhibits binding to E2F
proteins and releases cell cycle progression. A number
of stimuli can reactivate Rb proteins, including the
induction of cyclin-dependent kinase inhibitors such as
CIP/KIP family members, including p21, p27, and p57

ERRNVPHGLFRVRUJ
114 3  Molecular Biology of Bone Tumors
and INK4 family members such as p15, p16, p18, and
p19. In addition to the well-known function of Rb pro-
teins as regulators of cell cycle progression, emerging
evidence postulates that they are involved in chromo-
somal stability, senescence, apoptosis, differentiation, and
angiogenesis, all of which may contribute to malignant
transformation.174
In retinoblastoma, the RB gene initiates tumorigenesis
when both alleles are altered in retinal cells.184 In other
types of tumors, loss of a functional Rb protein may have
a similar mechanism, or the RB gene product may be
inhibited by other mechanisms, such as the overexpres-
sion of cyclin D1.150 Human patients with one altered RB
allele are normal except that they have an increased risk
of developing cancer. Their risk for the development of
retinoblastoma is 36,000 times that of people without this
mutation. Human patients with germline RB mutations
also have 2000 times the normal risk for osteosarcoma
and an undefined but increased risk for other tumors,
predominantly melanoma and soft tissue sarcomas.
Alterations of the RB gene in human cancers are of
two main types: deletions and mutations (see Fig. 3-8).
The first consists of major deletions of large segments of
the gene, which cause the absence of a properly function-
ing gene product. The second consists of substitutions of
nucleotides, which alter the function of the gene by creat-
ing improperly located initiation signals, splicing sites,
stop codons and amino acid substitutions.135,147,150,240 They
destabilize the transcript, produce a truncated gene
product, or otherwise modify mRNA, causing the absence
of a functional Rb protein.
The RB gene represents a model tumor suppressor
gene with frequent alterations in a variety of common
human malignant neoplasms.129,164,207 It serves as a para-
digm of molecular alterations that predispose the human
body to the development of osteosarcoma as the second
malignancy in families affected by retinoblastoma. Similar
to TP53, the RB gene is also frequently altered in sporadic
osteosarcomas not associated with retinoblastoma.234,235,240
The alterations of RB in sporadic osteosarcoma are
similar to those seen in retinoblastoma when the retino-
blastoma is associated with osteosarcoma (allelic loss and
functional absence of the protein as a result of altered
remaining alleles).115,235 The absence of the RB gene tran-
script or the presence of its truncated fragments is a
frequent finding in sporadic osteosarcomas. The pres-
ence of an altered RB gene and the presence of allelic
deletions in the RB locus are associated with more aggres-
sive variants of osteosarcoma.115,142 Loss of heterozygosity
in the RB gene locus has also been documented in chon-
drosarcomas and chordomas.138
DNA Helicases
Genome maintenance is a complex physiologic mecha-
nism that involves multiple proteins that are essential for
the preservation of the structural and functional integrity
of cellular genetic material. This system involves multiple
genes and their respective encoded proteins organized in
several closely interacting regulatory pathways. In this
paragraph, we describe the role of one particular class of
enzymatic proteins, referred to as helicases because of
ERRNVPHGLFRVRUJ
their unique role in cancer development, including
sarcoma predisposing syndromes such as Rothmund-
Thomson, Baller-Gerold, RAPADILINO, and Werner
syndromes (Fig. 3-14).117,125,244 Helicases are defined as
molecular engines that are coupling nucleoside triphos-
phate hydrolysis, typically of ATP, to unwind the double
helix of nucleic acids.124,200,210,221 These enzymes move
along the double strand directionally from 5′ to 3′ or in
reverse direction. They catalytically disrupt base pairs
between complementary strands of DNA in a manner
that is dependent on ATP. They also participate in anneal-
ing of the double-stranded DNA by promoting pairing
of the base pairs. In general, these enzymes help cells to
recover from both endogenous and exogenous stress-
induced DNA damage. Therefore, it is understandable
that their impaired function by mutations causes unique
clinical syndromes characterized by genomic instability
and sensitivity to environmental DNA damage such as
sun exposure, resulting in premature aging and an
increased risk for cancer.128,206 There are nearly 100
known helicases and an additional 30 putative helicases
encoded by the human genome.117,181 The list of helicases
whose defects have been linked to unique clinical syn-
dromes and increased risk for cancer are provided in
Table 3-1.
The two helicases on which we focus in this section
are referred to as RECQL4 and WRN helicases, whose
mutations are associated with the predisposition to a
number of solid and hematologic malignancies, including
osteosarcomas. RECQL4 plays a role in several DNA
repair pathways, which are mediated by its specific
helicase domain.134 Mutations of RECQL4 have been
identified in three distinct cancer predisposing syn-
dromes: as Rothmund-Thomson, RAPADILINO, and
Baller-Gerold.168
The WRN helicase gene on chromosome 8p12 encodes
RecQ helicase, which possesses a helicase and DNA exo-
nuclease domains.148 The gene is mutated in the Werner
syndrome, which is a mendelian autosomal recessive dis-
order manifested by features of accelerated aging and
increased risk for multiple malignancies, including osteo-
sarcoma.155,227 The WRN helicase functions as a key
regulator of recovery from replication arrest at replica-
tion forks and acts at the replication checkpoint. The
basic biologic effect of malfunctioning WRN helicase is
a lack of recovery from arrested replication forks, result-
ing in chromosomal rearrangements.208,217,228
Chromosomal Translocations
The significance of recurrent chromosomal transloca-
tions to understanding the biology of sarcomas and espe-
cially their use in the differential diagnosis of these
malignancies warrants a more detailed discussion.337 The
transfer of one fragment of a chromosome to another
chromosome may put two genes together in one place.
This in turn can fuse the two coding sequences near the
breakpoint, creating a hybrid messenger RNA (mRNA)
coding for a new protein, which can have a profound
effect on cell biology.179,195,196 The biologic effect of the
hybrid gene results from overexpression of a fused protein
driven by a new strong promoter or may be related to a
 3  Molecular Biology of Bone Tumors 115

RECQL4

Exon 10
Exon 11
Exon 12

Exon 13
Exon 14
Exon 15

Exon 16

Exon 17
Exon 18

Exon 19
Exon 20

Exon 21

Exon 22
Exon 1
Exon 2
Exon 3

Exon 4

Exon 5

Exon 6

Exon 7
Exon 8
Exon 9
cds
Chr 8
23.3 23.2
23.1 tel cen
c.118+27del25
22
21.3 21.2 c.84+6del16 c.1048_1049AG
21.1
12 c.1391-1g>A c.1390+2delT c.1878+5G>A
c.2492-2493delAT
11.2 11.1 c.1483+25del11 c.1483+27del11 c.1878+32del24
11.1 c.2506_2518del13bp
11.22 11.21 c.1885del4
11.23 c.1568delG c.1573delT c.2547-2548delGT
12 c.1887del4
13 c1650del7 c.2059-1G>A c.2552delC
21.1 c.2059-1G>T c.2886-2A>T
c.1704G>A c.1705-1G>A
21.2 c.3056-2A>C
21.3 c.1718delA c.2207insC
c.3072delA
22.1 c.2335del22
22.2 c.3072-3073delAG
22.3 Rothmund-Thomson Syndrome c.2419ins5
23 c.3270delG
RAPADILINO Syndrome c.2464-1G>C
c.3276delG
24.1
Baller-Gerold Syndrome c.3599_3600delCG
24.2 24.3
RECQL4
RECQL4
492 820
1 1208 aa
402418 477 677 683 850
p.Gln166X p.Gln253His p.Trp383X p.Pro466Leu
p.Phe637Ser p.Leu926Arg
p.Leu638Pro p.Leu927Arg
A p.Phe697Leu
p.Ala741Thr
p.Arg1021Trp
p.Ile1051Val
p.Gln757X#
p.Arg1072X
p.Gln800X
p.Gln810X p.Gln1091X
p.Gln821X p.Pro1170Leu
p.Arg826X# p.Gln1175X

DNA
RecA-like domain 2
replication 3’
P466L 5’
F697L 5’
5’ 3’
3’ 5’
flap Homologous
recombinatiom D-loop
F637S

5’ Telomere 3’
3’ 5’
maintenance
5’
RecA-like domain 1
3’
fork Holliday junction
B DNA repair
C
FIGURE 3-14  ■  The structure and biologic effects of the RECQL4 helicase gene and its encoded protein. A, Chromosomal location,
exonal structure, and the functional domains of the encoded protein of the RECQL4 helicase gene. The distribution of mutations in
the Rothmund-Thomson, RAPADILINO, and Baller-Gerold syndromes are superimposed over the gene and protein diagrams.
(A, Adapted and reprinted with permission from Larizza L, et al: Orphanet J Rare Dis 5:1750–1172, 2010.) B, The crystal structure of
RECQL4. The important motifs are highlighted in yellow and the RecA-like domains 1 and 2 are indicated. Labels indicate the
examples of mutations in the protein. (B, Reprinted with permission from Jensen MB, et al: Aging (Albany NY) 4:790–802, 2012.) C, The
inferred RECQL helicase substrates and their roles in DNA metabolism. RECQ helicases are able to unwind and release DNA flaps
(upper left); promote replication fork progression, regression, or remodeling (lower left); release an invading 3′ DNA tail in a D-loop
(upper right); and branch migrate and, in the case of BLM in conjunction with topoisomerase IIIα, resolve separate DNA duplexes
joined in a Holliday junction (lower right). (C, Reprinted with permission from Monnat RJ Jr: Semin Cancer Biol 20:328–339, 2010.)

new function of a protein that does not exist in normal
cells. The molecular structures of the vast majority of
cytogenetically detectable translocations have been iden-
tified. New translocations continue to be discovered for
rare variants or for cytogenetically silent translocations
or those occurring in the background of complex aber-
rant karyotypes by genome profiling and sequencing
techniques.167,173,209,232,242 The list of currently known
translocations in both soft tissue and bone sarcomas is
provided in Table 3-2. Elucidation of the molecular
structures of breakpoints and identification of the genes
affected by the translocations in many bone or soft tissue
malignancies have revealed some striking functional simi-
larities. It appears that a majority of translocations found
in bone and soft tissue, including the prototypic translo-
cations in Ewing’s sarcoma and related lesions, result in
the production of a new fusion transcript that consists of
a portion of a gene that has an RNA binding domain
(EWSR1) replaced by another gene exhibiting overall
biologic activity of the transcription factor (FLI1, ERG,
WT1).113,131,151,185,194,216,223,241 Moreover, it seems that the
EWSR1 gene is fused with other genes that code for
DNA binding molecules in several distinct tumors appar-
ently not related to Ewing’s sarcoma. Thus the translo-
cational patterns of this gene represent a unique model
of molecular mechanism associated with several distinct
types of bone and soft tissue sarcomas (Fig. 3-15). It is
evident that the same fusion partner can be involved in

ERRNVPHGLFRVRUJ
116 3  Molecular Biology of Bone Tumors

TABLE 3-1  DNA Helicase Gene Defects Linked to Cancer

Genome Metabolic
Gene Disease Cancer Type Pathway Biochemical Function
WRN Werner syndrome Thyroid neoplasms, DSB repair and 3′-5′ helicase, 3′-5′
melanomas, replication distress exonuclease, HJ
meningiomas, sarcomas, response branch migration, G4
hematologic and resolution, replication
lymphoid neoplasms, fork regression, and
and osteosarcoma strand annealing
BLM Bloom syndrome Adult epithelial tumors, DSB repair and repair of 3′-5′ helicase, HJ branch
leukemias, lymphomas, replication-associated migration, G4
and rare pediatric DNA damage resolution, replication
tumors fork regression, and
strand annealing
RECQL4 RTS, BGS, and Osteosarcomas and Replication, mitochondrial 3′-5′ helicase and strand
RAPADILINO syndromes lymphomas genome stability, and annealing
repair of endogenous
base damage
RECQL1 Pancreatic cancer Replication and oxidative 3′-5′ helicase, HJ branch
(polymorphisms) DNA damage response migration, and strand
annealing
FANCJ FA Acute myeloid leukemia DSB repair and ICL repair 5′-3′ helicase and G4
and breast cancer resolution
(heterozygotes)
XPD Xeroderma pigmentosum, Skin cancer NER and transcription 5′-3′ helicase
xeroderma pigmentosum
with Cockayne syndrome,
TTD, and COFS
XPB Xeroderma pigmentosum, Skin cancer NER and transcription 3′-5′ helicase
xeroderma pigmentosum
with Cockayne syndrome,
and TTD
RTEL1 Dyskeratosis congenita Adult glioma Telomere maintenance 5′-3′ helicase and
(polymorphisms) and homologous disassembly of
recombination D-loops and T-loops
PIF1 Breast cancer Replication fork 5′-3′ helicase and G4
predisposition progression, telomere resolution
maintenance, and
mitochondrial DNA
metabolism

BGS, Baller-Gerold syndrome; COFS, cerebro-oculo-facial-skeletal syndrome; D-loop, displacement loop; DSB, double-strand break;
FA, Fanconi anemia; G4, G-quadruplex; HJ, Holliday junction; ICL, interstrand crosslink; NER, nucleotide-excision repair; RAPADILINO
syndrome involving radial hypoplasia/aplasia, patellar hypoplasia/aplasia and cleft or highly arched palate, diarrhea and dislocated joints,
little size (height at least 2 standard deviations smaller than average) and limb malformation, nose slender and normal intelligence;
RTS, Rothmund-Thomson syndrome; T-loop, telomeric displacement loop; TTD, trichothiodystrophy.
From Brosh RM Jr: Nature Reviews Cancer 13:542–558, 2013.

TABLE 3-2  Specific Genetic Aberrations in Bone and Soft Tissue Tumors
Neoplasm Translocation Involved gene(s)
Ewing’s sarcoma/PNET t(11;22)(q24;q12) EWSR1-FLI1
t(21;22)(q22;q12) EWSR1-ERG
t(7;22)(p22;q12) EWSR1-ETV1
t(17;22)(q12;q12) EWSR1-ETV4
t(2;22)(q33;q12) EWSR1-FEV
t(16;21)(p11;q22) FUS-ERG
t(2;16)(q35;p11) FUS-FEV
Ewing’s sarcoma-like tumors t(6;22)(p21;q12) EWSR1-POU5F1
without ETS involvement Inv(22)(q12) EWSR1-ZSG (ZNF278)
t(4;22)(q31;q12) EWSR1-SMARCA
t(2;22)(q31;q12) EWSR1-SP3
t(1;22)(p36.1;q12) EWSR1-ZNF278
Complex ring chromosome with EWSR1-NFATc2
amplification of the translocated segments
t(4;19)(q35;q13) CIC-DUX4
Inversion involving Xp11.4; Xp11.22 BCOR-CCNB3

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 3  Molecular Biology of Bone Tumors 117

TABLE 3-2  Specific Genetic Aberrations in Bone and Soft Tissue Tumors—cont’d
Neoplasm Translocation Involved gene(s)
Angiomatoid fibrous histiocytoma t(2;22)(q34;q12) EWSR1-CREB1
t(12;22)(q13;q12) EWSR1-ATF1
t(12;16)(q13;p11) FUS-ATF1
Clear cell sarcoma t(12;22)(q13;q12) EWSR1-ATF1
t(2;22)(q34;q12) EWSR1-CREB1
Desmoplastic small round cell tumor t(11;22)(p13;q12) EWSR1-WT1
Extraskeletal myxoid t(9;22)(q22;q12) EWSR1-NR4A3
chondrosarcoma t(9;17)(q22:q11) TAF15-NR4A3
t(9;15)(q22;q21) TCF12-NR4A3
t(3;9)(q12;q22) TFG-NR4A3
Myoepithelioma, soft tissue t(19;22)(q13;q12) EWSR1-ZNF444
t(1;22)(q23;q12) EWSR1-PBX1
t(6;22)(p21;q12) EWSR1-POU5F1
t with 16p11 FUS
Myxoid/round cell liposarcoma t(12;16)(q13;p11) FUS-DDIT3
t(12;22)(q13;q12) EWSR1-DDIT3
Aneurysmal bone cyst t(16;17)(q22;p13) CDH11-USP6 (Tre2)
t(1;17)(p34.1-34.3;p13) TRAP150-USP6
t(3;17)(q21;p13) ZNF9-USP6
t(9;17)(q22;p13) OMD-USP6
t(17;17)(q12;p13) COL1A1-USP6
Mesenchymal chondrosarcoma NA HEY1-NCOA2
t(1;5)(q42;q32) IRF2BP2-CDX1
Myoepithelial tumor of bone t(6;22)(p21;q12) EWSR1-POU5F1
t(19;22)(q13;q12) EWSR1-ZNF444
t(1;22)(q23;q12) EWSR1-PBX1
Bizarre parosteal t(1;17)(q32;q21) RDC1
osteochondromatous proliferation
(Nora’s lesion)
Subungual exostosis t(X;6)(q24-q26;q15-21) COL12A1-COL4A5
Alveolar rhabdomyosarcoma t(2;13)(q35;q14) PAX3-FOXO1
t(1;13)(p36;q14) PAX7-FOXO1
Other t with 2q35 PAX3
Alveolar soft part sarcoma t(X;17)(p11.2;q25) ASPSCR1-TFE3
Angiofibroma t(5;8)(p15;q13) AHRR-NCOA2
Dermatofibrosarcoma protuberans/ +ring/marker chromosome from t(17;22) COL1A1-PDGFB
giant cell fibroblastoma (q22;q13)
Desmoplastic fibroblastoma t(2;11)(q31;q12) Unknown
Epithelioid sarcoma-like t(7;9)(q22;q13) Unknown
hemangioendothelioma
Epithelioid hemangioendothelioma t(1;3)(p36.3;q25) WWTR1-CAMTA1
t(X;11)(p11.2;q22.1) TFE3-YAP1
Infantile fibrosarcoma t(12;15)(p13;q25) ETV6-NTRK3
Inflammatory myofibroblastic tumor t with 2p23 ALK fusion with:
TPM4 (19p13.1), TPM3 (1q21), CLTC
(17q23), RANBP2 (2q13), ATIC (2q35),
SEC31A (4q21), CARS (11p15)
Lipoblastoma t with 8q12 PLAG1 fusions
Lipoma, ordinary t with 12q14.3 HMGA2 fusions
t with 6p21 HMGA1 fusions
Lipoma chondroid t(11;16)(q13;p13) C11orf95-MKL2
Low-grade fibromyxoid sarcoma t(7;16)(q33;p11) FUS-CREB3L2
t(11;16)(p11;p11) FUS-CREB3L1
Mesenchymal chondrosarcoma del(8)(q13.3q21.1) HEY1-NCOA2
Myxoinflammatory fibroblastic der(10)t(1;10)(p22;q24) TGFBR3-MGEA5
sarcoma/hemosiderotic
fibrolipomatous tumor
Nodular fasciitis t(17;22)(p13;q13.1) MYH9-USP6
Ossifying fibromyxoid tumor t with 6p21 PHF1 fusions
Pericytoma t(7;12)(7p22;q13) ACTB-GLI1
Sclerosing epithelioid fibrosarcoma t(7;16)(q33;p11.2) FUS-CREB3L2
t(11;16)(p13;p11.2) FUS-CREB3L1
Solitary fibrous tumor inv(12)(q13q13) NAB2-STAT6
Spindle cell rhabdomyosarcoma t with 8q13 NCOA2 fusion with: SRF(6p21), TEAD1
(11p15)
Synovial sarcoma t(X;18)(p11.2;q11.2) SS18-SSX1
SS18-SSX2
SS18-SSX4
Tenosynovial giant cell tumor t(1;2)(p13;q37) CSF1-COL6A3

Other t with 1p13 CSF1

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118 3  Molecular Biology of Bone Tumors

Myoepithelial *
POU5F1
tumors

Ewing-like sarcoma
NFATc2

20
6

Myoepithelial tumors ZNF444

19

Myoepithelial tumors PBX1

1
Desmoplastic small round cell tumor

Angiomatoid fibrous histiocytoma

Angiomatoid fibrous histiocytoma

Acute myeloid leukemia
Clear cell sarcoma

Clear cell sarcoma

EWSR1

Extraskeletal myxoid chondrosarcoma

Myxoid liposarcoma
WT1 22

Ewing sarcoma Ewing-like sarcoma

FLI1
11

ERG
21 ETV1
SP3
TAF15
Acute myeloid leukemia
Ewing sarcoma

E1AF CREB1
CREB3L2 17 FEV
2
7
myxoid sarcoma

NR4A3
Low-grade fibro-

9
Acute myeloid
NMP4
leukemia
ETS TF family
DDIT3 ATF1
FUS
CREB/ATF TF family Ewing sarcoma
12
TET family of proteins
16
Angiomatoid fibrous histiocytoma
FIGURE 3-15  ■  An overview of translocation partnerships of the TET family of genes in various tumors. Translocation to various
genes in the same gene family is believed to be pathognomonic to a given entity (e.g., EWSR1 translocation to members of the ETS
family of transcription factors in Ewing’s sarcoma). Complementation by another TET member, FUS, has taken away this specificity
and the presence of FUS/ERG translocation both in Ewing’s sarcoma and acute myeloid leukemia brings additional complications
to molecular diagnostics. Similar shared translocation variants have been observed in clear cell sarcoma and angiomatoid fibrous
histiocytoma. Arrows point from the TET family translocation partners to translocation partners; members of a gene family are
indicated with identical colors. Annotation on arrows indicates associated tumor entities. The asterisk (*) indicates myoepithelial
tumors, which include soft tissue myoepithelioma and myoepithlelial carcinoma. (Modified and printed with permission from Szuhai
K, et al: Cancer Genet 205:193–204, 2012.)

ERRNVPHGLFRVRUJ

many, sometimes pathogenetically unrelated, entities;
therefore the identification of the second fusion partner
by additional tests provides more precise information and
can be helpful in classifying the lesion. In general, the
results of genetic and molecular testing should always be
interpreted within the histologic, clinical, radiographic,
as well as other biomarker contexts. In the chimeric
genes, the EWSR1 component provides the promoter
activity that upregulates the production of the chimeric
transcript. The second partner of the chimeric gene sup-
plies the DNA binding domain and is responsible for the
transcriptional activity of the chimeric protein. It is
very interesting that unique chromosomal translocations
and fusion partner genes have also been identified in
several soft tissue and bone lesions that were considered
to be, by conventional pathogenetic concepts, of rather
reactive than neoplastic origin. Such translocations were
identified in myositis ossificans, aneurysmal bone cyst,
nodular fasciitis, bizarre parosteal osteochondromatous
proliferation (Nora’s lesion), and subungual exosto-
sis.140,182,202-205,229,231,246,247 Because of the presence of clonal
chromosomal translocations, these conditions should be
considered to represent unique neoplastic proliferations
with self-limiting growth potential. The translocations
have been identified in a wide range of neoplastic lesions,
including soft tissue and bone tumors as well as common
solid malignancies, due to the wide use of genomic
sequencing, which is capable of detecting the hybrid
genes even in the absence of cytogenetically detectable
abnormalities or in the background of complex genomic
rearrangements.
For practical purposes to help detect chromosomal
translocations and their respective chimeric genes in
diagnostic workups of individual cases, several ancillary
genetic techniques are now widely used. In addition to
chromosomal karyotyping by conventional cytogenetics
and spectral karyotyping, fluorescence in situ hybridiza-
tion with the fusion and break-apart probes as well as
sequencing of fusion transcripts are now routinely used
in differential diagnosis of both soft tissue and bone sar-
comas. In describing these techniques we use the proto-
typic translocation in Ewing’s sarcoma involving the
EWSR1 and FLI1 genes as a model translocation used in
differential diagnosis of small cell sarcomas.
Karyotyping
Chromosomal karyotyping is the classic methodology for
demonstrating translocations and traditionally represents
the initial approach for identifying genetic markers in
these tumors.220 Fresh tumor cells are cultured, and cells
in metaphase are obtained for staining and visualization
under microscopy. The preparations are treated with
trypsin and Giemsa stains to produce G-banding, allow-
ing an experienced cytogeneticist to identify individual
chromosomes and often visualize translocations between
two chromosomes (Fig. 3-16). Computer-aided imaging
and initial analysis represent a clear improvement over
traditional techniques that involve photographing the
cells in metaphase, cutting out individual chromosomes,
organizing the chromosomes in a standard format, and
examining differences between them. Although this
ERRNVPHGLFRVRUJ
3  Molecular Biology of Bone Tumors 119
technique certainly can produce valid and reproducible
results, it requires the often-difficult culture of fresh
tumor tissue and highly skilled personnel to produce and
interpret the karyotypes. In the case of simple balanced
translocations or the involvement of large chromosomal
segments, this traditional method is reliable and repre-
sents the historic gold standard. However, in cases with
complex karyotypes, demonstration of characteristic
translocations can be more challenging. A new technique
known as spectral karyotyping (SKY) can more defini-
tively demonstrate chromosomal aberrations, especially
in complex karyotypes, and can identify complicated
translocations that involve several chromosomes (Figs.
3-16 and 3-17). This technique uses chromosome-specific
probes that create a unique color spectrum for each of
the 22 autosomal pairs and the two sex chromosomes that
is then optimized by computer-generated pseudocolor-
ation. In complex karyotypes, the color-coding of SKY
improves recognition of individual chromosomes and
translocation events by the trained eye.169,214 Like
G-banding, SKY requires a chromosomal metaphase
preparation for analysis. The strength of both of these
techniques is that they will reveal all karyotypic aberra-
tions within their limits of detection since all the chro-
mosomes are examined. On the other hand, both
techniques can miss cryptic translocations, in which the
translocated chromosomal segments are minute. Unfor-
tunately, these techniques are not very effective for diag-
nostic purposes because in clinical practice only about
50% of sarcoma samples can be successfully cultured.
Therefore the absence of cytogenetically detectable spe-
cific chromosomal translocations may provide a false
negative result. Results that yield a normal chromosomal
complement are particularly suspicious and suggest that
the cells analyzed may not represent tumor cells.
Fluorescence In Situ Hybridization
This technique, fluorescence in situ hybridization (FISH),
uses fluorescently labeled nucleic acid probes that hybrid-
ize to regions flanking the loci of interest and can detect
aberrant localization of these probes. FISH can be used
to identify abnormalities in cases where conventional
karyotypic analysis is inconclusive or where metaphase
spreads are not available; for example, in cases with only
formalin-fixed, paraffin-embedded tissue. The advantage
of FISH is that it can be applied easily to touch prepara-
tions, fresh tissue, karyotype preparations, frozen speci-
mens and formalin-fixed, paraffin-embedded samples.
The signal is visualized by fluorescent microscopy and
computerized image analysis. It is particularly useful in
mapping studies in which the hypervariable probes for
chromosomes are used to identify chromosomal dele-
tions, numerical aberrations, and translocations that
cannot be identified by conventional banding techniques.
The two basic strategies used to design the FISH probes
are referred to as fusion and break-apart strategies.183
With the fusion strategy, one uses two probes (labeled
with two distinct chromophores) targeted to the two loci
that are known to recombine (giving two red signals and
two green signals in cells that are negative for the fusion
event) (Fig. 3-18). Translocation involving two probed
120 3  Molecular Biology of Bone Tumors

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

der(21)

19 20 21 22 X X

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 X Y

B
FIGURE 3-16  ■  Chromosomal abnormalities in Ewing’s sarcoma and osteosarcoma. A, Karyotype of a Ewing’s sarcoma with the
t(11;22)(q24;q12). Extra copies of chromosomes 2, 7, and 9 are also present. Trisomy 8 is a frequent secondary abnormality found
in Ewing’s sarcoma and PNET. (A, Reprinted with permission from Sandberg AA, Bridge JA: Cancer Genet Cytogenet 123:1–26, 2000.)
B, Representative spectral karyotype from an osteosarcoma showing multiple chromosomal rearrangements. (B, Courtesy of Lu X:
MD Anderson Cancer Center, Houston, TX.)

ERRNVPHGLFRVRUJ
 3  Molecular Biology of Bone Tumors 121

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

der(21)

19 20 21 22 X Y
A

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18
der(21)

19 20 21 22 X Y
B
FIGURE 3-17  ■  Complex chromosomal rearrangements in Ewing’s sarcoma. A, A G-banded karyotype showing the three-way trans-
location 46, XX, t(1;21;7)(q25;q22.3;q22) (black arrows). B, Computerized spectral karyotype confirmed the three-way translocation
with rearrangement of chromosomes 1, 21, and 7 (white arrows). (A and B, Reprinted with permission from Jinwath N, et al: Cancer
Genet Cytogenet 201:42–47, 2010.)

loci generates nuclei with three signals, one yellow (indi-
cating the recombination product),and one orange and
one green signal (corresponding to the two other loci/
chromosomes not involved in the translocation). The
fusion probes are highly specific and can precisely iden-
tify both partners of the chimeric gene, but a different
probe pair would be needed to query for each of the pos-
sible partners in the translocation product, usually requir-
ing multiple tests.
With the break-apart strategy, one can use probes
labeled with two different fluorescent chromophores,
often orange/red and green that hybridize to sequences
that flank the fusion partner gene, EWSR1 (Fig. 3-19).
When these two probes hybridize at an intact gene/locus,
they are in close proximity and appear as a combined or
single signal due to the mixture of the dye spectra of
the two probes (when the probes are orange and green,
the combined signal approximates yellow). Two such

ERRNVPHGLFRVRUJ
122 3  Molecular Biology of Bone Tumors

11t
22

FLI-1 Probe (green)

Probe

R EWSR1

Probe
G

FLI1

A EWSR1 Probe (red)

11t B
22t

EWSR1/FLI-1 Fusion
Probes
G

R EWSR1 FLI1
breakpoint

FLI1 EWSR1
silent breakpoint

C 11

t(11:22)
22
22
Normal 22
Normal 11

11
E
t(11:22)

FIGURE 3-18  ■  Schematic diagram of fluorescence in situ hybridization (FISH) using fusion probes for the EWSR1 and FLI1 loci in
diagnosis of Ewing’s sarcoma. A, Specific DNA components of the probe hybridize to the telomeric (fluorescently labeled green)
region flanking the FLI1 gene and centromeric (fluorescently labeled red) region flanking the EWSR1 gene. B, In the absence of
the chimeric gene (the fusion of EWSR1 and FLI1 genes) these probes generate two green and two red hybridization signals in
cells with normal diploid (two copies) complement in the EWSR1 and FLI1 loci. C, The t(11;22)(q24;q12) translocation results in
transfer of the telomeric portion of the q-arm of chromosome 22 to the q-arm of chromosome 11, generating no hybridization signal.
In contrast, the transfer of the telomeric portion of chromosome 11 to chromosome 22 fuses the hybridization signals from the
centromeric side of the ESWR1 gene with the telomeric side of the FLI1 gene. D, The translocation depicted in C generates an
overlapped green and red (sometimes yellow) hybridization signal. In the diploid complement the remaining nonfused copies of
the ESWR1 and FLI1 genes generate additional split green and red hybridization signals. E, FISH performed on a normal control
metaphase cell with the fusion probe described in A-D showing two duplicates of hybridization signals flanking the FLI1 gene on
chromosome 11 (green) and the EWSR1 gene on chromosome 22 (red) (left panel). FISH performed on a Ewing’s sarcoma metaphase
cell showing the fusion of green and red signals on chromosome 22 (right panel). Inset, Enlarged image of chromosome 22 showing
the fusion of hybridization signals. (E and Inset; Modified and reprinted with permission from Sandberg AA, et al: Cancer Genet Cytogenet
123:1–26, 2000.)

ERRNVPHGLFRVRUJ
 3  Molecular Biology of Bone Tumors 123

22
22 22

Probes
G

R EWSR1
B

C
11t

22t

11t

22 22t
Probe Probe
G

FLI1 EWSR1 R EWSR1 FLI1

silent breakpoint breakpoint

E
D

F
FIGURE 3-19  ■  Schematic diagram of fluorescence in-situ hybridization (FISH) using break-apart probes for the EWSR1 locus in
diagnosis of Ewing’s sarcoma. A, Specific DNA components of the probe hybridize to the centromeric (fluorescently labeled red)
and telomeric (fluorescently labeled green) regions flanking the EWSR1 gene. B, The two components of the probe are in close
proximity when there is no rearrangement within the EWSR1 locus. The overlapping emission spectra yield a yellow signal. C, The
EWSR1 locus at both chromosomes is intact in these three depicted nuclei, and two overlapping pairs of red and green signals are
present (yielding two yellow signals) as seen using FISH in formalin-fixed, paraffin-embedded tumor sections. The nucleus is identi-
fied by DAPI stain and appears blue. D, The t(11;22)(q24;q12) translocation results in transfer of the telomeric portion of the q-arm
of chromosome 22 (with green hybridization signal) to the q-arm of chromosome 11. In addition, the telomeric portion of the q-arm
of chromosome 11 (with red hybridization signal) is transferred to the q-arm of chromosome 22. E, This translocation involves only
one of the two chromosomes, and the nonrearranged chromosome 22 has adjacent hybrization signals (green and red overlap to
produce a yellow signal). The rearranged chromosomes 11 and 22 have only green and red signals, respectively. F, Chromosomes
11 and 22 segregate independently and thus separate green and yellow signals are visualized in the nucleus when examined by
FISH. (Modified and reprinted with permission from Lazar A, et al: Arch Pathol Lab Med 130:1199–1207, 2006.)

ERRNVPHGLFRVRUJ
124 3  Molecular Biology of Bone Tumors

Ewing’s Sarcoma

SK-ES1
ARhSa
EWSR1 mRNA

A4573
TC71
UC2

UC6

PBL
RNA binding domain

SM

SM
NC
forward primer
FLI1 mRNA
ETS
reverse primer

EWSR1-FLI1
Fusion transcript
ETS

EWSR1 portion FLI1 portion B

A

EWSR1 (exon 7) FLI1 (exon 6)

Q Q S S S Y G Q Q N P S Y D S V R R V

CAACAGAGCAGCAGCTACGGGCAGCAGAACCCTTCTTATGACTCAGTCAGAAGAGG
A

EWSR1 (exon 10) FLI1 (exon 6)

M D E G P D L D L D P S Y D S V R R G

ATGGATGAAGGACCAGATCTTGATCTAGACCCTTCTTATGACTCAGTCAGAAGAGGA

EWSR1 FLI1 EWSR1 FLI1

1 23 4 5 6 7 6 7 8 9 1 23 4 5 6 7 89 6 7 8 9

C E 10

EWSR1 (exon 7) FLI1 (exon 5)

Q Q S S S Y G Q Q S S L L A Y N T T S

CAACAGAGCAGCAGCTACGGGCAGCAGAGTTCACTGCTGGCCTATAATACAACCTCC

EWSR1 FLI1
123 4 5 6 7 5 6 7 8 9

D
FIGURE 3-20  ■  Reverse transcriptase polymerase chain reaction (RT-PCR) analysis to demonstrate chimeric fusion transcripts in
Ewing’s sarcoma cell lines. A, Using primers specific to 5′ sequences of EWSR1 mRNA and 3′ sequences of FLI1 mRNA, the fusion
transcripts produced by chimeric EWSR1/FLI1 genes were amplified by RT-PCR. B, The results of RT-PCR reaction performed on
RNA extracted from Ewing’s sarcoma cell lines. Note the presence of fusion transcripts in RNA corresponding to Ewing’s sarcoma
cell lines. C through E, Verification of the identity of the amplified fragments by DNA sequencing, disclosing fusion transcripts cor-
responding to alternative breakpoints within EWSR1 and FLI1 chimeric genes.
ARhSa, Alveolar rhabdomyosarcoma; NC, negative control without template DNA; PBL, normal peripheral blood lymphocytes;
SM, size marker; TC71, SK-ES1, A4573, Ewing’s sarcoma cell lines; UC2, UC6, human urothelial carcinoma cell lines. (Reprinted with
permission from Lazar A, et al: Arch Pathol Lab Med 130:1199–1207, 2006.)

combined signals (one for each chromosome) will appear Sequencing of Fusion Transcripts
in cells in which the locus of interest is intact. When a
translocation occurs in the gene between the two probes, The DNA sequences of the genes that recombine to
the signals are split and distinct and separate orange and produce the chimeric fusion genes are known, and enough
green signals are detected along with the remaining intact examples have been characterized and sequenced to
yellow signal representing the nonrearranged locus/ determine where in the gene breaks tend to occur. The
chromosome. In practice, the break-apart methodology identification of long exonal/intronal DNA sequences of
is more common and is used in most commercially avail- the chimeric genes by polymerase chain reaction (PCR)
able products for sarcoma. The break-apart strategy is technically challenging and is practically never used
offers the advantage of demonstrating any rearrangement for diagnostic purposes. Instead, the amplification of
at the locus probed, but it cannot identify the transloca- fused mRNA (fusion transcripts) encoded by the specific
tion partner. Thus, the same set of probes can be used chimeric gene can be easily accomplished after its conver-
to demonstrate a rearrangement at the EWSR1 gene sion into cDNA using reverse transcriptase (Fig. 3-20).
locus in any tumor associated with this event, but cannot This methodology, the reverse transcriptase polymerase
identify the specific fusion partners involved in a wide chain reaction (RT-PCR) assay, can be used with fresh,
range of tumors. frozen, or paraffin-embedded tissue. The identity of the

ERRNVPHGLFRVRUJ

amplified fragment can be confirmed using multiple tech-
niques, including DNA gel electrophoresis, restriction
fragment digestion or, most rigorously, direct DNA
sequencing (Figure 3-20). RT-PCR can be used to deter-
mine which binding partner is participating in the forma-
tion of the fusion gene when multiple potential partners
are possible. The technology is limited in that it probes
for very specific forms of chimeric gene formations,
requiring multiple probe sets to examine all of the most
common sites of recombination within the gene; rare or
aberrant chimeric gene types thus can be missed or
require multiple to numerous amplifications to detect.
Moreover, the RT-PCR technique is prone to produce
false positive results due to annealing of the primers to
alternative homologous genomic sites, resulting in the
amplification of nonspecific fragments. Therefore, it is
recommended that the identity of amplified fragments
should be verified by sequencing.
In practice, it is wise to use a combination of various
techniques in the diagnostic setting. We recommend
using karyotype analysis complemented with FISH or
SKY for complicated cases when fresh tumor is available.
FISH is used as the first-line diagnostic modality for
paraffin-embedded tissue, with appeal to PCR-based
testing when FISH results are uninterpretable or confus-
ing. Many laboratories successfully use PCR-based
testing of fresh, frozen, or paraffin-embedded tumors as
first-line modalities. None of these tests can be inter-
preted in isolation and cannot be reliably applied outside
the context of a sensible morphologic and clinical dif-
ferential diagnosis.
Chromothripsis
The generally accepted model of cancer development
postulates a progression of malignant transformation
through a series of progressively increasing waves
of mutational and epigenetic changes that gradually
change cell behavior from normal to malignant states.
Such models of progression were developed for many
common solid human cancers; they involve progression
through microscopically recognizable precursor condi-
tions referred to as dysplasia and carcinoma in situ. These
microscopically recognizable phases of cancer develop-
ment are biologically underpinned by waves of clonal
expansion as cells acquire and accumulate multiple
genetic and epigenetic changes. Such modifications of
genetic material are believed to be essentially random,
but they generate phenotypic variations in cell popula-
tions that are subject to selection through Darwinian
evolution. Recently, the phenomenon referred to as chro-
mothripsis was identified in a subset of human cancers; this
postulates that myriads of mutations involving selected
chromosomes can occur in one catastrophic mitotic
cycle that can trigger the initiation of the carcinogenic
process.123,146,172,225 This phenomenon explains the
well-known puzzle of many human cancers, especially
sarcomas developing in relatively young patients or
often in childhood without any recognizable precursor
conditions.215,236 In general, this phenomenon is operat-
ing in a small fraction of all human cancers, not exceeding
2% to 3% of investigated cases. In contrast, up to 25%
ERRNVPHGLFRVRUJ
3  Molecular Biology of Bone Tumors 125
of bone cancers, especially osteosarcomas and chordo-
mas, demonstrate chromothripsis, making this newly dis-
covered mechanism contributory to the development of
a significant proportion of sarcomas arising in bone.225
Chromothripsis occurs in a single catastrophic shattering
event and it is followed by the disorderly stitching
together of genomic fragments.187,190 The features of
chromothripsis include multiple and complex rearrange-
ments that alter selected chromosomes, which can be
restricted to one chromosomal arm or its region (Fig.
3-21). In some instances, there is an exchange of multiple
fragments between the involved chromosomes. Copy
number changes associated with chromothripsis are
minimal and show either heterozygous deletions or no
copy change. The rearrangements within the involved
regions are typically very complex and there is a pro-
nounced clustering of breakpoints. The arrangement of
broken chromosomal fragments is not related to their
proximity in the normal genome.177
The mechanisms of double-stranded DNA breaks that
trigger chromothripsis are still unclear. Experimental evi-
dence suggest that exposure to ionizing radiation while
the chromosomes are condensed during mitosis is a pos-
sibility. Another possibility is a stress which causes DNA
replication forks to collapse in the S phase, triggering
multiple breakpoints. Breakpoints in chromothripsis typ-
ically involve the telomeric regions and therefore short-
ened telomeres can contribute to the initiation of a
breakage-fusion cycle. The shattering of chromosomes
found in chromothripsis is similar to the previously iden-
tified phenomenon of premature chromosomal compac-
tion.162 Chromothripsis may also represent an incomplete
apoptotic event, in which cells survive programmed cell
death by initiating DNA repair with a random assembly
of chromosomal fragments.
The mechanisms that put the shattered fragments
together are as interesting as those that trigger the entire
process. A template-independent DNA double-strand
break repair is the main mechanism involved. In addition,
such replicative processes that have been previously iden-
tified in complex genomic rearrangements, including
fork stalling, template switching and microhomology-
mediated break-inducing repair, are contributing factors.
Interestingly, there is solid evidence that chromothrip-
sis plays a role in the development of germline transmis-
sion of genetic disorders and may have a profound effect
not only on tumor progression, but also on human
development.175
CELL-CYCLE AND MITOTIC REGULATION
It is generally agreed that during cell growth and espe-
cially in the exponential growth phase, cells double their
constituents before mitosis. Most housekeeping proteins
double their content before the onset of DNA replica-
tion. It is also of interest that minimum threshold levels
of total RNA and proteins are essential for entry into the
S phase. On the basis of these parameters, it is possible
to separate cells in the G phase into subpopulations of
those that are in the early G phase (G1A) and those that
are in the late G phase (G1B).254-256 Similar minimum
 A
PD3808a: Chr 9p Chr 8p Chr 4q

To chr 7q To chr 8p To chr 7q

* * *

2
1
0
1
0

CDKN2A WRN FBXW7

17 20 23 26 29 32 35 38 152 154 156 158 160

Genomic location (Mb) Genomic location (Mb) Genomic location (Mb)
B
8505C: Chr 9p PD3175a (CLL)
CDKN2A
CDKN2A

2 Chr 9
0
18Mb 24Mb
4
2 To chr 10
0
1
0

2
0
21.5 21.75 22 22.25 22.5 45Mb 52Mb 98Mb 101Mb168Mb 171Mb

Genomic location (Mb) Chr 13 Chr 4

miR-15a / 16-1
C D
FIGURE 3-21  ■  The concept of chromothripsis and its biologic effects. A, Stimulating stress initiates the shattering of chromosomes
in localized regions, which are subsequently recombined together at random (left). The double-strand breaks caused by the stressed
stimuli are reconnected and may result in the deletion of some of the regions. The breakpoint junctions reveal homology without
additional insertions, supporting the concept that they are being generated by nonhomologous end-joining (right). (A, Reprinted with
permission from Maher CA, Wilson RK: Cell 148:29–32, 2012.) B, Microhomology-mediated break-induced repair results in small dupli-
cation or triplication of the reassembled segment, represented by additional open rectangles above the reassembled segments of
the altered chromosome. C, Examples of chromothripsis involving selected chromosomes in osteosarcoma (left) and chordoma
(right). The diagrams shows rearrangements of chromosomal segments and their position on the chromosomal map depicted by
continuous arcs. The inner ring shows SNP-based allelic ratios and the outer ring shows the copy number profile of the selected
chromosomes. D, Loss of tumor suppressor genes, CDKN2A and the microRNA (miR-15a/16-1) cluster by rearrangements involving
chromosomes 4, 9, and 13. (B through D, Reprinted with permission from Stephens PJ, et al: Cell 144:27–40, 2011.)
ERRNVPHGLFRVRUJ

thresholds exist for individual protein levels.254-258 Further,
many cell proteins follow the same overall pattern of cell
cycle-related expression. The most common qualitative
difference between benign and transformed cells is that
transformed cells have increased variability of postmitotic
G1 cells and an increased ratio in gene expression levels
among G1A and G1B cell populations. According to a pos-
tulated concept of asymmetric distribution of gene prod-
ucts after mitosis, this can be the result of increased
asymmetry of malignant post­mitotic daughter cells com-
pared with benign cells.257 This phenomenon was docu-
mented in reference to some tumor-transforming and
tumor suppressor genes expressed in human cancer cell
lines growing in vitro.267 The increased postmitotic asym-
metry of cancer cells and the uneven distribution of their
regulatory proteins account for the asynchrony of the
cell-cycle transverse by placing the cells with higher
levels of regulatory protein closer to the G1-S phase tran-
sition.257,267 This explains why the cells with a lower level
of these constituents have a longer time of residency in
the G1 phase. On the other hand, the increased asym-
metry of the postmitotic distribution of cell-cycle regula-
tory elements increases the pool of postmitotic cells with
levels of multiple proteins sufficient for immediate entry
into the S phase.
Mitotic cycle and cell cycle have several variants that
are characteristic of specific developmental stages (Fig.
3-22).158 A prototypic cell cycle of all eukarytotic cells has
three major checkpoints referred to as G1-S, G2+M, and
spindle checkpoints. The cycles of embryonic cells are
rapid, and some phases of the full cell cycle can be
skipped. In mature differentiated cells, they often repeat
the endoreplication in which the S phase is not concluded
by M phase but is followed by another S phase, resulting
in polyploidy.
The traverse of a cell across the cell cycle can be envi-
sioned as a sequence of checkpoints that act in concert.
On the individual cell level, the phenomenon of cancer
results from a profound deregulation of this system, and
almost certainly, each cell population has some distinctive
alterations and biologic features. This explains why it is
so difficult, and most likely even impossible, to link the
development and progression of most human cancers,
including those that affect the skeleton, to a single genetic
or molecular alteration.
A central dogma of cell-cycle regulation is that its
progression is controlled by the activity of a specific class
of serine/threonine kinases referred to as CDKs, which
contain a highly conserved PSTAIRE sequence in their
domain that binds cyclins (Fig. 3-22).158,266,271,279,287,290
CDK1 controls mitosis and CDK2 controls entry into S
phase in concert with CDK4 and CDK6. Specific CDK-
cyclin complexes have specific functions, but it appears
that the overall level of CDK activity is more important
for controlling the cell-cycle progression than their spe-
cific function.159,249,260,261,264,265,266,282 In this model devel-
oped primarily for yeast but also likely functional for all
eukaryotic cells, the CDK activity is at its lowest in G1,
is moderate at the start of S phase, and rises steadily
through G2, preventing reinitiation of replication and
reaches its peak level at the start of mitosis. After mitosis,
the CDK activity is shut down and it returns to the lowest
ERRNVPHGLFRVRUJ
3  Molecular Biology of Bone Tumors 127
level of G1. The overall sequence homology of CDKs
across the species is minimal, but the cyclin binding
domain is highly conserved. In view of this fact, it is
surprising that the regulatory network, especially of G1-S
control, has a strikingly similar network architecture
across species. The transcriptional regulation of E2F/RB
in animals and SBF/Whi5 in yeast are controlled by one
CDK-cyclin complex (Cdk4/6CycD in animals and
Cdc28-Cin3 in yeast) and then by a second CDK-cyclin
complex (CDK2-CycE in animals and Cdc28-Cin2 in
yeast). A third CDK-cyclin complex is activated by
Cdk2-CycA in animals and Cdc-Cib5 in yeast. The
third complex also requires the inactivation of CDK
inhibitors such as p27 in animals and Sic1 in yeast to
complete the S phase. In addition, Cdk4/6-CycD plays a
role in titrating p27, preventing the inhibition of
Cdk2-CycE complexes. New layers of complexity are
added to this regulatory network by the orchestration of
mRNA stability, including modulation by miRNA.280,293
The main tumor suppressor genes, TP53 and RB1, play
a central role in the regulation of cell-cycle progression
by interactions with the transcription factors, cyclins,
and DNA responsive motifs connecting the direct
cell-cycle regulatory machinery to diverse cellular path-
ways controlled by growth factors and extracellular
signaling.171,259,261,266,276
The regulatory mechanisms of cell-cycle progression
and especially of the G1 and S phase transits have been
extensively studied, but the molecular machinery of the
mitotic spindle has only recently been elucidated.281
These studies disclose a formidable complex molecular
machine built by the cells to segregate chromosomes into
two daughter cells after cell division.199,252,263,284,291 The
biologic function of mitosis is to accomplish the segrega-
tion of one copy of each chromosome into daughter cells.
The apparatus responsible for this process, the so-called
mitotic spindle, is composed of hundreds of proteins with
the overall architecture of microtubules attached to the
specific part of the chromosome referred to as the centro-
mere and to the pole of the mitotic spindle referred to as
the centrosome.268,291,294 Similar to chromosomes, the cen-
trosomes are delivered into the daughter cell after cell
division and are duplicated in the following S phase. The
centrosome duplication cycle shares common regulatory
pathways with the cell-cycle regulators and involve
CDKs.277,292 The microtubules forming the spindle can
be considered as microengines acting as springs and dash-
pots. They are arranged longitudinally and laterally and
propagate the segregation of chromosomes due to their
viscoelastic nature and tiled-array architecture. The
overall orientation of the mitotic spindle is regulated by
a highly conserved set of molecules that govern cell
polarity. In both mesenchymal and epithelial cells, the
apical to basal polarity regulates the position of the
mitotic spindle and secures equal segregation of chromo-
somes into daughter cells. Overall, more than 1000 pro-
teins show a mitotic-specific phosphorylation and many
of them belong to the superfamily of kinases. Among
them, the Aurora kinases play a prominent role as regula-
tors of the mitotic spindle and progression of mitosis
(Fig. 3-23).161,269,273 Aurora kinase A, a major component
of centrosomes, controls mitotic entry, centrosome
128 3  Molecular Biology of Bone Tumors

(a) (b) (c)

S G2 S

G1-S G2-M
check check G S
point P point P
M M
M M
A
G1 T T A
spindle
check
point
A

Threshold level for mitosis Mitosis

M Cyclin Cdc2
chromosomes
S Cyclin Cdc2

G1 Cyclin Cdc2
DNA licensing

G 1 S G2 M

B
CYCDs CycD Cln3

CDKA;1 Cdk4/6 Cdc28

E2F RBR1 E2f Rb SBF Whi5

FBL17 Skp2 Cdc4

Kip1
KRPs p27 Sic1

CDKA;1 Cdk2 Cdc28

CYCDs CycE Cln2

CDKB1s

CYCAs CycA Clb5

Arabidopsis Mammals Budding yeast

C
FIGURE 3-22  ■  Cell-cycle control. A, Mitotic cell cycle and its variants typically associated with different cell stages. (a) A typical
eukaryotic cell cycle with three major checkpoints. (b) Embryonic cell cycle with skip phases, resulting in rapid multiplication. (c)
Cell cycle of differentiating tissue with frequent and replicative cycles in which S phase is followed by M phase, resulting in poly-
ploidy. P, M, A, and T designate prophase, metaphase, anaphase, and telophase, respectively. B, Quantitative changes of major
regulatory components of the cell cycle. Total cyclin-dependent kinase (CDK) activity is shown in relation to cell-cycle phases. The
model was developed for Schizosaccharomyces pombe but is anticipated to be relevant to all eukaryotic cells. C, Cell-cycle control
networks at the G1-S transition. Note considerable homology among the regulatory networks across the species. (A through
C, Reprinted with permission from Harashima H, et al: Trends Cell Biol 23:345–356, 2013.)

ERRNVPHGLFRVRUJ
 3  Molecular Biology of Bone Tumors 129

_ +

+ _

+ _
+ _

B
Key
Mechanical symbols Molecular symbols
Spring Microtubule Kinesin-14
Dashpot Centrosome
Kinesin-5
Force Chromosome
arm Kinetochore
A
kinetochore
sister chromatid
interpolar MT

centrosome

K-fibre

Aurora A Aurora B Aurora A + B

Mitotic entry Chromosome biorientation

Centrosome separation
Centrosome maturation
Chromosome alignment
Microtubule stability
Spindle assembly checkpoint
Anaphase spindle disassembly
Sister chromatid cohesion
Cytokinesis

C
FIGURE 3-23  ■  Mitotic spindle micromechanics. A, The spindle can effectively be considered to be many springs and dashpots in
parallel arranged both longitudinally and laterally. Both elastic and viscous elements originate from the viscoelastic nature of
molecular motors (upper left), microtubule elasticity and turnover, and the tiled-array architecture of the spindle. Multiple motors
cooperate and slide antiparallel microtubules apart, but oppose each other and lock and parallel microtubules together (upper right).
A large external force can lead to rapid detachment of half of the motors, breaking microtubule-microtubule crosslinking and leading
to a plastic spindle response. B, Robust spindle architecture depends on properly homogeneous “filing” of the spindle interior by
microtubules. This cannot be achieved by random microtubule nucleation with the RanGTP cloud (shaded region, top); the micro-
tubules are too spread out and disjointed. Nor can this be achieved by the autocatalytic nucleation (bottom) of short microtubules,
which leads to dense, disjointed clumps of microtubules. The optimal regimen (middle) is a combination of autocatalytic microtu-
bules branching with a RanGTP-mediated enhancing effect and fast microtubule growth and turnover dynamics. (A and B, Mogilner
A, Craig E: J Cell Sci 123:3435–3445, 2013.) C, Summary of Aurora kinases in the mitotic spindle mechanics and function. (C, Hocheg-
ger H, et al: Open Biol 3:120185, 2013.)

separation, maturation, and chromosome alignment.275,277
On the other hand, Aurora kinase B is implicated in
chromosomal orientation, spindle assembly checkpoint,
sister chromatin adhesion, and cytokinesis.275 Both of the
Aurora kinases collaborate to accomplish microtubule
stability and disassembly of the mitotic spindle in ana-
phase. Lack of function of Aurora kinases in experimental
systems contributes to various mitotic dysfunctions and
may be lethal. Interestingly, the overall activity of Aurora
kinases, and especially of Aurora kinase A, is a frequent
phenomenon due to amplification and overexpression
that is observed in many human cancers, including bone
cancers. The overactive Aurora kinase A produces super-
numerary centrosomes, resulting in multipolar mitosis
and chromosomal misseggregation with aneuploidy.277
These observations provide new insights into molecular
mechanisms of aneuploidy and explain the microscopic
hallmark of malignant cells, the so-called atypical mitosis.
In summary, complex regulatory mechanisms that
operate on the promoter level of cell cycle-mediating
genes influence the proliferation activities of cells.
The regulation of histone gene expression is used as a

ERRNVPHGLFRVRUJ
130 3  Molecular Biology of Bone Tumors

Histone Gene

S1-PHASE: MAXIMAL TRANSCRIPTION

IRF-1
HinF-D (CDC2/CLN-A/RB)
HS IRF-2
HS
Nuclear
AFF1 matrix SP-1
NMP-1 ATF1 RNA pol II
H4UA-1
H4UA-3 YY-1 HinFA mRNA

Site IV Site III Site I Site II HinFA

Distal promoter Proximal promoter

DIFFERENTIATED: INACTIVE
mRNA

Site IV Site III Site I Site II

Distal promoter Proximal promoter

A

Osteocalcin Gene

DHS-1 Positioned DHS-1

nucleosome AP-1 TFIIB TAFS
AP-1 YY-1
OCBP2 OCBP1 RNA pol II

AML VDR/ AML

AP-1 GR AP-1 AML HLH MSX TFIID mRNA
RXR
GRE A VDRE B TGRE C E-box TATA GRE

-0.6 kB AP-1 YY-1 -0.4 kB -0.2 kB OC-BOX II OC-BOX I SIL

Far distal Distal promoter Proximal promoter

promoter
B
FIGURE 3-24  ■  Organization of regulatory elements (promoters) of histone and osteocalcin genes. A, Maximal transcription in S
phase is associated with binding of multiple transcription factors in sites I and II of proximal promoter and sites III and IV of distal
promoter. Differentiated (inactive) state is associated with complete inhibition of transcription and dissociation of multiple growth
factors from sites I, II, and IV. Occupation at site I is retained in differentiated (inactive) state. B, In contrast, promoter of osteocalcin
gene has several overlapping motives that respond to multiple transcription factors in differentiated nonproliferative state. They
contain elements responsible for tissue-specific expression (silencer domains, TATAboxes, and HOX homeodomain). Several AP-1
binding sites regulate expression in relation to cell differentiation. In addition, hormone-related expression is mediated by vitamin
D–responsive elements (VDRE) and multiple glucocorticoid-responsive elements (GRE). (Modified and reprinted with permission from
Stein GS, et al: Mechanisms regulating osteoblast proliferation and differentiation. In Bilezikian JP, Raisz LG, Rodan GA, eds. Principles of
bone biology, San Diego, 1996, Academic Press.)

paradigm of ubiquitous regulatory mechanisms in prolif-
erating cells (Fig. 3-24).286 In general, the transcription
of histone genes is upregulated at the beginning of the
S phase and is suppressed in differentiated or quiescent
cells.251,286 Accordingly, the promoter of the histone gene
responds to various regulatory proliferation signals such
as those from CDC2, cyclin A, the Rb-related protein,
and 1RF-2, among many others.278,283,285,289 Suppression
of histone gene expression at transition to the differen-
tiation or quiescent state is associated with dissociation
of the histone gene from the nuclear matrix and from
transcription factors at several binding sites within the
promoter.
In bone, the regulation of the osteocalcin gene in
osteoblastic cells signifies a model regulatory mechanism
in the transition from proliferation to differentiation
phases (Fig. 3-24). In contrast to the histone gene, the
organization of the osteocalcin gene promoter contains
several elements that upregulate the gene in a differenti-
ated postproliferative state and enhance its expression

ERRNVPHGLFRVRUJ

in parallel to matrix mineralization and differentiation
of osteoblastic cells. The osteocalcin gene contains
three major groups of DNA motives that bind factors
responsible for (1) tissue-specific expression (silencer
domain, TATA box, HOX homeodomain), (2) regula-
tion of its expression in parallel to cell differentiation
(AP-1 sites), and (3) regulation of hormone-dependent
expression (vitamin D–responsive element and multiple
glucocorticoid-responsive elements).250,253,262,270,272,274,288
The individual elements of the osteocalcin gene pro-
moter have an overlapping organization. It has been sug-
gested that the unique organization of the regulatory
motives of the osteocalcin gene maintains responses to
multiple factors.
MOLECULAR CONCEPTS
OF BONE NEOPLASIA
From the molecular point of view, human malignant neo-
plasms, including those that affect the skeleton, can be
divided into two broad groups: (1) tumors that exhibit
distinct molecular alterations that have been implicated
as playing a significant role in tumor pathogenesis and
(2) tumors with widespread genomic alterations that
seem to develop by means of a multistep cumulative
process. In tumors with distinct molecular alterations,
the changes are typically not single alterations, and
additional secondary hits are required for the develop-
ment of the complete malignant phenotype. They also
occur less frequently than those that seem to develop by
a complex multistep process.
The molecular mechanisms that play a role in the
pathogenesis of human malignant tumors are of several
major types:
1. A gene with a negative growth-regulatory effect
(tumor suppressor gene) is altered or lost.
2. A gene with positive regulation of growth is acti-
vated by upregulation or alteration (mutation) that
enhances its transforming activity.
3. The fusion of two genes by translocation results in
a new hybrid gene that exhibits a strong activity as
a transforming factor.
4. A gene involved in the stabilization of DNA tran-
scriptional fidelity (DNA repair gene) is altered or
lost. This results in failure to repair DNA tran-
scriptional mistakes and in turn causes a cascade of
alterations that affects many genes.
This simplified view of the role of individual genetic
alterations should be placed in the context of the complex
landscape of genomic alterations that affect multiple inter-
acting pathways contributing to the phenomenon referred
to as malignant transformation. Because tumors are begin-
ning to be investigated with increasing frequency by
genome profiling rather than by individual gene or pathway
approaches, it is appropriate to view tumors, including
skeletal neoplasms, as complex genomic disorders. This
view does not eliminate the concept and importance of key
driver type alterations and potential targetable genes as
well as their respective pathways that offer new, hopefully
more effective, therapeutic interventions.
ERRNVPHGLFRVRUJ
3  Molecular Biology of Bone Tumors 131
In subsequent paragraphs, we briefly discuss some
general molecular concepts of osteosarcoma, chondrosar-
coma, chordoma and Ewing’s sarcoma and examine the
significance of so-called dedifferentiation as a unique
phenomenon observed in several low-grade skeletal
neoplasms.
Osteosarcoma
The vast majority of osteosarcomas are sporadic de
novo tumors that develop without any known predis-
posing conditions. Small fractions of osteosarcomas
develop, however, in the background of well defined,
typically familial, predisposing syndromes. These syn-
dromes provide important clues for molecular mecha-
nisms involved in the development of these aggressive
mysterious malignancies. They include the retinoblas-
toma and Li-Fraumeni syndromes, which are asso-
ciated with the mutation of the RB and TP53 genes,
respectively, as well as a group of cancer predisposing
syndromes associated with germline mutations of heli-
cases.295,305,307,308,312,318,325,329-331,333,339,342 The mutations of
helicases, primarily the RECQL4, are the hallmarks of
several cancer predisposing syndromes, the most impor-
tant of which include Rothmund-Thomson, RAPADI-
LINO, Baller-Gerold, and Werner. The unifying features
of these syndromes represent genomic instability, prema-
ture aging, and increased risk for multiple cancers includ-
ing osteosarcoma. Although the mutations of helicases
are unusual in sporadic osteosarcomas, the mutations of
RB and TP53 genes, as well as their respective regula-
tory pathways, are among the most frequent molecu-
lar alterations seen in these tumors.309 Osteosarcomas
are extremely unstable tumors and exhibit pronounced
aneuploidy with alterations of multiple chromosomes
and their extra copies.296,310,311,313,315,316,321-323,334,341,361 A
novel mechanism involved in the development of several,
malignancies, both solid and hematologic, including
osteosarcoma, has been proposed and is referred to as
chromothripsis (described in more detail above).123,172,225
In general, the key regulatory pathways involved in
osteosarcoma represent a component of cell cycle check-
points.324,360,363 Some of these alterations were shown to
be of prognostic value (e.g., the deletions in the CDKN2A
locus are associated with poor survival in patients
with osteosarcoma).350,358 Similarly, the molecular mecha-
nisms involved in the maintenance of telomeres, such
as overexpression of mRNA for telomerase reverse
transcriptase, also predict poor outcome. Several gene
expression and miRNA studies have identified specific
signatures associated with an outcome in osteosarcoma.
The miRNA network studies have shown that miR-1
and miR-133b are involved in proliferation and cell cycle
control.348 The involvement of long noncoding RNAs
as a gene regulatory network has also been identified in
osteosarcoma.328
The frequent presence of cartilaginous differentiation
and a large proportion of undifferentiated mesenchymal
cells in most high-grade osteosarcomas suggest that early
osteoprogenitor cells with the ability for chondroblastic
differentiation are affected in the development of osteo-
sarcoma. On the other hand, a phenotypic switch to
132 3  Molecular Biology of Bone Tumors
another mesenchymal cell lineage is extremely rare in
osteosarcoma. This suggests that cells with a commit-
ment to perform skeleton-forming functions are affected
in the development of osteosarcoma. This observation
also strongly suggests the existence of such a mechanism
that seems to be highly protected and remains unaltered
in osteosarcoma, but its molecular mediators remain to
be elucidated.
Most conventional osteosarcomas produce easily rec-
ognizable amounts of osteoid but lack its organization
and the lamellar maturation seen in normal bone. This
is in keeping with the phenotypic heterogeneity of various
osteosarcoma cells and their functions, such as their
ability to produce individual elements of extracellular
matrix. Osteosarcomas can produce or even overexpress
some elements of the matrix. On the other hand, they are
not able to produce the whole gamut of matrix compo-
nents in the appropriate amount and sequence required
for the complete maturation of bone. The discovery of
differentiation activities of matrix polypeptides related to
growth factors (BMPs) explains a microscopically recog-
nizable phenomenon referred to as normalization (i.e.,
osteocyte-like appearance of osteosarcoma cells embed-
ded in solid areas of osteoid).
Chondrosarcoma
In general, chondrosarcomas develop from cells com-
mited to cartilaginous differentiation. They represent a
heterogeneous group of neoplasms with diverse biologic
behaviors. They range from low-grade, locally aggressive
malignancies (grade 1) to highly aggressive tumors with
a high propensity for metastases (grade 3). Grade 2
tumors represent an intermediate group. Some grade 2
tumors metastasize, and some behave as locally aggressive
lesions. A subset of chondrosarcomas exhibit myxoid
changes. Most skeletal myxoid chondrosarcomas are
grade 2 lesions and are pathogenetically distinct from soft
tissue myxoid chondrosarcomas. A small subset of bone
myxoid chondrosarcomas are high-grade lesions and may
be pathogenetically similar to extraskeletal myxoid chon-
drosarcomas. Mesenchymal chondrosarcoma is an outlier
and has more similarities with small cell malignancies,
including the presence of the two fusion genes HEY1-
NCOA2 and IRF2BP2-CDX1 than with the rest of the
cartilaginous neoplasm. Central and especially secondary
peripheral chondrosarcomas evolve via distinct molecular
pathways. Both central chondromas, commonly referred
to as enchondromas, and central chondrosarocmas share
some molecular similarities and are characterized by het-
erozygous mutations of isocitrate dehydrogenase 1
(IDH1) and isocitrate dehydrogenase 2 (IDH2).300,349
There are two hot spots where most of the mutations
occur, and they involve R132C and R132H in IDH1 and
R172S in IDH2. These genes are also frequently involved
in Ollier’s disease and Maffucci’s syndrome. They cata-
lyze the oxidative decarboxylation of isocitrate into
α-ketoglutarate of the Krebs tricarboxylic acid cycle.
IDH1 is a predominantly cytoplasmic and peroxisomal
enzyme; IDH2 catalyzes the mitochondrial Krebs cycle.
The mutations of these genes are not only present in
benign cartilage lesions, but are also identified in a high
ERRNVPHGLFRVRUJ
percentage of primary and secondary central as well as
periosteal chondrosarcomas. The progression mecha-
nisms of chondrosarcoma are largely unknown, but
high-grade lesions are characterized by aneuploidy and
multiple chromosomal abnormalities. As in osteosar-
coma, TP53 and RB genes are relatively frequently altered
in chondrosarcoma, and these alterations are associated
with the clinical aggressiveness of the tumor.345 Allelic
losses of 17p are ubiquitous in chondrosarcomas and may
play an important role in their pathogenesis. The activa-
tion of several oncogenic pathways that may represent
targets for novel therapeutic interventions have been
identified; they involve IHH/PTHLH/Bcl-2, Src, Akt,
and PDGRF, IGF, and estrogen signaling as well
as hypoxic and glycolytic pathways.299,300,301,303,317 The
Hedgehog signaling pathway plays a major role in carti-
lage development and continues to be activated in the
progression of chondrosarcomas, possibly contributing
to their proliferative states.307 Overall, the alterations of
TP53 and RB pathways can be identified in a significant
proportion of high-grade chondrosarcomas.304,345 This is
concurrent with the frequent amplification of 12q13 and
loss of 9p21, which contain many genes involved in the
regulation of these pathways. The PI3K-AKT pathway
and MAPK-AP-1-Runx2 axis are the most frequently
activated kinase pathways in chondrosarcoma.350,351 Alter-
ations of programmed cell death play a significant role in
the pathogenesis of low- to intermediate-grade chondro-
sarcoma. On the other hand, high-grade lesions most
likely develop by means of a multistep mechanism that
involves multiple transforming and tumor suppressor
genes. In general, aneuploidy and overexpression of
Aurora kinases are adverse prognostic factors.332,338The
complex network of regulatory miRNA contributed to
this process.362
The identification of EXT1 and EXT2 genes, which
are implicated in the development of hereditary multiple
exostoses, suggests that their alterations may play a role
in secondary malignancies (i.e., chondrosarcomas that
develop in this syndrome).314 Secondary peripheral chon-
drosarcomas, especially those associated with osteochon-
droma, carry the same mutations of EXT1 and EXT2
genes as an underlying osteochondroma.
In chondrosarcoma, a number of genetic alterations
(altered genes) correlate with the clinical aggressiveness
of the lesion, and most high-grade tumors are aneuploid.
Karyotyping studies indicate that alterations involving
multiple chromosones are frequent in chondrosarcoma
of bone.302,352 Moreover, recent differential genomic
hybridization studies show losses and gains of genetic
material on multiple chromosomes that may play a role
in the pathogenesis of these neoplasms.326
The progression of a low-grade, locally aggressive
neoplasm to a high-grade malignancy is referred to as
dedifferentiation; dedifferentiated chondrosarcoma is a
prototype of this phenomenon. Dedifferentiation may
also occur in low-grade intramedullary osteosarcoma,
parosteal osteosarcoma, giant cell tumor, and chordoma.
The development of a similar, highly lethal sarcoma in
several distinct precursor conditions may in fact repre-
sent a pathogenetically similar process that has common
molecular pathways of development.

Cytogenetic studies and our own observations with
the use of hypervariable chromosomal probes indicate
that the two components of dedifferentiated chondrosar-
coma are closely related and that the high-grade sarco-
matous component represents a subclone of a low-grade
precursor condition.340,357,359 Virtually all reported cases
of dedifferentiated chondrosarcoma exhibit strong over-
expression of the p53 protein in the dedifferentiated
components.304,355 Lack of an immunohistochemically
detectable Rb protein is seen in more than 50% of dedif-
ferentiated sarcomatous components. The bcl-2 protein
is typically present in the low-grade precursor conditions
but is absent in the sarcomatous component. Our data
indicate that extensive losses of genetic material on
chromosome 17p play a role in the development of
dedifferentiation.
Chordoma
The signature molecular mechanism involved in the
development of chordoma is chromothripsis. In fact,
chordoma is the prototypic tumor in which this novel
mechanism of cancer development has been identi-
fied.123,172,225 Hence, the signature of chordoma is the
presence of complex rearrangements involving selected
chromosomes. On the other hand, brachyury is a major
regulator of notochord development and displays major
biologic effects on the behavior of chordoma cells (Fig.
3-25).346 Elucidation of the molecular structure of brachy-
ury provided novel insights into its function as a tran-
scription factor binding to a unique DNA motif and
controlling the expression of multiple genes.344 In experi-
mental systems, silencing of brachyury induces growth
arrest of chordoma cells in vitro. Brachyury binds to the
T-box motif that is highly conserved among species. It
directly binds to nearly 100 target genes and influences
the expression patterns of a myriad of downstream targets.
It has been shown that brachyury, in fact, acts as a master
regulator of an elaborate oncogenic network involving
diverse pathways affecting the cell cycle and cellular
interactions with matrix components. In addition,
PDGRFB and RTCs, belonging to Flt3 and MCSFR1,
as well as the EGFR family (HER1, HER2/neu, and
HER4), are activated in a majority of chordomas. It has
also been shown that PI3K/AKT and RAS/ERK 1-2
pathways are also frequently activated in chordomas, but
such major players in these pathways as PI3Kp110, PTEN,
RAS, and BRAF are not mutated. Moreover, the mTOR
complex 1 (raptor) is also frequently overexpressed and
hyperactivated in chordomas.354 These findings provide
novel insights into the biology of chordomas and may
represent novel therapeutic targets.
Ewing’s Sarcoma
The biology of Ewing’s sarcoma focuses on the effects of
the EWSR1 gene fused to one of five ETS (erythroblast
transformation-specific) factors (Fig. 3-26).145,297,298,343,347,353
FLI1 (Friend leukemia virus integration 1) is the domi-
nant fusion partner involved in more than 80% of Ewing’s
sarcomas. ERG (v-ets erythroblastosis virus E26 oncogene
homolog) is the second most important fusion partner,
ERRNVPHGLFRVRUJ
3  Molecular Biology of Bone Tumors 133
involved in approximately 10% of Ewing’s sarcomas.152
In very rare cases, the FUS gene fuses with ERG or FEV
(ETS family members). In rare instances EWSR1 forms
a chimeric gene with non-ETS partners.144,306 Although
the molecular structures of common translocations
are elucidated, new subgroups of small cell malignancies
with unique translocations continue to be identified.306
An example is a novel class of small cell malignancy
with Ewing’s sarcoma-like microscopic features and
characterized by the translocation of CIC-DUX4 and
BCOR-CCNB3 genes.154,167,173,209 Typically, cytogeneti-
cally detectable translocations occur in the background
of an almost normal karyotype with a limited number of
secondary alterations usually representing chromosomal
duplications. There is, however, a subset of Ewing’s sar-
comas that exhibit complex copy number alterations and
chromosomal rearrangements.319,320,335 At the time of this
writing, there is not much information on the biologic
effects of alternative fusion partners; the bulk of the
information on target partners and involved pathways is
available for the signature translocation involving EWSR1
and FLI1.353,356 Multiple upregulated and downregulated
genes responsible for transcriptional activation and a
repressor function of EWSR1-FLI1 have been identified.
Several direct targets of EWSR1-FLI1 have been identi-
fied via a demonstration of binding to their upstream
promotor regions.336 It has been documented that
EWSR1-FLI1 acts as an aberrant transcription factor
and binds to GGAA microsatellites within the regulatory
elements of the target genes. The direct target genes
of EWSR1-FLI1 include hsRPB7, UPP1, tenascin-C,
ID2, p21, PTPL1, phospholipase D2, TGFBR1, IGFBP3,
MK-STYX, TERT, GLI1, and Aurora A and B. There is a
long list of so-called secondary interacting genes that are
affected downstream of the primary target genes; their
direct interactions with EWSR1-FLI1 have not been
identified (Table 3-3).
The interest in these genes and their respective path-
ways has two aspects. The first is the elucidation of
Ewing’s sarcoma biology. The second, and most impor-
tant, is the identification of possible therapeutic targets
TABLE 3-3 A Summary of EWSR1/FLI1 Genetic
Targets
Regulate Gene Name
Direct Targets
  Upregulated RPB7/POLR2G, TNC, UPP1, ID2,
TERT, PTPL1/PTPN13, PLD2,
MK-STYX, FLI1, Aurora A and B
  Downregulated p21/CDKN1A, TGFBR2, IGFBP3
Indirect Targets
  Upregulated EAT-2/SH21B, MFNG, UBE2C,
CCND1, MAPT, PP1R1A, NEK2,
MYC, PIM3, NKX2-2, CCK, CAV1,
CD99, VEGF-A, EZH2, TOPK/PBK,
IGF1/IGF1R, DAX1/NR0B1
  Downregulated p21/CDKN1B, p57/CDKN1C, ZYX,
NOTCH-p53, thrombospondin 1
and 2
From Mackintosh C, et al: Cancer Biol Therapy 9:655–667,
2010.
134 3  Molecular Biology of Bone Tumors

Chr 6
25 Brachyury (T)
24
23
22.3

Exon 1

Exon 2

Exon 3

Exon 4
Exon 5

Exon 6

Exon 7

Exon 8
22.2 22.1

cds
21.3
21.2
21.1
12
11.2
11.1 tel
11.1 cen
12
13
14
15 Brachyury (T)
16.1
16.2 16.3
21
1 435 aa
42 222
22.1
22.2 Transcription factor, T-box domain
22.3
23.1 23.2
23.3
24
25.1 25.2
25.3 26
27 Brachyury (T)

A B

Xenopus
in vitro

Zebrafish
in vitro

Mouse
in vitro

U-CH1
in vitro

C D
80 IL8 FZD4
60 30
40
20 10

20 10

5kb 5kb

60
MTMR7 FGF1
30 40

10 20

10 20

5kb 5kb

E
FIGURE 3-25  ■  Structure and biologic effects of brachyury. A, Chromosomal location and exonal structure of the brachyury (T) gene
as well as the functional domains of the encoded protein. B, Molecular structure of the brachyury protein bound to DNA. A ribbon
diagram of the dimer protein bound to DNA is shown in a view perpendicular to the DNA axis. C, The binding motif for brachyury
identified in the chordoma cell line, U-CH1, showing sequence homology across the species. (C, Reprinted with permission from Muller
CW, Herrmann BG: Nature 389:884–888, 1997.) D, Representative chromatin precipitation peaks (ChiP-seq peaks) surrounding the
brachyury target genes. E, Representative ChIP-seq peaks surrounding brachyury target genes. (D and E, Reprinted with permission
from Nelson AC, et al: J Pathol 228:274–785, 2012.)

ERRNVPHGLFRVRUJ
 3  Molecular Biology of Bone Tumors 135

Break Point Break Point

IGFBP3
NH2 COOH NH2 COOH c-KIT
DHR RRM AD ETS-DBD IGF1
AMG 479
EWSR1 (chromosome 22) FLI1 (chromosome 11)
t(11;22) IMC-A12
SCH 717454 PDGFR VEGFR
R1507 IGF1R
NH2 COOH CP-751,871
DHR variable ETS-DBD
EWSR1-FLI1 t(11;22)(q24;q12)
A PIP2
PIP3 PI3K
Ras
EWSR1 Akt
U1C Pazopanib
NH2 hsRBP7 Imatinib
YK-4-279 Raf
TSC2
activation Rheb Dasatinib
domain TSC1
Pol II MEK1/2
DBD
GBL Rictor GBL Raptor Temsirolimus
GGAA mTOR mTOR Everolimus
ERK1/2
mTORC2 mTORC1 G1
RHA COOH
M
FLI1 MLN8237
Aurora
kinase
Transcriptional activation and repression G2 Cyclin
C D1
Alteration of splice site selection S
Modulation of RNA half-life
B
FIGURE 3-26  ■  Molecular genetics and its implication for targeted therapies in Ewing’s sarcoma. A, Schematic drawing summarizing
the EWSR1-FLI1 t(11;22)(q24;q12) translocation. The EWSR1-FLI1 fusion includes the N-terminal activation domain of EWSR1, which
contains multiple degenerate hexapeptide repeats (consensus SYGQQS), and the C-terminal ETS DNA-binding domain (ETS-DBD)
of FLI1. Variation in the sites of chromosomal breakpoints leads to multiple fusion types (bracketed region). B, Putative molecular
function of the EWSR1-FLI1 protein and selected protein-protein interactions. As an aberrant transcription factor, EWS-FLI1 regulates
genes in part by binding to GGAA microsatellites upstream of target genes. EWSR1-FLI1 has been shown to interact with the splic-
ing factor U1C (also known as SNRPC, small nuclear ribonucleoprotein polypeptide c), RNA helicase A (RHA), and the hRBP7 subunit
of RNA polymerase II (PolII), which links the protein to splicing and transcription. The small molecule that blocks the EWSR1-FLI1-
RHA interaction is indicated in red. C, Signaling pathways and targeted therapies in Ewing’s sarcoma. EWSR1-FLI1 modulation of
IGFBP3 and IGF1 and overexpression of IGF1R promote increased IGF1 signaling. ES also expresses PDGFR, c-KIT, and VEGFR.
Activation of IFG1R, PDGFR, c-KIT, and VEGFR leads to downstream signaling through the PI3K and MAPK pathways (indicated by
gray dashed line and arrows). EWSR1-FLI1 upregulates Aurora kinase A and cyclin D1, promoting progression through the cell cycle.
Targeted therapeutic agents used in recent clinical trials for Ewing’s sarcoma are indicated in red. Genes modulated by EWSR1-FLI1
are indicated in purple. Receptors overexpressed in Ewing’s sarcoma are indicated in red. ES, Ewing’s sarcoma; ETS, erythroblast
transformation-specific; FLI1, Friend leukemia virus integration 1; IGFBP, insulin-like growth factor binding protein; IGF1, insulin-like
growth factor 1; IFG1R, IGF1 receptor; MAPK, mitogen-activated protein kinase; PDFG, platelet-derived growth factor; PDGFR, PDGF
receptor; PI3K, phophoinositol3-kinase; VEGFR, vascular endothelial growth factor receptor. (Reprinted with permission from Anderson
JL, et al: Pediatric Res 72:112–121, 2012.)

and the design of more effective management for these
highly aggressive tumors (Fig. 3-26).113,327 Downregula-
tion of the IGF binding protein 3 connects the tumor
pathogenesis to the IGF pathway. Because Ewing’s
sarcoma cell lines ubiquitously express IGF1 receptor,
and EWSR1-FLI1 hybrid protein has been shown to
upregulate IGF1 in mesenchymal progenitor cells, the
anti-IGF1R therapies are of major interest. Because
EWSR1-FLI1 upregulates Aurora A and B kinases, which
act as major regulators of mitosis, the inhibition of Aurora
kinases represents another experimental therapeutic
approach. The preclinical studies with Aurora kinase A
inhibitor in a Ewing’s sarcoma animal xenograft model
show promising responses and open an avenue for clinical
applications. The direct binding of EWSR1-FLI1 with
RNA helicase A, which increases the transcriptional
activity of the complex, offers another therapeutic
approach, and it has been shown that the block of RNA
helicase A-EWSR1-FLI1 interaction induces apoptosis
and inhibits tumor growth in xenograft models. These
biologically driven therapeutic interventions open some
new avenues for targeted therapies, but their clinical
application remains to be proven.
Systems biology approaches to biologic effects of the
EWSR1-FLI1 fusion protein have identified a complex
crosstalk network of pathways affecting cell proliferation
and apoptosis. The network containing the signaling
pathways involved in apoptosis signaling includes CASP3
and cytochrome C as well as such cell cycle regulators as
TNF, TFGβ, MAPK, IGF, NFκB, c-Myc, and RB/E2F
among others.
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 C H A P T E R 4 
Benign Osteoblastic Tumors
CHAPTER OUTLINE
OSTEOID OSTEOMA
BENIGN OSTEOBLASTOMA
Benign osteoblastic tumors were first recognized as a
distinct group by Jaffe and Mayer in 1932.54 The identi-
fication of osteoid osteoma as a separate entity came
later in a 1935 report by Jaffe.52 Once osteoid osteoma
had been established as a diagnostic category, other
benign bone-forming lesions were recognized. The term
benign osteoblastoma was introduced independently by
Jaffe and Lichtenstein in 1956 to delineate a benign
osteoblastic tumor that has greater growth potential than
osteoid osteoma.53,70,71 Most authors now regard osteoid
osteoma and osteoblastoma as separate, though related,
entities.44,71 In the majority of cases, fairly consistent
differences in size, location, degree of reactive sclerosis,
and pain pattern are useful features for selecting the
proper diagnostic category.46 However, there are cases
with composite features that defy classification. More-
over, a few cases of transition from osteoid osteoma
to osteoblastoma have been reported, supporting the
concept of a close relationship between these two
lesions.16,17,25,122 It is important to realize that osteoid
osteomas and osteoblastomas have nearly identical micro-
scopic features and must be distinguished from one
another by some means other than microscopy. Several
arbitrary but still useful diagnostic criteria have been
proposed to resolve this diagnostic dilemma. Maximum
diameters for the osteoid osteoma nidus of 1 and 2 cm
have been proposed as criteria.110 McLeod et al.81 arbi-
trarily designated all lesions measuring less than 1 cm in
diameter as osteoid osteomas and those larger than 2 cm
in diameter as osteoblastomas. These authors also pro-
posed an arbitrary dividing line of 1.5 cm for lesions with
composite features.
More recent experience with benign osteoblastic
tumors has indicated that some lesions may reach a con-
siderable size, usually exceeding 4 cm in diameter. These
lesions have a locally destructive growth pattern and a
high recurrence rate after curettage. Although the basic
histologic pattern of these tumors is similar to that of
conventional osteoblastoma, the presence of so-called
epithelioid osteoblasts is their distinct diagnostic
feature.1,42,59,60 We have designated these tumors as aggres-
sive osteoblastomas, a term tentatively proposed in 1973.39
The more definitive recognition of aggressive osteoblas-
toma as an entity was made in a 1984 report by Dorfman
and Weiss.42 Such intermediate or borderline osteoblastic
144
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AGGRESSIVE OSTEOBLASTOMA
lesions have been referred to by a variety of terms, includ-
ing aggressive osteoblastoma,42 malignant osteoblastoma,110 or
even low-grade osteosarcoma.15,78,79,82,84,98 Therefore there
are three main categories of benign osteoblastic tumors:
osteoid osteoma, benign osteoblastoma, and aggressive
osteoblastoma. However, benign osteoblastic tumors
represent a continuum of lesions that have different
growth potentials and different levels of extrinsic humoral
activity. This results in a mosaic of lesions that vary con-
siderably in size and in their ability to induce secondary
changes in the adjacent tissue (Fig. 4-1). In such lesions,
hemorrhage, secondary reparative changes, and bizarre
degenerating nuclei can raise the suspicion of malignancy
(“pseudoanaplasia”).9,83
Almost a century after the first conceptual identifica-
tion of this group of bone forming tumors, relatively little
is known about their biology. Cytogenetic studies on
a few benign osteoblastic tumors have demonstrated
clonal chromosomal alterations involving 22q in osteoid
osteoma, benign osteoblastoma, and aggressive osteo-
blastoma.11,34 A single cytogenetic report on an aggressive
osteoblastoma showed a distinct pseudodiploid clone
with balanced translocations involving chromosomes 4,
7, and 14.10 The study of alterations in cell cycle regulator
genes such as mutations in the TP53 and RAS genes, loss
of heterozygosity at the p53, p16, and Rb-locus, and
amplification of the MDM2 gene and the c-myc gene, as
indicators of graded genetic instability in borderline
osteoblastic tumors, may prove useful in their differential
diagnosis.100 A recent study of genomic aberrations in
several osteoblastomas and two examples of aggressive
osteoblastoma disclosed multiple chromosomal rear-
rangements in aggressive osteoblastomas.93 Moreover,
deletions of 22q were seen in several conventional osteo-
blastomas and in aggressive osteoblastomas, confirming
the relationship between these two entities. The chromo-
somal alterations, especially those involving 22q, involve
the genes controlling osteogenesis and are implicated to
have a role in the development of several solid and hema-
topoietic malignancies. The genomic alterations point
toward the involvement of MN1 and NF2 as well as
ZNRF3 and KREMEN1, known inhibitors of the Wnt/
beta-catenin signaling pathway. In line with these obser-
vations increased levels of beta-catenin were detected in
osteoblastomas.93

1.5 cm
Benign with
Limited Growth
Adjacent bone
Sclerosis of
Osteoid
Osteoma
FIGURE 4-1  ■  Benign osteoblastic tumors. Comparative features of biologic behavior and growth potential of osteoid osteoma,
benign osteoblastoma, and aggressive osteoblastoma.
OSTEOID OSTEOMA
Definition
Osteoid osteoma is a benign tumor that consists of a
well-demarcated osteoblastic mass called a nidus that is
surrounded by a distinct zone of reactive bone sclerosis.
The zone of sclerosis is not an integral part of the tumor
and represents a secondary reversible change that gradu-
ally disappears after removal of the nidus. This zone
should be specifically excluded in taking measurements
of these lesions. The nidus tissue has a limited local
growth potential and usually is less than 1 cm in
diameter.
Incidence and Location
Osteoid osteomas are common lesions that account for
about 10% to 12% of all benign bone tumors. They
usually occur in teenagers and young adults. The male/
female sex ratio is approximately 2 : 1. Familial occur-
rence has been reported rarely.55 More than 80% of
patients are between age 5 and 25 years, and the peak
incidence is in the second decade of life. About 50% of
all osteoid osteomas occur in the long bones of the lower
extremities, and the femoral neck is the single most fre-
quent anatomic site. In the long bones, osteoid osteoma
is usually located near the end of the shaft. Osteoid
osteoma occurs less frequently in the long bones of the
upper extremities, and the bones of the elbow are the
most frequent anatomic site in the upper extremity.
Osteoid osteomas are often present in the small bones of
the hands and feet. They occur rarely in the axial skeleton
but if present are usually found in the lumbar portion of
the spine. In vertebrae, they are nearly exclusively located
in the posterior arch. The primary location in the verte-
bral body is very rare. Osteoid osteomas occur very rarely
in flat bones and almost never in craniofacial bones.13,36,110
The peak age incidence and the most frequent sites of
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4  Benign Osteoblastic Tumors 145
Local Continuous
Growth
Benign with
Increased Size, but
Limited Growth
Bone Expansion
Size >3 cm
Osteoblastoma
Aggressive
Osteoblastoma
skeletal involvement are shown in Figure 4-2. The skel-
etal and age distribution patterns of individual osteoid
osteomas are shown in Figure 4-3.
Clinical Symptoms
Osteoid osteoma is associated with characteristic and
quite often virtually diagnostic symptoms. The most fre-
quently reported symptom is pain of increasing severity
that is relieved by aspirin and other nonsteroidal anti-
inflammatory agents. The typical clinical symptoms
occur in approximately 80% of patients.5,13,48 The pain
is frequently worse at night and is sometimes referred
to the nearest joint. If the tumor is located in the
proximity of a joint, the patient may have symptoms of
arthritis. If the involved bone is superficial, painful swell-
ing of the adjacent soft tissue may be present. This often
occurs in the small bones of the hands and feet, where
osteoid osteoma can be clinically mistaken for an inflam-
matory process. With vertebral involvement, there is
often an associated painful scoliosis that results from a
unilateral spasticity of spinal muscles. Some patients
with vertebral lesions may have clinical symptoms sug-
gestive of a neurologic disorder, lumbar disk disease, or
both.8,62 Lesions of the extremities in young patients with
open growth plates may produce significant length dis-
crepancy, caused by the increased growth rate of the
affected bone.95 In neglected cases, the patient may have
severe dysfunction of the extremity and muscle atrophy.
Some degree of muscle atrophy is present in nearly 20%
of cases.
In the past, the presence of nerves within the nidus,
documented by the axonal silver stain and electron
microscopy, was thought to be the cause of the patient’s
pain.113 More recently, high levels of prostaglandin E2 and
prostacyclin have been found directly in the nidus tissue
and its explants incubated in vitro.47,76,130 Large amounts
of prostaglandin E2 and prostacyclin released from the
nidus have since been implicated as being responsible for
 Peak
incidence
5 25
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 4-2  ■  Osteoid osteoma. Peak age incidence and frequent sites of skeletal involvement. The most frequent site is indicated
by the solid black arrow.

Osteoid Osteoma
30 40
Mean Age: 17.3
35 Male/Female Ratio: 1.56
25
30
Number of Cases

Number of Cases

20
25

15 20

15
10
10
5
5

0 0
Rib

1 2 3 4 5 6 7 8 9
Vertebra

Ilium

Tibia
Humerus
Ulna
Fibula
Radius
Phalanx
Carpal
Tarsal
r al
Femur

Metatars

Age in Decades
B

Flat Major Small bones of

bones long bones hands and feet

Axial Appendicular
skeleton skeleton
A
FIGURE 4-3  ■  Skeletal sites and age frequency distribution patterns of osteoid osteoma. A, Skeletal distribution of osteoid osteoma.
B, Age frequency distribution of osteoid osteoma.
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reactive sclerosis, nonspecific inflammatory changes of
soft tissue, and pain in osteoid osteomas.47 Moreover, it
has been documented that the urinary excretion rate of
the major metabolite of prostacyclin (i.e., 2,3-dinor-6-
keto-prostaglandin F1α) is significantly higher in patients
with osteoid osteoma and returns to normal after the
nidus is removed.30 Recent studies on the expression of
the cyclooxygenases (COX-1 and COX-2), which were
thought to be the source of the excess prostaglandins in
osteoid osteomas, have shown that COX-2 is one of the
main mediators of pain and inflammatory effects on sur-
rounding tissues, including adjacent synovium.57,87
Radiographic Imaging
The radiographic features of osteoid osteoma are
characteristic and diagnostic. Conventional radiographs
reveal a well-demarcated lytic lesion (nidus) surrounded
by a distinct zone of sclerosis. A zone of central opacity
that represents a more sclerotic portion of the nidus and
is surrounded by a lucent halo may be present within the
nidus. The intracortical lesions of long bones produce
extensive fusiform thickening of the cortex with dense
radiopacity that sometimes obscures the nidus (Figs. 4-4
and 4-5). In such instances the nidus may not be visible
on conventional radiographs, so additional imaging tech-
niques, such as computed tomography, radioisotope scan-
ning, and magnetic resonance imaging, may be necessary
to document the lesion.18,49,50,75,123,129 Occasionally, several
distinct foci of osteoid osteoma occur at the same ana-
tomic site, giving the appearance of a multifocal nidus.7
The tumors may exhibit different levels of matrix miner-
alization and may have different degrees of radiographic
density and scintigraphic activity.48 The adjacent perios-
teal reaction sometimes mimics a stress fracture. The
intramedullary lesion and the lesion located in cancellous
bone produce less distinctive sclerosis. However, such
lesions may provoke a multilaminar, exuberant periosteal
reaction that may involve long segments of the diaphysis
(Fig. 4-5). Minimal or absent perilesional sclerosis is also
a common feature of osteoid osteomas that are located
near the end of bone (juxtaarticular) and in subperiosteal
lesions. In vertebral locations, conventional radiographs
show increased density of the pedicle, loss of a distinct
contour, or both features. In vertebrae the nidus is often
not seen on conventional radiographs. Exact anatomic
localization of the nidus usually requires computed
tomography (Figs. 4-6 and 4-7). Most frequently, the
nidus is present in the area of the posterior arch or at the
base of a pedicle. In very unusual instances, it is present
within the transverse or spinous process.
Gross Findings
The nidus tissue, when examined intact in its anatomic
setting, appears as a distinct oval or round, reddish area
that can be easily separated from its bed (Fig. 4-8). This
tissue varies in consistency from friable, soft, and granu-
lar to densely sclerotic. The central portion of the nidus
is sometimes more sclerotic than its periphery. The nidus
is usually surrounded by a large zone of dense sclerotic
bone (Fig. 4-8). The surrounding sclerotic bone may be
ERRNVPHGLFRVRUJ
4  Benign Osteoblastic Tumors 147
minimal or even completely absent. The nidus is rarely
surrounded by normal cancellous bone with no evidence
of sclerosis. Sometimes, it may be difficult to identify the
nidus grossly, particularly in sclerotic intracortical lesions.
Preoperative tetracycline labeling is therefore of great
assistance because the nidus tissue stands out from the
reactive bone when it is examined under ultraviolet
light.6,68 Intraoperative scintillation probes after the
administration of a radioisotope may be used to confirm
identification.64,68,96,124
Microscopic Findings
At low magnification the nidus consists of an interlacing
network of bone trabeculae with different levels of min-
eralization (Figs. 4-9 to 4-11). The trabeculae are usually
thin and uniformly distributed in loose stromal vascular
connective tissue. The size, thickness, and mineralization
of the trabeculae can vary considerably in different lesions
(Figs. 4-9 to 4-13). The trabeculae also may vary in dif-
ferent areas of the same nidus (Fig. 4-9). The entire nidus
may be composed of densely sclerotic bone tissue with a
disordered (pagetoid) pattern of cement lines. Prominent
osteoblasts rim the osteoid trabeculae and are accompa-
nied by numerous osteoclast-like, multinucleated giant
cells. The nidus may have a clearly recognizable zonal
architecture with a more completely ossified central
portion (Fig. 4-9). The central portion, which is heavily
ossified, is usually less cellular compared with the less
mineralized and highly cellular peripheral zone. As a rule,
cartilage is not an integral component of the nidus and
should not be present in typical osteoid osteoma. In some
exceptional cases, however, small foci of clearly recogniz-
able cartilage with occasional myxoid features may be
present within the nidus (Fig. 4-14).
The bone surrounding the nidus may be cancellous
with thickened trabeculae and stroma consisting of rich
vascular connective tissue and rarely small foci of mono-
nuclear inflammatory cell infiltrate. Prominent large
blood vessels may be present in the connective tissue
surrounding the nidus and within enlarged haversian
canals in the surrounding densely sclerotic cortical bone
(Fig. 4-15). The adjacent synovium may be thickened,
with prominent chronic inflammatory cell infiltrates that
have lymphofollicular features. The changes in the syno-
vial membrane occasionally simulate rheumatoid arthritis
(Fig. 4-20). Special techniques such as immunohisto-
chemistry and ultrastructural investigations are practi-
cally never used in the diagnosis of osteoid osteoma.3,120,121
Osteoid osteomas express master regulatory proteins
involved in skeletal development, such as Runx2 and
Osterix, confirming the osteoblastic nature of the lesion.36
Differential Diagnosis
Osteoid osteoma should be differentiated from chronic
and acute osteomyelitis, bone abscess, intracortical hemangi-
oma, bone island, stress fracture, Ewing’s sarcoma, and intra-
cortical osteosarcoma. This long list of diverse entities
indicates that in some instances the differential diagnosis
of this well-known lesion can be very complex and
difficult.
148 4  Benign Osteoblastic Tumors

A B

C D

FIGURE 4-4  ■  Intracortical osteoid osteomas of long bones. A, A 15-year-old boy whose pain was worse at night and relieved by
aspirin was found to have a well-defined lytic intracortical lesion in the proximal femoral shaft. Note fusiform thickening around,
and extending for several centimeters above and below, nidus. B, Computed tomogram shows marked perilesional sclerosis of
bone (same case as A). C, Lateral radiograph of distal femur of 41-year-old man who had symptoms typical of osteoid osteoma for
3 months. Cortical thickening and sclerosis of bone failed to show lucent nidus; inset, computed tomogram of patient shown in
C reveals lucent nidus within markedly thickened posterior cortex. D, Photomicrograph of nidus containing irregular, randomly
oriented trabeculae of osteoid and woven bone. Abundant osteoblasts and osteoclasts border trabeculae (same case as A and B)
(D, ×100) (D, hematoxylin-eosin).

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 4  Benign Osteoblastic Tumors 149

A B

C D

FIGURE 4-5  ■  Osteoid osteoma: radiographic features. A, Radiograph with diffuse fusiform cortical thickening and sclerosis of tibial
shaft. No nidus tissue can be seen on this plain radiograph. B, Specimen radiograph of same case shows resected fragment of
anterolateral tibial cortex with dense sclerotic area representing nidus (arrows). C, Anteroposterior radiograph of intramedullary
nidus of osteoid osteoma in femoral shaft. D, Lateral radiograph of the same case shown in C. Note mild sclerosis of adjacent cortex
and prominent multilayered periosteal new bone formation.
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150 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-6  ■  Osteoid osteoma: radiographic and microscopic features. A, Computed tomogram of osteoid osteoma shows well-
circumscribed nidus involving the lateral elements of the neural arch. B, Low power photomicrograph of the nidus tissue shows
haphazardly arranged bony trabeculae of woven bone in a background of hypercellular stroma with abundant osteoblast and mul-
tinucleated osteoclastic giant cell (B, ×70). C and D, Intermediate power photmicrographs of the nidus tissue showing trabeculae of
woven bone rimmed by plump osteoblasts and occasional osteoclastic cells (C and D, ×100). (B-D, hematoxylin-eosin.)

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 4  Benign Osteoblastic Tumors 151

A C
FIGURE 4-7  ■  Osteoid osteoma: radiographic features. A, Anteroposterior plain radiograph with ill-defined sclerosis of the right
pedicle of the L1 lumbar vertebra. B, Computed tomogram shows well-circumscribed nidus with mineralized center in lamina.
C, Whole-mount specimen of the resected posterior neural arch showing a well-circumscribed nidus (arrows).

Radiographically and clinically, osteoid osteoma can
be confused with inflammatory conditions, such as bone
abscess and osteomyelitis of acute or chronic sclerosing
types. This problem is most evident in osteoid osteomas
affecting the small bones of the hands and feet. In juxta-
articular locations, monoarticular rheumatoid arthritis
can be simulated microscopically and radiographically
because of the associated prominent lymphoproliferative
synovitis. In each of these cases, histologic identification
of the nidus tissue disposes of the diagnostic difficulty.
Lesions that present as intracortical lucencies resem-
bling osteoid osteoma include abscesses, hemangiomas and,
in very unusual circumstances, intracortical osteosarcomas.
In all these entities, positive findings on bone scans can
be anticipated; therefore bone scans are of limited diag-
nostic usefulness in discriminating between osteoid
osteoma and the other lesions. In most cases, enostoses,
or small bone islands, can be separated from osteoid
osteomas by the absence of clinical symptoms, lack of
perilesional sclerosis, and usually negative bone isotope
scans.
Periosteal new bone formation associated with osteoid
osteomas can simulate stress fractures and even avulsion
injuries on radiographs when the nidus is not clearly
discernible on plain films.
Exuberant periosteal reactions also can mimic Ewing’s
sarcoma or acute osteomyelitis on plain radiographs. This
problem may be accentuated by the associated prominent
swelling of surrounding soft tissue.
Rarely, accessory growth centers can be confused
radiologically with osteoid osteoma. Such growth centers
are most likely to occur in tarsal or carpal bones.
The histologic appearance of osteoid osteoma nidus
tissue is usually so distinctive that differential diagnostic
problems on this level rarely occur. However, when taken
Text continued on p. 160

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152 4  Benign Osteoblastic Tumors

A B

C D

E G
FIGURE 4-8  ■  Gross, radiographic, and microscopic features of resected osteoid osteoma. A, Resected specimen with central round,
well-demarcated nidus tissue. Note ivory appearance of surrounding sclerotic bone. B, Low power photomicrograph shows topog-
raphy of intracortical nidus and surrounding bone. Note sharply demarcated nidus surrounded by sclerotic cortical bone with
thickened medullary and periosteal bone trabeculae. C, Resected specimen with a well-demarcated nidus tissue and sclerotic ivory
appearance of surrounding bone. D, Radiograph of the specimen shown in C shows lucent well-demarcated nidus surrounded by
sclerotic bone with thickened trabeculae. E, Radiograph of resected fragment of bone with sharply demarcated oval nidus surrounded
by densely sclerotic bone. F, Radiograph of perpendicular section of long bone with nidus. There is prominent periosteal reaction
with numerous parallel spiculae of newly formed bone. Nidus shows prominent dense center surrounded by less ossified peripheral
zone. Note dense sclerotic bone with coarse trabecular pattern around nidus. G, Low power photomicrograph shows topography
of nidus and surrounding bone. Note sharply demarcated nidus with peripheral lucency and sclerotic trabeculae of surrounding
bone. (B and G, hematoxylin-eosin).

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 4  Benign Osteoblastic Tumors 153

A B

C D

FIGURE 4-9  ■  Osteoid osteoma: microscopic features. A, Low power view showing topographic features of nidus in osteoid osteoma.
B, Higher power of A showing a well-delineated somewhat sclerotic center of the nidus and less sclerotic peripheral zone. C, Higher
magnification of B showing the periphery of the nidus composed of uniformly distributed bony trabeculae in cellular and vascular
stroma. Note merging of trabeculae structures of osteoid osteoma with adjacent sclerotic bone. D, Sclerotic bone at the periphery
of osteoid osteoma (A, ×100; B, ×25; C and D, ×100) (A-D, hematoxylin-eosin).

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154 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-10  ■  Microscopic features of osteoid osteoma. A, Intermediate power view of nidus with numerous bony trabeculae uni-
formly distributed in cellular and vascular stroma. B, Intermediate power view of nidus with numerous irregular bony trabeculae.
Supporting tissue consists of numerous osteoblasts and prominent vessels (×100). C, Intermediate power view of nidus with promi-
nent irregular bony trabeculae. D, Intermediate power view shows irregular interconnecting bony trabeculae. Note variable pattern
of matrix deposition in osteoid osteomas. (A-D, ×100) (A-D, hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 155

A B

C D
FIGURE 4-11  ■  Patterns of bony trabeculae with different levels of mineralization in nidus of osteoid osteoma. A, Poorly mineralized
ill defined areas of early osteoid deposition (×100). B, Poorly mineralized irregular areas of woven type haphazardly distributed in
highly cellular stroma with numerous osteoblasts, prominent vessels, and occasional osteoclast-like giant cells. C, Intermediate
power photomicrograph shows trabeculae of woven bone rimmed by osteoblasts and occasional osteoclasts. D, Low power pho-
tomicrograph showing irregular trabeculae of woven bone in highly cellular hemorrhagic stroma with numerous osteoblasts,
prominent vessels, and occasional osteoclast-like giant cells. (A, B, and D, ×100; C, ×200) (A-D, hematoxylin-eosin)

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156 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-12  ■  Patterns of bony trabeculae and osteoid deposition in nidus of osteoid osteoma. A, Bony trabeculae forming intercon-
necting network with prominent dialated vascular channels in stroma. B, Higher magnification of specimen A shows interconnecting
well mineralized bony trabeculae rimmed by plump osteoblasts (×200). C, Thick, irregular bony trabeculae in a highly cellular stroma
with plump osteoblastic cells and occasional osteoclast-like giant cells. D, Thin, poorly developed bony trabeculae and irregular
osteoid depositions in a background of highly cellular stroma composed of osteoblastic cells, dilated vessels, and occasional
osteoclast-like giant cells. (A, ×100; B-D, ×200) (A-D, hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 157

A B

C D
FIGURE 4-13  ■  Patterns of osteoid depositions in osteoid osteoma. A, Thick, irregular bony trabeculae of well-mineralized
bone obliterating highly cellular stromal tissue. B, Higher magnification of A shows irregular areas of osteoid deposition (×100).
C, Well-mineralized trabeculae form interconnecting network and solid areas of osteoid. D, Irregular, poorly developed osteoid
with collagen-like features produces interconnecting network in a highly vascular spindle cell stromal tissue. (A, ×100; B-D, ×200)
(A and B, hematoxylin-eosin)

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158 4  Benign Osteoblastic Tumors

B
FIGURE 4-14  ■  Cartilage in osteoid osteoma, rare finding. A, Unusual case of osteoid osteoma with area of cartilage in center of
otherwise typical nidus. B, Higher magnification of area marked in A shows well-developed cartilage with myxoid changes. Caution:
This finding is extremely rare in nidus tissue of osteoid osteomas. Diagnosis in such cases should be made only after careful cor-
relation with clinical and radiographic data. (A, ×50; B, ×100) (A and B, hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 159

A B

C D
FIGURE 4-15  ■  Reactive changes adjacent to osteoid osteoma. A and B, Sclerotic cortex at the periphery of osteoid osteoma.
C, Extensive remodeling and sclerosis of cortex adjacent to osteoid osteoma. D, Sclerosis and remodeling of medullary bone in the
vicinity of osteoid osteoma. (A-D, ×100) (A-D, hematoxylin-eosin)

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160 4  Benign Osteoblastic Tumors
out of clinical and radiologic context, it can be confused
with osteosarcoma. Reactive new bone formation usually
can be distinguished by its parallel or radially oriented
bone trabeculae, which often show gradual peripheral
maturation to lamellar bone. These can be easily distin-
guished from the random disorderly pattern of osteoid
and woven bone trabeculae in nidus tissue. In curetted
material, sclerotic nidus tissue may present special prob-
lems in microscopic recognition.
Treatment and Behavior
Osteoid osteomas have limited growth potential and
rarely exceed 1 cm. The majority of lesions are about
0.5 cm in diameter. Some tumors may even sponta-
neously regress.51,116 The primary treatment is surgi-
cal removal of the nidus and some of the surrounding
bone by en bloc excision after precise localization of the
nidus.99,128 Curettage with bone grafting is an acceptable
modality of treatment in anatomic sites where en bloc
excision cannot be performed. However, this approach is
generally discouraged because of the risk of incomplete
removal of the nidus and recurrence of symptoms. Recur-
rence may occasionally happen many years after removal
of the primary lesion.103 In some cases, no nidus tissue can
be found in the resected specimen. According to Mayo
Clinic data, this occurs in nearly 20% of patients with
osteoid osteomas that have a radiologically documented
nidus.117 It is important to consider whether the lesion
was missed at surgery or the pathologist failed to identify
it. The persistence of symptoms suggests that the nidus
was not removed. Such patients need reevaluation and
further surgery if there is evidence of a nidus. The nidus
tissue can be found in a relatively high proportion of
patients who undergo further surgery.117 Still, in some
patients whose symptoms are relieved, no nidus tissue
or other abnormality can be documented in the resected
specimen other than bone sclerosis.
Although en bloc excision is the preferred treat-
ment, in some cases a lesion may be inaccessible to
the surgeon. In such instances, its complete removal
may cause more disability than that associated with
the original disease. Some of these patients can be
managed with prolonged treatment with nonsteroidal
anti-inflammatory drugs. As reported by Kneisl and
Simon,65 prolonged anti-inflammatory treatment (30-40
months) can induce permanent relief of symptoms, and
regression of the nidus may be seen on radiographs. Abla-
tion of the nidus with a percutaneously placed radiofre-
quency electrode that produces thermocoagulation has
become widely accepted. This technique may be of value
in anatomic sites where it is difficult to surgically remove
the tumor.4,5,20,22,31,80,81,106,107 Osteoid osteomas of the verte-
brae present special problems with this type of treatment
because of the risk of nerve root damage, but to date, a
number of tumors at this site have been treated success-
fully without nerve root or spinal cord injury. Reported
success rates for treatment by thermocoagulation with
radiofrequency electrodes have ranged between 80%
and 90% (no need for additional procedures or medica-
tions for 2 years). A needle biopsy guided by computed
ERRNVPHGLFRVRUJ
tomography should be performed before introducing the
electrode with percutaneous thermocoagulation therapy
of osteoid osteomas, because other intracortical or sub-
periosteal lesions can mimic their radiologic appearance.
Among these are intracortical abscess and intracortical
chondroma.
Osteoid Osteoma in Different
Anatomic Sites
The microscopic appearance of nidus tissue in osteoid
osteoma is identical regardless of the anatomic location.
There is no correlation between the pain pattern and the
degree of associated bone sclerosis. In different anatomic
sites and age groups, osteoid osteomas may induce quite
distinct secondary changes in the adjacent bone and soft
tissue that lead to various diagnostic and therapeutic
dilemmas. Therefore it is important from both the patho-
logic and the clinical points of view to discuss osteoid
osteoma separately in three major anatomic locations:
long tubular bones, small bones of the hands and feet,
and the vertebral column. In addition, there are separate
descriptions of subperiosteal and juxtaarticular lesions
because of their distinct clinicoradiologic and pathologic
features.
Osteoid Osteoma of Long Tubular Bones
Osteoid osteomas that occur in long tubular bones are
most often found within the proximal or distal portions
of the bone shafts (Fig. 4-16). Approximately 50% of
cases are diagnosed in the lower extremities; the femoral
neck is the single most frequent anatomic site. The tibia
is the second most frequently involved long tubular bone;
fibular lesions are very rare. In the upper extremities, the
humerus is the most frequently involved bone, and a
majority of cases occur around the elbow joint.108 Involve-
ment of the distal ulna and radius is very rare. Radio-
graphically, the intracortical lesions of long bones are
usually associated with distinct fusiform cortical thicken-
ing that is sometimes accompanied by periosteal reaction.
Occasionally, the periosteal reaction can be very exuber-
ant, with multiple layers of new bone formation. The
exuberant periosteal reaction can mimic that seen in
stress fracture or that associated with Ewing’s sarcoma
(Figs. 4-5 and 4-16). The intramedullary lesions usually
produce less surrounding sclerosis. The absence of dis-
tinct sclerosis around the intramedullary nidus is proba-
bly related to its distant location from labile periosteum.
A rare complication of osteoid osteoma of long tubular
bones is localized overgrowth of bone, angular deformity,
or both95 (Fig. 4-17). These complications typically
happen in very young patients whose symptoms begin
before age 5 years. Long-standing hyperemia induced by
prostaglandins is probably a factor in accelerated growth
of bone in osteoid osteoma. The resulting bone defor-
mity and discrepancy in limb length may disappear after
excision of the nidus. In some patients, however, the
deformity and length discrepancy never completely
resolve. This is particularly true in cases of many years’
duration.95
 4  Benign Osteoblastic Tumors 161

A B C

D E
FIGURE 4-16  ■  Osteoid osteoma in long bones. A, Radiograph of hip of an 8-year-old girl shows nidus with moderate bone sclerosis
surrounding lesion. B, Computed tomogram at this level shows nidus more clearly with cortical thickening and medullary sclerosis.
C, Bone scan shows large zone of increased uptake corresponding to nidus and perilesional sclerosis. D, Radiograph of a 17-year-
old athletic boy with proximal leg pain and localized cortical thickening that at first was thought to represent a stress fracture.
E, Computed tomogram of tibia shown in D reveals punctate lucency diagnostic for intracortical osteoid osteoma.

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162 4  Benign Osteoblastic Tumors

A B C

D E F
FIGURE 4-17  ■  Osteoid osteoma with prominent overgrowth and deformity of bone. A, Osteoid osteoma of the proximal humerus
with prominent diffuse sclerosis and periosteal reaction deforming bone contour. B, Anteroposterior radiograph showing diffuse
sclerosis and length discrepancy of the left femur. C, Radiograph of a 1-year-old boy with painful swelling of left leg. Note sclerosing
lesion of left tibial diaphysis and pronounced length discrepancy. Biopsy showed reactive bone formation. Lesion was diagnosed
as osteomyelitis and was treated with antibiotics. D and E, Five years later, same patient had recurrent pain. Note pronounced
bowing deformity of left tibia and diffuse cortical sclerosis. A biopsy documented nidus of osteoid osteoma. F, Clinical photograph
of the same patient 1 year later, showing discrepancy in limb length and persistent bowing deformity of involved tibia.

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Osteoid Osteoma of Small Bones
of Hands and Feet
In our mainly consultation series of osteoid osteomas,
slightly more than 20% of osteoid osteomas occur in the
small bones of the hands and feet, with tumors occurring
twice as frequently in the hands as in the feet. In the
hands, the phalanges are the most frequently involved
sites.23,88 In small bones, the nidus is usually surrounded
by a distinct zone of sclerosis. The bone contour can be
expanded, and the entire bone can be markedly enlarged.
Osteoid osteomas of small peripheral bones are almost
always associated with a distinct swelling of soft tissue and
synovitis of the adjacent joints. Therefore in this location,
long delays in arriving at the correct diagnosis may occur
because the tumor may frequently mimic an inflamma-
tory process.26 Thus it is not unusual for patients with
osteoid osteoma of the hands and feet to be treated ini-
tially for chronic osteomyelitis or other inflammatory
conditions (Fig. 4-18).
Osteoid Osteoma of Vertebral Column
Approximately 10% to 15% of osteoid osteomas occur in
the vertebral column. Most frequently, they are located
in the lumbar and lower thoracic portions of the spine.
Spinal lesions are difficult to detect on plain radiographs
and are known to be responsible for unexplained back-
ache and painful scoliosis.8,21,58,62,97,102,115 In some patients,
clinical symptoms may suggest a neurologic disorder,
lumbar disk disease, or both conditions. It is recom-
mended that an underlying osteoid osteoma be ruled out
in virtually all cases of unexplained back pain and painful
scoliosis that occur in children and young adults.8,20,62,109,115
Although removal of the lesion usually results in gradual
regression of the curve, in neglected cases a prolonged
delay in treatment may result in persistent structural sco-
liosis.102 As mentioned, a vertebral nidus of osteoid
osteoma is difficult to detect on plain radiographs. At
best, the radiographs may show an area of sclerosis, a
thickened and distorted sclerotic transverse process, or a
deformed sclerotic pedicle with indistinct borders. Locat-
ing the exact anatomic site of the nidus requires com-
puted tomography (Figs. 4-6 and 4-7). In vertebrae the
nidus is most frequently located in the posterior arch.
Magnetic resonance imaging also may facilitate the iden-
tification of an inconspicuous nidus. High signal in T2-
weighted images of nidus tissue correlates well with its
increased vascularity. Other frequent locations include
articular facets and pedicles. Less frequently the nidus is
located in the transverse and spinous processes. A primary
tumor in the vertebral body is extremely rare. Within the
body the nidus is usually located eccentrically near the
base of a transverse process.
Juxtaarticular Osteoid Osteoma
Osteoid osteomas located within the articular capsule are
rare and difficult to detect.12,16,24,28,37,45,56,61,94,112,114,126,132
Any joint may be involved, but the most vexing diagnostic
problems involve the elbow, hip, and ankle joints. They
are typically associated with nonspecific symptoms similar
ERRNVPHGLFRVRUJ
4  Benign Osteoblastic Tumors 163
to other common joint disorders. Pain is usually less
intense, and its response to nonsteroidal antiinflamma-
tory drugs is less dramatic. On plain radiographs the
intraarticular nidus is difficult to identify (Fig. 4-19). In
addition, the adjacent sclerosis is typically absent, and
there is no periosteal reaction. Consequently, there is
usually a considerable delay between the onset of
symptoms and identification of the nidus. Bone scintig-
raphy, computed tomography, and magnetic resonance
imaging are virtually essential for early detection of
the nidus. In addition, these techniques usually reveal
minimal periosteal reaction and sclerosis at a distance
from the lesion on either side of the joint. The absence
of distinct sclerosis around these lesions is probably
related to a lack of functional periosteum in the immedi-
ate vicinity of the intracapsular nidus. To the contrary,
intraarticular osteoid osteoma can provoke periarticular
osteoporosis similar to that associated with inflammatory
arthropathy.
In rare instances, the intraarticular lesions may even
induce degenerative changes within the articular carti-
lage, promote proliferation of chondrocytes with angio-
genesis, and promote migration of mesenchymal cells in
the subchondral bone. These changes are responsible for
the development of secondary osteoarthritis with osteo-
phyte formation and occasionally extensive joint destruc-
tion.94 In unusual instances, osteoid osteoma may induce
premature fusion of the epiphysis.19
The intraarticular lesions typically are associated with
an inflammatory response of the synovium, which is
edematous and thickened and shows villous overgrowth.
Histologically, it is characterized by a lymphoprolifera-
tive synovitis with multiple lymphoid follicles indistin-
guishable from rheumatoid arthritis (Fig. 4-20). However,
destruction of the joint with formation of pannus and
subsequent ankylosis does not occur. Synovial changes
spontaneously subside after removal of the nidus. It is
postulated that increased levels of prostaglandins can
play a major role in secondary synovitis and soft tissue
edema commonly associated with intraarticular osteoid
osteoma.119 It has also been found that the occurrence of
synovitis in patients with osteoid osteoma coincides with
the presence of DR4, DR7, and MT3 types of histocom-
patibility antigens (HLA), the types frequently found in
patients with rheumatoid arthritis.119
Subperiosteal Osteoid Osteoma
Subperiosteal osteoid osteoma is a relatively rare lesion
that has unique radiographic and microscopic features.
Conventional radiographs demonstrate a lucent lesion on
the surface of bone with adjacent periosteal reaction. The
nidus is typically radiolucent with no evidence of central
opacity. It has been suggested that the absence of restrict-
ing compressive force exerted on the lesion growing on
the surface of bone is at least in part responsible for the
generally larger size of subperiosteal osteoid osteoma.63
The lack of confinement may also explain other distinct
histologic features of surface lesions. The subperiosteal
nidi are on average less sclerotic and have thinner tra-
beculae and a greater proportion of stromal tissue com-
pared with intracortical lesions.
164 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-18  ■  Osteoid osteoma in short tubular bones masquerading as chronic osteomyelitis. A, Radiograph of sclerotic nidus in
proximal phalanx of long finger (arrows) of a 26-year-old woman who noted pain and swelling for 2 years before diagnosis was
established. She had been followed and treated for suspected osteomyelitis throughout this period. B, Clinical photograph of case
A showing soft tissue edema and deformity of long finger. C, Radiograph showing lucent nidus with sclerosis in the adjacent bone
in proximal phalanx of fifth finger. D, Radiograph of a 22-year-old man with pain, swelling of soft tissue, and expanded radiolucent
nidus in proximal phalanx of index finger (arrows). Diagnosis of chronic osteomyelitis resulted in prolonged treatment with antibiot-
ics. Cultures were always negative, and even after synovial biopsy, chronic inflammation was diagnosed. Finally, after 5 years
radiologic diagnosis of osteoid osteoma was suggested, and curettage resulted in permanent relief of symptoms.

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 4  Benign Osteoblastic Tumors 165

A B

C D
FIGURE 4-19  ■  Juxtaarticular osteoid osteoma of elbow joint. A, Radiograph of elbow joint with diffuse, poorly demarcated area of
sclerosis of proximal ulnar metaphysis (arrows). No nidus tissue can be identified. B, Computed tomogram of case shown in
A documents juxtaarticular sclerotic nidus in ulna that is surrounded by lucent halo (arrow). Nidus is not centrally located in sclerotic
area. C, Radiograph of elbow showing ill defined sclerosis and prominent periosteal reaction involving the distal end of humerus.
D, Magnetic resonance imaging shows inhomogeneous subarticular nidus of intermediate signal intensity (arrows). Note prominent
periosteal reaction of the distal humerus and fluid accumulation in the elbow joint.

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166 4  Benign Osteoblastic Tumors

B
FIGURE 4-20  ■  Synovial changes associated with osteoid osteoma. A, Lymphoproliferative synovitis with lymphocytic infiltrate of
synovium and multiple lymphoid follicles with germinal centers. B, Higher magnification of follicle shown in A. Note scattered
predominantly perivascular inflammatory infiltrate (A, ×50; B, ×100) (A and B, hematoxylin-eosin)

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Personal Comments
Problems with the identification of nidus tissue and the
simulation of reactive, posttraumatic, and inflammatory
conditions have predominated in diagnostic case material
submitted for consultation. The recurring theme of
confusion between reactive bone and suspected nidus
tissue, when the nidus has not actually been sampled, is
exemplified by Figure 4-21. The humoral effects of
osteoid osteoma on surrounding bone and soft tissue
have often masked the presence of a nidus and have
led to long delays in diagnosis and treatment. As a con-
sequence, the patient may undergo inappropriate therapy
for many months or even years under the mistaken diag-
nostic impression of an infection or inflammatory condi-
tion. Frequent use of computerized imaging techniques
in diagnostic workup in bone lesion in modern practice
has dramatically reduced the incidence of such lesions.
Our own experience with the exceptional cases in
which nidus tissue is never documented microscopically
in the face of typical clinical and radiologic features coin-
cides with that described by Sim et al.117 This remains an
unresolved issue, but recent evidence of spontaneous or
therapy-induced regression of osteoid osteoma may
provide an explanation for this discrepancy.65
BENIGN OSTEOBLASTOMA
Definition
Benign osteoblastoma is a rare osteoblastic tumor that
is closely related to osteoid osteoma. In fact, the micro-
scopic features of the nidus in osteoid osteoma are similar
and quite often identical to those of osteoblastoma.
Benign osteoblastoma differs from osteoid osteoma in
that it has a higher growth potential because it exceeds
2 cm in diameter. Moreover, it frequently lacks distinct
nocturnal pain that can be relieved by aspirin. Secondary
peripheral sclerosis may be minimal or absent. Still, there
are cases with composite features that fall between osteoid
osteoma and osteoblastoma. These have been designated
in the past as giant osteoid osteomas. This problem has been
resolved by arbitrarily designating all lesions as osteoblas-
tomas when the nidus is more than 1.5 cm in diameter.
The lesion designated as cementoblastoma in the oral
pathology literature is an osteoblastoma located in jaw
bones in the vicinity of the roots of teeth. Benign osteo-
blastomas of the mandible do not differ in their morpho-
logic features and behavior from those located in other
anatomic sites. They are included among the osteoblas-
tomas of the craniofacial bones in our series.
Incidence and Location
The peak age incidence and frequent sites of skeletal
involvement are shown in Figure 4-22. The skeletal and
age distribution patterns of individual osteoblastomas are
shown in Figure 4-23. Benign osteoblastoma is a very
rare tumor that accounts for less than 1% of all primary
bone tumors. Most patients are between age 5 and 45
years, and the peak incidence is in the second and third
ERRNVPHGLFRVRUJ
4  Benign Osteoblastic Tumors 167
decades of life. The male/female ratio is the same as that
for osteoid osteoma, approximately 2 : 1.
Benign osteoblastoma has a unique predilection for
the axial skeleton, with more than 40% of cases involving
the vertebral column, sacrum, and the proximal parts
of the appendicular skeleton such as pelvis and femur
(Figs. 4-24 and 4-25).21,81,85,111,125 The second most fre-
quent site is the jaw bone, followed by other craniofacial
bones (Figs. 4-26 and 4-27). Benign osteoblastoma also
occurs frequently in the extremities, where its overall
distribution is similar to that of osteoid osteoma. Conse-
quently the proximal femur in the area of the femoral
neck is its most frequent site in the appendicular skeleton.
In the upper extremities, the humerus is most frequently
involved. Benign osteoblastoma is rarely present in ribs
and flat bones. Rare instances of osteoblastomas associ-
ated with severe systemic symptoms of fever, weight loss,
cachexia, clubbing of fingers and toes, and diffuse peri-
ostitis (“toxic osteoblastoma”) have been observed.35 A
case of a conventional osteoblastoma arising extraskele-
tally in the laryngeal cricoid cartilage has been reported.67
Osteoblastomas are uncommonly associated with onco-
genic phosphaturic syndromes.29
Radiographic Imaging
The radiographic features of some benign osteoblasto-
mas are similar to those of osteoid osteoma. Benign
osteoblastoma produces a round or oval, well-demarcated
metaphyseal lytic defect surrounded by a zone of reactive
sclerosis.66,77,81,85,125 Less commonly in long bones, it may
arise entirely within the epiphysis.132 The main difference
from osteoid osteoma is that the nidus is larger, exceeding
1.5 cm in diameter.81,110 Moreover, the sclerotic zone is
frequently less extensive compared with that of an ordi-
nary osteoid osteoma. In fact, sclerosis may not be present
at all. It is believed that the predilection of benign osteo-
blastoma for cancellous bone may at least in part account
for the absence of distinct sclerosis. In the vertebral
column and the sacrum, the tumor is located posteriorly
within the dorsal elements of the arch (Figs. 4-24 and
4-25).89,91 A primary tumor within the vertebral body is
unusual.92 The osteoblastic nature of the lesion can be
documented on radiographs in nearly 50% of all cases by
the presence of patchy or cloudlike radiopacities. Exten-
sive reactive changes in the surrounding tissue and appar-
ent soft tissue masses on magnetic resonance imaging
may overestimate the extent of the lesion, so computed
tomography should continue to be the imaging modality
of choice for the demonstration and local staging of sus-
pected vertebral osteoblastomas.26 Osteoblastomas of the
spine frequently develop a secondary aneurysmal bone
cyst and may present as expansile destructive lesions
involving the adjacent vertebra and ribs.
Mandibular lesions are located in the vicinity of a
tooth root and almost invariably show central opacity
surrounded by a lucent halo (Fig. 4-26). Their pathoge-
netic relationship to the root of the tooth is most likely
incidental. In other words, they do not arise from the
odontogenic apparatus itself but rather from adjacent
bone.
Text continued on p. 174
168 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-21  ■  Eighteen-year-old man who noted pain in right hip region on weight bearing and developed progressively worsening
limp. A, Plain radiograph shows bone sclerosis of ischium with prominent periosteal new bone formation. Inset shows bone scan
with high uptake of isotope. B, Computed tomogram reveals central nidus, which was obscured by profuse reactive changes. Inset,
Magnetic resonance image shows central nidus surrounded by sclerotic bone and extensive reactive changes. C and D, This lesion
was originally considered to be benign reactive bone-forming process related to trauma even after two biopsies. These showed
only reactive bone formation. Later, on third exploration for continuing symptoms and persistent sclerosis, easily distinguished
nidus tissue was excised from interior of ischium. (C and D ×100; hematoxylin eosin)

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 Peak
incidence
10 40
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 4-22  ■  Osteoblastoma. Peak age incidence and frequent sites of skeletal involvement.

Osteoblastoma
30 35
Mean Age: 25
30 Male/Female Ratio: 1.43
25

25
Number of Cases

Number of Cases

20

20
15
15
10
10

5 5

0 0
1 2 3 4 5 6 7 8 9
Vertebra
Mandible
Skull
Sacrum
Maxilla
Rib
Ilium

Tibia
Humerus
Fibula
Radius
Ulna
Tarsal
Carpal
Phalanx
Femur

Age in Decades
B
Flat Major Small bones of
bones long bones hands and feet

Axial Appendicular
skeleton skeleton
A
FIGURE 4-23  ■  Skeletal sites and age frequency distribution patterns of osteoblastoma. A, Skeletal distribution of osteoblastoma.
B, Age frequency distribution of osteoblastoma.

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170 4  Benign Osteoblastic Tumors

A C
FIGURE 4-24  ■  Osteoblastoma radiographic and microscopic features. A, Anteroposterial plain radiograph of lumbar spine showing
ill defined sclerotic lesion involving the left pedicle of L5 lumbar vertebra (arrows). B, Computed tomogram shows well-circumscribed
lytic tumor with foci of mineralized bone matrix in lateral body and neural arch. C, Trabeculae of woven bone with irregular scal-
loped borders in hypercellular stroma with abundant osteoblasts and osteoclast-like giant cells. (C, ×100). (C, hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 171

A B

C D
FIGURE 4-25  ■  Osteoblastoma of lumbar and cervical vertebrae. A, Osteoblastoma of lumbar vertebra in a 27-year-old man with
radicular pain related to L5 computed tomogram shows lobulated posterior extradural mass displacing dural sac to left and anteri-
orly. Origin of tumor from within lamina is shown by central lucency (arrow). B, Magnetic resonance sagittal image shows destruc-
tion of lamina with soft tissue mass in spinal canal. Mass demonstrates high signal with foci of signal void corresponding to tumor
matrix mineralization. Same case as shown in A. C, Osteoblastoma of third cervical vertebra of a 36-year-old man. Magnetic reso-
nance image shows high signal at site of eccentric tumor involving posterolateral portion of third cervical vertebral body and pedicle
on left. D, Computed tomogram shows well-circumscribed lytic tumor containing foci of mineralized bone matrix in base of pedicle,
lamina, and body. Dural sac is displaced to right. Same case as shown in C.

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172 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-26  ■  Osteoblastoma of mandible. A, Nineteen-year-old man who reported pain at site of previously extracted lower tooth.
Well-circumscribed radiolucent area with central opacity represents benign bone-forming tumor. B, Bone-forming mass with ill
defined punctuated mineralization pattern at the root of bicuspid. C, Twenty-two-year-old man with tumor arising adjacent to root
of first molar tooth. D, Gross photograph of tumor shown in C; tumor consists of firm, gritty mass attached to tooth root.

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 4  Benign Osteoblastic Tumors 173

A B

E
FIGURE 4-27  ■  Osteoblastoma of skull: radiographic features. A and B, Plain lateral and anteroposterior radiographs of osteoblastoma
arising in left frontoparietal region of skull of 18-year-old woman. Notice beveled edge surrounding totally radiolucent tumor. Double
contour of margin is caused by unequal destruction of inner and outer tables of calvarium. Mass was present for 4 years without
significant increase in size. Throbbing headaches and blurring of vision were present. There was incomplete relief with aspirin.
C, Computed tomogram shows shell of reactive bone peripherally and smaller intracranial bulge. D, Gross photograph of resected
specimen showing well-circumscribed, tan external surface of osteoblastoma. E, Gross photograph of bisected resection specimen
of calvarial osteoblastoma. Note sharp circumscription and greater destruction of outer table than of inner cortex.

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174 4  Benign Osteoblastic Tumors
Osteoblastoma may expand the bone contour with a
markedly thinned cortex (Fig. 4-27). The cortex can be
at least focally destroyed with or without periosteal new
bone formation. These features are responsible for the
radiologic confusion with malignant tumors that may
occur in approximately 20% of osteoblastomas.81 In a
large study of osteoblastomas comprising over 300 cases,
radiographic evidence of bone expansion and destruction
was present in nearly 40% of the cases.74 In 12% of
the lesions, radiographic presentation was suggestive of
malignancy.74 Occasionally, osteoblastomas are located
on the surface of bone (subperiosteal osteoblastomas) and
produce a lucent lesion that may erode the cortex.90
Surface lesions may be surrounded by a thin shell of
periosteal new bone (Fig. 4-28).
Gross Findings
The gross appearance of the nidus in benign osteoblas-
toma is similar to that of osteoid osteoma. Because of its
rich stromal vasculature, the tissue is granular, friable, and
reddish and may bleed profusely when curetted. The
nidus is well demarcated at its periphery and can be easily
separated from the surrounding bone. The bone contours
can be markedly expanded, especially in small bones. The
cortex is thinned and may be focally destroyed. There
may be gross evidence of hemorrhage and cystic degen-
eration with blood-filled spaces characteristic of second-
ary aneurysmal bone cyst. The hemorrhage and secondary
reparative changes are particularly frequent in larger
lesions and may significantly alter the gross appearance.
Microscopic Findings
The microscopic features of osteoblastoma are similar to
those of ordinary osteoid osteoma (Figs. 4-29 to 4-31). At
low magnification the nidus tissue consists of an interlac-
ing network of bone trabeculae evenly distributed in a
loose fibroblastic stroma with a prominent vasculature.
The osteoid formed may be deposited in coarse trabecu-
lae or sparsely cellular sheets. Areas focally approaching
a lacelike appearance can be present but are uncom-
mon. Prominent rimming osteoblasts and multinucle-
ated osteoclast-like giant cells are present. In general, the
osteoblasts do not form solid sheets that fill the intertra-
becular spaces. The mitotic rate can be focally quite high,
but atypical mitoses are not seen. Although the lesion is
grossly well demarcated, microscopically the osteoid tra-
beculae merge gradually with the adjacent normal bone.
Varying degrees of mineralization of osteoid can be seen.
When the tumor extends beyond the cortex, the soft
tissue margin usually has a clearly recognizable shell of
reactive bone. Large, expanded lesions usually have gross
and microscopic evidence of secondary aneurysmal bone
cyst with multiple cystic spaces filled with blood.
As a rule, cartilage should not be present in benign
osteoblastoma. However, in our consultation material,
foci of benign cartilage were found in several otherwise
typical osteoblastomas with proven benign clinical behav-
ior (Fig. 4-32).
In rare instances stromal cells in osteoblastoma
may show pronounced atypia, such lesions are referred
ERRNVPHGLFRVRUJ
to as atypical or pseudosarcomatous osteoblastomas (Fig.
4-33). The atypia is of a degenerative type similar to
that more often seen in ancient schwannomas. The
absence of mitotic activity and specifically of atypical
mitoses is helpful in distinguishing such lesions from an
osteosarcoma.9
Differential Diagnosis
Osteoblastoma should be differentiated from osteosar-
coma, osteoid osteoma, and aneurysmal bone cyst. The distin-
guishing features of osteoid osteoma and osteoblastoma
were discussed in the opening paragraph of this chapter.
The main differences of size, pain pattern, and perile-
sional sclerosis are usually sufficient to separate these two
entities, which are histologically indistinguishable. An
arbitrary size limit of 1.5 cm has been proposed for
lesions with composite features; those exceeding this
dimension are classified as osteoblastomas.
Osteoblastomas that attain sizes exceeding 4 cm and
that show prominent or exuberant periosteal new bone
formation present problems in their radiographic dif-
ferentiation from osteosarcoma. This group of osteoblas-
tomas may also show histologic features that can be
misinterpreted as signs of malignancy by the pathologist.
These features include foci of lacelike osteoid deposition,
high cellularity, and more than a few scattered mitotic
figures. This may be further complicated by the rare
finding of small foci of cartilage in otherwise benign-
appearing osteoblastomas. Fortunately, these exceptional
disturbing features usually occur separately and focally in
a tumor that otherwise represents a conventional benign
osteoblastoma. A tumor that exhibits all the mentioned
atypical features is best regarded as an osteosarcoma.
Although aneurysmal bone cysts have not been
observed in association with osteoid osteomas, they
present a distinct problem because they frequently occur
as secondary phenomena superimposed on underlying
osteoblastomas. Moreover, primary aneurysmal bone
cysts not associated with underlying lesions have a pre-
dilection for the same anatomic sites as osteoblastomas.
This is particularly true with regard to their occurrence
in the posterior neural arch of vertebrae.
Reactive bone formation in solid areas or septa of an
aneurysmal bone cyst should not be interpreted as evi-
dence of an underlying osteoblastoma. Aneurysmal bone
cysts may contain microscopic zones of reactive osteoid
and new bone that differ from the small, irregular, anas-
tomosing trabeculae of nidus tissue.
Similar to osteoid osteomas, osteoblastomas express
transcription factors controlling osteoblastic lineage dif-
ferentiation, such as Runx2 and Osterix.36
Treatment and Behavior
Osteoblastomas have a higher growth potential than
osteoid osteomas and may occasionally attain consider-
able size. Typical lesions are approximately 2 cm in
diameter. Similar to osteoid osteoma, osteoblastomas fre-
quently present as painful lesions.91 Lesions located in the
axial skeleton frequently present as back pain, neurologic
Text continued on p. 181
 4  Benign Osteoblastic Tumors 175

A B C

D E

FIGURE 4-28  ■  Two examples of subperiosteal osteoblastoma. A, Radiograph of 30-year-old woman who reported posterior thigh
pain above knee. Lateral radiograph of femur with surface lesion (arrow) attached to posterior cortex. B and C, Sagittal and axial
magnetic resonance T1-weighted images show subperiosteal location with cortical erosion. Note low signal in adjacent marrow and
signal void of normal cortical bone. D, Radiograph of 15-year-old boy with knee pain, who was found to have eccentric lytic lesion
of distal femoral metaphysis. Anteroposterior view shows periosteal elevation with cortical erosion (arrow). E, Computed tomogram
shows encapsulation by peripheral shell of subperiosteal bone and cortical erosion. Central opacity is present. Note unusual degree
of adjacent sclerosis.

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176 4  Benign Osteoblastic Tumors

B C
FIGURE 4-29  ■  Osteoblastoma of pelvis: radiographic and microscopic features. A, Axial computed tomogram of pelvis showing
well-circumscribed osteoblastoma involving the iliac bone in the vicinity of the sacroiliac joint. B, Low power photomicrograph of
osteoblastoma showing irregular ill defined trabeculae of woven bone in hypercellular stromal tissue. C, Intermediate power pho-
tomicrograph of osteoblastoma with irregular bony trabeculae surrounded by prominent rims of osteoblasts. Note hypercellular
spindle cell stromal tissue. (B and C, ×100) (B and C, hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 177

A B

C D
FIGURE 4-30  ■  Osteoblastoma: patterns of osteoid deposition. A, Irregular bony trabeculae in highly cellular vascular stroma.
B, Irregular, ill defined sheets of osteoid with entrapped osteoblastic cells (×100). C, Ill defined irregular areas of poorly mineralized
osteoid. D, Higher power view shows prominent osteoblastic cells bordering irregular poorly mineralized bony trabeculae. (A-C,
×100; D, ×200) (A-D, hematoxylin-eosin)

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178 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-31  ■  Osteoblastoma: patterns of osteoid deposition. A, Irregular haphazardly arranged bony trabeculae of woven
bone surrounded by plump osteoblastic cells in a highly cellular spindle cell stromal tissue with dilated vessels. B, Irregular,
thick trabeculae of woven bone in osteoblastoma. C, Small focus of lacelike poorly mineralized osteoid with entrapped
osteoblastic cells. D, Small focus of ill defined osteoid deposition with entrapped osteoblastic cells. (A and B, ×100; C and D, ×200).
(A-D, hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 179

B
FIGURE 4-32  ■  Cartilage in osteoblastoma. A, Unusual case of osteoblastoma with area of well-developed cartilage in otherwise
typical osteoblastoma. B, Higher power view of A. Well-developed areas of endochondral ossification. (A, ×50; B, ×100) (A and
B, hematoxylin-eosin)

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180 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-33  ■  Atypical osteoblastoma with pseudosarcomatous changes: microscopic features. A, Low power photomicrograph
shows well-developed haphazardly oriented trabeculae of bone in hypercellular stroma with atypia. B, High power photomicrograph
of stromal tissue shows prominent nuclear atypia. C and D, High power photomicrographs of bony trabeculae in stromal tissue
showing prominent atypia. Note the degenerative nature of atypia and the absence of mitotic activity in this osteoblastoma with
pseudosarcomatous change. (A, ×100; B-D, ×200) (A-D, hematoxylin-eosin)

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disorders, or painful scoliosis.43,89,91 In unusual cases, the
tumor may induce a pronounced inflammatory reaction
in the surrounding soft tissue similar to the reaction that
occurs in osteoid osteoma.32 The preferred primary treat-
ment is surgical en bloc excision. Complete removal of
the tumor is not always possible, especially in the spine.
In such instances, radiotherapy is sometimes used to
control the disease. The recurrence rate after surgical
removal may be as high as 25%. In some cases, there may
be multiple recurrences. Malignant transformation has
been reported rarely for osteoblastoma.39,40,78,79,82,114,131
AGGRESSIVE OSTEOBLASTOMA
Definition
Aggressive osteoblastoma is a rare tumor that represents
a borderline lesion between benign osteoblastoma and
osteosarcoma. These tumors are likely to recur, do not
metastasize, and are characterized microscopically by the
presence of so-called epithelioid osteoblasts. Transition to
osteosarcoma has not been observed to date, and these
rare tumors therefore are not considered to be precursors
of conventional osteosarcoma.
Incidence and Location
This is a very rare tumor, and its true incidence and its
age distribution are not exactly known. The original
series, reported in 1984, consisted of 15 cases,39 and an
update published in 199641 dealt with 21 additional cases
of aggressive osteoblastoma. A further 11 cases observed
as consultations since 1996 are included in the present
chapter. The limited experience with these tumors based
on the analyses of 47 cases indicates that they occur in a
slightly older group of patients than conventional osteo-
blastomas. The peak age incidence is in the second and
third decade of life. The ages of 47 patients with aggres-
sive osteoblastoma ranged between 7 and 80 years. Only
3 patients were younger than age 10 years. The male-to-
female ratio in this group was 1.5 : 1 Fifteen of the tumors
were in the vertebral column, three in the sacrum, one in
the scapula, five in the proximal femur, one in the
humerus, four in the ilium, one in the pubic ramus, three
in the skull, two in the mandible, and one in the maxilla.
Six tumors were located in small bones of the hands and
feet. This indicates that the overall distribution pattern
of aggressive osteoblastoma is similar to that of conven-
tional osteoblastoma, with clear predilection for the
axial skeleton. The second most frequent location of
occurrence is in the small bones of the hands and feet.
This distribution pattern is clearly different from that
of conventional osteosarcoma, further supporting the
close pathogenetic relationship between aggressive
osteoblastoma and conventional osteoblastoma. Aside
from the personally collected series reported here and
based largely on consultation material, the recent litera-
ture contains individual case reports of these very rare
tumors.1,2,10,73,101,118,127 Multifocal, primary soft tissue, and
cutaneous aggressive osteoblastomas have also been
described.27,33,38,72 Aggressive osteoblastomas can also be
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4  Benign Osteoblastic Tumors 181
associated with vitamin D-resistant rickets.69 The peak
age incidence and the most frequent sites of skeletal
involvement of aggressive osteoblastoma are shown in
Figure 4-34. The skeletal and age distribution patterns
of individual aggressive osteoblastomas are shown in
Figure 4-35.
Radiographic Imaging
Aggressive osteoblastomas share many of the radio-
graphic features of conventional osteoblastoma. The
lesion consists of a circumscribed lytic defect sometimes
surrounded by a rim of sclerosis (Fig. 4-36). The bone
contour can be markedly expanded and have a rim of
reactive bone. The main difference from conventional
osteoblastoma is that aggressive osteoblastomas are
larger, usually exceeding 4 cm in diameter.42 In our series,
the range of maximum dimensions was 2 to 8.5 cm. The
vertebral lesions do not differ in appearance from con-
ventional osteoblastoma and represent lucent masses
located in the posterior elements of the neural arch
(Fig. 4-37). Similarly, the lesions of the sacrum are located
within its dorsal elements and expand posteriorly
(Fig. 4-38). The lesions of long bones and the skull may
have a distinct rim of moderate sclerosis. In small bones,
the soft tissue is frequently involved (Fig. 4-39).
In small anatomic structures (vertebral column, bones
of the hands and feet), the lesion may cross a joint space
to involve the adjacent bone, providing clear evidence of
its local aggressive nature. In some cases, prominent peri-
osteal new bone formation can be present, raising the
radiologic suspicion of malignancy. The osteoblastic
nature of the lesion can sometimes be documented by the
presence of patchy, cloudlike opacities (Fig. 4-39). Similar
to conventional osteoblastomas, aggressive osteoblas-
toma can lead to the development of secondary aneurys-
mal bone cysts that present as expansile destructive
lesions (Fig. 4-40).
Gross Findings
The gross appearance of aggressive osteoblastoma is
similar to that of osteoblastoma. Intact in its anatomic
setting, the lesion is oval or round with well-defined
margins (Figs. 4-41 and 4-48). The tissue is granular,
friable, and reddish in color. Similar to conventional
osteoblastoma, it may bleed profusely during curettage
because of its rich stromal vasculature. The bone contour
can be markedly expanded with a thinned and focally
disrupted cortex. Extension into the adjacent soft tissue
may be present, often with an encasing shell of reactive
bone peripherally.42 The main difference from conven-
tional osteoblastoma is the size of the lesion, which typi-
cally exceeds 4 cm in diameter.
Microscopic Findings
Aggressive and conventional osteoblastomas share many
of the same microscopic features. The main difference
and the most prominent feature of aggressive osteoblas-
toma is the presence of so-called epithelioid osteoblasts that
Text continued on p. 189
 Peak
Incidence
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 4-34  ■  Aggressive osteoblastoma. Peak age incidence and frequent sites of skeletal involvement.

Aggressive Osteoblastoma
16 20
Mean Age: 25.4
14 18 Male/Female Ratio: 1.61
16
12
14
Number of Cases

Number of Cases

10
12

8 10

8
6
6
4
4
2
2

0 0
1 2 3 4 5 6 7 8 9
Vertebra

Maxilla

Sacrum

Skull

Mandible

Pelvis

Scapula

Humerus

Tarsal

Phalanx

Metatarsal
Femur

Age in Decades
B

Flat Major Small bones of

bones long bones hands and feet

Axial Appendicular
skeleton skeleton
A
FIGURE 4-35  ■  Skeletal sites and age frequency distribution patterns of aggressive osteoblastoma. A, Skeletal distribution of aggres-
sive osteoblastoma. B, Age frequency distribution of aggressive osteoblastoma.
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 4  Benign Osteoblastic Tumors 183

A B

C D
FIGURE 4-36  ■  Aggressive osteoblastoma: radiographic features. A, Ill defined tumor with irregular mineralization pattern and diffuse
sclerosis of the adjacent bone involving proximal tibia. B, Mixed lytic and sclerotic tumor with ill defined margins and sclerosis in
the adjacent bone of proximal tibia. C, Ill defined lytic tumor of distal femur with sclerosis in the adjacent bone. D, Mixed lytic and
sclerotic tumor with ill defined margins involving the medial condyle of femur.

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184 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-37  ■  Aggressive osteoblastoma of vertebra. A, Radiograph of cervical spine in a 19-year-old man who had pain and par-
esthesias for 112 years. Expanded lytic lesion involves mainly transverse process of C5. B, Computed tomogram of case in A shows
expanded but well-delimited lesion with focal radiodensities in lateral aspect of vertebra. Although body is involved, lesion appears
to originate in lateral and posterior vertebral elements. C, Axial computed tomogram (bottom) and sagittal cut scout film (top).
Patient was a 53-year-old man with 3-week history of back pain radiating to lower extremities. D, Axial section of vertebra shown
in A documents eccentric lytic lesion primarily involving vertebral body and extending posteriorly into spinal canal.

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 4  Benign Osteoblastic Tumors 185

B C
FIGURE 4-38  ■  Aggressive osteoblastoma of sacrum with secondary aneurysmal bone cyst. Patient, a 16-year-old girl, incidentally
was found to have osteopoikilosis, which is shown in radiographs of pelvis. A, Anteroposterior view reveals lytic lesion in left side
of sacrum. Punctate opacities are not related and merely represent osteopoikilosis. B, Lateral view of sacrum shows posteriorly
expanded contour of tumor with superimposed aneurysmal bone cyst. C, Computed tomogram reveals expanded lytic lesion with
radiopaque delimiting capsule.

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186 4  Benign Osteoblastic Tumors

A B C

D E
FIGURE 4-39  ■  Aggressive osteoblastoma of short tubular bones. A, Radiograph of right long finger of a 19-year-old woman shows
lytic area of recurrent tumor in middle phalanx. Benign osteoblastic tumor was removed from this site 1 year previously. Review
of this material and histologic study of recurrence showed aggressive osteoblastoma. B, Second recurrence, 2 years later, shows
extension to adjacent soft tissue. This led to ray amputation because of likelihood of further recurrences. C, Sagittally cut amputa-
tion specimen shows tumor in middle phalanx that extends into soft tissue on volar aspect. D, Radiograph of thumb metacarpal
tumor in a 21-year-old man who had pain and swelling for 5 months. The patient received radiation therapy, and amputation was
done 1 year later. Note expanded cortical contour and dense radiopacities within lesion. E, Forty-six-year-old woman with painless
swelling of her right second toe of several years’ duration. Proximal phalanx shows that bone-forming tumor has caused extensive
destruction and has extended into soft tissue.

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 4  Benign Osteoblastic Tumors 187

A B

C D
FIGURE 4-40  ■  Aggressive osteoblastoma involving right superior pubic ramus. A, Radiograph of a 18-year-old man 3 months before
admission shows 5-cm lytic lesion at junction of acetabulum and ramus. B, Large, expanded mass at same site 3 months later is
shown in this anteroposterior film. C, Computed tomogram of pelvis. The “blown-out” area of juxtaacetabular bone represents
secondary aneurysmal bone cyst superimposed on aggressive osteoblastoma. D, Radioisotope scan shows marked uptake at site
of combined bone-forming tumor and secondary aneurysmal bone cyst.

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188 4  Benign Osteoblastic Tumors

A C

D E
FIGURE 4-41  ■  Aggressive osteoblastoma involving left acetabular region of ilium. A, Anteroposterior radiograph of a 61-year-old
woman with 6-month history of increasing left hip pain shows well-circumscribed lytic lesion with central opacity (arrows). B and
C, Computed tomograms show lesion adjacent to acetabulum and reactive sclerosis in surrounding bone. D, Specimen radiograph
shows multiple areas of patchy density not visible on computed tomogram or plain film. E, Specimen photograph shows granular
hemorrhagic tumor with bony central foci.

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rim osteoid trabeculae and occasionally form loosely
cohesive solid sheets that fill the intertrabecular spaces
(Fig. 4-42). Large solid areas of epithelioid osteoblasts
with mild to moderate atypia can be present (Figs. 4-43
to 4-45).1,28,29,31,86,98,104,105
At low magnification, the lesion consists of an irreg-
ular network of bone trabeculae haphazardly distrib-
uted in a loose fibroblastic stroma with a prominent
vasculature. The trabeculae occasionally appear wider
and more irregular than those of conventional osteo-
blastoma. The deposition of osteoid may focally be in
a nontrabecular, lacelike pattern surrounding individual
cells. There may also be broad zones of solid osteoid
enveloping individual epithelioid osteoblasts (Figs. 4-46
and 4-47).
Chondroid differentiation has not been observed in
aggressive osteoblastomas. Numerous benign osteoclast-
type multinucleated giant cells are often present. In some
cases, they may be present only focally.
As mentioned, the presence of epithelioid osteoblasts
is a hallmark of aggressive osteoblastoma. These cells are
round; are at least twice the size of ordinary osteoblasts;
and show abundant eosinophilic cytoplasm and an eccen-
tric large, oval or round nucleus with a prominent nucle-
olus (Fig. 4-48). Within the cytoplasm, there is usually a
large, clear area that sometimes compresses and displaces
the nucleus. Ultrastructurally, this structure represents an
enlarged Golgi center. The remaining cytoplasm has a
few mitochondria and numerous prominent channels of
rough endoplasmic reticulum. The cells form loosely
cohesive sheets, with the formation of small, irregular,
glandlike spaces seen ultrastructurally. The mitotic activ-
ity within the epithelioid osteoblasts ranges from 1 to 4
mitoses per 20 high-power fields. Atypical mitoses are
not present. The mitotic activity of the associated stromal
cells is very low or absent. No mitotic activity is present
within the giant osteoclast-like cells.
Gross and microscopic evidence of secondary aneurys-
mal bone cyst is frequently present. Microscopic evidence
of a peripheral shell of reactive bone bordering soft
tissue extensions is an interesting feature of this tumor
and one that it shares with giant cell tumor of bone
(Fig. 4-40).
Differential Diagnosis
Aggressive osteoblastoma should be differentiated from
osteoid osteoma, benign osteoblastoma, and osteosarcoma. The
distinction from osteoid osteoma and osteoblastoma is
based on size of the lesion and the presence of epithelioid
osteoblasts.
Although occasional isolated large osteoblasts with
abundant cytoplasm can be seen in osteoid osteoma or
benign osteoblastoma, they do not occur in cohesive
ERRNVPHGLFRVRUJ
4  Benign Osteoblastic Tumors 189
sheets that fill intertrabecular spaces as they do in aggres-
sive osteoblastoma.
The distinction from osteosarcoma is based on the
absence of cellular atypia, high mitotic rate, atypical
mitotic figures, prominent and abundant lacelike osteoid
deposition, permeative growth into adjacent bone and
soft tissue, and presence of neoplastic cartilage. The pres-
ence of a peripheral shell of reactive bone over the soft
tissue extensions of aggressive osteoblastomas also helps
distinguish this lesion from osteosarcoma. Sampling of
the borders of the lesion is necessary to establish its pres-
ence. Furthermore, all the comments in the discussion of
differential diagnosis of benign osteoblastoma also apply
to aggressive osteoblastoma.
Personal Comments
The principal diagnostic problem with regard to the enti-
ties classified as osteoblastoma and aggressive osteoblas-
toma centers around their distinction from osteosarcoma.
This problem is further complicated by a recently pro-
posed category of low-grade osteosarcoma that resembles
osteoblastoma (osteoblastoma-like osteosarcoma).14
We believe that aggressive osteoblastoma is a separate
entity and should not be confused with osteosarcoma.
Furthermore, there is as yet no evidence that it undergoes
spontaneous transformation to osteosarcoma. In our col-
lected series, 19 of the 47 cases have recurred one or
more times (40%), which is significantly higher than the
25% risk for benign osteoblastomas. We have not seen a
well-documented case of aggressive osteoblastoma that
has shown metastatic behavior.
All the diagnostic criteria cited are important in evalu-
ating the biologic potential of an osteoblastic tumor. The
mere finding of epithelioid osteoblasts does not qualify
the lesion as an aggressive osteoblastoma. Indeed, it is
possible to find plump epithelioid osteoblastic cells in
conventional osteosarcomas otherwise containing frankly
malignant histologic features. This approach was the
basis for an assertion in one published series that aggres-
sive osteoblastomas are merely low-grade osteosarcomas,
superficially resembling osteoblastomas.15 This concept
has since been modified because the series on which it
was based included clearly identifiable high-grade osteo-
sarcomas that focally simulated osteoblastomas. The same
authors have recently embraced the concept of aggressive
osteoblastoma as a distinct entity.14 The established histo-
logic criteria for the recognition of aggressive osteoblas-
toma were found to be predictive of a significantly higher
recurrence rate than that of conventional osteoblastoma
and of an absence of metastasizing potential.9
We believe that all aggressive osteoblastomas should
be treated by wide local excision when technically
feasible.
Text continued on p. 197
190 4  Benign Osteoblastic Tumors

A C
FIGURE 4-42  ■  Aggressive osteoblastoma: radiographic and microscopic features. A, Anteroposterior radiograph showing well-
circumscribed lytic tumor involving lateral malleolus. Note periosteal reaction proximally and expansion of bone contour. B, Mag-
netic resonance imaging shows tumor mass of low signal intensity expanding the bone contour. Note sharp demarcation of the
medullary margin. C, Photomicrograph of the curetted specimen showing irregular trabeculae or bone with intertrabecular spaces
filled by plump epithelioid osteoblasts. (C, ×100). (C, hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 191

A B

C D
FIGURE 4-43  ■  Aggressive osteoblastoma: microscopic features. A, Solid areas of so-called epithelioid osteoblasts (×100). B, Higher
magnification of A. Note numerous epithelioid osteoblasts that are at least 2 times the size of those of ordinary osteoid osteoma
and osteoblastoma. C, Solid areas of epithelioid osteoblasts. D, Higher magnification of epithelioid osteoblasts with small foci of
osteoid-like deposits. Note large eccentrically located nuclei with prominent irregular nucleoli. (A and C, ×100; B and D, ×200) (A-D,
hematoxylin-eosin)

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192 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-44  ■  Aggressive osteoblastoma: microscopic features. A, Low power magnification of osteoblastoma with solid areas
of epithelioid osteoblasts. B, Higher magnification of A showing solid proliferation of large epithelioid osteoblasts.
Note some mild degree of atypia. C, Low power magnification of osteoblastoma with solid areas of epithelioid osteoblasts. D, Higher
magnification of C shows solid proliferation of osteoblasts with immature osteoid deposition. (A and C, ×100; B and D, ×200) (A-D,
hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 193

A B

C D
FIGURE 4-45  ■  Aggressive osteoblastoma: microscopic features. A, Low power magnification of osteoblastoma with solid areas of
epithelioid osteoblasts. B, Higher magnification of A showing solid proliferation of large epithelioid osteoblasts with prominent
nucleoli. C, Low power magnification of osteoblastoma with solid areas of epithelioid osteoblasts and irregular deposition of imma-
ture osteoid. D, Higher magnification of C shows solid proliferation of epithelioid osteoblasts and deposition of unmineralized
immature osteoid. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin)

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194 4  Benign Osteoblastic Tumors

A B

C D
FIGURE 4-46  ■  Aggressive osteoblastoma: patterns of osteoid deposition. A, Low power magnification shows confluent sclerotic
areas of osteoid and solid proliferations of epithelioid osteoblasts. B, Higher magnification of A shows confluent areas of osteoid
and solid foci of epithelioid osteoblasts. C and D, Patterns of osteoid deposition in form of irregular trabeculae of woven bone with
intertrabecular spaces filled by solid proliferations of epithelioid osteoblasts. Such patterns of osteoid deposition associated with
solid proliferation of atypical epithelioid osteoblastic cells may be misinterpreted as malignancy, leading to an incorrect diagnosis
of osteosarcoma. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin)

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 4  Benign Osteoblastic Tumors 195

A B

C D
FIGURE 4-47  ■  Aggressive osteoblastoma: patterns of osteoid deposition. A and B, Low and intermediate power photomicrographs
showing osteoid deposition associated with atypical epithelioid osteoblastic cells. C and D, Low and intermediate power photomi-
crographs showing osteoid deposition associated with atypical epithelioid osteoblastic cells. Such patterns of tumor osteoid associ-
ated with atypical epithelioid osteoblasts may be misinterpreted as malignancy, leading to an incorrect diagnosis of osteosarcoma.
(A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin)

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196 4  Benign Osteoblastic Tumors

A B

D E
FIGURE 4-48  ■  Aggressive osteoblastoma of talus. A, Lateral radiograph of foot of a 27-year-old man with painful lesion of antero-
superior portion of talus. Note soft tissue calcifications. B, Tomogram shows sharply demarcated lytic lesion. C, Gross photograph
of bisected specimen of excised talus. Note granular reddish tumor tissue within medullary cavity and bulging into adjacent soft
tissue (arrows). D, Whole-mount photomicrograph shows intraosseous and extraosseous components of aggressive osteoblastoma.
Shell of reactive bone is present at periphery of tumor extension into soft tissue (arrow). E, High power photomicrograph showing
solid proliferation of epithelioid osteoblasts. Note prominent nucleoli and dense eozynophilic cytoplasm with prominent Golgi
centers seen as cytoplasmic halo displacing nucleus. (E, ×400) (E, hematoxylin-eosin)

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 C H A P T E R 5 
Osteosarcoma
CHAPTER OUTLINE
INTRAMEDULLARY OSTEOSARCOMA
Conventional Osteosarcoma
Telangiectatic Osteosarcoma
Well-differentiated Intramedullary
Osteosarcoma
OSTEOSARCOMA ASSOCIATED WITH SPECIFIC
CLINICAL SYNDROMES
SECONDARY OSTEOSARCOMA
Osteosarcoma is the most common primary malignant
tumor of bone. When all aspects of its presentation are
taken into consideration, it is evident that this term is
used to describe a heterogeneous group of lesions with
diverse morphology and clinical behavior. From the
morphologic point of view, osteosarcoma can be divided
into several subgroups (e.g., osteoblastic, chondroblastic,
fibroblastic). These terms reflect the great microscopic
variability of the tumor, and almost invariably a mixture
of several different components is present in one lesion.
It is understood that these terms are used in a descriptive
sense only and do not necessarily imply difference in
prognosis or clinical behavior. With regard to the growth
pattern of these lesions, osteosarcomas can be subdivided
into lesions that originate and grow primarily inside the
bone (intramedullary osteosarcoma) and those that grow
on the surface of bone (surface osteosarcoma) within
periosteal or parosteal tissue. Radiographically, lesions
can be predominantly lytic or sclerotic, but usually there
is a combination of these features. There is no uniformity
among the many current classification systems of osteo-
sarcoma. However, all systems, including the one adopted
in this chapter, are based on a combination of micro-
scopic, radiographic, and clinical features that help sepa-
rate osteosarcoma into several categories with a distinct
clinical behavior and prognosis. The system of classifica-
tion used here recognizes the diversity of osteosarcomas
and may reflect, at least to some extent, the different
pathways of their development (Table 5-1).
INTRAMEDULLARY OSTEOSARCOMA
Conventional Osteosarcoma
Definition
Osteosarcoma can be defined as a malignant tumor of bone
in which malignant mesenchymal tumor cells have the
ability to produce osteoid or immature bone. There may
200
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SURFACE OSTEOSARCOMA
Parosteal Osteosarcoma
Periosteal Osteosarcoma
High-grade Surface Osteosarcoma
INTRACORTICAL OSTEOSARCOMA
EXTRASKELETAL OSTEOSARCOMA
be profuse osteoid matrix production and extensive min-
eralization throughout the tumor, or both may be minimal
in extent and very focally distributed. The osteoblastic
nature of the tumor can be easy to identify both radio-
graphically and microscopically, or extensive sampling
and a great deal of expertise may be required for its rec-
ognition. In the past, the term osteogenic sarcoma (i.e.,
sarcoma arising in bone) was used in a more general sense
to designate all sarcomatous neoplasms arising in bone.134
More recently, it was used interchangeably with osteosar-
coma, but this use of the term is no longer acceptable
from the pathogenetic point of view.
Incidence and Location
Osteosarcoma accounts for approximately 20% of all
primary sarcomas of bone, excluding multiple myeloma
and other hematopoietic neoplasms. The most frequent
sites of skeletal involvement and the peaks of age inci-
dences are shown in Figure 5-1. The age distribution is
bimodal, with the first major peak occurring during the
second decade of life, and the second, much smaller, peak
being observed in patients older than age 50 years. The
presence of the second peak was originally documented
in the Memorial Sloan-Kettering Cancer Center series96
and has been confirmed by data from the National Cancer
Institute’s Surveillance, Epidemiology, and End Results
(SEER) Program56 (Fig. 5-2). The SEER Program, con-
taining population-based data on approximately 5000
cases of osteosarcoma, provides a detailed view on epide-
miologic trends and survival rates for osteosarcoma.56,157
The overall incidence rates are clearly age specific and
indicate that individuals, during the first two decades of
life and over age 60, have similar risk for the development
of osteosarcoma with incidence rates of 4.4 and 4.2
per million respectively. The population between the
third and sixth decades of life have a lower incidence
rate of osteosarcoma, in a range of 1.7 per million. Osteo-
sarcoma is rare in the first decade of life (<5% of cases).
Most patients (~60%) are between 10 and 20 years old.

TABLE 5-1 Types of Osteosarcoma and
Descriptive Terms Used in
Their Diagnosis
Intramedullary Osteosarcoma
Conventional
Osteoblastic
Chondroblastic
Fibroblastic
Malignant fibrous histiocytoma-like
Osteoblastoma-like
Giant cell-rich
Small cell
Epithelioid
Telangiectatic
Well-differentiated (low-grade intraosseous)
Secondary Osteosarcoma
Paget’s disease
Postradiation
Bone infarct
Fibrous dysplasia
Metallic implant
Chronic osteomyelitis
Osteosarcoma Associated with Specific Clinical Syndromes
Familial
Rothmund-Thomson syndrome
Retinoblastoma
Multifocal
Surface Osteosarcoma
Parosteal (juxtacortical)
Periosteal
High-grade surface (de novo and dedifferentiated)
Intracortical Osteosarcoma
Extraskeletal Osteosarcoma
The sex ratio varies among the series but a male predomi-
nance is clear (1.3 : 1 to 1.6 : 1). The higher rate in males
is attributed to their longer period of skeletal growth. It
appears that osteosarcoma has a tendency to develop
earlier in females than in males, with a median age of 17
years compared with 18 years for males,96 but the distri-
bution of the age-related incidence and frequency from
the SEER Program data do not confirm this trend56 (Fig.
5-3). There are no major differences among races (white
versus black), but it appears that the peak incidence
during the second decade of life is somewhat higher in
black males than in white males or in black or white
females (Fig. 5-3).
The peak incidence of osteosarcoma in adoles-
cents corresponds to the peak period of skeletal
growth.64,65,71,76,90,163,174,175 The portions of the skeleton
with the highest growth rate are the most frequently
affected. The frequency of tumor occurrence within a
specific bone corresponds to the site of greatest growth
rate. Accordingly, the distal femoral and proximal tibial
metaphyses, where most growth occurs during adoles-
cence, are the most common sites for osteosarcoma.
Some studies have documented that, on average, patients
with osteosarcoma are taller than their peers in the corre-
sponding age group and have increased levels of somato-
medin.71,136 In adolescents, osteosarcoma predominantly
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5  Osteosarcoma 201
involves the appendicular skeleton. Approximately 50%
of cases are located in the knee region. The distal femoral
metaphysis is affected 2.5 times more frequently than
the proximal tibial metaphysis. The humerus is the third
most frequently involved bone in young patients and is
the site of 15% of all cases, with the majority of osteo-
sarcomas developing in the proximal humeral metaphy-
sis and diaphysis. The distal portion of the humerus is
seldom involved. Osteosarcoma is unusual in the bones of
the forearm and in the small bones of the hands and feet.
In older patients, the predilection for the appendicular
skeleton and the knee region is less clear59,94 (Figs. 5-4
and 5-5). In patients older than age 50 years, only 15% of
the tumors occur in the knee area. In this age group, the
axial skeleton and flat bones are more frequently affected
(~40% of cases). Approximately 10% of osteosarcomas
occur in the pelvis, and the ilium is the most frequently
involved flat bone. Less than 10% of osteosarcomas occur
in the mandible and other craniofacial bones.
Clinical Symptoms
The most common symptom is pain that has usually con-
tinued for several weeks to months. The pain gradually
becomes more severe and eventually is accompanied by
swelling. The overlying skin feels warm and has promi-
nent superficial vasculature. Swelling is often accompa-
nied by some limitation of motion. Pain in the adjacent
joint and accumulation of fluid may also be present. At
the time of presentation, some patients may have weight
loss; this is usually associated with disseminated disease,
which is most frequently in the form of lung metastases.
The serum alkaline phosphatase level is frequently
elevated in patients with osteosarcoma. It can be particu-
larly high in patients with a heavy tumor burden or in
those who have tumors that exhibit prominent osteoblas-
tic differentiation. Elevation of the alkaline phosphatase
level after surgery indicates persistent, recurrent, or met-
astatic disease.
Radiographic Imaging
The radiographic presentation of osteosarcoma varies
greatly. The tumor may be completely lytic or sclerotic,
but usually a combination of these features enables a
preoperative radiographic diagnosis of osteosarcoma in
the majority of cases99 (Fig. 5-6). The mineralization of
tumor matrix produces cloudy opacities that vary in size,
shape, and density. These opacities can be relatively uni-
formly distributed throughout the lesion or can cluster
in one area to form large, irregular sclerotic masses (Figs.
5-7 to 5-10). Occasionally, the tumor may appear to have
a uniform ivory-like density with minimal or no lytic
component (Figs. 5-11 and 5-12). The tumor exhibits
a destructive growth pattern with a gradual transition
from lytic or sclerotic areas to normal bone, which makes
the borders of the lesion ill-defined. The process can
be limited to the medullary space, but in most instances
the cortex is also involved and often is destroyed, at
least focally. In the area of penetration, the outer limits
of the cortex are indistinct, but its original outline can
usually still be traced. Usually the tumor extends into the
202 5  Osteosarcoma
Peak
incidence
10 20
Incidence
Second
50
1 2 3 4 5 6
Age in decades
FIGURE 5-1  ■  Conventional osteosarcoma. Peak age incidence and frequent sites of skeletal involvement. The most frequent sites
are indicated by solid black arrows.
soft tissue, and its mineralized shadow can be seen overly-
ing the area of cortical penetration (Figs. 5-13 and 5-14).
Tumors that extend beyond the cortex can vary in size
and degree of mineralization. In general, the size of the
extracortical soft tissue component corresponds with the
size of intramedullary tumor and to the extent of cortical
destruction. The greater the extent of tumor within the
bone and the more extensive the cortical disruption, the
larger the extracortical soft tissue component is likely to
be. In exceptional cases, long plugs of tumor can extend
within the medullary cavity well beyond the level of corti-
cal discontinuity. The pattern of destructive growth and
extension into soft tissue is usually asymmetric with one
side of the bone being more involved (see Figs. 5-6 and
5-8). Initially there is a single area of cortical penetration
and expansion into soft tissue, but eventually with tumor
progression, it may form an extensive soft tissue mass that
circumferentially involves the affected long bone (see
Figs. 5-7, 5-9, 5-10, 5-12, 5-14, and 5-16).
The outer surface of the cortex overlying the tumor
may demonstrate a prominent periosteal reaction that
can be in the form of parallel periosteal new bone,
hazy cortical irregularity and fuzziness, or both features
(Fig. 5-15). Occasionally the tumor may form perpen-
dicular or radiating striations (“sunburst”). This type of
periosteal reaction can be seen on the bone surface
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peak
7 8
without radiographic evidence of extension into soft
tissue but is usually observed within the soft tissue com-
ponent of the tumor that overlies an area of cortical
disruption. The tumor growing on the surface of bone
can elevate the periosteum and induce a periosteal reac-
tion in the form of an open triangle overlying the diaphy-
seal side of the lesion. This type of reaction is known as
Codman’s triangle (see Figs. 5-6 and 5-15). Sometimes the
periosteal reaction can be in the form of multiple layers
(“onion skin”), which are more typically seen in small-cell
tumors involving bone and in osteosarcomas that are in
a diaphyseal rather than metaphyseal location.
Rapidly growing tumors can produce predominantly
lytic masses with a permeative pattern of bone destruc-
tion and minimal or no periosteal reaction53 (see Figs. 5-8
and 5-14). This type of osteosarcoma is more difficult to
diagnose from radiographs and requires special care to
distinguish it from other destructive lesions of bone, such
as osteomyelitis. Osteosarcoma is usually suspected
because of the presence of a destructive lesion in the
metaphyseal area of a long bone in an adolescent, even
when the characteristic pattern of tumor matrix mineral-
ization is lacking. Occasionally osteosarcoma of quite
high histologic grade can produce deceptively innocent
radiographic defects with sharp or even sclerotic margins.
Text continued on p. 215
 5  Osteosarcoma 203

1 25

0.8 20
(cases/100,000 persons)

Age distribution (%)

Incidence rate

0.6 15

0.4 10

0.2 5

0 0
0-4

5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+
Age at diagnosis
FIGURE 5-2  ■  Epidemiology of conventional osteosarcoma. National Cancer Institute Surveillance, Epidemiology, and End Result
Program 1973-2009. Age-adjusted incidence rate and age-specific frequency, all races, both sexes, 4962 cases.

Black, male
Black, female
Incidence rate (cases/100,000 persons)

1.5 White, male

White, female

0.5

0
0-4

5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

Age at diagnosis
FIGURE 5-3  ■  Epidemiology of conventional osteosarcoma. National Cancer Institute Surveillance, Epidemiology, and End Result
Program 1973-2009. Age-adjusted incidence rates by race and sex, 4962 cases.

ERRNVPHGLFRVRUJ
204 5  Osteosarcoma

0.5

Bones of skull and face and associated joints

Vertebral column
0.4 Rib, sternum, clavicle and associated joints
Extremities
Pelvic bones, sacrum, coccyx and associated joints
(cases/100,000 persons)

0.3
Incidence rate

0.2

0.1

0
00-19 20-49 50+
Age at diagnosis
FIGURE 5-4  ■  Epidemiology of conventional osteosarcoma. National Cancer Institute Surveillance, Epidemiology, and End Result
Program 1973-2009. Age-adjusted incidence rates by sites of skeletal involvement, all races, both sexes, 4962 cases.

120

Bones of skull and face and associated joints

Vertebral column
100 Rib, sternum, clavicle and associated joints
Extremities
Skeletal distribution by age (%)

Pelvic bones, sacrum, coccyx and associated joints

80

60

40

20

0
00-19 20-49 50+
Age at diagnosis
FIGURE 5-5  ■  Epidemiology of conventional osteosarcoma. National Cancer Institute Surveillance, Epidemiology, and End Result
Program 1973-2009. Age-adjusted frequency distribution by sites of skeletal involvement, all races, both sexes, 4962 cases.

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 205

A B

C D
FIGURE 5-6  ■  Conventional intramedullary osteosarcoma of distal femoral metaphysis. A, Anteroposterior plain distal femoral ra-
diograph showing a destructive sclerotic lesion with soft tissue extension. B, Fat-saturated T2-weighted magnetic resonance image
(MRI) showing distal femoral lesion with inhomogeneous signal, cortical destruction, and extension of tumor into soft tissue. The
tumor penetrates the growth plate and extends to the epiphysis. C, Fat-saturated T1-weighted axial MRI with contrast documents the
eccentric intramedullary lesion with partial circumferential extension into soft tissue medially. D, Frontal section, after limb-salvage
procedure, shows sclerotic metaphyseal lesion with soft tissue extension medially and penetration of the growth plate.

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206 5  Osteosarcoma

A B

C D
FIGURE 5-7  ■  Conventional intramedullary osteosarcoma of proximal tibia. A, Coronal computed tomography reformation of tibia
showing intramedullary mixed-sclerotic and lytic lesion with soft tissue extension. B, Fat-saturated T2-weighted coronal magnetic
resonance image showing extensive intramedullary lesion with cortical penetration and circumferential soft tissue extension.
C, Gross photograph of sclerotic intramedullary tumor extensively involving metaphyseal proximal tibia and showing massive
circumferential extension into the soft tissue. D, Microscopic features of the same tumor, showing extensive tumor osteoid disposi-
tion and anaplastic mesenchymal cells. (D, ×100) (D, hematoxylin-eosin.)

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 5  Osteosarcoma 207

A B

C D
FIGURE 5-8  ■  Conventional intramedullary osteosarcoma of distal femur. A, Anteroposterior plain radiograph shows an eccentric
predominantly lytic destructive process in the lateral aspect of the distal femoral metaphysis. A discreet shadow of the tumor
extending to the soft tissue is seen medially (arrows). B, Fat-saturated T2-weighted coronal magnetic resonance image showing
destructive tumor with high signal intensity involving the lateral aspects of distal femoral metaphysis with extension into epiphysis
and involvement of soft tissue medially. C, Gross photograph showing intramedullary tumor involving posterior aspects of femoral
metaphysis with extension to the epiphysis and massive involvement of retrofemoral soft tissue. D, Microscopic features of the
tumor, showing highly pleomorphic mesenchymal tumor cells and tumor osteoid deposition. (D, ×100) (D, hematoxylin-eosin.)

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208 5  Osteosarcoma

A B

C D
FIGURE 5-9  ■  Intramedullary osteosarcoma of distal femur. A, Lateral plain radiograph showing extensive mixed lytic and sclerotic
tumor of the distal femur with circumferential soft tissue extension. B, T1-weighted sagittal magnetic resonance image (MRI) with
contrast, showing extensive intramedullary lesion with irregular patches of signal void corresponding to extensive mineralization
of tumor matrix. Note extensive circumferential involvement of paraosseous soft tissue. C, Coronal MRI showing similar features
as in B, documenting massive circumferential involvement of the paraosseous soft tissue. D, Sagittal section of the resection speci-
men, showing extensive intramedullary tumor with circumferential soft tissue extension.

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 5  Osteosarcoma 209

A C
FIGURE 5-10  ■  Conventional intramedullary osteosarcoma of the proximal tibia. A, Plain radiograph showing mixed sclerotic and
lytic lesion of the proximal tibia. B, Sagittal fat-saturated T2-weighted magnetic resonance image of the proximal tibia, showing
intramedullary tumor with high signal intensity and cortical penetration anteriorly and posteriorly. C, Gross photograph showing
sagittal image of a fleshy tumor involving the proximal end of the tibia.

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210 5  Osteosarcoma

A B

C D
FIGURE 5-11  ■  Conventional intramedullary osteosarcoma of the distal femur. A, Fat-saturated T2-weighted coronal magnetic reso-
nance image (MRI) showing intramedullary tumor with signal enhancement. B, Fat-saturated T2-weighted axial MRI showing low
signal intensity in the intramedullary tumor. C, Gross photograph showing sagittal section of a highly sclerotic intramedullary tumor
involving the distal femur. D, Closer view of the image shown in C, documenting the penetration of the growth plate.

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 5  Osteosarcoma 211

A B

C D
FIGURE 5-12  ■  Osteosarcoma of femoral diaphysis. A, Lateral plain radiograph shows highly sclerotic destructive tumor involving
femoral shaft and extending into adjacent soft tissue. B, Fat-saturated T2-weighted coronal magnetic resonance image (MRI) showing
extensive intramedullary lesion with inhomogeneous signal and circumferential extension into adjacent soft tissue. C, T1-weighted
axial MRI with contrast, documenting extensive circumferential involvement of adjacent soft tissue. D, Gross photograph showing
intramedullary tumor with massive involvement of adjacent soft tissue.

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212 5  Osteosarcoma

A B

C D

FIGURE 5-13  ■  Conventional intramedullary osteosarcoma of the distal femur. A, Anteroposterior plain radiograph showing the
destructive mixed sclerotic and lytic lesion with cortical breakthrough medially and soft tissue extension. B, Fat-saturated T2-weighted
coronal magnetic resonance image (MRI) showing intramedullary tumor with areas of signal void and patches of signal enhance-
ment penetrating the cortex circumferentially. C, T1-weighted axial MRI with contrast, showing extensive circumferential involve-
ment of soft tissue. D, Gross photograph disclosing extensive tumor of the distal femur with variegated mineralization pattern
extending to the epiphysis and soft tissue.

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 5  Osteosarcoma 213

A B

C D

FIGURE 5-14  ■  Conventional intramedullary osteosarcoma of the proximal femur. A, Anteroposterior plain radiograph showing a
destructive lytic lesion of the proximal femur. B, Fat-saturated T2-weighted axial magnetic resonance image (MRI) showing extensive
tumor with signal enhancement of the proximal femur extending to the adjacent soft tissue. C, T1-weighted axial MRI with contrast,
documenting foci of signal void in the extensive tumor involving soft tissue adjacent to proximal femoral area. D, Gross photograph
documenting extensive fleshy and mucinous tumor involving the femoral neck and intertrochanteric area with extensive involve-
ment of paraosseous tissue.

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214 5  Osteosarcoma

A B C

D E
FIGURE 5-15  ■  Conventional intramedullary osteosarcoma of the distal femur. A, Anteroposterior plain radiograph showing sclerotic
destructive tissue involving the distal femur. B, Bilateral T1-weighted coronal magnetic resonance image (MRI) showing extensive
destructive tumor mass of the distal femur with involvement of the epiphysis and adjacent soft tissue. C, Fat-saturated T2-weighted
coronal MRI showing patches of signal enhancement within the tumor mass. D, Gross photograph showing extensive, partially
necrotic, tumor mass involving distal femur and extension to epiphysis and adjacent soft tissue. Note transverse pathologic
fracture. E, Microscopic image showing extensive tumor osteoid deposition and pleomorphic mesenchymal tumor cells (×100,
hematoxylin-eosin).

ERRNVPHGLFRVRUJ

In very rare instances, osteosarcoma can originate within
the epiphysis (epiphyseal osteosarcoma) and may be mis-
taken on radiographs for chondroblastoma or clear-cell
chondrosarcoma205 (see Figs. 5-19 and 5-20).
Computed tomography and especially magnetic reso-
nance imaging (MRI) are used to evaluate the extent of
disease.52,74,83,193 These types of imaging are especially
useful in evaluating the extent of intramedullary involve-
ment and extension into soft tissue. Of particular impor-
tance for the therapy plan (limb-sparing procedure) is the
relationship between the soft tissue extension and the
neurovascular bundle. MRI is particularly useful to evalu-
ate the extent of the tumor and plan the resection planes
for surgical excisions.102 MRI reveals the heterogeneous
nature of the tumor by exhibiting variable levels of signal
intensity in different areas of the tumor tissue. Heavily
mineralized areas typically show no signal on the
T2-weighted images. On the contrary, well-vascularized
sarcomatous areas may exhibit various degrees of signal
enhancement. In general, in MRI techniques, contrast
enhancement, combined with fat saturation, discloses the
heterogeneous nature of the tumor and is helpful to eval-
uate tumor extent and its relationship to anatomic struc-
tures in the surrounding normal tissue (Fig. 5-16; see also
Figs. 5-6 to 5-15).
Gross Findings
The gross appearance of osteosarcoma is best described
in its typical location (i.e., in the metaphyseal portion of
a long bone). Osteosarcoma can be composed of pre-
dominantly ossified or nonossified tissue, but usually a
combination of bony and soft tissue areas is responsible
for the characteristic gross appearance of this tumor. In
most instances, the tumor’s cut surface is very heteroge-
neous, with areas that vary in color, consistency, and
degree of ossification (Fig. 5-17). Highly ossified ivory-
like areas are yellow-white and may be as hard as normal
cortical bone (see Fig. 5-11). The less ossified areas are
soft and less yellow in appearance. Areas with minimal or
no ossification are tan, fleshy, or of chondroid consis-
tency. They can also exhibit features of hemorrhage and
necrosis (see Figs. 5-17 and 5-18).
The large, densely ossified areas are usually the result
of interaction between tumor osteoid and preexisting
nontumor bone. In the central intramedullary portions
of the tumor, large areas of bony condensation are pro-
duced by superimposition of tumor osteoid on the pre-
existing cancellous bone of the medullary cavity. Outside
the medullary cavity, within the soft tissue extension,
solid bony areas are formed by the deposition of tumor
bone between spicules of reactive nontumor bone of peri-
osteal origin. Overall, the tumor exhibits an invasive and
bone-destroying pattern of growth (Figs. 5-18 to 5-20).
The borders between the tumor tissue and adjacent
structures are indistinct and irregular. This is particularly
evident in the areas where heavily ossified tumor tissue
merges with the adjacent cortex.
The smaller lesions are usually eccentrically located
within the medullary cavity. Even relatively small lesions
that do not fill the medullary cavity have a high propen-
sity to invade the cortex and to induce periosteal reaction.
ERRNVPHGLFRVRUJ
5  Osteosarcoma 215
More advanced lesions fill the medullary cavity and prog-
ress toward the shaft and growth plate (Figs. 5-21 and
5-22). At this stage, lesions usually exhibit clear areas of
cortical destruction, elevation of periosteum, expansion
into the soft tissue, or a combination of the features.
These features correspond to the deposition of periosteal
new bone, which can be detected on radiographs. Further
growth produces an eccentric soft tissue mass that over-
lies the large cortical defect. Signs of periosteal impinge-
ment with associated periosteal bony reaction often can
be seen at the periphery of the lesion, particularly in the
diaphysis. This corresponds to the Codman’s triangle
seen in radiographs (see Fig. 5-18). As a rule, the intra-
medullary progression of the tumor is more extensive
than can be appreciated on plain radiographs. The intra-
medullary border may be irregular or may form a sharply
demarcated dome-shaped structure. The growth plate
serves as a substantial barrier to tumor growth and is
seldom penetrated except in more advanced lesions (see
Figs. 5-13 and 5-15). Serial block sections of the epiphy-
seal area may document foci of perforation of the physis
and microscopic extension into the epiphysis, even in less
advanced cases.62,187 Rarely, the articular cartilage can be
destroyed with extension of tumor into the joint cavity.
The synovium is more frequently involved in advanced
cases by tumor growth along the bone surface rather than
by transarticular penetration.
Microscopic Findings
Osteosarcoma represents one of the most heterogeneous
tumors known in human pathology. The microscopic
features may vary considerably among different lesions
and in different areas of the same tumor. However, some
common microscopic patterns can be used to subdivide
osteosarcomas into several morphologically distinct
groups.
The two basic microscopic components of osteosar-
coma are the sarcomatous tumor cells and the extracel-
lular matrix (see Fig. 5-23). The relationship between the
tumor cells and the matrix is very important for diagno-
sis. Evidence of direct production of osteoid matrix by
sarcomatous tumor cells is required to classify the lesion
as an osteosarcoma (Figs. 5-23 to 5-25). Osteosarcomas
can be subdivided into three main categories on the basis
of their predominant matrix product: osteoblastic, chondro-
blastic, and fibroblastic.47-50,94,96,100,121,209 Osteosarcoma often
presents as an undifferentiated sarcoma with predomi-
nance of giant pleomorphic, round or spindle cells
with little intervening matrix (Figs. 5-26 to 5-28). Usually
a mixture of several cellular components leads to a varie-
gated pattern of matrix production. The tumor cells may
have densely eosinophilic cytoplasm with eccentrically
placed nuclei and resemble osteoblasts, but they are
usually much larger than normal or even activated osteo-
blasts. They vary considerably in size and often exhibit
pronounced nuclear atypia. These cells grow in large,
cohesive sheets and may form areas with epithelioid fea-
tures.85,86,108 Focal epithelioid features are quite common
in conventional osteosarcoma. Tumors with predominant
organoid growth of cells with epithelioid features are
Text continued on p. 229
216 5  Osteosarcoma

B C

D
FIGURE 5-16  ■  Conventional intramedullary osteosarcoma of the proximal humerus. A, Anteroposterior radiograph showing a
destructive predominantly lytic tumor of the proximal humerus with pathologic fracture. B, Fat-saturated T2-weighted coronal mag-
netic resonance image of an extensive destructive process involving the medullary cavity of the proximal humerus with massive
soft tissue extension in the shoulder area. C, Gross photograph showing a fleshy tumor involving proximal humerus. D, Closer view
of specimen shown in C, disclosing fleshy destructive tumor with areas of necrosis and displacement of the bone axis due to patho-
logic fracture and fragmentation of proximal humerus.

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 5  Osteosarcoma 217

A B

C D
FIGURE 5-17  ■  Gross morphology of conventional osteosarcoma. A, Distal femur containing conventional osteosarcoma in metaphy-
sis. There is extensive cortical disruption and subperiosteal expansion. Tumor is confined to metaphyseal side of cartilaginous
growth plate. Hemorrhagic area represents biopsy site. B, Osteosarcoma of distal femoral metaphysis with epiphyseal extension
through incomplete, partially fused growth plate. C, Densely sclerotic osteosarcoma of tibial metaphysis extending into diaphysis.
Note that tumor is limited proximally by growth plate. D, Sclerotic osteosarcoma of distal femur with extensive involvement of the
epiphyseal end of bone. (B-D, courtesy Dr. A.G. Ayala, Houston.)

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218 5  Osteosarcoma

A B

C D
FIGURE 5-18  ■  Periosteal reactions in osteosarcoma with extension into soft tissue. A, Gross photograph of tibial metaphyseal
osteosarcoma with lateral cortical breakthrough and subperiosteal mass. Note perpendicular spicules of reactive bone and angular
elevation of periosteum at lower aspect of extracortical mass. B, Specimen radiograph of slab of specimen shown in A. Cortex is
breached laterally with periosteal elevation. Resulting periosteal new bone is in form of Codman’s triangle below and horizontal
striations of reactive bone above. C, Whole-mount low power photomicrograph of extracortical extension of osteosarcoma delimited
by elevated periosteum. Note acute angle formed by stripped and elevated periosteum, under which reactive bone is being depos-
ited. D, Specimen radiograph of tumor shown in C demonstrates perpendicular striation of reactive bone traversing extracortical
tumor and oblique lines of subperiosteal bone forming Codman’s triangle below. (C, hematoxylin-eosin.)

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 5  Osteosarcoma 219

A B

C D
FIGURE 5-19  ■  Osteosarcoma of tibia and epiphyseal osteosarcoma. A and B, Thirteen-year-old girl fell 2 months before these antero-
posterior (AP) and lateral radiographs. Pain and swelling were interpreted as osteomyelitis, and the patient was treated with anti-
biotics without beneficial effect. Note ill defined radiodense lesion with associated periosteal reactive bone and large lucent
extraosseous tumor mass posterior to tibia. Prominent Codman’s triangles are seen in both views. C, AP radiograph of distal femur
shows totally epiphyseal, circumscribed lesion with cloudy opacities in a 15-year-old boy. D, Oblique radiograph of the epiphyseal
high-grade osteoblastic osteosarcoma in medial femoral condyle shown in C.

ERRNVPHGLFRVRUJ
220 5  Osteosarcoma

E F
FIGURE 5-20  ■  Epiphyseal osteosarcoma. A, T1-weighted coronal magnetic resonance image (MRI) showing low signal intensity
region in the epiphysis of the distal femur. B, T1-weighted sagittal MRI showing the epiphyseal lesion involving the lateral condyle.
C, T2-weighted sagittal MRI showing signal enhancement of the lesion. D, Axial computed tomogram discloses patchy signal
enhancement corresponding to tumor matrix mineralization. E, Gross photograph showing gelatinous well demarcated tumor
involving the femoral epiphysis with gritty and granular mineralization pattern. F, Microscopic image showing anaplastic tumor cells
and irregular tumor osteoid deposition. (D, ×100) (D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 221

A B

C D E
FIGURE 5-21  ■  Osteosarcoma: gross morphology. A, Coronal section of conventional medullary osteosarcoma of distal femoral shaft.
There is extensive tumor necrosis in both intramedullary and soft tissue components. Note extension beyond periosteum. B, Speci-
men radiograph of tumor shown in A. Extraosseous component contains cloudlike densities representing tumor bone matrix min-
eralization. C, Extensively necrotic metaphyseal osteosarcoma of distal femur delineated by zone of hemorrhagic tumor. Note growth
plate barrier blocking distal growth of tumor. D, Osteosarcoma of proximal femur with involvement of intertrochanteric region and
femoral neck. E, Osteosarcoma of the proximal femur with extensive intramedullary involvement spanning nearly the entire femur.
(A, courtesy Dr. A.G. Ayala, Houston.)

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222 5  Osteosarcoma

A B

C D
FIGURE 5-22  ■  Osteosarcoma: gross morphology. A, Osteosarcoma of proximal humerus with extensive cortical disruption and
extension into soft tissue. B, Osteosarcoma of distal tibial metaphysis with circumferential extension into soft tissue and elongated
proximal intramedullary component occupying tibial shaft. C, Metaphyseal osteosarcoma of distal tibia demarcated distally by intact
cartilaginous growth plate. D, Whole-mount photomicrograph of tumor shown in C. Note that tumor has destroyed cortex and
extended into soft tissue but does not violate growth plate barrier. (D, hematoxylin-eosin.) (A and B, courtesy Dr. A.G. Ayala, Houston.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 223

A B

C D
FIGURE 5-23  ■  Osteoblastic osteosarcoma, high grade. A, High-grade osteoblastic osteosarcoma with an abundance of tumor bone
(×100). B, Higher power of A showing irregular tumor osteoid deposits and anaplastic tumor cells (×200). C, High-grade osteoblastic
osteosarcoma with abundant irregular tumor bone (×100). D, High-grade osteoblastic osteosarcoma with abundant tumor osteoid.
Note fragments of residual normal lamellar bone surrounded by the tumor. (A, C, and D, ×100; B, ×200) (A-D, hematoxylin-eosin.)

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224 5  Osteosarcoma

A B

C D
FIGURE 5-24  ■  Osteoblastic osteosarcoma, high grade. A, Low power photomicrograph of sclerosing osteosarcoma fused with the
cortex on the right and obliterating marrow spaces. B, Higher magnification of A showing sheetlike osteoid fused with normal
lamellar bone on the lower left. Note the presence of highly pleomorphic atypical tumor cells. C, Low power photomicrograph
of sclerosing osteosarcoma producing abundant osteoid fused with lamellar medullary bone, obliterating marrow spaces.
D, Higher magnification of C showing abundant tumor osteoid fused with the lamellar medullary bone. Note hyperchromatic pleo-
morphic tumor cells. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

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 5  Osteosarcoma 225

A B

C D
FIGURE 5-25  ■  Osteoblastic osteosarcoma, high grade: variations in osteoids and bone formation patterns. A, Irregular osteoid
bands interspaced with islands of tumor cells. B, Irregular deposits of unmineralized tumor osteoid. C, Prominent solid areas
of osteoid. D, Interconnected seams of osteoid and islands of anaplastic tumor cells. (A and C, ×100; B and D, ×200)
(A-D, hematoxylin-eosin.)

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226 5  Osteosarcoma

A B

C D
FIGURE 5-26  ■  Fibroblastic osteosarcoma, high grade. A and B, Low power microphotograph showing proliferations of atypical
spindle cells characteristic of fibroblastic osteosarcoma. C and D, Intermediate power views of A and B, respectively, showing con-
fluent proliferations of atypical spindle cells and irregular deposits of unmineralized matrix. Inset shows nuclear details of fibroblastic
cells with mitotic activity. (A and B, ×50; C and D, ×100; inset, ×200) (A-D and inset, hematoxylin-eosin.)

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 5  Osteosarcoma 227

A B

C D
FIGURE 5-27  ■  Conventional osteosarcoma, high grade. A, Pleomorphic sarcomatoid cells. B, Higher magnification of highly pleo-
morphic sarcomatoid cells. C, Densely packed anaplastic sarcomatoid tumor cells. D, Higher magnification of C showing nuclear
pleomorphism of tumor cells. (A and C, ×100; B, ×400; D, ×200) (A-D, hematoxylin-eosin.)

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228 5  Osteosarcoma

A B

C D
FIGURE 5-28  ■  Conventional osteosarcoma, high grade: morphologic variants of tumor cells. A, Densely packed epithelioid anaplastic
tumor cells. B, Sarcomatoid spindle cells with scattered multinucleated giant cells. C, Mixture of atypical spindle and pleomorphic
cells. D, Loosely arranged epithelioid tumor cells in a background of hemorrhage. (A-D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

refered to as epithelioid osteosarcoma, described in more
detail below. The osteoblastic nature of the tumor cells
is best recognized by their close apposition to trabeculae
of tumor bone or by their entrapment in lacelike osteoid
deposits (Figs. 5-29 and 5-30). A full gamut of sarcoma-
tous features ranging from undifferentiated round, oval,
or polygonal cells through various patterns of pleomor-
phic sarcoma and spindle-cell sarcoma may be seen. This
mixture of patterns is best observed in predominantly
lytic lesions with minimal osteoid production. Those
lesions typically exhibit pronounced nuclear atypia and
brisk mitotic activity with numerous atypical mitoses (see
Figs. 5-27 and 5-38) and are easily diagnosed as malig-
nant, but their bone-forming features can be very focal
and inconspicuous. Such cases may simulate pleomorphic
malignant fibrous histiocytoma of bone. As in other high-
grade sarcomas, prominent stromal vascular patterns that
mimic hemangiopericytoma can be found in osteosar-
coma (see Fig. 5-38). At the opposite end of the spectrum
are highly ossified, sclerosing lesions in which a full range
of tumor bone production can be observed.
The production of tumor bone matrix begins with the
elaboration of extracellular fibrillar collaginous matrix
(osteoid). In its early stages, it can be recognized by
the presence of a dense, fibrillar eosinophilic substance
deposited between small groups of cells. At this stage,
seams of dense eosinophilic matrix material separate and
enmesh individual tumor cells. Larger areas of osteoid
produce a lacelike pattern, in which rows of tumor cells
are surrounded by a fibrillar ground substance that may
begin to show early mineralization (Figs. 5-29 to 5-31).
Further advance of ossification produces wide sheets of
osteoid that separate tumor cells and show deposits of
calcification (Figs. 5-32 and 5-33). More advanced min-
eralization produces clearly recognizable trabeculae of
woven tumor bone. The tumor bone trabeculae differ
considerably in size, shape, and degree of mineralization.
They are haphazardly arranged, have highly irregular
borders, and merge gradually with areas of less mature
osteoid (Figs. 5-34 to 5-37). The tumor bone frequently
is in direct contact with preexisting nontumor bone that
represents cancellous bone trabeculae of the medul-
lary cavity, the cortex, or the reactive bone of perios-
teal origin. The tumor bone characteristically fuses and
merges with the preexisting nontumor lamellar bone and
often forms large, ossified, solid areas (see Fig. 5-24). In
such instances, the nontumor bone serves as a scaffold for
the tumor bone and both occasionally form large solid
areas of ossified tissue as dense as the normal cortex.
Usually, however, there is a clearcut separation of the
immature, woven tumor bone where it attaches to the
lamellar, nontumor bone. In contradistinction, a gradual
conversion of woven bone into mature lamellar bone
can be seen in reactive lesions, such as fracture callus.
The advancing tumor can partially or completely destroy
the original bone, replacing it with tumor bone or with
nonossified tumor tissue. The tumor osteoid can form
well-defined islands that mimic trabecular bone or can
be deposited in irregular sheets that contain entrapped
tumor cells (see Fig. 5-32). Interestingly, the tumor
cells entrapped by the osteoid are usually smaller and
less pleomorphic than the tumor cells lying outside the
ERRNVPHGLFRVRUJ
5  Osteosarcoma 229
osteoid and they more closely resemble normal osteo-
blasts. Jaffe100 described this phenomenon as normal-
ization in referring to the less malignant appearance of
tumor cells deeply embedded in osteoid. Normalization
can also be used in a general sense to describe a more
mature appearance of osteosarcoma in highly ossified
solid areas (see Fig. 5-32). The trabecular pattern of
tumor bone sometimes focally mimics the appearance of
benign reactive woven bone or that of benign osteoblastic
tumors (i.e., osteoid osteoma and osteoblastoma). The
major difference is in the cells that fill the intertrabecular
spaces, which in osteosarcoma exhibit atypical, sarcoma-
tous features. The infiltrating pattern within such areas,
with destruction or engulfment of preexisting nontumor
bone, facilitates the diagnosis of a malignant process.
These tumors may have a deceptively benign look and
may be mistaken for osteoblastomas of the conventional
or aggressive type (for a more detailed description see
Chapter 4 and the section on osteosarcoma with unique
microscopic features in this chapter).
Osteosarcomas can also exhibit cartilaginous differen-
tiation. In some instances, the cartilaginous component
can be quite extensive and dominant throughout the
lesion (Figs. 5-39 and 5-40). The cartilaginous differen-
tiation in osteosarcoma can be very heterogeneous and
represents all stages of cartilaginous matrix formation.
The earliest stages represent the formation of a loose
basophilic intercellular substance with cells lying in
lacunar spaces. Mineralization of the matrix produces
bluish granular or linear deposits of calcium. Other pat-
terns of cartilage differentiation parallel those seen in
chondrosarcoma and vary from areas similar to those seen
in high-grade chondrosarcoma through myxoid change
to well-differentiated areas with a deceptively benign
appearance. Often a full spectrum of cartilage differentia-
tion representing different degrees of matrix maturation
and cellular atypia is seen in one tumor. Even in a pre-
dominantly chondroid tumor, at least focal direct osteoid
production by sarcomatous tumor cells is required for the
recognition of its osteosarcomatous nature. The cartilage
and bone-forming areas are frequently intermingled and
there can be a gradual transition between them with
zones in which it is difficult to classify the matrix.
Fibroblastic differentiation in osteosarcoma is charac-
terized by the presence of a predominant spindle-cell
component similar to that seen in fibrosarcoma. In
conventional osteosarcomas, the spindle-cell component
usually shows high-grade cytologic features (see Fig.
5-26). The production of tumor bone by fibroblast-like
cells discloses the bone-forming nature of these predomi-
nantly spindle-cell lesions and helps differentiate them
from other spindle-cell neoplasms of bone. Occasionally,
these tumors resemble pure fibrosarcomas that contain
inconspicuous foci of homogenous eosinophilic material
(see Fig. 5-26). These foci cannot be identified with cer-
tainty as early osteoid when mineralization is not present.
Such tumors, if found in an appropriate clinical setting,
are still best classified as osteosarcoma. Furthermore,
these almost purely fibroblastic lesions occasionally can
produce very heavily ossified metastases. Low-grade
fibroblastic osteosarcomas (intramedullary and surface)
Text continued on p. 242
230 5  Osteosarcoma

A B

C D
FIGURE 5-29  ■  Conventional osteosarcoma, high grade: variants of osteoids and primitive bone formation by tumor cells. A, Discrete
lacelike pattern of osteoid deposition. B, Higher magnification of A showing lacelike pattern of osteoid deposition and courts of
anaplastic tumor cells. C, Lacelike pattern of osteoid formation by tumor cells. D, Higher magnification of C showing interconnected
seams of osteoid encircling tumor cells. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 231

A B

C D
FIGURE 5-30  ■  Conventional osteosarcoma, high grade: variants of osteoid and primitive bone formation by tumor cells. A, Nearly
solid sheetlike osteoid encircling small clusters of tumor cells with lacuna spaces. B, Delicate seams of osteoid and clusters of
anaplastic tumor cells. C and D, Variants of seamlike osteoid deposition encircling small clusters of tumor cells and occasionally
individual tumor cells. (A, ×100; B-D, ×200) (A-D, hematoxylin-eosin.)

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232 5  Osteosarcoma

A B

C D
FIGURE 5-31  ■  Conventional osteosarcoma, high grade. A, Loosely arranged anaplastic tumor cells with epithelioid features. B, Higher
magnification of A showing loosely arranged epithelioid tumor cells with oval densely eosinophilic cytoplasm. C, Early osteoid
deposition by tumor cells. D, Higher magnification of C showing early seams of unmineralized osteoid among tumor cells. (A and
C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 233

A B

C D
FIGURE 5-32  ■  Conventional osteosarcoma, high grade: patterns of osteoid deposition. A, Coarse deposits of osteoid separating
groups of malignant cells. B, Interconnected coarse deposits of osteoid encircling and separating clusters of tumor cells. C, Clearly
defined interconnected osteoid separating clusters of tumor cells. D, Well developed interconnected irregular trabecular pattern
produced by tumor osteoid. (A and B, ×100; C and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
234 5  Osteosarcoma

A B

C D
FIGURE 5-33  ■  Conventional osteosarcoma, high grade: patterns of osteoid deposition and mineralization. A, Irregular separated
trabecular pattern of osteoid deposition. B, Prominent trabecular pattern of well mineralized osteoid. C, Profuse matrix
deposition in osteosarcoma. D, Coarse trabecular pattern of well mineralized osteoid. (A and B, ×100; C and D, ×200)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 235

A B

C D
FIGURE 5-34  ■  Conventional osteosarcoma, high grade: patterns of osteoid deposition and mineralization. A, Coarse interconnected
trabecular pattern of well mineralized osteoid. B, Higher magnification of A showing well mineralized coarse osteoid. Note entrap-
ment of individual tumor cells residing within lacunar spaces of osteoid. C, Conspicuous, well mineralized, osteoid deposition pattern
separating and encircling larger clusters of loosely arranged tumor cells. D, Higher magnification of C showing well mineralized
osteoid and loosely arranged anaplastic tumor cells. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
236 5  Osteosarcoma

A B

C D
FIGURE 5-35  ■  Conventional osteosarcoma, high grade: patterns of osteoid deposition and mineralization. A, Sheetlike osteoid with
early mineralization. B, Higher magnification of A showing a less developed area of osteoid deposition with sparse seams of matrix
deposition. C, Coarser deposition of osteoid with early mineralization. D, Coarse sheetlike deposition of osteoid. (A and D, ×100;
B and C, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 237

A B

C D
FIGURE 5-36  ■  Conventional osteosarcoma, high grade: patterns of osteoid deposition and mineralization and epithelioid features
of tumor cells. A, Large irregular areas of osteoid with entrapped tumor cells. B, Higher power of A showing irregular solid areas
of osteoid with entrapped tumor cells. Note well demarcated dense eosinophilic cytoplasm of tumor cells. C, Irregular solid
areas of osteoid separating large clusters of epithelioid tumor cells. Note dense eosinophilic cytoplasm responsible for epithelioid
appearance of tumor cells. D, Higher power of C showing irregular areas of osteoid with entrapped tumor cells. (A and C, ×100;
B and D, ×200) (A-D, hematoxylin-eosin.)

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238 5  Osteosarcoma

A B

C D
FIGURE 5-37  ■  Conventional osteosarcoma, high grade. A and B, Infiltrative growth pattern of high-grade osteosarcoma permeating
intratrabecular marrow spaces. C, Higher power of B showing permeation of intratrabecular marrow spaces by an osteosarcoma.
D, Variegated osteoid deposition and mineralization patterns in osteosarcoma permeating marrow spaces. (A and B, ×50; C and
D, ×100) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 239

A B

C D
FIGURE 5-38  ■  Conventional osteosarcoma, high grade with hemangiopericytoma-like pattern. A, Hemangiopericytoma-like pattern
of tumor growth bordering endothelial-lined spaces. B, Higher magnification of A showing prominent vascular spaces
and sheetlike osteoid deposition. C, Hemangiopericytoma-like pattern with prominent vasculature and sheetlike osteoid deposition.
D, Higher magnification of C showing prominent engorged vessels and osteoid deposition by tumor cells. (A and C, ×100; B and
D, ×200) (A-D, hematoxylin-eosin.)

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240 5  Osteosarcoma

A B

C D
FIGURE 5-39  ■  Chondroblastic osteosarcoma, high grade. A, Mixed chondroid and osteoid matrix in high-grade osteosarcoma.
B, Higher magnification of A showing gradual transition between hypercellular sarcomatoid component and areas of more solid
matrix deposition. C, Islands of cartilaginous differentiation. D, Higher power of C showing a gradual transition between solid areas
of anaplastic tumor cells and the cartilage matrix. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 241

A B

C D
FIGURE 5-40  ■  Chondroblastic osteosarcoma, high grade. A and B, Low and intermediate power views of osteoid deposition by
anaplastic tumor cells. C and D, Low and intermediate power views of cartilaginous differentiation in the same tumor as shown in
A and B. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
242 5  Osteosarcoma
represent distinct types of osteosarcoma, and these are
described separately. Occasionally a highly anaplastic
tumor, typically located in the metaphysis of a long
bone, shows no osteoid production but is otherwise
cytologically similar to an osteosarcoma. These lesions,
previously classified as undifferentiated (osteolytic) osteo-
sarcoma, are now designated as high-grade, pleomorphic,
malignant fibrous histiocytoma of bone. The distinction
is an academic one because both tumors are treated with
similar chemotherapeutic regimens.
By convention, a four-tier system has been used
for histologic grading of conventional osteosar-
coma.137,141,207,208 However, the majority of grade 1 osteo-
sarcomas seem to belong in the categories of distinct
types of osteosarcoma described as separate entities.
Moreover, separation of conventional osteosarcoma into
four grades is based on subjective evaluation of nuclear
atypia and seems to have minimal clinical value. The
current trend is to separate conventional osteosarcoma
into two major categories: low and high grade. This sim-
plified grading system seems to be more reproducible and
clinically valid.
Osteosarcoma with Unique Microscopic Features.  of small cell osteosarcomas with molecular aberrations
The vast majority of osteosarcomas have obvious features
of atypia and osteoblastic differentiation, which make
them readily recognizable as malignant bone-forming
tumors. In rare instances, these tumors may present with
microscopic features that overlap with other malignant
or even benign conditions. In this section, we describe
microscopic variants of conventional intramedullary
osteosarcoma that mimic small cell malignancies, includ-
ing Ewing’s sarcoma or lymphoma, metastatic carcinoma,
myxoid sarcoma, and giant cell tumor of bone, as well as
benign bone-forming tumors such as osteoblastoma and
chondroblastoma.
Small cell osteosarcoma is a microscopic variant char­
acterized by a proliferation of undifferentiated small
round cells that contain minimal amounts of cyto-
plasm.6,26,29,54,132,146,168,186,190 These tumors, in which the
bone and osteoid matrix production is usually incon-
spicuous, can be confused with other small cell malig-
nancies such as lymphoma and Ewing’s sarcoma (Fig.
5-41). Typically, unequivocal tumor osteoid formation
can be identified focally, which clearly defines the entity
as a malignant bone-forming tumor. Whether small cell
osteosarcoma represents a distinct entity, with its own
characteristic clinical and radiologic features, or is merely
a histologic variant of conventional medullary osteosar-
coma continues to be the subject of debate. On the other
hand, the presence of translocation between chromo-
somes 11 and 22, which characterize Ewing’s sarcoma and
related tumors, has been documented in some of these
cases.149 More modern data indicates that a significant
proportion of small cell osteosarcomas have gene fusions
involving EWSR1 similar to those of Ewing’s sarcoma.127
In addition, these tumors may have microscopic features
overlapping with those of Ewing’s sarcoma. Therefore
some of the small cell osteosarcomas diagnosed in the
past on the basis of purely morphologic criteria may actu-
ally represent variants of Ewing’s sarcoma. In fact, with
the availability of cytogenetic studies, molecular probes,
ERRNVPHGLFRVRUJ
and immunohistochemical markers of greater specificity,
the diagnosis of small cell osteosarcoma is made with
decreasing frequency. In general, our diagnostic philoso-
phy is to diagnose tumors of bone that are composed
of small cells that mimic those of Ewing’s sarcoma and
show focal tumor osteoid production as well as being
characterized, molecularly, by the presence of the gene
fusions involving EWSR1 reported in Ewing’s sarcoma
as variants of this tumor. This is not to deny the pres-
ence of small cell osteosarcoma composed of small cells
with non-Ewing’s sarcoma morphology that are negative
for the gene fusions involving EWSR1. Such tumors, in
our opinion, represent true small cell variants of osteo-
sarcoma. The diagnostic controversy related to the clas-
sification of small cell osteosarcoma is, however, further
complicated by the recent report of a novel EWSR1-
CREB3L1 fusion transcript in small cell osteosarcoma.51
This unique chimeric gene has not been reported in
Ewing’s sarcoma or in any other tumors at the time of
this writing. The fusion of CREB3L1 with FUS, creat-
ing the FUS-CREB3L1 fusion transcript, however has
been reported in low-grade fibromyxoid sarcomas of soft
tissue. Therefore, it may well be that there is a subset
distinct from Ewing’s sarcoma. More detailed discussion
of this problem can be found in Chapters 3 and 11.
Epithelioid osteosarcoma is a rare variant of osteosar-
coma that is composed of epithelioid cells frequently
growing in cords and forming well defined nests (Fig.
5-42).38,45,105,167,222 The cells may have polarized nuclei and
dense eosinophilic cytoplasm. The growth pattern can
be trabecular, nested, or organoid, and rosette-like struc-
tures can be present focally.38,45,105,151 Solid areas exhibiting
such a growth pattern can dominate the tumor; evidence
of tumor osteoid and bone deposition may be focal and
may require extensive sampling to be documented. Some
of these tumors were reported to be focally or even dif-
fusely strongly positive for cytokeratins.86,108,152 Overall,
the microscopic features and positivity for epithelial
markers mimic epithelial malignancy and may cause the
misdiagnosis of metastatic carcinoma in bone. Meticu-
lous correlation with radiographic presentation that, in
the vast majority of cases, shows typical features con-
sistent with a malignant bone-forming tumor and the
fact that these tumors usually affect patients of younger
age, in whom metastatic carcinoma is exceedingly rare,
are helpful in making the correct diagnosis. Microscopic
identification of direct tumor bone production is the most
reliable discriminatory feature that aids in the diagnosis
in this rare variant of osteosarcoma.
Myxoid osteosarcoma is a rare variant of osteosarcoma
that mimics myxoid sarcoma or the myxoid variant of
malignant fibrous histiocytoma (Fig. 5-43). We recently
encountered several examples of this form of osteosar-
coma; all of them originated in the maxillary bone. The
mesenchymal component of the tumor is composed of
loosely arranged, undifferentiated short plump spindle
cells growing in abundant myxoid stroma. Large areas
of the tumor are composed of paucicellular mucinous
lakes. Nuclear atypia and pleomorphism are minimal to
moderate, and the tumor may have a deceptively benign
appearance. There are also ill-defined areas of increased
 5  Osteosarcoma 243

A B

C D
FIGURE 5-41  ■  Small cell variant of osteosarcoma. A, Monotonous proliferation of small tumor cells. B, Higher magnification of
A showing undifferentiated tumor cells with oval cytoplasm and somewhat eccentrically located nuclei. C, Interconnected trabeculae
of tumor osteoid engulfing small clusters of tumor cells in the same tumor as shown in A and B. D, Coarse deposits of osteoid in
the same tumor. (A, C, and D, ×200; B, ×400) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
244 5  Osteosarcoma

A B

C D
FIGURE 5-42  ■  Epithelioid osteosarcoma. A, Trabecular and organoid growth pattern of epithelioid tumor cells interspersed by well
developed interconnected trabecular pattern of tumor bone. B-D, Higher magnification showing epithelioid tumor cells growing in
a nested and trabecular pattern that mimic carcinoma. (A, x100; B-D, x200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 245

A B

C D

FIGURE 5-43  ■  Myxoid osteosarcoma. A, Low power photomicrograph shows tumor cells dispersed in myxoid stroma and focal
deposition of tumor osteoid. B, Higher power photomicrograph of A showing interface between myxoid tumor and osteoid
deposits. C, More cellular area of the tumor composed of undifferentiated tumor cells dispersed in myxoid stroma (×100).
D, Low power photomicrograph showing lakes of mucin and overall blunt appearance of the tumor. Inset shows higher magnifica-
tion of D, depicting mucin lakes and paucity of tumor cells. (A and D, ×50; B, C, and inset, ×100) (A-D and inset,
hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
246 5  Osteosarcoma
cellularity. Evidence of tumor bone production is difficult
to appreciate and requires extensive sampling. Correla-
tion with radiographic imaging discloses the destructive
aggressive growth pattern of the lesion and may alert the
pathologist to radiographic evidence of the bone-forming
nature of the tumor.
Giant cell-rich osteosarcoma accounts for approximately
3% of all cases of osteosarcoma and most of them appear
to arise in the appendicular skeleton.24,73,145,176 The char-
acteristic feature is the presence of large numbers of
osteoclast-like giant cells distributed among sarcomatous
tumor cells (Fig. 5-44).24,73,145,148,211 The stromal cells of
such tumors may have a deceptively benign appearance
and the lesion may be mistaken for a giant cell tumor.
Similar to other variants of osteosarcoma described in
this section the bone-forming nature of giant cell-rich
osteosarcoma may require extensive sampling, correla-
tion with radiographic features, or both. Highly atypical
pleomorphic giant cells are a constant feature in a large
proportion of conventional osteosarcoma. Tumors con-
taining such cells are not designated as giant cell-rich
osteosarcoma. The term giant cell-rich osteosarcoma is
reserved only for those tumors that contain a prominent
population of benign appearing multinucleated osteo-
clastic giant cells and in which there is overall mimicry
of the giant cell tumor of bone. The features helpful in
differentiating this variant of osteosarcoma from giant
cell tumor consist of the presence of malignant stromal
cells as well as tumor bone production.
Osteoblastoma-like osteosarcoma accounts for less than
1% of all osteosarcomas; two small series of this entity
were described from the Rizzoli Institute and the Mayo
Clinic.25,27 Most of the reports represent single case
communications.1,30,89,113,194 The difficulty in interpreting
published results is related, in part, to the fact that
the diagnostic philosophy to classify the lesion as
osteoblastoma-like osteosarcoma differs among various
schools of pathology and some of the cases in these
reports may overlap with our concept of aggressive osteo-
blastoma. We reserve the term osteoblastoma-like osteosar-
coma for a tumor with overall trabecular osteoid pattern
that mimics that of osteoblastoma but is distinct from an
aggressive osteoblastoma, characterized by solid prolif-
eration of epithelioid osteoblasts (Fig. 5-45). A more
detailed description of this problem is included in
Chapter 4. In addition, the stromal composition with
scattered giant cells and prominent vasculature further
mimics that of osteoblastoma. The tumor, however, has
an infiltrating pattern of the host bone and there are areas
of more solid and irregular deposits of osteoid with obvi-
ously atypical osteoblastic cells. The microscopic evi-
dence of an aggressive growth pattern is further supported
by poorly defined infiltrating borders and frequent corti-
cal destruction documented radiographically. The domi-
nance of an osteoblastoma-like pattern creates diagnostic
difficulties; a significant proportion of the reported cases
are initially diagnosed as benign lesions. This further
amplifies the need for strict correlations between micro-
scopic and radiographic presentations of the lesion that
can alert the pathologist to the aggressive growth pattern
inconsistent with the diagnosis of a benign osteoblastic
lesion. Small core needle biopsies of these lesions are
ERRNVPHGLFRVRUJ
invariably challenging, and a generous sampling of the
tumor using open biopsy is often required to disclose the
malignant nature of the process.
Chondroblastoma-like osteosarcoma is most likely the
rarest of the variants of osteosarcoma described in this
section and only a handful of single case reports are avail-
able in the literature.7,177 The overall microscopic features
of this lesion mimic that of chondroblastoma. The irreg-
ular matrix deposition areas resemble those frequently
seen in chondroblastoma and the cellular composition
with mononuclear cells having eccentric nuclei and well
defined eosinophilic cytoplasm admixed with scattered
osteoclast-like giant cells are responsible for frequent
confusion of this variant of osteosarcoma with a benign
chondroblastoma on initial biopsies (Figs. 5-46 and 5-47).
The presence of obvious atypia and infiltrating growth
pattern of the tumor differentiate this lesion from a chon-
droblastoma. In addition, virtually all of the reported
chondroblastoma-like osteosarcomas show an ill defined
aggressive growth pattern radiographically. Therefore, as
in virtually every instance of diagnostic difficulties in
skeletal pathology, strict correlation with radiographic
imaging data is the best aid for correct diagnosis.135
Pathologic Assessment of Preoperative
Chemotherapy Effect
The clinical and radiographic data, as well as postopera-
tive microscopic examination, indicate that current mul-
tidrug chemotherapeutic regimens result in substantial
reduction of tumor mass in at least 50% of patients with
osteosarcoma. In addition, in some of these patients,
complete or nearly complete (90%) necrosis of the
tumor can be accomplished.5,8,19,48,77,96,123,162 The latter is
associated with substantially better prognosis (i.e., longer
relapse-free time and survival rates) than in tumors that
respond less favorably to chemotherapy. These observa-
tions provided the foundation for the pathologic assess-
ment of the effect of therapy in postoperative specimens.
Pathologic assessment of chemotherapy effect is now
universally accepted as an integral element of the multi-
modal approach (Table 5-2).5,8,9,21,77,162,165,166 Moreover,
the degree of response (necrosis) is used as a factor in
modifying the subsequent (postoperative) treatment pro-
tocol. Spontaneous necrosis, however, is a common event
in a variety of malignant neoplasms, including osteosar-
coma.29,212 Therefore the presence of necrosis may not
TABLE 5-2 Histologic Grading of Chemotherapy
Effect in Osteosarcoma
Grade Tumor Response
1 None or minimal
2 Extensive necrosis with more than 10% of viable
tumor
3 Extensive necrosis with scattered foci of viable
tumor (<10%)
4 Complete necrosis
Modified from Huvos A: Bone tumors: diagnosis, treatment
and prognosis, ed 2, Philadelphia, 1991, WB Saunders.
 5  Osteosarcoma 247

A B

C D
FIGURE 5-44  ■  Giant cell-rich osteosarcoma. A and B, Prominent population of osteoclast-like multinucleated giant cells. Note back-
ground anaplastic tumor cells. C, Higher magnification of B documenting the microscopic features of numerous osteoclastic multi-
nucleated giant cells. Note highly atypical anaplastic tumor cells in the background. D, Evidence of tumor osteoid production in
another area of the same tumor. (A and B, ×50; C and D, ×100) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
248 5  Osteosarcoma

A B

C D
FIGURE 5-45  ■  Osteoblastoma-like osteosarcoma. A, Low power photomicrograph showing interconnected coarse trabeculae of
tumor osteoid and prominent vascular stroma resembling osteoblastoma. B, Higher magnification of A showing interconnected
trabeculae of tumor osteoid. Note prominent dilated vessels in the stroma. C, Tumor osteoid deposits and vascularized stromal
tissue with osteoblastic cells growing in the intertrabecular spaces. Note scattered multinucleated giant cells. D, Low power photo-
micrograph showing extensive tumor osteoid deposits comprised of interconnected trabecular pattern and solid areas of osteoid
deposition. Inset shows higher magnification of solid areas of osteoid with numerous atypical osteoblastic cells. Note the overall
resemblance to osteoblastoma; the distinguishing microscopic feature is the presence of solid areas of osteoid with highly atypical
osteoblastic cells. (A and D, ×50; B and C, ×100; inset, x200) (A-D and inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 249

A B

C D

FIGURE 5-46  ■  Chondroblastoma-like osteosarcoma. A, Anteroposterior radiograph showing destructive lesion in the periacetabular
area. B, T1-weighted magnetic resonance image of tumor shown in A reveals heterogeneous signal enhancement in the
tumor, infiltrating medullary cavity of the periacetabular area. C, Low power magnification with matrix deposition resembling
chondroblastoma. D, Irregular areas of matrix deposition and more cellular areas of tumor with solid growth pattern. (C, ×100;
D, ×200) (C-D, hematoxylin-eosin.)

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250 5  Osteosarcoma

A B

C D
FIGURE 5-47  ■  Chondroblastoma-like osteosarcoma. A and B, Low power photomicrographs showing matrix deposition and the
overall cytoarchitectural features resembling chondroblastoma. Insets show higher magnification of matrix deposits. C and D, Higher
power photomicrographs of the tumor shown in A and B depicting solid growth pattern with the cellular compositions comprising
mononuclear and scattered multinucleated giant cells with distinct eosinophilic cytoplasm. Note that the overall pattern of the matrix
deposition and cellular components resemble osteoblastoma. The distinguishing features represent an aggressive growth pattern
documented radiographically and the pronounced atypia throughout the lesion. (A and B, ×100; B, C, and inset, ×200) (A-D and
insets, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

necessarily reflect the effect of treatment. It has been
estimated that up to 60% of necrosis can be spontaneous
and may not necessarily reflect a treatment effect, but
subtotal (90%) or complete necrosis almost never occurs
spontaneously in osteosarcoma and can be attributed to
treatment.
In this section, we discuss some of the technical aspects
of the pathologic evaluation of a therapeutic effect
according to the approach used at the University of
Texas MD Anderson Cancer Center. Theoretically, the
accurate assessment of the extent of necrosis requires
complete sampling of the entire tumor. However, this
approach is impractical and in many cases could require
examination of several hundred histologic sections. For
practical purposes, complete sampling (the so-called his-
tologic mapping) of the central slice of the tumor provides
a reasonably good and clinically valid assessment of
the effect of therapy. The postoperative specimen is
bivalved along the central plane of tumor growth. In
smaller specimens, such as those shown in Figure 5-48,
a whole-mount embedding technique can be used. In the
majority of cases, the central slice is further subdivided
into smaller samples suitable for embedding in conven-
tional cassettes (Fig. 5-49). The position of each sample
can be recorded on the gross photograph, specimen
radiograph, or sketch of the tumor.
Tumor necrosis is characterized by the death of sarco-
matous cells with pyknosis and fragmentation of their
nuclei or by complete disappearance of tumor tissue.
The prenecrotic changes attributed to therapy consist of
the development of bizarre nuclei, homogenization of the
chromatin structure, and vacuolization of the cytoplasm.
The complete elimination of sarcomatous cells within
tumor osteoid or residual host bone is often seen. In such
areas, the sarcomatous tissue is replaced by a hyalinized
vascular stroma (Fig. 5-50). Cystic cavities filled with
mucoid material are remnants of more solid sarcomatous
areas with minimal or no tumor bone formation.
For research purposes, planimetric techniques are used
to calculate the percentage of necrosis and the amount of
residual viable tumor. Figure 5-48 shows an example of
the assessment of treatment effect from a planimetric
reconstruction of a whole-mount preparation. This labo-
rious approach, which requires special equipment that is
not available in standard pathologic laboratories, is not
absolutely necessary to evaluate the therapeutic effect on
routine cases. Visual assessment of individual sections and
rough estimates of the extent of necrosis are sufficient
and clinically valid. The refinement of imaging tech-
niques, especially of sequential postcontrast MRI, may
permit preoperative imaging assessment of a therapeutic
effect. This technique is based on the identification
of signal enhancement by viable tumor after contrast
injection versus signal void in areas of necrosis. Various
combinations of contrast enhanced MRI techniques
have been applied to evaluate tumor necrosis after che-
motherapy.60,80,82,170,206 More recently, a combination of
18
F-fluorodeoxyglucose positron emission tomography
(FDG PET) and MRI was used to formulate a prediction
model of chemotherapy response in osteosarcoma.41
Figure 5-51 shows examples of MRI compared with con-
ventional pathologic evaluation of postoperative speci-
ERRNVPHGLFRVRUJ
5  Osteosarcoma 251
mens. In summary, MRI, possibly combined with PET,
may have the potential to provide estimates of residual
viable tumor before surgery, although its true clinical
value continues to be investigated. The most accurate
assessment of therapeutic effect is still based on patho-
logic mapping of resection specimens.
Special Techniques
Ultrastructurally, osteosarcoma is composed of pleomor-
phic, undifferentiated mesenchymal cells (Fig. 5-52).
Features of osteoblastic differentiation consist of eccen-
tric nuclei, abundant and frequently dilated rough
endoplasmic reticulum, and prominent Golgi centers.
However, these features are nonspecific and of no diag-
nostic value. Large amounts of intracytoplasmic lipid
material may be present. Foci of cartilaginous differentia-
tion with prominent glycogen and deposition of loose
extracellular fibrillar matrix may be seen. Two types of
multinucleated giant cells may be present. One repre-
sents a large undifferentiated sarcoma cell, and the other
type has features of a benign osteoclast with prominent
mitochondria and cytoplasmic projections.67,104,159,185 The
extracellular matrix in osteosarcoma has features of dis-
organized, incomplete ossification. It is composed of col-
lagen fibrils with deposition of calcium hydroxyapatite
crystals. The process of tumor matrix ossification takes
place along or among collagen fibrils and in close associa-
tion with the so-called matrix vesicles. The crystals grow
in size, coalesce, and form irregular solid aggregates216
(Fig. 5-53). Scanning electron microscopic studies reveal
that the calcium deposits form globules of calcification
that grow in size by the deposition on their surfaces of
smaller globular deposits that are 0.1 to 0.3 µm.184
Immunohistochemistry continues to be of marginal
help in the diagnosis of osteosarcoma and is predomi-
nantly used to rule out other neoplasms. Osteosarcomas
express a full spectrum of osteoblastic lineage biomark-
ers, including bone morphogenetic proteins, osteocalcin,
and osteopontin, as well as master regulatory proteins
involved in skeletal development such as Osterix and
Runx2. 2,3,23,32,36,37,81,85,106,117,126,147,183,188,192,198,202,213,217
Although these proteins are involved in the development
of osteoblastic lineage cells, their role in differential diag-
nosis of osteosarcoma is hampered by the fact that they are
also expressed in other human tumors, playing a role in
organogenesis of their respective tissue lineages. In addi-
tion, they can be upregulated in many solid tumors as a
part of the so-called epithelial to mesenchymal transition
phenomenon. Therefore, they can be used to evaluate
the osteoblastic nature of the cells but can not absolutely
identify malignant cells in question as osteosarcoma.
Osteosarcoma cells are consistently and strongly positive
for vimentin. Strong positivity for S-100 protein is typi-
cally seen in the areas that exhibit cartilaginous differen-
tiation, but it can also be present focally in osteoblasts
of undifferentiated sarcomatous areas. Focal positivity
for epithelial markers (keratins and epithelial membrane
antigen) and muscle markers (smooth muscle actin and
desmin) have been reported.42,43,54 However, intense and
diffuse positivity for these markers is practically never
Text continued on p. 258
252 5  Osteosarcoma

A B

C D
FIGURE 5-48  ■  Preparation of postoperative resection specimen and assessment of therapeutic effect in conventional osteosarcoma
on basis of whole-mount embedding and planimetry. A, Specimen radiograph. B, Gross photograph. C, Whole-mount histologic
section of proximal humerus. D, Extent of tumor necrosis and amount of residual viable tumor (blue) based on planimetric evalu-
ation of specimen shown in B. Amount of residual viable tumor (>10%) is considered as an unfavorable (grade 2) response. (Courtesy
Dr. A.G. Ayala, Houston.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 253

A B

C D
FIGURE 5-49  ■  Assessment of therapeutic effect in conventional osteosarcoma on basis of conventional embedding. A, Specimen
radiograph of osteosarcoma of distal femur. B, Gross photograph of central tumor slice after sectioning to create smaller fragments
suitable for embedding in conventional cassettes. C, Specimen radiograph after central tumor slice was sectioned. D, Graphic
reconstruction of specimen shows residual viable tumor (blue areas). (Courtesy Dr. K. Raymond, Houston.)

ERRNVPHGLFRVRUJ
254 5  Osteosarcoma

A B

C D
FIGURE 5-50  ■  Chemotherapeutic effect in osteosarcoma. A-C, Replacement of sarcomatous with amorphous stromal material among
tumor osteoid. D, Necrotic tumor infiltrating marrow spaces. Note occasional residual tumor cells with pyknotic nuclei. (A-D, ×100)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 255

A B

C D
FIGURE 5-51  ■  Magnetic resonance imaging of osteosarcoma of proximal tibia for evaluation of therapeutic effect in comparison
with histologic mapping. A, T1-weighted sagittal magnetic resonance image (MRI) of proximal tibia reveals marrow replacing tumor
with epiphyseal extension. B, Sagittal spin-echo T2-weighted MRI at slightly different plane reveals abnormal high signal intensity
within tumor replacing medullary cavity. C, T2-weighted sagittal MRI with contrast reveals focal areas of high signal intensity that
were presumed to contain residual viable neoplasm. D, Histologic mapping of extent of tumor necrosis. Blue areas represent residual
viable tumor. Note that overall there is good correlation between pathologic and MRI assessment of therapeutic effect. (A-C, courtesy
Dr. D.G. Varna, Houston.)

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256 5  Osteosarcoma

B
FIGURE 5-52  ■  Conventional osteosarcoma: ultrastructural features. A and B, Undifferentiated pleomorphic sarcomatous cells are
the most frequent cellular component seen in majority of high-grade conventional osteosarcoma. (A, ×4500; B, ×6000.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 257

FIGURE 5-53  ■  Conventional osteosarcoma: ultrastructural features. A and B, Ultrastructural features of matrix mineralization with
deposition of calcium hydroxyapatite crystals along collagen fibers. (A, ×3500; B, ×9000; inset, ×14,000.)

ERRNVPHGLFRVRUJ
258 5  Osteosarcoma
seen in osteosarcoma. If present, other tumors should be
seriously considered.
DNA ploidy studies have documented that a majority
of conventional osteosarcomas have prominent, often
multiple, aneuploid clones.13,16,31,88,91,109,110,130,131,138 The
degree of aneuploidy has some prognostic implica-
tions.109,110,130 The relapse-free time and survival rates are
better in a tumor with a prominent, near-diploid cell
population (as a sole clone or dominant but coexistent
with more aneuploid cell clones).125 The conversion from
aneuploidy to near diploidy after chemotherapy corre-
lates with a good histologic response (complete or almost
complete necrosis).11,22
On the chromosomal level, most conventional osteo-
sarcomas show multiple rearrangements, multiplications,
and the presence of marker chromosomes.34 Chromo-
somal complements in osteosarcoma can be divided into
two major groups: grossly aneuploid and near diploid.
Grossly aneuploid complements show multiple extra
chromosomes, chromosomal rearrangements, and marker
chromosomes. This complement corresponds to highly
aneuploid cell populations identified by flow cytometry
or image analysis. The other complement is character-
ized by multiple chromosomal deletions, rearrangements,
and a lesser degree of chromosomal multiplication. This
pattern corresponds to the so-called near-diploid or even
occasionally hypodiploid cell populations documented by
flow cytometry. Several chromosomal alterations seem to
be distributed in a nonrandom fashion. Structural rear-
rangements cluster to 1p, 1q, 3p, 3q, 11p, 17p, and 22q.
The following bands were documented to be most fre-
quently altered: 1q11, 1q21, 1q42, and 7q11. Loss of
chromosomes 3, 10, 12, and 15 are the most frequent
numerical abnormalities; the most frequent complex
recurrent rearrangements involve chromosomes 8, 17,
and 20.
On the molecular level, the retinoblastoma (RB) gene
seems to play the most important role in the pathogenesis
of osteosarcoma (see indices for osteosarcoma associated
with retinoblastoma).18,44,57,178-180 Several studies have
shown that the patterns of alterations (mutations) of the
RB gene in osteosarcoma are similar to those seen in
retinoblastoma. These alterations result in the absence of
a functional RB gene product. The development of these
changes follows the double-hit kinetics postulated for the
development of retinoblastoma. The first mutation or
deletion alters one allele, and the subsequent “hit” results
in the loss of function of the remaining allele. These data
are consistent with clinical observations that document
an increased incidence of osteosarcoma in patients with
retinoblastoma. In addition to the loss of heterozygosity
at the RB locus on chromosome 13, osteosarcoma fre-
quently shows loss of heterozygosity of loci on 3q, 17p,
and 18q.219
Alteration of TP53 is frequently present in osteosar-
comas.133,144,154,179,180,201 Germ cell line mutations of TP53
were identified in some cancer-predisposing syndromes,
such as the Li-Fraumeni syndrome, with high incidence of
osteosarcoma.200 Tumors with altered TP53 are also more
aggressive and have a high propensity for metastases.
Amplification of the human homolog of the Mouse
double minute 2 gene (MDM2) with a p53 protein–
ERRNVPHGLFRVRUJ
binding function was frequently found in metastatic
lesions.115 This finding indicates that in metastatic
osteosarcoma, p53 can be functionally inactive because of
high levels of MDM2 products. Alterations of other
genes such as MYC seem to be infrequent in osteosar-
coma.116 A recent study from the Rizzoli Orthopedic
Institute suggests that an upregulation of the multidrug
resistance gene (MDRI) coding for P-glycoprotein
(a transmembrane adenosine triphosphate–dependent
efflux pump) in osteosarcoma is associated with a
significantly increased risk of adverse events.11 Increased
levels of P-glycoprotein may confer chemotherapy resis-
tance and are associated with significantly lower survival
rates of patients with osteosarcoma. These original
reports concerning the molecular prognostic factors in
osteosarcoma were followed by numerous publications
reporting the relationship between the expression
pattern of numerous genes and their encoded proteins,
including VEGF, CXCL12, c-kit, NDRG1, URG4, EBF2,
RUNX2, ERBB2, WWOX, KAI1, Ezrin (EZR), and
cancer-testis antigen as potential prognostic factors
in osteosarcoma.10-12,14,42,63,92,93,106,114,118,158,161,173,218,220,221,224
These reports provide interesting clues on the biology of
osteosarcoma, but their role in the diagnosis and manage-
ment of this disease is uncertain.
The past decade of research on osteosarcoma
is highlighted by the applications of various high
throughput genomic mapping platforms, includ-
ing genome sequencing, to investigate the myriad of
genetic and epigenetic alterations observed in these
malignancies.40,68,69,103,111,120,124,156
Comparative genomic hybridization (CGH) microar-
ray analysis confirmed earlier-known large amplicons at
12q11-115, 8q24, 6p12-p13, and 17p11-p13 and identi-
fied novel amplicons at 14q11, 17q25, and 22q11-q13.4
These data implicate the TOM1L2 and CYP27B1 genes
as novel targets for 17p and 12q amplicons. The inte-
grated use of high resolution DNA methylation, genomic
imbalance, and gene expression profiling platforms
reveals a complex genetic and epigenetic deregulation of
the MYC network in the cell lines of osteosarcoma.171,204
Similar approaches applied to human samples disclose
multiple osteosarcaroma driver genes, many of which
belong to the superfamily of genes controlling genomic
stability.46,68,111,112,203 Interactive analysis of gene networks
discloses upregulation of histone cluster 2 genes at chro-
mosome 1q21.1q21.3, loss of chromosome 8p21.2-p21.3,
and inhibition of the DOCK5 and TNFRSF10A/D genes,
complemented by the amplification-related overexpres-
sion of RUNX2 at chromosome 6p12.3-p21.1.172 Activa-
tion of RUNX2 disrupts G2/M cell-cycle checkpoints;
inactivation of DOCK5 signaling in synchrony with TP53
and TNFRSF10A/D-related changes plays a role in inac-
tivating cell death pathways. MicroRNA analyses identi-
fied several novel miRNA species, which include the
MIR21, MIR93, MIR143 and MIR145, miRNA199, and
the miRNA-17-92 cluster, as potential regulatory targets
in osteosarcoma.15,58,66,143,155,223 Genome-wide analyses
disclose complex miRNA deregulation involving signal-
ing pathways important for the development of osteosar-
coma, including Notch, RAS/p21, MAPK, Wnt, and Jun/
FOS.128 Preliminary genome sequencing data shows that

a subset of osteosarcomas can develop through a novel
genetic mechanism referred to as chromothripsis.139,191 It
postulates that if, in one catastrophic event, apoptosis is
not completed, the shattered chromosomes are reassem-
bled at random by nonhomologous end-joining. Such
reassembly creates hundreds of translocations that involve
multiple target genes with oncogenic potentials. An
example of such a mechanism evidenced by genomic
sequencing of an osteosarcoma is shown in Fig. 5-54.
The conceptual implication of this finding is that, in the
predisposed individual, a single event can trigger the
development of cancer without the long pathway of pre-
neoplastic conditions. This concept is in keeping with the
clinical development of the majority of de novo osteosar-
comas, which affect young individuals who are without
any evidence of longstanding predisposing lesions.
In summary, molecular techniques, including recently
applied genomic platforms, provide some interesting
clues about the pathogenesis of osteosarcoma. The recent
data contribute to our understanding of the complex
biology of this tumor; there is hope that such approaches
in the future may identify novel diagnostic, prognostic,
and therapeutic targets.
Differential Diagnosis
Conventional intramedullary osteosarcoma can be con-
fused with both benign and malignant bone lesions.
Careful correlation with radiographic findings and
knowledge of the clinical setting will serve to avoid these
pitfalls in most cases.
Fracture callus can simulate a malignant bone-forming
neoplasm when the bone-forming features include
enlarged, highly active, immature but uniform osteo-
blasts that have prominent mitotic activity. The osteoid
and woven bone trabeculae in callus usually show a
pattern of parallel arrangement with prominent osteo-
blastic rimming. This purposeful orientation is not seen
in osteosarcoma, where the bone matrix is deposited in a
disorganized and haphazard fashion. Atypical (multipo-
lar) mitotic figures are often present in osteosarcoma
together with pronounced nuclear atypia. Neither of
these cytologic abnormalities should be present in frac-
ture callus. Fracture callus frequently contains foci of
cartilage matrix production that may blend imperceptibly
with woven bone–producing osteochondroid material.
The latter finding sometimes contributes to its confusion
with osteosarcoma.
In some cases of osteogenesis imperfecta tarda, incon-
spicuous fractures can be associated with exuberant callus
that can mimic osteosarcoma both radiologically and
histologically.
Acute suppurative osteomyelitis characteristically involves
the metaphyses of long bones of children and is associ-
ated with prominent periosteal new bone formation that
simulates Codman’s triangles. For this reason, patients
with this inflammatory lesion may have a misdiagnosis of
osteosarcoma; the misdiagnosis is based on radiographs.
Similarly, osteosarcomas in the same clinical setting can
be radiographically mistaken for osteomyelitis, and unless
a biopsy is performed, patients may receive inappropriate
antibiotic therapy.
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5  Osteosarcoma 259
The differentiation of osteosarcoma from osteoblas-
toma and aggressive osteoblastoma is discussed in Chapter
4. It should be emphasized that some osteosarcomas may
contain focal areas that have a superficial microscopic
resemblance to osteoblastoma. In very rare instances, the
entire tumor may exhibit a histologic pattern similar to
that seen in osteoblastoma, with relatively uniform tumor
bone trabeculae and less conspicuous nuclear atypia. Such
variants of osteosarcoma are referred to as osteoblastoma-
like osteosarcoma. These variants usually contain atypi-
cal mitoses, grow to a larger size than osteoblastomas
(generally >5 cm), and exhibit a permeative and destruc-
tive growth pattern with engulfment of preexistent bone
trabeculae. These tumors in particular can be confused
histologically with aggressive osteoblastoma.
Chondrosarcoma is usually easily distinguished from
osteosarcoma on clinical, radiologic, and pathologic
grounds. Problems in distinguishing between these
tumors arise when an osteosarcoma is predominantly car-
tilaginous or when a low-grade chondrosarcoma exhibits
enchondral ossification. The cartilaginous component of
a chondroblastic osteosarcoma is usually of high grade
histologically and is accompanied by foci of direct tumor
bone production from sarcomatous stromal cells. Enchon-
dral ossification is usually seen within cartilage lobules
of an otherwise typical low-grade chondrosarcoma. Fur-
thermore, clear cell chondrosarcomas characteristically
show microscopic features of bone formation that may
mimic osteosarcoma. The typical epiphyseal location
and unique clear cell population in the intertrabecular
spaces help to distinguish this lesion from osteosarcoma.
The anaplastic sarcomatous component of a dedifferenti-
ated chondrosarcoma may take the form of a high-grade
osteoblastic osteosarcoma. This form of chondrosarcoma
can be distinguished from de novo osteosarcoma only
when the low-grade cartilaginous component is identi-
fied. This distinction is aided by careful radiographic cor-
relation, which usually reveals the presence of a heavily
calcified low-grade chondrosarcoma component.
Malignant fibrous histiocytoma of bone has some over-
lapping features with osteosarcoma.97 Indeed, this tumor
was classified as a highly anaplastic osteolytic form of
osteosarcoma before it was recognized as a distinct tumor
entity. However, some forms of osteosarcoma closely
resemble malignant fibrous histiocytoma because their
principal cell population is highly pleomorphic and
osteoid and tumor bone formation is focal and incon-
spicuous (malignant fibrous histiocytoma-like osteosar-
coma). The prevailing criteria for the diagnosis of
malignant fibrous histiocytoma of bone include the
absence of bone or cartilage matrix production by the
tumor cells, typical occurrence in an older population,
paucity of periosteal reactive bone, and frequent associa-
tion with underlying bone conditions. When this tumor
occurs in the metaphyses of long bones in children or
adolescents, the distinction from conventional osteosar-
coma may be only academic because their biologic poten-
tials and treatments do not differ.
Giant cell tumor of bone may be simulated histologically
in cases of osteosarcoma that are rich in osteoclast-like
giant cells and show minimal bone matrix produc-
tion. Radiographic studies showing the characteristic
260 5  Osteosarcoma

AA BB CC D D EE FF GG HH I I J J

Telomere Centromere
Shattering

F
B
A

E
C

F
J
H

H
A
E D

I
C

G
B D

Stitching

D C E F H G
AB CH I A B A B I J D E C D E F H I J

Deletion-type
4
2 Tandem dup-type
0
Tail-to-tail inverted
1
Head-to-head inverted
0
Interchromosomal

0 5 10 15 20 25 30 35 40 45 50 55 60 65
Genomic location (Mb)
B
Chr 8
Chr 14

C Chr 12

FIGURE 5-54  ■  Genome sequencing provides evidence for chromothripsis involved in the development of osteosarcoma. A, Diagram-
matic representation of chromosomal shattering and random reassembly resulting in a myriad of translocations. B, An example of
chromosomal maps documenting complex rearrangements that involve deletions, tandem duplications, tail-to-tail inversion, head-
to-head inversion, and interchromosomal insertions. C, Circos diagram of representative chromosomes, documenting multiple
chromosomal translocations depicted as colored arch lines.

ERRNVPHGLFRVRUJ

localization of giant cell tumor in the epiphyseal end
of a long bone in a skeletally mature patient serve to
distinguish it from giant cell–containing osteosarcoma.
Furthermore, osteosarcomas usually affect metaphyseal
sites in skeletally immature individuals in whom the car-
tilaginous growth plate acts as a barrier to epiphyseal
extension. Sampling also plays a role in this distinction
because the majority of giant cell–rich osteosarcomas
also contain more typical conventional osteosarcoma-like
areas and the dominant giant cells are usually focally dis-
tributed. The distinction is further aided by the presence
of nuclear anaplasia and atypical mitoses in the stromal
cells of osteosarcoma.
The rare small cell variant of osteosarcoma can be
confused microscopically with other round-cell tumors,
such as Ewing’s sarcoma, peripheral neuroectodermal
tumor, and lymphoma. The small cell components of
osteosarcoma are usually more pleomorphic than the
cells that comprise Ewing’s sarcoma, lymphoma, and
other round-cell tumors, the differential diagnosis of
which is aided by appropriate cell markers and electron
microscopic study. For details of the differential diagnosis
of small cell bone tumors, the reader is referred to
Chapters 11 and 12.
Metastatic carcinoma rarely presents problems in dif-
ferential diagnosis when the epithelial tumor provokes
marked osteoblastic reaction, as is most frequently seen
in prostate or breast carcinomas. On the other hand,
some osteosarcomas may contain large osteoblasts with
densely eosinophilic or vacuolated cytoplasm that grows
in cohesive sheets or nests and may simulate metastatic
carcinoma. Appropriate immunohistochemical studies
for epithelial markers and tumor-associated antigens may
be useful in facilitating this diagnosis.
Treatment and Behavior
Conventional osteosarcoma belongs to the category of
the most aggressive and highly lethal osseous neoplasms.19
Before the advent of chemotherapy, treatment by surgery
alone resulted in low 5-year survival rates, within the
range of 10% to 20%.214 With the introduction of che-
motherapy and especially with the development of
modern multiple-modality treatment protocols, this
dismal prognosis has improved.8,9,19,20,21,28,39,101,123,169,182
The initial evaluations of the treatment effect and sur-
vival rates in osteosarcoma were complicated by the fact
of spontaneously changing survival rates disclosed by
analysis of data from the Mayo Clinic.75,195,196 Higher
5-year survival rates (60% to 70%) can be achieved only
in a subset of patients with osteosarcoma—those who
present with surgically resectable lesions and without evi-
dence of metastases.181,189,197 The general treatment plan
consists of preoperative (neoadjuvant) chemotherapy and
sometimes irradiation followed by limb-sparing surgical
excision (if possible) and a postoperative chemotherapeu-
tic regimen modified according to the extent of tumor
necrosis.72,164 Data from the University of Texas MD
Anderson Cancer Center indicate that 90% and more of
tumor necrosis is associated with nearly 90% 5-year
disease-free survival.165,166 On the contrary, less than 90%
of tumor necrosis is associated with only a 14% 5-year
ERRNVPHGLFRVRUJ
5  Osteosarcoma 261
disease-free survival rate. The overall 5-year survival rate
in this group was 64%, whereas the continuous disease-
free survival rate was 58%.
The introduction of chemotherapy in the 1970s
resulted in a gradual increase in the national survival rates
for osteosarcoma, which improved significantly between
1973 and 1983 and again between 1984 and 1993.140
More modern chemotherapy protocols, including stem
cell support, improved the rates of pathologic response
but had minimal impact on survival.87,119,160 In summary,
there has been no dramatic improvement in survival rates
since 1993.140
Osteosarcomas frequently metastasize, and this
outcome is observed in approximately 80% of patients
treated by surgical excision alone. Such high metastatic
rate is related to high propensity of osteosarcoma for early
lymphatic spread.215 The most frequent sites of metastases
are the lungs and liver. Apparently, there is a somewhat
increased rate of skeletal metastases in patients treated
with chemotherapy. The presence of pulmonary metas-
tases can be associated with hypertrophic pulmonary
osteoarthropathy.55,78 Surgical excision of metastases with
adjuvant chemotherapy prolongs life.17,33,84 In the group
of surgically resectable, especially solitary, metastases, this
approach sporadically results in cure. The prognosis in
osteosarcoma is also related to the site of involvement.35,42
Surgically resectable lesions of the appendicular skeleton
are associated with a nearly 50% 5-year survival rate. On
the other hand, osteosarcoma that involves the trunk
bones is associated with a less favorable survival rate (e.g.,
only 20% at 5 years for patients with pelvic osteosar-
coma).56 Osteosarcomas of the craniofacial bones, espe-
cially those of the mandible, were originally reported to
have a more indolent course than other conventional
osteosarcomas.207,208 Satellite intramedullary foci (“skip”
metastases) were considered to be a major source of local
recurrence.61,129 The extensive use of MRI has shown that
the so-called skip foci are in fact extremely rare.
Originally, it was postulated that classification of con-
ventional osteosarcoma into histologic subtypes had
some prognostic value. With the advent of modern che-
motherapeutic protocols, the consensus is that histologic
subtypes of conventional osteosarcoma should be used
only in a descriptive sense and have no prognostic impli-
cations. In summary, the final outcome in osteosarcoma
is related to multiple factors, such as site of involvement,
tumor size, resectability, presence of metastases, and
perhaps to some extent the histologic grade or even the
age of the patient and the dose of chemotherapy that can
be tolerated.
Based on the recent analysis of SEER data, it appears
that survival rates are age specific.140 The relative 5-year
survival rate of young-onset osteosarcoma (aged 0-24
years) is 61%. A similar survival rate of 58% was observed
for patients aged 29 to 59 years. A dramatic drop in the
survival rate, to 24%, was recorded for patients older
than age 60 years.
The most important factor is the biologic potential of
the tumor, which is beginning to be investigated on a
genome-wide scale by novel high throughput techniques.
There is hope that this approach may identify novel
therapeutic targets and will guide the design of more
262 5  Osteosarcoma
effective chemotherapeutic protocols that may further
improve the outcomes of patients affected by these highly
aggressive and still poorly understood malignancies.
Conventional Osteosarcoma in Different
Anatomic Sites
Osteosarcoma has a clear predilection for the metaphyses
of long bones in adolescent patients. It is important
to remember, however, that osteosarcoma sporadically
occurs in virtually every part of the skeleton regardless of
the patient’s age. It appears that there is a significant dif-
ference in anatomic distribution between young and
elderly patients. In the older age group, the tumor is less
likely to occur in long bones and more frequently involves
flat bones and the axial skeleton.56,95 There is disagree-
ment as to the age and anatomic distribution of major
histologic subtypes of osteosarcoma (i.e., osteoblastic,
chondroblastic, and fibroblastic). Some data indicate that
chondroblastic osteosarcoma has a predilection for the
trunk bones and more frequently occurs in older patients.
The discrepancies in overall distribution of histologic
types of osteosarcoma are at least partially related to
interobserver differences in classifying lesions. They are
also related to the fact that some believe almost totally
chondroblastic osteosarcomas are better classified as
chondrosarcomas. Some authors postulate that osteosar-
coma of the jaws, especially the mandible, has a distinctly
different natural history and perhaps should be regarded
as a separate clinicopathologic entity.50,207,208
Osteosarcoma of Appendicular Skeleton.  Nearly 80%
of osteosarcomas occur in the long tubular bones of ado-
lescents. Almost 50% of cases are located in the knee
area. The distal femoral metaphysis is 2.5 times more
frequently involved than the proximal tibial metaphysis.
The relative frequency of tumor occurrence can be cor-
related with the growth potential of individual long
bones. The femur is the most frequently affected bone
(nearly 50% of cases) and is followed by the tibia (~20%)
and the humerus (~10%). More specifically, the part of
the bone with the highest growth rate is most frequently
involved. Accordingly, the distal femoral metaphysis,
where most growth occurs during adolescence, is approx-
imately 8 times more frequently involved than the proxi-
mal femur. The ratio between tumor occurrence in the
proximal and the distal tibia is approximately 10 : 1. A
similar 10 : 1 ratio of the frequency of involvement by
osteosarcoma is observed between the proximal and distal
ends of the humerus. The fibula, which is even more
rarely involved, accounts for approximately 3% of cases,
with tumor clustered in the proximal portion. Osteosar-
coma is extremely rare in the bones of the forearm. The
diaphyses of long bones are unusual sites for osteosar-
coma, and no more than 6% of osteosarcomas are exclu-
sively diaphyseal lesions. The femoral diaphysis is most
frequently involved, followed by the diaphyses of the tibia
and humerus. Fewer than 1% of osteosarcomas occur in
short tubular bones of the hands and feet (Figs. 5-55 and
5-56).142,153 Osteosarcoma is exceptionally rare distal to
the ankle and wrist joints. Very few well-documented
cases of primary epiphyseal osteosarcoma are described
ERRNVPHGLFRVRUJ
in the literature. Radiographic data strongly indicate that
most osteosarcomas originate as intramedullary metaph-
yseal lesions with secondary involvement of the cortex.
The extremely rare intracortical osteosarcoma has been
reported only in the shafts of the tibia and femur. This
curious lesion is not a precursor or an in situ lesion of
the majority of osteosarcomas and is discussed in further
detail at the end of this chapter.
Osteosarcoma of Craniofacial Bones.  Osteosarcoma
of craniofacial bones accounts for 6% to 10% of all
cases.43,70,79,92,107,122,150 The mandible and the maxilla are
the most frequently involved bones, representing 50%
and 25%, respectively, of cases involving craniofacial
bones (see Figs. 5-58, 5-59 and 5-62).210 Among the man-
dibular cases, the body is more frequently involved than
the ramus (see Figs. 5-59 and 5-62), and the alveolar
ridge is the most common location in the maxilla (see
Figs. 5-59 and 5-62). Osteosarcoma of the skull is very
rare and accounts for less than 2% of all cases located in
this site.98 It typically involves the cranial vault and practi-
cally never occurs in the base (see Figs. 5-58 and 5-60).
Osteosarcoma of the skull is often related to Paget’s
disease. This association is reported in nearly half of the
cases in this location. When osteosarcoma occurs in the
cranium, it almost always arises in bone formed by mem-
branous ossification and practically never occurs in the
bones of the base of the skull that are preformed in car-
tilage. Interestingly, in this connection, the mandibular
body, formed by membranous ossification, gives rise to
most of the osteosarcomas at this site. The involvement
of other craniofacial bones such as the palate, shown in
Fig. 5-61, is extremely rare.
These osteosarcomas typically affect skeletally mature
patients; nearly 80% of the cases are reported in patients
older than age 20 years. The age range is wide, but rare
cases are seen in children younger than age 10 years. The
peak incidence of craniofacial osteosarcoma is during the
third and fourth decades of life, and there is no sex
predominance.
The radiographic appearance of craniofacial osteosar-
comas does not differ significantly from that of tumors
located in the long tubular bones. However, the complex
anatomic structure of craniofacial bones requires special
expertise in evaluating lesions involving this site. The
constellation of bone destruction, mineralized matrix
production, and periosteal new bone formation is typical
for the radiographic presentation of osteosarcoma (see
Figs. 5-57 to 5-62). A thickened vault and blurred cortical
outlines, especially when associated with a focus of bone
sclerosis, can be early radiographic signs of osteosarcoma.
Small lytic or sclerotic foci, especially in a background of
Paget’s disease, are difficult to interpret and can be easily
overlooked. Periosteal changes in the form of laminated
or perpendicular new bone formation and cortical irregu-
larities are quite often present but may require special
views for demonstration on plain radiographs.
Cortical destruction in the mandible is almost invari-
ably associated with the disappearance of the lamina dura
of the adjacent teeth and with secondary invasion of
the mandibular nerve canal. Computed tomography and
Text continued on p. 267
 5  Osteosarcoma 263

A B

C D
FIGURE 5-55  ■  Osteosarcoma of the acral skeleton. A, Plain radiograph showing a mineralized intramedullary lesion involving the
head of the fifth left metacarpal bone. B, Gross photograph of the bisected resection specimen showing gritty intramedullary lesion
involving the head of the fifth left metacarpal bone. C, Whole-mount specimen showing heavily mineralized intramedullary growth
pattern of an osteosarcoma extensively infiltrating the medullary cavity. D, Low power photomicrograph showing coarse depositions
of osteoid and anaplastic tumor cells characteristic of a high-grade osteosarcoma. (D, ×50) (D, hematoxylin-eosin.)

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264 5  Osteosarcoma

A B

C
FIGURE 5-56  ■  Osteosarcoma of the calcaneus. A, Lateral plain radiograph showing heavily mineralized tumor involving the entire
calcaneus. B, Fat-saturated T2-weighted sagittal magnetic resonance image showing inhomogeneous signal enhancement involving
the entire calcaneus and extending to the soft tissue. C, Gross photograph of sagittally bisected resection specimen depicting heavily
mineralized mass involving almost the entire medullary cavity. Note soft tissue extension plantar and around calcaneal
tuberosity.

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 5  Osteosarcoma 265

B
FIGURE 5-57  ■  Osteosarcoma of navicular bone. A, Lateral radiograph of right foot shows expansile destructive lesion in navicular
bone. Inset, Computed tomogram of foot shows lytic destructive process with cortical disruption in navicular bone. B, Sagittal cut
section (amputation specimen) of tarsal (navicular) bone shows high-grade osteoblastic osteosarcoma that has broken out into the
soft tissue.

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266 5  Osteosarcoma

A B

C
FIGURE 5-58  ■  Osteosarcoma of craniofacial bones. A, Radiograph of large destructive mass in right maxilla of a 22-year-old woman
who had a recurrence of a lesion previously thought to represent fibrous dysplasia. Note cloudlike opacity in upper and central area
of lytic tumor mass. B, Coronal computed tomogram of the lesion in A shows maxillary replacement with bone-forming tumor that
extends to nasal cavity, orbit, and buccal soft tissue. C, Lateral radiograph showing de novo osteosarcoma of a skull in a child. A
destructive lesion involves the cranial vault of an 11-year-old boy who had noted a painless lump in frontoparietal region for 1 year.
Note homogeneous density anteriorly and cloudlike density within lytic area.

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 5  Osteosarcoma 267

B C
FIGURE 5-59  ■  Osteosarcoma of mandible. A, Panorex radiograph of jaw of a 26-year-old man who reported right-sided numbness
of chin for several months. Note patchy radiodensity (arrows) adjacent to roots of molar tooth with impingement on mandibular
canal. B, Computed tomogram shows radiodense tumor in right side of mandible (arrow). Periosteal new bone formation is present
on inner aspect. C, T1-weighted magnetic resonance image of mandible shows replacement of marrow by osteosarcoma in right
side of mandible. Tumor mass produces a low signal consistent with tumor bone formation.

MRI greatly enhance the preoperative assessment of
these lesions. These techniques make it possible to evalu-
ate the degree of involvement of adjacent anatomic struc-
tures and of the extent of soft tissue involvement. In
reference to calvarial lesions, the techniques are particu-
larly useful in demonstrating intracranial extension of the
tumor. These imaging techniques permit better preop-
erative planning of the definitive surgical procedure in
the case of craniofacial osteosarcomas.
Osteosarcomas of craniofacial bones do not differ
microscopically from those located in the long bones.
The only significant difference is the preponderance of
the chondroblastic type, which, in the mandible and the
maxilla, accounts for approximately 30% of the cases.
These lesions produce tumor osteoid, but this can be very
focal and minimal in extent. In some cases, the cartilagi-
nous differentiation of the tumor is so dominant that
some observers postulate that these tumors should be
classified as chondrosarcomas. This disagreement may be
academic but highlights the less aggressive biologic
behavior of these tumors compared with that of conven-
tional high-grade osteosarcomas. In addition, chondro-
blastic osteosarcomas of the craniofacial bones affect the
same age population as the more typical osteoblastic
osteosarcomas in the same anatomic site, and there is no
significant difference in survival and response to therapy
between patients with these two lesions.
If secondary osteosarcomas related to Paget’s disease
and radiation therapy are excluded, cellular atypia is less
evident in craniofacial lesions, especially in the mandible.
Nearly half of the cases involving the jaw bone are his-
tologic grades 1 and 2. Whether the less aggressive
behavior of osteosarcoma of the jaws is related to their
chondroblastic features or to their better differentiation
is still unclear. Regardless of minimal atypia, chondroid
differentiation in craniofacial bone tumors, especially in
the mandible and maxilla, should be considered a warning
signal of malignancy. Exclusive of callus, cartilaginous
differentiation is almost never seen in benign conditions
of these bones.

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268 5  Osteosarcoma

A B

C D
FIGURE 5-60  ■  Osteosarcoma of the skull. A, T2-weighted sagittal magnetic resonance image (MRI) with contrast showing a destruc-
tive intramedullary lesion of the cranial vault extending to the paraosseous soft tissue externally and internally. B, T1-weighted
coronal MRI with contrast of the tumor shown in A. C, Gross photograph of the bisected resection specimen showing mineralized
intramedullary lesion with destructive growth pattern and extension to the paraosseous soft tissue. Note cap-shaped extension to
the subcutaneous tissue externally. D, Sagittal computed tomography reformation of the same lesion documenting the extent of
intramedullary bone involvement.

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 5  Osteosarcoma 269

A B

C D
FIGURE 5-61  ■  Osteosarcoma of the palate. A, Axial computed tomogram with contrast, soft tissue window, depicting a mass pro-
truding into the oral cavity. B, Coronal CT, bone window, showing the tumor involving the hard palate and protruding into the oral
cavity. C, Gross photograph of the resection specimen depicting lobulated mass extending from roof of oral cavity. D, Bisected
specimen showing a fleshy mass originating in the hard palate and growing downward from the roof of the oral cavity.

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270 5  Osteosarcoma

B
FIGURE 5-62  ■  Osteosarcoma of the jaw. A, Specimen radiograph of mandibular resection specimen. Note destructive
intramedullary lesion and prominent radiating (sunburst) of periosteal new bone formation. B, Gross photograph of bisected man-
dibular specimen shown in A with high-grade chondroblastic osteosarcoma. Note lobules of tumor cartilage and ill-defined borders
of intraosseous component. Extension into soft tissue has radiating sunburst appearance of reactive bone spicules.

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The most important reason for therapeutic failure in
craniofacial osteosarcoma is local recurrence. Nearly 50%
of mandibular osteosarcomas recur locally after resection.
The recurrence rate is even higher with maxillary and
skull lesions (80% and 75%, respectively). Metastases are
less frequent than local recurrence and occur in about
one third of patients with craniofacial osteosarcomas.
They typically occur within 2 years of initial treatment,
predominantly in the lungs. Occasionally cervical lymph
nodes can be involved, necessitating a radical neck dissec-
tion. Once metastases are identified, the average survival
rate is less than 1 year. The overall 5-year survival rate for
mandibular tumors after combined modality treatment is
approximately 75%. The survival rates for maxillary and
skull de novo lesions are similar. However, analysis of the
SEER data indicates a much lower 5-year survival rate
(in the range of 40%). Osteosarcomas of the craniofacial
bones that develop in association with Paget’s disease are
clearly much more aggressive than de novo lesions.
Osteosarcoma of Flat Bones and Ribs.  Approximately
10% of osteosarcomas are located in flat bones. Almost
90% of osteosarcomas involving flat bones are located in
the pelvis. The scapula is rarely involved, and less than
2% of all osteosarcomas occur in that site. Osteosarcoma
of flat bones has clinicopathologic characteristics similar
to those of osteosarcoma of craniofacial bones and osteo-
sarcomas arising in the vertebral column. They typically
occur in skeletally mature patients and are rare during
the second decade of life. In older patients, flat bones in
general and the ilium in particular are relatively frequent
sites of osteosarcoma. As in the osteosarcomas that arise
in craniofacial bones and the vertebral column, approxi-
mately 30% of tumors have a predominant chondroblas-
tic component. A further similarity is the frequent
association with underlying conditions, such as Paget’s
disease and radiation damage. In contrast to the fre-
quency of low histologic grade of osteosarcoma in cra-
niofacial sites, the pelvic and scapular lesions are usually
of high grade. Approximately 2% of osteosarcomas occur
in the ribs, sternum, and clavicle (Figs. 5-63 and 5-64).
They are far less common than chondrosarcomas of these
sites.
Osteosarcoma of Vertebral Column.  Osteosarcoma is
extremely rare in the vertebral column: less than 4% of
cases occur in this location.199 A significant proportion of
these lesions represent secondary osteosarcoma related to
previous radiation therapy or Paget’s disease. The sacrum
is the most frequently involved bone of the vertebral
column. It appears that osteosarcoma is more frequent in
the lower thoracic and lumbar portion of the vertebral
column. In the spine, osteosarcoma occurs in a much
older population than osteosarcoma of the appendicular
skeleton. In patients older than age 60 years, osteosar-
coma of the flat bones and the vertebral column accounts
for approximately 40% of cases in this age group. On
radiographs, osteosarcoma of the vertebral column typi-
cally presents as a mixed lytic and sclerotic destructive
mass (Fig. 5-65). The exact location and extent of involve-
ment of adjacent structures are best evaluated by com-
puted tomography, MRI, or both modalities. The mass
ERRNVPHGLFRVRUJ
5  Osteosarcoma 271
is typically located in the vertebral body and grows into
the spinal canal and the paraspinal soft tissue. Densely
sclerotic osteosarcomas, especially those involving the
posterior arch, can occasionally mimic a benign osteo-
blastic lesion (i.e., osteoid osteoma and osteoblastoma)
on radiographs (see Fig. 5-65). Because chondroblastic
osteosarcoma has some predilection for the trunk bones
(i.e., the vertebral column and pelvis), the punctate cal-
cifications seen in some osteosarcomas of this location
may simulate chondrosarcoma on radiographs.
Personal Comments
The majority of cases of conventional osteosarcoma
present with clinical and radiologic features that strongly
suggest the diagnosis on the basis of the patient’s age,
tumor location, and radiographic patterns of bone
destruction, matrix mineralization, and periosteal new
bone formation. Diagnostic difficulties arise when occa-
sional osteosarcomas present in an older age group, in
nonmetaphyseal sites, or with a histologic pattern that
deviates significantly from the classic one. Often, the
diagnostic impression can be confirmed by the use of
closed biopsy techniques using computed tomographic
control and a large-bore needle or trephine. Because
most, if not all, high-grade osteosarcomas are now treated
with one or more courses of multidrug chemotherapy
before definitive surgery, the adequacy of the initial
biopsy material is more important than ever. Effective
chemotherapy may render it impossible to do special
studies, such as cytogenetics, DNA analysis, immunos-
taining, or electron microscopy of the tumor when the
resected specimen becomes available. It may even be
impossible to identify any viable tumor cells in a post-
chemotherapy specimen. Even more than in other bone
tumors, sampling problems are of particular importance
with regard to osteosarcoma because of its variability. For
example, when the radiographic findings point toward a
highly aggressive bone-forming tumor, the biopsy sample
may show only an anaplastic sarcoma composed of pleo-
morphic spindle cells and tumor giant cells without either
osteoid or tumor bone. In these cases, it may be necessary
to resort to a presumptive pathologic diagnosis of osteo-
sarcoma on the basis of the radiographic findings in con-
junction with these microscopic features. Perhaps even
more important, a dilemma arises when the biopsy mate-
rial contains a sample of the tumor that exhibits a decep-
tively benign appearance or nonneoplastic tissue related
to secondary phenomena (e.g., fracture callus and reac-
tive fibrosis). Careful attention to the radiographic find-
ings and knowledge of the biopsy site help to resolve this
difficulty.
The widespread use of MRI in the diagnosis of bone
tumors has contributed greatly to the planning of ade-
quate surgical resections because it demonstrates exqui-
sitely the intramedullary and extramedullary extent of
tumor involvement. Even though the method does not
image bone and other mineralized tissues, it is useful in
picking up separate sites of marrow involvement. Skip
areas are now known to be much rarer in osteosarcoma
as a result of widespread use of MRI. Refinements of
this technique continue to allow for better assessment
272 5  Osteosarcoma

A B

C D
FIGURE 5-63  ■  Osteosarcoma of rib. A and B, Axial computed tomogram with contrast showing a destructive lesion involving the
anterior portion of the rib. C, Gross photograph of the bisected specimen shows heavily mineralized tumor involving the rib and
circumferentially involving the paraosseous soft tissue. D, Low power microphotograph showing malignant bone-forming tumor
with irregular patches of osteoid deposits consistent with high-grade osteosarcoma. (D, ×50) (D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 273

A B

D E
FIGURE 5-64  ■  Osteosarcoma of sternum and clavicle. A, Axial computed tomogram (CT) showing mineralized mass of the sternal
manubrium. Note circumferential extension to the paraosseous soft tissue. B, Gross photograph of the resection specimen in
A shows heavily mineralized tumor with destructive growth pattern and extension to the parasternal soft tissue involving the sternal
manubrium consistent with osteosarcoma. C and D, Axial CTs showing destructive tumor involving the sternal end of the clavicle.
E, Bisected resection specimen showing destructive tumor involving the sternal end of the clavicle with variegated mineralization
pattern, cystic changes, and mucinous changes consistent with osteosarcoma.

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274 5  Osteosarcoma

A D

B F

FIGURE 5-65  ■  Osteosarcoma of vertebra. A and B, Anteroposterior (AP) and lateral radiographs of lumbar spine of a 15-year-old boy
with back pain and extradural block after collapse of body of second lumbar vertebra. C, Computed tomogram (CT) of L2 in A and
B shows tumor destruction with radiodense tissue extending into spinal canal and paraspinal soft tissue. D and E, AP and lateral
radiographs of lumbar spine of a 59-year-old man with 3-month history of back pain. Level of serum alkaline phosphatase was
elevated to twice normal level. Irregular, dense lesion involves right pedicle of third lumbar vertebra, suggesting osteoblastoma.
F, CT of L3 in D and E shows radiodense tumor mass impinging on spinal canal and extending into paraspinal soft tissue with
pattern more consistent with osteosarcoma.

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of tumor response to chemotherapy before definitive
surgery. Pathologic assessment of postchemotherapy
resection specimens by mapping continues to be the
mainstay in evaluating tumor response to treatment and
in planning alternative or further treatment in cases
where there has been an unfavorable response to the
initial treatment plan.
The explosion of data generated by high throughput
genomic approaches provides interesting insights into
the complexity of molecular alterations involved in the
development of osteosarcoma. There is hope that these
approaches may identify novel diagnostic, prognostic,
and therapeutic targets for these highly aggressive
malignancies.
Telangiectatic Osteosarcoma
Definition
Telangiectatic osteosarcoma is a malignant bone-forming
tumor microscopically composed of blood-filled spaces
divided by septa containing neoplastic sarcomatous cells.
There may be only minimal and focal osteoid production.
Radiologically as well as microscopically, it superficially
mimics aneurysmal bone cyst.
Incidence and Location
Telangiectatic osteosarcoma is rare, accounting for less
than 4% of all cases of osteosarcoma. Originally, it was
thought to be a variant of conventional osteosarcoma,
but recently it has been categorized as a distinct form
of osteosarcoma. The peak incidence and the anatomic
distribution are generally similar to those of conven-
tional osteosarcoma.233,239,252 Telangiectatic osteosarcoma
most frequently occurs during the second decade of life
and is dominated by males (1.9 : 1 male-to-female sex
ratio). It usually involves the appendicular skeleton, with
more than 50% of cases located in the knee area. The
distal femoral metaphysis is the single most common
anatomic site followed by the proximal tibia and the
proximal humerus. Approximately 10% of telangiectatic
osteosarcomas are exclusively diaphyseal lesions that
predominantly involve the femur, tibia, and humerus.
Individual cases have been reported in flat bones, the
axial skeleton, and craniofacial bones, but for practi-
cal purposes, telangiectatic osteosarcoma is a disease of
long tubular bones.225,227,249 Rare examples of multicentric
and extraskeletal telangiectatic osteosarcoma have also
been described.232,243 The peak age incidence and the
most frequent skeletal sites of involvement are shown in
Figure 5-66. In rare instances, telangiectatic osteosar-
coma may involve extraskeletal sites or may develop as
dedifferentiation of preexisting low-grade lesions such
as parosteal osteosarcoma and chondrosarcoma or other
solid extraskeletal tumors.233,235,238,240,242,244,250,253
Clinical Symptoms
Most patients initially have pain in the affected extremity
that has continued for several weeks to months. The pain
is often accompanied by swelling and limitation of
ERRNVPHGLFRVRUJ
5  Osteosarcoma 275
motion. In general, the symptoms are similar to those of
conventional osteosarcoma. The high level of alkaline
phosphatase frequently seen in osteosarcoma is not a
feature of telangiectatic osteosarcoma.
Radiographic Imaging
Telangiectatic osteosarcoma is typically a purely lytic
lesion with a permeative destructive growth pat­
tern.230,231,237,241,251 This rapidly growing tumor often
expands the contour of bone and shows features of corti-
cal disruption with minimal or no periosteal new bone
formation (Fig. 5-67). In this type of osteosarcoma, the
periosteal new bone formation is often a multilayered
structure referred to as onion skin. Overall, the radio-
graphic appearance is not that of typical osteosarcoma,
which has a mixture of blastic and lytic areas. Indeed, a
purely lytic radiographic appearance is one of the diag-
nostic requirements for this designation (Figs. 5-67 and
5-68). The radiographic features of telangiectatic osteo-
sarcoma are less diagnostically specific than those of
conventional osteosarcoma and are similar to other lytic,
rapidly growing malignant tumors of bone, such as
Ewing’s sarcoma. The massive expansile growth pattern
of telangiectatic osteosarcoma can superficially simulate
aneurysmal bone cyst (Figs. 5-69 and 5-70). This type of
osteosarcoma, in particular, can have a deceptively inno-
cent radiographic appearance with sharply demarcated
margins, simulating a benign bone cyst.234 The multi-
locular cystic nature of the lesion and the so-called fluid
level sign are best documented by MRI (see Figs. 5-68
and 5-69).
Gross Findings
Telangiectatic osteosarcoma is very hemorrhagic, and its
gross appearance is frequently described as a bag of blood.
A fleshy sarcomatous component is typically not present.
The tumor grossly mimics aneurysmal bone cyst and pres-
ents as a lytic lesion filled with hemorrhagic cystic or
spongy tissue or both (Figs. 5-69 to 5-71). The cystic
spaces can vary considerably in size and may occasionally
measure several centimeters in diameter. More often, there
is a mixture of large cystic and spongy areas. The spongy
areas represent tissue honeycombed with smaller cysts that
measure up to several millimeters in size. The borders of
the lesion are usually well demarcated, but often there are
features of invasive growth with extensive irregular cortical
erosion, complete disruption of cortical continuity, and
invasion of soft tissue. The soft tissue component is ini-
tially outlined by a rim of elevated periosteum. With tumor
progression, there is usually massive destruction of the
involved bone and formation of a large palpable mass.
Microscopic Findings
Typically this tumor consists of cystlike spaces divided
by septa similar to those seen in aneurysmal bone cyst
(Figs. 5-72 and 5-73). However, the septa are composed
of highly atypical sarcomatous tissue (Figs. 5-74 to 5-78).
Less frequently, instead of cystlike spaces divided by
septa, there are large areas of hemorrhage with “floating”
276 5  Osteosarcoma
Peak
incidence
10 20
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 5-66  ■  Telangiectatic osteosarcoma. Peak age incidence and frequent sites of skeletal involvement.
individual pleomorphic sarcomatous cells (Figs. 5-79 and
5-80). The cystic spaces have no endothelial lining, and
the tumor cells are in direct contact with areas of hemor-
rhage. Usually there is a high degree of nuclear atypia,
cellular pleomorphism, and brisk mitotic activity with
numerous atypical mitoses. In addition to multinucleated
sarcomatous giant cells with bizarre nuclei, there may
be clearly benign osteoclast-like giant cells, which can
contribute to the mimicry of aneurysmal bone cyst by
telangiectatic osteosarcoma. The osteoid production is
usually minimal and focal (see Figs. 5-73 and 5-74). In
fact, often the osteoid formation can only be found after
prolonged search. If the tumor has overall telangiectatic
architecture (i.e., produces septa) or if highly pleomor-
phic sarcoma cells are found floating in the large areas of
hemorrhage, the lesion should be classified presump-
tively as a telangiectatic osteosarcoma, even without evi-
dence of osteoid production.
Typically, telangiectatic osteosarcoma is a high-grade
lesion with easily recognizable sarcomatous septa (Fig.
5-80). The concept that telangiectatic osteosarcoma is an
entity sui generis and not simply a variant of conventional
osteosarcoma is borne out by the fact that the telangiec-
tatic architecture is frequently reproduced in metastatic
lesions from this tumor. The formation of telangiectatic
blood-filled spaces is therefore not considered to be a
secondary degenerative phenomenon. It can even be
ERRNVPHGLFRVRUJ
7 8
observed in small peripheral foci of this tumor. The
advancing edge of the tumor, as it permeates marrow
spaces, sometimes shows an affinity for small, preexisting
blood vessels.
Occasionally, the tissue within the septa can be similar
to that seen in aneurysmal bone cyst with very few
atypical cells (see Fig. 5-78). In such cases, a careful
search for atypical mitoses can disclose the true nature of
the lesion. Telangiectatic osteosarcoma with a deceptively
benign histologic appearance is sometimes referred to as
low-grade telangiectatic osteosarcoma. This term is not
widely accepted in the literature, but it is sometimes
applied to cases in which repeated biopsies over time are
misdiagnosed as recurrent aneurysmal bone cyst until the
sarcomatous nature of the tumor becomes obvious.229,234,248
Controversial cases of telangiectatic osteosarcomas that
develop within a preexisting aneurysmal bone cyst have
also been described in the literature.236
Special Techniques
Special techniques do not aid in the diagnosis of telangi-
ectatic osteosarcoma. Ultrastructurally, the tumor shows
undifferentiated pleomorphic sarcomatous cells with
minimal focal matrix mineralization.245 DNA ploidy mea-
surements typically show a high degree of aneuploidy,
Text continued on p. 291
 5  Osteosarcoma 277

A B

C D
FIGURE 5-67  ■  Telangiectatic osteosarcoma. A, Slightly expanded, apparently well-circumscribed lytic lesion is shown in this plain
radiograph of femoral diaphysis of young adult. It was initially thought to represent a bone cyst or fibrous dysplasia. B, Purely lytic
lesion of proximal end of humerus shows cortical destruction of medial aspect. C, Anteroposterior plain radiograph shows ill-defined
radiolucent tumor in distal femoral shaft. D, Lateral view of specimen radiograph of same case in C documenting pathologic fracture
(arrow).

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278 5  Osteosarcoma

A B

C D
FIGURE 5-68  ■  Telangiectatic osteosarcoma: radiographic features. A and B, Anteroposterior and lateral plain radiographs show ill-
defined lytic and permeative lesion of distal femoral metaphysis with pathologic fracture. C, Lytic lesion with sclerotic, well-defined
margin. Note deceptively benign radiographic appearance of this high-grade telangiectatic osteosarcoma. D, T1-weighted coronal
magnetic resonance image shows multiloculated architecture of lesion with different levels of signal intensity.

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 5  Osteosarcoma 279

C D
FIGURE 5-69  ■  Telangiectatic osteosarcoma. A, Anteroposterior plain radiograph shows ill-defined lytic and permeative lesion of
distal metaphysis. Note extension to the soft tissue laterally with elevation of the paraosteum (Codman’s triangle) proximal to lesion.
Inset, Fat-saturated T2-weighted axial magnetic resonance image showing multiloculated cystic architecture of the lesion with fluid
levels. B, Gross photograph of the lesion in A shows expansile hemorrhagic tumor of the distal femoral metaphysis extending to
the soft tissue laterally. Note elevation of the periosteum proximal to lesion corresponding to Codman’s triangle shown in A.
C, Low power microphotography showing multilocular cystic architecture of the lesion. Inset, Higher power of septum
with histiocyte-like neoplastic cells showing nuclear atypia. D, Microscopic features of telangiectatic osteosarcoma septations
containing pleomorphic neoplastic cells and scattered multinucleated giant cells. (C, ×50; D, ×100; inset, ×100) (C, D, and
inset, hematoxylin-eosin.)

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A B

C D
FIGURE 5-70  ■  Telangiectatic osteosarcoma. A, Lateral plain radiograph showing expansile blowout lesion with permeative growth
pattern of the proximal tibia. B, Gross photograph of A showing hemorrhagic and partially necrotic tumor of the proximal tibial
metaphysis with massive soft tissue expansion posteriorly. C, Low power photomicrograph showing multilocular cystic architecture
of the lesion. D, Higher magnification of C showing a small cystic space lined by a mantle of highly atypical neoplastic cells. Some
of the tumor cells are free floating in the cystic space. (C, ×50; D, ×200) (C and D, hematoxylin-eosin.)

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A B

C D
FIGURE 5-71  ■  Telangiectatic osteosarcoma. A, Expansile hemorrhagic tumor replacing proximal end of fibula. Note cortical blowout
destruction. B, Massive extension into soft tissue from intramedullary osteosarcoma of humerus forms large encircling mass with
hemorrhagic loculi in fleshy background. C, Septa bordering blood field spaces. D, Higher magnification of C shows nuclear atypia
of tumor cells within the septum. (C, ×50; D, ×200) (C and D, hematoxylin-eosin.)

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A B

C D
FIGURE 5-72  ■  Telangiectatic osteosarcoma: microscopic features. A, Low power photomicrograph shows multilocular cystic archi-
tecture of the lesion. B, Higher magnification of A showing a meandering septum containing neoplastic cells and scattered multi-
nucleated giant cells. Inset shows higher magnification of B. Note irregular mantles of anaplastic tumor cells lining the septum and
a multinucleated giant cell in the center. C, Collapsed cystic spaces with clustered septations, a common feature in telangiectatic
osteosarcoma. D, Higher magnification of C shows nuclear atypia of neoplastic cells within the septa. Note scattered multinucleated
giant cells. (A, ×20; B and C, ×50; D, x200; inset, ×400) (A-D and inset, hematoxylin-eosin.)

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A B

C D
FIGURE 5-73  ■  Telangiectatic osteosarcoma: microscopic features. A and B, Low power photomicrograph showing blood filled spaces
separated by irregular septa. C, Higher magnification of B showing tumor osteoid deposits within the septum. D, Microscopic cyst-
like space surrounded by an irregular mantle of histiocyte-like neoplastic cells and scattered multinucleated giant cells. (A and
B, ×20; C, ×50; D, ×200) (C and D, hematoxylin-eosin.)

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A B

C D
FIGURE 5-74  ■  Telangiectatic osteosarcoma: microscopic features. A, A low power photomicrograph showing cystlike spaces of
various sizes and a more solid component of the tumor. Note delicate osteoid deposits. B, Higher magnification of A showing osteoid
matrix within the septum. C, Higher magnification of A showing an irregular cystlike space lined by a mantle of partially free-floating
tumor cells. D, Higher magnification showing the interface between the septum and cystic space lined by a mantle of partially free-
floating, highly atypical tumor cells. (A, ×50; B and C, ×100; D, ×200) (A-D, hematoxylin-eosin.)

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 5  Osteosarcoma 285

A B

C D
FIGURE 5-75  ■  Telangiectatic osteosarcoma: microscopic features. A, Low power photomicrograph showing irregular blood-filled
spaces of different sizes within the cellular solid component of the tumor. B, Medium powered magnification of septum containing
sheets of malignant cells. C, Solid area of the tumor composed of highly pleomorphic tumor cells. D, Higher magnification of
C documenting atypia and pleomorphism of tumor cells. (A, ×50; B and C, ×100; D, ×200) (A-D, hematoxylin-eosin.)

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B C
FIGURE 5-76  ■  Telangiectatic osteosarcoma: microscopic features. A, Low power photomicrograph showing partially collapsed
irregular blood-filled spaces separated by meandering septations. B, Higher magnification of A showing meandering septations
bordering blood-filled spaces. C, Higher magnification of B showing atypia of histiocyte-like tumor cells within the septa. (A, ×20;
B, ×100; C, ×200) (A-C, hematoxylin-eosin.)

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 5  Osteosarcoma 287

A B

C D
FIGURE 5-77  ■  Telangiectatic osteosarcoma: microscopic features. A, Low power photomicrograph showing cystlike spaces and solid
components of the tumor. B, Intermediate power magnification of A showing interface between solid and cystic components of the
tumor. C, Another intermediate power magnification of A showing smaller cystic space within the solid component of the tumor.
D, Higher magnification of C showing the solid area of the tumor composed of histiocyte-like malignant cells with scattered multi-
nucleated giant cells. (A, ×20; B and C, ×100; D, ×200) (A-D, hematoxylin-eosin.)

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B C
FIGURE 5-78  ■  Telangiectatic osteosarcoma: microscopic features. A, Large partially collapsed cystic spaces separated by irregular
septations. Inset, Cellular composition of the septum. Note overall bland appearance of cellular components within the septum that
may cause misdiagnosis and confusion with aneurysmal bone cyst. B, Low power photomicrograph showing interface between
cystic and solid components of the tumor. C, Higher magnification of A showing high cellularity and atypia of tumor cells within
the septa. (A and B, ×20; C, ×100; inset, ×200) (A-C, hematoxylin-eosin.)

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A B

C D
FIGURE 5-79  ■  Telangiectatic osteosarcoma: microscopic features. A, Solid component of the tumor with extensive interstitial fresh
hemorrhage (upper right) and smaller cystic spaces (lower left). B, Higher magnification of A showing mineralized osteoid bands
within the solid component of the tumor bordering the area of fresh hemorrhage. C, Partially collapsed hemorrhagic spaces sepa-
rated by irregular septations. D, Higher magnification of C showing bands of osteoid matrix within the septum. (A and C, ×20;
B and D, ×100) (A-D, hematoxylin-eosin.)

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B C
FIGURE 5-80  ■  Telangiectatic osteosarcoma: microscopic features. A, Low power photomicrograph showing irregular cystlike spaces
with fresh hemorrhage and septations composed of highly cellular tumor tissue. B, Higher magnification of A showing cystlike
spaces filled with hemorrhage and septations composed of anaplastic tumor cells. Inset, Higher magnification of septum composed
of histiocyte-like atypical tumor cells. C, Areas of interstitial fresh hemorrhage with floating, noncohesive tumor cells. (A, ×20;
B and C, ×100; inset, ×200) (A-C and inset, hematoxylin-eosin.)

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which is consistent with morphometric analysis that dis-
closes great variability in the nuclear area and volume.247
Immunohistochemically, the tumor cells of telangiectatic
osteosarcoma are positive for vimentin and negative for
other markers.
Differential Diagnosis
This uncommon form of osteosarcoma must be distin-
guished principally from aneurysmal bone cyst and con­
ventional osteosarcoma with focal telangiectatic features.248
At times, it may suggest the possibility of malignant forms
of giant cell tumor, but this distinction can be made on the
basis of age (skeletal maturity) and localization in epiphy-
seal sites characteristic of giant cell tumors. It is important
to apply strict radiologic and microscopic criteria. Radio-
logic absence of sclerotic features and histologic paucity
of tumor bone formation are required to distinguish tel-
angiectatic osteosarcoma from otherwise conventional
osteosarcoma that may exhibit focal and minor histologic
features of high vascularity or blood-filled channels. Simi-
larly, the microscopic feature of hemangiopericytoma-
like areas with branching endothelial-lined vascular
channels described in the section on conventional osteo-
sarcoma should not be misinterpreted as telangiectatic
osteosarcoma. The most important aspect of differential
diagnosis is the mimicry of the benign aneurysmal bone
cyst. Errors in diagnosis can occur in both directions
when close attention is not paid to the cytologic features
of the septal cells or if there is undue alarm over the
presence of reactive osteoid or reactive bone formation
in aneurysmal bone cyst. Bands of osteoid or delicate
woven bone trabeculae oriented parallel to the long axes
of aneurysmal bone cyst septa should not be overinter-
preted as features of malignancy. Careful scrutiny of the
surrounding cells helps avoid this pitfall.
Clinical Behavior
Originally, it was thought that telangiectatic osteosar-
coma had a particularly doleful prognosis, much worse
than conventional osteosarcoma. Its pattern of metastatic
spread is similar to that seen in conventional osteosar-
coma. The original Mayo Clinic data indicated that more
than 80% of patients with this form of osteosarcoma die
of the disease within 2 years of diagnosis. On the other
hand, the experience with modern combined modality
treatment indicates that the particularly bad prognosis
formerly associated with telangiectatic osteosarcoma
probably no longer applies.225,226,228,246 In fact, telangiec-
tatic osteosarcoma usually shows a better response to
chemotherapy than conventional osteosarcoma. Survival
rates with current chemotherapy protocols are within the
range of 65% after 5 years.
Well-differentiated
Intramedullary Osteosarcoma
Definition
A distinct form of intramedullary low-grade fibroblastic
osteosarcoma, well-differentiated intramedullary osteo-
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5  Osteosarcoma 291
sarcoma is characterized microscopically by deceptively
benign cytologic features in the spindle-cell component
and relative maturity of the tumor bone. It also follows
an indolent course.
Incidence and Location
This very rare variant of osteosarcoma accounts for
approximately 1% of all osteosarcomas.255,258,264 The peak
incidence is during the third decade of life, in which
nearly 50% of the cases occur. Individual cases are diag-
nosed during the second decade of life and in people
older than age 50 years. There is no sexual predilection.
Most cases occur in the major long bones of the lower
extremities, the femur being the most frequently involved
(approximately 50%). The tibia is the second most fre-
quently involved bone. As in other forms of osteosar-
coma, the knee area is involved in the majority of cases.
Intraosseous well-differentiated osteosarcoma has also
been reported in the bones of the trunk and the cranio-
facial bones. This tumor typically involves the metaphy-
seal parts of the long bones of skeletally mature patients.
Rare examples of intracortical or multicentric well-
differentiated osteosarcoma have been described.254,260
The peak age incidence and the most frequently involved
skeletal sites are shown in Figure 5-81.
Clinical Symptoms
Most patients initially have pain in the affected extremity
with a duration of many months to several years, in
contrast to conventional osteosarcoma, in which the
duration of symptoms is measured in weeks to months.
Occasionally, the patient notices a palpable mass as the
initial symptom. Some patients have a history of a recur-
rent lesion, previously diagnosed pathologically as fibrous
dysplasia or other benign spindle-cell lesions.
Radiographic Imaging
These tumors exhibit a wide range of radiographic fea-
tures, but most show a variable pattern of lytic foci
and dense cloudlike areas that are poorly demarcated
(Figs. 5-82 to 5-86).256,259,263,265 In contrast to conventional
osteosarcoma, periosteal new bone formation is minimal
or absent, even in advanced lesions that have significant
cortical involvement. The ill-defined medullary tumor
can frequently extend to the end of the bone to involve
the subarticular bony end plate. The shaft may be exten-
sively involved for a considerable distance from the
metaphyseal area. In addition to alternating areas of
amorphous density and lytic foci, a coarse trabeculated
pattern of ossification has been observed (see Figs. 5-83
to 5-86). Expansion of the bone contour indicating slow
growth may be seen. Complete cortical destruction may
be followed by significant extraosseous extension with an
ill-defined soft tissue mass (Fig. 5-86). The fact that the
radiologic interpretation of these lesions is overwhelm-
ingly that of a malignant process highlights the necessity
for the pathologist to obtain radiologic correlative data
in the interpretation of any microscopically atypical
fibroosseous bone lesion.
292 5  Osteosarcoma
Peak
incidence
20 40
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 5-81  ■  Low-grade intramedullary osteosarcoma. Peak age incidence and frequent sites of skeletal involvement.
Gross Findings
The tumors are predominantly centrally located in
the medullary cavity of the long bone metaphysis and
diaphysis. Some are eccentrically placed, and the cortical
destruction may be striking. The tumor tissue is grayish
and gritty with fleshy areas, reflecting the fibrous and
osseous makeup (Fig. 5-84). Poor demarcation from
uninvolved bone is most frequently present, although
some tumors may have sharply demarcated margins in
heavily ossified areas. The tumor tends to fuse with the
inner surface of the cortex. Extension into soft tissue is
usually associated with minimal periosteal bone forma-
tion, and Codman’s triangles are rarely present.
Microscopic Findings
This tumor differs markedly in its histologic appearance
from conventional osteosarcoma because its fibroblastic
and osseous components are well differentiated and
reproduce within the medullary cavity, the pattern seen
in parosteal osteosarcoma (Fig. 5-87).255,258,261-263 The
mature fibroblast-like appearance of tumor cells embed-
ded in a dense collaginous stroma is best seen under the
electron microscope (Fig. 5-88). In some cases the bland
hypercellular spindle-cell components and the delicate
osseous trabeculae can closely simulate fibrous dysplasia
ERRNVPHGLFRVRUJ
7 8
(Fig. 5-89). Even the branching and curved “Chinese
character” appearance of woven bone trabeculae seen in
fibrous dysplasia can be found. The fibroblast-like spindle
cells are plump with elongated nuclei that contain promi-
nent nucleoli, but they are generally uniform in appear-
ance (Figs. 5-89 and 5-90). Atypia is usually minimal.
Mitoses are infrequent but easily found, and atypical
mitoses are rare. The bone formed in this tumor varies
in its degree of maturation from slender woven bone
trabeculae to thick, irregular bone spicules that can
coalesce to form solid bony areas, which can approach
lamellar maturation. True lamellar architecture, if it is
present, implies residual host bone. An interesting affin-
ity for peritrabecular growth by this tumor may be
observed at its periphery. In some cases, small foci of
atypical cartilage may be present in the tumor.
Areas of high-grade pleomorphic osteosarcoma can
be found within a low-grade intramedullary osteosar-
coma.258,264 This can be observed in the primary tumor
but more frequently occurs in recurrences after incom-
plete removal of the primary tumor. The low- and high-
grade components are sharply demarcated (Fig. 5-91), as
is generally the case when low-grade tumors dedifferenti-
ate. These tumors are referred to as dedifferentiated
low-grade intramedullary osteosarcomas.257 The current
pathogenetic concept postulates that dedifferentiation
Text continued on p. 297
 5  Osteosarcoma 293

A B

C D

FIGURE 5-82  ■  Low-grade intramedullary osteosarcoma: radiographic features. A and B, Anteroposterior (AP) and lateral plain radio-
graphs of distal femur in a 12-year-old girl. Tumor is expansile and shows trabeculated pattern of bone destruction. No periosteal
reactive bone is seen, and proximal border is indistinct. C, AP view of low-grade intramedullary osteosarcoma of distal femoral
shaft. Note expanded contour produced by this slow-growing tumor, which had been previously biopsied and diagnosed as fibrous
dysplasia. D, Lateral radiograph of C shows extramedullary extension posteriorly and trabeculated radiolucent appearance of intra-
medullary component.

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294 5  Osteosarcoma

A B

C D
FIGURE 5-83  ■  Low-grade intramedullary osteosarcoma. A, Lateral plain radiograph shows ill-defined sclerotic intramedullary lesion
involving the proximal tibial metaphysis. B, Reformatted computed tomogram in coronal plane of A shows ill-defined intramedullary
lesion of the proximal tibial metaphysis. C, Anteroposterior plain radiograph of sclerotic ill-defined intramedullary lesion of the
proximal tibia extending to the soft tissue laterally and medially. D, Low power photomicrograph of the tumor shown in C, with
well developed bone trabeculae that simulates those seen in fibrous dysplasia. (D, ×50) (D, hematoxylin-eosin.)

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 5  Osteosarcoma 295

A B

C D
FIGURE 5-84  ■  Low-grade intramedullary osteosarcoma. A, Reformatted sagittal computed tomogram (CT) in sagittal plane showing
intramedullary lesion of the mandible. B, Reformatted CT in coronal plane showing intramedullary lesion of the mandible with ill-
defined borders and increased signals, centrally. C, Axial CT showing intramedullary mental protuberance region of the mandible.
Note ill-defined borders and cortical penetration anteriorly. D, Gross photographs of the bisected resection specimens showing
overall fibrous appearance of the lesion with focal granularity. Note ill-defined borders and cortical penetration anteriorly.

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296 5  Osteosarcoma

B
FIGURE 5-85  ■  Low-grade intramedullary osteosarcoma: radiographic features. A, radiograph showing extensive predominantly lytic
destructive lesion of the left ilium. B, Axial computed tomogram showing extensive destructive process involving the entire iliac
bone and extending to the sacroiliac region.

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 5  Osteosarcoma 297

A B
FIGURE 5-86  ■  Low-grade intramedullary osteosarcoma: radiographic features. A, Anteroposterior plain radiograph showing sclerotic
intramedullary lesion expanding the distal end of the ulna. B, Lateral plain radiograph showing a mixed lytic and sclerotic lesion
with ill-defined margins involving the distal femur. Note soft tissue extension by sclerotic tumor posteriorly.

represents a progression of a preexisting low-grade fibro-
blastic osteosarcoma to a high-grade sarcomatoid malig-
nancy. The dedifferentiated component typically has
features of high-grade osteoblastic osteosarcoma (Fig.
5-92). Less frequently, it may have features of a high-
grade unclassified sarcoma with overall architecture
similar to malignant fibrous histiocytoma. A similar phe-
nomenon occurs in parosteal osteosarcoma (dedifferenti-
ated parosteal osteosarcoma), which is described later.
Differential Diagnosis
The striking difference in biologic behavior and survival
when this tumor is compared with conventional intramed-
ullary osteosarcoma mandates its distinct separation from
the more common high-grade tumor. Often, it overlaps
with the fibroblastic type of medullary osteosarcoma,
but the degree of nuclear pleomorphism and the rate of
mitosis are far less in the well-differentiated variant. In
addition, the tumor bone trabeculae tend to be larger,
more abundant, and more mature. These distinguishing
features of well-differentiated medullary osteosarcoma
can produce a superficially benign microscopic appear-
ance that can lead to its misdiagnosis as fibrous dysplasia of
bone. This is one of the most common misinterpretations
and is sometimes carried through several serial biopsies
of recurrences until the malignant nature of the tumor
becomes apparent.
Fibrous dysplasia can usually be recognized by its dis-
tinctly nonaggressive appearance on radiographs, but
in certain anatomic sites where fibrous dysplasia is
particularly common (e.g., the craniofacial bones), the
recognition of well-differentiated osteosarcoma may be
especially challenging. Microscopically, the coarseness
of the tumor bone trabeculae, compared with the deli-
cate branching and curved woven trabeculae of fibrous
dysplasia, provides a useful guide. Careful search for
atypical nuclei and mitotic activity in the spindle-cell ele-
ments is essential for the diagnosis of well-differentiated
osteosarcoma.
Other malignant spindle-cell tumors of bone such as
fibrosarcoma, malignant fibrous histiocytoma, and leiomyosar-
coma can sometimes be confused with this tumor, but they
do not show evidence of tumor bone formation, and
specific markers can be useful in their recognition. The
benign but locally aggressive desmoplastic fibroma of bone
is also devoid of tumor bone components, although it
may contain reactive bone at its periphery.
Treatment and Behavior
Inadequate treatment of this indolent, low-grade malig-
nancy in the form of curettage or partial resection inevi-
tably leads to recurrence.255,258,264 Difficulty in making the
histologic diagnosis and confusion with benign entities
contribute to the delay in diagnosis and inappropriate
treatment. Furthermore, the likelihood of increase in
grade (dedifferentiation) rises with each recurrence.
Metastasis occurs in patients whose tumors show areas of
high-grade transformation and hence in those whose
initial mode of therapy was inadequate. The overall
Text continued on p. 304

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298 5  Osteosarcoma

A B

C D
FIGURE 5-87  ■  Low-grade intramedullary osteosarcoma: microscopic features. A, Low power photomicrograph shows branching
well-developed bone trabeculae that simulate the pattern of fibrous dysplasia. B, Intermediate power magnification of A shows
interconnected bone trabeculae in fibrous stroma. Lack of rimming by osteoblastic cells contributes to the similarity of fibrous
dysplasia. C, Low power photomicrograph shows similar features in another area of the same tumor with well-developed intercon-
nected bone trabeculae resembling fibrous dysplasia. D, Intermediate power magnification of C showing branching bone trabeculae
without osteoblastic rimming in a fibrous stroma. (A and C, ×50; B and D, ×200) (A-D, hematoxylin-eosin.)

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 5  Osteosarcoma 299

B
FIGURE 5-88  ■  Low-grade intramedullary osteosarcoma: ultrastructural features. A, Fibroblast-like spindle tumor cells surrounded
by dense collagen stroma. B, Higher magnification of A. (A, ×3500; B, ×9000) (A-B, hematoxylin-eosin.)

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300 5  Osteosarcoma

A B

C D
FIGURE 5-89  ■  Low-grade intramedullary osteosarcoma: microscopic features. A, Low power photomicrograph showing well-
developed bone trabeculae resembling fibrous dysplasia. B, Higher magnification of A showing branching bone trabeculae
in somewhat hypercellular stromal tissue with spindle cells. C, Low power photomicrograph showing the bone trabecular
pattern mimicking fibrous dysplasia. D, Trabecular osteoid pattern of low-grade intramedullary osteosarcoma resembling fibrous
dysplasia. Note somewhat hypercellular stromal proliferation of spindle cells with loose texture. (A and C, ×50; B and D, ×100)
(A-D, hematoxylin-eosin.)

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 5  Osteosarcoma 301

A B

C D

FIGURE 5-90  ■  Low-grade intramedullary osteosarcoma: microscopic features. A, Osteoid deposition pattern with well-developed
branching bone trabeculae. B, Intermediate power magnification of A showing branching and somewhat parallel tumor bone tra-
beculae with well mineralized core and unmineralized surface osteoid deposits. Note somewhat hypercellular stromal tissue com-
posed of spindle cells. C, Low power photomicrograph showing branching pattern of tumor bone trabeculae. D, Slightly higher
magnification of C showing osteoid deposition in the form of interconnected and branching bony trabeculae. Inset shows higher
magnification of D and depicts focal parallel arrangement of bone trabeculae. (A and D, x50; B and inset, x100; C, x20) (A-D and
inset, hematoxylin-eosin.)

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302 5  Osteosarcoma

B
FIGURE 5-91  ■  Low-grade intramedullary osteosarcoma with dedifferentiation: microscopic features. A and B, Low and high power
views of junction of well-differentiated tumor (right) and high-grade dedifferentiated osteosarcoma (lower left). Inset, Marked nuclear
pleomorphism, hyperchromatism, and tumor giant cells in high-grade dedifferentiated component. (A, ×100; B, ×200; inset ×200)
(A, B, and inset, hematoxylin-eosin.)

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 5  Osteosarcoma 303

A B

C D
FIGURE 5-92  ■  Low-grade intramedullary osteosarcoma with dedifferentiation: microscopic features. A and B, Intermediate power
magnification showing low-grade fibroblastic osteosarcoma infiltrating medullary cavity. The tumor is composed of spindle cell
stromal tissue and well developed branching bone trabeculae. Note residual fat cells of marrow infiltrated by the tumor.
C and D, High-grade osteosarcoma corresponding to a dedifferentiated component of the same tumor shown in A and B. Note
pronounced atypia and pleomorphism of tumor cells and coarse irregular tumor osteoid deposits consistent with high-grade osteo-
sarcoma. (A-D, ×100) (A-D, hematoxylin-eosin.)

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304 5  Osteosarcoma
incidence of metastasis is 15%. The treatment of choice
is wide excision or amputation. The use of adjuvant
chemotherapy is reserved for those cases showing dedif-
ferentiation in the primary tumor or in a recurrence.
OSTEOSARCOMA ASSOCIATED WITH
SPECIFIC CLINICAL SYNDROMES
High-grade conventional osteosarcomas can be
associated with certain clinical syndromes, such as
familial osteosarcoma, retinoblastoma-associated osteo-
sarcoma, Rothmund-Thomson syndrome, and multifocal
osteosarcoma.
Osteosarcoma in siblings is extremely rare and occurs
in 1 : 1000 to 1 : 3000 cases of conventional (sporadic)
osteosarcoma.307,308,314,363 An autosomal dominant predis-
position can be anticipated when it affects several genera-
tions of one family.281 Familial osteosarcoma has two basic
forms. It may occur sporadically in siblings without an
inherited pattern of transmission.275,276,283,284,296,304,307 The
more frequent form is inherited familial osteosarcoma,
which occurs in several generations of families, who are
most frequently affected by retinoblastoma.282,298,315 This
peculiar association between two apparently unrelated
malignant neoplasms led to the conclusion that there
may be a common molecular genetic mechanism.326 For
that reason, osteosarcoma associated with retinoblastoma
seems to be separate from other conventional osteosar-
comas and perhaps should be considered as a distinct
entity.
Families affected by retinoblastoma carry the germ
line alteration in the predisposing locus on chromosome
13, which contains the RB gene. This alteration also
increases the risk of developing osteosarcoma many hun-
dreds of times more than the chance of its occurring
in an individual who does not carry the genetic
alteration.279,295,298,299,301 This genetic mutation not only
increases the risk for development of de novo osteosar-
coma, but also potentiates the osteosarcoma-inducing
modality of external beam irradiation.266,273,274,277,302,311,321
A potential ancillary role of TP53 in the development
of osteosarcoma in association with retinoblastoma has
also been postulated.285 Familial forms of osteosarcomas
without retinoblastoma have also been described.306,316
Li-Fraumeni syndrome is an autosomal dominant
familial disorder of a complex cancer predisposing syn-
drome and the missense germline mutations of the TP53
gene predominantly involving the DNA binding domain
represent its underlying molecular defect causing genetic
instability.271,286,293-295,305,309,312,317,320,324 Cancer risk in muta-
tion carriers is very high and has been estimated to be
50% by age 40 and nearly 90% by age 60. It is estimated
that only 70% of families with Li-Fraumeni syndrome
carry germline mutations of TP53. A subset of patients
with this syndrome, who are negative for T53 mutations,
carry mutations of CHEK2 in chromosome 22q11 or may
show alteration in PTEN.272 In addition, some Li-Fraumeni
families show positive linkage to 1q23, possibly repre-
senting the third predisposing locus in this disorder.269
Li-Fraumeni syndrome predisposes to a wide range of
sarcomas, including osteosarcoma.
ERRNVPHGLFRVRUJ
Rothmund-Thomson syndrome, or congenital poikilo-
derma, is a rare autosomal recessive familial syndrome
characterized by erythematous and maculopapular skin
lesions with areas of hyperpigmentation, cataracts, pho-
tosensitivity, hypogonadism, psychomotor retardation,
and various skeletal abnormalities. Extensive data indi-
cate that Rothmund-Thomson syndrome belongs to a
group of unique diseases caused by missense mutations
in DNA helicases. A subset of patients with Rothmund-
Thomson syndrome have inactivating mutations in the
RECQL4 helicase linked to chromosomal instability, a
hallmark of this disorder.291,303,325 RECQL4 mutations
are also seen in related disorders such as Baller-Gerold
syndrome or RAPADILINO.318,319 Rothmund-Thomson
syndrome predisposes an individual to the development
of squamous cell carcinoma of the skin and also to osteo-
sarcoma, which may be multicentric.278,289 The osteosar-
comas associated with this syndrome are of conventional
intramedullary type and show a tendency to develop in
unusual skeletal sites. Autosomal recessive inheritance
has been suggested in this condition (see Chapter 24).
Multifocal osteosarcoma can be subdivided into two clin-
ical forms: the synchronous type that more often occurs
in childhood and adolescence (Figs. 5-93 and 5-94) and
the metachronous type that typically occurs in adults (see
Fig. 5-96).268,270,280,287,290,292,297,300,310,313,322 But there is such
a significant overlap between these two forms of clinical
presentation of multifocal osteosarcoma that metachro-
nous lesions can occur in childhood and adolescence and
synchronous lesions may affect adults. The synchronous
type is practically always a high-grade sclerosing intra-
medullary osteosarcoma that principally involves long
bones in a symmetric distribution. The metachronous
type is asymmetrically distributed in adults and does not
necessarily have sclerosing features on radiographs. It
more often affects trunk bones and is associated with
longer survival compared with the highly lethal synchro-
nous juvenile type (Fig. 5-95). Average survival for the
latter is only 6 to 8 months. The less aggressive behavior
of the adult metachronous type may be related to the
lower histologic grade of these tumors. The synchronous
type of multifocal osteosarcoma with symmetric involve-
ment of long bones and without a dominant mass and
initial absence of pulmonary metastases almost certainly
represents separately developing primary tumors. On the
contrary, the adult metachronous form of this condition
most likely represents sequentially developing skeletal
metastases.267,270 This concept is further supported by the
fact that some of the metachronous skeletal foci may
have features of skip metastases or may develop as soft
tissue lesions (Fig. 5-96). Multifocal osteosarcoma result-
ing from heavy tumor burden can be associated with
particularly high levels of serum alkaline phosphatase.
SECONDARY OSTEOSARCOMA
Osteosarcoma can develop in association with several
neoplastic and nonneoplastic precursors.360 This subject
is covered in detail in Chapter 24. Paget’s disease is
the most common precursor and is the prototype
Text continued on p. 309
 5  Osteosarcoma 305

B
FIGURE 5-93  ■  Multifocal osteosarcoma (juvenile/adolescent type). A and B, Sixteen-year-old boy was first seen with multifocal pelvic
lesions and subsequently (7 months later) developed sclerotic lesions in vertebrae, ribs, clavicles, and skull. Death from widespread
metastases of this high-grade osteosarcoma occurred 2 years and 4 months after onset of symptoms.

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306 5  Osteosarcoma

A C
FIGURE 5-94  ■  Multifocal osteosarcoma (juvenile/adolescent type). A, Radioisotopic bone scan showing increased uptake in the
primary osteosarcoma of the distal right femur and multifocal skeletal lesions involving the right distal tibia, pelvis, left proximal
humerus, and the sternal end of the left clavicle. In addition, there are bilateral axillary metastases. B, Anteroposterior plain radio-
graph showing matrix-producing lesion in the proximal humerus, the sternal end of the clavicle, and in the soft tissue of axilla.
C, Sclerotic destructive tumor with extensive involvement of the paraosseous soft tissue laterally, most likely representing the
primary tumor site.

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 5  Osteosarcoma 307

B
FIGURE 5-95  ■  Multifocal osteosarcoma (adult type). A, Plain radiograph of pelvis shows two separate foci of sclerosing osteosarcoma
involving ilium and fifth lumbar vertebra in young woman. B, Computed tomogram of pelvis shows intraosseous and exophytic
radiodense tumor seen in A.

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308 5  Osteosarcoma

FIGURE 5-96  ■  Multifocal osteosarcoma (adult type). A, Radioisotopic bone scan showing increased uptake in the proximal humerus
and the soft tissue in the right proximal tibial/fibular region. B, Anteroposterior (AP) radiograph showing calcified tumor mass in
the intertibial/fibular region. Note external scalloping of the underlying tibial and fibular cortex consistent with soft tissue metastasis.
Inset, Positron emission tomography/computed tomography (PET/CT) fused image showing fluorodeoxyglucose (FDG) avid lesion
in the intertibial/fibular soft tissue. C, AP radiograph showing a mixed lytic sclerotic ill-defined lesion of the proximal humerus with
extension into the soft tissue. Note skipped metastasis in the humeral shaft (arrows). Inset, PET/CT shows FDG-avid tumor in the
proximal humerus. Collectively the imaging data implicates the primary osteosarcoma of the left humerus with skipped metastases
in the same humeral shaft and a distant soft tissue metastasis in the right lower leg.

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nonneoplastic condition that precedes the development
of osteosarcoma.328,335,336,339,343,347,350,353,359,361,362 The tumors
are usually of high grade, and the skeletal sites most
frequently involved are the pelvis, humerus, and femur,
in that order. The radiologic pattern is usually that of a
lytic destructive focus within an area of involvement by
Paget’s disease. The prognosis for Paget-related sarcomas
is significantly worse than that for de novo conventional
high-grade osteosarcoma.
Radiation-induced osteosarcomas may develop after both
external and internal radiation exposure. Dosage in excess
of 3000 Gy and with a latency period of more than 3 years
is recorded in most cases, but shortening of the latency
period has been noted in patients treated with chemother-
apy. The tumors are of high grade and follow an aggres-
sive course with short survival.288,302,323,338,342,344,355,357,358
Bone infarcts rarely give rise to sarcomas, and
most are either malignant fibrous histiocytomas or
fibrosarcomas.331-333 The latter form is disappearing
as a diagnostic designation as the current trend is to
classify virtually all high-grade spindle-cell sarcomas
of bone as malignant fibrous histiocytoma rather than
fibrosarcoma. A small number of high-grade osteo-
sarcomas have been reported in patients with bone
infarcts and in patients who have had metallic prosthetic
implants.327,334,337,340,346,348,349,351
Fibrous dysplasia is associated with a very low incidence
(0.4%) of secondary malignancy and most of these
patients had prior irradiation.329,330,341,345,352,354,356 Most
patients are in the third and fourth decade of life, and
osteosarcomas of high grade are the most frequent his-
tologic type.
Chronic osteomyelitis with sinus track formation associ-
ated with reactive squamous hyperplasia is a predispos-
ing factor for the development of squamous carcinoma
associated with this condition. Rarely do sarcomas,
including osteosarcoma, develop in association with this
condition.
Osteosarcoma rarely complicates treatment of hemato-
logic malignancies. Typically these tumors develop after
the treatment of childhood hematologic malignancies
such as non-Hodgkin’s lymphoma and lymphoblastic leu-
kemia. It is uncertain whether there is a real pathogenetic
relationship between chemotherapy during the first
decade of life and later occurrence of osteosarcoma. It
cannot be excluded that such cases represent mere coin-
cidences rather than a pathogenic relationship.
SURFACE OSTEOSARCOMA
Osteosarcomas that originate and grow predominantly
on the surface of a bone were recognized more than 40
years ago. Jaffe and Selin,367 Geschickter and Copeland,365
as well as Dwinnell, Dahlin, and Ghormley,364 recognized
this variety of osteosarcoma in the early 1950s and coined
the term parosteal or juxtacortical osteogenic sarcoma for
these tumors. Later, this group of lesions was recognized
to have diverse radiographic and microscopic features
and clinical behavior. In 1958, Jaffe366 separated them
into low- and high-grade surface osteosarcomas and cor-
related the increasing histologic grades with the degree
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5  Osteosarcoma 309
of radiodensity. Radiolucent lesions were of higher his-
tologic grade and exhibited a higher recurrence rate than
low-grade radiodense lesions. Subsequent publications
from the Mayo Clinic and others resulted in the current
classification of malignant osteoblastic tumors of bone
surface. The present concept recognizes the heterogene-
ity of this group in terms of their microscopic and radio-
graphic features, as well as their clinical behavior. Those
features are related to the particular growth pattern of
each tumor and its putative site of origin on the surface
of bone. The clinical behavior of these lesions correlates
with their histologic grade of malignancy.363
Surface osteosarcomas are divided into two main cat-
egories: parosteal and periosteal. The term paraosseous
osteosarcoma is sometimes used in reference to tumors
arising adjacent to the bone within the soft tissue. His-
torically the term juxtacortical osteosarcoma was used as a
synonym for parosteal osteosarcoma. Recently, it has
been used in a more general sense to designate all osteo-
sarcomas growing on the surface of bone. The terms
periosteal and parosteal osteosarcoma imply that these tumors
originate in the distinct structures of a bone surface (Fig.
5-97). It is postulated that periosteal osteosarcoma origi-
nates in the deep layer of the periosteum or in the outer
layer of the cortex. Hence, its growth is manifested by a
separation and elevation of the periosteum from the
cortex. Parosteal osteosarcoma is derived from the outer
layer of the periosteum and grows in an exophytic
mushroom-like pattern without elevation of the perios-
teum or evidence of periosteal new bone formation.
These tumors are typically of low to intermediate histo-
logic grade, but sometimes they may exhibit marked ana-
plasia and are then referred to as high-grade surface
osteosarcomas. Occasionally, parosteal osteosarcoma may
dedifferentiate into a high-grade lesion in which low- and
high-grade parosteal osteosarcomas are present within
the same tumor. Such tumors are referred to as dediffer-
entiated parosteal osteosarcomas.
Parosteal Osteosarcoma
Definition
Parosteal osteosarcoma is a low-grade bone-forming
tumor that grows predominantly on the surface of
long bones in an exophytic pattern without elevating
the periosteum. A spindle-cell fibroblast-like compo-
nent and well-developed trabeculae of tumor bone are
characteristic.
Incidence and Location
This rare neoplasm accounts for approximately 3% of all
osteosarcomas. It typically occurs in skeletally mature
patients. The peak incidence is during the third and
fourth decades of life. Approximately 20% of cases occur
during the second decade of life, and there is a clear
female sex predominance.
Parosteal osteosarcoma has a peculiar anatomic distri-
bution, with more than 80% of cases located in the distal
portion of the femoral shaft on its posterior aspect, within
the superior popliteal area. The second most common
310 5  Osteosarcoma
Cartilaginous
cap
- No elevation of
periosteum
- No new periosteal
bone
Elevated periosteum with
PAROSTEAL
FIGURE 5-97  ■  Surface osteosarcomas. Diagrammatic presentation of differences in growth patterns between parosteal and periosteal
osteosarcomas.
site of involvement is in the tibia, where nearly all cases
involve the proximal shaft and the proximal metaphyseal
region. Individual cases have been reported in the
proximal humerus and other long tubular bones. Rare
examples of parosteal osteosarcoma involving the acral
skeleton and the craniofacial bones have also been
described.368,371,380,387,388 The development of parosteal
osteosarcoma has also been linked to previous radiation
exposure.386 The age distribution and most common skel-
etal sites are shown in Figure 5-98.
Clinical Symptoms
These slow-growing tumors usually present as painless,
firm, fixed masses of long duration. Pain may be present,
and the location adjacent to a joint can limit motion.
There may be a history of previous biopsy and attempts
at excision of what was thought to be a benign, reactive
process.
Radiographic Imaging
The tumor grows on the surface of bone attached to the
cortex along a broad base (Fig. 5-99). Peripherally, it
grows in a mushroom-like fashion with a space separating
the tumor from the underlying cortex.375,382,383,400 The
tumor mass is typically densely mineralized and has lobu-
lated outlines. Often the mineralization is uneven and
has irregularly coalesced opacities. If this occurs, the base
and the central portions of the tumor are usually more
ERRNVPHGLFRVRUJ
new bone formation
PERIOSTEAL
mineralized than its periphery. These features, along with
its unique ability to encircle the shaft of the affected
bone, are best demonstrated by computed tomography
and MRI. In rare instances, parosteal osteosarcoma can
present as a relatively radiolucent lesion with only small
irregular opacities (Fig. 5-100).
As mentioned, the tumor grows on the surface of the
periosteum. Hence, there is no associated elevation of
the periosteum and no radiographically recognizable
periosteal new bone formation. The unique ability of
parosteal osteosarcoma to encircle the shaft may result in
the formation of a large, heavily ossified lobulated mass
that forms a cuff around the bone and involves a large
segment of the shaft. The lack of penetration into the
medullary cavity may only be demonstrable through the
use of computed tomography and MRI. The latter
methods are used predominantly to document the extent
of bone and soft tissue involvement. They usually show
an intact cortex beneath the lesion and a broad area
of attachment in the central portion of the tumor
(Figs. 5-100 to 5-103).
The presence of a cartilaginous cap partially covering
the tumor is usually not demonstrated on conventional
radiographs, but MRI may render it visible. Computed
tomography and MRI also may reveal satellite nodules
within the soft tissue that are usually present in recurrent
lesions.383 The presence of lucent areas at the periphery
of lesions can be associated with the development
of large, predominantly cartilaginous areas. The main
significance of this finding is that it may represent a sign

Peak
incidence
20 30
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 5-98  ■  Parosteal osteosarcoma. Peak age incidence and frequent sites of skeletal involvement. Most frequent site is indicated
by solid black arrow.
of dedifferentiation (i.e., transformation to a high-grade
sarcoma).370
Medullary involvement is difficult to evaluate on plain
radiographs. It is usually present in advanced stages and
is best documented by MRI and computed tomography
(Fig. 5-104). Cases with medullary involvement may pres-
ent a difficult diagnostic problem centering on whether
the lesion represents a medullary well-differentiated
osteosarcoma with extension into soft tissue (Fig. 5-101).
In surface lesions, the main tumor mass is usually within
the soft tissue and has a relatively minor intramedullary
component (Fig. 5-104).390
Gross Findings
Parosteal osteosarcoma typically presents as a firm, exo-
phytic, polypoid, bony mass attached to the cortex of a
long bone by a broad base (Fig. 5-99). The surface is
lobulated or bosselated with overhanging edges. It can
grow along the long axis of the bone or form an encircl-
ing cuff. One or more satellite nodules may be found
completely separate from the main tumor mass or partly
attached to it at the periphery. Multiple satellite nodules
are more often found in recurrent lesions. The cut surface
presents a tan to ivory bony mass that may contain fleshy
areas or foci of grossly recognizable hyaline cartilage (see
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5  Osteosarcoma 311
7 8
Figs. 5-100 to 5-104). The latter may form a peripheral
irregular cap. Heavily ossified areas have a tendency to
coalesce at the base of the lesion centrally and to fuse with
the outer layer of the cortex. The periphery of the mass is
softer and fleshier than the base. The soft tissue border of
the lesion is usually lobulated and sharply demarcated.
Microscopic Findings
This tumor is characterized by the presence of a
spindle-cell fibroblastic component that is deceptively
benign appearing and admixed with relatively well
developed tumor bone trabeculae (Figs. 5-105 and
5-106).372,384,389,393,397 The latter may coalesce and form
solid bony areas. The spindle cells show minimal atypia,
and although mitoses can be found with difficulty, atypi-
cal forms are not present. Similar to low-grade intra-
medullary osteosarcoma, the tumor cells have features
of fibroblasts embedded in a dense collagenous stroma.
Foci of cartilage are frequently found in parosteal osteo-
sarcoma (Figs. 5-107 and 5-108). They range in size from
small ill defined areas of immature cartilaginous matrix to
large irregular areas of well developed hyaline cartilage.
In some instances, large irregular areas of gradual tran-
sition between cartilage and tumor bone can be present
Text continued on p. 322
312 5  Osteosarcoma

A B

C D
FIGURE 5-99  ■  Parosteal osteosarcoma. A, Parosteal osteosarcoma of distal femoral shaft with large focus of radiolucency peripher-
ally. Such areas should be preferentially sampled to exclude possibility of dedifferentiation. B, Large bulky tumor shows peripheral
lobulation. C, Specimen radiograph of distal femoral tumor shows central attachment to cortex, overhanging edges, and cancellous
bonelike trabeculation distally. Early penetration of medullary cavity at base was associated with reactive bone formation. D, Lobu-
lated parosteal osteosarcoma of distal femur extending into intercondylar notch.

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 313

A B

C D
FIGURE 5-100  ■  Parosteal osteosarcoma. A, Anteroposterior radiograph shows focally mineralized bone surface lesion in the medial
supracondylar aspect. B, Fat-saturated T2-weighted coronal magnetic resonance image showing relatively homogeneous high signal
intensity of the bone surface lesion. Note focal penetration of the underlying cortex and involvement of medullary cavity (arrow).
C, Coronally bisected resection specimen showing dense fibrous bone surface mass involving the distal medial aspect of the femur.
Note focal invasion into medullary cavity (arrow). D, Low power photomicrograph of the same tumor showing parallel arrangement
of well developed tumor bone trabeculae and low cellular bland-appearing fibrous stromal tissue. (D, ×50) (D, hematoxylin-eosin.)

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314 5  Osteosarcoma

A B

C D
FIGURE 5-101  ■  Parosteal osteosarcoma. A, Anteroposterior radiograph showing sclerotic lesion encircling both the tibia and the
fibula. B, Sagittally bisected resection specimen showing dense fibrous bone surface mass encircling the tibia and invading the
underlying medullary cavity. C and D, Low power photomicrographs show various patterns of tumor osteoid forming interconnected
well developed bone trabeculae in fibroblastic stromal tissue. (C and D, ×50) (C and D, hematoxylin-eosin).

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 5  Osteosarcoma 315

A B

C D
FIGURE 5-102  ■  Parosteal osteosarcoma. A, Lateral radiograph showing mineralized bone surface lesion encircling the distal femoral
metastasis. B, Fat-saturated T2-weighted sagittal magnetic resonance image with contrast of A showing a bulky tumor encircling
the distal femoral metastasis with signal enhancement and large patches of signal void. C, Gross photograph of sagittally bisected
resection specimen showing bulky tumor mass encircling the distal femoral metastasis. Note, the overall fibrous appearance of the
lesion and small cystic changes in the central portion of the posterior tumor mass. D, Low power photomicrograph shows well
mineralized coarse tumor bone trabeculae in fibrous stroma. (D, ×20) (D, hematoxylin-eosin).

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316 5  Osteosarcoma

A B

C D
FIGURE 5-103  ■  Parosteal osteosarcoma. A, Anteroposterior radiograph showing a sclerotic tumor mass involving the proximal
humeral metaphysis. B, Fat-saturated T2-weighted coronal magnetic resonance image showing inhomogeneous enhancement in
the tumor encircling the surface of the proximal humeral metaphysis. C, Gross photograph of coronally bisected resection specimen
showing a fleshy and fibrous tumor mass encircling the proximal humerus. D, Low power photomicrograph showing well developed
coarse bone trabeculae in fibrous stroma. (D, ×20) (D, hematoxylin-eosin).

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 5  Osteosarcoma 317

A B

C D
FIGURE 5-104  ■  Parosteal osteosarcoma. A, Lateral plain radiograph showing heavily mineralized tumor attached to the posterior
distal aspect of the femoral bone. B, Fat-saturated T2-weighted sagittal magnetic resonance image of A showing inhomogeneous
signal enhancement in the tumor involving the posterior aspect of the distal femoral bone. Note high signal intensity in the tumor
penetrating the underlying cortex and invading the medullary cavity (arrow). C, Gross photograph of the same tumor showing sagit-
tally bisected resection specimen. Note fibrous tumor growing on the surface of posterior distal femur. The tumor penetrates
underlying cortex and invades the medullary cavity (arrow). D, Low power photomicrograph showing well developed interconnected
tumor bone trabeculae and inconspicuous fibrous stromal tissue. (D, ×20) (D, hematoxylin-eosin).

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318 5  Osteosarcoma

A B

C D
FIGURE 5-105  ■  Parosteal osteosarcoma: microscopic features. A, Low power photomicrography showing tumor bone trabeculae
pattern and fibroblastic stromal tissue. B-D, Higher power magnifications showing well developed bony trabeculae of various shapes
and spindle-cell fibroblastic stromal tissue. (A, ×20; B-D, ×100) (A-D, hematoxylin-eosin.)

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 5  Osteosarcoma 319

A B

C D
FIGURE 5-106  ■  Parosteal osteosarcoma: microscopic features. A, Low power photomicrograph showing interconnected tumor bone
trabeculae and inconspicuous, well vascularized stromal tissue. B, Higher magnification of A showing somewhat parallel arrange-
ment of tumor bone trabeculae and low cellular fibroblastic stromal tissue. C, Low power photomicrograph corresponding to a
heavily mineralized sclerotic portion of the tumor with large solid areas of well developed tumor bone. D, Advancing tumor edge
growing into the skeletal muscle. Note a continuous shell-like bone outlining the peripheral aspect of the tumor. (A, C, and D, ×20;
B, ×100) (A-D, hematoxylin-eosin.)

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320 5  Osteosarcoma

A B

C D
FIGURE 5-107  ■  Parosteal osteosarcoma: microscopic features. A and B, Intermediate power views showing somewhat hypercellular
spindle-cell stromal tissue and various patterns of tumor bone formation in a low-grade parosteal osteosarcoma. C, Low
power photomicrograph showing ill-defined areas of cartilaginous differentiation in parosteal osteosarcoma. D, Higher magnification
of C showing a focus of cartilaginous differentiation. Note nuclear atypia of cartilage cells. (A, B, and D, ×100; C, ×20)
(A-D, hematoxylin-eosin.)

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 5  Osteosarcoma 321

A B

C D
FIGURE 5-108  ■  Parosteal osteosarcoma: microscopic features. A, Low power photomicrograph showing coarse irregular bone tra-
beculae in fibrous stroma. Note engorged prominent vessels in the lower aspect of the photomicrograph. B, Higher power of A
showing irregular well-developed bone trabeculae and somewhat hypercellular spindle cell stromal tissue. C, Low power photomi-
crograph showing large areas of cartilaginous differentiation in parosteal osteosarcoma. D, Higher magnification of C showing
mineralized cartilage matrix and tumor cartilage cells occupying lacunar spaces. Note variability in size and nuclear atypia of cartilage
cells. (A and C, ×20; B and D, ×100) (A-D, hematoxylin-eosin.)

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322 5  Osteosarcoma
(Fig. 5-109). Some of those areas may form large solid
masses of gradually merging osteochondroid matrix.
The cartilage contains atypical chondrocytes and such
areas do not show the orderly enchondral ossification
sequence found in osteochondromas. A unique feature
found in some parosteal osteosarcomas is the presence
of large cartilage caps that can be seen on radiographs
as radiolucent areas. They represent solid areas of well
developed hyaline cartilage that have an overall archi-
tectural arrangement similar to cartilaginous caps seen
in osteochondromas. The cap-shaped outer surface is
oriented toward the periphery of the lesion; the more
central or baseline aspects of the cartilaginous areas may
display disorganized areas of enchondral ossification
similar to the base of an osteochondroma (Fig. 5-110).
The cartilage cells of the cartilaginous cap reside in
well developed lacunar spaces and have some columnar
arrangement. The overall mimicry of osteochondroma
is quite striking and biopsies containing such areas can
be confused with a benign cartilage lesion if evaluated
without correlation to a radiographic presentation of the
lesion. In most cases, the diagnosis of parosteal osteosar-
coma is evident on radiographic imaging and radiolucent
areas are specifically targeted for preoperative biopsies to
rule out high-grade dedifferentiation.370 Therefore, well
developed cartilage areas may be present in such biop-
sies as they typically present radiographically as radio-
lucent lesions. At the base of the lesion centrally, an
intact cortex, to which the tumor bone trabeculae fuse, is
usually present. However, in some cases, erosion through
the cortex with tumor invasion of the medullary cavity
may be present. Because parosteal osteosarcoma grows in
an exophytic fashion without elevating the periosteum,
histologic evidence of periosteal new bone deposition is
lacking, as is the Codman’s triangle found in other forms
of osteosarcoma. This tumor differs completely from the
histologic appearance of conventional osteosarcoma, but
cellular foci of high-grade tumor may be found. Such
foci represent a progression of a low-grade fibroblastic
osteosarcoma to a high-grade sarcoma and are referred
to as dedifferentiation.369,374,377,378,391,398,399 Radiographically,
foci of dedifferentiation are seen as radiolucent areas
with a mineralization pattern that differs from that of
low-grade parosteal osteosarcoma, which typically pres-
ents as a heavily mineralized bone surface lesion (Figs.
5-111 to 5-113).376 On gross inspection, such areas may
have fleshy gelatinous or myxoid appearance (see Figs.
5-111 to 5-113). In general, dedifferentiated parosteal
osteosarcoma represents an evolution of a preexisting
low-grade surface tumor to a high-grade sarcomatoid
malignancy and is seen in approximately 10% to 15%
of all parosteal osteosarcomas. Foci of dedifferentiation
most frequently have features of high-grade conven-
tional osteosarcoma. Dedifferentiation may also have
features of high-grade sarcoma with malignant fibrous
histiocytoma–like features. Rare examples of dedifferen-
tiation resembling giant cell tumors or with features of
telangiectatic osteosarcoma have been described.373,395 A
phenotypic switch to rhabdomyosarcoma can also occur
in a dedifferentiated component.392 It can also be in the
form of high-grade spindle-cell or pleomorphic sarcoma
with malignant fibrous histiocytoma–like features. The
ERRNVPHGLFRVRUJ
phenomenon is similar to that observed in dedifferenti-
ated chondrosarcoma.
Differential Diagnosis
The most important factor underlying the misdiagnosis
of parosteal osteosarcoma is the deceptively innocent
appearance of the well-differentiated fibroblastic compo-
nent and the relative maturity of the tumor bone in this
low-grade neoplasm. Consequently, it is commonly mis-
interpreted as a benign reactive lesion. Among the condi-
tions with which it can be confused are posttraumatic
periostitis, florid reactive periostitis, juxtacortical myositis ossi-
ficans, and postavulsive lesions such as cortical irregularity
syndrome in children. Clinical and radiologic correlations
are essential in distinguishing these conditions, even
when the microscopic features are equivocal. Generally,
the reactive surface lesions show greater radiodensity
peripherally and central lucency. This pattern is the
reverse of that seen in parosteal osteosarcomas. For
details of the differential diagnoses of these conditions,
see Chapter 23.
Periosteal and high-grade surface osteosarcomas must be
distinguished from parosteal osteosarcoma. The radio-
graphic pattern of growth of periosteal osteosarcoma is
significantly different because the tumor elevates the
periosteum to produce Codman’s triangles and a fusiform
surface enlargement. In addition, the mineralization
pattern of periosteal osteosarcoma is more delicate, is
feathery, and often shows perpendicular striations. His-
tologically, the tumor usually contains abundant hyaline
cartilage matrix, and the areas of osteogenesis are
of intermediate to high grade. These tumors also tend
to occur in young patients. Parosteal osteosarcoma
can usually be distinguished from high-grade surface
osteosarcoma on purely histologic grounds in biopsy
samples, but these tumors may contain residual areas of
low-grade appearance if they developed through dedif-
ferentiation of parosteal osteosarcoma. Such areas can be
anticipated radiologically if attention is paid to localized
areas of low density or complete lucency in otherwise
typical parosteal osteosarcomas.
Occasionally an intramedullary low-grade osteosarcoma
has a significant soft tissue component that is histologi-
cally indistinguishable from parosteal osteosarcoma of
low grade. The distinction is made easier through com-
puted tomography and MRI, which demonstrate that the
tumor’s major component is intramedullary.
Sessile osteocartilaginous exostoses are among the benign
lesions most frequently mistaken for parosteal osteosar-
coma on radiographs, but the intact cortex beneath the
parosteal sarcoma can be easily demonstrated in com-
puted tomographic and MRI studies. Similarly, when the
lesion is an osteochondroma, continuity between the fatty
marrow of the stalk and the underlying medullary bone
is evident. The cartilage cap, which can be found in either
lesion, may contribute to the confusion, but the distinc-
tive microscopic morphology of parosteal osteosarcoma
is lacking in an osteochondroma stalk.
Fibromatosis and fasciitis can secondarily involve the
adjacent bone and occasionally originate from the
Text continued on p. 328
 5  Osteosarcoma 323

A B

C D
FIGURE 5-109  ■  Parosteal osteosarcoma: microscopic features. A, Low power photomicrograph showing irregular large deposits of
tumor osteoid. B, Higher magnification of A showing irregular ill-defined areas of osteoid. C, Highly variable and irregular pattern
of tumor bone trabeculae in parosteal osteosarcoma. D, Highly sclerotic area of parosteal osteosarcoma showing confluent solid
areas of osteoid gradually transitioning into chondroid matrix. (A, C, and D, ×50; B, ×100) (A-D, hematoxylin-eosin.)

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324 5  Osteosarcoma

A B

C D
FIGURE 5-110  ■  Parosteal osteosarcoma: microscopic features. A, Low power photomicrograph showing a large confluent area of
cartilaginous differentiation in parosteal osteosarcoma referred to as a cartilaginous cap. Solid area of well developed hyaline car-
tilage facing the outer peripheral surface of the tumor is in the upper portion of the photomicrograph. The lower portion shows a
disorganized pattern of enchondral ossification mimicking the growth plate. B, Outer surface of the cartilaginous cap covered by
fibrous tissue. C, Intermediate power photomicrograph showing the baselike aspect of the cartilaginous cap with a growth platelike
enchondral ossification pattern. D, Architectural features of the outer peripheral areas of the cartilaginous cap showing cartilage
cells of variegated size located in well defined lacunar spaces. (A and B, ×20; C, ×50; D, ×100) (A-D, hematoxylin-eosin.)

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 5  Osteosarcoma 325

A B

C D
FIGURE 5-111  ■  Dedifferentiated parosteal osteosarcoma. A, Lateral radiograph of distal femur showing heavily mineralized tumor
encircling the distal femoral surface. Note the bulky tumor with an increasing mineralization pattern toward the base of the lesion
in the posterior aspect of the femoral bone. Arrows indicate a focus with changed fluffy mineralization pattern corresponding to
dedifferentiation. B, Fat-saturated T2-weighted sagittal magnetic resonance image showing inhomogeneous signal enhancement.
Arrows indicate a focus of signal enhancement in the lower posterior aspect of the lesion corresponding to dedifferentiation.
C, Gross photograph of sagittally bisected resection specimen showing a heavily mineralized tumor involving the distal femoral
surface with the bulky tumor mass in the posterior aspect (arrows). D, Magnification of the lower posterior aspect of the tumor
showing a discrete fleshy, somewhat myxoid, area of the tumor corresponding to dedifferentiation (arrows). Note heavily mineral-
ized upper portion of the tumor with grossly visible trabeculae pattern.

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326 5  Osteosarcoma

A B

C D
FIGURE 5-112  ■  Dedifferentiated parosteal osteosarcoma. A, Lateral radiograph showing heavily mineralized tumor involving the
posterior distal aspect of the femoral surface. Note change in the mineralization pattern with a loosened fluffy area in the upper
aspect of the tumor corresponding to dedifferentiation (arrows). B, Gross photograph of sagittally bisected resection specimen
showing bulky tumor of the posterior aspect of the distal femoral surface. Note the fleshy appearance of the tumor corresponding
to dedifferentiation of the upper aspects of the lesion (arrows). C, Low power photomicrograph showing well developed intercon-
nected tumor bone trabeculae pattern and fibrous stroma corresponding to preexisting low-grade parosteal osteosarcoma.
D, Dedifferentiated area of the tumor showing high-grade osteosarcoma with lacelike osteoid and anaplastic tumor cells. (C, ×20;
D, ×100) (C and D, hematoxylin-eosin.)

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 5  Osteosarcoma 327

A B

C D
FIGURE 5-113  ■  Dedifferentiated parosteal osteosarcoma. A, Gross photograph of coronally bisected distal femoral resection speci-
men showing parosteal osteosarcoma growing on the medial aspect of the distal femoral surface (arrows). B, Magnified view of
A showing interface between the low-grade well mineralized upper portion of the tumor and an area of dedifferentiation with fleshy
myxoid appearance (arrows). A cystic area in the medullary cavity represents a regressed tumor after preoperative chemotherapy.
C, Low-grade component of the tumor with well developed tumor trabeculae. D, Focus of viable postchemotherapy tumor
with features of a high-grade osteosarcoma corresponding to the dedifferentiated portion of the tumor. (C, ×50; D, ×100) (C and
D, hematoxylin-eosin.)

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328 5  Osteosarcoma
periosteum itself. Such lesions can present formidable
problems in differential diagnosis from parosteal osteo-
sarcoma, particularly when reactive bone is produced as
in ossifying parosteal fasciitis, a rare but clearly benign
condition. The spindle-cell component usually differs
sufficiently from parosteal osteosarcoma to permit its
recognition.
Treatment and Behavior
Parosteal osteosarcoma is a slowly enlarging tumor that
recurs if it is not completely excised and in which areas
of dedifferentiation are associated with the capacity to
metastasize to distant sites.379,381,385,394,396,398 Overall the
5-year survival rate ranges from 85% to 90%, and tumors
in patients in whom metastases develop almost invariably
show dedifferentiation to a higher grade. On the other
hand, patients who had radical excision of a completely
low-grade tumor had small risks of local recurrence and
metastasis. Medullary involvement occurs more fre-
quently in patients with higher-grade tumors, including
dedifferentiated ones; it is related to multiple recurrences
and does not, in itself, correlate with a poor prognosis.
Its demonstration in cross-sectional radiographs can indi-
cate the necessity for more extensive excision. Higher-
grade and dedifferentiated lesions are treated with
chemotherapy in addition to radical surgery.
Periosteal Osteosarcoma
Definition
Periosteal osteosarcoma is a low- to intermediate-grade
bone-forming sarcoma with predominantly chondroblas-
tic differentiation that develops on the surfaces of long
bones in children. It arises beneath the periosteum, ele-
vating it and provoking prominent periosteal new bone
formation. Some authors designated these extensively
cartilaginous osteosarcomas as juxtacortical chondrosarco-
mas.417 This term is no longer acceptable for these lesions
because it confuses the entity of periosteal osteosarcoma
with a true periosteal chondrosarcoma, which is described
in Chapter 7.
Incidence and Location
Periosteal osteosarcoma is a rare tumor that represents
less than 2% of osteosarcomas. The peak incidence is
during the second decade of life, and the tumor occurs
more commonly in female patients, with a 1 : 1.7 male-
to-female ratio. It occurs almost exclusively on the long
tubular bones of a lower extremity.401-403,406,407 The tibia is
most frequently involved, followed by the femur, with
diaphyseal location predominating over metaphyseal.
More rarely, the long bones of an upper extremity are
involved, and individual cases have been reported in the
acral skeleton and craniofacial bones (the mandible).412,420
Multifocal synchronous and metachronous involvement
of the long bones of the lower extremities has also been
reported.408,409 The most common skeletal sites and peak
age incidence are shown in Figure 5-114.
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Clinical Symptoms
Swelling of an extremity with or without pain of relatively
short duration (several weeks to months) is characteristic
for this tumor.
Radiographic Imaging
Periosteal osteosarcoma is a predominantly radiolucent
fusiform lesion that presents on the surface of a long
bone401-404,411 (Figs. 5-115 to 5-118). The periosteum
appears to have been elevated by the tumor’s expansion
external to the cortex, which provokes prominent perios-
teal new bone formation in the form of both perpendicu-
lar striae and peripheral Codman’s triangles seen on
plain radiographs (Fig. 5-119). In addition to the linear
densities external to the cortex, patchy focal cartilage
calcification may be visible. The subperiosteal location of
the tumor is clearly demonstrated in cross-sectional com-
puted tomographic scans and MRI (see Figs. 5-115 and
5-118). The outer layer of the cortex beneath the tumor
may show irregularity and erosion, but the medullary
cavity is usually not invaded. Some authors use the
absence of medullary involvement as a sine qua non for
the diagnosis of periosteal osteosarcoma. They argue that
if the cortex is completely disrupted, small primary med-
ullary osteosarcomas with subperiosteal extension cannot
be ruled out.
Gross Findings
The fusiform tumor is well demarcated and attached to
the surface of the cortex. Periosteal elevation with reac-
tive bone spicules may be seen traversing the tumor cen-
trally and parallel to the surface peripherally where it
attaches to the cortex (Fig. 5-118). Grossly visible carti-
lage is frequently present, and a lobular architecture may
be seen.
Microscopic Findings
This tumor exhibits predominant features of cartilage
differentiation that may be in the form of poorly delin-
eated lobules separated by bands of primitive sarcoma-
tous cells. In these areas, direct tumor osteoid and
immature bone production can be found (Figs. 5-120 to
5-122).401-403,413,418,419 The perpendicular striations seen
grossly are represented by spicules of reactive bone that
have prominent osteoblastic rimming. The cartilaginous
component usually shows obvious nuclear atypia equiva-
lent to a grade 2 or 3 chondrosarcoma (Figs. 5-123
to 5-125). It frequently contains areas of heavy calcifica-
tion. Areas of primitive tumor bone in the undifferenti-
ated spindle-cell component identify this surface tumor
as an osteosarcoma. Special techniques do not aid in
the diagnosis of this form of osteosarcoma as areas of
solid prolipherations of anaplastic mesenchymal cells can
be present (Fig. 5-126). Ultrastructural study reveals
undifferentiated sarcomatous cells, areas of osteoblastic
differentiation with matrix mineralization, and promi-
nent cartilaginous areas.410

Peak
incidence
10 35
Incidence
1 2 3 4
Age in decades
FIGURE 5-114  ■  Periosteal osteosarcoma. Peak age incidence and frequent sites of skeletal involvement.
Differential Diagnosis
Periosteal osteosarcoma is distinguished from parosteal
osteosarcoma on the basis of distinct differences in loca-
tion, age of the patient, and radiographic growth pattern.
Recognition is usually made easier by the fact that the
periosteal osteosarcoma is predominantly cartilaginous
and of intermediate- to high-grade differentiation. In
contrast, parosteal osteosarcomas are predominantly
spindle-cell (fibroblastic) tumors of low grade and contain
abundant tumor bone.
High-grade surface osteosarcoma presents greater diffi-
culties in differential diagnosis from this tumor because
some periosteal osteosarcomas have high-grade differen-
tiation. Although the distinction may be purely academic,
periosteal osteosarcoma generally contains much more
prominent cartilaginous differentiation and usually shows
a more pronounced lobular pattern than high-grade
surface osteosarcoma. The latter shows a predominantly
osteoblastic histologic pattern with greater anaplasia.
The frequency of metastasis is significantly greater in
high-grade surface osteosarcoma, and the prognosis
is correspondingly poorer than that for periosteal
osteosarcoma.
Conventional intramedullary osteosarcoma can occasion-
ally present a problem in differential diagnosis when the
ERRNVPHGLFRVRUJ
5  Osteosarcoma 329
5 6 7 8
surface component is sampled without full visualization
of the intramedullary extent of the tumor. This problem
is easily solved through the use of computed tomography
and MRI, which should confirm the absence of medullary
involvement in periosteal osteosarcoma.
In the past, periosteal osteosarcomas were not fully
accepted as bone-forming neoplasms, and some authors
suggested that they were better classified as juxtacortical
chondrosarcomas. In some cases the inconspicuous nature
of the tumor bone formation contributed to this contro-
versy, but it is now generally agreed that a distinction
can be made between these two lesions on the bases of
clinical, radiologic, and histologic findings. Juxtacortical
chondrosarcoma tends to occur in older patients, is
usually more metaphyseal in location, and shows a differ-
ent (coarser) pattern of matrix calcification and little per-
turbation of the periosteum. Histologically, it differs
from periosteal osteosarcoma in that the cartilage is
usually very well differentiated and there is no direct
tumor bone formation.
Whereas periosteal chondroma is usually a small, well-
defined surface lesion that is easily distinguished from the
more irregular periosteal osteosarcoma, some larger
examples of this benign cartilage tumor may suggest the
diagnosis of periosteal osteosarcoma. The distinction is
made without difficulty on histologic grounds.
330 5  Osteosarcoma

C
FIGURE 5-115  ■  Periosteal osteosarcoma: radiographic features. A, Anteroposterior plain radiograph of periosteal osteosarcoma
shows no matrix mineralization but fusiform soft tissue density that erodes external cortical surface. B, T1-weighted coronal magnetic
resonance image of lesion shows low signal in subperiosteal mass. Medullary cavity is not involved. C, Axial computed tomogram
of tumor shown in A and B.

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A B
FIGURE 5-116  ■  Periosteal osteosarcoma: radiographic features. A, Anteroposterior radiograph shows fusiform surface tumor of tibial
shaft in a 13-year-old girl. B, Close-up view of periosteal osteosarcoma of proximal tibial shaft shows radiating spicules at the base
of the fusiform mass.
Treatment and Behavior
Radical surgical excision with wide margins and amputa-
tion are the treatment methods that provide the best
results for patients with this tumor.414,415 Chemotherapy
appears to have questionable effects on the development
of metastatic deposits in periosteal osteosarcoma. The
limited clinical experience with this variant indicates that
approximately 25% of the patients die with metastatic
tumor, usually to the lungs, within 2 to 3 years after
primary treatment.401,403,416,419 These original observations
from the Mayo Clinic and Rizzoli Institute were recently
confirmed by the European Musculo Skeletal Oncology
Society study.405
High-grade Surface Osteosarcoma
Definition
This de novo tumor is an exclusively high-grade osteo-
sarcoma that develops on the surface of a long bone
without medullary involvement.
Incidence and Location
This is the least common variety of surface osteosarcoma,
constituting less than 1% of all osteosarcomas.421-424 As
with conventional osteosarcoma, there seems to be a male
predominance. The limited experience with this tumor
indicates that it principally occurs in adolescents and
young adults. The skeletal distribution is somewhat
ERRNVPHGLFRVRUJ
5  Osteosarcoma 331
similar to conventional medullary osteosarcoma, with
most cases arising on the surface of the metaphyses. The
distal femur and proximal humerus are involved most
frequently. The peak age incidence and the most frequent
sites of skeletal involvement are shown in Figure 5-127.
Clinical Symptoms
Pain is the most common presenting symptom, in addi-
tion to swelling. The duration varies from months to
several years.
Radiographic Imaging
High-grade surface osteosarcoma typically presents
radiographically as a mineralized bone surface mass. The
pattern of matrix mineralization tends to mimic that of a
conventional medullary osteosarcoma with irregularly
distributed cloudlike opacities (Fig. 5-128). The degree
of mineralization varies considerably. Cortical erosion
may be present, but the medullary cavity is usually not
involved. As in periosteal osteosarcoma, Codman’s tri-
angles may be present.
Gross Findings
The gross features generally mimic those of a conventional
medullary osteosarcoma as described previously. This
tumor presents as a multilobulated fungating mass on the
bone surface with a broad-based attachment. The cortex is
usually roughened and focally deeply eroded, but any
332 5  Osteosarcoma

C
FIGURE 5-117  ■  Periosteal osteosarcoma: radiographic features. A, Periosteal osteosarcoma of tibial shaft in skeletally immature
patient. Note Codman’s triangles at upper and lower limits of tumor. B and C, Axial and coronal T1-weighted magnetic resonance
images of tumor shown in A. Note absence of medullary involvement and irregular cortical surface. Subperiosteal location of tumor
is well demonstrated.

significant medullary penetration should exclude the tumor Differential Diagnosis

from the diagnostic category of surface osteosarcoma.
Microscopic Findings
High-grade surface osteosarcoma is indistinguishable
from conventional medullary osteosarcoma because it
shows anaplastic cellular features and osteoid and imma-
ture bone and cartilage formation without any of the
low-grade fibroblastic features seen in parosteal osteosar-
coma (Fig. 5-128). If microscopic evidence of medullary
extension is present, it is minimal.
The main lesions to be distinguished from this tumor are
parosteal osteosarcoma, dedifferentiated parosteal osteosarcoma,
periosteal osteosarcoma, and extramedullary extension from
a conventional central osteosarcoma. The prognosis for
dedifferentiated parosteal osteosarcoma and for high-
grade surface osteosarcoma is the same as that for high-
grade medullary osteosarcoma. Therefore the distinction
among these entities has no therapeutic implications.
The distinction from periosteal osteosarcoma is of more
Text continued on p. 342

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 333

A B

C D
FIGURE 5-118  ■  Periosteal osteosarcoma: radiographic and gross features. A, Lateral radiograph shows radiolucent lesion of the tibial
shaft with elevation of periosteum on both sides of the lesion. B, Fat-saturated T2-weighted axial magnetic resonance image showing
periosteal signal enhancing lesion in the anterior aspect of the tibia. Note elevation of the periosteum in the peripheral aspects of
the lesion. C, Gross photographs of sagittally bisected tibial shaft resection specimen showing an oval lesion originating in the outer
layers of the cortex and elevating the overlying periosteum. D, Magnified view of C showing gritty ill-defined lesion originating in
the periosteal outer aspects of the cortex beneath the periosteum. Note the elevation of the periosteum forming a buttress-like eleva-
tion in the peripheral aspects of the lesion with a thin layer of fibrous periosteal tissues covering the entire outer surface of the
lesion.

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334 5  Osteosarcoma

A B

C D
FIGURE 5-119  ■  Periosteal osteosarcoma: gross and microscopic features. A, Bisected segmentally resected tibial shaft tumor shows
surface location and subperiosteal growth. Peripheral hemorrhagic defect represents biopsy site. B, Whole-mount photomicrograph
of periosteal osteosarcoma shows peripheral reactive bone formation at site of the Codman’s triangle (arrows). Cartilage is discern-
ible even in low power views. C, Photomicrograph of tumor in B shows atypical cartilage with calcifications in periosteal osteosar-
coma. D, Whole-mount photomicrograph of periosteal osteosarcoma with reactive periosteal new bone formation at the periphery
(arrows). (C, ×100) (B-D, hematoxylin-eosin.)

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 5  Osteosarcoma 335

B
FIGURE 5-120  ■  Periosteal osteosarcoma: microscopic features. A, Low power photomicrograph showing the overall architecture of
the lesion. The peripheral zone shows hypercellular mantle while the portion at the bottom of the photograph contains areas of
cartilaginous and osseous differentiation. Inset, Higher magnification of A showing more of the hypercellular area of the tumor.
B, Deeper area of the tumor showing areas of cartilaginous matrix gradually blending with well developed irregular areas of osteoid.
(A, ×20; B, ×50; inset, ×100) (A, B, and inset, hematoxylin-eosin.)

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336 5  Osteosarcoma

A B

C D
FIGURE 5-121  ■  Periosteal osteosarcoma: microscopic features. A-D, Areas of cartilaginous and osseous differentiation with gradual
transition from cartilaginous to osteoid matrix deposition in periosteal osteosarcoma. (A-D, ×100) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 337

A B

C D
FIGURE 5-122  ■  Periosteal osteosarcoma: microscopic features. A-D, Extensive cartilaginous differentiation gradually blending
with well developed areas of osteoid matrix and irregular trabeculae of tumor bone in periosteal osteosarcoma. (A-D, ×100)
(A-D, hematoxylin-eosin.)

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338 5  Osteosarcoma

B
FIGURE 5-123  ■  Periosteal osteosarcoma: microscopic features. A, Low power photomicrograph showing peripheral aspects of
periosteal osteosarcoma with large areas of cartilaginous differentiation forming bulging lobules. B, Intermediate power
photomicrograph of cartilage matrix area gradually blending with more cellular areas of the tumor. (A, ×20; B, ×100) (A and
B, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 339

B
FIGURE 5-124  ■  Periosteal osteosarcoma: microscopic features. A, Low power photomicrograph showing large areas of cartilaginous
differentiation in peripheral parts of the tumor. Note hypercellular zone at the tumor periphery in upper portion of the photomicro-
graph. B, Higher magnification of A showing the gradual transition of well developed cartilage areas with the spindle-cell component
of the tumor. (A, ×50; B, ×100) (A and B, hematoxylin-eosin.)

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340 5  Osteosarcoma

FIGURE 5-125  ■  Periosteal osteosarcoma: microscopic features. A, Low power microphotograph showing myxoid areas of the tumor
with irregular focal calcifications. Note the overall lobular arrangement of the tumor. B, Tumor periphery with extensive areas of
cartilaginous differentiation and hypercellular areas. Inset, Higher magnification of B showing a hypercellular area. (A, ×20; B, ×50;
inset, ×100) (A, B, and inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 5  Osteosarcoma 341

A B

C D
FIGURE 5-126  ■  Periosteal osteosarcoma: microscopic features. A-D, Low and high power views of cellular solid areas of a tumor
composed of undifferentiated mesenchymal cells with nuclear atypia and brisk mitotic activity (A, ×100; B, ×200; C, ×100; D, ×200).
(A-D, hematoxylin-eosin.)

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342 5  Osteosarcoma
Probable
peak incidence
20 40
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 5-127  ■  High-grade surface osteosarcoma. Peak age incidence and most frequent sites of skeletal involvement.
prognostic importance and is based on the fact that high-
grade surface osteosarcoma shows more anaplasia and
less prominent chondroid differentiation than periosteal
osteosarcoma. The microscopic picture of periosteal
osteosarcoma is typically dominated by prominent chon-
droid differentiation.
Treatment and Behavior
High-grade surface osteosarcoma has the same prognosis
as its conventional (high-grade) intramedullary counter-
part. This tumor has a great propensity for distant metas-
tasis, principally to the lungs. The same combined
modality treatment with chemotherapy and radical surgi-
cal procedures used for conventional intramedullary
tumors is indicated.
INTRACORTICAL OSTEOSARCOMA
Definition
In 1960, Jaffe426 described a peculiar form of osteosar-
coma that originated within the cortex and at the time
of clinical presentation was still confined to the cortical
bone. He separated his original two cases from ordinary
medullary osteosarcoma and proposed the term intracor-
tical osteosarcoma to designate these lesions. Intracortical
ERRNVPHGLFRVRUJ
7 8
osteosarcoma is a distinctly rare, high-grade osteosar-
coma that is confined to the cortex of a major long bone.
Incidence and Location
Fewer than 10 cases of intracortical osteosarcoma have
been described.425-431 The age range is 10 to 30 years, with
all reported cases diagnosed in patients who were in
the second and third decades of life. Four of six cases
occurred in the tibial diaphysis and the other two in the
femoral shaft. This lesion appears to affect male more
often than female patients. The majority of conventional
osteosarcomas originate within the medullary cavity.
Intracortical osteosarcoma represents a medical curiosity
rather than a precursor or incipient form of conventional
osteosarcoma.
Clinical Symptoms
Pain, tenderness, and swelling over the affected bone of
less than 1 year’s duration are characteristic.
Radiographic Imaging
The radiographic findings are distinct and consist of
intracortical lucency with sclerosis of the surrounding
bone (Fig. 5-129). The outline of the defect is somewhat
 5  Osteosarcoma 343

A B

FIGURE 5-128  ■  High-grade surface osteosarcoma: radiographic and microscopic features. A, Anteroposterior plain radiograph shows
ill-defined lesion with multiple opacities attached to proximal femoral shaft. B and C, Photomicrographs of the same case show
high-grade osteoblastic osteosarcoma (B, ×200; C, ×400). (B and C, hematoxylin-eosin.)

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344 5  Osteosarcoma

A B

C D
FIGURE 5-129  ■  Intracortical osteosarcoma: radiographic and microscopic features. A, Small radiolucent defect in cortex of tibia 7
months after onset of pain in a 10-year-old girl. Because of the benign appearance of this tumor, it was at first considered to be
osteoid osteoma and the lesion was treated conservatively for several months before an en bloc resection revealed high-grade
osteosarcoma. B, Low power photomicrograph shows high-grade osteoblastic osteosarcoma. C, Low power photomicrograph shows
border between high-grade osteoblastic tumor and cortical bone. D, Permeative growth of high-grade osteoblastic osteosarcoma.
(B-D, ×100) (B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

irregular. The radiologic appearance typically simulates
a benign process that is typically 1.0 to 2.0 cm in diam-
eter. There is no evidence of intramedullary or soft tissue
involvement. Periosteal reactive changes are minimal or
absent.
Gross Findings
An intracortical, well-demarcated tumor with irregular
borders is seen within a thickened and expanded cortex.
The mass is gray to tan with a gritty consistency.
Microscopic Findings
All tumors described to date have been high-grade
osteoblastic osteosarcomas with abundant tumor bone
formation and surrounding sclerosis425-431 (Fig. 5-129).
Microscopic invasiveness is demonstrated at the borders,
with engulfed remnants of cortical bone separated by
layers of anaplastic cells. Cartilage matrix production by
tumor cells is minimal.
Differential Diagnosis
This tumor has been confused on radiographs with a
variety of benign conditions, such as stress fracture, osteoid
osteoma, osteoblastoma, intracortical abscess, fibrous dysplasia,
and nonossifying fibroma. Because of its frequent origin
in the diaphyseal cortex of the tibia, adamantinoma of
long bones is also included among the lesions considered
radiographically.
Microscopically, the obvious osteoblastic nature of the
lesion excludes all possible lesions except osteoid osteoma
and osteoblastoma. The presence of prominent nuclear
atypia and an invasive growth pattern indicates the malig-
nant nature of this lesion.
Treatment and Behavior
The clinical and follow-up data of single case reports
on intracortical osteosarcoma were summarized by
Kyriakos.427 Half of the reported patients who were
treated initially by excisional biopsy were disease-free 3
to 10 years after treatment. Patients treated by curettage,
irradiation, or both experienced recurrences locally, and
two had lethal metastases.
EXTRASKELETAL OSTEOSARCOMA
Extraskeletal osteosarcoma arising in soft tissue is
extremely rare and accounts for not more than 1% to 2%
of all soft tissue sarcomas. The detailed description of this
entity is beyond the scope of this textbook; the interested
reader is referred to textbooks on soft tissue sarcomas for
a more comprehensive description of this entity.
Definition
Extraskeletal osteosarcoma is defined as a malignant mes-
enchymal neoplasm that produces osteoid, immature
bone, and chondroid matrix. It is microscopically indis-
ERRNVPHGLFRVRUJ
5  Osteosarcoma 345
tinguishable from a conventional high-grade osteosar-
coma arising in bone.
Incidence and Location
In contrast to osteosarcomas arising in bone, extraskeletal
osteosarcoma is typically seen in patients older than
age 40 years and male or female predominance is
uncertain.438-441 Deep muscles of the thigh and the large
muscles of the pelvic and shoulder girdles as well as ret-
roperitoneum are typical sites.432-434 High-grade osteosar-
comas were also described in breast, bladder, prostate,
and virtually every other organ. It is, in general, believed
that many of these lesions represent a progression of
preexisting epithelial malignancies.443 Osteosarcoma can
also present as a progression of preexisting soft tissue
malignancies such as liposarcoma.
Radiographic Presentation
These tumors present as soft tissue masses with at least
focal cloudlike mineralization patterns. Typically, the
center of the lesion is more heavily mineralized than
the periphery. MRI discloses the heterogeneous nature
of the lesion with irregular signal enhancement pattern
and permits accurate assessment of its relationship to the
surrounding normal anatomic structures such as neuro-
vascular bundles, important for planning surgical exci-
sions (Fig. 5-130).
Gross Findings
The gross appearance of extraskeletal osteosarcoma is
similar to that of high-grade conventional osteosarcoma.
The tumors may have fleshy sarcomatoid appearance and
areas of necrosis and hemorrhage can be present. The
mineralization pattern can vary from discrete areas dis-
playing a gritty pattern to solid irregular masses of heavily
mineralized tumor bone.
Microscopic Findings
Similar to a conventional high-grade osteosarcoma of
bone, the tumor is composed of two basic microscopic
components representing sarcomatous tumor cells and
extracellular matrix, which may represent osteoid depos-
its, immature tumor bone, and cartilaginous matrix.436,437
All features described in the section on conventional
high-grade osteosarcoma arising in bone can be present
in extraskeletal osteosarcoma (Fig. 5-130). Rarely,
extraskeletal osteosarcoma may have features of well dif-
ferentiated fibroblastic osteosarcoma similar to parosteal
osteosarcoma or telangiectatic osteosarcoma.435,442
Differential Diagnosis
Differential diagnosis of extraskeletal osteosarcoma
includes myositis ossificans and reactive reparative pro-
cesses that may show metaplastic bone. Differential
diagnosis of malignant tumors include synovial sarcoma,
epithelioid sarcoma, malignant fibrous histiocytoma, liposar-
coma, and other soft tissue tumors that may contain
346 5  Osteosarcoma

A B

C D
FIGURE 5-130  ■  Soft tissue osteosarcoma. A, Fat-saturated T2-weighted coronal magnetic resonance image (MRI) showing hetero-
geneous high signal in soft tissue mass of the upper arm. Inset, T1-weighted axial MRI showing low signal intensity in a well-
circumscribed soft tissue mass of the upper arm. B, Gross photograph of coronally bisected resection specimen showing extensively
necrotic gritty well-circumscribed tumor mass in the deep muscle of the upper arm. C, Low power photomicrograph showing irregu-
lar interconnected tumor osteoid deposits and anaplastic tumor cells consistent with high-grade osteosarcoma. D, Well developed
tumor bone trabeculae and pleomorphic tumor cells of high-grade osteosarcoma. (C, ×50; D, ×100) (C-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

metaplastic bone or may show osteosarcoma as a sign of
their progression.
Treatment and Behavior
Extraskeletal osteosarcomas are highly aggressive and
most patients develop distant metastases, typically to the
lungs within 2 to 3 years after original diagnosis. The
survival rates are dismal; 5-year survival rates are within
the 20% range.
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 C H A P T E R 6 
Benign Cartilage Lesions
CHAPTER OUTLINE
ENCHONDROMA
PERIOSTEAL CHONDROMA
ENCHONDROMATOSIS
Ollier’s Disease
Maffucci’s Syndrome
Malignant Transformation in
Enchondromatosis
CHONDROBLASTOMA
Traditionally, cartilage lesions are considered to be
of neoplastic, dysplastic, hamartomatous, and reactive
origin. Reactive cartilage containing lesions are described
in Chapters 20 and 23. Enchondroma is an example of a
benign cartilage neoplasm that most frequently occurs
within the medullary cavity. It rarely presents as a bone
surface subperiosteal (juxtacortical) lesion such as a peri-
osteal chondroma. Enchondromatosis is considered to
represent a dysplastic cartilage condition rather than a
true neoplasm. It occurs in two main clinical settings:
Ollier’s disease and Maffucci’s syndrome. Although soli-
tary enchondromas and enchondromatosis in Ollier’s
disease and Maffucci’s syndrome are clinically distinct,
they share similar genetic abnormalities with frequent
mutations of IDH1 and IDH2 genes. More recent experi-
ence discloses the heterogeneous nature of enchondro-
matosis, which, in addition to Ollier’s disease and
Maffucci’s syndrome, can be separated into at least five
unique clinical syndromes with different patterns of skel-
etal involvement, genetic background, and means of
familial transmission. Chondroblastomas and chondro-
myxoid fibromas are two examples of benign cartilage
neoplasms that are characterized by immature cartilage
cells and an extracellular matrix component. Osteochon-
droma, or osteocartilaginous exostosis, is traditionally
presented as a developmental anomaly of the hamarto-
matous type. The most frequent expression is a solitary
exostosis. The less frequent form is a clinical syndrome
of multiple hereditary exostosis in which osteochondro-
mas are associated with other anomalies of skeletal mod-
eling. In view of recent identification of unique genetic
abnormalities characterized by the silencing of EXT1 and
EXT2 genes in both forms of the disease, the traditional
hamartomatous concept has to be revisited and an osteo-
chondroma is better described as a unique benign neo-
plasm recapitulating epiphyseal skeletal development.
Some of the benign cartilage lesions are precursor lesions
356
ERRNVPHGLFRVRUJ
CHONDROMYXOID FIBROMA
OSTEOCHONDROMA
Solitary Osteochondroma
(Osteocartilaginous Exostosis)
Multiple Hereditary Exostoses
Malignant Transformation in
Osteochondroma
for malignant neoplasms. Although this chapter deals
with benign cartilage lesions, secondary bone sarcomas
developing in association with some preexisting benign
cartilage lesions are also discussed.
ENCHONDROMA
Definition
Enchondroma is a common intramedullary benign neo-
plasm composed of mature cartilage. It has a limited
growth potential, and a majority of enchondromas are
small, asymptomatic lesions less than 3 cm in diameter.
Incidence and Location
Enchondroma is a frequently occurring benign tumor
that, in different series, accounts for 12% to 24% of
benign bone tumors and 3% to 10% of all bone tumors.
The age of patients varies widely, and in some series,
enchondromas are fairly evenly distributed throughout
all decades of life.5 In other series, the peak age incidence
seems to be during the third and fourth decades of life.
More than 60% of patients are age 10 to 40 years.7,10,29,30
There is no clear sex predilection, and the male-to-female
sex ratio is about 1 : 1. The small bones of the hands and
feet are the most frequent anatomic sites for enchon-
droma, and approximately 60% of cases are located in
these sites. The small bones of the hands are more fre-
quently involved than the bones of the feet (ratio approxi-
mately 7 : 1). Involvement of the long tubular bones is
next in frequency. The femur is the most frequently
involved long tubular bone and makes up approximately
17% of all cases. Enchondromas of the femur are typi-
cally located near the proximal or distal ends. Midshaft
involvement is very rare. The proximal humerus is

Wide age distribution
10 40
Incidence
10
1 2 3 4 5 6
Age in decades
FIGURE 6-1  ■  Enchondroma. Age distribution and common sites of skeletal involvement. Most common sites are indicated by large
black arrows.
involved in approximately 7% of cases. Enchondromas
occur less commonly in the bones of the forearm, tibia,
and fibula. They are very rare in the pelvis, ribs, scapulae,
and vertebrae. Moreover, in several major series of bone
tumors, there is not a single report of an enchondroma
in the craniofacial bones. In general, enchondromas are
extremely rare in the sites most commonly affected by
chondrosarcoma: the trunk bones. To the contrary, they
occur frequently in the acral skeleton, where chondrosar-
comas almost never occur. The site where significant
overlap between the skeletal distribution of enchondroma
and chondrosarcoma occurs is in the long tubular bones,
where both lesions occur with similar frequency. The
peak age incidence and most common sites of enchon-
droma are depicted in Figure 6-1.
Clinical Symptoms
Typically, enchondroma is an asymptomatic lesion inci-
dentally discovered on radiographs or radioisotope scans
performed for other reasons. In the small bones of the
hands and feet, an enchondroma can expand the bone
contour and present as a palpable mass. Pathologic
fracture can be the presenting sign of enchondroma in
phalanges, metacarpals, and metatarsal bones. Pain in
cartilage lesions often correlates with growth activity.
ERRNVPHGLFRVRUJ
6  Benign Cartilage Lesions 357
70
7 8
Therefore, if such growth cannot be explained by recent
injury, pathologic fracture, or the presence of other unre-
lated conditions, pain should raise the suspicion of
malignancy.
Radiographic Imaging
Enchondroma produces a localized, radiolucent defect
with punctate or less frequently linear calcifications (see
Figs. 6-2 to 6-5). Whether the lesion is sharply defined
or has indefinite outlines within bone depends on the
skeletal site. The degree of radiographic calcification
can vary considerably. Occasionally, there may not be a
sufficient amount of mineralization to be detected on
plain radiographs, and the lesion can be purely lytic in
appearance (see Figs. 6-6 and 6-7). In some radiolucent
lesions, computed tomographic (CT) imaging may reveal
the presence of calcifications. On magnetic resonance
imaging (MRI), calcifications appear as small signal voids.
MRI is better suited to demonstrate the noncalcified
chondroid lesions within the marrow cavity as a low-
signal–intensive area on T1-weighted images and a high-
signal–intensive area on T2-weighted images (see Figs.
6-2 to 6-5). In the major long bones, the cortex and bone
contour are usually not altered, and there is no periosteal
Text continued on p. 364
358 6  Benign Cartilage Lesions

A B C D

E G

FIGURE 6-2  ■  Enchondroma: radiographic features. A, Anteroposterior (AP) radiograph of distal femur with heavily calcified intra-
medullary tumor occupying the diaphysis. B, AP radiograph of proximal femur with calcified intramedullary tumor occupying
diaphysis and metaphyseal area. C, Lateral radiograph of distal tibia showing calcified intramedullary lesion involving the metaphy-
sis. D, AP radiograph of proximal humerus with calcified lesion of humeral head and neck. E, AP radiograph of distal femur showing
intramedullary lesion with patchy calcifications. F, Fat-saturated T2-weighted axial magnetic resonance image (MRI) showing irregu-
lar signal enhancement within a well delineated intramedullary lesion. G, Fat-saturated T2-weighted axial MRI with contrast showing
mild irregular signal enhancement within a well delineated intramedullary lesion.

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 6  Benign Cartilage Lesions 359

A B

C D

E F

FIGURE 6-3  ■  Enchondroma: radiographic features. A and B, Anteroposterior and lateral radiographs of proximal humerus showing
a calcified intramedullary lesion extending to the intercondylar eminence. C, Reformatted coronal computed tomogram (CT) shows
patchy signal intensity of intramedullary lesion. D, Fat-saturated T2-weighted sagittal magnetic resonance image (MRI) showing
patchy signal enhancement of the intramedullary lesion. E, Fat-saturated T1-weighted axial MRI with contrast showing patchy
enhancements of signal intensity. F, Axial CT showing intramedullary lesion with linear and patchy signal.

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A B

C E

FIGURE 6-4  ■  Enchondroma: radiographic features. A and B, Anteroposterior and lateral radiographs of distal femur showing calcified
intramedullary lesion involving distal femoral metaphysis. C, T1-weighted coronal magnetic resonance image (MRI) showing well
demarcated intramedullary lesion of low signal intensity involving the distal femoral diaphysis. Note lobulated well demarcated
borders of the lesion. D, T1-weighted axial MRI showing low signal intensity in the intramedullary lesion. The outline of the lesion
shows lobulated architecture with well demarcated satellite nodules at the periphery. E, Fat-saturated T1-weighted axial MRI with
contrast shows mild signal enhancement and discloses lobular/nodular architecture of the lesion.

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 6  Benign Cartilage Lesions 361

A B C D

E F G H
FIGURE 6-5  ■  Enchondroma: radiographic features. A and B, Anteroposterior (AP) and lateral radiographs of proximal tibia show
intramedullary calcifications involving the diaphysis. C, Fat-saturated T2-weighted coronal magnetic resonance image (MRI) of lesion
shown in A and B showing patchy signal enhancement within extensive medullary lesion. D, T1-weighted coronal MRI showing
intramedullary lesion of low signal intensity. Note well delineated lesion with scalloped outline. E and F, AP and lateral view of
distal femur showing extensive intramedullary lesions with punctate calcification. G and H, AP and oblique views of proximal
humerus showing extensive intramedullary lesion involving humeral neck and metaphyseal/diaphyseal area.

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A B

C D E

FIGURE 6-6  ■  Enchondroma of short tubular bones: radiographic features. A, Expanded lucent area at distal metaphyseal area of
index metacarpal bone in adult (arrow). B, Base of third proximal phalanx shows well-circumscribed expanded lesion with punctate
matrix calcification (arrow). C and D, Plain radiographs of expanded lucencies in middle phalanges of fingers in two patients who
sustained pathologic fractures through thin cortical shells of bone around enchondromas. E, Pathologic fracture through enchon-
droma in fifth metatarsal shaft.

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 6  Benign Cartilage Lesions 363

A B C

F G
FIGURE 6-7  ■  Enchondroma of short tubular bones: radiographic features. A and B, Anteroposterior and lateral radiographs showing
a mildly calcified and expansile lesion of the index proximal phalanx. C, T2-weighted sagittal magnetic resonance image (MRI)
showing a lesion of the index proximal phalanx involving almost the entire medullary cavity. Note the expanded contour of bone
with thin but intact overlying cortex. D, E, and F, Axial fat-saturated T2-weighted MRI, T1-weighted MRI, and fat-saturated T1-weighted
MRI with contrast showing various degrees of signal intensity in the intramedullary lesion involving the proximal index phalanx.
Note a characteristic lacunar pattern of signal enhancement and the void in MRI shown in F. G, Expanded radiolucent lesion involv-
ing the base of the metacarpal bone of thumb.

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364 6  Benign Cartilage Lesions
new bone formation (see Figs. 6-2 to 6-6). Enchondro-
mas that fill the medullary cavity of short tubular bones
may show some cortical thinning (see Figs. 6-6 and 6-7).
The contour of the small bones is typically expanded
along with cortical thinning. Radiographic evidence of
true extension into soft tissue with a completely disrupted
cortex, as well as the presence of reactive periosteal new
bone formation, should be regarded as indicators of malig-
nancy. In rare cases, eccentric expansion of one cortex
can produce the picture of enchondroma protuberans
(Fig. 6-8).4,5,8 In the small tubular bones, the lesion is
usually diaphyseal, but epiphyseal extension is also fre-
quently present. In the long tubular bones, enchondro-
mas are most frequently located in the metaphysis. A
midshaft or epiphyseal localization is extremely uncom-
mon (see Figs. 6-6 and 6-7).22 In the long bones, enchon-
dromas typically do not show distinct outlines on plain
radiographs as they tend to do in short tubular bones. On
the other hand, MRIs demonstrate their sharply defined,
often lobulated borders (see Figs. 6-2 to 6-5).
Gross Findings
Although curettage specimen material is the rule, in the
occasionally received intact resection specimen the car-
tilaginous nature of the lesion is easy to recognize on
gross examination (Figs. 6-9 and 6-10). Enchondroma is
composed of confluent lobules of cartilage. The lobules
vary in size from less than 1 mm through several milli-
meters to more than 1 cm. The periphery of the lesion is
often somewhat irregular because the individual lobules
can bulge into the adjacent marrow spaces or separate
satellite foci can be present. Occasionally enchondroma
can grow in the form of sparsely separated small cartilage
nodules. Calcifications, ossifications, or both are respon-
sible for foci of ivory-white, and they may accentuate the
overall lobular architecture of the lesion when they are
concentrated on the periphery of cartilage islands.
Microscopic Findings
Enchondromas are composed of mature cartilage that
has lobular architecture (Figs. 6-11 and 6-12).7,10,26 The
individual lobules can be separated by normal bone
marrow spaces with hematopoietic elements (Fig. 6-12).
More frequently, the individual lobules are incompletely
separated by thin fibrovascular septa.7,10,29,30 Individual
lobules of cartilage are often partially encased by
mature lamellar bone. This feature is well preserved in
incidentally resected enchondromas (see Figs. 6-11 and
6-12), but can also be observed in curettage specimens
(Fig. 6-13). Lobules of cartilage, especially at the periph-
ery of the lesion, can be sparsely separated and may
appear as satellite nodules. In rare instances, lobules of
cartilage can grow around the lamellar medullary bone
(Fig. 6-12). Such a growth pattern should not be confused
with the aggressive infiltration of the medullary cavity
frequently seen in chondrosarcoma. The overall cellular-
ity is very low, and in general, enchondromas appear very
bland and have relatively few chondrocytes more or less
evenly distributed within the hyaline cartilage matrix (see
Figs. 6-14 and 6-15). More frequently, the cells form
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loosely arranged clusters, at least focally (Fig. 6-16). The
individual chondrocytes are small, lie in lacunar spaces,
and have small, dark nuclei (see Figs. 6-14 and 6-16). In
general, the chondrocytes of enchondromas are similar
to those seen in normal hyaline cartilage. Occasional
binucleated cells and cells with so-called open nuclear
chromatin can be present. The presence of more than
one chondrocyte in a lacuna should not be considered an
ominous finding and is not equated with binucleation or
multinucleation of cartilage cells. The chondroid matrix
is typically of hyaline type. Foci of fine or coarse calcifica-
tions and even of enchondral ossification can be present.
Prominent myxoid change should not be present in
enchondroma. If present, even when the cellularity is low,
it usually suggests malignancy. One exception to this is
in the small bones of the hands and feet, which may show
prominent foci of myxoid change. In addition, enchon-
dromas of the acral skeleton may show focal areas of
hypercellularity with open chromatin architecture (Fig.
6-17). Such features would be considered a sign of malig-
nancy in cartilage lesions of the major tubular bones but
are within the spectrum of changes observed in enchon-
dromas of the acral skeleton when combined with nonag-
gressive radiographic features. However, even at these
skeletal sites, the change should be focal and the overall
matrix should be hyaline. The lesion is usually clearly
demarcated from the surrounding bone, and the periph-
ery of cartilage lobules often shows encasement by a rim
of lamellar bone (Fig. 6-13). In addition, especially in the
short tubular bones, mild focal scalloping of the inner
cortical surface can be present.
Special Techniques
Special techniques are of little or no help in the diagnosis
of enchondroma. Ultrastructurally, the cartilage cells
have irregular cell surfaces and centrally located nuclei
with condensed chromatin and a convoluted nuclear
envelope (Fig. 6-18).
Similar to other cartilage lesions, in enchondroma, a
thickening of the inner nuclear membrane is present.
Immunohistochemically, the cells of enchondroma are
positive for S-100 protein and vimentin. Enchondromas
express cartilage lineage differentiation markers and
invariably show nuclear positivity for SOX9 protein.
SOX9 protein is also positive on all other tumors, benign
or malignant, that express cartilage lineage differentia-
tion. The cartilaginous nature of enchondroma is clearly
evident on conventional hematoxylin-eosin sections, and
special techniques are practically never required to
support the diagnosis. Special techniques are also of no
help in differentiating an enchondroma from a low-grade
chondrosarcoma.
Image analysis and DNA flow cytometry show a
diploid DNA histogram pattern with low proliferation
rate.1,3,13,15 Cytogenetic studies detect diploid or near-
diploid chromosomal complement with structural aber-
rations and translocations most often involving
chromosomes 6, 12, and 24.12,28 Occasionally enchondro-
mas may exhibit complex translocations involving several
chromosomes such as 12, 15, and 21.12,24,28 Interestingly,
Text continued on p. 376
 6  Benign Cartilage Lesions 365

A C

D E

FIGURE 6-8  ■  Enchondroma of proximal humerus: radiographic features. A, Anteroposterior (AP) radiograph of proximal humerus
showing patchy and punctate calcifications within the lesion involving femoral head and neck and extending to humeral metaphysis.
B, T1-weighted axial magnetic resonance image (MRI) showing intramedullary lesion of low signal intensity with overall lobular/
nodular architecture. C, Fat-saturated T2-weighted axial MRI showing irregular signal enhancement within the intramedullary lesion.
D and E, AP radiograph and fat-saturated T2-weighted coronal MRI of an eccentric intramedullary cartilage tumor that causes medial
cortex of shaft of fibula to bulge consistent with enchondroma protuberans.

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366 6  Benign Cartilage Lesions

D E
FIGURE 6-9  ■  Enchondroma: radiographic and gross features. A, Anteroposterior radiograph shows calcified intramedullary tumor
with ill-defined borders in metaphyseal area. Note absence of any cortical abnormality. B, Axial computed tomogram of enchon-
droma of proximal humerus shows discrete, punctate intramedullary calcifications. C, Gross photograph of enchondroma in
metaphysis of proximal humerus discovered incidentally in chest radiograph. Note sharply circumscribed lobulated hyaline cartilage.
D and E, Low power and whole-mount photomicrographs showing nodular architecture of enchondroma. (D and E, ×10 and ×4,
respectively) (D and E, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 367

A B

C D
FIGURE 6-10  ■  Enchondroma: gross features. A, Enchondroma of fibular head. Note lobular hyaline cartilage tumor occupying medul-
lary cavity. B, Proximal fibular enchondroma producing expansile contour of diaphysis designated as enchondroma protuberans
(same case as shown in Fig. 6-11). C, Coronal section of humeral head shows intramedullary enchondroma with confluent lobules
of hyaline cartilage. D, Specimen radiograph of humerus shown in C with prominent matrix calcification in cartilage lobules.

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368 6  Benign Cartilage Lesions

B C
FIGURE 6-11  ■  Enchondroma: microscopic features. A-C, Low power photomicrographs showing lobular/nodular architecture of
enchondroma. Note well delineated cartilage lobules. Some of the cartilage lobules are outlined by medullary bony trabeculae
forming narrow shells of bone partially encasing tumor lobules (A and B, ×10; C, ×20). (A-C, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 369

A B

C D
FIGURE 6-12  ■  Enchondroma: microscopic features. A-D, Low power photomicrographs showing lobular/nodular architecture of
enchondroma, which grows in the form of well demarcated sparse lobular/nodular structures. Some nodules (shown in A and B)
grow around intramedullary bony trabeculae. The presence of bony trabeculae within the well demarcated nodules of enchondroma
should not be confused with an aggressive infiltrating growth pattern diagnostic of chondrosarcoma (A, C, and D, ×10; B, ×20).
(A-D, hematoxylin-eosin.)

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370 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-13  ■  Enchondroma: microscopic features. A-D, Medium power photomicrographs of lobules of hyaline cartilage in a speci-
men obtained by curettage. Note that the lobular/nodular architecture of the lesion with narrow shells of bone partially encasing
tumor lobules can be reconstructed in curettage specimens (A-D, ×40). (A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 371

C D
FIGURE 6-14  ■  Enchondroma: microscopic features. A-D, Low power photomicrographs show low cellularity and small uniform nuclei
of chondrocytes residing in lacunar spaces. Inset, Microscopic details of chondrocytes showing uniform nuclei with condensed
chromatin (A-D, ×100; inset, ×400). (A-D and inset, hematoxylin-eosin.)

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372 6  Benign Cartilage Lesions

A B

C D

FIGURE 6-15  ■  Enchondroma: microscopic features. A-D, Low power photomicrographs of enchondroma show low to intermediate
cellularity and small chondrocytes residing in lacunar spaces with uniform nuclei (A-D, ×100) (A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 373

A B

FIGURE 6-16  ■  Enchondroma: microscopic features. A and B, Low and intermediate power photomicrographs of enchondroma
showing clustering pattern of chondrocytes residing in lacunar spaces without nuclear pleomorphism or size variation. C and
D, Low and intermediate power photomicrographs show low cellularity and uniform nuclei of chondrocytes. Insets, Higher magni-
fication documenting nuclear and cytoplasmic details of chondrocytes residing in lacunar spaces. Note and example of a double
nucleated chondrocyte in D. (A, C, and D, ×100; B, ×200; insets, ×400.) (A-D and insets, hematoxylin-eosin.)

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374 6  Benign Cartilage Lesions

A B

C D

FIGURE 6-17  ■  Enchondroma: microscopic features. A-D, Low and medium photomicrographs show increased cellularity and cluster-
ing of chondrocytes. Note the enlarged nuclei with open chromatin architecture without nuclear pleomorphism and cell size variation.
The levels of cellularity with the enlargement of nuclei are worrisome features and should be correlated carefully with radiographic
presentation. In this particular instance, the lesion was accepted as an enchondroma because it involved a finger and there was no
radiographic feature of an aggressive growth pattern. Such features in a cartilage lesion involving long tubular bones that was clini-
cally symptomatic (pain) and showed an aggressive growth pattern documented radiographically would be diagnostic of a low-grade
chondrosarcoma. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 375

B
FIGURE 6-18  ■  Enchondroma: ultrastructural features. A, Chondrocyte with multiple cytoplasmic processes and markedly indented
nuclear contour corresponding to dense homogeneous nuclear appearance in light microscopy (×3500). B, Higher magnification of
enchondroma in A. Note rough endoplasmic reticulum adjacent to highly indented nuclear membrane (×12,000).

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376 6  Benign Cartilage Lesions
chromosomal aberrations involving 6q13-21 have been
associated with locally aggressive behavior of several
benign cartilage lesions, including enchondroma.25
Recent identification of isocitrate dehydrogenases 1 and
2 (IDH1 and IDH2) gene mutations mapping to the long
arms of chromosomes 2 and 15, respectively, in solitary
enchondromas, chondrosarcomas, and multiple enchon-
dromas of Ollier’s disease and Maffucci’s syndrome
provide interesting clues concerning the biology of car-
tilage neoplasia. Approximately 40% of solitary enchon-
dromas show mutations of IDH1 or IDH2, whereas
nearly 80% of multiple enchondromas and hemangiomas
associated with Ollier’s disease and Maffucci’s syndrome
show mutations of those genes, suggesting an important
and possible driver role of these mutations in the devel-
opment of cartilage neoplasia. Surprisingly, the same
genes are frequently mutated in gliomas of the central
nervous system and acute myeloid leukemia and less fre-
quently in some other solid tumors. More detailed
descriptions of the role of the IDH1 and IDH2 genes in
the biology of cartilage neoplasia is provided in the
section on enchondromatosis below.
Differential Diagnosis
Enchondromas must be distinguished from low-grade
chondrosarcomas, particularly when they involve the
metaphyses of long bones in middle-aged to elderly
patients. The distinction can usually be made on the basis
of absence of pain, no disturbance of the architecture of
the surrounding cancellous bone or adjacent cortex, and
a lack of cytologic atypia.7,10,11,29,30 The nuclei of cartilage
cells in an enchondroma are small and uniform, and a
homogeneous chromatin pattern is present.9,19 Multinu-
cleated chondrocytes are infrequent, and the chondroid
matrix is well formed, without prominent myxoid
features.9,19
Chondroid differentiation in fibrous dysplasia can be
distinguished from large solitary enchondromas on
radiographs by the more diaphyseal localization and
ground-glass appearance of the fibroosseous areas. The
presence of fibroosseous elements in the sections adjacent
to cartilaginous nodules is diagnostic for fibrocartilagi-
nous dysplasia.
Enchondroma in Different Anatomic Sites
Enchondromas have a very characteristic anatomic dis-
tribution that differs significantly from that of chondro-
sarcoma. For that reason, the specific anatomic location
of the lesion and its radiographic features are important
and often decisive elements of the differential diagno-
sis.7,10,29,30 Therefore we provide separate descriptions of
enchondroma with some principles of differential diag-
nosis in various anatomic sites.
Enchondroma of the Small Bones of the Hands and
Feet.  As previously stated, the small bones of the hands
and the feet are the most frequent anatomic sites for
enchondroma, with approximately 60% of all cases
located in these sites.2,7,10,11,29,27,30 The hands are more
frequently involved than are the feet.
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Enchondromas of the short tubular bones are typically
diaphyseal lesions that sometimes involve the bone
ends.14,21 They regularly produce endosteal scalloping
and expand the bone contour (see Figs. 6-6 and 6-7). In
the bones of the acral skeleton, these radiographic find-
ings are not considered to be indicative of malignancy.
Moreover, enchondromas in these sites are typically more
cellular than enchondromas of other parts of the skele-
ton, and they may exhibit some nuclear atypia. The car-
tilage matrix is typically hyaline, but foci of myxoid
change can be present in acral enchondromas. Regardless
of the site, lesions that are exclusively myxoid, even if
they have low cellularity, are suspicious for malignancy.
In general, in the small bones of the hands and feet, a
cartilage lesion can show features of endosteal scalloping,
bone expansion, and increased cellularity and still behave
as a benign enchondroma.2,7,10,15 If the same features are
present in other anatomic sites, such as long tubular and
flat bones, they should be considered suggestive of a low-
grade malignant cartilage lesion. Typically small bone
enchondromas are made clinically manifest by pain
related to small infractions of the thinned cortex or com-
plete pathologic fracture with displacement (see Fig. 6-6).
Enchondroma of Long Tubular Bones.  Enchondro-
mas of the long tubular bones account for approximately
45% of cases.7,26,30 The femur and humerus are the most
frequently involved long bones. The proximal metaphysis
and shaft of the humerus and distal metaphysis of the
femur are the most frequently involved sites (see Figs.
6-2 to 6-5). Enchondromas located in the midshaft are
rare. Enchondromas are also considerably less common
in the fibula and bones of the forearm.
Enchondromas of the long tubular bones present dif-
ferential diagnostic problems with low-grade chondro-
sarcomas, which also occur in this part of the skeleton
with comparable frequency. They may be microscopically
indistinguishable from low-grade chondrosarcomas. The
following are benign features of a solitary intramedullary
cartilage lesion of the long bones. Such lesions are typi-
cally asymptomatic and are incidentally discovered on
radiographic images or isotope scans performed for other
reasons. They are small and usually measure less than
3 cm. The adjacent bone and the overlying cortex are
normal. Microscopically, the cellularity is low, the chon-
drocytes have small dark nuclei, the matrix is hyaline, and
the lesion is well demarcated (i.e., the islands of cartilage
are bordered by bone trabeculae and there is no evidence
of invasion of the haversian canals of the cortex). Any
deviation from this pattern should be considered suspi-
cious for malignancy.
Enchondroma of Trunk Bones.  Enchondromas of the
pelvis, spine, ribs, and sternum are very rare. Any carti-
lage lesion in these sites that is not reactive or metaplastic
in nature and belongs in the neoplastic cartilage category
should be considered potentially clinically aggressive.
This is especially true for lesions that measure more than
3 cm in diameter. Rare cases of enchondromas reported
at these sites should be diagnosed after complete excision
and thorough evaluation of their clinical, radiographic,
and pathologic features. They represent well-demarcated

lesions (less than 3 cm in diameter) that uniformly have
low cellularity, exhibit no nuclear atypia, and produce
mature hyaline matrix. Any—even minimal—deviation
from this pattern should suggest a clinically aggressive
lesion (low-grade chondrosarcoma). Cartilaginous tumors
of the jaws, facial bones, and base of the skull should be
approached with particular circumspection. No major
series has reported enchondromas arising in the cranio-
facial bones.
Treatment and Behavior
Enchondromas of long bones that are small and asymp-
tomatic require no treatment. The patient is advised to
report the onset of symptoms, particularly any pain in the
affected area, and is followed by serial radiographs and
clinical evaluation. Lesions that are borderline in size,
symptomatic, or predominantly lytic or that appear
otherwise suspicious in nature should be curetted and
evaluated under the microscope. It is important to evalu-
ate the entire lesion. Limited sampling may not reveal
the focal features indicative of malignancy. Enchondro-
mas of the small tubular bones are frequently treated with
curettage and bone grafting, especially if they expand the
bone contour or disturb the function of the affected site
in any way.16,18,20 The approach to biopsy of suspected
cartilaginous lesions of the trunk bones should take into
account the fact that most of them are clinically aggres-
sive. In fact, lesions that involve the ribs, sternum, scapula,
or pelvis are best treated by wide local excision on the
basis of clinical and radiographic evidence and should be
subjected to careful pathologic evaluation. This reduces
the likelihood of local tissue contamination and thereby
decreases the risk of local recurrence if the lesion proves
to be low-grade chondrosarcoma. Enchondromas typi-
cally heal with consolidation after curettage and bone
grafting. Recurrence of enchondroma suggests malig-
nancy, especially in lesions that affect the long bones.23
Nevertheless, an incompletely curetted enchondroma,
especially in the short tubular bones, can occasionally
recur and can be successfully treated by a second curet-
tage.9,17,19,20,22,26 Rare and somewhat questionable exam-
ples of enchondroma progressing to a chondrosarcoma
have been described.6,17
Personal Comments
In the assessment of cartilaginous lesions of bone in
general and of enchondromas in particular, it is essential
that an orderly and stepwise procedure be followed. The
age of the patient and the anatomic site of the lesion
should first be considered in addition to the presence or
absence of clinical symptoms. The presence of pain
is extremely important and may be the only indicator
of malignancy. Other causes of pain should be ruled
out before factoring this finding into the equation. Patho-
logic fractures in short tubular bones containing enchon-
dromas are very common and do not suggest unusual
aggressiveness.
Next, radiographs should be examined to determine
the precise anatomic site, the size of the lesion, the pres-
ence of matrix calcification, the character of the lesion’s
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6  Benign Cartilage Lesions 377
borders, the presence or absence of endosteal scalloping
or thickening of the adjacent cortex, the involvement of
any associated periosteal bone, and possible extension
of the tumor to the surrounding soft tissue. Evidence of
multiple lesions or characteristic features of a cartilage
dysplasia, such as Ollier’s disease, should be sought. Only
after these factors have been considered should the his-
tologic features be studied and a diagnostic conclusion
reached in the context of all available clinical and radio-
graphic data. Omission of any of these steps or taking
“shortcuts” to the diagnosis of a cartilage tumor is fraught
with danger. Serious errors have been made in overdiag-
nosis of incidentally discovered enchondromas, as well as
underestimation of medullary cartilage tumors, which, in
retrospect, showed indisputable radiologic features of
aggressiveness.
Central cartilage tumors of acral parts of the skeleton
are almost invariably benign but may become malignant
if they are part of the picture of dyschondroplasia (Ollier’s
disease). Central cartilage tumors of the ribs, sternum,
and pelvis are unlikely to be benign, particularly if they
exceed 4 cm in size.
PERIOSTEAL CHONDROMA
Definition
Periosteal chondroma is a benign cartilage neoplasm that
develops on the surface of bone under the periosteum.42
It is also referred to as juxtacortical chondroma.38,46
Incidence and Location
Periosteal chondromas are rare lesions and account for
less than 1% of all chondromas.32,41 The majority of cases
are diagnosed during the second and third decades of
life. The limited experience with these lesions indicates
that male patients are probably more frequently affected
than are female patients. Periosteal chondromas typically
affect the long tubular bones of the extremities.32,40,43,44,50
The proximal humerus is the single most frequently
affected site; nearly 50% of cases are diagnosed at this
site. The acral skeleton with the involvement of the short
tubular bones of the hands is the second most frequently
affected site. Rare examples of periosteal chondroma
have been described in the spine, clavicle, ribs, and
toes.31,35-37,39,49,52,53 The peak age incidence and most com-
monly affected skeletal sites are shown in Figure 6-19.
Clinical Symptoms
This surface lesion most often presents as a palpable
mass. Because periosteal chondromas are frequently
found near tendon insertion sites and disturb their func-
tion, pain and local discomfort on activity can be initial
symptoms. Periosteal chondromas are sometimes discov-
ered incidentally on radiographs.
Radiographic Imaging
Periosteal chondroma presents as a well-circumscribed
surface lesion of bone with punctate calcifications on
378 6  Benign Cartilage Lesions
Peak
incidence
10 30
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 6-19  ■  Periosteal chondroma. Peak age incidence and most common anatomic sites of involvement. Most common site is
indicated by a large black arrow.
radiographs33,34 (see Figs. 6-20 to 6-22). The degree
of matrix mineralization can vary from purely lytic to
heavily calcified (see Figs. 6-20 to 6-22). In a typical
case, the cartilaginous nature of juxtacortical chon-
droma is easy to recognize on plain radiographs. The
cortex beneath the lesion is usually eroded, with elevated
edges forming a craterlike excavation (see Figs. 6-20 to
6-22). The presence of an elevated periosteum overlying
the lesion is best documented on MRI (see Figs. 6-20
and 6-22). It can sometimes be clearly seen on plain
radiographs or CT (Fig. 6-21). The affected area may
also show minimal evidence of a zone of subcortical scle-
rosis beneath the lesion. Although the cortex underly-
ing the lesion is excavated, there is no complete cortical
disruption, and the lesion is clearly demarcated from
the medullary cavity by a continuous rim of cortical
bone (see Figs. 6-20 to 6-22). CT or MRI may be
needed to evaluate the extent of involvement and the
relationship between the lesion and adjacent structures.51
The elevated periosteum surrounding the lesion is
represented on plain radiographs by solid buttresses of
mature subperiosteal bone that can sometimes slightly
overhang the edges of the central excavation. This
appearance is quite characteristic for smaller periosteal
chondromas.
ERRNVPHGLFRVRUJ
7 8
Gross Findings
On gross examination, periosteal chondroma is a lobu-
lated cartilaginous mass covered by fibrous tissue that
represents an elevated periosteum (see Figs. 6-21 and
6-23). Calcifications can often be seen within the lobules.
The cortex beneath is eroded and usually smoothly exca-
vated, but sometimes it has a scalloped border. The lesion
is clearly separated from the medullary cavity by a rim of
sclerotic cortical bone. The size of periosteal chondromas
varies from less than 1 cm to 5 cm.
Microscopic Findings
Microscopic features are those typical of a chondroma
with a hyaline cartilage matrix (see Figs. 6-22 to 6-24).
On average, juxtacortical chondromas are more cellular
than are enchondromas of long bones and can show mild
nuclear atypia or binucleated chondrocytes. Scalloping
and erosion of the outer cortex are seen microscopically.
A sectioning artifact may give the impression of small
satellite cartilaginous foci of cellular cartilage in the scle-
rotic border (see Figs. 6-25 and 6-26). This does not
indicate invasiveness. Some periosteal chondromas may
Text continued on p. 386
 6  Benign Cartilage Lesions 379

A B

C D

FIGURE 6-20  ■  Periosteal chondroma: radiographic features. A and B, Lateral and oblique plain radiographs of unusually large peri-
osteal chondroma of proximal humerus in young man. Note sharply defined borders and intralesional matrix calcification. C and
D, Fat-saturated T1-weighted and T2-weighted sagittal magnetic resonance images (MRI) of a large femoral periosteal chondroma
in a 13-year-old boy. Inset, T1-weighted axial MRI with contrast of lesion shown in C and D. Cortex beneath lesion is thinned but
intact.

ERRNVPHGLFRVRUJ
380 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-21  ■  Periosteal chondroma: radiographic and gross features. A, Plain radiograph shows concave cortical erosion near
insertion of biceps muscle on lateral aspect of humeral shaft. B, Computed tomogram of lesion shown in A. External aspect of cortex
is eroded with solid periosteal bone buttressing. C, Specimen radiograph of lesion shown in A and B. Note sharply defined borders
of cortical erosion and intact cortex beneath lesion. D, Gross photograph of periosteal chondroma of humerus shows chondroid
tumor beneath periosteum, eroding underlying cortex. Medullary cavity is not involved.

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 381

A B

C D

FIGURE 6-22  ■  Periosteal chondroma: radiographic and microscopic features. A, T1-weighted sagittal magnetic resonance image
shows periosteal lesion growing on the popliteal surface of the femur. The lesion is covered by elevated periosteum and the under-
lying cortex is eroded but the medullary cavity is not involved. B, Whole-mount photomicrograph showing a fibrous capsule cor-
responding to elevated periosteum covering the surface of the lesion and the partially eroded cortical bone beneath the lesion.
C and D, Low power photomicrographs showing increased cellularity and clustered growth pattern of chondrocytes (C and D, ×50).
(B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
382 6  Benign Cartilage Lesions

A B

C D

FIGURE 6-23  ■  Periosteal chondroma: gross and microscopic features. A, Gross photograph of periosteal chondroma shows chon-
droid tumor beneath periosteum eroding underlying cortex. B, Composite whole-mount photomicrograph of periosteal chondroma
showing a cap-shaped lesion growing beneath the periosteum and eroding the underlying cortex. C and D, Low power photomi-
crographs showing base of periosteal chondroma with interface between lesion and underlying cortex. Note scalloping of underlying
cortical bone, but there is in general a sharp demarcation between periosteal chondroma and cortex with no feature of infiltrative
aggressive growth pattern (C and D, ×40). (B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 383

A B

C D

FIGURE 6-24  ■  Periosteal chondroma: microscopic features. A and B, Low power photomicrographs of the lateral aspect of periosteal
chondroma showing elevations of periosteum and erosion of the underlying cortex. C and D, Low power photomicrographs of the
base of periosteal chondroma showing erosion of underlying cortex. Note that the underlying cortex is thin but there is a sharp
demarcation between the lesion and the underlying cortical bone. (A and C, ×20; B and D, ×40.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
384 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-25  ■  Periosteal chondroma: microscopic features. A-D, Low power photomicrographs showing satellite nodules in perios-
teal chondromas. The satellite nodules are typically present in the superficial and lateral aspects of the lesion. Occasionally they
can be present at the base of the periosteal chondroma. The presence of satellite nodules typically represent tangentially cut
marginal irregularities and should not be considered as signs of aggressive invasive growth. (A, B, and D, ×20; C, ×60.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 385

B
FIGURE 6-26  ■  Periosteal chondroma: microscopic features. A, Lobulated cartilaginous tumor bordered by extensive subperiosteal
lamellar bone. Apparent satellite nodules at periphery (arrows) represent tangentially cut marginal irregularities. B, Nodular marginal
extension of periosteal chondroma with central calcification and endochondral ossification. Inset, High cellularity and mild atypia
of chondrocytes (A, ×20; B, ×60; inset, ×200). (A, B, and inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
386 6  Benign Cartilage Lesions
bulge for a short distance into the underlying medullary
cavity, but there is always a border of intervening lamellar
bone.
Special Techniques
Similar to enchondromas, periosteal chondromas ex-
presses a full roster of markers characteristic of cartilage
lineage differentiation. In such a sense, these lesions are
immunohistochemically indistinguishable from ordinary
enchondromas. Like enchondroma, periosteal chondro-
mas harbor mutations of IDH1 and IDH2 genes. Several
distinct clonal chromosomal abnormalities have been
described in periosteal chondromas; they include rear-
rangements of 2q37, 4q21-25, 11q13-15, and 12q13.
Differential Diagnosis
Juxtacortical chondrosarcoma can usually be distinguished
with ease by the large size of the lesion (>5 cm) and the
absence of radiologic evidence of solid periosteal new
bone buttressing at the margins. The latter is a charac-
teristic feature of periosteal chondroma. Microscopically,
the degree of cellularity, variation in size and shape of
nuclei, and frequent multinucleate chondrocytes are the
basis for differentiating these two tumors. Juxtacortical
chondrosarcomas are also more likely to show irregular
invasion of surrounding soft tissue and lack the limiting
periosteal shell that is present in periosteal chondromas.
Periosteal osteosarcoma, a predominantly cartilaginous form
of surface osteosarcoma, can be recognized by the feath-
ery perpendicular calcific striae seen on radiographs.
Although Codman’s triangles may be seen at the limits
of this tumor, periosteal osteosarcoma usually lacks the
solid buttresses seen in periosteal chondroma. Periosteal
osteosarcoma is diagnosed from the presence of sheets of
primitive mesenchymal cells between the cartilage lobules,
with tumor osteoid and bone deposition between the cells.
Treatment and Behavior
Because periosteal chondromas may demonstrate radio-
logic overlap with juxtacortical chondrosarcoma, the
preferable mode of treatment is wide local excision that
includes the underlying cortex.47 Earlier reports on fre-
quent local recurrences after curettage of juxtacortical
chondroma are controversial because some of these
lesions might have been surface chondrosarcomas.48 In
selected skeletal sites such as the ribs and fibula, segmen-
tal resection is the preferable mode of treatment. In
other sites, en bloc excision is preferred over curettage.
The latter may be followed by recurrence and require
reoperation. Complete local excision of juxtacortical
chondroma is a curative procedure. In some instances
periosteal chondroma may cause growth disturbance of
the affected bone. In such cases the presence of the lesion
is associated with shortening of the bone.50
ENCHONDROMATOSIS
Enchondromatosis, also called dyschondroplasia and mul-
tiple enchondromas, occurs in two clinical settings, referred
ERRNVPHGLFRVRUJ
to as Ollier’s disease and Maffucci’s syndrome, and should
not be regarded simply as multifocal enchondromas of
bone (i.e., as multifocal benign cartilage neoplasms).
Enchondromatosis represents a pathogenetically distinct
developmental disorder of enchondral ossification that is
probably more accurately described as cartilage dysplasia.
The term dyschondroplasia was introduced by Ollier in his
description of the entity in 1900.66 Maffucci’s syndrome,
in which multifocal skeletal cartilage lesions coexist with
extraskeletal hemangiomas of skin, soft tissue, and viscera,
was described 19 years earlier in 1881.63
More recent experience indicates that enchondro-
matosis is more heterogeneous than originally thought.
In addition to the two main forms of enchondroma-
tosis referred to as Ollier’s disease and Maffucci’s
syndrome, which are somatic noninheritable disorders,
there are at least five additional forms of enchondroma-
tosis, referred to as metachondromatosis, genochondromato-
sis, spondyloenchondrodysplasia, dysspondyloenchondromatosis,
and cheirospondyloenchondromatosis.52-62,64,65,67-70,95 They are
characterized by distinct patterns of transmission (auto-
somal dominant vs. recessive), clinical presentations, and
radiographic presentations, as well as unique genetic
backgrounds known for some of the disorders. Moreover,
they are associated with dissimilar risks for secondary
chondrosarcoma. Detailed description of these syndromes
is beyond the scope of this textbook, but their main
differentiating features are summarized in Table 6-1
(Figs. 6-27 and 6-28).
Ollier’s Disease
Definition
Ollier’s disease is a rare, nonhereditary skeletal disorder
characterized by a multifocal intramedullary proliferation
of hypercellular dysplastic cartilage. The lesions have a
tendency to be metaphyseal and are sometimes eccentri-
cally placed, with predominant unilateral involvement of
the appendicular skeleton. The clinical manifestations
typically appear during childhood, and the extent of skel-
etal involvement is variable.
Incidence and Location
As stated, Ollier’s disease is rare, and its true incidence is
unknown. The largest series reported from the Rizzoli
Institute consisted of 51 cases of multiple en­chondromas
presumably representing enchondromatosis compared
with 334 solitary enchondromas encountered in the same
period.77 There is no clear sex difference in incidence.
The extent of involvement of the skeleton varies
widely from case to case.77,82,86 At one end of the spectrum
are the cases in which there is limited involvement of one
bone or only a few short tubular bones. On the other end
of the spectrum are the cases with massive involvement
of multiple bones and severe deformities. The most fre-
quent presentation is a tumor affecting one extremity,
but bilateral involvement is often present. Cases with
symmetric involvement of both extremities are seen
infrequently. Even in cases with diffuse involvement of
multiple bones, the disease has a tendency to predomi-
nate on one side of the body.
 6  Benign Cartilage Lesions 387

TABLE 6-1  The Classification of Different Types of Enchondromatosis

Involved
Enchondromatoses Clinical Subtypes Genes
Nonhereditary
Ollier’s Disease IDH1, IDH2,
• Manifests in early childhood PTH1R
• Enchondromas primarily affect the short and long tubular bones
of the extremities
• Craniofacial bones and vertebrae usually not involved
Maffuci’s Syndrome IDH1
• Manifests in early childhood
• Skeletal involvement by enchondromas identical to Ollier’s disease
• Cavernous and spindle-cell hemangiomas in the dermis, subcutis,
and internal organs
Autosomal Dominant
Metachondromatosis PTPN11
• Manifests in early childhood
• Skeletal involvement by enchondromas involving iliac crest and
metaphyses of long bones of lower extremities
• Osteochondroma-like lesions involving hands and feet
Genochondromatosis TYPE 1 PTHLH
• Manifests in early childhood • Additional enchondromas in clavicle
• Symmetric enchondromas in the metaphyses of the proximal TYPE 2
humerus and distal femur
• Additional enchondromas in short
• Enchondromas do not cause bone deformities and tend to
tubular bones of hand, wrist, and feet
regress in adulthood

Autosomal Recessive
Spondyloenchondrodysplasia TYPE 1 ACP5
• Manifests at birth to later infancy • Classic
• Vertebral dysplasia combine with enchondromas involving pelvis TYPE 2
and long tubular bones
• Central nervous system involvement
• Short stature associated with short limbs, lumbar lordosis, and
with spasticity and developmental
facial abnormalities
delay, late-onset cerebral classifications

Unknown Pattern of Transmission

Cheirospondyloenchondromatosis Unknown
• Manifests in early age and associated with mental retardation
• Symmetrically distributed enchondromas with preponderance for
involvement of metacarpals and phalanges, resulting in short
hands and feet with platyspondyly
• Moderate dwarfism and enlarged joints
Dysspondyloenchondromatosis Unknown
• Manifests at birth and during infancy
• Enchondromas involving the long tubular and flat bones
• Bones of hands and feet are not or only mildly affected
• Malformations of spine with severe segmentation of vertebral
column
• Unequal limb length and facial deformations

Ollier’s disease has a predilection for the appendicular
skeleton, but in more severe forms the trunk bones can
also be involved. The short tubular bones of the hands
are most frequently affected. The bones most often
affected after the hand are the short tubular bones of
the feet, femur, and humerus and the bones of the
forearm. The femur is the most frequently involved long
tubular bone, followed by the tibia and humerus. The
pelvis is the most frequently involved trunk bone. The
lesions in Ollier’s disease can sporadically occur in
other trunk bones, such as the scapula and ribs. Typically,
they do not involve the vertebral column or craniofacial
bones. The peak age incidence and most common
skeletal sites involved in Ollier’s disease are shown in
Figure 6-29.
Clinical Symptoms
In general the more diffuse and severe the skeletal
involvement, the earlier in life symptoms appear.77,82
Typically, individuals with presentation in early child-
hood develop extensive and severe forms of the disease.
In general, symptoms appear early, and most cases are
typically diagnosed in childhood. The symptoms that
lead to discovery of the disease vary with the anatomic
distribution and the extent to which they alter the

ERRNVPHGLFRVRUJ
388 6  Benign Cartilage Lesions
Onset of
symptoms
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 6-27  ■  Ollier’s disease. Peak age incidence at onset of symptoms and most common anatomic sites of involvement. Most
frequent sides are indicated by arrows.
anatomy and growth of the affected bone. The most
common symptom is slowly increasing swelling of the
fingers. With the involvement of the long tubular bones,
angular deformity of the affected extremity can be a pre-
senting symptom. The involvement of long tubular bones
is typically associated with length discrepancy.72,94,110 The
affected bones grow more slowly. Retarded growth and
length discrepancy are particularly evident in the lower
extremities. In severe cases, the discrepancy can be in a
range of several centimeters in early childhood (age 2 to
3 years). Pathologic fracture may be a presenting
symptom, but more often occurs later in the course of
the disease with the progression of bone involvement. If
one of the patient’s bones, such as in the forearm, is
altered, the retarded growth of the affected bone can
produce bony deformity of the unaffected or less affected
paired bone. Patients with severe enchondromatosis may
be seen in adult life with shortening and bowing deformi-
ties of the extremities that severely affect motor function.
Other secondary changes, such as compensatory scolio-
sis, can be present.
Radiographic Imaging
Enchondromatosis presents with radiographic features
that are distinctive and in some cases diagnos-
ERRNVPHGLFRVRUJ
7 8
tic.77,82,86,91,96,99,111 The lesions have a tendency to be
metaphyseal and diaphyseal, eccentric, and multifocal
(see Figs. 6-30 to 6-33). Metaphyseal involvement is less
evident in the short tubular bones, where the eccentricity
of the lesions with multiple lytic defects oriented perpen-
dicularly to the long axis and extending toward the soft
tissue is most pronounced. The lesions often show punc-
tate calcifications that are typical for the radiographic
appearance of the cartilaginous matrix. The combined
metaphyseal and diaphyseal involvement is best seen in
the long tubular bones (see Figs. 6-31 and 6-32). In these
locations, the lesion forms elongated grooves or longitu-
dinal lucent columns along the long axis of bone. The
radiographic appearance is best understood if the changes
are envisioned as a parallel arrangement of rows of dys-
plastic cartilage that extend from the growth plate toward
the diaphysis. The radiologic appearance is sometimes
referred to as the fluted-column sign (Fig. 6-31). With
progression of the lesion as a result of the continuous
growth of cartilage, larger expanding masses that extend
to involve the diaphysis are formed. At this stage, the
parallel arrangement of the cartilaginous lesion may
become so distorted that it presents as a large multilobu-
lar mass that involves the bone end. Severe involvement
of both proximal and distal metaphyses can produce a
Text continued on p. 395
 6  Benign Cartilage Lesions 389

A B

C D

FIGURE 6-28  ■  Ollier’s disease: radiographic features. A-D, Radiographic manifestations of Ollier’s disease involving the hands of
four different patients with multiple disfiguring lucent lesions corresponding to dysplastic cartilage involving multiple bones.

ERRNVPHGLFRVRUJ
390 6  Benign Cartilage Lesions

B
FIGURE 6-29  ■  Ollier’s disease: radiographic features. A, Lateral radiograph of distal femur of a 13-year-old girl with Ollier’s disease
shows typical pattern of intramedullary linear lucencies that extend from growth plate upward into shaft (fluted-column sign). In
addition, small eccentric subperiosteal lucency is seen in posterior cortex. B, Radiograph of proximal tibia and fibula of the same
patient shown in A. Healed pathologic fracture of tibial shaft with angular deformity and bowing of fibula. Fluted-column sign is
present, but epiphysis is uninvolved.

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 391

A B

C
FIGURE 6-30  ■  Ollier’s disease: radiographic features. A, Fan-shaped radiolucencies are seen in anteroposterior radiograph of the
pelvis of an 8-year-old boy with Ollier’s disease. Elongated columns of dysplastic cartilage extend from iliac crest growth plate into
body of ilium. Proximal femoral shaft is also involved. B, Radiograph of right hip shows characteristic medial intertrochanteric
lucency seen in about one third of cases of Ollier’s disease. Pelvis is involved as well. C, Asymmetric involvement of right pelvis
and proximal femur in 5-year-old girl with Ollier’s disease.

ERRNVPHGLFRVRUJ
392 6  Benign Cartilage Lesions

A B C D

E F G

FIGURE 6-31  ■  Ollier’s disease: radiographic features. A-G, Extensive disfiguring Ollier’s disease involving multiple bones in one
patient.

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 393

A B C

FIGURE 6-32  ■  Ollier’s disease: radiographic features. A-D, Anteroposterior radiographs showing extensive disfiguring Ollier’s disease
predominantly involving right pelvis and bones of right lower extremity.

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394 6  Benign Cartilage Lesions

Chr 2
25.3
IDH1 IDH2
25.1 25.2
24 Exon 10

Exon 11
Exon 10
Chr 15
Exon 9
Exon 8

Exon 7

Exon 6

Exon 5

Exon 4

Exon 3

Exon 2
Exon 1

Exon 9
Exon 8

Exon 7
Exon 6
Exon 5
Exon 4

Exon 3
Exon 2

Exon 1
23
22
209100952

209119806

90627211

90645708
13
21 12
16 11.2
11.1
11.1 11.2
15 12
14 13
13 14

12 IDH1 21.1
15
IDH2
21.2
11.2 Isopropylmalate dehydrogenase-like domain 21.3 Isopropylmalate dehydrogenase-like domain
11.1 22.2 22.1
11.1
11.2 22.3
12 1 414 aa 23 1 452 aa
13 11 399 24 45 440
14.1 25
14.3
14.2 IDH2 208
21.1 26.1
21.2 26.2
21.3 5148 26.3
766
22
23
102531392 bp
24.1
24.2
24.3
1 414 aa 1 452 aa
31
32.1 Missense substitution Synonymous substitution
32.2
32.3 Deletion Missense substitution
33
Nonsense substitution - Stop codon Nonsense substitution - Stop codon
34 IDH1
35
36 B
37.1
37.2
37.3

243199373 bp

A Tumor cell

Citrate Histone
Mitochondria
demethylases
Isocitrate
Citrate
IDH1
Isocitrate
TCA cycle

IDH3 IDH2
-KG TET1 KDM2a
-KG TET2
IDH2 IDH1
mut
Nucleus
mut
2-HG
OH
2-HG
Nucleosome

HIF-1 H3K4me1, H3K4me3,

stabilization H3K9me2, H3K27me2,
Endostatin H3K79me2
5-Hydroxymethylcytosine
HIF1-
Cancer biomarker?

VEGF Dysregulation of
epigenetic and
Cytoplasm gene expression profiles

C
Glucose Acetyl-CoA Fatty acids

Lactate Pyruvate Citrate Isocitrate

NADP
IDH1 or
Acetyl-CoA IDH2
TCA NADPH NADP
KG 2-HG
IDH1 mutant or
Glutamine or glutamate IDH2 mutant
D
FIGURE 6-33  ■  Molecular mechanisms of enchondromatosis. A, Chromosomal location, exonal structure, functional domain, and the
distribution of mutations of the IDH1 gene. B, Chromosomal location, exonal structure, functional domain, and the distribution of
mutations of the IDH2 gene. C, Molecular mechanisms controlled by IDH1 and IDH2 genes and functional implications of their muta-
tions. (C, Reprinted with permission from Prensner JR, Chinnaiyan AM: Nature Med 17:291-293, 2011.) D, Significance of IDH1 and IDH2
mutations for NADP/NADPH energy cycle within the mitochondria. (D, Reprinted with permission from Cairns RA, et al: Nature Rev
Cancer 11:85-95, 2011.)

ERRNVPHGLFRVRUJ

dumbbell appearance of the affected long bone. Some-
times the dysplastic changes may affect only a portion of
the growth plate, leading to asymmetric involvement
with uneven growth and resulting bowing deformities. A
very characteristic radiologic finding is an exophytic
eccentric lucency in the intertrochanteric region of the
femur (Fig. 6-32). It shows associated radiolucent stria-
tions that are oriented oblique to the long axis of the
femur. The broad base is usually centered over the lesser
trochanter. In the flat bones, the parallel arrangement of
an elongated lytic lesion that originates at the junction of
the secondary ossification center, such as the iliac crest,
can be seen (see Figs. 6-30 and 6-32). This produces
characteristic fan-shaped grooves that extend into the
metaphysis.
Gross Findings
The affected area is typically expanded and the entire
bone is shortened. On a cut section, the affected metaph-
yseal regions show extensive involvement and contain
longitudinal extensions composed of numerous pea-sized
cartilage masses. Parallel arrangement of rows of carti-
lage masses can be focally present, but in many cases of
severe involvement the lesion can be grossly distorted. It
is composed of irregular masses of cartilage that range in
length from 1 cm to several centimeters, located in the
metaphyseal parts of the long bone and extending into
the diaphysis. Eccentric subperiosteal hyaline cartilage
nodules can be seen.
Microscopic Findings
The morphology of lesions in Ollier’s disease is some-
what similar to that of solitary enchondroma. Enchon-
dromas in Ollier’s disease have overall lobular architecture
with encasement of individual cartilage lobules by mature
medullary bone similar to solitary enchondromas (Fig.
6-35). In general, the lesions in Ollier’s disease are more
cellular and less calcified than most typical solitary
enchondromas. Moreover, the cartilage cells in enchon-
dromatosis are larger than the cells of solitary enchon-
droma. They have an open chromatin structure, and
double nucleated cells are also frequently present (see
Figs. 6-36 and 6-37). Features of nuclear atypia and
immaturity of the extracellular matrix with frequent
myxoid change further complicate the microscopic
pattern, making the microscopic differential diagnosis
of enchondromatosis and low-grade chondrosarcoma
extremely difficult.
In summary, the cartilage in Ollier’s disease has fea-
tures consistent with grade 1 chondrosarcoma if cytology
of the lesion is evaluated out of context without careful
consideration of its radiographic and clinical setting.
Special Techniques
Similar to ordinary enchondromas, chondromas of Olli-
er’s disease express markers of cartilage lineage differen-
tiation and are immunohistochemically indistinguishable
from solitary enchondromas. In fact, genome-wide
expression studies show that enchondromas of Ollier’s
ERRNVPHGLFRVRUJ
6  Benign Cartilage Lesions 395
disease are similar to solitary enchondromas.89,104 The
hallmark genetic abnormality of Ollier’s disease is the
presence of somatic mutations involving the isocitrate
dehydrogenase genes, IDH1 and IDH2, mapping to the
long arms of chromosomes 2 and 15 repectively71,97,98
(Fig. 6-33). These mutations are seen in nearly 80% of
patients with Ollier’s disease but are also present in soli-
tary enchondromas, periosteal enchondromas, and some
central chondrosarcomas, further confirming the unified
pathologic mechanisms contributing to the development
of these neoplasms. The mutations affecting the IDH
genes are also frequently found in gliomas of the central
nervous system and acute myeloid leukemia.83,93,114 This
explains some known clinical associations showing that
patients with Ollier’s disease are prone to developing
central nervous system gliomas.73,92 The mutations of
the IDH genes are less frequently present in some other
solid tumors. These genes encode the cytoplasmic and
mitochondrial NADP+-dependent isocitrate dehydroge-
nases, which convert isocitrate to α-ketoglutarate (Fig.
6-33). Mutations in enchondromatosis most frequently
affect the Arg132 position in exon 4 of IDH1 and also
include R132C, R132H, R132G, or rare variants affect-
ing R132. The mutations in enchondromatosis of Olli-
er’s type typically involve the IDH1 gene. The IDH2
gene (R172S) appears to be rarely involved. Maffucci’s
syndrome is characterized by exclusive involvement of
IDH1. Mutations of IDH genes result in the new ability
of the enzyme to catalyze the NADPH-dependent
reduction of α-ketoglutarate to (R)-2-hydroxyglutarate
(2HG).81,100,102,108 Excess accumulation of 2HG acts as an
oncometabolite and contributes to the development of
enchondromas76,113,115 (Fig. 6-33). In addition, the IDH
mutations impair histone demethylation and are associ-
ated with a DNA hypermethylator phenotype, resulting
in defective cellular differentiation.83,88
A small fraction of patients (less than 5%) with Ollier’s
disease carry mutations of the PTH1R gene encoding a
receptor for parathyroid hormone, resulting in upregula-
tion of the Indian hedgehog (IHH) pathway.80,85,105,106
Mutations of PTH1R include R150C, G121E, A122T, and
R255H. Mutant PTH/PTHrP1 receptor complex consti-
tutively activates IHH signaling and is sufficient to trigger
the formation of enchondroma-like lesions in animal
models (Fig. 6-34).
Differential Diagnosis
The dysplastic chondroid tissue in this condition charac-
teristically extends in columns from the physis through
the metaphysis into the diaphysis. Although such lesions
can simulate low-grade chondrosarcomas microscopically,
close correlation with the radiologic pattern of involve-
ment usually provides a solid basis for distinguishing them
from chondrosarcoma. The richly cellular dysplastic car-
tilage may show mild nuclear atypia and multinucleation
of chondrocytes, which may raise questions of secondary
malignant change. Although the lesions of Ollier’s disease
may be eccentrically placed in bone, the soft tissue itself is
not involved. Conversion to low-grade chondrosarcoma
is usually signaled by a change in symptoms and exten-
sion beyond the bony cortex into the adjacent soft tissue.
396 6  Benign Cartilage Lesions

Chr 3
26
PTH1R
25

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
24.3
24.2

Exon 1

Exon 2

Exon 3

Exon 4

Exon 5
Exon 6
Exon 7
Exon 8
Exon 9
24.1
23
22

46919235

46945289
21.3
21.2 PTH1R
21.1
14.3 14.2
14.1
13
12
PTH1R
11.2
11.1
11.2 11.1
12
13.1 1 594 aa
13.2
13.3 47 179 187 463
21
22
23 GPCR, family 2, extracellular hormone receptor domain
24
25.1
GPCR, family 2-like domain
25.2
25.3
26.1
26.2
Synonymous substitution
26.3 Missense substitution
27
28 Non stop extension
29
Deletion frameshift
198022430 bp
FIGURE 6-34  ■  Molecular mechanisms of enchondromatosis. Chromosomal location, exonal structure, functional domains, and the
distribution of mutations of the PTH1R gene.

Radiologically, there is some overlap between enchon-
dromatosis and polyostotic fibrous dysplasia because both
involve multiple skeletal sites. Enchondromatosis more
frequently involves the small bones of the hands and also
shows a more pronounced unilateral predominance than
fibrous dysplasia. The frequency of craniofacial involve-
ment in fibrous dysplasia and the fact that enchondro-
matosis is limited to bones preformed in cartilage aids in
the differential diagnosis of these two lesions. Enchon-
dromatosis almost never involves the skull, and the skin
pigmentation seen in polyostotic fibrous dysplasia is not
seen in Ollier’s disease.
Treatment and Behavior
The cartilage of Ollier’s disease has the propensity for
continuous slow growth. In most cases, the progression
of the lesions has stabilized at puberty, but occasionally
they continue to grow even during adulthood. The
potential for progressive growth of dysplastic cartilage in
enchondromatosis constitutes a basic biologic difference
between Ollier’s disease and solitary enchondroma, which
as a benign neoplasm has limited growth potential. There
is no specific treatment available and affected patients
require surveillance for their entire lifetime because of
the possibility of secondary sarcomatous change. Correc-
tive surgery is sometimes performed for deformities and
length discrepancy, and occasionally severely stunted
(nonfunctioning) extremities have to be amputated. More
commonly, osteotomies and lengthening procedures are
required to correct growth disturbances.
Maffucci’s Syndrome
Maffucci’s syndrome is a rare condition in which enchon-
dromatosis identical to that of Ollier’s disease coexists
with extraskeletal, predominantly soft tissue, angioma-
tosis. The angiomas in Maffucci’s syndrome typically
involve the soft tissues or skin but occasionally can
involve viscera, such as the lungs and liver.118,120,122,123,127,133
Vascular lesions in Maffucci’s syndrome most typically
represent cavernous hemangiomas with frequent throm-
bosis and calcified thrombi that are often seen on plain
radiographs. Hemangiomas in Maffucci’s syndrome
have a tendency to be more pronounced in the areas
of skeletal involvement by enchondromatosis but are
not restricted to these regions. Usually the cartilaginous
skeletal dysplastic changes manifest earlier, and the dis-
order is initially classified as Ollier’s disease. Vascular
lesions develop later in life in some patients. Minimal soft
tissue hemangiomas may not be recognized initially.
Other soft tissue anomalies include arteriovenous aneu-
rysms or fistulas, lymphedema, and lymphangiomas.
Vascular anomalies also can involve the gastrointestinal
tract. Maffucci’s syndrome most likely represents more
severe mesodermal dysplasia in which both the skeletal
and extraskeletal-forming tissues are altered. In keeping
with this concept, patients with Maffucci’s syndrome are
prone to develop cartilage neoplasm in extraskeletal sites
such as the trachea.125,129 Coexistence of nodular goiter
and adrenal insufficiency has also been reported.128 As
stated, the risk of secondary malignancy in Maffucci’s
syndrome is even higher than that in Ollier’s disease.128
Similarly to Ollier’s disease, enchondromas and spindle-
cell hemangiomas in Maffucci’s syndrome carry the
mutations of the IDH genes.97 It appears that in Maf-
fucci’s syndrome the IDH1 gene is almost exclusively
involved.
Similar to Ollier’s disease, patients with Maffucci’s
syndrome may develop low-grade conventional chondro-
sarcomas.128,130,131,133 The manifestation and diagnostic
criteria of chondrosarcoma in Maffucci’s syndrome are
identical to those of chondrosarcoma complicating Olli-
er’s disease. Rare instances of dedifferentiated chondro-
sarcoma and soft tissue angiosarcoma in Maffucci’s
syndrome have been reported.119,132 Earlier studies
have postulated that the overexpression of neurotrans-
mitters with mitogenic activities may play a role in the
biology of the soft tissue and bone lesions of Maffucci’s
syndrome.126

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 397

A B

C D

FIGURE 6-35  ■  Ollier’s disease: microscopic features. A and B, Low power photomicrographs showing lobular growth pattern of
cartilage in enchondroma. Note encasement of cartilage lobules by well developed medullary bone trabeculae. C and D, Intermedi-
ate power photomicrographs of hyaline cartilage nodules in Ollier’s disease. Inset, Whole-mount photograph showing a growth
pattern of cartilage within the intramedullary cavity in Ollier’s disease. (A and B, ×20; C and D, ×50; inset, ×100.) (A-D, inset,
hematoxylin-eosin.)

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398 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-36  ■  Ollier’s disease: microscopic features. A-D, Low and medium power photomicrographs show increased cel-
lularity of dyschondroplastic tissue involving metaphyseal and diaphyseal areas in Ollier’s disease (A-C, ×100; D, ×200).
(A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 399

A B

C D

FIGURE 6-37  ■  Ollier’s disease: microscopic features. A-D, Low and intermediate power photomicrographs showing dysplastic
cartilage with high cellularity and minimal variation in size and shape of nuclei. Note the presence of binucleated chondrocytes
(A-C, ×100; D, ×200). (A-D, hematoxylin-eosin.)

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400 6  Benign Cartilage Lesions
Malignant Transformation
in Enchondromatosis
In 1958, Jaffe86 suggested that 50% or more of patients
with Ollier’s disease would have secondary malignancy,
usually in the form of one or more chondrosarcomas,
but the actual risk of malignant change is difficult to
assess. More recent studies have led to a revised view
of this risk. In 1987, Liu et al.88 showed that malignant
neoplasms develop in approximately 30% of patients
with Ollier’s disease. Usually these lesions are low-grade
conventional chondrosarcomas, but the series also con-
tained two dedifferentiated chondrosarcomas, one osteo-
sarcoma, and one chordoma. In the series reported by
Schwartz et al.,107 there was a 25% incidence of second-
ary malignancy in Ollier’s disease, but the incidence in
Maffucci’s syndrome was considerably higher. A total
of 7 patients with soft tissue hemangiomas associated
with skeletal enchondromatosis had a total of 10 second-
ary malignancies, 3 of which were nonskeletal. Ollier’s
disease is associated with an increased risk for the devel-
opment of extraskeletal neoplasms, particularly of central
nervous gliomas and rare ovarian tumors (granulosa cell
and Sertoli-Leydig cell tumors).67,79,101,103,109,112,116 Indi-
viduals affected by Maffucci’s syndrome have a much
higher risk for the development of extraskeletal neo-
plasms and, in addition to angiosarcoma have, similar to
Ollier’s disease, increased risk for central nervous system
gliomas and juvenile granulosa cell tumors. In addition,
a long list of extraskeletal neoplasms, including pituitary
adenoma, pancreatic adenocarcinoma, and fibroadenoma
of the breast, were reported in patients with Maffucci’s
syndrome.67,117,119,121,124 Patients with widespread skeletal
involvement are more prone to have malignant transfor-
mation than those who have less severe lesions or those
with localized disease limited to a few bones.84,88,99 Malig-
nant transformation typically becomes manifest during
adult life. Therefore it can be stated that it usually occurs
after many years of continuous apparently benign growth.
Cases in which secondary chondrosarcoma developed in
two separate sites have also been reported.74,75,78,84,87,88,90
In summary the development of secondary malignan-
cies in Ollier’s disease and Maffucci’s syndrome is well
documented in the literature. In contrast, primarily due
to the rarity of other variants of enchondromatosis listed
in Table 6-1, it is not well established. In fact, malig-
nant transformation of enchondromas has not yet been
reported for metachondromatosis, genochondromatosis,
or dysspondyloenchondromatosis.
Clinically and radiographically, chondrosarcoma in
Ollier’s disease manifests with rapid enlargement of one
of the affected sites and the development of a mass that
breaks out of the bone and invades the adjacent soft tissue
(see Figs. 6-38 and 6-39). Microscopically, it has fea-
tures of a conventional chondrosarcoma. In fact, some of
those lesions retain a lobular architecture and the overall
microscopic features of Ollier’s enchondromas. They are
classified as low-grade chondrosarcomas on the basis
of their continuous locally destructive growth pattern
and invasion of adjacent soft tissue (see Figs. 6-38 and
6-40). In other instances, chondrosarcomas developing
in association with Ollier’s disease show obvious micro-
scopic features of malignancy with increased cellularity,
ERRNVPHGLFRVRUJ
nuclear atypia, and myxoid change that are more pro-
nounced than in the benign cartilage of Ollier’s disease
(Fig. 6-41). Therefore the diagnosis of chondrosarcoma
developing in Ollier’s disease requires familiarity with the
morphologic features of benign lesions in this disorder.
Strict correlation with radiographic and clinical data is
of great importance. The prognosis in secondary chon-
drosarcoma of Ollier’s disease is exactly the same as in
ordinary conventional chondrosarcoma and is related to
its histologic grade and affected site.
CHONDROBLASTOMA
Definition
Chondroblastoma is a distinct benign tumor character-
ized by a proliferation of immature cartilage cells with
foci of cartilage matrix formation that typically involves
the epiphyses of long bones and predominantly occurs in
skeletally immature patients.
Incidence and Location
Chondroblastoma is much less common than giant cell
tumor, with which it has been confused in the past. It
makes up less than 1% of bone tumors. The peak inci-
dence is during the second decade of life, and approxi-
mately 50% of cases are diagnosed in skeletally immature
patients. Reported cases have been diagnosed during the
first and sixth decades of life, but fewer than 10% are
diagnosed during the fifth decade of life or older. There
is a definite male sex predominance, and the male-to-
female ratio is approximately 1.4 : 1. Chondroblastomas
have a predilection for the epiphyses of the major long
tubular bones.141,150,204,210
Similar to giant cell tumor, chondroblastoma most
frequently occurs in the distal femoral and proximal tibial
epiphyses. Approximately 30% of cases are diagnosed in
the knee area. The third most frequently involved bone
is the proximal humerus, followed by the proximal femur.
Chondroblastomas also occur in the epiphyseal-equivalent
sites of flat bones. The acetabular area of the pelvis is a
frequent site, followed by the iliac crest. Chondroblasto-
mas also occur in the scapula, spine, and ribs.137,146,165,218
Less frequent but typical sites are in the patella and
calcaneus or other tarsal bones.152,176,195 Occasionally
chondroblastomas involve the craniofacial bones, most
typically the base of the skull and the temporal
fossa.140,157,209 Very rarely the tumor is found entirely
within the metaphysis or diaphysis of a long bone.138,147,208
Rare cases of multifocal chondroblastomas with synchro-
nous involvement of several typical sites have been
reported.198 Extremely rare, exclusively soft tissue chon-
droblastomas have also been reported.134,159,167 The peak
age incidence and most frequent skeletal sites are shown
in Figure 6-42.
Clinical Symptoms
Pain in the affected area is a constant initial symptom of
chondroblastoma. Pain can last for several months or
Text continued on p. 405
 6  Benign Cartilage Lesions 401

A B C

F G
FIGURE 6-38  ■  Ollier’s disease with secondary chondrosarcoma: radiographic and gross features. A, Extensive involvement of lower
extremity bones by Ollier’s disease. Note the destructive lesion involving the distal femur corresponding to a secondary chondro-
sarcoma. B and C, Fat-saturated T2-weighted coronal magnetic resonance image (MRI) with contrast showing extensive involvement
of the femur and tibia by Ollier’s disease. Note a large destructive tumor mass of the distal femur (arrow) corresponding to second-
ary chondrosarcoma. D, T1-weighted axial MRI showing a low signal intensity tumor involving the distal femur. E, Fat-saturated
T2-weighted axial MRI showing lobular signal enhancement within a tumor mass of the distal femur. F, T1-weighted axial MRI with
contrast showing irregular signal enhancement corresponding to the lobular architecture of the tumor. G, Coronally bisected resec-
tion specimen of the distal femur showing a destructive cartilage mass with lobular architecture. Inset, Whole-mount photograph
showing a lobular growth pattern of a cartilage mass.

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402 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-39  ■  Ollier’s disease with secondary chondrosarcoma: radiographic and gross features. A, Anteroposterior radiograph of
proximal humerus shows focally mineralized bone surface lesion. Note the presence of intramedullary calcifications corresponding
to Ollier’sdisease. Inset, Fat-saturated T1-weighted axial magnetic resonance image (MRI) with contrast showing low signal intensity
bone surface lesion corresponding to secondary chondrosarcoma. B, Fat-saturated T2-weighted coronal MRI showing high signal
intensity within the bone surface lesion corresponding to a chondrosarcoma and the presence of multifocal high signal nodularities
within the medullary cavity representing underlying Ollier’s disease. C, Bisected resection specimen showing the proximal humerus
with a partially cystic mucinous bone surface lesion corresponding to a chondrosarcoma and the presence of a more extensive
intramedullary cartilage lesion representing underlying Ollier’s disease. D, Enlargement of the specimen in C showing intramedul-
lary Ollier’s disease growing in the form of multiple focally coalescent cartilage nodules.

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 6  Benign Cartilage Lesions 403

A B

C D
FIGURE 6-40  ■  Ollier’s disease with secondary chondrosarcoma shown in Figure 6-38: microscopic features. A-D, Low and intermedi-
ate power photomicrographs showing a hypercellular cartilage lesion corresponding to a low-grade chondrosarcoma developing
in a background of Ollier’s disease (A and C, ×100; B and D, ×200). (A-D, hematoxylin-eosin.)

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404 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-41  ■  Ollier’s disease with secondary chondrosarcoma shown in Figure 6-39: microscopic features. A and B, Atypical carti-
lage cells with open chromatin structure in a myxoid stroma characteristic of secondary chondrosarcoma developing in Ollier’s
disease. C and D, Hypercellular cartilage lesion with proliferation of atypical cartilage cells in a secondary chondrosarcoma develop-
ing in Ollier’s disease (A, C, and D, ×200; B, 400). (A-D, hematoxylin-eosin.)

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Peak
incidence
10 20
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 6-42  ■  Chondroblastoma. Peak age incidence and most common skeletal sites of involvement. Most frequent site is indicated
by a large solid black arrow.
many years (>10 years). Chondroblastomas are epiphy-
seal lesions and can be associated with joint symptoms
from the involvement of the articular cartilage or the
synovium with joint effusion.
Radiographic Imaging
Chondroblastoma usually presents as a sharply demar-
cated oval or round lytic epiphyseal defect surrounded by
a rim of sclerotic bone.141,150,179,203,204,210,216 The lesion is
usually relatively small, most frequently within the range
of 3 to 6 cm in diameter. In contrast to giant cell tumor,
which is frequently an eccentric lesion, chondroblastoma
is typically centrally located within the epiphysis (Figs.
6-43 to 6-46). In a typical case, the lesion is radiolucent,
but occasionally it can have fine trabeculations. Occa-
sionally some irregular calcifications can be seen on
radiographs (Fig. 6-45). In rare cases, the lesion can
present as a heavily calcified epiphyseal mass. On
T1-weighted MRIs, chondroblastoma is typically of low
signal intensity.169,171 T2-weighted images typically show
signal enhancement. Multilocular signal enhancement
with fluid levels are typically seen when secondary aneu-
rysmal bone cyst develops in association with chondro-
blastoma (Fig. 6-47). On gadolinium-enhanced images,
lesions show marginal or septal enhancements.169 Low
signal intensity on T2-weighted images correlates with
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6  Benign Cartilage Lesions 405
7 8
an abundance of chondroid matrix, hypercellularity, cal-
cifications, and hemosiderin deposits.169
In a typical case, the bony end plate, the cortex, and
the bone contour are not altered, but larger lesions may
expand the bone end and provoke some periosteal new
bone formation. These changes are most frequently seen
in the flat bones, such as the pelvis, scapula, and cranio-
facial bones (Figs. 6-48 and 6-49). They are also usually
present if chondroblastoma involves smaller bones, such
as the ribs and the fibula. Chondroblastoma is one of the
rare lesions that can occur in the patella and in the acral
skeleton, predominantly in the calcaneus or talus (see
Figs. 6-50 and 6-51). Marked expansion with blowout
features may be present with secondary aneurysmal bone
cyst formation. This complication is seen in about 15%
to 20% of chondroblastomas and is most common in
tarsal bones. Associated synovitis with collection of fluids
in the joint adjacent to chondroblastoma is a frequent
finding, but occasionally florid synovitis can be a domi-
nant presenting sign.172
Gross Findings
Tumor tissue typically represents curetted material that
is reddish, gritty, and friable with calcific foci (Fig. 6-52).
In rare instances when an involved bone is resected,
Text continued on p. 416
406 6  Benign Cartilage Lesions

A B

C E

FIGURE 6-43  ■  Chondroblastoma: radiographic features. A and B, Anteroposterior and lateral radiographs showing a well demarcated
lytic lesion of the proximal tibial epiphysis. C, Fat-saturated T1-weighted sagittal magnetic resonance image (MRI) with contrast
showing well demarcated lesion of low signal intensity involving the proximal tibial epiphysis. D and E, Fat-saturated T1-weighted
axial MRI with contrast and axial computed tomogram showing well demarcated intramedullary tibial lesion. Note mild patchy
signal enhancement in D and signal void in E.

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 6  Benign Cartilage Lesions 407

FIGURE 6-44  ■  Chondroblastoma: radiographic features. A, Anteroposterior radiograph of distal end of femur of a 29-year-old man
with heavily calcified, mummified chondroblastoma in femoral epiphysis. B, Lateral radiograph shows epiphyseal and metaphyseal
extent of tumor and its anterior location. C, Axial computed tomogram of lesion shown in A and B.

ERRNVPHGLFRVRUJ
408 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-45  ■  Chondroblastoma: radiographic features. A and B, Anteroposterior and lateral radiographs of the right knee of a
12-year-old boy with chondroblastoma of proximal tibial epiphysis. C and D, Coronal and sagittal T2-weighted magnetic resonance
image showing high signal intensity in a well demarcated intramedullary lesion involving the proximal tibial epiphysis. The sagittal
image documents the posterior epiphyseal location of chondroblastoma.

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 6  Benign Cartilage Lesions 409

A B

D E

FIGURE 6-46  ■  Chondroblastoma: radiographic features and microscopic features. A and B, Anteroposterior radiographs of proximal
humerus with a lytic well circumscribed lesion involving the humeral head. C, Axial computed tomogram showing a well demarcated
intramedullary lesion involving the humeral head. D and E, Proliferation of chondroblastic cells with well delineated polygonal or
oval cytoplasm characteristic of a chondroblastoma (D, ×400; E, ×200). (D-E, hematoxylin-eosin.)

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410 6  Benign Cartilage Lesions

A B C D

F G

FIGURE 6-47  ■  Chondroblastoma: radiographic features and microscopic features. A and B, Anteroposterior and oblique radiographs
of proximal femur showing a lytic lesion involving the greater trochanter. Note well demarcated intramedullary border and a thin
shell of bone outlining the expanded trochanter. C and D, Fat-saturated T2-weighted and T1-weighted coronal magnetic resonance
images (MRIs) showing low signal intensity lesion of the greater trochanter with focal signal enhancement. E and F, T1-weighted
and fat-saturated T2-weighted axial MRIs showing low signal intensity lesion with focal signal enhancement involving greater
trochanter. G, Proliferation of chondroblastic cells and scattered multinucleated osteoclastic giant cells characteristic of a chondro-
blastoma. Inset, Higher magnification showing microscopic details of chondroblastic cells (G, ×200; inset, ×400). (G and inset,
hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 411

B
FIGURE 6-48  ■  Chondroblastoma: radiographic features. A, Anteroposterior radiograph of pelvis shows large chondroblastoma in-
volving ischium and acetabular portion of ilium in a 7-year-old boy. B, Axial computed tomogram shows radiolucent lesion expand-
ing into left ischium.

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412 6  Benign Cartilage Lesions

B
FIGURE 6-49  ■  Chondroblastoma: radiographic features, unusual sites. A and B, Two cases of temporal bone chondroblastomas in
men. Tumors are clearly demonstrated in magnetic resonance imaging (MRI), showing low-signal intensity in axial T1-weighted
MRI and high signal intensity in T2-weighted MRI with contrast.

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 6  Benign Cartilage Lesions 413

A C

D E
FIGURE 6-50  ■  Chondroblastoma: radiographic features, unusual sites. A and B, Lateral and sunrise views of left knee with circum-
scribed lucent lesion of patella that proves to be chondroblastoma with extensive secondary cystic changes. C, High power photo-
micrograph showing chondroblastic cells with discrete cytoplasm. D and E, Proliferation of mononuclear chondroblastic cells and
scattered multinucleated giant cells characteristic of chondroblastoma. (C, ×400; D and E, ×200.) (C-E, hematoxylin-eosin.)

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414 6  Benign Cartilage Lesions

A B

C D

FIGURE 6-51  ■  Chondroblastoma: radiographic features. A, Lateral radiograph showing a lytic lesion of a 23-year-old man with chon-
droblastoma of the anterior two thirds of calcaneus. B, Conventional tomogram showing a well demarcated lytic lesion of the cal-
caneus. C, Axial computed tomogram showing a well delineated lesion within the calcaneus. D, Fat-saturated T2-weighted sagittal
magnetic resonance image showing high signal intensity in a well demarcated chondroblastoma of calcaneus.

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 6  Benign Cartilage Lesions 415

A B

C D
FIGURE 6-52  ■  Chondroblastoma: gross and microscopic features. A, Curetted tissue from chondroblastoma of humeral head shows
soft, gelatinous, red-tan tumor with flecks of chalky calcification. B, Prominent osteoclast-like giant cell component in chondroblas-
toma can suggest giant cell tumor of bone. However, intervening tumor cells are plump and polygonal. C, Typical chondroblastoma
tissue with fine, linear streaks of calcification (chicken wire calcification) outlining cells. D, Higher power photomicrograph shows
delicate chicken wire calcifications. (B and C, ×100; D, ×400). (B-D, hematoxylin-eosin.)

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416 6  Benign Cartilage Lesions
chondroblastoma examined in situ represents a well
demarcated, gray-tan mass with foci of calcification and
hemorrhage; cystic change can be present. In fact, the
lesion can be almost entirely cystic with only a small focus
of solid tumor tissue at the periphery.
Microscopic Findings
The current universally accepted concept of chondro-
blastoma as a separate entity distinct from giant-cell
tumor was postulated by Jaffe and Lichenstein in 1942.168
The basic cells are considered to represent chondro-
blasts.141,179,182,185,210,220 The cytoplasm of these cells is
round to oval, and the cells have a centrally or eccentri-
cally placed oval or round nucleus that frequently exhibits
a longitudinal cleft (see Figs. 6-47, 6-50 and 6-52). The
cells are closely packed in solid areas in which scattered
osteoclast-like giant cells are usually seen (see Figs. 6-52
to 6-56). The presence of principally mononuclear cells
with scattered, multinucleated giant cells is responsible
for the mimicry of giant cell tumor of bone. In fact,
before chondroblastoma was separated from that group,
it was designated as a calcifying epiphyseal variant of
giant cell tumor (Codman’s tumor).148 Within these areas
of immature cartilage cells are foci that exhibit more
distinct cartilage differentiation and formation of an
immature cartilaginous matrix (see Figs. 6-53 to 6-55).
The proportion of differentiated and immature areas can
vary considerably. In typical cases, cartilaginous matrix
differentiation is easily discerned. The level of cartilagi-
nous differentiation can vary, and mature hyaline matrix
is often not present. Calcification is an integral part of
chondroblastoma and serves as an important diagnostic
feature. The most typical pattern of calcification is in a
form of fine linear deposits between and around imma-
ture mononuclear cells (chicken wire pattern) (Fig. 6-52).
More abundant and coarse calcifications typically involve
the areas with more mature hyaline cartilage matrix for-
mation. In fact, some of the tumor can be heavily calci-
fied. The patterns of calcifications in chondroblastoma
are best examined with tissue that is processed without
decalcification. It is particularly important to docu-
ment small foci of so-called chicken wire type calcifica-
tion within the undifferentiated mononuclear areas of
the tumor. Extensive calcification of the cartilaginous
matrix affects the viability of the immature cartilage cells.
The chondrocytes within such heavily calcified areas are
usually dead. In well-preserved areas, the chondroblasts
may show mitotic activity in excess of the usual 1 or 2
per 10 high-power fields. Atypical mitoses are not seen.
Chondroblastoma can have overlapping features with
chondromyxoid fibroma, and hybrid lesions with chon-
droma and chondroblastoma-like appearance were also
described.145
Several deviations from this classic pattern may alter
the microscopic appearance of chondroblastoma and
make its diagnosis more difficult. Spindle-cell change in
chondroblastoma is frequently present, at least focally.
The spindle cells can represent transformed mononu-
clear cells that are an integral part of the tumor. Some-
times they can be of fibroblastic origin and part of a
secondary reparative process. Occasionally the spindle
ERRNVPHGLFRVRUJ
cells dominate the lesion. In such predominantly spindle-
cell lesions, typical features of chondroblastoma usually
are focally present. Extensive myxoid change and accu-
mulation of pools of intercellular proteinaceous fluid can
occur in some examples of chondroblastoma.
Secondary aneurysmal bone cyst in chondroblastoma
is found very frequently (in 15% to 20% of cases). In
fact, chondroblastoma is considered the prototype pre-
cursor condition for the development of secondary aneu-
rysmal bone cyst (see Fig. 6-56 to 6-58). Small foci of
blood-filled cystic spaces are frequently identified micro-
scopically in these tumors. A significant component
of aneurysmal bone cyst, which can be the dominant
radiographic feature, is often present. In such cases of
secondary aneurysmal bone cyst, the presence of a chon-
droblastoma precursor may not be suspected before his-
tologic study (also see Chapter 15).
The cystic change in chondroblastoma also may be in
the form of unilocular or multilocular cystic spaces filled
with serous fluid.166 Occasionally this type of change can
dominate the tumor, and a lesion can radiographically
and clinically present as a cystic lesion filled with fluid.
Small foci of residual chondroblastoma can be identified
by careful microscopic examination of these lesions. This
phenomenon should be distinguished from the secondary
aneurysmal bone cyst. Tumors with these changes are
referred to as cystic chondroblastomas.
Special Techniques
Ultrastructurally, chondroblastomas are composed of
round or ovoid cells with deep indentations of the nuclear
membrane corresponding to nuclear grooves seen under
light microscopy156,164,187,188,193,211 (Fig. 6-59). These cells
are focally surrounded by a mineralized stroma that
represents the so-called chicken wire calcifications
(Fig. 6-60). The presence of a thick nuclear lamina along
the inner membrane of the nuclear envelope is an ultra-
structural hallmark of chondroblastoma. However, it is
also present in chondromyxoid fibroma and in a variety
of other cells. The functional significance of this peculiar
structure is not known. Immunohistochemically, chon-
droblastomas are positive for S-100 protein and vimen-
tin. In a typical case the S-100 protein is strongly positive
in the majority of mononuclear cells. The multinucleated
giant cells are negative for S-100 protein.142,154,173,189,219
In cases with secondary changes (aneurysmal bone cyst,
cystic change, and fibrohistiocytic reaction), the S-100
protein is positive focally only. Reports on positivity
of chondroblastomas for keratins are questionable and
are subject to further verification.205 As chondroblasto-
mas develop from immature cells of cartilage lineage
they express SOX9 protein but are in general negative
for RUNX2 and Osterix.151,175 They also express carti-
lage growth plate signaling molecules such as FGFR1,
FGFR3, bcl2, p21, parathyroid hormone-related
hormone (PTHrP), and parathyroid hormone-related
peptide receptor (PTHR1).201 Some chondroblastomas
may showfocal positivity for osteoblastic lineage markers
such as RUNX2 and Osterix, however. Type II colla-
gen, the main component of cartilage matrix, is diffusely
Text continued on p. 425
 6  Benign Cartilage Lesions 417

A B

C D
FIGURE 6-53  ■  Chondroblastoma: microscopic features. A, Typical chondroblastoma tissue composed of plump polygonal mono-
nuclear chondroblastic cells and prominent osteoclast-like giant cell component. B, Higher magnification of A showing loosely
arranged plump and polygonal chondroblastic cells and scattered giant cells. C, Irregular sheets of eosinophilic matrix in chondro-
blastoma. D, Higher magnification of C showing irregular deposits of eosinophilic matrix separating sheets of chondroblastic cells.
(A and C, ×100; B and D, ×200). (A-D, hematoxylin-eosin.)

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A B

C D
FIGURE 6-54  ■  Chondroblastoma: microscopic features. A, Sheets of chondroblasts and scattered osteoclast-like giant cells (×200).
B, Higher magnification of A showing nuclear details of chondroblastic cells (×400). Some of them have characteristic grooves.
C, Chondroblastoma showing ill circumscribed areas of chondroid matrix depositions (×100). D, Higher magnification showing
ill defined areas of eosinophilic matrix deposits with chondroblastic cells residing in the lacunar spaces. (A and D, ×200; B, ×400;
D, ×100). (A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 419

A B

C D
FIGURE 6-55  ■  Chondroblastoma: microscopic features. A, Sheets of chondroblasts in chondroid matrix (upper portion of photo-
graph). B, Higher magnification shows tumor cells within well-defined lacunae of chondroid matrix. C, Higher magnification of
chondroblastic cells with discrete cell borders. D, Cytologic details of chondroblastic cells. Note indented nuclei and occasional
nuclear grooves. (A and B, ×200; C and D, ×400). (A-D, hematoxylin-eosin.)

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420 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-56  ■  Chondroblastoma: microscopic features. A and B, Cystic change chondroblastoma associated with reactive bone
formation consistent with secondary aneurysmal bone cyst in chondroblastoma. C and D, Higher magnifications of B showing
cystic changes and adjacent sheets of chondroblasts with scattered multinucleated giant cells. (A and B, ×50; C and D, ×100.)
(A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 421

A B

C D
FIGURE 6-57  ■  Chondroblastoma: microscopic features. A and B, Low and intermediate power photomicrographs showing typical
features of chondroblastoma, composed of sheets of chondroblastic cells with scattered multinucleated giant cells. C and D, Sec-
ondary aneurysmal bone cyst area in the same case of chondroblastoma. Note cystic change and the composition of thick
septa showing features of chondroblastoma with irregular chondroid matrix deposits. (A, ×100; B, ×200; C, 50; D, 100.)
(A-D, hematoxylin-eosin.)

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422 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-58  ■  Chondroblastoma: microscopic features. A and B, Cystic change consistent with secondary aneurysmal bone cyst in
chondroblastoma. Note reactive bone formation and proliferation of sheets of chondroblastic cells within the septum. C and D, Low
and intermediate photomicrographs showing large eosinophilic cartilage matrix deposits in chondroblastoma. Note clustering of
multinucleated giant cells at the border of the matrix deposits. (A, ×50; B, ×100; C, ×100; D, ×200.) (A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 423

B
FIGURE 6-59  ■  Chondroblastoma: ultrastructural features. A, Low power magnification of chondroblastic cells in loose stromal matrix
(×5000). B, Higher magnification of A shows chondroblasts with deep indentations of nuclear membranes corresponding to nuclear
grooves seen under light microscopy (arrows). Note prominent rough endoplasmic reticulum and mitochondria. Inset, Glycogen
granules in cytoplasm. (B, ×9500; inset, ×22,000).

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424 6  Benign Cartilage Lesions

B
FIGURE 6-60  ■  Chondroblastoma: ultrastructural features. A, Low magnification of calcified area of chondroblastoma corresponding
to chicken wire mineralization shows chondroblastic cells in collagenous matrix impregnated with hydroxyapatite crystals. B, Higher
magnification of A shows a portion of chondroblast with numerous mitochondria and surface microvilli in a mineralized collagenous
stroma. (A, ×5000; B, ×19,000).

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expressed in chondroblastoma.136,192 The more myxoid
bluish, pseudochondroid areas are predominantly com-
posed of aggrecan proteoglycan.135,177 Mononuclear chon-
droblastic cells express receptor activator of NFκB ligand
(RANKL), which is a key molecule essential for regulat-
ing osteoclast formation and activity.160 This suggests that
RANKL may be involved in the tumor cell recruitment
of osteoclast-like cells to chondroblastoma.160
Flow cytometric studies show that typical chondro-
blastomas are diploid with a low proliferation index.149,155
Cytogenetic studies document heterogeneous arrange-
ments of individual chromosomes, with chromosomes 5
and 8 being most frequently involved.143,144,184,213,215 Recur-
rent breakpoints involving 2q34, 3q21-23, and 18q21 as
well as ring chromosome 4 have also been identified in
chondroblastomas.207,217 Additional rare rearrangements
such as t(5;17) (p15;q22-23) have been also identified
in chondroblastomas.200 Surprisingly, chondroblastomas
share loss of heterozygosity on 5q, 9p, 11p, 13q, and 19q
with chondrosarcomas.191
Differential Diagnosis
Chondromyxoid fibroma generally affects the same age
group as chondroblastoma, but it usually involves the
metaphysis of long bones rather than the epiphysis. Nev-
ertheless, areas of chondroblastic differentiation can be
found microscopically in chondromyxoid fibroma, which
can lead to morphologic overlap. Calcification, which
is very common in chondroblastomas, is usually absent
from chondromyxoid fibroma. The myxoid pseudolobu-
lation of the latter lesion is not seen in chondroblastomas.
Although giant cells of the osteoclastic type can be
very numerous in chondroblastomas, true giant cell tumors
usually occur in skeletally mature individuals, in contrast
to chondroblastomas. The presence of chondroid matrix
with or without calcification in chondroblastoma excludes
giant cell tumor.
Eosinophilic granuloma of bone and intraosseous ganglion
can present radiologically as epiphyseal lucencies in
children and young adults and may simulate the radio-
logic appearance of chondroblastoma. However, their
microscopic features render them easily separable from
this tumor.
Both aneurysmal bone cyst and solitary bone cyst enter into
the differential diagnosis of chondroblastoma. Aneurys-
mal bone cysts can become engrafted on chondroblasto-
mas and can enlarge rapidly, partially or almost completely
obliterating the chondroblastic precursor. When this
happens, the radiologic features of the lesion may be
completely converted to those of an aneurysmal blowout
lesion. Only the localization to an epiphysis or a tarsal
bone and the young age of the patient may provide clues
that a chondroblastoma may be present. In such instances,
careful histologic study of all the curettings, including
immunohistochemical markers (S-100 protein), may be
necessary to identify the chondroblasts. Solitary bone
cyst can be simulated by a chondroblastoma that has
undergone extensive secondary cystic change with a
serous-filled cavity largely replacing the tumor. The
location of a solitary bone cyst in the metaphysis and
diaphysis of long bones, in contrast to the typically
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6  Benign Cartilage Lesions 425
epiphyseal localization of chondroblastoma, helps distin-
guish such cases.
In older patients an epiphyseal cartilaginous lesion
seen radiologically should raise the question of clear-cell
chondrosarcoma. These are often well-circumscribed lytic
lesions with sclerotic borders in the end of a long bone,
and they are usually more heavily calcified than chondro-
blastomas. Furthermore, the microscopic features of
chondroid tissue that contains clearly malignant chon-
drocytes and the characteristic large cells with clear cyto-
plasm are not seen in chondroblastomas.
Treatment and Behavior
Chondroblastomas are benign lesions, so curettage and
bone grafting are usually sufficient treatment. About 10%
of cases recur after curettage. They can recur within the
bone or in the adjacent soft tissue. The recurrence of
benign chondroblastoma may require a second curet-
tage.153,163,181,183,194,212 Satisfactory results of treatment of
chondroblastoma with radiofrequency ablation have been
reported; specifically, out of 17 patients treated, only 2
required additional surgical intervention.202 Similar to
giant cell tumor, benign chondroblastoma can metasta-
size to the lungs.158,178,190,197,214,221 These nodules are
appropriately referred to as benign lung implants rather
than as true metastatic deposits. They are clinically non-
progressive; that is, they do not result in the development
of disseminated, clinically malignant pulmonary disease.
The benign lung implants of chondroblastoma have been
successfully treated by surgery.
The term aggressive chondroblastoma is sometimes used
in reference to lesions that are microscopically typically
chondroblastoma but that radiographically or clinically
exhibit features of local destructive growth. They usually
are larger than the typical chondroblastoma, erode the
cortex, and invade the soft tissue at the time of diagno-
sis.139,161,162,174,188,196 Extremely rare cases of malignant
transformation in chondroblastoma have been reported
in the literature.170,176,180,186,199,206
Personal Comments
Even though chondroblastoma usually presents no diffi-
culties in histologic diagnosis, extensive cystic change in
these tumors can present diagnostic problems. Particular
care should be exercised in evaluating aneurysmal blowout
lesions of tarsal bones, which frequently contain incon-
spicuous chondroblastic components.
The fact that chondroblastic osteosarcomas can rarely
present as epiphyseal lesions can occasionally lead to mis-
diagnoses of chondroblastoma and inadequate treatment.
CHONDROMYXOID FIBROMA
Definition
Chondromyxoid fibroma is a benign tumor composed of
immature myxoid mesenchymal tissue with features of
early primitive cartilaginous differentiation. It has a defi-
nite predilection for the metaphyseal regions of long
tubular bones and is often eccentrically placed. The
426 6  Benign Cartilage Lesions
Peak
incidence
10 30
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 6-61  ■  Chondromyxoid fibroma. Peak age incidence and common anatomic sites. Most frequent sites are indicated by black
arrows.
current concept and the term chondromyxoid fibroma, as
well as its distinction from chondrosarcoma, were postu-
lated by Jaffe and Lichtenstein in 1948.240
Incidence and Location
Chondromyxoid fibroma is a rare tumor, accounting for
less than 1% of all bone tumors.228,234,247,254,266,269 It is
definitely less common than chondroblastoma. Chondro-
myxoid fibroma has a predilection for males, with a male-
to-female sex ratio of about 1.5 : 1, and it preferentially
affects young patients during the second or third decades
of life. Individual cases, however, are widely scattered
throughout the later decades, and some cases are diag-
nosed in patients who are age 50 years and older. Chon-
dromyxoid fibroma occurs in the metaphyseal parts of the
major tubular bones, predominantly of the lower extrem-
ity. Approximately one third of the cases are diagnosed
around the knee, where the proximal tibial metaphysis is
the most frequently involved site, followed by the distal
femoral metaphysis. The small bones of the feet are also
involved. The bones of the upper extremities are rarely
affected. The pelvis, especially the ilium, is the most
frequently affected flat bone. In general, the knee area,
the small bones of the feet, and the ilium are the three
most frequent sites of involvement. Chondromyxoid
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7 8
fibromas also have been reported to involve the cranio-
facial bones, the ribs, the clavicle and sternum, the spine,
and the short tubular bones of the hands and
feet.222,226,232,252,257,264 The peak age incidence and most
common sites of skeletal involvement are shown in
Figure 6-61.
Clinical Symptoms
Pain is the most common presenting symptom in chon-
dromyxoid fibroma and is sometimes of several years’
duration. In some cases, local swelling of the soft tissue
overlying the lesion can be noted clinically.
Radiographic Imaging
Chondromyxoid fibromas are typically benign-appearing,
oval, eccentric, metaphyseal lesions with long axes paral-
lel to that of the bone.231,234,247,265,278 They may extend into
the epiphyseal and diaphyseal regions, but it is unusual
for the tumor to cross an open growth plate (Fig. 6-62).
The intramedullary margins of the tumor are character-
istically sharply defined with sclerotic and scalloped
borders (see Fig. 6-62 to 6-64). When the narrow zone
of marginal sclerosis is lacking, the radiologic diagnosis
is more difficult.
 6  Benign Cartilage Lesions 427

C D
FIGURE 6-62  ■  Chondromyxoid fibroma: radiographic and microscopic features. A, Plain radiograph of large chondromyxoid fibroma
of distal femoral metaphysis in a 10-year-old girl. Lesion is completely radiolucent, sharply marginated, and eccentric in location.
B, Axial computed tomogram of lesion in A shows eccentric location on medial aspect of metaphysis. C and D, Intermediate and
low power photomicrographs showing loose fibromyxoid tissue gradually merging with hypercellular areas characteristic of chon-
dromyxoid fibroma (C, ×100; D, ×50) (C-D, hematoxylin-eosin.)

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428 6  Benign Cartilage Lesions

A B

C D

FIGURE 6-63  ■  Chondromyxoid fibroma: radiographic features. A-D, Chondromyxoid fibromas of ilium in four adults: A, A 55-year-old
man; B, a 19-year-old man; C, a 36-year-old woman; and D, a 60-year-old man. All four lesions are contiguous with iliac crest or
sacroiliac joint.

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 6  Benign Cartilage Lesions 429

A B

C D

FIGURE 6-64  ■  Chondromyxoid fibroma: radiographic features. A and B, Lateral and oblique radiographs of eccentric metaphyseal
distal tibial chondromyxoid fibroma. Note sclerotic scalloped medullary margin. C, Lytic lesion involving the third proximal phalan-
geal base. Note the absence of eccentricity, a frequent feature of chondromyxoid fibromas when it involves short tubular bones.
D, Lytic lesion in distal phalanx of great toe of a 30-year-old man. Note central location of lesion, typical in small bones.

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430 6  Benign Cartilage Lesions
The lesions are usually totally lytic, but matrix cal-
cification can rarely be seen on radiographs. Histologic
evidence of calcification is more frequently seen than
radiographic evidence. Eccentric expansion of the cortex
may be present; when marked, it may represent the for-
mation of a secondary aneurysmal bone cyst. Computed
tomography and MRI are useful to evaluate precisely
the intramedullary and soft tissue components of chon-
dromyxoid fibroma. On T1-weighted MRIs, chondro-
myxoid fibromas have hypointense to intermediate signal
intensity. On T2-weighted images, lesions typically show
some degree of signal enhancement. Contrast-enhanced
images show either diffuse or nodular signal enhance-
ment.242,247,267 On fluorodeoxyglucose positron emission
tomography (FDG PET) chondromyxoid fibromas are
metabolically active and show an increased uptake of
FDG.237
In small bones of the hands and feet, chondromyxoid
fibromas are usually central, uniformly expanding the
bone, but eccentric lesions can also occur104 (Fig. 6-64).
Lesions in the flat bones (e.g., pelvis) may be large and
irregular in outline with prominent intralesional locula-
tions (Fig. 6-63). Rib lesions can show fusiform expansion
or marked eccentricity when associated with secondary
aneurysmal bone cyst. Involvement of vertebrae may be
associated with radiographic findings that deviate from
the benign appearance usually seen with chondromyxoid
fibroma. The vertebral and sacral lesions may appear to
extend beyond the cortical confines of the bone into the
spinal canal.255 Examples of intracortical, juxtacortical
subperiosteal as well as epiphyseal chondromyxoid
fibroma have been described.225,233,241,246,258
Gross Findings
Chondromyxoid fibroma presents as a firm, gray-white
lobulated mass that is sharply demarcated. The lesion is
eccentrically located and is always confined by intact
periosteum, even when the cortical shell is not docu-
mented on radiographs. Areas of semisolid, myxoid
appearance may be identified, but chondroid foci are not
usually seen grossly.
Microscopic Findings
Chondromyxoid fibroma typically has an overall pseudol-
obulated architecture with myxomatous and chondroid
areas separated by zones of hypercellular mononuclear
tissue containing sparse multinucleated giant cells (Fig.
6-65).229,234,244,247,254,266,269 The basic component of this
lesion seems to be immature myxoid mesenchymal tissue
that has undergone cartilaginous differentiation (see Figs.
6-66 to 6-68). The myxoid areas form a geographic or
pseudolobulated pattern. The cellularity of myxoid areas
composed of stellate or plump spindle cells increases at
their peripheries (see Figs. 6-65 and 6-66). Areas of solid
cellularity are composed of plump, oval mononuclear
cells representing chondroblasts; sparse multinucleated
giant cells may intervene between pseudolobules (Fig.
6-69). The tumor cells within pseudolobules may be
pleomorphic and show hyperchromatism and multinu-
cleation. Sometimes, large, bizarre hyperchromatic nuclei
ERRNVPHGLFRVRUJ
are present. Because of these cellular characteristics, a
diagnosis of chondrosarcoma may be considered. Mitoses
are extremely rare in this tumor. Areas of more mature
cartilaginous differentiation with fine or coarse calcifica-
tions may be present. In general, some of the microscopic
features of chondromyxoid fibroma overlap with those of
chondroblastoma. In fact, in some cases it can be difficult
to distinguish the two entities on purely microscopic
grounds. In such instances, the radiographic features help
resolve the ambiguity.
Deviation from this classic pattern may cause diagnos-
tic difficulties. Extensive coarse calcification occasionally
obscures the lobular structure of the lesion. In general,
heavily calcified lesions are more often found in older
patients and in unusual sites such as the pelvis. Multi-
nucleated giant cells may not be present, and the exten-
sive myxoid change can alter the pseudolobulated
structure. Often, but not universally, lesions that lack
giant cells do not exhibit chondroblastic differentiation.
An aneurysmal bone cyst may be present in association
with chondromyxoid fibroma and typically correlates
with the radiographic features of an expansile multilocu-
lated lesion.
Special Techniques
Ultrastructurally, chondromyxoid fibromas are composed
of immature stellate mesenchymal cells with long, irregu-
lar processes embedded in a loose myxoid matrix (Fig.
6-70). The cells of the pseudosepta have ultrastructural
features similar to those seen in chondroblastoma; that
is, they show inner nuclear membrane thickening and
aggregates of glycogen in their cytoplasm260,262,263 (Fig.
6-71). Immunohistochemically, the cells of the myxoid
zones and the cells of hypercellular pseudosepta are
weakly positive for S-100 protein.223,263,269 The cells within
the areas that exhibit more mature chondroblastic dif-
ferentiation are typically strongly positive for S-100,
whereas the cells of the loose myxoid areas show only
focal positivity for S-100 protein. All of these features
indicate that chondromyxoid fibroma is cartilaginous in
nature, but it represents a less mature, earlier level of
cartilaginous differentiation than that seen in chondro-
blastoma. The chondroblastic nature of cells in chondro-
myxoid fibroma is further confirmed by the expression of
SOX9 protein.151,239,243 Similar to chondroblastomas,
chondromyxoid fibromas are in general negative for
osteoblastic lineage markers such as RUNX2 and
Osterix.151 Expression and morphologic comparative
studies with fetal bone indicate that there is substantial
similarity between chondromyxoid fibroma and vascular-
ized fetal cartilage canals.270 Chondromyxoid fibromas
may show focal positivity for SMA and MSA, a feature
of their partial myofibroblastic differentiation that may
contribute to confusing this tumor with other myxoid
mesenchymal neoplasms.249 Genome-wide expression
studies indicate that chondromyxoid fibroma has a profile
distinct from that of other cartilage neoplasms such as
chondroblastoma, enchondroma, and chondrosarcoma.250
Chondromyxoid fibromas show focal deposition of type
II collagen. In addition, they may also show expression
Text continued on p. 438
 6  Benign Cartilage Lesions 431

A B

C D
FIGURE 6-65  ■  Chondromyxoid fibroma: microscopic features. A and B, Periphery of pseudolobule shows both stellate and spindle
cells in loose myxoid stroma and sheets of more rounded cells resembling chondroblasts mixed with multinucleated giant cells.
C and D, Higher magnification of peripheral and central areas of pseudolobule shows details of chondromyxoid fibroma cells.
(A, ×100; B-D, ×200.) (A-D, hematoxylin-eosin.)

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432 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-66  ■  Chondromyxoid fibroma: microscopic features. A and B, Intermediate and low power photomicrographs showing
loose fibromyxoid stromal tissue with scattered chondromyxoid fibroma cells. Note gradual transition from hypocellular to
hypercellular areas. C and D, Paucicellular mucinous areas of the tumor shown in A and B. (A, C, and D, ×50; B, ×100.)
(A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 433

B
FIGURE 6-67  ■  Chondromyxoid fibroma: microscopic features. A and B, Medium power photomicrographs showing stellate and
spindle cells in myxoid stroma. (A and B, ×200) (A and B, hematoxylin-eosin.)

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434 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-68  ■  Chondromyxoid fibroma: microscopic features. A and B, Ill defined hypercellular areas showing chondromyxoid
fibroma cells dispersed in somewhat eosinophilic stromal tissue. C and D, Variants of stromal background in chondromyxoid fibroma
showing more eosinophilic matrix in C and a mixture of hyalinized and myxoid tissue in D resembling early chondroid matrix with
lacunar spaces. (A and C, ×50; B and D, ×100.) (A-D, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 435

B C
FIGURE 6-69  ■  Chondromyxoid fibroma: microscopic features. A, Hypercellular areas of chondromyxoid fibroma gradually transition-
ing to an immature chondroid matrix. B, Higher magnification of A showing early cartilage matrix formation. C, Higher magnification
of A showing hypercellular area. Note the similarity of hypercellular area of chondromyxoid fibroma to chondroblastoma. (A, x100;
B and C, ×200) (A-C, hematoxylin-eosin.)

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436 6  Benign Cartilage Lesions

B
FIGURE 6-70  ■  Chondromyxoid fibroma: ultrastructural features. A, Tumor cells at periphery of pseudolobule with primitive spindle
and stellate cells (left) and rounded chondroblast-like cells in septal zone (right). B, Higher magnification of stellate cell from myxoid
central zone (A, ×6000; B, ×14,000).

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 6  Benign Cartilage Lesions 437

FIGURE 6-71  ■  Chondromyxoid fibroma: ultrastructural features. A, Septal cells of chondromyxoid fibroma show spindled
chondroblast-like cells. Inset, Abundant cytoplasmic glycogen. B, Higher magnification of A shows spindle chondroblastic cells with
granular endoplasmic reticulum and mitochondria. Inset, Indented nucleus and thick nuclear fibrous lamina (arrowheads). (A, ×6000;
inset, ×16,000; B, ×12,000; inset, ×30,000.)

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438 6  Benign Cartilage Lesions
of collagen types I, III, and VI. The less cellular myxoid
portions of the tumor are characterized by the presence
of hydrated proteoglycans and only minor amounts of
collagens.256 Cytogenetically, chondromyxoid fibromas
are characterized by chromosome 6 aberrations that are
heterogeneous in nature. The commonly involved regions
include 6p23-25, 6q12-15, and 6q23-27.227,235,236,248,251,259,268
The rearrangements involving inv(6)(p25q13) and t(6,9)
(q25; q22) are the most frequent and may represent
sole cytogenetic abnormalities or may be present in the
background of other karyotypic anomalies. In general,
the cytogenetic findings imply the involvement of
chimeric genes in the development of chondromyxoid
fibroma, but the genetic alterations are heterogeneous
and result in cryptic rearrangements.224,248 Abberations
involving 6q13-21 were linked to the locally aggressive
behavior of cartilage tumors, including chondromyxoid
fibroma.253
Differential Diagnosis
Conventional chondrosarcoma may be confused with chon-
dromyxoid fibroma when myxoid stromal changes pre-
dominate and there is prominent peripheral cellularity in
the lobules. The presence of large amounts of well-
formed hyaline cartilage matrix helps distinguish chon-
drosarcoma from chondromyxoid fibroma. The latter
usually contains little or none of that matrix. Further-
more, the central multinucleated atypical cells in chon-
drosarcoma lobules most often lie within lacunae and lack
the long cytoplasmic processes characteristic of chondro-
myxoid fibroma. The resemblance to dedifferentiated chon-
drosarcoma can be resolved by the absence of an abrupt
transition between the spindle cells and the gradual
merging with the central myxoid areas. In both forms of
chondrosarcoma, the radiologic findings differ markedly
from the sharply defined chondromyxoid fibroma with
scalloped sclerotic borders.
The presence of zones of chondroblastic differentia-
tion surrounding the myxoid pseudolobules in some
chondromyxoid fibromas may raise the possibility of
chondroblastoma as the diagnosis. This morphologic
overlap may extend to the radiologic features when the
normally metaphyseal chondromyxoid fibroma occupies
a position that bridges the growth plate into the epiphysis
of a long bone. The presence of abundant calcification
both radiologically and histologically favors the diagnosis
of chondroblastoma.
Myxomas of bone, also referred to as extragnathic fibro-
myxomas, may be distinguished from chondromyxoid
fibroma by their lack of pseudolobulation and the
absence of pleomorphism or atypia in the stellate or
spindle cells.
Treatment and Behavior
Primary and preferable treatment of chondromyxoid
fibroma should be en bloc resection. Simple curettage is
likely to leave tumor behind and contribute to recur-
rence. The overall recurrence rate is approximately 20%
and does not correlate with any histologic features of
the lesion. The recurrence can be within the bone at the
ERRNVPHGLFRVRUJ
site of curettage, in the adjacent soft tissue, or rarely
in both.238,245,261
Radiation therapy has been used to treat surgically
inaccessible tumors. However, in rare instances the devel-
opment of high-grade sarcomas have been reported in
association with this approach.230 One case in our consul-
tation series illustrated a potential complication of this
approach.269 A 20-year-old woman with chondromyxoid
fibroma of a cervical vertebra was treated with intrale-
sional excision and radiation therapy. Seven years later
she had an acute cervical spinal compression caused by a
malignant fibrous histiocytoma.
Spontaneous malignant transformation in chondro-
myxoid fibroma is an extremely rare and somewhat con-
troversial phenomenon. An example of such complications
is shown in Figure 6-72, which documents a chondro-
myxoid fibroma of the scapula with a history of multiple
local recurrences spanning almost a decade with the
involvement of adjacent soft tissue in the form of satellite
nodules. Microscopically, the tumor showed obvious
atypia but retained readily recognizable features of chon-
dromyxoid fibroma.
Personal Comments
Chondromyxoid fibromas are among the rarest of bone
tumors, and yet errors in diagnosis are relatively common.
Most of these errors involve myxoid chondrosarcomas
that are misinterpreted as chondromyxoid fibromas. If a
significant period of time intervenes between the diagno-
sis and the first evidence of malignant behavior, these
instances may be classified incorrectly as malignant trans-
formation of chondromyxoid fibromas.
Conversely, chondromyxoid fibromas may be overdi-
agnosed as chondrosarcomas because of the nuclear pleo-
morphism of the stellate cells in myxoid areas and the
high cellularity of the pseudosepta. Careful attention to
the radiographic features of sharp circumscription of the
scalloped sclerotic borders in a young patient are helpful
in avoiding this diagnostic pitfall. An eccentrically placed,
crisply demarcated metaphyseal lesion in the long bone
of an extremity of a child or adolescent is likely to be a
chondromyxoid fibroma in spite of any abundance of
myxoid change.
OSTEOCHONDROMA
By convention, osteochondroma or osteocartilaginous
exostosis is considered an anomaly of the hamartomatous
type that occurs in two distinct clinical settings: as a
solitary lesion (solitary osteochondroma) or as multiple
hereditary exostoses associated with other anomalies of
skeletal modeling. Because both conditions are linked to
defects in EXT1 and EXT2 genes, which are involved in
the development of solitary, sporadic, and hereditary
multifocal forms of the disease, an osteochondroma
should be considered a unique form of a benign bone
tumor rather than a hamartoma (Fig. 6-73). The cartilage
cap in the majority of sporadic and hereditary multifocal
osteochondromas is composed of a mixture of wild-type
and mutated cells.
 6  Benign Cartilage Lesions 439

A B

C D
FIGURE 6-72  ■  Chondromyxoid fibroma with aggressive clinical behavior: microscopic features. A, Irregular paucicellular myxoid
areas gradually transitioning to areas of hypercellularity. B, Higher magnification of A showing a transition between paucicellular
and hypercellular areas of the tumor. C, Large hypercellular areas of the tumor with atypia (×100). D, Higher magnification of
C showing cellular pleomorphism and nuclear atypia of tumor cells. Inset, Higher magnification of two highly atypical tumor
cells with dense oval cytoplasm. After original treatment, the tumor showed multiple local recurrences with invasion and
satellite nodules in the adjacent soft tissue over a period of nearly a decade. (A and C, ×100; B, ×200; D, ×400; inset, ×600)
(A-D, hematoxylin-eosin.)

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440 6  Benign Cartilage Lesions

EXT1 EXT2
Chr 8 Chr 11
Exon 11

Exon 10

Exon 10
Exon 11

Exon 12
Exon 13
Exon 14
Exon 15
Exon 9

Exon 8

Exon 7
Exon 6
Exon 5

Exon 4

Exon 3
Exon 2

Exon 1

Exon 1

Exon 2
Exon 3
Exon 4
Exon 5
Exon 6
Exon 7

Exon 8

Exon 9
23.3 23.2 15.5
118810000

119120000
15.4

44117098

44270000
23.1 15.3
15.2
22 15.1
21.3 21.2 14
21.1
12 13
12
11.2
11.1 11.1 11.2 EXT2
11.22 11.21
11.23
EXT1 11.11 11.12
11
EXT2
12 12
13 Transmembrane helicos 13.1
13.2
21.1 Low complexity 13.4 13.3
13.5 alpha-1,4-N-
21.2 Exostosin Glycosyl transferase 64 14.1
14.2 Exostosin acetylhexosaminyltransferase
21.3 14.3
21
22.1 1 746 aa 22.1 1 718 aa
22.2 22.2
22.3 22.3
111 396 480 729 23.1 101 380 456 701
23.2
23 EXT1 7 26 29 41 23.3
24.1 24
24.2 25
24.3
1 746 aa 135006516 bp 1 718 aa
146364022 bp
Synonymous substitution Synonymous substitution
Missense substitution Missense substitution
A B
HS6ST1
HS6ST2
EXTL3
HS6ST3
FGFR HSGLCE Antithrombin GLCAT1 GALT1
6S 6S 6S 6S 6S
1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-4 1-3 1-4 1-4 

NS NS 2S FGF 2S NS NS 2S NS n
3S
EXT1 GALT2 XYLT1
NDST1 HS2ST EXT2 XYLT2
NDST2 HS3ST1–6
NDST3
NDST4 Gal Xyl GlcA IdoA GlcNAc GalNAc

C
Disaccharide repeating region Linkage region
i) in the presence of EXT1
EXT1/EXT2
Polymerization Initiation
GlcNAcT-II/GlcAT-II GlcNAcT-I

GLcUA GlcNAC GLcUA GlcNAC GLcUA GlcNAC GlcUA Gal Gal Xyl Ser

EXTL1 ? EXTL3
EXTL3 ? (EXTL2 ?)

ii) in the absence of EXT1 EXT2 EXTL2

Polymerization Initiation
GlcNAcT-II/GlcAT-II GlcNAcT-I

GLcUA GlcNAC GLcUA GlcNAC GLcUA GlcNAC GlcUA Gal Gal Xyl Ser
D

FIGURE 6-73  ■  Molecular mechanisms of multiple hereditary exostosis. A, Chromosomal location, exonal structure, and functional
domains of the EXT1 gene. B, Chromosomal location, exonal structure, and functional domains of the EXT2 gene. C, Assembly of
heparin sulfate and formation of binding sites for ligands. (C, Reprinted with permission from Bishop JR, et al: Nature 446:1030-1037,
2007.) D, Deficiency of heparin sulfate synthesis when one EXT gene is deficient in its function caused by a mutation. An example
shows the assembly of heparin sulfate when EXT1 is inactivated by a mutation. (D, Reprinted with permission from Okada M, et al:
Biochem J 428, 463-471, 2010.)

ERRNVPHGLFRVRUJ

Initial cytogenetic studies performed on patients
and families affected by multiple hereditary exostosis
identified putative loci of the disease mapping to chro-
mosomes 8, 11, and 19.299,315,325 These data guided the
cloning of EXT1 and EXT2 genes mapping to 8q24 and
11p11-13, respectively.271,320 Subsequently, it was shown
that EXT1 and EXT2 genes were also involved in the
development of solitary osteochondromas.
The EXT genes encode exostosin glycosylase 1 and 2,
which are type II transmembrane glycoproteins that form
a Golgi-localized heterooligomeric complex involved in
heparin sulfate (HS) proteoglycan biosynthesis.274,276,286,296
In the presence of functional EXT genes, an EXT1-EXT2
complex has dual functions to initiate HS biosynthesis
and to polymerize HS chains. HS proteoglycans are
essential regulators of endochondral ossification, forming
an osmotic gradient around epiphyseal chondrocytes and
controlling critical signal transduction pathways involved
in the longitudinal growth of bone.274,323 In the absence
of one of the EXT genes, most often the EXT1 gene, the
remaining gene alone cannot effectively execute the HS
polymerization and a shorter HS form is synthesized in
EXT-deficient cells.287,308 The EXT genes are inactivated
by mutations and large deletions, most likely in cartilage
precursor cells involved in the development of an epiphy-
seal cap.289,293,294,301,311,312 Loss of HS related signal trans-
duction is responsible for the proliferative advantage
of epiphyseal chondrocytes via activation of Hedgehog
and Wnt signaling. The perturbation of Hedgehog and
Wnt signaling pathways is considered to disrupt the
pattern of enchondral ossification in the growth plate,
resulting in defective formation of the bony collar.306
As a result, EXT mutated and HS deficient cells lose
polarity, continue to grow, and by recruiting other normal
cells form an osteochondroma.279,286 In solitary osteo-
chondromas the inactivation of EXT genes is somatic
and restricted to the cartilage cap of the lesion.312 Fami-
lies affected by multifocal hereditary exostosis carry
germline alterations of EXT genes in the form of point
mutations or large deletions.312,318,322,326 In such instances,
the germline alterations are heterozygotic while the
lesional tissue frequently, but not always, shows homozy-
gous loss of EXT function.294,302,316,329 Interestingly not
all patients with multiple hereditary osteochondromas
carry the alterations of EXT1/EXT2 genes, and alterna-
tive mechanisms with involvement of microRNA that
disturbs the cartilage development signaling have been
postulated.298,327,330
Solitary Osteochondroma
(Osteocartilaginous Exostosis)
Osteochondromas are classified as benign bone tumors,
and it was originally postulated that they result from
aberrant epiphyseal development with displacement of
physeal cartilage through the perichondrial fibrous ring
and subsequent growth at right angles to the long axis of
the bone.304 Indeed, lesions indistinguishable from osteo-
chondromas have been produced experimentally by sur-
gical implantation of growth plate cartilage beneath
the periosteum in animals.277 Although the majority of
ERRNVPHGLFRVRUJ
6  Benign Cartilage Lesions 441
solitary osteochondromas are sporadic de novo lesions, a
small number have been reported to develop after exter-
nal irradiation for malignant nonosseous tumors in child-
hood such as Wilms’ tumor and neuroblastoma.283,300 The
secondary osteochondromas have developed in metaphy-
seal areas of the vertebral column and pelvis, up to 16
years after irradiation.
Definition
Solitary osteochondroma is a developmental anomaly of
bone that results in the formation of an exophytic out-
growth on the surface of bone. It is composed of a mature
bony stalk that is covered by a cartilaginous cap. Other
terms applied include osteocartilaginous exostosis and simple
exostosis.
Incidence and Location
Solitary osteochondroma is the most common benign
tumorlike lesion, accounting for approximately 35% of
benign bone tumors and 10% of all bone tumors in any
major series. Osteochondromas have a definite male sex
predominance, and the male-to-female sex ratio is 1.8 : 1.
Osteochondromas have a predilection for the appendicu-
lar skeleton and most frequently occur on the surface of
metaphyseal portions of major long tubular bones. The
knee area is most frequently affected, with approximately
35% of cases occurring in this site. The proximal femoral
and humeral metaphyses are the next most common sites.
Osteochondromas also frequently occur in the flat bones
and often involve the ilium and scapula. They are rare
in small tubular bones of the hands and feet, in the ribs,
and in the vertebral column.273,285,328 Osteochondromas
practically never occur in the craniofacial bones. Figure
6-74 depicts the peak age incidence and most common
skeletal sites.
Clinical Symptoms
A hard swelling, usually of many years’ duration, is the
most common symptom. In rare cases a fracture, usually
at the base of the stalk, can be a presenting symptom. A
bursa may be present over the cap, which may become
inflamed or accumulate synovial fluid or loose bodies,
thereby producing symptoms.275,280,284 Nerve or blood
vessel impingement also may call attention to the pres-
ence of an osteochondroma.288,319
Radiographic Imaging
The typical radiographic presentation is that of a pedun-
culated surface lesion of bone arising from the metaphy-
sis (see Figs. 6-75 and 6-76). The lesion is composed of
a mature bony stalk that is continuous with the adjacent
cortex and underlying spongiosa. The long axis of the
stalk points away from the nearest joint. The stalk is
frequently slender, and its extremity is covered by a
lobulated cartilaginous cap that may contain calcifica-
tions.291,305,313,317 Especially in the flat bones, the lesion can
have a broad base that presents as a sessile surface mass
442 6  Benign Cartilage Lesions
Peak
incidence
10 30
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 6-74  ■  Osteochondroma. Peak age incidence and most frequent sites of skeletal involvement. Most common side is indicated
by a large solid black arrow.
(see Figs. 6-76 and 6-77). The stalk can measure several
centimeters along its long axis, but the cartilage cap is
typically thin (2 to 3 mm). The sessile lesions are larger,
and occasionally they can have a base that measures
more than 10 cm in greatest dimension. A long bone
harboring a solitary osteochondroma can show slight
localized distortion of the contour at its base, but the
overall modeling deformity, clubbing of the bone end,
and growth disturbance typical of multiple hereditary
exostoses are absent. The thickness of the cartilaginous
cap can occasionally not be evaluated on plain radio-
graphs, but MRI can provide a more precise assessment
of thickness. Large sessile osteochondromas may be dif-
ficult to distinguish from other cartilage-containing bone
surface lesions (see Figs. 6-76 to 6-79). In such instances,
CT and MRI may be needed to evaluate the architecture
of the lesion in question. These scans are also helpful in
establishing the continuity of the lesion with the adjacent
cortex and underlying spongiosa.
An overlying bursa (exostosis bursata) may be present
external to the cartilaginous cap. The bursa can develop
synovial chondromatosis and produce a mass adjacent to
the lesion that contains punctate calcifications (Fig. 6-75).
ERRNVPHGLFRVRUJ
7 8
This phenomenon may raise the radiographic suspicion
of secondary chondrosarcoma. The body and stalk of an
osteochondroma also may show irregular calcific densi-
ties that represent unresorbed calcified cartilage. These
may also contribute to the impression of secondary neo-
plastic change.
Gross Findings
The external surface of an osteochondroma shows a lobu-
lated cartilage cap covered by a fibrous membrane (peri-
chondrium) that is continuous with the periosteum
covering the stalk (Fig. 6-78). The cartilage cap covers
the distal part of a pedunculated osteochondroma and the
elevated surface of a sessile one (see Figs. 6-78 to 6-81).
The cut surface shows the hyaline composition of the
cap, which usually measures from 2 mm to 1 cm in thick-
ness. At the junction of the cartilage cap with underlying
spongiosa, a narrow, wavy, chalklike zone that corre-
sponds to the zone of provisional calcification of an
epiphyseal plate is present (see Figs. 6-80 and 6-81). This
reflects the endochondral ossification sequences present
Text continued on p. 450
 6  Benign Cartilage Lesions 443

A B

C D
FIGURE 6-75  ■  Osteochondroma: radiographic features. A, Pedunculated osteochondroma of the proximal tibial metaphysis in
a skeletally immature individual. B, Sessile osteochondroma of the proximal fibula and in a skeletally immature individual. Inset.
Axial computed tomogram (CT) showing a sessile osteochondroma originating in the fibula. Note the continuity between the
internal space of osteochondroma and the underlying medullary cavity of the involved bone. Inset, Axial CT showing an osteochon-
droma arising from the fibula. C, Pedunculated osteochondroma of the distal femoral metaphysis in a skeletally immature individual.
D, Pedunculated osteochondroma of the distal femoral metaphysis with synovial chondromatosis in bursa overlying the
cartilage cap.

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444 6  Benign Cartilage Lesions

B C

D E
FIGURE 6-76  ■  Osteochondroma: radiographic features. A, Osteochondroma involving the clavicle. B, Axial computed tomogram (CT)
showing an osteochondroma originating in the clavicle. C, Osteochondroma of the costal aspect of the scapula. D, Anteroposterior
radiograph showing a large broad-based osteochondroma arising from the neck of the left femur. E, Lateral radiograph showing a
large broad-based osteochondroma arising from the posterior aspect of the proximal tibia. Inset, T1-weighted axial magnetic reso-
nance image showing a large osteochodromatous mass arising from the posterior aspect of the tibial surface.

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 445

B
FIGURE 6-77  ■  Osteochondroma: radiographic features. A, A large osteochondroma originating from the superior pubic ramus.
B, Large osteochondroma originating from the plantar surface of the calcaneus.

ERRNVPHGLFRVRUJ
446 6  Benign Cartilage Lesions

A B

C D

E F
FIGURE 6-78  ■  Osteochondroma: gross features. A and B, Surface and bisected broad-based osteochondroma arising from the proxi-
mal fibular metaphysis. Note lobulated cartilage cap. C and D, Surface and bisected peduculated osteochondroma arising from the
proximal femoral metaphysis. E and F, Bisected broad-based osteochondroma with a corresponding specimen radiograph arising
from the proximal fibular metaphysis.

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 447

A B

C E
FIGURE 6-79  ■  Osteochondroma: radiographic and gross features. A and B, Oblique radiograph and axial computed tomogram (CT)
of a large osteochondroma arising from calcaneus. Inset, Bisected osteochondroma. Note the thick cartilaginous cap. C and
D, Anteroposterior radiograph and axial CT showing a large sessile osteochondroma of the clavicle. E, Bisected resection specimen
of the case in C and D showing an irregular thick cartilage cap covering the surface of this osteochondroma.

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448 6  Benign Cartilage Lesions

A B

C D

FIGURE 6-80  ■  Osteochondroma: gross features. A-D, External surface and serial sections of a large broad-based osteochondroma
arising from the iliac surface.

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 6  Benign Cartilage Lesions 449

A B

C D

FIGURE 6-81  ■  Osteochondroma: gross features. A and B, Cut surface and macrophotograph of histologic sections show relationship
of cartilage cap to underlying cancellous bone in sessile osteochondroma. C and D, Cut surface and whole-mount macrophotograph
of narrow pedicled osteochondroma show cartilage cap at surface.

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450 6  Benign Cartilage Lesions
in all osteochondromas in the growing skeleton. In adults
the cartilage cap may be extremely thin or absent because
endochondral ossification and growth of the osteochon-
droma cease at skeletal maturation or shortly thereafter.
In young children, actively growing osteochondromas
typically , have a cartilaginous cap that exceeds 1 cm in
thickness (Fig. 6-79). In such instances, the thickness of
the cap exceeding 1cm should not be used as a feature
of malignant transformation and the development of
chondrosarcoma. Deep to the cap, the central portion of
the spongy bone may contain irregular islands of calcified
cartilage that can be seen grossly as gritty, opaque white
deposits. The spongiosum of the stalk is continuous with
the cancellous bone of the underlying medullary cavity
and is bordered by compact cortical bone that flares from
the adjacent cortex.
Microscopic Findings
The cartilage cap is composed of moderately cellular
hyaline cartilage that in a young individual recapitulates
all the zones of an epiphyseal growth plate (see Figs. 6-82
and 6-83). The periphery is covered by a fibrous peri-
chondrium that blends imperceptibly with the outer layer
of hyaline cartilage. At the junction with the underlying
cancellous bone, the cartilage of the cap shows all of the
microscopic features of endochondral ossification, and it
is through this mechanism that an osteochondroma
grows during childhood and adolescence (see Figs. 6-82
and 6-83). This process decelerates and ceases at skeletal
maturation (Fig. 6-84). As cell replication diminishes in
the cartilage cap, its thickness diminishes, and it may
entirely disappear in older adults. The spongy bone
beneath the cap may contain one or more irregular
masses of necrotic calcified chondroid, which represent
unresorbed portions of the calcified zone of the cap.
These masses often can be seen on plain radiographs as
jagged opacities. The cartilage cap may show foci of
increased cellularity, and individual atypical and even
multinucleated chondrocytes may be present. These foci
do not form discrete nodules but blend imperceptibly
with the rest of the cap (Fig. 6-85).
The bursa that may form at the periphery of some
osteochondromas is usually intimately attached to the
perichondrium of the cap.277,284 The bursal wall is lined
by synovium that may show inflammatory changes with
the formation of fibrinous rice bodies. In some cases,
chondroid metaplasia in this bursal synovial lining can
be associated with numerous cartilaginous loose bodies
in the bursa. If calcified, these metaplastic chondroid
synovial nodules can simulate secondary chondrosarcoma
on radiographs.
Differential Diagnosis
The most important lesion to distinguish from osteo-
chondroma is parosteal osteosarcoma. This surface malig-
nancy of bone is characteristically more radiodense
than an osteochondroma, especially at the base and
center of the bony excrescence. The cartilage cap some-
times found at the periphery of a parosteal osteosarcoma
ERRNVPHGLFRVRUJ
differs from that of an osteochondroma because it con-
tains cytologically malignant cartilage cells without evi-
dence of enchondral ossification at the interface
with the underlying bony and spindle-cell components.
Unless a fracture has occurred in the stalk of an osteo-
cartilaginous exostosis, the cancellous bone is composed
of mature lamellar trabeculae with fatty marrow. Conti-
nuity with the marrow cavity of the underlying bone
can be found consistently in osteochondromas, and
an intact cortex is usually present beneath a parosteal
osteosarcoma.
Juxtacortical myositis ossificans and other posttraumatic
surface lesions (florid reactive periostitis, subungual exostosis,
bizarre parosteal osteocartilaginous proliferation) can also be
confused with an osteocartilaginous exostosis. All these
reactive processes have the distinguishing feature of an
intact cortex beneath their attachments to bone. There
is no flaring of the cortical bone into the lesion and no
continuity with the undisturbed cancellous bone of the
adjacent medullary cavity that characterizes osteochon-
dromas. The reactive bony excrescences are most com-
monly found on the surfaces of short tubular bones of the
hands and feet.
Periosteal chondroma can occasionally simulate a sessile
osteochondroma on radiographs, but this lesion rests on
an intact cortex and lacks the cancellous bone composi-
tion of an osteochondroma’s stalk.
Treatment and Behavior
Osteochondromas are benign lesions with self-limited
growth that ceases after skeletal maturity. In fact, some
osteochondromas may spontaneously regress.272,310,324
They are usually treated by simple excision for cosmetic
reasons or when symptoms of pain, limitation of motion,
or impingement on adjacent structures such as nerves and
blood vessels become clinically manifest.288,295,309,319,325
Recurrence after surgical excision is rare but may
develop when a portion of the cartilage cap or attached
perichondrium is left in situ. In solitary osteochondro-
mas, the risk of secondary malignant change is low
and is discussed later in connection with multiple
osteochondromas.
Multiple Hereditary Exostoses
Synonyms for multiple hereditary exostoses include
diaphyseal aclasia and multiple osteochondromas. Mul-
tiple hereditary exostoses are an autosomal dominant
hereditary disorder transmitted by both sexes with
incomplete penetrance in female patients, which results
in a slight male predominance. It is characterized by the
presence of multiple osteochondromas associated with
bone deformities of the affected sites (see Figs. 6-86 to
6-88). Growth disturbances with shortening of the
affected bones and bowing deformities of paired bones
are frequently present.291,292,313,317 Osteochondromas in
this syndrome tend to be larger and more sessile
with abundant lobulated cartilage caps than typical soli-
tary exostoses. Similar to solitary osteochondroma,
Text continued on p. 458
 6  Benign Cartilage Lesions 451

B
FIGURE 6-82  ■  Osteochondroma: microscopic features. A, Low power microphotograph showing cartilage cap that is undergoing
enchondral ossification at the base with overall architectural features recapitulating the growth plate. B, Higher magnification of
A showing a zone of enchondral ossification at the interface of the cartilage cap and cancellous bone. Inset, Columns of hypertrophic
chondrocytes at the base of the cartilage cap (×200). (A,B, and inset, hematoxylin-eosin.)

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452 6  Benign Cartilage Lesions

B
FIGURE 6-83  ■  Osteochondroma: microscopic features. A and B, Zones of ossification at the base of cartilage caps in enchondroma.
Inset, Whole-mount photomicrograph showing cap-shaped cartilage areas on the surface of osteochondroma transitioning via
the enchondral ossification pattern to cancellous bone within stalk. Note nodular growth pattern on some of the cartilage on surface
of osteochondroma. (A and B, ×100.) (A,B, and inset, hematoxylin-eosin.)

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 6  Benign Cartilage Lesions 453

B
FIGURE 6-84  ■  Osteochondroma: microscopic features. A and B, Low power photomicrographs of two osteochondromas with thin
cartilage layer showing no active enchondral ossification pattern. Such lesions are sometimes referred to as senescent osteochon-
dromas. Insets document low cellularity within the cartilage caps. Note the absence of columnar arrangements of hypertrophic
chondrocytes and the absence of enchondral ossification, both characteristic of actively growing osteochondromas. (A and B, ×50;
insets, ×100.) (A,B, and insets, hematoxylin-eosin.)

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454 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-85  ■  Osteochondroma: microscopic features. A-D, Microscopic features of cartilage caps composed of mineralized hyaline
cartilage matrix with disorganized growth pattern of chondrocytes residing in lacunar spaces. Enchondral ossification is present in
A. Note the absence of columnar arrangement recapitulating epiphysis. Such features are typically seen in independently growing
nodular cartilage areas on the surface of osteochondroma (A and B, ×100; C and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 455

A B
FIGURE 6-86  ■  Multiple hereditary exostoses: radiographic features. A and B, Anteroposterior and lateral radiographs of knee and
leg of teenage patient showing involvement of proximal and distal tibial metaphyses and fibular metaphysis. Note modeling defor-
mities of metaphysis resulting in broadening and loss of metaphyseal flare.

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456 6  Benign Cartilage Lesions

A B
FIGURE 6-87  ■  Multiple hereditary exostoses: radiographic features. A, Radiograph of tibia and fibula shows proximal and distal
metaphyseal osteochondromas and modeling defects. B, Lateral radiograph of left tibia and fibula shows symmetric proximal and
distal metaphyseal involvement (same patient as in A).

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 457

A B

C D

FIGURE 6-88  ■  Osteochondroma: radiographic and gross features. A, Anteroposterior radiograph of large proximal fibular osteochon-
droma projecting medially and posteriorly to tibia. B, Arteriogram of patient in A demonstrates deviation of major vessels and
compression. C, Specimen radiograph of osteochondroma of proximal fibula in A. Cortex of stalk of this broad-based exostosis is
continuous with that of fibula. D, Gross photograph of specimen shows unremodeled calcified cartilage remnants in osteochondroma
stalk.

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458 6  Benign Cartilage Lesions
multiple hereditary exostoses have a predilection for
the metaphyseal parts of the long tubular bones, espe-
cially of the lower extremity. The knee region is invari-
ably affected, so plain radiographs of the knees can be
used in the initial screening for this entity. The proximal
femur and the proximal humerus are the next most
common sites. The flat bones, such as the scapula and
pelvis, also are frequently involved. The membranous
bones of the skull are not affected. The disorder usually
involves bones of the extremities symmetrically. In severe
forms, widespread involvement of multiple skeletal sites
with severe bony deformities and functional impairment
is present.
The disorder usually is diagnosed during childhood
at an earlier age than solitary osteochondroma, often
because of the associated deformities and growth distur-
bances. Secondary deformities of the long tubular bones
include the so-called pseudo-Madelung’s deformity of the
forearm with ulnar shortening and bowing of the radius.
A similar deformity of the lower extremity results from
fibular shortening. Large osteochondromas of paired
bones can produce impingement excavations on the adja-
cent bone, a finding that can also occasionally be observed
with solitary osteochondromas. In addition to the gross
deformity produced by large osteochondromas, shorten-
ing of long bones, and bowing of long bones, there is
usually clubbing of long bone ends caused by altered
bone remodeling. This results in loss of the normal
metaphyseal-diaphyseal flare and produces a shortened,
broadened appearance of the femoral necks and other
long bone metaphyses.
The gross and microscopic features of osteochondro-
mas in multiple hereditary exostoses do not differ signifi-
cantly from those described for solitary osteochondroma.
Corrective surgery is often necessary in the manage-
ment of these patients to deal with the multiple secondary
deformities, growth disturbances, and functional impair-
ment. Individual symptomatic osteochondromas are
treated by surgical removal as in the management of soli-
tary osteochondroma.295,297 Lifetime surveillance of these
patients is mandated by the relatively high risk for the
development of secondary malignancy.
Malignant Transformation
in Osteochondroma
Because a significant number of solitary osteochondro-
mas are clinically silent and are undiagnosed, the real risk
of secondary malignancy is difficult to determine. More-
over, the data on the incidence of malignant change in
both solitary and multiple osteochondromas are derived
from surgically treated subpopulations and thereby add a
selection factor. This bias contributes to the artificially
high estimates of risk for the development of chondro-
sarcoma in published reports. The reported risk for soli-
tary osteochondromas is 1% to 2%, and it is 5% to 25%
for multiple osteochondromas. The figures for solitary
osteochondroma are more likely to be inflated for the
reason stated previously than those quoted for multiple
hereditary exostoses, a condition that is almost always
clinically symptomatic. Even in this group, analyses of
pedigrees in families with multiple hereditary exostoses
ERRNVPHGLFRVRUJ
suggest that the risk may be as low as 1% to 2%. The
average age at the onset of secondary malignancy in
osteochondromas is 30 years, about 15 years earlier than
that of de novo conventional chondrosarcoma.
The radiographic and pathologic criteria for the diag-
nosis of secondary malignancy in osteochondromas are
the same for solitary and multiple types. Clinically, malig-
nancy can be suspected when a sudden increase in size or
the onset of pain is noticed at the site of an osteochon-
droma.307 Radiographic signs of secondary malignancy
include the development of areas of lucency or the pres-
ence of an overlying soft tissue mass containing new and
separate areas of calcification (see Figs. 6-89 to 6-92).
Destruction of the base or adjacent bone is a clear-cut
sign of malignancy of high histologic grade. The devel-
opment of chondrosarcoma in large sessile osteochon-
dromas may be difficult to document on plain radiographic
images (see Figs. 6-90 and 6-91). CT and MRI are typi-
cally used for precise assessment of the thickness of the
cartilage cap and the presence of an independently
growing cartilage mass signifying the progression to
chondrosarcoma (Figs. 6-90 to 6-94). The malignancies
associated with solitary osteochondromas are typically
low-grade conventional chondrosarcomas.278,282,290,321 High-
grade sarcomas (malignant fibrous histiocytoma or
osteosarcoma) develop rarely in multiple hereditary exos-
toses.281,303 The series reported by Garrison et al.282 indi-
cates that secondary malignancies in solitary lesions are
evenly distributed regardless of anatomic site of the
osteochondroma, whereas those that complicate multiple
osteochondromas typically occur in the flat bones of the
trunk.
The pathologic criteria for diagnosis of low-grade
chondrosarcoma arising in osteochondroma are based
on gross (thickness of the cap) and microscopic features.
Increased thickness of the cartilage cap with the forma-
tion of discrete, grossly detectable peripheral nodules
that may extend outside the fibrous perichondrium is
present in the majority of typical cases. The thickened
cap usually exceeds 2 cm in the area of nodular prolif-
eration (see Figs. 6-95 and 6-96). In a typical case, the
development of secondary chondrosarcoma in an osteo-
chondroma is associated with the presence of a bulky
cartilaginous mass and the diagnosis is obvious on radio-
graphic imaging and gross inspection of the resected
specimen (see Figs. 6-93 and 6-94). Microscopically, the
proliferating nodular areas show increased cellularity and
clustering of plump chondrocytes that contain enlarged
nuclei with an open chromatin structure. Mild to mod-
erate nuclear atypia with frequent binucleate and mul-
tinucleate cells are usually present (see Figs. 6-95 and
6-96). Most secondary tumors show the features of grade
1 to 2 chondrosarcoma. Rare examples of dedifferenti-
ated chondrosarcomas associated with osteochondroma
have been described. In such instances, the most aggres-
sive component of the lesion with features of malignant
fibrous histiocytoma or osteosarcoma can dominate the
radiographic and clinical presentation.281,303,307,314 Careful
analysis of radiographic data and meticulous inspection of
the resected specimen are required to disclose the pres-
ence of a preexisting condition.
Text continued on p. 467
 6  Benign Cartilage Lesions 459

A
FIGURE 6-89  ■  Secondary chondrosarcoma arising in osteochondroma: radiographic features. A, Anteroposterior (AP) radiograph
showing a large mass arising in the intertrochanteric region of the femur representing a chondrosarcoma complicating a preexisting
osteochondroma. B, AP radiograph of a large buttock mass in a 47-year-old man with extensive chondroid matrix calcification in
grade 1 chondrosarcoma arising in an osteochondroma of the ilium.

ERRNVPHGLFRVRUJ
460 6  Benign Cartilage Lesions

B C
FIGURE 6-90  ■  Secondary chondrosarcoma arising in osteochondroma: radiographic features. A, Anteroposterior radiograph of pelvis
shows large peripheral chondrosarcoma arising in a cap of an osteochondroma. B, Enlarged view of secondary chondrosarcoma
shown in A. C, Axial computed tomogram shows large, calcified, soft tissue mass on external surface of ilium.

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 461

B
FIGURE 6-91  ■  Radiation-induced osteochondroma: radiographic features. A, Anteroposterior radiograph of pelvis shows large,
broad-based osteochondroma that developed 16 years after irradiation for Wilms’ tumor when patient was 2 years old. Previous
pelvis radiographs had shown no lesion. B, Axial computed tomogram of iliac osteochondroma that developed within the portal of
radiation for Wilms’ tumor. Microscopic islands of secondary low-grade chondrosarcoma were present focally in the cartilage cap
of this radiation-induced osteochondroma. (Courtesy Jane Chatten, MD, Philadelphia.)

ERRNVPHGLFRVRUJ
462 6  Benign Cartilage Lesions

B C
FIGURE 6-92  ■  Secondary chondrosarcoma arising in osteochondroma: radiographic features. A, Anteroposterior (AP) radiograph of
pelvis showing a large calcified mass representing a chondrosarcoma arising in a broad-based osteochondroma of the pubic bone.
Inset, Axial computed tomogram of pelvis showing a calcified mass arising in osteochondroma. B, AP radiograph showing a large
calcified mass representing a secondary chondrosarcoma arising in an osteochondroma of the ischium. C, T1-weighted coronal
magnetic resonance image of the case shown in B documenting a lobulated mass representing a chondrosarcoma arising in an
osteochondroma of the ischium.

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 463

B C
FIGURE 6-93  ■  Secondary chondrosarcoma arising in osteochondroma: radiographic and gross features. A, Anteroposterior radio-
graph showing a large calcified mass of the right ilium representing a chondrosarcoma arising in an osteochondroma. B, Axial
computed tomogram showing a large sessile osteochondroma of the ilium. Note a calcified mass attached to the base of osteo-
chondroma representing a secondary chondrosarcoma. C, Bisected resection specimen showing a large cartilaginous mass associ-
ated with a sessile osteochondroma of the ilium.

ERRNVPHGLFRVRUJ
464 6  Benign Cartilage Lesions

B C
FIGURE 6-94  ■  Secondary chondrosarcoma arising in osteochondroma: radiographic and gross features. A, Oblique radiograph of
pelvis showing a calcified mass arising in the osteochondroma of the right iliac crest. B, T2-weighted coronal magnetic resonance
image showing signal enhancement in a cartilage mass associated with an osteochondroma of the right iliac crest. C, Bisected
resected specimen showing a cartilage mass associated with an osteochondroma.

ERRNVPHGLFRVRUJ
 6  Benign Cartilage Lesions 465

A B

C D
FIGURE 6-95  ■  Secondary chondrosarcoma arising in osteochondroma: microscopic features. A-D, Hypercellular hyaline cartilage
mass on the surface of osteochondroma consistent with a secondary chondrosarcoma. Note cellular pleomorphism and nuclear
atypia of cartilage cells. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
466 6  Benign Cartilage Lesions

A B

C D
FIGURE 6-96  ■  Secondary chondrosarcoma arising in osteochondroma: microscopic features. A-D, Hypercellular cartilage with atypi-
cal cartilage cells consistent with a secondary chondrosarcoma associated with osteochondroma. (A and C, ×100; B and D, ×200.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

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 C H A P T E R 7 
Malignant Cartilage Tumors
CHAPTER OUTLINE
INTRAMEDULLARY CHONDROSARCOMA
Conventional Chondrosarcoma
Dedifferentiated Chondrosarcoma
Clear Cell Chondrosarcoma
Mesenchymal Chondrosarcoma
Chondrosarcoma is the second most frequent primary
malignant tumor of bone. It represents one fourth of all
primary bone sarcomas. The term chondrosarcoma is used
to describe a heterogeneous group of lesions with diverse
morphologic features and clinical behavior. The behavior
of these lesions ranges from slowly growing, nonmetas-
tasizing tumors to very aggressive metastasizing sarco-
mas. More than 90% of these tumors are designated as
conventional chondrosarcomas. On the basis of histo-
logic features (nuclear atypia and cellularity), conven-
tional chondrosarcoma is further subdivided into three
grades, 1 through 3, which correlate well with their clini-
cal behavior. The majority of conventional chondrosar-
comas are low- to intermediate-grade tumors that have
indolent clinical behavior and low metastatic potential.
High-grade (grade 3) tumors are less frequent and have
high metastatic potential.27,38 The current analysis of
data from the National Cancer Institute Surveillance,
Epidemiology and End Results (SEER) Program com-
prising 2048 conventional chondrosarcomas indicates
that 80% of them represent low-grade to intermediate-
grade (grade 1 or 2) lesions and the remaining 20% are
classified as high-grade (grade 3), potentially aggressive
tumors.
The fundamental biologic difference between a grade
1 chondrosarcoma and a benign enchondroma is signified
by the limited growth potential of the enchondroma and
the slow but continuous locally invasive growth of a low-
grade chondrosarcoma. A distinction between these two
conditions solely on the basis of microscopic cytologic
details is often impossible. Therefore the pathologist
should consider other data, such as clinical presentation
and radiographic features, in arriving at a diagnosis. For
example, it is known that cartilage lesions involving some
parts of the skeleton (small bones of the hands and feet)
are almost always benign, whereas cartilaginous lesions
of the ribs, sternum, and flat bones such as the pelvis and
scapula frequently behave in a clinically aggressive
manner. On the microscopic level, the pattern of growth
and the relationship of the lesion to adjacent structures
should also be taken into consideration. All these data are
used to provide clues about the biologic potential of the
lesion in question and about the lesion’s ultimate clinical
474
ERRNVPHGLFRVRUJ
JUXTACORTICAL CHONDROSARCOMA
SECONDARY CHONDROSARCOMAS
behavior. Virtually all de novo chondrosarcomas of bone
are intramedullary lesions. Primary juxtacortical (surface)
chondrosarcomas are extremely rare, but malignant
change is a known secondary complication of osteochon-
dromas. Secondary chondrosarcomas that complicate
other conditions (e.g., in Ollier’s disease) are morpho-
logically similar to conventional chondrosarcoma, but
they form a distinct group of lesions and are defined by
the clinical setting in which they occur. They provide
useful models in which to study the factors (clinical,
pathologic, and molecular) that predispose to the devel-
opment of malignant lesions of cartilage. The special
types of chondrosarcomas include dedifferentiated, mes-
enchymal, and clear-cell chondrosarcomas. These tumors
have distinct morphologic features and clinical behaviors
and should be considered as entities separate from con-
ventional chondrosarcoma. The differences in the bio-
logic potential of cartilage lesions as related to their
degree of differentiation are provided in Figure 7-1.
INTRAMEDULLARY CHONDROSARCOMA
Conventional Chondrosarcoma
Definition
Chondrosarcoma can be defined as a malignant tumor
of cartilage in which the matrix formed is uniformly
and entirely chondroid in nature. This definition is per-
tinent to all conventional chondrosarcomas irrespective
of the site of the tumor. Tumors that exhibit bone-
forming capability and the presence of primitive mesen-
chymal sarcomatous elements in addition to cartilaginous
differentiation should not be classified as chondrosarco-
mas. Such tumors most frequently represent chondro-
blastic variants of osteosarcoma. The validity of this
distinction is confirmed by the observed differences in
clinical behavior and therapeutic response between con-
ventional chondrosarcoma and predominantly chondro-
blastic osteosarcoma. The latter is a tumor that is
predominantly cartilaginous in nature but focally shows
tumor osteoid being directly produced by sarcomatous
 7  Malignant Cartilage Tumors 475

Type of Differentiation
Mesenchymal Chondroblastic Chondrocytic

Matrix production

Myxoid Hyaline

Limited Growth
Chondromyxoid Fibroma

Chondroblastoma

Enchondroma
Cartilage Lesions

Enchondromatosis

Chondrosarcoma grade 1-2

Continuous Growth
Chondrosarcoma grade 3

Clear Cell Chondrosarcoma

Mesenchymal Chondrosarcoma

Dedifferentiated Chondrosarcoma

Metastatic
Potential
Degree of Differentiation
FIGURE 7-1  ■  Differences in biologic potential of cartilage lesions. Graphic representation related to their degree of differentiation
and clinical behavior.

cells. It is important to realize that large portions of
conventional chondrosarcoma can be composed of calci-
fied tumor matrix, can exhibit myxomatous change, or
can show enchondral ossification. The development of
ossification in the preexisting cartilage (enchondral ossi-
fication) in a conventional chondrosarcoma should not be
considered diagnostic of osteosarcoma.
Incidence and Location
Chondrosarcomas represent the second most common
group of primary bone sarcomas, and their frequency of
occurrence varies in different series from approximately
20% to 27% of all primary bone sarcomas.6,27,35,38 The
most common sites of skeletal involvement and the peak
age incidence are shown in Figure 7-2. The analysis of
SEER data indicates that chondrosarcomas represent
25% of all primary sarcomas of bone. The currently
available SEER data, which comprise 2757 chondrosar-
comas indicates that 74% of them represent conventional
chondrosarcomas. The age distribution of patients with
chondrosarcoma shows a gradual age-related increase,
with the peak incidence occurring during the sixth and
seventh decades of life (Fig. 7-3). The majority of patients
are older than age 50 years. Chondrosarcomas in people
younger than age 45 years are rare. Individual cases are
reported in very young patients (age 20 years and
younger), but the occurrence of chondrosarcoma in chil-
dren is very rare.46,98 It is therefore recommended that
other, more frequent chondroid lesions of bone be ruled
out before the diagnosis of chondrosarcoma is rendered
in young patients with cartilage tumors. The male-to-
female ratio is almost equal. There is no major difference
in incidence between black and white subjects (Fig. 7-4).
Chondrosarcoma has a predilection for the trunk bones,
which are involved in nearly 40% of cases (pelvis ~20%
and ribs ~20%) (Fig. 7-5). The ilium is the most fre-
quently involved bone (~20% of all cases), followed by
the femur (15%) and humerus (10%). Chondrosarcoma
is extremely rare in the spine and craniofacial bones. The
majority of cartilage lesions of the small bones of the
hands and feet are benign. However, chondrosarcomas

ERRNVPHGLFRVRUJ
476 7  Malignant Cartilage Tumors

Peak
incidence
50
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 7-2  ■  Conventional chondrosarcoma. Peak age incidence and frequent sites of skeletal involvement. Most frequent sites are
indicated by solid black arrows.

1 25

0.8 20
(cases/100,000 persons)

Age distribution (%)

Incidence rate

0.6 15

0.4 10

0.2 5

0 0
0-4

5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

Age at diagnosis
FIGURE 7-3  ■  Epidemiology of conventional chondrosarcoma. National Cancer Institute Surveillance, Epidemiology and End Results
Program, 1973-2010. Age-adjusted incidence rate and age-specific frequency for all races and both sexes in 2048 cases.

ERRNVPHGLFRVRUJ
 7  Malignant Cartilage Tumors 477

Incidence rate (cases per 100,000 persons)

Black, male
Black, female
0.8 White, male
White, female

0.6

0.4

0.2

0
0-4

5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+
Age at diagnosis
FIGURE 7-4  ■  Epidemiology of conventional chondrosarcoma. National Cancer Institute Surveillance, Epidemiology and End Results
Program, 1973-2010. Age-adjusted incidence rate by race and sex for 2048 cases.

60

50

40
Frequency (%)

30

20

10

0
Craniofacial Spine Ribs Extremities Pelvis
FIGURE 7-5  ■  Skeletal distribution of chondrosarcoma. National Cancer Institute Surveillance, Epidemiology and End Results
Program, 1973-2010. Skeletal distribution of 2048 cases of conventional chondrosarcoma.

ERRNVPHGLFRVRUJ
478 7  Malignant Cartilage Tumors
do occasionally occur in these acral sites, and it is impor-
tant to pay close attention to the correlation of clinical
and radiologic details in the differential diagnosis between
benign and malignant cartilage lesions in these locations.
Chondrosarcomas also occur in extraskeletal sites. Chon-
drosarcomas that occur in soft tissue are typically myxoid
and represent a pathogenetically distinct group.18,35,39,80 A
detailed description of extraskeletal chondrosarcoma
is beyond the scope of this book. The involvement of
laryngeal cartilaginous structures by a chondrosarcoma
is a rare but well-recognized feature of these neo-
plasms.24,44,75,78,79 Rare examples of chondrosarcomas in
the parenchymal organs most frequently represent diver-
gent cartilaginous differentiation in the sarcomatoid
components of epithelial neoplasms.16,66 New and unex-
pected association between breast cancer and chondro-
sarcoma has been identified by epidemiologic studies of
the European cohort. It appears that a subset of estrogen
positive breast cancer patients is prone to develop central
conventional chondrosarcomas suggesting a putative
novel genetic trait distinct from BRCA1 and BRCA2
predisposition.20,68
Clinical Symptoms
Pain is usually the presenting complaint in chondrosar-
coma. It is typically described as a dull aching that is
sometimes intermittent. The pain is noted at rest and
may become severe at night. The symptoms are usually
of several months’ duration, but it is not uncommon to
obtain a history of pain that has continued for several
years. If the lesion is located near the end of a bone in
proximity to a joint, some restriction of motion can be
present. A local swelling may be palpable as a conse-
quence of the expansion of a bone contour or extension
into soft tissue. Pain is an important element in the dif-
ferential diagnosis between malignant and benign carti-
lage lesions. Benign intramedullary cartilage lesions, such
as enchondroma, are typically asymptomatic, and many
appear as incidental findings on radiographs.
Radiographic Imaging
The presence of discrete calcified opacities is a radio-
graphic hallmark of cartilage lesions.8,17,21,45,76 Typically,
the cartilage lesion presents as an area of radiolucency
with more or less evenly distributed punctate or ringlike
opacities (Figs. 7-6 and 7-7). The level of mineralization
may vary from lesion to lesion. At one end of the
spectrum are predominantly lytic lesions, and their car-
tilaginous nature can be difficult to identify radiographi-
cally (Figs. 7-7 to 7-9). On the opposite end are heavily
calcified lesions with consolidated areas of opacity that
can be difficult to distinguish from bone-forming lesions.
Typically the lesion appears as a radiolucent area with
moderate numbers of punctate opacities, and its cartilagi-
nous nature can be easily recognized on plain radio-
graphs. In the long bones, a large segment of the
medullary cavity may be involved (Fig. 7-7). The bone
contour in the affected region is at least somewhat
expanded. Typically, the cortex is thinned or shows mul-
tiple inner surface erosions (endosteal scalloping), but
ERRNVPHGLFRVRUJ
many chondrosarcomas provoke cortical thickening that
may be very striking in degree (Figs. 7-6 and 7-7). The
outer surface of the cortex overlying the tumor may show
a prominent periosteal reaction. This reaction may be in
the form of hazy cortical irregularity and fuzziness or of
parallel periosteal new bone formation. The multiple
perpendicular striations (“sunburst”) often seen in osteo-
sarcoma are usually not present in cartilage lesions. The
lesion may have a more or less lobulated contour. Because
most chondrosarcomas grow slowly, they do not readily
erupt from the bone. Initially, mild expansion of the bone
contour is observed with focal thinning of the cortex (Fig.
7-7). An area of complete cortical disruption with an
extension into soft tissue is usually present in more
advanced lesions. Nearly all lesions of flat bones show
features of cortical disruption and significant extension
into soft tissue at the time of clinical presentation (Figs.
7-8 and 7-9). The slow growth of chondrosarcoma is
associated with a clear radiographic demarcation of the
lesion and its low tendency for cortical disruption (Figs.
7-6 and 7-7). Indeed, in long bones, marked thickening
of the cortex adjacent to a low-grade chondrosarcoma
(Fig. 7-6), which reflects the microscopic permeation of
haversian and Volkmann’s canals with subsequent bone
apposition over a prolonged course, is a definite radio-
graphic indication of malignancy. Early cortical disrup-
tion, a destructive (permeative or moth-eaten) pattern of
growth, or both features are radiographic signs that indi-
cate a high-grade lesion (Figs. 7-7 and 7-8).
Magentic resonance imaging (MRI) and computed
tomography (CT) are indispensable techniques used to
evaluate the extent of bone and soft tissue involve-
ment.32,36 In addition, MRI typically shows a low signal
(signal void) on T1 images and a high signal on T2
images. Although not entirely specific, this feature helps
identify the presumptive cartilaginous nature of the lesion
in question when the typical pattern of punctate calcifica-
tion is present on plain radiographs. In addition, CT
scans can identify discrete calcifications of the lesion that
cannot be resolved on plain radiographs or that are invis-
ible on MRI. This is usually present as punctate signal
voids on T1-weighted images.
Gross Findings
In a typical case, the cartilaginous nature of the lesion is
readily recognized on gross examination of the bisected
tumor. The lesion has a grossly lobulated architecture
that is composed of translucent hyaline nodules that, to
some extent, resemble normal cartilage (Figs. 7-10 and
7-11). The lobulated nature of the lesion is accentuated
by more intense mineralization of the peripheral parts of
the lobules. The mineralized areas are opaque, chalklike,
or granular and yellow. The presence of extensive enchon-
dral ossification can be grossly identified as focal, ivory-
like bony areas in a chondrosarcoma (Fig. 7-29). On the
other hand, the tumor may be soft and myxomatous, and
hemorrhage or necrosis can be present (Fig. 7-11). The
low- to intermediate-grade lesions typically have a grossly
recognizable cartilaginous nature, but the central por-
tions of large tumors may become cystic (Fig. 7-11). The
Text continued on p. 485
 7  Malignant Cartilage Tumors 479

A B C
FIGURE 7-6  ■  Chondrosarcoma: radiographic features. A, Anteroposterior (AP) radiograph of a low-grade chondrosarcoma of tibia
has punctate intramedullary calcifications. B, AP radiograph of a heavily calcified grade 1 chondrosarcoma of proximal femoral
shaft. Discrete ringlike and coarse punctate opacities predominate. Note irregularities of inner cortical margins. C, AP radiograph
of discrete punctate calcifications in intramedullary low-grade chondrosarcoma occupying upper humeral shaft.

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480 7  Malignant Cartilage Tumors

A B C D

E F

FIGURE 7-7  ■  Chondrosarcoma: radiographic features. A, Anteroposterior (AP) radiograph of a low-grade chondrosarcoma of the
femoral shaft with punctate intramedullary calcifications and thickening of the overlying cortex. B, Lateral radiograph of a low-grade
chondrosarcoma of the distal femoral shaft with discrete punctate and ringlike opacities and more lytic component seen proximally.
C and D, AP and lateral radiographs show large intramedullary heavily calcified lesion that has ringlike, punctate, and curvilinear
opacities in low-grade chondrosarcoma. E and F, AP radiographs of high-grade chondrosarcoma presenting as lytic destructive
lesion of the proximal humeral end. Such radiographic presentations of chondrosarcoma have overlapping features with giant cell
tumor of bone.

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 7  Malignant Cartilage Tumors 481

B C
FIGURE 7-8  ■  Chondrosarcoma: radiographic features. A, Anteroposterior radiograph showing a destructive lytic lesion of the left
periacetabular area representing a high-grade chondrosarcoma. B, Axial computed tomogram showing a large periacetabular mass
with involvement of soft tissue of the lower pelvis. C, Fat-saturated T1-weighted coronal magnetic resonance image with contrast
showing a mass of low signal intensity with extensive involvement of the adjacent soft tissue and the displacement of the pelvic
organs.

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482 7  Malignant Cartilage Tumors

A C

D E

FIGURE 7-9  ■  Chondrosarcoma: radiographic features. A, Anteroposterior radiograph of a well delineated lesion with discrete min-
eralization pattern involving the glenoid region of the right scapula. B, Axial computed tomogram showing a destructive process
involving the glenoid region of the scapula with expansion and focal penetration of the overlying cortex. Note punctate mineraliza-
tion pattern in the central portion of the lesion. C, T1-weighted axial magnetic resonance image (MRI) showing signal enhancement
of the lesion in the glenoid region of the scapula. D, T1-weighted coronal MRI showing a destructive mass of low signal intensity
originating in the scapula and extending to the adjacent soft tissue. E, Fat-saturated T2-weighted coronal MRI showing lobular signal
enhancement in chondrosarcoma of the scapula.

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 7  Malignant Cartilage Tumors 483

A B

C D
FIGURE 7-10  ■  Conventional chondrosarcoma: gross features. A, Bisected sternum contains cartilaginous tumor with focal chalklike
gritty areas. B, Specimen radiograph of tumor shown in A demonstrates irregular discrete calcifications in lobules of chondrosar-
coma and extension of tumor into soft tissue. C, Bisected proximal femur contains low-grade chondrosarcoma involving neck and
intertrochanteric area. D, Pronounced lobulation in grade 1 chondrosarcoma of rib. (C, Courtesy Dr. A.G. Ayala, Houston.)

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484 7  Malignant Cartilage Tumors

A B

C D

FIGURE 7-11  ■  Conventional chondrosarcoma: gross features. A, Large low-grade chondrosarcoma involving inner surface of ilium
shows central cystic changes. B, Chondrosarcoma involving outer surface of ilium shows prominent lobulated growth pattern.
C, Chondrosarcoma of scapula with prominent cavitation. D, Chondrosarcoma of tibia with extensive cortical disruption and exten-
sion into soft tissue. (B and C, Courtesy Dr. A.G. Ayala, Houston.)

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presence of gray, friable, and hemorrhagic tissue with a
fleshy sarcomatous appearance is indicative of more
aggressive high-grade lesions (Fig. 7-12).
In the long tubular bones, large portions of the medul-
lary cavity may be filled with a lobulated cartilaginous
tissue. The cortex overlying the affected area is thick-
ened, roughened, and pitted. These features are the result
of the slow infiltrative advance of the tumor, with scal-
loping of the inner cortex and deposition of reactive bone
on the outer cortical surface. Initially the lesion grows
within the medullary canal, but eventually complete cor-
tical disruption ensues, and the tumor advances through
this soft tissue area (Fig. 7-12). Eventually a large lobu-
lated extraosseous mass that is attached to the bone
is formed. The extraosseous component often grows on
the bone surface, encircling the affected area. Cortical
disruption develops earlier in the flat bones, such as
the pelvis, scapula, and cranium, which have relatively
narrow medullary cavities. Virtually all chondrosarcomas
that occur at these sites develop a significant extraosse-
ous component by the time they are clinically symptom-
atic (Figs. 7-11 and 7-12). In the pelvis, they typically
present as sessile lobulated masses with large extraosseous
components.
Microscopic Findings
To be classified as a chondrosarcoma, the tumor should
be uniformly cartilaginous. The cartilaginous nature of
the lesion is typically easy to recognize (Fig. 7-13). The
tumor cells resemble normal chondrocytes and lie in
lacunar spaces embedded within hyaline cartilage matrix
that may be partially calcified or myxoid or that may
exhibit foci of enchondral ossification. The level of min-
eralization can vary in different lesions and in different
areas of the same tumor, but typically chondrosarcoma
shows mild to moderate levels of calcification. Foci of
myxoid change can be present, and some lesions are pre-
dominantly myxoid. Chondrosarcoma has an overall
lobulated architecture. The individual lobular structures
may vary in size, ranging from less than 1 mm to several
millimeters in diameter. The individual lobules can
be separated by narrow fibrovascular bands. At the
periphery, lobules of tumor can be seen permeating the
marrow spaces and engulfing cancellous trabeculae of
bone (Figs. 7-14 to 7-16). There is usually little or no
evidence of reactive bone at the periphery of tumor
lobules in the marrow spaces. The lesion can be com-
posed of homogeneous areas of varying size centrally or
can have a mixed homogeneous and lobular architecture.
Deposition of periosteal new bone can be seen micro-
scopically in areas of complete cortical disruption.
The cells can be more or less uniformly distributed
in the cartilaginous matrix or more typically form
small clusters (Figs. 7-17 to 7-19). The chondrocyte cyto-
plasm may show marked multivesicular vacuolization and
even ballooning of cells (Figs. 7-19, 7-21, and 7-23).
These swollen cells may take on features that suggest
clear cell differentiation in chondrosarcoma. However,
this finding in an otherwise conventional chondrosar-
coma should not be construed as evidence for the diag-
nosis of the clear cell chondrosarcoma variant. In rare
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7  Malignant Cartilage Tumors 485
cases, chondrosarcoma exhibits some unusual micro-
scopic features such as the signet-ring appearance or the
presence of prominent intranuclear inclusions.25,29,47
From the diagnostic point of view, chondrosar-
comas can be divided into two main groups: low- to
intermediate-grade differentiated tumors and high-grade
tumors. Those that require supportive evidence other
than microscopic features to be definitely classified as
chondrosarcomas comprise the group of borderline, low-
grade tumors. Those that can be independently identified
by microscopic features as malignant cartilage lesions
include grade 2 tumors, and those that are frankly ana-
plastic are grade 3 tumors. Low-grade chondrosarcoma
manifests cytologic features similar to those of benign
cartilage lesions such as enchondroma. It is important
to mention that some benign lesions of cartilage, such
as synovial chondromatosis, multiple enchondromatosis
(Ollier’s disease), and metaplastic cartilage of reactive
conditions, may exhibit levels of nuclear atypia and cel-
lularity approximating or even exceeding those of a low-
grade chondrosarcoma. Therefore it is mandatory that
nuclear atypia and cellularity of the lesion be considered
in light of the overall clinical, radiographic, and patho-
logic patterns of the lesion in question.
In general, a solitary cartilage lesion should be sus-
pected of being a low-grade chondrosarcoma if it
shows, even focally, hypercellularity, plump cells with the
so-called open nuclear chromatin pattern and prominent
nucleoli, the presence of nuclear pleomorphism, and
more than occasional double nuclei. As stated, this type
of lesion requires clinical and radiologic data to support
the diagnosis of chondrosarcoma.17,21,29,33,34,72,76,83
A cartilage lesion should be regarded as chondrosar-
coma microscopically if it shows prominent nuclear
atypia, mitotic activity with atypical mitoses, and multiple
pleomorphic or multinuclear cartilage cells.
Contrary to other bone and soft tissue sarcomas, his-
tologic grading of chondrosarcomas correlates well with
their clinical behavior.6,8,10,17,31,35,37,42,58,64,81,82 Chondrosar-
comas of different grades most likely represent pathoge-
netically distinct conditions with different biologic
potential and clinical behavior.58-60,96 The most widely
accepted method of grading is based on a three-tier
system (Fig. 7-23). The diagnostic criteria for the three
grades of chondrosarcomas are described next.
Grade 1 Chondrosarcoma.  Grade 1 chondrosarcoma
is cytologically very similar to enchondroma. The micro-
scopic differences are minimal, and the distinction
may be a subjective one.21,29,33,37,49 Overall the cellularity
is higher than in enchondroma, and there are more
than occasional plump nuclei with an open chromatin
structure and double nuclei (Fig. 7-13). The lesion typi-
cally has an infiltrative growth pattern with features of
endosteal erosion and engulfment of the adjacent cancel-
lous bone. Clinical and radiologic features of extraosse-
ous extension can be present. The pattern of growth and
the relationship of the lesion to the adjacent bone and
soft tissue often cannot be evaluated in limited biopsy
material. The diagnosis of grade 1 chondrosarcoma
nearly always requires supportive evidence from the
Text continued on p. 494
486 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-12  ■  High-grade conventional chondrosarcoma. A, Myxoid appearance in high-grade chondrosarcoma of proximal femoral
shaft. B, Hemorrhagic necrosis and extension into soft tissue in high-grade chondrosarcoma of shaft of humerus. C and D, Bisected
distal femur shows tumor necrosis and soft tissue invasion by high-grade chondrosarcoma. (A and B, Courtesy Dr. A.G. Ayala,
Houston.)

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 7  Malignant Cartilage Tumors 487

A B

C D

FIGURE 7-13  ■  Conventional chondrosarcoma: microscopic features. A-C, Intermediate photomicrographs showing low-grade chon-
drosarcoma with hyaline cartilage matrix and high cellularity. Malignant cartilage cells are residing in lacunar and surrounding
hyaline matrix. D, High power photomicrographs showing malignant cartilage cells with irregularities in size and shape of nuclei.
(A-C, ×100; D, ×200) (A-D, hematoxylin-eosin)

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A B

C D
FIGURE 7-14  ■  Conventional chondrosarcoma: microscopic features. A and B, Low power photomicrographs showing aggressive
growth pattern of chondrosarcoma with permeation of intertrabecular spaces within the medullary cavity. C and D, Advancing
edge of chondrosarcoma infiltrating the intratrabecular spaces within the medullary cavity. (A and B, ×10; C and D, ×20)
(A-D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 489

A B

C D
FIGURE 7-15  ■  Conventional chondrosarcoma: microscopic features. A and B, Low power photomicrographs showing permeation
of intertrabecular spaces by myxoid chondrosarcoma. Note thickened trabeculae of bone in A and advancing edge of the tumor in
B. C, and D, Intermediate power photomicrographs showing myxoid matrix and immature cartilage cells of myxoid chondrosarcoma
in C and advancing edge of the tumor in D. (A and B, ×10; C and D, ×100) (A-D, hematoxylin-eosin)

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490 7  Malignant Cartilage Tumors

A B

C D

FIGURE 7-16  ■  Conventional chondrosarcoma: microscopic features. A-D, Low power photomicrographs showing aggressive growth
pattern on chondrosarcoma with permeation of the cortex. (A-D, ×10) (A-D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 491

A B

C D
FIGURE 7-17  ■  Conventional chondrosarcoma: microscopic features. A and B, Low and intermediate power photomicrographs
showing grade 2 chondrosarcoma with pronounced hypercellularity and irregularities in size and shape of nuclei. The matrix in
this tumor is predominantly myxoid. C and D, Low and intermediate power photomicrographs of another area in the same
tumor showing hypercellularity and clustering of cells within predominantly myxoid matrix. (A and C, ×100; B and D, ×200)
(A-D, hematoxylin-eosin)

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492 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-18  ■  Conventional chondrosarcoma: microscopic features. A-D, Low and intermediate power photomicrographs of grade
2 chondrosarcoma with myxoid matrix. Note hypercellularity and variations of size and shape of nuclei. (A and C, ×100; B and
D, ×200) (A-D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 493

A B

C D
FIGURE 7-19  ■  Conventional chondrosarcoma: microscopic features. A-D, Low and intermediate power photomicrographs of
grade 2 chondrosarcoma. Note high degree of hypercellularity and nuclear atypia of cartilage cells. (A and C, ×100; B and D, ×200)
(A-D, hematoxylin-eosin)

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494 7  Malignant Cartilage Tumors
clinical and radiographic data. For example, lesions in
certain anatomic locations, such as the ribs, sternum, and
flat bones, nearly always behave in an aggressive manner.
By contrast, cartilage lesions located distal to the wrist
and ankle joints are nearly always clinically benign.
However, it must be mentioned that enchondromas do
occur in the axial skeleton, and well-documented exam-
ples of benign cartilage lesions in the ribs, sternum, and
flat bones have also been reported. Pain is an important
symptom of cartilage malignancy and is believed to be
related to an infiltrative growth pattern. Radiographic
data are indispensable in the evaluation of cartilage
lesions. The large size of the mass indicates a continuous
growth potential and a clinically aggressive lesion. Radio-
graphic evidence of bone contour expansion, cortical
thinning, endosteal scalloping, and the presence of solid
periosteal new bone formation with cortical thickening
in the vicinity of the tumor all indicate a clinically aggres-
sive lesion.43 Grade 1 chondrosarcoma is a slowly growing,
locally aggressive tumor with an indolent course and
recurrent growth potential. Metastatic spread is not a
feature of grade 1 chondrosarcoma, but uncontrolled
local recurrence can lead to a fatal outcome.
Grade 2 Chondrosarcoma.  Grade 2 chondrosarcoma
is characterized by a definite and uniformly increased
cellularity. The cells can be more or less evenly distrib-
uted in the cartilaginous matrix, or they can form loose
clusters that vary in size (Figs. 7-17 to 7-19). The carti-
lage cells are plump and have definitely enlarged nuclei
with an open chromatin pattern; distinct nucleoli are
present in the majority of cells (Fig. 7-20). Binucleated
cells are frequent and occasionally, multinucleated cells
with highly atypical nuclei can be seen. Foci of myxoid
change are frequently present. Myxoid tumors are classi-
fied as grade 2 chondrosarcomas, even when the cellular-
ity of the lesion is relatively low (i.e., similar to that of
grade 1 chondrosarcoma) (Fig. 7-21). Grade 2 chondro-
sarcomas are locally aggressive tumors with a great
potential for local recurrence. Approximately 10% to
15% of such tumors metastasize. The most frequent sites
of metastasis are lung, regional lymph nodes, and liver.
Local recurrence with multiple soft tissue nodules at the
site of prior excision is typical for this tumor. The recur-
rences of grade 1 chondrosarcomas sometimes show an
increase in grade sufficient to be classified as grade 2.
Grade 3 Chondrosarcoma.  High-grade chondrosarco-
mas are rare and make up approximately 5% to 10% of
all chondrosarcomas. These tumors are characterized by
high cellularity, prominent nuclear atypia, and the pres-
ence of mitoses (Figs. 7-22 and 7-23). These features can
be uniformly present throughout the tumor or can be
seen only focally within a tumor that has overall morpho-
logic features similar to those of grade 2 chondrosar-
coma. In general, lesions that are cytologically grade 2
chondrosarcomas and are found to have more than
one mitosis per high-power field in focal areas should
be classified as grade 3 chondrosarcoma. Grade 3 chon-
drosarcomas are highly aggressive, rapidly growing
lesions with definite metastatic potential. It is estimated
that more than 50% of these lesions eventually metasta-
size. Chondrosarcomas that recur can show an increase
ERRNVPHGLFRVRUJ
in grade.55 That usually happens in grade 2 lesions, which
may recur as grade 3 chondrosarcomas.
Special Techniques
Immunohistochemically chondrosarcoma express
markers of cartilage lineage delineation such as SOX9
and S-100 and as such have overlapping immunohisto-
chemical profiles with other cartilage lesions including
enchondroma, chondroblastoma, and chondromyxoid
fibroma.95 Therefore, the cartilage lineage expression
profile is of minimal use in differential diagnosis of
various types of benign and malignant cartilage lesions. It
can be of help in those rare instances when the cartilage
nature of the tumor in question is not evident on conven-
tional histologic preparations. Chondrosarcoma is usually
easy to identify on conventional hematoxylin-eosin–
stained sections; immunohistochemical stains are rarely
needed to identify the cartilaginous nature of the lesion.
Typically S-100 protein is uniformly strongly positive,
but in grade 3 lesions, it can be focally negative, especially
in less differentiated areas.95 The issue of coexpression of
epithelial markers by some cartilage lesions in the central
axis (skull and spine) and their significance for differential
diagnosis of chordoma, chondroid chordoma, and chon-
drosarcoma is discussed in Chapter 18.
Ultrastructurally, grade 1 chondrosarcomas are similar
to enchondromas.30 The cells of grade 2 chondrosarco-
mas have enlarged round or oval nuclei with prominent
nucleoli. The cytoplasm of cartilage cells shows promi-
nent rough cytoplasmic reticulum, mitochondria, and
large amounts of glycogen (Fig. 7-24). Myxoid chondro-
sarcomas are characterized by the presence of loose gran-
ular extracellular matrix and stellate mesenchymal cells
(Fig. 7-25). The cytoplasm of these cells has enlarged
(dilated) endoplasmic reticulum that forms multiple vac-
uoles. Grade 3 chondrosarcomas show prominent cellu-
lar and nuclear pleomorphism of cartilage cells and
focally have undifferentiated mesenchymal cells. Ultra-
structural features are of limited value in the differential
diagnosis of chondrosarcoma and are almost never
required to support the diagnosis.
DNA ploidy measurements have shown that virtually
all grade 1 chondrosarcomas are diploid. Conversely,
nearly all grade 3 and some grade 2 tumors are aneuploid.
Aneuploidy in chondrosarcoma correlates with aggres-
sive clinical behavior (i.e., an increased recurrence rate
and high propensity for metastasis).1,2,49,54,60 Similarly, an
increased proportion of cells in the S phase (>14%) is
usually seen in high-grade tumors and correlates with a
high propensity for metastases.2 Some preliminary data
suggest that the morphometric analysis of nuclear volume
can be helpful in the differential diagnosis of enchon-
droma versus grade 1 chondrosarcoma.12,49
Chromosomal analysis shows that chondrosarcomas,
especially of high histologic grade, have complex aberra-
tions with nonreciprocal translocations and deletions of
numerous chromosomes.57,69 It appears that rearrange-
ment of 1p and possibly 4, 5, 9, and 20 are nonrandom
and may play a role in the biology of these neoplasms.
The accumulation of p53 protein that results from the
mutation of its coding gene preferentially occurs in the
Text continued on p. 501
 7  Malignant Cartilage Tumors 495

A B

C D
FIGURE 7-20  ■  Conventional chondrosarcoma: microscopic features. A-D, Intermediate and high power photomicrographs of grade
2 chondrosarcoma showing hypercellularity and nuclear atypia with open chromatin architecture. Note the presence of prominent
nucleoli. The cytoplasm of the cartilage cells is oval, densely eosinophilic with occasional vacuoles displacing the nucleus eccentri-
cally. (A and C, ×200; B and D, ×400) (A-D, hematoxylin-eosin)

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496 7  Malignant Cartilage Tumors

A B

C D

FIGURE 7-21  ■  Conventional chondrosarcoma: microscopic features. A-D, Grade 2 chondrosarcoma with myxoid features. Note
prominent myxoid stroma with dispersed immature cartilage cells. Some areas of the tumor contain malignant cartilage cells with
vacuolated cytoplasm. (A-C, ×100; D, ×200) (A-D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 497

A B

C D

FIGURE 7-22  ■  Conventional chondrosarcoma: microscopic features. A-D, Examples of grade 3 chondrosarcoma with pronounced
cellularity, cellular pleomorphism, and nuclear atypia. Inset, High power photomicrograph showing malignant cartilage cells with
dense eosinophilic cytoplasm and nuclear atypia. (A-D, ×200; inset, ×400) (A-D and inset, hematoxylin-eosin)

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498 7  Malignant Cartilage Tumors

FIGURE 7-23  ■  Conventional chondrosarcoma: microscopic features. A, Grade 1 chondrosarcoma. B, Grade 2 chondrosarcoma. C and
Insets, Grade 3 chondrosarcoma. Note the increasing cellularity that parallels the progression from grades 1 through 3 with pro-
nounced cellular pleomorphism and nuclear atypia in grade 3 chondrosarcoma. (A-C and insets, ×200) (A-C and insets,
hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 499

N1

GC

N2

FIGURE 7-24  ■  Conventional chondrosarcoma: ultrastructural features. A, Tumor cells with prominent rough endoplasmic reticulum
and abundant glycogen (G). Note loose fibrillar stroma and calcifications (right). B, Cluster of three chondrosarcoma cells. Inset,
Binuclear (N1 and N2) tumor cell with prominent perinuclear Golgi center (GC). (A, ×4000; B, ×3500; inset, ×18,000).

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500 7  Malignant Cartilage Tumors

DC

DC

B
FIGURE 7-25  ■  Myxoid chondrosarcoma: ultrastructural features. A, Stellate mesenchymal cells in amorphous granular stroma of
low density. B, High magnification of A shows tumor cell with dilated channels of endoplasmic reticulum (DC). (A, ×2000; B, ×4000)

ERRNVPHGLFRVRUJ

high-grade lesions and may be an indicator of poor prog-
nosis in chondrosarcoma.26 Loss of heterozygosity (LOH)
of 5q, 9p, 11p, 13q, and 19q in chondrosarcoma and
chondroblastoma suggest the involvement of genes such
as TP53, RB1, CDKN2/p16, ERC, and XRCC in the devel-
opment of these tumors.70 Genomic profiling using array
comparative hybridization supports the notion that poly-
ploidization of initially hyperhaploid/hypodiploid cell
populations is a common mechanism of chondrosarcoma
progression.40 Such studies also suggest the involvement
of ribosomal protein S6 and cyclin-dependent kinase 4 in
these tumors.77
The presence of IDH1 and IDH2 mutations in approx-
imately 50% of central conventional chondrosarcomas
suggests the important role of these genes in the develop-
ment of chondrosarcoma. The identification of similar
mutations in solitary enchondromas and the multiple
chondromas of Ollier’s disease and Maffucci’s syndrome
as well as periosteal chondromas provides a unifying
concept for the pathogenesis of these diverse conditions.3
Interestingly, similar mutations of IDH1 and IDH2 genes
were detected in central nervous system gliomas, acute
myelocytic leukemia, and several other solid human
tumors.51,71 For central nervous system gliomas and acute
myelocytic leukemia IDH mutations identify a distinct
subset of patients with prognostic implications.5,23,52,65,74,88,97
No such relationship between IDH mutations and prog-
nosis has been reported for chondrosarcomas. The IDH
mutations cause the accumulation of oncometabolite (R)-
2-hydroxyglutarate affecting cell differentiation, survival,
and proliferation.94 A detailed description of IDH biology
in cartilage neoplasia is provided in Chapter 6, in the
section describing Ollier’s disease.
Several oncogenic pathways affecting the key cellular
functions such as migration, cell-stroma interaction, dif-
ferentiation, and proliferation essential for aggressive
behavior of cartilage cells have been implicated in the
biology of chondrosarcoma.9 Integrin activation with
upregulation of matrix metalloproteinases and extracel-
lular matrix degradation leading to increased cell migra-
tion appears to be dependent on phosphoinositide-3
kinase and MEK-extracellular signal-regulated kinase
(ERK) signaling.11,84 Additionally, chondrosarcoma cell
proliferation and matrix degradation are controlled
by peroxisome proliferator-activated receptor-gamma
(PPAR-γ) activity.11 Ephrin-A5 (EFNA5) downregulation
is a consistent finding in chondrosarcoma and may con-
tribute to its progression associated with altered cell
adhesion.53 Chondrosarcoma cells are also dependent on
such well known regulators of cartilage differentiation
and proliferation as hedgehog, p53, insulin-like growth
factor, cyclin-dependent kinase 4, hypoxia-inducible
factor, SRC, and AKT.14,91 All these pathways are impli-
cated as potential therapeutic targets for chondrosar-
coma, but no effective targeted therapy is available at the
time of this writing.19,50,85
Differential Diagnosis
Because of its predominantly cartilaginous features, chon-
droblastic osteosarcoma may be mistaken for chondrosar-
coma. This mimicry can lead to the error of underestimating
ERRNVPHGLFRVRUJ
7  Malignant Cartilage Tumors 501
the metastasizing potential of a primary bone sarcoma
when small amounts of tumor bone or osteoid formation
go undetected because of sampling problems. Careful
attention to clinical and radiologic correlation helps
prevent these mistakes. Chondrosarcomas are more
common in patients beyond the fifth decade of life
and are very rare in adolescents. Osteosarcomas with
abundant cartilage matrix formation usually show radio-
logic features more consistent with a bone-forming
tumor, including cloudlike radiodensity and prominent
periosteal new bone formation in response to cortical
disruption. The latter often takes the form of a sunburst
or “hair-on-end” appearance that is rarely seen in
chondrosarcomas.
Enchondromas and low-grade conventional chondro-
sarcomas can be almost indistinguishable on cytologic
grounds, and attention must be paid to the clinical setting
and radiologic response of the surrounding bone, as well
as the presence or absence of pain, the age of the patient,
and whether the lesion was detected as an incidental
finding. The last becomes a factor when asymptomatic
enchondromas are discovered only because radiographs
are obtained after an injury or bone isotope scans reveal
the presence of an undiagnosed central cartilage tumor.
Histologically, enchondromas tend to be less cellular, the
chondroid matrix tends to be uniformly hyaline, and the
matrix calcification may be abundant. The nuclei of the
benign cartilage tumor cells are small, uniform, and
round and have homogeneous chromatin density, in con-
trast to the larger nuclei with open chromatin patterns
seen in chondrosarcomas. Multinucleation of chondro-
sarcoma cells is far more frequent than it is in enchon-
dromas. The matrix in chondrosarcomas may show
prominent myxoid change, and the tumor tends to infil-
trate the intertrabecular spaces and the haversian canals
rather than showing the discrete lobules bordered by
lamellar bone associated with enchondromas.
The cellular dysplastic cartilage seen in enchondroma-
tosis (Ollier’s disease) may present serious problems in the
differential diagnosis because of its high cellularity and
more frequent binucleation of chondrocytes. The diffi-
culty in distinguishing between enchondromatosis and
low-grade chondrosarcoma is further complicated by the
fact that highly eccentric dyschrondroplastic lesions and
even subperiosteal ones can simulate extraosseous exten-
sion of chondrosarcoma. Radiologic demonstration of
the typical pattern of polyostotic lesions of Ollier’s disease
facilitates this distinction.
Fibrous dysplasia with abundant cartilage differentiation
(fibrocartilaginous dysplasia) may be difficult to distin-
guish from chondrosarcoma, particularly with limited
biopsy samples having only the cartilage component. The
radiographic features of fibrous dysplasia, especially when
multiple skeletal sites are affected, offer a good opportu-
nity to make this distinction. The cartilage in a lesion of
fibrous dysplasia may also show microscopic evidence
of an orderly enchondral ossification sequence that
mimics a growth plate. This is usually not found in
chondrosarcomas.
Fracture callus and the exuberant reparative changes
associated with pubic osteolysis can contain an abun-
dance of proliferating cartilage tissue that sometimes
502 7  Malignant Cartilage Tumors
suggests cartilage neoplasia. These can usually be rec-
ognized as nonneoplastic conditions when all of the clini-
cal and radiographic data, in addition to the absence of
true microscopic anaplasia of the reparative tissue, are
considered.
Synovial chondromatosis, particularly when it is associ-
ated with bone erosion, has occasionally led to the mis-
diagnosis of chondrosarcoma. This uncommon situation
arises most often in connection with synovial chondro-
matosis of the hip and of the temporomandibular joint,
where extension into bone by cortical erosion occurs
more often. Clinical and radiologic suspicion of the syno-
vial origin of the cartilaginous nodular tissue can often
be confirmed microscopically.
Conventional Chondrosarcoma
in Different Anatomic Sites
Similar to other bone sarcomas, conventional chondro-
sarcoma has identical microscopic features and biologic
potential regardless of its anatomic location. However, it
has a unique predilection to involve certain anatomic sites
and is extremely rare in some parts of the skeleton. In
general, the overall anatomic distribution of chondrosar-
coma differs significantly from that of enchondroma,
although some overlap exists. Moreover, the clinical sig-
nificance, technical feasibility of complete removal, and
chance for cure differ in relation to the anatomic site. For
this reason, separate descriptions of chondrosarcoma and
its differential diagnosis in various anatomic sites are
provided.
Chondrosarcoma of Long Tubular Bones.  Approxi-
mately 40% of chondrosarcomas occur in the long tubular
bones of the extremities.6,17,37,38,42 The proximal femur is
the most frequently affected site in the appendicular skel-
eton (~12% of cases), followed by the distal femur (8%),
proximal humerus (8%), and proximal tibia (5%). It is
important to remember that benign intramedullary car-
tilage lesions of long bones are typically small and clini-
cally asymptomatic and are often discovered as incidental
findings on radiographs. On the other hand, chondrosar-
comas of long bones are symptomatic calcified intramed-
ullary tumors that alter the adjacent trabecular and
cortical bone as they infiltrate the marrow cavity and
provoke cortical bone thickening (Figs. 7-6 and 7-7).
Intramedullary cartilage lesions should be suspected of
being grade 1 chondrosarcoma if the following features
are present: foci of increased cellularity with plump nuclei
and open nuclear chromatin structure; an infiltrative or
destructive growth pattern; size that exceeds several cen-
timeters in greatest dimension; pain, particularly at rest;
and radiographic features of destructive growth.
Chondrosarcoma of Flat Bones.  The pelvis is the
single most frequent site involved by chondrosarcoma
(~25% of all cases).27,38,62 The ilium is the most frequently
involved bone (~15% of all cases), followed by the pubis
and ischium (9%). A second flat bone frequently involved
is the scapula (5%). Benign enchondromas are extremely
rare at all of these sites. Therefore for practical purposes,
any cartilage lesion identified at these sites as neoplastic
ERRNVPHGLFRVRUJ
in nature and not part of a reactive or metaplastic
condition (pubic osteolysis), fibrous dysplasia, or enchon-
dromatosis (Ollier’s disease) should be presumptively
considered to be malignant until proven otherwise. The
flat bones have relatively narrow medullary cavities, and
cortical disruption occurs at these sites much earlier than
in the long tubular bones. Virtually all chondrosarcomas
of flat bones show features of cortical disruption and
extensive soft tissue involvement at the time of diagnosis.
Typically they present as larger masses than those occur-
ring in long bones (Figs. 7-8 and 7-9). Their prognosis
is significantly worse than that for tumors occurring in
long bones because the stage at diagnosis tends to be
higher and their location renders complete surgical
removal more complicated. Exceptional cases of pelvic
chondrosarcoma are those that originate in the periace-
tabular region. These are often diagnosed more promptly
because early onset of pain is related to the proximity of
the tumor to the hip joint.
Chondrosarcoma of Ribs and Sternum.  The ribs and
sternum are frequent sites (~12% of all cases).15,27,28,61
Enchondromas at these sites are extremely rare and
are typically small, asymptomatic lesions (2 cm in diam-
eter). Chondrosarcomas of the ribs and sternum may
occasionally be discovered incidentally on chest radio-
graphs, and the peak age incidence is lower than that for
conventional chondrosarcoma at other sites. Typically
an expansile lucent lesion is seen with punctate calcifica-
tions that are better visualized on CT and MRI (Figs.
7-26 and 7-27). Wide en bloc excision, including of
the surrounding chest wall, is required to obtain local
control of these tumors. The histologic differentiation
is usually grade 1 or 2 in rib and sternal tumors. The
clinical differences associated with tumors that arise in
this particular location suggest that they may repre-
sent a pathogenetically distinct group of chondrosarco-
mas. For practical purposes, all cartilage lesions of the
ribs and sternum with enchondroma-like morphologic
features that exceed 2 to 3 cm in diameter should be
considered potential chondrosarcomas. Other benign
cartilage-containing lesions that should be considered in
the differential diagnosis of chondrosarcoma at these sites
are cartilage-containing reactive lesions such as fracture
callus, fibrous dysplasia with foci of cartilage, and costo-
chondritis. Clinical and radiographic evidence of trauma
can be extremely helpful in the differential diagnosis. The
periosteal location of the lesion with swelling at the costo-
chondral junction also helps identify the benign reactive
process. It should be remembered that fibrous dysplasia
is the lesion occurring most frequently in the ribs. In this
condition, massive amounts of cartilage may be present.
The cartilage can be confused with chondrosarcoma.
Chondrosarcoma of Craniofacial Bones.  Chondro-
sarcomas of the craniofacial bones are rare (2% of all
cases). Typically they occur at the base of the skull (Fig.
7-28), but they may present clinically as orbital, nasal,
sinus, or pharyngeal masses.7,13,41,44,48,56,63,78,86,89 They tend
to be histologically of low grade with prominent punctate
calcifications best demonstrated on CT or MRI (Fig.
7-28). The cartilage-containing lesions of the maxilla and
 7  Malignant Cartilage Tumors 503

B C

E G H
FIGURE 7-26  ■  Chondrosarcoma of ribs and sternum: radiographic and gross features. A, Axial computed tomogram (CT) showing
a destructive mass involving the head and shaft of the vertebra and the rib. B, Fat-saturated T1-weighted axial magnetic resonance
image (MRI) with contrast of case in A showing irregular signal enhancement in a chondrosarcoma of the rib. C, Bisected specimen
of the case shown in A and B with extensive cartilaginous mass involving the head and shaft. D, Axial CT showing destructive
sternal mass with punctate calcifications. E, Bisected sternal resection specimen showing a cartilaginous mass involving the body
of the sternum. F and G, Fat-saturated T1-weighted axial MRIs with contrast showing a destructive sternal mass with focal calcifica-
tions. H, Axially bisected resection sternal specimen showing a cartilaginous intramedullary mass involving the sternal body.

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504 7  Malignant Cartilage Tumors

B
FIGURE 7-27  ■  Chondrosarcoma of rib. A, Anteroposterior radiograph of chest shows expansile mass in anterior end of rib in an
18-year-old man who had noted palpable mass for several months. B, Bisected specimen shows eccentric growth of intramedullary
grade 1 chondrosarcoma near junction with costal cartilage. Tumor expands through convex surface into adjacent soft tissue external
to rib cage.

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 7  Malignant Cartilage Tumors 505

A B

C D

FIGURE 7-28  ■  Chondrosarcoma of skull base: radiographic features. A and B, T1-weighted coronal magnetic resonance images
(MRIs) with contrast of two skull base chondrosarcomas showing the right sided parasellar masses. C and D, Coronal and axial
T1-weighted MRIs with contrast showing two examples of maxillary chondrosarcomas.

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506 7  Malignant Cartilage Tumors
mandible most frequently represent chondroblastic
osteosarcoma rather than true chondrosarcomas.7 It
should be emphasized that in chondroblastic osteosar-
coma the cartilaginous component can dominate the
lesion, and microscopic evidence of direct osteoid pro-
duction by sarcomatous tumor cells can be inconspicuous
and difficult to document in limited biopsy material.
Chondrosarcomas of the base of the skull should also be
differentiated from chondroid chordomas.48 A detailed
description of this entity is provided in Chapter 18. Syno-
vial chondromatosis may involve the temporomandibular
joint and can erode the adjacent bone, presenting as a
cartilaginous mass at the base of the skull, mimicking a
chondrosarcoma.
Chondrosarcoma of Vertebral Column and Sacrum.  what similar manner. The overall 5-year survival rate
Chondrosarcomas of the vertebral column and sacrum
are relatively infrequent (~5% of all cases). Typically they
originate in a vertebral body and extend into the adjacent
soft tissue and spinal canal.73,87,90 Chondrosarcoma has
some predilection for the lower thoracic and lumbar
segment of the spine and for the sacrum. It is somewhat
less common in the upper thoracic and cervical spine.
Radiologically chondrosarcoma presents as a radiolucent
defect. If typical punctate calcifications are present, the
cartilaginous nature of the lesion can be suspected
on radiographs. The extent of involvement is best dem-
onstrated by CT and MRI. Radiographically, chondro-
sarcoma of the spine must be differentiated from
osteosarcoma, giant cell tumor, osteoblastoma, and meta-
static tumors. Plain radiographs may reveal only a com-
pression fracture of the body of a vertebra.
Chondrosarcoma of Small Bones of Hands and Feet.  considered if conservative management of a cartilage
The majority of cartilaginous lesions of the small bones
of the hands and feet are clinically benign and represent
enchondromas. On average, enchondromas in this loca-
tion are more cellular and have more nuclear atypia than
in other parts of the skeleton. Pathologic fractures are
often present, and reparative change may complicate the
microscopic interpretation of enchondromas. Although
very rare (1% of all cases), chondrosarcomas do occur in
the acral skeleton (Figs. 7-29 to 7-31). The diagnosis of
rare cases of chondrosarcoma distal to wrist and ankle
joints is based on strict correlation between the radio-
graphic and pathologic data.22,92 A solitary cartilaginous
lesion of the acral skeleton should be suspected of being
a chondrosarcoma if it shows increased cellularity micro-
scopically with multiple plump cells exhibiting an open
nuclear structure and atypia. The cartilage lesions at
these sites should be considered chondrosarcomas if an
infiltrative destructive growth pattern is documented
microscopically and is confirmed by radiographic imaging
(Figs. 7-30 and 7-31).
Treatment and Behavior
The successful eradication of a malignant cartilage tumor
depends on complete wide excision, if this is technically
feasible. Surgery is the primary and most effective treat-
ment for chondrosarcoma. Other modalities, such as irra-
diation and chemotherapy, play a minor role and only
ERRNVPHGLFRVRUJ
apply to high-grade chondrosarcomas. Consequently the
lesions located in anatomic sites where wide local excision
is technically possible have better prognoses than those
located at sites where complete removal is not possible.
The overall prognosis is related to the size of the lesion,
anatomic location, and histologic grade.17,29,31,33,42 In
general, lesions of the appendicular skeleton have better
prognoses than those of the axial skeleton. Data from the
University of Texas M.D. Anderson Cancer Center indi-
cate that the survival rate is strictly related to the histo-
logic grade of the tumor,31 with 5-year survival rates of
90% for grade 1, 81% for grade 2, and 29% for grade 3
tumors. It is evident that the most significant difference
in clinical behavior is between grade 2 and 3 chondrosar-
comas. Grade 1 and 2 lesions behave clinically in a some-
varies between 48% and 60%. Recurrences in chondro-
sarcoma typically occur 5 to 10 years or more after
surgery. In some instances, recurrence can be associated
with an increase in histologic grade and more aggressive
clinical behavior than that of the primary neoplasm.55
Distant metastases are most often observed in grade 3
chondrosarcoma (66%), and the lungs are the most fre-
quent site. Grade 2 lesions sometimes give rise to distant
metastases (10%). Chondrosarcoma metastasizes to the
lymph nodes more frequently than other bone sarcomas.
Other less frequent sites of metastasis are the liver,
kidneys, and brain. Grade 1 chondrosarcomas do not
metastasize, but a fatal outcome in 10% of cases results
from local uncontrollable growth. In addition, in rare
cases, low-grade chondrosarcoma can recur as a high-
grade pleomorphic (dedifferentiated) neoplasm. Although
remote, the possibility of dedifferentiation should be
lesion is planned.
Tumors that are not amenable to complete excision
because of their location, such as the skull base, are
treated by conventional radiotherapy for limited local
control in the postoperative setting or in advanced inop-
erable cases with definitive intent. The use of proton
therapy after maximal surgical resection in such locations
offers increased probability of a long-term cure with rela-
tively low risk of significant complications.4,67
Personal Comments
The most common diagnostic problem in chondrosar-
coma is the evaluation of an intramedullary cartilage
tumor, most often in a long bone of an extremity that
shows equivocal histologic features and is borderline in
size. The presence of radiologic changes in the adjacent
cortex and surrounding cancellous bone and the clinical
history regarding the events that led to the discovery of
the cartilage lesion are of paramount importance in the
recognition of a low-grade chondrosarcoma. The wide-
spread use of radioisotope scanning with bone-seeking
isotopes and MRI, both of which are extremely sensitive
in demonstrating focally increased mineral turnover and
marrow alterations produced by small asymptomatic
lesions, have led to more frequent identification of
cartilage tumors. The use of these techniques has multi-
plied the frequency with which these cartilaginous masses
 7  Malignant Cartilage Tumors 507

B
FIGURE 7-29  ■  Conventional chondrosarcoma: radiographic and gross features. A, Lateral radiograph of foot shows radiodense,
heavily calcified chondrosarcoma in medullary cavity of calcaneus. B, Sagittally cut specimen from below-knee amputation shows
grade 1 chondrosarcoma of calcaneus with extension into soft tissue. Note ivory-like areas corresponding to zones of enchondral
ossification in hyaline cartilage of tumor.

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508 7  Malignant Cartilage Tumors

A B

C D

FIGURE 7-30  ■  Conventional chondrosarcoma of phalanx. A and B, Frontal and oblique radiographs of chondrosarcoma involving
proximal phalanx in third finger of a 72-year-old man. Tumor has ill-defined margins, permeative growth pattern, and matrix calci-
fication. C, Ray amputation specimen cut sagittally to show expanded contour of phalanx and extension of tumor into soft tissue.
D, Intermediate-power photomicrograph shows features of grade 2 chondrosarcoma. (D, ×200) (D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 509

A B C

D E

FIGURE 7-31  ■  Conventional chondrosarcoma of thumb. A, Lateral radiographic image showing a destructive lesion involving the
proximal phalanx of the thumb. Note a lesion with punctuate calcifications involving the distal phalanx corresponding to an enchon-
droma. B, Fat-saturated T2-weighted sagittal magnetic resonance image showing a signal intensity lesion of the proximal phalanx
with extension to the paraosseous soft tissue. C, Bisected resection specimen showing a diffusely growing intramedullary lesion
with the cortical breakthrough to the soft tissue (arrow) involving the proximal phalanx. D and E, Low power photomicrographs
showing aggressive growth pattern of a chondrosarcoma permeating the medullary cavity of the thumb. Inset, Intermediate power
photomicrograph documenting the high cellularity of this chondrosarcoma present universally throughout the lesion. (D and E, ×20;
inset, ×100) (D, E, and inset, hematoxylin-eosin)

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510 7  Malignant Cartilage Tumors
must be evaluated histologically. In general, a borderline
lesion should be suspected to be a chondrosarcoma if
radiologically it provokes a sclerotic reaction with thick-
ening of the adjacent cortex, if there is an alteration in
the trabecular pattern in the surrounding cancellous bone
(usually loss of trabeculae), and if there is associated pain,
particularly at rest. Enchondromas can certainly produce
endosteal scalloping in the adjacent cortex, especially in
small tubular bones, but in large lesions of long bones,
this must always be regarded as a radiologic sign of
growth.
In enchondromatosis (Ollier’s disease), the recognition
of secondary malignant change may be extremely difficult
if the pathologist is not familiar with the spectrum of
radiologic appearances of this disorder because the diag-
nosis of secondary malignancy often cannot be based on
histologic criteria alone. This results from the fact that
in Ollier’s disease, the dysplastic cartilage can be highly
cellular and show mild to moderate atypia and prominent
myxoid changes. Extension of cellular cartilaginous tissue
into the adjacent soft tissue and a clinical history of a
newly discovered mass and associated pain are the most
consistent signals of malignant transformation.
Synovial chondromatosis is a lesion of soft tissue or
joints that offers many interpretive pitfalls to the unsus-
pecting pathologist, particularly when it involves unusual
sites, such as the temporomandibular joint and spinal
facet joints. Prominent nuclear pleomorphism and chon-
drocyte multinucleation should not be regarded as evi-
dence of malignancy in this synovial metaplastic condition.
When bone erosion occurs in long-standing synovial
chondromatosis, it can be mistaken for chondrosarcoma.
In these cases, it is essential to look for the presence
of affected synovium to distinguish this lesion from
chondrosarcoma.
Chondrosarcoma also may be mimicked in two other
nonneoplastic conditions: pubic osteolysis and topha-
ceous pseudogout. In bulky soft tissue deposits of calcium
pyrophosphate dihydrate (pseudogout), erosion into
bone (hip joint, temporomandibular joint) can occur, and
the chondroid metaplasia frequently found in the con-
nective tissue surrounding the tophaceous pseudogout
deposit can be misinterpreted as chondrosarcoma. This
error can be avoided by the recognition of the specific
nature of the pseudogout crystalline deposit, which is not
seen in the calcifications of chondrosarcoma.
Pubic osteolysis is a reparative nonneoplastic condi-
tion that is often rich in cellular cartilage associated with
pelvic insufficiency fractures. When the fracture callus
produces a significant soft tissue mass, it can raise suspi-
cion of a pubic chondrosarcoma. If a pathologist is
presented with a small biopsy sample from such a mass,
it is all too easy to make an erroneous diagnosis of
chondrosarcoma unless radiologic correlation is pursued
scrupulously.
Cartilaginous lesions of the testes, ovaries, and perito-
neal or mediastinal soft parts are typically teratomatous
in nature. In such instances, meticulous search for other
components of germ cell neoplasia is advised before the
lesion is classified as chondrosarcoma in these unusual
sites.
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Dedifferentiated Chondrosarcoma
Definition
The phenomenon of the transformation of a low-grade
(grade 1 or 2) chondrosarcoma into a high-grade sarcoma
that most frequently exhibits features of malignant fibrous
histiocytoma or osteosarcoma is referred to as dedifferen-
tiation. Described in 1971 by Dahlin and Beabout,109
dedifferentiated chondrosarcoma is a prototype for all
dedifferentiated tumors. More generally, the term dedif-
ferentiation is used when a high-grade sarcoma develops
in association with a preexisting locally aggressive low-
grade tumor. In addition to chondrosarcoma in bone,
dedifferentiation occurs in giant cell tumor, low-grade
intramedullary and surface (parosteal) osteosarcomas,
and some soft tissue neoplasms such as liposarcoma.
Dedifferentiation also occurs in extraskeletal chondrosar-
coma and chondrosarcomas arising in preexisting condi-
tions (secondary chondrosarcomas).100,101,104,126
Microscopically, dedifferentiated chondrosarcoma is
defined as a lesion in which the two components—a high-
grade sarcoma with or without heterologous elements
(e.g., malignant fibrous histiocytoma, osteosarcoma,
and rhabdomyosarcoma) and a low-grade cartilaginous
lesion—coexist in one tumor and there is abrupt clear
demarcation between them.106,109,110,114,119,124,139 The onset
of dedifferentiation is signified clinically by a sudden
increase in aggressiveness, usually with lethal conse-
quences. On the other hand, a gradual increase in the
grade of malignant cartilage tumors in itself does not
warrant the use of the term dedifferentiation.
Incidence and Location
In all major series, dedifferentiated chondrosarcoma rep-
resents less than 10% of all chondrosarcomas. The SEER
data analysis, based on 2757 cases of chondrosarcoma,
shows that only 5.3% of these tumors fall into the cate-
gory of dedifferentiated chondrosarcoma. Therefore, it
can be anticipated that dedifferentiation theoretically
may occur in approximately 1 of 10 to 20 untreated chon-
drosarcomas.93,109,110,114,119,124 The anatomic distribution of
dedifferentiated chondrosarcoma is similar to that of
conventional chondrosarcoma and supports the relation-
ship between the two conditions (i.e., the development
of a high-grade sarcoma in association with a preexisting
conventional chondrosarcoma). The femur is the most
frequently involved bone, where nearly 30% of all cases
of dedifferentiated chondrosarcoma are diagnosed. It is
followed by the pelvis (20%), humerus (16%), ribs (7%),
and scapula (7%). The age range is wide, but the majority
of tumors occur in patients older than age 50 years. The
mean age is approximately 60 years. The peak age inci-
dence and most common skeletal sites are shown in
Figure 7-32.
Clinical Symptoms
Pain is usually the presenting complaint. Occasionally, a
clinical history of prolonged local discomfort that had

Peak
incidence
50
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 7-32  ■  Dedifferentiated chondrosarcoma. Peak age incidence and frequent sites of skeletal involvement. Most frequent sites
are indicated by solid black arrows.
changed more recently with the development of a rapidly
enlarging mass can be obtained. Dedifferentiation of a
preexisting low-grade lesion can result in pathologic frac-
ture, and almost 50% of the patients initially have this
complication.
Radiographic Imaging
The existence of the two components (low- and high-
grade) of dedifferentiated chondrosarcoma frequently
can be recognized radiographically.106,109-111,114,119,124,136
The typical radiographic presentation of dedifferentiated
chondrosarcoma is an area of punctate opacities sur-
rounded by purely lytic areas that exhibit a complete loss
of bony architecture or a permeative growth pattern.
Complete cortical disruption and extension into soft
tissue, with or without a displaced pathologic fracture,
are almost always present (Figs. 7-33 and 7-34). The
high-grade component can dominate the lesion, and only
small areas of calcified cartilaginous tumor may be identi-
fied on radiographs. On the other hand, in the initial
stages of dedifferentiation, a relatively minor component
of dedifferentiated sarcoma may not be identifiable on
radiographs. As previously mentioned, features such as
early cortical disruption in a relatively small lesion or the
presence of lytic areas with a destructive growth pattern
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7  Malignant Cartilage Tumors 511
7 8
indicate that a high-grade lesion is present. When these
features are present in association with an otherwise
radiographically typical cartilaginous lesion, they suggest
dedifferentiation.
Computed tomography and MRI may be used for
more accurate resolution of smaller lytic areas of dedif-
ferentiation or the presence of a residual calcified tumor
within large lytic areas. These imaging techniques also
help in evaluating the extent and relationships of any
associated soft tissue component (Figs. 7-33 and 7-34).
They are also useful in guiding needle biopsies to
obtain material from areas suspected of representing
dedifferentiation.136
Gross Findings
The two components of the tumor—a low-grade carti-
laginous lesion and a high-grade dedifferentiated
sarcoma—can often be identified grossly. The precursor
lesion has the typical gross appearance of a lobulated
cartilaginous mass that is present at the periphery of or
within a sarcomatous fleshy mass (Figs. 7-33 to 7-36).
The high-grade sarcomatous component may show
hemorrhage and necrosis. Cortical disruption and
extension into soft tissue are frequently present. The
Text continued on p. 516
512 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-33  ■  Dedifferentiated chondrosarcoma: radiographic and gross features. A, Frontal radiograph of right proximal humerus
of a 69-year-old man with destructive tumor in humeral head and proximal shaft. Punctate calcifications are present within lytic
area proximally, and cortex is absent medially. B, T1-weighted coronal magnetic resonance image of tumor in A reveals tumor mass
of low-density signal; tumor is invading soft tissue. C, Resected specimen of tumor shown in A. Lobulated cartilage can be seen in
proximal and mid-portion surrounded by fleshy hemorrhagic tumor that erodes cortex. D, Specimen radiograph of C shows calcified
chondroid matrix.

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 7  Malignant Cartilage Tumors 513

A B

C D
FIGURE 7-34  ■  Dedifferentiated chondrosarcoma: radiographic and gross features. A, Anteroposterior radiograph of the proximal
humerus showing a destructive lytic process involving the head and neck and a calcified lesion corresponding to a preexisting low
grade chondrosarcoma (arrows). B, Fat-saturated T2-weighted coronal magnetic resonance image showing biphasic tumor with a
high signal intensity component corresponding to a dedifferentiated high-grade sarcoma with soft tissue extension medially. The
low-grade intramedullary chondrosarcoma shows intermediate signal intensity and corresponds to calcified component shown on
plain radiograph in A. C, Bisected resection specimen shows an intramedullary cartilaginous component distally and a high-grade
destructive mass involving the head and neck with soft tissue extension medially. D, Closer view of C showing cortical breakthrough
and soft tissue extension.

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514 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-35  ■  Dedifferentiated chondrosarcoma: gross features. A, Coronal section through distal femoral tumor in a 74-year-old
woman. Lobulated, peripherally calcified, cartilaginous tumor is seen distally, and fleshy high-grade sarcoma is seen proximally,
extending into adjacent soft tissue. B, Coronal section through proximal femoral tumor. Lobulated cartilaginous intramedullary
tumor is seen distally, and hemorrhagic necrotic high-grade sarcoma involves neck area proximally. C, Intramedullary low-grade
cartilaginous component is seen on both sides of pathologic fracture in proximal femoral shaft. High-grade sarcoma with hemor-
rhage and necrosis is present at site of pathologic fracture. D, Pathologic fracture at site of dedifferentiation in tumor involving distal
femur. (C and D, courtesy Dr. A.G. Ayala, Houston.)

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 7  Malignant Cartilage Tumors 515

A B

C D
FIGURE 7-36  ■  Dedifferentiated chondrosarcoma. A, Anteroposterior radiograph of right hip of a 72-year-old woman with 2-month
history of pain. Central area of dense calcification is bordered by large zone of lucency medially. B, Coronally sectioned proximal
femur shown in A after radical en bloc excision. Note separate appearances of two components of tumor with fleshy sarcomatous
portion above and medial to calcified cartilage. C, Low power photomicrographs show sharp transition between low-grade chon-
drosarcoma component and high-grade spindle-cell tumor above (×100). D, Higher power view of dedifferentiated component with
features of malignant fibrous histiocytoma. (C, ×100; D, ×200) (C and D, hematoxylin-eosin)

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preexisting cartilage tumor can be engulfed and partially
destroyed by the high-grade component. In such
instances, the low-grade tumor can be reduced to several
scattered residual foci that can be easily overlooked on
gross examination. If a pathologic fracture is present,
extensive hemorrhage can obscure the gross details of the
lesion. Careful sampling of the intramedullary compo-
nent can reveal the microscopic foci of the precursor
cartilage lesion.
Microscopic Findings
The hallmark of dedifferentiated chondrosarcoma is the
coexistence of its two components: a low-grade cartilagi-
nous precursor lesion and a high-grade sarcoma.106,190-
111,114,119,123,124,126
Typically, there is an abrupt zone where
a low-grade cartilage lesion changes to a high-grade
sarcoma. If the precursor lesion was partially destroyed,
it can be present in the form of several separate nodules
measuring from less than 1 cm to several centimeters.
The low-grade cartilage lesion is sharply demarcated
from the surrounding dedifferentiated component
(Figs. 7-36 to 7-41). The absence of any gradual transi-
tion between the cartilage lesion and the high-grade
sarcoma is an important feature diagnostically. It is
useful in distinguishing dedifferentiated chondrosarcoma
from other sarcomas that can contain malignant cartilage
and that may show gradual transition to a spindle-cell
morphology.
The precursor cartilage lesion is typically located
within the intramedullary portion of the tumor. The rel-
atively small volume of the low-grade chondrosarcoma
component may require intensive sampling to establish
its presence. Most frequently, the precursor cartilagi-
nous lesion has features of a grade 1 chondrosarcoma, or
so-called borderline cartilage lesion, with an enchondroma-
like appearance (Fig. 7-41). Sometimes the underlying
cartilage tumor is a grade 2 chondrosarcoma that may
have myxoid features. In general, the precursor carti-
lage tumor in which dedifferentiation occurs is a low-
to intermediate-grade (grade 1 or 2) chondrosarcoma
(Figs. 7-36 to 7-40). Grade 3 chondrosarcoma is a
rare precursor lesion of dedifferentiated chondrosar-
coma. The dedifferentiated component most frequently
exhibits features of a high-grade spindle-cell sarcoma
that has features of malignant fibrous histiocytoma or
osteosarcoma (Figs. 7-36 to 7-41). The dedifferenti-
ated osteosarcomatous component may show features
of telangiectatic osteosarcoma.130,132 More rarely, dedif-
ferentiation may occur as a high-grade sarcoma rich in
giant cells that resembles a giant cell variant of malignant
fibrous histiocytoma (Figs. 7-42 and 7-43). Such tumors
can be mistaken for giant cell tumors.113 Rhabdomyo-
blastic differentiation is less frequent, but occasionally
the dedifferentiated component can have microscopic,
immunohistochemical, and ultrastructural features of
rhabdomyosarcoma of the pleomorphic type (Fig.
7-44).121,129,133 Features of smooth muscle differentiation
can also be present.112,128 The dedifferentiated compo-
nent is typically of high histologic grade regardless of its
phenotype. Examples of dedifferentiation with features
of a low-grade fibroblastic osteosarcoma or fibrosarcoma
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are extremely rare. Divergent epithelial differentiation
within a dedifferentiated component is extremely rare.112
It must be mentioned that several distinct pathways of
divergent differentiation (i.e., smooth muscle, rhabdo-
myoblastic, epithelial) can be observed within one tumor.
In the past, lesions that exhibited these features were
classified as malignant mesenchymomas. Currently this
diagnostic designation is rarely used in reference to these
lesions.
Special Techniques
The two components of dedifferentiated chondrosarcoma
have distinct immunohistochemical profiles.112,120,124,143,144
The low-grade cartilage precursor lesion recapitulates
the immunohistochemical profile of enchondroma/
conventional chondrosarcoma and expresses the markers
of cartilage lineage differentiation such as SOX9 and
S-100. The dedifferentiated component typically loses
the phenotype of a well differentiated cartilage lesion
and has immunohistochemical features overlapping with
high-grade spindle-cell sarcoma or malignant fibrous
histiocytoma. The immunohistochemical features of
cartilaginous differentiation may be occasionally posi-
tive within the high-grade component, especially in the
areas of divergent cartilaginous differentiation. Diver-
gent differentiation in the high-grade component can be
documented by appropriate smooth and skeletal muscle
and epithelial markers such as SMA, desmin, myoglobin,
keratin, and epithelial membrane antigen.128,129,143,144
Ultrastructural features of the precursor cartilage
lesion are identical to those seen in grades 1 and 2 chon-
drosarcoma. The dedifferentiated component consists of
highly pleomorphic mesenchymal cells that may show
features of divergent differentiation (i.e., osteoblastic,
chondroblastic, smooth muscle, or rhabdomyoblastic)
(Fig. 7-44).99,118,143
DNA ploidy measurements have shown that the low-
grade precursor cartilage lesion is diploid and that the
dedifferentiated component is almost always aneuploid,
usually having multiple clones of cells with an abnormal
DNA content.103,122,145 Multiple genetic and molecular
studies provide strong evidence that the dedifferenti-
ated component represents a clonal evolution from the
low-grade cartilaginous component.102,105,122,131,140-142
These studies also indicate that the so-called collision
concept of dedifferentiated chondrosarcoma is no longer
valid and is only of historical interest. Molecular studies
disclose complex chromosomal alterations with involve-
ment of multiple molecular pathways in the develop-
ment of dedifferentiation. These include the genetic and
epigenetic alterations of TP53, RB1, H-ras, cell-cycle
regulatory pathway (p21WAF1, p16INK4, p14ARF),
apoptosis (DAPK, FHIT), DNA repair (hMLH1), and
cell adhesion (E-cadherin).107,108,116,125,134,135,137,140,142 Acti-
vation of enzymes that participate in the destruction of
the intercellular matrix and their interacting molecules is
a common event in a high-grade sarcomatous component
of the dedifferentiated chondrosarcoma and may play
a contributory role to the aggressive behavior of these
malignancies.117,138
Text continued on p. 525
 7  Malignant Cartilage Tumors 517

A B

C D
FIGURE 7-37  ■  Dedifferentiated chondrosarcoma: microscopic features. A, Abrupt demarcation between low-grade (grade 1) cartilage
precursor lesion and high-grade dedifferentiated component. B, Two components of dedifferentiated osteosarcoma. Note osteoid
deposition within dedifferentiated tumor. C, Somewhat irregular but still abrupt demarcation between low-grade cartilaginous
and dedifferentiated components. D, Grade 2 myxoid chondrosarcoma as precursor lesion in dedifferentiated chondrosarcoma.
(A-D, ×200; A-D, hematoxylin-eosin)

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518 7  Malignant Cartilage Tumors

A B

C D

FIGURE 7-38  ■  Dedifferentiated chondrosarcoma: microscopic features. A, Low power photomicrograph shows overall architecture
of dedifferentiated chondrosarcoma with abrupt demarcation between low-grade cartilage precursor lesion (lower part) and high-
grade dedifferentiated component (upper part). B, High power photomicrograph of A shows cytoarchitectural details of a high-grade
spindle-cell component. C, Osteoid production in other areas of the same tumor, disclosing osteoblastic lineage differentiation in
dedifferentiated component. D, Highly pleomorphic features in other parts of the same tumor. Inset, Nuclear details of the pleomor-
phic component of the tumor. (A and C, ×100; B and D, ×200; inset, ×400) (A-D and inset, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 519

A B

C D
FIGURE 7-39  ■  Dedifferentiated chondrosarcoma: microscopic features. A and B, Less clear demarcation between dedifferentiated
high-grade sarcomatoid component of the tumor and cartilaginous precursor lesion. C and D, Intermediate and high power photo-
micrographs showing pleomorphic features of a high-grade sarcomatoid component of the same tumor shown in A and B. (A and
B, ×100; C, ×200; D, ×400) (A-D, hematoxylin-eosin)

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520 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-40  ■  Dedifferentiated chondrosarcoma: microscopic features. A, Sharp demarcation between the cartilaginous lesion (lower
part) and high-grade sarcomatoid component of the tumor (upper part). B, Intermediate photomicrograph showing the morphology
of the cartilage precursor lesion in the tumor shown in A. C and D, Intermediate and high power photomicrographs showing extreme
pleomorphism and bizarre nuclear features within a dedifferentiated sarcomatoid component of the tumor shown in A and B.
(A, ×100; B and C, ×200; D, ×400) (A-D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 521

A B

C D
FIGURE 7-41  ■  Dedifferentiated chondrosarcoma: microscopic features. A, Sharp demarcation between cartilaginous (lower part) and
dedifferentiated (upper part) components of the tumor (×100). B, Higher magnification showing spindle-cell component of the tumor
shown in A (×200). C, Higher magnification showing low cellularity and bland nuclear features of the cartilaginous precursor lesion
(×200). D, Lobular growth pattern with trabeculae of bone embracing cartilage islands within the cartilaginous precursor component
of the tumor. The bland nuclear features and the lobular growth pattern throughout the entire cartilaginous precursor lesion implicate
that the precursor lesion in this particular instance may in fact represent an enchondroma rather than a low-grade chondrosarcoma.
(A, ×100; B and C, ×200; D, ×50) (A-D, hematoxylin-eosin)

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522 7  Malignant Cartilage Tumors

A B

C D

FIGURE 7-42  ■  Dedifferentiated chondrosarcoma mimicking giant cell tumor: radiographic and microscopic features. A, Frontal
radiograph of left proximal humerus with destructive tumor in humeral head and proximal metaphyseal area. B, Fat-saturated
T2-weighted coronal magnetic resonance image (MRI) of tumor reveals heterogeneous signal intensity with low signal intensity
areas composed of cartilage lobules. Note multifocal cortical destruction. C, T2-weighted coronal MRI with lobulated focally
confluent high signal intensities corresponding to the cartilaginous component of the tumor. D, Low power photomicrograph
showing typical pattern of dedifferentiated chondrosarcoma with sharp transition between low-grade chondrosarcoma and non-
chondroid dedifferentiated component. (D, ×50) (D, hematoxylin-eosin) (Reprinted with permission from Estrada EG, et al: Ann Diagn
Pathol 6:159-163, 2002.)

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 7  Malignant Cartilage Tumors 523

A B

C D

FIGURE 7-43  ■  Dedifferentiated chondrosarcoma mimicking giant cell tumor: microscopic features. A, Photomicrograph showing
low-grade chondrosarcoma juxtaposed to the nonchondroid giant cell-rich lesion (×100). B, View of nonchondroid component with
many multinucleated osteoclastic giant cells mimicking conventional giant cell tumor of bone (×200). C, High power view of dedif-
ferentiated component devoid of giant cells and composed predominantly of mononuclear cells (×200). D, Area of dedifferentiated
component with stromal spindle cells showing atypia. Inset, Atypical nuclei within dedifferentiated component. (A, ×100; B-D, ×200;
inset, ×400) (A-D and inset, hematoxylin-eosin)

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524 7  Malignant Cartilage Tumors

FIGURE 7-44  ■  Dedifferentiated chondrosarcoma: ultrastructural features. A, Low power magnification of cartilaginous precursor
lesion exhibits features of low-grade conventional chondrosarcoma. Note cartilage cell with abundant glycogen surrounded by
fibrillar matrix. B, Dedifferentiated component exhibits features of divergent differentiation ranging from smooth muscle (inset: top)
to rhabdomyoblastic with well-developed sarcomeric structures (inset: bottom). (A, ×5000; B, ×4000; insets, ×13,000)

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Differential Diagnosis
High-grade conventional chondrosarcoma may show spin-
dling of the tumor cells at the periphery of tumor lobules,
but the transition from malignant chondrocytes is a
gradual one. The distinct biphasic character of dediffer-
entiated chondrosarcoma with sharp demarcation of the
two components is lacking. Mesenchymal chondrosarcoma
also shows a more gradual transition between the chon-
droid elements and the undifferentiated round-cell or
spindle-cell component than that seen in dedifferentiated
chondrosarcoma. The latter occurs generally in a much
older population of patients than mesenchymal chondro-
sarcoma. Because the most common form of dedifferen-
tiation in chondrosarcoma is that of malignant fibrous
histiocytoma, small biopsy samples may be misinterpreted
as malignant fibrous histiocytoma when the cartilaginous
elements are not found. Primary malignant fibrous his-
tiocytoma in bone has a better prognosis than dediffer-
entiated chondrosarcoma; hence, the differential diagnosis
is important in predicting the outcome of therapy. Atten-
tion to the radiographic finding of cartilage matrix calci-
fication is essential in recognizing the true nature of the
tumor in such cases and in guiding the selection of a
biopsy site. Fibrous dysplasia containing abundant cartilage
(fibrocartilaginous dysplasia) may be mistaken for dedif-
ferentiated chondrosarcoma, but the bland appearance of
the cells in the fibrous component and the lack of cellular
atypia in the cartilaginous lobules, as well as the nonag-
gressive radiologic features of this lesion, are helpful in
recognizing this rare benign entity.
Metastatic high-grade spindle-cell sarcomas in bone,
including leiomyosarcoma and rhabdomyosarcoma, can
suggest the diagnosis of dedifferentiated chondrosar-
coma. In such cases, a careful search for a precursor
cartilaginous tumor is essential.
Treatment and Behavior
Dedifferentiated chondrosarcoma is highly lethal, and
20% of patients have metastasis at the time of initial
diagnosis.115,127 The initial prognosis was dismal with less
than a 10% survival rate after 1 year. Widespread hema-
togeneous metastases are the rule, and the response to
chemotherapy is poor. In general, the dedifferentiated
component is more resistant to chemotherapy and radia-
tion therapy than de novo malignant fibrous histiocytoma
or osteosarcoma. Widespread metastases occur early
despite surgery. Modern chemotherapy protocols seem
to be more effective than older regimens, and the survival
rates of recently treated cases appear to be improv-
ing.115,127 However, the overall long-term prognosis is
still dismal, with practically no long-term survivors.
Recent analysis of 266 patients with dedifferentiated
chondrosarcoma by a European group provide a more
optimistic scenario and indicated that the overall survival
of patients with dedifferentiated chondrosarcoma treated
with modern chemotherapy protocols was 28% at 10
years.115 The poor prognostic factors were the presence
of a pathologic fracture at diagnosis, a pelvic location,
and being older than age 60 years.115 A low-grade
chondrosarcoma rarely recurs as a highly aggressive
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7  Malignant Cartilage Tumors 525
dedifferentiated sarcoma. The possibility of this highly
lethal phenomenon should be taken into account when
conservative management of relatively indolent low-
grade chondrosarcoma is considered.
Clear Cell Chondrosarcoma
Definition
Clear cell chondrosarcoma is defined as a low-grade
malignant cartilaginous tumor in which the tumor cells
contain a significant amount of glycogen, which is respon-
sible for the clear cell appearance of their cytoplasm.
The hallmark of this tumor is its overall mimicry of
chondroblastoma.
Incidence and Location
Clear cell chondrosarcoma is a rare tumor that accounts
for less than 5% of all chondrosarcomas. The SEER data
indicate that only 36 (1.3%) of all 2757 chondrosarcomas
were classified as clear cell chondrosarcomas. Therefore,
clear cell chondrosarcoma is among the rarest forms of
cartilage tumors. The limited experience with these
lesions indicates that the peak incidence is during the
third and fourth decades of life, but individual cases are
scattered from the second to ninth decades.149,159,163,174,176
There is a clear male predominance with a male-to-
female ratio of 2.4 : 1. Clear cell chondrosarcoma has a
predilection for the ends of long tubular bones and
extends to the articular cartilage. The proximal end of
the femur is the most frequently affected site, where
approximately 45% of the cases occur. The second most
frequently affected site is the proximal end of the humerus.
The remaining cases are relatively uniformly scattered
throughout the skeleton. The trunk bones, including the
spine, as well as craniofacial bones, including extraskel-
etal sites such as the larynx, can also be sporadically
involved.156,165,170 The most common skeletal sites and
peak age incidence are shown in Figure 7-45.
Clinical Symptoms
Pain in the affected area is usually the presenting
symptom. Clear cell chondrosarcoma is a slow-growing
lesion, and frequently there is a history of pain or minor
regional discomfort of several years’ duration.
Radiographic Imaging
Clear cell chondrosarcoma typically involves the ends of
long tubular bones and extends to the epiphysis and the
articular cartilage.151,159,169,173 It produces lytic defects that
may resemble chondroblastoma. The lesion can be radio-
lucent or heavily mineralized. The defect is usually
sharply demarcated and can have sclerotic margins (Figs.
7-46 to 7-49). More advanced lesions produce expansion
of the end of a bone. Secondary aneurysmal bone cyst
may be responsible for blowout features. Clear cell chon-
drosarcomas are relatively slowly growing lesions that
expand the bone contour (Fig. 7-49). Cortical disruption
is not a typical feature of this tumor. Because of the
526 7  Malignant Cartilage Tumors
Peak
incidence
20 40
Incidence
1 2 3 4
Age in decades
FIGURE 7-45  ■  Clear cell chondrosarcoma. Peak age incidence and frequent sites of skeletal involvement. Most frequent site is indi-
cated by solid black arrow.
involvement of the ends of long tubular bones, it must
be differentiated from chondroblastoma and giant cell
tumor on radiographs.
Gross Findings
The cartilaginous nature of the lesion is difficult to rec-
ognize on gross examination. The lesion is typically well
circumscribed and is composed of soft, gray tissue that
can be focally calcified (Figs. 7-47 to 7-49). The presence
of multiple trabeculae of bone within the tumor and
cartilage calcification may impart a gritty consistency to
the tissue. Prominent cystic change and hemorrhage
can be present. Small lesions are confined to the bone
and are typically well demarcated. The larger masses
expand the bone contour, erode the cortex, and promote
periosteal new bone formation (Fig. 7-49). The tumor
can occasionally cause disruption of the bony end plate
and extend to involve joint tissues.
Microscopic Findings
This tumor exhibits one of the most distinctive histologic
appearances of all bone tumors.147,153,155,158,162,169,171,173,174,176,177
The characteristic feature is the abundant clear cytoplasm
5 6 7 8
of the tumor cell embedded in a loose cartilaginous matrix.
The cells are large with an oval contour and distinct cell
boundaries (Fig. 7-50). The centrally located nuclei have
prominent nucleoli. Multinucleated osteoclast-like giant
cells are typically present. Scattered trabeculae of bone
between groups of clear cells are frequently seen (Figs.
7-51 and 7-52). Foci of coarse calcification are present, and
occasionally large areas of the tumor can be heavily calci-
fied. Large solid areas with more conventional appearance
and well developed hyaline cartilage matrix can be present
(Fig. 7-53). The cellularity of the lesion is very high, but
the nuclei of the tumor cells are relatively uniform and
have a low mitotic rate. The lesion has an overall lobu-
lated architecture accentuated by thin fibrovascular cores.
Although it is grossly and radiographically well demar-
cated, microscopically the periphery of the lesion dis-
closes an infiltrative growth pattern similar to that seen in
conventional chondrosarcomas. Although this tumor has
overlapping clinical and radiographic features with chon-
droblastoma, its microscopic appearance is distinct from
chondroblastoma. The latter does not contain prominent
clear cells or trabeculae of bone. These trabeculae seem
to be a part of the lesion; their nature (i.e., tumor bone
versus reactive bone) is unclear and remains the subject of
Text continued on p. 535
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 7  Malignant Cartilage Tumors 527

A B

FIGURE 7-46  ■  Clear cell chondrosarcoma: radiographic features. A and B, Anteroposterior and lateral radiographs showing a lesion
with calcified matrix involving the distal femoral end. C and D, T2-weighted sagittal magnetic resonance images (MRIs) showing an
intermediate signal intensity lesion involving the anterior aspect of the femoral head. Inset, Fat-saturated T2-weighted axial MRI
showing signal enhancement in the lesion involving the medial femoral condyle.

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528 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-47  ■  Clear cell chondrosarcoma: radiographic and gross features. A, Anteroposterior radiograph of left hip shows tumor
involving femoral head and neck in a 35-year-old man. Note punctate and ringlike calcifications in central portion of lesion.
B, Radiograph of hip shows calcified tumor occupying femoral head of a 27-year-old man. C, Anteroposterior radiograph of right
shoulder of a 35-year-old man with tumor in proximal end of humerus containing punctate calcifications. D, Anteroposterior radio-
graph of lytic tumor with sclerotic margins involving right femoral neck area. Inset, Resected femoral head shows variegated appear-
ance of tumor with gritty hemorrhagic and chalklike foci of calcification.

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FIGURE 7-48  ■  Clear cell chondrosarcoma: radiographic and gross features. A, Anteroposterior radiograph of pelvis shows a tumor
with punctuate calcification occupying the left femoral head. B, T1-weighted coronal magnetic resonance image showing a tumor
of low signal intensity involving the femoral head. Note punctate signal voids to tumor matrix calcifications. C, Bisected resection
specimen shows a mineralized tumor involving the femoral head. Inset, Closer view documenting variegated appearance of the
tumor.

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530 7  Malignant Cartilage Tumors

A B

C D

F G

FIGURE 7-49  ■  Clear cell chondrosarcoma: radiographic and gross features. A, Anteroposterior (AP) radiograph showing a well
demarcated lytic lesion of the femoral head. B, Axial computed tomogram showing well demarcated lesion of the femoral head
with punctate calcifications. C, Fat-saturated T2-weighted coronal magnetic resonance image (MRI) showing well demarcated lesion
of the femoral head with high signal intensity. D, Bisected resection specimen showing a well demarcated lesion within the femoral
head with variegated mineralized pattern. E, AP radiograph showing a lesion expanding the proximal fibular end with delicate
punctate calcifications. F, Fat-saturated T2-weighted coronal MRI of the lesion shown in A documenting high signal intensity in the
clear cell chondrosarcoma of the proximal fibular end. G, Bisected resection specimen of the lesion shown in A and F shows var-
iegated mineralization pattern in the clear cell chondrosarcoma expanding the proximal end of the fibula.

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 7  Malignant Cartilage Tumors 531

A B

C D

FIGURE 7-50  ■  Clear-cell chondrosarcoma: microscopic features. A and B, Intermediate and high power photomicrographs show
sheets of clear cells with discrete focal woven trabeculae of bone, typically present in clear cell chondrosarcoma. C and D, Interme-
diate and high power photomicrographs show solid proliferation of clear cells with centrally located nuclei. (A and C, ×200; B and
D, ×400) (A-D, hematoxylin-eosin)

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A B

C D

FIGURE 7-51  ■  Clear-cell chondrosarcoma: microscopic features. A-D, Solid proliferation of clear tumor cells with interspaced well
developed woven bone in clear cell chondrosarcoma. This feature can lead to problems in differential diagnosis with osteosarcoma.
(A and C, ×200; B and D, ×400) (A-D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 533

A B

C D
FIGURE 7-52  ■  Clear-cell chondrosarcoma: microscopic features. A, Areas of conventional hyaline cartilage (lower part) and prominent
woven trabeculae of bone (upper part) in clear cell chondrosarcoma. B, A higher magnification of A showing gradual transition from
cartilage matrix to bony matrix production. C and D, Intermediate and high power photomicrographs showing prominent woven
trabeculae in clear cell chondrosarcoma. Again, these features can present differential diagnostic problems with osteosarcoma, in
particular of chondroblastic type. (A, ×100; B and C, ×200 D, ×400) (A-D, hematoxylin-eosin)

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534 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-53  ■  Clear-cell chondrosarcoma: microscopic features. A-D, Low and intermediate power photomicrographs showing solid
areas of hyaline cartilage matrix and its gradual transition to osteoid appearing deposition. Such deposits are referred to as osteo-
chondroid matrix. (A-C, ×100; D, ×200) (A-D, hematoxylin-eosin)

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debate. Similar to conventional osteosarcoma, clear cell
chondrosarcoma can dedifferentiate.158 Dedifferentiation
in the form of high-grade undifferentiated sarcoma can
occur in a primary tumor at the time of initial diagnosis
or can present as a recurrence or as metastatic disease at
distant sites.158
Special Techniques
Ultrastructurally, the tumor cells contain a large amount
of glycogen, which is responsible for the clear cell appear-
ance of their cytoplasm and which can be documented
histochemically by the demonstration of large amounts
of material positive for periodic acid-Schiff stain, which
is diastase sensitive in the cytoplasm of these cells (Fig.
7-54).147,150,155,161,162,167 Matrix composition studies identify
the expression of cartilage collagen type II and proteogly-
cans, confirming the cartilaginous nature of tumor cells
in clear cell chondrosarcoma.146,150,153 Consistent with
this impression, clear cell chondrosarcomas are strongly
positive for S-100 protein.146,175-177 Our personal experi-
ence with these tumors indicates that they also express
SOX9. The cartilaginous nature of the tumor is further
confirmed by the expression of parathyroid hormone-
related peptide (PTHrP) and PTH/PTHrP receptor,
which are involved in the biology of cartilage.160 The
presence of well developed trabeculae of bone in these
tumors is considered to be an integral part of the lesion
and implicates the bone-forming activity of tumor cells.
Consistent with this concept is the expression of the
so-called bone forming proteins, which contribute to the
discussion on the possible histogenesis and nature of
these enigmatic tumors.150 More recent studies confirm
frequent expression of epithelial markers, with the most
frequent expression of AE1/AE3 keratins in the majority
of clear cell chondrosarcomas and occasional expressions
of CK7, CK8, CK18, and CK20.164 Clear cell chondro-
sarcomas frequently show overexpression of p53 protein
but without associated mutations.168 Limited cytogenetic
studies provide information on clonal chromosomal
abnormalities with considerable case-to-case heterogene-
ity. Extra copies of chromosome 20 and rearrangements
of 9p appear to be recurrent.166,172
Differential Diagnosis
Because of its location in the epiphyseal ends of long
bones, its cartilaginous matrix with calcification, and
its occasional occurrence beyond the second and third
decades of life, benign chondroblastoma may present dif-
ferential diagnostic problems with clear cell chondro-
sarcoma. Benign chondroblastoma can be recognized by
the absence of clear cell morphologic features or the
reactive trabeculae of bone that are characteristic of
clear cell chondrosarcoma. Furthermore, chondroblas-
tomas almost invariably manifest a self-limited indolent
growth pattern. The presence of trabeculae of bone
with osteoblastic and osteoclastic rimming in clear cell
chondrosarcoma may lead to the misdiagnosis of osteo-
blastoma or even osteosarcoma. The presence of a promi-
nent cartilage matrix and clear cell morphologic features
militates against the diagnosis of osteoblastoma, and the
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7  Malignant Cartilage Tumors 535
absence of malignant osteoblastic components excludes
osteosarcoma.
Conventional chondrosarcomas may show prominent vac-
uolization of the malignant cartilage cells, even in low-
grade tumors. This artifact can usually be distinguished
from the clear cell morphologic features of this variant.
The absence of the other common microscopic features
of prominent osteoclast-like giant cells and trabeculae of
reactive bone in conventional chondrosarcoma helps in
the differential diagnosis.
Metastatic clear cell carcinoma in bone and other clear
cell lesions involving bone can be distinguished by the
absence of a chondroid matrix and by the immunohisto-
chemical demonstration of S-100 protein, which is
intensely positive in the characteristic cells of clear cell
chondrosarcoma.
Treatment and Behavior
Clear cell chondrosarcomas are low-grade malignant
tumors, but they have definite metastatic poten-
tial.148,149,152,154,157,163 Because of their relatively indolent
clinical course and radiologic overlap with chondroblas-
toma, some of these tumors have been initially inade-
quately treated. Marginal excision or curettage usually
results in recurrence. The overall recurrence rate is 16%.
Complete en bloc excision should be performed if cure
is expected in the treatment of clear cell chondrosarcoma.
In nearly all larger series of clear cell chondrosarcoma,
there are cases in which the tumor metastasized. Of the
reported cases, approximately 10% of patients died of
tumor-related causes. Seven of eight cases in which the
tumors metastasized had recurrences and then spread to
the lungs. Brain and bone metastases have also occurred.
Recurrences have been noted up to 13 years after incom-
plete removal. Patients in whom metastases developed
died an average of 7 years after initial therapy. Although
there are insufficient data to evaluate the effectiveness of
chemotherapy, it appears to provide some lengthening of
survival. Several patients lived for years with known
pulmonary metastases while receiving adjuvant chemo-
therapy. In view of the fact that clear cell chondrosarcoma
occurs so frequently at the ends of the long bones of the
extremities, en bloc resection with joint replacement may
provide ideal surgical treatment by combining radical
excision and limb preservation. More recent follow-up
studies confirm these trends of clinical behavior.157 It
appears that the overall recurrence rate is in the range of
20% with a median of 1.7 years after the initial diagnosis.
The rate of distant metastasis is similar (approximately
20%), with a median time to original diagnosis of approx-
imately 8 years.157
Mesenchymal Chondrosarcoma
Definition
Mesenchymal chondrosarcoma is a rare, distinct malig-
nant neoplasm characterized by the presence of solid,
highly cellular areas composed of round or slightly spin-
dled primitive mesenchymal cells with foci of cartilagi-
nous differentiation. The noncartilaginous elements
536 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-54  ■  Clear-cell chondrosarcoma: microscopic features. A, Solid areas of tumor cells with clear cytoplasm, granular cyto-
plasm, or both and centrally located nuclei. Woven trabeculae of bone are interspersed among tumor cells. B, Tumor cells are
strongly positive for S-100 protein. C, Tumor cells are strongly positive for periodic acid-Schiff stain. D, High magnification shows
abundance of cytoplasmic granules positive for periodic acid-Schiff stain. (A-C, ×200; D, ×800.) (A, hematoxylin-eosin)

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Peak
incidence
10 30
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 7-55  ■  Mesenchymal chondrosarcoma. Peak age incidence and frequent sites of skeletal involvement.
usually predominate, and such lesions can be confused
histologically with Ewing’s sarcoma or hemangiopericy-
toma. Mesenchymal chondrosarcoma was described by
Lichtenstein and Bernstein200 in 1959. It is clinically,
radiographically, and microscopically distinct from con-
ventional and dedifferentiated chondrosarcoma.
Incidence and Location
Mesenchymal chondrosarcoma is extremely rare and
accounts for less than 5% of all chondrosarco-
mas.179,191,192,195,205,213,219 The SEER data indicates that
only 98 (3.6%) out of 2757 chondrosarcomas were clas-
sified as mesenchymal chondrosarcoma. The limited
experience with these lesions indicates that they usually
affect young adults and teenagers. The peak incidence is
during the third decade of life. Male and female patients
are almost equally affected. The maxilla and mandible are
the frequent sites of involvement.198,210,216,220 The other
frequent sites are the vertebrae, ribs, pelvis, and humerus.
The involvement of the central nervous system both
cranial and spinal is typical for this tumor.212,214,221 The
bones of the appendicular skeleton are rarely involved.
Approximately 30% of mesenchymal chondrosarcomas
present as extraskeletal soft tissue lesions. Rare examples
of mesenchymal chondrosarcoma arising in visceral
ERRNVPHGLFRVRUJ
7  Malignant Cartilage Tumors 537
7 8
organs were also described.197,209 The peak age incidence
and sites most frequently involved are shown in Figure
7-55.
Clinical Symptoms
Pain and swelling of the affected area are the primary
initial symptoms. The symptoms may persist for more
than 1 year. Mesenchymal chondrosarcoma can present
as a soft tissue mass.
Radiographic Imaging
Mesenchymal chondrosarcoma appears radiographically
as a radiolucent lesion with varying degrees of
matrix calcification. Lesions involving craniofacial bones
frequently represent masses at the base of the skull or
maxillary tumor masses with a destructive growth pattern
(Figs. 7-56 and 7-57). In long tubular bones the lesions
are often eccentrically located (Fig. 7-58). In extraskeletal
locations, the lesions are well demarcated and frequently
affect the paraosseous soft tissue (Figs. 7-57 and 7-58). It
is estimated that in nearly half stippled calcifications are
frequently present and may coalesce to form large, dis-
crete opacities (Figs. 7-60 to 7-62). Occasionally, mesen-
chymal chondrosarcomas present as heavily calcified
538 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-56  ■  Mesenchymal chondrosarcoma of the craniofacial bones: radiographic features. A, Fat-saturated T1-weighted coronal
magnetic resonance image (MRI) with contrast showing high signal intensity lesion involving the orbit and the anterior cranial fossa.
B, Fat-saturated T2-weighted axial MRI showing intermediate signal intensity mass involving the sphenoid sinus. C and D, Fat-
saturated T1-weighted axial MRIs with contrast showing tumors of variegated signal intensity involving the left and right maxillary
sinus, respectively. Note extension to the interior cranial fossa in C.

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 7  Malignant Cartilage Tumors 539

A B

C D

FIGURE 7-57  ■  Mesenchymal chondrosarcoma: radiographic features. A and B, Reformatted coronal bone and soft tissue computed
tomographic (CT) images of skull of a 16-year-old boy with calcified tumor involving the right ethmoid and maxillary sinuses and
extending into orbit and anterior cranial fossa. C and D, Anteroposterior radiographic image and axial CT image of a paraspinal
mass in a 55-year-old woman. Heavy calcified eccentric tumor at junction of rib and vertebral transverse process is present.

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540 7  Malignant Cartilage Tumors

A B

C D

FIGURE 7-58  ■  Mesenchymal chondrosarcoma: radiographic features. A, Lytic lesion in body of mandible, which is devoid of matrix
calcification. B, Heavily mineralized chest wall mass in a 10-year-old boy. C, Soft tissue mass with prominent punctate calcifications
adjacent to proximal femoral shaft in a 48-year-old woman. D, Eccentric lucent tumor involving anterior surface of distal tibial shaft.

ERRNVPHGLFRVRUJ

masses. Stippled calcifications disclosing the cartilagi-
nous nature of the lesion are also frequently present in
the soft tissue lesions.193,196,216 Prominent extensions into
soft tissue are seen in about 50% of cases (Figs. 7-59 to
7-61). The overall growth pattern is that of a highly
aggressive lesion with permeative or moth-eaten radio-
graphic appearance (Figs. 7-59 and 7-60). Surprisingly,
this highly aggressive tumor may occasionally have a
sharply demarcated sclerotic margin.
Gross Findings
The tissue is gray to pink with foci of calcification. The
level of mineralization can vary, and occasionally large
areas of heavily calcified tissue can be present. The tumor
may have an overall lobulated architecture and is typically
well demarcated from the surrounding bone and soft
tissue (Figs. 7-60 to 7-62). Disruption of the cortex and
extension into soft tissue are frequently seen. Larger
areas of cartilaginous differentiation can sometimes be
grossly identified. Zones of necrosis and hemorrhage can
be present.
Microscopic Findings
Mesenchymal chondrosarcoma is composed of solid areas
of primitive round or slightly spindle-shaped mesenchymal
cells (Figs. 7-63 to 7-69). The primitive mesenchymal
component frequently exhibits hemangiopericytoma-
like features with multiple endothelial-lined vascular
spaces. Islands of cartilage are present within these solid
areas.179,191,192,195,205,213,216,219 The level of cartilaginous
differentiation can vary from small foci with a loose
arrangement to large areas of mature cartilage with a
relatively well-differentiated appearance (Figs. 7-63 to
7-67). The cartilaginous component frequently contains
foci of coarse calcification. Enchondral ossification or
even the formation of bone with marrow spaces contain-
ing hematopoietic elements can be seen (Fig. 7-72). The
proportion of cartilaginous and primitive elements can
vary among the tumors and in different areas of the same
lesion. At one end of the spectrum are tumors composed
predominantly of primitive mesenchymal cells, which
require differentiation from other round-cell malignan-
cies such as Ewing’s sarcoma and small cell osteosarcoma.
On the opposite side of the spectrum are predominantly
cartilaginous lesions with a relatively benign appearance,
in which the presence of a minor primitive mesenchymal
component can be overlooked (Fig. 7-64). The carti-
laginous foci contain cells that show strong reactivity
for S-100 protein, whereas the undifferentiated cells are
negative for this marker (Fig. 7-70). Pleuropulmonary blas-
toma, or the so-called pulmonary blastoma of childhood, is
a tumor that occurs in the soft tissue of the chest wall
and lungs in young children.178,180,188,196,199,201,211,215,222,223
These neoplasms are characterized by the presence of
small primitive cells with blastomatous qualities and
may exhibit divergent rhabdomyoblastic, cartilaginous,
and lipoblastic differentiation. The prognosis for these
patients is grave because more than 50% die within 2
years after diagnosis. At least some of these tumors have
microscopic features similar to those of mesenchymal
ERRNVPHGLFRVRUJ
7  Malignant Cartilage Tumors 541
chondrosarcoma. The difference is in the mesenchymal
component, which shows rhabdomyoblastic or lipoblas-
tic differentiation either focally or diffusely distributed
in the undifferentiated mesenchyme surrounding the
cartilage (Fig. 7-71). The two patterns (i.e., focal and
diffuse) can coexist in one lesion. There are very few
cases described in the literature, and this limited experi-
ence does not permit a definitive statement as to whether
these lesions represent a distinct entity or whether some
of them are variants of mesenchymal chondrosarcoma.
The tumor cells in the cartilaginous areas of these lesions
stain positively for S-100 protein, and the cells exhibiting
rhabdomyoblastic differentiation are strongly positive for
desmin (Fig. 7-72). Lipoblastic differentiation, if present,
is associated with positivity for S-100 protein.
Special Techniques
Ultrastructurally, mesenchymal chondrosarcoma is com-
posed of oval or plump elongated primitive mesenchymal
cells.202,217 Foci of cartilaginous differentiation show more
mature cells with well-developed cytoplasm containing
glycogen, rough endoplasmic reticulum, and numerous
mitochondria (Fig. 7-73). The cells in these foci are sur-
rounded by a granular low-density matrix consistent with
chondroid. Mesenchymal chondrosarcomas are distinct
from the rest of conventional chondrosarcomas and do
not carry IDH mutations. The immunohistochemical
staining pattern is nonspecific and implicates cartilage
lineage differentiation.182,185
The small cell component of mesenchymal chondro-
sarcoma has a phenotype of chondroprogenitor cells and
shows strong nuclear expression of SOX9 protein.225
These cells also express p30/34 (MIC2) protein.194
Cartilaginous areas continue to express SOX9 and
gain the expression of S-100 protein.186,204,207,218,225 The
latter is typically negative in the small cell component
of the tumor. The small cells of mesenchymal chon-
drosarcoma frequently show divergent differentiation.
Scattered positivity of isolated small cells for desmin is a
relatively common finding.187,190,194 In rare instances, the
small cell component of mesenchymal chondrosarcoma
may show diffuse rhabdomyoblastic differentiation that
is associated with positivity for skeletal muscle differ-
entiation and expression of such markers as desmin and
myogenin.190,194
SOX9 is a valuable marker of mesenchymal chon­
drosarcoma, differentiating it from other small cell
malignancies. It is not however entirely specific because
its expression is common in all cartilage lineage tumors,
both benign and malignant. It is also expressed in other
soft tissue tumors such as synovial sarcoma.183 A wide
range of solid tumors including carcinomas can express
SOX9 as a part of the phenomenon referred to as epithe-
lial to mesenchymal transition. In addition, the lack of
expression of FLI1 can be used as a biomarker in the
differential diagnosis of mesenchymal chondrosarcoma
with Ewing’s sarcoma.199
Recent identification of HEY1-NCOA2 and IRF2BP2-
CDX1 gene fusions in mesenchymal chondrosarcoma is
of potential major importance for differential diagnosis
Text continued on p. 557
542 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-59  ■  Mesenchymal chondrosarcoma: radiographic features. A, Lateral radiograph showing a destructive tumor with anterior
extension involving the distal femoral metaphysis. B, T1-weighted sagittal magnetic resonance image (MRI) showing a low signal
intensity intramedullary tumor with anterior cortical penetration and soft tissue extension. C, Fat-saturated T2-weighted sagittal MRI
showing increased signal intensity in the intramedullary tumor involving the distal femoral metaphysis. D, Fat-saturated T2-weighted
axial MRI showing high signal intensity of the intramedullary tumor with anterior cortical penetration and semi-circumferential
extension to the paraosseous soft tissue anteriorly.

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 7  Malignant Cartilage Tumors 543

A B

C D

FIGURE 7-60  ■  Mesenchymal chondrosarcoma: radiographic and gross features. A, Anteroposterior radiograph showing a calcified
destructive tumor mass involving proximal humerus. Note circumferential cortical destruction and extension to soft tissue with
radiating mineralized spicules. Such a mineralization pattern can be radiographically misinterpreted as an osteosarcoma. B, Fat-
saturated T2-weighted axial magnetic resonance image showing high signal intensity tumor with circumferential extension to
paraosseous soft tissue. C and D, Gross photographs of the bisected resection specimen in A and B showing fleshy tumor mass
involving medullary cavity of proximal humerus with circumferential soft tissue extension.

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544 7  Malignant Cartilage Tumors

C
FIGURE 7-61  ■  Mesenchymal chondrosarcoma: radiographic and gross features. A and B, Oblique and anteroposterior radiographs
showing a calcified tumor involving the scapula. C, Resected specimen shows a tan lobulated tumor extending anteriorly and pos-
teriorly to the periscapular soft tissue.

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 7  Malignant Cartilage Tumors 545

C
FIGURE 7-62  ■  Mesenchymal chondrosarcoma: radiographic and gross features. A, Anteroposterior radiograph shows a calcified
mass in the right paraspinal region. B, Axial computed tomogram demonstrates a calcified mass in the soft tissue of the right
paraspinal region. C, Resection specimen shows a well demarcated soft tissue mass.

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546 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-63  ■  Mesenchymal chondrosarcoma: microscopic features. A, Low power photomicrograph showing small cell tumor with
discreet ill-defined patches of early cartilaginous differentiation shown as less cellular areas. B, Interface between an island of atypi-
cal cartilage and small cell undifferentiated components of the tumor. C, Small cell proliferation with prominent open vascular
channels of various sizes and shapes (×100). D, Higher magnification showing solid proliferation of undifferentiated small cells. (A-C,
×100; D, ×200) (A-D, hematoxylin-eosin)

ERRNVPHGLFRVRUJ
 7  Malignant Cartilage Tumors 547

A B

C D

FIGURE 7-64  ■  Mesenchymal chondrosarcoma: microscopic features. A and B, Biphasic nature of mesenchymal chondrosarcoma
exemplified by ill-defined islands of cartilaginous differentiation and poorly differentiated small cell component. C, Large area of
cartilaginous differentiation with well developed hyaline cartilage matrix and lacunar pattern of cartilage cells. D, Higher magnifica-
tion of poorly differentiated somewhat spindle-cell component of the tumor. (A-C, ×100; D, ×200) (A-D, hematoxylin-eosin)

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548 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-65  ■  Mesenchymal chondrosarcoma: microscopic features. A and B, Interface between the cartilaginous areas and a small
cell poorly differentiated component of the tumor. Note ill-defined irregular interface between the hyaline cartilage areas and undif-
ferentiated component. C, Large cartilaginous area of the tumor with well developed hyaline cartilage matrix. Note atypia of cartilage
cells. D, Intermediate power view of poorly differentiated small cell component of the tumor. (A and B, ×100; C and D, ×200)
(A-D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 549

A B

C D
FIGURE 7-66  ■  Mesenchymal chondrosarcoma: microscopic features. A, Low power photomicrograph of the central portion of a large
cartilaginous area showing vascular ingrowth and enchondral ossification of the calcified matrix. B, More cellular, poorly differenti-
ated component of the tumor. C and D, Variations of morphology within the poorly differentiated component of the tumor showing
spindle (C) and round (D) cell variants within the same tumor. Inset, Higher magnification showing nuclear details of the round cell
component of the tumor. (A, ×50; B, ×100; C and D, ×200; inset, ×400) (A-D and inset, hematoxylin-eosin.)

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550 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-67  ■  Mesenchymal chondrosarcoma: microscopic features. A and B, Low power photomicrographs showing dense prolif-
eration of undifferentiated tumor cells with prominent capillary vasculature. C and D, Low and intermediate power photomicrographs
showing ill-defined islands of cartilaginous differentiation. (A-C, ×100; D, ×200) (A-D, hematoxylin-eosin)

ERRNVPHGLFRVRUJ
 7  Malignant Cartilage Tumors 551

A B

C D
FIGURE 7-68  ■  Mesenchymal chondrosarcoma: microscopic features. A and B, Low and intermediate power photomicrographs
showing spindle cell variant of mesenchymal chondrosarcoma. Tumors with such features can be confused with synovial sarcoma.
C and D, Low and intermediate power photomicrographs showing mesenchymal chondrosarcoma with prominent vasculature.
(A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin)

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552 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-69  ■  Mesenchymal chondrosarcoma: microscopic features. A-D, Intermediate and high power photomicrographs
of mesenchymal chondrosarcoma showing proliferation of short plump spindle cells. (A and D, ×200; B, ×400; C, ×100)
(A-D, hematoxylin-eosin)

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 7  Malignant Cartilage Tumors 553

A B

C D
FIGURE 7-70  ■  Mesenchymal chondrosarcoma: microscopic features. A-D, Low and high power photomicrographs of mesenchymal
chondrosarcoma show intense immunoreactivity for S-100 protein in cartilaginous areas and absence of staining in primitive mes-
enchymal cells. (A and C, ×150; B and D, ×300)

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554 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-71  ■  Thoracopulmonary blastoma: microscopic features. A and B, Low and medium power photomicrographs of S-100
protein immunoreactivity confined to cells in chondroid component of thoracoblastoma. C and D, Same tumor as in A and B dem-
onstrates strongly positive desmin stain in primitive spindle-cell elements of this unique tumor. (A and C, ×100; B and D, ×200)
(Courtesy Dr. J.Y. Ro, Houston.)

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 7  Malignant Cartilage Tumors 555

B
FIGURE 7-72  ■  Mesenchymal chondrosarcoma: microscopic features. A, Low power photomicrograph of mesenchymal chondrosar-
coma of rib. Tumor contained radiographic evidence of marked calcification. Note coarse foci of calcification of cartilaginous
component. B, Higher power magnification of A shows vascular ingrowth and endochondral ossification of calcified matrix.
Note osteoclastic resorptive activity. Inset, Detail of matrix calcification. (A, ×100; B, and inset, ×200) (A, B, and inset,
hematoxylin-eosin)

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556 7  Malignant Cartilage Tumors

B
FIGURE 7-73  ■  Mesenchymal chondrosarcoma: ultrastructural features. A, Focus of cartilaginous differentiation shows tumor cells
surrounded by fibrillar matrix. B, Undifferentiated mesenchymal cells have scanty cytoplasm and sparse organelles. Inset, High
magnification of area exhibiting early chondroid differentiation shows loose substance with fibrillary elements. (A, ×4000; B, ×3000;
inset, ×30,000)

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 7  Malignant Cartilage Tumors 557

NCOA2
Chr 8
23.3 23.2
23.1
22
4 3 2 1
21.3
21.1 21.2
12 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5
11.2
11.1 breakpoint
11.1
11.22
11.21
11.23 HEY1
12
13 NCOA2 Interstitial deletion
or
21.1 5 4 32 1
21.2 HEY1 t(8;8)(q13;q21) translocation breakpoint
21.3
22.1 NCOA2 HEY1
22.2
22.3
23

24.1
23 22 2120 19 1817 16 15 14 13 4 3 2 1
24.2
24.3
breakpoint
A 148364022 bp NCOA2 portion HEY1 portion
HEY1
308 aa

NCOA2
1464 aa
Fusion protein
HEY1 NCOA2
706 aa

breakpoint bHLH – basic helix-loop-helix motif

PAS – Per Arndt-Sim motif
HEY1 portion NCOA2 portion MYC-TYPE – Myc-type, basic, helix-loop-helix (bHLH) domain
MOT01-04 – LXXLL motif
NID – nuclear receptor interaction domain
AD1/CID – transcriptional activation domain I/CBP/p300 interaction domain
MOTLXX – LLXXLXXXL motif
Q-rich – glutamine rich region
B AD2 – transcriptional activation domain 2
FIGURE 7-74  ■  Molecular structure of HEY1-NCOA2 fusion gene and its chimeric protein in mesenchymal chondrosarcoma.
A, Chromosomal locations and exon-intron structures of NCOA2 and HEY1 genes. Solid black arrows indicate the locations of the
breakpoints within introns. The molecular structure of the resulting chimeric gene includes coding sequences of the segment of
NCOA2 and segment of HEY1. B, Functional domains of the two proteins. The HEY1 protein contains MYC-type domain at the
N-terminus part of the protein. The NCOA2 protein contains multiple functional domains throughout the protein. In the chimeric
protein the C-terminus transcriptional activation domains (AD1/CID and AD2) of NCOA2 partner genes are present and are respon-
sible for the transcriptional upregulation of the target genes.

and may offer new therapeutic targets for these aggres-
sive malignancies.208,224
The HEY1 and NCOA2 genes are about 10 Mb apart,
mapping to 8q21.1 and 8q13.3, and the HEY1-NCOA2
fusion most likely results from a cryptic interstitial dele-
tion of del(8)(q13.3q21.1) (Fig. 7-74). The NCOA2 gene
is a 3′ fusion partner and belongs to the p160 nuclear
hormone receptor transcriptional coactivator family.
NCOA2 binds the ligand-bound nuclear receptor through
its nuclear receptor interaction domain (NID) and its
C-terminal transcriptional activation domains (AD1/
CID and AD2). The complex recruits histone acetyl-
transferases and methyltransferases, inducing chromatin
remodeling and transcriptional activation of target genes.
The 5′ partner of the fusion, HEY1, is a downstream
effector of the Notch pathway, which activates its expres-
sion. It is hypothesized that the HEY1-NCOA2 chimeric
protein causes global transcriptional activation of the
genes involved in cell proliferation.
The second fusion gene identified in mesenchymal
chondrosarcoma involves IRF2PB2-CDX1, resulting
from cytogentically detectable reciprocal translocation
t(1;5)(q42;q32) (Fig. 7-75). The 3′ partner of the fusion,
CDX1, belongs to the homeobox gene family, which
share their homeobox domain encoding a DNA binding
protein functioning as a transcription factor. The CDX1
gene is an upstream regulator of Hoxgene expression,
implicated in the development of leukemias and some
solid human tumors such as colon cancer. The 5′ end
partner, IRF2BP2, encodes two isoform proteins result-
ing from alternative splicing of the gene. Both isoforms
contain a Zinc finger motif at their N-terminus involved
in DNA binding. The direct involvement of IRF2BP2
in human carcinogenesis has not been reported but its

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558 7  Malignant Cartilage Tumors

Chr1 Chr5 der(1) der(5)

36.3 15.3 36.3 15.3
36.2 36.2
15.2 15.2
36.1 15.1 36.1 15.1
35 14 35 14
34.3 34.3
34.1
34.2 13.3 13.2 34.1
34.2 13.3 13.2
IRF2BP2 1q42.3
33 13.1 33 13.1
32.3 12 32.3 12
32.1 32.2 11 11.1 32.1 32.2 11 11.1 Isoform A
31.3 11.2 31.3 11.2
31.2 31.2
12 12 Isoform B
31.1 13.1 31.1 13.1
13.3 13.2 13.3 13.2 1 2
22.3
22.2
22.3
22.2
breakpoint
22.1 14 22.1 14 breakpoint
21
15
21
15 CDX1 5q32
21 21
13.3 13.3
13.2 22 13.2 22
13.1 12 23.1 13.1 12 23.1
11 23.2 11 23.2 1 2 3
11 23.3 11 23.3
12 31.1 12 31.1
31.2 31.2
31.3 CDX1 31.3
21.1 21.1 41
21.2 33.1 32 21.2 silent
21.3 21.3
22 33.3 33.2 22
23 34 23
35.1 35.2
24 24
25
35.3
25 IRF2BP2 CDX1 Isoform A

31 31
1 2 3 Isoform B
32.1 32.1
32.2 32.2 32.3 breakpoint
32.3
IRF2BP2 IRF2BP2 portion CDX1 portion
41 IRF2BP2 41
42.1 CDX1
42.2 42.3 fusion gene Fusion transcripts
43
44 B
t(1;5)(q42;q32)

IRF2BP2
587 aa
CDX1
Fusion proteins 265 aa
IRF2BP2 CDX1
466 aa

450 aa

breakpoint Interferon regulatory factor 2-binding protein 1&2,

Zink finger domain
IFR2BP2 portion CDX1 portion Caudal-like activation region
C Homeodomain
FIGURE 7-75  ■  Molecular structure of reciprocol translocation t(1;5)(q42;q32) and IRF2BP2-CDX1 fusion genes in mesenchymal chon-
drosarcoma. A, Chromosomal locations of the IRF2BP2 and CDX1 genes and the diagram representing the reciprocal translocation
with IRF2BP2-CDX1 fusion on der(1). The breakpoint on der(5) is silent. B, Exon-intron structures of the IRF2BP2 and CDX1 genes.
Solid black arrows indicate the locations of the breakpoints within introns. The molecular structure of the resulting chimeric gene
includes coding sequences of the N-terminal domain of IRF2BP2 and the homeodomain with the C-terminal segment of CDX1.
C, Functional domains of the two proteins. The IRF2BP2 protein contains a Zinc finger motif at the N-terminus involved in DNA
binding. The CDX1 protein contains caudal-like activation region and homeodomain. In the chimeric protein the C-terminus of the
IRF2BP2 protein is linked to the N-terminus of the CDX1 protein. The resulting hybrid protein contains a Zinc finger domain from
IRF2BP2 and homeodomain from CDX1 and is anticipated to transcriptionally upregulate multiple target genes involved in
self-proliferation.

ERRNVPHGLFRVRUJ

interacting proteins involve such well-known tumor sup-
pressor genes as TP53 and the oncogene IRF2. Similar to
other chimeric proteins, the IFR2PB2-CDX1 hybrid
protein is anticipated to induce transcriptional upregula-
tion of multiple target genes involved in cell prolifera-
tion. Additional chromosome translocations and sole
cytogenetic abnormalities were identified and imply
genetic diversity of the underlying mechanisms.189,206
The limited experience with both fusion genes
does not permit a definite statement concerning their
frequency of involvement and specificity for differential
diagnosis of mesenchymal chondrosarcoma, but extrap-
olating the usefulness of similar gene fusions in other
human malignancies one can anticipate major use of
these findings in the differential diagnosis of small cell
malignancies. Additional findings suggest involvement of
MYC and mTOR pathways.181,203
Differential Diagnosis
The distinction between mesenchymal chondrosarcoma
and dedifferentiated chondrosarcoma usually is not difficult
because of the abrupt boundaries seen histologically
between the cartilaginous components of dedifferenti-
ated chondrosarcomas and the high-grade, anaplastic
component. In mesenchymal chondrosarcoma, the two
elements of this biphasic tumor blend more gradually.
Furthermore, the distinctive round-cell or hemangio-
pericytomatous appearance of the nonchondroid element
facilitates the recognition of mesenchymal chondro-
sarcoma. The rather striking age differences between
these two variants of chondrosarcoma are also useful.
Mesenchymal chondrosarcoma is a tumor of the young,
whereas dedifferentiated chondrosarcoma almost always
occurs in elderly patients. Dedifferentiated chondrosar-
comas are most common in the appendicular skeleton,
whereas mesenchymal chondrosarcomas often affect the
axial and craniofacial skeleton. Histologically, dediffer-
entiated chondrosarcomas most frequently present as
malignant fibrous histiocytomas or as high-grade osteo-
sarcomas complicating low-grade chondrosarcoma; they
do not manifest the undifferentiated round-cell–like or
hemangiopericytoma-like pattern characteristic of mes-
enchymal chondrosarcoma.
The resemblance to a malignant round-cell neoplasm
in the nonchondroid parts of a mesenchymal chondro-
sarcoma causes confusion in some cases with Ewing’s
sarcoma of bone or its related tumors (e.g., primitive neu-
roectodermal tumors, Askin’s tumor) as well as with
embryonal rhabdomyosarcoma and malignant lymphoma
involving bone. Similarly, small cell osteosarcoma could
conceivably be confused with mesenchymal chondrosar-
coma. The differential diagnosis of these tumors, gener-
ally referred to as small cell malignancies, is a complex
process that involves a combination of microscopic
features and biomarker profiles revealed by immunohis-
tochemistry or histochemistry, complemented by cytoge-
netic and molecular studies. The expression of SOX9 and
the absence of FLI1 are the features of mesenchymal
chondrosarcoma. In contrast, Ewing’s sarcomas are typi-
cally FLI1 positive and SOX9 negative. Rhabdomyosar-
comas and lymphomas are typically excluded by the
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7  Malignant Cartilage Tumors 559
absence of their respective skeletal muscle and lymphoid
biomarkers. The complementary cytogenetic and molec-
ular studies for specific chromosomal translocation and
fusion genes are used to further classify the tumors.
Ewing’s sarcomas typically are positive for the break-
points and fusion genes involving EWSR1. It can be
anticipated that the newly discovered HEY1-NCOA2
and IRF2BP2-CDX1 fusion genes will be used in the
nearest future to confirm the diagnosis of mesenchymal
chondrosarcoma in difficult cases. In rare instances, other
round-cell tumors such as small cell variant of synovial
sarcoma can be confused with extraskeletal mesenchymal
chondrosarcomas. The diagnostic difficulties can be
further amplified by the frequent positivity of synovial
sarcoma for SOX9. In such instances molecular testing
for SYT breakpoints or fusion transcripts typical for
synovial sarcoma can solve the diagnostic dilemma. The
diagnostic criteria for small cell osteosarcoma and its dif-
ferential diagnosis are described in Chapter 5.
The distinct problems in differential diagnosis of mes-
enchymal chondrosarcoma are created by the presence
of extensive areas with relatively mature cartilage and
minimal atypia. In such lesions, the small cell compo-
nent can be obliterated by the cartilaginous areas and is
not as striking to the observer on microscopic inspec-
tion as in typical cases. Such lesions can be mistaken
for benign cartilage conditions or can be misclassified
as conventional chondrosarcomas or chondroblastic
osteosarcomas. Familiarity with the spectrum of dif-
ferent presentations of mesenchymal chondrosarcoma
as well as attention to the presence of undifferentiated
small cell or spindle cell components among larger
areas of cartilaginous differentiation is helpful to avoid
misdiagnosis.
Hemangiopericytomas and other primary spindle-cell
malignancies that arise in bone do not show the chon-
droid components that are present in mesenchymal
chondrosarcomas.
Treatment and Behavior
Surgery is the primary treatment in mesenchymal chon-
drosarcoma.213 Some suggest that tumors with so-called
Ewing-like microscopic features respond somewhat
better to combination chemotherapy than those with
spindle-cell and hemangiopericytoma-like areas.195 How­
ever, this concept is not universally accepted, and the
clinical data that justify this approach are not convincing.
The limited experience with these rare tumors indicates
that mesenchymal chondrosarcomas are clinically aggres-
sive, highly lethal lesions that have a high propensity to
metastasize. The overall 10-year survival rate is approxi-
mately 28%. More than 50% of affected patients die
within 5 years. More recent studies with long-term
follow-up confirm this initial impression and indicate
that for patients who are treated with complete surgical
excision and chemotherapy, the 10-year disease-free sur-
vival is 76%. In patients who cannot have their tumors
completely excised due to anatomic location or advanced
state of disease and cannot successfully complete chemo-
therapy protocols, the 10-year disease-free survival drops
to 17%.184
560 7  Malignant Cartilage Tumors
JUXTACORTICAL CHONDROSARCOMA
Definition
Juxtacortical chondrosarcoma (periosteal chondrosar-
coma) is a type of conventional chondrosarcoma that
develops on the surface of bone. It may show cortical
erosion, but the tumor is extramedullary.
Incidence and Location
Juxtacortical chondrosarcoma is a very rare lesion, with
only individual cases reported in the major series of bone
tumors.226,229,232-234,236 In the current SEER data, only 26
(0.9%) of 2757 chondrosarcomas were classified as juxta-
cortical chondrosarcomas.227,229,236,237 This data indicates
that juxtacortical chondrosarcoma is among the rarest
forms of all chondrosarcomas. This lesion typically
involves the surface of the diaphysis or metaphysis of
major long tubular bones, such as the femur or tibia.
Single cases involving the flat bones and craniofacial
bones have also been reported.228,235 Most patients with
this tumor are adults in the third or fourth decade of life;
the male-to-female ratio is 1 : 1.
Clinical Symptoms
A firm, bulky mass adherent to the surface of bone is a
typical presenting sign of juxtacortical chondrosarcoma.
The patient may also report pain, discomfort, and ten-
derness over the affected area. If the lesion is near a joint,
limitation of motion can be present. The duration of
symptoms is usually long. In some instances, regional
lymph node metastasis can be present at the time of
original diagnosis.231
Radiographic Imaging
Juxtacortical chondrosarcoma radiographically pres-
ents as a radiolucent surface bone lesion (Figs. 7-76 to
7-78).226,227,232-234,236,237 If the typical punctate matrix cal-
cifications are present, its cartilaginous nature may be
recognized (Fig. 7-76). The subperiosteal location of the
lesion, which is separated from the medullary cavity by a
rim of cortical bone and covered by an elevated perios-
teum, is best documented by CT and MRI (Fig. 7-76).
Erosion of the underlying outer cortical surface is usually
present. The lesion is usually well demarcated from the
adjacent soft tissue and from the underlying cortex. Cod-
man’s triangles are not seen. Elevation of the periosteum
with multilayered periosteal new bone formation can be
present on the bone surface adjacent to the lesion. The
prominent perpendicular new bone formation with a hazy
lesional-cortical border seen in periosteal osteosarcoma
is typically not present in juxtacortical chondrosarcoma.
Gross Findings
A lobulated mass adherent to the bone surface and sur-
rounded by a fibrous capsule is easily identified as car-
tilaginous on gross examination. The gross appearance
of the tumor tissue is identical to that of conventional
ERRNVPHGLFRVRUJ
intramedullary chondrosarcoma. The typical lesion pres-
ents as a large mass that measures more than 5 cm in
diameter.
Microscopic Findings
Microscopic features are those of conventional chondro-
sarcoma. Most frequently, juxtacortical chondrosarcoma
is a low- to intermediate-grade (grade 1 or 2) lesion (Figs.
7-77 and 7-79). The high-grade cartilaginous lesions of
the bone surface should be differentiated from periosteal
osteosarcoma, which typically contains prominent carti-
laginous components, and its bone-forming component
may not be represented in limited biopsy material. The
most important features differentiating juxtacortical
chondrosarcoma from juxtacortical chondroma are the
presence of nuclear atypia throughout the lesion and the
aggressive infiltrative growth into the underlying cortex.
Rare examples of dedifferentiated juxtacortical chondro-
sarcoma have been described.230
Differential Diagnosis
The most important lesions that present differential
diagnostic problems for this type of chondrosarcoma are
periosteal chondroma (juxtacortical chondroma) and periosteal
osteosarcoma.
Periosteal chondromas seldom exceed 2 to 3 cm in size
and usually show radiographic features of solid periosteal
bone buttresses. Histologically, they show less overall
cellularity than juxtacortical chondrosarcomas and lack
the cytologic atypicality of chondrosarcoma. Periosteal
osteosarcoma is a malignant surface lesion of bone with
cells that produce a predominantly chondroid matrix;
however, tumor osteoid and bone production by tumor
cells can always be found in spindle-cell areas between
the cartilage lobules. It is this finding that allows this
low- to intermediate-grade osteosarcoma to be distin-
guished from surface chondrosarcoma.
Less frequent surface lesions such as florid reactive peri-
ostitis, subungual exostosis, and bizarre parosteal osteocarti-
laginous proliferation (Nora’s lesion) have been mistaken for
surface chondrosarcomas because of their often cellular,
proliferative, nonneoplastic cartilage components. The
usual anatomic site (acral parts) and lack of true cytologic
atypia, as well as the clinical and radiologic features of
these lesions, are helpful in separating them from the
neoplastic group.
SECONDARY CHONDROSARCOMAS
Secondary chondrosarcomas are morphologically and
radiographically similar to conventional chondrosar-
coma and cannot be distinguished microscopically
without other supportive data, such as clinical and radio-
graphic findings. Secondary chondrosarcomas are dis-
tinguished by their development in association with a
predisposing condition that can be identified clinically,
radiographically, or occasionally microscopically. A
list of predisposing conditions for the development
Text continued on p. 565
 7  Malignant Cartilage Tumors 561

C D
FIGURE 7-76  ■  Juxtacortical chondrosarcoma: radiographic features. A and B, Anteroposterior and lateral radiographs of juxtacortical
focally calcified tumor on anterior surface of distal femoral shaft in a 25-year-old woman (arrows). C and D, T1-weighted sagittal
magnetic resonance images (MRIs) with and withour contrast of juxtacortical chondrosarcoma of proximal tibial metaphysis in a
13-year-old boy. Inset, Fat-saturated T2-weighted axial MRI demonstrates high-intensity signal in surface cartilage tumor. Histologi-
cally, this tumor showed prominent myxoid features and microscopic evidence of marrow invasion.

ERRNVPHGLFRVRUJ
562 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-77  ■  Juxtacortical chondrosarcoma: radiographic, gross, and microscopic features. A, Lateral radiograph showing bone
surface lesion on the posterior aspect of femoral metaphysis. Note cortical erosions and its thickening beneath the lesion. B, Bisected
resection specimen showing cartilaginous bone surface lesion. C, Closer view of specimen shown in A and B depicting cartilaginous
nature of the lesion and erosions of the underlying cortex. D, Low power photomicrograph showing well differentiated cartilaginous
tumor within increased cellularity and nuclear atypical consistent with grade 1 chondrosarcoma . (D, ×100) (D, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
 7  Malignant Cartilage Tumors 563

A B

C D

FIGURE 7-78  ■  Juxtacortical chondrosarcoma: radiographic and gross features. A, Anteroposterior radiograph showing a calcified
bone surface lesion involving the proximal humerus. B, Bisected resection specimen showing cartilaginous bone surface mass.
C, Closer view of specimen shown in B depicting globular cartilaginous structure of the tumor with chalky calcifications. Note infil-
tration of the underlying cortex. D, Gross photograph of the bisected regional lymph node with metastatic chondrosarcoma. Inset,
Whole-mount specimen showing a focus of metastatic chondrosarcoma almost completely replacing the involved lymph node.

ERRNVPHGLFRVRUJ
564 7  Malignant Cartilage Tumors

A B

C D
FIGURE 7-79  ■  Juxtacortical chondrosarcoma: microscopic features. A, Base of the lesion showing infiltrative growth pattern into the
underlying cortex. Inset, Higher magnification showing hypercellularity (×100). B, Interface between the tumor and underlying cortex.
C, Deeper portion of cortex showing permeative growth pattern of the tumor. D, Medullary cavity beneath the juxtacortical chon-
drosarcoma showing aggressive tumor invasion. This is the same case as presented in Figure 7-78. Note that cytoarchitectual
features including nuclear atypia are not impressive and convincingly diagnostic of chondrosarcoma. In contrast, the infiltrative
growth pattern into the cortex and underlying medullary cavity discloses the aggressive nature of the lesion. In addition, the pres-
ence of axillary lymph node metastasis shown in Figure 7-78 is an ultimate proof for the aggressive nature of the lesion. (A-D, ×50;
inset, ×100) (A-D and inset, hematoxylin-eosin)

ERRNVPHGLFRVRUJ

TABLE 7-1 Predisposing Conditions in
Secondary Chondrosarcoma
Ollier’s disease and Maffucci’s syndrome
Multiple hereditary exostoses
Solitary osteochondroma
Solitary enchondroma
Paget’s disease
Radiation injury
of chondrosarcoma is shown in Table 7-1. A detailed
description of secondary chondrosarcoma is provided in
chapters describing those predisposing conditions.
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drosarcoma of the mandible: report of a unique case and review
of the literature. Int J Oral Maxillofacial Surg 34:94–98, 2005.
236. Vanel D, De Paolis M, Monti C, et al: Radiological features of 24
periosteal chondrosarcomas. Skel Radiol 30:208–212, 2001.
237. Zenmyo M, Komiya S, Nakashima M, et al: Giant juxtacortical
chondrosarcoma of the humerus. Orthopedics 23:497–498, 2000.
 C H A P T E R 8 
Fibrous Dysplasia and
Related Lesions
CHAPTER OUTLINE
FIBROUS DYSPLASIA
Fibrous Dysplasia in Different Anatomic Sites
FIBROUS DYSPLASIA
This disorder was recognized as a clinical syndrome of
disseminated skeletal deformities long before it was given
the name fibrous dysplasia by Lichtenstein and Jaffe in two
classic publications that appeared in 1938 and 1942.41,42
In older literature, it had been discussed under the term
osteitis fibrosa or generalized fibrocystic disease of bone, which
also included such conditions as renal osteodystrophy and
hyperparathyroidism. The craniofacial lesions were clas-
sified as leontiasis ossea or cherubism. They were linked
to fibrous dysplasia as an underlying condition by Pugh65
in 1945. Fibrous dysplasia as a solitary lesion was last to
be linked to a disseminated polyostotic form of the
disease. Albright-McCune syndrome was independently
described by two groups in 1937, and the skeletal abnor-
malities in this condition were originally classified as
osteitis fibrosa.1,45 They were reclassified as polyostotic
fibrous dysplasia in 1942 by Lichtenstein and Jaffe.42 In
1967, Mazabraud et al.52 described an association of
fibrous dysplasia with soft tissue myxomas.94
Fibrous dysplasia is best explained if it is considered
as a dysplastic anomaly of bone-forming mesenchymal
tissue. The hallmark of this disease is a solitary focal or
generalized multifocal inability of bone-forming tissue to
produce mature lamellar bone. It is arrested at the level
of woven bone. Even if a large amount of osteoid is pro-
duced, it cannot mature to lamellar bone. The remark-
able consistency of this feature in various clinical forms
of fibrous dysplasia ranging from solitary asymptomatic
lesions to severe generalized conditions suggests that the
underlying molecular mechanism involves the fundamen-
tal cell differentiation process. The differences in the
extent of skeletal involvement and the coexistence of
extraskeletal abnormalities can be related to somatic
mosaicism of the defect. The disease is evolutionary con-
served; recent evidence indicates that Homo sapiens’ ances-
tors such as Neanderthals were affected by a similar
disorder.57
The involvement of a gene or genes playing a funda-
mental role in modulation of cellular differentiation into
mature osteocytes capable of producing lamellar bone can
be postulated. In fact, mutations of signal-transducing
G proteins have been implicated in the development
570
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FIBROCARTILAGINOUS DYSPLASIA
of multiple endocrinopathies of the Albright-McCune
syndrome and fibrous dysplasia.2,11,15,35,43,48,50,55,84-86,101,103
However, not all cases of fibrous dysplasia or Albright-
McCune syndrome can be linked to mutations of G pro-
teins, indicating that other molecular mechanisms may be
involved.31,40,49 G proteins form heterotrimeric complexes
and bind guanine nucleotides.13,107 They couple a large
number of cell surface receptors to their corresponding
intracellular signal transduction pathways. Mutations of
G proteins alter these pathways and may disturb the
tissue differentiation process (Fig. 8-1).81 The mutations
in fibrous dysplasia involve the α chain of the heterotri-
meric G subunit and result in the substitution of histidine,
cysteine, or serine for arginine at position 201.2,30 These
substitutions are caused by single nucleotide mutations
involving predominantly exon 8 and less frequently exon
9 of the gene encoding for Gsα (GNAS1) located on the
long arm of chromosome 20 at 20q13.2-3. These muta-
tions disrupt the inherent guanosine triphosphate activity
of the α chain, stimulate adenyl cyclase, and result in
independent cell proliferations.40,51 Identical mutations
are also present in pituitary and other endocrine tumors
associated with Albright-McCune syndrome and in the
soft tissue myxomas associated with fibrous dysplasia such
as Mazabraud’s syndrome.60 They can be also detected in
solitary soft tissue myxomas unrelated to fibrous dyspla-
sia.60,100 The osteoblastic cells expressing mutant Gsα show
increased proliferations and inappropriate differentiation
that results in overproduction of a disorganized fibrotic
bone lesion. In animal studies the implantation of human
marrow progenitor cells with mutant Gsα admixed with
nonmutant cells results in the formation of abnormal
ectopic ossicle recapitulating fibrous dysplasia.6,75 The
mutations of the GNAS1 gene have also been explored
as potential biomarkers in the differential diagnosis of
fibrous dysplasia and other fibroosseous lesions, includ-
ing well-differentiated fibroblastic osteosarcoma.10,63,77,88
Unfortunately, the presence of GNAS1 mutations in
well-differentiated fibroblastic osteosarcoma, both paros-
teal and intramedullary, limits the diagnostic applications
of those mutations in the differential diagnosis of fibrous
dysplasia and low-grade fibroblastic osteosarcoma.12,63
The increased levels of the c-fos and c-jun oncoproteins
have been documented in lesions of fibrous dysplasia,
 Receptor Effector

o o
CH3O-Cys-S HN-Gly Cys-S
C

 GDP

A
GTP
A
GDP

Receptor Effector

o o B
CH3O-Cys-S HN-Gly Cys-S
Second
 Messenger/

Response
A 

Gs- splice variants:

Gs- long ± Ser,
Gs- short ± Ser
meth

Chr 20 Maternal NESP XLs 1A Gs- +/- +/-

C
allele 2 4 5 6-13
1 1 1 1 3 A
G

13
12 BMSCs: BMSCs: R201 mutation Exon 8
11.2 XLas biallelic Gs- biallelic, asymmetry paternal or maternal allele
11.1 11.1
11.2 meth meth
12
13.1 Paternal NESP XLs 1A Gs- +/-
+/-
C
allele 2 4 5 6-13
13.2 3 A
GNAS 1 1 1 1 G

13.3

Gs- imprinted:
C kidney, thyroid, pituitary, ovary

GNAS Exon 8
p.R201G p.R201S Exon 9
p.R201C p.R201P p.Q227L p.Q227K
p.R201H p.R201L p.Q227R p.Q227H

1 394 aa

P-loop containing nucleoside triphosphate hydrolase, 33-64

G protein alpha subunit, helical insertion, 58-202
D P-loop containing nucleoside triphosphate hydrolase, 198-393
FIGURE 8-1  ■  Biologic effects of the G protein signaling pathway. A, The heterotrimeric guanine nucleotide-binding regulatory pro-
teins (G proteins) are localized to the inner surface of the cell membrane. They transduce signals from transmembrane receptors.
In the inactive state (top diagram) the G protein exists as a trimer containing α, β, and γ subunits. Interaction of the G protein complex
with agonist-bound receptor stimulates the activation of GTP to GDP on the α subunit and the β and γ subunits from the active α
subunit (bottom diagram). The GTP-bound α subunit and the free β-γ dimer can independently stimulate effectors and second mes-
senger response. The hydrolysis of GTP to GDP deactivates the α subunit, allowing the reassociation of the α, β, and γ trimer and
the recoupling of the complex to the receptor. (A, Modified from Casey PJ: Curr Opin Cell Biol 6:219-225, 1994.) B, Molecular model
of the heterotrimeric complex containing α, β, and γ subunits highlighting regions that are known from biochemical experiments to
contact receptors (purple). (B, Reprinted with permission from Lambright DG, et al: Nature 379:311-319, 1996.) C, The human GNAS
gene is located in an imprinted gene locus at 20q13.2-3 and encodes several transcripts and alternative isoforms of the G1α protein.
The GNAS chromosomal region with maternal and paternal alleles showing promoters (solid boxes) and first exons specific for
each transcript (NESP55, SLαs, 1A, and Gs-α) as white boxes and exons common to all GNAS transcripts as gray boxes (exons 2-13)
are depicted. NESP55 is expressed from the maternal allele (red), whereas SLαs and 1A are expressed from the paternal allele (blue)
due to methylation patterns (meth). In clonogenic bone marrow stromal cells derived from either normal or fibrous dysplasia tissue,
NESP55 is restricted to a subset of clonal cells and is expressed from the maternal allele. However, unlike in other tissues, SLαs is
expressed from both the maternal and paternal alleles in normal and fibrous dysplasia bone marrow stromal cells (dashed arrows).
Gs-α is expressed from both alleles in most (but not all) normal tissues; four different splice variants have been reported: Gs-α-1
(short, without exon 3), GS-α-3 (long form with CAG immediately upstream of exon 4) (codon CAG), and Gs-α-4 (short form with
CAG). The R201 fibrous dysplasia mutation site is in exon 8. In kidney, thyroid, pituitary, and ovarian tissues, GS-α is only expressed
from the paternal allele (black arrow), but in normal and fibrous dysplasia bone marrow stromal cells, overall, it is expressed from
both alleles (dashed arrows), although a great deal of asymmetry of expression is noted in clonal bone marrow stromal cell strains.
The mutations predominantly involving exon 8 of the gene result in substitutions of arginine (A) for glycine (G), cysteine (C), histidine
(H), serine (S), proline (P), and leucine (L) at position 201 and less frequently in exon 9 at position 227 resulting in substitution of
glutamine (G) for leucine (L), arginine (R), lysine (K), and histidine (H). These mutations interfere with the formation of the tight
complex among α, β, and γ subunits and promote their dissociated active state, causing hyperproliferation and abnormal maturation
of bone forming cells. They also affect proliferations of cells in multiple neuroendocrine organs, skin melanocytes, and mesenchymal
cells. (C, Modified and reprinted with permission from Riminucci M, et al: J Mol Endocrinol 45:355-364, 2010.) D, Structure of the GWAS
ERRNVPHGLFRVRUJ
protein and its functional domains. The positions of most frequent mutations in exons 8 and 9 are indicated.
572 8  Fibrous Dysplasia and Related Lesions

but their role in the pathogenesis of this disorder is
unclear.9,44,76 The alterations of Gsα affect downstream
regulatory pathways, playing an important role in the
proliferation of cells involved in the development of the
skeleton, neuroendocrine sites, and skin melanocytes as
the most frequently affected tissues. Transcriptional acti-
vation of the c-fos- and c-jun protooncogenes as well as
Runx2 and Wnt/β-catenin, which play important roles in
skeletal development, is caused by activating mutations of
Gsα protein.30,67,72 The human GNAS locus is maternally
and paternally imprinted and encodes multiple transcripts
and alternative isoforms. The genetic imprinting of both
maternal and paternal alleles and of different alternative
isoforms produces a mosaic of transcripts with restricted
expressions to specific tissues. This complexity, coupled
with a background of somatic mutations and a mixture
of mutant and nonmutant alleles, is responsible for the
variable phenotypic presentations of GNAS related dis-
orders. In individual skeletal progenitors, the transcrip-
tional activity of two Gsα alleles can be different and each
allele can be selectively expressed or completely silenced.
This is believed to be responsible for the highly variable
clinical manifestations of GNAS related disorders ranging
from a single focus to widespread skeletal involvement
as well as distinctive alterations in predominantly neu-
roendocrine sites and skin melanocytes but also affect-
ing soft tissue, including cardiac muscle, among others.
The presence of clonal structural alterations involving
chromosomes 3, 8, 10, 12, and 15 suggests that fibrous
dysplasia may represent a neoplastic condition with a
predisposition to somatic mutations of skeleton-forming
mesenchymal tissue.16,19,54 Extremely rare cases of familial
association between multiple endocrine neoplasia type 1
and Albright-McCune syndrome have been described,
and this suggests a possible pathogenetic link between
these two conditions.59 Deletions involving chromosome
9q37.3 were found in several individuals with Albright-
McCune syndrome, suggesting the possible involvement
of this chromosome region in the development of the
syndrome.62 Rare familial transmission of fibrous dyspla-
sia has also been reported.40
Definition
Fibrous dysplasia represents a dysplastic disorder of bone
characterized by solitary or multifocal polyostotic intra-
medullary lesions composed of proliferations of fibroblast-
like spindle cells with a characteristic whorled pattern
in which trabeculae of immature woven bone may be
present. The latter are typically not bordered by palisad-
ing osteoblasts.
Clinical Symptoms
Fibrous dysplasia can occur in several distinct clinical
settings (Table 8-1). It has two basic clinical forms:
monostotic and polyostotic (Figs. 8-2 and 8-3).46,69 It can
be associated with extraskeletal symptoms, which occur
more frequently in patients with the polyostotic form.
The most common extraskeletal symptom is hyperpig-
mentation of the skin (café au lait spots)(Fig. 8-4).4,70
More severe forms of polyostotic fibrous dysplasia may
be associated with endocrine abnormalities, such as pre-
cocious puberty in female subjects (Albright-McCune
syndrome).1,45,53 Other less frequent endocrine dysfunc-
tions include acromegaly, hyperthyroidism, hyperpara-
thyroidism, and Cushing’s syndrome.5,20,26 Association
of fibrous dysplasia, typically of the polyostotic form,
with soft tissue myxomas (Mazabraud’s syndrome) is
the rarest form of clinical manifestation of this disease
(Fig. 8-5).3,52,64
Monostotic fibrous dysplasia occurs more frequently
than the polyostotic variant. The ratio between the
monostotic and polyostotic forms varies among series
from 8 : 1 to 10 : 1. Monostotic fibrous dysplasia affects a
single bone, and typically one focus of involvement is
identified. Polyostotic fibrous dysplasia is characterized
by multiple foci involving several bones. The polyostotic
form is further subdivided into monomelic and polymelic
subtypes. The lesions in polyostotic fibrous dysplasia
tend to be unilateral and to involve the bones of one
extremity (monomelic polyostotic fibrous dysplasia).
More severe forms can exhibit widespread skeletal
involvement (polymelic polyostotic fibrous dysplasia).
The disease usually manifests during the first three
decades of life (approximately 70% of cases). Monostotic
fibrous dysplasia may be asymptomatic and is discovered
incidentally on radiographs obtained for other reasons.
The most common clinical symptom is swelling or
deformity of the affected site. In fact, severe deformi-
ties of the affected sites represent a major problem in
the clinical management of fibrous dysplasia (Fig. 8-6).
The lesion may occasionally be heralded by mild to
moderate pain of long duration. Pathologic fracture, par-
ticularly in the long tubular bones, may also be a present-
ing symptom. Often, the growth of the lesion stabilizes

TABLE 8-1 Summary of Clinicoradiographic Features of Fibrous Dysplasia

Variant of Fibrous Dysplasia Distribution of Lesions and Clinical Features
Monostotic Single focus in one bone
Polyostotic Multiple foci in several bones
  Monomelic Predominant or exclusive unilateral involvement of one extremity and of homolateral pelvis
or scapula
  Polymelic Widespread skeletal involvement
Albright-McCune syndrome Polyostotic (typically polymelic) fibrous dysplasia with endocrine abnormalities (most
frequently precocious puberty in female patients); less frequent anomalies include
acromegaly, hyperthyroidism, hyperparathyroidism, and Cushing’s syndrome
Mazabraud’s syndrome Polyostotic fibrous dysplasia associated with soft tissue myxomas

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Monostotic Monomelic
FIGURE 8-2  ■  Fibrous dysplasia: sites of involvement. Typical sites of skeletal involvement in various forms of fibrous dysplasia.
at a certain point. This usually occurs during puberty.
Skin pigmentations may correspond to sites of skeletal
involvement.
The more extensive the disease, the earlier the onset
of symptoms. In the monostotic form, the most frequent
sites of involvement are the ribs, craniofacial bones, prox-
imal femur, and tibia. The monomelic variant of the
polyostotic form frequently affects the lower extremity
and the homolateral hemipelvis. The polymelic form (the
most severe generalized variant) shows widespread
involvement of both extremities, the trunk, and craniofa-
cial bones. Even in this form, the disease may predomi-
nantly involve one side. Involvement of the vertebral
column is extremely rare in fibrous dysplasia.58
Albright-McCune syndrome is clinically defined by
the triad of fibrous dysplasia, café au lait spots, and
precocious puberty.17,24,78 Clinical manifestations of
Albright-McCune syndrome relative to age and their
clinical behavior are summarized in Figure 8-7. It is a
rare syndrome with estimated prevalence of 1/100,000
to 1/1,000,000. Typically, the signs of precocious puberty
or symptoms related to skeletal involvement by fibrous
dysplasia as well as early onset of café au lait spots are the
initial presentations. In girls, precocious puberty usually
presents as vaginal bleeding or spotting accompanied by
the premature development of breast tissue and pubic
hair. In boys, it is associated with testicular and penile
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8  Fibrous Dysplasia and Related Lesions 573
Polyostotic
Polymelic
enlargement and premature development of pubic and
axillary hair. The café au lait spots are usually present at
birth or develop shortly thereafter. They are classically
described as having jagged outlines referred to as a coast
of Maine outline. They show some respect to the midline
but there are frequent exceptions to this rule. The devel-
opment of café au lait spots with midline lateralism in the
adjacent skin regions may produce a harlequin pattern
of hyperpigmentation. The prevalence of major clinical
findings in fibrous dysplasia/Albright-McCune syndrome
is described in Table 8-2. Less common clinical find-
ings are summarized in Table 8-3. Two thirds of patients
show involvement of the thyroid with hyperparathy-
roidism. Some patients with extensive fibrous dysplasia
may have hypophosphatemia due to the overproduction
of a circulating phosphaturic hormone caused by over-
production of FGF23 in the fibrous dysplasia tissue.17,18
Overproduction of growth hormone is caused by the
presence of GNAS mutations in the anterior pituitary
causing hyperplasia manifesting as adenomas. Cushing’s
syndrome is one of the rarest endocrine abnormali-
ties found in Albright-McCune syndrome and typically
occurs in the neonatal period. Other extraskeletal mani-
festations include gastrointestinal reflux, gastrointestinal
polyps, pancreatitis, and cardiac abnormalities potentially
resulting in tachycardia and sudden death.
Text continued on p. 578
574 8  Fibrous Dysplasia and Related Lesions

A B
FIGURE 8-3  ■  Fibrous dysplasia: radionucleotide scanning with technetium-99. A, Skeletal survey reveals a single lesion involving the
left proximal femur proved histologically to be fibrous dysplasia. B, Polyostotic fibrous dysplasia showing multifocal involvements
of predominantly left lower extremity. Note less prominent involvement of the controlateral (right lower) extremity.

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 8  Fibrous Dysplasia and Related Lesions 575

B D E
FIGURE 8-4  ■  Representative café au lait spots seen in Albright-McCune syndrome. A and B, A spectrum of café au lait spots is seen
that both respect the midline and display “coast of Maine” borders. C, A very unusual café au lait spot seen in a child with Albright-
McCune syndrome and neonatal Cushing’s syndrome. While the spot respects the midline, the borders are smooth and the spots
alternate from left to right in a harlequin pattern. D, A very large café au lait spot with somewhat smooth borders in a patient with
relatively little fibrous dysplasia. E, A café au lait spot that clearly does not respect the midline. (Reprinted with permission from Collins
MT, et al: Orphanet J Rare Dis 7:54-67, 2010.)

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576 8  Fibrous Dysplasia and Related Lesions

A B

C D
FIGURE 8-5  ■  Mazabraud’s syndrome: radiographic features. A, Plain radiograph of right forearm shows extensive polyostotic fibrous
dysplasia and soft tissue mass. B and D, T1- and T2-weighted magnetic resonance images (MRIs) show well-circumscribed soft
tissue mass and multiple low signal intensity (T1) intramedullary lesion of radius. Note uniform high signal intensity on T2-weighted
image of soft tissue mass. C, Gross appearance of excised soft tissue myxoma from same case.

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 8  Fibrous Dysplasia and Related Lesions 577

A B
FIGURE 8-6  ■  Fibrous dysplasia: clinical manifestations. A and B, Severe facial deformity in fibrous dysplasia of craniofacial bones.

Fibrous dysplasia
Café-au-lait
Precocious Puberty
Thyroid
Phosphaturia
Growth Hormone Excess
Cushings
0 5 10 15 20 30 50
Age
Pre-clinical Persistent abnormal menses
Clinically evident Spontaneous resolution possible
FIGURE 8-7  ■  Clinical manifestations relative to age in Albright-McCune syndrome. The relative age at which any given aspect of
the disease is preclinical or clinically evident is depicted. The possibility of spontaneous resolution of the symptoms in a fraction
of patients is also provided. The period of time during which abnormal menstruation can be expected is also depicted. (Reprinted
with permission from Collins MT, et al: Orphanet J Rare Dis 7:54-67, 2010.)

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578 8  Fibrous Dysplasia and Related Lesions

(Fig. 8-12). Predominantly radiopaque lesions occur more

TABLE 8-2 Prevalence of Major Findings
frequently in the craniofacial bones than in other parts of
in the NIH Cohort of Patients
the skeleton. This is related to the particular prevalence
with Fibrous Dysplasia/
of well-mineralized bone trabeculae in fibrous dyspla-
Albright-McCune Syndrome
sia of craniofacial bones. The bone contour is usually
Clinical Finding % Patients* expanded. This feature is particularly evident in bones
with small diameter (ribs and fibulas) and in flat bones but
Fibrous dysplasia 98
Café au lait spots 66 can also be seen in the major long tubular bones (Figs.
Gonadal abnormalities 8-8 and 8-9). In the femur, tibia, or humerus, fibrous
  Male: (ultrasound)† 70 dysplasia may cause expansion of the bone contour with
  Female: precocious puberty 50 cortical thinning and endosteal scalloping (Figs. 8-9 and
Thyroid abnormalities
  Abnormal ultrasound (U/S) 66
8-13). In the long tubular bones, the shaft is typically
  Hyperthyroid + abnormal U/S 28 involved, but the metaphyses are also frequently affected.
Renal phosphate wasting 43 Lesions extending to the epiphyseal end of a bone are
  Hypophosphatemia 10 unusual. Foci of punctate and ringlike calcification may
Growth hormone excess 21 be present and represent the areas of cartilaginous differ-
Cushing’s syndrome 4
entiation that may be found in fibrous dysplasia.79 When
*N = 140; 58 males, 82 females cartilaginous differentiation is extensive, the radiographic
†
Detected on ultrasound. appearance is similar to that seen in cartilage lesions.
Collins MT, et al: Orphanet J Rare Dis 7:S4, 2012. This variant of fibrous dysplasia is sometimes referred to
as fibrocartilaginous dysplasia.
The lesions in fibrous dysplasia are often well circum-
TABLE 8-3 Prevalence of Less Common scribed and are typically surrounded by a relatively wide
Findings in the NIH Cohort of rim of sclerotic bone sometimes referred to as a rind
Patients with Fibrous Dysplasia/ (Figs. 8-10, 8-11 and 8-12). This feature is often seen in
Albright-McCune Syndrome long-standing asymptomatic solitary lesions. Even the
expansile lesions are usually delineated by a thin rim of
Other Clinical Findings % Patientsa newly formed bone. Bony deformities, particularly of the
Gastrointestinal 7 weight-bearing bones, are associated with more extensive
  History of hepatitisb 4 involvement (Figs. 8-9 and 8-14 to 8-16).7,9,21 An example
  Refluxb 5 is the shepherd’s crook deformity of the proximal femur
  Pancreatitisb 3 (Figs. 8-14 and 8-15). In extremely rare cases, fibrous
  Polypsc 5
Cardiac 6 dysplasia can form an exophytic extraosseous mass or can
  Tachycardiad 4 grow on the surface of bone (Figs. 8-17 and 8-18). This
  Aortic root dilatation (GH excess)e 2 rare form typically occurs in smaller bones, such as the
Hematologic 1 ribs or short tubular bones of the hands and feet. These
  Platelet dysfunction 1
Cancer 4
lesions are sometimes attached to the adjacent bone by a
  Thyroidf 1 bony stalk or form exophytic sessile masses. This unusual
  Breastf 2 variant of fibrous dysplasia is also referred to as fibrous
  Bonef 1 dysplasia protuberans.23
  Testicularf 1
Hyperparathyroid 1
Neuropsychiatric 9 Gross Findings
a
b
N = 140; 58 males, 82 females. When a focus of fibrous dysplasia is examined in situ,
Appeared in childhood, common causes excluded. as in a resected rib or fibula, it presents as a centrally
c
Atypical, upper GI tract polyps, myxomatoid pathology more
common. located lesion composed of fibrous tan to gray gritty
d
Unexplained/not associated with hyperthyroidism. tissue (Fig. 8-19). Lesions that are more heavily ossified
e
Only seen in patients with growth hormone excess. may be yellow to white focally. Fibrous dysplasia usually
f
All tumors bear GNAS1 mutation, adjacent normal tissue mutation has sharp borders, and the bone contour is expanded
negative.
Collins MT, et al: Orphanet J Rare Dis 7:S4, 2012.
with a thinned cortex. Areas of cartilaginous tissue are
sometimes recognized as discrete translucent blue-white
nodules. Hemorrhage and cystic change may be present,
Radiographic Imaging and areas of prominent xanthogranulomatous reaction
have a yellow appearance. Some lesions may develop
On radiographs, fibrous dysplasia appears as a medul- extensive cystic change. Hemorrhagic, blowout areas
lary lesion with the so-called ground-glass appearance usually signify secondary aneurysmal bone cyst formation.
(Figs. 8-8 and 8-9).7-9 The radiographic density of the
lesion varies and depends on the relative proportions of Microscopic Findings
bone and fibrous elements. Lesions with abundant bone
elements are more radiopaque (Figs. 8-10 and 8-11). On Fibrous dysplasia is composed of spindle cells that have
the other hand, the predominance of fibrous tissue is a whorled or storiform arrangement with interspersed
associated with a more lucent radiographic appearance Text continued on p. 591

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 8  Fibrous Dysplasia and Related Lesions 579

A B
FIGURE 8-8  ■  Fibrous dysplasia: radiographic features. A, Multifocal fibrous dysplasia of fibula. B, Enlargement of lesions shown in
A. Note central (intramedullary) location of lesions and their ground-glass appearance.

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580 8  Fibrous Dysplasia and Related Lesions

A B C
FIGURE 8-9  ■  Fibrous dysplasia: radiographic features. A, Shepherd’s crook deformity of proximal femoral shaft with external bowing
in patient with polyostotic fibrous dysplasia. B, Opposite femur of patient shown in A demonstrates anterior bowing and multiple
healed fractures and pseudarthrosis of proximal diaphysis. C, Expansile lesion in left humeral diaphysis of same patient. Note
ground-glass density of lesional tissue in A to C.

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 8  Fibrous Dysplasia and Related Lesions 581

C
FIGURE 8-10  ■  Fibrous dysplasia: radiographic features. A, Anteroposterior radiograph of humerus shows intramedullary lesion with
central opacities. B, T1-weighted magnetic resonance image shows low signal lesion with irregular signal void in heavily mineral-
ized areas, same case as in A. C, A lateral radiograph of left hip shows isolated fibrous dysplasia in intertrochanteric region of
femoral shaft. Note ringlike sclerosis of bone at periphery, which is characteristic of fibrous dysplasia in long bones.

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582 8  Fibrous Dysplasia and Related Lesions

B
FIGURE 8-11  ■  Fibrous dysplasia: radiographic features. A, Anteroposterior radiograph of proximal femur shows intramedullary lesion
with ill-defined opacities. B, T1-weighted magnetic resonance image shows low signal lesion involving the intertrochanteric region
and extending to the femoral neck.

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 8  Fibrous Dysplasia and Related Lesions 583

B C
FIGURE 8-12  ■  Fibrous dysplasia: radiographic features. A, Lateral radiograph shows radiolucent lesion with sclerotic margins involv-
ing calcaneus. B, T1-weighted magnetic resonance image shows low signal lesion of the calcaneus, same lesion as in A. C, Fat
suppression sequence reveals signal irregularities within the lesion as well as well-defined low signal intensity (sclerotic) margin,
same lesion as shown in A and B.

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584 8  Fibrous Dysplasia and Related Lesions

A B
FIGURE 8-13  ■  Polyostotic fibrous dysplasia: radiographic features. A and B, Plain radiographs of humerus and tibia of same patient
show extensive intramedullary involvement of multiple bones with cortical thinning and scalloping.

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 8  Fibrous Dysplasia and Related Lesions 585

FIGURE 8-14  ■  Fibrous dysplasia: radiographic features. A, Anteroposterior (AP) radiograph of pelvis and proximal femora shows
intramedullary lesion of left proximal femur with shepherd’s crook deformity. B, AP radiograph of pelvis and proximal femora in a
28-year-old woman with polyostotic fibrous dysplasia and Albright-McCune syndrome. There is asymmetric involvement with more
severe changes on right side (monomelic form). Note malunited femoral shaft fracture on right (arrows).

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586 8  Fibrous Dysplasia and Related Lesions

B C
FIGURE 8-15  ■  Fibrous dysplasia: radiographic features. A, Extensive skull involvement in polyostotic fibrous dysplasia with Albright-
McCune syndrome. Note marked thickening with ground-glass opacity. B, Pathologic fracture of femoral shaft in fibrous dysplasia,
same case as in A. C, Bowing deformity with transverse fractures on convex side of femur in fibrous dysplasia.

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 8  Fibrous Dysplasia and Related Lesions 587

B C D
FIGURE 8-16  ■  Polyostotic fibrous dysplasia: radiographic features (Albright-McCune syndrome). A, Anteroposterior view of pelvis
and proximal femora shows shepherd’s crook deformity of proximal femur on left. B-D, Expansile diaphyseal lesions in humerus,
femur, and second metatarsal, respectively, in same patient.

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588 8  Fibrous Dysplasia and Related Lesions

A C
FIGURE 8-17  ■  Exophytic fibrous dysplasia (fibrous dysplasia protuberans). A, Lateral radiograph shows sclerotic, well-delineated
lesion at distal end of tibia with protrusion posteriorly. B and C, T1- and T2-weighted magnetic resonance images of same lesion
demonstrate exophytic nature of lesion.

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 8  Fibrous Dysplasia and Related Lesions 589

A B

C
FIGURE 8-18  ■  Exophytic fibrous dysplasia: radiographic features. A, Exophytic, sharply circumscribed mass in shaft of right tibia is
seen in this axial computed tomogram (CT). Note sclerotic margin on medullary aspect. B, Plain radiograph of chest shows heavily
calcified, pedunculated mass attached to surface of left sixth rib. C, CT of chest shows parosteal mass with matrix calcification.
(From Dorfman HD, Ishida T, Tyuneyoshi M: Hum Pathol 25:1234-1237, 1994.)

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590 8  Fibrous Dysplasia and Related Lesions

A B

C D
FIGURE 8-19  ■  Fibrous dysplasia of rib: gross features. A and B, Rib resections show fusiform expansion of anterior portion of rib
with gritty gray-tan solid fibrous tissue in medullary cavity. C, Rib resection shows expansile fusiform lesion with gritty gray-tan
fibrous tissue. D, Rib resection shows fusiform expansion by fibrous lesion with brown areas of old hemorrhage.

ERRNVPHGLFRVRUJ

trabeculae of immature woven bone devoid of rimming
osteoblasts (Fig. 8-20).36,66,71,98 The number and distribu-
tion of bone trabeculae and their level of maturation may
vary among different lesions and in different areas of
the same lesion (Figs. 8-21 to 8-23). The most common
and characteristic pattern of bone produced in fibrous
dysplasia consists of slender, curved, and branching tra-
beculae of bone without surface osteoblasts. These are
frequently described as resembling Chinese characters
(Fig. 8-22), although no such characters actually exist in
written Chinese. In some cases, the trabeculae of bone
are sparsely distributed with a predominance of cellular
fibrous tissue. At the other end of the spectrum are heavily
ossified lesions in which relatively mature bone trabec-
ulae overshadow the fibrous component of the lesion
(Figs. 8-23 and 8-24). The lesions with abundant bony
components frequently contain foci of matrix mineraliza-
tion that resemble cementoid bodies (Fig. 8-24). These
concentrically laminated calcified structures are most fre-
quently seen in fibrous dysplasia involving craniofacial
bones but may also be present in other sites.89,92,99 In the
past, lesions with prominent cementoid structures were
designated, especially in the oral pathology literature, as
fibrocementomas or cementifying fibromas.
Examination under polarized light reveals a very char-
acteristic and diagnostically important feature: All bone
trabeculae in fibrous dysplasia, despite their mature
appearance, show a polarization pattern that forms dis-
organized, haphazard deposits characteristic of woven
bone (Fig. 8-25). Secondary changes in fibrous dysplasia
may alter the typical microscopic appearance and make
it difficult to diagnose. Hemorrhage and secondary fibro-
histiocytic reaction may be present focally. Occasionally
a diffuse infiltrate of foamy histiocytes may obscure the
characteristic microscopic features of the lesion. Such
lesions may be incorrectly designated as xanthomas of
bone. Intralesional hemorrhage in fibrous dysplasia can
provoke extensive giant cell reaction, which leads to con-
fusion with giant cell tumor (Figs. 8-26 and 8-27). Myxoid
change of stromal tissue can be focal or quite extensive
in some lesions. These secondary changes are more likely
to be found in the older lesions of fibrous dysplasia.
Reactive bone with prominent osteoblastic rimming
may be seen focally in fibrous dysplasia complicated by
pathologic fracture. Small fractures of the thinned cortex
may not be clinically and radiographically evident; there-
fore the stimulus to reactive bone formation remains
unrecognized. Secondary aneurysmal bone cyst with
radiographic evidence of an expansile lesion is a common
complication (Figs. 8-26 to 8-28).91,96 Cystic change with
accumulation of serous fluid in fibrous dysplastic tissue is
a distinct phenomenon and should not be automatically
interpreted as a secondary aneurysmal bone cyst. The
underlying fibrous dysplasia can be almost completely
obliterated by either type of secondary cystic change.
Microscopic foci of cartilaginous differentiation are fre-
quently present in fibrous dysplasia, but in rare cases the
cartilage matrix may dominate the microscopic and
radiographic pictures. These rare cases are referred to as
fibrous dysplasia with massive cartilaginous differentiation or
fibrocartilaginous dysplasia. This peculiar variant of fibrous
dysplasia is separately described in further detail.
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8  Fibrous Dysplasia and Related Lesions 591
Differential Diagnosis
Fibrous dysplasia is most frequently confused histologi-
cally with other benign fibroosseous lesions, in particular
with osteofibrous dysplasia. This entity is composed of a
mixture of fibrous tissue and mature bone trabeculae that
exhibit classic osteoblastic rimming. Osteofibrous dyspla-
sia is an intracortical lesion that occurs in children,
whereas fibrous dysplasia tends to be more centrally
located in the medullary cavity and is often first diag-
nosed in adults.47 It affects the tibia and fibula almost
exclusively, whereas fibrous dysplasia can occur in any
bone. Desmoplastic fibroma, because it can mimic the
fibrous component of fibrous dysplasia, is sometimes
considered when a small biopsy sample does not include
the osteoid and woven bone elements found in fibrous
dysplasia. Reactive bone formation in desmoplastic
fibroma at the edge of the lesion can usually be recog-
nized by the prominent osteoblastic rimming. It is most
important to distinguish between fibrous dysplasia and
low-grade intramedullary osteosarcoma. The latter lesion
can be difficult to diagnose when the bone trabeculae of
the tumor forms the branching or interconnected pattern
usually associated with fibrous dysplasia. However, the
spindle-cell areas in this entity usually show nuclear
atypia and larger nuclei with a coarser chromatin pattern
than those found in fibrous dysplasia. As opposed to the
circumscribed expansile growth pattern of fibrous dyspla-
sia with peripheral bone sclerosis, low-grade intramedul-
lary osteosarcoma permeates cancellous bone trabeculae
with an infiltrative growth pattern. Preliminary evidence
indicates that the presence of mutations involving a gene
coding for Gsα subunit in fibrous dysplasia may be a useful
marker in differential diagnosis of this disorder and other
fibroosseous lesions, including well-differentiated fibroblas-
tic osteosarcoma.11,63,77
Polyostotic fibrous dysplasia may mimic enchondroma-
tosis on radiographs because of the multiplicity of lesions
in both conditions, but enchondromatosis tends to show
a much greater unilateral predominance. Histologically,
these lesions may be confused when fibrous dysplasia
contains an abundance of cartilage. In these cases, atten-
tion to the radiographic features and careful study of the
histologic material for evidence of fibroosseous elements
usually resolves the dilemma. In more florid examples of
massive chondroid differentiation in fibrous dysplasia,
there is also the danger of confusion with conventional
chondrosarcoma. This can be excluded by the absence of
chondrocyte atypia and the presence of enchondral ossi-
fication at the borders of the dysplastic chondroid foci.
Treatment and Behavior
In fibrous dysplasia the multifocal skeletal lesions develop
more or less synchronously. Therefore the initially diag-
nosed monostotic forms typically do not progress to
polyostotic generalized forms. However, additional foci
of fibrous dysplasia occasionally develop in an affected
bone.9,36 A solitary focus may enlarge in size, and the
extent of involvement can progress over time. In rare
instances, such locally progressive lesions may expand
Text continued on p. 601
592 8  Fibrous Dysplasia and Related Lesions

A B

C D
FIGURE 8-20  ■  Fibrous dysplasia: microscopic features. A-D, Different patterns of branching and focally anastomosing trabeculae of
woven bone in fibrous stroma (A-C, ×100; D, ×200). (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 8  Fibrous Dysplasia and Related Lesions 593

A B

C D
FIGURE 8-21  ■  Fibrous dysplasia: microscopic features. A-D, Different patterns of branching and anastomosing trabeculae of imma-
ture woven bone in fibrous stroma (A-C, ×200; D, ×100). (A-D, hematoxylin-eosin.)

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594 8  Fibrous Dysplasia and Related Lesions

A B

C D
FIGURE 8-22  ■  Fibrous dysplasia: microscopic features. A-D, Mineralized trabeculae of woven bone in fibrous stroma
(A-D, ×100) (A-D, hematoxylin-eosin).

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 8  Fibrous Dysplasia and Related Lesions 595

A B

C D
FIGURE 8-23  ■  Fibrous dysplasia: microscopic features. A-D, Different patterns of branching and anastomosing trabeculae of woven
bone in moderately cellular fibrous stroma (A-D, ×100) (A-D, hematoxylin-eosin).

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596 8  Fibrous Dysplasia and Related Lesions

A B

C D
FIGURE 8-24  ■  Fibrous dysplasia: microscopic features. A-D, Different patterns of cementum-like, round, calcified spherules of woven
bone in otherwise typical fibrous dysplasia. This finding is noted in a minority of cases in extragnathic sites. They may be numerous
or few and arranged in clusters (A and B, ×50; C and D, ×100). (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 A

FIGURE 8-25  ■  Fibrous dysplasia: microscopic features. A, A pattern of lamellar mineralization in cortical bone overlaying a focus of
fibrous dysplasia shown in B. Inset, Higher magnification of A with clear lamellar mineralization pattern showing parallel lines of
mineralization under polarized light. B, Focus of fibrous dysplasia showing well delineated trabeculae of woven bone in cellular
fibrous stroma. Inset, Haphazardous woven bone mineralization pattern under polarized light (A and B, ×100; insets, ×200).
(A, B, and insets, hematoxylin-eosin.)

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598 8  Fibrous Dysplasia and Related Lesions

A B

C D
FIGURE 8-26  ■  Fibrous dysplasia: microscopic features. A and B, Different patterns of woven bone trabeculae with anastomosing
features in fibrous stroma. C and D, Areas of fresh hemorrhage and giant cell reaction consistent with secondary aneurysmal bone
cyst in the same case of fibrous dysplasia (A-D, ×100) (A-D, hemotoxylin-eosin).

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 8  Fibrous Dysplasia and Related Lesions 599

A B

C D
FIGURE 8-27  ■  Fibrous dysplasia with secondary changes: microscopic features. A, Typical pattern of immature bone trabeculae in
fibrous dysplasia of rib. B, Extensive giant cell reaction associated with intralesional hemorrhage. Different lesion of case shown in
A. C, Higher magnification of B shows prominent giant cell and spindle-cell reactions. D, Features of aneurysmal bone cyst super-
imposed on fibrous dysplasia (same case as in A and B) (A, B and D, ×100; C, ×200). (A-D, hematoxylin-eosin.)

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600 8  Fibrous Dysplasia and Related Lesions

C
FIGURE 8-28  ■  Fibrous dysplasia: radiographic features. A, Anteroposterior radiograph shows fluid level in expanded cystic mandibu-
lar lesion. B, Panorex radiograph of jaw shows expanded lucent lesion at left angle of mandible. C, Computed tomogram shows
multiloculation in lesion of fibrous dysplasia with extensive secondary aneurysmal bone cyst formation.

ERRNVPHGLFRVRUJ

beyond the bone contour into the soft tissue.39 This
occurs most frequently during the skeletal growth period.
The lesions have a tendency to stabilize after puberty,
and new foci rarely develop during adulthood. The
enlargement of lesions of fibrous dysplasia after puberty
is more frequently related to secondary aneurysmal bone
cyst and simple cystic degeneration rather than to actual
proliferative activity of the lesion. Superimposition of
aneurysmal bone cyst and rapid enlargement of the
lesion may prompt surgical intervention.106 Pregnancy
seems to promote enlargement of the lesions, but the
mechanism of this phenomenon is unclear. It is unknown
whether it is related to increased proliferative activity
or simply to secondary changes such as hyperemia and
hemorrhage.
Bone deformities in fibrous dysplasia are treated by
corrective surgery. A solitary focus that is prone to patho-
logic fracture, especially in the long bones, is treated by
curettage and bone grafting with or without internal fixa-
tion. Lesions of small-diameter expendable bones, such
as the ribs or fibula, are usually treated by segmental
resection.
The development of secondary sarcoma in fibrous dys-
plasia is an extremely rare but well-established phenom-
enon.9,22,25,29,32,38,56,61,68,73,74,82,83,90,93,95,105 It occurs in less
than 1% of patients during adult life in long-standing
lesions. Lesions treated with radiation therapy are more
likely to develop sarcomatous transformation, but rare
cases of spontaneous malignant transformation also have
been reported.34 Malignant transformation is related to
the extent of involvement, and patients with polyostotic
fibrous dysplasia have a greater risk of the development
of sarcomatous transformation than those with mono-
stotic forms. The average lag between the diagnosis and
the development of a malignancy is 13.5 years, and
patients are generally in the third and fourth decades of
life. The types of sarcoma that complicate fibrous dyspla-
sia are most frequently malignant fibrous histiocytoma
(fibrosarcoma) or osteosarcoma of high histologic grade.
Chondrosarcoma that develops in association with fibrous
dysplasia has also been reported.22,32 An extremely rare
case of association between desmoplastic fibroma and
fibrous dysplasia was documented in one report.102 The
craniofacial skeleton and femur are the most common
sites of malignant transformation. This generally corre-
lates with the frequency of distribution of bones involved
in fibrous dysplasia. The prognosis for patients who
develop sarcomatous transformation is poor. Pulmonary
metastasis develops in most patients, and the mean sur-
vival period is 3.4 years. Alterations in the clinical course
in patients older than age 40 years with known fibrous
dysplasia, such as pain and swelling, should be carefully
evaluated.
Fibrous Dysplasia in Different
Anatomic Sites
The biologic potential of fibrous dysplasia is not related
to the site of involvement. Differential diagnosis, clinical
presentation, and treatment may vary in different ana-
tomic sites. Moreover, fibrous dysplasia in certain loca-
tions, such as the craniofacial bones, has some distinct
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8  Fibrous Dysplasia and Related Lesions 601
microscopic features. For these reasons, separate descrip-
tions of the disorder in various anatomic sites are
provided.
Fibrous Dysplasia of Craniofacial Bones.  Craniofacial
bones are the most frequent sites of involvement by soli-
tary fibrous dysplasia (Figs. 8-28 and 8-29).27,28,37,87,104
They may also be involved in the polyostotic generalized
form (Fig. 8-30). The most frequently affected bone is
the maxilla, followed by the bones of the cranial vault and
the mandible. Clinically the disease is manifested by
malar enlargement (cherubism) or unilateral facial hyper-
trophy. The most typical radiographic presentation of
fibrous dysplasia in the craniofacial bones is in the form
of a cloudy opacity of the maxillary bone. The lesions of
the mandible and of the cranial bones produce fusiform
expansion of the bone contour. Computed tomography
and magnetic resonance imaging are particularly helpful
in delineating the extent of involvement in this region
and in showing the expansile lesion surrounded by a
thinned and scalloped cortex that is intact (Fig. 8-29).14,97
In severe polyostotic disease, extensive involvement of
the craniofacial bones can produce pronounced disfigur-
ing deformities (Figs. 8-6, 8-15, and 8-29).
Microscopically, fibrous dysplasia of the craniofacial
bones tends to produce more bone trabeculae than in
other skeletal sites.27 The bone production is usually pro-
nounced, with formation of an anastomosing network of
well-mineralized woven bone arranged in broader tra-
beculae. Sometimes these trabeculae approach lamellar
maturation. The calcification pattern may include con-
centric spherical structures designated as cementoid bodies
(Fig. 8-24). Such lesions, especially in the oral pathology
literature, have been designated as fibrocementomas with
the implication that they are pathogenetically distinct
from fibrous dysplasia. The current trend is to consider
them as examples of fibrous dysplasia with a peculiar
pattern of mineralization rather than as a distinct entity.
The presence of similar cementum-like structures in
fibrous dysplasia involving other skeletal sites supports
the concept that they are not specific for dental cemen-
toid differentiation.
Fibrous Dysplasia of Ribs.  Ribs are frequently involved
by a solitary focus of fibrous dysplasia.33,80,98 In some
studies, they represent the most frequently affected site.
Involvement of the ribs can also occur in polyostotic
forms. The lesion usually presents as an asymptomatic,
palpable, fusiform enlargement of the rib. Radiographi-
cally, it is a lucent mass of ground-glass density expanding
the rib contour (Figs. 8-31 and 8-32). Clinically and
radiographically, fibrous dysplasia must be differentiated
from cartilage lesions (chondrosarcoma), especially if the
mass is growing and is associated with pain. In this site,
fibrous dysplasia is treated by segmental excision. The
lesions in the ribs frequently show minimal bone produc-
tion and are predominantly fibrous. Secondary changes
(myxoid, xanthogranulomatous, giant cell, and reactive
bone formation) frequently occur in the rib lesions.
These changes are probably the result of repeated
mechanical stress related to respiratory movements and
Text continued on p. 606
602 8  Fibrous Dysplasia and Related Lesions

A B

C D
FIGURE 8-29  ■  Fibrous dysplasia: radiographic features. A, Computed tomogram (CT) of maxilla shows extensive involvement by
fibrous dysplasia with obliteration of left maxillary sinus and nasal cavity. B, CT of skull shows expansile lesion of fibrous dysplasia
in left frontal bone. C, Severe craniofacial distortion by polyostotic fibrous dysplasia in a 35-year-old woman. Note extensive involve-
ment of mandible, maxilla, and frontal region of skull. D, Three-dimensional CT of skull shown in B. Bulging lesion depresses roof
of orbit and expands frontal bone.

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 8  Fibrous Dysplasia and Related Lesions 603

A B

C D
FIGURE 8-30  ■  Polyostotic fibrous dysplasia: radionuclide scanning. A-D, Technetium-99 radionuclide scans in a 22-year-old woman
who had right arm pain associated with humeral shaft lesion proved histologically to be fibrous dysplasia. Skeletal survey revealed
lesions in contralateral humerus (A), base of skull (B), left femur (C), and left ilium (D).

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604 8  Fibrous Dysplasia and Related Lesions

C D
FIGURE 8-31  ■  Fibrous dysplasia: radiographic features. A, Radiograph of thorax shows expanded anterior portion of right upper rib
involved by isolated lesion of fibrous dysplasia. Inset, Computed tomogram (CT) shows fusiform expansion of rib anteriorly with
hazy lucency in medullary cavity and intact shell of cortical bone. B, Anteroposterior radiograph of chest shows fusiform expansion
produced by single focus of fibrous dysplasia (arrows). C, Technetium 99 radionuclide scan shows lesion involving second left rib.
D, CT documents presence of fusiform lesion in rib with cortical thinning.

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 8  Fibrous Dysplasia and Related Lesions 605

C D
FIGURE 8-32  ■  Fibrous dysplasia: radiographic features. A and B, Anteroposterior radiographs of left and right hands of patient with
polyostotic fibrous dysplasia show bilateral involvement of metacarpal shafts and phalanges. Note broadening of diaphysis with
ground-glass medullary opacity. C, Expansile lytic lesion of rib incidentally discovered on chest radiograph. D, Low-power photo-
micrograph shows network of woven bone in fibrous stroma (D, ×25, hematoxylin-eosin).

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606 8  Fibrous Dysplasia and Related Lesions
may overshadow the diagnostic features of fibrous dys-
plasia. Consequently, some fibrous dysplasia lesions in
the ribs cannot be recognized with certainty and are des-
ignated as unclassified fibroosseous lesions.
Fibrous Dysplasia of Extremity Bones.  The long
tubular bones of the appendicular skeleton are frequently
involved in the monostotic and polyostotic forms of
fibrous dysplasia. Involvement of the short tubular bones
of the hands and feet is extremely rare. It typically occurs
in the polyostotic form with associated involvement of
other bones of the same extremity, widespread skeletal
involvement, or both (Figs. 8-13, 8-14, 8-16, and 8-32).
In monostotic fibrous dysplasia, the proximal femoral
shaft is involved in approximately 40% of patients, fol-
lowed by the tibia (15%), humerus (5%), and radius (5%).
In severe polyostotic fibrous dysplasia, the femur is
usually involved. The tibia is involved in approximately
50% of patients, followed by the humerus (30%). Severe
deformities (shepherd’s crook deformity), pathologic
fractures, or both (Figs. 8-9, 8-14, and 8-16) may develop
in long tubular bones, especially the weight-bearing
bones.
Fibrous Dysplasia of Flat Bones.  Monostotic fibrous
dysplasia of the flat bones (pelvis or scapula) is rare.
Involvement of the flat bones is typical in polyostotic
fibrous dysplasia. In these patients, the flat bones are
involved in addition to the corresponding bones of the
appendicular skeleton (i.e., the pelvis and femur or
scapula and humerus). Multifocal involvement of the
pelvic bones is present in approximately 50% of patients
with severe polyostotic fibrous dysplasia.
Personal Comments
This dysplastic anomaly of bone formation commonly
presents as a solitary lesion in a rib, the maxilla, or a major
long bone, but it is very rare in its polyostotic form. Much
of the diagnostic confusion with regard to fibrous dyspla-
sia is related to the variable clinical presentations and the
variety of histologic patterns associated with this condi-
tion. It has been known since the initial pathologic
description by Lichtenstein41 that, in addition to the
fibrous and osseous components, cartilage differentiation
is frequently found and may be voluminous, causing con-
fusion with cartilaginous neoplasms in the skeleton. In
addition, extensive intralesional hemorrhage with giant
cell reaction can lead to a misdiagnosis of giant cell tumor
or giant cell reparative granuloma. We have seen exam-
ples with extensive xanthomatous reactions interpreted
pathologically as fibroxanthomas or as Erdheim-Chester
disease. We have also seen rare examples of highly eccen-
tric and even exophytic fibrous dysplasia producing pro-
tuberant lesions that could be mistaken on radiographs
for osteochondromas.
In the past, there has been much emphasis on the dif-
ficulty in distinguishing histologically between osteofi-
brous dysplasia (formerly called ossifying fibroma of long
bones) and fibrous dysplasia. This distinction should not
be difficult, however, since osteofibrous dysplasia occurs
exclusively in the tibia and fibula of children and is a
ERRNVPHGLFRVRUJ
lesion that is generally confined to the cortex. Fibrous
dysplasia is almost always an intramedullary lesion.
FIBROCARTILAGINOUS DYSPLASIA
In 1984, Dahlin et al.111 described a rare lesion of bone
that contained fibroosseous components and extensive
areas of cartilage as fibrocartilaginous mesenchymoma of
bone and believed that it had a low-grade malignant
potential. Several additional similar lesions were described
under the name of fibrocartilaginous mesenchymoma of
bone.108,113,114 Our own experience with eight cases of
similar lesions indicates that it should be considered as a
variant of fibrous dysplasia rather than as a separate and
distinct neoplasm. Moreover, the long-term clinical
follow-up data indicate no evidence of malignant behav-
ior.108 For all these reasons, we designate these lesions as
fibrous dysplasia with massive cartilaginous differentiation or
fibrocartilaginous dysplasia.115 The main significance of this
condition is that it may be misinterpreted as a cartilage
neoplasm. The lesion is extremely rare; the Mayo Clinic
recently reported only 12 cases of this entity from their
files.73 Several additional individual cases of fibrocarti-
laginous dysplasia have been described in the litera-
ture.110,112,117,118,120 A case of what is probably the same
entity was originally reported by Telford119 in 1930.
A series of eight additional cases was reported by
Choi et al.109
Incidence and Location
Massive chondroid differentiation in fibrous dysplasia is
extremely rare, and eight cases of this entity were found
in our consultation files. The clinical data for these eight
cases are summarized in Table 8-4. The age of patients
ranged from 4 to 26 years, with an average age of 17.5
years. Four patients were male, and four were female.
Two patients had an associated polyostotic form of
fibrous dysplasia. One patient had a history of Wilms’
tumor of the right kidney at age 4 years and had under-
gone nephrectomy, chemotherapy, and radiation therapy.
This patient also had fibromatosis of the buttock at age
14 years.
The proximal portion of the femur is the most common
site of fibrocartilaginous dysplasia. Five of the eight cases
involved the femoral neck or proximal shaft of the femur.
Tibial involvement was seen in one case and involvement
of the midfemur and distal femur was seen in another
case. This distribution is distinct from that seen by the
Mayo Clinic, which reported a majority of their cases to
be localized in the tibia.108
Clinical Symptoms
The symptoms of fibrocartilaginous dysplasia vary. The
presenting symptoms are usually pain with or without
swelling. In our series, two patients had swelling or a
mass, and two patients were asymptomatic. Three patients
had pain, and one patient had a pathologic fracture.
The duration of symptoms ranged from a few weeks to
15 years.
 8  Fibrous Dysplasia and Related Lesions 607

TABLE 8-4 Summary of Clinical Data of Fibrocartilaginous Dysplasia

Age Duration of Calcification Preconsultation
Case (yr)/sex Location Type Symptoms Symptoms on Radiograph Diagnosis Other Findings
1 20/M Femur Polyostotic Mass 15 yr + Chondrosarcoma −
(proximal)
2 23/F Tibia Polyostotic − − + FD with cartilage Ovarian
(proximal) dysgenesis
3 8/F Femur Monostotic Pain 7 mo + Cartilage tumor −
(proximal)
4 20/M Femur Monostotic Pain ? − FD with cartilage −
(proximal)
5 26/F Ischiopubic Monostotic Mass 8 yr + Chondrosarcoma −
bone
6 14/F Femur Monostotic − − + Cartilage tumor Wilms’ tumor,
(proximal) fibromatosis
7 25/M Femur Monostotic Pain, 2 yr (pain) + Enchondroma, R/O −
(proximal) fracture chondrosarcoma
8 4/M Femur Monostotic Limp ? −* ? −
(proximal)

*Chondroid tumor suggested by magnetic resonance imaging.

FD, fibrous dysplasia; R/O, rule out.
From Ishida T, Dorfman HD: Am J Surg Pathol 17:924-930, 1993.

Radiographic Imaging myxoid change of the cartilaginous matrix was seen in

On radiographs the lesions are generally well demarcated
and show ground-glass opacity or have an osteolytic
appearance (Figs. 8-33 and 8-34). When the shaft of the
femur or tibia is involved, cortical expansion can be seen;
however, the cortex is always intact (Figs. 8-33 and 8-34).
In one case a typical shepherd’s crook deformity was
found in the femoral neck. In six cases, stippled or ring-
like calcifications suggesting chondroid elements were
evident on plain radiographs (Figs. 8-33 and 8-34). In one
case, magnetic resonance imaging showed a low-intensity
signal in T1-weighted images and a high intensity signal
with lobulation in T2-weighted images, suggesting a
chondroid lesion with a lobular architecture (Fig. 8-34).
Gross Findings
When curettage is performed, the gross appearance of
the lesion is similar to that of enchondroma or low-grade
chondrosarcoma and consists of fragments or irregular
masses with an obvious cartilaginous appearance. In cases
with less prominent cartilaginous components, the lesion
can have a fibrous, soft, or gritty appearance similar to
that seen in typical fibrous dysplasia.
Microscopic Findings
A large amount of hyaline cartilage and a disproportional
amount of cartilage versus fibroosseous elements are
troublesome findings. Cartilaginous differentiation in
this variant of fibrous dysplasia is usually in the form of
large lobules surrounded by fibroosseous tissue that con-
tains features typical of fibrous dysplasia (Fig. 8-35). The
cartilage in this condition has microscopic features of
immaturity (i.e., increased cellularity and mild nuclear
atypia) (Figs. 8-36 to 8-38). The level of matrix matura-
tion can approach that seen in hyaline cartilage, but foci
of myxoid change can also be seen. More extensive
only one case. The lobules of cartilage are sharply demar-
cated from the surrounding fibroosseous tissue. A more
irregular pattern of cartilage matrix deposition is fre-
quently present. Enchondral ossification is commonly
seen in the peripheral regions of the cartilage islands
(Figs. 8-36 to 8-38). Focally, hypertrophic chondrocytes
are arranged in columns with calcification of the matrix
and formation of irregular columns of enchondral ossifi-
cation similar to that seen in the epiphyseal growth plate.
Prominent capillaries between the vertical columns of the
areas mimic primary spongiosa, and osteoclastic resorp-
tion is present. Active enchondral ossification is seen
focally in the majority of cases. Enchondrally ossified
trabeculae merge into the irregularly shaped bone tra-
beculae in the surrounding fibroosseous lesion (Figs.
8-37 and 8-38). Although the fibroosseous lesion shows
the typical histologic appearance of fibrous dysplasia,
bone trabeculae around the cartilage islands are focally
surrounded by osteoblasts, which represent the process
of enchondral ossification. Prominent immature osteoid
formation can be seen focally. Larger areas of predomi-
nantly fibrous tissue show more typical features of fibrous
dysplasia. Fibrous septa separating sharply demarcated
islands of cartilage may exhibit hypercellularity with
prominent plump fibroblastic cells.
Differential Diagnosis
Although cartilaginous differentiation in fibrous dyspla-
sia is usually inconspicuous, its presence is well known,
and all textbook descriptions of fibrous dysplasia include
at least a passing reference to the occasional presence of
cartilage islands. In rare instances, there may be massive
amounts of cartilage elements that reach several cen-
timeters in diameter.80 In these cases, large dysplastic
cartilage islands may be misinterpreted as benign or even
malignant cartilaginous neoplasms. It is of the utmost
Text continued on p. 614

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608 8  Fibrous Dysplasia and Related Lesions

B C
FIGURE 8-33  ■  Fibrous dysplasia with cartilage differentiation (fibrocartilaginous dysplasia): radiographic features. A, Femoral neck
lesion shows stippled calcification in well-demarcated lytic area. B, Ringlike, punctate, and curvilinear arclike calcifications in lytic
lesion occupying upper femoral shaft and femoral neck. C, Slightly expansile lytic lesion occupying proximal two thirds of tibial
shaft. Note overall ground-glass appearance with punctate and ringlike calcifications corresponding to cartilage matrix in proximal
part of lesion. (From Ishida T, Dorfman HD: Am J Surg Pathol 17:924-930, 1993.)

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 8  Fibrous Dysplasia and Related Lesions 609

A B C

D
FIGURE 8-34  ■  Fibrous dysplasia with cartilage (fibrocartilaginous dysplasia). A, Anteroposterior radiograph of femur of a 4-year-old
boy shows expanded contour of diaphysis with well-circumscribed borders delineating lobulated, lucent intramedullary lesion.
B, T1-weighted magnetic resonance image (MRI) shows low signal area with sharp borders. C, T2-weighted MRI shows high signal
area with lobulated pattern corresponding to high water content of cartilage lobules. D, Expansile lytic lesion of pubic bone contain-
ing predominantly punctate calcification. (From Ishida T, Dorfman HD: Am J Surg Pathol 17:924-930, 1993.)

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610 8  Fibrous Dysplasia and Related Lesions

B C
FIGURE 8-35  ■  Fibrous dysplasia with cartilage differentiation (fibrocartilaginous dysplasia): microscopic features. A, Low power
view, showing islands of hyalinized cartilage (left) and fibrous stroma with trabeculae of woven bone characteristic of fibrous
dysplasia. B, Higher magnification of A showing an interface between cartilage islands and fibrous stroma. Note an
irregular contour of the cartilage islands and the trabeculae of woven bone within the fibrous stroma. C, Higher magnification of
another area from A showing trabeculae of woven bone in fibrous stroma characteristic of fibrous dysplasia (A, ×50; B and C, ×100).
(A-C, hematoxylin-eosin.)

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 8  Fibrous Dysplasia and Related Lesions 611

B
FIGURE 8-36  ■  Fibrous dysplasia with cartilage differentiation (fibrocartilaginous dysplasia): microscopic features. A and B, Low
and intermediate power view of the interface between large areas of hyaline cartilage and fibrous stroma. Note irregular ragged
border of the cartilage island with enchondral ossification characteristic of fibrocartilaginous dysplasia (A, ×50; B, ×100). (A and
B, hematoxylin-eosin.)

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612 8  Fibrous Dysplasia and Related Lesions

A B

C D
FIGURE 8-37  ■  Fibrous dysplasia with cartilage differentiation (fibrocartilaginous dysplasia): microscopic features. A-D, Large area
of hyaline cartilage and intervening stromal fibrous tissue showing irregular outline of cartilage and features of enchondral ossifica-
tion (A and B, ×50; C and D, ×100). (A-D, hematoxylin-eosin.)

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 8  Fibrous Dysplasia and Related Lesions 613

A B

C D

FIGURE 8-38  ■  Fibrous dysplasia with cartilage differentiation (fibrocartilaginous dysplasia): microscopic features. A-C, Cartilage
island and fibrous tissue interface showing columnar arrangement of chondrocytes and endochondral ossification mimicking
epiphyseal growth plate frequently seen in fibrocartilaginous dysplasia. D and Inset, Higher magnification of cartilage island showing
enlarged atypical chondrocytes (A-C, ×100; D, ×200; inset, ×400.)

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614 8  Fibrous Dysplasia and Related Lesions
importance to be aware of the possibility of finding car-
tilaginous predominance in an otherwise typical lesion of
monostotic or polyostotic fibrous dysplasia and to avoid
the risk of diagnosing cartilage neoplasia.
Although the chondrocytes in fibrocartilaginous dys-
plasia are generally small with condensed nuclei, they
may also show atypical findings such as hypercellularity,
binucleate cells, and enlargement in focal areas.115 Large
amounts of atypical cartilage are diagnostic pitfalls in the
histologic diagnosis. The presence of a fibroosseous
lesion typical of fibrous dysplasia adjacent to the cartilage
islands is the most important diagnostic feature that dif-
ferentiates this entity from other cartilaginous neoplasms
such as enchondroma and chondrosarcoma.
The cartilage islands become calcified peripherally and
show enchondral ossification merging with the surround-
ing fibroosseous lesion. Such prominent enchondral ossi-
fication is not usually found in conventional chondroid
neoplasms. This is another characteristic finding of fibro-
cartilaginous dysplasia and is helpful in distinguishing
these lesions from true cartilage neoplasms.
In addition to enchondroma and conventional chon-
drosarcoma, the differential diagnosis also includes dedif-
ferentiated chondrosarcoma. Fibrous areas within fibrous
dysplasia sometimes show high cellularity. In such cases,
dedifferentiated chondrosarcoma must be considered.
However, careful microscopic examination of this tumor
reveals malignant cartilage and anaplastic dedifferentiated
sarcomatous elements. It is not difficult to distinguish
dedifferentiated chondrosarcoma from fibrocartilaginous
dysplasia when the radiologic features are considered.
Furthermore, the absence of nuclear anaplasia in the
spindle-cell elements is crucial in recognizing fibrocar-
tilaginous dysplasia.
Clinical Behavior
Foci of well-developed hyaline cartilage nodules are
present in a small percentage of fibrous dysplasia and they
vary from small microscopic foci to large, grossly evident
masses. The appellation of fibrocartilaginous dysplasia is
used for those cases in which the cartilage is abandoned
and may overshadow the underlying fibroosseous process.
The clinical experience with this lesion is extremely
limited but it is evident that foci of abundant cartilage
can develop in polyostotic fibrous dysplasia and may
affect only one or several affected sites. The clinical
symptomatology indicates an indolent protracted disease.
The single case observations, based on many years of
follow-up, indicate benign but continuous growth that
may cause considerable disfiguring deformation necessi-
tating ablative surgery.116
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moma of the distal femur: case report and literature review. Pathol
Int 51:638–642, 2001.
114. Gibson JNA, Reid R, McMaster MJ: Fibrocartilaginous mesen-
chymoma of the fifth lumbar vertebra treated by vertebrectomy.
Spine 19:1992–1997, 1994.
115. Ishida T, Dorfman HD: Massive chondroid differentiation in
fibrous dysplasia of bone (fibrocartilaginous dysplasia). Am J Surg
Pathol 17(9):924–930, 1993.
116. Kyriakos M, McDonald DJ, Sundaram M: Fibrous dysplasia with
cartilaginous differentiation (“fibrocartilaginous dysplasia”): a
review, with an illustrative case followed for 18 years. Skeletal
Radiol 33:51–62, 2004.
117. Pelzmann KS, Nagel DZ, Salyer WR: Case report 114. Skeletal
Radiol 5(2):116–118, 1980.
118. Sumner TE, Ward WG, Kilpatrick SE, et al: Fibrocartilaginous
mesenchymoma of bone: case report and review of the literature.
Pediatr Radiol 30:315–317, 2000.
119. Telford ED: A case of osteitis fibrosa (with formation of hyaline
cartilage). Br J Surg 18:409–414, 1930.
120. Vargas-Gonzalez R, Sanchez-Sosa S: Fibrocartilaginous dysplasia
(fibrous dysplasia with extensive cartilaginous differentiation).
Pathol Oncol Res 12:111–114, 2006.

Fibrous and
Fibrohistiocytic Lesions
CHAPTER OUTLINE
NONOSSIFYING FIBROMA (FIBROUS
CORTICAL DEFECT)
Multifocal Nonossifying Fibroma Associated
with Clinical Syndromes
BENIGN FIBROUS HISTIOCYTOMA
FIBROMYXOMA
ANGIOMATOID FIBROUS HISTIOCYTOMA
NONOSSIFYING FIBROMA
(FIBROUS CORTICAL DEFECT)
Definition
The terms nonossifying fibroma (nonosteogenic fibroma),
fibrous cortical defect, and metaphyseal fibrous defect have
been applied to the same metaphyseal fibrohistiocytic
process. The location of the lesion in the growing por-
tions of long tubular bones of skeletally immature patients
and its frequent spontaneous resolution indicate that it
represents a self-limiting process most likely related to
incomplete ossification.
Incidence and Location
The peak age incidence and the most frequent sites of
skeletal involvement are shown in Figure 9-1. Radio-
graphic evidence of fibrous cortical defect of long tubular
bones can be found in approximately 30% of young indi-
viduals with unfused growth plates.7,16,17,34,41 The majority
of lesions are asymptomatic and are incidental radio-
graphic findings. A small percentage of these lesions can
produce larger lytic defects that can become symptom-
atic. The larger ones are prone to pathologic fracture
and may require prophylactic curettage.3,10,29 The peak
incidence is in the second decade of life. The distal
femoral metaphysis is the most common site. The second
most frequent site is the proximal tibial metaphysis
followed by the distal tibial metaphysis. Nonossifying
fibroma occurs less commonly in the upper extremity,
where it may be found in the proximal humerus and
distal radius. Occasionally the lesions may be multifocal,
simultaneously involving several symmetric metaphyseal
sites, most frequently in the long bones of the lower
extremity.27 The lesion is metaphyseal but can also
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C H A P T E R 9 
SKELETAL FIBROMATOSES
Desmoplastic Fibroma
Juvenile Multifocal Myofibromatosis
Congenital Fibromatosis–like Fibrosarcoma
(Infantile Fibrosarcoma)
MALIGNANT FIBROUS HISTIOCYTOMA
FIBROSARCOMA
involve the diaphysis. Its long axis is parallel to the
long axis of the affected bone. The radiographic findings
are specific, and the diagnosis can be made with certainty
if the lesion is present in a typical skeletal site and appro-
priate age group. On this basis, such a lesion can be
observed untreated. The rarity of both fibrous cortical
defects and nonossifying fibroma on radiographs of
adults is indirect evidence of a natural history character-
ized by spontaneous regression of most of these lesions
over time.
Clinical Symptoms
Most nonossifying fibromas are asymptomatic. The
lesion is usually incidentally identified on radiographs
obtained for other reasons such as trauma. Larger lesions
can cause pain or expansion of the affected area. In
some instances, pathologic fracture can be a presenting
symptom.3,10,29 Superimposed aneurysmal bone cyst with
the development of an expansive, rapidly enlarging mass
can also call attention to the lesion.
Radiographic Imaging
Metaphyseal fibrous defect produces an eccentric cortical-
based lytic lesion with distinct and frequently scalloped,
sclerotic margins (Figs. 9-2 to 9-6).4,7,13,16,20,32 The cortex
overlying the lesion is usually minimally to moderately
expanded and markedly thinned but intact (Figs. 9-2 to
9-5). There is no matrix mineralization, but in older
patients evidence of bone sclerosis can accompany healing
of the lesion. The distance from the growth plate usually
increases with age and in older adolescents.30,39 The
lesion appears to migrate in a shaftward direction as a
result of skeletal growth. The lesions typically are
lytic. Incomplete trabeculation is frequently seen and is
617
618 9  Fibrous and Fibrohistiocytic Lesions
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 9-1  ■  Nonossifying fibroma. Peak age incidence and frequent sites of skeletal involvement. Most frequent sites of involve-
ment are indicated by black solid arrows.
accentuated in the peripheral parts of the defect (Figs.
9-3 and 9-4). Older lesions may show prominent mar-
ginal or intralesional sclerosis (Figs. 9-4 and 9-5). In
smaller bones, such as the fibula, an eccentric location is
less common, and the lesion may appear as a central,
expansile trabeculated lytic defect (Fig. 9-2). Pathologic
fracture is a frequent presenting sign (Fig. 9-7). Com-
puted tomography (CT), magnetic resonance imaging
(MRI), or both modalities can precisely document the
relationship between the lesion, the medullary cavity, the
cortex, and the periosteum (Figs. 9-4 to 9-6).15,18,31 These
imaging techniques show that the lesion represents an
eccentric defect delineated from the medullary cavity by
a rim of sclerotic bone and covered by a thinned, intact
cortical bone and periosteum (see Figs. 9-4 to 9-6).
Gross Findings
When evaluated intact in its setting, nonossifying fibroma
is an eccentric and cortically based lesion with an inner
boundary that is scalloped and distinctly demarcated.
The cortex can be markedly thinned and expanded but
intact. The tissue is fibrous, fleshy, and yellow or tan-
brown (Fig. 9-8). There may be evidence of cystic change,
hemorrhage, or extensive necrosis, particularly in asso-
ciation with pathologic fracture of larger lesions.
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7 8
Microscopic Findings
The nonossifying fibroma is composed of fibroblastic,
usually highly cellular, stromal tissue with a prominent
storiform pattern (Fig. 9-9). In this stroma, there are a
few multinucleated giant cells and foci of xanthomatous
reaction with foamy histiocytes present (Figs. 9-9 to 9-11
and 9-16). Usually, there is a substantial amount of hemo-
siderin pigment clearly visible in the stromal cells (Fig.
9-16). Minimal numbers of mononuclear inflammatory
cells may be present. Fresh hemorrhage and cystic change
similar to that seen in aneurysmal bone cyst may be
present. Secondary aneurysmal bone cyst formation can
lead to rapid enlargement and a “blowout” expansion into
the soft tissue. Occasionally multinucleated giant cells
dominate, but they are usually focally distributed (Fig.
9-14). With low power magnification, it is possible to
observe the localization of prominent giant cell reaction
to areas of hemorrhage. Ghosts of giant cells and patterns
demonstrating the storiform architecture of the lesion
may be perceived in areas of necrosis. Necrosis, as well
as the presence of occasional normal mitotic figures, are
not worrisome features in otherwise typical nonossifying
fibroma and should not be considered as microscopic fea-
tures of malignancy. Atypical mitoses are absent. Rarely
Text continued on p. 629
 9  Fibrous and Fibrohistiocytic Lesions 619

A B

C D
FIGURE 9-2  ■  Nonossifying fibroma: radiographic features. A and B, Anteroposterior (AP) radiographs showing two examples of
nonossifying fibroma of distal radial metaphysis in adolescents. Thinning of slightly expanded overlying cortex is present in both.
C, AP radiograph showing slightly expansile, well-marginated lytic lesion of proximal fibular shaft in teenage patient. D, AP radio-
graph of distal metaphyseal lesion with trabeculated pattern, expanded bone contour, and sharp demarcation. In fibula, nonossifying
fibroma often involves the entire medullary cavity and does not show eccentric features.

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620 9  Fibrous and Fibrohistiocytic Lesions

A B

C D

FIGURE 9-3  ■  Nonossifying fibroma: radiographic features. A and B, Anteroposterior (AP) radiographs showing large bilateral, eccen-
tric, lucent lesions in proximal tibial metaphyses of a 12-year-old girl. Scalloped borders and incomplete trabeculation are typical
of nonossifying fibroma. Note expanded and scalloped but intact cortex. C and D, AP and lateral radiographs of ankle region show
large, well-demarcated lucent lesion in distal tibial diametaphysis. Note slightly expansile contour and narrow zone of transition to
normal bone.

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 9  Fibrous and Fibrohistiocytic Lesions 621

A B

C D

FIGURE 9-4  ■  Nonossifying fibroma: radiographic features. A and B, Anteroposterior (AP) and lateral radiographs showing an eccen-
tric lesion in the tibial metaphysis with scalloped sclerotic margins and coarse trabeculation characteristic of nonossifying fibroma.
C, AP radiograph of a large nonossifying fibroma in the distal femoral metaphysis. Note sclerotic margins and an expanded cortex
overlaying the lesion. D, Coronal magnetic resonance image (MRI) showing an eccentric well demarcated lesion in the distal femoral
metaphysis. Same case as shown in C. Inset, Axial CT scan showing an eccentric lytic lesion with scalloped well demarcated margins.

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622 9  Fibrous and Fibrohistiocytic Lesions

A C

D E
FIGURE 9-5  ■  Nonossifying fibroma: radiographic features. A, Anteroposterior radiograph showing an eccentric lesion in the distal
tibial diaphysis with sclerotic margins and expanded overlying cortex. B and C, Axial computed tomography (CT) scans showing
eccentric lesion of the tibia. Note well demarcated sclerotic medullary margin. D and E, Sagittal and coronal T1-weighted magnetic
resonance images showing low density eccentric lesion of distal tibial metaphysis with well demarcated sclerotic scalloped margins.

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 9  Fibrous and Fibrohistiocytic Lesions 623

A B

D E
FIGURE 9-6  ■  Nonossifying fibroma: radiographic and microscopic features. A, Anteroposterior radiograph showing an eccentric lytic
lesion of the proximal tibial metaphysis with fine trabeculations and expanded overlying cortex. B, Fat-saturated T2-weighted coronal
magnetic resonance image (MRI) of the lesion shown in A shows signal enhancement in an eccentric tibial metaphyseal lesion.
C and D, Axial fat-saturated T2-weighted and T-weighted MRIs showing an eccentric well demarcated lesion involving the proximal
tibia. E, Low power microphotograph of nonossifying fibroma showing fibrohistiocytic proliferation with storiform pattern (E, ×100)
(E, hematoxylin-eosin).

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A B

C D
FIGURE 9-7  ■  Nonossifying fibroma: radiographic features. A and B, Nonossifying fibroma in distal shaft of radius with pathologic
fracture shown in anteroposterior and lateral views of forearm. C and D, Fracture healing with normal callus formation several
months later in patient shown in A and B.

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A B

C D
FIGURE 9-8  ■  Nonossifying fibroma: gross features. A, Bisected fibular segment shows two separate cortically oriented lesions, one
containing abundant lipid and the other with extensive hemosiderin deposits. B, Whole-mount section of fibular shaft shows cortical
orientation of nonossifying fibroma and circumscription by a narrow zone of sclerotic bone on medullary aspect. C, Brown, gelati-
nous tissue excised from proximal tibial metaphysis reflects high content of hemosiderin pigment. D, Segmental resection of fibula
contains fibrous lesion with focal brown discoloration in medullary cavity.

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626 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-9  ■  Nonossifying fibroma: microscopic features. A and B, Low and intermediate power photomicrographs show bundles
of spindle cells with rare interspersed multinucleated giant cells. C and D, Low and intermediate power photomicrographs showing
spindle cell proliferations with interspersed multinucleated giant cells. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

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 9  Fibrous and Fibrohistiocytic Lesions 627

A B

C D
FIGURE 9-10  ■  Nonossifying fibroma: microscopic features. A-D, Low and intermediate power photomicrographs showing fibrohis-
ticytic proliferation with storiform pattern and rare interspersed multinucleated giant cells and histiocytes. (A and C, ×100; B and
D, ×200.) (A-D, hematoxylin-eosin.)

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A B

C D
FIGURE 9-11  ■  Nonossifying fibroma: microscopic features. A and B, Low and intermediate power photomicrographs showing a
proliferation of histiocytic cells with occasional vacuolated foamy cytoplasm and prominent multinucleated giant cells. C and
D, Low and intermediate power photomicrographs showing spindle cells growing in a storiform pattern showing scattered multi-
nucleated giant cells. Note an angulated cytoplasmic outline of multinucleated giant cells and their somewhat pyknotic nuclei, a
frequent feature of giant cells in nonossifying fibroma. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

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nonossifying fibroma can be markedly hypercellular and
is composed of plump fibrohistiocytic cells with enlarged
nuclei (Figs. 9-12 to 9-14). Such lesions may raise sus-
picion of malignancy but the true cytologic atypia and
atypical mitosis are absent. In addition, correlation with
radiographic features showing typical radiographic pre-
sentation of nonossifying fibroma with the absence of
imaging features indicating an aggressive growth pattern,
confirm the benign nature of such lesions. Focal myxoid
change as well as areas of reactive bone formations
can be present (Fig. 9-15). In summary, the lesion has
microscopic features that overlap with those of the fibro-
histiocytic reactive lesions commonly seen in extraskel-
etal sites and with the reactive changes superimposed
on various preexisting skeletal conditions.15 The best
example of this is giant cell tumor of bone, which may
contain a substantial component of reactive fibrohistio-
cytic changes resembling nonossifying fibroma or benign
fibrous histiocytoma. As a consequence, nonossifying
fibroma can be confused with many other conditions if
its microscopic appearance is evaluated without clinico-
radiologic correlation.16,17
Special Techniques
Ultrastructural studies suggest the histiocytic rather than
fibroblastic origin of nonossifying fibroma.14,16,36 This
observation is consistent with the strong positivity
of nonossifying fibroma for CD68. Cytogenetically,
nonossifying fibromas have a near-diploid chromosomal
complement.39 Several clonal chromosomal aberrations,
including translocation t(1;4)(p31;q34), suggest the true
neoplastic nature of at least a subset of nonossifying
fibromas.6,28,39
Differential Diagnosis
The presence of multinucleated giant cells in a spindle-
cell background without the formation of bone or carti-
lage matrix may raise the question of giant cell tumor in
the microscopic differential diagnosis of nonossifying
fibroma. The distinction is easily made on clinical and
radiologic grounds because giant cell tumor occurs almost
exclusively in adult patients at the ends of long bones, not
in the metaphyses.
Fibrous dysplasia may be considered when small corti-
cal fractures occur in nonossifying fibroma and lead to
reactive bone formation. Biopsy samples from such areas
show parallel arrays of immature bone trabeculae with
bordering osteoblasts. Although a storiform pattern is
sometimes present in fibrous dysplasia, the multinucle-
ated giant cells seen in nonossifying fibroma are not a
common feature of fibrous dysplasia. Furthermore, the
radiologic eccentricity of nonossifying fibroma is not
characteristic of fibrous dysplasia.
Desmoplastic fibroma may be mimicked by the more
heavily collagenized areas of nonossifying fibromas
undergoing involutional changes. Eccentric radiolucent
lesions of the medial supracondylar side of the femur
in the cortical irregularity syndrome can have overlapping
features with fibrous cortical defects, but this avulsive
lesion usually does not show the multinucleated giant
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9  Fibrous and Fibrohistiocytic Lesions 629
cell elements or storiform pattern of nonossifying
fibroma.
Benign fibrous histiocytoma is a term applied to lesions
that are histologically identical with nonossifying fibroma
but that occur in unusual locations such as the flat bones,
ribs, or vertebrae.
Treatment and Behavior
As stated, nonossifying fibromas are frequently asymp-
tomatic, self-healing lesions that do not require treat-
ment. The larger lesions that expand the bone, develop
secondary aneurysmal bone cysts, or pose a danger of
fracture are treated by curettage and bone grafting.35,40,42
Most lesions stabilize at puberty and show signs of healing
by peripheral sclerosis or solid opacification.7,30,32 In rare
instances nonossifying fibroma may continue to grow and
show considerable increase in size over time.42
In one study of 23 cases of pathologic fractures through
nonossifying fibromas, it was found that the distal tibia
was most frequently involved. Lesions that occupied
more than 50% of the transverse diameter of the involved
bone were likely to fracture. Pathologic fractures through
these lesions can be treated by cast bracing until the
fracture heals; then curettage with or without bone graft-
ing can be done.3,10,11
Cases in which a malignant tumor was present inde-
pendently in a bone that also contained a nonossifying
fibroma have been reported.19,22 The malignancies have
all been osteosarcomas.
Several rare cases of apparent malignant transforma-
tion of nonossifying fibroma have been described.5,25,38 In
all of these cases, the original radiographic presentation
of the lesion was not characteristic of nonossifying
fibroma. Bone production and periosteal reaction were
present in the first instance and loss of anterior cortex in
the second. In the third example, the lesion involved the
mandible, which is a very unlikely location for nonossify-
ing fibroma. This raises the possibility that the original
lesion in all of those instances was most likely malignant
from the time of presentation. Furthermore, benign-
appearing, whorled fibrous tissue and foam cells, which
microscopically characterize nonossifying fibroma, can
be seen focally in several bone malignancies.
Personal Comments
Surprisingly, nonossifying fibromas are still occasionally
diagnosed histologically as giant cell tumors, even though
review of the clinical and radiologic features would
suffice to exclude this diagnosis when considering a
metaphyseal lesion in a preadolescent patient. Radiologic
correlation would also serve to explain the presence of
reactive bone in curetted material when a recent or old
pathologic fracture is present in the thin cortex of such a
lesion. Nonossifying fibromas produce eccentrically ori-
ented lucencies, whereas a focus of fibrous dysplasia is
indicative of a central intramedullary lesion. Knowledge
of the latter helps prevent the less frequent error of diag-
nosing a nonossifying fibroma with reactive bone as
fibrous dysplasia.
Text continued on p. 634
630 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-12  ■  Nonossifying fibroma: microscopic features. A-D, Low and intermediate power photomicrographs showing highly
cellular variant of nonossifying fibroma composed of plump mononuclear cells with somewhat hyperchromatic nuclei. Such features
can raise suspicion of malignancy. In such instances, correlation with a radiographic presentation of the lesion is helpful to avoid
misclassification of hypercellular variants of nonossifying fibroma. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

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 9  Fibrous and Fibrohistiocytic Lesions 631

A B

C D
FIGURE 9-13  ■  Nonossifying fibroma: microscopic features. A and B, Low and intermediate power photomicrographs showing
hypercellular nonossifying fibroma. Inset shows details of plump mononuclear cells with hyperchomatic nuclei. C and D, Low
and intermediate power photomicrographs showing more typical presentation of nonossifying fibroma composed of fibro-
histiocytic proliferation with intracytoplasmic deposition of hemosiderin. (A and C, ×100; B and D, ×200; Inset, ×400).)
(A-D, hematoxylin-eosin.)

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632 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-14  ■  Nonossifying fibroma: microscopic features. A-D, Low and intermediate power photomicrographs showing
storiform fibrohistiocytic formations with prominent scattered multinucleated giant cells. (A and C, ×100; B and D, ×200.)
(A-D, hematoxylin-eosin.)

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 9  Fibrous and Fibrohistiocytic Lesions 633

A B

C D
FIGURE 9-15  ■  Nonossifying fibroma: microscopic features. A, Low power photomicrograph showing storiform fibrohistiocytic pro-
liferation. B, Low power photomicrograph showing irregular hypocellular areas with stromal myxoid change. C and D, Low and
intermediate power photomicrographs showing an area of reactive woven bone formation at the periphery of the nonossifying
fibroma. (A, B, and D, ×100; C, ×50.) (A-D, hematoxylin-eosin.)

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634 9  Fibrous and Fibrohistiocytic Lesions
Multifocal Nonossifying Fibroma
Associated with Clinical Syndromes
Multifocal nonossifying fibromas can occur in several
extremely rare clinical settings. The first is familial mul-
tifocal nonossifying fibromas. Evans and Park12 reported
three patients in the same family who had multiple non-
ossifying fibromas in long bones with many associated
abnormalities. Patients with neurofibromatosis (von
Recklinghausen’s disease) have a greater likelihood of
developing multifocal nonossifying fibromas in the typical
long bone sites.23,33 Moser et al.27 found that 5% of 900
patients with multifocal nonossifying fibromas had
underlying neurofibromatosis. In both of these clinical
syndromes, the nonossifying fibromas are found in the
usual sites (i.e., metaphyses of long bones), and they may
be bilateral and symmetric.
Jaffe-Campanacci syndrome is an uncommon, congeni-
tal disorder in which multifocal nonossifying fibromas of
bone are associated with café au lait pigmentation, various
nonskeletal anomalies, and mental retardation.1,2,8,21,24,26,37
Originally, it was thought that neurofibromatosis is not a
component of this syndrome. More recent observations
indicate, however, that Jaffe-Campanacci syndrome may
represent a unique presentation of neurofibromatosis
type 1 because some of these patients may have other
stigmata of neurofibromatosis, such as cutaneous neuro-
fibromas.9 The nonossifying fibromas in Jaffe-Campanacci
syndrome tend to be more pronounced in the metaphy-
seal areas of the long tubular bones, but they also form
separate diaphyseal lesions. Widespread, more or less
symmetric involvement of the long tubular bones of the
extremities is typical in this syndrome (Figs. 9-17 and
9-18). In Jaffe-Campanacci syndrome, the trunk, axial
skeleton, and craniofacial bones are also typically involved.
Each individual lesion has the radiographic appearance
of a nonossifying fibroma, but occasionally each focus
coalesces, especially in the metaphyseal parts, and forms
a larger trabeculated lesion. Pathologic fracture fre-
quently occurs in this syndrome, especially in younger
patients. Similar to ordinary nonossifying fibroma,
skeletal lesions in Jaffe-Campanacci syndrome have a
tendency to stabilize and heal after puberty. The nonskel-
etal anomalies in this syndrome are hypogonadism,
cryptorchidism, ocular anomalies, and cardiovascular
malformations, including mitral insufficiency and aortic
stenosis. In some cases, precocious puberty and kypho-
scoliosis have been reported. These patients appear to
have a generalized defect of mesenchymal tissue. Rarely,
familial distribution has been reported. Nonossifying
fibromas in Jaffe-Campanacci syndrome have micro-
scopic features identical to those seen in ordinary nonos-
sifying fibromas.
BENIGN FIBROUS HISTIOCYTOMA
Definition
Benign fibrous histiocytoma of bone is a spindle-cell lesion
composed of fibroblast-like cells with a storiform pattern.
Foamy histiocytes and multinucleated giant cells are
usually present. When xanthomatous changes dominate
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the histologic picture, the diagnosis of xanthoma, xantho-
fibroma, or fibrous xanthoma of bone may be suggested.
Microscopically, it is similar to the more common benign
fibrous histiocytoma of soft tissue. In bone, it is micro-
scopically indistinguishable from nonossifying fibroma or
from the prominent fibrohistiocytic reaction found in
some giant cell tumors. There is controversy about
whether this is a distinct benign bone neoplasm or merely
a reactive lesion superimposed on a preexisting condition
that cannot be easily identified.
Incidence and Location
Benign fibrous histiocytoma is a very rare entity with
strict radiologic and microscopic criteria.44-46,51 Lesions
with the clinical and radiographic features of nonossify-
ing fibroma or giant cell tumor should be excluded from
the category of benign fibrous histiocytoma. Patient age
has a wide range from 5 to 75 years, and there is no clear
sex predilection. The ilium and ribs are the most fre-
quently involved sites. Individual cases have been reported
in flat bones, including the craniofacial bones, vertebrae,
and sacrum.43,47,49,50,52-58,65,66 Occasionally, benign fibrous
histiocytoma may present as a central intramedullary
diaphyseal lesion of the long tubular bones.63 Examples
of benign fibrous histiocytoma involving the acral skel-
eton have also been described.60 The age distribution
and typical sites of skeletal involvement are shown in
Figure 9-19.
Clinical Symptoms
The most frequent symptom is pain, ranging in duration
from months to several years. Pathologic fracture is rarely
a presenting symptom.
Radiographic Imaging
On radiographs, benign fibrous histiocytoma appears as
a purely lytic, sharply demarcated lesion. A sclerotic rim
and fine trabeculations may be present (Figs. 9-20 and
9-21). The tumor can disrupt the cortex and expand into
soft tissue, but usually it is delineated by a thin rim of
newly formed bone. In the long bones, the diaphysis and
metaphysis are usually involved. The reported cases
located in the ends of long tubular bones are controver-
sial because it is difficult, or perhaps even impossible, to
exclude a giant cell tumor with a prominent fibrohistio-
cytic component.59
Gross Findings
The lesion evaluated in situ represents an intramedul-
lary, well-demarcated lesion that is tan-gray with yellow
and brown areas related to the presence of lipids and
hemorrhage.
Microscopic Findings
The spindle-shaped, fibroblast-like cells have elongated
plump nuclei and small prominent nucleoli.44,45,61,62 A sto-
riform pattern is typically present, at least focally. Foamy,
 9  Fibrous and Fibrohistiocytic Lesions 635

A B

C D
FIGURE 9-16  ■  Nonossifying fibroma: microscopic features. A and B, Intermediate power photomicrographs show fibrohistiocytic
lesion with storiform pattern. Note hemosiderin deposits in B. C, Multinucleated giant cells concentrated in area of fresh hemor-
rhage. D, Clusters of xanthoma cells (A-D, ×200) (A-D, hematoxylin-eosin).

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636 9  Fibrous and Fibrohistiocytic Lesions

A B
FIGURE 9-17  ■  Jaffe-Campanacci syndrome: radiographic features. A and B, Anteroposterior radiographs of bilateral, multifocal
nonossifying fibromas of humeri. (Courtesy Dr. M. Campanacci, Bologna, Italy.)

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 9  Fibrous and Fibrohistiocytic Lesions 637

A B
FIGURE 9-18  ■  Jaffe-Campanacci syndrome: radiographic features. A and B, Multiple, bilateral, lower-extremity long bone nonossify-
ing fibromas in an 11-year-old boy with mental retardation, leg-length discrepancies, and skin pigmentation. (Courtesy Dr. M. Cam-
panacci, Bologna, Italy.)

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638 9  Fibrous and Fibrohistiocytic Lesions
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 9-19  ■  Benign fibrous histiocytoma. Age distribution and frequent sites of skeletal involvement. Most frequent sites of
involvement are indicated by solid black arrows.
lipid-filled macrophages are interspersed among spindle
cells and occasionally form larger solid areas (Fig. 9-20).
Multinucleated giant cells are almost always present and
are sparsely distributed among the other elements. Fea-
tures of fresh and old hemorrhage with hemosiderin
deposits can be found. Cystic changes can frequently be
seen microscopically. Occasional mitotic figures can be
present, but atypical mitoses are absent. Overall, the cel-
lularity can be high with occasional hyperchromatic
nuclei, but true nuclear atypia is absent. Similar to nonos-
sifying fibroma, ultrastructural studies confirmed the his-
tiocytic nature of cells in benign fibrous histiocytoma,
which are CD68 positive.62
Differential Diagnosis
Benign fibrous histiocytoma is histologically indistin-
guishable from nonossifying fibroma, differing only in its
clinical and radiographic features. In the ribs, pelvis,
skull, scapula, and vertebral column, such lesions may
contain large amounts of lipids and may be referred to as
xanthofibromas or xanthogranulomas of bone. Indeed, such
lipid-filled lesions in ribs have been mistaken for local-
ized lesions of Erdheim-Chester disease.48
Giant cell tumor of bone may be characterized by fibro-
histiocytic elements with a prominent storiform pattern,
ERRNVPHGLFRVRUJ
7 8
abundant lipids within histiocytes, and reactive bone for-
mation. These changes can be very extensive or only
focal. Such areas sampled in small biopsy fragments
may be interpreted as benign fibrous histiocytoma.
The radiographic features of such cases are usually diag-
nostic for giant cell tumor of bone. Indeed, adequate
sampling of a lytic tumor in the end of a long bone of an
adult patient that shows “benign fibrous histiocytoma”
features usually reveals small areas of classic giant cell
tumor.
The diagnosis of benign fibrous histiocytoma of bone
is made by exclusion of other entities (eosinophilic granu-
loma, fibrous dysplasia, giant cell tumor, and giant cell
reparative granuloma) that may exhibit prominent fibro-
histiocytic reactions.
Treatment and Behavior
Benign fibrous histiocytoma should be treated by curet-
tage and bone grafting. Lesions that can be resected (i.e.,
rib, fibula) because of their anatomic site should be
treated by en bloc excision. Recurrences can occur in
the bone after curettage, but local aggressive behavior
and particularly distant metastasis indicate that the
diagnosis of benign fibrous histiocytoma was inappropri-
ate. These cases, in our opinion, were in all probability
 9  Fibrous and Fibrohistiocytic Lesions 639

A B

C D

FIGURE 9-20  ■  Benign fibrous histiocytoma (xanthofibroma) of bone: radiographic and microscopic features. A, Well-marginated,
radiolucent, asymptomatic lesion discovered on intravenous pyelogram of a 13-year-old girl. She had nephrectomy for a renal tumor
at age 8, and follow-up studies revealed this lesion, samples of which were taken at subsequent biopsy. B, Fibrohistiocytic prolifera-
tion with scattered multinucleated giant cells. C and D, Xanthomatous and spindle-cell features without cytologic atypia. Note the
overall similarity of the lesion to a nonossifying fibroma. (B, C, ×100; D, ×200.) (B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
640 9  Fibrous and Fibrohistiocytic Lesions

B C
FIGURE 9-21  ■  Benign fibrous histiocytoma: radiographic features. A, Oblique radiograph of foot of a 16-year-old boy with pathologic
fracture through well-demarcated lytic lesion in calcaneus. B and C, Axial computed tomograms show lytic lesion with sclerotic
borders and cortical infarction. Histologic features of benign fibrous histiocytoma closely resembling nonossifying fibroma were
present in curettage specimen.

ERRNVPHGLFRVRUJ

misdiagnosed examples of giant cell tumor or low-grade
malignant fibrous histiocytoma of bone.64
Personal Comments
This controversial entity is undoubtedly overdiagnosed
when the designation is applied to giant cell tumors con-
taining extensive areas of fibrohistiocytic reaction.59 A
thorough histologic search for foci of conventional giant
cell tumor usually reveals the true nature of the lesion,
but sometimes all the available material is composed of
fibrohistiocytic reaction. In such cases, the characteristic
radiographic features of a lytic lesion at the end of a long
bone in a skeletally mature individual allow the inference
to be drawn that the lesion is a giant cell tumor with
secondary changes. This is analogous to making a diag-
nosis of giant cell tumor or any other bone lesion in
which secondary aneurysmal bone cyst formation is so
profuse that it obscures the precursor lesion.
It is best to reserve the term benign fibrous histiocytoma
for lesions that are indistinguishable from nonossifying
fibroma but are located in unusual skeletal sites or present
in older patients.
FIBROMYXOMA
Fibromyxoma is a rare lesion that bears certain simi­
larities to chondromyxoid fibroma, but the few cases
described in the literature occurred in older individu-
als.67-75 In addition, such lesions lack the lobular architec-
ture and the chondroid matrix that are characteristic of
chondromyxoid fibroma. Radiographically, fibromyxoma
appears as a lytic defect with scalloped margins (Fig.
9-22). Microscopically, fibromyxoma is uniformly myxoid
with low to intermediate cellularity (Fig. 9-22). Some
investigators believe that these lesions represent variants
of chondromyxoid fibroma.
ANGIOMATOID FIBROUS
HISTIOCYTOMA
In 1979, Enzinger81 described a distinct tumor predomi-
nantly occurring in the subcutaneous soft tissue of chil-
dren and young adults that is composed of solid nests of
histiocytoid cells with multiple blood-filled cystic spaces.
He proposed the term angiomatoid malignant fibrous his-
tiocytoma. This lesion has been renamed angiomatoid
fibrous histiocytoma to reflect the relative rarity of metas-
tasis and the overall favorable prognosis.78 The originally
suggested fibrohistiocytic origin of the lesion is question-
able.81,87,103 We have seen five examples of this lesion
arising in bone. Additional single case report of angioma-
toid fibrous histiocytoma involving bone have been dis-
cussed in the literature.88,90,94
Clinical Symptoms
Angiomatoid fibrous histiocytoma occurs primarily in
children and young adults. It is extremely rare in patients
older than age 40 years. When it occurs in bone, the
ERRNVPHGLFRVRUJ
9  Fibrous and Fibrohistiocytic Lesions 641
patient has local pain, tenderness, and expansion of bone
contour. The characteristic and unique feature is the
frequent presence of general symptoms such as fever,
anemia, hypogammaglobulinemia, and weight loss. Local
lymphadenopathy was also present in two of our cases
that presented as primary bone lesions.
Radiographic Imaging
All lesions presented as expansile lytic lesions with eccen-
tric cortical disruption and extension into soft tissue
(Figs. 9-23 and 9-24). One lesion was originally diag-
nosed as nonspecific inflammatory reaction and recurred
3 months after initial curettage. Compterized imaging
techniques can document the multilocular cystic nature
of the lesion.90
Gross Findings
The curetting available for gross examination consisted
of irregular tan-gray and hemorrhagic fragments of soft
tissue.
Microscopic Findings
The microscopic appearance of angiomatoid fibrous his-
tiocytoma of bone is similar to that described for soft
tissue lesions. The tumor is composed of solid areas of
undifferentiated mesenchymal cells with a histiocytoid
appearance (Figs. 9-24 and 9-25). Multiple blood-filled
cystic (telangiectatic) spaces are present within these areas
(Figs. 9-24 and 9-26). In fact, some lesions can be domi-
nated by extensive multilocular cystic change that may
obscure the details of the underlying lesion.82 The overall
microscopic appearance mimics aneurysmal bone cyst or
telangiectatic osteosarcoma, and the lesion in bone must
be distinguished from these entities. In fact, one of our
cases was initially classified as telangiectatic osteosar-
coma. In addition, the lesion can be confused with heman-
giopericytoma or glomus tumor of bone. Solid areas with
histiocytoid cells with foci of inflammatory cells are typi-
cally present (Fig. 9-25). Areas of old and fresh hemor-
rhage and focal myxoid and xanthomatous changes also
can be seen. The lesion is typically surrounded (especially
in the area of extension into soft tissue) by a thick fibrous
capsule. Prominent lymphoplasmocytic infiltration can
cause confusion with chronic osteomyelitis (Fig. 9-25).
Some lesions may focally show a whorllike arrangement
of cells and psammoma bodies similar to those commonly
seen in menigiomas. An unusual intraosseous angioma-
toid fibrous histiocytoma with sclerotic features mimick-
ing an osteosarcoma has also been described.88 Soft tissue
lesions may have extensive areas of pleomorphic cells, but
such variants of angiomatoid fibrous histiocytoma have
not been observed in bone.77,89,101
Special Techniques
Ultrastructurally, the histiocytoid cells of angiomatoid
fibrous histiocytoma represent undifferentiated mesen-
chymal cells.86,96 Immunohistochemically, they are positive
Text continued on p. 647
642 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-22  ■  Fibromyxoma: radiographic and microscopic features. A, Anteroposterior (AP) radiograph of proximal femur showing
a lytic lesion of intertrochanteric area with scalloped sclerotic margin. Note similarity of this radiographic presentation with more
conventional chondromyxoid fibroma. B, AP radiograph showing a lytic, well demarcated defect of ilium with sclerotic margins and
trabeculations. Note similarity between this lesion and more conventional chondromyxoid fibroma at this site. C and D, Uniformly
myxoid lesion with low cellularity. Note absence of lobulated architecture with septa containing chondroblasts and giant cells seen
in typical chondromyxoid fibroma. (C and D, ×100) (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 643

A B
FIGURE 9-23  ■  Angiomatoid fibrous histiocytoma of bone: radiographic features. A and B, Internal rotation and anteroposterior views
of humerus of 8-year-old boy show expansile lytic lesion with blowout features and prominent periosteal reaction. There was associ-
ated axillary and supraclavicular lymphadenopathy, high fever, episodic nausea and vomiting, and a 6-pound weight loss in 6 weeks.
Lesion was initially treated by curettage with recurrences 3 and 9 months after original curettage. Finally, patient was treated with
proximal humeral resection.

ERRNVPHGLFRVRUJ
644 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-24  ■  Angiomatoid fibrous histiocytoma: radiographic and microscopic features. A, Axial computed tomogram of skull (bone
window) shows right-sided mandibular destruction and large associated soft tumor mass in a 7-year-old girl. There is no evidence
of matrix mineralization. B, Multicystic hemorrhage in tumor tissue producing pseudoangiomatous low power appearance.
C, Higher magnification shows pseudoangiomatoid architecture. D, High power photomicrograph shows bland nuclear features in
round-to-oval tumor cells and two foci of calcification. (B, ×50; C, ×100; D, ×400). (B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 645

A B

C D
FIGURE 9-25  ■  Angiomatoid fibrous histiocytoma: microscopic features. A, Low power photomicrograph showing prominent band
of inflammatory cells at the periphery of the lesion. B, Intermediate power photomicrograph shows sheets of plump spindle and
histiocytoid cells. C and D, Proliferation of plump histiocytoid cells with concentric whorllike arrangement of cells. (A-C, ×100;
D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
646 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-26  ■  Angiomatoid fibrous histiocytoma: microscopic features. A and B, Low power photomicrographs showing multicystic
architecture in tumor tissue producing pseudoangiomatous appearance. C and D, Solid proliferations of indistinct plump histiocytoid
cells. (A and B, ×25; C and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

for vimentin and negative for histiocytic and endothelial
markers.83,91,100 The presence of scattered CD68 (KP-1)–
positive cells can be documented in approximately 50%
of cases.96 They most likely represent true macrophages
attracted to the lesion by hemorrhage. In some cases, the
expression of desmin suggests muscle differentiation, but
other muscle markers are typically negative.83,91 Angio-
matoid fibrous histiocytomas are diploid by cytometric
measurements.80 In general, the immunohistochemi-
cal profile is not specific. The hallmark of angiomatoid
fibrous histiocytoma is the presence of three distinct
chromosomal translocations resulting in the presence of
chimeric genes: EWSR1-ATF1 t(12;22)(q13;q12) (72%),
EWSR1-CREB1 t(2;22)(q34;q12) (21%), and FUS-ATF1
t(12;22)(q13;q12) (7%).76,79,84,85,92,93,102 The first two trans-
locations are the most frequent and involve the EWSR1
gene, a prototypic gene of the translocations in Ewing’s
sarcoma and several other soft tissue tumors. The EWSR1
gene located on chromosome 22 is a 5′ fusion partner for
the two main translocations, while the 3′ partners involve
most frequently ATF1, from chromosome 12, and less
frequently CREB1, from chromosome 2 (Fig. 9-27). In
the chimeric proteins, EWSR1 contributes primarily its
strong promoter and its TAD-transactivation N-terminal
domain. Both of the 3′ fusion partners (i.e., ATF1 and
CREB1) provide leucine zipper C-terminal domains in
the chimeric protein (Fig. 9-28). The less frequent trans-
location involves the FUS gene on chromosome 16 and
again ATF1 on chromosome 12 (Fig. 9-29). The FUS
gene is the 5′ fusion partner in this translocation while
the ATF1 gene is a 3′ fusion partner. In the chimeric
protein, the FUS gene provides the N-terminal QGSY-
rich domain while ATF1, similarly to the main two
translocations, contributes the leucine zipper C-terminal
domain. These translocations are well documented in the
soft tissue variant of angiomatoid fibrous histiocytoma;
however, their presence in the lesions affecting bone is
very preliminary. They represent potential therapeutic
targets and are useful in differential diagnosis of angio-
matoid fibrous histiocytoma.97-99
Treatment and Behavior
The soft tissue lesions have a potential for locally aggres-
sive behavior but they are typically successfully managed
by complete local excision, which results in the reversal
of systemic symptoms. Resection of three of the five bone
lesions resulted in the prompt reversal of the systemic
symptoms and signs (fever, anemia, and weight loss). In
two of these cases treated by simple curettage, the tumor
recurred within 3 to 4 months and displayed radiographic
features of a destructive growth pattern, which prompted
more aggressive resections with prosthetic replacement.
But long-term follow-up and the ultimate outcome is not
available for these cases.
SKELETAL FIBROMATOSES
The term skeletal fibromatosis, as well as the pathogenetic
concept of fibromatosis, was proposed by Stout.138,139 It
encompasses lesions with similar microscopic appearance
ERRNVPHGLFRVRUJ
9  Fibrous and Fibrohistiocytic Lesions 647
and biologic potential occurring in different anatomic
sites and occasionally involving the skeleton. The term
fibromatosis covers a broad spectrum of fibroblastic pro-
liferations that are intermediate in their biologic behavior
between benign and malignant lesions; that is, they exhibit
indolent local destructive growth but do not metastasize.
Soft tissue fibromatoses are subdivided into several major
groups based on their site and organ involvement. Their
description is beyond the scope of this book. Skeletal
fibromatoses occur less frequently than their soft tissue
counterparts and are found in several basic clinical
settings—as the solitary lesion referred to as desmoplastic
fibroma6 and even more rarely seen forms designated
infantile multifocal skeletal myofibromatosis and congenital
fibromatosis–like fibrosarcoma (infantile fibrosarcoma).
Desmoplastic Fibroma
Definition
Desmoplastic fibroma is a rare, locally aggressive, solitary
tumor microscopically composed of well-differentiated
myofibroblasts with abundant dense collagen deposition.
Microscopically, it is identical to soft tissue fibromatosis.
Jaffe16 first used this term in 1958 to describe five cases
of a previously unclassified central fibrous tumor histo-
logically similar to desmoid tumor of the abdominal wall.
The term periosteal desmoid was initially introduced for
a process that produces a cortical defect in the postero-
medial aspect of the distal femoral diaphysis at the inser-
tion of the tendon of the adductor magnus muscle. This
benign, avulsive, self-limited process is discussed in
further detail in Chapter 23 in the section on cortical
irregularity syndrome.
Incidence and Location
Desmoplastic fibroma is an extremely rare tumor
that accounts for less than 0.1% of all bone tumors,
and the vast majority of reports present single
cases.113,114,118,122,123,126,136,137,140 Reports documenting larger
series are rare and typically come from major reference
centers.105,109-111,117,125,133-135 The lesions have been reported
from age 20 months to the seventh decade of life, but
typically they affect adolescents and young adults. There
appears to be no sex predilection. Any bone may be
affected, but the long bones and mandible are most com-
monly involved. In the long bones, the lesion is usually
metaphyseal but may also involve the epiphysis. The
most characteristic site is in the mental region of the
mandible, but the femur, tibia, and humerus are also
frequent sites of involvement. In general, it appears that
the craniofacial bones are most frequently involved. The
peak age incidence and most frequent sites of skeletal
involvement are shown in Figure 9-30.
Clinical Symptoms
Pain and swelling of the affected area are the most
common symptoms. Pathologic fracture or deformity
of the affected bone can occasionally be a presenting
symptom.
648 9  Fibrous and Fibrohistiocytic Lesions

der(2) Chr2
25.3 25.3
25.1 25.2 25.2
25.1
24 24
23 23
22 22
21 21
16 16
Chr12
15 15 13.3
14 14 13.1 13.2 der(22)
13 12.3 13
13 12.2 12.1
12 12 11.2 12 der(12)
11 11.1 11.2
11.2 11.2 11.1 13.3
11.1 11.1 der(22) 11.1 Chr22 13.1
12 11.1
13.1 13.2
11.1 11.2
11.2
13 11.2 13 ATF1 EWSR1-ATF1 12.2
12.3
12 12 13.3 13.2 chimeric gene 12.1
13 12 12 11.2
13 14 11.1
14.1 11.2 11.1 14.1 11.2 11.1 11
14.2 11.1 11.2 14.2 11.1 15 12
14.3 14.3 11.2 21.1 13.1
21.2 21.1 EWSR1-CREB1 21.2 21.1 EWSR1 EWSR1 21.2 Silent
21.3 34
chimeric gene 21.3 12.1 12.2 21.3
breakpoint
22 22 12.3 13.1 22
13.2
23 23 13.3 23
24.1 24.1 24.1
24.2 24.2
24.3 24.3 24.2
24.31 24.32
31 31 24.33
32.1 32.1
32.2 32.2
32.3 32.3
33 33
34 Silent 34 CREB1
breakpoint 35
36
37.1
37.2
37.3

A
E10
E11

E12
E13
E14
E15
E16
E17
E1

E2
E3
E4

E5

E6

E7
E8

E9

EWSR1

E4

E5
E6

E7
E1

E2

E3
ATF1

Type 1 (50%) Exon 8 Exon 4

breakpoint
B EWSR1-ATF1 t(12;22)(q13;q12) EWSR1 portion ATF1 portion
Chimeric transcripts
E10
E11

E12
E13
E14
E15
E16
E17
E1

E2
E3
E4

E5

E6

E7

E8

E9

EWSR1
E1

E2

E3
E4

E5
E6

E7
E8

E9

CREB1

Exon 7 Exon 7

breakpoint
EWSR1-CREB1 t(2;22)(q34;q12) EWSR1 portion CREB1 portion
C Chimeric transcripts

FIGURE 9-27  ■  Angiomatoid fibrous histiocytoma: chromosomal translocation. A, Chromosomal translocations involving chromo-
somes 2:22 and 12:22 resulting in EWSR1-CREB1 t(2;22)(q34;q12) and EWSR1-ATF1 t(12;22)(q13;q12). B, Exon-intron structures of
EWSR1 and ATF1. Solid black arrows indicate the locations of the breakpoints within the introns. The molecular structure of the
resulting chimeric gene, which includes coding sequences of the N-terminal domain of EWSR1 and the C-terminal segment of ATF1,
is shown. C, Exon-intron structures of EWSR1 and CREB1. The molecular structure of the resulting chimeric gene, which includes
coding sequences of the N-terminal domain of EWSR1 and the C-terminal segment of CREB1, are shown.

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 649

EWSR1
1 656 aa

breakpoint
TAD - transactivation (glycine/glutamine/serine/tyrosine “SYGQ” rich) domain 1-285 aa
SF1int - interaction with SF1 domain 228-264 aa
IQ - binds calmodulin domain 256-285 aa
RG1 - arginine/glycine rich domain 300-340 aa
RRM - RNA recognition motif domain 361-447 aa
RG2 - arginine/glycine/proline rich domain 454-513 aa
ZF - zinc finger (RanBP2 type) domain 518-549 aa

ATF1
1 271 aa

Coactivator CBP, pKID domain 31-90 aa breakpoint

Basic leucine zipper domain 211-268 aa

CREB1
1 341 aa

Coactivator CBP, pKID domain 101-160 aa breakpoint

Basic leucine zipper domain 281-339 aa

EWSR1-ATF1 chimeric protein t(2;22)(q33;q12)

1 431 aa

EWSR1-CREB1 chimeric protein t(12;22)(q13;q12)

1 426 aa

B
FIGURE 9-28  ■  Angiomatoid fibrous histiocytoma: functional domains and chimeric proteins involved in translocations. A, The func-
tional domains of EWSR1, ATF1, and CREB1. B, Chimeric EWSR1-ATF1 and EWSR1-CREB1 proteins. The EWSR1-ATF1 chimeric
protein contains the N-terminal of TAD-transactivation domain of EWSR1 and leucine zipper C-terminal domain of ATF1. The EWSR1-
CREB1 chimeric protein again contains the N-Terminal of TAD-transactivation domain of EWSR1 and leucine zipper C-terminal
domain of CREB1.

Radiographic Imaging Gross Findings

The radiographic appearance is usually that of an expans-
ile, lucent lesion with well-defined margins (Figs. 9-31
and 9-32).120,128,141,145 There is often destruction of the
overlying cortex with extension into the soft tissue (Fig.
9-32). Features of a more destructive growth pattern with
irregular, ill-defined margins and pathologic fracture may
be present (Fig. 9-31). Honeycombed or moth-eaten pat-
terns have been described, but the radiographic presenta-
tion is nonspecific. Desmoplastic fibroma can at least be
suspected if the lesion is completely lytic, is present in a
young patient, and involves a typical site (i.e., the
mandible) (Fig. 9-33). Desmoplastic fibroma rarely pres-
ents as a surface lesion. In such instances, a secondary
involvement of bone by the more common soft tissue
fibromatosis should be considered in the differential
diagnosis. CT and MRI are useful techniques to delineate
the lesion and its relationship to the adjacent structures,
especially in anatomically complex locations such as cra-
niofacial bones (Fig. 9-32).145 MRI typically shows a
lesion with lobulated architecture and strong T2 signal
enhancement.115
The tumors typically range in size from 3 to 10 cm, but
tumors up to 20 cm have been reported. They are gray-
white, fibrous, solid lesions that resemble desmoid lesions
of soft tissue.
Microscopic Findings
Microscopically, the lesion is similar to soft tissue fibro-
matosis, consisting of spindle-shaped fibroblasts within
an abundant, dense matrix of collagen (Figs. 9-34 and
9-35). Mitotic figures are rare. The cellularity varies in
different areas of the lesion. It can be focally high, with
less intercellular collagen gradually merging with pre-
dominantly fibrous (scarlike) areas composed of dense
eosinophilic material with sparsely distributed fibroblas-
tic cells. The lesion exhibits an infiltrative destructive
growth pattern with permeation of bone marrow spaces
and haversian canals. The borders of the tumor, espe-
cially in soft tissue, are irregular, with fingerlike projec-
tions infiltrating adipose tissue and skeletal muscle. At the
periphery, it is occasionally difficult to distinguish the

ERRNVPHGLFRVRUJ
650 9  Fibrous and Fibrohistiocytic Lesions

Chr12 Chr16 der(12) der(16)

13.3 13.3 13.3 24
13.1 13.2 13.2 13.1 13.2 23
12.3 13.1 12.3
12.2 12.2 22
12.1 12 12.1
11.2 11.2 21
11.1 11.2 FUS 11.1 13
11 11.1 11 12.2 12.1
12 11.1 12
11.2 11.2 11.1
13.1 ATF1 12.1 13.1 FUS
13.3 12.2 11.2
11.1 FUS-ATF1
13.2 13
14 21
12
13.3 chimeric gene
13.1 13.2
15 22 13.2
21.1 14
23 13.3 15
21.2
21.3 24 21.1
21.2
22 21.3
23 22
24.1 23
24.2 24.1
24.31 24.32
24.33 24.2
24.31 24.32
24.33
A

FUS

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14

Exon 15
Exon 1

Exon 2
Exon 3

Exon 4
Exon 5

Exon 6

Exon 7

Exon 8

Exon 9
ATF1
Exon 1

Exon 2

Exon 3

Exon 4

Exon 5
Exon 6

Exon 7
Exon 1

Exon 2
Exon 3

Exon 4

Exon 5

Exon 5
Exon 6

breakpoint Exon 7
FUS-ATF1 t(12;16)(q13;p11) FUS portion ATF1 portion
B Chimeric transcripts

Chimeric gene
FUS
265 388
1 1 526 aa
415 454 501
165 285 371
breakpoint
QGSY - rich domain RNA recognition motif domain
RGG - Arginine glycine box domain Zinc finger, RanBP2 - type domain
Nucleotide - binding, alpha-beta plait domain PY-NLS - proline-tyrosine nuclear localization signal domain

ATF1
1 271 aa
31 90 211 268
breakpoint
Coactivator CBP, pKID domain
Basic leucine zipper domain
C

FUS-ATF1 chimeric protein

1 342 aa

D
FIGURE 9-29  ■  Angiomatoid fibrous histiocytoma: chromosomal translocation. A, Chromosomal translocation t(12;16)(q13;p11)
resulting in FUS-ATF1 chimeric gene. B, Exon-intron structures of FUS and ATF1. Solid black arrows indicate the locations of the
breakpoints within the introns. The molecular structure of the resulting chimeric gene, which includes coding sequences of the
N-terminal domain of FUS and the C-terminal segment of ATF1, is shown. C, Functional domains of FUS and ATF1 proteins are
shown. D, FUS-ATF1 chimeric protein contains the N-terminal QGSY-rich domain of FUS and coactivator CBP, pKID as well as leucine
zipper domains of the C-terminal portion of ATF1.

ERRNVPHGLFRVRUJ

Incidence
1 2 3 4 5 6
Age in decades
FIGURE 9-30  ■  Desmoplastic fibroma. Peak age incidence and most frequent skeletal sites of involvement. Most frequent sites of
involvement are indicated by solid black arrows.
tumor tissue from secondary reactive fibrosis. Rare exam-
ples of desmoplastic fibroma with extensive cartilaginous
metaplasia have been described.108 Desmoplastic fibro-
mas associated with other conditions such as fibrous dys-
plasia melorheostosis and Paget’s disease have also been
described.122,126,144
Special Techniques
Ultrastructural and immunohistochemical studies reveal
prominent myofibroblastic differentiation.124,130 Most
desmoplastic fibromas show at least focal positivity for
smooth muscle markers such as smooth muscle actin
(SMA). The hallmark of sporadic extraskeletal fibromato-
ses arising in deep soft tissue is the mutation of β-catenin
(Fig. 9-36).104,107,127 β-catenin plays an important role in
the embryonic development of mesenchymal cells affect-
ing proliferation, motility, and invasiveness. It mediates
the canonical Wnt (wingless) signaling pathway.119,129,132,142
The quiescent status of the Wnt pathway promotes
interaction between a multiprotein complex, includ-
ing adenomatous polyposis coli (APC), β-catenin, axin,
and glycogen synthase kinase-3β and serine and thero-
nine residues in the N-terminals of β-catenin, inducing
their phosphorylation. The phosphorylated protein is a
target for ubiquitination and degradation. The activa-
tion of the Wnt signaling pathway inhibits the inter-
ERRNVPHGLFRVRUJ
9  Fibrous and Fibrohistiocytic Lesions 651
7 8
action of the multiprotein complex to phosphorylate
β-catenin. Unphosphorylated β-catenin is stable and
after translocation to the nucleus activates transcrip-
tion by binding to Tcf-Lef family proteins. Mutations
of β-catenin are found in numerous tumors. In fibroma-
toses, they typically cluster in the sequences encoding
the N-terminal component of the protein, essentially
affecting codons 41 and 45. Clustering of these muta-
tions at threonine 41 (T41A) and serine 45 (S45F and
S45P) is consistent with their role as phosphorylation
targets. Functionally, these mutations prevent phos-
phorylation and stabilize β-catenin, which upregulates
nuclear transcription. As a consequence, myofibroblastic
cells in fibromatoses frequently contain mutated stable
β-catenin protein that can be detected immunohisto-
chemically in the nucleus of tumor cells.106,112 In soft
tissue, the presence of mutations involving β-catenin is
associated with more aggressive growth pattern with a
higher rate of local recurrences as compared to those
lesions that do not carry mutations of β-catenin.116,124,131
Such associations are not, however, available for skeletal
lesions. Moreover, preliminary data indicate that muta-
tions of β-catenin (CTNNB1) gene are not present in
skeletal fibromatoses.121 Desmoplastic fibromas show;
however, occasionally strong positive nuclear staining
for β-catenin.121 The mechanisms stabilizing β-catenin in
Text continued on p. 657
652 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-31  ■  Desmoplastic fibroma: radiographic features. A, Anteroposterior (AP) radiograph showing a pathologic fracture
through lytic lesion in shaft of distal radius in a 33-year-old woman. Curettage showed fibrous lesion with benign cytologic features.
The lesion was bone grafted and healing was achieved. B, One year later, lesion shown in A recurred, and recurrent desmoplastic
fibroma had broken through cortex on ulnar side of radius. Patient was clinically asymptomatic 2 years after second curettage and
bone grafting. C and D, AP and lateral radiographs of knee in a 20-year-old woman with expanded lytic lesion involving proximal
end of tibia. Note trabeculated appearance and absence of periosteal reaction.

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 653

A B

C D
FIGURE 9-32  ■  Desmoplastic fibroma: radiographic features. A and B, Anteroposterior (AP) and lateral radiographs of a destructive
lytic lesion involving the proximal fibula. C, Fat-saturated T2-weighted coronal magnetic resonance image showing signal enhance-
ment and overall macroglobular arrangement of desmoplastic fibroma. Same case as shown in A and B. D, AP radiograph showing
a recurrent desmoplastic fibroma surrounding an intramedullary metallic rod of the femur.

ERRNVPHGLFRVRUJ
654 9  Fibrous and Fibrohistiocytic Lesions

A B

D
FIGURE 9-33  ■  Desmoplastic fibroma of mandible: clinical, radiographic, and microscopic features. A, Clinical photograph of
a 29-year-old woman with palpable mass in submental region. B and C, Radiographs show well-circumscribed lytic lesion of
mandible in same patient. D, Low-power photomicrograph shows spindle-cell fibrous lesion. Note involvement of skeletal muscle
(×50; hematoxylin-eosin).

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 655

A B

C D

FIGURE 9-34  ■  Desmoplastic fibroma: microscopic features. A-D, Low and intermediate power photomicrographs showing bundles
of spindle cells with abundant intercellular collagen. There is no osteoid or cartilage matrix seen. Inset, Nuclear details of spindle
cells. (A and C, ×100; B and D, ×200; inset, ×400.) (A-D, and inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
656 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-35  ■  Desmoplastic fibroma: microscopic features. A and B, Low and intermediate power photomicrographs showing
uniform spindle cells with abundant collagen. Inset shows strong positive nuclear staining for β-catenin (CTNNB1). C and D, Low
and intermediate power photomicrographs showing somewhat hypercellular areas of desmoplastic fibroma with proliferation of
plump spindle cells. (A and C, ×100; B and D, and inset, ×200.) (A-D and inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 657

CTNNB1
Chr 3 B

Exon 10

Exon 11
Exon 12
Exon 13

Exon 14

Exon 15

Exon 16
26

Exon 1

Exon 2
Exon 3
Exon 4
Exon 5
Exon 6

Exon 7

Exon 8
Exon 9
25
24.3 24.2
24.1

41240941

41281939
23
22
21.3
21.2
CTNNB1
21.1
14.3 14.2
14.1
13
12
11.1 11.2 CTNNB1 S45P, S45F
11.2 11.1
12
13.1
13.2
13.3

T41A
395
15
21

692
22
23

49

18
10
5

13
261
417
24

8
7

9
78

874
25.1

36
12

16

90
434
25.2

4
19

13
14
14
12
25.3

7
4
4
6
8
9
6

5
6
8
6
9
26.1
26.2
26.3
27
28
29
A 198022430 bp SYLDSCIHSGATTTAPSLSG
Phosphorylation by GSK-3
Missense substitution
Nonsense substitution - Stop
Insertion inframe
Deletion inframe
Insertion frameshift
13
4

6
4
Deletion frameshift
Complex - deletion in frame
Unknown 1 781 aa
Substitution - coding silent -catenin FIBROMATOSIS Armadilo-type fold domain 134-664
Complex - frameshift C
FIGURE 9-36  ■  Mutations of β-catenin (CTNNB1) gene in extraskeletal soft tissue fibromatoses. A, Chromosomal localization of
β-catenin gene on the short arm of chromosome 3. B, Exon-intron structure of the β-catenin gene. C, Distribution of mutations in
relation to functional domains of β-catenin. Note clustering of mutations corresponding to the phosphorylation sites by GSK3β,
including T41A, S45P, and S45F, frequently found in fibromatoses.

desmoplastic fibromas are uncertain. Therefore, fibro- Furthermore, engulfed trabeculae of lamellar bone in
matoses arising in bone may develop without mutations desmoplastic fibroma can be misinterpreted as fibrous
involving B-catenin and other genetic mechanisms have dysplastic bone. Attention to its lamellar composition is
been postulated.121,143 important in avoiding this error.

Differential Diagnosis Treatment and Behavior

Soft tissue fibromatosis has microscopic features that overlap
with desmoplastic fibroma and can be difficult to distin-
guish in cases in which the soft tissue lesion invades bone
sufficiently deeply to produce defects that are visible on
radiograph. More important is the distinction from low-
grade fibrosarcoma of bone. This lesion is rarely so well differ-
entiated that it does not show, in adequate biopsy samples,
some nuclear irregularity and hyperchromatism, as well
as a degree of mitotic activity not present in desmoplastic
fibroma. Conversely, some low-grade fibrosarcomas show
heavy collagenization and deceptively benign-appearing,
small dark nuclei in focal areas. Furthermore, the radio-
logic features may be paradoxical, in that fibrosarcoma
can be well circumscribed and appear to be noninvasive,
whereas desmoplastic fibroma not only shows aggressive
radiologic features, but also grows in an invasive, locally
infiltrative manner. Hence, the distinction in the border
zone of these two lesions, both of which exhibit local
aggressiveness, may not be a clinically significant one.
Fibrous dysplasia is sometimes mistaken for desmoplas-
tic fibroma when the sample does not contain histologic
evidence of osteoid or delicate woven bone trabeculae.
Desmoplastic fibroma exhibits locally aggressive behav-
ior without the capacity to metastasize. Earlier reports
indicate that simple curettage and bone grafting resulted
in a recurrence rate as high as 40%. Wide resection is the
preferable mode of treatment, although recurrences have
also been reported with this mode of treatment. Rare
association of desmoplastic fibroma with other lesions
such as fibrous dysplasia or melorheostosis has been
reported.64,75
Personal Comments
Desmoplastic fibroma is among the rarest of bone tumors,
although it is sometimes diagnosed inappropriately on
histologic grounds when the biopsy sample in fibrous
dysplasia is from a heavily collagenized area devoid of
woven bone spicules. True desmoplastic fibroma is a
locally aggressive, intraosseous lesion that histologically
reproduces the pattern of fibromatosis in soft tissue. Its
clinical behavior can closely resemble that of aggressive
fibromatosis of soft tissue in that the lesion can infiltrate
locally but does not metastasize. Whether it differs

ERRNVPHGLFRVRUJ
658 9  Fibrous and Fibrohistiocytic Lesions
essentially from low-grade fibrosarcoma seems academic
because both lesions have the same biologic potential.
Both should be treated by wide local excision. We are not
aware of any report indicating the transformation of a
desmoplastic fibroma to a fully malignant metastasizing
sarcomatous tumor.
Juvenile Multifocal Myofibromatosis
Juvenile multifocal myofibromatosis was first described
by Stout165 in 1954 as congenital generalized fibromatosis.
The lesions are typically multifocal, but occasionally the
disorder can present as a solitary focus.147-152,154-157,162,166,168
It has two basic clinical forms. Somatic involvement is
limited to the subcutaneous, muscular, or skeletal tissue;
in the combined somaticovisceral form, in addition to
soft tissue, viscera can be involved. This separation is
prognostically valid. The somatic form has a benign
course that leads to the resolution of cutaneous soft tissue
and skeletal lesions within a few months to a few years.
Some authors postulate that spontaneous apoptosis can
be a putative molecular mechanism causing regression of
these lesions.153 The combined somaticovisceral form has
a poor prognosis, with death occurring in the first months
of life. Skeletal involvement can occur in both forms. A
few cases with extensive primary involvement of the skel-
eton have been reported.148,151,152,155,163,167 Extensive
involvement of an extremity by multifocal myofibroma-
tosis may cause length discrepancy.160
The disease has a predilection for the metaphyses of
the long tubular bones. It presents radiographically as
multiple, lytic, sharply demarcated defects that tend to
be eccentric. Flat bones (pelvis, scapula, ribs, and skull)
can also be involved. Microscopically, the lesions are
similar to conventional fibromatosis but overall are
more cellular and less fibrous. The cells are arranged in
interlacing bundles with a prominent network of thin-
walled sinusoidal vascular channels that produce a
hemangiopericytoma-like pattern (Fig. 9-37). The pres-
ence of a hemangiopericytoma-like pattern is a distinctive
microscopic feature of infantile myofibromatosis.159 It is
found at least focally and is typically most prominent in
the central portion of the lesion. The ultrastructural
studies, as well as immunohistochemical stains, reveal
prominent myofibroblastic differentiation. In fact, some
studies suggest that there is a continuous spectrum of
lesions ranging from typical fibromatosis to infantile
hemangiopericytoma.158 Cytogenetic reports document
interstitial deletion of 6q, del(6)(q12;q15), and unbal-
anced translocation of 9q resulting in 9q monosomy and
trisomy of 16q.161,164 Infantile fibromatosis is negative for
t(12;15)(p12;q25) translocation and the ETV6-NTRK3
gene fusion.146
Congenital Fibromatosis–like
Fibrosarcoma (Infantile Fibrosarcoma)
This rare tumor typically occurs in the soft
tissue.172,173,178-181,185,188,191,194,197,200,203,204,211 It is even more
rare as a primary lesion in bone, with only a few single
case reports of its occurrence.96,102 Typically the tumor is
congenital and clinically evident at birth, or it is
ERRNVPHGLFRVRUJ
discovered during the first 3 months of life.174,182,209 Most
often the lesion involves the soft tissue of the limb but
can also involve the soft tissue of the trunk and the head
and neck area.195,207,208,210,211 The bone lesions occasionally
become manifest much later in life and have been diag-
nosed several years after birth.
Microscopically, congenital fibrosarcoma is more cel-
lular than desmoplastic fibroma and is composed of less
mature fibroblasts with minimal deposition of collagen
(Fig. 9-38). Mitoses and scattered inflammatory cells are
frequently present. Overall, the microscopic picture is
similar to adult fibrosarcoma.
Data on clinical behavior are available only in refer-
ence to the soft tissue lesions. Originally, congenital
fibrosarcoma was considered to be a tumor with no meta-
static potential, but analysis of larger series indicated that
the risk of metastasis ranges from 5% to 10%.210 A spon-
taneous regression similar to that seen in congenital
fibromatosis has been reported.190,196,199 On the other
hand, progression to a high-grade sarcoma with malig-
nant fibrous histiocytoma–like features has also been
reported.201 A few cases of congenital fibrosarcoma, with
the primary tumor in bone, have recurred after local exci-
sion and required ablative surgery to control the disease.
Our personal experience is confined to one case seen in
consultation. This patient was seen at age 3 years with a
destructive lytic lesion in the parietooccipital region of
the skull. After 17 years the fatal outcome was the result
of multiple recurrences with uncontrolled local growth,
eventually involving vital central nervous system struc-
tures (Fig. 9-39). There are too few cases to evaluate the
metastatic potential of skeletal lesions. The available data
support the notion that congenital fibrosarcoma is more
aggressive than conventional fibromatosis. In terms of its
biologic potential, it is probably intermediate between
conventional fibromatosis and adult fibrosarcoma.
Various nonrandom cytogenetic abnormalities distinct
from those seen in cases of adult fibrosarcoma or malig-
nant fibrous histiocytoma have been reported in con-
genital juvenile fibrosarcoma.169,171,175,183,202 The described
anomalies range from trisomy 11 and other trisomies
to nonrandom translocations involving chromosomes
12 and 13.206 The distinctive molecular abnormality
of fibromatosis-like fibrosarcoma comprises t(12;15)
(p13;q25) translocations resulting in ETV6-NTRK3 gene
fusion (Fig. 9-40).170,186,187,205 The 5′ partner of the fusion
is the ETV6 gene located on chromosome 12 and the 3′
partner is NTRK3 located on chromosome 15. The ETV6
fusion genes participate in translocations of several solid
and hematologic malignancies.184 In the chimeric protein
the N-terminal of the protein comprises SAM/PNT
(Sterile alpha motif/PNT pointed domain from ETV6)
while the C-terminal contains the cysteine-rich flank-
ing region. This translocation has been well documented
in the more frequent soft tissue variant of the tumor.
The preliminary evidence indicates that it may also be
present in the rare instances of infantile fibromatosis–
like fibrosarcoma involving bone. The presence of this
translocation is a useful tool in the differential diagnosis
of this rare pediatric malignancy and may also represent
its potential therapeutic target.176,177,189,192,193,198,205
Text continued on p. 663
 9  Fibrous and Fibrohistiocytic Lesions 659

B C
FIGURE 9-37  ■  Juvenile fibromatosis of tibia: microscopic features. A, Low power photomicrograph shows spindle-cell proliferation
with hemangiopericytoma-like pattern. Note increasing cellularity in central portion of lesion. B and C, Intermediate and high power
photomicrographs of the central portion of the lesion showing proliferations of plump myofibroblastic cells. Note prominent vas-
culature mimicking hemangiopericytoma. (A, ×50; B, ×100; C, ×200.) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
660 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-38  ■  Infantile fibromatosis–like fibrosarcoma: microscopic features. A-D, Low and intermediate power photomicrographs
show cellular spindle-cell fibroblast-like lesion. Note uniformly higher level of cellularity compared with more typical desmoplastic
fibroma. Inset, Bland nuclear features with finely dispersed chromatin in plump spindle cells. (A and C, ×100; B and D, ×200; inset,
×400.) (A-D and inset, hematoxylin-eosin.) (Courtesy Dr. H. Sonobe, Kochi, Japan.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 661

A B

C D
FIGURE 9-39  ■  Infantile fibromatosis–like fibrosarcoma: radiographic features. A, Lateral plain radiograph shows destructive lesion
in parietooccipital area. B, Axial computed tomogram shows destructive lesion on the right. C, Same patient at age 12 years with
recurrent tumor in same area. D, Uncontrolled local growth of tumor extensively involving cranial bone. (Courtesy Dr. H. Sonobe,
Kochi, Japan.)

ERRNVPHGLFRVRUJ
662 9  Fibrous and Fibrohistiocytic Lesions

Chr12 Chr15 der(12) der(15)

26.3 26.2
13.3 13.2 13 13
13.1 12 26.1 NTRK3-ETV6 12
ETV6 11.2 no transcription
12.2 12.3 11.2
11.1 11.1 12.2 12.3 11.1
11.2 12.1 11.2 11.1 11.2
12 11.2 12.1 12
11 11.1 13 11.1 13
14 11 14
12 12
15 15
13.1 21.1 13.1 21.1
13.3 13.2 21.2 13.2 21.2
21.3 13.3 21.3
14 22.1 14 22.1
22.2 22.2
15 22.3 15 22.3
21.1 23 23
21.2 21.1 24
24 21.2
21.3 21.3 ETV6-NTRK3
22
25 NTRK3 25
chimeric gene
26.1 22 13.2
23 26.2 13.1
26.3 23 13.3
24.1 24.1
24.2 24.2
24.31 24.32 24.31
24.33 24.32
24.33

A
NTRK3

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14

Exon 15

Exon 16
Exon 17

Exon 18
Exon 19
Exon 1
Exon 3
Exon 4
Exon 5

Exon 6
Exon 7
Exon 8
Exon 9
Exon 2

ETV6
Exon 1

Exon 2

Exon 3

Exon 4

Exon 5

Exon 6
Exon 7
Exon 8

Exon 5 Exon 15

breakpoint
ETV6-NTRK3 t(12;15)(p13;q25) ETV6 portion NTRK3 portion
B Chimeric transcripts

ETV6 NTRK3
1 452 aa 1 839 aa
18 127 339 420 31 63 160 208 309 321 399 538 828

breakpoint breakpoint
SAM/PNT- Sterile alpha motif/PNT pointend domain Leucine-rich repeat-containing N-terminal domain
Winged helix-turn-helix DNA - binding/Ets domain Cysteine-rich flanking region, C-terminal domain
Immunoglobulin-like fold domain
Protein kinase-like domain

ETV6-NTRK3 chimeric protein

1 648 aa

C
FIGURE 9-40  ■  Infantile fibromatosis–like fibrosarcoma: chromosomal translocation. A, Schematic diagram of t(12;15)(p13;q25) trans-
location. B, Exon-intron structures of the NTRK3 and ETV6 genes. Solid black arrows indicate the locations of the breakpoints. The
molecular structure of the resulting chimeric gene, which includes coding sequence of the N-terminal domain of ETV6 and the
C-terminal segment of NTRK3, are shown. C, The functional domains of the two proteins are depicted. The chimeric protein contains
SAM dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3.

ERRNVPHGLFRVRUJ

MALIGNANT FIBROUS HISTIOCYTOMA
The terms malignant histiocytoma and malignant fibrous
xanthoma were coined by Stout and his coworkers in the
early 1960s.249,251 The concept that these tumors are
derived from fibrohistiocytic cells was based on tissue
culture observations. These experiments have shown that
the cells derived from these lesions look and behave
in culture as fibroblasts.227,251 In the initial stages of
culture, they exhibit features of ameboid movement
and phagocytosis. These observations, together with the
ultrastructural data, led to the use of the term fibrous
histiocytoma. This is a somewhat misleading term because
it implies that the origin is from macrophage-monocyte
lineage. We now understand that these tumors are not
derived from macrophage-monocyte precursors. The
phenotypic features of these lesions are of primitive
mesenchymal derivation that exhibit, at least in part,
fibroblastic or more often myofibroblastic differentia-
tion.212,227,237,243,253-255 The controversy about the histogen-
esis of this tumor persists. Moreover, it is still not clear
whether this tumor is a specific entity with uniform
pathogenesis or simply represents a microscopic pattern
common to a heterogeneous group of undifferentiated or
poorly differentiated sarcomas of different origins. The
latter view is supported by its frequent occurrence as a
secondary sarcoma complicating various benign precur-
sors. Moreover, tumors with morphologic features indis-
tinguishable from de novo malignant fibrous histiocytoma
frequently arise as dedifferentiated components of low-
grade, locally aggressive tumors in bone and soft tissue.
In fact, sarcomatoid carcinomas developing in many
organs in association with a preexisting epithelial neo-
plasm share many similarities with malignant fibrous
histiocytoma.
In spite of these controversies, the term malignant
fibrous histiocytoma is widely used in diagnostic pathology
and defines a group of lesions that may not be histoge-
netically and pathogenetically uniform but that have
some common features defining them as a distinct clini-
copathologic group.220,223,225,229,232,240,242,246,249,259,260 The
identification of malignant fibrous histiocytoma in bone
as a distinct entity in the 1970s resulted in a sharp decline
in the use of other diagnostic terms (predominantly osteo-
lytic osteosarcoma and fibrosarcoma) to describe non–bone-
forming sarcomatous neoplasms of bone.
The investigations of malignant fibrous histiocytoma
during the past two decades have revolved around two
major themes. The first one and most common postulates
that these tumors represent a common pattern of pro-
gression similar to many mesenchymal neoplasms irre-
spective of their original lineage differentiation. The
second theme postulates that malignant fibrous histiocy-
toma is not a result of dedifferentiation but develops de
novo by transformation of mesenchymal stem cells.238
Extensive use of novel differentiation markers and molec-
ular testing provide evidence of diverse differentiation
in a subset of malignant fibrous histiocytoma. Using
these approaches several mesenchymal differentiation
patterns can at least be focally detected in many malig-
nant fibrous histiocytomas to subclassify them as myo-
genic, myoepithelial, myofibroblastic, lipoblastic, and
ERRNVPHGLFRVRUJ
9  Fibrous and Fibrohistiocytic Lesions 663
osteoblastic subtypes.239,241,257,265 On the other hand, gene
expression profiling studies disclose the mesenchymal
stem cell-like phenotype and the involvement of the Wnt
pathway in malignant fibrous histicytoma, supporting the
stem cell origin of these neoplasms.228,230,239
Modern classifications, including the recent WHO
Classifications of Tumours of Soft Tissue and Bone,
propose the term undifferentiated high-grade pleomorphic
sarcoma instead of malignant fibrous histiocytoma.226 In
fact, this term is widely used in diagnostic practice
but does not solve all of the problems because some of
these tumors are not necessarily pleomorphic and many
have predominantly spindle, rhabdoid, or epithelioid cell
morphology.
Definition
Malignant fibrous histiocytoma is a malignant neoplasm
characterized by a mixture of spindle and pleomorphic
cells with a prominent storiform arrangement of the
spindle cells. The latter exhibit focal myofibroblastic dif-
ferentiation. These neoplasms in bone formerly were
classified as high-grade, pleomorphic, undifferentiated
osteosarcomas or high-grade fibrosarcomas.
Incidence and Location
Malignant fibrous histiocytoma of bone is relatively
rare and makes up less than 2% of all primary malig-
nant bone tumors. The peak age incidence and frequent
sites of skeletal involvement are shown in Figure 9-41.
The age-related incidence rate and frequency distribu-
tion show a gradual increase, with the peak incidence
in patients older than age 50 years, but there is a wide
distribution from the second to the seventh decades of
life (Fig. 9-42). Approximately 10% of cases are diag-
nosed in patients younger than age 20 years. Malignant
fibrous histiocytoma has a predilection for the major
long tubular bones, and the femur is most frequently
involved. Approximately 30% of cases occur in the knee
area with involvement of the distal femoral and proxi-
mal tibial metaphyses. The pelvis is the most frequently
involved trunk bone. Individual cases are reported in
other parts of the skeleton, and almost any bone can be
involved.221,256,259,260,261,264 Extremely rare cases of mul-
tifocal and familial skeletal malignant fibrous histio-
cytoma have been described.216,218,224,250 About 20% of
malignant fibrous histiocytomas in bone occur as a result
of underlying conditions. Malignant fibrous histiocy-
toma is a well known complication of such conditions
as Paget’s disease, bone infarct, and radiation damage.
It also arises as a dedifferentiation of such low-grade
preexisting bone tumors as chondrosarcoma, paraosteal
osteosarcoma, low-grade intraosseous osteosarcoma, and
giant cell tumor. In addition, a rare autosomal dominant
familial syndrome known as diaphyseal medullary steno-
sis predisposes to the development of malignant fibrous
histiocytoma. It is estimated that approximately 30% of
patients affected by this syndrome develop malignant
fibrous histiocytoma. Radiographically, it is characterized
by diffuse diaphyseal medullary stenosis with the overly-
ing cortex showing extensive thickening. There are also
664 9  Fibrous and Fibrohistiocytic Lesions

Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 9-41  ■  Malignant fibrous histiocytoma. Peak age incidence and frequent sites of skeletal involvement in fibrous histiocytoma.
Most frequent sites of involvement are indicated by solid black arrows.

1 25

0.8 20
(cases/100,000 persons)

Age distribution (%)

Incidence rate

0.6 15

0.4 10

0.2 5

0 0
0-4

5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85+

Age at diagnosis
FIGURE 9-42  ■  Epidemiology of malignant fibrous histiocytoma. National Cancer Institute Surveillance Epidemiology, and End Result
Program, 1973-2005. Age-adjusted incidence rate and age-specific frequency, all races, both sexes, 1277 cases.

ERRNVPHGLFRVRUJ

metaphyseal striations, scattered foci of infarctions, and
diffuse sclerosis involving the long bones.213,231,236,244,248
Radiographic Imaging
Radiographically the tumor presents as a purely lytic,
ill-defined intramedullary defect. The lesion most fre-
quently involves the metaphyseal parts of long tubular
bones and may extend into the epiphysis.240,245,247 Diaphy-
seal locations are less common. The tumor exhibits a
geographically destructive growth pattern, but moth-
eaten or permeative patterns also have been described.
Early cortical disruption and extension into soft tissue
occur (Figs. 9-43 and 9-44). Typically, there is little or no
periosteal new bone formation associated with the tumor.
The radiographic features are not specific, and the exact
diagnosis cannot be established from findings on radio-
graphs (Figs. 9-43 to 9-46). Pathologic fracture is fre-
quent, especially in the weight-bearing bones.
Gross Findings
The gross appearance of malignant fibrous histiocytoma
is highly variable (see Figs. 9-46, 9-47, and 9-48). The
consistency varies from soft to fibrous. Most tumors are
tan-gray with fleshy yellow areas. The tumor has irregu-
lar, ill-defined borders. Areas of necrosis and hemorrhage
are frequently present. Cortical disruption with poorly
demarcated infiltration of the adjacent soft tissue is fre-
quently seen.
Microscopic Findings
The mixture of spindle cells in storiform arrangement
and pleomorphic cellular areas is a hallmark of malignant
fibrous histiocytoma (Figs. 9-49 to 9-52).217,219,220,221,232,247
The microscopic diversity of this tumor is broad, and the
range of patterns varies from almost exclusively spindle
cell through hemangiopericytoma-like, epithelioid to
highly pleomorphic lesions (see Figs. 9-52 to 9-58).
The amount of collagen also varies. In more differenti-
ated spindle-cell areas, the tumor can form thick
fibrillar deposits surrounding individual cells that mimic
osteoid. This feature accounts for earlier inclusion of
these tumors in the group of osteosarcomas. The most
distinct feature of these tumors is the storiform arrange-
ment of spindle cells, which is present focally in most
cases. Malignant fibrous histiocytoma of soft tissue has
been subclassified into several types: storiform-
pleomorphic, myxoid, giant cell–rich, and inflammatory.
All these histologic subtypes may be found in primary
malignant fibrous histiocytoma of bone (Figs. 9-49, 9-51,
9-56, and 9-58).
Angiomatoid malignant fibrous histiocytoma has
recently been reclassified and is no longer considered a
variant of malignant fibrous histiocytoma on the basis of
its distinct pathologic and clinical features. For this
reason, a separate description of this entity is provided.
The most frequent types of malignant fibrous histio-
cytoma in bone are the storiform-pleomorphic and giant
cell variants. Rare cases of myxoid and inflammatory sub-
types have been reported (Fig. 9-56). These designations
ERRNVPHGLFRVRUJ
9  Fibrous and Fibrohistiocytic Lesions 665
are descriptive and do not necessarily imply distinct
pathogeneses or differences in clinical behavior.
The storiform-pleomorphic variant represents a pro-
totype pattern of malignant fibrous histiocytoma. The
spindle cells resemble fibroblasts and are arranged in
storiform patterns. Areas with less differentiated spindle
cells exhibit prominent nuclear atypia and brisk mitotic
activity. Mononuclear cells with abundant cytoplasm
that resemble histiocytes containing pleomorphic, highly
atypical nuclei represent undifferentiated mesenchymal
components. Multiple atypical mitoses are common.
Giant cells of both the malignant type and the benign
osteoclastic type are present. The cytoplasm of these cells
is usually densely eosinophilic and can be responsible for
superficial mimicry of pleomorphic rhabdomyoblasts. On
the other hand, vacuolar change of the cytoplasm can
mimic lipoblastic differentiation. Foci of necrosis, scat-
tered foamy histiocytes, and inflammatory cells are fre-
quently present. The overall pattern is characteristic and
easy to recognize.
The classic pattern of malignant fibrous histiocytoma
is rarely confused with benign conditions, but occasion-
ally the tumor is composed predominantly of mature
fibroblastic cells with inconspicuous atypia (Fig. 9-57).
The presence of numerous multinucleated, osteoclast-
like giant cells is a frequent feature of malignant fibrous
histiocytoma of bone. These cells occasionally dominate
the picture, and giant cell–rich malignant fibrous histio-
cytoma can be confused with giant cell tumor or other
benign giant cell–containing conditions of bone (Fig.
9-51). Inflammatory cells are frequently present in malig-
nant fibrous histiocytoma of bone, but a distinct inflam-
matory variant of malignant fibrous histiocytoma is rarely
identified in bone (Fig. 9-57).
Numeric grading of malignant fibrous histiocytoma
that applies a conventional Broders’ system remains con-
troversial. Many authors simply divide these tumors into
low- and high-grade variants. The data suggest that pre-
dominantly fibroblastic tumors with minimal atypia have
a better prognosis than highly atypical lesions. Convinc-
ing clinical data supporting the relationship between
clinical behavior and complex histologic grading in these
tumors are lacking for bone lesions. Nevertheless, modern
combined-modality treatment protocols require subdivi-
sion of these tumors and other sarcomas into low and
high grades.
Special Techniques
Immunohistochemistry plays little direct role in the diag-
nosis of malignant fibrous histiocytoma. It is used pre-
dominantly to exclude other malignant neoplasms
considered in the differential diagnosis. The tumor cells
are strongly and uniformly positive for vimentin. Weak
positivity for SMA is a frequent finding. Other markers,
such as keratin, S-100 protein, and desmin, are predomi-
nantly used to rule out other primary and metastatic
neoplasms of bone. The immunohistochemical markers
for macrophage-monocyte lineage, such as KP-1 (CD68),
have not proved useful in the diagnosis of malignant
fibrous histiocytoma because they are not expressed in
Text continued on p. 682
666 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-43  ■  Malignant fibrous histiocytoma: radiographic features. A, Lateral radiograph of distal femur of a 28-year-old man with
large lytic tumor in shaft with wide zone of transition and anterior cortical destruction. B, T2-weighted sagittal magnetic resonance
image (MRI) shows cortical breakthrough and overlying soft tissue component of tumor. Inset, Axial computed tomogram shows
permeative bone destruction and extension into soft tissue. Calcified material within the tumor represents residual bone. C, Lateral
radiograph of distal femur in a 20-year-old woman. Ill-defined permeative destruction is present in distal metaphysis without associ-
ated cortical destruction or periosteal reaction. D, T2-weighted sagittal MRI of tumor shown in C reveals greater extent of tumor
proximally than can be appreciated from plain film. Note that scar of growth plate delimits tumor distally.

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 9  Fibrous and Fibrohistiocytic Lesions 667

A B

C
FIGURE 9-44  ■  Malignant fibrous histiocytoma: radiographic features. A, Anteroposterior radiograph showing a destructive perme-
ative lesion involving periacetabular region extending to ischium and pubic ramus. B, Axial computed tomogram of same case as
A showing a destructive lesion of the left pelvis with soft tissue extension. C, T1-weighted axial magnetic resonance image of case
in A and B showing extensive low density tumor involving the left pelvis and adjacent soft tissue.

ERRNVPHGLFRVRUJ
668 9  Fibrous and Fibrohistiocytic Lesions

A C

D E
FIGURE 9-45  ■  Malignant fibrous histiocytoma: radiographic features. A, Anteroposterior (AP) radiograph of pelvis of a 39-year-old
man with large destructive tumor in left sacroiliac region of pelvis. B, Axial computed tomogram (CT) (bone window) shows moth-
eaten destruction of right ilium and sacral wing with cortical breakthrough and soft tissue mass. C, Soft tissue window CT shows
extent of large soft tissue mass. D, AP radiograph of thoracic spine and ribs shows destructive changes in posterior rib and adjacent
vertebral body in a 27-year-old man. E, Axial CT reveals completely lytic tumor expanding posterior part of rib (vertebral end) and
involving adjacent thoracic vertebra.

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 9  Fibrous and Fibrohistiocytic Lesions 669

A B

C D

FIGURE 9-46  ■  Malignant fibrous histiocytoma: radiographic and gross features. A, Anteroposterior radiograph showing a destructive
moth-eaten lesion of the proximal humerus. B, Fat-saturated T2-weighted coronal magnetic resonance image showing a high signal
intensity lesion of the proximal humerus. C and D, Gross photomicrographs of bisected resection specimen showing an intramedul-
lary tumor of the proximal humerus with mixed fleshy and mucinous appearance.

ERRNVPHGLFRVRUJ
670 9  Fibrous and Fibrohistiocytic Lesions

A B

C D

FIGURE 9-47  ■  Malignant fibrous histiocytoma: gross features. A, Fleshy intramedullary tumor of distal femur. B, Intramedullary
fleshy tumor of proximal humerus with soft tissue extension and elevation of periosteum seen medially. C, Fleshy intramedullary
tumor of the proximal tibia fused with the overlaying cortex. Note relatively sharp demarcation of the intramedullary component
of the tumor. D, Fleshy mass of proximal tibia with areas of hemorrhage and cystic change. Note cortical disruption.

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 671

A B

C D
FIGURE 9-48  ■  Malignant fibrous histiocytoma: gross features. A, Fleshy intramedullary tumor of distal femur with cystic changes
and hemorrhage proximally. B, Circumferential soft tissue extension of distal femur with extensive necrosis and multifocal hemor-
rhage grossly mimicking telangiectatic osteosarcoma. C, Fleshy tumor with soft tissue extension involving distal end of femur.
D, Destructive fleshy mass with cortical disruption and soft tissue extension of distal tibia end.

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672 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-49  ■  Malignant fibrous histiocytoma: microscopic features. A and B, Low and intermediate power views showing plump
malignant spindle cells with brisk mitotic activity. C and D, Low and intermediate power views of pleomorphic spindle cells. (A and
C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 673

A B

C D
FIGURE 9-50  ■  Malignant fibrous histiocytoma: microscopic features. A and B, Low power views showing malignant spindle cells
with atypical nuclei. Inset shows atypical nuclei with prominent nucleoli. C and D, Intermediate and high power views showing
atypical plump cells. (A, ×50; B and C, ×100; D and inset, ×200.) (A-D and inset, hematoxylin-eosin.)

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674 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-51  ■  Malignant fibrous histiocytoma: microscopic features. A and B, Intermediate and high power views of pleomorphic
tumor with scattered multinucleated giant cells with osteoclast-like features. C and D, Low and intermediate power views of a
spindle-cell tumor with a somewhat parallel arrangement of cells. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 675

A B

C D

FIGURE 9-52  ■  Malignant fibrous histiocytoma: microscopic features. A and B, Low and intermediate power views of the advancing
edge of malignant fibrous histiocytoma permeating the marrow spaces. C and D, Low and intermediate power views of tumor
in A and B showing pleomorphic features of tumor cells. (A, ×10; B, ×50; C, ×100; D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
676 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-53  ■  Malignant fibrous histiocytoma: microscopic features. A-D, Low and intermediate power views of a tumor composed
of plump atypical cells with prominent eosinophylic cytoplasm. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 677

A B

C D
FIGURE 9-54  ■  Malignant fibrous histiocytoma: microscopic features. A-D, Intermediate and high power views of a tumor composed
of atypical somewhat epithelioid cells with dense eosinophilic cytoplasm. Tumors with such features can be confused with
rhabdomyosarcoma. All markers of skeletal muscle differentiation were negative in this case. (A and C, ×100; B and D, ×200.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
678 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-55  ■  Malignant fibrous histiocytoma: microscopic features. A and B, Pleomorphic tumor with prominent hemangiopericytoma-
like vasculature. C and D, More solid components of the same tumor with prominent pleomorphism and nuclear atypia. (A and
C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 679

A B

C D
FIGURE 9-56  ■  Malignant fibrous histiocytoma: microscopic features. A-D and Inset, Malignant fibrous histiocytoma with
prominent component of inflammatory cells admixed with foamy histiocytic cells. (A and C, ×100; B and D, and inset, ×200.)
(A-D, hematoxylin-eosin.)

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680 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-57  ■  Malignant fibrous histiocytoma: microscopic features. A-D, Intermediate and high power views of tumor composed
of short, plump, somewhat epithelioid cells with prominent collagen matrix depostion. (A and C, ×100; B and D, ×200.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 9  Fibrous and Fibrohistiocytic Lesions 681

A B

C D
FIGURE 9-58  ■  Malignant fibrous histiocytoma: microscopic features. A, Anaplastic spindle cells in malignant fibrous histiocytoma.
B, Pleomorphic cells with some epithelioid features. C, Giant cell variant of malignant fibrous histiocytoma (×200). D, Myxoid variant
of malignant fibrous histiocytoma (A, ×100; B-D, ×200). (A-D, hematoxylin-eosin.)

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682 9  Fibrous and Fibrohistiocytic Lesions
the pleomorphic tumor cells, but rather show positivity
in attracted, nontumorous, inflammatory cells. Bone
morphogenetic protein markers are found in sarcomas of
bone of various origins. Therefore these markers cannot
be used in distinguishing malignant fibrous histiocytomas
from osteosarcoma.268 Ultrastructural studies show that
malignant fibrous histiocytoma in bone exhibits similar
features to its soft tissue counterpart.220,222,229,237,266
Extensive use of lineage differentiation markers in
several recent studies have shown that some malignant
fibrous histiocytomas can be subclassified into several
categories based on their myogenic, myoepithelial, myo-
fibroblastic, lipoblastic, and osteoblastic phenotypes.241
At least focal positivity for smooth muscle markers is seen
in approximately 50% of these tumors. There is no evi-
dence however that such subclassification segregates
malignant fibrous histiocytomas into clinical categories
with distinct behavior or unique therapeutic response.
Cytogenetically, malignant fibrous histiocytomas
show complex chromosomal complements with numer-
ous structural aberrations and marker chromosomes.
Microarray-based studies disclosed a similar disarray of
genome-wide copy number variations with preferential
amplifications of 8q24 and overexpression of MYC.258,262
Surprisingly, the rate of mutation of TP53 and MDM2
amplification is relatively low and is seen in less than 20%
of these tumors.234,263 Deletions of 9p21-22 are present
in both sporatic malignant fibrous histiocytoma and
malignant fibrous histiocytoma associated with diaphy-
seal medullary stenosis, but CDKN1A is not a target
gene.235,258
Personal Comments
The problem of deciding whether a high-grade pleomor-
phic spindle-cell sarcoma primary in bone represents an
“undifferentiated osteolytic sarcoma” or a malignant
fibrous histiocytoma is approached differently on the
basis of one’s own preferences with regard to the inter-
pretation of foci of coarse collagenous bundles that
resemble tumor osteoid. Some pathologists tend to
regard any high-grade pleomorphic spindle-cell sarcoma
in bone as an undifferentiated osteosarcoma, regardless
of whether tumor bone or osteoid production can be
found. We regard the finding of even small amounts of
definite tumor osteogenesis as tantamount to a diagnosis
of osteosarcoma.
Differential Diagnosis
The same entities discussed in the differential diagnosis
of fibrosarcoma of bone are relevant to this entity, namely
osteosarcoma, fibrosarcoma, desmoplastic fibroma, and meta-
static tumors with spindle-cell features.
Fibrosarcoma, which exhibits a herringbone pattern as
well as more uniformity of cells, is now largely replaced
as a diagnostic category by malignant fibrous histiocy-
toma of bone. Fibroblastic osteosarcoma and high-grade
pleomorphic variants of osteosarcoma are distinguished
from malignant fibrous histiocytoma only by the finding
of microscopic evidence of unequivocal osteoid and
tumor bone.
ERRNVPHGLFRVRUJ
The differential diagnostic features of metastatic car-
cinomas with spindle-cell features and solitary metastases
of spindle-cell sarcomas are discussed in the section on
fibrosarcoma.
Treatment and Behavior
Data from the National Cancer Institute’s Surveillance,
Epidemiology, and End Results (SEER) Program (1973-
2005) containing more than 1200 cases indicate that
there has been improvement of the 5-year survival rate
for patients with malignant fibrous histiocytoma of bone
over the past decade. The national 5-year survival rates
in the 1980s and 1990s were in the range of 30% to
40%. The establishment of modern combined surgery
and chemotherapy protocols have resulted in improve-
ment of the 5-year survival rate to 67%. This represents
a substantial improvement when compared to the preche-
motherapy era, when the survival rates of patients treated
with surgery alone were less than 20%.214 In general, the
survival rates of patients with malignant fibrous histio-
cytoma of bone and soft tissue are similar. In addition,
there is significant overlap between the survival rates
and chemosensitivity between malignant fibrous histiocy-
toma of bone and osteosarcoma.233 Tumors that arise in
preexisting conditions (e.g., secondary malignant fibrous
histiocytoma) behave in a more aggressive manner than
de novo lesions. In this group, a majority of patients
die within 1 to 2 years after diagnosis, and there are no
long-term survivors. In general, malignant fibrous histio-
cytoma of bone is a highly aggressive tumor with a high
propensity for metastasis. Metastases typically present
in the lungs; it appears that nearly 50% of patients with
malignant fibrous histiocytoma develop this serious com-
plication. Metastatic spread to regional lymph nodes
is very unusual. Combined multiple modality treat-
ment with chemotherapy, surgery, and adjuvant radio-
therapy is a standard approach in the management of
these lesions.214-216 Similar to osteosarcoma, the propor-
tion of necrosis after chemotherapy is a strong prog-
nostic factor in the management of malignant fibrous
histiocytoma.252,267
FIBROSARCOMA
Definition
Fibrosarcoma is a malignant spindle-cell neoplasm that
exhibits myofibroblastic differentiation. It is distinguished
from malignant fibrous histiocytoma and fibroblastic
osteosarcoma by the absence of osteoid production and
by its uniform spindle-cell myofibroblastic features. With
the recognition in the 1970s that malignant fibrous his-
tiocytoma arising in bone was a separate entity, there was
a sharp decline in the use of this diagnostic designation.
There is some controversy regarding the specificity of the
term fibrosarcoma of bone, and many authors now tend to
classify these tumors as variants of malignant fibrous his-
tiocytoma. We retain the description of fibrosarcoma in
bone in this new edition, but the readers should be aware
that this diagnostic designation is rarely used to define

Incidence
1 2 3 4 5 6
Age in decades
FIGURE 9-59  ■  Fibrosarcoma. Peak age incidence and frequent sites of skeletal involvement.
spindle-cell malignancies in bone. Modern reports on
fibrosarcoma of bone are extremely rare, and typically
they are combined with malignant fibrous histiocytoma
of bone.219,257,276
Incidence and Location
It is difficult to establish the frequency of this tumor
because of different criteria used to establish the diagno-
sis. Data from the SEER Program indicates that although
fibrosarcoma was more frequently diagnosed in the past,
it is now exceedingly rarely used as a diagnostic designa-
tion for bone sarcomas. This trend suggests that this
tumor is combined either with fibroblastic osteosarcoma
or malignant fibrous histiocytoma. It most frequently
involves the metaphyseal portions of long tubular
bones.269-272,274,277 Similar to conventional osteosarcoma,
nearly 50% of cases occur in the distal femoral and proxi-
mal tibial metaphyses, but every bone of the skeleton can
be affected.278,279 It is rarely diagnosed in the first decade
of life and is widely distributed from the second through
seventh decades with a bell-shaped curve. The peak inci-
dence is in the fifth decade of life. There is no clear sex
predilection, but male patients seem to be slightly more
frequently affected than female patients. In the past, it
was reported as a secondary sarcoma complicating giant
ERRNVPHGLFRVRUJ
9  Fibrous and Fibrohistiocytic Lesions 683
7 8
cell tumor, Paget’s disease, irradiation damage, chronic
osteomyelitis, fibrous dysplasia, and bone infarct. More
recently, secondary sarcomas complicating these condi-
tions that do not exhibit bone-forming features are
usually classified as malignant fibrous histiocytomas.
Similar to malignant fibrous histiocytoma, rare cases of
multifocal skeletal fibrosarcoma were reported.273 The
peak age incidence and frequent sites of skeletal involve-
ment are shown in Figure 9-59.
Clinical Symptoms
Pain is the most common initial symptom of fibrosar-
coma. Swelling and tenderness of the affected area may
be present. Pathologic fracture may also be a presenting
symptom.
Radiographic Imaging
The lesion is purely lytic and exhibits a destructive growth
pattern with ill-defined irregular borders (Fig. 9-60).281
Permeative or moth-eaten patterns of bone destruction
may be present. Features of early, sometimes multifo-
cal, cortical disruption and extension into soft tissue are
present. Periosteal elevation with Codman’s triangles
and periosteal new bone formation also may be present.
684 9  Fibrous and Fibrohistiocytic Lesions

A B

C D
FIGURE 9-60  ■  Fibrosarcoma: radiographic and microscopic features. A and B, Anteroposterior and lateral radiographs show
destructive lytic lesion of proximal tibia. C and D, Anaplastic spindle cells arranged in interlacing bundles in high-grade fibrosarcoma.
Note overlapping microscopic features with spindle-cell variant of malignant fibrous histiocytoma. (C and D, ×100.) (C and
D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

The lesion is most frequently located in the metaphysis.
In skeletally immature patients, the growth plate forms
a barrier to extension into the epiphysis, which may
be penetrated in more advanced lesions. In skeletally
mature patients, the tumor frequently extends into the
epiphysis.
Gross Findings
Fibrosarcoma has a fleshy, fibrous appearance with indis-
tinct irregular borders and foci of tan to gray soft tissue.
Foci with a more myxoid appearance, necrosis, or hemor-
rhage can be present.
Microscopic Findings
Fibrosarcoma is characterized by the presence of
uniform fibroblast-like spindle cells arranged in parallel
bundles (Fig. 9-60). The spectrum ranges from well-
differentiated, heavily collagenized lesions to highly
cellular tumors with obvious nuclear atypia and brisk
mitotic activity.269-272,274,277-282 Microscopic evidence of
bone and cartilage matrix production is totally absent
from these tumors. The hallmark of fibrosarcoma and
its most striking feature is the herringbone arrangement
of bundles of spindle cells that are present focally. The
tumor may exhibit focal myxoid features as well. Tumors
that are predominantly myxoid are sometimes referred to
as myxofibrosarcoma or myxoid fibrosarcoma of bone. Tradi-
tionally, fibrosarcomas have been graded numerically on
their degree of pleomorphism and mitotic rates. More
recently, the trend among bone tumor pathologists has
been to avoid the use of the term fibrosarcoma for high-
grade pleomorphic tumors. It is typically reserved for
better-differentiated lesions with features of grade 1 or
2 fibrosarcoma. The high-grade pleomorphic lesions are
now almost universally classified as malignant fibrous
histiocytoma. Ultrastructurally, these lesions uniformly
exhibit myofibroblastic differentiation with variable extra-
cellular collagen production.280 The potential overlap of
microscopic features in fibrosarcoma with malignant
fibrous histiocytoma of bone was mentioned by several
investigators early during the development of diagnostic
concepts for non–bone-forming sarcomas.257,280,282 Immu-
nohistochemically, the cytoplasm of the tumor cells is
strongly positive for vimentin and exhibits weak positiv-
ity for smooth muscle markers, such as SMA and muscle
common actin.
Differential Diagnosis
Malignant fibrous histiocytoma, fibroblastic osteosarcoma, and
desmoplastic fibroma are the three entities that are consid-
ered most often in the differential diagnosis of fibrosar-
coma of bone. In many cases, particularly those diagnosed
in recent years, the distinctions between malignant
fibrous histiocytoma and fibrosarcoma have been based
on arbitrary criteria rather than on distinct morphologic
differences. Tumors with a well-defined storiform pattern,
an admixture of large round histiocytic cells with vacu-
olated cytoplasm, and bizarre tumor giant cells have been
termed malignant fibrous histiocytoma. Those exhibiting a
ERRNVPHGLFRVRUJ
9  Fibrous and Fibrohistiocytic Lesions 685
herringbone pattern with few giant cells, either osteoclast
or tumor, are designated as fibrosarcomas.
If more than a few areas of coarsely hyalinized collagen
are present, especially exhibiting evidence of mineraliza-
tion, the tumors are interpreted as fibroblastic osteosarcoma.
At the better-differentiated end of the spectrum of
non–bone-forming spindle-cell tumors, those with little
or no nuclear atypia, absence of mitotic activity, and
coarser collagen bundles overlap with desmoplastic fibroma.
When well-differentiated cartilage islands are present
in what otherwise resembles a fibrosarcoma of bone, it is
important to recognize that the tumor represents a dedif-
ferentiated chondrosarcoma and not a primary fibrosarcoma
of bone. As with sarcomas that complicate Paget’s disease,
dedifferentiated chondrosarcomas have a poorer progno-
sis than de novo fibrosarcomas, and they tend to occur in
older patients. Similarly, fibrosarcomas can be found in
association with bone infarcts, and this association should
be verified by radiologic correlation. The underlying
lesion (e.g., infarct) may not be present in histologic
samples and may be detected only on accompanying
radiographs.
Metastatic carcinoma with spindle-cell features can simu-
late fibrosarcoma. The former usually presents in
an appropriate clinical setting and is associated with mul-
tifocal lesions. Diagnosis is facilitated by the use of
immunohistochemical techniques to demonstrate the
fundamental epithelial nature of the lesion. Occasionally,
a solitary metastatic focus of a spindle-cell sarcoma (e.g.,
leiomyosarcoma) can simulate a primary fibrosarcoma of
bone. The use of appropriate tumor marker techniques
can help the clinician avoid this pitfall.
Treatment and Behavior
In general, purely spindle-cell lesions with overall low-
grade features are considered to be less aggressive than
malignant fibrous histiocytoma but in comparison with
fibromatosis they have definite metastatic potential.275
Data from the SEER Program show, however, a signifi-
cant overlap in terms of clinical behavior for patients with
fibrosarcoma and malignant fibrous histiocytoma of
bone. Similar to malignant fibrous histiocytoma, there
has been an improvement of the 5-year survival rate,
from 37% in the 1970s to 54% during the past decade.
The long-term survival rates for patients with exclusively
low-grade fibrosarcoma are more optimistic; it is esti-
mated that nearly 80% of them are alive after 10 years.276
There is a tendency to treat low-grade tumors by radical
excision (limb-salvage procedure) or amputation. The
treatment of high-grade fibrosarcomas does not differ
from that of malignant fibrous histiocytoma.276
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 C H A P T E R 1 0 
Giant Cell Lesions
CHAPTER OUTLINE
CONVENTIONAL GIANT CELL TUMOR
OF BONE
Multifocal Conventional Giant Cell Tumor
Conventional Giant Cell Tumor with
Pulmonary Metastases
GIANT CELL TUMOR IN PAGET’S DISEASE
Giant cell lesions form a group of entities with diverse
clinical presentations and behaviors unified by the pres-
ence of a prominent population of multinucleated giant
cells. They have been, by convention, divided into two
major groups: those that were considered to be truly
neoplastic and those that were perceived as being reactive
in nature. The prototypic example of neoplastic giant cell
lesions is a giant cell tumor of bone; giant cell reparative
granuloma was traditionally considered as a reactive
process. Recent investigations appear to confirm the neo-
plastic nature of a giant cell tumor. In contrast, the condi-
tions characterized by overlapping microscopic features
in general referred to as giant cell reparative granuloma are
subdivided into several categories based on their unique
clinical presentation and genetic background. These two
groups of conditions are characterized by somewhat dis-
tinct but occasionally overlapping microscopic features,
and careful correlation with their clinical and radio-
graphic presentations is required for correct classification
of these lesions.
In addition, the ubiquitous presence of multinucleated
giant cells in many unrelated lesions of bone further
complicates their classification. Moreover, two giant cell–
containing lesions—neoplastic and reactive—frequently
coexist, and the latter can overshadow the underlying
neoplasm. Neoplastic giant cell lesions can be benign or
malignant. Malignant giant cell tumors can arise de novo
or through transformation of a preexisting benign condi-
tion. Secondary reactive changes in a benign lesion some-
times mimic malignant transformation, and a great deal
of expertise may be needed to recognize its benign nature.
On the other hand, features of malignancy can be focal
and inconspicuous, requiring careful examination of mul-
tiple sections.
Clinicopathologic correlation on the basis of careful
consideration of the radiologic features is of paramount
importance in reaching a correct diagnosis in this diverse
group of histologically overlapping entities.
Giant cell tumor is a prototypic giant cell–containing
neoplastic process that shows locally aggressive behavior
and is referred to as a conventional giant cell tumor. It
692
ERRNVPHGLFRVRUJ
MALIGNANT GIANT CELL TUMOR
Secondary Malignant Giant Cell Tumor
Primary Malignant Giant Cell Tumor
GIANT CELL REPARATIVE GRANULOMA
CHERUBISM AND RELATED SYNDROMES
is composed of proliferating mononuclear histiocytic/
macrophage cells and multinucleated osteoclast-like
giant cells. It frequently undergoes secondary changes
that complicate its classic morphology, and its diagnosis
can be challenging. In addition, a small proportion of
giant cell tumors may be de novo malignant or may
develop secondary malignant transformation. In addi-
tion, the so-called conventional giant cell tumor may give
rise, in extremely rare instances, to distant metastases,
typically in the lung. The vast majority of giant cell
tumors are solitary lesions, but occasionally they can
present as multifocal metachronous and synchronous
lesions. A unique form of multifocal giant cell tumor is
associated with Paget’s disease.
CONVENTIONAL GIANT CELL
TUMOR OF BONE
Definition
Giant cell tumor of bone is a distinct, locally aggressive
neoplasm composed of oval or plump, spindled mono-
nuclear cells and uniformly distributed multinucleated
giant cells. The tumor most frequently involves the ends
of long bones in skeletally mature individuals. In other
skeletal sites, it is almost invariably located in epiphyseal
or epiphyseal-equivalent portions of bone.
Incidence and Localization
Giant cell tumor of bone accounts for approximately 4%
of all primary bone tumors. Most patients are between
ages 20 and 55 years, and the peak age incidence is in the
third decade of life. Approximately 70% of cases are
diagnosed in patients between ages 20 and 40 years, and
it is very unusual for giant cell tumor to occur in patients
younger than age 20 years or older than age 55 years.
Although the diagnosis of giant cell tumor in these age
groups should be treated with skepticism, the unusual
occurrence of giant cell tumor in the first two decades of

life, as well as its occasional presentation in patients older
than age 55 years, has been reported.14,15,64-66,110 During
the second decade of life, giant cell tumor usually occurs
in female patients with fused growth plates.80
Giant cell tumor is found most often in the epiphyseal
ends of long tubular bones, with the distal end of the
femur, proximal end of the tibia, and the distal end of the
radius being the most frequent sites. It is uncommon in
short tubular bones of the hands and feet. It is extremely
rare in the vertebral bodies, but the sacrum is the most
common site in the axial skeleton. Giant cell tumor is
unusual in flat bones and ribs and very rarely affects cra-
niofacial bones in the absence of Paget’s disease. The
association of giant cell tumor with Goltz syndrome
(focal dermal hypoplasia), a rare condition in which there
are multiple congenital anomalies of skin, teeth, and
bone, has been reported.107 Its presence in two cases sug-
gests that it may represent an integral element of the
spectrum of anomalies observed in this very rare condi-
tion. Giant cell tumor may occur more frequently in
Chinese people than in people who live in Western
countries. The estimated rate in the Chinese population
has been reported to account for about 20% of all
primary tumors of bone.106 The peak age incidence and
the most common skeletal sites of involvement are shown
in Figure 10-1.
Peak
incidence
20 40
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 10-1  ■  Giant cell tumor. Peak age incidence and frequent sites of skeletal involvement in giant cell tumor. Most frequent sites
are indicated by solid black arrows.
ERRNVPHGLFRVRUJ
10  Giant Cell Lesions 693
Radiographic Imaging
The radiographic picture of a giant cell tumor is quite
characteristic and diagnostic if present in the specific
anatomic site of skeletally mature patients. Radiographs
reveal a well-defined, eccentric, lytic subchondral lucency
that involves the former epiphysis and metaphysis (Figs.
10-2 and 10-3). The cortex is frequently expanded and,
at least focally, destroyed. In a small percentage of cases,
there can be minimal periosteal reaction when the cortex
is breached. The borders, although well defined, usually
do not show marginal sclerosis, and trabeculation usually
is not present. Occasionally, particularly in a weight-
bearing bone, a giant cell tumor can show marked tra-
beculation and marginal sclerosis that produces the
nontypical “soap bubble” appearance (Fig. 10-4). These
changes can be correlated with the microscopic findings
of extensive reactive fibrohistiocytic features (see later
section). Pathologic fracture is found in 5% to 10% of
giant cell tumors.37 It may be the presenting clinical
feature for patients with such tumors in weight-bearing
bones (Figs. 10-5 and 10-6).
Some observers have proposed a radiologically based
classification defining three main types of giant cell
tumor: quiescent (type I), active (type II), and aggressive
Text continued on p. 699
7 8
694 10  Giant Cell Lesions

A B

C D
FIGURE 10-2  ■  Giant cell tumor in a skeletally mature 16-year-old girl: radiographic features. A and B, Anteroposterior and lateral
plain radiographs show involvement of lateral condyle. C, T2-weighted coronal magnetic resonance image (MRI) shows high signal
in tumor. D, Axial T1-weighted (upper) and T2-weighted (lower) MRIs show signal characteristics of tumor in lateral condyle.

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 695

A B

C
FIGURE 10-3  ■  Giant cell tumor of proximal end of tibia: radiographic and microscopic features. A, Radiograph of knee of an 18-year-
old skeletally mature woman with giant cell tumor involving lateral tibial plateau and extending into metaphysis. B, Photomicrograph
of curetted tibial lesions shows even distribution of giant cells in spindle-cell stroma (×100). C, Higher magnification of tumor shown
in B (×200) (B and C, hematoxylin-eosin.)

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696 10  Giant Cell Lesions

A B

C D

FIGURE 10-4  ■  Giant cell tumor with sclerotic margins and trabeculation: radiographic features. A and B, Anteroposterior (AP) and
lateral views of giant cell tumor in distal femur of a 27-year-old man. Note expanded contour of femur. C, AP radiograph of giant
cell tumor in distal femur of a 52-year-old woman with marginal sclerosis. D, Computed tomogram of tumor shown in C clearly
demonstrates dense cortexlike rim surrounding tumor. This finding is unusual in giant cell tumor.

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 10  Giant Cell Lesions 697

A B

C D
FIGURE 10-5  ■  Giant cell tumor with pathologic fracture: radiographic features. A and B, Radiographs of right knee of a 31-year-old
man who fell and sustained displaced pathologic fracture through medial cortex as well as midarticular surface of femur. C and
D, Anteroposterior and lateral radiographs of distal femoral giant cell tumor with impacted pathologic fracture. Patient was a 40-year-
old man who noticed aching pain and slight swelling above his knee for 1 year. While involved in strenuous activity, he felt his knee
give way.

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698 10  Giant Cell Lesions

A B

C D
FIGURE 10-6  ■  Neglected pathologic fracture through giant cell tumor: radiographic and gross features. A, Anteroposterior radio-
graph of distal femoral giant cell tumor with impacted pathologic fracture. B, Pathologic fracture associated with giant cell tumor
of proximal humerus. C, Radiograph of left knee of a 54-year-old woman who had pins placed in distal femoral fracture 1 year previ-
ously. Fact that giant cell tumor was present was not appreciated, and tumor grew into soft tissue around femur. D, Coronally
bisected amputation specimen of case shown in C with giant cell tumor within fractured distal femur and adjacent soft tissue.

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(type III).14,15,29 These three varieties were referred to by
Enneking29 as surgical stages. The quiescent type is char-
acterized by a lytic defect limited to the medullary cavity
of the bone with minimal or no involvement of the corti-
cal bone. Usually the defect is surrounded by a more or
less clear rim of sclerosis, and fine trabeculation can be
present. The active radiologic type is characterized by a
thinned, expanded cortex and somewhat unclear margins.
The aggressive radiologic type is characterized by a lytic
defect with ill-defined margins, invasion of the cortex,
and extension of the tumor into surrounding soft tissue.
This radiologic classification of giant cell tumor has
limited usefulness. So-called radiologic features of aggres-
siveness do not necessarily correlate with microscopic
criteria of malignancy or the ultimate clinical behavior of
the tumor. In the authors’ shared opinion, the terms
quiescent, active, or aggressive should not be used even in
the descriptive sense in reference to radiographic presen-
tations of giant cell tumors. These are clinically irrelevant
and misleading terms because they overlap with terms
used to describe histologic features. Radiologic features
of aggressiveness with huge destructive lesions, massive
invasion into the cortex, and extension of the tumor into
surrounding soft tissue are merely reflections of the stage
of the disease. They do not necessarily correlate with
aggressive histologic features in our experience.
Overlap in radiologic presentation with fibrosarcoma,
malignant fibrous histiocytoma, multiple myeloma, and
other destructive lesions can occur. Consequently, in
many cases, the exact radiologic diagnosis of giant cell
tumor cannot be made.
In very unusual instances, giant cell tumor may occur
in the metaphyseal portion of bone without involving the
epiphysis (Fig. 10-7). This may occur in young patients
whose epiphyseal plates are still open. Nonepiphyseal
localization of the lesion sometimes occurs in skeletally
mature patients. So-called nonepiphyseal giant cell tumor
represents a medical curiosity and is extremely rare.
Marked bone expansion and secondary aneurysmal
bone cyst are frequent secondary changes seen in giant
cell tumor that are best assessed by computed tomog­
raphy and magnetic resonance imaging (Figs. 10-8
and 10-9).
Gross Findings
Giant cell tumor of bone in its typical location and intact
in its setting is soft, friable, fleshy, and red-brown with
yellowish areas (Figs. 10-10 and 10-11). The tumor tissue
is well demarcated and usually extends to the articu-
lar cartilage. The articular cartilage is unlikely to be
invaded or perforated. The lesion usually occupies an
eccentric position in the epiphyseal end of the bone. Its
shaftward portion (i.e., advancing toward the medullary
cavity) is usually more centrally located. It is delimited
in its periphery by a thin layer of fibrous and reactive
bone tissue. The cortical bone may not be involved,
and the original contour of the bone may be preserved.
However, more frequently, the original cortex has been
destroyed, and the bone contour has been expanded. A
thin shell of subperiosteal bone surrounding the periph-
ery of the lesion is sometimes seen. Often there is gross
ERRNVPHGLFRVRUJ
10  Giant Cell Lesions 699
evidence of hemorrhage, cyst formation, and necrosis.
All these changes can be present in one tumor. There
also may be evidence of pathologic fracture, most fre-
quently involving the subchondral bony endplate.
Hemorrhage and necrosis are particularly frequent and
extensive in the weight-bearing bones (Fig. 10-10). They
may be present with or without associated pathologic
fracture.
Microscopic Findings
Histologically, the basic pattern of giant cell tumor is that
of a moderately vascularized stroma with oval or plump,
spindle-shaped mononuclear cells uniformly interspersed
with multinucleated giant cells (Figs. 10-12 to 10-14).
The latter can have nuclei sometimes numbering 50 to
100 or even more, which are clustered in the middle of
the cell (Figs. 10-14 and 10-15). The nuclei of stromal
and giant cells are similar. They are round or oval with
regular outlines, evenly distributed fine chromatin, and
a prominent nucleolus. In addition to these two cell
populations, occasional binucleated and trinucleated cells
can be seen, suggesting a gradual transition of some
mononuclear cells into multinucleated giant cells. This
phenomenon can be seen particularly well in cytologic
preparations in which whole intact cells are analyzed.
Occasionally, stromal and giant cells may show pyknotic
changes of the nuclei. Giant cells usually have dense
eosinophilic cytoplasm with clear, sharp, oval borders.
Occasionally, cells can be irregular in shape and vacuo-
lated (Figs. 10-14 and 10-15).
Morphologically, several types of mononuclear stromal
cell can be distinguished. The stroma can be composed
of small or intermediate-sized oval cells. The spindle cells
can be short and plump or elongated and fibroblast-like
(Figs. 10-16 and 10-17). All these types of cells can be
present in one tumor, sometimes accounting for a super-
ficial impression of pleomorphism. True pleomorphism,
not related to the presence of various types of stromal
cells, should not be seen in a conventional giant cell
tumor. The mitotic rate of mononuclear stromal cells can
be quite high, but atypical mitoses are not present. There
is no mitotic activity within multinucleated giant cells.
No bone or cartilage matrix production by tumor cells is
seen. The classic account of the histologic criteria for the
diagnosis of giant cell tumors by Jaffe et al.47 emphasized
the relationship between clinical behavior and histologic
evidence of spindle-cell predominance, focal attenuation
of giant cells, and increased mitotic activity. This early
histologic description included a numeric grading system
(grades 1 through 3) that was designed to predict recur-
rent behavior and metastatic potential. Subsequent expe-
rience has shown that the use of numeric histologic
grading lacks predictive value.
The classic microscopic pattern of giant cell tumor
is frequently modified by a secondary reactive prolifera-
tion of fibrohistiocytic tissue, hemorrhage, necrosis, and
aneurysmal bone cyst formation. Reactive fibrous tissue
with a prominent storiform pattern and xanthogranulo-
matous reaction can be documented, at least focally,
in nearly all appropriately sampled lesions. In some
Text continued on p. 711
700 10  Giant Cell Lesions

A B

C D

FIGURE 10-7  ■  Nonepiphyseal giant cell tumor: radiographic features. A, Anteroposterior radiograph of giant cell tumor in skeletally
immature patient shows no involvement of epiphysis. B, Lateral view of tumor shown in A shows no extension to secondary growth
center. Patient was a 14-year-old girl with knee pain. C, Lateral radiograph of distal femur of a 27-year-old woman with pain in
lower thigh. Giant cell tumor is confined to metaphysis. D, T1-weighted magnetic resonance image shows that giant cell tumor seen
in C is limited to shaft.

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 10  Giant Cell Lesions 701

A B

D E
FIGURE 10-8  ■  Giant cell tumor of distal radius: radiographic and gross morphologic features. A, Anteroposterior radiograph of distal
radial giant cell tumor. B, T2-weighted coronal magnetic resonance image (MRI) shows expansile distal radial tumor with multilocular
architecture and variegated signal enhancement. C and D, Radial T1-weighted MRI and T2-weighted MRI with contrast with fluid
levels. E, Bisected distal radial resection specimen showing an expansile multilocular giant cell tumor composed of dark and light
tan tissue with focal yellowish areas.

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702 10  Giant Cell Lesions

A B

C E
FIGURE 10-9  ■  Giant cell tumor of proximal fibula: radiographic and gross morphologic features. A, Anteroposterior radiograph
showing an expansile lytic lesion of the proximal fibula with fine trabecular pattern. B, Bisected proximal fibula resection specimen
showing an expansile giant cell tumor with multilocular cystic architecture. C, T2-weighted coronal magnetic resonance image (MRI)
shows lobular signal enhancement within the expansile lesion involving the proximal fibula. D and E, Radial T2-weighted MRI and
T2-weighted MRI with contrast show multilocular cystic lesion in the fibula.

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 703

A B

C D
FIGURE 10-10  ■  Giant cell tumor: gross mophologic features. A, Bisected distal femoral resection specimen shows light and dark tan
giant cell tumor with marbling fibrous tissue. Mild expansion of the bone contour with intact cortex and sharp demarcation of the
tumor from the surrounding medullary bone is present. B, Expansile giant cell tumor of distal femur composed of light and dark
tan tissue with central fibronecrotic areas. Impacted pathologic fracture is present. C, Giant cell tumor of tibia extending to the
articular plate and expanding the bone contour laterally. The lesion is composed of light and dark tan tissue with areas of fibrosis.
Note small hemorrhagic cystic spaces. D, A large expansile giant cell tumor of the proximal humerus composed of light and dark
tan tissue. Large areas of yellowish necrotic tissue in the central portion of the lesion are present.

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704 10  Giant Cell Lesions

A B

C D
FIGURE 10-11  ■  Giant cell tumor: gross morphologic features. A, Bisected distal segment of femur with well-demarcated tumor tissue.
Note destroyed cortex and expansion of tumor into soft tissue. B, Posterior aspect of specimen shown in A shows destroyed cortex
and expansion of tumor into popliteal fossa. C, Bisected distal end of radius with well-demarcated eccentric tumor mass expanding
bone contour. Tumor tissue is red-brown with fine yellowish septations. D, Specimen radiograph of tumor shown in C. Note focal
destruction of cortex.

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 705

A B

C D
FIGURE 10-12  ■  Giant cell tumor: microscopic features. A, Classic microscopic pattern of giant cell tumor with oval or plump spindle
mononuclear cells uniformly interspersed with multinucleated giant cells. B, Higher power view of A shows multinucleated giant
cells and oval or plump mononuclear cells. C, Classic microscopic features of giant cell tumor composed of mononuclear histiocytic
cells with evenly distributed multinucleated giant cells. D, Higher magnification of C shows mononuclear histiocytic cells and mul-
tinucleated giant cells with hemosiderin deposits. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

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706 10  Giant Cell Lesions

A B

C D
FIGURE 10-13  ■  Giant cell tumor: microscopic features. A, Classic microscopic pattern of giant cell tumor with oval or plump spindle
mononuclear cells uniformly interspersed with multinucleated giant cells. B, Higher power view of A shows multinucleated giant
cells and oval or plump mononuclear cells. C, Classic microscopic features of giant cell tumor composed of mononuclear histiocytic
cells with evenly distributed multinucleated giant cells. D, Higher magnification of C shows mononuclear histiocytic cells and mul-
tinucleated giant cells with hemosiderin deposits. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 707

A B

C D
FIGURE 10-14  ■  Giant cell tumor: microscopic features. A, Variant of giant cell tumor with numerous multinucleated giant cells. Some
of the cells have more than 100 nuclei. B, Higher power view of A shows multinucleated giant cells with more than 100 nuclei and
dense eosinophilic cytoplasm. C, Conventional giant cell tumor with spindling of mononuclear cells and scattered multinucleated
giant cells with ragged contours of their cytoplasm. D, Higher magnification of C showing multinucleated giant cells with large
irregular cytoplasm. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

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708 10  Giant Cell Lesions

A B

C D

E F

G H
FIGURE 10-15  ■  Giant cell tumor: microscopic features. A-H, Spectrum of multinucleated giant cells frequently seen in giant
cell tumors ranging in size of their cytoplasm and the number of nuclei from a few to several hundred. (A-H, ×200)
(A-H, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 709

A B

C D
FIGURE 10-16  ■  Giant cell tumor with fibrohistiocytic changes: microscopic features. A, Xanthogranulomatous reaction in giant cell
tumor obliterating its classical cytoarchitectural features. B, Higher magnification of A showing foamy histiocytic infiltrate. C, Fibro-
histiocytic reaction in giant cell tumor. Ill-defined bands of spindle-cell proliferations interspaced with histiocytic infiltrate are present.
D, Higher magnification of C showing mixed fibrous and histiocytic infiltrate with occasional atypical cells. (A and C, ×100; B and
D, ×200) (A-D, hematoxylin-eosin.)

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710 10  Giant Cell Lesions

A B

C D
FIGURE 10-17  ■  Giant cell tumor with atypia: microscopic features. A-D, Giant cell tumor exhibiting enlargement and nuclear atypia
of the mononuclear histiocytic cells. This type change is present focally in many giant cell tumors and is not indicative of malignant
transformation. (A-D, ×200). (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

instances, reactive bone formation can be associated with
these changes. Occasionally, fibrohistiocytic reaction
massively replaces the underlying tumor so that it mimics
lesions such as nonossifying fibroma or benign fibrous
histiocytoma. In such instances, the analysis of radio-
graphic data and additional sampling of the tumor are
usually sufficient to document the existence of an under-
lying giant cell tumor. The presence of prominent, reac-
tive fibroblastic tissue and xanthogranulomatous reaction
correlates with radiographically prominent sclerotic
margins and coarse trabeculations (Fig. 10-18).
Prominent focal reactive bone sometimes can be cor-
related with the presence of small cortical infractions. A
shell of reactive bone usually is seen at the periphery of
the lesion (Fig. 10-19). Although there is usually no peri-
osteal reactive bone seen on radiographs, a thin rim of
periosteal new bone formation is nearly always present
microscopically. This peculiar capacity of giant cell tumor
to induce reactive peripheral ossification is maintained in
recurrences in soft tissues, in pulmonary implants, and
even in the transplanted fragments of tumor tissue to
athymic nude mice.6 In approximately 30% of resected
giant cell tumors, intravascular invasion of tumor tissue
can be observed in the adjacent soft tissue. This inciden-
tal finding does not appear to correlate with local aggres-
siveness or the development of pulmonary implants.
Hemorrhage, necrosis, or both usually result from
fracture or mechanical compression. Old and fresh hem-
orrhage, as well as necrosis, can be present without any
obvious cause and can be quite extensive. For unknown
reasons, the mononuclear stromal cells usually develop
the recognizable features of necrosis first. It is common
to observe well-preserved giant cells in a completely
necrotic stroma. Early necrotic changes associated with
nuclear pyknosis and increased nuclear variability can
mimic malignant change (Figs. 10-20 and 10-21). The
focal nature of this necrosis-related atypia in an otherwise
conventional giant cell tumor and the absence of atypical
mitoses are helpful in avoiding a misdiagnosis of malig-
nant change. In general, focal necrosis is a common
finding in giant cell tumor and its presence is not indica-
tive of aggressive behavior or malignant change.
Microscopic foci of aneurysmal bone cyst can be fre-
quently documented if appropriate samples are available.
The presence of such foci does not necessarily correlate
with radiographic and gross features of a fully developed
aneurysmal bone cyst. Typical radiographic and gross
features of an expansile lesion with honeycombed blood-
filled spaces can develop in some giant cell tumors (Figs.
10-8 and 10-9). A giant cell tumor is reported to be an
underlying condition in 10% of secondary aneurysmal
bone cysts. On the other hand, solid areas containing
numerous multinucleated giant cells in a spindle-cell
stroma are frequently present in an aneurysmal bone cyst
and can be readily misinterpreted as an underlying giant
cell tumor. This finding should be interpreted only with
reference to appropriate radiographic features and clini-
cal setting to avoid misdiagnosis of giant cell tumor.
In rare instances, florid proliferation of spindle cells
that sometimes mimic so-called tissue culture fibroblastic
proliferations can be present in giant cell tumors, further
complicating the microscopic presentation of the lesion
ERRNVPHGLFRVRUJ
10  Giant Cell Lesions 711
(Fig. 10-21). The overall similarity of these proliferations
to nodular fasciitis is helpful to distinguish such benign
reactive processes from sarcomatoid transformation.
Cytology
Fine needle aspirates of giant cell tumor typically show
two populations of cells with predominating mononu-
clear cells and less abundant multinucleated giant cells
(Fig. 10-22). Mononuclear cells, which show a histiocyt-
oid appearance, are singly dispersed or may be arranged
in small three-dimensional clusters (Fig. 10-22). Mul-
tinucleated giant cells are similar to osteoclasts but
usually contain many more nuclei. Characteristically,
the nuclei of mononuclear histiocytoid cells are identi-
cal to nuclei of giant osteoclast-like cells. This is a dis-
tinct cytologic feature of giant cell tumor of bone. The
cytologic features of giant cell tumor of bone are often
obscured by secondary changes, such as proliferation of
fibrous tissue accompanied by foamy histiocytes. In such
instances, correlation of cytologic findings with clinical
and radiologic data may help to establish the correct
diagnosis.
Differential Diagnosis
Giant cell tumor should be differentiated from giant
cell reparative granuloma and other reactive giant cell–
containing lesions, such as the brown tumor of hyper-
parathyroidism. Less frequently, it can be confused
with nonossifying fibroma, chondroblastoma, chondromyxoid
fibroma, and the solid areas of aneurysmal bone cysts. A more
substantial problem arises in separating this lesion from
malignant fibrous histiocytoma and giant cell–rich osteosar-
coma. Bone erosion in pigmented villonodular synovitis can
sometimes present difficulties in differential diagnosis.
Giant cell reparative granuloma most frequently
occurs in the jaws, where true giant cell tumors do not
arise in the absence of underlying Paget’s disease. The
most useful histologic criterion in making this distinction
is the uniformity of distribution of the multinucleated
giant cells and the absence of reactive bone formation
and stromal collagenization in unaltered giant cell tumor.
Brown tumor of hyperparathyroidism, which represents
a giant cell reparative granuloma of known etiology, can
be recognized by the characteristic biochemical find-
ings of hypercalcemia, hypophosphatemia, and elevated
parathormone levels. The absence of chondroid matrix
and the characteristic plump, spindle-shaped appear-
ance of the mononuclear cell component are impor-
tant in excluding a giant cell–rich chondroblastoma or
chondromyxoid fibroma. The exclusion of nonossifying
fibroma should offer no substantial difficulty if atten-
tion is paid to radiologic signs of skeletal immaturity
and metaphyseal location. Irregular distribution of com-
pressed and attenuated multinucleated giant cells in a
more fibroblastic background is also characteristic of
nonossifying fibroma. Giant cell–rich osteosarcoma and
malignant fibrous histiocytoma are differentiated on
the basis of nuclear anaplasia, abnormal mitotic figures,
and neoplastic osteoid production, which are present
Text continued on p. 717
712 10  Giant Cell Lesions

A B

C D
FIGURE 10-18  ■  Giant cell tumor with prominent fibrohistiocytic reaction: radiographic and microsocpic features. A, Anteroposterior
radiograph shows marginally sclerotic giant cell tumor in proximal end of tibia. B, Computed tomogram shows no cortical break-
through and prominent sclerosis of surrounding bone. C, Fibroxanthomatous reaction in giant cell tumor with conventional tumor
tissue in upper right corner. D, Higher power photomicrograph of fibroxanthomatous component that is commonly seen in giant
cell tumors with reactive sclerosis and trabeculation. (C, x100; D, ×200). (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 713

A B

C
FIGURE 10-19  ■  Giant cell tumor: microscopic features. A, Giant cell tumor with engorgement of stromal vessels and cytoplasmic
vacularization. B, Higher magnification of B shows multinucleated giant cells and dialated stromal vessels. C, Giant cell tumor
extending to soft tissue. The periphery of the tumor is delineated by a shell of reactive bone. (A and C, ×100; B, ×200).
(A-C, hematoxylin-eosin.)

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714 10  Giant Cell Lesions

A B

C D
FIGURE 10-20  ■  Necrosis in giant cell tumor: microscopic features. A, A focus of viable giant cell tumor in a background of diffuse
necrosis. B, Higher magnification of A showing the so-called anoxic atypia affecting predominantly the mononuclear cells. C, Area
of extensive necrosis with spindle-cell proliferation. D, Higher power view of C shows florid spindle-cell proliferation at the border
of necrosis and viable tumor. (A and C, ×100; B, ×400; C, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 715

A B

C D
FIGURE 10-21  ■  Necrosis in giant cell tumor: microscopic features. A, Low power view of an interface between necrosis on the left
and viable tumor on the right. B, Higher power of A showing hyperchromasia of cells in the interface between necrosis and viable
tumor. C, Interface between necrotic area and viable tumor showing a loose texture and nuclear hyperchromasia. D, Complete
necrosis. Note well preserved multinucleated giant cells. (A, ×100; B-D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
716 10  Giant Cell Lesions

A B C

E F

D G
FIGURE 10-22  ■  Giant cell tumor of proximal tibia: radiographic, gross, and aspiration cytology features. A, Anteroposterior view of
giant cell tumor in plain radiograph involving epiphysis of proximal tibial. Note expanded contour of tibia. B, Gross photograph of
resection specimen shown in A with expansile red-brown tumor containing fine yellowish septations. The cortex overlying tumor
is destroyed and expanded bone contour is delineated by thin fibrous capsule. C, High magnification showing two multinucleated
giant cells within the mononuclear stroma. Note that the nuclei of mononuclear stromal cells and of multinucleated giant cells look
similar. D, Histologic appearance of the same tumor showing scattered multinucleated giant cells within mononuclear stromal cells
resembling histiocytes. E and F, Fine needle aspirates containing multiple mononuclear stromal cells and multinucleated osteoclastic
cell. G, Higher power demonstrating mononuclear stromal cells with oval nuclei and discrete nucleoli. Inset, An oval histiocytic cell
with two nuclei and densely eosinophilic cytoplasm. (C, E, and F, ×400; D, ×200; G and inset, ×600.) (C-G, hematoxylin-eosin.)
(C-G and inset, reprinted with permission from Czerniak B, et al: In Koss LG, Melamed MR, editors: Koss’ diagnostic cytology and its his-
topathologic bases, ed 5, Philadelphia, 2006, Lippincott Williams & Wilkins.)

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FIGURE 10-23  ■  Giant cell tumor. Secondary phenomena observed in conventional giant cell tumor.
in the former. The summary of secondary changes
complicating the cytoarchitectural features of conven-
tional giant cell tumors and various clinical phenomena
observed during its clinical course are summarized in
Figure 10-23.
Treatment and Behavior
Approximately 25% of conventional giant cell tumors are
considered to be locally aggressive on clinical or radio-
logic grounds.5 These tumors show extensive bone
destruction, cortical expansion, and invasion into soft
tissue.93 These features cannot be correlated with any
specific histologic findings. Approximately 25% to 35%
of giant cell tumors recur after simple curettage.14,64-66,93
Recurrence typically occurs within 3 years of curettage.64-66
In unusual instances, the lesion may recur many years or
even decades after removal of the primary tumor. The
recurrent lesion usually has the same morphologic fea-
tures as the primary tumor (Fig. 10-24). Curettage sup-
plemented by cryotherapy is used in some centers to
reduce the rate of local recurrence. However, it is not
universally accepted as a primary mode of treatment.
Wide excision with allograft or prosthetic replacement
significantly reduces, but does not completely eliminate,
recurrences and is performed when appropriate and tech-
nically feasible.14,15,65 The preferred mode of primary
treatment of a conventional giant cell tumor is still thor-
ough curettage and bone grafting.14,15,65,96 This general
approach is modified in relation to the anatomic site and
clinical stage of the disease. Recurrent lesions are usually
adequately treated by a second curettage. Recurrence in
soft tissue is a rare local complication of a conventional
giant cell tumor (Fig. 10-25). Typically, it is a result of
tumor implantation into soft tissue at the time of surgical
treatment.30 It usually occurs within the first 3 years after
ERRNVPHGLFRVRUJ
10  Giant Cell Lesions 717
surgical treatment of the primary lesion. In some unusual
instances, it may occur many years after the removal of
the primary tumor.36,67 Recurrence can be identified on
radiographs by a prominent shell of reactive bone sur-
rounding its periphery (Fig. 10-25). Simple excision is
usually sufficient to control the disease. In the past, radia-
tion therapy was frequently used to control the disease
locally and has been proved to be effective in preventing
local recurrences. Because the majority of malignant
transformations in giant cell tumor are linked to prior
radiation, radiotherapy is no longer recommended as a
primary mode of treatment.21 It is still, however, used to
control the disease in anatomic sites, such as the spine, for
which it is technically difficult to perform en bloc exci-
sion or complete curettage.2,17,96,100,103 Vasoocclusive
therapy by arterial embolization may be considered as an
alternative approach in anatomic sites for which it is tech-
nically difficult to remove the tumor mass surgically.19
Pulmonary metastases, or so-called benign pulmonary
implants, may develop in approximately 1% to 2% of
patients with conventional giant cell tumors. Typically
the pulmonary nodules grow slowly and are amenable to
surgical excision with a prospect for cure.10,11,24,25,51,62 Still,
some patients may die of disease as a result of pulmonary
miliary spread or progressive growth of multiple lung
lesions.21,24
In general, surgery is the main treatment modality for
giant cell tumor and is occasionally complemented by
radiation therapy.74,103,108,110,113 Recent advances in molec-
ular biology of giant cell tumor has provided new
treatment options, with the RANKL inhibitor (deno-
sumab) and bisphosphonates, which inhibit osteoclast
driven bone resorption.2,27,42,103,109,113 These two treatment
options are most frequently used for primary tumors
that cannot be resected or for metastatic disease that
cannot be surgically controlled. The reported partial and
718 10  Giant Cell Lesions

A B

C D
FIGURE 10-24  ■  Recurrence of conventional giant cell tumor: radiographic and microscopic features. A, Radiograph of knee of 17-year-
old skeletally mature girl with a 6-month history of knee pain whose giant cell tumor involved lateral half of tibial plateau; subchon-
dral bone was curetted and bone grafted. B, Histologic appearance of original tumor shows conventional giant cell tumor.
C, Radiograph of same knee 5.5 years later when symptoms recurred. Note that radiolucency is larger in extent and bony septum
is present. D, Histologic appearance of recurrent giant cell tumor is identical to primary neoplasm. (B and D, ×200) (B and
D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 719

A B C

D E
FIGURE 10-25  ■  Recurrence of giant cell tumor of bone in soft tissue: radiographic and microscopic features. A, Radiograph of knee
of a 27-year-old woman shows eccentric lytic tumor on medial side of tibial plateau. Two years later, recurrence was curetted and
bone grafted. B, Eighteen months later patient returned with palpable nodule in soft tissue beneath surgical scar (arrows) with
peripheral calcification seen on radiograph. C, Specimen radiograph film of excised recurrence (implant) in soft tissue. Note streaks
of mineralization peripherally and traversing nodule. D, Histologic appearance of primary tumor shown in A. E, Photomicrograph
of recurrent tumor nodule with peripheral shell of reactive bone. (D, ×200; E, ×50) (D and E, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
720 10  Giant Cell Lesions
complete responses to anti-RANKL therapy are causing
an increased interest in this treatment modality.
Development of sarcoma in conventional giant cell
tumor is the most serious complication but fortunately is
rare. As mentioned previously, the majority of secondary
sarcomas that arise in association with conventional giant
cell tumor are linked to prior radiation therapy.21,40 A
primary (de novo) malignant giant cell tumor is a well-
known but extremely unusual phenomenon. With the
decline in the use of therapeutic irradiation for giant cell
tumors, malignant transformation has become exceed-
ingly rare.
Special Techniques
It appears that several cell types that belong to the
macrophage/osteoclastic and osteoblastic lineages con-
tribute to the development of giant cell tumors. Ultra-
structurally, the cytoplasm of mononuclear cells contains
abundant rough endoplasmic reticulum, moderate num­
bers of mitochondria, a few lysosome-like bodies, and
occasionally multiple lipid vacuoles.105 The cytoplasm of
the multinucleated giant cell contains numerous mito-
chondria, few lysosomes, and sparse, rough endoplasmic
reticulum and appears to originate from mononuclear
cells. Occasionally, filamentous viruslike intranuclear
inclusions that are morphologically identical to those
found in Paget’s disease of bone are present.1,22,32,68,98
Unlike the inclusions seen in the osteoclasts of Paget’s
disease and in giant cell tumors that arise in a setting of
Paget’s disease, these intranuclear inclusions can be found
only after prolonged and careful survey of great numbers
of cells. In summary, the ultrastructure is of little help
to elucidate various dilemmas related to the origin of a
giant cell tumor. It suggests, however, that the mononu-
clear cells have some ultrastructural similarities with cells
of histiocytic lineage, macrophage lineage, or both. In
fact, some of the mononuclear cells express the receptor
for the immunoglobulin G crystallizable fragment and
differentiation antigens associated with a macrophage-
monocyte lineage.13,52,57 Both mononuclear and multi-
nucleated giant cells are also positive for α1-antitrypsin.57
The other major population of mononuclear cells in giant
cell tumor does not express antigens of monocyte lineage,
is strongly positive for tartrate-resistant acid phospha-
tase, and expresses parathormone and calcitonin recep-
tors, indicating that the cells are undergoing osteoclastic
differentiation (Fig. 10-26).13,52 These cells also are func-
tionally dependent on parathormone and calcitonin and
increase their level of cyclic adenosine monophosphate
on exposure to these hormones.38,39,52 An intermediate
population of mononuclear cells expressing phenotypic
features of both monocyte-macrophage and osteoclas-
tic lineages can also be found. The cells of monocyte-
macrophage lineage do not proliferate well in vivo and
are usually eliminated from tissue culture explants.39 In
contrast, the osteoclastic cells proliferate well in tissue
culture, forming multinucleated giant cells. In summary,
the main population of cells in giant cell tumor have
phenotypic features of both macrophage-like and osteo-
clastic cells.26,60 Recent cDNA microarray studies have
identified that the TP63 gene encoding the p63 protein is
ERRNVPHGLFRVRUJ
ubiquitously overexpressed in giant cell tumor (approxi-
mately 70% of the cases) and can be used in the differential
diagnosis of giant cell-containing lesions.56 More recent
investigations implicate that there is a subpopulation of
stromal cells in giant cell tumors that are in fact osteo-
blastic in nature which have clonogenic potential and
produce osteoclast differentiation signals.3,27,31,54,70,109,118
One of such signaling pathways involves a ligand for
receptor activator of nuclear factor κB (RANKL).4,45,54
In giant cell tumors, neoplastic stromal cells that express
RANKL are thought to stimulate giant cell formation
from the monocytic cells that express receptor activator of
NFκB (Fig. 10-26).109 The mechanisms of overexpression
of RANKL by stromal cells are not well understood, but
it is postulated that parathyroid hormone-related protein
(PTHrP), also expressed by stromal cells in giant cell
tumors, may play a role in the stimulation of RANKL.20,73
PTHrP is in turn regulated by microRNA-126-5p, which
has been shown to play a role as the upstream regulator
in the PTHrP-RANKL axis.119 Surprisingly, mutations of
the isocitrate dehydrogenase (IDH) genes, also frequently
seen in gliomas, acute myeloid leukemias, and cartilagi-
nous lesions, are often found in giant cell tumors.50 The
mutations involve the IDH2-R172S gene and can be
documented in nearly 80% of giant cell tumors.50 The
mutations of the histone H3.3 encoding gene exclusively
involving H3F3A and leading to a p.Gly34Trp change in
the majority of cases were found in approximately 90% of
giant cell tumors.7 Surprisingly, mutations of the histone
H3.0 encoding gene were also found in a large propor-
tion of chondroblastoma.7 Both of these mutations (i.e.,
those involving IDH2 and H2F3A) because of their high
frequency, may represent driver mutations for giant cell
tumor of bone but their exact biologic role in the devel-
opment of this tumor is yet unknown.
Little is known about the factors governing local
aggressive behavior, recurrence rate, and metastatic
potential of conventional giant cell tumors. DNA ploidy
measurements show that a high proportion of these
lesions are aneuploid. This does not correlate with the
clinical behavior of the lesion and cannot be used as a
reliable factor for predicting recurrence or pulmonary
metastases.53,95,97 A majority of giant cell tumors show
random or clonal chromosomal aberrations, with telo-
meric fusion being the most striking abnormality.12,99 It
has been suggested that this unique chromosomal aber-
ration may correlate with aggressive local behavior, a
high recurrence rate, or the metastatic potential of a
conventional giant cell tumor.12 This observation is based
on analysis of a limited number of cases, and its true
clinical value remains to be elucidated. Allelic losses of
1p, 9q, and 19q are frequent in giant cell tumors but do
not correlate with local recurrence or metastatic poten-
tial.83 In contrast, loss of genetic material on 17p in prox-
imity to the p53 locus and on 9p appear to correlate with
the metastatic potential of giant cell tumors.83 This
observation is in concert with the identification of TP53
mutations and deletions that parallel the malignant trans-
formation of giant cell tumors.76,77,92 The pathways that
may play a role in the aggressive behavior of giant cell
tumors include the upregulation of p53 signaling, osteo-
clast differentiation, and Wnt signaling. Among these
 10  Giant Cell Lesions 721

A B

C D
FIGURE 10-26  ■  Giant cell tumors: immunohistochemical features. A, Classic microscopic pattern of giant cell tumors. B, Immuno-
histochemical stains for CD-68 showing strong positive cytoplasmic stain of multinucleated giant cells and of scattered mononuclear
cells. Note that not all mononuclear cells are showing a phenotype of macrophage cells. C, Immunohistochemical stain showing
strong expression of RANKL among mononuclear stromal cells. Note that multinucleated giant cells do not express RANKL. D, High
proliferation rate documented by positive immunohistochemical staining for Ki67. Note the proliferation is restricted to mononuclear
cells. (A-D, ×200) (A, hematoxylin-eosin; C and D, immunohistochemical stains, DAB.)

ERRNVPHGLFRVRUJ
722 10  Giant Cell Lesions
pathways the upregulation of IGF1, MDM2, STAT1,
and RAC1 appear to be most significantly associated
with a recurrence, while genomic amplifications involv-
ing CCND1 and MET were found in association with
malignant transformation.18,91 Similar to many other
tumors, giant cell tumor of bone, both primary and meta-
static, may ectopically upregulate beta-human chorionic
gonadotropin.55
Personal Comments
Giant cell lesions in bone are the most frequently encoun-
tered diagnostic problems in consultation material. The
ubiquitous distribution of multinucleated giant cells of
osteoclastic type accounts for this morphologic overlap
and for difficulties in segregating true giant cell tumors
from unrelated giant cell–containing lesions. The key to
distinguishing these lesions is in the unswerving adher-
ence to clinicoradiologic correlation to arrive at a
diagnosis.
Generally, a diagnosis of giant cell tumor is suggested
by the presence of a radiolucent lesion in the end of a
long bone or an equivalent epiphyseal site in a skeletally
mature individual. Other common locations include the
sacrum and “epiphyseoid” bones, such as the carpal and
tarsal bones and the patella. The true giant cell tumor, for
practical purposes, does not arise in the craniofacial skel-
eton, and it very rarely develops in nonepiphyseal loca-
tions. The short tubular bones of the hands and feet
present a particular problem because of the morphologic
overlap with giant cell reparative granuloma, which has a
predilection for this skeletal site. In this situation, atten-
tion to the specific site of involvement with respect to
epiphyseal location and skeletal maturity is particularly
important. Perhaps the most important problem in histo-
logic recognition of true giant cell tumor is created by
the tendency for this tumor to undergo fibrohistiocytic
reactive changes that can simulate benign or malignant
primary tumors of fibrohistiocytic origin. Such changes
can largely or even completely obscure the classic histo-
logic appearance of giant cell tumor. It is this tendency
that has led to the misapplication of the term benign or
malignant fibrous histiocytoma of bone to some examples
of altered giant cell tumor. Strict adherence to the use of
clinicoradiologic correlation and thorough sampling of
the tumor tissue avoid most of these errors in diagnosis.
Another question that frequently arises is the extent
to which the aggressiveness of a giant cell tumor can be
predicted on the basis of histologic criteria. Whether to
assign numeric grades or to use adjectival modifiers in
designating local aggressiveness or metastasizing poten-
tial has been debated extensively. Our experience indi-
cates that the use of such devices is without merit, except
to designate giant cell tumor as conventional or malig-
nant (either primary or secondary) on the basis of the
presence or absence of frankly sarcomatous features.
Conventional Giant Cell Tumor in Different
Anatomic Sites
The conventional giant cell tumor has identical micro-
scopic features and biologic potential regardless of its
ERRNVPHGLFRVRUJ
anatomic location. However, in different anatomic sites
and age groups, it may cause various diagnostic dilem-
mas. The clinical significance, the technical feasibility of
complete removal, and consequently the chance for cure
can also significantly differ in relation to the anatomic
site. For this reason, it is necessary to provide separate
descriptions of giant cell tumor and its differential diag-
nosis in various anatomic sites.
Giant Cell Tumor of Long Tubular Bones.  The
tumor is most often found in the epiphyseal ends of long
tubular bones, with the distal end of the femur and proxi-
mal end of the tibia being the most frequent sites (Fig.
10-1 to Fig. 10-6). Approximately 60% of cases occur
around the knee. Giant cell tumor occurs approximately
4 times more frequently in the lower extremities than in
the upper extremities. The other common locations of
giant cell tumor in the epiphyses of long tubular bones
are the distal radius, proximal femur, humerus, and proxi-
mal fibula (Fig. 10-27). Giant cell tumor occurs less com-
monly in the distal tibia, very rarely in the distal ulna and
fibula, and very uncommonly around the elbow joint.
When it occurs in the elbow joint, it is seen more fre-
quently in the distal humerus and very rarely in the proxi-
mal ulna and the radius.
In the epiphyses of the long tubular bones, a giant cell
tumor has radiologic features of an eccentric epiphyseal
or metaphyseal defect with well-defined margins and an
expanded cortex that is very frequently, at least focally,
destroyed. Usually, there is no radiologically recogniz-
able periosteal reaction. In a small percentage of cases,
periosteal reaction can be present and is usually minimal.
In thinner bones, such as the distal ulna or fibula,
the lesion is usually centrally located with marked expan-
sion of the bone contour. Although hemorrhage, necro-
sis, and a fibrohistiocytic xanthogranulomatous reaction
can develop in any giant cell tumor, regardless of its
location, such effects are seen much more frequently
and are much more extensive in the weight-bearing
bones of the lower extremities. Radiologic evidence of
fracture may be present. In this location, it is common
for the tumor to be nearly completely replaced by necro-
sis and secondary fibrohistiocytic xanthogranulomatous
reaction.
In the long tubular bones, giant cell tumor should be
differentiated radiologically from chondroblastoma, nonos-
sifying fibroma, chondromyxoid fibroma, aneurysmal bone cyst,
pigmented villonodular synovitis, and osteogenic sarcoma.
Occasionally, fibroblastic tumors, such as desmoplastic
fibroma, fibrosarcoma, and malignant fibrous histiocytoma,
may enter into the differential diagnosis.
Chondroblastoma occurs in children and adolescents
who have open epiphyses and typically has radiologically
detectable calcifications. Chondroblastomas at the ends
of long bone seldom cause expansion of the contour
unless they contain secondary aneurysmal bone cysts, and
cortical disruption is usually not present. Nonossifying
fibroma is radiologically an eccentric metaphyseal-
diaphyseal lesion with well-developed scalloped sclerotic
margins in skeletally immature patients. These features
are particularly helpful in distinguishing a giant cell
tumor with an extensive secondary fibrohistiocytic
 10  Giant Cell Lesions 723

A B

C D
FIGURE 10-27  ■  Giant cell tumor involving long bones of extremities: radiographic features. A, Radiograph of distal end of radius
with disruption of cortex by expansile giant cell tumor. This is third most common site after femoral condyles and tibial plateau.
B, Radiograph of wrist shows eccentric tumor involving distal end of ulna. Note expanded contour, marginal sclerosis, and trabecu-
lation. C, Eccentric, totally lytic, distal tibial tumor. D, Giant cell tumor involving head of fibula.

ERRNVPHGLFRVRUJ
724 10  Giant Cell Lesions
reaction from a nonossifying fibroma. Chondromyxoid
fibroma is an eccentric metaphyseal lesion with scalloped
margins, fine trabeculations, and intact cortex. Its histo-
logic features are so characteristic that only in the most
unusual circumstances can it be confused with a giant cell
tumor.
De novo aneurysmal bone cysts produce lytic, eccen-
trically expansile defects in long bones that are easily
distinguished from giant cell tumors by their predilection
for the diaphysis or metaphysis. Conversely, it is usual for
secondary aneurysmal bone cysts to occur in association
with giant cell tumors of long bones. This combination
usually alters the radiologic appearance by accentuating
the expansile and destructive features of the giant cell
tumor. For this reason, aneurysmal bone cysts that occur
in the ends of long bones of adults should always raise the
possibility of an underlying giant cell tumor.
Pigmented villonodular synovitis of major joints
sometimes invades the ends of long bones and produces
lytic defects that can superficially resemble a giant cell
tumor. This mimicry is complicated by the presence of
many giant cells in the histologic sample of such lesions,
but the clinical and radiologic evidence of bone defects
in more than one bone bordering a joint can obviate this
diagnostic problem.
High-grade osteogenic sarcomas may occasionally
produce osteolytic defects that mimic giant cell tumor.
Usually the patient’s age, the metaphyseal-diaphyseal
location of the lesion, its ill-defined margins and features
of massive cortical destruction, and the presence of
prominent periosteal reaction are radiologic features
favoring malignancy. Fibroblastic tumors, such as desmo-
plastic fibroma, fibrosarcoma, and malignant fibrous his-
tiocytoma, can radiologically mimic giant cell tumor.
However, they are typically diaphyseal in location and
show massive destruction of bone and cortex. Their his-
tologic features are usually diagnostic, but occasionally it
is difficult to distinguish a de novo malignant fibrous
histiocytoma from secondary malignant change in an
underlying giant cell tumor. In such instances, the clinical
history, radiographs, and careful sampling of the tumor
are very helpful.
Giant Cell Tumor of Small Bones of Hands and
Feet.  Approximately 3% to 4% of all giant cell tumors
are found in the small bones of the hands and feet. Giant
cell tumors in younger patients appear to occur in these
locations more frequently than lesions in the long
bones.115 These tumors probably occur more frequently
in the metacarpal and metatarsal bones than in other
bones of the hands and feet. In the small bones, it is
unusual to see the eccentric epiphyseal origin unless the
lesion is detected very early. The majority of lesions have
radiologic features of a central epiphyseal-metaphyseal
lytic defect with prominent enlargement of bone contours
(Fig. 10-28). Involvement of the epiphysis is almost a rule,
although in small bones a significant portion of the shaft
or even the entire bone can be involved. A giant cell tumor
of the acral skeleton may show somewhat more aggressive
behavior than one in the long tubular bones (i.e., a higher
recurrence rate and a tendency to invade soft tissue),
probably more because of its location in small bones and
ERRNVPHGLFRVRUJ
the difficulty in completely removing the tumor rather
than because of an intrinsically aggressive nature.
A giant cell tumor of small tubular bones should
be differentiated mainly from a giant cell reparative gran-
uloma. Occasionally, these two entities may have very
similar microscopic features. If this diagnostic dilemma
occurs, radiologic evidence of involvement of the epiphy-
sis in a skeletally mature patient should favor the diagnosis
of a giant cell tumor. On the contrary, lack of epiphy-
seal involvement and the presence of unfused epiphy-
seal plates should be considered as radiologic features in
favor of a giant cell reparative granuloma. Enchondroma
is seldom confused with giant cell tumor because of its
location in the shaft and its characteristic calcification
pattern. Pigmented villonodular synovitis arising in tendon
sheaths of the hands and feet can erode short tubular
bones and thus simulate giant cell tumors.
Giant Cell Tumor of Vertebral Column.  Giant cell
tumor of the vertebral column exclusive of the sacrum is
extremely rare.25,48,94 In fact, many of the lesions previ-
ously classified as giant cell tumor in this site probably
represent other giant cell–containing entities. On the
other hand, the sacrum is one of the more frequently
involved skeletal sites (Figs. 10-29 and 10-30). Patients
with giant cell tumors of the vertebral column have a
tendency to be younger than patients with lesions of long
tubular bones. When giant cell tumor affects a vertebral
body, it usually occurs in a skeletally immature patient.
A high proportion of giant cell tumors that involve the
vertebral column occur in women during the second
decade of life.94 The bodies of vertebrae are usually the
site of origin, and it almost never arises in the posterior
arch or in the vertebral processes (Fig. 10-31). Radiologi-
cally, the tumor presents as a well-circumscribed defect
best demonstrated by computed tomography and mag-
netic resonance imaging. Plain radiographs may reveal
only compression fracture of the body or an abnormal
contour and deformed or missing pedicles. The radio-
logic features are nonspecific, and the exact diagnosis
usually cannot be made before biopsy. The clinical symp-
toms are related to pathologic fracture and compression
of the cord and nerve roots. Complete removal of the
tumor in the spine and sacrum is technically difficult to
perform. For this reason, radiotherapy and other alterna-
tive modalities, such as arterial embolization, are used to
control the disease in the axial skeleton.
The differential diagnosis of a giant cell tumor of
the vertebral column should radiologically include aneu-
rysmal bone cyst, osteoblastoma, and giant cell reparative
granuloma. Rarely, eosinophilic granuloma in skeletally
immature patients may present a diagnostic problem.
Giant cell reparative granuloma of the vertebrae can
mimic a giant cell tumor both radiologically and histo-
logically. Aneurysmal bone cyst and osteoblastoma are
more likely to arise in the posterior neural arch in con-
trast to giant cell tumor and giant cell reparative granu-
loma, which characteristically involve the vertebral body.
The distinctive anatomic locations of these lesions are
best demonstrated by computed tomography and mag-
netic resonance imaging. The rapidly evolving, waferlike
collapse of vertebral bodies involved by eosinophilic
 10  Giant Cell Lesions 725

A B C

D E

F
FIGURE 10-28  ■  Giant cell tumor involving bones of hands and feet: radiographic features. A, Radiograph of thumb shows lytic lesion
in base of proximal phalanx of a 37-year-old woman (arrows). B, Giant cell tumor in metacarpal head of a 27-year-old woman.
C, Radiograph of same tumor shown in B 1 year later shows progressive enlargement and further cortical destruction. D, Giant
cell tumor of medial cuneiform of a 12-year-old girl (arrows). E, Computed tomogram of giant cell tumor of cuneiform bone shown
in D. F, Giant cell tumor in calcaneus of an adult woman.

ERRNVPHGLFRVRUJ
726 10  Giant Cell Lesions

A B

C D
FIGURE 10-29  ■  Giant cell tumor of the coccyx: radiographic and gross morphologic features. A, Sagittal computed tomogram (CT)
showing a large presacral tumor originating in the coccyx and filling the lower pelvic space and impinging on the rectum. B, Tran-
sected sacral resection specimen of the same case as shown in A showing a soft tan and partially hemorrhagic presacral tumor that
originates in the coccyx. Insert. Axial CT shows a sacrococcygeal mass with peripheral calcifications. C, T1-weighted sagittal mag-
netic resonance image (MRI) showing presacral low signal mass. D, Post-contrast T2-weighted MRI showing moderate signal
enhancement within the lesion.

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 727

A B C

D E
FIGURE 10-30  ■  Giant cell tumor of sacrum: radiographic features. A, Anteroposterior radiograph of lumbosacral spine of a 16-year-
old girl with pain in lower back for 3 months. A lytic tumor was found in the sacrum. B, T2-weighted sagittal magnetic resonance
image (MRI) of sacral tumor shows high signal. C, Photomicrograph of conventional giant cell tumor. D and E, CT and T1-weighted
axial MRI demonstrate location of giant cell tumor in body of sacrum. (C, ×100) (C, ×100, hematoxylin-eosin).

granuloma helps distinguish this lesion from rare verte-
bral giant cell tumor of skeletally immature patients.
Giant Cell Tumor of Flat Bones.  Giant cell tumor
rarely occurs in flat bones. The pelvis is the most frequent
site, accounting for approximately 4% of all giant cell
tumors. Nearly half of the cases involving flat bones
occur in the ilium and pubis, with the iliac crest and the
acetabulum being the most frequent sites. Individual
cases have been reported in the scapula, sternum, and
ribs. In the flat bones, giant cell tumor has radiologic
features of large lytic defects with markedly expanded
contours of bone and a large soft tissue component. In
these anatomic sites, the extent of the disease and its
relationship to adjacent structures are best evaluated by
computed tomography and magnetic resonance imaging.
The radiographic features are nonspecific and overlap
with those of chondroblastoma, fibrosarcoma, and malig-
nant fibrous histiocytoma. The diagnosis of giant cell
tumor is less likely to be made on radiologic grounds in
flat bones, such as the pelvis, because of the nonspecificity
of its imaging characteristics in this site. Because the
pelvis is one of the more common sites of involvement
by Paget’s disease, when a giant cell tumor occurs in the
pelvis, it is important to rule out this underlying condi-
tion, particularly in patients older than age 50 years.
Giant Cell Tumor of Craniofacial Bones.  Giant cell
tumor of the craniofacial bones is extremely rare in the
absence of Paget’s disease; therefore, all cases of giant cell
tumor in this location should be carefully examined for
evidence of underlying Paget’s disease. The few cases that
fulfill the criteria of de novo giant cell tumor of craniofa-
cial bones are most frequently located in the sphenoid
bone or other anatomic locations within the base of the
skull such as the clivus90,116 (Fig. 10-32). The extent of the
disease and its relation to other structures are best evalu-
ated by computed tomography and magnetic resonance
imaging. It usually extends into the orbit, superior nasal
cavity, or anterior cranial fossa, causing a variety of clinical

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728 10  Giant Cell Lesions

A B

C D
FIGURE 10-31  ■  Giant cell tumor of vertebral column: radiographic and microscopic features. A, Anteroposterior radiograph of lumbar
spine in a 18-year-old woman shows radiolucency and partial collapse of L4. B, Lateral view of giant cell tumor involving body
of fourth lumbar vertebra. C, Computed tomogram of L4 shows radiolucent expansile tumor of vertebral body that is beginning
to compress dural sac. D, Photomicrograph of conventional giant cell tumor shown in previous images (D, ×200) (D, ×200,
hematoxylin-eosin).

symptoms related to the involvement of the adjacent
structures.116 An exact radiologic diagnosis is usually not
possible because the radiographic features are indistin-
guishable from more frequent primary bone lesions such
as fibrous dysplasia, brown tumor of hyperparathyroid-
ism, and giant cell reparative granuloma. These lesions
often have been inappropriately classified as giant cell
tumors, especially in oral pathology and ophthalmic lit-
erature. Giant cell reparative granulomas are reactive
fibroosseous lesions with prominent giant cell compo-
nents that may closely resemble giant cell tumors histo-
logically, but they do not share their biologic characteristics.
Pigmented villonodular synovitis of the temporomandib-
ular joint occasionally produces temporal bone destruc-
tion that can be mistaken for a true giant cell tumor.
Multifocal Conventional Giant
Cell Tumor
Multifocal giant cell tumors are extremely rare without
underlying Paget’s disease. However, there are well-
documented cases of concurrent involvement of more

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 729

C
FIGURE 10-32  ■  Giant cell tumor involving sphenoid bone of a 19-year-old man with headaches and blurred vision: radiographic
features. A and B, Computed tomograms (CTs) show lytic expansile lesion involving wall of sphenoid sinus. C, Sagittal reconstruc-
tion CT demonstrates posterior placement of tumor in sphenoid bone.

ERRNVPHGLFRVRUJ
730 10  Giant Cell Lesions
than one, usually two or three, anatomic sites without any
evidence of underlying Paget’s disease.23,28,34,43,44,101,102,104 A
multifocal giant cell tumor often involves its typical ana-
tomic sites, such as the epiphyses of long tubular bones.
Sometimes both sides of the knee joint can be involved
(i.e., separate lesions can be present in the distal femur
and the proximal tibia of the same extremity). In these
rare cases, pigmented villonodular synovitis enters into the
differential diagnosis. Lesions can also be present in
several diverse anatomic sites such as separate bones of
one extremity or in extremity bones on one side of the
body.89 However, in some cases the lesions are distributed
without any apparent anatomic order. The behavior of
multifocal giant cell tumors does not differ from that of
a unifocal lesion.79 In these cases, it is essential to rule out
multifocal giant cell reparative granuloma and underlying
brown tumor of hyperparathyroidism.
Conventional Giant Cell Tumor
with Pulmonary Metastases
A number of well-documented cases of conventional
giant cell tumors have metastasized to the lungs (Figs.
10-33 to 10-35).10,51,62,63,69,86,88,114 This phenomenon is rare
and probably occurs in not more than 1% to 2% of
patients with conventional giant cell tumors. The pulmo-
nary metastases, or so-called pulmonary implants, in his-
tologically benign giant cell tumor should be distinguished
from the true metastases observed in malignant giant cell
tumors. They have distinct radiologic and pathologic
features, self-limited growth potential, and a relatively
good prognosis.114 Some tumors may even spontaneously
regress. Therefore such lesions should be resected when
it is technically feasible with a good prospect of cure.
However, some patients may die as a result of progressive
growth of multiple inoperable lung lesions. The clinical
behavior of pulmonary implants in conventional giant
cell tumor is therefore unpredictable. Although the
overall prognosis of pulmonary implants is much better
than that of conventional pulmonary metastatic disease,
approximately 25% of patients eventually die of the
disease. Pulmonary metastases in histologically benign
giant cell tumor occur typically within 3 years after the
removal of the primary lesion in bone. In some instances,
pulmonary metastases may appear many years or even
decades after removal of the primary lesion.117 It is con-
ceivable that they are the result of curettage and mechan-
ical seeding of blood vessels or lymphatics with small
fragments of tumor tissue that are subsequently implanted
in the lung. They are, however, occasionally observed in
patients without prior surgery at the time of diagnosis of
the primary bone tumor. In such instances, pulmonary
metastasis is most likely related to invasion by a giant cell
tumor into blood vessels, a finding that can be docu-
mented in approximately 30% of conventional giant cell
tumor resection specimens. In extremely rare cases the
so-called histologically benign giant cell tumor of bone
can metastasize to other sites (e.g., lymph nodes, bone,
and skin).82,111,117
Initially, the pulmonary metastases are asymptomatic
and are usually an incidental finding on chest x-ray films
taken during follow-up of the patient with a history of
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giant cell tumor of bone. They have classic radiologic
features of lung metastasis but may be partly calcified.
Usually, there are few nodules measuring 1 to 2 cm in
diameter. Pulmonary metastasis can also occur as a soli-
tary metastatic lung tumor. Occasionally, the patient may
have multiple miliary-type small nodules that measure
several millimeters in diameter. The nodules have micro-
scopic features of conventional giant cell tumor. The
periphery of the nodule has a thick rim of reactive fibrous
tissue and, at least focally, a shell of reactive bone. The
latter may be identifiable on plain radiographs or com-
puted tomograms of the chest. There is nothing charac-
teristic in the radiologic or histologic findings of the
primary lesion, including the presence of blood vessel
invasion that can reliably predict the development of pul-
monary implants in a patient with conventional giant cell
tumor. The reported development of pulmonary implants
in a male patient who tested positive for the human immu-
nodeficiency virus and who had a conventional giant cell
tumor and in an immunocompromised patient who had
had an allograft bone marrow transplant suggest that the
host’s immune response may play an important role in
controlling the clinical behavior of these neoplasms.58
GIANT CELL TUMOR
IN PAGET’S DISEASE
Giant cell tumors may complicate Paget’s disease of bone
but do so much less frequently than osteosarcoma or
malignant fibrous histiocytoma (Figs. 10-36 and 10-37).41
When they do, they are morphologically indistinguish-
able from a conventional giant cell tumor in patients
without underlying Paget’s disease (Fig. 10-36). Giant
cell tumor that occurs with Paget’s disease may be mul-
tifocal and has a predilection for the craniofacial bones
and other anatomic sites frequently involved in Paget’s
disease.33,41,43,49,71,81 Unlike with conventional giant cell
tumor, when it occurs with Paget’s disease it shows no
predilection for the epiphyses of long tubular bones. The
neoplastic nature of giant cell tumor in Paget’s disease
and its true relationship to conventional giant cell tumor
are questionable. There is usually no recurrence after
simple curettage, and it can be controlled by systemic
treatment with steroids. Subsequent multifocal lesions
may develop in the vicinity of the primary tumor or in
other skeletal sites involved by Paget’s disease.78 A giant
cell tumor arising in association with Paget’s disease may
represent a reactive process that only superficially mimics
a neoplasm. This is further supported by the fact that
patients with Paget’s disease may develop a giant cell
lesion that is microscopically more similar to a giant
cell reparative granuloma than to a conventional giant
cell tumor.112 A familial variant of Paget’s disease has been
described in several families living in New Jersey whose
members had multifocal giant cell tumors involving the
craniofacial bones and the vertebral bodies. Ancestors
of these families were traced to the southern Italian city
of Avellino in the Campania region.46,85 Subsequently, a
high prevelance of Paget’s disease with unique familial
clustering was identified in the entire Campania region.84
Text continued on p. 736
 10  Giant Cell Lesions 731

A B

C D
FIGURE 10-33  ■  Conventional giant cell tumor with pulmonary implants: microscopic features. A, Metastatic conventional giant
cell tumor in lung. B, Higher magnification of A showing conventional (nonmalignant) cytoarchitectural features of giant cell tumor
in pulmonary implant. C, Formation of reactive osteoid associated with pulmonary implants of conventional giant cell tumor.
D, Pulmonary implant of giant cell tumor delineated by a reactive shell of bone and peripheral scarring. (A and D, ×25; B, ×100;
C, ×200) (A-D, hematoxylin-eosin.)

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732 10  Giant Cell Lesions

A C

D E

FIGURE 10-34  ■  Conventional giant cell tumor with pulmonary implants: microscopic features. A, Small (miliary) pulmonary implants
of conventional giant cell tumor in lung. B and C, Higher magnification of A showing well defined nodules of conventional
giant cell tumor with peripheral scarring in lung. D, Small (miliary) implant of conventional giant cell tumor in subpleural
lung associated with prominent reactive bone forming an incomplete peripheral shell. E, Higher magnification of D shows a pulmo-
nary implant predominantly composed of mononuclear cells with prominent reactive bone. (A and D, ×25; B, C, and E, ×50.)
(A-E, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 733

A B

C D
FIGURE 10-35  ■  Conventional giant cell tumor with pulmonary implants: microscopic features. A and B, Pulmonary implants of
conventional giant cell tumor with prominent reactive bone. C and D, Higher magnifications of A and B showing prominent
interconnecting bone trabeculae. The tumor is composed predominantly of mononuclear histiocytic cells with stromal fibrosis
obscuring, together with reactive bone, the classic microscopic architecture of giant cell tumor. (A and B, ×25; C and D, ×50.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
734 10  Giant Cell Lesions

A B

C D
FIGURE 10-36  ■  Giant cell tumor of vertebral column complicating Paget’s disease of bone: radiographic features. A, Lateral radio-
graph of skull of a 69-year-old woman with an 8-year history of Paget’s disease. Note “cotton-wool” densities and thickened cal-
varium. B, Radiograph of lumbar spine shows “picture frame” vertebral characteristics of involvement by Paget’s disease (arrows).
C, Oblique view of thoracic spine with partial collapse of bodies of T5 and T6 at site of giant cell tumor (arrows). D, T1-weighted
sagittal magnetic resonance image shows tumor (arrows) with low signal compressing dural sac.

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 735

A B

C D
FIGURE 10-37  ■  Giant cell tumor complicating Paget’s disease of bone: microscopic features. A, Photomicrograph shows pagetoid
changes in vertebral bone of patient shown in Figure 10-28. Note mosaic pattern of cement lines, as well as prominent osteoclastic
resorption and osteoblastic rimming. B, Conventional giant cell tumor arising in thoracic vertebra involved by Paget’s disease.
C, Electron micrograph of nucleus of giant cell containing viruslike filamentous inclusion. D, Higher magnification of filamentous
inclusion body resembling paramyxovirus particles. Inset, Inclusions could be identified by light microscopy as eosinophilic bodies
within giant cell nuclei. (A, ×50; B, ×150; C, ×1400; D, ×30,000; inset, ×200).

ERRNVPHGLFRVRUJ
736 10  Giant Cell Lesions
It appears that Paget’s disease in these patients shows a
higher clinical severity and greater frequency of neoplas-
tic transformations including giant cell tumor of bone.84
Some of the patients from this group responded well to
treatment with high doses of dexamethasone. A large
pedigree-based analysis of giant cell tumor associated
with familial Paget’s disease failed to identify a single
predisposing locus within the human genome.35 Giant
cell tumors in Paget’s disease frequently contain intra-
nuclear inclusions, the presence of which can sometimes
be distinguished in conventional histologic sections as
intranuclear eosinophilic bodies. They are best docu-
mented by electron microscopy, which reveals 10-nm
thick filamentous intranuclear inclusions as well as occa-
sional cytoplasmic bodies (Fig. 10-37). They resemble
paramyxovirus inclusions, but the precise nature of these
structures remains to be determined.1,16,61 Attempts to
identify measles virus in giant cell tumor of Paget’s
disease and in Paget’s disease itself with polymerase chain
reaction (PCR)–based techniques failed to document ele-
ments of the measles genome.75
MALIGNANT GIANT CELL TUMOR
Giant cell tumor has a tendency to progress to a high-
grade malignancy, which may develop within the preex-
isting conventional giant cell tumor typically after several
recurrences.5,8,9 Such tumors are referred to as secondary
malignant giant cell tumors. A primary de novo malig-
nant giant cell tumor is extremely rare.
Secondary Malignant Giant Cell Tumor
Malignant change typically occurs after multiple local
recurrences of a conventional giant cell tumor. It
can also happen after a single local recurrence.8,9,36,40,93
Occasionally, malignant change can be identified in the
primary conventional giant cell tumor at the time of its
initial diagnosis. Sarcomatous change is more likely to
happen in a previously irradiated lesion, usually 5 years
or more after the initial radiation exposure. Sarcomatous
change can also develop many years or even decades after
removal of the primary lesion.36,72,87 A giant cell tumor
with malignant change has radiologic features of a
large destructive lesion with cortical destruction and
prominent invasion into soft tissue (Fig. 10-38). However,
these features are frequently observed in a locally
advanced conventional giant cell tumor. On the other
hand, a sarcomatous component can be present in a giant
cell tumor that has no radiologic features of aggressive-
ness (Fig. 10-40). Therefore as previously mentioned,
radiologic features of aggressiveness in giant cell tumors
do not correlate well with histologic criteria of malig-
nancy or with metastatic potential.
Microscopically, malignant change in giant cell tumor
may be in the form of fibrosarcoma, malignant fibrous his-
tiocytoma, osteosarcoma, or undifferentiated high-grade pleo-
morphic sarcoma (Figs. 10-39 to 10-42). In extremely rare
cases, a phenotypic switch to epithelial malignancy with
squamous differentiation has been reported.59 A focus
of conventional benign giant cell tumor usually can be
ERRNVPHGLFRVRUJ
documented if the tumor is carefully sampled. The key
microscopic features in diagnosing malignant change in
giant cell tumor are the presence of atypical mitoses and
true nuclear pleomorphism in a spindle-cell component
that is next to or intermixed with a conventional giant
cell tumor. These features are easily recognizable in high-
grade tumors. However, a distinction between low-grade
fibrosarcoma or malignant fibrous histiocytoma and reac-
tive fibrohistiocytic proliferation is not always easy. This
is a particularly frequent diagnostic problem in small
biopsy samples in which the architecture of the tissue in
question and especially its interaction with other compo-
nents of the lesion cannot be evaluated. In such instances,
an examination of additional biopsy material may be
required to solve this diagnostic dilemma. Occasionally,
a florid reactive proliferation of fibroblasts with high
mitotic activity may mimic fibrosarcoma. In such instances,
attention should be directed toward the gradual blending
of such suspicious areas with clearly benign reactive tissue
to avoid a false diagnosis of sarcomatous change. In addi-
tion, it is sometimes helpful to note the resemblance of
such areas to a monolayer culture of proliferating fibro-
blasts. Bone production is not a feature of a conventional
giant cell tumor, and there is no direct production of
osteoid by tumor cells. However, reactive bone is nearly
always present at the periphery of the lesion and at times
can extend within it for a considerable distance. The
diagnosis of osteosarcoma complicating a conventional
giant cell tumor requires the presence of a malignant
bone-forming tumor (i.e., the presence of pleomorphic
cells with atypical mitoses that produce tumor osteoid).
Primary Malignant Giant Cell Tumor
As mentioned, a primary de novo malignant giant cell
tumor is extremely rare and most frequently occurs in
typical anatomic sites involved by a conventional giant
cell tumor.67 The microscopic pattern is that of high-
grade pleomorphic sarcoma with occasional telan-
giectatic features. There is no collagen and no direct
osteoid production by tumor cells. Reactive bone can be
present focally and should be appropriately identified as
not being an integral part of the lesion. There is high
mitotic activity of both stromal and tumor giant cells,
with multiple atypical mitoses present. These features
can be uniformly present in the entire lesion or can be
focal. In reference to focal changes, it may be difficult
in some cases to distinguish between primary malignant
giant cell tumor and secondary malignant change in a
conventional giant cell tumor. In cases with prominent
atypia and numerous atypical mitoses, the diagnosis of
malignancy is easy. However, as pointed out originally by
Jaffe et al.,47 there is a continuum of microscopic change
between clearly benign (conventional) and malignant
giant cell tumors. The degree of biologic aggressiveness
increases as stromal cells become more prominent and
show an increase in mitotic activity. This is accompanied
by a decrease in the number of giant cells. According to
this concept, Jaffe et al. divided giant cell tumors into
three grades. Grade 1 corresponds to a conventional,
microscopically benign giant cell tumor, and grade 3 is
Text continued on p. 742
 10  Giant Cell Lesions 737

A B

C D
FIGURE 10-38  ■  Secondary malignant giant cell tumor: radiographic and microscopic features. A, Anteroposterior radiograph of a
recurrent giant cell tumor presenting as a large expansile lesion, which destroyed the cortex of distal femoral epiphysis. B, Micro-
scopic features of the tumor in A showing a conventional component of this giant cell tumor. C and D, High-grade undifferentiated
sarcomatoid component of the lesion shown in A and B with pronounced atypia and brisk mitotic activity (B-D, ×200.)
(B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
738 10  Giant Cell Lesions

A B

C D
FIGURE 10-39  ■  Secondary malignant giant cell tumor: microscopic features. A, A component of the tumor showing cytoarchitectural
features consistent with a conventional giant cell tumor. B, Higher magnification of A showing mononuclear histiocytic cells and
scattered multinucleated giant cells. C, Sarcomatoid component of the tumor showing proliferation of atypical spindle cells. Note
the absence of multinucleated giant cells. D, Higher magnification of C showing disorganized proliferation of undifferentiated sar-
comatoid cells with pronounced atypia. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 739

A B

C D
FIGURE 10-40  ■  Secondary malignant giant cell tumor: radiographic and microscopic features. A, Eccentric lytic lesion of distal
femoral epiphysis. B, Computed tomogram of lesion in A shows eccentric, sharply demarcated defect with focally destroyed
cortex. C and D, Areas of typical osteosarcoma with prominent tumor osteoid were present in addition to conventional giant cell
tumor. (C and D, ×100.) (C and D, hematoxylin-eosin.)

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740 10  Giant Cell Lesions

A B

C D
FIGURE 10-41  ■  Primary malignant giant cell tumor: microscopic features. A, A component of the tumor with features resembling
conventional giant cell tumor. Note the dominance of mononuclear cells with a few multinucleated giant cells. B, Sarcomatoid
component of the tumor composed of undifferentiated mesenchymal cells in confluent growth. C, Higher magnification of
B showing sarcomatoid plump, spindle, and oval undifferentiated mesenchymal cells. D, Sarcomatoid cells growing in a dense col-
lagenous stroma mimicking osteoid. (A and B, ×100; C and D, ×200) (A-D, hematoxylin-eosin.)

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 10  Giant Cell Lesions 741

A B

C D
FIGURE 10-42  ■  Primary malignant giant cell tumor: microscopic features. A, Undifferentiated pleomorphic sarcoma of the distal
femeral epiphysis. B, Higher magnification of A showing pronounced atypia and mitotic activity in sarcomatoid cells. C, Undifferenti-
ated sarcomatoid cells with pronounced atypia and focal clear cell change in another area of the tumor shown in A and B. D, Higher
magnification of C showing pronounced atypia and focal clearing of the cytoplasm in sarcomatoid cells. (A and C, ×100; B and
D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
742 10  Giant Cell Lesions
a clearly histologically malignant lesion with metastatic
potential. Grade 2 corresponds to an intermediate tumor
with increased stromal cellularity, high mitotic activity,
and more than usual local aggressiveness. Grade 3 tumors
frequently behave in a malignant fashion. However, it is
very difficult to predict the behavior of grade 1 and 2
lesions in terms of their local growth potential and ten-
dency for recurrence. For this reason, Jaffe himself, along
with many others, discontinued the numeric grading of
giant cell tumors. The abandoned grading system and the
overall approach to giant cell tumors have alerted clini-
cians and pathologists to a spectrum of biologic behaviors
in these lesions.
GIANT CELL REPARATIVE GRANULOMA
A group of lesions microscopically designated as giant
cell reparative granuloma is pathogenetically heteroge-
neous and represents a range of conditions with overlap-
ping microscopic presentations. These can be separated
into several distinct clinicopathologic entities on the basis
of their unique presentation, associated disorders, and
genetic background. Giant cell reparative granulomas
that are associated with primary or secondary hyperpara-
thyroidism are truly reactive conditions and are referred
to as the brown tumor of hyperparathyroidism. However,
giant cell reparative granulomas of the appendicular skel-
eton, especially those involving the bones of the hands
and feet, are related to a solid aneurysmal bone cyst and
frequently carry the USP6 gene rearrangement.121 Giant
cell reparative granulomas affecting the craniofacial
bones are pathogenetically distinct from those in the
appendicular skeleton and typically do not carry the
USP6 gene rearrangement.121 Most giant cell reparative
granulomas are solitary lesions except those that are asso-
ciated with hyperparathyroidism or Paget’s disease, which
are often multifocal. Multifocal giant cell reparative gran-
ulomas of the jaw bones are associated with a unique
genetic abnormality most often involving the SH3BP2
gene and are clinically referred to as cherubism. Giant
cell–containing lesions resembling giant cell reparative
granulomas involving both bones and soft tissue are an
integral part of Noonan’s syndrome, characterized by
multiple developmental abnormalities in a background of
heterogeneous mutations involving SOS1, RAF1, NRAS,
SHOC2, CBL, and NF1.201 The involvement of the RAS-
MAPK pathway and mutations of PTPN11 appear as a
dominant theme in Noonan’s syndrome.
Definition
Giant cell reparative granulomas are uncommon benign
lesions with a predilection for the craniofacial bones.
Since Jaffe’s original description in 1953,162 multiple
reports of this entity in craniofacial bones and in other
skeletal sites have appeared in the literature. In 1962,
Ackerman and Spjut120 described the first two cases
involving the small tubular bones of the hands and des-
ignated the lesions as giant cell reactions. In 1980 the term
giant cell reparative granuloma was proposed by Lorenzo
and Dorfman176 in reference to reactive lesions with a
ERRNVPHGLFRVRUJ
giant cell–containing fibrous appearance in the short
tubular bones of hands and feet. Subsequently, micro-
scopically similar lesions of vertebrae and ethmoid bones
were described by Sanerkin et al.194 under the name solid
variant of aneurysmal bone cyst. All such lesions are micro-
scopically similar and were perceived as representing a
similar process that merely presents in different skeletal
sites.153,154,158,189,194,207,209-211 Modern data implies that giant
cell reparative granulomas in different anatomic sites
have distinct pathogenesis and unique genetic back-
grounds but are characterized microscopically by over-
lapping features with the presence of multinucleated
giant cells that form unevenly distributed clusters within
fibrous stroma that contains areas of reactive bone
formation.
Initially, giant cell reparative granulomas were per-
ceived as a peculiar reaction linked to intraosseous hem-
orrhage, trauma, or both that may develop in normal
bone or in preexisting lesions, such as fibrous dyspla-
sia, hyperparathyroid bone disease, or rarely Paget’s
disease.126,142,144,198,204 The relationship to aneurysmal
bone cyst was postulated because solid components of
aneurysmal bone cysts carry many microscopic similari-
ties with giant cell reparative granulomas. In fact, giant
cell reparative granulomas were considered as an initial
stage in the spectrum of intraosseous responses that,
in some instances, can culminate as rapidly expanding
destructive multicystic lesions.137,142,150,151,199,202,207,209 Fur-
thermore, in nearly 30% of giant cell reparative granu-
lomas, there are microscopic foci with multiple cavities
filled with blood resembling aneurysmal bone cysts.199
Incidence and Location
The peak age incidence of giant cell reparative granu-
loma is in the second decade of life, and most patients
are between ages 10 and 25 years.124,138 This lesion
usually occurs in the craniofacial bones, such as the
mandible and maxilla.122,124,137,154,162,180 A second common
location is in the small bones of the hands and
feet.128,131,145,148,153,177,181,183,187,189 It is extremely rare in long
tubular bones and vertebrae.142,152,155,200 Single cases have
also been reported in the flat bones such as the pelvis. It
appears that patients with giant cell reparative granuloma
of the long tubular bones and the vertebrae are somewhat
older; the peak age incidence in these anatomic sites is in
the third decade of life. Most giant cell reparative granu-
lomas that are not associated with hyperparathyroidism
or Paget’s disease and are not a part of cherubism or
Noonan’s syndrome are solitary lesions. Only in rare
instances do they involve multiple bones (e.g., of the acral
skeleton).136 The peak age incidence and the most fre-
quent sites of involvement are shown in Figure 10-43.
Radiographic Imaging
In craniofacial bones, giant cell reparative granuloma
produces a round or oval area of lucency with occasional
fine trabeculations (Fig. 10-44). It has distinct borders
with minimal reactive sclerosis. The contour of bone can
be expanded with markedly thinned but usually intact
cortex and no periosteal reaction.132

Peak
incidence
10 25
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 10-43  ■  Giant cell reparative granuloma. Peak incidence and frequent sites of skeletal involvement. Most frequent site is
indicated by solid black arrow.
In the small tubular bones of the hands and feet, the
lesion may be metaphyseal, diaphyseal, or both and does
not cross the unfused growth plate (Fig. 10-45). In skel-
etally mature patients, the lesion can involve the epiphy-
sis or even the entire bone. Epiphyseal involvement is
secondary to progression from the metaphysis, and there
is always a significant metaphyseal and sometimes a
diaphyseal component. In the small tubular bones, the
lesion is centrally located with markedly expanded
contour of the bone and a thinned but intact cortex.
A giant cell reparative granuloma of the long tubular
bones produces an eccentric metaphyseal or diaphyseal
lytic defect (Fig. 10-46). The contour of bone can be
eccentrically expanded with a thinned intact cortex. In
vertebrae, it presents as an expansile lytic lesion of the
body (Fig. 10-47).
Gross Findings
The lesion is composed of friable, gritty tissue that is
tan-gray or brown. There may be evidence of cystic
change and hemorrhage.
Microscopic Findings
Giant cell reparative granuloma is composed of fibrous
stromal tissue with spindle-shaped fibroblasts and varying
ERRNVPHGLFRVRUJ
10  Giant Cell Lesions 743
7 8
amounts of collagen. The cellularity of the stromal tissue
is moderate to high. Normal mitoses are rarely found in
fibroblasts. The key feature is the presence of multinucle-
ated giant cells that are unevenly distributed and form
clearly recognizable clusters separated by bundles of scar-
like stromal tissue (Figs. 10-48 and 10-49). The giant
cells and their clustering are particularly evident in areas
of hemorrhage. Microscopic evidence of fresh and old
hemorrhage is almost always present. Usually, there are
few mononuclear inflammatory cells and trabeculae of
newly formed reactive bone rimmed by osteoblasts. The
reactive bone components sometimes are quite extensive
and obscure other elements of the lesion (Figs. 10-49 and
10-50). Microscopic evidence of hemorrhagic cyst forma-
tion resembling an aneurysmal bone cyst is frequently
present. On the other hand, some giant cell reparative
granulomas may be hypercellular, showing florid prolif-
eration of plump fibrohistiocytic cells. Such lesions
should not be confused with malignancy (Fig. 10-51).
Special Techniques
Ultrastructurally, multinucleated giant cells of giant cell
reparative granuloma are similar to those present in giant
cell tumor and express features of osteoclasts.124,143,161,174,195
On the other hand, the surrounding stromal spindle
cells typically show myofibroblastic differentiation.143 In
744 10  Giant Cell Lesions

C
FIGURE 10-44  ■  Giant cell reparative granuloma of craniofacial bones: radiographic features. A, Lytic lesion in left maxilla (arrows).
B, Lytic focus in right maxilla. C, Axial computed tomogram showing destructive lesion in right mandible.

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 745

A B C

D E F
FIGURE 10-45  ■  Giant cell reparative granuloma of short tubular bones: radiographic features. A, Lytic lesion of fourth metacarpal
bone in a 14-year-old boy. Note that lesion is adjacent to but does not cross physis. B, Typical appearance of giant cell reparative
granuloma of fifth metacarpal bone in a skeletally mature 15-year-old boy with involvement of epiphysis. C, Expansile eccentric
lesion involving distal phalanx of fifth finger. D, Expansile lytic lesion of a 7-year-old boy. Note that lesion is diaphyseal and does
not cross physis. E, A seventeen-year-old boy with pathologic fracture through expanded lytic diaphyseal lesion involving shaft of
first metatarsal bone. F, Extensive lytic lesion involving almost entire first metatarsal bone in a skeletally mature 17-year-old girl.

ERRNVPHGLFRVRUJ
746 10  Giant Cell Lesions

A B

C D
FIGURE 10-46  ■  Giant cell reparative granuloma of long bones: radiographic features. A, Lytic metaphyseal lesion of proximal fibula
in a skeletally immature 15-year-old boy. Note marked expansion of bone contour. B, T1-weighted coronal magnetic resonance
image of lesion in A shows high signal in tumor. Note that tumor does not cross physis. C, Sharply demarcated lytic lesion of distal
fibular shaft in a skeletally mature 16-year-old girl. D, Lytic lesion with marginal sclerosis in distal femoral shaft (metaphysis).

ERRNVPHGLFRVRUJ

A B
FIGURE 10-47  ■  Giant cell reparative granuloma of vertebral column: radiographic features. A, Lateral view of lytic lesion involving
body of C2. B and C, T2-weighted coronal magnetic resonance imageshows high signal in lesion involving body of C2.
contrast with giant cell tumor, mononuclear stromal cells
with a macrophage-like ultrastructure are not present.
Cytogenetic testing performed on a few cases of giant cell
reparative granuloma show some clonal rearrangement
involving different chromosomes, including t(1;17;18)
and t(X;4)(q22; q31.3), suggesting that although tradi-
tionally perceived as reactive proliferations, they may in
fact represent clonally expanding peculiar neoplastic pro-
cesses.178 Some studies have shown upregulation of SRC
and WWOX genes in giant cell reparative granulomas of
the jaw bones.123,165 Genetic profiling of a single case of
giant cell reparative granuloma using microarray tech-
nology has shown an upregulation of cell cycle and sig-
naling transduction genes.133
Differential Diagnosis
Giant cell reparative granuloma should be differenti-
ated from brown tumor of hyperparathyroidism, giant cell
tumor, nonossifying fibroma, and pigmented villonodular
tenosynovitis.
Microscopically, giant cell reparative granuloma is
indistinguishable from a brown tumor of hyperparathy-
roidism. Therefore in every case of giant cell reparative
granuloma, it is important to establish the serum calcium
and phosphorus levels and to evaluate radiographic and
clinical data to rule out underlying hyperparathyroidism.
In fact, the multifocality of giant cell reparative granu-
loma can provide a clue that it may be associated with a
metabolic disorder or is a part of a genetic predisposing
syndrome.163
ERRNVPHGLFRVRUJ
10  Giant Cell Lesions 747
C
Giant cell reparative granuloma can be microscopi-
cally confused with giant cell tumor. The clustering
of giant cells and the absence of typical mononuclear
stromal cells are features of a giant cell reparative gran-
uloma. Conversely, the uniform distribution of multi-
nuclear giant cells in mononuclear stromal cells favors
giant cell tumor. Sometimes a secondary fibrohistio-
cytic reaction in giant cell tumor can be microscopically
indistinguishable from giant cell reparative granuloma.
In such instances, the presence of foci of conventional
giant cell tumor and its typical radiographic features are
helpful in making the diagnosis. The metaphyseal loca-
tion, diaphyseal location, or both of the lesion and the
presence of unfused growth plates are features favor-
ing giant cell reparative granuloma. On the other hand,
the involvement of the epiphyseal end of the bone in
a skeletally mature patient should favor a giant cell
tumor.
Nonossifying fibroma, especially with a prominent
multinucleated giant cell reaction, can occasionally be
confused with a giant cell reparative granuloma. Charac-
teristic microscopic features of nonossifying fibroma
consist of a fibrohistiocytic stroma with a storiform
pattern and a prominent xanthogranulomatous reaction.
Radiographically, nonossifying fibroma produces an
eccentric metaphyseal lytic defect with scalloped and
sclerotic margins and occurs predominantly in the long
tubular bones of the lower extremities in skeletally imma-
ture patients. This anatomic site is very unusual for a
giant cell reparative granuloma.
Text continued on p. 752
748 10  Giant Cell Lesions

A B

C D
FIGURE 10-48  ■  Giant cell reparative granuloma: microscopic features. A, Scattered multinucleated giant cells in a background of
hemorrhagic stroma. B, Low power view showing an area of hemorrhage with multinucleated giant cells juxtaposed with fibrous
areas containing reactive bone formation. C, Higher magnification of B showing multinucleated giant cells in a background of fresh
hemorrhage with adjacent fibrous area containing reactive bone formation. D, Reactive bone formation with prominent osteoblastic
rims. (A, C, and D, ×100; B, ×50) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 10  Giant Cell Lesions 749

A B

C D
FIGURE 10-49  ■  Giant cell reparative granuloma: microscopic features. A, Low power view of giant cell reparative granuloma showing
an even distribution of giant cells, which cluster in the areas of hemorrhage. B, Higher magnification of A showing an area of hem-
orrhage with a cluster of multinucleated giant cells. C, Low power view showing fibrous area with reactive bone formation. D, Higher
magnification of C showing reactive osteoid with prominent osteoblastic rims within loose fibrous stromal tissue. (A and C, ×50;
B and D, ×100) (A-D, hematoxylin-eosin.)

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750 10  Giant Cell Lesions

A B

C D
FIGURE 10-50  ■  Giant cell reparative granuloma: microscopic features. A, Irregular distribution of multinucleated giant cells. Note
that the multinucleated giant cells cluster in the area of hemorrhage. B, Higher power view of A showing multinucleated giant cells
in a background of fresh hemorrhage. C and D, Higher magnification showing multinucleated giant cells with hemosiderin granules
within their cytoplasm (A, ×50; B, ×100; C and D, ×200). (A-D, hematoxylin-eosin.)

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 10  Giant Cell Lesions 751

A B

C D
FIGURE 10-51  ■  Giant cell reparative granuloma: microscopic features. A, Irregular distribution of multinucleated giant cells in spindle-
cell stroma associated with hemorrhage and inflammatory cell infiltrate. B, Higher magnification of A showing an aggregate of
unevenly distributed multinucleated giant cells associated with fresh hemorrhage. C, Irregular distribution of multinucleated giant
cells in fibrous stroma. D, Higher magnification of C showing a cluster of multinucleated giant cells associated with hemorrhage
and inflammatory cell infiltrate. Florid proliferations with nuclear atypia in some giant cell reparative granuloma may raise suspicion
of malignancy. (A and C, ×25; B and D, ×100) (A-D, hematoxylin-eosin.)

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752 10  Giant Cell Lesions
Pigmented villonodular synovitis can be problematic,
particularly if it involves unusual articular sites such as
the temporomandibular and spinal facet joints and teno-
synovial structures of the hands and feet with secondary
involvement of bone. Radiographically, it can produce
eccentric bone erosions that result from the proliferating
juxtaarticular synovial masses. Microscopically, identifi-
cation of synovial membrane containing the characteris-
tic histiocytic and giant cell infiltrates serves to distinguish
pigmented villonodular synovitis from giant cell repara-
tive granuloma. Radiographic involvement of bone on
both sides of the joint favors the diagnosis of pigmented
villonodular synovitis with secondary bone erosion.
Treatment and Behavior
Giant cell reparative granulomas of the jaws or short tu-
bular bones are generally adequately treated by curettage
with or without bone grafting.130,151,166,176,189,190,192,205,211,212
Giant cell reparative granuloma of the maxilla has been
reported to show good, although transient, response to
steroid, calcitonin, and interferon alfa-2b treatment.129,140
In phalangeal, metacarpal, or metatarsal lesions that
destroy most or all of the bone of origin, digital or ray
amputation may be necessary, particularly in recurrent
cases. Recurrence does occur in a significant proportion
of cases, ranging from 33% to 50% that are treated by
curettage and bone grafting.176,189 No recurrences have
been reported after resection or ray amputation, and
malignant transformation has not been observed. Pulmo-
nary implantation, as seen in conventional giant cell
tumor, does not occur in giant cell reparative granuloma.
Recurrence usually occurs within 15 months of curettage,
with a range of 3 months to 4 years. Most patients are
adequately treated by second curettage and bone graft-
ing.179,189 Some giant cell granulomas show a progressive
locally destructive growth pattern and may have a high
propensity for recurrence.160 No radiologic or histologic
features of giant cell reparative granuloma predict its
local aggressive behavior, response to therapy, or ten-
dency to recur.
Personal Comments
Although originally giant cell reparative granuloma was
considered a reactive condition, current studies indicate
that many of them are associated with unique mutations
that are clonal and may represent driver alterations
playing an important role in the development of some of
these lesions. Giant cell reparative granulomas associated
with hyperparathyroidism are still best understood if
considered as reactive because they regress when the
underlying metabolic disorder is corrected or cured. As
a reactive process the lesion develops in relation to
intraosseous hemorrhage, either in normal bone or within
certain preexisting conditions such as fibrous dysplasia or
hyperparathyroid bone disease. At times and in certain
specific locations, it can be difficult to distinguish such
lesions from true giant cell tumors. It is evident that
giant cell reparative granulomas, especially of the small
bones of the hand and feet, are clearly related to the
so-called solid aneurysmal bone cyst and they carry the
ERRNVPHGLFRVRUJ
rearrangement of the same USP6 gene. This gene is not
involved in lesions developing in the craniofacial bones.
Most examples of this lesion occur in the jaw bones
and nonepiphyseal sites of short tubular bones of the
hands and feet, where the cause of disease is more obscure.
Although these two groups of lesions have overlapping
pathologic features, the current evidence indicates that
they may evolve via distinct pathologic mechanisms. The
most difficult differential diagnosis between giant cell
tumor and giant cell reparative granuloma involves those
lesions that develop in the epiphyseal ends of phalanges,
metacarpals, and metatarsal bones, where the distinction
often cannot be made on histologic grounds. The diffi-
culty is further complicated by the fact that giant cell
reparative granuloma in short tubular bones has a ten-
dency to recur after curettage and bone grafting in a
significant proportion of cases.
CHERUBISM AND
RELATED SYNDROMES
Cherubism is an autosomal dominant inherited syn-
drome characterized by extensive bone remodeling of
the jaw bones followed by the development of giant
cell–containing fibrous lesions microcopically similar to
more common sporadic giant cell reparative granuloma
(Figs. 10-52 and 10-53).146,156,179,184,188,196,197 The onset
of cherubism is early, typical age 2 to 5 years, at
which time patients develop facial swelling and cervi-
cal lymphadenopathy. The facial swelling is due to the
development of bilateral giant cell reparative granulo-
mas of the maxilla and mandible (Fig. 10-52). Radio-
graphically cherubism is characterized by symmetric jaw
involvement that is confined to the maxilla and mandi-
ble. Imaging data typically shows expansile involvement
of the maxillary and mandibular bones, with thinning
of the cortex and multilocular radiolucencies with
coarse trabeculations.125 The lesions and facial swelling
substantially regress after puberty but bone deformi-
ties and osseous defects can be detected in old age.172,206
Some cases may show a persistent destructive growth
pattern after puberty associated with major facial dis-
figurement.208 The mutations encoding c-Abl-binding
protein SH3BP2 mapped to the 4-16.3 region cause
cherubism (Fig. 10-52).134,135,139,141,149,157,159,168,169,175,182,203
The gene is a critical regulator of osteoclast function
and its mutations hyperactivate osteoclastogenesis,
which is responsible for the excessive bone remodeling
in cherubism.171
Multiple giant cell reparative granulomas of the
facial bones can also be associated with Noonan’s syn-
drome, a dysmorphic condition characterized by hyper-
telorism, short stature, congenital heart defects, short
and webbed neck, skeletal anomalies, and bleeding dia-
thesis.132,167,170,173,185 Germline mutations that affect com-
ponents of the RAS-MAPK (mitogen-activated protein
kinase) pathway are implicated in the pathogenesis
of Noonan’s syndrome, with the missense mutations
of PTPN11 (protein tyrosine phosphatase, nonrecep-
tor type 11), a gene mapped to chromosome 12q24.1,
appearing to be most frequent.127,147,164,186,191 Noonan’s
 10  Giant Cell Lesions 753

C
FIGURE 10-52  ■  Cherubism: clinical and radiographic features. A, Individual with cherubism at age 6 years. The facial swelling in this
severe case affects the upper and lower jaws. The right side is somewhat more prominent than the left. B, Computed tomography
(CT) three dimensional reconstruction image shows extensive bone destruction and replacement by soft tissue masses. Insert,
Coronal CT reveals marked expansion of the mandible, which is filled with soft tissue density mass and delineated by thinned,
focally disrupted cortex. C, Panoramic radiograph of the jaw shows multilocular osteolytic lesions, bilaterally in the mandible, with
centrally dislocated teeth.

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754 10  Giant Cell Lesions

16.1 kb

9 10 11 12
1 2 3 45 67 8 13

561 aa
1 25 133 201 210 453 555
PH Domain SH3 Binding SH2 Domain
Domain

415 418 420

H L QR S P P DGQ S F
D
C
FIGURE 10-53  ■  Cherubism: microscopic features and molecular mechanism. A, Microscopic features of giant cell reparative granu-
loma from a patient shown in Figure 10-50. Note irregular distribution of multinucleated giant cells in fibrous stroma. B, Higher
magnification of A showing a cluster of giant cells and mononuclear histiocytic cells. C, Higher magnification of B showing a pro-
liferation of mononuclear histiocytic cells. D, Gene structure and functional domains of SH3BP2. The gene consists of 13 exons
extending over 16.1 kilobases. The 561-amino acid (aa) protein consists of three modular domains (pleckstrin homology [PH] domain,
SH3-binding domain, and SH2 domain). All mutations found are located within a 6-aa sequence 33-38 aa upstream of the SH2
domain. (A, ×25; B, ×50; C, ×100) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

syndrome has a somewhat heterogeneous genetic back-
ground, and multifocal giant cell reparative granulomas
involving both bone and soft tissue have been reported
in association with a wide range of mutations involv-
ing the SOS1, RAF1, NRAS, SHOC2, CBL, and NF1
genes.186,191,193
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 C H A P T E R 1 1 
Ewing’s Sarcoma and
Related Tumors
CHAPTER OUTLINE
CHROMOSOMAL TRANSLOCATIONS
UNIFIED PATHOGENETIC CONCEPT OF EWING’S
SARCOMA AND RELATED TUMORS
EWING’S SARCOMA
PRIMITIVE NEUROECTODERMAL TUMOR
In the early 1920s, James Ewing identified a peculiar
round-cell tumor that he called diffuse endothelioma of bone.1
The tumor predominantly affected the long tubular bones
of young patients. This lesion was distinguished from
the general category of unclassified round-cell sarcomas
and lymphohematopoietic tumors based on its clinico-
pathologic features (i.e., small, round-cell morphology),
a predilection for the long tubular bones of skeletally
immature patients, and the absence of a lymphoma-like
or leukemia-like clinical picture.1,2 Although many of
the original pathogenetic theories proposed by Ewing
and other early investigators have been significantly
modified, Ewing’s sarcoma remains recognized as a dis-
tinct entity and represents a prototype of nonhemato-
logic round-cell malignancy.10 The delineation of this
entity also serves as an example of the brilliant corre-
lations of clinical, radiographic, and microscopic find-
ings that set us on a quest to understand the biology of
this unique tumor, providing the foundation for its
diagnosis and treatment. Several additional lesions with
clinicopathologic features different from classical Ewing’s
sarcoma have subsequently been described in the soft
tissue and specific anatomic regions; these are referred
to as Askin’s tumor and primitive neuroectodermal tumor
(PNET). Tumors with microscopic features similar to
classical Ewing’s sarcoma or PNET have also been
described in parenchymal and reproductive organs. The
consistent presence of a chromosomal abnormality—
the reciprocal translocation of chromosomes 11 and
22, which involves bands q24 and q12 of the chromo-
somes, respectively—is a unique finding in this group of
tumors.6,64,65 This finding is essential in understanding
these malignancies, collectively referred to as the Ewing’s
sarcoma/PNET family of tumors. During the past three
decades, molecular studies have elucidated the structure
of the chromosomal breakpoint and have identified the
fusion partners of the chimeric gene. Subsequent inves-
tigations and recent genome-based sequencing studies
have expanded the list of chromosomal translocations and
760
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ASKIN’S TUMOR
IMMUNOHISTOCHEMICAL FEATURES OF
EWING’S SARCOMA AND PNET
DIFFERENTIAL DIAGNOSIS OF SMALL ROUND-
CELL TUMORS OF BONE
their specific chimeric genes to over 15 distinct transloca-
tions, many of which have multiple variants (Fig. 11-1).
This data has expanded our current understanding of
the complex biology of these tumors and is the basis
of an emerging novel classification of Ewing’s sarcoma
and related tumors. There is also hope that the evolv-
ing molecular data can guide us to more effective tar-
geted therapies for these tumors. From a diagnostic point
of view, Ewing’s sarcoma and related tumors serve as a
prototype for a modern diagnostic approach in which
clinical, radiographic, microscopic, and molecular data
contribute to the diagnosis. The emergence of molecular
techniques as a significant aid in the diagnosis of this
group of malignancies should be particularly emphasized.
In this chapter conventional descriptions of Ewing’s
sarcoma, PNET, and Askin’s tumors are retained, but the
reader should understand that in view of modern molecu-
lar data, these tumors are considered as variants of the
same entity. Moreover, recent genomic data has expanded
this group of tumors exponentially by the inclusion of
tumors deviating somewhat from the classical Ewing’s
sarcoma morphology; these are referred to as Ewing’s
sarcoma-like and are characterized by chromosomal
translocations and gene fusions differing from those orig-
inally identified. The description of molecular features of
this group of tumors is focused on the nature of translo-
cations and their genes as potential biomarkers in clas-
sification and differential diagnosis. The interested reader
is referred to Chapter 3, where the biologic effects of
signature hybrid proteins in this group of tumors are
described.
CHROMOSOMAL TRANSLOCATIONS
Breaks in chromosomes may result in the abnormal
assembly of genetic material, resulting in the transfer of
one fragment of a chromosome to another. These, in
turn, can fuse together the coding sequences of genes
 11  Ewing’s Sarcoma and Related Tumors 761

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 X Y
A

Chr 11 Chr 22 der Chr 11 der Chr 22

15.5 15.4 13 15.5 15.4 13
15.3 15.2 12 15.3 15.2 11.2 12
15.1 11.2 15.1 11.1 11.1
11.1
14 11.1 11.2 14 chimeric 11.2
breakpoint EWSR1 EWSR1
13 13 gene FLI1
12 12.1 12.2 12
11.2 12.3 13.1 11.2 25
11.11 11.12 11.11 11.12
11 13.2 13.3 11
12 13.1 12 13.1
13.2 13.3 13.2 13.3
13.4 13.5 13.4 13.5
14.1 14.2 14.1 14.2
14.3 21 14.3 21
22.1 22.2 22.1 22.2
22.3 23.1 22.3 23.1
23.2 23.2
23.3 23.3
24
breakpoint FLI1
24 silent
25 breakpoint

11 11

22
22

breakpoint breakpoint silent Chimeric

breakpoint EWSR1/FLI1
gene

C
FIGURE 11-1  ■  Representative karyotype and diagram of reciprocal translocation t(11;22)(q24;q12) in Ewing’s sarcoma. A, Female
karyotype showing t(11;22) and t(7;16) translocations. B, Schematic diagram of the t(11;22)(q24;q12) translocation characteristic of
Ewing’s sarcoma. C, Magnified view of the t(11;22) translocation. This genetic abnormality can be detected in nearly 90% of Ewing’s
sarcomas/primitive neuroectodermal tumors. The translocation results in one active chimeric gene and one silent breakpoint where
an active chimeric gene is not formed. (Modified and reprinted with permission from Lazar A, et al: Arch Pathol Lab Med 130:1199-1207,
2006.)

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762 11  Ewing’s Sarcoma and Related Tumors

that, in normal genomes, function as separate indepen-

TABLE 11-1 Translocation Involving EWSR1 in
dent coding units.21 Such fusions create abnormal hybrid
Bone and Soft Tissue Sarcomas
mRNAs that contain coding sequences of both genes and
result in the expression of a new protein, which can have Tumor Type Cytogenetics Genes Involved
profound effects on cell biology, contributing to malig-
Angiomatoid fibrous t(2;22)(q34;q12) EWSR1-CREB1
nant transformation.32 histiocytoma t(12;22)(q13;q12) EWSR1-ATF1
The unifying feature of the group of tumors described Clear cell sarcoma t(12;22)(q13;q12) EWSR1-ATF1
in this chapter is the presence of distinct chromosomal t(2;22)(q34;q12) EWSR1-CREB1
translocations that are clonal and result in the expression Desmoplastic small t(11;22)(p13;q12) EWSR1-WT1
round-cell tumor
of new proteins that do not exist in normal cells. These Extraskeletal myxoid t(9;22)(q22;q12) EWSR1-NR4A3
translocations drive the biology of tumors, are diagnos­ chondrosarcoma
tically specific, and may represent future therapeutic Myoepithelioma, t(6;22)(p21;q12) EWSR1-POU5F1
targets. In fact, the Ewing’s sarcoma/PNET family of soft tissue t(19;22)(q13;q12) EWSR1-ZNF444
tumors carry a unique abnormality, t(11;22)(q24;q12), t(1;22)(q23;q12) EWSR1-PBX1
Myoepithelial tumor t(6;22)(p21;q12) EWSR1-POU5F1
resulting in the expression of a chimeric protein, EWSR1- of bone t(19;22)(q13;q12) EWSR1-ZNF444
FLI1, which represents a prototypic chromosomal abnor- t(1;22)(q23;q12) EWSR1-PBX1
mality in soft tissue and bone tumors. In addition to this Myxoid/round-cell t(12;22)(q13;q12) EWSR1-DDIT3
prototypic translocation found in the majority of Ewing’s liposarcoma
sarcoma family of tumors, over 15 distinct chromosomal
translocations and hybrid genes have been identified in
this group of tumors, providing new unifying concepts
for their diagnosis and treatment.39,52 tions in soft tissue and bone tumors. It is involved in
all the alternative translocations identified in Ewing’s
Prototypic Chromosomal Translocations sarcoma/PNET, as well as in distinct translocations in
desmoplastic small round-cell tumor, clear cell sarcoma
Involving EWSR1 and ETS Partners (melanoma of soft parts), some cases of extraskeletal
Multiple chromosomal translocations resulting in hybrid myxoid chondrosarcoma, angiomatoid fibrous histiocy-
genes identified in the Ewing’s family of tumors can be toma, myxoid liposarcoma, and myoepithelial tumors of
divided into two main groups: those containing hybrid soft tissue and bone (Table 11-1).22,34,41,63,68 The EWSR1
genes with fusion partners that belong to the E-26 trans- gene has 17 exons and spans approximately 40 kb.45 It
formation specific (ETS) transcription factors and those encodes a protein with homology to a putative RNA-
that contain hybrid genes with fusion partners that do binding site of RNA polymerase II. Nearly 80% of the
not belong to this family, referred to as non-ETS part- breakpoints found in Ewing’s sarcoma/PNET are located
ners.12,41 The ETS family represents one of the largest within introns 7 and 8.31 A breakpoint in these introns
groups of transcription factors, which are evolutionary results in a chimeric transcript that includes exons 1
highly conserved and play important roles in cell devel- through 7 of the EWSR1 gene. Regardless of whether the
opment and can have major transforming effects contrib- breakpoint is within intron 7 or 8, the exon 8 sequence
uting to tumor development.26 There are 29 members in is spliced out of the chimeric transcript. The second
this group in humans, with FLI1 and ERG representing component in the most common fusion variant is the
the most frequently involved ETS members in the human homolog of the murine Fli1 gene located on chro-
Ewing’s sarcoma/PNET family of tumors. mosome 11q24.38 The murine Fli1 gene contains a ret-
rovirus integration site for the Friend murine leukemia
Translocation t(11;22)(q24;q12) with virus and is rearranged in erythroleukemias induced by
EWSR1-FLI1 Chimeric Gene this virus.46 Both human and murine variants of the FLI1
gene belong to a family of DNA-binding proteins.8 The
Ewing’s sarcoma and related tumors exhibit a unique human FLI1 protein shares approximately 70% sequence
karyotypic abnormality, t(11;22)(q24;q12), that results in homology with the protein encoded by the ETS1 gene
the expression of the chimeric protein EWSR1-FLI1(Fig. (which is expressed during cranial neural crest migration
11-2).13,14,17,58,64 This genetic abnormality occurs in nearly and possibly during vasculogenesis) and seems to func-
90% of Ewing’s sarcoma family tumors.22,51,65,67 The tion primarily as a transcription factor.7,13,14 In the chime-
reciprocal translocation of portions of chromosomes 11 ric protein, the RNA-binding domain of the protein
and 22, involving bands (q24;q12), in Ewing’s sarcoma/ encoded by the EWSR1 gene is substituted for the DNA-
PNET represents a prototypic chromosomal abnormal- binding domain of the FLI1 gene product. The chimeric
ity in soft tissue and bone tumors. EWSR1-FLI1 gene is transcribed under control of the
An initial molecular analysis showed that the chromo- EWSR1 promoter.9 Expression of both of these individual
some 22 breakpoint is located within the EWSR1 gene, genes is virtually ubiquitous in normal human tissues.
whereas the chromosome 11 breakpoint is located The molecular downstream targets for chimeric proteins
within the FLI1 gene.9,38,69,70 The reciprocal translocation are still poorly understood.4 It has been reported that the
between these two chromosomes creates a new chimeric cyclin E, protein tyrosine phosphatase (PTLP1), cyclin-
protein, consisting of portions of the EWSR1 and FLI1 dependent kinase inhibitor 1A (p21/WAF1/CIP1), and
proteins.70 The EWSR1 gene located within 22q12 plays the LAMB3 gene encoding the β3 chain basement mem-
a recurrent major role in several chromosomal transloca- brane laminin 5 are molecular targets for EWSR1-ETS

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 11  Ewing’s Sarcoma and Related Tumors 763

EWSR1 22q12

Exon 10
Exon 11
Exon 12

Exon 13

Exon 14
Exon 15
Exon 16
Exon 17
Exon 18
Exon 1

Exon 2
Exon 3

Exon 4
Exon 5

Exon 6

Exon 7

Exon 8

Exon 9
cds
cen tel

FLI1 11q24 22q12

Exon 1

Exon 2

Exon 3

Exon 4

Exon 5

Exon 6
Exon 7
Exon 8
Exon 9
cds
cen tel

EWSR1-FLI1 fusion gene

Exon 1

Exon 2
Exon 3

Exon 4
Exon 5

Exon 6

Exon 7
Exon 6

Exon 7

Exon 8

Exon 9
cen tel

breakpoint
EWSR1 portion FLI1 portion
A

EWSR1 protein
1 656 aa

TAD - transactivation domain, 1-285 aa RNA recognition motif, 361-447 aa

Interaction with SF1 domain, 228-264 aa Arginine/glycine/proline rich domain, 454-513 aa
IQ domain, binds calmodulin, 256-285 aa Zinc finger (RanBP2 type) domain, 518-549 aa
Arginine/glycine rich domain, 300-340 aa Arginine/glycine rich domain, 559-640 aa
FLI1 protein
1 452 aa

Sterile alpha motif -pointed domain, 99-105 aa

Winged helix-turn-helix DNA binding, Ets domain, 251-383 aa

EWSR1-FLI fusion protein

1 497 aa

breakpoint
EWSR1 portion FLI portion

C
FIGURE 11-2  ■  Molecular structure associated with translocation t(11;22)(q24;q12) resulting in the EWSR1-FLI1 fusion gene. A, Exon-
intron structures of the EWSR1 and FLI1 genes. Large solid arrows indicate the most frequent locations of the breakpoints within
introns, and the open arrows indicate less frequent variants. The molecular structure of one of the most frequent (type 1) chimeric
genes, which includes coding sequences for the N-terminal domain of the EWSR1 gene and the DNA-binding domain of the FLI1
gene, is illustrated. B, Functional domains of the two proteins involved in the translocation are depicted. The C-terminus end of the
EWSR1 protein contains an RNA-binding domain; the FLI1 protein’s C-terminus contains a DNA-binding domain. The ETS domain
defines a broad family of transcription factors; half of all EWSR1 chimeric partners in the Ewing’s sarcoma/PNET family of tumors
are members of this group. C, The structure of the chimeric protein encoded by the two genes is shown. In the chimeric protein,
the amino terminus of the EWSR1-encoded protein is combined with the DNA-binding domain of the FLI1-encoded protein; the
expression of the chimeric fusion gene is driven by the EWSR1 promoter. In concert with additional cofactors, it acts as a transcrip-
tion factor, resulting in aberrant activation of genetic targets that drive the pathogenesis of this tumor.

ERRNVPHGLFRVRUJ
764 11  Ewing’s Sarcoma and Related Tumors

A B C

D
FIGURE 11-3  ■  Complex karyotype of Ewing’s sarcoma using spectral karyotyping (SKY) to demonstrate the t(11;22) (q24;q12).
A, Chromosomal complement of a cultured Ewing’s sarcoma metaphase cell. B, The same chromosomes hybridized with the SKY
probes. C, Computer processed pseudocolored image of the karyogram of the case shown in A and B. D, The analysis of SKY clearly
demonstrates a translocation involving the long arms of chromosomes 11 and 22 as well as polyploidization of chromosomes 4, 5,
and 8. (Courtesy of Dr. L. Abruzzo, Cytogenetics Laboratory, The University of Texas M. D. Anderson Cancer Center, Houston, TX.)

fusion proteins.3,24,33,40 The expression of the EWSR1-
FLI1 fusion protein upregulates genes associated
with neural crest development and is responsible for
the phenotype of Ewing’s sarcoma/PNET family of
tumors.23,56 In general, the expression signature of these
tumors is characterized by upregulation of the genes
that are the targets of the ETS family of transcription
factors.
This and other translocations in Ewing’s sarcoma
and related tumors can be detected by a variety of cyto-
genetic and molecular techniques.5,18,37,51,55 In typical
cases, conventional cytogenetics identifies the recipro-
cal rearrangements between chromosomes 11 and 22
characteristic of Ewing’s sarcoma. However, when such
a rearrangement occurs in the background of complex
chromosomal abnormalities, its conventional cytogenetic
identification may be problematic. In such instances,
spectral karyotyping (SKY) is useful to demonstrate the
specific genetic abnormality (Fig. 11-3). Other tech-
niques that are commonly used to identify the transloca-
tions identify the presence of breakpoints within the gene
using fluorescence in situ hybridization (FISH) with the
so-called break-apart or fusion probes. Both cytogenetic
and FISH techniques can be complemented by reverse
transcription polymerase chain reaction (RT-PCR) and
DNA sequencing, which identify the specific fusion tran-
scripts.11,43 More detailed description of these techniques
is provided in Chapter 3.
Translocation t(21;22)(q22;q12) with
EWSR1-ERG Chimeric Gene
It has been shown that EWSR1 may be translocated to
other locations and can form chimeric genes with alterna-
tive partners (Table 11-2). A second alternative cytoge-
netic abnormality, t(21;22)(q22;q12), is present in
approximately 10% of Ewing’s sarcomas and PNETs
(Fig. 11-4). This translocation fuses the portion of the
EWSR1 gene from 22q12 to the ERG gene located on
21q22.19,54 In some instances, complex multistep rear-
rangements of chromosomes 19, 21, and 22 are involved
in a reciprocal inversion-insertion mechanism that
results in the EWS1-ERG fusion.19,36 The ERG gene
encodes a protein that belongs to the ETS family of
transcription factors, which, in cell physiology, regulates
embryonic development, cell proliferation, differentia-
tion, angiogenesis, inflammation, and apoptosis. The
major source of lethal effects of loss of function of

ERRNVPHGLFRVRUJ
 11  Ewing’s Sarcoma and Related Tumors 765

Biologically, they represent functional substitutes for the

TABLE 11-2 Genetic Aberrations in Ewing’s
two main EWSR1 fusion partners, FLI1 and ERG,
Sarcoma/PNET Tumors
described previously in this chapter.29 These fusions
Neoplasm Translocation Involved gene(s) develop in the absence of the common translocations
such as EWSR1-FLI1 and EWSR1-ERG. They appear to
Ewing’s sarcoma/ t(11;22)(q24;q12) EWSR1-FLI1
PNET with t(21;22)(q22;q12) EWSR1-ERG functionally replace these more common translocations
involvement of t(7;22)(p22;q12) EWSR1-ETV1 in oncogenic transformation.
ETS t(17;22)(q12;q12) EWSR1ETV4
t(2;22)(q33;q12) EWSR1-FEV
t(16;21)(p11;q22) FUS-ERG Translocations with Non-ETS
t(2;16)(q35;p11) FUS-FEV Fusion Partners
Ewing’s sarcoma- t(6;22)(p21;q12) EWSR1-POU5F1
like tumors Inv(22)(q12) EWSR1-ZSG Multiple translocations with fusion partners that do
without ETS (ZNF278) not belong to the ETS family of transcriptional factors
involvement t(4;22)(q31;q12) EWSR1-SMARCA have been identified in Ewing’s sarcoma/PNET family
t(2;22)(q31;q12) EWSR1-SP3
t(1;22)(p36.1;q12) EWSR1-ZNF278
of tumors (Fig. 11-7). They can be divided into two
Complex ring EWSR1-NFATC2 main groups: those that involve EWSR1 as the 5′ partner
chromosome fused to a non-ETS 3′ partner and those that involve
t(4;19)(q35;q13) CIC-DUX4 a completely new 5′ partner such as CIC or BCOR
Inversion involving BCOR-CCNB3 combined with a non-ETS 3′ partner. The first group
Xp114; Xp11.22 CIC-FOXO4
t(X;19) (q13;q13.3) comprises the following translocations: t(6;22)(p21;q12)
EWRS1-POU5F1, Inv(22)(q12) EWSR1-ZSG(ZNF278),
t(4;22)(q31;q12) EWSR1-SMARCA, t(2,22)(q31;q12)
EWSR1-SP3, t(1;22)(p36.1;q12) EWSR1-ZNF278, ring
chromosome with amplification and translocations result-
ing in EWSR1-NFATC2.15,50,60,61,66 The second group of
ERG in mutagenesis animal experiments is related to tumors characterized by involvement of non-ETS genes
hematopoietic stem cell defects. In addition to Ewing’s fused to non-EWSR1 5′ partners include: t(4;19)(q35;q13)
sarcoma, this gene is a common fusion partner of hybrid CIC-DUX4 and an inversion involving Xp11.4; Xp11.22
genes in prostate cancer such as TMPRSS2-ERG and resulting in BCOR-CCNB3.25,30,44,47,53,57 Preliminary data
NDRG1-ERG. Its biologic effects and potential contribu- implicates small cell sarcomas of bone and soft tissue
tion to Ewing’s sarcoma depends on its similarity to FLI1. characterized by these abnormalities that have a differ-
ERG and FLI1 have similar structures and are likely to ent gene expression profile from the group of Ewing’s
have similar biologic effects in chimeric fusions with sarcomas containing fusions with ETS partners.57
EWSR1. ERG shares 68% of the amino acid sequence The 3′ fusion partners in this group of Ewing’s/PNET
identity with FLI1. Moreover, the ETS common domain sarcomas represent a diverse group of transcription
required for sequence specific binding to DNA shows factors with distinct DNA sequence binding domains.
98% identity with FLI1. The formation of the EWSR1- The POU5F1 gene contains a POU homeodomain that
ERG chimeric gene develops in the absence of the most plays a key role in embryonic development and stem
frequent EWSR1-FLI1 fusion and is likely to be able to cell pluripotency. The ZSG gene encodes an A-T hook
replace EWSR1-FLI1 in the oncogenic pathway contrib- DNA binding motif, which plays an important role in
uting to the development of Ewing’s sarcoma. Consider- chromatin remodeling and transcriptional regulation.
ing the similarities between these two fusion partners, it It also contains the Poz domain, which functions as a
is very likely that both chimeras use similar mechanisms site of protein-to-protein interactions and transcriptional
to orchestrate an overlapping repertoire of target genes. repression, as well as the zinc-fingers DNA binding
domain. The SMARCA1 gene encodes a member of the
SWI/SNF family of proteins with helicase and ATPase
Translocations with Alternative
activities that regulate chromatin structure around the
ETS Fusion Partners
target genes. The SP3 gene encodes a protein that regu-
Several additional translocations with alternative ETS lates transcription by binding to a consensus GC- and
fusion partners have been identified in the Ewing’s GT-box regulatory element in target genes. It contains
sarcoma/PNET family of tumors. Three of them involve several other DNA binding domains, including a zinc
EWSR1 combined with ETV1, ETV4, or FEV: t(7;22) finger. The ZNF278 gene encodes a protein that contains
(p22;q12) EWRS1-ETV1, t(17:22)(q12;q12) EWRS1- several transcriptional factor domains, including an A-T
ETV4, and t(2;22)(q33;q12) EWSR1-FEV.16,27,49,66 In hook DNA binding motif that plays an important role in
addition, two translocations of ERG or FEV with FUS chromatin remodeling and transcription regulation. The
were identified: t(16;21)(p11;q22) FUS-ERG and t(2;16) NFATC2 gene is a major transcription factor of activated
(q35;p11) FUS-FEV.16,194 All of these genes belong to the T cells and has several DNA binding domains with REL-
ETS family of transcription factors and contain the ETS and NFAT-homology regions.
domain required for sequence specific binding to DNA The two recently identified fusion genes, CIC-DUX4
in the regulatory elements of the target genes. Overall, and BCOR-CCNB3, are unique because each represents
they have high sequence homology and are nearly identi- a fusion of two genes with distinct transcription factor
cal in terms of the ETS sequence domain (Fig. 11-7). activities (Figs 11-5 and 11-6).25,30,44,47,53,57 The 5′ partner

ERRNVPHGLFRVRUJ
766 11  Ewing’s Sarcoma and Related Tumors

EWSR1
EWSR1 - ERG Translocation t(21;22)(q24;q12)

Exon 10
Exon 11
Exon 12

Exon 13

Exon 14
Exon 15
Exon 16
Exon 17
Exon 18
Exon 1

Exon 2
Exon 3
Exon 4
Exon 5

Exon 6

Exon 7

Exon 8

Exon 9
cds
Chr 21 der(21) der(19)
13 13.3 cen tel
12
11.2 13.2
11.1 11.1 13.1
11.2 12 breakpoint
21 11 11
12
22.1
13.2 der(22) ERG
22.2 ERG 13.3
22.3

Exon 12

Exon 11
Exon 10
13.4

Exon 9
Exon 8
Exon 7
Exon 6

Exon 5

Exon 4
Exon 3

Exon 2

Exon 1
Chr 22

cds
Chr 19 EWSR1
Chr 21
ERG
Chr 22 der(22) 13.3 cen tel
13 13.2 Chr 19
12 13.1
12 breakpoint
11.2 11.1 11 11
11.1 11.2 12
EWSR1
12.1 EWSR1 13.1
12.3 12.2 ERG 13.2
inversion
13.1
13.2
13.4
13.3 EWSR1-ERG fusion gene
13.3

Exon 10
Exon 11

Exon 12
A
Exon 1

Exon 2
Exon 3
Exon 4
Exon 5

Exon 6

Exon 2

Exon 3
Exon 4

Exon 5

Exon 6
Exon 7
Exon 8
Exon 9
cen tel

breakpoint
B EWSR1 portion ERG portion

EWSR1 protein
1 656 aa

TAD - transactivation domain, 1-285 aa RNA recognition motif, 361-447 aa

Interaction with SF1 domain, 228-264 aa Arginine/glycine/proline rich domain, 454-513 aa
IQ domain, binds calmodulin, 256-285 aa Zinc finger (RanBP2 type) domain, 518-549 aa
Arginine/glycine rich domain, 300-340 aa Arginine/glycine rich domain, 559-640 aa

ERG protein
1 486 aa

Sterile alpha motif -pointed domain, 117-216 aa

Winged helix-turn-helix DNA binding, Ets domain, 287-418 aa
C

EWSR1-ERG fusion protein

1 518 aa

breakpoint
D EWSR1 portion ERG portion

FIGURE 11-4  ■  Complex rearrangement of chromosomes 19, 21, and 22 with reciprocal inversion-insertion with the EWS-ERG fusion
gene. A, Schematic diagram of the complex translocation of t(21;22)(q13;q12) resulting from a two-step insertion-inversion also
involving chromosome 19 and resulting in EWSR1-ERG fusion on the der(22). B, Exon-intron structures of the EWSR1 and ERG
genes are shown. Arrows indicate the frequent locations of the breakpoints within the introns. The molecular structure of the result-
ing chimeric gene, which contains the coding sequences of EWSR1 at the 5′ end and the ERG coding sequences at the 3′ end of the
chimeric gene, is shown. C, Functional domains of the two proteins involved in the translocations are depicted. Note that the ERG
protein contains the ETS domain similar to that present in the FLI1 protein. D, The structure of the chimeric protein encoded by the
two genes. In the chimeric EWSR1-ERG protein, the N-terminus portion contains sequences encoded by EWSR1 and the C-terminus
contains the ETS DNA binding domain encoded by ERG.

ERRNVPHGLFRVRUJ
 11  Ewing’s Sarcoma and Related Tumors 767

der(4)
16
15.3 CIC
Chr 4 15.2

Exon 10

Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
Exon 17
Exon 18
Exon 19
Exon 20
15.1

Exon 1

Exon 2
Exon 3
Exon 4
Exon 5
Exon 6

Exon 7
Exon 8
Exon 9
16 14

cds
13
15.3 12
15.2 Chr 19 11
11 der(19)
15.1 12
14 13.3 13.1 13.3 cen tel
13 13.3 13.2 13.2
12 13.2 21.1
11 13.1 21.2 13.1
11 12 21.3 12 breakpoint
12 11 11 11
13.1 11 22 12
13.2 12 23 13.1

Exon 1
13.3 24
21.1 13.1 CIC-DUX4
21.2 25
DUX4

cds
21.3 13.2 CIC chimera
26
22 13.3
23 13.4 27
24 cen tel
25 28
26 31.1
27 31.2 breakpoint
31.3
28 32
31.1 33 CIC-DUX4 fusion gene
31.2 34
31.3 35

Exon 10

Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
Exon 17
Exon 18
Exon 19
Exon 20
32

Exon 1

Exon 2
Exon 3
Exon 4
Exon 5
Exon 6

Exon 7
Exon 8
Exon 9

Exon 1
33
34
35
DUX4
cen tel
A
B breakpoint
CIC portion DUX4 portion

CIC protein DUX4 protein

1 1608 aa 1 424 aa

HMG - High-mobility group domain HD1, HD2 - Homeodomain

CHD2, CHD1 - Capicua homology domains
NLS - Nuclear localization sequence domain
C
CIC-DUX4 fusion protein
1 1644 aa

breakpoint
D CIC portion DUX4 portion

FIGURE 11-5  ■  Molecular structure associated with translocation t(4:19)(q35;q13) resulting in the CIC-DUX4 fusion gene. A, Sche-
matic diagram of the reciprocal translocation between the long arms of chromosomes 4 and 19 resulting in CIC-DUX4 fusion on
the der(19). B, Exon-intron structures of the CIC and DUX4 genes. Arrows indicate the frequent locations of the breakpoints. The
molecular structure of the resulting chimeric gene, which contains almost the entire coding sequence of the CIC at the 5′ end and
a portion of the encoding exon of DUX4 at the 3′ end. C, Functional domains of the two proteins involved in the translocation.
D, The structure of the chimeric protein encoded by the two fused genes. It contains almost the entire amino acid sequence of CIC
with its three functional domains at the 5′ end and a portion of exon 1 encoding sequence of DUX4 at the 3′ end.

of the first fusion, the CIC gene, is a human homolog
of a high mobility group (HMG) box transcription
factor that has been shown to mediate c-ErbB signaling.
The 3′ partner in this fusion is the DUX4 gene,
which encodes to two homeoboxes, the repeat-array
and ORF. The protein functions as a transcriptional acti-
vator. In the second fusion, the 5′ partner is BCOR,
encoding the BCL6 corepressor and the 3′ partner,
CCNB3, is encoding the testis-specific cyclin B3 and
plays an essential role in the control of cell cycle. The
group of Ewing’s sarcoma-like tumors is consistently
expanding; a new CIC-FOXO4 gene fusion has been
recently identified.59 Moreover, new cytogenetic abnor-
malities continue to be identified, as well as complex
chromosomal abnormalities with still uncertain clinical
significance.28,42,48
Preliminary data indicate that the diversity of molecu-
lar abnormalities in Ewing’s sarcoma and related lesions
has an impact on their biologic behavior and may repre-
sent clinically useful prognostic factors.4,11,20,42,68,70
UNIFIED PATHOGENETIC CONCEPT
OF EWING’S SARCOMA AND
RELATED TUMORS
When t(11;22)(q24;q12) was cytogenetically identified, it
represented, until the elucidation of the molecular struc-
ture of the breakpoint, the only specific finding in Ewing’s
sarcoma. However, the tumors were still mostly classified
as Ewing’s sarcoma on the basis of their small cell mor-
phology and clinicoradiologic features (i.e., a predilection
for long tubular bones of young individuals and the
absence of a lymphoma-like or leukemia-like picture
clinically). Therefore several lesions with clinicopatho-
logic features distinct from those of classic Ewing’s
sarcoma, such as the presence of neural differentiation
microscopically or a predilection for the thoracopulmo-
nary region as in Askin’s tumor, were not originally linked
to the Ewing’s sarcoma family of tumors.71,85,89,96-98 Sub-
sequent investigations showed that t(11;12)(q24;q12) was

ERRNVPHGLFRVRUJ
768 11  Ewing’s Sarcoma and Related Tumors

BCOR

Exon 10

Exon 11

Exon 12
Exon 13
Exon 14

Exon 15
Exon 1

Exon 2
Exon 3

Exon 4

Exon 5
Exon 6

Exon 7
Exon 8
Exon 9
cds
Chr X Chr X
22.3 22.3 tel cen
22.2 22.2
22.1 22.1
21.3 21.3
21.2 21.1 21.2 21.1
11.4 BCOR 11.4 CCNB3
11.23 11.3 CCNB3-CCNB3

Exon 10
Exon 11
Exon 12
CCNB3

Exon 1
Exon 2
Exon 3

Exon 4

Exon 5
Exon 6
Exon 7

Exon 8

Exon 9
11.21 11.22 11.21 11.22
11.1 11.1 11.1 11.1

cds
12 11.2 12 11.2
21.1 13 21.1 13
21.2 21.2 cen tel
21.3 21.3
22.1 22.1
22.2 22.3 22.2 22.3
23 23 breakpoint
24 24
25 25
26 26 BCOR-CCNB3 fusion gene
27 27
28 28

Exon 10

Exon 11

Exon 12
Exon 13
Exon 14

Exon 15

Exon 10
Exon 11
Exon 12
A
Exon 1

Exon 2
Exon 3

Exon 4

Exon 5
Exon 6

Exon 7
Exon 8
Exon 9

Exon 5
Exon 6
Exon 7

Exon 8

Exon 9
cen tel

breakpoint
B BCOR portion CCNB3 portion

BCOR protein
1 1755 aa
Ankyrin domains
CCNB3 protein
1 1395 aa

Cyclin-like domains
C

BCOR-CCNB3 fusion protein

1 3001 aa

breakpoint
BCOR portion CCNB3 portion
D
FIGURE 11-6  ■  Molecular structure of the inversion involving Xp11.4;Xp11.22 with the BCOR-CCNB3 fusion gene. A, Schematic
diagram showing the cryptic inversion within the short arm of chromosome X, which results in BCOR-CCNB3 fusion. B, Exon-intron
structures of the BCOR and CCNB3 genes. Arrow shows an example of a breakpoint within CCNB3. The molecular structure of the
resulting chimeric gene, which contains the entire coding sequence of BCOR at the 5′ end and exons 5-12 of CCNB3 at the 3′ end.
C, Functional domains of the two proteins involved. D, The structure of the chimeric protein encoded by the two fused genes. It
contains the entire sequence of amino acid encoded by BCOR at N-terminus and a portion of the amino acid sequence of CCNB3,
including its cyclinlike domain at the C-terminus.

a consistent cytogenetic abnormality in these lesions; this neural crest lineage differentiation opens the possibility
contributed to the current understanding of these condi- that, occasionally, pathways other than neural differentia-
tions as variants of Ewing’s sarcoma62,77,85,87,92,93 (Fig. tion can occur in a tumor with basic small round-cell
11-8). Although our current understanding is that these morphologic features.
tumors are related pathogenetic entities, there is still a Finally, the concept of pluripotential differentiation
clinical tendency to analyze them separately.72,94 Further in tumors with small round-cell components similar to
investigations revealed that the same cytogenetic abnor- those of Ewing’s sarcoma, such as seen in extremely rare
mality can be identified in at least some of the tumors examples of lesions designated as primitive pluripotential
classified as small cell osteosarcomas.76,78,90 Most likely sarcoma, polyhistioma, or ectomesenchymoma, has been
some of the tumors diagnosed in the past as small cell postulated.80,82,83,91,99 Review of a large series of small cell
osteosarcomas would be classified today as variants of tumors disclosed the presence of rare cases of ill-defined
Ewing’s sarcoma.73,79,88 The production of tumor bone in primitive sarcomas.127 Neural, muscular, and epithelial
a lesion with microscopic, immunohistochemical, and differentiation was documented immunohistochemically
molecular features of Ewing’s sarcoma should be consid- in some of these lesions and was confirmed by ultrastruc-
ered as divergent differentiation rather than a feature of tural studies. It seems that the tendency for pluripotential
a distinct pathologic entity. This is not, however, to deny differentiation is more often seen in lesions involving
the existence of small cell osteosarcoma distinct from the thoracopulmonary region. Moreover, the presence of
Ewing’s sarcoma. MIC2 gene expression confined to primitive round-cell
The concept that Ewing’s sarcoma originates from areas has been shown in some of these lesions.99 The pres-
undifferentiated mesenchymal cells with a propensity for ence of an EWSR1-FLI1 fusion gene has been identified

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 11  Ewing’s Sarcoma and Related Tumors 769

FLI1

ERG

FEV

ETV4

ETV1

Same amino acid

A Similar amino acids (K and Q, N and S, A and S, and Q and R)
B

POU5F1 1 360 aa 100

ETS region
Lambda repressor-like, DNA-binding domain Whole protein

Sequence homology (%)

POU-specific domain 80
Homeodomain-like

ZGS 1 687 aa 60
BTB/POZ fold
Zinc finger, C2H2-like domain
40
SMARCA 1 954 aa
HARP domain 20
P-loop containing nucleoside triphosphate hydrolase domain
Helicase superfamily 1/2, ATP-binding domain
SNF2-related domain
P-loop containing nucleoside triphosphate hydrolase domain 0
Helicase, C-terminal domain
ERG FEV ETV4 ETV1
C
SP3 1 781aa
Zinc finger C2H2-type/integrase DNA-binding domain
Zinc finger, C2H2-like domain

NFATC2 1 925 aa
p53-like transcription factor, DNA-binding domain
Immunoglobulin E-set domain
Immunoglobulin-like fold domain

DUX4 1 424 aa
HD1, HD2 - Homeodomain

CCNB3 1 1395 aa
Cyclin-like domains

D
FIGURE 11-7  ■  Structure and functional domains of ETS and non-ETS fusion partners involved in chromosomal translocations of
Ewing’s sarcoma/PNET tumors. A, Molecular structure and the complementary DNA binding sequence of the FLI1 gene and its ETS
domain. It binds to a central GGA(A/T) DNA sequence in regulatory elements of the target genes. B, Sequence homology of the ETS
domains within the genes involved in translocations of Ewing’s sarcoma/primitive neuroectodermal tumors (PNETs), which belong
to the ETS transcription factor family. Note the high degree of similarity of the ETS amino acid sequence of ERG, FEV, ETV4, and
ETV1 as compared to FLI1. C, The analysis of sequence homology of the ETS domains for genes involved in Ewing’s sarcoma/PNET
translocations. D, Protein structures and their functional domains encoded by the genes involved in translocations of Ewing’s
sarcoma/PNET tumors, which form a heterogeneous group defined as non-ETS members. Note that each of these genes has com-
pletely distinct amino acid composition as well as functional domains. (A, Reprinted with permission from Liang H, et al: Nature Struc-
tural Biology 1:871–876, 1994.)

in biphenotypic sarcoma with divergent myogenic/neural
differentiation and in tumors exhibiting adamantinoma-
like cytoarchitecture, providing objective evidence that at
least some of these lesions may have a common patho-
genesis with the Ewing’s sarcoma group.74,75,81,84,86,95,100
The identification of multiple variants of reciprocal
translocations with the EWSR1 gene and other fusion
partners belonging to the ETS and non-ETS tran-
scriptional factor families as well as translocations with
gene fusions in which the 5′ partners are different than
ESWR1, such as FUS, CIC, and BCOR, is the foundation
of novel emerging molecular classifications of this family
of tumors (Fig. 11-8). It appears that using this infor-
mation, the Ewing’s sarcoma/PNET family and related
tumors can be divided into the following groups: (1)
classical Ewing’s sarcoma/PNET group with most fre-
quent fusion genes (EWSR1-FLI1 and EWSR1-ERG), (2)
classical Ewing’s sarcoma/PNET group with alternative
3′ ETS fusion partners (EWSR1-EVT1, EWSR1-EVT4,
EWSR1-FEV, FUS-ERG, and FUS-FEV), and (3) Ewing’s
sarcoma-like tumors with non-ETS 3′ fusion partners
(EWSR1-POU5F1, EWSR1-ZNF287, EWSR1-SMARCA,

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770 11  Ewing’s Sarcoma and Related Tumors

Relative frequency (%-log)

1 10 100

PNET 1

containing fusions with ETS

Ewing’s sarcoma/PNET
Neural 2
differentiation 3

6
Ewing’s sarcoma 7

containing fusions with non-ETS

Ewing’s sarcoma/PNET
9
? 10
Askin’s tumor Small cell
osteosarcoma 11
(ES/PNET of
thoracopulmonary 12
region) Primitive 13
pluripotential
sarcoma 14
Adamantinoma-like ES
A B
FIGURE 11-8  ■  Unified concept of Ewing’s sarcoma/PNET tumors and related entities. A, Ewing’s sarcoma is considered the prototype
tumor of group. Primitive neuroectodermal tumors (PNETs) represent a variety of closely related lesions distinguished on the basis
of an arbitrarily defined degree of neural differentiation. Askin’s tumor represents either classic Ewing’s sarcoma or PNET involving
thoracopulmonary region. t(11;22)(q24;q12) has been also identified in some small cell osteosarcomas. Link between Ewing’s
sarcoma and primitive sarcoma with pluripotential differentiation has been postulated but is not well established. B, Tentative
molecular classifications of Ewing’s sarcoma/PNETs based on the type of fusion genes. The tumors can be classified in two major
groups containing fusion genes with ETS and non-ETS partners.

EWSR1-SP3, EWSR1-NFATC2 , CIC-DUX4, and BCOR-
CCNB3). The emerging data suggests that all fusions
with the ETS members are functionally similar and that
tumors with such characteristics form a uniform group
with similar gene expression profiles. On the other hand,
the group containing fusions with non-ETS partners is
heterogeneous due to the involvement of transcriptional
factors belonging to different families and to targeting
different sets of genes. Such evidence is available for
at least some of the distinct fusion genes, such as CIC-
DUX4 and BCOR-CCNB3.47,57 Most interestingly, these
tumors appear to have microscopic features somewhat
different from those of classical Ewing’s sarcoma/PNET,
with a tendency to fall into the atypical category, and may
be clinically distinct, exhibiting a propensity for lymph
node metastasis rather than the lung metastasis charac-
teristic of classical Ewing’s sarcoma/PNET.47,57
EWING’S SARCOMA
Definition
Ewing’s sarcoma is a distinct, round-cell sarcoma of
bone that occurs predominantly in the long bones of
skeletally immature patients. The tumor is composed
of undifferentiated, round, mesenchymal cells that are
rich in glycogen and exhibit a karyotypic abnormality
representing reciprocal t(11;22)(q24;q12) and resulting in
the expression of a chimeric EWSR1-FLI1 protein. This
genetic abnormality can be documented in approximately
90% of tumors morphologically classified as Ewing’s sar-
comas. In a small proportion of Ewing’s sarcomas, alter-
native chromosomal translocations involving EWSR1 and
other genes can occur. In general, the expanded family of
Ewing’s sarcoma tumors can be separated into two major
groups containing chimeric genes with ETS and non-ETS
fusion partners.
Incidence and Location
The peak age incidence and frequent skeletal sites of
involvement are shown in Figure 11-9. Ewing’s sarcoma
accounts for 6% to 8% of all primary malignant tumors
of bone. It is the most frequently occurring primary
sarcoma of bone after osteosarcoma and chondrosar-
coma. It has a peculiar predilection for whites and practi-
cally never occurs in blacks. In the 1973 to 2010
Surveillance, Epidemiology, and End Results (SEER)
program series, only approximately 3.5% of Ewing’s
sarcoma cases occurred in black patients. This striking
difference in the incidence of Ewing’s sarcoma, which
shows a tenfold higher incidence in the white population
compared to the black population, is potentially of major
pathogenetic significance and may provide important
clues to the genetic predisposition for this unusual malig-
nancy.114 The peak incidence is during the second decade
of life, and there is a male predilection (male-to-female
ratio, 1.3 : 1 to 1.4 : 1) (Figs. 11-10 and 11-11). Approxi-
mately 80% of all patients are younger than age 20 years,

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 11  Ewing’s Sarcoma and Related Tumors 771

Askin’s
tumor
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 11-9  ■  Ewing’s sarcoma: peak age incidence and frequent sites of skeletal involvement. Most frequent sites are indicated
by solid black arrows.

1 30

0.9
25
0.8
(cases/100,000 persons)

0.7
20
Incidence Rate

0.6
Frequency (%)
0.5 15

0.4
10
0.3

0.2
5
0.1

0 0
0

+
1-

5-

-1

-1

-2

-2

-3

-3

-4

-4

-5

-5

-6

-6

-7

-7

-8

85
10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

Age Group
FIGURE 11-10  ■  Epidemiology of Ewing’s srcoma. Age-specific incidence rates and frequency distribution pattern of 1142 cases. All
races, both sexes, SEER data for 1973 to 2010.

ERRNVPHGLFRVRUJ
 772 11  Ewing’s Sarcoma and Related Tumors

0.7

0.6 White Male

(cases per 100,000 persons)

White Female
0.5 Black Male
Incidence Rate

Black Female
0.4

0.3

0.2

0.1

0
0

+
1-

5-

-1

-1

-2

-2

-3

-3

-4

-4

-5

-5

-6

-6

-7

-7

-8

85
10

15

20

25

30

35

40

45

50

55

60

65

70

75

80
Age Distribution
FIGURE 11-11  ■  Epidemiology of Ewing’s sarcoma. Age-specific incidence rates by sex and race; 1142 cases from SEER data for 1973
to 2010.

35 metastatic neuroblastoma or acute leukemia should also

be ruled out. These entities are traditionally listed as
30 potential differential diagnostic problems with Ewing’s
sarcoma and other round-cell malignancies. With the
25 advent of molecular probes and immunohistochemical
Frequency (%)

techniques, differentiation among these tumors rarely

20
presents a diagnostic problem. Ewing’s sarcoma has a
15
tendency to involve the shafts of long tubular bones, the
pelvis, and ribs, but practically every bone can be affected,
10 including the acral skeleton, craniofacial bones, and the
clavicle (Fig. 11-12).
5
Radiographic Imaging
0
Typically Ewing’s sarcoma presents as an ill-defined, per-
l

m r
es
ia

s
e

m r
is

es
tre pe

tre w e
ib
in
ac

meative or focally moth-eaten, destructive intramedul-

lv
iti

iti
R

Ex Up
Sp

Pe

Ex L o
of

lary lesion that affects the diaphysis of a major long

ni
ra

tubular bone. The presence of a large, ill-defined density

C

FIGURE 11-12  ■  Distribution of Ewing’s sarcoma by skeletal
sites. Distribution of Ewing’s sarcoma in major sites of skeleton
as shown by 1142 cases from SEER data for 1973 to 2010.
and 50% are affected in the second decade of life. The
remaining cases are diagnosed in patients between ages
20 and 30 years. Ewing’s sarcoma is extremely rare in
patients older than age 30 years. When confronted with
the possibility of Ewing’s sarcoma in patients older than
age 30 years, the clinician must first eliminate small cell
carcinoma and large cell lymphoma from the differential
diagnosis. In very young patients, the possibility of
in soft tissue in addition to the permeative intramedullary
lesion is a frequent feature (Figs. 11-13 to 11-18). The
lesion is often accompanied by a prominent multilayered
periosteal reaction (onion skin) (Figs. 11-13 and 11-15).
The perpendicular “sunburst” type of periosteal new
bone formation can be present but is less common com-
pared with its occurrence in osteosarcoma. The cortex
overlying the lesion can exhibit diffuse sclerosis and
thickening (Fig. 11-19). The radiographic features are
nonspecific, but with the clinical features, the diagnosis
of Ewing’s sarcoma is correctly suspected in the majority
of cases. The lesion involves the medullary cavity and
soft tissue more extensively than is usually documented
Text continued on p. 780

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 11  Ewing’s Sarcoma and Related Tumors 773

C
FIGURE 11-13  ■  Ewing’s sarcoma of bone: radiographic features. A, Plain radiograph of forearm of a 19-year-old woman with large
soft tissue mass surrounding intramedullary tumor of proximal radial shaft. No periosteal bone formation is present, and cortex
appears intact. B and C, T1- and T2-weighted magnetic resonance images show extensive intramedullary tumor involving radial
shaft and including head of radius. Bulky soft tissue mass developed by tumor permeating through cortex without leaving gross
evidence of destruction in plain films.

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774 11  Ewing’s Sarcoma and Related Tumors

A B

C
FIGURE 11-14  ■  Ewing’s sarcoma: radiographic features. A and B, Lateral and anteroposterior radiographs of the femur in a 20-year-
old woman show a destructive intramedullary tumor with lamellated periosteal reations; margins are ill defined. C, Computed
tomogram (soft tissue window) of tumor shown in A and B. Image on left shows intramedullary tumor and large extraosseous mass
in posterior muscle group.

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 11  Ewing’s Sarcoma and Related Tumors 775

A
FIGURE 11-15  ■  Ewing’s sarcoma of bone: radiographic features. A, Plain radiograph of humerus of a 19-year-old man shows large
area of diaphyseal destruction with permeative features. Note lamellated pattern of periosteal reaction in areas of cortical break-
through. B, T1-weighted magnetic resonance image of tumor shown in A reveals large extraosseous mass and intramedullary tumor.

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776 11  Ewing’s Sarcoma and Related Tumors

A B

C D
FIGURE 11-16  ■  Ewing’s sarcoma of bone: radiographic features. A, Anteroposterior radiograph shows a destructive lytic lesion
involving the distal fibula. B, Magnetic resonance image (MRI) shows a high signal intensity mass originating in the distal fibula
with circumferential soft tissue extension. C and D, Axial MRI showing different signal characteristics in T1-weighted (C) and
T2-weighted (D) images.

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 11  Ewing’s Sarcoma and Related Tumors 777

A B

C D
FIGURE 11-17  ■  Ewing’s sarcoma of bone: radiographic features. A, Anteroposterior radiograph shows a permeative lesion of the
distal femoral metaphysis with soft tissue extension and elevation of periosteum (Codman’s triangle). B, Coronal magnetic resonance
image of the lesion in A shows high signal intensity in an intramedullary tumor with extensive involvement of the parosteal soft
tissue. C, Radioisotope bone scan of the same lesion shows increased uptake in the right distal femur. D, Positron emission
tomogram/computed tomogram of the same tumor identifies an fluorodeoxyglucose (FDG)-avid tumor in the distal femur. Note
particularly high activity in the extraosseus component of the tumor.

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778 11  Ewing’s Sarcoma and Related Tumors

A B

C D E
FIGURE 11-18  ■  Ewing’s sarcoma: radiographic and gross features. A, A-P radiograph showing a permeative lesion of femoral shaft
with extension into soft tissue. Note radiating periosteal new bone formation and concave cortical defect (saucerization). B, Magnetic
resonance image (MRI) shows abnormal medullary density and lateral subperiosteal mass; impression of bone surface causes
concave defect (saucerization). C, A-P radiograph showing a permeative lesion of femoral shaft. Note thickening of the overlying
cortex and concave cortical defect. D, MRI shows abnormal medullary density and subperiosteal mass filling the concave cortical
defect. E, Gross photograph of the same case shown in C and D shows intramedullary mass permeating overlying thickened cortex
with subperiosteal mass.

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 11  Ewing’s Sarcoma and Related Tumors 779

A B
FIGURE 11-19  ■  Ewing’s sarcoma: radiographic features. A, Permeative lesion of proximal femoral shaft associated with cortical
thickening. B, Magnetic resonance image (MRI) shows low-signal intramedullary tumor involving long segment of tibial shaft and
extending into intertrochanteric area. Note that involvement documented by MRI extends beyond anticipated area demonstrated
on plain film in A.

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780 11  Ewing’s Sarcoma and Related Tumors
on plain radiographs. Magnetic resonance imaging and
computed tomography permit more accurate preopera-
tive assessment of the lesion than plain radiographs.
They typically demonstrate intramedullary lesions that
involve large segments of the intramedullary cavity and
extend beyond the area shown to be involved on plain
radiographs. Ewing’s sarcoma can produce a concave
defect on the bone surface that is referred to as sauceriza-
tion (Figs. 11-18 and 11-20). This type of radiographic
appearance is typically seen in predominantly subperios-
teal lesions. More often, saucerization is seen in intra-
medullary lesions in which the cortex is permeated and a
secondary subperiosteal and soft tissue mass that com-
presses the outer surface of the cortex is formed (Fig.
11-18). The majority of Ewing’s sarcomas are purely lytic
lesions (Figs. 11-20 to 11-24). Occasionally, Ewing’s
sarcoma can induce a prominent diffuse thickening of the
preexisting bone and may present radiographically as a
sclerotic lesion, or it may contain focal cloudy opacities.
The sclerotic features or focal opacities are more often
seen in lesions involving the metaphyseal portions of long
bones or in flat bones and are practically never seen in
diaphyseal lesions. On the other hand, diaphyseal lesions
of long bones are often associated with diffuse sclerosis
and thickening of the overlying cortex. Presentation
at an advanced stage with a large mass is a recurring
theme for patients with Ewing’s sarcoma (Figs. 11-25 and
11-26).
Gross Findings
Intact in its setting, Ewing’s sarcoma presents as a gray
to white intramedullary mass with distinct borders. The
tumor can involve large segments of the medullary cavity
without causing cortical disruption. Although complete
cortical disruption is not a characteristic feature, the
cortex is typically permeated by small nests of the tumor.
These finally penetrate the cortex completely and grow
subperiosteally. Early involvement of adjacent soft tissue
is a constant feature of most Ewing’s sarcomas (Figs.
11-27 and 11-28). Formation of a large extraosseous
mass, which often exceeds the size of the intraosseous
component, is frequently seen. A large proportion of
Ewing’s sarcomas have a large circumferential soft tissue
mass at presentation that is fusiform in shape.
Microscopic Findings
Ewing’s sarcoma is the prototype of a nonhematologic,
small round-cell tumor characterized by a proliferation
of undifferentiated mesenchymal cells (Fig. 11-29). The
cells grow in solid, densely packed sheets and nests filling
intertrabecular spaces. They have round, centrally located
nuclei with indistinct cytoplasmic features (Fig. 11-30).
The nuclear chromatin is finely granular, and there
are usually one to three clearly identifiable small- to
intermediate-sized nucleoli. The presence of a prominent
nucleolus is generally not a feature of Ewing’s sarcoma.
The cytoplasm is indistinct and forms an ill-defined
narrow rim around the nucleus. Often a biphasic pattern
is simulated by the presence of so-called dark cells and
light cells (i.e., cells with an open chromatin structure and
ERRNVPHGLFRVRUJ
cells with dark condensed nuclei). The latter represent
tumor cells undergoing apoptosis. These types of cells
are sometimes referred to as principal (light) and secondary
(dark) cells, respectively. The ratio between these two
types of cells varies from tumor to tumor and in different
areas of the same lesion. In some tumors, cords or clus-
ters of dark apoptotic cells form an interconnecting
network of irregular patches that create a pseudoorgan-
oid pattern. Necrosis is a frequent finding in Ewing’s
sarcoma and varies from small patchy foci to large irregu-
lar geographic areas (Fig. 11-31).
Tumor cells occasionally form rosettelike structures
(Figs. 11-25 and 11-30). Several types of rosettes can be
present in Ewing’s sarcoma. In general, less than 20% of
tumor tissue contains these structures. The presence of
rosettes in more than 20% of tumor tissue is considered
by some authors to be diagnostic of PNET. For a specific
description of these structures, the reader is referred to
the section on PNET in this chapter.
Typically, a minimal amount of stromal elements or
none at all is found among tumor cells that fill medullary
intertrabecular spaces and replace normal marrow ele-
ments (Fig. 11-32). The tumor cells permeate the cortex,
invading its haversian and Volkmann’s canals. Complete
permeation of the cortex and its eventual disruption are
associated with the formation of a mass that initially
forms subperiosteally and then extends into soft tissue
(parosteal). Penetration of the cortex and disturbance of
the periosteum are associated with new bone formation.
The proportion of stromal reticular elements and blood
vessels is increased near the advancing edge of the tumor
compared with its more central intramedullary portion.
A more dispersed pattern of growth, including inter-
spersed collagen bundles, strands of stromal tissue, and
the presence of infiltrated skeletal muscle is characteristic
of soft tissue involvement (Fig. 11-33). Multilayered
periosteal new bone formation, corresponding to an
identifiable onion-skin appearance on radiographs, can
accompany the advancing tumor cells. Periosteal bone
formation is associated with plump reactive osteoblasts
and multinucleated osteoclast-like giant cells and may
have foci of cartilage metaplasia. Peripheral areas of the
tumor within soft tissue may show more dispersed tumor
cells invading collagenized stroma, adipose tissue, and
skeletal muscle. Occasionally, a distinct growth pattern in
the form of larger lobules or nests composed of compact
tumor cells and separated by fibrous septa can be seen.
This is usually present within the extraosseous compo-
nent and is rarely seen within the intramedullary portion
of the lesion. The absence of inflammatory cell infiltrates
and the paucity of stromal elements are constant features
of Ewing’s sarcoma. Vascular formation in the central
portion is inconspicuous and is represented by slitlike
capillaries with fine endothelial cells among tumor
cells. Larger, thick-walled vessels can be seen within
stromal bands separating tumor cells. Examination of
cytologic preparations obtained by fine-needle aspira-
tions, imprints, and scrapings are important elements of
the microscopic examination of Ewing’s sarcoma and
other small cell malignancies. The morphologic features
of cells, and especially the details of the nuclei, are often
Text continued on p. 795
 11  Ewing’s Sarcoma and Related Tumors 781

B C
FIGURE 11-20  ■  Ewing’s sarcoma: radiographic features. A Computed tomogram shows intramedullary tumor with cortical disruption
posteriorly and extension into soft tissue. B and C, Anteroposterior and lateral plain radiographs show permeative lesion in metaphy-
seal region; so-called cortical saucerization (concave defect) can be seen on posterior surface in C.

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782 11  Ewing’s Sarcoma and Related Tumors

B
FIGURE 11-21  ■  Ewing’s sarcoma of bone: radiographic features. A, Large destructive tumor of body and glenoid regions of scapula
with associated soft tissue mass. B, Soap-bubble expansion of proximal phalanx of second toe in young adult. This atypical plain
radiographic appearance was interpreted initially as probable vascular tumor. C, Expansile tumor with moth-eaten pattern of bone
destruction in distal end of fibula in young adult.

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 11  Ewing’s Sarcoma and Related Tumors 783

C
FIGURE 11-22  ■  Ewing’s sarcoma of acral skeleton: radiographic features. A, Destructive lesion of second metatarsal bone with eleva-
tion of periosteum. B, Radiograph of amputation specimen shows destruction of proximal plate of great toe and ill-defined soft
tissue mass. C, Permeative destructive lesion involving entire shaft of proximal phalanx of finger is shown in this oblique
radiograph.

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784 11  Ewing’s Sarcoma and Related Tumors

B C
FIGURE 11-23  ■  Ewing’s sarcoma of bone: radiographic features. A, Lateral radiograph of ankle and foot of young adult shows rar-
efaction of posterior part of os calcis. B, Anteroposterior radiograph shows permeative destruction of cancellous bone with ill-defined
border. C, Technetium 99 bone scan shows high uptake of isotope in os calcis, which is more intense posteriorly. Although distal
tibia showed increased isotope uptake, tumor was not present in this site.

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 11  Ewing’s Sarcoma and Related Tumors 785

A B
FIGURE 11-24  ■  Ewing’s sarcoma: radiographic features. A and B, Plain radiographs show destructive lytic mass of proximal tibia
with increase of new periosteal bone formation.

ERRNVPHGLFRVRUJ
786 11  Ewing’s Sarcoma and Related Tumors

A B

C D
FIGURE 11-25  ■  Ewing’s sarcoma: radiographic features. A, A large destruction lesion of the right iliac bone. B, Coronal magnetic
resonance image (MRI) showing a large pelvic tumor. C and D, Axial MRIs showing a large pelvic tumor with low signal intensity.

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 11  Ewing’s Sarcoma and Related Tumors 787

A B

C D
FIGURE 11-26  ■  Askin’s tumor (Ewing’s sarcoma of the thoracopulmonary region): radiographic features. A and B, Coronal and sagit-
tal computed tomograms showing a large tumor involving the upper portions of the left thoracic wall and pulmonary cavity. C and
D, Axial and sagittal magnetic resonance images showing a large low signal intensity tumor involving the left paraspinal region
and thoracic wall.

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788 11  Ewing’s Sarcoma and Related Tumors

A B

C D
FIGURE 11-27  ■  Ewing’s sarcoma: gross features. A, Ewing’s sarcoma of humeral diaphysis. Note intramedullary tumor involving
large segment of femoral shaft. Fusiform extension into soft tissue with elevation of periosteum is evident. B, Posttreatment Ewing’s
sarcoma of proximal femur. Tumor is completely necrotic. Note prominent cortical thickening, a frequent feature of diaphyseal
lesions. C, Ewing’s sarcoma of proximal humerus. Proximal circumferential soft tissue extension with elevation of periosteum is
evident. D, Ewing’s sarcoma of fibula. Note large subperiosteal lesion with concave cortical surface; defect is referred to as
saucerization.

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 11  Ewing’s Sarcoma and Related Tumors 789

A B
FIGURE 11-28  ■  Ewing’s sarcoma: gross features. A, Distal femoral resection specimen. Intramedullary tan-gray tumor with posterior
subperiosteal and soft tissue extension associated with concave cortical defect. B, Ewing’s sarcoma of distal tibia with circumferential
subperiosteal and soft tissue extension. C, Closer view of specimen shown in B shows intramedullary tumor with cortical permeation
and periosteal elevation.

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790 11  Ewing’s Sarcoma and Related Tumors

A B

C D

FIGURE 11-29  ■  Ewing’s sarcoma of bone: microscopic features. A, Low power photomicrograph shows typical patterns in Ewing’s
sarcoma that include solid areas of uniform undifferentiated round cells with minimal amount of cytoplasm. B, High power photo-
micrograph of the case shown in A. Note uniformity of nuclei and absence of brisk mitotic activity. Stroma is minimal and confined
to few delicate fibrous tissue strands and blood vessels. C, Low power photomicrograph shows prominent Homer Wright rosettes.
D, Higher magnification of C shows uniform tumor cells with minimal amount of cytoplasm. Inset, High power photomicrograph of
Homer Wright rosette consisting of a central fibrillar core bounded by concentrically arranged tumor cells. (A and C, ×100; B and
D, ×200; Inset, ×400). (A-D and Inset, hematoxylin-eosin.)

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 11  Ewing’s Sarcoma and Related Tumors 791

A B

C D

FIGURE 11-30  ■  Ewing’s sarcoma: microscopic features. A, Low power photomicrograph shows typical pattern in Ewing’s sarcoma.
B, High power photomicrograph showing clear cell change frequently observed in Ewing’s sarcoma. C, Low power photomicrograph
with clear cell change accentuating the cytoplasm and cell membranes of Ewing’s sarcoma cells. D, High power photomicrograph
of Ewing’s sarcoma showing rosette-like arrangement. Inset, Homer Wright rosette with central fibrillar core. (A and C, ×100; B and
D, ×200; Inset, ×400). (A-D and Inset, hematoxylin-eosin.)

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792 11  Ewing’s Sarcoma and Related Tumors

A B

C D
FIGURE 11-31  ■  Ewing’s sarcoma: microscopic features. A, Typical pattern in Ewing’s sarcoma composed of uniform cells showing
focal clear cell change. B, Biphasic pattern in Ewing’s sarcoma produced by scattered pyknotic (dark) cells. C, Extensive geographic
necrosis of Ewing’s sarcoma. Note the presence of apoptotic dark cells at the interphase of viable and necrotic tumor. D, Higher
magnification of the interphase between viable and necrotic tumor tissue showing prominent dark apoptotic cells. (A, B and D, ×200;
C, ×100). (A-D, hematoxylin-eosin.)

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 11  Ewing’s Sarcoma and Related Tumors 793

A B

C D
FIGURE 11-32  ■  Ewing’s sarcoma: microscopic features. A, Typical pattern of Ewing’s sarcoma. B-D, Minor variations of the patterns
seen in various areas of the same tumor. (A-D, ×200) (A-D, hematoxylin-eosin.)

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794 11  Ewing’s Sarcoma and Related Tumors

A B

C D
FIGURE 11-33  ■  Ewing’s sarcoma: microscopic features. A and B, Somewhat less compact arrangement of tumor cells in Ewing’s
sarcoma. C and D, Low and high power magnifications showing Ewing’s sarcoma cells infiltrating the skeletal muscle. (A, B, and
D, ×200; C, ×100.) (A-D, hematoxylin-eosin.)

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easier to evaluate in cytologic preparations than in smaller
biopsy specimens. Therefore in many centers, fine-needle
aspiration is used as the initial diagnostic approach
when Ewing’s sarcoma is suspected from radiographic
findings.
These classic morphologic features are seen in a
majority of Ewing’s sarcomas. Microscopic cystic changes
with blood-filled spaces, as well as changes resembling
aneurysmal bone cyst, can be superimposed on Ewing’s
sarcoma. In a small number of tumors, the microscopic
appearance of tumor cells may deviate from the so-called
classic pattern. Tumors that deviate from the usual pattern
are referred to as atypical Ewing’s sarcomas.108,119,122,126,133,145
In some cases, the tumor cells are larger than those seen
in conventional tumors, may show cytoplasmic vacuoliza-
tion, and may exhibit greater heterogeneity. These fea-
tures are more often seen in recurrent and treated lesions
but can also be present in primary tumors. In addition,
some lesions may show focal spindle-cell change in the
tumor cells. In such areas the tumor cells have short,
plump, oval nuclei. The deviation from the classic mor-
phologic features in atypical variants of Ewing’s sarcoma
is rather minimal and is not striking at low-power mag-
nification. The large cells are only slightly increased in
size (20 to 24 µm), and they do not have features observed
in pleomorphic or large cell sarcomatoid or epithelial
neoplasms.128-130 Similarly, spindle-cell change represents
a rather minimal deviation from classic Ewing’s sarcoma,
and the tumor cells do not appear to be the type of cells
seen in typical spindle-cell lesions such as malignant
fibrous histiocytoma or fibrosarcoma. Molecularly veri-
fied cases of Ewing’s sarcoma-like tumors with significant
deviation from classical morphology have been published;
they include lesions with the presence of desmoplastic
stroma, organoid and glandular patterns, as well as
adamantinoma- or Merkel cell carcinoma-like fea-
tures.35,74,75,81,84,86,100,180 Such tumors can mimic a wide
range of epithelial and nonepithelial neoplasms, and their
diagnosis can be very challenging.
Cytology
Aspirates from Ewing’s sarcoma/PNET are usually very
cellular and contain a population of dispersed small
undifferentiated mesenchymal cells (Fig. 11-34). A deli-
cate, finely granular chromatin pattern and clearly iden-
tifiable small to medium nucleoli are characteristic. The
cytoplasm is indistinct and forms only a narrow rim
around the nucleus. Aspirates from Ewing’s sarcoma are
important elements in the diagnostic workup.116 The
morphologic features of cells, and especially the details
of the nuclei, are often easier to evaluate on cytologic
preparations than in small biopsy specimens. Therefore,
fine-needle aspiration is used as the initial diagnostic
approach when Ewing’s sarcoma is suspected from radio-
graphic findings. Immunohistochemical and molecular
study allowing differential diagnosis with other small
cell malignances may be performed on material obtained
for cytologic preparations.148 Overall Ewing’s sarcoma/
PNET represent a primary bone sarcoma that can be
definitively diagnosed by aspiration cytology in most
cases.
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11  Ewing’s Sarcoma and Related Tumors 795
Electron Microscopic Findings
In the past, ultrastructural studies provided essential
support for the diagnosis of Ewing’s sarcoma and
were frequently used to categorize small round-cell
tumors.128,130,131,134 They have, at best, marginal use in
differential diagnosis of Ewing’s sarcoma today. The
description of ultrastructural features of Ewing’s sarcoma
is retained here as they explain the light microscopic
appearance of this tumor and provide support for the
primitive undifferentiated nature of tumor cells.
Classic Ewing’s sarcoma is composed of primitive oval
to round mesenchymal cells. The cellularity is high, and
the tumor cells are densely packed with almost nonexis-
tent stroma. Occasionally, tight and desmosome-like
junctions can be present. Two types of cells as defined by
light microscopy—a principal type (light with open intact
chromatin) and a secondary type (dark with condensed
chromatin)—can also be recognized at the ultrastructural
level. Minimal amounts of stromal elements associated
with endothelial-lined capillaries and occasional larger
vessels are seen focally. In conventional Ewing’s sarcoma,
the average size of tumor cells is approximately 14 µm,
and the cells are rather uniform. Centrally located nuclei
are oval to round and have outlines with occasional
indentations of the nuclear membrane. The chromatin is
fine, granular, and evenly distributed. Typically, there are
one to three medium-sized nucleoli. The cytoplasm is
primitive, with sparse inconspicuous organelles (Fig.
11-35). Mitochondria are few and rather small. Some
intracytoplasmic reticulum and poorly developed small
Golgi centers are present. The most relevant ultrastruc-
tural feature, with an overall primitive mesenchymal
appearance of tumor cells, is the abundance of glycogen
arranged in rosettelike deposits (Fig. 11-35). This feature
is present in appropriately fixed and processed specimens
(i.e., in nonaqueous solutions). Inappropriately fixed and
processed samples, especially those retrieved from paraf-
fin blocks, may show washed-out areas within the cyto-
plasm, which are devoid of organelles (Fig. 11-36).
Ultrastructurally, there is a continuous transition from
intact principal cells to dark apoptotic cells, and in some
areas, the so-called dark cells can predominate. The
ultrastructure of the dark cells may show all the features
of nuclear condensation and segmentation described for
apoptosis. Fully developed apoptotic bodies seem to be
the final destiny of dark cells.
Treatment and Behavior
Ewing’s sarcoma belongs to the category of the most
aggressive tumors and has a high propensity for local
recurrences and distant metastases, which occur predom-
inantly in the lungs. Before the advent of chemotherapy,
the prognosis was dismal, with a 5-year survival rate of
less than 20%. The use of multimodality treatment plans
of irradiation and multidrug chemotherapy plus surgery
has significantly changed this survival rate. Those patients
who initially have localized, resectable disease and are
treated with multidrug chemotherapy in addition to
surgery have a 5-year survival rate of approximately
70%.75,101-103,125,151 For patients with disseminated disease
796 11  Ewing’s Sarcoma and Related Tumors

A B

C D

FIGURE 11-34  ■  Ewing’s sarcoma: fine-needle aspiration cytology. A-D, Fine-needle aspirate containing undifferentiated round
cells with occasional nucleoli and indistinct cytoplasm, occasionally forming rosette-like structures (arrows). Inset, Rosettelike struc-
ture formed by circumferential arrangement of tumor cells around central core containing delicate fibrillar cytoplasmic material.
(A-D, ×300; Inset, ×400). (A-D and Inset, hematoxylin-eosin.)

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 11  Ewing’s Sarcoma and Related Tumors 797

B
FIGURE 11-35  ■  Ewing’s sarcoma of bone: ultrastructural features. A and B, Undifferentiated mesenchymal cells containing sparse
cytoplasmic organelles and prominent deposits of glycogen. Note fine, evenly dispersed, granular chromatin of tumor cell nuclei
(A, ×5000; B, ×14,000).

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798 11  Ewing’s Sarcoma and Related Tumors

B
FIGURE 11-36  ■  Ewing’s sarcoma: ultrastructural features. A, Undifferentiated tumor cells containing sparse cytoplasmic organelles
and regular round nuclei with freely dispersed chromatin on occasional nucleoli. B, Tumor cell with prominent washed-out glycogen
pools (A, ×2500; B, ×6000).

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at diagnosis, the 5-year survival rate is significantly lower,
in the range of 30%. Similar to osteosarcoma, it has been
shown that surgical removal of the resectable lung metas-
tases improves survival. Thus the presence of metastases
is the single most important factor adversely affecting the
survival of patients with Ewing’s sarcoma. The incidence
of disseminated disease at the time of diagnosis is high,
and approximately 15% to 28% of patients initially have
metastatic disease.109,114,115,117,119,121,124,125,132,141,146
A variety of clinical factors, such as age and sex, site
of primary tumor and its size, and some clinical labora-
tory parameters, have been postulated to be predictive of
the prognosis.58,104,105,118,123,140,146,149 The relationship
between survival, gender, and age appears to be inconsis-
tent among the published reports; the consensus is that,
most likely, these parameters do not significantly affect
the prognosis.103,109,113,120,124,125,135,137 Similarly, SEER data
implies that female patients show more favorable survival
rates as compared to males, but the data are not consis-
tent in time intervals and are not statistically significant.
SEER data show significant improvement of national
survival rates in the three 5-year intervals spanning 1973
to 1988, which parallel the introduction of modern neo-
adjuvant chemotherapy protocols (Fig. 11-37). The
Ewing’s sarcoma/PNET family of tumors are obvious
candidates for targeted therapy which is under experi-
mental testing, but the potential benefits of this novel
therapeutic modality are not yet reflected in the
population-based survival statistics.
The site of the primary tumor is another prognostic
factor. Patients who have resectable lesions of the extrem-
ity bones have a better survival rate than those who have
lesions affecting the trunk bones, such as the pelvis and
the thoracopulmonary region. In addition, lesions in the
80
1973-1977
70
1978-1982
Relative Survival Rate (%)
1983-1988
60
50
40
30
20
10
0
Both Sexes
FIGURE 11-37  ■  Ewing’s sarcoma: survival rates. Five-year survival rate of 1142 patients with Ewing’s sarcoma by sex and time periods
for all races from SEER data for 1973 to 2005.
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11  Ewing’s Sarcoma and Related Tumors 799
latter sites are significantly larger at presentation and
show extensive soft tissue involvement. The tumor
volume estimated from radiographs also correlates with
survival.101,124,138 Patients who have lesions smaller than
100 ml have an 80% 3-year survival compared with 32%
for patients who have larger tumors.108 The relationship
between tumor volume and survival has been confirmed
by other studies, although the cutoff point for small-
versus large-volume lesions was higher (i.e., 200 ml).101
Several studies have shown that some clinical labo-
ratory parameters (increased levels of serum lactate
dehydrogenase, increased sedimentation rate, and ele-
vated white blood cell count) are adverse prognostic
factors most likely related to more advanced stages of
presentation.117,120,124,125
Some microscopic features are implicated as predic-
tors of more aggressive behavior. Extensive spontaneous
necrosis of untreated lesions is a predictor of more
aggressive clinical behavior and is linked to lower survival
rates.111,113,129 Other studies have shown that the presence
of dark (apoptotic) cells and a so-called filigree pattern are
more predictive of a poor prognosis than necrosis.132 The
association between poor outcome and the filigree pattern
was originally recognized in a large series of interinstitu-
tional cases.127 This peculiar pattern of Ewing’s sarcoma
is typically seen in the soft tissue component and is prac-
tically never observed in the central intramedullary
portion of the tumor. Its presence is considered by some
authors to be synonymous with invasion into soft tissue
and may signify a higher stage and volume of lesions.128
It is of importance that in patients with localized disease,
the presence of this pattern has been associated with poor
prognosis regardless of differences in morphology and
phenotypic differentiation.146
1989-1994
1995-2000
2001-2005
Male Female
800 11  Ewing’s Sarcoma and Related Tumors
A correlation between a high mitotic index (one or
more mitoses per high-power field) and poor survival was
found in one study.111 Conversely, the presence of glyco-
gen, the degree of tumor tissue vascularization, and the
presence of vascular invasion were shown to have no rela-
tion to clinical behavior in patients treated with modern
multidrug protocols.129,139
Postoperative evaluation of necrosis induced by
therapy similar to that used for osteosarcoma appears to
be an important factor in predicting the length of local
control and disease-free time.123,136,141-144,149 The technical
aspects of histologic mapping of therapeutic responses
in Ewing’s sarcoma are identical to those described
for osteosarcoma (see Chapters 1 and 5). Favorable
response, which is defined as total or subtotal (90%
to 100%) necrosis, appears to be a strong predictor
of long-term survival. The link between favorable prog-
nosis and good chemotherapy response has been consis-
tently shown in several independent studies. Moreover,
the degree of postchemotherapy necrosis seems to cor-
relate with the rate of disease-free survival. In a study
from the Rizzoli Institute, the 5-year disease-free survival
rate was 90% for patients with complete necrosis, 53%
for those with microscopic residual tumors, and 32%
for those whose lesions had gross evidence of residual
tumor.137
Alterations of several oncogenes such as c-erb-B2,
TP53, and MDM2 occur very infrequently and do not
seem to play a major role in either the pathogenesis or
prognosis of Ewing’s sarcoma. Immunohistochemical
features of overexpression of the genes involved in the
development of drug resistance, such as P glycoprotein,
show some promising results, but too few cases have been
studied to assess the practical application of these
findings.140,186
More than ten different fusion transcripts containing
exons of EWSR1 and FLI1 have been identified in Ewing’s
sarcoma.69,70 In addition, other translocations in this
group of tumors continue to have multiple variants due
to the mobile positions of breakpoints, which creates
incomprehensive diversity of fusion proteins and poten-
tially different biologic effects. It is uncertain whether
this diversity is of clinical significance, but several reports
indicate that type I fusion transcript for the EWSRI-
FLI1 chimera is associated with better survival when
compared with type II fusion transcripts independent of
tumor site and stage.42,112,150 Moreover, Ewing’s sarcomas
with secondary genetic changes revealed by a compara-
tive genomic hybridization have high propensity for
distant metastasis.106 Ewing’s sarcomas carrying fusion
genes with non-ETS members may be biologically and
clinically different from conventional Ewing’s sarcomas
carrying fusion genes with ETS members.
A novel group of prognostic factors is emerging from
genome profiling studies. These studies documented that
Ewing’s sarcoma has one of the lowest mutational
burdens. It is not unusual to see gene fusions as sole
structural genomic abnormalities. A small fraction of
Ewing’s sarcoma carries the somatic mutations in the
cohesin complex subunit STAG2, which are mutually
exclusive with CDKN2A mutations.107 They frequently
coexist with TP53 mutations.107,110 The presence of
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STAG2 and TP53 mutations is associated with poor out-
comes, and they define a clinically aggressive variant of
Ewing’s sarcoma.147
PRIMITIVE NEUROECTODERMAL TUMOR
Definition
PNET occurs less frequently than conventional Ewing’s
sarcoma. In addition to Ewing’s sarcoma-like features,
it exhibits primitive neural differentiation. Neural dif-
ferentiation in PNET can be identified by light micros-
copy, which reveals the formation of unequivocal Homer
Wright rosettes, and immunohistochemically by the
expression of neural markers. Electron microscopy is
considered by many authors as the most reliable tech-
nique to document the neural differentiation of PNET.
Like Ewing’s sarcoma, PNET exhibits reciprocal
t(11;22)(q24;q12), resulting in expression of the chimeric
EWSR1/FLI1 protein.152,154,158,165 This genetic abnormal-
ity can be identified in a majority of tumors morphologi-
cally classified as PNET. Most authors consider Ewing’s
sarcoma and PNET to be related entities within a con-
tinuous spectrum of minimal to prominent primitive
neural differentiation. Similar to classical Ewing’s
sarcoma, alternative translocations involving EWSR1 and
other genes can occur; the PNET group can be divided
into tumors characterized by chimeric genes containing
fusions with ETS and non-ETS partners.
Incidence and Location
If strict criteria are applied to the diagnosis (i.e., more
than one unequivocal feature of neural differentiation
is required), PNET is a relatively rare lesion. At The
University of Texas M.D. Anderson Cancer Center,
where virtually all Ewing’s sarcoma-like tumors were, in
the past, examined by electron microscopy in addition to
other techniques, PNET represented approximately 10%
of the lesions classified by light microscopy as Ewing’s
sarcoma–like tumors. The peak age incidence and skele-
tal distribution patterns and the radiographic features of
PNET are identical to those of Ewing’s sarcoma.
Microscopic Findings
Microscopically, the tumor has all the features of Ewing’s
sarcoma. It is composed of small, round, primitive, mes-
enchymal cells.152-154,156 In a typical case, the presence of
unequivocal rosettes of Homer Wright type is a promi-
nent and easily recognizable feature (Fig. 11-38). It is
proposed that approximately 20% or more of the tumor
tissue should bear clearly recognizable Homer Wright
rosettes to be considered as morphologic evidence of
neural differentiation and to permit the designation of a
tumor as PNET on the basis of light microscopic evi-
dence alone. In our experience, PNETs with this micro-
scopic feature, prominent Homer Wright rosettes in
more than 20% of tumor tissue, are exceedingly rare.
Several types of rosettes can be present in PNET. This
structure represents a clearly recognizable circular
 11  Ewing’s Sarcoma and Related Tumors 801

FIGURE 11-38  ■  PNET: microscopic features. A and B, Prominent rosette formations in Ewing’s sarcoma cells. Inset, Enlarged image
of Homer Wright rosette (A and B, ×100; Inset, ×300). (A, B, and Inset, hematoxylin-eosin.)

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802 11  Ewing’s Sarcoma and Related Tumors
arrangement of cells with processes that form a fibrillar
material oriented toward the center of the structure.
These types of rosettes are identical to those seen in
neuroblastoma (Fig. 11-29). Less mature, smaller (primi-
tive) rosettelike arrangements formed by several (6 to 10)
cells oriented around a corelike space without clearly
recognizable fibrillar centers can also be present (Fig.
11-30). These types of rosettes should not be used as sole
microscopic evidence of neural differentiation. Flexner-
Wintersteiner rosettes containing a clear, sharply delin-
eated, central lumen, similar to that described in
ependymoma and retinoblastoma, can be present but are
exceptionally rare in PNET of bone.
Electron Microscopic Findings
It is generally accepted that ultrastructural identification
of neural differentiation within a tumor that has the
overall morphology of Ewing’s sarcoma is the most reli-
able way to identify PNET. Ultrastructurally, the neural
differentiation is rather discrete and typically focal in a
tumor otherwise consistent with Ewing’s sarcoma (Fig.
11-39).152,153,159-161,164 Several ultrastructural features of
neural differentiation are usually present. Sparse neuro-
secretory granules are associated with both developing
Golgi centers and cell processes. Neurosecretory gran-
ules are 100 to 140 nm in size and represent electron-
dense, round or oval structures composed of a central
dense core surrounded by a membrane (Fig. 11-40).
These granules can be finely distributed in the cytoplasm,
but in more mature PNETs, they have a tendency to
group together to form loose clusters. The formation
of cytoplasmic projections is a frequent feature of
PNET. Occasionally, these projections are organized and
form typical Homer Wright rosettes in which the cyto-
plasmic projections are oriented toward the central
core (Fig. 11-39). The outer perimeter of the cells
forming the rosette can sometimes be delineated by an
incomplete basal lamina–like material. The cytoplasm of
better-differentiated cells may contain filaments or even
neurotubules, which represent the ultrastructural fea-
tures of the neuralxcc differentiation (Fig. 11-40).
Treatment and Behavior
The treatment plan for PNET is identical to that for
Ewing’s sarcoma. The presence of neural differentiation
in Ewing’s sarcoma has been reported by several studies
to be associated with more aggressive behavior, but that
association is not supported by other studies.155-157,162,163
It appears that the diagnostic criteria for classifying a
tumor as a PNET differ among the series, and these dif-
ferences may be responsible for the discrepancies. In a
recent interinstitutional study involving several centers in
the United States and Europe, the analysis of 315 cases
showed no association between neural differentiation and
more aggressive behavior.146 In contrast, a study based on
the German tumor registry in Kiel showed that neural
differentiation can be associated with more aggressive
behavior if stringent diagnostic criteria for PNET are
used (i.e., if the presence of strong positivity for at least
two neural markers can be documented).162 In this study,
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classic Ewing’s sarcoma had a 60% survival rate after 7 1 2
years of follow-up compared with a 45% rate for PNET.
Similar results have been documented in the study
from the National Cancer Institute, which showed that
patients with Ewing’s sarcoma are more likely to have
localized disease than patients with PNET. The presence
of neural differentiation in Ewing’s sarcoma may have
prognostic significance only if stringent criteria for clas-
sification of tumors as PNET are applied. In summary,
from diagnostic and therapeutic points of view, PNET
and Ewing’s sarcoma can be considered one group of
tumors.
ASKIN’S TUMOR
In 1979, Askin et al. described a small round-cell tumor
of the thoracopulmonary region that affected children.
In the original report, the authors postulated that this
lesion had a distinct pathogenesis and apparently arose in
the ribs, predominantly in the periosteum, but could also
arise in the soft tissue, and possibly within the lung.71
Microscopically, the tumor is indistinguishable from
the group of tumors that include Ewing’s sarcoma and
PNET. Since the original publication, several subsequent
studies have focused on the issue of whether the lesion
represents a distinct clinicopathologic entity or is a
variant of Ewing’s sarcoma and PNET involving the tho-
racopulmonary region.152,157,168,170,171 The lesion may show
classic features of Ewing’s sarcoma or may exhibit light
microscopic, immunohistochemical, and ultrastructural
features of primitive neural differentiation as seen in
PNET. Atypical variants of the tumor that resemble
those described for Ewing’s sarcoma and PNET have also
been described.153
Immunohistochemical studies have shown phenotypic
features similar or identical to those of Ewing’s sarcoma
and PNET. The lesions are frequently positive for one
or several of the so-called neural markers, including
neuron-specific enolase and neurofilaments of 70 kD,
and may also express neuroendocrine markers such as
chromogranin.152,164,168 Occasionally, these tumors can be
focally positive for low-molecular-weight keratins, and
the staining for the MIC2 gene product is similar to that
for conventional Ewing’s sarcoma.130,152,199 Moreover,
cytogenetic analysis has revealed the same t(11;22)
(q24;q12) as seen in Ewing’s sarcoma and PNET.166 In
general, genetic abnormalities and especially the gene
fusions overlap with those of Ewing’s sarcoma.
The current consensus is that Askin’s tumor is a variant
of Ewing’s sarcoma and PNET that involves the thora-
copulmonary region. The unique features seem to be
frequent primitive neural or neuroendocrine differentia-
tion, as well as focal epithelial differentiation. Although
the lesion is considered to be a variant of Ewing’s sarcoma
and PNET, it has a higher propensity for pluripotential
divergent differentiation than does conventional Ewing’s
sarcoma.
Review of a large series of this tumor indicates the
aggressive nature of Askin’s tumor, with a 15% five year
survival.167 The patients with Askin’s tumor frequently
present with locally advanced disease and large tumors; a
 11  Ewing’s Sarcoma and Related Tumors 803

B
FIGURE 11-39  ■  PNET: ultrastructural features. A, Tumor cells with sparse cytoplasmic organelles as seen on low power magnifica-
tion. Axonal differentiation is focally present (arrow). B, Centrally placed cytoplasmic processes correspond to core of rosette
(asterisk). Inset, Cross section of cytoplasmic processes of tumor cells. (A, ×1500; B, ×3000; Inset, ×8000)

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804 11  Ewing’s Sarcoma and Related Tumors

D
FIGURE 11-40  ■  PNET of bone: ultrastructural features. A, Axonal differentiation of tumor cells with formation of interconnecting
cytoplasmic processes (arrows). B, Neurosecretory granules (arrows) in tumor cell cytoplasm. C, Interdigitalizing cytoplasmic pro-
cesses with neurosecretory granules (arrows). D, Neurotubules with the cytoplasmic process of tumor cell (asterisk). (A, ×3500;
B, ×9000; C, ×24,000; D, ×35,000)

ERRNVPHGLFRVRUJ

Ewing’s
PNET
sarcoma
Light microscopic
neural differentiation
(Homer Wright rosettes)
20% of tumor tissue
Ultrastructural
neural differentiation
Expression of
neural markers
MIC2 expression
Vimentin
FIGURE 11-41  ■  Ewing’s sarcoma versus PNET: phenotypic dif-
ferences. Ewing’s sarcoma and primitive neuroectodermal
tumor (PNET) are related entities. Distinguishing feature is
degree of neural differentiation. Generally, two or more major
features of neural differentiation are needed for diagnosis of
PNET.
significant proportion of them have evidence of meta-
static disease at presentation.167,169,172,173
IMMUNOHISTOCHEMICAL FEATURES
OF EWING’S SARCOMA AND PNET
It is unnecessary to provide separate descriptions of
immunophenotypic features for Ewing’s sarcoma and
PNET because most authors consider these lesions to be
related entities within a continuum of overlapping immu-
nophenotypic features. As a consequence, specific desig-
nation of a lesion as either Ewing’s sarcoma or PNET is
based on subjective, arbitrary, and/or semiquantitative
assessment of the amount of neural differentiation
(Fig. 11-41).
Expression of the MIC2 gene product (CD99) in a
majority of Ewing’s sarcomas and PNETs is a diagnosti-
cally important feature of these lesions.174 Although it is
not specific for Ewing’s sarcoma and PNET, it provides
great support for the diagnosis of these tumors if used
with other features (Figs. 11-42 and 11-43). Understand-
ing the biology of this gene in normal tissue and its
pattern of expression in Ewing’s sarcoma, PNET, and
other tumors is helpful for its application as a diagnostic
tool. MIC2 is a gene located in the X-Y pairing region
and is mapped to the Xp22,32p-ter region of the X chro-
mosome.183 This region corresponds to the euchromatin
region p11.2p-ter on the Y chromosome. It codes for a
30-kD cell adhesion-membrane glycoprotein (p30/32)
involved in the proliferation and migratory ability of
Ewing’s sarcoma cells.182,189,190 The product was originally
known as the antigen involved in the T-cell adhesion
process and recognized by the 12E7 antibody. The
HBA-71 antibody was raised against Ewing’s sarcoma
cells. These two antibodies identify the antigen in
formalin-fixed, paraffin-embedded tissue.179,184,192 Several
studies have shown that the MIC2 (CD99) product can
be identified in almost 90% of Ewing’s sarcomas and
ERRNVPHGLFRVRUJ
11  Ewing’s Sarcoma and Related Tumors 805
PNETs.174,179,191,203 In evaluating the positivity of a lesion
for the MIC2 gene product, it is important to remember
that it is not specific for Ewing’s sarcoma and related
conditions. It is also positive in pediatric lymphomas,
lymphocytic lymphoma, and occasionally in rhabdomyo-
sarcoma and even synovial sarcoma.174,179,203,205
Vimentin is the most consistently positive marker and
can be documented in 80% to 90% of Ewing’s sarcomas
and PNETs (Fig. 11-42).198-200 Features of neural dif-
ferentiation are frequently seen in Ewing’s sarcoma and
PNET. On one end of the spectrum are the so-called
classic examples of Ewing’s sarcoma, which are posi-
tive for vimentin only, express the MIC2 gene product,
contain large amounts of diastase-sensitive material
(glycogen) positive for periodic acid–Schiff, and are
completely negative for any neural markers. A strong
positivity for periodic acid–Schiff is present in at least
70% of Ewing’s sarcomas and PNETs. On the opposite
end of the spectrum are PNETs with obvious micro-
scopic neural differentiation (Homer Wright rosettes in
20% or more of tumor tissue), strong diffuse immuno-
histochemical expression of several neural markers, and
ultrastructural features supportive of neural differentia-
tion (see the section on electron microscopic findings in
PNET).130,199,202,207,208 Between these two extremes is a
continuous spectrum of lesions that exhibit focal features
of neural differentiation as revealed by the expression of
one or another neural marker. It is generally accepted
that more than one obvious feature of neural differentia-
tion is required to classify a lesion as PNET.
Positivity for neuron-specific enolase is generally dis-
regarded as a specific marker of neural differentiation.
On the other hand, if its expression can be correlated
with other features of neural differentiation, it provides
a valuable tool with which to assess the degree of neural
phenotypic expression.129,177 We agree with the authors
who defend the applicability of using neuron-specific
enolase for the assessment of the neural phenotype seen
in Ewing’s sarcoma and PNET in conjunction with other
features that support neural differentiation.130,177 Patterns
of expression similar to those for neuron-specific enolase
can be documented with other neural markers in Ewing’s
sarcoma and PNET (Fig. 11-44). These neural markers
are Leu-7, HNK-1, protein gene product 9.5 (PGP9.5),
neurofilaments of 200 kD, glial fibrillary acidic protein,
and S-100 protein.176,177,185,187,193,197,204
Neuroendocrine differentiation can be revealed by
ultrastructural studies for the presence of neurosecretory
granules or by immunohistochemical testing for the pres-
ence of the chromogranin family of markers such as CgA,
CgB, and CgC-SgII. It has been shown that Ewing’s
sarcoma and PNET are typically strongly positive for
a distinct class of chromogranin proteins, designated as
SgII and are negative for CgA and CgB.202 Neuroblasto-
mas are typically positive for CgA and CgB components.
Interesting clues for phenotypic differentiation and of
potential significance for the biology of Ewing’s sarcoma
and PNET were recently provided by studies of the Trk
family of tyrosine kinases, which belong to the superfam-
ily of transmembrane receptors.178,201 These proteins are
essential for neural differentiation and are molecular
receptors for nerve growth factors.175,196 The presence of
806 11  Ewing’s Sarcoma and Related Tumors

A B

C D
FIGURE 11-42  ■  Ewing’s sarcoma: microscopic features. A, Intermediate power view of small round-cell tumor with sparse stromal
elements. B, Strong diffused positivity of tumor cells for vimentin. C and D, Low and high power views of strong membranous posi-
tivity of tumor cells for MIC2 (CD99) gene expression. (A, B, and D, ×200; C, ×100.) (A, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 11  Ewing’s Sarcoma and Related Tumors 807

A B

C D
FIGURE 11-43  ■  Ewing’s sarcoma: microscopic features. A, Ewing’s sarcoma composed of small round cells. B. Diffuse cytoplasmic
expression of the MIC2 gene. C and D, Tumor cell exhibits strong positivity for periodic acid–Schiff stain, which is diastase sensitive
(A-D, ×400). (A, Hematoxylin-eosin; B, DAB; C, PAS; D, PAS after digestion with diastase.)

ERRNVPHGLFRVRUJ
808 11  Ewing’s Sarcoma and Related Tumors

A B

C D
FIGURE 11-44  ■  Ewing’s sarcoma and PNET: immunohistochemical features. A, Focal positivity for synaptophysin. B, Cytoplasmic
positivity for neuron-specific enolase. C, Strong diffuse cytoplasmic positivity for MIC2 gene product revealed with HBA-71 antibody.
D, Strong, diffuse cytoplasmic positivity for vimentin (A-D, ×400).

ERRNVPHGLFRVRUJ

TrkB and TrkC receptors seems to be a feature of Ewing’s
sarcoma without any additional neural differentiation,
whereas the expression of TrkA predominantly occurs
with other neural differentiation features.201
Ewing’s sarcoma and PNET are typically negative for
epithelial markers. Scattered positivity of individual
tumor cells for keratins can be seen in approximately
10% of these tumors.181,209 In extremely rare instances the
diffuse strong positivity of tumor cells in otherwise typical
Ewing’s sarcoma for keratin can be identified.209 It is
uncertain whether lesions with such phenotype carry the
genetic abnormality characteristic of Ewing’s sarcoma/
PNET family of tumors. On the other hand, several cases
of unusual tumors with obvious epithelial differentiation
and adamantinoma- or Merkel cell carcinoma-like fea-
tures carrying the EWSR1/FLI1 chimeric gene have been
described (Fig. 11-45).74,81,84,86,100,180
Modern immunohistochemistry offers an opportunity
to identify at least some of the fusion partners.191 Strong
expression of FLI1 suggests that the tumor may contain
the EWSR1-FLI1 hybrid gene, in which the overexpres-
sion of FLI1 is driven by the EWSR1 promoter. Simi-
larly, the strong positivity for ERG is a useful surrogate
suggesting the presence of the EWSR1-ERG hybrid
gene.210 It has also been shown that the presence of
newly identified hybrid genes such as BCOR-CCNB3 can
be suggested immunohistochemically by the strong over-
expression of CCNB3 protein.44,47 Morphoproteomic
profiling with multiple markers is being explored to
identify the upregulation of potentially therapeutic path-
ways such as mTOR and Ras/Raf/ERK in this group of
malignancies.206
DIFFERENTIAL DIAGNOSIS OF SMALL
ROUND-CELL TUMORS OF BONE
Diagnostic features specific for Ewing’s sarcoma/PNET
tumors should be evident from the preceding descrip-
tions of these entities. In general, the differential diagno-
sis of small round-cell tumors of bone include not only
the entities described in this chapter, but also a variety of
mesenchymal and epithelial (primary and metastatic)
tumors that may occur in children, adolescents, and
adults.
Ewing’s sarcoma and PNET must be differentiated in
children and adolescents from metastatic neuroblastoma,
small-cell osteosarcoma, mesenchymal chondrosarcoma,
rhabdomyosarcoma, and hematopoietic malignan-
cies.211,212,215,216,220 Rare examples of Ewing’s sarcoma and
PNET in older patients require differentiation primarily
from metastatic small-cell carcinoma and lymphoma. In
addition, Ewing’s sarcoma/PNET tumors can also rarely
originate in the internal organs. It is recommended that
rendering such a diagnosis in an unusual clinical setting
should be verified by molecular testing.
The diagnostic molecular verification of Ewing’s
sarcoma may be accomplished using several technolo-
gies.213,214,217,218,224,225,230 Conventional cytogenetics is still
being used to identify the chromosomal translocations,
but because it requires fresh tumor tissue and tissue
culture, it has been largely replaced by the so-called
ERRNVPHGLFRVRUJ
11  Ewing’s Sarcoma and Related Tumors 809
interphase cytogenetics, which identifies genetic abnormali-
ties in nondividing cells and can be applied to formalin-
fixed and paraffin-embedded tissues. The most popular
technique is FISH, with a breakapart probe documenting
rearrangement of the EWSR1 gene. This test is positive
regardless of the type of EWSR1 3′ fusion partner and
can detect the vast majority of Ewing’s sarcoma/PNET
tumors. These cytogenetic techniques can be performed
on both conventional cytologic preparations and
formalin-fixed paraffin-embedded histologic sections. It
should be emphasized that a negative test for EWSR1
rearrangement with the breakapart probe does not abso-
lutely disqualify the diagnosis of Ewing’s sarcoma/PNET
tumor; there are rare examples in which the 5′ fusion
partners may involve genes other than EWSR1, such as
FUS, CIC, or BCOR.
The other frequently applied technology is the
RT-PCR detection of the fusion transcripts. Such tests
are typically designed with multiple primers and are
capable of detecting several variants of fusion transcripts.
However, this approach is not absolutely safe because
the technique can generate false-positive results due to
primer annealing to alternative nonspecific sequences.
The test is highly effective in detecting fusion transcripts
in RNA extracted from formalin-fixed paraffin-embedded
tissue. Sequencing of RT-PCR fusion transcripts pro-
vides confirmation of the specificity of the test by iden-
tifying the sequences of the genes involved in the fusion.
Novel emerging approaches that are not yet widely
available are based on genome sequencing technologies
and are designed to identify all possible fusions using a
panel of primers and massive genomic sequencing. Such
tests are capable of detecting all translocations in sarco-
mas and may dominate future molecular testing of sarco-
mas. These technologies also offer the genome-wide
identification of mutations in therapeutically targetable
genes.
Neuroblastoma typically presents in infancy and child-
hood.188,194,231 The majority of cases occur in children
during the first 5 years of life. The tumor frequently
metastasizes to bone, liver, lymph nodes, and skin. Meta-
static disease can be a presenting sign. The elevated level
of catecholamines and their metabolites in the urine is an
important, diagnostically helpful feature. Histologically,
the presence of neuropil and ganglionic differentiation is
helpful in distinguishing the tumor from Ewing’s sarcoma
and PNET, but in small biopsy specimens, neuroblas-
toma can be indistinguishable from other small-cell
tumors. Many neural markers (i.e., chromogranin and
glial fibrillary acidic protein) that overlap with the neural
differentiation of Ewing’s sarcoma and PNET can be
positive in all three types of lesions. Even glycogen-rich
forms of neuroblastoma that closely resemble Ewing’s
sarcoma have been described.232 On the other hand,
neural differentiation in Ewing’s sarcoma and PNET
can be confused with neuroblastoma.227 The marker
that seems to be extremely helpful is the MIC2 gene,
the expression of which is notably absent in neuroblas-
toma. Moreover, the typical t(11;22)(q24;q12) and the
alternative EWSR1 gene translocations are absent in
neuroblastoma. The typical cytogenetic abnormalities of
neuroblastoma consist of chromosome 1 deletion distal
810 11  Ewing’s Sarcoma and Related Tumors

A B

D
FIGURE 11-45  ■  Adamantinoma-like Ewing’s sarcoma. A and B, Plain radiograph and magnetic resonance image showing permeative
tumor diffusely involving the fibula with prominent cortical thickening. C, Clusters of epithelial cells resembling adamantinoma of
long bone. Inset, The presence of EWSR1/FLI1 chimeric gene documented by the EWSR1/FLI1 fluorescent in situ hybridization fusion
probe. Arrow indicates the fused hybridization signal. The presence of EWSR1/FLI1 chimeric gene was confirmed by the DNA
sequencing of the fusion transcript. D, High power photomicrograph of an epithelial cluster shown in C. E, Strong diffuse staining
for keratin in tumor cells. Insets, Desmosome (upper right) and tonofilaments (lower left) confirming epithelial differentiation in
these unusual tumors. (C, ×100; D, ×400; E, ×200; Insets, ×40,000) (C and D, hematoxylin-eosin.) (Modified with permission from Bridge
J, et al: Am J Surg Pathol 23:159–165, 1999.)

ERRNVPHGLFRVRUJ

to 1p32 (present in 70% to 80% of these tumors). The
second consistent abnormality is the presence of homo-
geneously stained chromosomal regions and the presence
of double-minute chromosomes. These represent a mor-
phologic manifestation of the N-myc gene amplification.
From this description, the reader may get an impression
that the distinction between neuroblastoma and Ewing’s
sarcoma is extremely difficult and often impossible. On
the contrary, if the entire clinical presentation (i.e., the
presence of suprarenal mass, elevated levels of catechol-
amines, and pattern of skeletal involvement) is consid-
ered, the majority of cases can be easily distinguished
from Ewing’s sarcoma.
Small cell osteosarcoma may be confused with Ewing’s
sarcoma and PNET.211,215,219,223,226,228 We believe that the
lesions showing microscopically direct bone production
by tumor cells and exhibiting immunohistochemical and
molecular characteristics of Ewing’s sarcoma, the pres-
ence of t(11;22)(q24;q12) or characteristic fusion tran-
scripts, should be classified as Ewing’s sarcoma rather
than small cell osteosarcoma. Expression of galectin
GAL-1) may be useful in the differential diagnosis
of small cell osteosarcoma and Ewing’s sarcoma. It is
frequently expressed in osteoblastic tumors, including
small cell osteosarcoma and is expressed in less than 10%
of Ewing’s sarcomas.195
Mesenchymal chondrosarcoma can represent a differ-
ential diagnostic problem if the cartilaginous component
is not present in the biopsy specimen or is inconspic-
uous. Microscopically, the presence of a prominent
hemangiopericytoma-like pattern and foci of atypical
cartilage that stain positive for S-100 protein are dis-
tinguishing features.212,221,229 The expression of a master
regulator of chondrogenesis, Sox9 protein, in primitive
mesechymal cells is consistent with their chondroprogen-
itor nature distinguishing mesenchymal chondrosarcoma
from other small round-cell tumors.234 Identification of
two distinct chromosomal translocations, t(1;5)(q42;q32)
with the IRF2PB2-CDX1 fusion gene and a cryptic inter-
stitial deletion of del(8)(q13.3q21.1) with the HEY1-
NCOA2 fusion gene, in mesenchymal chondrosarcoma
provides new diagnostic tools in the differential diagnosis
of small cell malignancies.222,233
Rhabdomyosarcoma of embryonal type, especially the alve-
olar variant, belongs to the category of small round-cell
tumors and should be differentiated from Ewing’s
sarcoma, especially in soft tissue lesions found in young
children.215,220 The confusion between embryonal rhab-
domyosarcoma and Ewing’s sarcoma occurs most often
when analyzing frozen-section specimens. Examination
of paraffin-embedded material typically reveals rhabdo-
myoblastic features in most embryonal rhabdomyosarco-
mas. On the other hand, alveolar rhabdomyosarcoma is
a true round-cell tumor and may present the diagnostic
problem. Positivity of the tumor cells for muscle markers
and the presence of nesting and alveolar patterns are
distinguishing features. The presence of t(2;13)(q34;q14)
or t(1;13)(p36;q14) and their respective FKHR-PAX3 and
FKHR-PAX7 fusion genes are the molecular characteris-
tics of alveolar rhabdomyosarcoma.
Small round-cell tumors in older patients are very unlikely
to represent Ewing’s sarcoma. Metastatic carcinoma and
ERRNVPHGLFRVRUJ
11  Ewing’s Sarcoma and Related Tumors 811
lymphoma are entities that frequently involve the skele-
ton in patients older than age 40 years and can be diag-
nosed with the support of appropriate epithelial and
lymphoma marker studies. We believe that the diagnosis
of Ewing’s sarcoma and PNET in an unusual clinical
setting such as older patients should be confirmed by
appropriate molecular studies.218
When it is not clear whether the lesion in question is
a primary soft tissue or bone tumor, several additional
conditions, such as high-grade soft tissue myxoid chon-
drosarcoma and poorly differentiated synovial sarcoma,
must also be ruled out. Occasionally, sclerosing epitheli-
oid fibrosarcoma, malignant melanoma, and even vil­
lonodular tenosynovitis can mimic a small round-cell
tumor.215,220
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Hematopoietic Tumors
CHAPTER OUTLINE
CLASSIFICATION OF HEMATOPOIETIC TUMORS
PLASMA CELL MYELOMA AND PLASMA CELL
NEOPLASMS
Amyloidosis Associated with Multiple
Myeloma
Distinct Forms of Myeloma
NON-HODGKIN’S LYMPHOMA
Diffuse Large B-cell Lymphoma
Adult T-cell Lymphoma/Leukemia
CLASSICAL HODGKIN’S LYMPHOMA
This chapter addresses some of the issues pertaining to
skeletal manifestations of hematopoietic tumors, espe-
cially when they present as primary tumors in bone. In
such instances, a bone pathologist or even a general
pathologist, rather than a hematopathologist, is more
likely to be confronted with diagnostic challenges. For
these reasons, familiarity with skeletal manifestations of
hematopoietic lesions should be of general interest. This
chapter also discusses plasma cell myeloma and other
plasma cell neoplasms, non-Hodgkin lymphomas, leuke-
mias, histiocytic and dentritic cell proliferations, and
mastocytosis, with particular reference to their involve-
ment of skeletal tissue.
CLASSIFICATION OF
HEMATOPOIETIC TUMORS
In general, the approach to classifying hematopoietic
tumors parallels the current knowledge of lineage dif-
ferentiation, naming the diseases in terms of their postu-
lated normal cell counterparts (Fig. 12-1). The earliest
hematopoietic stem cells are capable of producing
cells of all blood lineages. Although there is still contro-
versy regarding the degree and timing of lineage com-
mitment, two prevailing models are considered here.
Both models begin with a long-lived uncommitted hema-
topoietic stem cell that then differentiates into a short-
lived multipotent hematopoietic stem cell. At this point,
the models diverge.
The first model, the classical myeloid-lymphoid
model, postulates that the first step occurs with lineage
commitment to myeloid or lymphoid differentiation.
The common myeloid precursor then gives rise to two
ERRNVPHGLFRVRUJ
C H A P T E R 1 2 
April Ewton, MD
HISTIOCYTIC AND DENDRITIC CELL
PROLIFERATIONS
Langerhans Cell Histiocytosis
Erdheim-Chester Disease
Sinus Histiocytosis with Massive
Lymphadenopathy (Rosai-Dorfman
Disease)
MYELOID SARCOMA
MASTOCYTOSIS
lines of differentiation, a megakaryocyte/erythroid line,
and a granulocyte/monocyte lineage.
The second model, the myeloid-based model2,3 (Fig.
12-1), suggests that there is a common precursor that
maintains the capacity to produce both myeloid and lym-
phoid progeny. Experimental evidence that the myeloid-
based model is more accurate than the myeloid-lymphoid
model continues to accumulate; however, at present there
is no universal agreement. The myeloid-based model of
lineage differentiation is also supported by examples of
neoplasms exhibiting lineage plasticity such as acute leu-
kemias of ambiguous lineage with both myeloid and lym-
phoid features.5 There are even reported cases of
Langerhans cell histiocytosis with clonally rearranged
T-cell or B-cell receptors1 and Langerhans cell histiocy-
tosis occurring with clonally related T-cell acute lympho-
blastic leukemia4 or acute leukemia of ambiguous lineage.6
T lymphocytes, B lymphocytes (and later plasma
cells), and natural killer cells arise from the common
lymphoid precursor. Dendritic cells arise from a common
macrophage/dendritic precursor. Normal Langerhans
cells arise from fetal macrophages that differentiate
after migrating to the skin. Neoplastic Langerhans cells,
however, are thought to arise from a myeloid precursor.
Currently, the most widely accepted classification is
the World Health Organization Classification of Hematopoi-
etic and Lymphoid Tissues, first published in 2001 and
revised in 2008.5 There is a trend toward classification of
distinct neoplasms by their molecular and genetic fea-
tures when warranted, within the context of clinical and
morphologic features. As targeted therapy becomes more
and more prevalent, the molecular alteration of pathways
that drive the proliferation and survival of these hemato-
poietic neoplasms is becoming important in the descrip-
tion of these entities.
817
818 12  Hematopoietic Tumors

Plasma cell myeloma

Lymphoma
B cell
ce

Lymphoma
CLP
T cell

Myeloid sarcoma
Granulocyte
Granulocyte
l
Sinus Histiocytosis with
massive lymphadenopathy
LMPP Erdheim-Chester disease
Monocyte Macrophage
Macr
rop
oph
pha
hage
g Myeloid sarcoma

Langerhans cell histiocytosis

HSC GMP MDP

Dendritic cell

F l
Fetal Langerhans
CMP macrophage cell

Erythrocytes
Myeloid sarcoma

MkEP

Platelets
FIGURE 12-1  ■  Classification of hematopoietic and lymphoid tumors in the context of lineage commitment and postulated cell of
origin. Uncommited hematopoietic stem cells give rise to cells with progressive commitment to development of various cell lineages.
Hematopoietic neoplasms arise from cells of specific committed lineages or their precursors. HSC, hematopoietic stem cell;
LMPP, lymphoid-primed multipotent progenitor; CMP, common myeloid progenitor; CLP, common lymphoid progenitor;
GMP, granulocyte/monocyte progenitor; MkEP, megakaryocyte/erythroid progenitor; MDP, myeloid/dendritic progenitor. (Based on
and adapted from Luc S, et al: Delineating the cellular pathways of hematopoietic lineage commitment. Semin Immunol 20:213–220, 2008.)

PLASMA CELL MYELOMA AND PLASMA
CELL NEOPLASMS
Definition
Plasma cell myeloma is a monoclonal, neoplastic prolif-
eration of plasma cells that involves the bone marrow and
occasionally involves extraskeletal sites. Lytic bone lesions
are a prominent feature of typical cases.
Clinical Features
Plasma cell myeloma is one of the most frequently occur-
ring hematopoietic neoplasms and accounts for approxi-
mately 1% of all malignant neoplasms in white patients
and approximately 2% in black patients. It is the second
most common hematopoietic malignancy, accounting for
approximately 10% of hematopoietic neoplasms, and the
most frequent neoplasm presenting as skeletal lesions.30,40,58
The skull, vertebral bodies, pelvis, and proximal parts of
the major long tubular bones are most frequently involved
(Fig. 12-2). More than 95% of cases are diagnosed in
patients older than age 40 years, with a peak incidence
between ages 65 and 74 years (Fig. 12-3).57 Plasma cell
myeloma is more common in the black population (Fig.
12-4).57 Plasma cell myeloma is always preceded by
monoclonal gammopathy of undetermined significance
(MGUS), but MGUS may not be detected in this early
subclinical phase of disease. Patients with MGUS prog-
ress to plasma cell myeloma at the rate of approximately
1% per year.39 The incidence of plasma cell myeloma is
increasing, and there is currently no definitive cure;

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 819

55
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 12-2  ■  Plasma cell myeloma. Peak age incidence and most frequently involved skeletal sites are indicated by solid black
arrows. Less frequently involved sites are indicated by clear arrows.

30 9

8
25
(cases/100,000 persons)

7
Age distribution (%)

20 6
Incidence rate

5
15
4
10 3

2
5
1
0 0
<20 20-34 35-44 45-54 55-64 65-74 75-84 >84
e

es

es

es
e
al

al

al

al

al

al
m

m
fe

Age at diagnosis
s,

fe

fe
te

k
e

s,

ac
ac

hi

te

k
e

ac
Bl
W
ac

hi

FIGURE 12-3  ■  Age distribution of multiple myeloma cases. The

lr

Bl
W
Al

lr

peak age of incidence is 65 to 74 years. SEER Data, 1973-2010.

Al

FIGURE 12-4  ■  Distribution of plasma cell myeloma by race and

however, with greater understanding of the pathogenesis,
patient survival is improving.
Plasma cell myeloma usually presents with multifocal
osteolytic lesions, proliferation of plasma cells, and
monoclonal gammopathy. Typically, patients have multi-
focal bone pain (especially in the weight-bearing sites),
anemia, hypercalcemia, renal failure, proteinuria, and
sex. The most commonly affected group is black males. SEER
Data, 1973-2010.
a history of recurrent infections. In the majority of
patients, increased levels of monoclonal immunoglobu-
lins (M-protein) can be detected by serum or urine elec-
trophoresis. Recommended laboratory testing includes
complete blood count, serum creatinine, serum calcium,

ERRNVPHGLFRVRUJ
820 12  Hematopoietic Tumors

serum protein electrophoresis with immunofixation,

TABLE 12-1 Laboratory Tests for
Multiple Myeloma
History and physical examination
Complete blood count and differential; peripheral blood
smear
Chemistry screen, including calcium and creatinine
Serum protein electrophoresis, immunofixation
Nephelometric quantification of serum immunoglobulins
Routine urinalysis, 24-hour urine collection for
electrophoresis and immunofixation
Bone marrow aspirate or biopsy
Cytogenetics (metaphase karyotype and fluorescence in
situ hybridization [FISH])
Radiologic skeletal bone survey, including spine, pelvis,
skull, humerus, and femur; magnetic resonance imaging
in certain circumstances
Serum β2-microglobulin and lactate dehydrogenase
Measurement of serum-free light chains
Adapted from Dimopoulos M, et al: Consensus
recommendations for standard investigative workup: report
of the International Myeloma Workshop Consensus Panel 3.
Blood 117:4701-4705, 2011.
serum free light chain assay, and urine protein analysis
(Table 12-1).18
Diagnostic criteria used to subclassify plasma cell neo-
plasms include laboratory and clinical features. MGUS is
defined as the presence of an M-protein at levels below
3 g/dL in the absence of any other defining features of
plasma cell myeloma. Two broad categories of plasma cell
myeloma are designated smoldering (asymptomatic) myeloma
and symptomatic myeloma. By the 2008 WHO criteria, a
diagnosis of asymptomatic plasma cell myeloma may be
made if there are more than 10% clonal plasma cells in
the bone marrow or the serum M-protein is greater than
3 g/dL. A diagnosis of symptomatic plasma cell myeloma
requires the presence of a clonal plasma cell population
of any quantity (usually with associated detectable
M-protein) and end-organ damage, as represented by the
acronym CRAB (hyperCalcemia, Renal insufficiency,
Anemia, lytic Bone lesions) (Table 12-2).18,38,40,42
The main prognostic factors are related to cytogenetic
findings, extent of disease, patient age, and renal func-
tion. Factors that can be evaluated in the laboratory

TABLE 12-2 Diagnostic Criteria for Plasma Cell Disorders

Disorder/ Criteria Comment
Monoclonal gammopathy Serum monoclonal protein <3 g/dL All three criteria must
of undetermined Clonal bone marrow plasma cells <10% be met
significance (MGUS) Absence of end-organ damage, such as hypercalcemia, renal
insufficiency, anemia, or bone lesions
Smoldering Serum monoclonal protein (IgG or IgA) ≥3 g/dL or clonal bone marrow Both criteria must be
(asymptomatic) plasma cells ≥10% met
multiple myeloma Absence of end-organ damage, such as lytic bone lesions, anemia,
hypercalcemia, or renal failure
Symptomatic multiple Clonal bone marrow plasma cells ≥10% All three criteria must
myeloma Presence of serum or urinary monoclonal protein (except in patients with be met except as
nonsecretory multiple myeloma) noted
Evidence of end-organ damage (CRAB):
HyperCalcemia: serum calcium ≥11.5 mg/dL
Renal insufficiency: serum creatinine >2 mg/dL
Anemia: normochromic, normocytic with a hemoglobin value of >2 g/dL
below the lower limit of normal, or a hemoglobin value <10 g/dL
Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures
Nonsecretory myeloma >10% clonal plasma cells confirmed by biopsy
<0.5 mg/dL serum protein by SPEP
<200 mg/24 hrs of light chain proteinuria by UPEP
Unquantifiable free light chain measurement
Solitary plasmacytoma of Minimal or absent M-protein in serum or urine
bone Single area of bone destruction due to clonal plasma cells
Bone marrow <10% clonal plasma cells
Normal skeletal survey (and MRI if done)
No related organ or tissue impairment (CRAB) other than solitary bone
lesion
Extramedullary Minimal or absent M-protein in serum or urine
plasmacytoma Extramedullary tumor of clonal plasma cells
Bone marrow <5% clonal plasma cells
Normal skeletal survey
No related organ or tissue impairment (end- organ damage, including
bone lesions)

Adapted from Kyle RA, et al: Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report
of the International Myeloma Working Group. Br J Haematol 121:749-757, 2003 and Kilciksiz S, et al: A review for solitary
plasmacytoma of bone and extramedullary plasmacytoma. Scientific World Journal 2012:1-6, 2012.
SPEP, serum protein electrophoresis; UPEP, urine protein electrophoresis.
Adapted from Dimopoulos M, et al: Consensus recommendations for standard investigative workup: report of the International
Myeloma Workshop Consensus Panel 3. Blood 117:4701-4705, 2011 and Kilciksiz S, et al: A review for solitary plasmacytoma of
bone and extramedullary plasmacytoma. Scientific World Journal 2012:1-6, 2012.

ERRNVPHGLFRVRUJ

40
35
Relative Survival (%) 30
25
20
15
10
0
73
75
77
79
81
83
85
87
89
19
19
19
19
19
19
19
19
19
FIGURE 12-5  ■  Plasma cell myeloma: 5-year survival. Five-year survival for multiple myeloma from 1973 through 2006. Survival has
been improving with newer therapies. SEER Data, 1973-2006.
include cytogenetic status, proliferation index, neoplastic
plasma cells as a percentage of total plasma cells, free
light chain ratio, serum lactate dehydrogenase, and β2-
microglobulin level.40
With current therapeutic approaches, the progression-
free survival and overall survival for patients with plasma
cell myeloma has improved (Fig. 12-5).57 Before 1962, in
the absence of any known treatment, the median survival
for newly diagnosed myeloma patients was less than 1
year.37 Although there has been steady improvement in
survival over the years, median overall survival in the
early 2000s was still only 2 to 3 years. In the current era
of novel therapeutic agents, overall median survival is
now approximately 8 years.44
Patient prognosis and choice of therapy are most com-
monly determined by cytogenetic risk factors and age. An
example of risk stratification as delineated by the Mayo
group identifies high risk, intermediate risk, and standard
risk groups based on cytogenetic features or gene expres-
sion profiling in the context of response to currently
available therapies. High risk features are deletion of 17p,
t(14;16), t(14;20), or a high risk signature by gene expres-
sion profiling. Intermediate risk features are t(4;14), dele-
tion of 13, hypodiploidy, and a plasma cell labeling index
greater than 2. Standard risk patients have none of the
preceding features and may have t(11;14) or t (6;14).44
The current median overall survival for high risk, inter-
mediate risk, and standard risk is 3 years, 4 to 5 years,
and 8 to 10 years, respectively.44
The most widely used therapeutic regimens include
dexamethasone or prednisone and one or more novel
agents, in some cases augmented with alkylating agents
or anthracyclines. Patients under age 70 years are poten-
tially eligible for autologous stem cell transplant, and
ERRNVPHGLFRVRUJ
12  Hematopoietic Tumors 821
91
93
95
97
99
01
03
05
19
19
19
19
19
20
20
20
currently cytoreductive therapy followed by transplant
is the standard of care; however, treatment with novel
agents may replace this approach in the future. Com-
monly used novel agents are immunomodulatory drugs
such as lenolidamide or thalidomide, and the proteasome
inhibitor bortezomib. Commonly used chemotherapeu-
tic drugs include melphalan and cyclophosphamide.44
Radiographic Imaging
The International Myeloma Working Group (IMWG)
consensus guidelines for imaging studies were last updated
in 2009. A skeletal survey, consisting of a series of plain
radiographs, is recommended for every patient. If the
skeletal survey detects no lesions, or if the initial diagno-
sis is solitary plasmacytoma of bone, magnetic resonance
imaging (MRI) should be performed to detect possible
occult bone lesions. Computed tomography (CT) scan or
MRI are required for any patient with suspected spinal
cord compression. Positron emission tomography (PET)
scan is not routinely recommended.19
Distinctive radiographically detectable changes are
present in approximately 80% of patients with multiple
myeloma. The axial skeleton and the trunk bones are
preferentially involved. The most pronounced and earli-
est changes are typically seen in the skull, vertebrae, ribs,
and pelvis and correspond to the predominance of hema-
topoietic marrow at these sites in patients older than age
50 years.15 They represent multifocal, sharply demar-
cated, lytic foci and are often called punched-out lesions
(Figs. 12-6 to 12-8). Erosions of the cortex are frequently
seen, and prominent periosteal new bone formation is
typically not present. Bones with a smaller diameter, such
as the ribs, can exhibit expanded contours. Pathologic
822 12  Hematopoietic Tumors

B C D E
FIGURE 12-6  ■  Plasma cell myeloma: radiographic features. A, Lateral radiograph showing extensive multiple lytic lesions of cal-
varium. B and C, Anteroposterior (AP) radiographs of extensive multiple lytic lesions of both humeri. D and E, AP radiographs of
multiple lytic lesions of bilateral femora and fibulae. All images are from the same patient showing extensive involvement of virtu-
ally the entire skeleton.

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 12  Hematopoietic Tumors 823

A B C

D E
FIGURE 12-7  ■  Plasma cell myeloma: radiographic features. A, Anteroposterior (AP) radiograph of humerus showing a destructive
lytic lesion centered in the shaft with involvement of the surrounding soft tissue. B, AP radiograph of lytic lesion of the humeral
shaft. C, Lateral radiograph of the calvarium showing multiple lytic lesions. D, AP radiograph of femoral head and neck showing
a destructive lytic lesion. E, Radioisotopic bone scan showing increased uptake in the left proximal humerus. Same case as
shown in D.

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824 12  Hematopoietic Tumors

A B

C D
FIGURE 12-8  ■  Plasma cell myeloma: radiographic features. A, Lateral radiograph of skull showing large expansile lytic lesion in
vertex of skull with multiple, small, punched-out foci of lucency in parietal and occipital areas. B, Radioisotope scan (technetium
99) showing increased uptake in region of destructive skull lesions. Note photon deficit in center of large lesion at vertex. C, Magnetic
resonance image of head and neck shown in A reveals skull defect and tumor at vertex impinging on cerebral hemisphere. D, Pho-
tomicrograph showing features of atypical plasma cells (×200, hematoxylin-eosin).

ERRNVPHGLFRVRUJ

fractures are frequent and can be the presenting sign. In
fact, collapse of the vertebral body is frequently a pre-
senting symptom (Fig. 12-9). The disease typically first
appears in the axial skeleton and trunk bones, but with
progression of the process, extensive involvement of
the appendicular skeleton and multiple pathologic frac-
tures can develop. Surprisingly, despite extensive bone
destruction, the results of radioisotopic bone scans are
frequently negative in patients with multiple myeloma.
This is explained by the predominant bone destructive
activity of myeloma cells with typically minimal new
bone production. A small number of patients do not
have lytic punched-out lesions at presentation and may
show generalized osteoporosis that is sometimes quite
pronounced. In some instances, the lesions in multiple
myeloma may appear sclerotic on radiographs (Figs.
12-10 and 12-11). Sclerotic lesions are typical for POEMS
syndrome (discussed in the section on osteosclerotic
myeloma in this chapter).28
Gross Findings
Antemortem gross examination is typically restricted
to small biopsy or curettage samples from the site of
pathologic fracture and show fragments of tan-gray soft
tissue. At autopsy the principal growth patterns can be
appreciated: diffuse involvement of bone marrow and
growth in the form of discrete nodules (Fig. 12-12). Most
likely, the diffuse involvement represents a more advanced
stage and is produced by the confluence of individual
nodules. On the other hand, some patients have general-
ized osteoporosis at presentation, and nodular lytic
changes develop later in the course of the disease. The
individual nodules are best seen in the vertebral bodies. A
more advanced process is associated with the collapse of
one or several vertebral bodies. The ribs typically show
multiple extended foci. The long bones in the appendicu-
lar skeleton show nodules or diffuse involvement with
cortical thinning and disruption. Pathologic fractures are
frequent, especially at the weight-bearing sites. The prox-
imal parts of the appendicular skeleton are initially pref-
erentially involved.
Microscopic Findings
Plasma cell myeloma consists of a proliferation of cells
that usually include at least a subset of cells that resemble
normal plasma cells. The cells form clusters or sheets
within the bone marrow of involved tissue. These cells
are round or oval and have an eccentric nucleus and
a clumped “clockface” chromatin pattern with the chro-
matin clustered at the periphery of the nucleus near the
nuclear membrane. The plasma cell cytoplasm has a
prominent perinuclear hof, corresponding ultrastructur-
ally to a prominent Golgi region, and rough endoplastic
reticulum appropriate for active immunoglobulin pro-
duction and packaging.
When multiple myeloma is suspected, smears should
always be prepared because the plasma cell nature of
the round-cell infiltrate is quite often more evident in
cytologic preparations than in conventional histologic
sections. The cytoplasm is dense and eosinophilic in
ERRNVPHGLFRVRUJ
12  Hematopoietic Tumors 825
hematoxylin-eosin–stained sections, and deeply baso-
philic in Wright-Giemsa or Diff-Quik (Romanovsky’s)
stained smears. As described by Bartl et al in 1987, the
plasma cells may vary considerably in cytomorphology
(Fig. 12-13).11 The morphologic range includes cells with
polymorphous or asynchronous features, as well as forms
resembling normal mature plasma cells, small lympho-
cytes, blasts, or lymphocytes with cleaved nuclei. These
morphologic variants may pose diagnostic challenges,
raising the differential diagnosis of lymphoma, leukemia
or other blastic neoplasms, or even carcinoma in cases
with marked pleomorphism.
The degree of immaturity of the myeloma cells is a
prognostic factor.26 Loss of the morphologic plasma
cell phenotype with the presence of forms resembling
blasts is associated with more aggressive behavior and a
poorer prognosis. In most myelomas, clearly recogniz-
able features of plasma cells can be found at least
focally.
Numerous Russell bodies representing cytoplasmic
spherical structures of polymerized immunoglobulins can
be present. The accumulation of cytoplasmic immuno-
globulins can be present in the form of morular or
Mott cells, representing grapelike cytoplasmic structures.
These structures are best seen in Giemsa stained cyto-
logic preparations. Although Russell bodies are frequently
seen in reactive plasma cells, intranuclear inclusions, or
Dutcher bodies, almost always indicate neoplastic plasma
cells (Fig. 12-14). The cytoplasm of myeloma cells has
ultrastructural features of maturity with well-developed
rough endoplasmic reticulum and a prominent Golgi
region (Fig. 12-16). The latter can be seen by light
microscopy as a perinuclear clearing.
Immunohistochemistry and
Differential Diagnosis
Plasma cells represent the end stage of B-cell differen-
tiation, but they typically do not express common pan–
B-cell antigen CD20. They are also typically negative
for most T-cell markers. A summary of microscopic ultra-
structural and immunophenotypic features of myeloma
cells is provided in Table 12-3. Myeloma cells are of
the plasma cell lineage and have many of the same fea-
tures. The most characteristic feature of myeloma cells
is their monotypic expression of κ or λ immunoglobu-
lin. They typically brightly express normal plasma cell
markers CD38, CD138, and MUM1.41 In the majority
of cases, the cells show aberrant expression of CD56,
an adhesion molecule, which may be lost in plasma
cell leukemia and extramedullary plasmacytomas. The
second most common aberrantly expressed marker is
CD117.
The differential diagnosis includes reactive plasmacy-
tosis, reactive inflammatory conditions with a prominent
plasma cell component, and other neoplasms. Normal
bone marrow plasma cells are located primarily in a peri-
vascular distribution, in contrast to myeloma plasma cells,
which form sheets and clusters in a predominantly inter-
stitial pattern. Binucleate plasma cells without nuclear
atypia can frequently be found in reactive infiltrations.
Text continued on p. 832
826 12  Hematopoietic Tumors

A B

C D

FIGURE 12-9  ■  Plasma cell myeloma: radiographic features. A, Anteroposterior radiograph of right shoulder shows destructive lesion
in axillary border of scapula with soap-bubble appearance and small lucent foci in proximal humeral metaphysis. B and C, Lateral
radiographs of lumbar spine show osteopenia and partial collapse of vertebral bodies. D, Lytic lesion of humeral shaft with patho-
logic fracture.

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 827

B C
FIGURE 12-10  ■  Sclerosing plasma cell myeloma: radiographic features. A, Lateral radiograph of skull shows multiple foci of radioden-
sity varying from a few millimeters to more than a centimeter in diameter. B, Right side of pelvis and proximal femur seen in this
anteroposterior radiograph contain small focal densities with diameters ranging up to several centimeters. C, Lateral radiograph of
thoracic spine shows osteopenia and focus of radiodensity within upper border of vertebral body.

ERRNVPHGLFRVRUJ
828 12  Hematopoietic Tumors

B
FIGURE 12-11  ■  Sclerosing plasma cell myeloma: radiographic features. A, Radiograph of pelvis shows multiple radiodense foci.
B, Sclerotic lesions of thoracic and lumbar vertebral bodies. C, Proximal humerus with several radiodense foci.

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 829

A B

C D
FIGURE 12-12  ■  Plasma cell myeloma: radiographic, gross, and microscopic features. A, Radiograph of skull shows multiple lytic
punched-out lesions. B, Gross photograph of autopsy specimen shows multiple lytic foci composed of soft gray tissue (same case
as in A). C, Whole-mount specimen of perpendicular section of parietal bone shows nodular growth pattern of multiple myeloma.
D, Higher magnification of C shows nodules to be composed of sheets of plasma cells (×200, hematoxylin-eosin).

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830 12  Hematopoietic Tumors

A B

C D
FIGURE 12-13  ■  Plasma cell myeloma: cytologic features. A, Blastoid plasma cells with high nuclear cytoplasmic ratio and prominent
nucleoli. B, Mature plasma cells with feathered cytoplasmic borders. C, Pleomorphic plasma cells, immature forms, and multinucle-
ated forms. D, Small lymphocyte-like variant of multiple myeloma with small nuclei and scant cytoplasm (A-D, ×1000) (A-D, Wright-
Geimsa stain).

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 12  Hematopoietic Tumors 831

A B

C D

FIGURE 12-14  ■  Plasma cell myeloma: microscopic features. A, Intranuclear inclusions of immunoglobulin (Dutcher bodies) (×1000).
B, Small lymphocyte-like variant resembling lymphoma (×400). C, Blastic variant with prominent nucleoli resembling acute leukemia
(×400). D, Pleomorphic variant with markedly atypical nuclei and multinucleated plasma cells (×400). Inset, Higher magnification of
Wright-Geimsa stain of same case as D (×1000). (A-D, hematoxylin-eosin.)

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832 12  Hematopoietic Tumors
TABLE 12-3 Summary of Microscopic and
Immunophenotypic Features
of Myeloma Cells
Microscopic
Cytoplasm
Dense eosinophilic to amphophilic cytoplasm
Perinuclear hof
Variable immunoglobulin inclusions: Russell bodies, Mott
cells, rare crystals/rods or granules
Nucleus
Clumped “clock face” chromatin pattern
Variable features: Prominent nucleoli, open blastic
chromatin
Variable immunoglobulin inclusions: Dutcher bodies
Ultrastructure
Clumped chromatin
Prominent Golgi
Immunophenotypic
Cytoplasm
CD138+, CD79a+, CD56+ (majority)
CD19−, CD20−, CD45− or dim (majority)
κ or λ light chain restriction by immunohistochemistry or
in situ hybridization
Variable: Small lymphocyte-like variant may express CD20
Nucleus
MUM1+
Variable: Subset of cases show overexpression of cyclin
D-1
Variable: Small lymphocyte-like variant may express PAX5
Pitfalls
Various carcinomas and occasional melanomas may be
positive for CD138
The majority of melanomas are positive for MUM1
Immunohistochemical stains or in situ hybridization for
immunoglobulin κ and λ are very helpful in distinguish-
ing reactive polytypic plasma cell infiltrates from plasma
cell myeloma. The normal κ-to-λ ratio is approximately
2 or 3 : 1. Increased polytypic plasma cells may be seen
in a number of reactive conditions, including viral and
bacterial infections, autoimmune disease, cirrhosis, and
solid tumors.23
The presence of other inflammatory cells together
with associated fibrosis and a prominent vasculature
favors a reactive process. The clinical and radiographic
data in such cases with the absence of bone marrow plas-
macytosis, a lack of multifocal skeletal changes, and the
absence of the M component are additional general clini-
cal, radiologic, and laboratory features that support the
diagnosis of a benign disorder.
An unusual pattern of immunoproliferation, including
numerous polyclonal plasma cells and reactive immu-
noblasts, may mimic plasma cell myeloma. This prolif-
eration has been termed systemic polyclonal immunoblastic
proliferation and may present with systemic symptoms and
plasma cell infiltrates mimicking plasma cell myeloma.
The proliferation involves blood and bone marrow with
variable involvement of other organs and tissues. The
ERRNVPHGLFRVRUJ
infiltrates may be composed by up to 50% of plasma
cells.51 The polyclonal nature of the plasma cells may
be demonstrated by immunohistochemical stains, in
situ hybridization, or polymerase chain reaction (PCR)
studies for immunoglobulin clonality.
Neuroendocrine tumors and melanoma may have
plasmacytoid cytomorphology but can be differentiated
from plasma cell myeloma by staining for neuroendo-
crine markers such as synaptophysin and chromogranin
(CD56 will not resolve this diagnostic dilemma). The
majority of melanomas express MUM1, and a subset
of melanoma cases may show variable expression of
CD138.27,48 Most plasma cell myelomas are strongly and
uniformly positive for CD138 and MUM1, while the
staining is typically more variable in melanoma. Κ and λ
immunohistochemical stains will show monotypic light
chain expression in the majority of plasma cell myeloma
cases, whereas melanoma is negative for light chain
expression and positive for S-100 in the majority of cases.
HMB-45 or Melan-A may stain unusual S-100– negative
cases of melanoma.
Pleomorphic variants of plasma cell myeloma may
resemble carcinoma or lymphoma histologically. Care
should be taken in selecting and interpreting immuno-
histochemical stains in tumors with pleomorphic or ana-
plastic morphology. Several types of carcinomas may
show variable expression of CD138 and MUM1.47,55
Again, staining for CD138 and MUM1 is typically
uniform in plasma cell myeloma and more variable in
carcinomas. Κ and λ immunohistochemical stains will
show monotypic light chain expression in the majority of
plasma cell myeloma cases. Although carcinoma and
plasma cell myeloma may be positive for EMA, a variety
of cytokeratin stains will be positive in the majority of
carcinomas and negative in plasma cell myeloma. Most
T-cell lymphomas will express some combination of
T-cell lineage markers (CD2, CD3, CD4, CD5, CD7,
CD8), which are absent in plasma cell myeloma. Inter-
pretation of B-cell lineage markers is more problematic,
because the majority of markers expressed by plasma cell
myeloma may also be expressed in various subtypes
of B-cell lymphomas. Plasma cell myeloma is typically
negative for CD20, but a subset of myelomas, including
the small lymphocyte-like variant, may express CD20
and PAX5 (Fig. 12-15). In difficult cases, staining for
CD56, CD117, or uniform strong staining for cyclin D1
support a diagnosis of plasma cell myeloma. Clinical
workup for myeloma may help distinguish B-cell lym-
phoma from plasma cell myeloma in cases with overlap-
ping features.43
Finally, the small lymphocyte-like variant of plasma
cell myeloma has many morphologic and immunohisto-
chemical similarities with mature B-cell lymphomas with
small cell cytomorphology.29 In particular, this variant
may be misdiagnosed as mantle cell lymphoma on the
basis of staining with CD20 and cyclin D1 (Fig. 12-15).
Mantle cell lymphoma will be positive for CD5 in the
majority of cases, and cyclin D1, while positive in the
majority of cells, will show variable intensity of staining
from cell to cell. Plasma cell myeloma will be negative
for CD5 and typically shows strong homogeneous stain-
ing of the myeloma cells.43
 12  Hematopoietic Tumors 833

C D
FIGURE 12-15  ■  Plasma cell myeloma, small lymphocyte-like variant: microscopic and immunohistochemical features. A, Multiple
myeloma small lymphocyte-like variant involving bone marrow (×200). Inset, Small lymphocyte-like variant of multiple myeloma
with small nuclei and scant cytoplasm (×1000). B, Cyclin D1 immunohistochemical stain of small lymphocyte-like plasma cells. Note
bright homogeneous nuclear staining (×200). C, PAX5 immunohistochemical stain of small lymphocyte-like plasma cells (×200).
D, CD20 immunohistochemical stain of small lymphocyte-like plasma cells (×200). (A-D, hematoxylin-eosin; inset, Wright-Geimsa
stain)

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834 12  Hematopoietic Tumors

A B

C D
FIGURE 12-16  ■  Plasma cell myeloma: microscopic and ultrastructural features. A, Intermediate power photomicrograph shows
proliferation of atypical plasma cells (×200). B, Amorphous eosinophilic extracellular deposition of amyloid associated with myeloma
(×200). C, Higher power photomicrograph of B showing amyloid associated with myeloma (×400). D, Ultrastructural features of
myeloma cells. Note resemblance to normal plasma cells. Cells have eccentric nuclei with prominent nucleolus and peripherally
clumped chromatin. Cytoplasm contains abundant rough endoplasmic reticulum (×3500). (A-C, hematoxylin-eosin.)

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 12  Hematopoietic Tumors 835

Initiation Progression
Germinal Center Bone marrow Peripheral blood

Post-germinal- Smoldering Plasma cell

MGUS Myeloma
center B cell myeloma leukemia

Inherited variants
Primary genetic events:
• IGH @ translocations
• Hyperdiploidy
Secondary genetic events:
• Copy number abnormalities
• DNA hypomethylation
• Acquired mutations

Competition selection for bone marrow niche Migration and

founder effect

Clonal advantage
g

Tumor cell diversity

Genetic lesions

FIGURE 12-17  ■  Initiation and progression of plasma cell myeloma. Monoclonal gammopathy of undetermined significance (MGUS)
is an indolent, asymptomatic condition that transforms to myeloma at a rate of 1% per annum. Smoldering myeloma lacks clinical
features; by contrast, symptomatic myeloma has various clinical features that are collectively referred to as calcium, renal, anemia,
and bone abnormalities (CRAB), which provide an indication that treatment is required. Later in the disease progression, the
myeloma plasma cells are no longer restrained to growth within the bone marrow and can be found at extramedullary sites and as
circulating leukemic cells. It is thought that transition through these different states requires the acquisition of genetic abnormalities
that lead to the development of the biologic hallmarks of myeloma. The initial deregulated cell belongs to the MGUS clone; however,
subsequent to the development of sufficient genetic abnormalities, it acquires a clonal advantage, expands, and evolves. This clonal
evolution is through the branching pathways that are typically associated with Darwin’s explanation of the origin of species. During
the evolution of MGUS to myeloma, these processes lead to the development of numerous ecosystems, which correspond to the
clinically recognized phases of disease. At the end of this evolutionary process, at the stage of plasma cell leukemia (PCL), the clone
is proliferative and no longer confined to the bone marrow; the clone expands rapidly and leads to patient death. Cells at this stage
are substantially altered genetically, and the precursor subclones will be present at low levels because of competition for access to
the stromal niches in the bone marrow: these clones may be eradicated by more aggressive clones. In evolutionary terms, this
phase of disease could be considered to be initiated by a migration and founder effect whereby a cell that is able to survive
and grow in the peripheral blood is faced with no competition, thus limiting its clonal expansion. IGH@, immunoglobulin heavy
chain locus. (Modified and reprinted with permission from Morgan G, et al: The genetic architecture of multiple myeloma. Nature Rev
12:335-348, 2012.)

Genetic Features and Pathogenesis
The normal cell counterpart is a postgerminal center
plasma cell with clonal immunoglobulin gene rearrange-
ments and somatic hypermutation of immunoglobulin
genes, typically secreting antibody. Following early
molecular events, the abnormal plasma cells migrate to
the bone marrow, where the cells are supported by their
interactions with constituents of the marrow microenvi-
ronment. Subclones with slightly different mutations
compete for survival within the marrow microenviron-
ment. This stage of disease represents MGUS. Random
mutations result in progression of disease and clonal evo-
lution of multiple subclones. These subclones undergo
natural selection, resulting in survival and proliferation
of the best adapted clone or clones, at this stage repre-
senting plasma cell myeloma and in some cases plasma
cell leukemia (Fig. 12-17).46
Plasma cell myeloma can be broadly divided into two
major molecular categories: hyperdiploid and nonhyper-
diploid. The majority of both hyperdiploid and non-
hyperdiploid cases show features of dysregulation of D
cyclins, driving cell growth. Overall, hyperdiploid cases
have a better prognosis. Hyperdiploidy in plasma cell
myeloma is the result of trisomies of the odd-numbered
chromosomes 3, 5, 7, 9, 11, 15, 19, and 21. Nonhy-
perdiploid cases are associated with reciprocal transloca-
tions involving immunoglobulin genes. Hyperdiploidy

ERRNVPHGLFRVRUJ
836 12  Hematopoietic Tumors

TABLE 12-4 Genetic Events Underlying the Initiation and Progression of Myeloma to Plasma
Cell Leukemia
Inherited Variations Molecular Hallmarks
Single-Nucleotide Polymorphisms Immortalization
2p: DTNB and DNMT3A G1/S abnormality: CDKN2C, RB1 (3%), CCND1 (3%), and
3p: ULK4 and TRAK1 CDKN2A
7p: DNAH11 and CDCA7L Proliferation: NRAS (21%), KRAS (28%), BRAF (5%), and MYC
(1%)
Primary Genetic Events (% of tumors) Resistance to apoptosis: PI3K and AKT
IGH@ Translocations and Genes Affected NFĸB pathway: TRAF3 (3%), CYLD (3%), and I-ĸB
Abnormal localization and bone disease: DKK1, FRZB, and
t(4;14): FGFR3 and MMSET (11%) DNAH5 (8%)
t(6;14): CCND3 (<1%) Abnormal plasma cell differentiation: (XBP1 (3%), BLIMP1
t(11:14): CCND1 (14%) (also known as PRDM1) (6%), and IRF4 (5%)
t(14;16): MAF (3%) Abnormal DNA repair: TP53 (6%), MRE11A (1%), and PARP1
t(14;20): MAFB (1.5%) RNA editing: DIS3 (13%), FAM46C (10%), and LRRK2 (5%)
Hyperdiploidy (57%) Epigenetic abnormalities: KDM6A (also known as UTX) (10%),
MLL (1%), MMSET (8%), HOXA9, and KDM6B
Trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 Abnormal immune surveillance
Secondary Genetic Events (% of tumors) Abnormal energy metabolism and ADME events
Gains Epigenetic Events
1q: CKS1B and ANP32E (40%) Global hypomethylation (MGUS to myeloma)
12p: LTBR Gene-specific hypermethylation (myeloma to plasma cell
17q: NIK leukemia)
Secondary Translocations
t(8;14): MYC
Other non-IGH@ translocations
Deletions
1p: CDKN2C, FAF1, and FAM46C (30%)
6q (33%)
8p (25%)
11q: BIRC2 and BIRC3 (7%)
13: RB1 and DIS3 (45%)
14q: TRAF3 (38%)
16q: CYLD and WWOX (35%)
17p: TP53 (8%)

Reprinted with permission from Morgan GJ, Walker BA, Davies FE: The genetic architecture of multiple myeloma, Nature
Reviews 12:335-348, 2012..
ADME, absorption, distribution, metabolism, and excretion; ANP32E, acidic (leucine-rich) nuclear phosphoprotein 32 family, member E;
BIRC, baculoviral IAP repeat-containing protein; BLIMP1, B lymphocyte-induced maturation protein 1; CCND, cyclin D; CDCA7L, cell
division cycle-associated 7-like; CDKN, cyclin-dependent kinase inhibitor; CKS1B, CDC28 protein kinase regulatory subunit 1B;
CYLD, cylindromatosis; DNAH, dynein, axonemal, heavy chain; DNMT3A, DNA methyltransferase 3α; DTNB, dystrobrevin, beta;
FAF1, FAS-associated factor 1; FAM46C, family with sequence similarity 46, member C; FGFR3, fibroblast growth factor receptor 3;
HOXA9, Homeobox A9; IGH@, immunoglobulin heavy chain locus; IRF4, interferon regulatory factor 4; I-ĸB, inhibitor of nuclear factor
ĸB, KDM, lysine demethylase; LRRK2, leucine-rich repeat kinase 2; LTBR, lymphotoxin beta receptor; MGUS, monoclonal gammopathy
of undetermined significance; MLL, mixed-lineage leukemia; MMSET, multiple myeloma SET domain; MRE11A, meiotic recombination
11A; NFĸB, nuclear factor ĸB; PARP1, poly (ADP-ribose) polymerase 1; TP53, TRAF3, TNF receptor-associated factor 3;
TRAK1, trafficking protein, kinesin binding 1; ULK4, unc-51 like kinase 4;WWOX, WW domain-containing oxidoreductase; XBP1, X
box-binding protein 1.

and immunoglobin gene translocations represent early
molecular events in plasma cell neoplasia, and the major-
ity of cases of MGUS harbor one of these abnormalities.
In addition to these major molecular categories, inher-
ited single nucleotide polymorphisms and monosomy or
partial deletion of chromosome 13 are recognized as ini-
tiating events (Table 12-4 and Fig. 12-18).36
Early chromosomal translocations in MGUS and
plasma cell myeloma most frequently involve the immu-
noglobulin heavy chain gene IGH@ on chromosome 14,
and less frequently involve lambda light chain gene IGL@
on chromosome 22. These translocations are thought to
arise from aberrant class switch recombinations or
somatic hypermutations mediated by activation-induced
deaminase (AID). As a result of these translocations,
expression of partner genes is placed under the control
of the immunoglobulin gene enhancer, with associated
enhanced expression of the partner gene product. The
most frequent gene partners in these translocations are
CCND1, CCND3, MMSET, FGFR3, MAF, MAFB, and
MMSET/FGFR (Table 12-4 and Figs. 12-19 and 12-20).
CCND genes encode D cyclins involved in cell cycle
progression. Overall, these translocations are associated
with worse prognosis, with the exception of t(11;14)
IGH@/CCND1 (Fig. 12-19), which confers a better
prognosis.46
Mutations associated with disease progression and
proliferation are additional genetic gains and losses,

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 837

Rare de novo MM

Germinal center Intramedullary Extramedullary

MGUS
B cell myeloma myeloma

Karyotype and epigenetic abnormalities

Nonhyperdiploid
1ry Ig tx
Secondary (Ig) TLC
11q13
6p21 NF-κB - activating mutations
16q23
PIsK/AKT dysregulation: DEPTOR, PTEN, PIK3CA
20q11
4p16
other

DEL 13

Protein translation/RNA processing

Trisomy FAM46C, DIS3, XBP1, LRRK2 mutation
3, 5, 7,
9, 11,15, N-RAS
Hyperdiploid

19, 21 K-RAS, FGFR3, BRAF

MYC (Ig) rearrangement
↑MYC RNA P18, RB inactivation
Cyclin D dysregulation ± MYC rearrangement p53 inactivation
? BLIMP1, IRF4 mutation

Definite
Uncertain TR1 TR2
FIGURE 12-18  ■  Model for molecular pathogenesis of monoclonal gammopathy of undetermined significance and plasma cell
myeloma. The initial transition (TR1) to a recognizable tumor involves two mostly nonoverlapping pathways (IGH translocations
versus multiple trisomies) that include primary events associated with disregulated cyclin D expression in monoclonal gammopathy
of undetermined significance (MGUS) and multiple myeloma (MM). The transition from MGUS to MM (TR2) is associated with
increased MYC expression and sometimes with activating mutations of K-RAS or chromosome 13 deletion. Early and late progres-
sion events for symptomatic MM tumors are shown. (Modified and reprinted with permission from Kuehl WM, et al: Molecular patho-
genesis of multiple myeloma and its premalignant precursor. J Clin Invest 122:3456-3463, 2012.)

secondary translocations involving immunoglobulin
genes, translocations involving MYC, epigenetic changes,
and mutations resulting in dysregulation of various sig-
naling pathways (Table 12-4 and Fig. 12-18). NFκB is an
example of a key pathway that is constitutively activated
as a result of both activating and inactivating mutations
of the regulators of this pathway. NFκB activation is
important for cell survival.8
Genome sequencing of 38 cases of plasma cell myeloma
detected 23 translocations and 35 point mutations that
resulted in an amino acid changes. These mutations were
detected in several classes of genes with various functions
and included genes known to be mutated in plasma cell
myeloma as well as several genes in which mutations had
not previously been detected. These mutations included
oncogenes and genes involved in RNA processing,
protein homeostasis, histone modification, and cell sig-
naling. Frequently mutated genes included TP53, NRAS,
KRAS, and genes involved in the NFκB signaling pathway.
Although not common, mutations of BRAF were also
detected in 4% of patients.13
Several microRNAs are upregulated or downregulated
in myeloma and other neoplasms.17,194 For example,
microRNAs 15a and 16 are downregulated in myeloma.
When present at normal levels, microRNAs 15a and 16
are thought to decrease BCL-2 expression, inhibit the
NFkB pathway, and inhibit angiogenesis.54 Levels of cir-
culating microRNAs have also been shown to have prog-
nostic and theragnostic significance in myeloma.7
In addition to being secreted, microRNAs, cytokines,
and other proteins can also be directly transferred from
bone marrow stromal cells and internalized by myeloma
cells via exosomes, small membrane bound vesicles. In
particular, a recent study found that bone marrow stromal
cells in plasma cell myeloma produced exosomes contain-
ing increased interleukin-6 (IL-6) and decreased microR-
NA15a relative to normal bone marrow stromal cells.
The study demonstrated transfer of these altered exo-
somes from the mesenchymal cells to the myeloma cells.53
The mechanism by which microRNA 15a is decreased is
unknown; however, a recent sequencing study detected
mutations of DIS3, an exosome-based RNase, in approxi-
mately 10% of myeloma samples.59
The neoplastic plasma cells in plasma cell myeloma
share complex interactions with constituents of the
bone marrow microenvironment, including bone marrow

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838 12  Hematopoietic Tumors

Chr 11 Chr 14 Chr der(11) Chr der(14)

15.5 13 Reciprocal
15.4 12 product
15.3
15.1 15.2 11.2
11.1 11.1
14 11.2
13 12
12 13
11.2 11.12
11.11 21
11
12 13.1 22
13.2 CCND1 23
24.1
13.4 13.3 24.2
14.1 13.5 24.3
14.3 14.2 31
22.1 21 32.1 IgH Enhancer
22.2 32.2 32.3
22.3
23.2 23.1 CCND1
IgH REGION
23.3 Fusion
24
25 product

CCND1

Exon 1

Exon 2
Exon 3

Exon 4

Exon 5
69455872

69469242
Chr 11
cen tel
B 11q13 breakpoints

IgH REGION
Constant JH ∼20kb DH ∼50kb VH ∼900kb
region IgH Enhancer (1-4) (1-12) (1,2,...,n)
Chr 14
14q32 breakpoint
Exon 1

Exon 2
Exon 3

Exon 4

Constant Exon 5
region IgH Enhancer

cen tel

Fusion product t(11;14)(q13;q32)

C
FIGURE 12-19  ■  Translocation t(11; 14)(q13;q32). A, Chromosomal diagrams depicting reciprocal translocation involving fragments
of the q arm of chromosome 11 with a breakpoint at q13 and a small fragment of q arm of chromosome 14 with a breakpoint at
q32. The breakpoint on chromosome 11 involves the CCND1 locus and juxtaposes this gene in front of the IgH on chromosome 14.
B, The genomic structure of the involved genes with the position of the most frequent breakpoints. The breakpoints with CCND1
occur centromerically to exon 1; the breakpoints within the IgH region involve the region telomeric to the IgH enhancer. C, The
resulting hybrid gene contains the entire reading frame of CCND1 regulated by the strong IgH enhancer.

matrix, stromal cells, endothelial cells, T cells, dendritic and survival, such as IL-6, insulin growth factor-1, B-cell
cells, and osteoclasts and osteoblasts and their precursors activating factor, and a proliferation inducing ligand.36
(Fig. 12-21). These interactions can be categorized as IL-6 is one of the key cytokines produced by both
adhesion-mediated and cytokine-mediated. myeloma cells and the cells of the bone marrow microen-
Adhesion molecules play a role in homing and local- vironment. IL-6 promotes proliferation and blocks apop-
ization of myeloma cells to the bone marrow and mediate tosis of myeloma cells. IL-6 is secreted by bone marrow
the direct cell interactions between myeloma cells and stromal cells, osteoclasts, and osteoblasts. The normal
the constituents of the bone marrow microenvironment. homeostasis of bone formation and resorption is disrupted
Two adhesion molecules expressed by myeloma cells are in plasma cell myeloma and is mediated by cytokines such
syndecan 1 (CD138) and neural cell adhesion molecule as macrophage inflammatory protein-1α (MIP-1α) pro-
(CD56). Myeloma cells that are bound to bone marrow duced by plasma cells and receptor activator of nuclear
constituents demonstrate resistance to chemotherapy.31 factor κB ligand (RANKL) produced by marrow stromal
The binding of plasma cells to the stromal cells via adhe- cells. Increased MIP-1α and RANKL promote osteo-
sion molecules results in upregulation of the secretion of clast differentiation and activation. Increased Dickkopf-
multiple cytokines that enhance plasma cell proliferation related protein 1 (DKK1) produced by myeloma cells and

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 839

FGFR3

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
Exon 17

Exon 18
Exon 1
Exon 2

Exon 3
Exon 4

Exon 5
Exon 6
Exon 7

Exon 8

Exon 9
Chr 4
Chr 14
MMSET FGFR3
13
16 12
15.3 11.2
15.2
15.1
11.1 11.1 FGFR3
11.2
14 12 1 806 aa
13 13 39 112 151 248 253 358 461 777
12 11
11 21
12 Immunoglobuline-like domain Protein kinase, catalytic domain
13.1 22
13.3 13.2 23
21.1 24.1
21.2 24.2
21.3 24.3
22 31
23 32.1
24 32.2
25 32.3
26 IgH REGION
27
MMSET
28 t(4;14)

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
Exon 17
Exon 18

Exon 19
Exon 20
Exon 21
Exon 22
31.1

Exon 2
Exon 3

Exon 4
Exon 5

Exon 6
Exon 7
Exon 8
Exon 9
Exon 1
31.2
31.3
32
33
34
35
A MMSET
1 1365 aa
219 287 433 522 632 713 816 891 943 1011 1062 1186 1205 1296

PWWP (Pro-Trp-Trp-Pro) AWS domain Zinc Finger domain

HMG (High Mobility Group) SET domain
B

P P P P P*
Chr14q32 Em Im Sm Sg g 3’Ea Chr4p16 FGFR3 1 3 MMSET

Switch recombination
t(4;14)
P DJ P P P P*
Chr14q32 Em Im Sm Im Ig Sg g 3’Ea der(4) Em Im Sm 3 MMSET

C P P
der(14) FGFR3 1 Sg g 3’Ea

Eµ - IgH enhancer P - promoter

Eα - 3’IgH enhancer P* - cryptic promoter
D
FIGURE 12-20  ■  Translocation t(4;14)(p16.3;q32.2) in plasma cell myeloma involving the IgH locus. A, Chromosomal diagrams depict-
ing reciprocal translocation involving small fragments of the p arm of chromosome 4 with a breakpoint at p16.3 and a fragment of
q arm of chromosome 14 with a breakpoint at q32.2. The translocation is undetectable by conventional cytogenetic analysis.
B, Genomic and protein structures of the FGFR and MMSET genes involved t(4 : 14) and mapping to 4p16.3. The breakpoints on
chromosome 4 at p16.3 involve two alternative genes. They can occur in the region mapping to the FGFR3 or MMSET genes.
C, Translocations involving an immunoglobulin (Ig) locus—an early event that dysregulates an oncogene by juxtaposing it near a
strong Ig enhancer—are important in many B-cell neoplasms. The translocation breakpoints in the non-Ig chromosome (chr.) are
usually mediated by unknown mechanisms, but the location of the breakpoints in the Ig loci indicates involvement of three B-cell
mechanisms that generate double-stranded DNA breaks while remodeling the Ig loci during development. VDJ recombinase break-
points occur close to sites that are involved in VDJ recombination, somatic hypermutation breakpoints occur in the mutation-
susceptible region downstream of Ig promoters, and Ig heavy chain (IgH) switch breakpoints occur within or very near repetitive
switch regions that are located upstream of each IgH constant region. Breakpoints that are mediated by VDJ recombination or
somatic hypermutation occur telomeric to the intronic IgH enhancer (Eµ), which remains associated with the 3′ IgH enhancer(s) (Eα)
located downstream of one or both of the α-IgH genes on the derivative of chromosome 14 [der(14) ]. By contrast, breakpoints that
are mediated by switch recombination dissociate Eµ and Eα, so that distinct genes can be dysregulated by an IgH enhancer on each
derivative chromosome. During normal IgH switch recombination from µ (line 2) to γ, there is formation of a hybrid µ/γ switch region,
with deletion of intervening sequences (line 1). D, Similarly, a translocation that is mediated by an error in IgH switch recombination
generates separate double-stranded DNA breaks in µ and γ switch regions. These two ends are joined to the two ends created by
a third double-stranded break in another chromosome (4p16.3 in line 3), again with loss of intervening sequences. In this way, the
intronic enhancer (Eµ) on der(4) becomes juxtaposed to MMSET, which encodes a nuclear SET domain protein. This results in hybrid
mRNA transcripts that initiate from the JH and Iµ promoters, but also from a cryptic promoter (P*) on 4p16. The 3′ enhancer (3′ Eα)
on der(14) dysregulates the expression of FGFR3 (fibroblast growth factor receptor 3), and sometimes results in reciprocal hybrid
mRNA transcripts between the noncoding exons of MMSET and a constant region (γ). (Based on and adapted from data from Kalff A,
et al: The t4;14) translocation and the FGFR3 overexpression in multiple myeloma: prognostic implications and current clinical strategies.
Blood Cancer J 2, e89; doi:10.1038/bcj.2012.37, 2012 and Dalton WS, et al: Multiple myeloma. Hematology Am Soc Hematol Educ Program
157–177, 2001. Kuehl WM, et al: Multiple myeloma: evolving genetic events and host interactions. Nature Reviews Cancer 2:175–187,
2002.)

ERRNVPHGLFRVRUJ
840 12  Hematopoietic Tumors

osteoblast OPG osteoclast

MIP-1

DKK1
IL-6
IL-6
6
RANKL
RANK
RANKL
IL-3

adhesion m
Dysregulated ole
cu
les
MYC
Hypoxia HIF-1α
IGF-1
MM
IL-6
IL 6

BAFF/APRIL
cell
T cell

RANKL stromal cell

VEGF IGF-1

Endothelial cell
Endothelial
FIGURE 12-21  ■  Interactions of plasma cell myeloma tumor cells with the bone marrow microenvironment. Five kinds of cells in the
bone marrow (BM) microenvironment are depicted, as well as a few of the complex interactions among these cells and myeloma
plasma cells. Some critical survival and growth factors, such as interleukin-6 (IL-6), are made by more than one kind of BM cell.
External stimuli such as hypoxia and internal signals resulting from dysregulated MYC, stimulate HIF-1α and VEGF secretion, which
in turn stimulate endothelial cells to secrete insulin-like growth factor-1 (IGF-1). The hallmark uncoupling of bone remodeling is
partially explained by an increase in osteoclast activity (mediated by RANKL/RANK interactions, decreased osteoprotegerin [OPG],
and increased MIP-1α) and a decrease in osteoblast activity (mediated by DKK1 and IL-3). The resultant increase in osteoclast activity
stimulates the survival and growth of MM cells, at least partially by increased IL-6. Potential therapeutic agents that directly inhibit
some of these interactions include bisphosphonates (which inhibit osteoclast function), anti-RANKL antibody, anti-DKK1 antibody,
and exogenous OPG. (Modified and reprinted with permission from Kuehl WM, et al: Molecular pathogenesis of multiple myeloma and its
premalignant precursor. J Clin Invest 122:3456–3463, 2012.)

decreased osteoprotegerin result in decreased osteoblast
differentiation and activation. This disruption results in
net loss of bone and the characteristic osteolytic lesions
seen in plasma cell myeloma.36
Increased vessel density supports tumor growth and is
associated with poor prognosis in plasma cell myeloma.
Vascular endothelial growth factor (VEGF) is produced
by myeloma cells, marrow stromal cells, and vascular
endothelial cells. VEGF promotes vascular proliferation
and also upregulates secretion of IL-6 from marrow
stromal cells. VEGF secretion is upregulated by MYC
expression and hypoxia inducible factor-1α (HIF-1α).36
Amyloidosis Associated with
Multiple Myeloma
Amyloidosis with significant impairment of the functions
of involved organs is present in approximately 10% of
patients with plasma cell myeloma.39 These cases repre-
sent primary amyloidosis (also known as AL or immuno-
globulin light chain amyloidosis), in which clonal plasma
cells secrete AL amyloid consisting of light chains or light
chain fragments. AL amyloid is most frequently depos-
ited in the bone marrow, kidneys, gastrointestinal tract,
liver, spleen, muscle (e.g., tongue), skin, and nervous
system. The involvement of the kidneys, the heart, or
both is most ominous. Involvement of the heart muscle
occurs in 60% of primary amyloidosis, and patients with
amyloidosis-related congestive heart failure have a
median survival of approximately 6 months, compared to
a median survival of 2 years for primary amyloidosis as a
group.39 The t(11;14) is more common in primary amy-
loidosis than in plasma cell myeloma as a group.22
Distinct Forms of Myeloma
The majority of myelomas present with a triad of
obvious radiologic, laboratory, and pathologic findings,
but in a small percentage of cases, the presentation may
significantly deviate from this pattern. These distinct
forms of myeloma are designated as solitary plasmacy-
toma of bone, extramedullary plasmacytoma, nonsecre-
tory myeloma, plasma cell leukemia, and osteosclerotic
myeloma (POEMS).

ERRNVPHGLFRVRUJ

A B
FIGURE 12-22  ■  Solitary plasma cell myeloma. A, Lateral radiograph of tibia shows large, expansile lytic lesion in diaphysis with
pathologic fracture of midshaft. B and C, T1- and T2-weighted magnetic resonance images show replacement of marrow by tumor
mass and fracture line extending from anterior cortex to posterior surface.
Solitary Plasmacytoma of Bone.  Solitary plasmacy-
toma of bone is a localized form of neoplastic plasma cell
proliferation accounting for less than 5% of plasma cell
neoplasms.60 It represents a clonal neoplastic prolifera-
tion of plasma cells that produces a solitary destructive
bone lesion as seen on a radiologic skeletal survey (Fig.
12-22) but is otherwise without bone marrow involve-
ment or features of end-organ damage (CRAB) (Table
12-2).38 The natural history of this disease is somewhat
unpredictable but is distinct from ordinary multiple
myeloma. Patients usually have levels of monoclonal
gammopathy lower than 3 g/dL. Approximately 25% of
patients with solitary myeloma have no M component in
the serum by electrophoresis. An abnormal serum free
light chain ratio can be detected in more than half of the
patients with no M component by electrophoresis.
Solitary plasmacytoma of bone most frequently affects
vertebral bodies (approximately 50% of cases). The other
typical sites of involvement are the pelvis, femur, and
humerus.62 Radiographically, the lesion presents as a
lytic and destructive process with minimal or no blastic
reaction.
From 65% to 84% of patients with solitary plasmacy-
toma of bone will progress to plasma cell myeloma within
5 years, and 65% to100% will progress to myeloma in 10
years.34 After progression to plasma cell myeloma, patients
with the initial presentation of solitary plasmacytoma of
ERRNVPHGLFRVRUJ
12  Hematopoietic Tumors 841
C
bone have longer overall survival than plasma cell
myeloma patients with typical presentation.60
The treatment of solitary plasmacytoma of bone is
primarily local and consists of radiation therapy with
surgical stabilization when needed.25
Extramedullary Plasmacytoma.  Extramedullary plas-
macytoma is a localized neoplastic plasma cell prolifera-
tion otherwise without bone marrow involvement or
features of end-organ damage (CRAB) (Table 12-2). It
accounts for less than 5% of plasma cell neoplasms.60 The
majority of extramedullary plasmacytomas develop in the
upper respiratory tract but have been described in virtu-
ally every organ.25,33,35,50
Extramedullary plasmacytoma has a better prognosis
than solitary plasmacytoma of bone. Head and neck plas-
macytomas have a more favorable prognosis. The recur-
rence rate is less than 10%. From 30% to 50% of patients
will progress to plasma cell myeloma but have longer
survival (50-80% 10-year survival) than plasma cell
myeloma patients with typical presentation.34
Nonsecretory Myeloma.  In approximately 5% of
patients with multiple myeloma, no monoclonal protein
can be demonstrated in the serum or urine by electro-
phoresis. By serum free light chain assay, less than 3% of
patients have undetectable monoclonal protein.42 These
842 12  Hematopoietic Tumors
myelomas are referred to as nonsecretory myelomas.21 In the
majority of these cases, immunohistochemical studies
reveal monoclonal immunoglobulin synthesis restricted
to the light or heavy chains.32 This indicates that the
tumor cells retain the ability to synthesize immunoglobu-
lin but the products cannot be secreted extracellularly.42
Rare cases (approximately 15%) show no evidence of
immunoglobulin production by immunohistochemis-
try.38 In one nonsecretory myeloma patient, a κ light
chain frameshift mutation was detected that prevented
linking of the immunoglobulin chains.14 Some series have
reported better prognosis in nonsecretory myeloma,
while others report statistics similar to conventional
plasma cell myeloma.56 These discrepancies may be due
to varying cytogenetic findings that were not investigated
specifically. In one series of patients with IgM or IgD
nonsecretory myeloma, 83% harbored t(11;14), which
may account in part for the better prognosis reported in
some series.9,42
Plasma Cell Leukemia.  Plasma cell leukemia is diag-
nosed when more than 20% of the white blood cells in
the peripheral blood represent neoplastic plasma cells or
the absolute number of tumor plasma cells exceeds 2 ×
109/L.52 Plasma cell leukemia typically presents as a late
complication of advanced multiple myeloma. It is seen in
approximately 2% to 5% of terminal multiple myeloma
cases.52 In extremely rare cases, plasma cell leukemia may
be present de novo.43 In all instances, plasma cell leuke-
mia heralds a particularly aggressive form of myeloma
that is associated with massive replacement of the bone
marrow and poor survival (usually <6 months).18,24,49,63
Plasma cell leukemia is more frequently observed in
IgE, IgD, and light chain only myelomas.55,61 Plasma
cell leukemia cells often exhibit an immature blastic
morphology.12
Osteosclerotic Myeloma (POEMS).  POEMS syn-
drome is a paraneoplastic syndrome caused by a clonal
plasma cell population. Historically, the clinical manifes-
tations, as represented by the acronym, were polyneu-
ropathy, organomegaly, endocrinopathy, monoclonal
protein in serum or urine, and skin changes.10,28 However,
the original components of the syndrome as listed do
not always manifest. Mandatory major criteria required
for the diagnosis of POEMS are polyneuropathy and
the presence of a clonal plasma cell proliferation. Λ
light chain is expressed in more than 95% of cases. A
definitive diagnosis requires meeting at least one addi-
tional major criterion (Castleman disease, one or more
osterosclerotic lesion, or vascular endothelial growth
factor [VEGF] elevation) and one minor criterion
(organomegaly, extravascular volume overload, endocri-
nopathy, skin changes, papilledema, or thrombocytosis
and polycythemia).20
Greater than 95% of patients with POEMS syndrome
have one or more bone lesion, typically sclerotic, but
often mixed lytic and sclerotic or lytic with a sclerotic rim
as visualized by conventional radiographs. Some authors
consider 18F-fluorodeoxyglucose (FDG) PET/CT to be
a better method for visualizing osteosclerotic lesions and
assessing their degree of activity.45
ERRNVPHGLFRVRUJ
Histologically, the bone lesions are composed of sheets
of plasma cells similar to those seen in typical myeloma.
In contrast to typical plasma cell myeloma, the nonle-
sional bone marrow in POEMS syndrome typically con-
tains less than 10% plasma cells and may be completely
normal in approximately 10% of cases. The bone marrow
in the majority of cases shows megakaryocyte clustering.
In approximately half of the cases, the marrow shows
megakaryocyte hyperplasia or lymphoid aggregates sur-
rounded by light chain restricted, usually λ-expressing,
plasma cells.16 The immunohistochemical features are
identical to those described for plasma cell myeloma.
The cell of origin is typically a λ light chain-expressing
plasma cell. The majority of the clinical manifestations
are thought to be mediated by cytokines. VEGF pro-
duced by platelets and the clonal plasma cells is elevated
in all cases of POEMS syndrome. IL-6, tumor necrosis
factor-alpha (TNFα), and IL-1β are also elevated.
POEMS syndrome is treated with radiation or chemo-
therapy. Radiation therapy at the site of bone lesions is
the treatment of choice for patients with two or fewer
bone lesions without other clonal bone marrow plasma-
cytosis. Systemic chemotherapy is given to patients with
three or more bone lesions and to any patient with clonal
bone marrow plasmacytosis. The median overall survival
is approximately 14 years.20
NON-HODGKIN’S LYMPHOMA
Definition
Primary non-Hodgkin’s lymphoma of bone is a prolifera-
tion of malignant lymphocytes classified according to its
extraskeletal counterparts.68,73 Although there is no uni-
versal definition, by convention, an interval of 4 to 6
months between skeletal manifestation of the lesion and
the development of extraskeletal disease is required for
the lesion to be considered a primary tumor in bone. In
every case of lymphoma presenting as a bone lesion, the
appropriate staging procedure is required to rule out the
presence of extraskeletal disease.
Historically, the description of lymphoma as a primary
lesion in bone is credited to Oberling, although he did
not make the distinction between true lymphomas and
Ewing’s sarcoma.97 The recognition of primary lym-
phoma of bone as a clinicopathologic entity distinct from
other lymphomas and especially from Ewing’s sarcoma
was made by Parker and Jackson in 1939.99 Two parallel
classifications based on the functional and phenotypic
features of tumor cells as delineated by marker studies
were proposed by Lukes and Collins in the United States
and by Lennert in Germany (Kiel classification) in 1975
and 1974, respectively.112,115 The simplified Revised
Working Formulation105,106 was published in 1982 in an
effort to bridge the gap between morphologic and clinical
aspects of lymphoma classification, combining some pre-
vious descriptive terms, mainly from the Rappaport
system, with the biologic concepts and terminology pro-
posed by Lukes and Collins.
The Revised European-American Classification System
of Lymphoid Neoplasms (REAL Classification) proposed

Incidence
40
1 2 3 4 5 6
Age in decades
FIGURE 12-23  ■  Epidemiology of non-Hodgkin’s lymphoma of bone. Peak age incidence and frequent skeletal sites of involvement.
Most frequent sites are indicated by solid black arrows.
by the International Lymphoma Study Group74,85 was
published in 1994 and represented a consensus effort to
define the known distinct hematolymphoid neoplasms
in terms of clinical, morphologic, immunophenotypic,
and molecular features. The REAL classification was the
starting point for 7 years of efforts to build the now
generally accepted consensus classification, the World
Health Organization (WHO) Classification of Tumours
of Haematopoietic and Lymphoid Tissues.111
Diffuse Large B-cell Lymphoma
Clinical Features
Primary lymphoma of bone is rare and accounts for 3%
to 7% of bone tumors and less than 2% of adult lympho-
mas overall.79,88 Because of the infrequency of primary
bone lymphoma and the disagreement as to its clinical
definition, there have been few published series docu-
menting patient outcomes, clinical characteristics, and
biological aspects. The following discussion focuses on
diffuse large B-cell lymphoma and is based primarily on
three published large series of primary lymphoma of
bone including several histologic subtypes; however, in
these series, at least 70%, 79%, and 83% of the cases
were classified as diffuse large B-cell lymphoma.66,87,102
ERRNVPHGLFRVRUJ
12  Hematopoietic Tumors 843
7 8
The peak age incidence and most frequent sites of
primary bone lymphoma are shown in Figure 12-23. The
incidence of primary bone lymphoma is rising (Fig.
12-24). More than 50% of primary lymphomas in bone
occur in patients older than age 60 years (Fig. 12-25)87,102
There is a slight male predominance in several major
series, with a male-to-female ratio of approximately 1.2 : 1
(Fig. 12-26).87 The vertebrae, femur, and pelvis are the
most frequently involved bones, accounting for approxi-
mately 29%, 12%, and 13% of lesions, respectively. The
humerus, ribs, and skull are next in frequency, and each
is involved in approximately 10% of cases.102 In general,
non-Hodgkin’s lymphomas have a predilection for the
trunk bones, including the ribs, sternum, and clavicle.
The major long tubular bones, such as the femur and
humerus, are the most frequently involved sites in the
appendicular skeleton. Lymphomas of bone often present
as multifocal lesions. The multifocality can be in the form
of several foci within one bone, or several bones can be
simultaneously affected. The rate of multifocal lesions is
approximately 15%.87
Pain is the most common symptom. Other symptoms,
such as nerve compression, are related to the location of
the tumor. Local tenderness, redness, and swelling may
be present. Pathologic fracture can be the initial symptom.
In contrast with symptoms of Ewing’s sarcoma and
844 12  Hematopoietic Tumors

0.2

0.15
(cases/100,000 persons)
Incidence rate

0.1

0.05

0
73

75

77

79

81

83

85

87

89

91

93

95

97

99

01

03

05
19

19

19

19

19

19

19

19

19

19

19

19

19

19

20

20

20
FIGURE 12-24  ■  Incidence of non-Hodgkin’s lymphoma of bone. A general increase in incidence of cases from 1973 to 2006, similar
to the increased incidence of lymphoma of all sites over this time period. SEER Data, 1973-2006.

12

10
Age distribution (%)

0
9

4
9

+
1

-4

-5
0-

1-

5-

-1

-1

-2

-2

-3

-3

-4

-5

-6

-6

-7

-7

-8

85
50
10

15

20

25

30

35

40

45

55

60

65

70

75

80

FIGURE 12-25  ■  Age distribution of non-Hodgkin’s lymphoma of bone. The peak age of incidence is age 75 to 79 years. There is a
significant increase in incidence after age 45. SEER Data, 1973-2010.

generalized lymphoma, fever is uncommon. Features of
generalized systemic disease, such as lymphadenopathy
and hepatosplenomegaly, are not present at presentation
by definition.
Radiation therapy and chemotherapy are the primary
treatments for non-Hodgkin’s lymphoma of bone.69,78,104
There is no consensus as to the optimal therapy for
localized bone involvement. Conflicting results have
been published, with no clear advantage to radiation
versus chemotheraphy alone versus combined chemo-
therapy and radiation therapy.66
The most important prognostic factors for primary
lymphoma of bone are age at diagnosis and stage of
disease. Patients under age 30 years have high rates of

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 845

0.25

0.2

(cases/100,000 persons)
Incidence rate
0.15

0.1

0.05

es

es

es

es
al

al

al

al

al

al
,m

em

m
fe

fe
es

,f

te

k
ac
es
ac

hi

te

k
ac
Bl
W
ac

hi
lr

Bl
W
Al

lr
Al
FIGURE 12-26  ■  Non-Hodgkin’s lymphoma of bone. Distribution of non-Hodgkin’s lymphoma by race and sex. The most commonly
affected group is white males. SEER Data, 1973-2010.

remission, with approximately 75% survival at 400
months versus 0% survival in patients age 60 years or
older. Patients with lymphoma limited to the bone have
better survival than systemic lymphoma. The 5- and
10-year survival rates for primary bone lymphoma are
65% and 53%, compared with 53% and 43% for patients
with systemic lymphoma in addition to bone masses.87
Radiographic Imaging
Radiographic features of non-Hodgkin’s lymphoma are
not specific and overlap with other small cell tumors.
They usually do not permit a specific diagnosis. Typically,
non-Hodgkin’s lymphoma presents as a lytic destructive
lesion with a permeative or “moth-eaten” pattern (Fig.
12-27).76,101 Prominent periosteal new bone formation
with multiple concentric or so-called onion-skin layers
may be present but is usually less evident than in Ewing’s
sarcoma. In long bones, the shaft is preferentially
involved, and disease may extend to the end of the bone.
A lytic lesion with periosteal reaction at or near the end
of a long bone, while not specific, raises the index of
suspicion for lymphoma (Fig. 12-28).89 Non-Hodgkin’s
lymphoma is usually lytic, but in some cases it provokes
bone sclerosis and presents as a blastic lesion. Rarely,
plain radiographs may show little or no abnormality.96
Computed tomography or MRI are helpful in evaluat-
ing the extent of involvement within bone, to detect
cortical erosion and soft tissue extension of tumor, as well
as to evaluate the extent of involvement of vertebral and
paraspinous lesions. MRI is particularly useful for detect-
ing marrow involvement, which is characteristic in bone
lymphoma. Bone marrow involvement may be detected
by T1-weighted (low signal) or T2-weighted (bright
signal) magnetic resonance images.96 A clue to the diag-
nosis is prominent marrow and soft tissue involvement
with relatively minor cortical bone involvement.89
Radionuclide scintigraphy is helpful in documenting
additional foci of bone involvement, a common feature
of non-Hodgkin’s lymphomas in the skeleton. FDG
PET/CT is useful in staging and confirming disease
limited to the bone.96
Gross Findings
On gross examination, diffuse large B-cell lymphoma of
bone resembles its nodal counterpart and presents as a
pink-tan or gray-white and fleshy lesion (Fig. 12-29).
Areas of necrosis, hemorrhage, and cystic degeneration
may be present. The cortex and the bone at its periphery
show patchy erosions and permeation of the medullary
cavity. Complete cortical disruption and extension into
soft tissue are frequently present. Large masses may show
sharp demarcation at their peripheries. Reactive sclerosis
presents as firm ivory-like areas and may occasionally
occupy a significant portion of the tumor.
Microscopic Findings
The conventional diffuse growth pattern with solid pro-
liferation of round tumor cells permeating the bone
marrow spaces and haversian canals is most frequently
seen. Sclerosing diffuse growth is often focally present in
bone. In this pattern, the tumor cells are separated by
dense fibrous bands and can form nests, cords, or organ-
oid structures. Occasionally, they may have spindle cell
morphology and grow in storiform structures (Fig.
12-30). Compressed tumor cells may also develop a spin-
dled morphology. The presence of reactive lymphocytes
can alter the appearance of these lesions. Deviations from
the classic lymphoma morphology can lead to an errone-
ous diagnosis of an inflammatory condition or nonlym-
phoid tumor, as in the case of the rare signet ring cell
variant of diffuse large B-cell lymphoma (Fig. 12-30).
Immunohistochemical Stains and
Differential Diagnosis
A variety of special studies may be used to supplement
the diagnosis of lymphoma of bone, including flow

ERRNVPHGLFRVRUJ
846 12  Hematopoietic Tumors

A B C
FIGURE 12-27  ■  Non-Hodgkin’s lymphoma of bone: radiographic features. A, Lateral radiograph of humerus of adult who complained
of pain that had been present for several months. Permeative bone destruction with slight expansion of contour is noted over long
segment of humeral diaphysis. Borders of lesion are poorly demarcated. B and C, Anteroposterior and lateral radiographs of lower
tibia and fibula of middle-aged adult show ill-defined destructive lesion in lower tibial shaft. Lesion has moth-eaten appearance.
Rectangular defect seen in B represents previous biopsy site. Biopsy material removed several months earlier was erroneously
interpreted as chronic osteomyelitis.

cytometry, classical cytogenetics, fluorescence in situ
hybridization (FISH) studies for common translocations,
PCR for detection of translocations, and clonal immuno-
globulin gene rearrangement. Gene expression profiling
is useful for subclassifying diffuse large B-cell lymphoma
but is still not widely used in clinical practice. Exome or
whole genome sequencing is becoming more widely
available and likely will be one of the major tools used to
identify actionable genetic alterations, allowing design
and application of regimens, including specific targeted
therapeutic agents.
Immunohistochemistry remains a useful tool in the
diagnosis and subclassification of diffuse large B-cell lym-
phoma. Lymphoma must be distinguished from other
hematopoietic neoplasms, such as plasma cell myeloma,
myeloid sarcoma, Langerhans cell histiocytosis, and masto-
cytosis. The differential diagnosis also includes nonhe-
matologic round-cell tumors such as Ewing’s sarcoma,
rhabdomyosarcoma, and metastatic small cell and poorly dif-
ferentiated non–small cell carcinoma. The use of nonlym-
phoma markers, such as cytokeratins, desmin, smooth
muscle actin, and FLI1 (Ewing’s sarcoma), can help rule
out other round-cell tumors.
A minimalist approach to suspected diffuse large B-cell
lymphoma is initial evaluation of CD20 immunohisto-
chemical stain; however, more often a panel including
CD45 (leukocyte common antigen), CD20 (pan–B-cell
marker), and CD3 (T-cell marker) is ordered, in addition
to other lineage markers if the differential diagnosis is
broad. The majority of untreated diffuse large B-cell
lymphomas are positive for CD20. In cases of CD20-
negative diffuse large B-cell lymphoma, PAX5 or CD79
will usually be positive. Once a diagnosis of diffuse large
B-cell lymphoma is established, additional prognostic
studies may be considered depending on the needs of the
patient and treating physicians. A typical follow-up panel

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 847

A B

C D
FIGURE 12-28  ■  Non-Hodgkin’s lymphoma of bone: radiographic features. A, Lateral radiograph of humerus showing a destructive
mass with extensive involvement of the adjacent soft tissue. B, Coronal magnetic resonance image (MRI) of same case as A showing
a destructive lesion involving the proximal humerus with extensive involvement of the adjacent soft tissue. C, Oblique radiograph
showing a destructive lytic lesion with soft tissue extension of the proximal ulna. D, Axial MRI of the same case as in C showing a
lesion of variable signal intensity involving the proximal ulna and adjacent soft tissue.

ERRNVPHGLFRVRUJ
848 12  Hematopoietic Tumors

A B

FIGURE 12-29  ■  Non-Hodgkin’s lymphona of bone: gross features. A and B, Sagittally bisected tibia shows extensive gray-tan mass
with extensive involvement of tibial shaft and adjacent soft tissue.

includes Ki-67 to evaluate proliferation rate, and CD10,
BCL6, and MUM1 (with or without additional markers)
to subclassify diffuse large B-cell lymphoma as either
germinal center subtype or activated B-cell subtype (also
see the discussion on genetic features and pathogenesis)
(Figs. 12-31 and 12-32). In addition, Epstein-Barr encod-
ing region (EBER) in situ hybridization may be consid-
ered in patients older than age 50 years to confirm or
exclude a diagnosis of Epstein-Barr virus (EBV)-positive
diffuse large B-cell lymphoma of the elderly.
If the Ki-67 proliferation index is above 80%, some
recommend FISH testing for translocations involving
BCL-2, BCL-6, and MYC, to identify possible “double
hit” or “triple hit” lymphomas, which have BCL2 and/or
BCL-6 translocations in addition to MYC translocations.
Double hit and triple hit lymphomas are particularly
aggressive lymphomas with poor prognosis and poor
response to conventional chemotherapy. Others question
the use of a Ki-67 proliferation limit as a guide to con-
sider FISH testing.92 An immunohistochemical score for
double hit lymphomas has also been described. In this
scoring system, patients with at least 70% of lymphoma
cells positive for BCL2 and at least 40% of lymphoma
cells positive for MYC had a worse prognosis when
treated with conventional chemotherapy.82
Hematologic neoplasms are frequently included in the
differential diagnosis of diffuse large B-cell lymphoma.
Multiple myeloma, especially the pleomorphic type, can
resemble diffuse large B-cell lymphoma. Review of serum
and urine protein electrophoresis, if available, may help
distinguish myeloma from lymphoma. In addition, immu-
nohistochemical stains for κ and λ immunoglobulin
chains are negative in most diffuse large B-cell lympho-
mas and positive in the vast majority of plasma cell
myeloma cases.
Myeloid sarcoma may mimic diffuse large B-cell lym-
phoma. The most sensitive immunohistochemical stains
for myeloid sarcoma are CD43 and lysozyme. The major-
ity of diffuse large B-cell lymphomas are also positive for
CD43 but are negative for lysozyme, CD34, and myelo-
peroxidase. Eosinophilic myeloblasts, when present, are
a clue to the diagnosis of myeloid sarcoma. The myeloid

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 849

A B

C D
FIGURE 12-30  ■  Diffuse large B-cell lymphoma of bone: microscopic features. A, The tumor is composed of large lymphocytes with
variably prominent nucleoli, with inflammatory response and bone destruction (×200). B, The rare signet ring cell variant has lym-
phocytes with prominent cytoplasmic vacuoles and peripheral displacement and indentation of the nuclei (×400). C, Diffuse large
B-cell lymphoma showing large lymphocytes with one to multiple prominent nucleoli (×400). D, Diffuse large B-cell lymphoma with
bone destruction (×400). (A-D, hematoxylin-eosin)

ERRNVPHGLFRVRUJ
850 12  Hematopoietic Tumors

A B

C D
FIGURE 12-31  ■  Diffuse large B-cell lymphoma of bone, germinal center type: microscopic and immunohistochemical features.
A, Photomicrograph of diffuse large B-cell lymphoma showing centroblastic and plasmacytoid features (×400). B, Photomicrograph
of diffuse large B-cell lymphoma stained for CD10 showing diffuse membranous staining (×200). C, Photomicrograph of diffuse large
B cell lymphoma stained for BCL-6 showing nuclear staining (×200). D, Photomicrograph of diffuse large B cell lymphoma stained
for MUM-1 showing fewer cells with nuclear staining (×200).

ERRNVPHGLFRVRUJ

GCB
Non-GCB
+ +
CD10 MUM-1
− + − GCB
BCL-6
− diagnosed as chronic osteomyelitis. This error can be
Non-GCB
FIGURE 12-32  ■  Hans classifier for diffuse large B-cell lymphoma
subtyping. Three immunohistochemical stains approximate
gene expression profile-based subtyping of diffuse large B-cell
lymphoma into germinal center subtype and non-germinal
center subtype. GCB, germinal center B-cell subtype; non-GC,
non-germinal center B-cell subtype. (Modified and reprinted with
permission from Hans CP, et al: Confirmation of the molecular clas-
sification of diffuse large B-cell lymphoma by immunohistochemis-
try using a tissue microarray. Blood 103:275-282, 2004.)
nature of the cells in question is often easier to recognize
on touch preparations stained with Wright-Giemsa.
Chloracetate esterase is inactivated by acid decalcifica-
tion, and stains performed on decalcified tissue can
provide false-negative results. Immunohistochemical
stains for lysozyme myeloperoxidase are useful in identi-
fying the myeloid nature of the tumor cells.
Langerhans cell histiocytosis can be easily distinguished
from lymphoma by the presence of a mixture of histio-
cytic cells with a prominent eosinophilic infiltrate. Occa-
sionally, when Langerhans cells predominate, it can be
difficult to distinguish Langerhans cell histiocytosis from
diffuse large B-cell lymphoma. The strong positivity of
Langerhans cells for S-100, the younger age of the
patients, and radiographic features usually help distin-
guish this disorder from lymphoma.
Mastocytosis can be suspected if the entire clinical pre-
sentation, the presence of skin lesions and systemic symp-
toms, is taken into consideration. The mast cell nature of
the cells in question can be suspected if a round-cell
infiltrate is negative for common leukocyte and epithelial
markers. Mast cells are positive for CD117 and mast cell
tryptase, and their granules can be revealed in prepara-
tions stained with Giemsa, toluidine, or alcian blue.
Diffuse large B-cell lymphoma may be differentiated
from pediatric small round blue cell tumors such as
Ewing’s sarcoma/primitive neuroectodermal tumor (ES/
PNET) by evaluating an immunohistochemical panel,
including CD99, FLI1, and cytokeratin. CD99 is positive
in ES/PNET; however, 55% of myeloid sarcomas may
also be positive for CD99.118 ES/PNETs are negative for
CD43 and lysozyme, positive for FLI1, and show cyto-
keratin expression in a subset of cases. Ewing’s sarcoma
is extremely rare in patients older than age 40 years, an
age when most non-Hodgkin’s lymphomas are diagnosed.
Multifocal skeletal lesions are extremely rare in Ewing’s
sarcoma. On the other hand, multifocality is a frequent
feature of skeletal lymphomas. In addition, detection of
t(11;12) (q24,q12) by karyotyping, PCR, or FISH con-
firms a diagnosis of ES/PNET.
Metastatic small cell carcinoma occasionally can be very
difficult to distinguish from lymphoma because it may
have similar features, especially with sclerotic bone
ERRNVPHGLFRVRUJ
12  Hematopoietic Tumors 851
involvement by lymphoma. The use of appropriate
markers to document the epithelial nature of cells and
frequent neuroendocrine differentiation, as demonstrated
by positivity for CD56, synaptophysin, crhomogranin,
and TTF1, in small cell carcinomas are helpful distin-
guishing features.
Non-Hodgkin’s lymphoma of bone is frequently mis-
avoided if attention is paid to the clinicoradiographic
features. The involvement of the shaft of long tubular
bones in patients older than age 40 years is rarely a
feature of chronic osteomyelitis. The presence of reactive
lymphocytes in malignant lymphoma is frequently
responsible for this error. In this instance, the recognition
of atypical lymphoid cells and the identification of the
phenotypic features consistent with lymphoma are the
keys to the correct diagnosis.
Genetic Features and Pathogenesis
The normal cell counterpart is a mature B cell that has
been exposed to antigen and undergone somatic hyper-
mutation of immunoglobulin genes in the germinal
center. The normal cell counterpart may be a germinal
center B cell (GCB) or post-germinal center B cell.
The post-germinal center subtype of diffuse large B-cell
lymphoma is commonly referred to as activated B cell
(ABC) subtype. The neoplastic B cells show clonal rear-
rangement of immunoglobulin genes and show somatic
hypermutation of immunoglobulin variable chain genes,
as is seen in normal germinal center and post-germinal
center B cells.
The molecular profile of diffuse large B-cell lym-
phoma of bone is similar to that for the diffuse large
B-cell lymphoma occurring at other sites. In 2000, Aliza-
deh et al. divided diffuse large B-cell lymphoma into two
subtypes on the basis of gene expression profiles and
showed that diffuse large B-cell lymphoma of GCB has
a better prognosis than ABC type.67 The prognostic sig-
nificance of these subtypes has been confirmed by some
studies and have been challenged by authors of other
studies.86,107 In 2004, Hans et al. described a simple
immunohistochemical panel (CD10, BCL6, and MUM1),
now commonly named the Hans classifier (Fig. 12-32) that
loosely reproduced cDNA microarray-based subtyping
with a positive predictive value of 87% for GCB subtype
and 73% for ABCsubtype.84 The panel also predicted
better survival for the lymphoma classified as GCB
subtype, similar to the gene expression profile classifica-
tion. Subsequently, several groups have proposed algo-
rithms based on more extensive immunohistochemical
panels that slightly improve correlation between sub-
grouping based on gene expression-based and immuno-
histochemical features.75,95
There is a tremendous degree of genetic variation
among diffuse large B-cell lymphomas, resulting in highly
variable response to current treatment regimens. It is
estimated that an individual case of diffuse large B-cell
lymphoma harbors between 30 and 100 different muta-
tions.100 A comprehensive discussion of molecular genet-
ics in diffuse large B-cell lymphoma is clearly beyond the
scope of this chapter. Table 12-5 lists common genetic
852 12  Hematopoietic Tumors
TABLE 12-5 Diffuse Large B-Cell Lymphoma:
Common Genetic Abnormalities
Germinal Center Type Activated B cell Type
BCL2 translocations TNFAIP3 mutations/deletions
[e.g., t(14;18)] MYD88 mutations
MYC translocations CD79A/CD79B mutations
EZH2 mutations CARD11 mutations
MEF2B mutations BCL2 amplifications
BCL6 translocations/ BLIMP1 mutations/deletions
mutations CREBBP/EP300 mutations
PTEN deletions MLL2/MLL3 mutations
CREBBP/EP300 mutations B2M mutations/deletions
MLL2/MLL3 mutations CD58 mutations/deletions
B2M mutations/deletions BCL6 translocations
CD58 mutations/deletions
Adapted from Pasqualucci L, et al: The genetic basis of diffuse
large B-cell lymphoma. Curr Opin Hematol 20:336-344, 2013.
B2M, Beta2 microglobulin; BCL2, B cell CLL/lymphoma 2; BCL6, B
cell CLL/lymphoma 6; BLIMP1, B lymphocyte-induced protein 1;
CARD11, caspase recruitment domain-containing protein
11;CREBBP, cAMP response element-binding protein; EP300,
E1A binding protein p300; EZH2, enhancer of zeste 2 polycomb
repressive complex 2 subunit; MEF2B, myocyte enhancer factor
2B; MLL2/3 = mixed lineage leukemia 2/3; MYD88, myeloid
differentiation primary response 80; PTEN, phosphatase and
tensin homolog; TNFAIP3, tumor necrosis factor, alpha-induced
protein 3.
abnormalities in diffuse large B-cell lymphoma. In one
large study, exome sequencing of diffuse large B-cell lym-
phomas detected recurrent mutations in 322 genes. The
types of mutations included copy number alterations,
intergenic mutations, and mutations of coding and regu-
latory regions of various genes. The types of genes
mutated included genes implicated in apoptosis, cell
adhesion, cell cycle, cell differentiation, metabolism, epi-
genetic modification, DNA repair, immune response,
membrane transport, protein modification, signal trans-
duction, and ubiquitin cycle.117
Frequent mutations are being discovered in genes pre-
viously not known to be affected in lymphomas. These
genes include epigenetic modifiers, genes involved in
immune surveillance, and genes that regulate signaling
pathways (Table 12-5). Mixed lineage leukemia 2 (MLL2)
is an example of a gene encoding a histone methyltrans-
ferase that is mutated in more than 30% of diffuse large
B-cell lymphomas. Inactivating mutations of β2 micro-
globulin (B2M) are seen in approximately 30% of diffuse
large B-cell lymphomas, resulting in the inability of cyto-
toxic T cells to recognize lymphoma cells.100
Constitutive activation of nuclear factor κB (NFκB) is
a frequent finding in diffuse large B- cell lymphoma,
particularly the ABC subtype.90 Mutations of several
regulatory genes may be implicated in the constitutive
activation of NFκB, including myeloid differentiation
primary response 88 (MYD88, mutated in 30% of ABC
diffuse large B-cell lymphomas), TNFα-induced protein
3 (TNFAIP3/A20, mutated in approximately 30% of ABC
diffuse large B-cell lymphomas), and caspase recruitment
domain-containing protein 11 (CARD11, mutated in 9%
of ABC diffuse large B-cell lymphomas).100
B-cell lymphomas are thought to harbor many muta-
tions at least in part due to mistargeting of physiologic
ERRNVPHGLFRVRUJ
DNA breakage that occurs during normal B-cell develop-
ment. The mechanisms that produce immunoglobulin
diversity via DNA breakage and reassembly include
variable, diversity, and joining [V(D)J] immunoglobulin
segment recombination, class switch recombination, and
somatic hypermutation of immunoglobulin genes. The
mediators of these processes, such as recombination acti-
vating genes (RAG, which is required for V(D)J recom-
bination) and activation induced cytidine deaminase
(AID, which initiates somatic hypermutation and class
switch recombination) have been implicated in many of
the translocations and point mutations seen in B-cell
lymphoma.83
The most common translocations in diffuse large
B-cell lymphoma involve the B-cell lymphoma 6 (BCL6)
gene on the long arm of chromosome three at 3q27 (Fig.
12-33).98 Translocations involving BCL6 are present in
30% to 40% of diffuse large B-cell lymphomas and are
more common in the ABC type.100 In normal B cells,
BCL6 is expressed only during the time the B cell is
within the germinal center. BCL6 is a transcriptional
repressor that maintains germinal center B-cell functions
until the cells mature into post-germinal center memory
B cells or plasma cells. BCL6 protein also represses TP53,
which is a checkpoint gene and activator of DNA repair
mechanisms. The absence of TP53 promotes genetic
instability, allowing somatic hypermutation of immuno-
globulin variable segment genes.91 In normal B-cell mat-
uration, somatic hypermutation produces mature memory
B cells and plasma cells that produce high affinity immu-
noglobulin specific for a given antigen. In the setting of
lymphoma, aberrant somatic mutation may be seen as a
primary event or may be associated with transformation
to a more aggressive lymphoma.
BCL6 can rearrange with more than 30 different gene
partners. The translocation partner is an immunoglobu-
lin gene in more than half of cases, with the remaining
translocation partners represented by nonimmunoglobu-
lin genes.64,91 The majority of the breakpoints for BCL6
gene rearrangement are located in major translocation
clusters, including exon 1 and an intronic sequence
between exon 1 and exon 2 (Fig. 12-33). The result is
translocation of a nearly complete BCL6 gene under the
control of the promotors of several different gene part-
ners. The BCL6 breakpoints have sequences that are tar-
geted by AID in normal immunoglobulin class switch
recombination, and it is thought that these translocations
occur in the germinal center under the influence of AID.
In addition, the BCL6 gene in normal B cells and lym-
phoma undergoes somatic hypermutation, also thought
to be mediated by AID.91,100
Another common translocation, seen in up to 40% of
diffuse large B-cell lymphomas, is t(14;18)(q32;q21) (Fig.
12-34).116 This translocation involves the immunoglobu-
lin heavy chain gene (IGH) on chromosome 14 and B-cell
lymphoma 2 (BCL2) on chromosome 18, resulting in
overexpression of BCL2 under the control of the IgH
enhancer (Fig. 12-34). Increased expression of BCL2
increases cell survival by inhibiting apoptosis. The trans-
location alone is not sufficient to cause lymphoma. The
t(14;18) is present in small numbers of B cells in normal
germinal center B cells.109
 12  Hematopoietic Tumors 853

Chr 3 BCL6
26
25

Exon 7

Exon 6

Exon 5

Exon 4

Exon 3

Exon 2

Exon 1
24.3 24.2
24.1 23

187442728

187452695
22
21.3
21.2 21.1
14.3 14.2 cen tel
14.1
13
12 BCL6
11.1 11.2

4
11.2 11.1
12
13.1 13.2
13.3 1 706 aa
21
22
23 Missense substitution
24 BTB/POZ fold domain
25.1 Nonsense substitution - Stop
25.2 25.3 Zinc finger, C2H2-like domain
26.1 Insertion frameshift
26.2 Zinc finger C2H2-type/integrase DNA-binding domain
26.3 27 Deletion frameshift
28 BCL6
29 Substitution - coding silent
A

MTC
Chr 3 5’ 1 2
3’
BCL6
1kb
S
breakpoint
hyper-cluster Xh S

200bp
B
FIGURE 12-33  ■  B-cell lymphoma 6 (BCL6): gene, protein, mutations, and gene rearrangement breakpoints in B-cell lymphoma.
A, Location of BCL6 gene on chromosome 3 at 3q27. BCL6 gene includes 6 exons. BCL6 protein functional domains include Bric-a-
brac tamtrack broad complex/poxvirus and Zinc finger (BTB/POZ) fold domain, Zinc finger C2H2-like domain, and Zinc finger C2H2-
type/integrase DNA binding domain. Various types of mutations are depicted. B, BCL6 rearrangement breakpoints occur most
frequently within the Major translocation cluster (MTC), including exon 1 and 3′ intronic sequence between exon 1 and exon 2. An
enlarged MTC is depicted and shows the breakpoint hypercluster. Red lines represent breakpoints for immunoglobulin/BCL6 rear-
rangements. Blue lines represent breakpoints for non-immunoglobulin/BCL6 rearrangements. Green bars represent deletions. (Modi-
fied and based on Akasaka H,et al: Cancer Res 60:2341-2355, 2000.)

The t(14;18) IGH breakpoints are within the joining
segments (JH). Approximately 50% of the BCL2 break-
points are clustered within the major breakpoint region,
with the majority of the remaining breakpoints within the
minor cluster region (25%) and intermediate cluster
region.65,77 The breakpoints in the BCL2 major break-
point cluster show an overrepresentation of sequences
that are targeted by AID, and it is thought that t(14;18)
occurs in bone marrow B-cell progenitors during VDJ
recombination under the influence of AID.77
Adult T-Cell Lymphoma/Leukemia
Definition
Adult T-cell lymphoma/leukemia is a malignancy of
mature CD4-positive T cells caused by infection with
human T-cell lymphotrophic virus-1 (HTLV-1). It is
characterized by the presence of numerous, mostly non-
recurrent, genetic abnormalities and atypical cytologic
features with marked nuclear irregularity. Lytic bone
lesions and hypercalcemia are common.113
Clinical Features
The geographic distribution of adult T-cell lymphoma/
leukemia is uncommon in North America and parallels
that of endemic HTLV-1 prevalence, most common in
the Caribbean, Central America, South America, and
Japan. The virus is transmitted via blood, sexual inter-
course, or breast milk. Although up to 40% of the popu-
lation in these areas have been infected by HTLV-1, only
2% to 3% percentage of these individuals go on to
develop lymphoma/leukemia. The average age at diagno-
sis is 55 years.114
The four clinical forms of adult T-cell lymphoma/
leukemia are smoldering, chronic, lymphomatous, and
acute. These forms vary in sites of involvement and
numbers of HTLV-infected T cells in the peripheral
blood. In the smoldering form, there are circulating
polyclonal, oligoclonal, or monoclonal HTLV-infected
T cells at levels insufficient to produce absolute lympho-
cytosis. There is no evidence of involvement of other
organs, other than limited skin or lung involvement. In
the chronic form, there is absolute lymphocytosis with a
monoclonal T-cell population, skin rash and papules,
mild lactate dehydrogenase elevation, and mild hepato-
splenomegaly and lymphadenopathy.
The acute and lymphomatous forms represent aggres-
sive disease, in which bone masses may be present. The
acute form accounts for 60% of cases and presents
with lymphadenopathy, a leukemic picture, and a mono-
clonal absolute T lymphocytosis as well as atypical
morphology. The lymphomatous form, accounting for

ERRNVPHGLFRVRUJ
854 12  Hematopoietic Tumors

Chr 14 Chr 18 der(14) der(18)

13 11.32 13 11.32 11.31
12 11.31 12
11.2 11.2 11.2
11.2 11.1 11.1
11.1 11.1 11.1 11.1 11.1 11.1
11.2 11.2 11.2 11.2
12.1 12 12.1
12 12.2 12.2
13 12.3 13 12.3
21.1 21.1
21 21.2 21 21.2 21.3
21.3
22 22 BCL2 22
23 23
24.1 23 24.1
24.2 24.2
24.3 24.3
31 32.1 31 32.1 IgH
32.2 32.3 32.2 32.3 REGION
IgH REGION BCL2
A

Exon 3

Exon 2
Exon 1
BCL2
Chr 18
cen tel
Major breakpoint region
BCL2
1 239 aa
BH4 BH3 BH1 BH2 TM
Apoptosis regulator, Bcl-2, motif Transmembrane region
B

IgH REGION
Constant JH ∼20kb DH ∼50kb VH ∼900kb
region IgH Enhancer (1-6 ) (1-12) (1,2,...,n)
Chr 14
cen tel
IgH breakpoints

der(14)t(14;18)
Exon 3

Exon 2
Constant Exon 1
region IgH Enhancer JH6

C
FIGURE 12-34  ■  t(14;18)(q32.3:q21.3) in diffuse large B-cell lymphoma. A, Chromosomal diagrams depicting reciprocal translocation
involving the IGH locus on chromosome 14 (Chr14) at 14q32.3 and the BCL2 locus on chromosome 18 (Chr18) at 18q21.3. The
translocation results in two derivative chromosomes, chr der(14) and chr der(18). B, The BCL2 gene consists of three exons and an
intron of approximately 250 kb (upper diagram). Approximately 50% of BCL2 translocation breakpoints occur within the major
breakpoint region in the 5′ untranslated region of exon 3. The BCL2 protein is 239 amino acids in length and includes BCL-2 Homol-
ogy motifs 1, 2, 3, and 4 (BH1-4) and a transmembrane region (TM) (lower diagram). The BH4 domain of BCL-2 is necessary for the
antiapoptotic function of BCL-2. C, The IGH breakpoints are located in the joining segments of the immunoglobulin heavy chain
(JH). The resulting derivative chromosome 14, der(14)t(14;18), places BCL2 gene expression under the control of the IgH enhancer,
resulting in expression of BCL-2 protein under the control of the IgH enhancer. (Based on data from Godon A, et al: Is t(14;18)(q32;q21)
a constant finding in follicular lymphoma? An interphase FISH study on 63 patients. Leukemia 17:255-259, 2003.)

20% of cases, presents without lymphocytosis but with a
monoclonal proliferation of atypical T cells replacing
lymph nodes. Both of these forms are associated with
elevated lactate dehydrogenase and may typically involve
the liver, spleen, skin, or bone.70,110,111 Bone involvement
is most commonly seen in the acute form of adult T-cell
lymphoma/leukemia. Hypercalcemia is a characteristic
clinical finding, present in 70% of patients with the acute
form, not all of whom have lytic bone lesions.70
Chemotherapy has had little success in the treatment
of adult T- cell lymphoma/leukemia, with low response
rates and high rates of relapse. Recent studies have shown
that the acute, smoldering, and chronic forms have a
better response to antiviral therapy with interferon
alfa-2b and zidovudine than to chemotherapy. A recent
clinical trial comparing front-line antiviral therapy with
chemotherapy for the acute form of adult T-cell
lymphoma/leukemia resulted in a 5-year survival rate of
28% for the antiviral arm versus 10% for the chemo-
therapy arm. Antiviral treatment of the chronic form
resulted in a 100% 5-year survival rate compared with
less than 20% with no treatment in another study.70,72 In
contrast to leukemic forms of adult T-cell lymphoma/
leukemia, patients with the lymphomatous form respond
better to chemotherapy.70
Radiographic Findings
Patients with the acute form typically have multiple lytic
bone lesions involving both the axial and appendicular

ERRNVPHGLFRVRUJ

skeleton.80 PET scan will show increased uptake in loca-
tions of lytic bone lesions and in involved lymph nodes
and organs (Fig. 12-35).
Microscopic Findings
Adult T-cell lymphoma/leukemia may show significant
variation in morphology from case to case. The chronic
and smoldering forms are usually composed of small lym-
phocytes with mild pleomorphism. Acute and lympho-
matous forms may display small lymphocyte morphology
but are more likely to show marked pleomorphism. The
acute form typically shows marked pleomorphism, with
circulating T cells with characteristic deeply lobulated
nuclei known as flower cells. Lytic bone lesions show
resorption of bone by osteoclasts (Fig. 12-36). There may
or may not be an associated lymphomatous infiltrate.
When present, the infiltrate frequently consists of large
pleomorphic lymphocytes (Fig. 12-36).
Immunohistochemical Stains and
Differential Diagnosis
The neoplastic T cells are CD4 positive, CD8 negative,
and show bright expression of CD25 (Fig. 12-36). In the
majority of cases, the T cells show a loss of CD7 expres-
sion and maintain expression of CD2 and CD5.
The differential diagnosis includes diffuse large B-cell
lymphoma, other T-cell lymphomas, and myeloid sarcoma.
Adult T-cell lymphoma/leukemia has a characteristic
although not specific immunophenotype. The T cells are
positive for CD4 and strongly positive for CD25. Dem-
onstration of HTLV-1 seropositivity confirms the diag-
nosis. B-cell markers, such as CD20, will be negative.
Myeloid markers such as lysozyme, CD34, and myelo-
peroxidase will be negative. Other T-cell lymphomas,
particularly peripheral T-cell lymphoma not otherwise speci-
fied are also considered in the differential diagnosis and
may have the same immunophenotype. Confirmation of
seropositivity for HTLV-1 is needed for a definitive diag-
nosis of adult T-cell lymphoma/leukemia.
Genetic Features and Pathogenesis
The normal cell counterpart is an HTLV-1-infected
mature T cell with features of a regulatory T cell (Treg).
Direct infection of the T cells by HTLV-1 is required for
malignant transformation. HTLV-1 viral DNA is clonally
integrated into the T cell DNA.70
Transformation is largely mediated by HTLV-1 TAX
protein. Examples of the myriad effects of TAX include
dysregulation of cyclins involved in cell-cycle progres-
sion, impairment of DNA repair mechanism via inactiva-
tion of p53, upregulation of cytokines IL-2 and IL-15,
and constitutive activation of NFκB. Upregulation of
cytokines IL-2 and IL-15 promotes tumor cell growth in
an autocrine fashion. Constitutive activation of NFκB
results in decrease in apoptotic activity and transcription
of several genes.70,81,103 TAX protein expression is fre-
quently decreased in late stages of disease, when HTLV-1
basic leucine-zipper (bZIP) transcription factor (HBZ) is
thought to maintain cellular proliferation via effects on
ERRNVPHGLFRVRUJ
12  Hematopoietic Tumors 855
multiple cell-cycle mediators and signal transduction
pathways.94,119 TP53 deletion is associated with progres-
sion of disease.108
Clonally rearranged T-cell receptor genes can be dem-
onstrated in the vast majority of cases. Virtually all cases
are aneuploid.93 As a result of TAX-mediated genomic
instability, numerous genetic defects have been detected
in adult T-cell lymphoma/leukemia by cytogenetic studies
and comparative genomic hybridization. The majority of
these are nonrecurrent abnormalities.
The hypercalcemia associated with adult T-cell
lymphoma/leukemia is a result of increased osteoclast
activity. Adult T-cell lymphoma/leukemia cells overexpress
Wnt5, which has been shown to transform granulocyte/
monocyte precursors into osteoclasts. It is thought that
activation of Wnt5a/Ror (receptor tyrosine kinase-like
orphan receptor) β-catenin independent noncanonical sig-
naling results in a shift toward osteoclastic bone resorption
and decreased osteoblastic bone formation.71
CLASSICAL HODGKIN’S LYMPHOMA
Definition
Classical Hodgkin’s lymphoma is a proliferation of large
atypical B lymphocytes in a characteristic microenviron-
ment of mixed benign inflammatory cells. The classifica-
tion includes four types of classical Hodgkin’s lymphoma:
nodular sclerosis, mixed cellularity, lymphocyte-depleted,
and lymphocyte-rich.145 A separate disease entity, nodular
lymphocyte predominant Hodgkin’s lymphoma, has fea-
tures more closely resembling B-cell lymphoma and will
not be discussed further here, as it very rarely presents as
a bone mass.146
Clinical Features
Classical Hodgkin’s lymphoma commonly involves lymph
nodes, with an incidence of 2.8 per 100,000 persons. The
peak age of incidence is in young adults ages 20 to 34.
White males are the most commonly affected group. The
5-year survival rate is 85%, with most disease-related
deaths occurring in patients over age 55 years.144
Bone involvement in Hodgkin’s lymphoma is seen
radiographically as detectable changes in only 1% to 3%
of patients. Most frequently, patients with demonstrable
bone lesions have end-stage (stages IIIB or IV) disease
with clinically apparent lymph node involvement. In one
series of 25 patients with osseous classical Hodgkin’s
lymphoma, 3 patients (12%) had unifocal or multifocal
disease limited to bone.139 Bone involvement can occur
early or late in the disease. Overall, with modern treat-
ment, radiographically identifiable bone involvement
is extremely unusual during the course of the disease
because most patients (90%) are disease-free for a very
long time and are often considered cured.
Several rare case reports of apparently primary
Hodgkin’s lymphoma of bone have been pub-
lished.124,125,133,135,136,138 If a patient presents with skeletal
changes, it is very likely that there is also extraskeletal
disease. The age and sex distributions of patients with
856 12  Hematopoietic Tumors

A B

C D
FIGURE 12-35  ■  Adult T-cell lymphoma of bone: radiographic features. A, Anteroposterior (AP) radiograph of femur in an adult
showing involvement of femoral neck, greater trochanter, and proximal femur by adult T-cell lymphoma. B, Radioisotopic bone
scan showing multiple foci of increased uptake throughout the skeleton. C, AP radiograph of humerus in an adult showing lytic
lesions of adult T-cell lymphoma. D, Axial computed tomography scan showing a destructive lesion involving the thoracic vertebral
body.

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 12  Hematopoietic Tumors 857

A B

FIGURE 12-36  ■  Adult T-cell lymphoma of bone: microscopic and immunophenotypic features. A, Photomicrograph of adult T-cell
lymphoma showing lytic bone lesion with osteoclasts (×200). B, Higher power photomicrograph of case seen in A (×400). C, Photo-
micrograph of adult T-cell lymphoma showing lymphocytes with pleomorphic nuclei (×200). Inset; Higher magnification of adult
T-cell lymphoma shown in C (×1000). D, Photomicrograph of adult T-cell lymphoma with immunohistochemical IMM stain showing
positive CD4 (×1000). (A-C, hematoxylin-eosin.)

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858 12  Hematopoietic Tumors
skeletal changes are identical to those for nodal Hodg-
kin’s lymphoma.122,126,127,131,134 Hodgkin’s lymphoma has a
predilection for the trunk bones.113,123 The vertebral
bodies (lower thoracic and lumbar) are preferentially
involved. The involvement of the pelvis is next in fre-
quency. In the appendicular skeleton, the proximal parts
of major tubular bones, such as the femur and humerus,
are preferentially involved.139
Bone pain, especially in weight-bearing sites, is fre-
quently a symptom in Hodgkin’s lymphoma and may be
present without radiographically detectable changes. For
unknown reasons, the pain is frequently precipitated by
alcohol consumption. Pathologic fracture can occur as an
initial symptom.
Radiographic Imaging
Bone lesions in Hodgkin’s lymphoma are typically mul-
tiple. The changes can be lytic, blastic, or mixed.139 Scle-
rotic changes of the vertebral bodies with an “ivory”
appearance are frequent findings. Periosteal new bone
formation, although not very prominent, is often seen.125
Lesions in the long tubular bones have a tendency to be
more lytic and may have a permeative or moth-eaten
appearance. Blastic sclerotic changes can also be present
in the appendicular skeleton (Fig. 12-37). Associated
local soft tissue lesions may be seen in up to 50% of
patients.139
Microscopic Findings
By conventional definition, the diagnosis of Hodgkin’s
lymphoma requires the identification of diagnostic Reed-
Sternberg cells in the appropriate cellular microenviron-
ment (Fig. 12-38).120 Diagnostic Reed-Sternberg cells in
bone have the same morphologic characteristics as those
that occur in the lymph nodes (Fig. 12-38). They are
large cells with round or lobulated nuclei, and they are
frequently binucleate or multinucleate. The striking
feature is the presence of homogenous acidophilic,
inclusion-like nucleoli that approximate 25% of the size
of the nucleus.
The cellular microenvironment includes T cells,
histiocytes, plasma cells, eosinophils, neutrophils, and
fibroblasts. The classical lymphocyte-rich variant is
the exception and is associated with a background of
mantle zone B lymphocytes and variable numbers of his-
tiocytes and T cells. Some cases are associated with sig-
nificant fibrosis, resulting in distortion of the histology
(Fig. 12-39).
The microscopic and phenotypic features of major
types of Hodgkin’s lymphoma are summarized in
Table 12-6.
Immunohistochemical Stains and
Differential Diagnosis
The typical Reed-Sternberg cells in conventional Hodg-
kin’s lymphoma are positive for CD15 and CD30 and are
negative for CD45 and B- and T-cell markers.123,129,141,147
Reed-Sternberg cells are also variably positive for
PAX5 (Fig. 12-39). Although the expression of B-cell
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TABLE 12-6 Histopathologic and
Immunophenotypic Features of
Classical Hodgkin’s Lymphoma*
Cell Type Phenotypic Features
Reed-Sternberg Cells CD15+ CD45−
Large vesicular nuclei with CD30+ T cell−
macronucleoli
May have one, two, or multiple PAX5+ B cell−
nuclei (variable)
EMA−
Cellular Environment
T cells (Th2) CD3+, CD4+
Eosinophils CD15+
Histiocytes CD68+
Plasma cells (variable) CD138
Neutrophils (variable) CD15+
*The immunophenotype of the Reed-Sternberg cells is the same
in all subtypes of classical Hodgkin’s lymphoma. The
immunophenotype of the cellular environment listed above is
characteristic of nodular sclerosis and mixed cellularity
subtypes, which represent the majority of cases. In lymphocyte-
rich classical Hodgkin’s lymphoma, the cellular environment
consists predominantly of mantle zone B cells. In lymphocyte-
depleted classical Hodgkin’s lymphoma, the cellular
environment consists predominately of histiocytes.
phenotype is not considered a feature of conventional
Reed-Sternberg cells, occasionally the cells may show
focal variable positivity for CD20 and other B-cell
markers. In the background, CD4-positive T cells pre-
dominate. Reed-Sternberg cells are uncommon or absent
in lymphocyte predominant Hodgkin’s lymphoma in
which large neoplastic cells express B-cell antigen
CD20, are positive for CD45, and often coexpress EMA.
Typically, they are negative for the two most common
antigens expressed by conventional Reed-Sternberg cells:
CD15 and CD30. The background lymphocytes in this
variant of Hodgkin’s lymphoma represent a mixture of B
and T cells.
The classic architectural features of variants of Hodg-
kin’s lymphoma are difficult to evaluate in bone biopsies.
The types that are frequently found in bone have features
of nodular sclerosis and mixed cellularity subtypes. The
predominance of reactive fibrosis is frequently seen in
bone lesions regardless of the variant of Hodgkin’s lym-
phoma. In addition, the background cells may often be
polymorphous, with plasma cells and eosinophils causing
frequent confusion with osteomyelitis.
The complex differential diagnosis of Hodgkin’s lym-
phoma and other lymphohematopoietic lesions contain-
ing Reed-Sternberg-like cells is beyond the scope of this
book. To avoid confusion with reactive or inflammatory
disorders such as osteomyelitis, it is important to con-
sider the entire clinicopathologic picture. The correct
diagnosis is based on identification of Reed-Sternberg
cells or variants and demonstration of the appropriate
immunophenotype by immunohistochemical stains.120
The morphologic recognition of these cells can be sup-
ported by the identification of their phenotypic features
in the appropriate background cells.
 12  Hematopoietic Tumors 859

A B

C D
FIGURE 12-37  ■  Hodgkin’s lymphoma of bone: radiographic features. A, Sagittal magnetic resonance image (MRI) showing multifocal
involvement of lumbar vertebra by Hodgkin’s lymphoma. B, Axial MRI of the same case as in A showing diffuse involvement of the
vertebral body by Hodgkin’s lymphoma. C, Sagittal MRI showing involvement of a lumbar vertebra and sacrum by Hodgkin’s lym-
phoma. D, Axial MRI of the same case as in C showing diffuse involvement of lumbar vertebra by Hodgkin’s lymphoma.

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860 12  Hematopoietic Tumors

A B

C D
FIGURE 12-38  ■  Hodgkin’s lymphoma of bone: radiographic and microscopic features. A, Lytic lesions in patient previously
treated for Hodgkin’s lymphoma. B, Photomicrograph of Hodgkin’s lymphoma showing classic binucleate Reed-Sternberg cell,
mononuclear Hodgkin’s cell, and a background of small lymphocytes and histiocytes (×400). C, Higher power photomicrograph of
case in A (×1000). D, Photomicrograph of lacunar cells with cytoplasmic retraction artifact and many background eosinophils (×400).
(B-D, hematoxylin-eosin.)

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 12  Hematopoietic Tumors 861

A B

C D
FIGURE 12-39  ■  Hodgkin’s lymphoma: microscopic and immunohistochemical features. A, Photomicrograph of lacunar cells with
cytoplasmic retraction artifact and many background eosinophils. B and C, Photomicrograph of Hodgkin’s lymphoma showing a
fibrotic background with rare classic binucleate Reed-Sternberg cell, and a background of lymphocytes and histiocytes. D, Photo-
micrograph of immunohistochemical stains showing Reed-Sternberg cells positive for CD30 (top), PAX5 (middle), and CD15
(bottom). Note dim PAX5 staining of Reed-Sternberg cells compared to bright staining of normal small B cells (A-C, ×400; D, ×200).
(A-C, hematoxylin-eosin.)

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862 12  Hematopoietic Tumors
Genetic Features and Pathogenesis
The Reed-Sternberg cell is thought to arise from a ger-
minal center B cell with mutations resulting in loss of
functional immunoglobulin. Discovery of genetic altera-
tions in Hodgkin’s lymphoma has lagged somewhat
behind that of other lymphomas. Most studies require
microdissection of Reed-Sternberg cells from the cellular
microenvironment. In addition to translocations involv-
ing immunoglobulin genes common to many B-cell lym-
phomas, Reed-Sternberg cells have been found to have
complex genetic abnormalities, including aneuploidy,
gains and losses of multiple chromosome loci, and mul-
tiple translocations and mutations (Table 12-7).
Some of these genetic abnormalities result in de­
regulation of crucial signaling pathways. Constitutive
activation of NFκB and JAK/STAT pathways has been
implicated as a key driver of cell proliferation and sur-
vival, while mutations of FAS are associated with in-
creased cell survival via inhibition of apoptosis.137 Genetic
alterations contributing to NFκB activation are gains of
c-REL and NFκB-inducing kinase (NIK, also known as
MAP3K14), deletions of TRAF, and inactivating muta-
tions of TNFα-induced protein 3 and NFκB inhibitors
A and E.132,140
Reed-Sternberg cell proliferation and survival are also
driven by their interactions with the cells of the micro-
environment of classical Hodgkin’s lymphoma. Reed-
Sternberg cells have direct and indirect interactions with
the surrounding cells and secrete various cytokines and
chemokines that attract the various constituents of the
cellular microenvironment. For example, CD40 ligand
on a subset of helper T cells (Th2 cells) binds directly to
TABLE 12-7 Classical Hodgkin’s Lymphoma:
Common Genetic Abnormalities
Loss of function immunoglobulin gene mutations
Immunoglobulin gene translocations
FAS mutations
JAK2 translocations and and copy number gains
NFKBIA/NFKBIE mutations
SOCS1 mutations
TP53 mutations
CIITA translocations
TNFAIP3 mutations
TRAF3 deletion
MAP3K14 copy number gains
REL copy number gains
Aneuploidy
CIITA, Class II MHC transactivator;JAK2, Janus kinase 2;
MAP3K14, nuclear factor κ B-inducing kinase kinase kinase 14;
NFKBIA/NFKBIE, nuclear factor of κ light polypeptide gene
enhancer in B cells B inhibitor α and ε; SOCS1, suppressor of
cytokine signaling 1; TNFAIP3, tumor necrosis factor, alpha-
induced protein 3; TP53, tumor protein 53; TRAF3, tumor
necrosis factor receptor-associated factor 3.
Adapted from Otto C, et al: Genetic lesions of the TRAF3 and
MAP3K14 genes in classical Hodgkin lymphoma. Br J
Haematol 157:702-708, 2012; Kuppers R: New insights in the
biology of Hodgkin lymphoma. Hematology Am Soc
Hematol Educ 2012:328-334, 2012; Shaffer AL, et al:
Pathogenesis of human B cell lymphomas. Annu Rev
Immunol 30:565-610, 2012; and Kuppers R, et al: Hodgkin
lymphoma. J Clin Invest 122:3439-3447, 2012.
ERRNVPHGLFRVRUJ
CD40 on the surface of Reed-Sternberg cells, resulting
in activation of the NFκB signaling pathway.132 Increased
macrophages in the cellular background of classical
Hodgkin’s lymphoma, as demonstrated by gene expres-
sion profiling or CD68 immunohistochemical stain,
have been associated with worse disease-specific sur-
vival.121,130,143 Increased histiocytes have also been associ-
ated with EBV-positive classical Hodgkin’s lymphoma.
EBV positivity confers a worse overall survival in patients
older than age 45 years.128 Gene expression profiling pre-
dicts worse overall survival in patients with a profile
suggesting T helper 1 (Th1) reaction, including upregu-
lated expression of interferon gamma (IFNG) and IFNG-
regulated genes CXCL11, IRF1, STAT1, TNFSF10, and
major histocompatibility class I (MHC I) genes.142
HISTIOCYTIC AND DENDRITIC
CELL PROLIFERATIONS
The mononuclear phagocytic lineage consists of mono-
cytes, macrophage/histiocytes, and dendritic cells. Mono-
cytes circulate in the peripheral blood and can be localized
to tissues, especially lymph nodes, spleen, and bone
marrow. Macrophage/histiocytes and dendritic cells are
tissue based. Macrophages ingest cells, cellular debris,
and microorganisms and secrete inflammatory cytokines.
Dendritic cells ingest antigens and present antigen to T
cells. Bone marrow macrophage/dendritic precursors
give rise to monocytes and common dendritic precursors.
Circulating monocytes give rise to macrophage/
histiocytes and a subset of dendritic cells. The majority
of dendritic cells arise from common dendritic precur-
sors.160,165,201 Dendritic cells of the skin (Langerhans cells)
are also derived from a myeloid precursor.207 Primitive
macrophages migrate to the mesoderm during embry-
onic development and differentiate into mature Langer-
hans cells only under the influence of the microenvironment
of their final location in the skin.185 Immunohistochemi-
cal features of normal and pathologic histiocytic and den-
dritic cells are summarized in Table 12-8.
Proliferations of monocytic/histiocytic cells range
from solitary benign lesions to indolent multifocal disor-
ders to aggressive systemic diseases. Identification of the
functional status of monocytic/histiocytic cells and of
their interaction with other elements of the immunohe-
matopoietic system provided a basis for modern classifi-
cation of this group of disorders. This discussion is
limited to the histiocytic/dendritic cell proliferations that
involve the skeleton: Langerhans cell histiocytosis,
Erdheim-Chester disease, and Rosai-Dorfman disease
(sinus histiocytosis with massive lymphadenopathy).
These three diseases have distinctive clinical and mor-
phologic findings, but a subset of patients may have more
than one histiocytosis.175,183,195
Langerhans Cell Histiocytosis
Definition
Langerhans cell histiocytosis is a proliferation of cells
with features of Langerhans cells, characterized by
 12  Hematopoietic Tumors 863

TABLE 12-8 Immunophenotypic Features of TABLE 12-10 Langerhans Cell Histiocytosis

Histiocytes and Dendritic Cells Frequency of Involvement of
Various Organ Systems
Normal Erdheim- Langerhans
Marker Histiocyte SHML* Chester Cell Bone 77%
CD1a − − − + Multisystem disease 44%
CD4 + + + + Craniofacial lesions 43%
CD68 + + + +/− Skin 39%
CD123 − − − − Vault 21%
CD163 + + + − Ears 20%
Langerin − − − + Lymph nodes 19%
Lysozyme + Weak +/− + +/− Liver 16%
S100 +/− + Weak +/− + Bone marrow 13%
CD21 − − − − Spleen 13%
CD35 − − − − Eyes 13%
Oral 13%
*Sinus histiocytosis with massive lymphadenopathy. Cervical nodes 13%
Adapted from Swerdlow SH, et al, eds: World Health Lung 10%
Organization classification of tumours of haematopoietic Gastrointestinal tract 4%
and lymphoid tissues, Lyon, 2008, IARC Press. Genital mucosa 3%
Skull base 2%

Adapted from Grois N, et al: Risk factors for diabetes insipidus

TABLE 12-9 Classification of Langerhans
Cell Proliferations
Langerhans Cell Histiocytosis
Single organ
Multifocal bone
Multisystem
Pulmonary Langerhans Cell Histiocytosis
Langerhans Cell Sarcoma
expression of CD1a and langerin (CD207) by immuno-
histochemistry and the presence of Birbeck granules by
electron microscopy. Normal Langerhans cells have den-
dritic processes, and pathologic Langerhans cells have
rounded cytoplasmic borders without classical dendritic
cell morphology.
A broad classification of Langerhans cell proliferations
is listed in Table 12-9.179,203 Langerhans cell histiocytosis
may present as a unifocal lesion, multifocal bone involve-
ment, or multisystem disease. Pulmonary Langerhans
cell histiocytosis occurs in smokers and is clinically dis-
tinct from other forms of Langerhans cell histiocytosis.
Langerhans cell sarcoma is a tumor composed of mor-
phologically malignant Langerhans cells.179,203 Particu-
larly fulminant forms of Langerhans cell histiocytosis,
sometimes in association with malignant lymphoma or
leukemia, have also been described.155,170,192
The previous designation of histiocytosis X, eosino-
philic granuloma, and the clinical syndromes Hand-
Schuller Christian and Letterer-Siwe are no longer used
for classification but are useful in describing the organ
systems most commonly involved. Of the three terms,
eosinophilic granuloma is still relatively commonly used to
refer to unifocal or multifocal bone involvement by
Langerhans cell histiocytosis, usually without involve-
ment of other organ systems. The term Hand-Schüller-
Christian disease referred predominantly to disease in
young patients with extensive multifocal involvement of
the skeleton, predominantly of the craniofacial bones,
in Langerhans cell histiocytosis. Pediatr Blood Cancer
46:228-233, 2006.
often resulting in Christian’s triad (lytic skull lesions,
exophthalmos, and diabetes insipidus). Letterer-Siwe
disease was described as an aggressive systemic form of
Langerhans cell histiocytosis involving multiple organs
and systems with associated functional impairment of the
affected sites. Frequent sites of involvement in Letterer-
Siwe disease were lymph nodes, liver spleen, lung, and
skin.207
Clinical Features
Langerhans cell histiocytosis primarily affects young
individuals during the first three decades of life (Fig.
12-40). Approximately 80% of cases are diagnosed in
patients younger than age 30 years, and 50% of patients
are children younger than age 10 years. Multisystem
forms of Langerhans cell histiocytosis predominntly
occur during the first 2 years of life (Fig. 12-41). The
disease more commonly affects whites and is slightly
more common in males (Fig. 12-42).175
Bone is the most common site of involvement, with
77% of patients having bone lesions.172 The craniofacial
bones are most frequently affected by this disorder, and
the cranial vault is the most frequently affected site.
Other common sites include the mandible, vertebral
bodies, ribs, pelvis, and femur. These sites are most fre-
quently involved as solitary lesions but are also sites of
predilection in multisystem disease. In the appendicular
skeleton, the major long tubular bones are most fre-
quently affected. The acral skeleton (i.e., the bones of the
hands and feet) are rarely involved. In the long bones, the
lesions are predominantly diaphyseal or metaphyseal and
almost never extend to the end of a bone. Rarely, epiphy-
seal lesions are seen in young children (Fig. 12-40). Other
common sites of involvement are skin, ears, lymph nodes,
and liver, with other organs involved less frequently
(Table 12-10).172

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864 12  Hematopoietic Tumors
Disseminated
aggressive forms
predominantly occur
during first 2 years
of life
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 12-40  ■  Langerhans cell histiocytosis: skeletal distribution. Most frequent sites of involvement are indicated by solid black
arrows.
Treatment and prognosis of Langerhans cell histiocy-
tosis depend largely on age at presentation and the
site(s) and extent of involvement. Virtually all patients
with unifocal bone involvement are cured. Features asso-
ciated with inferior event-free survival and overall sur-
vival are age at diagnosis less than 1 year, multisystem
involvement, and the presence of multiple bone lesions.179
The group of patients with the worst overall survival are
neonates with multisystem disease, who have a 5-year
survival rate of only 57%.187
In pediatric clinical trials, patients have been stratified
into those with single system involvement, multisystem
involvement of low risk organs, and multisystem involve-
ment including risk organs (spleen, liver, or hematopoi-
etic system). Patients with craniofacial or vertebral bone
lesions are also considered higher risk with regard to
central nervous system (CNS) involvement.186
Disease limited to unifocal or multifocal non-CNS
risk bone involvement may be treated with observation
or curettage followed by steroid injection. If bone sta-
bilization is needed, radiotherapy may be considered.
Patients with multisystem disease, risk organ involve-
ment, or bone lesions conferring CNS risk should be
treated with chemotherapy.186 Patients who present
before age 2 years or who have involvement of risk
ERRNVPHGLFRVRUJ
7 8
organs may benefit from intensified chemotherapy.169
Cladribine (2-chlorodeoxyadenosine; 2CdA) has been
used to treat adults with Langerhans cell histiocytosis
bone lesions. Cytarabine (cytosine arabinoside; ara-C)
may be superior.157
Radiographic Imaging
The lesions are lytic and sharply demarcated, “punched-
out” intramedullary defects (Figs. 12-43 to 12-46). They
are rarely intracortical. The intracortical lesions are
almost exclusively seen in larger-diameter bones, such as
the major long tubular bones. The size of a typical lesion
is within 1 to 2 cm. Sometimes a thin sclerotic rim can
be seen. The larger lesions (4 to 5 cm) can erode or even
completely disrupt the cortex and expand into the adja-
cent soft tissue. In the vertebral column, the lesion rep-
resents a lytic involvement of the vertebral body with
frequent collapse (vertebra plana) (Fig. 12-45).150 Typi-
cally, there is minimal or no periosteal new bone forma-
tion, but an expanded thin rim of elevated periosteum
may be seen in younger patients (Fig. 12-46). In rare
instances, especially in small-diameter bones such as ribs,
Langerhans cell histiocytosis can produce lesions with a
permeative or moth-eaten appearance (Fig. 12-47). This
 12  Hematopoietic Tumors 865

35

30

25
Age distribution (%)

20

15

10

0
1

+
0-

1-

5-

-1

-1

-2

-2

-3

-3

-4

-4

-5

-5

-6

-6

-7

-7

-8

85
10

15

20

25

30

35

40

45

50

55

60

65

70

75

80
Age at diagnosis
FIGURE 12-41  ■  Langerhans cell histiocytosis. Data shows the peak incidence of Langerhans cell histiocytosis is in children under
age 5 years. SEER Data, 1973-2010.

0.035

0.03
(cases/100000 persons)

0.025
Incidence rate

0.02

0.015

0.01

0.005

0
e

es

es

es
e
al

al

al

al

al

al
m

m
fe
,

fe

fe
es

te

k
,

ac
es
ac

hi

te

k
ac
Bl
W
ac

hi
lr

Bl
W
Al

lr
Al

FIGURE 12-42  ■  Langerhans cell histiocytosis. Distribution of Langerhans cell histiocytosis by race and sex. The most commonly
affected group is white males. SEER Data, 1973-2010.

feature is seen more often in young children and does not demonstrating the activity of disease, the response to
preclude more aggressive behavior, compared with lesions treatment, and reactivation of disease.181
that have more classic presentations. The extent of skel-
etal involvement ranges from a solitary focus to a dis- Gross Findings
seminated multifocal skeletal and extraskeletal disorder.
CT is useful in delineating the extent and exact location Solitary lesions appear as sharply demarcated gray-tan
of a given bone lesion. MRI is more instructive in delin- lytic foci with frequent cortical disruption. Foci of tan or
eating soft tissue extension.150 FDG PET/CT is useful in Text continued on p. 871

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866 12  Hematopoietic Tumors

B
FIGURE 12-43  ■  Langerhans cell histiocytosis: radiographic features. A and B, Calvarial destructive lesions in two cases of eosinophilic
granuloma in children. Lesions involve full thickness of skull and are sharply circumscribed.

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 12  Hematopoietic Tumors 867

A B

C D

FIGURE 12-44  ■  Langerhans cell histiocytosis: radiographic features. A, Lytic lesion of cranial bone. B, Lytic punched-out lesion of
scapula. C, Lytic destructive lesion of humoral shaft. D, Destructive lesion of ulna with moth-eaten pattern.

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868 12  Hematopoietic Tumors

A B

C D

FIGURE 12-45  ■  Langerhans cell histiocytosis: radiographic features. A, Lateral radiograph of cervical spine of a teenage boy with
neck pain. Body of third cervical vertebra shows partial collapse because of involvement by Langerhans cell histiocytosis (eosino-
philic granuloma). B, Two weeks later, same vertebra shown in A is further flattened as a result of continued bone destruction
(vertebra plana). C, Lateral radiograph of humerus of a young child with Langerhans cell histiocytosis involving midshaft of humerus.
Note permeative pattern of destruction with poorly demarcated borders and prominent periosteal new bone formation. D, Antero-
posterior radiograph of Langerhans cell histiocytosis shown in C. Note periosteal reaction.

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 12  Hematopoietic Tumors 869

A B

C D
FIGURE 12-46  ■  Langerhans cell histiocytosis: radiographic features. A, Anteroposterior (AP) radiograph of proximal femur showing
a lytic lesion with cortical destruction. B, Coronal magnetic resonance image (MRI) of case shown in A showing a high signal density
lesion of the proximal femur. C, AP radiograph of humerus showing a lytic lesion involving shaft. D, Coronal MRI of the same case
as in C showing a high signal intensity lesion with cortical disruption of the humeral shaft.

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870 12  Hematopoietic Tumors

A C

FIGURE 12-47  ■  Langerhans cell histiocytosis: radiographic features. A, Left hip of young adult with lytic lesions in supraacetabular
portion of ilium and femoral neck. B, Chest radiograph shows diffuse bilateral infiltrates in lung fields. C, Technetium-99 bone scan
of pelvis shows increased uptake in region of supraacetabular destruction shown in A.

ERRNVPHGLFRVRUJ

yellowish tissue and fibrosis can be present in lesions
overgrown with ordinary histiocytes and in lesions under-
going regression.
Microscopic Findings
Langerhans cell histiocytosis is composed of two basic
cell types, eosinophils and Langerhans cells, but only the
Langerhans cells are pathognomonic (Fig. 12-48). In
addition to these two basic types of cells, an admixture of
other inflammatory cells may be present. The proportion
of Langerhans cells and inflammatory cells, especially
eosinophils, can vary among different lesions and in
various areas of the same lesion.
In a typical case, Langerhans cells represent mono-
nuclear histiocyte-like cells with oval nuclei and clearly
demarcated round or oval cytoplasm. The majority of
nuclei show a prominent nuclear groove parallel to the
long axis of the nucleus (coffee-bean nuclei) (Fig. 12-48).
It represents a deep longitudinal indentation of the
nuclear membrane that is best seen in electron micro-
graphs. Some of the nuclei may have oval or completely
round nucleoli. The variability in nuclear shapes and sizes
is, to some extent, related to the plane of sectioning of
the individual nucleus. In a typical case, there is little to
no nuclear atypia. Mitotic activity is typically low, and
usually fewer than five mitoses can be found per 10 high-
power fields. Atypical mitoses are not present. Occasion-
ally, mild to moderate atypia of Langerhans cells can be
seen. Atypical Langerhans cells have hyperchromatic
enlarged nuclei, an increased nuclear-to-cytoplasmic
ratio, and medium-sized nuclei. Occasionally, multinu-
cleated giant cells may be present and can have some
nuclear features typical of Langerhans cells or can resem-
ble ordinary osteoclasts. In cases which show a high
degree of nuclear atypia, Langerhans cell sarcoma should
be considered.
The accompanying inflammatory cells may both aid
and hinder the diagnosis. Ordinary histiocytes may be
present and are distinguished microscopically by their
high phagocytic activity and the absence of nuclear
grooves. They may appear as lipid-laden foam cells or
may contain nuclear debris or fragments of degenerated
eosinophils, such as Charcot-Leyden crystals. The prom-
inent reaction of foamy histiocytes is often seen in chronic
lesions. On the other hand, Langerhans cells may also
contain phagocytized material. In general, the presence
of prominent phagocytosis can alter the classic features
of Langerhans cell histiocytosis, making its microscopic
diagnosis very difficult.
Other inflammatory cells, especially eosinophils,
may predominate (Fig. 12-49). Occasionally, they form
aggregates with necrosis (eosinophilic abscesses). Lang-
erhans cells are usually seen at the periphery of such
abscesses. A predominance of other inflammatory cells,
lymphocytes, and plasma cells, especially with associated
fibrosis, can lead to a misdiagnosis of osteomyelitis. Indi-
vidual lesions can undergo spontaneous regression that
is associated with progressive fibrosis and foamy histio-
cytic infiltrates. Regressive changes in Langerhans cell
histiocytosis simulate nonossifying fibroma or chronic
ERRNVPHGLFRVRUJ
12  Hematopoietic Tumors 871
osteomyelitis. Typically, intact foci of Langerhans cell
histiocytosis are seen focally. The surrounding bone may
show prominent resorptive osteoclastic activity, which is
mediated by cytokines produced by the Langerhans cells
and T cells.161 Reactive bone trabeculae with prominent
osteoblastic rimming are usually associated with patho-
logic fracture.
Immunohistochemical Stains, Special
Techniques, and Differential Diagnosis
Ultrastructurally, Langerhans cells contain prominent
indentations of the nuclear membrane (nuclear grooves)
and are distinguished from ordinary histiocytes by their
low phagocytic activity and the presence of Birbeck gran-
ules. Birbeck granules are distinctive organelles with a
tubular tennis racket–shaped membranous structure sur-
rounded by a unit membrane and containing a dense
homogenous core (Fig. 12-50).
Immunophenotypically, they have features consistent
with Langerhans cells. The microscopic and phenotypic
features of Langerhans cells are summarized in Table
12-8. By immunohistochemical staining, Langerhans
cells are strongly positive for S-100, CD1a, and langerin
(CD207). These stains help distinguish Langerhans cells
from normal histiocytes, which are negative for all three
stains (Table 12-8). Langerin is also expressed by a limited
subset of non-Langerhans dendritic cells. Langerin is a
lectin that can bind multiple types of antigens, including
viruses, fungi, and possibly malignant tumor cells.204 It
has been shown that binding of surface langerin is fol-
lowed by internalization of langerin and localization to
Birbeck granules, which cannot form in the absence of
langerin. Although the exact function of Birbeck granules
is uncertain, they have been shown to play a role in
antigen processing.185 Neoplastic Langerhans cells are
also positive for p53 (Fig. 12-48). VE1, an antibody spe-
cific for the BRAF V600E mutation, is positive in cases
bearing this mutation.
Langerhans cell histiocytosis must be distinguished
principally from inflammatory conditions, such as osteo-
myelitis, granulomatous inflammation, and Hodgkin’s lym-
phoma and non-Hodgkin’s lymphoma. In contrast to
Langerhans cell histiocytosis, osteomyelitis rarely affects
craniofacial bones, but the radiographic features can
overlap in some cases. Microscopically, the presence of
polymorphic inflammatory cell infiltrates with neutro-
phils and the presence of necrotic bone trabeculae favor
osteomyelitis.
Granulomatous inflammation can be confused with
Langerhans cell histiocytosis in cases in which granulo-
mas are ill defined. The presence of necrosis surrounded
by palisading histiocytes favors an inflammatory process.
The identification of acid-fast bacilli or fungi by use of
appropriate special stains help rule out Langerhans his-
tiocytosis; however, the sensitivity of these stains is low.
In addition, radiographs of patients with Langerhans cell
histiocytosis almost never show collapsed intervertebral
disk spaces or contiguous involvement of adjacent verte-
brae, a feature frequently seen in granulomatous inflam-
mation involving the spine.
872 12  Hematopoietic Tumors

A B

C F
FIGURE 12-48  ■  Langerhans cell histiocytosis: microscopic features. A, Low power photomicrograph of Langerhans cell histiocytosis
with many intermixed lymphocytes and eosinophils (×100). B, Photomicrograph of Langerhans cell histiocytosis with prominent
eosinophils (×200). C, Higher magnification of case in B shows Langerhans cells with indented bean-shaped nuclei and nuclear
grooves (×400). D, Langerhans cells positive for CD1a (×100). E, Langerhans cells positive for S-100 (×100). F. Langerhans cells with
overexpression of p53 (×100). (A-C, hematoxylin-eosin; D, DAB.)

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 12  Hematopoietic Tumors 873

B
FIGURE 12-49  ■  Langerhans cell histiocytosis: ultrastructural features. A and B, Electron micrographs show eosinophilic leukocytes
containing characteristic granules and portions of cytoplasmic borders of Langerhans cells. Note paucity of lysosomal structures
and irregular cytoplasmic projections in Langerhans cells. Inset shows features of cytoplasmic granules of eosinophilic leukocytes.
(A and B, ×3500; inset, ×15,000.)

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874 12  Hematopoietic Tumors
D
FIGURE 12-50  ■  Langerhans cell histiocytosis: ultrastructural features. A-D, Birbeck granules are pentalaminar rod-shaped cytoplas-
mic organelles (A-D, ×45,000).
Classical Hodgkin’s lymphoma almost never presents as
a primary skeletal lesion, and patients usually have
extraskeletal disease. The presence of diagnostic Reed-
Sternberg cells, associated fibrosis in the appropriate cel-
lular background, and the so-called lacunar cells in the
nodular-sclerotic variant is a typical microscopic feature
of classical Hodgkin’s lymphoma. The diagnosis may be
made by identification of Reed-Sternberg cells with char-
acteristic immunophenotypic features.
Langerhans cell histiocytosis can be confused with a
large-cell non-Hodgkin’s lymphoma. Most primary skeletal
non-Hodgkin’s lymphomas are diagnosed in patients
older than age 40 years. In this age group, Langerhans
cell histiocytosis is extremely rare. The misdiagnosis of
Langerhans cell histiocytosis as non-Hodgkin’s lym-
phoma is usually caused by a dominance of Langerhans
cells. The use of appropriate markers and the identifica-
tion of phenotypic features of Langerhans cells help to
avoid this error.
ERRNVPHGLFRVRUJ
Genetic Features and Pathogenesis
The normal cell counterpart is a cell with morphologic,
immunophenotypic, and ultrastructural features of Lang-
erhans cells. Normal Langerhans cells in mice are derived
from early yolk sac–derived monocytic/macrophage pre-
cursors that migrate to the early mesoderm destined to
become dermis, where they differentiate and form
Birbeck granules after birth.185,197 Normal human Lang-
erhans cells are thought to also derive from early myeloid
precursors found in fetal dermis around week 9 of devel-
opment.202 Pathologic human Langerhans cells were pre-
viously thought to be derived from mature epidermal
Langerhans cells.193 The current prevailing view is that
they are derived from a myeloid dendritic cell precur-
sor.148 The normal cell counterpart may be a more imma-
ture myeloid precursor in aggressive forms of disease and
a more mature differentiated cell in localized forms of
disease.152
 12  Hematopoietic Tumors 875

Chr 7 BRAF
22

Exon 18
Exon 17

Exon 16
Exon 15
Exon 14

Exon 13
Exon 12
Exon 11
Exon 10
21

Exon 9

Exon 8
Exon 7
Exon 6
Exon 5
Exon 4

Exon 3

Exon 2

Exon 1
15.3 15.2
15.1

140433812

140624564
14
13
12
11.2
11.1 11.1 cen tel
11.22 11.21
11.23
21.1
21.2
21.3
22

44
31.1
31.2
31.3

5
32
33
BRAF
35 34

21
36
BRAF

5
5
6

17

4
7

34.285
5

5
4
12
4

110

138
4

5
21

51

12

67
19

95

10
8

4
4

6
6
4

4
4

4
4
7

7
1 766 aa

V600E
Missense substitution Raf-like Ras-binding domain
Nonsense substitution - Stop Protein Kinase C-like, phorbol ester/diacylglycerol binding domain
Insertion inframe Protein Kinase-like domain
Deletion inframe
Insertion frameshift
Deletion frameshift
Complex - deletion inframe
Unknown
Substitution - coding silent
Complex - frameshift
Complex - insertion inframe
Nonstop extension
Complex - compound substitution
Complex
FIGURE 12-51  ■  BRAF V600E mutation in Langerhans cell histiocytosis and Erdheim-Chester disease. The chromosomal location and
the exonal structure of the BRAF gene are shown. The structure of the encoded protein with its functional domain with superimposed
positions of mutations identified in various tumors and available in the COSMIC database is also shown. The V600E mutation,
representing the most common genetic abnormality detected to date in both Langerhans cell histiocytosis and Erdheim- Chester
disease, is highlighted. BRAF V600E is an activating missense mutation involving the substitution from valine to glutamate at protein
kinase domain at codon 600, resulting in upregulation of the RAF/MET/ERK signaling pathway. (Based on data from Haroche J, et al:
High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood 120:2700-
2703, 2012.)

Clonality can be demonstrated in the majority of soli-
tary and multisystem disease, and in a significant minority
(29%) of isolated adult lung Langerhans cell histiocyto-
sis.208,209 A recent sequencing study of 61 pediatric cases
of Langerhans cell histiocytosis demonstrated recurrent
mutations in neoplastic Langerhans cells. The most
common of these is BRAF V600E mutation, detected in
57% of Langerhans cell histiocytosis (Fig. 12-51).151 The
same study detected mutations of TP53 and MET
in single samples. The protein p53 is overexpressed
in all cases of Langerhans histiocytosis; however, the
mechanism in most cases is unknown and is not the result
of a mutation involving TP53.
Patients with high risk and multisystem Langerhans
cell histiocytosis have recently been shown to have BRAF
V600E mutation not only in Langerhans cells within
lesions, but also within small numbers of bone marrow
CD34-positive myeloid dendritic cell precursors as well
as peripheral blood monocytes and dendritic cells. In
contrast, patients with limited disease have BRAF V600E
only in lesional Langerhans cells.152 This appears to at
least partially explain the variable presentations of Lang-
erhans cell histiocytosis, with the more aggressive forms
of disease arising from a bone marrow myeloid dendritic
cell precursor and the low risk disorders representing a
clonal expansion of more differentiated monocytic or
dendritic cells.
Erdheim-Chester Disease
Definition
Erdheim-Chester disease is a non-Langerhans cell histio-
cytosis. In 1930, Erdheim and Chester described two
patients who had distinct skeletal lesions and histiocytic
infiltrates of bone marrow that they believed to be

ERRNVPHGLFRVRUJ
876 12  Hematopoietic Tumors
Symmetric involvement
of major long tubular bones
Incidence
40
1 2 3 4 5 6
Age in decades
FIGURE 12-52  ■  Erdheim-Chester disease. Peak age incidence and frequent sites of skeletal involvement. Most frequent sites are
indicated by solid black arrows.
distinct from Langerhans cell histiocytosis.159 Jaffe
reported another case and also suggested that this disor-
der was distinct from what is currently considered Lang-
erhans cell histiocytosis.178 The distinction was based on
the peculiar radiographic appearance of the lesion (i.e.,
diffuse sclerotic lesions symmetrically involving diaphy-
seal and metaphyseal parts of the major long bones) and
the presence of lipid-laden histiocytes.
Erdheim-Chester disease is best described as a mul-
tisystem proliferative histiocytic disorder that almost
always involves bone, producing diffuse symmetric scle-
rotic lesions of major long bones in classic cases. Micro-
scopically, it is characterized by the presence of ordinary
(foam cell) histiocytic infiltrate with small microscopic
foci of histiocytes confirmed by immunohistochemical
stains. The histiocytes are positive for CD68, negative
for langerin, and usually negative for S-100. There are
variable numbers of intermixed T cells, predominately
Th1 cells.149 BRAF V600E mutation is present in up to
100% of patients using sensitive assays.156
Clinical Features
Erdheim-Chester disease is extremely rare but is being
recognized with increasing frequency and greater under-
ERRNVPHGLFRVRUJ
7 8
standing of its clinical features. Approximately 500 cases
have been described in the literature.175 Greater than
80% of patients present after age 40 years (Fig. 12-52),
with a mean age at diagnosis of 55, and a male-to-female
ratio of approximately 3 : 1.149,158 Occasionally other his-
tiocytoses, including Langerhans cell histiocytosis or
Rosai-Dorfman disease, may occur in patients with
Erdheim-Chester disease.175
The most frequent symptom at presentation is bone
pain, with diabetes insipidus, neurologic symptoms, and
constitutional symptoms also commonly seen. Although
bone involvement can be demonstrated in at least 95%
of cases, only about 50% of patients will experience bone
pain.175 The most distinctive finding is diffuse symmetric
involvement of the major long bones (Fig. 12-53). Bone
lesions at other sites such as ribs, sacrum, craniofacial
bones, and lumbar vertebrae can also be seen. Involve-
ment of craniofacial bones may be associated with diabe-
tes insipidus. Greater than 90% of patients have one
extrasekeletal manifestation.149 Although virtually any
organ system may be affected, commonly involved
extraskeletal sites include the cardiovascular system,
central nervous system (CNS), kidneys, and lungs.175
Involvement may result in encasement and compression
of structures such as the aorta or ureters.175
 12  Hematopoietic Tumors 877

B D
FIGURE 12-53  ■  Erdheim-Chester disease: radiographic features. A and B, Anteroposterior radiographs of knees and lower legs of
same case showing diffuse symmetric sclerosis of both tibia and distal left femur. C, Radioisotopic bone scan showing an increased
uptake in both tibia and left distal humerus. D, Positron emission tomography/computed tomography fused image showing
fluorodeoxyglucose-avid lesion within the medullary cavity of both tibiae.

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878 12  Hematopoietic Tumors
A B
FIGURE 12-54  ■  Erdheim-Chester disease: radiographic features. A, Early changes of sclerosis seen in midshaft of tibia and fibula of
middle-aged man. B and C, Radiographs taken 1 year later show progression of mixed diaphyseal lysis and sclerosis of tibia and
fibula.
Treatment and Behavior
Erdheim-Chester disease is typically a slowly progressive
disease, with a subset of cases showing rapid progression
and multisystem involvement. Current treatment of
Erdheim-Chester disease is largely immunomodulatory,
with interferon alpha. Prior to the use of interferon alpha,
mean patient survival was 19.2 months.175 The current
5-year survival rate is approximately 68%.149 Three
patients with V600E BRAF mutated Erdheim-Chester
(two also with Langerhans cell histiocytosis) treated with
the BRAF inhibitor, vemurafenib, showed significant
clinical improvement.176
Radiographic Imaging
The typical and virtually diagnostic changes are seen in
the major long tubular bones of the appendicular skele-
ton (Fig. 12-53) by radiography or bone scintigraphy.
Diffuse bone sclerosis is present in the diaphyseal and
metaphyseal parts of the long bones (Figs. 12-53 to
12-55). Additional foci can be seen in the trunk and
craniofacial bones (Fig. 12-56). Sclerosis is produced by
ERRNVPHGLFRVRUJ
C
a thickened trabecular pattern and endosteal cortical
thickening. Up to 30% of patients may also have lytic
bone lesions.196 CT scan of the chest and abdomen is
useful in detecting the characteristic distribution of
disease such as encasement of the aorta (“coated aorta”)
and involvement of the perirenal fascia (“hairy kidney”).
MRI is most useful for detecting cardiac and CNS
involvement. PET/CT is recommended for evaluation of
the initial extent of disease and for monitoring response
to treatment.175,190
Microscopic Findings
The most typical pattern is that of foamy histiocytic infil-
trates with associated fibrosis and thickened bone tra-
beculae. The majority of cells have microscopic features
of ordinary histiocytes. No nuclear grooves are seen (Fig.
12-57). Ultrastructurally, they have features of ordinary
histiocytes with numerous lysosomes and lipid vacuoles.
No Birbeck granules are present ultrastructurally. Occa-
sionally multinucleated (Touton) giant cells are present.
Proliferation of histiocytic cells is accompanied by thick-
ened bone trabeculae (Fig. 12-57).
 12  Hematopoietic Tumors 879

A B
FIGURE 12-55  ■  Erdheim-Chester disease: radiographic features. A and B, Anteroposterior and lateral radiographs of femur show
mixed sclerosis and lysis of diaphysis that spares bone ends. Coarse trabeculation confined to diaphysis is characteristic of marrow-
infiltrative process.

Immunohistochemical Stains and Erdheim-Chester disease must be distinguished from

Differential Diagnosis
Immunophenotypically, the majority of histiocytes in
Erdheim-Chester disease are positive for histiocyte anti-
gens such as CD68, CD163, and lysozyme and negative
for markers of Langerhans cells (S-100, CD1a, and
langerin/CD207). However, 20% of cases may show dim
S-100 expression.175 A subset of cases may have scattered
Langerhans cells or small clusters of Langerhans cells
within the dominant proliferation of histiocytes. In these
cases, small clusters (usually 10 to 100 cells) of Langer-
hans cells with nuclear grooves that are positive for S-100
protein and CD1a can be seen (Fig. 12-58). VE1, an
antibody specific for BRAF V600E mutation, is positive
in a subset of the histiocytes.156
other histiocytic cell proliferations, such as conventional
Langerhans cell histiocytosis; lysosomal storage disorders,
predominantly Gaucher’s disease; bone infarcts; and second-
ary foamy histiocytic reactions superimposed on other bone
lesions such as fibrous dysplasia. Correlation with the
very unique radiologic presentation of Erdheim-Chester
disease is the best way to diagnose this entity correctly.
In the absence of bone involvement, the diagnosis may
be quite difficult. Characteristic patterns of involvement
at various sites support this diagnosis, as do typical his-
tologic and immunophenotypic findings.
Although not specific, the presence of a BRAF V600E
mutation in the absence of other features of Langerhans
cell histiocytosis would also support the diagnosis while
simultaneously identifying a potential target for therapy.

ERRNVPHGLFRVRUJ
880 12  Hematopoietic Tumors

C
FIGURE 12-56  ■  Erdheim-Chester disease: radiographic features. A, Anteroposterior radiograph of ankle shows coarse trabeculation
in diaphysis of tibia and sparing of bone end. B, Lateral radiograph of skull shows lytic lesion in occipital region. C, Lateral radio-
graph of ankle shows mixed lucency and sclerosis in distal tibial shaft.

Genetic Features and Pathogenesis
The normal cell counterpart is a histiocyte. The litera-
ture reflects disagreement as to whether Erdheim-Chester
disease represents a clonal disorder or a reactive process.
While some investigators have demonstrated clonality
by HUMARA assay and cytogenetic abnormalities,
others have found no clonal populations.171,205,208 These
discordant results may be due to the variability of the
number of pathologic histiocytes in lesions containing
numerous recruited nonpathologic histiocytes. BRAF
V600E mutation has been detected in more than 50% of
cases by conventional assays and in up to 100% of cases
by ultrasensitive assays.156,177 The BRAF mutation can
also be demonstrated in a small number of circulating
monocytes in patients with Erdheim-Chester disease.156
As a result of the BRAF V600E mutation, the mitogen
activated protein kinase (MAPK) signaling pathway is
activated, resulting in increased proliferation. Dysregula-
tion of multiple chemokines and cytokines results in the
recruitment of Th1 cells and nonmutated histiocytes
to Erdheim-Chester lesions.149 A similar cytokine/
chemokine profile has been demonstrated in oncogene-
induced senescence, an inflammatory protective process

ERRNVPHGLFRVRUJ
 12  Hematopoietic Tumors 881

A B

C D
FIGURE 12-57  ■  Erdheim-Chester disease: microscopic features. A, Histiocytic infiltrate within intertrabecular spaces. Note thickened
bone trabeculae (×100). B, Foamy histiocytes with occasional multinucleated giant cells (×200). C, Higher magnification shows his-
tiocytic infiltrate within marrow (×200). D, Histiocytic infiltrate in dermis (extraskeletal involvement) in patient with Erdheim-Chester
disease (×200). (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
882 12  Hematopoietic Tumors

A B

C D
FIGURE 12-58  ■  Erdheim-Chester disease: immunohistochemical features. A and B, Low and intermediate power views of a dominant
proliferation of histiocytes negative for S-100, immunohistochemical stain IMM with a small cluster of Langerhans cells positive for
S-100. Note that the Langerhans cells comprise a minor population relative to histiocytes. C and D, Low and intermediate power
views of similar clusters positive for immunohistochemical stain IMM CD1a. Note presence of nuclear grooves. (A and C, ×100;
B and D, ×400.)

ERRNVPHGLFRVRUJ

that prevents malignant transformation despite the pres-
ence of an oncogenic mutation. It has been proposed that
the variety of cells seen in Erdheim-Chester lesions may
be the result of this proinflammatory response.156
Sinus Histiocytosis with
Massive Lymphadenopathy
(Rosai-Dorfman Disease)
Definition
Sinus histiocytosis with massive lymphadenopathy (Rosai-
Dorfman disease) is a rare, proliferative, histiocytic dis-
order that was described in 1965 by Destombes and
recognized as a clinicopathologic entity in 1969 by Rosai
and Dorfman.163,198 It is characterized by the enlargement
of lymph node sinuses caused by an aggregation of his-
tiocytic cells that exhibit marked emperipolesis; that is,
numerous intact cells, predominately lymphocytes, are
present in the cytoplasm of the histocytic cell. The disease
is often associated with marked gross enlargement of the
lymph nodes, predominantly in the head and neck area,
and primarily affects teenagers and young adults.199
Primary or secondary involvement of extranodal sites,
including the skeleton, is frequent.
Clinical Features
Rosai-Dorfman disease is rare but occurs more frequently
than was originally thought. By 1990, 423 cases had been
reported to the registry at Yale University.167 The epide-
miologic data, frequency of various sites of involvement,
and clinical behavior discussed here are based on the
series of data from the Sinus Histiocytosis with Massive
Lymphadenopathy registry published in 1990 by Foucar
et al167 and are supplemented with current data from this
registry as provided by Dr. Juan Rosai (Memorial Sloan-
Kettering Cancer Center, New York). The youngest
patient had congenital disease, and the oldest was in his
eighth decade of life. The majority of patients are teenag-
ers and young adults. The mean age at onset is 20 years.
The disease is slightly more common in blacks and
males.167 Nearly 80% of patients had cervical lymphade-
nopathy. Other frequently involved groups of lymph
nodes, in order of frequency, are the axillary, inguinal,
and mediastinal nodes. Involvement of extranodal sites
occurs quite frequently and is seen in approximately 25%
to 40% of patients. The most frequent extranodal sites
involved are various structures of the head and neck,
the upper respiratory tract airway, and skin. However,
virtually every organ, including the CNS, has been
reported to be involved. Skeletal involvement is relatively
uncommon and has been documented in only 25 of 423
cases reported to the Sinus Histiocytosis with Massive
Lymphadenopathy registry.166 Skeletal lesions can be soli-
tary or multifocal.174,182,200,206 They may be located in any
bone of the skeleton. In the long tubular bones, they may
be diaphyseal, metaphyseal, or epiphyseal. The involve-
ment of all these sites may be present in one patient. The
disease rarely presents as a primary skeletal lesion or
lesions. The majority of patients with skeletal disease also
ERRNVPHGLFRVRUJ
12  Hematopoietic Tumors 883
have other extranodal involvement, such as involvement
in the upper respiratory or gastrointestinal tract. The
mean age of onset for patients with skeletal lesions is
approximately 23 years.
Fever and massive cervical lymphadenopathy are
the most frequent symptoms at presentation. Other
symptoms include weight loss, malaise, and night sweats.
Bone involvement in the absence of lymphadenopathy is
rare, reported in only 2% of cases.173 Approximately 25%
of patients have evidence of immune disorders, most fre-
quently antibodies against red blood cells, joint disease
ranging from mild arthralgia to severe arthritis, and glo-
merulonephritis.168 Some patients may have unusually
severe infections, most frequently pneumonia. Quite
often the disease fully manifests after a short period
of a nonspecific fever and pharyngitis. To date, no evi-
dence of a viral or other infectious etiology has been
demonstrated.
Rosai-Dorfman disease is considered a histologically
benign, proliferative, histiocytic disorder with a variable,
but occasionally fatal, outcome. The majority of patients
have indolent regressive or clinically stable disease
after several years of follow-up.180 The most important
prognostic factors consist of the number and extent of
involvement of extranodal sites, clinically progressive
disease, and the presence of associated autoimmune dis-
orders, predominantly of autoimmune hemolytic anemia.
In the Sinus Histiocytosis with Massive Lymphadenopa-
thy registry data, 14 of 423 patients died of or with clini-
cally active disease.166,167 It appears that patients who died
of sinus histiocytosis with massive lymphadenopathy have
a tendency to have multiple and more extensive sites of
nodal and extranodal involvement. Among the extranodal
sites, involvement of the kidneys, liver, and lungs seems
to be particularly ominous because approximately 30%
of patients with disease at these sites die of or with the
disease. Approximately 10% of patients with bone
involvement die of the disease. The fatal outcome in
these cases is related to the frequent involvement of other
extraskeletal sites such as the lungs and kidneys.166
Radiographic Imaging
Skeletal involvement manifests by the presence of solitary
or multifocal lytic lesions with poorly or well-demarcated
borders (Fig. 12-59).162 The lesions are intramedullary
and are associated with cortical erosion, complete cortical
disruption, elevation of the periosteum, or a combination
of these features. Radiographic manifestations and clini-
cal symptoms suggest an inflammatory disorder, such as
osteomyelitis.
Microscopic Findings
In typical cases, the sinuses of lymph nodes are filled with
histiocytes.167,184,191 These cells have prominent pale
eosinophilic cytoplasm, indistinct borders, and round or
oval nuclei with a very fine chromatin pattern and a single
small nucleolus. Nuclear grooves are not present, and
some of these cells may have several nucleoli. Occasional
cells with multilobulated nuclei may be present. Mitotic
figures are rare but can be easily identified. Atypical
884 12  Hematopoietic Tumors

A B

C D
FIGURE 12-59  ■  Rosai-Dorfman disease: radiographic and microscopic features. A, Lateral radiograph of elbow of teenage boy shows
well-circumscribed, lytic, 2-cm intramedullary focus in lower humeral shaft. B and C, Mixed inflammatory cell infiltrates with promi-
nent components of multinucleated histiocytes as well as lymphocytes and plasma cells. Inset and D, Higher power magnification
shows a mixture of lymphocytes and large histiocytes with foamy cytoplasm. Some of the latter cells contain intracytoplasmic
lymphocytes (emperipolesis). (B and C, ×100; inset and D, ×200.) (B-D and inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

mitoses are not present. Aside from the distinct appear-
ance of the histiocytic cells, the most striking and diag-
nostically important feature of these cells is prominent
emperipolesis or lymphophagocytosis (i.e., the presence
of well-preserved lymphocytes within their cytoplasm)
(Fig. 12-59). In addition to lymphocytes, a smaller
number of phagocytized plasma cells, neutrophils, and
red blood cells are also present. Prominent neutrophilic
infiltrates with the formation of microabscesses may be
found in some cases. The lymph node capsule is typically
fibrotic and thickened, and the lymph node shows
reactive hyperplasia of follicular centers. Extranodal
disease has all these features except that histiocytic
cells, instead of growing in sinuses, form irregular geo-
graphic areas separated by other inflammatory cells.
Involvement of the skeleton has the same features. Ini-
tially the lesions may not have fully developed micro-
scopic diagnostic features; that is, they may show
nonspecific inflammatory cell infiltrates only. The diag-
nosis of Rosai-Dorfman disease can be more difficult in
extranodal sites, including the skeleton. In general, extra-
nodal disease exhibits less prominent emperipolesis, is
accompanied by extensive fibrosis, and has fewer histio-
cytic cells. Therefore the likelihood that it can be misdi-
agnosed is much higher in extranodal sites than in nodal
sites, especially in cervical disease. The histiocytic cells
in Rosai-Dorfman disease are positive for S-100 protein
and negative for CD1a, but they coexpress markers of
ordinary histiocytes.153,164
Genetic Features and Pathogenesis
The normal cell counterpart is a histiocyte. The etiology
remains uncertain. Some cases follow upper respiratory
infection, but no infectious etiology has been confirmed.
No genetic abnormalities have been demonstrated in
sporadic Rosai-Dorfman disease.
At least some cases previously thought to represent
familial Rosai-Dorfman disease have been shown to have
mutations of SLC29A3.189 SLC29A3 encodes human
equilibrative nucleoside transporter 3, which may trans-
port nucleosides between lysosomal, cytoplasmic, and
mitochondrial nucleoside pools. The term H syndrome
has been proposed to unify multiple disorders with muta-
tions of SLC29A3, encompassing Faisalabad histiocytosis
and at least some cases of familial Rosai-Dorfman
disease.154 Patients with H syndrome harbor biallelic
mutations and may present with lymphadenopathy with
histologic features similar to those seen in Rosai-Dorfman
disease. One of 79 patients with this disorder was reported
to have lytic bone lesions; however, histologic features
were not reported.154 The clinical features of H syndrome
vary from sporadic Rosai-Dorfman disease. The most
common feature of H syndrome is skin hyperpigmenta-
tion with hypertrichosis, followed by flexion contractures
of the fingers and toes.188
Notably BRAF V600E mutation has not been detected
in sporadic Rosai-Dorfman disease, as has been seen in
subsets of patients with Langerhans histiocytosis and
Erdheim-Chester disease. One study of comparative
genomic hybridization in patients with concurrent
sinus histiocytosis with massive lymphadenopathy and
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12  Hematopoietic Tumors 885
Langerhans cell histiocytosis detected genomic gains and
losses in the Langerhans cells but detected no abnormalt-
ies in the histiocytes in areas with features of sinus his-
tiocytosis with massive lymphadenopathy.195
MYELOID SARCOMA
Definition
Myeloid sarcoma is a localized tumor composed of
myeloblasts and variable numbers of more mature
myeloid cells. The first description of this lesion was in
1853 by King, who used the term chloroma to describe
the green color of the gross mass due to production of
myeloperoxidase.221
Clinical Features
Myeloid sarcoma can occur in three different clinical
settings: (1) as a solitary mass in patients without prior or
concurrent leukemia; (2) in association with myelodys-
plastic disorder or myeloproliferative neoplasm; and (3)
in association with acute myelogenous leukemia, either
concurrent with leukemia, or at relapse, in which setting
it may be the only site of relapse.
Myeloid sarcoma is considered a form of acute myeloid
leukemia. Not all patients present with leukemic involve-
ment of the blood and bone marrow; however, the major-
ity go on to develop frank acute myeloid leukemia with
a lag time ranging from 1 month to 4 years.229 There are
exceptional cases of spontaneous regression of myeloid
sarcomas and patients who do not develop acute leukemia
even at 16 years follow-up.227
Involvement of the skin and subcutaneous tissue is
typical.223,236 Other sites of involvement in order of
decreasing frequency are lymph nodes, testis, intestine,
bone, and CNS.210,224,226,230,234,235 Approximately 3% of
myeloid sarcomas involve bone.230 Common sites of
bone involvement include the orbit, sacrum, sinus, ver-
tebrae, sternum, and ribs; however, any bone may be
involved.214,218,231,238
A diagnosis of myeloid sarcoma is considered synony-
mous with a diagnosis of acute myeloid leukemia, and
as such should be treated with systemic chemotherapy,
followed by stem cell transplant in eligible patients.
Both chemotherapy and transplant improve event-free
survival.213
Radiographic Imaging
Radiographic presentation is nonspecific. However, the
diagnosis can be suspected if a destructive lytic bone
lesion develops in a patient with a history of acute myeloid
leukemia, a myelodysplastic disorder, or a myeloprolif-
erative neoplasm (Fig. 12-60). In the absence of a history
of a myeloid neoplasm, the radiographic findings may
overlap with a variety of reactive and neoplastic pro-
cesses. By CT and MRI, myeloid sarcoma is isointense
to bone marrow, and by CT it is isointense to muscle.219
FDG PET is more sensitive than a CT scan in detecting
early disease.220
886 12  Hematopoietic Tumors

A B

C D
FIGURE 12-60  ■  Myeloid sarcoma: radiographic features. A, Lateral radiograph of distal femur showing a destructive lytic lesion with
moth-eaten pattern. B, Sagittal magnetic resonance image of the same case as shown in A with destructive lesion of the distal femur
of intermediate signal intensity. C, Anteroposterior radiograph of the proximal femur showing a destructive lytic lesion involving
head, neck, and intertrochanteric region. D, Radioisotopic scan showing diffuse involvement of the axial and proximal appendicular
skeleton with a high signal intensity corresponding to the destructive lesion of the left proximal femur. Same case as shown in C.

ERRNVPHGLFRVRUJ

Microscopic Findings
Microscopically the lesion represents a space-occupying
proliferation of atypical myeloid cells that efface the
normal architecture of the involved tissue (Fig. 12-61).
The cellular composition ranges from a homogeneous
population of blasts to a mixed population of blasts and
more mature myeloid precursors, ranging from promy-
elocytes to neutrophils. Occasional cases may show more
than one line of myeloid differentiation, erythroid dif-
ferentiation, or megakaryoblastic features.230 Prominent
monocytic features are common, with more abundant
cytoplasm or folded nuclei.217 When present, immature
eosinophil myelocytes (Fig. 12-62) are a clue to the
diagnosis.
Immunohistochemical Stains and
Differential Diagnosis
If the diagnosis is suspected, fresh tissue may be submit-
ted for flow cytometric immunophenotyping, cytogenetic
studies, and molecular studies. If fresh tissue is not
reserved, immunohistochemical studies will confirm the
diagnosis in most cases. FISH for common leukemic
rearrangements should also be pursued if there is suffi-
cient tissue available.
The list of differential diagnostic possibilities is long.
The diagnosis is aided by history in cases of known pre-
ceding acute myeloid leukemia. The diagnosis of primary
myeloid sarcoma, however, may be quite difficult, with
misdiagnosis rates ranging from 25% to 100%.213,228 The
most common incorrect diagnoses are diffuse large Bcell
lymphoma and lymphoblastic lymphoma.
Flow cytometric immunophenotyping, including lym-
phoid, myeloid, and blast markers, is performed in sus-
pected cases. Often, however, a diagnosis of myeloid
sarcoma is not considered at the time of biopsy. A gener-
ous panel of immunohistochemical stains is needed to
confirm the diagnosis and rule out other diagnostic
possibilities. Lysozyme and CD68 are positive in the
majority of cases. Although CD45 is often among the
first round of stains when evaluating a “small round
blue cell tumor” or poorly differentiated tumor, the
majority of myeloid sarcomas are negative for CD45 by
immunohistochemical staining. Leukocyte origin is con-
firmed by CD43 positivity in the vast majority of cases.
Useful stains for blasts include CD34, CD117, and occa-
sionally TdT. The absence of CD34 staining does not
rule out myeloid sarcoma, because more than half of cases
may be negative for CD34 (Fig. 12-62).230
The myeloid nature of the blasts can be confirmed by
staining with lysozyme, myeloperoxidase, or CD33;
however, many cases of myeloid sarcoma have monocytic
or myelomonocytic features, and myeloperoxidase may
be negative or variably positive. Monocytic markers
include CD68 and CD163. CD68 was reported to be
positive in 100% of cases of myeloid sarcoma in a series
of 92 patients ; however, occasional cases negative for
CD68 have also been reported.230,232 The KP-1 clone of
CD68 is more sensitive than the PG-M1 clone.230 Non-
specific esterase cytochemical stain is also useful for dem-
onstrating monocytic differentiation (Fig. 12-62).
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12  Hematopoietic Tumors 887
Rare cases of myeloid sarcoma may exhibit erythroid
differentiation, variably positive for E-cadherin, gly-
cophorin A, or hemoglobin A.216 Those rare cases with
megakaryocytic differentiation may be identified by vari-
able staining with CD61, CD41, CD31, or Factor VIII.
Markers of lymphoid lineage are generally negative.
CD20, PAX5, and CD79a are helpful in ruling out B-cell
lymphoma or leukemia. However, in myeloid sarcoma
with t(8;21) the blasts frequently express CD19 and
PAX5. T cell markers (CD1a, CD3, CD5, CD8) should
be negative; however, a subset of myeloid leukemias may
be positive for CD7, and occasional cases of acute pro-
myelocytic leukemia with t(15;17) are positive for CD2.
Although monocytic leukemias frequently express CD4,
myeloid sarcomas are less commonly positive, seen in
only 1% of cases in a large study and 22% of cases in one
small study.230,232
Other neoplasms with blastic features, such as acute
lymphoblastic lymphoma and blastic mantle cell lymphoma,
must be ruled out. Mantle cell lymphoma expresses B cell
markers such as CD20, and nearly every case will show
overexpression of cyclin D1. Lymphoblastic lymphoma
expresses PAX5 and CD19 and is negative for myeloper-
oxidase and lysozyme. Blastic plasmacytoid dendritic cell
tumor is positive for CD123, CD4, TCL1, and CD56
and is negative for myeloperoxidase and lysozyme.232
Myeloid sarcoma may be differentiated from pediatric
small round blue cell tumors such as Ewing’s sarcoma/
primitive neuroectodermal tumor (ES/PNET) by evaluating
an immuohiostochemical panel that includes CD99,
FLI-1, and cytokeratin. CD99 is positive in ES/PNET;
however, 55% of myeloid sarcomas may also be positive
for CD99.240 ES/PNETs are negative for CD43 and lyso-
zyme, positive for FLI-1, and show cytokeratin expres-
sion in a subset of cases.
Extramedullary hematopoiesis may be a diagnostic con-
sideration; however, myeloid sarcoma will form a mass,
whereas the cells of extramedullary hematopoiesis will be
present within normal or slightly expanded spaces of the
preexisting architecture of the involved organ.
In summary, the most sensitive immunohistochemical
stains for myeloid sarcoma are CD43 and lysozyme;
however, these stains are by no means specific, and a full
panel of stains should be performed in cases in which this
diagnosis is suspected.
Genetic Findings and Pathogenesis
The normal cell counterpart is a myeloid blast, usually
with monocytic or granulocytic features, and occasionally
with megakaryocytic or erythroid features. The blasts
may show maturation to more mature myeloid forms.
The reasons for blast homing to extramedullary tissues
are uncertain; however, interactions between adhesion
molecules have been suggested as a possible mechanism.
In addition, matrix metalloproteinase 9 (MMP9), which
breaks down extracellular matrix, may play a role in extra-
medullary localization.237
Cytogenetic and FISH studies show no specific cyto-
genetic or molecular abnormality in myeloid sarcomas,
but rather these lesions share features commonly seen in
otherwise typical leukemias (Table 12-11). Common
888 12  Hematopoietic Tumors

A B

C D
FIGURE 12-61  ■  Myeloid sarcoma: microscopic, immunohistochemical and ultrastructural features. A, Myeloid sarcoma with poorly
differentiated myeloblasts (×200). B, Higher power photomicrograph of myeloid sarcoma in A, showing myeloblasts with scant
cytoplasm, open nuclear chromatin, and small nucleoli (×400). C, Photomicrograph of myeloid sarcoma with granulocytic differentia-
tion, showing myeloblasts intermixed with more mature granulocytes, including neutrophils and eosinophil precursors (×400).
D, Ultrastructure of myeloblasts, which exhibits cytoplasmic granules consistent with granulocytic myeloid differentiation (×3500).
(A-C, hematoxylin-eosin.)

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 12  Hematopoietic Tumors 889

A B

C D

FIGURE 12-62  ■  Myeloid sarcoma: microscopic, immunohistochemical and cytochemical features. A, Photomicrograph of myeloid
sarcoma showing myeloblasts with prominent nucleoli and intermixed eosinophil myelocytes (×200). B, Higher power photomicro-
graph of case seen in A (×400). C, Immunohistochemical stains show myeloblasts positive for CD68 (top) and majority negative
for CD34 (bottom), with rare blasts positive for CD34 (arrow) (×200). D, Photomicrograph of cytochemical stain for naphthol
AS-D chloroacetate esterase showing cytoplasmic staining of myeloblasts indicating monocytic differentiation (×200). (A and
B, hematoxylin-eosin.)

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890 12  Hematopoietic Tumors
TABLE 12-11 Myeloid Sarcoma: Common
Genetic Findings
Trisomy 8
Monosomy 7
t(8;21)(q22;q22); RUNX1-RUNX1T1
inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11
11q23 rearrangements; MLL and multiple partner genes
t(9;22)(q34;q11.2); BCR-ABL1
NPM mutations
FLT3 internal tandem duplications
Adapted from Alvarez P, et al: Granulocytic sarcoma of the
small bowel, greater omentum and peritoneum associated
with a CBFβ/MYH11 fusion and inv(16)(p13q22): a case
report. Int Arch Med 4:3, 2011; McKenna M, et al: Myeloid
sarcoma of the small bowel associated with a CBFβ/MYH11
fusion and inv(16)(p13q22): a case report. J Clin Pathol
62:757-759, 2009; Pileri SA, et al: Myeloid sarcoma: clinic-
pathologic, phenotypic and cytogenetic analysis for 92 adult
patients. Leukemia 21:340-350, 2007; Schwyzer R, et al:
Granulocytic sarcoma in children with acute myeloblastic
leukemia and t(8:21). Med Pediatr Oncol 31:144-149, 1998;
Xavier SG, et al: Granulocytic sarcoma of the small
intestine with CBFβ/MYH11 fusion gene: report of an
aleukaemic case and review of the literature. Leuk Res
27:1063-1066, 2003.
findings are t(8;21) RUNX1/RUNX1T1 and MLL (also
known as KMT2A) rearrangements (Fig. 12-63).230 The
t(8;21) RUNX1/RUNX1T1 is common in acute myeloid
leukemia (AML); in myeloid sarcoma, it is associated with
orbital masses in pediatric patients.222,233 MLL rearrange-
ments are common in AML with monocytic differentia-
tion, which involves skin more frequently than other
subtypes of AML. Chronic myelogenous leukemia may
progress to blast crisis as a granulocytic sarcoma. In such
cases, t(9;22) BCR-ABL is present. In addition, inv(16)
and various trisomies and monosomies have been reported
in myeloid sarcoma.230 Inv(16) CBFB-MYH11 myeloid
sarcoma shows characteristic involvement of intestine
and mesentery and less commonly breast and genitouri-
nary sites.211,225,239,241 Rarely, t(15;17) PML-RARA acute
promyelocytic leukemia has been reported to present as
a primary myeloid sarcoma.231
NPM mutations and FLT3 internal tandem duplica-
tions have each been detected in approximately 15% of
cases.212,217 A limited study of myeloid sarcomas by array
comparative genomic hybridization showed multiple
unbalanced chromosomal abnormalities in all seven cases
studied, with numeric abnormalities of chromosome 8
being the most common finding.215
MASTOCYTOSIS
Mast cell proliferations are broadly classified as cutane-
ous mastocytosis and systemic mastocytosis. The World
Health Organization classification of mast cell diseases is
provided in Table 12-12.265 Cutaneous mastocytosis
refers to localized involvement limited to skin lesions,
almost exclusively seen in the pediatric age group and
commonly associated with spontaneous regression. Sys-
temic mastocytosis is further subclassified as indolent
ERRNVPHGLFRVRUJ
TABLE 12-12 Classification of Mastocytosis
Cutaneous Mastocytosis
Urticaria pigmentosa/maculopapular cutaneous
mastocytosis
Diffuse cutaneous mastocytosis
Solitary mastocytoma of skin
Systemic Mastocytosis
Indolent Systemic Mastocytosis
Bone marrow mastocytosis
Smoldering systemic mastocytosis
Systemic Mastocytosis with Associated Clonal
Hematologic Non-Mast Cell Lineage Disease
Aggressive Systemic Mastocytosis
Lymphadenopathic masotycotis with eosinophilia
Mast Cell Leukemia
Mast Cell Sarcoma
Extracutaneous Mastocytoma
Adapted from Swerdlow SH, et al, eds: World Health
Organization classification of tumours of haematopoietic
and lymphoid tissues, Lyon, 2008, IARC Press.
systemic mastocytosis, aggressive systemic mastocytosis,
mast cell leukemia, and systemic mastocytosis associated
with a hematologic non-mast cell disorder, which may be
chronic or acute, myeloid or lymphoid in nature. Skeletal
involvement occurs in systemic mastocytosis and not in
localized cutaneous mastocytosis.
Definition
Systemic mastocytosis involves one or more organs in
addition to the skin. A diagnosis of systemic mastocytosis
requires the presence of mast cell aggregates of greater
than or equal to 15 cells within the bone marrow or other
noncutaneous site (major criterion) and the presence
of one additional minor criterion. In the absence of
mast cell aggregates, the diagnosis may be made by
meeting three minor criteria, which include the follow-
ing: greater than 25% of the mast cells have spindle or
atypical cell morphology, detection of KIT D816V muta-
tion, aberrant mast cell expression of CD2 or CD25, and
serum tryptase greater than 20 ng/mL.265 If a KIT muta-
tion is detected in a patient with mast cell–mediated
symptoms but criteria are not met for systemic mastocy-
tosis, a diagnosis of primary mast cell activation syn-
drome may be made.267
Clinical Features
Systemic mast cell disease is rare. Skeletal changes occur
in up to 80% of cases. Bone changes can be the primary
or only manifestations of the disorder and may play a
critical role in the initial diagnosis.244,257 In contrast to
pure cutaneous mastocytosis, which is seen more fre-
quently in children, systemic mast cell disease is usually
diagnosed in patients older than age 30 years. The male-
to-female ratio is approximately 1 : 1. The trunk bones,
 12  Hematopoietic Tumors 891

Chr 8 Chr 21 der(8) der(21)

23.3 23.2 13
23.1 12
22 11.2 11.1
21.3 21.2 11.1
21.1 11.2
12 21
11.2 11.1 Break point
11.1 RUNX1
11.22 11.21 22.2 22.1
12 11.23 22.3
13
21.1
21.2 RUNX1T1
21.3 RUNX1T1
22.1 RUNX1
22.2
22.3
23
24.1
24.2
A 24.3 RUNX1
Exon 1
Exon 2

Exon 3

Exon 4

Exon 5

Exon 6

Exon 7

Exon 8

Exon 9
tel cen
RUNX1T1

Exon 10
Exon 11

Exon 12
Exon 1

Exon 3
Exon 4
Exon 5

Exon 8
Exon 9
Exon 6
Exon 2

Exon 7
B tel
cen

RUNX1-RUNX1T1 fusion gene

Exon 12
Exon 10

Exon 11
Exon 3
Exon 4
Exon 5

Exon 6

Exon 7

Exon 8
Exon 9
Exon 1
Exon 2

Exon 3

Exon 4

Exon 5

tel cen
Fusion transcript
breakpoint

RUNX1 portion RUNX1T1 portion

C
RUNX1
1 453 aa

177
NRDBn/NRHn: negative regulatory region for DNA binding in N-terminal / TE1, TE2 and TE3: subelements within domain AD
negative regulatory region for heterodimerization domain 1-49 NMTS: nuclear matrix targeting signal domain 351-381
RUNT: p53/RUNT-type transcripton factor, DNA-binding domain 50-170 ID: transcription inhibition domain 371-411
NLS: nuclear localization signal domain 167-183 NRHc: negative regulatory region for heterodimerization
NRDBc: negative regulatory region for DNA binding in C-terminal domain 184-291 in C-terminal domain 372-453
AD: transcription activation domain 243-371 VWRPY: domain 450-453

29
RUNX1T1
1 604 aa

TAFH/NHR1: TATA-box-associated factor 110 / Nervy homology region 1 domain 120-215

NHR2-like: Nervy homology region 2 (promotes the formation RUNX1/RUNX1T1 homodimers) domain 337-403
Zink finger: MYND-type (myeloid, Nervy, and DEAF-1) domain 515-551

RUNX1-RUNX1T1 fusion protein

1 752 aa

breakpoint
RUNX1 portion RUNX1T1 portion
D
FIGURE 12-63  ■  RUNX1-RUNX1T1 fusion in t(8;21) acute myeloid leukemia and myeloid sarcoma. A, The RUNX1 gene is located on
the long arm of chromosome 21. The RUNX1T1 gene is located on the long arm of chromosome 8. As a result of this translocation,
two derivative chromosomes are formed. B, The RUNX1 breakpoint is between exons 5 and 6 at q22. The RUNX1 breakpoint results
in loss of transcription activation domains. The RUNX1T1 breakpoint is between exons 2 and 3 at q22. The RUNX1T1 breakpoint
maintains an almost complete RUNX1T1 gene. C, The resulting hybrid gene typically contains exons 1 through 5 of RUNX1 and
almost the entire reading frame of RUNX1T1. The resulting fusion transcript is transcribed from derivative chromosome 21. D, The
RUNX1-RUNX1T1 fusion protein conserves the RUNT domain and the negative regulatory regions for DNA binding and heterodi-
merization domains of RUNX1 and fuses to an almost complete RUNX1T1 gene. (Based on data from Licht JD: AML1 and the AML1-
ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene 20:5660-5676, 2001.)

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892 12  Hematopoietic Tumors
Incidence
30
1 2 3 4 5 6
Age in decades
FIGURE 12-64  ■  Mastocytosis: peak age incidence and skeletal distribution. Most frequent sites are indicated by solid black arrows.
especially the axial skeleton and the proximal parts of the
major long tubular bones, are preferentially involved
(Fig. 12-64).
Anaphylaxis, constitutional flushing, syncope, hypo-
tension, dyspnea, tachycardia, and headache are manifes-
tations of systemic mastocytosis that are mediated by
substances released by mast cells, such as histamine,
heparin, platelet activating factor, TNF, leukotrienes,
prostaglandins, cytokines, and growth factors. In addition
to these general, nonspecific symptoms, most patients
with indolent forms of mast cell disease have skin changes
typical of urticaria pigmentosa. In addition, gastrointes-
tinal symptoms such as abdominal pain, diarrhea, vomit-
ing, and steatorrhea are present in approximately 20% of
patients.255
The prognosis of systemic mastocytosis varies with
subtype. Patients with indolent systemic mastocytosis
have overall survival similar to age-matched controls,
with a median survival of 198 months. The median sur-
vival times of aggressive systemic mastocytosis, mast cell
leukemia, and systemic mastocytosis associated with a
hematologic non-mast cell disorder are 41 months, 2
months, and 24 months, respectively. Advanced age,
cytopenias, and hypoalbuminemia are predictors of
poorer prognosis.250
Treatment is multimodal and includes avoidance of
mast cell degranulation triggers and drugs that block
ERRNVPHGLFRVRUJ
7 8
mast cell mediators. Bisphosphonates may be given for
osteoporosis. Anaphylaxis is treated with epinephrine.
The most common treatment regimen includes inter-
feron alpha-2b, with or without corticosteroids. Treat-
ment with interferon alfa-2b has been shown to improve
symptoms secondary to mast cell mediator release, as well
as increasing bone density. Cladribine may be used in
cases with bulky disease.254,268
Tyrosine kinase inhibitors have been used with occa-
sional success but have not been shown to improve overall
survival in the majority of patients. Most patients do not
respond to imatinib because the KIT D816V mutation
most commonly seen is resistant to imatinib. Other KIT
inhibitors, such as dasatinib and midostaurin, are cur-
rently being investigated and appear to be effective in a
subset of patients. Mastocytosis patients with associated
non-mast cell neoplasms are treated as appropriate for
the associated neoplasm.254
Radiographic Imaging
The skeletal changes are variable and range from gener-
alized osteopenia or osteosclerosis to focal mixed lytic/
sclerotic changes (Fig. 12-65).260-262,264 Mast cells secrete
several substances that may play a role as mediators of
bone changes. Histamine, the major mast cell product,
stimulates bone formation and may be responsible, at
 12  Hematopoietic Tumors 893

A B
FIGURE 12-65  ■  Mastocytosis involving bone: radiographic features. A, Anteroposterior radiograph of hand shows generalized osteo-
penia and small punched-out erosions of phalanges and metacarpals. B, Radiograph of left hip of an elderly woman with nonunited
fracture of femoral neck. Generalized osteopenia was caused by mastocytosis involving the skeleton.

least in part, for blastic changes in mast cell disease. Two
other products, heparin and prostaglandins, can induce
bone destruction.
Tryptase levels have been shown to correlate with
the degree of osteoporosis, and biomarkers of bone turn-
over are also elevated.246 In addition to generalized
skeletal changes, localized destructive, sharply circum-
scribed lesions have also been described. The skeletal
manifestations of indolent mast cell disease have a
tendency to be in a form of generalized sclerotic or
osteopenic changes. In aggressive or malignant mast
cell disease, in addition to generalized skeletal changes,
there is a tendency for focal destructive lesions, which
may result in the development of pathologic fracture.258
The degree of skeletal involvement and tumor burden
can, to some extent, be obtained from the scintigraphic
patterns of skeletal involvement and urinary histamine
levels.259,262
Microscopic Findings
Mast cells can have a highly variable microscopic appear-
ance. The microscopic features range from spindled to
epithelioid, or they may have a “fried egg” appearance
with abundant clear cytoplasm (Fig. 12-66). Decreased
cytoplasmic granules and spindle cell morphology are
features of neoplastic mast cells.
Mast cell lesions in systemic mastocytosis may be
diffuse or nodular. Diffuse infiltrates typically are
composed of sheets of mast cells with spindle cell mor-
phology, often associated with fibrosis (Fig. 12-66).
Nodular lesions may be paratrabecular or perivascular.
The nodules may be composed predominantly of mast
cells or may be accompanied by a significant number of
inflammatory cells, including lymphocytes, eosinophils,
and histiocytes. Distinct targetoid zonation of cell types
may be seen. Nodules of mast cells may be intermixed
with eosinophils and surrounded by a rim of small
lymphocytes (Figs. 12-66 and 12-67), or nodules of lym-
phocytes may be surrounded by mast cells.
Immunohistochemical Stains, Special
Studies, and Differential Diagnosis
Mast cell granules are best documented by metachro-
matic staining with toluidine blue (Fig. 12-67) or
Giemsa.247,248,252,256 The granules of mast cells are best
documented by electron microscopy.249,251 Normal and
neoplastic mast cells are positive for mast cell tryptase
and CD117 by immunohistochemical staining. Neoplas-
tic mast cells may show aberrant expression of CD2 or
CD25. Interpretation of these stains may be difficult in
cases in which there are many T lymphocytes that are
positive for CD2 with a subset of T cells also positive for
CD25. CD30 is strongly expressed in 85% of aggressive
systemic mastocytosis, with weaker or no expression of
these aberrant markers in more indolent forms of the
disease.263

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894 12  Hematopoietic Tumors

A B

C D
FIGURE 12-66  ■  Mastocytosis: microscopic features. A, Low power photomicrograph showing mastocytosis with patchy infiltrates
hugging trabeculae (×100). B, Higher power photomicrograph of A showing some mast cells with spindle cell morphology
and associated fibrosis (×200). C, Mast cell lesion with central aggregate of mast cells surrounded by lymphocytes and eosinophils
(×200). D, Higher power magnification of C showing mast cells with fried egg appearance with abundant clear cytoplasm (×400).
(A-D, hematoxylin-eosin.)

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 12  Hematopoietic Tumors 895

A B

C D
FIGURE 12-67  ■  Mastocytosis: microscopic and cytochemical features. A and B, Low-power photomicrographs of skin in urticaria
pigmentosa show dermal infiltration of mast cells containing metachromatic granules positive for Geimsa stain. C and D, Intramed-
ullary infiltrates within bone of mast cells admixed with inflammatory cells and fibroblasts. (A-D, ×100.) (C and D, hematoxylin-
eosin.)

ERRNVPHGLFRVRUJ
896 12  Hematopoietic Tumors

KIT

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
Exon 17

Exon 18
Exon 19
Exon 20
Exon 21
Exon 1

Exon 2

Exon 3
Exon 4

Exon 5

Exon 6

Exon 7

Exon 8

Exon 9
Chr 4
16
15.3
15.2
15.1
14
13
12
11 11 KIT
KIT 5
13.1 12
13.3 13.2
21.2 21.1 1 977 aa
21.3
22 28 115 118 206 212 310 322 409 425 505 551 937
23
24 D816V
25
26 Synonymous substitution Immunoglobulin-like domain
27 Missense substitution Protein kinase, catalytic domain
28
Duplication
31.1
31.2 Insertion inframe
31.3 Deletion inframe
32
33
34
35

FIGURE 12-68  ■  Mastocytosis KITD816V mutation. The chromosomal location and exonal structure of the KIT gene are shown. The
encoded protein structure with its functional domain is also shown. The distribution of mutations detected in various tumors avail-
able in the COSMIC data base is also shown. The most common mutation detected in mastocytosis, D816V, is highlighted. This is
an activating missense mutation involving the substitution from aspartatis acid to valine at amino acid position 816, resulting in a
conformational change of the enzymatic pocket of the activation loop of the catalytic domain of KIT. This mutation causes constitu-
tive activation of KIT and the downstream signaling pathway, resulting in increased proliferation and decreased apoptosis of mast
cells. (Based on data from Verstovsek S: Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and pro-
gression. Eur J Heamat 90:89–98, 2012.)

3. Luc S, Buza-Vidas N, Jacobsen SEW: Delineating the cellular

Genetic Features and Pathogenesis
The normal cell counterpart is a mast cell. Mutation of
KIT is present in 90% of cases of systemic mastocytosis,
seen in both indolent and aggressive forms,242 and 76%
of cutaneous mastocytosis cases also have KIT muta-
tions.243 The most common mutation in both cutaneous
and systemic mastocytosis is point mutation D816V
involving the tyrosine kinase domain in exon 17 (Fig.
12-68).253,268 Other KIT mutations have also been identi-
fied in systemic and cutaneous mastocytosis. KIT in
normal mast cells is activated by binding of stem
cell factor (SCF). The KIT D816V mutation causes con-
stitutive activation of KIT, resulting in activation of
downstream signaling pathways including PI3-K/AKT/
mTOR, JAK2/STAT1/5, and SFK pathways. Activation
of KIT results in increased proliferation and survival of
mast cells and also plays a role in terminal differentiation,
adhesion, and release of mast cell mediators.243
Mutations in addition to KIT mutations are associated
with aggressive forms of mastocytosis. TET2 mutations
are seen in approximately 29% of cases of systemic mas-
tocytosis and confer a worse prognosis.266 Other rela-
tively common mutations involve ASXL1 and SRSF2.243
Mutations in LYN and BTK are less common, each occur-
ring in less than 10% of cases.245 Other mutations char-
acteristic of other myeloid neoplasms are seen in systemic
mastocytosis associated with these neoplasms.
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CHAPTER OUTLINE
BENIGN VASCULAR LESIONS
Hemangioma
Lymphangioma and Lymphangiomatosis
Angiomatoses
Glomus Tumor
MALIGNANT VASCULAR TUMORS
Epithelioid Hemangioendothelioma
Spindle-cell Hemangioendothelioma
The complex architecture of the human body requires an
efficient life-support system that transports gases, liquids,
and other nutrients as well as circulating cells that play
important roles in body defense systems. These interact-
ing tasks are carried out by a system that is ubiquitous to
all vertebrates and comprises two treelike branched
systems of tubules known as blood and lymphatic vessels
lined by highly specialized endothelial cells. These two
tubular systems are connected through a large lymphatic
vessel, which drains the lymph fluid to the blood circula-
tion and is referred to as the thoracic duct. The dysfunc-
tions and malformations of these systems contribute to
the pathogenesis of many human diseases and frequently
give rise to tumors and tumorlike malformations in the
skin, soft tissue, and viscera. In bone, the nutrient arteries
penetrate the cortex and branch into an abundant network
of small arteries and capillaries. The rich capillary
network in the medullary cavity is drained to efferent
venules and veins. The periosteal vessels supply the outer
portion of the cortex. Communication between the peri-
osteal and medullary vasculature is provided by anasto-
motic vessels within Volkmann’s and haversian canals. A
rich network of periosteal lymphatics is present. The
presence of medullary lymphatics can be best docu-
mented in abnormal conditions of lymph stasis. Despite
the rich vascularity of bone, skeletal vascular lesions are
rare, and consequently knowledge of their clinical and
pathologic features is still limited.
Solitary hemangiomas are the most common vascular
lesions of bone. Angiomatoses occur less frequently than
solitary hemangiomas. The clinical behavior and the
extent of skeletal involvement by angiomatoses provide a
means of descriptively dividing them into regional versus
disseminated and nonaggressive versus aggressive forms.
Skeletal angiomatoses typically present in two distinct
clinical settings: disseminated skeletal angiomatosis,
sometimes referred to as cystic angiomatosis, and massive
osteolysis (Gorham’s disease). Malignant vascular tumors
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C H A P T E R 1 3 
Vascular Lesions
Angiosarcoma
Hemangiopericytoma
Kaposi’s Sarcoma
REACTIVE VASCULAR LESIONS
Bacillary Angiomatosis of Bone
of bone occur less frequently than hemangiomas. Their
behavior ranges from that of indolent, low-grade tumors,
such as epithelioid hemangioendothelioma, to that of
lethal, high-grade angiosarcomas or hemangiopericyto-
mas. The classification of malignant vascular lesions is
still in a state of flux, and controversy continues about
the biologic potential of those tumors currently desig-
nated as low-grade or borderline endothelial tumors. The
situation has been further complicated by the human
immunodeficiency virus (HIV) pandemic and its associ-
ated vascular lesions in bone, such as bacillary angioma-
tosis and Kaposi’s sarcoma.
The most significant developments contributing to
our knowledge of vascular lesions stem from molecu-
lar biology, which provides new information on the
molecular mechanisms controlling vascular growth and
differentiation.1,3,14
In brief, vascular endothelial growth factor-A (VEGF-
A), which is a part of a large superfamily of growth
factors, is required for differentiation of endothelial pre-
cursor cells.8 The sprouting of endothelial cells is regu-
lated by Notch signaling receptors and their Delta-like 4
(DLL4) ligand. Precurser lymphatic endothelial cells
form a distinctive cluster in mid-gestation embryos on
the dorsal side of the jugular vein. The prospero related
homeobox-1 (PROX1) transcriptional factor and vascular
endothelial growth factor receptor-3 (VEGFR3) are
responsible for their differentiation into lymphatic endo-
thelial cells.5,9,17 Although endothelial cells of blood
vessels and lymphatics are somewhat similar, the lym-
phatics lack a continuous basement membrane and are
not tightly sealed by intercellular junctions, permitting
the free access of interstitial tissue fluid into the vessel.
Each component of both vascular and lymphatic systems
has its own expression signature. For example, the arterial
gene expression signature involves VEGFA, VEGFR2,
neuropilin-1 (NRPI), forkhead box protein C1 or C2
(FOXC1/2), Notch signaling, and ephrin-B2; the venous
903
904 13  Vascular Lesions
expression signature includes the COUP transcription
factor 2 (COUP-TFII), Notch signaling, and ephrin-B4.
From the diagnostic point of view, these investigations
have provided us with a new generation of markers iden-
tifying endothelial phenotypes useful in differential diag-
nosis of vascular lesions. The standard vascular markers
used in pathologic differential diagnosis of vascular
conditions include von Willebrand factor (vWF), factor
VIII-associated protein, platelet endothelial cell adhesion
molecule-1 (CD31), human hematopoietic progenitor
cell antigen (CD34), v-ets avian erythroblastosis virus
E26 oncogene homolog (ERG), human herpes virus 8
(HHV-8), latency-associated nuclear antigen (LANA1),
podoplanin (D2-40), and PROX1.
Factor VIII-associated protein is historically the first
immunohistochemical marker of endothelial cells. vWF
is least sensitive of the vascular markers and is present in
only 50% to 70% of vascular tumors.2
The CD31 marker, an adhesion molecule for platelets,
is one of the newer markers of endothelial cell differen-
tiation and is considered to be among the most specific
and sensitive markers in the differential diagnosis of vas-
cular tumors.11,15 It is believed to be expressed in more
than 90% of vascular tumors. It can occasionally be
expressed in carcinomas but the expression is very weak
and focal. It is consistently expressed in high levels in
tumor macrophages.
The transmembrane glycoprotein (CD34) is not
entirely specific for endothelial cells; it is also expressed on
hematopoietic cells, the interstitial cells of Cajal, dermal
dendritic cells, and nerve sheaths.18 It is also present
in several soft tissue tumors such as dermatofibrosar-
coma protuberans, solitary fibrous tumor, gastrointestinal
stromal tumor, and epithelioid sarcoma among others.
The ETS family of transcription factors play an
important role in the pathogenesis of several bone and
soft tissue tumors as fusion partners of chimeric genes.10
Ewing’s sarcoma is a prototypic tumor exhibiting a
translocation resulting in the EWSR1-FLI1 fusion gene
present in nearly 80% of these tumors. The ERG gene is
a rare partner of this fusion, seen in less than 10% of
Ewing’s sarcomas. It has been recently shown that it is a
major partner in the TMPRSS2-ERG fusion gene, present
in approximately 50% of prostatic adenocarcinomas.
Both FLI1 and ERG are expressed by endothelial cells
and are positive in nearly 95% of vascular tumors of all
types. ERG is currently considered one of the best
markers of endothelial differentiation.
The identification of the specific herpes virus HHV-8
and its associated antigens as markers of Kaposi’s sarcoma
has facilitated their use in the differential diagnosis of
vascular endothelial proliferations.4,6,13,16 LANA1 is par-
ticularly useful because it is present as a nuclear protein
in all forms of Kaposi’s sarcoma.4,16
Podoplanin (D2-40) is a transmembrane glycoprotein
expressed by lymphatic endothelial cells. It is also
expressed in glomerular podocytes, choroid plexus epi-
thelium, type 1 alveolar cells, osteoblasts, and mesothelial
cells. Its expression is regulated by PROX1, and both
proteins are considered to be markers of lymphatic endo-
thelial cells, but as with many other markers, they are not
fully specific for lymphatic endothelial cells.7,12
ERRNVPHGLFRVRUJ
Lectin proteins such as Ulex europaeus, frequently used
in the past, are rarely used as markers of endothelial cells
in modern diagnostics.
Recently, genome sequencing has identified a new
class of chromosomal translocation (1;3)(p36;q25) result-
ing in a WWTR1-CAMTA1 gene fusion that appears to
be specific for epithelioid hemangioendothelioma regard-
less of its site of origin, including those that arise in the
skeleton.115,129
BENIGN VASCULAR LESIONS
Hemangioma
Definition
Hemangioma is a benign solitary tumor composed of
newly formed vessels of capillary or cavernous types.
Incidence and Location
The peak age incidence and most common sites of skel-
etal involvement are shown in Figure 13-1. Hemangio-
mas of bone are rare lesions, accounting for less than 1%
of all primary tumors of bone.15,19,28,34,36 The identification
of skeletal hemangiomas of vertebral bodies in more than
10% of autopsies, however, indicates that they occur
more frequently. A significant number of solitary skeletal
hemangiomas are asymptomatic and are never diagnosed
during life. It should be anticipated that increasing the
use of magnetic resonance imaging, particularly for
symptoms of back pain, should increase the frequency of
incidentally diagnosed hemangiomas of bone. Heman-
giomas have a wide age distribution, ranging from the
first to eighth decades of life, with nearly 70% of cases
diagnosed in patients between ages 30 and 60 years.
Occasionally, hemangiomas become clinically evident
during the first decade of life. There is no clear sex pre-
dilection, but in some series, female patients are slightly
more frequently affected than male patients.
Hemangiomas frequently occur in the craniofacial
bones, predominantly in the calvarium, and in some
series nearly 50% of the lesions occur at this site. The
spine is involved in approximately 20% of cases. On the
other hand, if autopsy data on asymptomatic lesions are
included, the vertebral bodies represent the most fre-
quent site of involvement by hemangioma. The major
long tubular bones are the bones of the appendicular
skeleton most frequently involved. Hemangiomas can be
multifocal. The small multifocal lesions are most fre-
quently identified in the vertebral column involving adja-
cent vertebral bodies.
Radiographic Imaging
Radiographically, hemangiomas present as lucent, well-
demarcated defects.28,59 In flat bones, they markedly
expand the bone contour and produce rarefaction with
radially oriented striations (Fig. 13-2). The vascular
nature of the lesion is often suggested by its bubbly or
honeycomb, trabeculated appearance (Figs. 13-3 to 13-5).
The overlying cortex is expanded and thinned, but
 13  Vascular Lesions 905

30 60
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 13-1  ■  Hemangioma. Peak age incidence and most frequent sites of skeletal involvement are indicated by solid black arrows.

A B
FIGURE 13-2  ■  Hemangioma of bone: radiographic and gross features. A, Hemangioma of frontal bone with prominent striations of
bone trabeculae traversing lesion. B, Clinical photograph of lesion shown in A.

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906 13  Vascular Lesions

A B C

D E

FIGURE 13-3  ■  Hemangiomas of rib and nasal bones: radiographic, gross, and microscopic features. A, Expansile lesion of vertebral
end of rib has honeycomb appearance and spiculated reactive bone of periosteal origin. Lesion had been asymptomatic and was
diagnosed incidentally. B, Specimen radiograph shows radiating spicules of periosteal new bone and coarse trabeculation. C, Gross
photograph of resected rib shows radiating spicules of periosteal new bone and prominent trabeculation. D, Lateral plain radiograph
of face shows honeycomb appearance of nasal bone produced by cavernous hemangioma. E, Low power photomicrograph of nasal
bone hemangioma shown in D composed of cavernous vascular channels. Note prominent trabeculation throughout the lesion.
(E, ×50) (E, hematoxylin-eosin).

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 13  Vascular Lesions 907

A B
FIGURE 13-4  ■  Hemangioma of tibia: radiographic features. A and B, Anteroposterior and lateral radiographs of knee of young woman
who sustained pathologic fracture through large, previously asymptomatic honeycomb lesion occupying proximal half of tibia.
Radiating spicules of periosteal reactive bone are prominent, especially on lateral aspect, and suggest preoperative diagnosis of
primary malignant bone tumor.

complete cortical disruption and invasion into soft tissue
are not present. The characteristic sunburst appearance
of hemangioma is seen in skull lesions (Fig. 13-2) and is
produced by fine spicules of reactive new bone in the
periosteum radiating outward from the center of the
lesion. The sunburst type of periosteal new bone forma-
tion should not be confused with that seen in association
with osteosarcoma of long bone. Smaller lesions may
present as intracortical rarefactions with or without a
honeycomb appearance and adjacent sclerosis (Fig. 13-6).
They can mimic benign osteoblastic lesions (osteoid
osteoma, osteoblastoma) radiographically. Some heman-
giomas are purely lytic lesions with sharply demarcated
borders and should be differentiated from cystic lesions
(Fig. 13-7). Rarely a hemangioma may present as a
subperiosteal lesion (Fig. 13-8). Magnetic resonance
imaging of hemangiomas generally reveals a low signal
on T1-weighted images and a high signal on T2-weighted
images. The latter is explained by the fluid content of
tumor vessels. In vertebral body hemangiomas, the loss
of hematopoietic cells in the interstices of hemangiomas
and apparent increase in fat can produce a high signal in
T1-weighted images.
Gross Findings
Hemangioma presents as a brown-red or dark red, well-
demarcated, medullary lesion. Occasionally, it can be
intracortical or subperiosteal (Fig. 13-8). It may have a
honeycomb appearance with sclerotic bone trabeculae

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908 13  Vascular Lesions
A B
FIGURE 13-5  ■  Hemangioma of tibia: radiographic and microscopic features. A, Anteroposterior radiograph shows ex­pansible tra-
beculated lucent lesion of distal tibial shaft. B, Photomicrograph of biopsy material of same lesion shows engorged capillary-sized
vessels (×50; hematoxylin-eosin).
interspersed among hemorrhagic cavities. Some heman-
giomas provoke an abundance of reactive bone and
appear more sclerotic (Fig. 13-6). Some lesions are com-
posed exclusively of vascular tissue and contain no bone.
Perpendicular periosteal new bone formation and the
radiating spicules can be seen on the surface of some of
the resected hemangiomas (Fig. 13-3).
Microscopic Findings
Hemangiomas are composed of a conglomerate of thin-
walled blood vessels.28,59 The vessels can have dilated
open channels (cavernous hemangioma) or, less fre-
quently, may be composed of capillary-sized vessels (cap-
illary hemangioma) (Figs. 13-9 to 13-12). A majority of
bone hemangiomas are of cavernous or mixed types (cav-
ernous and capillary). Predominantly or exclusively capil-
lary hemangiomas are exceedingly rare in bone. The size
of cavernous vessels may vary, but occasionally hemangi-
oma can be composed of vessels that are relatively uniform
in size (Fig. 13-9). The vascular channels are lined by a
single layer of flat endothelial cells (Figs. 13-7 and 13-9).
Occasionally, these cells can have plump cytoplasm and
even epithelioid features (Fig. 13-10). The intercellular
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tissue is composed of loose connective tissue that may
exhibit myxoid change. The cancellous bone in the
affected area can be completely resorbed. In such cases,
the lesion is composed of vessels and stromal tissue, but
more often, some residual trabeculae of cancellous bone
are present. These trabeculae are usually thickened. Some
hemangiomas may cause pronounced sclerosis of the
intralesional and adjacent bone. The vascular channels of
hemangioma are complete, are separate, and do not show
an anastomosing pattern. In vertebral body hemangio-
mas, the blood-forming elements may be lost completely
in the interstices, leading to an unmasking of adipose
tissue. This apparent increase in fat in the interstitial
tissue of vertebral hemangiomas can be quite prominent.
Hemangiomas have a characteristic microscopic
appearance and in the majority of cases are easy to
recognize. However, secondary changes may alter this
classic pattern and make the diagnosis difficult. Hem-
angiomas of any type, but especially those with large
cavernous vessels, occasionally develop thromboses with
calcifications. This in turn can promote the develop-
ment of papillary endothelial hyperplasia (Fig. 13-11).
The presence of this change can alter the pattern of
vascular channels and lead to the misdiagnosis of a
 13  Vascular Lesions 909

A C
FIGURE 13-6  ■  Hemangioma of tibia: radiographic, gross, and microscopic features. A, Intracortical lucency with trabeculation in
tibia of patient who had pain for 8 months. Initial impression was that of osteoid osteoma. B, Specimen slices from intracortical
lesion shown in A. Note dark, spongy tissue, which is well circumscribed from surrounding thick cortex. C, Photomicrograph
of resected intracortical hemangioma demonstrates engorged vessels and trabeculated bony architecture of the lesion. (C, ×50)
(C, hematoxylin-eosin.)

malignant vascular tumor.20,22,23,25 Papillary endothelial
hyperplasia was described by Masson in 1923 under the
term hemangioendotheliome vegetant intravasculaire.45 It can
occur in any part of the body involving blood vessels
or soft tissue hemangioma or can be superimposed on
a preexisting vascular tumor.22,23,25,29,35,40,49,52,56 Most fre-
quently, it presents as a small mass in the skin and super-
ficial soft tissue.20,33,41,49 It is less common in vascular
lesions of bone. Papillary endothelial hyperplasia may
be so abundant that it tends to obscure the underlying
hemangioma, or it may be found only in focal areas.
Papillary proliferations of plump endothelial cells with
central fibrin or hyaline cores typically are seen. Micro-
scopic examination at low power is extremely important
because this magnification allows visualization of the
papillary structures within preexisting vascular spaces and
the pattern of progression toward the center of the vessel.
Similar orientation can be seen if the lesion develops in a
focus of hemorrhage. Under high power magnification,
cross-sectioned papillary structures appear to be floating
in the vascular lumina. The spaces between them can
form a network that simulates anastomosing channels,
which together with the presence of plump endothelial
cells, can be misinterpreted as the vascular pattern of

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910 13  Vascular Lesions

B
FIGURE 13-7  ■  Calcaneus hemangioma: radiographic and microscopic features. A, Lateral radiograph shows well-circumscribed,
lucent lesion occupying anterior half of calcaneus. Clinical diagnosis of solitary bone cyst was suggested until biopsy was performed.
B, Photomicrograph of curetted material from calcaneal lesion shows hemangioma characterized by vascular spaces lined by flat
endothelial cells (B, ×50) (B, hematoxylin-eosin.)

angiosarcoma. Fibrin with calcified cores may be present.
Calcified spherical structures sometimes mimic psam-
moma body–like structures or cementoid bodies. Various
phases of organization in the thrombotic material also
are present and are associated with an inflammatory cell
infiltrate. In rare instances, aneurysmal bone cyst can be
superimposed on a preexisting hemangioma.
Epithelioid Hemangioma
This variant of hemangioma affecting bone has been
more frequently diagnosed in recent years, and its
similarity to corresponding lesions occurring in soft
tissue has been recognized.30,37,43,46 Its biologic potential
is still not entirely clear, as indicated by a recently reported
case with regional lymph node involvement.32 Moreover,
a study of 17 vascular tumors of bone30 suggested that
epithelioid hemangioma could not be separated from epi-
thelioid hemangioendothelioma, and that rather than
representing a distinct benign entity, epithelioid heman-
gioma is part of the spectrum of hemangioendothelioma
of bone. Clearly, as of this writing, the place of epithelioid
hemangioma in the nosology of vascular tumors, espe-
cially those involving the skeleton, remains controversial.

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 13  Vascular Lesions 911

A C
FIGURE 13-8  ■  Subperiosteal hemangioma: radiographic and gross features. A, Anteroposterior radiograph shows lytic subperiosteal
lesion of tibial shaft. B, Computed tomography shows subperiosteal lesion with cortical erosion delineated by elevated periosteum.
C, Resected specimen showing perpendicular sections through intracortical hemangioma.

The recent identification of the t(1;3)(p36;q25) and
WWTR1-CAMTA1 fusion in epithelioid hemangioendo-
thelioma should help to resolve this controversy but the
experience with bone lesions is limited.115,129
An epithelioid change of endothelial cells lining the
vessels of hemangioma (epithelioid hemangioma) can
cause this benign vascular lesion to be misdiagnosed as
an epithelioid hemangioendothelioma. Epithelioid hem-
angioma is basically a benign hemangioma with plump
and somewhat more active endothelial cells (Fig. 13-10).
Other features, such as solid or cordlike proliferations of
endothelial cells and the anastomosing vascular pattern
characteristic of epithelioid hemangioendothelioma, are
not present.21,26,34,46,47 The presence of prominent spindle-
cell elements and hemorrhage rarely complicate the his-
tologic diagnosis.37,53
Epithelioid hemangioma as a distinctive neoplasm
was originally described as angiolymphoid hyperpla-
sia with eosinophilia and subsequently as inflammatory
angiomatoid nodule, pseudopyogenic granuloma, or his-
tiocytoid hemangioma.47,50,58 It is somewhat similar to
but pathogenetically distinct from the lesion designated
as Kimura’s disease.38,39,42 Some epithelioid hemangiomas
are rather reactive and are seen in association with an
injured vessel.31 Hemangiomas with epithelioid change
in bone have no apparent relationship to angiolymphoid

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912 13  Vascular Lesions

A B

C D
FIGURE 13-9  ■  Hemangioma of bone: microscopic features. A and B, Hemangioma engorged vessels occupying intertrabecular
marrow spaces. Thin-walled blood vessels are lined by flat endothelial cells. C and D, Hemangioma composed of capillary vessels
in fibrous stroma. (A-D, ×50) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 913

A B

C D
FIGURE 13-10  ■  Epithelioid hemangioma of bone: microscopic features. A and B, Angiomatous lesion composed of capillary-sized
vessels with thicker wall lined by plump endothelial cells that project into lumen in tombstone fashion. C and D, Larger vessels lined
by plump endothelial cells with regular vesicular nuclei. (A-D, ×200) (A-D, hematoxylin-eosin.)

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914 13  Vascular Lesions

A B

FIGURE 13-11  ■  Papillary endothelial hyperplasia (Masson’s type) in cavernous hemangioma. A, Plain radiograph of hemangioma of
distal humerus in adult. B, Papillary endothelial proliferation representing organized thrombotic vegetations in benign cavernous
hemangioma of humerus shown in A. C, Higher power photomicrograph shows cavernous hemangioma with papillary (vegetant)
endothelial proliferations. (B, ×60; C, ×150) (B and C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

B
FIGURE 13-12  ■  Hemangioma of sphenoid bone: radiographic features. A and B, Axial and coronal computed tomograms show
expansile tumor at base of skull involving sphenoid bone. C, Arteriogram shows tumor blush.
hyperplasia with eosinophilia or Kimura’s disease. There-
fore the term epithelioid hemangioma in bone should be
used in a descriptive sense only. The radiologic features
of bone hemangiomas and epithelioid hemangiomas
often overlap, and their radiographic differentiation is,
in such instances, not possible.43,57
Differential Diagnosis
The flat endothelial cells lining the capillary or cavernous
vascular channels of hemangiomas can be easily distin-
guished from the plump, enlarged endothelial cells
of hemangioendotheliomas. Individual lesions of skeletal
angiomatosis are histologically identical to those of solitary
bone hemangiomas; the distinction is based on the
mult-centric distribution of angiomatosis. Epithelioid
hemangiomas can be confused with a low-grade epithelioid
hemangioendothelioma. However, other diagnostic features
of epithelioid hemangioendothelioma—solid nest or
ERRNVPHGLFRVRUJ
13  Vascular Lesions 915
cords of endothelial cells and an anastomosing pattern of
irregular vascular channels—are not present in a benign
hemangioma with epithelioid change.
Treatment and Behavior
Asymptomatic small hemangiomas require no treatment;
some may even undergo spontaneous regression. Symp-
tomatic lesions or those that are large and may cause
pathologic fracture or vertebral collapse require treat-
ment. Curettage and bone grafting usually is sufficient.
Symptomatic vertebral lesions are treated by decompres-
sion laminectomy; radiotherapy may be added to curet-
tage. Surgically inaccessible hemangiomas may be treated
by radiotherapy alone. Transarterial embolization, verte-
brectomy, and vertebroplasty have become widely used
in the management of symptomatic vertebral hemangio-
mas.19 Hemangiomas of the cranial vault and those of
the facial bones are usually treated by en bloc excision.
916 13  Vascular Lesions
Hemangiomas in Different Anatomic Sites
Hemangiomas involving different parts of the skeleton
present unique radiographic and pathologic characteris-
tics. In addition, the lesions in different skeletal sites
present distinct diagnostic problems and can present with
different clinical features. For these reasons, separate
descriptions of hemangiomas in various anatomic sites
are provided.
Hemangiomas of Craniofacial Bones.  The craniofa-
cial bones are frequent sites of involvement by heman-
giomas,27,36,44,48,51,54,55 which typically occur in the frontal
area of the cranial vault (Fig. 13-2). Hemangiomas at
this site present with a sunburst effect of radiating bone
spicules that extend from the center of a lucent defect.27,28
The shape of the defect is circular in an en face view and
ellipsoid in a lateral view. Occasionally the typical honey-
comb appearance can be seen in craniofacial lesions (Fig.
13-3, D). Hemangiomas of the skull produce a convex
surface bulge of the cortex externally. Expansion of the
inner concave surface with signs of increased intracra-
nial pressure is rare but was observed in two cases in
our series. Hemangiomas very rarely involve the base
of the skull (Fig. 13-12). Microscopically, hemangiomas
of the craniofacial bones, especially those of the skull,
are cavernous and show more abundant interstitial con-
nective tissue than vertebral hemangiomas. The most
striking feature is the presence of prominent trabecular
bone between the engorged vascular elements. Rarely,
aneurysmal bone cyst can be superimposed on a preexist-
ing calvarial hemangioma.
Hemangiomas of Vertebral Column.  The involve-
ment of vertebral bodies, especially of the lower thoracic
and lumbar regions, is typical for hemangiomas (Figs.
13-13 and 13-14).19,24,28 There is a disparity between
the frequency of finding vertebral hemangiomas during
autopsies and their relatively rare clinical significance.
Many vertebral hemangiomas are asymptomatic. They
either are too small or do not disrupt the trabecular archi-
tecture sufficiently to be visualized on plain radiographs.
Symptomatic hemangiomas of the vertebral column are
usually diagnosed in patients older than age 40 years.
Vertebral hemangiomas that produce clinical symp-
toms are usually associated with back pain and muscle
spasm followed by an acute episode of severe pain and
neurologic symptoms of spinal cord compression. The
lesion is usually associated with collapse of the vertebral
body or bulging cortex that compresses the spinal cord
or nerve roots.
Vertebral hemangiomas appear on radiographs as areas
of rarefaction traversed by the thickened vertical bone
trabeculae, which give them a striated or corduroy-like
appearance (Fig. 13-13). The majority of lesions in this
location measure less than 1 cm. Large lesions can occupy
the entire vertebral body and expand its contour. Findings
on axial computed tomograms are very characteristic
because of the polka-dot appearance of thickened vertical
trabeculae seen on end (Fig. 13-13). T1-weighted mag-
netic resonance imaging clearly demonstrates the lesion
as a well-demarcated area of high signal as a result of the
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apparent increase of fat. Magnetic resonance imaging
occasionally reveals evidence of associated involvement
of soft tissue. T2-weighted images show an area of high
signal. An interesting relationship has been noted between
pregnancy and the development of clinical signs of spinal
cord compression by vertebral hemangiomas.24 The
mechanism of the phenomenon is unclear and can be
related to increased venous pressure in the paravertebral
plexus or can be the result of an increased growth rate of
hemangiomas during pregnancy. Symptomatic heman-
giomas of the vertebral column are treated by surgery
(spinal cord decompression), radiotherapy, or both.
Hemangiomas of Other Skeletal Sites.  Hemangiomas
that involve bones other than the vertebrae or skull are
very rare and usually occur in the bones of the lower
extremity and ribs; however, any bone can be involved
(Figs. 13-3 to 13-8). Hemangiomas that involve long
bones can reach considerable size before they become
symptomatic (Figs. 13-4 and 13-5). Consequently, lesions
of the long tubular bones are usually larger than those of
the skull and vertebral bodies. They involve the metaphy-
seal and diaphyseal parts of long tubular bones and present
radiographically as lytic areas with bone trabeculation
creating a soap-bubble or honeycomb appearance as a
result of the expansive proliferation of engorged vessels
and thickened, remodeled bone trabeculae. Expansion of
the bone contour with thinning of the cortex is frequently
seen. Spiculated periosteal reaction may be present. Long
bone hemangiomas are rarely diagnosed correctly preop-
eratively, and they are often misdiagnosed radiologically
as malignant lesions. Hemangiomas that involve the flat
bones, such as the pelvis and scapula, are rare and have
the same sunburst appearance as the calvarial lesions. In
extremely rare cases, hemangioma can present radio-
graphically as an intracortical lesion and mimic other
intracortical lesions that occur more frequently, such as
osteoid osteoma and abscess (Fig. 13-6). Hemangioma
can also present as a subperiosteal lesion (Fig. 13-8).
Personal Comments
The diagnosis of craniofacial and vertebral hemangiomas
on the basis of clinical and radiographic features usually
presents little difficulty, but large hemangiomas of long
bones may raise the suspicion of a malignant bone tumor
because of the prominent perpendicular pattern of reac-
tive new bone in the overlying periosteum. Intracortical
hemangiomas in long bones have been mistaken for
osteoid osteoma and even for adamantinoma before
biopsy because of their features on radiographs. Benign
hemangiomas of bone with secondary changes (epitheli-
oid or superimposed papillary endothelial hyperplasia)
are frequently overdiagnosed as malignant vascular neo-
plasms. Vertebral hemangiomas can present diagnostic
problems when both the centrum and posterior elements
are involved and there is associated soft tissue involve-
ment, with extradural impingement.
Although borderline vascular tumors involving bone
are relatively rare, few clinicopathologic entities have
engendered more controversy in the literature than epi-
thelioid hemangioendothelioma of bone and epithelioid
 13  Vascular Lesions 917

A B

C D
FIGURE 13-13  ■  Hemangioma of vertebra: radiographic and microscopic features. A, Lateral view of computed tomogram (CT) of
upper lumbar spine shows corduroy-like appearance of vertebral body produced by thickening of vertical bone trabeculae traversing
hemangioma. B, Anteroposterior radiograph of the vertebral body shown in A showing coarse trabeculation of vertebral body caused
by hemangioma. C, Axial CT of thoracic vertebra with hemangioma of vertebral body. Cross sections of thickened vertebral (weight-
bearing) trabeculae produce polka-dot appearance typical of this lesion. D, Biopsy material of the lesion shown in A-C documenting
enlarged vascular channels filled with blood and reactive bone trabeculae. (D, ×50) (D, hematoxylin-eosin.)

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918 13  Vascular Lesions

A B

FIGURE 13-14  ■  Hemangioma of vertebra: radiographic, gross, and microscopic features. A, T2-weighted magnetic resonance image
showing a high signal intensity lesion. B, Gross photograph of vertebral hemangioma identified as an incidental finding at autopsy.
Note well-delineated hemorrhagic lesion involving the vertebral body. C, Low power photomicrograph of hemangioma shown in
B composed of well-developed cavernous vessels. (C, ×50) (C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

hemangioma. As stated before, the identification of the
specific translocation in epithelioid hemangioendotheli-
oma should help to resolve this long-lasting controversy
as preliminary data indicates that epithelioid hemangio-
mas are negative for this abnormality. However, valida-
tion of this concept in a significant number of bone cases
is not available in the literature at the time of this writing.
Lymphangioma and Lymphangiomatosis
Lymphangioma represents a benign lesion composed of
newly formed lymph vessels, in the form of dilated cystic
spaces. They are usually diffuse or multiple and most
likely represent hamartomatous malformations rather
than true neoplasms.63,65,68,70 Solitary lymphangiomas
occur less frequently, and only single cases have been
reported in the literature.60,61,66,69 Dilated intraosseous
lymphatics can also present in association with lymph
stasis. Multiple lymphangiomas of the ribs can be associ-
ated with chylothorax or chylopericardium.62,63 Lymph-
angiomatosis of bone can be associated with soft tissue
(extraskeletal) lymphangioma.67
Microscopically, lymphangioma or lymphangiomato-
sis consists of dilated, thin-walled vessels filled with pro-
teinaceous fluid that has no blood elements (Fig. 13-15).
It may be difficult to distinguish between blood and other
lymphatic spaces when the contents have been lost during
tissue processing. Often a mixture of lymphatics and
blood vessels can be present in one lesion. Immunohis-
tochemical stains may help to identify the lymphatic
nature of vessels in both lymphangioma and lymphangi-
omatosis. The putative markers of lymphatic endothelial
differentiation are: VEGFR-3, podoplanin (D2-40), and
PROX1. However, none of these markers is entire spe-
cific for lymphatic endothelial cells and are expressed to
some degree in nonlymphatic vascular tumors as well as
in tumors of nonvascular origin. Lymphangiomatosis
predominantly occurs in children and rarely becomes
manifest after age 20 years. Diagnosis at birth is uncom-
mon; a latent period is required for lesions to achieve
sufficient size to become symptomatic. The lesion can
also occasionally present as a pathologic fracture, espe-
cially in the long bones.
On radiographs lymphangiomatosis can show pro-
nounced expansion of large affected areas of the entire
bone with sunburst periosteal reaction (Figs. 13-16 and
13-17). The lesions seem to be composed of multiple
coalescent lytic areas separated by thin sclerotic zones.
The use of lymphangiography helps establish the nature
of the lesion before biopsy. The overall prognosis is good,
unless there is significant visceral involvement.64 The
lesions eventually stabilize and sclerose, but the profound
bone deformity, if present, persists. Some cases of lymph-
angiomatosis of bone can pursue an aggressive clinical
course with progressive bone loss (massive osteolysis) and
may have radiographic features of disseminated general-
ized disease (cystic angiomatosis).
Angiomatoses
Classification of skeletal angiomatoses into distinct clini-
copathologic entities is based on their clinical behavior
ERRNVPHGLFRVRUJ
13  Vascular Lesions 919
TABLE 13-1  Skeletal Angiomatoses
Type of Angiomatosis Anatomic Distribution
Nonaggressive
Regional Involvement of one anatomic
region (one or several bones)
Extraskeletal angiomatosis may
be present
Disseminated (cystic Disseminated multifocal
angiomatosis) involvement predominantly
affecting trunk bones
Extraskeletal angiomatosis (soft
tissue or visceral) may be
present
Aggressive
Massive osteolysis Regional involvement
(Gorham’s disease) predominantly affecting trunk
bones
Aggressive clinical behavior with
progressive bone destruction
(aggressive versus nonaggressive) and patterns of skeletal
involvement (regional versus disseminated) (Table 13-1).
Regional angiomatosis involves one or several bones of
the same anatomic region (e.g., spine, shoulder, knee)
(Figs. 13-13 to 13-18). Disseminated generalized angio-
matosis, also referred to as cystic angiomatosis, is a general-
ized multifocal disorder that predominantly involves the
trunk bones. Aggressive angiomatosis, or massive oste-
olysis, is a peculiar form of angiomatosis that progres-
sively destroys (lyses) the affected bone or bones.
Cystic Angiomatosis
The term cystic angiomatosis is applied to extremely rare
conditions of disseminated multifocal hemangiomas in
the skeleton.71,78,81–83,85 The bone involvement may be
accompanied by soft tissue and visceral hemangiomas.
The sites of extraskeletal involvement include soft tissue,
lung, liver, and particularly spleen.78,84,86,88 The disease is
probably congenital and sometimes is clinically evident
during the first decade of life. Most cases are recognized
in the first three decades of life. The condition can be
asymptomatic and is often detected incidentally in radio-
graphs obtained for other reasons. The typical age of
diagnosis and most frequent skeletal sites of involvement
are presented in Figure 13-19.
The disorder preferentially affects the trunk and occa-
sionally cranial bones (Figs. 13-20 to 13-23). Radiolucent
lesions with a soap-bubble or honeycomb appearance are
present in the skull, spine, ribs, and pelvis. The disease
tends to spare the acral appendicular skeleton. As men-
tioned, the lesions are typically radiolucent but rarely
sclerotic. In rare instances, the disorder is manifested on
radiographs as disseminated osteoblastic lesions that
mimic osteoblastic metastases.81,89
Microscopically, the lesions consist of hemangiomas
that are predominantly cavernous (Fig. 13-22). Usually,
an admixture of dilated lymphatics is also present (Fig.
13-24). In fact, some of the foci may be composed entirely
of lymphatics. Foci composed of small capillary vessels
920 13  Vascular Lesions

A B

C D
FIGURE 13-15  ■  Lymphangiomatosis: microscopic features. A and B, Lymphangiomatosis of the rib showing cortical bone eroded by
medullary lymphangiomatous process composed of dilated, endothelial-lined channels. C and D, Dilated lymphatic channels of
varying sizes forming a spongy architecture within the medullary bone. (A and B, ×25; C and D, ×100.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 921

A B

C D
FIGURE 13-16  ■  Lymphangioma of fibula: radiographic, gross, and microscopic features. A, Radiograph of fibula shows area of corti-
cal expansion with coarse trabeculation. B, Gross photograph of bivalved resection segment of fibular shaft shows localized area
of honeycomb appearance located eccentrically in cortex. C and D, Low and intermediate power photomicrographs of lymphangioma
of bone show dilated, endothelial-lined channels with delicate walls. Lymphocytic infiltrate is seen focally in septa. (C, ×25; D, ×50.)
(C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
922 13  Vascular Lesions

C B
FIGURE 13-17  ■  Lmphangiomatosis of bone: radiographic features. A, Chest radiograph of a 7-year-old boy with lymphangiomatosis
of multiple right ribs and right-sided chylous effusion. B, Coarse trabeculation of multiple ribs on right side was produced by lymph-
angiomatosis. C, Computed tomogram of chest shows chylous effusion and rarefaction of posterior portion of rib.

can also be found. Some foci can be accompanied by Massive Osteolysis

prominent new reactive bone trabeculae that occasionally
can dominate the lesion (Fig. 13-24). In the sclerosing
variant of skeletal angiomatosis, individual vessels can be
surrounded by thick sclerotic bone (Fig. 13-25).
On radiographs, lytic lesions may be seen to contain
some residual lamellar bone and foci of reactive woven
bone. Blastic lesions contain prominent, thickened bone
trabeculae of mature lamellar bone with areas of woven
bone rimmed by osteoblasts. Features of osteoclastic
resorption can be present in lytic and blastic lesions. It
has been noted that the sclerotic lesions occur most often
in older patients. Evaluation of serial radiographs in this
disorder has shown that increasing osteosclerosis can be
an age-related phenomenon in angiomatous foci that are
originally lytic. It may be that the lesions spontaneously
heal or regress and that this process is accompanied by
sclerosis. The skeletal lesions in this disorder are usually
stable or may even regress. Fatal complications (i.e.,
internal bleeding) are caused by visceral lesions. Rare
cases of angiosarcoma arising from skeletal angiomatosis
have been described.90
Massive osteolysis, also referred to as disappearing or
phantom bone disease, was described in 1954 by Gorham
et al.76 One year later, Gorham and Stout77 established
the fact that a peculiar clinically aggressive form of angio-
matosis was responsible for this syndrome. The peak age
incidence and most frequent sites of skeletal involvement
are shown in Figure 13-26. The disease usually affects
children or young adults.72–75,78–80 It is sporadic, without
evidence of hereditary transmission, and has no sex pre-
dilection. Usually, it involves the shoulder and hip areas
and starts in the trunk bones, and it may separately
involve several bones in the same region. In the appen-
dicular skeleton, the proximal parts of the extremity
bones—the proximal humerus and femur—are typically
involved.
Microscopically, the vascular changes in Gorham’s
disease represent hemangiomas, lymphangiomas, or a
combination. They are indistinguishable from ordinary,
nonaggressive angiomatoses and represent a complex
Text continued on p. 931

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 923

A B

C D E

FIGURE 13-18  ■  Skeletal angiomatosis (regional): radiographic features. A, Angiomatosis of spine involving four lumbar vertebral
bodies. Note radiolucent lesions with longitudinal, parallel trabeculations. B, Multiple lucent areas with coarse trabeculation involv-
ing patella, proximal tibial metaphysis and epiphysis, and proximal fibular shaft in teenaged patient. C, Lucent areas with peripheral
sclerosis involving humerus. D, Lytic lesion with peripheral sclerotic margins involving the femur. Note pronounced bowing defor-
mity. E, Multilocular well-demarcated lucent lesions involving proximal humerus.

ERRNVPHGLFRVRUJ
924 13  Vascular Lesions

Predominantly
trunk bones
Age at diagnosis

1 2 3 4 5 6 7 8
Age in decades

FIGURE 13-19  ■  Cystic angiomatosis. Most frequent age at diagnosis and frequent sites of skeletal involvement.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 925

B
FIGURE 13-20  ■  Cystic angiomatosis of bone: radiographic features. A, Computed tomogram of pelvis and sacrum of 60-year-old
man with sclerosing variant of cystic angiomatosis. B, Radionuclide bone scan shows increased uptake in portions of pelvis showing
sclerotic lesions in A and in left second and fifth ribs.

ERRNVPHGLFRVRUJ
926 13  Vascular Lesions

FIGURE 13-21  ■  Cystic angiomatosis of bone (sclerotic variant): radiographic features. Lateral radiograph of lumbar spine shows
sclerotic lesions in vertebral bodies.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 927

B C

FIGURE 13-22  ■  Cystic angiomatosis of bone (sclerotic variant): radiologic and microscopic features. A, Sclerotic variant of cystic
angiomatosis involving both left and right pelvic bones. B, Sclerotic lesions mimicking osteoblastic metastases adjacent to sacroiliac
joint and iliac crest. C, Low power photomicrograph shows vascular lesion overgrown by well-developed thickened trabeculae of
bone (C, ×25) (C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
928 13  Vascular Lesions

FIGURE 13-23  ■  Cystic angiomatosis of bone (sclerotic variant): radiologic features. Sclerotic variant of angiomatosis involving both
left and right pelvic bones. Note multifocal sclerotic lesions mimicking osteoblastic metastasis adjacent to sacroiliac joints.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 929

B
FIGURE 13-24  ■  Skeletal angiomatosis: microscopic features. A, Low power photomicrograph shows dilated, thin-walled vessels in
marrow spaces of cancellous bone with delicate trabeculae of reactive woven bone surrounding angiomatosis elements. B, Medium
power photomicrograph shows thin-walled vascular channels in marrow spaces bordered by thickened mature bone trabeculae
(A and B, ×50; hematoxylin-eosin).

ERRNVPHGLFRVRUJ
930 13  Vascular Lesions

B
FIGURE 13-25  ■  Cystic angiomatosis of bone (sclerosing variant): microscopic features. A, Low power photomicrograph of sclerotic
focus in angiomatosis. Note vascular channels in marrow spaces surrounded by thick trabeculae of lamellar bone resembling corti-
cal bone (×50). B, Medium power photomicrograph of A shows osteoclastic resorption cavity (right) and embedded vascular struc-
tures (×100). (A and B, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

Incidence
1 2 3 4 5 6
Age in decades
FIGURE 13-26  ■  Massive osteolysis. Peak age incidence and most frequent sites of skeletal involvement are indicated by solid black
arrows.
network of dilated, thin-walled capillaries growing in the
marrow spaces. The active lesions are purely vascular, and
the osteoclastic resorptive activity can be seen near the
advancing edge. Stabilization of the lesion is associated
with an increased amount of intervening connective
tissue. On radiographs, massive osteolysis appears as lytic
lesions that progressively involve the affected bones and
eventually obliterate the cortical and cancellous architec-
ture (Figs. 13-27 and 13-28). The dilated cystic spaces can
be seen grossly (Fig. 13-29). Late lesions can be predomi-
nantly fibrous. The process tends to stabilize spontane-
ously. In some cases, extensive involvement of the chest
wall (ribs) is associated with pleural effusion and severe
pulmonary compromise, which can lead to a fatal outcome.
Because the clinical course of massive osteolysis is
variable and unpredictable, the choice of a particular
method of therapy is fraught with uncertainty. In fact,
any histologically benign angiomatosis of bone or soft
tissue may occasionally behave clinically as a slowly pro-
gressive disorder that eventually compromises the func-
tion of the affected organ. In such instances, major
resection procedures including amputation may be
required in order to control the process. Surgical resec-
tion, embolization, radiation therapy, steroids, and more
recently, interferon alfa have all been used in cases
showing progression.87
ERRNVPHGLFRVRUJ
13  Vascular Lesions 931
7 8
Vascular Malformations
Vascular malformations are developmental in nature and
typically grow proportionally with the host. They are
classified similarly to vascular neoplasms as of arterial,
venous, or capillary in nature. They often manifest arte-
riovenous shunting. They are frequently complicated
by vascular ectasia and thrombosis. They range from
superficial varicosities to large, deep masses that infiltrate
soft tissue and may involve large portions of the body
(Fig. 13-30). They are predominantly soft tissue lesions
and their involvement of the skeleton is rather secondary.
These conditions are best diagnosed in correlation with
clinical presentation and radiographic imaging data.
Glomus Tumor
The glomus body is a form of arteriovenous anastomosis
that plays a role in thermal regulation. It is distributed
throughout the body in the reticular dermis but is most
frequently seen in the subungual region. The normal
glomus body consists of an afferent arteriole that branches
into two to four connecting arterioles. The arterioles
have thick segments surrounded by concentric layers
of modified perivascular smooth muscle cells. These
segments are called Sucquet-Hoyer canals and consist of
932 13  Vascular Lesions
FIGURE 13-27  ■  Massive osteolysis (disappearing bone disease)
involving humerus. Proximal two thirds of right humerus in a
young adult has completely disappeared, and distal portion of
the shaft shows typical “sucked candy” attenuation. Fibrous
remnant showed capillary angiomatosis process in biopsy
samples. (Courtesy Dr. T. Bauer, Cleveland.)
arteriovenous anastomosing vessels connected with effer-
ent veins (Fig. 13-31). The glomus tumor was described
in 1924 by Masson,105 who linked this peculiar neoplasm
to a normal glomus body and proposed that in some cases
it may represent a hyperplasia of perivascular cells rather
than a true neoplasm. Normal glomus bodies can be
found within the bones and can be the source of an
intraosseous glomus tumor (Fig. 13-32).
Definition
Glomus tumor is a rare, benign distinctive neoplasm
composed of vascular channels and modified perivas-
cular muscle cells that recapitulate the structure of a
glomus body.
Incidence and Location
Glomus tumors are extremely rare lesions, and most are
diagnosed in patients between ages 20 and 40 years. The
ERRNVPHGLFRVRUJ
single most common site is the subungual region of the
fingers. Other common sites include the pelvis, wrist,
forearm, and foot. They also can occur in the tip of the
coccyx, where they arise from the glomus coccygeum.102
In rare instances, they may originate in the deep organs
without apparent association with normal glomus bodies.92
The subungual lesions typically erode the underlying
distal phalanges.95,100,103,106,108 The second most frequent
location is in the subcutaneous tissue.91,97 Intraosseous
glomus tumors are extremely rare, and only single cases
have been reported in the literature.93,94,96,103,104,109–111
Most of these reports describe lesions that were com-
pletely embedded in the distal phalanges. Others have
been described as periosteal lesions in long bones.98,101
In our opinion, the possibility that some of these lesions
secondarily erode the bone cannot be completely ruled
out. Exceptional cases of glomus tumor arising in other
bones such as the proximal phalanx, tibia, ulna, and pelvis
have also been reported.92,94,103,108,110,111 The peak age inci-
dence and most frequent sites of skeletal involvement are
shown in Figure 13-33.
Clinical Symptoms
Glomus tumors are extremely painful, and symptoms are
often out of proportion with the size of the tumor. Par-
oxysms of pain in the affected area can be triggered by
changes of temperature or even by minor mechanical
disturbance of the affected area. The paroxysms of pain
may also appear spontaneously with no apparent cause.
Intraosseous lesions that cause these symptoms raise
clinical suspicion of osteoid osteoma. In contrast to
osteoid osteoma, pain from a glomus tumor is not pre-
dominantly nocturnal, has a paroxysmal pattern, and does
not respond to salicylates.
Radiographic Imaging
The subungual glomus tumor erodes the underlying
distal phalanx93,103,105 (Fig. 13-34). Occasionally, it can be
multifocal, involving the phalanges bilaterally.104 Intraos-
seous lesions present as well-demarcated lytic defects that
measure less than 1 cm in diameter (Fig. 13-35). In addi-
tion to osteoid osteoma, intraosseous epidermal inclusion
cysts and invasive subungual keratoacanthomas of the
nail bed can produce lucent, painful lesions in the distal
phalanx that must be distinguished from intraosseous
glomus tumor. The lesions in bones other than phalanges
are intracortical, expand the cortex, and promote mild
sclerosis in the adjacent bone. In summary, together with
its clinical symptoms, the lesion resembles osteoid
osteoma on radiographs. In one of our cases the tumor
eroded the cortex of the ulna and extended into the sur-
rounding soft tissues.108
Gross Findings
Glomus tumor in its typical location—the subungual
region—represents a well-circumscribed, soft, tan-gray
mass that can be separated easily during curettage from
the surrounding soft tissue or bone (Fig. 13-34). The cut
Text continued on p. 939
 13  Vascular Lesions 933

B
FIGURE 13-28  ■  Massive osteolysis (disappearing bone disease) involving ribs. A, Plain radiograph of chest of young man with disap-
pearance of posterior portions of two upper ribs on left. Biopsy revealed capillary angiomatosis consistent with Gorham’s disease.
B, Enlargement of radiograph shown in A with disappearance of posterior portions of two left ribs. C, Radionuclide scan shows
absence of uptake in corresponding two ribs on left.

ERRNVPHGLFRVRUJ
934 13  Vascular Lesions

B
FIGURE 13-29  ■  Massive osteolysis: gross features. A, Bisected clavicle and portion of sternum. Note multiple cystic spaces and
replacement of bone by fibrous vascularized tissue. B, Higher magnification of A shows bisected claviculomanubrial joint. Note
multiple cystic changes in clavicle.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 935

A B

C
FIGURE 13-30  ■  Vascular malformation of the lower extremity: gross and radiographic features. A, Amputation specimen showing
large vascular structures representing tortuous thick-walled vasculature with cavernous dilations extensively involving the soft tissue
of the lower extremity. Inset, Higher magnification of specimen shown in A. B, T2-weighted magnetic resonance image showing
grapelike high signal intensities corresponding to soft tissue vascular lesions. C, Higher power gross photograph of the foot showing
extensive cystlike vascular lesions involving the soft tissue and eroding bones.

ERRNVPHGLFRVRUJ
936 13  Vascular Lesions

B
FIGURE 13-31  ■  Glomus body: microscopic features. A, Low power view of normal glomus coccygeum. B, Higher magnification of
A shows cluster of perpendicularly sectioned glomic arterioles of Sucquet-Hoyer canals (arrows) surrounded by thick layer of glomus
cells. Inset shows glomic arteriole surrounded by glomus cells and peripheral collecting vessel (denoted by asterisk). (A, ×50; B and
Inset, ×100) (A, B, and inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 937

A B
FIGURE 13-32  ■  Glomus body: microscopic features. A, Nail bed containing normal glomus bodies (×50). B, Incidentally discovered
intraosseous normal glomus body. (A and B, ×100) (A and B, hematoxylin-eosin.)

20 40
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 13-33  ■  Glomus tumor. Peak age incidence and most frequent sites of skeletal involvement are indicated by solid black arrows.

ERRNVPHGLFRVRUJ
938 13  Vascular Lesions

A B

C D
FIGURE 13-34  ■  Glomus tumor: radiographic, gross, and microscopic features. A and B, Radiographs of distal phalanges show pres-
sure erosion of bone by subungual glomus tumors. C, Gross photograph of enucleated glomus tumor on fingernail. Exposed con-
cavity of tumor bed in distal phalanx can be seen just proximal to base of nail. D, Photomicrograph of glomus tumor of subungual
region shows endothelial-lined vessels and perivascular glomus cells in small nests and sheets (D, ×50) (D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 939

B
FIGURE 13-35  ■  Intraosseous glomus tumor of ulna: radiographic features. A, Anteroposterior view of elbow in a young woman who
had severe pain. A 1-cm lytic lesion (arrow) is seen in proximal ulna. B, Lateral view of elbow shows ovoid lytic lesion in ulna
(arrow). Sharp circumscription but no sclerosis is present.

surface is usually tan but can be hemorrhagic. Older
lesions may have a fibrous appearance.
Microscopic Findings
Extraosseous glomus tumors are divided into three
microscopically distinct subtypes: glomus tumor proper,
glomangioma, and glomangiomyoma. The classification
is based on differing proportions of vascular, smooth
muscle, and epithelioid glomus cells. Glomus tumor
proper occurs most frequently in the fingers. Glomangio-
mas are more often seen in the soft tissue of the forearm.
Glomangiomyomas occur with equal frequency in the
upper and lower extremities. All the lesions reported as
primary bone tumors have been of the glomus tumor
proper category. The microscopic features are very char-
acteristic and easy to recognize. The lesion has a rich
vascular network surrounded by cuffs of epithelioid
glomus cells (Fig. 13-36). These structures can be densely
packed, forming highly cellular solid areas, or can be
separated by strands of loose connective tissue (compare
Figs. 13-36 and 13-37). More solid lesions can mimic
epithelial neoplasms. The rich, branching vascular
network can create a hemangiopericytoma-like pattern.

ERRNVPHGLFRVRUJ
940 13  Vascular Lesions

A B

FIGURE 13-36  ■  Glomus tumor: microscopic features. A and B, Common pattern within glomus tumor is composed of solid sheets
of cells with interspaced vessels. C, Low power photomicrograph shows large cystic spaces within solid sheets of tumor cells.
(A, ×60; B, ×100; C, ×50) (A-C, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 941

A B

C D
FIGURE 13-37  ■  Glomus tumor: microscopic patterns. A, Periphery of glomus tumor shows tumor cells in fibrous stroma.
B, Cluster of glomus cells separated by fibrous stroma. C, Solid area of tumor with less prominent stromal tissue.
D, Higher magnification of C shows tumor cells with eosinophilic cytoplasm and round or oval nuclei. (A and C, ×200; B and D, ×400)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
942 13  Vascular Lesions
Ultrastructurally the glomus tumor cells represent modi-
fied perivascular smooth muscle cells.99,107 There are
many deviations from this most frequent pattern, but
their description is beyond the scope of this book.
Treatment and Behavior
Glomus tumors are benign, and simple excision of both
the soft tissue and intraosseous forms is curative. Malig-
nant glomus tumor is extremely rare in soft tissue and has
not been described in bone.
MALIGNANT VASCULAR TUMORS
Epithelioid Hemangioendothelioma
In 1979, Rosai et al.50 proposed a unifying concept
of vascular tumors in which endothelial cells with abun-
dant cytoplasm and prominent vacuoles resembled his-
tiocytes. These tumors involved a variety of tissues,
including bone, and Rosai et al. called them histiocyt-
oid hemangiomas. Later, in 1982, Weiss and Enzinger131
proposed the term epithelioid hemangioendothelioma to
describe an unusual vascular tumor of soft tissue in
which endothelial cells had an epithelioid appearance.
Epithelioid hemangioendotheliomas are not unique to
the soft tissue and occur in deep organs, most frequently
the lungs and liver.112,113,119 They also arise within
bone.114,116,117,121,122,124,125,130 Epithelioid hemangioendo-
theliomas in different sites are morphologically and bio-
logically similar and pursue a clinical course between
that of a hemangioma and a conventional high-grade
angiosarcoma. They are classified as low-grade malig-
nancies and have an indolent clinical behavior.114,117,120,123
We believe that epithelioid hemangioma is a variant of
benign hemangioma and should not be confused with a
low-grade epithelioid hemangioendothelioma (also see
the section on hemangioma).
Recent transcriptomic sequencing combined with con-
ventional cytogenetics identified the translocation involv-
ing (1;3)(p36;q25) resulting in the WWTR1-CAMTA1
chimeric gene in epithelioid hemangioendothelioma
(Fig. 13-38).115,129 It involves the WW domain-containing
transcription regulator 1 (WWTR1) mapping to 3q25 and
calmodulin-binding transcription activator 1 (CAMTA1)
mapping to 1p36. The WWTR1-CAMTA1 chimeric gene
is under the transcription control of WWTR1 promoter.
The new protein contains the amino terminus compo-
nent of WWTR1 and a large portion of CAMTA1 at the
carboxyl terminus. The transcription factor WWTR1
is physiologically highly expressed in endothelial cells,
whereas CAMTA1 is normally expressed only in the central
nervous system. The fusion with WWTR1 upregulates
CAMTA1, causing its aberrant expression in endothelial
cells of epithelioid hemangioendothelioma. Preliminary
data indicate that this fusion is specific for epithelioid
hemangioendothelioma regardless of its site of origin,
including those that develop in bone and can be used
in the differential diagnosis of vascular conditions with
epithelioid features.115,129
ERRNVPHGLFRVRUJ
Definition
Epithelioid hemangioendothelioma is a unique, well-
differentiated endothelial vascular neoplasm with
an epithelioid appearance of its endothelial cells and a
tendency to be multifocal.
Incidence and Location
Epithelioid hemangioendotheliomas of bone are ex-
tremely rare. The limited experience with these lesions
indicates that they most frequently occur during the
second and third decades of life and there is a definite
predominance in male patients. Bones of the lower
extremities are preferentially involved. The tibia is the
most frequently involved, but any bone can be affected.
Most patients initially have multifocal lesions with a ten-
dency to involve bones of the same region (e.g., bones of
one extremity). Synchronous involvement of paired
bones, most frequently the tibia and fibula, is common,
but in some instances, completely separate synchronous
foci are present in distant anatomic sites such as the
clavicle and lumbar vertebrae. The peak age incidence
and most frequent sites of skeletal involvement are shown
in Figure 13-39.
Radiographic Imaging
The radiographic appearance of the lesion is not specific.
Epithelioid hemangioendotheliomas present as purely
lytic lesions with varying degrees of peripheral sclerosis
(Figs. 13-40 to 13-43). The margins are well demarcated,
and cortical erosion or complete disruption may be seen
(Figs. 13-44 and 13-45). Occasionally a more aggressive
growth pattern, such as a moth-eaten pattern, can be
seen. Invasion into soft tissue is rare, and periosteal new
bone formation is not present. The diagnosis of epithe-
lioid hemangioendothelioma of bone can be suspected
from findings on radiographs because of the multifocality
of the lytic defects and the peculiar tendency to involve
bones of one extremity (Figs. 13-45 and 13-46). In
unusual circumstances, the epithelioid hemangioendo-
thelioma can provoke sclerosis and may present as a
blastic lesion on radiographs.
Gross Findings
Typically epithelioid hemangioendotheliomas are well
demarcated with irregular scalloped borders and a bright
red hemorrhagic and sometimes gelatinous appearance
(Figs. 13-47 and 13-48). Erosions of cortex with complete
cortical disruption and extension into soft tissue can be
present. Multifocal lesions involving one bone or several
bones of an affected extremity are frequently seen.
Microscopic Findings
The tumor usually consists of solid nests or anastomosing
cords of epithelioid cells that occasionally form narrow
vascular channels (Figs. 13-49 and 13-50).117,120,124,130
Text continued on p. 956
 13  Vascular Lesions 943

Chr 1
Chr 3

cds
26
WWTR1 36.3
CAMTA1 36.2
25 36.1
24.3 35
24.1
24.2 cen tel 34.3
23 34.2
34.1
22 12 3 4 5 6 7 33
21.3 32.3
32.2
32.1
21.2 31.3
21.1

cds
31.2
14.3
14.1
14.2 CAMTA1 31.1
13 22.3
22.2
12 22.1
11.1 11.2 21
11.1
11.2 12 13.3
13.1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 13.1 13.2
13.2 12
11
13.3 11
21 12
22
23 21.1
21.2 21.3
24 WWTR1
25.1 22
25.2 23
25.3
26.1 24
26.2 25
26.3
27
28 1 2 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 31
29
32.1
706 aa 32.2 32.3
41
A 42.1
42.2 42.3
43
44

WWTR1
WW Q-rich CC PDZ

breakpoint
CAMTA1
CG-1 TIG ANK IQ

breakpoint
Fusion protein
WW TIG ANK IQ 1455 aa

breakpoint
WW – WW domain
WWTR1 portion CAMTA1 portion CC – Coiled-coil domain
PDZ – PDZ binding motif
CG-1 – CG-1 DNA binding domain
TIG – Transcription factor immunoglobulin domain
ANK – Ankyrin repeats
IQ – IQ calmodulin-binding motifs
Q-rich – Glutamine rich region
B
FIGURE 13-38  ■  Molecular structure and breakpoints associated with t(1;3)(p36;q25) resulting in WWTR1-CAMTA1 gene fusion in
epithelioid hemangioendothelioma. A, Chromosomal diagrams depicting the t(1;3)(p36;q25) resulting in WWTR1-CAMTA1 fusion.
The WWTR1 gene is located on the long arm of chromosome 3. The CANTA1 is located on the short arm of chromosome 1. As a
result of translocation two derivatives chromosomes are formed. The WWTR1-CAMTA1 fusion is transcribed from der(1). B, Exon-
intron structures of the WWTR1 and CAMTA1 genes are shown. The molecular structure of the hybrid gene, which includes the
coding sequences of the amino-terminus domain WW of WWTR1 and several transcriptionally active domains (TIG, ANK, and IQ)
of CAMTA1 at the carboxyl terminus is shown. In this fusion, the transcriptional domains of CAMTA1 are driven by the strong
promotor of WWTR1 and are overexpressed in cells of epithelioid hemangioendothelioma. C, The structures of the WWTR1 and
CAMTA1 proteins as well as the structure and functional domains of the fusion protein are shown. Solid arrows indicate the posi-
tion of breakpoints.

ERRNVPHGLFRVRUJ
944 13  Vascular Lesions

Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 13-39  ■  Epithelioid hemangioendothelioma. Peak age incidence and most frequent sites of skeletal involvement are indicated
by solid black arrows.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 945

A B

C E
FIGURE 13-40  ■  Epithelioid hemangioendothelioma: radiographic features. A and B, Lytic sharply demarcated lesion of distal humerus
with expansion of bone contour medially and posteriorly. C, Lytic focus in the tibial shaft with diffuse sclerosis of adjacent bone.
D, Destructive lytic lesions in distal femoral shaft. Note motheaten pattern of bone destruction. E, Computed tomogram of lesion
in D shows low signal intramedullary lesion with multiple erosions of cortex.

ERRNVPHGLFRVRUJ
946 13  Vascular Lesions

C
FIGURE 13-41  ■  Epithelioid hemangioendothelioma: radiographic features. A, Multiple lytic lesions of right pelvis. B and C, Computed
tomograms of lesions shown in A document multiple sharply demarcated lytic lesions of ilium.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 947

A B

C D
FIGURE 13-42  ■  Epithelioid hemangioendothelioma: radiographic features. A-C, Extensive involvement of metatarsal bones with
punched-out lytic lesions involving cortical bone and medullary cavities. D, Specimen radiograph of resected distal metatarsal
segment containing lytic focus of epithelioid hemangioendothelioma.

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948 13  Vascular Lesions

A
FIGURE 13-43  ■  Multicentric epithelioid hemangioendothelioma of bone: radiographic features. A, Anteroposterior radiograph of foot
of an 18-year-old man with multiple lytic lesions of metatarsal and tarsal bones. B, Opposite foot of patient in A shows pathologic
fracture of fourth metatarsal through focus of epithelioid hemangioendothelioma.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 949

FIGURE 13-44  ■  Multicentric epithelioid hemangioendothelioma: radiographic features. Computed tomograms of right and left tarsal
bones show multicentric, sharply demarcated lesions on right side.

ERRNVPHGLFRVRUJ
950 13  Vascular Lesions

B
FIGURE 13-45  ■  Multicentric epithelioid hemangioendothelioma: radiographic features. A and B, Anteroposterior and lateral radio-
graphs of foot of young man show multiple lytic foci without reactive sclerosis or periosteal new bone formation involving meta-
tarsals, phalanges, tarsal bones, and distal tibial shaft.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 951

A B

C D
FIGURE 13-46  ■  Multicentric epithelioid hemangioendothelioma of bone: radiographic features. A and B, Lateral and anteroposterior
radiographs of leg of a 29-year-old woman show multiple small, sharply circumscribed lytic lesions of right tibia and fibula.
C, Radionuclide scan of patient in A and B shows increased isotope uptake in multiple tarsal bones and distal tibia. D, Lateral radio-
graph of foot and ankle shows multiple lytic lesion in calcaneus and cuneiform bone.

ERRNVPHGLFRVRUJ
952 13  Vascular Lesions

C D
FIGURE 13-47  ■  Epithelioid hemangioendothelioma: radiographic and gross features. A, Lateral radiograph of leg show multiple
sharply demarcated lytic lesions of tibia and tarsal bones. B, Magnetic resonance image showing multifocal well-demarcated low
signal lesions involving distant tibia and tarsal bones. C, Gross photograph of bisected amputation specimen showing multifocal
well-demarcated hemorrhagic lesions involving distal tibia and tarsal bones. D, Higher magnification of the specimen shown in C.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 953

A B

C D
FIGURE 13-48  ■  Epithelioid hemangioendothelioma: gross features. A, Cut surface of distal segment of metatarsal bone containing
intramedullary focus of epithelioid hemangioendothelioma eroding cortex in neck region. B, Whole-mount section of lesion shown
in A. Note sharp circumscription of tumor tissue. C, Resected head and shaft of proximal radius containing gelatinous, dark red
lobulated tumor expanding into soft tissue. D, Hemangioendothelioma involving medullary cavity of proximal ulna.

ERRNVPHGLFRVRUJ
954 13  Vascular Lesions

A B

C D
FIGURE 13-49  ■  Epithelioid hemangioendothelioma: microscopic features. A, Solid nests of epithelioid endothelial cells and irregular
open vascular channels. B, Higher magnification of A shows irregular vascular channel lined by epithelioid endothelial cells.
Note multiple layers of endothelial cells with micropapillary structures. C, Irregular anastomosing vascular spaces within epithelioid
cells. D, Cords and small nests of epithelioid endothelial cells occasionally forming primitive vascular channels. (A, ×200; B-D, ×400)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 955

A B

C D

FIGURE 13-50  ■  Epithelioid hemangioendothelioma: microscopic features. A, Irregular anastomosing cords of epithelioid endothelial
cells. B, Higher magnification of A shows epithelial endothelial cells forming ill-defined cords and nests. C, Irregular anastomosing
vessels and cords of epithelioid endothelial cells. D, Higher magnification of C showing epithelioid endothelial cells lining vascular
channels and forming cords. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
956 13  Vascular Lesions
Scattered, more solid clusters of epithelioid cells also may
be present. The supporting connective tissue may exhibit
myxoid or chondroid change (Fig. 13-51). Focally, indi-
vidual epithelioid cells are embedded in a basophilic
matrix that mimics hyaline cartilage. Individual cells are
round or polygonal. Cellular pleomorphism is not con-
spicuous. Mitotic activity is low, within the range of 1 to
2 mitoses per 10 high-power fields. Tumors showing an
abundance of mitoses, marked nuclear pleomorphism,
and atypical, multipolar mitotic figures should be classi-
fied as angiosarcomas, with or without epithelioid fea-
tures. The cytoplasm of the epithelioid cells may be
densely eosinophilic (Fig. 13-52). The nuclei are
round with prominent nucleoli. The cytoplasm of the
epithelioid cells characteristically shows vacuolization,
and sometimes, a signet-ring–like appearance is produced
by a large vacuole that distorts the cell (Fig. 13-53). The
large cytoplasmic vacuoles probably signify attempts of
the tumor to form primitive vascular lumina.
Vascular channels in varying stages of angiogenesis
usually are present. Some channels have only single cells
with intracytoplasmic lumina, whereas others consist of
several cells with a compact, solid arrangement. Solid
nests of epithelioid cells that merge with capillary-sized
vessels mimic vessels of granulation tissue. Some cases
can be exclusively composed of anastomosing or branch-
ing cords of epithelioid cells in a background of chon-
droid and myxoid matrix. The individual epithelioid cell
cytoplasmic lumina may contain red blood cells, which
can also be found within the cords of epithelioid cells
that resemble primitive vessels. An inflammatory infil-
trate of varying degree is often present and consists of
eosinophils, lymphocytes, and plasma cells. In some
cases, the eosinophilic infiltrate can be very pronounced
and may obscure the endothelial tumor elements. The
lesion may have an overall nodular architecture com-
posed of areas of solid epithelioid endothelial cells with
poorly developed irregular anastomosing vascular chan-
nels (Figs. 13-54 and 13-55). Foci of hemorrhage and
necrosis may be present. Rarely, the stroma may contain
an abundance of osteoclast-like giant cells.132 The vacu-
oles of epithelioid cells are negative in periodic acid–
Schiff and alcian blue stains. Silver stains show reticulin
fibers encircling individual epithelioid cells and outline
their small nest or cords. Epithelioid cells express a full
roster of endothelial markers and are at least focally
positive for factor VIII-related antigen, CD31, CD34,
and ERG (Fig. 13-56).30,120,230 Less frequently, the coex-
pression of epithelial markers with focal positivity for
epithelial membrane antigen and keratin, particularly
low-molecular-weight keratin, can be present.57 Ultra-
structurally, the epithelioid cells are identified as endo-
thelial cells containing Weibel-Palade bodies. Reflecting
the light microscopic appearance, epithelioid endothe-
lial cells are seen lining the vascular spaces, sometimes
occluding them and showing abundant cytoplasm with
irregular free cytoplasmic borders with pinocytotic ves-
icles (Fig. 13-57). Abundant cytoplasmic aggregates of
intermediate filaments with a thickness of 10 nm can
be correlated with the epithelioid light microscopic
appearance (Fig. 13-58). The formation of primitive
intracellular vascular lumina representing early stages
ERRNVPHGLFRVRUJ
of angiogenesis can be documented ultrastructurally as
well (Fig. 13-58).128,130
Differential Diagnosis
The epithelioid features of this tumor, with clusters of
large endothelial cells as well as solid nests and cords,
can mimic metastatic carcinoma in bone. Immunohisto-
chemical demonstration of keratin and epithelial mem-
brane antigen usually identifies the adenocarcinoma cells
in the absence of reactivity for endothelial markers such
as factor VIII-related antigen, CD31, CD34, and ERG.
On the other hand, keratin reactivity in epithelioid
hemangioendothelioma has been reported and signifies
the need for the use of a panel of multiple antibodies to
distinguish these tumors.
Composite tumors containing areas of epithelioid
hemangioendothelioma and hemangioma30,127 as well as
epitheloid angiosarcomas arising in hemangioendotheli-
oma have been described.118
The distinction from angiosarcoma is based on the
uniformity of the proliferating endothelial cells, the low
mitotic rate, and the minimal nuclear pleomorphism
exhibited by the endothelial cells in these tumors. Angio-
sarcoma shows a much higher level of nuclear atypicality
and prominent spindle-cell differentiation. Intraluminal
budding of neoplastic endothelial cells with a high
nuclear/cytoplasmic ratio is commonly seen in angiosar-
coma but not in epithelioid hemangioendothelioma. The
myxoid and chondroid matrices, which may be found
in epithelioid hemangioendotheliomas, can sometimes
suggest a cartilage neoplasm in biopsy material. Their pres-
ence in areas of cells that contain cytoplasmic luminal
vacuoles can add to the resemblance to cartilage lesions,
but these cells often show immunoreactivity for factor
VIII-related antigen CD31, CD34, and ERG. They are
typically negative for cartilage markers. It is expected that
molecular tests for WWTR1-CAMTA1 fusion will play a
major role in differential diagnosis as preliminary evi-
dence indicates high specificity of this abnormality for
epithelioid hemangioendothelioma.
Treatment and Behavior
Epithelioid hemangioendotheliomas are low-grade, well-
differentiated borderline tumors with locally destructive
indolent behavior. There is no unanimity as to treatment.
Some lesions have been treated with en bloc excision or
curettage only. In some cases, especially with reference
to multifocal lesions, radiation therapy is used. Of seven
patients who had multicentric tumors and who were
available for follow-up, all were alive for 1 month to 10
years (mean, 4.3 years) after treatment. Four patients who
had solitary lesions and for whom follow-up data were
available were alive 9 months to 4 years (mean, 1.8 years)
after surgical treatment. In one patient in this group, a
nodule of the abdominal wall was excised, but the tumor
recurred 1 year after treatment. These data indicate that
epithelioid hemangioendotheliomas of bone pursue an
indolent course and can be controlled by limited surgery,
radiofrequency ablation,126 and radiotherapy.130
Text continued on p. 965
 13  Vascular Lesions 957

A B

C D
FIGURE 13-51  ■  Epithelioid hemangioendothelioma: microscopic features. A, Epithelioid endothelial cells forming poorly developed
vascular channels, cords, and nests in a chondroid-like stroma. B, Higher magnification of A shows epithelioid endothelial cells
forming cords and nests in chondroid-like stroma. C, Epithelioid endothelial cells forming solid sheets with slit vascular spaces.
D, Higher magnification of C shows solid sheets of epithelioid endothelial cells with poorly developed vascular spaces. (A and
C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
958 13  Vascular Lesions

A B

C D
FIGURE 13-52  ■  Epithelioid hemangioendothelioma: microscopic features. A and B, Low power photomicrographs showing solid
sheets and small nests of epithelioid endothelial cells. C and D, Higher power photomicrographs showing solid sheets and nests
of epithelioid endothelial cells occasionally forming poorly developed small vascular spaces. (A and B, ×100; C and D, ×200.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 959

B
FIGURE 13-53  ■  Epithelioid hemangioendothelioma of bone: microscopic features. A, Low power magnification of pattern of plump,
epithelioid cells arranged in cords in basophilic myxoid stroma. B, Higher magnification shows characteristic intracytoplasmic
vacuoles in epithelioid endothelial cells. Matrix has chondroid aura. Inset shows various-sized cytoplasmic vacuoles and dense
cytoplasm in same cells. Note signet-ring appearance of some endothelial cells. (A, ×100; B, ×200; Inset, ×400) (A, B, and
Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
960 13  Vascular Lesions

B
FIGURE 13-54  ■  Epithelioid hemangioendothelioma: microscopic features. A and B, Low power photomicrographs show overall
nodular architecture of this epithelioid hemangioendothelioma. (A, ×25; B, ×50.) (A and B, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 961

B
FIGURE 13-55  ■  Epithelioid hemangioendothelioma: microscopic features. A, Solid nests of epithelioid endothelial cells with anasto-
mosing vascular pattern. B, Higher magnification of A shows densely packed epithelioid endothelial cells with distinct cytoplasmic
borders. (A, ×200; B, ×400) (A and B, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
962 13  Vascular Lesions

A B

C D
FIGURE 13-56  ■  Epithelioid hemangioendothelioma: immunohistochemical features. A, B, and D, Strong reactivity of epithelial endo-
thelioid cells with Ulex europaeus lectin. C, Strong positivity of epithelial endothelioid cells for factor VIII-related antigen. (A, B, and
D, ×400; C, ×200.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 963

B
FIGURE 13-57  ■  Epithelioid hemangioendothelioma: light microscopic and ultrastructural features. A, Anastomosing pattern of
vessels lined by prominent epithelial endothelial cells. B, Ultrastructure of crowded epithelioid endothelial cells that line vascular
channel. (A, ×200; B, ×4000) (A, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
964 13  Vascular Lesions

B
FIGURE 13-58  ■  Epithelioid hemangioendothelioma: ultrastructural features. A, Perpendicularly cut cord of endothelial cells in fibrous
stroma. B, Higher magnification of A shows cytoplasms of two endothelial cells connected by tight junctions. Note prominent base-
ment membrane surrounding cord of endothelial cells. Inset documents densely packed intermediate filaments consistent with
vimentin within cytoplasm of endothelial cell. (A, ×3,000; B, ×6,500; Inset, ×15,000)

ERRNVPHGLFRVRUJ

Spindle-cell Hemangioendothelioma
Spindle-cell hemangioendothelioma was described in
1986 by Weiss and Enzinger142 as a peculiar vascular
tumor that exhibited features of cavernous hemangioma
and contained foci of spindle-cell proliferation with fea-
tures similar to Kaposi’s sarcoma. This rare tumor occurs
predominantly in the superficial soft tissue (subcutis and
dermis) of distal parts of the extremities, particularly in
the hand.137,140–142 In soft tissue, it grows locally in a mul-
tinodular pattern. The low power microscopic features
include the presence of large vascular spaces with throm-
bosis and adjacent proliferation of blunt spindle cells.
The spindle cells also can merge with cavernous vessels
that proliferate within the thickened intervascular septa.
We have seen only two examples of spindle-cell heman-
gioendothelioma in bone. One was in the form of two
separate foci in the calvarium, and the second involved
the body of a vertebra (Fig. 13-59). The two basic pat-
terns of spindle-cell proliferation described in soft tissue
lesions were observed in these cases (Fig. 13-60). In addi-
tion, the cranial lesions also contained foci of epithelioid
endothelial cells. Originally, spindle-cell hemangioendo-
theliomas were considered to be low-grade malignant
tumors.137,140,142 In recent reported series, the follow-up
data of these tumors indicate that there is no evidence of
malignant behavior after excision.134,135 The exact bio-
logic potential of these tumors in bone is unknown. The
two patients in our series who had spindle-cell heman-
gioendothelioma of bone are free of disease 5 and 7 years
after curettage. We are not completely convinced that
this lesion represents a distinct form of vascular neo-
plasm. In our opinion, the possibility that the spindle-cell
component may represent a secondary reactive change in
a preexisting vascular lesion cannot be completely ruled
out. In fact, several recent studies from different institu-
tions also advanced this concept.133,136 Additional reported
cases affecting the skeleton follow benign clinical behav-
ior.138,143 The current consensus is that, in the spectrum
of tumors designated as hemangioendothelioma, the
spindle-cell variant is very likely a benign condition.139
Angiosarcoma
The term angiosarcoma is applied to a wide range of
malignant endothelial vascular neoplasms that affect a
variety of extraskeletal sites. Angiosarcomas arising at
different sites and in different organs have some distinct
features and are regarded as separate clinicopathologic
entities. They occur most frequently in the dermis and
subcutis, especially in the head and neck region.147,153
Other frequent anatomic sites of involvement are the
breast, liver, and spleen.146,161,162 These neoplasms may
develop as complications of a preexisting condition.
Chronic lymphatic stasis is a widely recognized predis-
posing condition for angiosarcoma of the dermis and soft
tissue.148,149,151,157,159,163,167,170 Angiosarcomas can also be
induced by radiation exposure152,155,165,178 and are linked
to various chemical carcinogens such as arsenic trioxide–
containing insecticides, vinyl chloride,169,172 and long-
term treatment with androgenic anabolic steroids.161
Nearly 25% of hepatic angiosarcomas arise in patients
ERRNVPHGLFRVRUJ
13  Vascular Lesions 965
who received thorium dioxide (Thorotrast).172 A single
case of malignant papillary angioendothelioma (Dabska
tumor) arising in bone has been reported, which was
thought to have arisen in a hemangioma of the femur.168
Primary angiosarcoma of bone is very rare and accounts
for less than 1% of all angiosarcomas.158 In bone, this
term is reserved for malignant vascular endothelial neo-
plasms of intermediate to high histologic grade. In the
past, such terms as malignant hemangioendothelioma and
hemangioendothelial sarcoma of bone were used interchange-
ably with angiosarcoma.114,117,160,173–177 This created some
ambiguity; therefore, we recommend that the term
hemangioendothelioma of bone be used to designate very
low-grade to borderline endothelial vascular bone tumors
while the term angiosarcoma in bone should be used to
define intermediate to high-grade tumors with definitive
metastatic potential.
Definition
Angiosarcoma is an intermediate- to high-grade malig-
nant tumor composed of atypical endothelial cells that
have vasoformative features.
Incidence and Location
Angiosarcoma is an extremely rare tumor. Data from the
Surveillance, Epidemiology, and End Results study indi-
cate that less than 2% of primary bone sarcomas were
classified as angiosarcomas. These tumors usually occur
in long tubular bones. Like low-grade vascular tumors,
they can be multicentric, involving multiple bones of the
lower extremity. More typically, angiosarcoma presents as
a solitary lesion. This may explain the early observation
that multicentric malignant vascular tumors of bone seem
to have a better prognosis. The disparity may be more
related to better differentiation than to multicentricity.
Angiosarcomas of bone have been observed to occur as
secondary malignancies in bone infarcts,144,150 in fibrous
dysplasia,164 and after exposure to external irradiation.178
Radiographic Imaging
The radiographic presentation of angiosarcoma of bone
is not specific. A solitary lesion presents as a destructive
lytic mass with irregular borders. High-grade lesions
exhibit features of complete cortical destruction and
extension into soft tissue (Figs. 13-61 and 13-62). The
vascular nature of the lesion can be suspected on radio-
graphs if synchronous multicentric involvement of several
bones of one extremity or of one anatomic region is
present.
Microscopic Findings
The tumor is composed of atypical endothelial cells
and exhibits vasoformative features. In a typical case,
vascular differentiation is easy to recognize. The vessels
usually produce an anastomosing system of irregular
channels lined by plump endothelial cells (Figs. 13-63
to 13-67). High-grade tumors exhibit prominent nuclear
Text continued on p. 975
966 13  Vascular Lesions

B C
FIGURE 13-59  ■  Spindle-cell hemangioendothelioma of skull: radiographic features. A, Lateral radiograph of skull of a 19-year-old
woman with multifocal lytic lesions of frontal and parietal regions. B, Computed tomogram shows expansile lytic tumor of parietal
region. C, Axial magnetic resonance image with gadolinium enhancement shows both frontal and parietal lesions.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 967

A B

C D
FIGURE 13-60  ■  Spindle-cell hemangioendothelioma of bone: microscopic features. A, Low powered view shows two components
of tumor: vascular and solid spindle cells. B, Higher magnification of solid spindle-cell area composed of interlacing bundles of
plump spindle cells. Note hemosiderin deposits and scattered inflammatory cells. C, Higher magnification of vascular component.
D, Interference between vascular and spindle-cell components shows spindle-cell proliferation in septa of vascular spaces. (A, ×25;
B-D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
968 13  Vascular Lesions

FIGURE 13-61  ■  Angiosarcoma of bone: radiographic features. Destruction by tumor of distal tibial shaft with cortical breakthrough
laterally and slight periosteal new bone formation. Tumor shows wide transition zone and is completely lytic in appearance.

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 969

A C
FIGURE 13-62  ■  Angiosarcoma of bone: radiographic features. A, Sagittal magnetic resonance image (MRI) of spine shows low density
destructive tumor of sacrum. Note metastases involving multiple vertebral bodies. B and C, Coronal MRIs showing widespread
metastasis involving pelvic and femoral bones.

ERRNVPHGLFRVRUJ
970 13  Vascular Lesions

A B

C D
FIGURE 13-63  ■  Angiosarcoma of bone: microscopic features. A and B, Low and higher power photomicrographs showing irregular
anastomosing vascular channels lined by highly atypical endothelial cells. C and D, Irregular anastomosing vascular spaces and
solid areas of highly atypical spin cell proliferations. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 971

A B

C D
FIGURE 13-64  ■  Angiosarcoma of bone: microscopic features. A and B, Low and high power photomicrographs showing anastomos-
ing vascular channels lined by highly atypical endothelial cells. C and D, Low and high power photomicrographs showing irregular
anastomosing channels and solid glomeruloid proliferations of highly atypical endothelial cells inside of vascular spaces. (A and
C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
972 13  Vascular Lesions

A B

C D
FIGURE 13-65  ■  Angiosarcoma of bone: microscopic features. A and B, Low and intermediate power photomicrographs show poorly
developed anastomosing vascular spaces and solid areas of spindle cell proliferations. C and D, Intermediate and high power pho-
tomicrographs showing irregular anastomosing vascular spaces lined by highly atypical endothelial cells. (A, ×60; B and C, ×100;
D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 973

A B

C D
FIGURE 13-66  ■  Angiosarcoma of bone: microscopic features. A and B, Intermediate and high power photomicrographs showing
vascular spaces lined by highly atypical epithelioid endothelial cells forming occasionally solid nodules. C and D, High power
photomicrographs showing vascular channels lined by highly atypical epithelioid endothelial cells forming loosely arranged
nodules. Note single epithelioid cells dispersed in stromal tissue mimicking metastatic carcinoma. (A, ×100; B and C, ×200; D, ×400.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
974 13  Vascular Lesions

A B

C D
FIGURE 13-67  ■  Angiosarcoma of bone: microscopic features. A and B, Low and intermediate power photomicrographs showing
irregular cystlike vascular spaces and proliferations of atypical endothelial cells forming septations and cords. C and D, High power
photomicrograph showing highly atypical epithelioid cells forming solid nests, cords, and septations. (A, ×60; B, ×100; C, ×200;
D, ×400.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

atypia and brisk mitotic activity with atypical mitotic
figures. There is a marked tendency toward intralu-
minal budding of endothelial cells (Fig. 13-64). Large
solid areas of endothelial cells that mimic an epithelial
neoplasm can be present. Spindle-cell differentiation
with pleomorphic features can also be prominent (Fig.
13-63). Intermediate-grade, well-differentiated angio-
sarcomas may have better developed vascular channels
and exhibit less pronounced atypia of endothelial cells.
Immunohistochemically, cells that exhibit vasoforma-
tive features usually show reactivity for endothelial
markers (factor VIII-related antigens, CD31, CD34, and
ERG).11,18,144,145,151,154,156,166,171 Accentuation of reactiv-
ity can be seen at the luminal border of these cells for
cytoplasmic antogens. ERG belongs to the family of
transcription factors and typically shows strong nuclear
staining. In less differentiated areas lacking obvious vaso-
formative features, endothelial marker reactivity can be
very focal or absent. In contrast with low-grade endo-
thelial bone neoplasms, epithelial markers (epithelial
membrane antigen and cytokeratins) are less frequently
present.156,166,171
Differential Diagnosis
Vasoformative features may be inconspicuous in higher-
grade angiosarcomas of bone, and such tumors may
show only weak reactivity for endothelial immunohisto-
chemical markers. The absence of cytokeratin reactivity
and strong reactions to antibodies for vimentin helps to
distinguish these tumors from carcinomas of the spindle-cell
type. Distinguishing lower-grade angiosarcomas from epi-
thelioid hemangioendothelioma is discussed in the section
on the differential diagnosis for that neoplasm, but
coexistence of epithelioid hemangioendothelioma and
epithelioid angiosarcoma in the same lesion is possible.
Treatment and Behavior
High-grade angiosarcomas exhibit extremely aggressive
behavior with rapid local growth and early disseminated
metastases. Radical en bloc excision or amputation is
indicated. Some lesions have a less aggressive clinical
course, but the prognosis in a group of patients with
high-grade angiosarcomas is poor because these tumors
have a high propensity for metastases. Combinations of
radiation therapy and chemotherapy have been used as
adjuvant methods of treatment, but significant data of
their effectiveness are lacking.
Hemangiopericytoma
Hemangiopericytoma was described by Stout and
Murray in 1942.205 The authors postulated that the tumor
is composed of cells related to blood vessels similar to
those described by Zimmerman in 1923 and designated
as pericytes.209 Pericytes are smooth muscle–like perivas-
cular cells with contractile potential. They do not have
readily identifiable or specific phenotypic features and
are difficult to distinguish from other mesenchymal
spindle cells. For that reason, the diagnosis of this neo-
plasm is based on the recognition of its architectural
ERRNVPHGLFRVRUJ
13  Vascular Lesions 975
pattern.195,196,199,200,203,206 On the other hand, the so-called
hemangiopericytoma-like pattern frequently occurs in
a wide range of spindle-cell neoplasms—mesenchymal
chondrosarcoma, endometrial stromal sarcoma, malignant
fibrous histiocytoma, synovial sarcoma, and osteosar-
coma, among others. Therefore it is frequently stated that
the diagnosis of hemangiopericytoma requires exclusion
of other spindle-cell neoplasms in which this pattern can
be seen.198,208 As discussed in Chapter 22, bone and soft
tissue tumors with a hemangiopericytomatous pattern are
sometimes associated with the paraneoplastc syndrome
of oncogenic osteomalacia (phosphaturic mesenchy-
mal tumors).186,187 The modern concept unifies solitary
fibrous tumors and hemangiopericytomas as represent-
ing microscopic variants of a spectrum of tumors with
similar pathogenesis. They range from lesions displaying
bland spindle cells separated by prominent bands of ropy
collagen and diffuse positive staining for CD34 to more
classical hemangiopericytomas in which the stromal col-
lagen is less prominent and the lesion has an overall cel-
lular appearance with high vascularity and some mitotic
activity. It is not unusual to have those two components,
less cellular and more cellular, admixed in one lesion.
The cellular variants of hemangiopericytoma have a ten-
dency to be less strongly positive for CD34, which is
typically restricted to vasculature, but there are some
focal areas of positivity within the hypercellular areas.
The lesions seen in bone typically fall into the category
of hypercellular classical hemangiopericytomas, and the
so-called fibrous variants are less frequent as primary in
extracranial sites in the skeleton. The unified concept
is further confirmed by the presence of the same NAB2-
STAT6 gene fusion in these tumors.183,201,202 The fusion
can be detected by fluorescent in situ hybridization in
conventional histologic preparations. A convenient
surrogate of molecular testing is immunohistochemis-
try documenting the overexpression of STAT6 protein
driven by the NAB2 promoter in the solitary fibrous/
hemangiopericytoma family of tumors.202
Definition
Hemangiopericytomas are malignant neoplasms com-
posed of pericytic cells that grow in solid sheets and nests
around irregular branching vascular spaces. These chan-
nels are lined by a single layer of endothelial cells.
Incidence and Location
Hemangiopericytoma is an extremely rare neoplasm
in bone, and several series consisting of fewer than
10 cases have been reported from major bone tumor
centers.180,182,194,206 On the basis of published data, it seems
that this tumor usually involves the long bones of the
extremities, particularly of the leg, but any bone can
be affected.184,188,208 Hemangiopericytomas are relatively
frequent in the head and neck region. Some lesions in
this region exhibiting involvement of bone are prob-
ably not primary bone tumors and may originate in the
adjacent meningothelial or soft tissue. Most reported
cases are in adults. It is well known that any apparent
primary hemangiopericytomas in bone may prove to be
976 13  Vascular Lesions
metastatic from extraskeletal neoplasms. The hemangio-
pericytoma of meninges is the most frequent source of
these late metastases in bone (see Chapter 14).179,191–193
These tumors may rarely be associated with oncogenic
rickets and osteomalacia (see Chapter 22). Hemangio-
pericytomas show clonal chromosomal aberrations, and
some of them are aneuploid by flow cytometric mea-
surements.185,204 Similar clonal translocations involving
chromosomes 12 and 19 were seen in hemangioperi-
cytomas in different anatomic sites (intracranial and
extracranial).190 This suggests that hemangiopericytomas
involving different organs are related and form a patho-
genetically distinct group. These earlier observations are
in keeping with the modern concept postulating a unified
pathogenesis for the family of solitary fibrous tumors/
hemangiopericytomas at different anatomic sites based
on the presence of NAB2-STAT6 gene fusion in these
tumors.183,201,202
Radiographic Imaging
The radiographic presentation of hemangiopericytoma
is not specific and shows a purely lytic intramedullary
mass with a destructive growth pattern (Fig. 13-68). Cor-
tical disruption and extension into soft tissue may be
present.
Microscopic Findings
The tumor is composed of compact areas of spindle cells
that surround thin-walled, endothelial-lined vascular
FIGURE 13-68  ■  Hemangiopericytoma: radiographic features. Computed tomogram shows destructive lesion involving body of tho-
racic vertebra and adjacent rib.
ERRNVPHGLFRVRUJ
channels. The size of the vessels ranges from narrow
capillaries to large, open cavernous vessels (Fig. 13-69).
Characteristically, hemangiopericytoma shows branching
open vascular channels with antler or staghorn configura-
tions. The solid perivascular areas are composed of
plump, densely packed spindle cells that lack the fascicu-
lar arrangement seen in fibrosarcoma or synovial sarcoma.
The level of cellularity can vary in different tumors and
even in different areas of the same lesion. It can range
from predominantly fibrous areas with gradual transition
to more cellular foci. In soft tissue tumors the level
of mitotic activity, necrosis, and pronounced nuclear
atypia correlate to some extent with clinical behavior.
The value of these features in predicting the behavior of
hemangiopericytoma in bone has not yet been estab-
lished. Ultrastructurally, hemangiopericytoma cells have
some features of perivascular cells with smooth muscle
differentiation.180,181,189,197
Differential Diagnosis
It is essential to exclude other neoplasms that may exhibit
patterns of anastomosing branching vascular lumens that
suggest hemangiopericytoma in focal areas. These include
osteosarcoma, malignant fibrous histiocytoma, mesenchymal
chondrosarcoma, and synovial sarcoma. In our experience,
many tumors with indubitable features of hemangio-
pericytoma prove to be metastases from other sites,
most frequently the meningeal hemangiopericytoma or
gastrointestinal stromal tumors. The frequent immu-
nohistochemical positivity of hemangiopericytoma and
 13  Vascular Lesions 977

B C
FIGURE 13-69  ■  Hemangiopericytoma of bone: microscopic features. A, Intermediate power photomicrograph of spindle-cell tumor
with branching staghorn pattern of vascular spaces. B, Low power magnification shows spindle-cell tumor with branching staghorn
pattern of vascular spaces. C, Intermediate power photomicrograph shows bland nuclei in spindle cells. Vascular channels are lined
by flat, inconspicuous endothelial cells. (A and C, ×100; B, ×50) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
978 13  Vascular Lesions
gastrointestinal stromal tumors for CD34 can be another
confusing feature. A panel of immunohistochemical
and molecular markers is recommended; gastrointesti-
nal stromal tumors are typically positive for c-Kit and
DOG-1. In addition, they carry mutations of the c-Kit
and PDGFR genes. Patients with meningeal hemangio-
pericytoma metastatic to the extracranial skeletal sites
typically have a history of primary meningeal tumor.
More recent reappraisal of small series of cases previ-
ously diagnosed as hemangiopericytoma of bone with a
panel of immunohistochemical and molecular markers
indicates that some of these cases can be reclassified as
synovial sarcomas or solitary fibrous tumors.207
Treatment and Behavior
En bloc resection or amputation is performed. The
behavior of hemangiopericytoma is difficult to predict,
but the prognosis seems to be more favorable than that
of high-grade angiosarcoma. The tumor frequently
recurs locally, and distant metastases may occur.
Kaposi’s Sarcoma
Kaposi’s sarcoma occurs in four clinical forms: chronic,
lymphadenopathic, transplantation associated, and HIV
related.226,210
The chronic or classic form primarily affects men
older than age 50 years. It is most frequent in the
Eastern European/Mediterranean region (Italy) and
Central Africa.211,226 This form of Kaposi’s sarcoma is
associated with a second malignancy, usually of the lym-
phoreticular or hematopoietic system.234 This form of
Kaposi’s sarcoma usually presents with skin involvement
of distal parts of the lower extremities. The lesions slowly
progress proximally, coalesce, and may even ulcerate.
The lymphadenopathic form predominantly involves
young African children, who have cervical, inguinal, or
mediastinal lymphadenopathy.215,223,228,229,232 The course
of the disease is aggressive, with early involvement of
extranodal organs.
Transplantation-associated Kaposi’s sarcoma affects
fewer than 0.5% of patients who receive renal trans-
plants, but it has been reported in association with
other organ transplants and with immunosuppressive
therapy.216,217,220,221,224,230,231 The clinical course of this
form of Kaposi’s sarcoma is more aggressive than that of
the classic form. The disease usually develops in the
retroperitoneal lymph nodes or in some instances at
the site of previous surgery. The fatal outcome is usually
due to widespread involvement of the gastrointestinal
tract.
HIV-related Kaposi’s sarcoma affects young patients
and may clinically manifest in any location.212,235 The
disease has a tendency to involve deep lymph nodes and
the gastrointestinal tract in addition to the skin.
The identification of a novel type of herpesvirus
(HHV-8) as a causative agent for Kaposi’s sarcoma made
possible the targeting of its viral antigens as diagnostic
markers for this condition.4,6,16,214 The latency-associated
nuclear antigen (LANA1) that mediates the anchoring of
the viral DNA to the host protein is upregulated in
ERRNVPHGLFRVRUJ
virtually all cases of Kaposi’s sarcoma, regardless of its
type, and serves as the most efficient biomarker for this
condition.4,16,236
Incidence and Location
Involvement of bones has been reported in all four forms
of Kaposi’s sarcoma.210,213,218,219,222,225,227,233,237 The bone
lesions develop during the more advanced stages of the
clinical course. A patient who presents with the lesion in
a bone invariably has extraskeletal disease. In the classic
chronic form, the skeletal involvement usually occurs in
the region affected by the skin and soft tissue disease—
in the small bones of the feet, often by direct extension.
In other forms, the site of skeletal involvement is unpre-
dictable and may appear in any bone. In view of the
epidemic proportions of HIV infection and the large
number of Kaposi’s sarcomas diagnosed in extraskeletal
sites, bone involvement in this far from rare disease
is relatively uncommon. Our personal experience is
limited to several cases of both classic and HIV-related
Kaposi’s sarcomas involving bone. The peak age inci-
dence and typical sites of skeletal involvement for
classic (non–HIV-related) Kaposi’s sarcoma are shown in
Figure 13-70.
Radiographic Imaging
On radiographs, Kaposi’s sarcoma presents as a destruc-
tive lytic focus in bone. More advanced lesions show
complete cortical disruption and extension into soft
tissue. Pathologic fracture can be present. The nature of
the lesion can be suspected on radiographs if it occurs in
the appropriate clinical setting; otherwise, the radio-
graphic features are not specific. The involvement of
metatarsal bones by direct extension in a classic (non–
HIV-related) Kaposi’s sarcoma is shown in Figure 13-71.
Figure 13-72 depicts a destructive lytic lesion of the
rib in an HIV-positive man with disseminated Kaposi’s
sarcoma.
Microscopic Findings
There is no difference in microscopic appearance among
the clinical forms of Kaposi’s sarcoma. The early changes
referred to as the patch and the plaque phases have not
been described in bone. All lesions reported in bone are
diagnosed when the lesion is a well-established nodule
with bone destruction sufficient to cause symptoms. The
lesion is composed of intersecting arcs of bland spindle
cells similar to the pattern seen in well-differentiated
fibrosarcoma. Multiple slitlike spaces separate spindle
cells and occasionally contain intracytoplasmic erythro-
cytes (Fig. 13-73). Better-developed vascular channels
with open spaces are present at the periphery of the
lesion. Features of hemorrhage with hemosiderin depos-
its and scattered inflammatory cells are present. Intracy-
toplasmic and extracytoplasmic, diastase-resistant hyaline
globules positive for periodic acid–Schiff and measuring
1 to 7 µm are present. They are very characteristic of
Kaposi’s sarcoma and most likely represent residues of
extravasated degenerated erythrocytes. The lesion has an

Above 50
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 13-70  ■  Kaposi’s sarcoma. Peak age incidence and most frequent site of skeletal involvement in classic (non–HIV-related)
Kaposi’s sarcoma are indicated by a solid black arrow.
overall bland appearance and minimal pleomorphism.
Rare mitotic figures may be present.
Kaposi’s sarcoma cells typically express a full roster
of endothelial markers. CD31, CD34, and ERG are
expressed in both the spindle and endothelial cell com-
ponents of the lesion (Fig. 13-74). Kaposi’s sarcoma cells
also express VEGFR-3 and podoplanin (D2-40), which
are generally considered as markers of lymphatic endo-
thelial cells. The HHV-8 (LANA1) antigen shows strong
nuclear positivity in virtually all cases of Kaposi’s sarcoma
and serves as a useful marker differentiating this tumor
from other spindle-cell neoplastic lesions, including
spindle- cell variants of angiosarcoma (Fig. 13-74).
Differential Diagnosis
The separation from other forms of vascular sarcoma is
based on the distinctive microscopic appearance and
invariable association with extraskeletal disease. For
example, we have seen rib lesions of HIV-related Kaposi’s
sarcoma in a patient who already had pathologically
documented skin and gastrointestinal lesions. Direct
extension from overlying skin and involvement of soft
tissue in the classic form facilitate the diagnosis of this
type of bone lesion.
ERRNVPHGLFRVRUJ
13  Vascular Lesions 979
7 8
Treatment and Behavior
The behavior of Kaposi’s sarcoma varies in its different
clinical forms. The mortality rate for the classic form
ranges from 10% to 20% after a prolonged (approxi-
mately 10-year) indolent clinical course. The mortality
rate of the HIV-related form is much higher, within the
range of 40%, and is affected by additional risk factors
such as opportunistic infection and secondary malignancy.
Treatment of these lesions may involve curettage, en bloc
excision, and internal fixation of pathologic fractures.
Radiotherapy is also useful to control the disease locally.
REACTIVE VASCULAR LESIONS
Bacillary Angiomatosis of Bone
Bacillary angiomatosis of bone occurs in immunocom-
promised patients, particularly those infected with
HIV.239,240,242,248,249 The development of lesions is linked
to gram-negative rickettsial organisms of Rochalimaea
(Bartonella) species (predominantly Bartonella hense-
lae).238,244 In some cases, Bartonella quintana, known as the
agent of cat-scratch fever, was also isolated.245,247 These
980 13  Vascular Lesions

FIGURE 13-71  ■  Classic (non–HIV-related) Kaposi’s sarcoma involving bone: radiographic features. Multiple lytic lesions involving
first and second metatarsal bones in elderly man with long history of Kaposi’s sarcoma involving overlying skin and contiguous
soft tissue.

organisms have been isolated from lesions of skin, periph-
eral blood, and bone. The cutaneous lesions appear as
protuberant, nonerythematous, firm, dry lesions with a
collar of hyperkeratotic skin. They can also form larger
lobulated vascularized masses. The bone involvement can
be associated with the skin lesions, but it can also be the
presenting sign of the disease.241,243,246,248 It must be men-
tioned that bacillary angiomatosis is extremely rare in
bone, and only individual cases have been reported in the
literature. This infectious, nonneoplastic process can
mimic a low-grade vascular endothelial bone tumor both
radiographically and histologically.
On radiographs, bacillary angiomatosis of bone pres-
ents as a lytic defect that may disrupt the cortex and
extend into the soft tissue. Pain and tenderness in soft
tissue areas are usually the presenting symptoms. The
radiographic findings and clinical symptoms are sugges-
tive of acute osteomyelitis. Microscopically, the lesion is
composed of newly formed, well-developed vessels of
capillary or arteriole size, lined by a single layer of plump
endothelial cells (Fig. 13-75). Multiple concentric layers
of proliferating endothelial cells that form cuffs around
luminal spaces can be present focally. The nuclei of
the endothelial cells are enlarged and may show small
nucleoli. Mitotic figures are present, but atypical mitoses
are absent. The vessels can have a branching pattern
focally. The intervening hypercellular stromal tissue
shows an inflammatory cell infiltrate. In general, the
microscopic features mimic those of low-grade vascular
endothelial neoplasms. The infectious agent can some-
times be identified by silver stains (e.g., Warthin-Starry)
and confirmed by bacteriologic cultures of peripheral
blood and fresh lesional tissue. The most sensitive tech-
niques for identifying Bartonella species in biopsy mate-
rial are based on the polymerase chain reaction, which
can be performed on DNA extracted from fresh or
paraffin-embedded tissues.238,245,247
Text continued on p. 985

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 981

B
FIGURE 13-72  ■  HIV-related Kaposi’s sarcoma involving bone: microscopic features. A, Kaposi’s sarcoma involving rib in HIV-positive
38-year-old man. Skin and gastrointestinal tract lesions were also present. Ill-defined destructive lesion is present with eccentric
expansion and periosteal new bone formation. B, Computed tomogram of abdomen in patient shown in A reveals destructive lesion
in lower right rib.

ERRNVPHGLFRVRUJ
982 13  Vascular Lesions

A B

C D
FIGURE 13-73  ■  Kaposi’s sarcoma in bone: microscopic features. A, Medium power photomicrograph shows arrays of bland spindle
cells. Narrow slitlike vascular spaces are seen. B, Higher magnification shows details of endothelial-lined vascular slits and bland
nuclei in surrounding spindle cells. C, Medium power photomicrograph shows proliferation of spindle cells. D, Higher magnification
of C shows nuclei of spindle cells with some atypia and slitlike vascular spaces with red blood cells. (A and C, ×100; B and C, ×200)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 13  Vascular Lesions 983

A B

C D
FIGURE 13-74  ■  Kaposi’s sarcoma in bone: microscopic features. A, Low power photomicrograph shows arrays of bland spindle cells
and an occasional better-developed vascular structure. B, Strong nuclear positivity for HHV-8 LANA1 antigen in the majority of nuclei
of Kaposi’s sarcoma cells. C, Strong nuclear positivity of Kaposi’s sarcoma cells for ERG. D, Strong cytoplasmic expression of CD34
in Kaposi’s sarcoma (A-D, ×100) (A, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
984 13  Vascular Lesions

B
FIGURE 13-75  ■  Bacillary angiomatosis: microscopic features. A, Lytic lesion of maxillary bone is composed of proliferating vessels
with plump endothelial cell. B, Proliferating endothelial cells form cuffs obliterating vascular lumina. Note prominent inflammatory
infiltrate. Inset (top), Rickettsial organism documented by Warthin-Starry stain. Inset (bottom), Vessels with proliferating endothelial
cells forming concentric layers and obliterating vascular lumen. (Courtesy J. G. Batsakis, Houston.)

ERRNVPHGLFRVRUJ

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 C H A P T E R 1 4 
Neurogenous Tumors and
Neurofibromatosis Affecting Bone
Gregory N. Fuller, MD, PhD
CHAPTER OUTLINE
MENINGIOMA
SOLITARY FIBROUS TUMOR/
HEMANGIOPERICYTOMA FAMILY TUMORS
MYXOPAPILLARY EPENDYMOMA
INTRAOSSEOUS SCHWANNOMA
NEUROGENIC TUMOR PREDISPOSITION
SYNDROMES
Neurofibromatosis Type 1
Neurogenous tumors arising within bone are exceedingly
rare. Neural lesions frequently exert secondary effects
on bones, eroding them from the surface and deforming
and expanding neural canals and foramina because of
the pressure of expansile growth, as in the case of neuro-
fibromatosis. On the other hand, some of the most
common tumors of the central nervous system, namely
meningiomas and ependymomas, have a tendency to
invade bone and may provoke striking reactive changes in
affected bone that mimic primary bone neoplasms. The
rarest of primary neural tumors arising in bone are the
neurilemmomas (schwannomas) and malignant periph-
eral nerve sheath tumors. Neurofibromatosis, separated
into three distinct clinical syndromes referred to as types
1 through 3, is primarily a disorder of the soft tissues, but
it can affect many other organs and the skeleton. Von
Hippel-Lindau disease and its hallmark tumor, heman-
gioblastoma, is also included in this chapter, with the
discussion focusing on the skeletal manifestations of the
disease with the development of a unique papillary endo-
lymphatic sac tumor involving the petrous portion of the
temporal bone.
MENINGIOMA
Meningiomas are not generally considered to be neural
tumors of bone, but they are in fact the most common
tumors of the central nervous system to erode bone.
Meningiomas are common neoplasms that originate
from meningothelial cells. Although meningiomas may
invade the brain, they most often affect the central
nervous system structures by a pushing, expansile growth
rather than by invasion. On the other hand, meningiomas
990
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Neurofibromatosis Type 2
Neurofibromatosis Type 3
(Schwannomatosis)
VON HIPPEL-LINDAU DISEASE
Hemangioblastoma
Papillary Endolymphatic Sac Tumor
have a unique propensity to involve the contiguous bone
and may mimic a primary bone tumor.4,6,7,13,14 Involve-
ment of bone is not indicative of malignant behavior per
se. Meningiomas may alter adjacent bones by direct inva-
sion or may cause a hyperostotic reaction.15,18,19,26,31 In the
latter case, there is no true invasion of bone. This neo-
plasm provokes bone overgrowth of periosteal origin,
usually from the inner table of the cranial bones.
Most meningiomas become clinically evident in
patients older than age 40 years and are rare in children.
Meningiomas occur more frequently in women. The
male-to-female ratio is 2 : 3 for intracranial lesions;
for intraspinal meningiomas, the male-to-female ratio
is 1 : 10.
Meningiomas are slow-growing lesions, but their
indolent growth rate is increased during pregnancy. This
is partially explained by the presence of steroid receptors
in these tumors. Theoretically, meningiomas can develop
anywhere in the meninges; however, they appear fre-
quently in certain anatomic sites. The parasagittal area is
the most frequent location for cranial meningiomas.
Other common locations include the lateral aspects of the
cranial vault (over the cerebral convexities), the wing of
sphenoid bone (sphenoid ridge meningioma), the sella
turcica area (suprasellar meningioma), the cribriform
plate (olfactory groove meningioma), and the area of the
foramen magnum and the optic nerve. In addition to the
common locations within the central nervous system,
meningiomas can present as extracranial lesions in many
sites.17,23,25,36 The soft tissues of the head and neck are
the most frequent sites of involvement external to the
central nervous system.8,9,17,22,30 Rare examples of menin-
giomas in the lung, the mediastinum, and even the fingers
have been described. We have seen in consultation two
 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 991

examples of apparently primary meningiomas involving
the pubic ramus. Skull lesions may have the same or
similar radiographic features as metastatic carcinoma or,
less frequently, hemangioma or osteosarcoma.
Meningiomas usually occur sporadically but it is esti-
mated that approximately 5% are familial and fewer than
10% of individuals have multiple lesions. The environ-
mental risk factors, except for radiation, are uncertain.
An increased risk for the development of meningiomas
has been associated with several tumor susceptibility syn-
dromes such as neurofibromatosis type 2, Cowden syn-
drome, and Werner syndrome. These syndromes have
unique genetic backgrounds and are caused by mutations
in the NF2, PTEN, and RECQL2 genes, respectively.1
The mutations of the tumor suppressor gene NF2 are
present in more than 70% of meningiomas developing
in individuals affected by neurofibromatosis type 2. The
loss of the wild type NF2 allele is present in almost all
meningiomas associated with neurofibromatosis type 2.
The somatic mutations of the NF2 gene are also present in
the majority of sporadic meningiomas not associated with
neurofibromatosis type 2. Sporadic meningiomas appear
to have unique genetic alterations that are exclusive of
the NF2 gene mutations. A recent genomic analysis of
meningiomas has identified that sporadic meningiomas
not associated with neurofibromatosis type 2 are charac-
terized by mutations in TRAF7, a proapoptotic E3 ubiq-
uitin ligase, in approximately 25% of tumors (Fig. 14-1).2
These mutations are concurrent with the mutations in
KLF4, a transcription factor inducing pluripotency, or
AKT1 activating the PI3K pathway and SMO mutations
that activate Hedgehog signaling (Fig. 14-1).2 Extremely
rare cases of familial meningiomas without neurofibro-
matosis type 2 were shown to be associated with muta-
tions involving the SWI/SNF chromatin-remodeling
complex subunit genes SMARCE1 or SMARCB1.24,28

TRAF7 KLF4
Exon 10
Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
Exon 17
Exon 18
Exon 20
Exon 19
Exon 21
Chr 16 Chr 9
Exon 1
Exon 2

Exon 3
Exon 4
Exon 5
Exon 6
Exon 7
Exon 8
Exon 9

Exon 1

Exon 2

Exon 3

Exon 4

Exon 5
13.3 TRAF7 24
13.2

110247132

110252047
13.1 23
2205798

2228130

22
12 21
11.2 13
11.1 11.1 tel cen tel cen
12
11.2 11.1 11.1
12.1
13 12.2 TRAF7 12 KLF4
21 13
22 21.1
23 21.2
21.3
24 1 671 aa 22.1 1 594 aa
22.2
22.3
Zinc finger domain 31 KLF4
32 Zinc finger C2H2-type/integrase
TRAF like domain 33 DNA-binding domain
34.1
SIAH type domain 34.2 34.3 Synonymous substitution
Zinc Finger, TRAF type domain
Missense substitution
TRAF like domain
Insertion frameshift
W D40/YVTN repeat-like-containing domain B
Synonymous substitution
Missense substitution
Insertion frameshift
A

AKT1 SMO
Exon 10
Exon 11
Exon 12
Exon 13
Exon 14

Exon 10
Exon 11
Exon 12
Exon 1

Exon 2

Exon 3

Exon 4
Exon 5
Exon 6
Exon 7
Exon 8
Exon 9

Exon 1

Exon 2

Exon 3
Exon 4
Exon 5
Exon 6

Exon 7
Exon 8
Exon 9

Chr 14 Chr 7
13 22
12
128828712

128853385
105235686

105262080

11.2 21
11.1 11.1 15.3
11.2 15.1 15.2
12 tel cen 14 cen tel
13 13
21 AKT1 11.2 12 SMO
167

11.1 11.1
10

22 11.22 11.21
23 11.23
24.1
24.2
24.3 1 480 aa 21.1 21.2 1 788 aa
31 32.1 21.3
32.2 32.3 Pleckstrin homology-like domain 22 Frizzled domain
AKT1 Protein kinase-like domain 31.1 GPCR, family 2-like domain
31.2
AGC-kinase, C-terminal domain 31.3
SMO Synonymous substitution
33 32
Synonymous substitution 34 Missense substitution
35
Missense substitution 36 Nonsense substitution - Stop
C Insertion inframe
Deletion frameshift
D
FIGURE 14-1  ■  Mutations of genes in sporadic meningioma. A, Chromosomal location, exonal structure, functional domains, and the
distribution of mutations in the TRAF7 gene. B, Chromosomal location, exonal structure, functional domains, and the distribution
of mutations in the KLF4 gene. C, Chromosomal location, exonal structure, functional domains, and the distribution of mutations
in the AKT1 gene. D, Chromosomal location, exonal structure, functional domains, and the distributions of mutations in the SMO
gene.

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992 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

SMARCB1

Exon 1

Exon 2
Exon 3

Exon 4

Exon 5

Exon 6

Exon 7

Exon 8
Exon 9
24129149

24176705
Chr 22
13 cen tel
12
11.2
11.1
11.1 SMARCB1
SMARCB1
12.1

19
11.2

14
12.3 12.2

5
6

11

15
28
13.1

6
13.2
13.3
1 366 aa
Synonymous substitution
Missense substitution
Nonsense substitution - Stop
Insertion inframe
Deletion inframe
SMARCE1

Exon 10

Exon 11
Exon 4
Exon 5
Exon 6

Exon 7
Exon 8
Exon 9
Exon 1

Exon 2
Exon 3
Insertion frameshift
A Deletion frameshift
Chr 17

38783975

38804103
13
12 tel cen
11.2 11.1
11.1 11.2 SMARCE1
12 SMARCE1
21.2
21.1
22 21.3 1 412 aa
23 High mobility group (HMG) box
24
25 Synonymous substitution
Missense substitution
B Nonsense substitution - Stop

SUFU
Exon 10

Exon 11
Exon 12
Exon 1
Exon 2

Exon 3
Exon 4
Exon 5
Exon 6
Exon 7
Exon 8

Exon 9

Chr 10
15
46919235

46945289

14
13
12.2 12.3
12.1 cen tel
11.2
11.1 11.1
11.2
SUFU
21.1
21.2
21.3 1 594 aa
22.1
22.2 Suppressor of fused domain
22.3
23.1 23.2 Suppressor of fused C-terminal domain
23.3 SUFU
24.2 24.1 Synonymous substitution
25.1 24.3
25.3 25.2 Missense substitution
26.2 26.1 Nonsense substitution - Stop
26.3
Insertion inframe
Deletion frameshift
C
FIGURE 14-2  ■  Mutations of genes in familial meningioma. A, Chromosomal location, exonal structure, functional domains, and the
distribution of mutations in the SMARCB1 gene. B, Chromosomal location, exonal structure, functional domains, and the distribution
of mutations in the SMARCE1 gene. C, Chromosomal location, exonal structure, functional domains, and the distribution of muta-
tions in the SUFU gene.

Loss of SUFU, suppressor of fused homolog of Drosoph- anterior cranial fossa mass centered in the midline (olfac-
ila, dysregulating Hedgehog signaling was also identified tory groove meningioma) (Fig. 14-3). Meningioma may
in some families affected by multiple meningiomas also present as a purely intraosseous tumor. In such
(Fig. 14-2).1 instances, it may be mistaken for a different type of
primary bone lesion; for example, intraosseous menin-
gioma of the sphenoid bone may be mistaken for fibrous
Radiologic Features
dysplasia. In addition, some histologic subtypes of menin-
The classic radiologic presentation of meningioma is that gioma may contribute to misdiagnosis; for example,
of a homogeneously contrast enhancing dura-based mass intraosseous secretory meningioma may be mistaken for
with small peripheral extensions referred to as the dural metastatic carcinoma (Fig. 14-4).
tail (Fig. 14-3). Other radiographic presentations include Some meningiomas show involvement of three ana-
a flattened extensive lesion referred to as en plaque menin- tomic compartments: cranial bone, intracranial exten-
gioma or an intraventricular (choroid plexus) meningi- sion, and extracranial extension into the scalp (Fig. 14-5).
oma. In addition, classic presentation is as a very large Often, meningiomas induce prominent periosteal new

ERRNVPHGLFRVRUJ
 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 993

A B

C D
FIGURE 14-3  ■  Meningioma: radiographic features. A, T1-weighted axial postcontrast magnetic resonance image (MRI) showing a
dura-based meningioma with uniform signal enhancement and dural tail sign. B, T1-weighted coronal postcontrast MRI showing
en plaque meningioma with uniform signal enhancement (arrow). C, T1-weighted coronal postcontrast MRI showing left intraven-
tricular (glomus chorideum) meningioma with uniform signal enhancement. D, T1-weighted sagittal postcontrast MRI showing
olfactory groove meningioma with uniform signal enhancement.

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994 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-4  ■  Meningioma: radiographic and microscopic features. A, Axial computed tomogram showing thickening of the
sphenoid bone caused by intraosseous meningioma (arrows). B, T1-weighted axial magnetic resonance image (MRI) showing
thickening of the sphenoid bone caused by intraosseous meningioma (arrows). Same case as A. C, Low power photomicrograph
showing meningioma infiltrating bone (×100). D, High power photomicrograph showing secretory meningioma infiltrating fibrous
tissue (×200). Inset, Expression of carcinoembryonic antigen in meningioma cells revealed by immunohistochemistry (×400). (C and
D, hematoxylin-eosin.)

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 995

A B

C D
FIGURE 14-5  ■  Meningioma: radiographic features. A, Axial computed tomogram showing intraosseous meningioma of the frontal
bone (arrow). B, T1-weighted axial postcontrast magnetic resonance image (MRI) showing intraosseous meningioma. C, T1-weighted
axial postcontrast MRI showing hyperostotic meningioma of the frontal bone with extension intracranially and extracranially into
the soft tissues of scalp. D, T1-weighted coronal postcontrast MRI showing a markedly hyperostotic meningioma of the frontal bone
with intracranial and extracranial extension.

ERRNVPHGLFRVRUJ
996 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone
bone formation in the form of perpendicular striations
that radiate from the lesion on the inner and outer sur-
faces of the affected bone (Fig. 14-6). Meningiomas
must therefore be differentiated radiographically from
other primary and metastatic bone lesions. Higher grade
meningiomas frequently exhibit atypical radiographic
features as well, including a blurred or diffuse interface
with the subjacent brain parenchyma, or a multilobulated
appearance (mushroom sign). In addition, brain invasive
meningiomas are often accompanied by marked brain
edema (Fig. 14-7).
Microscopic Findings
Microscopically, meningiomas represent a group of neo-
plasms with various heterogenous features linked by focal
similarities to normal meningothelial cells (Table 14-1).10
The nuclei are round or oval with small nucleoli and fine,
evenly dispersed chromatin. Intranuclear inclusions are
frequently present. The four classic histologic subtypes
of meningioma are syncytial, fibroblastic, transitional,
and psammomatous (Fig. 14-8).
Syncytial meningioma is characterized by patternless
architecture, without other distinctive features. The lack
of a distinct cytoplasmic border (i.e., the syncytial appear-
ance of meningothelial cells) is explained at the ultra-
structural level by the complex interdigitating cytoplasmic
processes.
Fibroblastic or spindle-cell meningioma is characterized
by the presence of elongated spindle cells arranged in
fascicles with a focal storiform pattern. Focal syncytial
features with a whorled pattern and psammoma bodies
are present in some fibroblastic meningiomas.
Transitional meningioma shows the presence of clearly
recognizable syncytial areas and fibroblastic features.
Cellular whorls are typical for this type, which is also
known as mixed meningioma.
Psammomatous meningioma is characterized by promi-
nent numbers of calcifications with a concentrically
layered architecture referred to as psammoma bodies.
Scattered psammoma bodies can be seen in virtually any
subtype of meningioma; however, they are, by definition,
particularly abundant and densely packed in the psam-
momatous variant.
Angiomatous meningioma is characterized by prominent
vascularity. The outdated term angioblastic meningioma
encompassed at least three different types of tumor,
including angiomatous meningioma, hemangiopericy-
toma, and hemangioblastoma, which are considered dis-
tinctly different neoplasms today.12 The morphologic
features frequently overlap with those of microcystic
meningioma (Fig. 14-9).
Metaplastic meningioma exhibits focal areas of metapla-
sia, which may differentiate along cartilaginous, osseous,
or lipomatous lines. There is no prognostic significance
(Fig. 14-9).
Secretory meningioma has microscopic features similar
to those of syncytial or transitional meningioma. In
addition, individual tumor cells show discrete intracy-
toplasmic inclusion bodies that are strongly positive for
carcinoembryonic antigen. Ultrastructurally, these inclu-
sions are intracytoplasmic and represent deposits of dense
ERRNVPHGLFRVRUJ
fibrillogranular material surrounded by unit membrane
with microvilli (Fig. 14-9).
Lymphoplasmacyte rich meningioma is the least common,
least well characterized, and most controversial menin-
gioma subtype. Many examples previously reported in
the literature are now recognized as reactive or inflam-
matory lesions, rather than meningiomas. Nevertheless,
there are legitimate examples of meningiomas with
prominent intratumoral lymphoplasmacytic infiltrates.
The significance awaits further investigation (Fig. 14-9).
Microcystic meningioma exhibits a distinctive architec-
ture of spidery cell processes that form variously sized
microcysts to the extent that, to the uninitiated, the
tumor may not be recognized as a meningioma. Closer
inspection will reveal typical bland nuclei. Microcystic
meningioma often shows morphologic features that
overlap with those of angiomatous meningioma (rich
vasculature) and secretory meningioma (occasional
pseudopsammoma bodies) (Fig. 14-10). All three of
these meningioma variants—angiomatous, secretory, and
microcystic—frequently display “degenerative” nuclear
atypia, and in some tumors the morphologic features are
so overlapping that any of the three appellations might
be applied. In the absence of high-grade features (such as
elevated mitotic activity or brain invasion), all three are
benign, WHO grade I, subtypes with no prognostic
significance.
Chordoid meningioma is characterized by cords of
meningothelial cells typically surrounded by a rich
myxoid matrix (Fig. 14-11).
Clear cell meningioma is characterized by prominent
cytoplasmic clearing (Fig. 14-11).
Papillary meningioma represents a distinct variant of
meningioma. Recognition of this entity has clinical sig-
nificance because these neoplasms exhibit locally aggres-
sive growth and are associated with late metastases. These
neoplasms are composed of meningothelial cells arranged
in papillary structures with central fibrovascular cores
(perivascular pseudorosettes) (Fig. 14-11).
Rhabdoid meningioma is another meningioma subtype
with potential for aggressive clinical behavior. Tumor
cells exhibit characteristic rhabdoid morphology, often
lacking other typical architectural and cytologic features
of meningioma.
Atypical and anaplastic meningiomas comprise the higher
grade categories of meningiomas. Atypical meningiomas
(WHO grade II) exhibit at least three of the following
five histologic features: foci of micronecrosis, prominent
nucleoli, sheeting architecture, small cell formation, or
hypercellularity (Figs. 14-12). Anaplastic meningioma
(WHO grade III) exhibits morphologic features resem-
bling sarcoma, carcinoma, or melanoma. These are
among the rarest meningioma variants.
Brain invasive meningiomas exhibit increased potential
for early recurrence and are therefore classified as WHO
grade II. In cases in which it is uncertain whether the
invaded tissue is brain parenchyma or reactive leptomen-
ingeal tissue, immunostaining for GFAP or S-100 protein
can be performed (Fig. 14-13).
Grading of meningiomas is based on levels of mitotic
activity (Table 14-2).10 Upgrading of any meningioma
histologic subtype is warranted when increased mitotic
 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 997

A B

C D
FIGURE 14-6  ■  Meningioma: radiographic, gross, and microscopic features. A, Axial computed tomogram showing characteristic
“hair on end” or “starburst” sign in a hyperostotic frontal meningioma. B, Whole-mount gross photograph of hyperostotic frontal
bone shown in A. C, Low power photomicrograph of meningioma with reactive bone corresponding to the radiographic “hair on
end” sign (×100). D, Intermediate power photomicrograph of the characteristic bone spicules extending into subcutaneous tissue
in a hyperostotic meningioma (×200). (C and D, hematoxylin-eosin.)

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998 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-7  ■  Meningioma: atypical radiographic features. A, T1-weighted axial postcontrast magnetic resonance image (MRI)
showing a large falcine signal-enhancing tumor in the anterior cranial fossa. Note blurring of the tumor-brain interface in this atypi-
cal meningioma. B, T1-weighted coronal postcontrast MRI showing a signal-enhancing meningioma located in the right parietooc-
cipital region with lobulated contour (“mushrooming” sign) in this atypical meningioma. C, T1-weighted axial postcontrast MRI
showing a signal-enhancing meningioma with lobulated contour located in right frontal region in this anaplastic meningioma.
D, T1-weighted sagittal postcontrast MRI showing frontal signal-enhancing meningioma surrounded by marked cerebral edema.

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TABLE 14-1  Microscopic Variants of Meningioma

Type Microscopic Features
WHO Grade I
Meningothelial (syncytial) Syncytium-like histology (cell borders are not easily discernible).
Fibroblastic (fibrous) Compact fascicles of highly spindled cells (fibroblast-like) alternating with areas of syncytial
appearance, giving an alternating “on-edge” and “en face” feeling. Some tumors have
prominent collagen bands, which may calcify in a linear, spiculated fashion (distinct from
spherical psammoma bodies).
Transitional A swirling together of the syncytial and fibroblastic patterns, with resultant prominent cell whorls
that constitute the hallmark feature of this subtype. The whorls may calcify, beginning in the
center, creating a psammoma body.
Psammomatous Essentially a transitional meningioma in which a large percentage of the meningothelial cell
whorls have calcified (formed psammoma bodies). There is no specified number, percentage,
or density of psammoma bodies that is required to “qualify” as a psammomatous meningioma.
Angiomatous Meningioma in which the vasculature is especially dense and prominent. Frequently shows
degenerative nuclear atypia. An older term, angioblastic, is inaccurate and obsolete.
Metaplastic Displays focal areas of bone, cartilage of fatty metaplasia. As with the other grade I meningioma
subtypes, there is no prognostic significance.
Secretory The hallmark morphologic feature is the presence of pseudopsammoma bodies, which are
brightly eosinophilic intracystoplasmic globular inclusions (proteinaceous secretions) of varying
number and size. Pseudopsammoma bodies are strongly positive for carcinoembryonic antigen,
and the cells that produce them are strongly positive for epithelial membrane antigen and
keratin.
Lymphoplasmacyte-rich Among the rarest of meningioma subtypes, this exhibits prominent collections of chronic
inflammatory cells (lymphocytes and plasma cells).
Microcystic Characterized by prominent microcystic architecture throughout the tumor; may not otherwise
bear much resemblance to traditional meningioma morphology. Frequently displays prominent,
often hyalinized, vasculature and degenerative atypia, thus overlapping with the angiomatous
subtype.

WHO Grade II
Chordoid Cords of tumor cells separated by myxoid matrix.
Clear cell Cytoplasmic clearing in a majority of tumor cells can obscure the meningothelial nature of the
tumor; whorls can often be highlighted by immunostaining for vimentin or epithelial membrane
antigen.

WHO Grade III

Rhabdoid Rhabdoid morphology (small epithelioid cells with globular eosinophilic cytoplasm and eccentric
nuclei) predominates in this variant, which, like the microcystic subtype, may not be instantly
recognizable as meningothelial in origin by those not familiar with the entity. Mitotic activity is
typically elevated.
Papillary Tumor cells form perivascular pseudorosettes (similar to those seen in ependymoma), which may
artifactually dehisce, giving a papillary (pseudopapillary) appearance. As with the rhabdoid
subtype, mitotic activity is usually elevated.

activity is present. Specifically, meningiomas with four or
more mitoses per 10 contiguous high-power fields are
classified as WHO grade II, and meningiomas with 20 or
more mitoses per 10 contiguous high-power fields are
classified as WHO grade III (Fig. 14-13).
Meningiomas that invade osseous structures can
provoke prominent reactive bone formation. Sometimes
reactive new bone forms parallel striations. This orienta-
tion is best seen on specimen radiographs but can
also be demonstrated during low power microscopic
examination. Reactive bone formation may also take the
form of haphazardly arranged bone trabeculae. Occasion-
ally, the bone formation is so abundant that it overshad-
ows underlying tumor cells.
Immunohistochemically, meningiomas are positive for
epithelial membrane antigen.5,11,21 In the setting of cranial
lesions, this feature is very helpful in distinguishing
meningiomas from schwannomas and tumors of glial cell
origin. As in all cells of mesenchymal origin, vimentin
is strongly positive in meningiothelial cells. Approxi-
mately 20% of meningiomas show at least focal positivity
for S-100 protein. Keratin is typically not present in
meningioma, but it can be focally positive, especially in
secretory meningioma.
Clinical Behavior
The vast majority of meningiomas are clinically benign
and their eradication depends on the size of the lesion,
specific topographic involvement, as well as involvement
of the vital structures of the central nervous system.
A small proportion of meningiomas exhibit locally
aggressive behavior. These tumors rarely may exhibit
metastatic potential with involvement of extracranial
osseous sites.16,20,27,29 Both grading of meningiomas and
their molecular characteristics correlate to some degree
with clinical behaviors. In general, grade I meningiomas
behave as benign tumors, and grade II are locally aggres-
sive, whereas grade III meningiomas have some degree
of metastatic potential. Meningiomas characterized by
mutations of the TRAF7, KLF4, and SMO genes are
Text continued on p. 1006

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1000 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-8  ■  Meningioma: microscopic features. A, Intermediate power photomicrograph showing transitional (WHO grade I)
subtype meningioma with prominent whorl formation. B, Intermediate power photomicrograph showing syncytial (WHO grade I)
subtype of meningioma. C, Intermediate power photomicrograph showing fibrous (fibroblastic) (WHO grade I) subtype of menin-
gioma. D, Intermediate power photomicrograph showing psammomatous (WHO grade I) subtype of meningioma (A-D, ×200,
hematoxylin-eosin).

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1001

A B

C D
FIGURE 14-9  ■  Meningioma: microscopic features. A, Intermediate power photomicrograph showing angiomatous (WHO grade I)
subtype of meningioma with rich vasculature. B, Intermediate power photomicrograph showing metaplastic (WHO grade I) subtype
of meningioma with areas of cartilage formation. C, Intermediate power photomicrograph showing secretory (WHO grade I)
subtype of meningioma with prominent pseudopsammoma body formation. D, Intermediate power photomicrograph showing
lymphoplasmacyte-rich (WHO grade I) subtype of meningioma with prominent lymphoplasmacytic infiltrate between meningioma
whorls (A-D, ×200, hematoxylin-eosin).

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1002 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-10  ■  Meningioma: microscopic features. A, Low power photomicrograph of a microcystic subtype of meningioma, in which
the architecture is dominated by a microcyst formation (×100). B, Intermediate power photomicrograph of microcystic meningioma
showing the often spider web–like morphology of the microcystic architecture (×200). C, Low power photomicrograph of a menin-
gioma with mixed features of the angiomatous, microcystic, and secretory variants (×100). D, High power photomicrograph of a
meningioma with mixed angiomatous, microcystic, and secretory features. Meningiomas with this combination of features are not
uncommon, and they often display prominent degenerative (“aging”) nuclear atypia, as seen in this case. Note the pseudopsam-
moma bodies (secretory globules) in the center of the field (×400) (A-D, hematoxylin-eosin).

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1003

A B

C D
FIGURE 14-11  ■  Meningioma: microscopic features. A, Intermediate power photomicrograph showing chordoid (WHO grade II)
subtype of meningioma with nests and cords of meningioma cells in a myxoid background. B, Intermediate power photomicrograph
showing clear cell (WHO grade II) subtype of meningioma. C, Intermediate power photomicrograph showing papillary (WHO grade
III) subtype of meningioma with prominent perivascular pseudorosette formation. D, Intermediate power photomicrograph showing
rhabdoid (WHO grade III) meningioma (A-D, ×200, hematoxylin-eosin).

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1004 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-12  ■  Meningioma: microscopic features. A, Intermediate power photomicrograph showing a focus of micronecrosis in an
atypical (WHO grade II) meningioma. B, Intermediate power photomicrograph showing prominent nucleoli in an atypical (WHO
grade II) meningioma. C, Intermediate power photomicrograph showing “sheeting” architecture in an atypical (WHO grade II)
meningioma. D, Intermediate power photomicrograph showing small cell foci in an atypical (WHO grade II) meningioma (A-D, ×200,
hematoxylin-eosin).

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1005

A B

C D
FIGURE 14-13  ■  Meningioma: microscopic features. A, Low power photomicrograph showing invasion of brain by meningioma (×100).
B, Low power photomicrograph confirming brain invasion by expression of GFAP in invaded brain tissue (×100). C, Intermediate
power photomicrograph showing brisk mitotic activity in this anaplastic (WHO grade III) meningioma (×200). D, High power photo-
micrograph of mitotic figure identification using immunohistochemistry demonstrating expression of phosphohistone H3 in M-phase
cells (×400). (A and C, hematoxylin-eosin.)

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1006 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

hemangiopericytoma (also see Chapter 13). Intracranial

TABLE 14-2 World Health Organization (WHO)
hemangiopericytoma has a high propensity for extracra-
Grading of Meningiomas
nial skeletal metastases. In fact, most bone hemangioperi-
WHO Grade I cytomas are metastatic lesions, and a significant proportion
Benign Meningioma of them represent distant metastases from meningeal
Histologic variant other than clear cell, chordoid, papillary, hemangiopericytoma.12,16,20 Extracranial skeletal metasta-
or rhabdoid ses also occasionally occur in conventional (i.e., transi-
Lacks criteria of grades II and III meningiomas tional) meningiomas with or without features of cytologic
WHO Grade II
atypia.20,27,29 His­torically, central nervous system heman-
giopericytomas were lumped in with angiomatous menin-
Atypical Meningioma
giomas in a now discredited category of tumor termed
Mitotic index ≥4 per 10 high-power fields
or angioblastic meningioma.
At least 3 of 5 parameters:
Sheeting architecture (loss of whorling or fascicles)
Small cell formation (high N/C* ratio) Radiologic Features
Macronucleoli
Hypercellularity
The radiologic features of solitary fibrous tumor of the
Spontaneous necrosis (i.e., not induced by embolization central nervous system typically mimic those of menin-
or radiation) gioma; that is, they are dura-based circumscribed masses
or that show enhancement after contrast administration
Brain Invasion (Fig. 14-14). At the more aggressive end of the spectrum,
or hemangiopericytoma (cellular solitary fibrous tumor) has
a tendency for early recurrence and metastasis, including
Clear Cell Meningioma a high propensity for extracranial skeletal metastases.
or
Chordoid Meningioma Gross Findings
WHO Grade III Grossly the lesions are usually well delineated, firm, and
Anaplastic (Malignant) Meningioma nodular, with an overall fibrous appearance. On cut
Mitotic index ≥20 per 10 high-power fields section, the nodular nature of the lesion is evident and
or the great white fibrous mass may have foci of myxoid
Frank anaplasia (sarcoma, carcinoma, or melanoma-like
histology) change or hemorrhage.
or
Papillary Meningioma Microscopic Findings
or
Solitary fibrous tumors are composed of spindle cells
Rhabdoid Meningioma arranged in short ill-defined fascicles, described as a pat-
ternless pattern. A characteristic feature is the presence
*N/C, nuclear/cytoplasmic.
of striking hyalinization. The vasculature varies from
narrow vascular channels to prominent open branching
vessels referred to as hemangiopericytoma-like vasculature.
distinct and nearly always show a benign clinical course The cellular variants of solitary fibrous tumors have over-
with chromosomal stability and have a tendency to origi- lapping features with soft tissue hemangiopericytoma.
nate in the medial skull base. Meningiomas containing The solitary fibrous tumor family comprises a spectrum
the mutant NF2 gene frequently exhibit loss of chromo- of tumors ranging from relatively indolent solitary fibrous
some 22, are genomically unstable, and are more likely tumor at one end to aggressive hemangiopericytoma (cel-
atypical. These tumors have a tendency to originate over lular solitary fibrous tumor) at the other (Fig. 14-14).
the cerebral and cerebellar convexities. The microscopic features of solitary fibrous tumor in the
central nervous system overlap with those of the more
common ones that affect the soft tissue, predominantly
SOLITARY FIBROUS TUMOR/ the pleura.34,37,39,41-44,46,48 At the two ends of the spectrum,
the tumors exhibit distinctive classical morphologic fea-
HEMANGIOPERICYTOMA tures, with solitary fibrous tumor displaying bland spindle
FAMILY TUMORS cells separated by prominent bands of ropy collagen and
strong diffuse immunoreactivity for CD34, whereas clas-
The solitary fibrous tumor, considered by most authors sical hemangiopericytoma is a highly vascular, densely
as a separate entity, is also designated as intracranial cellular, mitotically active neoplasm in which CD34 reac-
hemangiopericytoma.32,33,35,38,40,47,49 Although the meningo- tivity is confined to the vasculature (Fig. 14-13). However,
thelial origin of these neoplasms is questionable, they it was recognized early on that many hemangiopericyto-
have age-distribution and site-predilection patterns mas display at least focal CD34 reactivity, and in fact the
within the central nervous system that are similar to those spectrum of solitary fibrous tumor embraces a wide range
of conventional meningiomas. The overall microscopic of transitional forms that blend in various proportions
appearance of this neoplasm is identical to that of the morphologic, immunophenotypic and proliferative

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1007

FIGURE 14-14  ■  Solitary fibrous tumor/hemangiopericytoma: radiographic and microscopic features. A, T1-weighted sagittal post-
contrast magnetic resonance image (MRI) showing heterogeneously signal enhancing tumor of parietal region. B, T1-weighted axial
postcontrast MRI showing signal enhancing mass in the right cavernous sinus region. C, Low power photomicrograph of the tumor
in A showing bland fibroblastic cells separated by dense bands of collagen characteristic of solitary fibrous tumor (×100). Upper
Inset, Strong diffuse expression of CD34 in solitary fibrous tumor revealed by immunohistochemistry (×200), Lower Inset, Nuclear
localization of STAT6 revealed by immunohistochemistry (×200). D, Intermediate power photomicrograph of the tumor in C showing
uniform hypercellular undifferentiated mesenchymal cells with brisk mitotic activity characteristic of hemangiopericytoma (cellular
solitary fibrous tumor) (×200). Upper Inset, In contrast to solitary fibrous tumor, only the blood vessels stain with CD34; the
tumor cells are negative (×200). Lower Inset, Reflecting the same underlying molecular driver as solitary fibrous tumor (NAB2-
STAT6 translocation and fusion), strong nuclear localization of STAT6 is also seen in hemangiopericytoma (x200). (C and
D, hematoxylin-eosin.)

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1008 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone
features of classical hemangiopericytoma and solitary
fibrous tumor. Recognition of the kinship between soli-
tary fibrous tumor and hemangiopericytoma was finally
conclusively demonstrated beyond doubt by discovery of
a shared underlying genetic signature.
Solitary fibrous tumors are characterized by the pres-
ence of a NAB2-STAT6 gene fusion in the vast majority
of both soft tissue and central nervous system tumors
(Fig. 14-15).36,44,45 The fusion is caused by an inversion
within chromosome 12 resulting in the juxtaposition of
NAB2 and STAT6 neighbor genes. The breakpoint within
STAT6 is conserved, and typically the fusion variants
contain almost the entire STAT6 reading frame. There
are shifting breakpoints within the NAB2 gene, but all of
the variants retain the early growth response protein 1
binding domain (EBD). The transcriptional activation
domain (TAD) of the STAT6 fusion partner is most likely
responsible for the proliferation inducing activity of the
chimeric NAB2-STAT6 protein. The nuclear localization
of STAT6 protein driven by the NAB2 promoter in soli-
tary fibrous tumors can be used as an auxiliary test in their
differential diagnosis.
MYXOPAPILLARY EPENDYMOMA
Myxopapillary ependymoma is a tumor that almost exclu-
sively occurs in the region corresponding to the filum
terminale and cauda equina.53,62,66,70-72 Microscopically,
myxopapillary ependymoma resembles embryonal struc-
tures of this region. In fact, some myxopapillary ependy-
momas may originate from the so-called ependymal
myxopapillary rests that occasionally are identified in
the sacrococcygeal region.67 Similar to meningiomas,
myxopapillary ependymomas can destroy bone and
present with features suggesting a primary bone tumor
(Fig. 14-16). Rare examples of these lesions have been
described in the presacral or postsacral soft tissue. Lesions
located in extradural soft tissue are frequently associated
with spina bifida, but myxopapillary ependymomas that
occur in soft tissue have also been reported without
any associated anatomic anomaly in the sacrolumbar
region.50,52,56,58,60 They can present as lytic bone lesions
that involve the lumbosacral region.51-53,61,65
As the name implies, myxopapillary ependymoma is
composed of ependymal cells arranged in papillary struc-
tures that show prominent stromal myxoid change. In
general, the architecture of this variant of ependymoma
mimics the normal embryonal structures of the filum
terminale and cauda equina. The cells are arranged in a
fernlike pattern around a central fibrovascular core (Fig.
14-10). The cytoplasmic processes of neoplastic cells
form radiating, rosette-like structures around vessels.
The papillary architecture is accentuated by the collarlike
arrangement of ependymal cells around the vessels. A
mucoid substance is often present in the form of vesicular
intercytoplasmic structures of varying sizes that separate
tumor cells (Fig. 14-17). Distinctive, peculiar structures
seen in myxopapillary ependymoma are eosinophilic
globoid bodies positive for periodic acid-Schiff, alcian
blue, Masson, and reticulin stains. Ultrastructurally, they
are composed of a collagen-rich substance surrounded by
tumor cell processes resting on basal lamina. A hallmark
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of all ependymomas, including the myxopapillary variant,
is their microscopically recognizable dualistic phenotype
(i.e., glial and epithelial). However, immunohistochemi-
cal coexpression of epithelial and glial markers such
as glial fibrillary acidic proteins, epithelial membrane
antigen, and keratin is variable. Most ependymomas are
positive for glial fibrillary acidic protein and often are
focally positive for epithelial membrane antigen.54,70
Myxopapillary ependymomas are slow-growing
tumors with a tendency for local recurrence. Lesions that
are completely excised are associated with an approxi-
mately 20-year mean survival rate. Typically, myxopapil-
lary ependymoma exhibits slow, local destructive growth.
Eventually the lesion disrupts the bone and extends to
the perisacral tissue.57,60-63,65,68,69 Recurrences are typically
multiple nodules that may coalesce. Local dissemination
with multiple metastatic or satellite nodules is frequently
seen in terminal stages of the disease.55,59,64,73 Long-term
lesions may grow to a considerable size and compress
pelvic and abdominal organs.
INTRAOSSEOUS SCHWANNOMA
Intraosseous schwannoma (neurilemmoma) is extremely
rare. We have seen only a few examples of this lesion in
bone, and fewer than 200 examples have been described
in the literature.74-76,82,83 Intraosseous schwannoma is
similar to more common soft tissue schwannomas. It
accounts for less than 0.2% of all primary bone tumors.
Schwannoma can involve bone by three mechanisms:
(1) secondary erosion by an extraosseous tumor; (2)
tumor arising from a nerve coursing through a canal in
a bone and causing erosion of the bone, creating a
dumbbell-shaped configuration; or (3) tumor arising
centrally (intramedullary) in a bone. The first two mecha-
nisms occur most frequently. A true intramedullary origin
is exceptional.
Definition
Schwannoma (neurilemmoma) is a benign peripheral
nerve sheath tumor composed of Schwann cells that are
frequently arranged in hypercellular and hypocellular
areas, referred to as Antoni A and B tissue, respectively.
Schwannomas are encapsulated and typically arise from
a recognizable nerve trunk.
Incidence and Location
Intraosseous schwannomas arise most frequently in
the mandible and sacrum.76,77,79,82,83,88,89 They have also
been reported in a number of other locations, includ-
ing the vertebral bodies, ulna, humerus, femur, tibia,
patella, scapula, rib, maxilla, and small bones of the
hands.77-80,85,91,92 Intraosseous schwannomas were also
described in a setting of neurofibromatosis type 3
(schawannomatosis).84
Clinical Symptoms
The most common symptoms are pain and localized
swelling over the affected area.
 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1009

NAB2

Exon 1

Exon 2

Exon 3

Exon 4
Exon 5
Exon 6

Exon 7
Chr 12
13.3
13.2
13.1 cen tel
12.3
12.2
12.1 STAT6

Exon 22
Exon 21
Exon 20

Exon 19
Exon 18
Exon 17
Exon 16
Exon 15
Exon 14

Exon 13
Exon 12

Exon 11
Exon 10
11.2

Exon 9
Exon 8
Exon 7
Exon 6
Exon 5
Exon 4
Exon 3
Exon 2

Exon 1
11.1
11
12

13.1
13.2 NAB2 cen tel
13.3
STAT6 invert
14 cen tel

15

Exon 10
Exon 11

Exon 12
Exon 13

Exon 14
Exon 15
Exon 16
Exon 17
Exon 18
Exon 19

Exon 20
Exon 21
Exon 22
Exon 1

Exon 2
Exon 3
Exon 4
Exon 5
Exon 6
Exon 7
Exon 8
Exon 9
21.1
21.2
21.3

22

23

24.1
24.2
24.31 cen tel
24.32 Fusion transcript
24.33
breakpoint
A NAB2 portion STAT portion

NAB2 STAT6
EBD NCD2 RD CCD1 DBD SH2 TAD
1 525 aa 1 847 aa
EBD - Early growth response protein 1 CCD1 - Coiled-coil domain
binding domain DBD - DNA-binding domain
NCD2 - NAB2 conserved domain
SH2 - Src (sarcoma) homology 2 domain
RD - Transcriptional repressor domain
TAD - Transcriptional activator domain
EBD NCD2 RD TAD
SFT-18 1 706 aa
EBD NCD2 RD SH2 TAD
SFT-3 1 779 aa
EBD NCD2 RD SH2 TAD
SFT-28 1 741 aa
EBD NCD2 RD CCD1 DBD SH2 TAD
SFT-31 1 1307 aa
EBD NCD2 RD CCD1 DBD SH2 TAD
SFT-40 1 1222 aa
EBD NCD2 RD SH2 TAD
SFT-44/10 1 755 aa
B
FIGURE 14-15  ■  Molecular structure of NAB2-STAT6 fusion gene and its chimeric protein in solitary fibrous tumor. A, Exon-intron
structures of NAB2 and STAT6 genes. The molecular structure of the resulting chimeric gene, which includes the entire STAT6 gene
after inversion and 3′ segment of NAB2, is shown. B, Functional domains of the two proteins are depicted. C, The structural variants
of the chimeric protein resulting from the alternative breakpoints of the two genes. Note that all variants contain the EBD (early
growth response protein 1 binding domain) of the NAB2 gene and TAD (transcriptional activator domain) of the STAT6 gene. (Adapted
from Robinson DR, et al: Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nature
Genetics 45:180–187, 2013).

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1010 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-16  ■  Myxopapillary ependymoma: radiographic features. A, T2-weighted sagittal magnetic resonance image (MRI) showing
signal enhancing circumscribed (“boxcar shaped”) mass in the lumbar cistern, characteristic of myxopapillary ependymoma.
B, T1-weighted sagittal postcontrast MRI showing signal enhancing circumscribed (“boxcar shaped”) mass in the lumbar cistern,
characteristic of myxopapillary ependymoma. C, T1-weighted sagittal MRI showing sacral myxopapillary ependymoma. D, T1-
weighted sagittal postcontrast MRI showing sacral myxopapillary ependymoma.

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1011

A B

C D
FIGURE 14-17  ■  Myxopapillary ependymoma: microscopic features. A, Intermediate power photomicrograph of cytologic smear
preparation showing fibrillary cytoplasmic processes and myxoid material characteristic of myxopapillary ependymoma (×200).
B, Intermediate power photomicrograph showing prominent perivascular myxoid cuffing and myxoid microcysts (×200). C, Inter-
mediate power photomicrograph showing papillary architecture of sacral myxopapillary ependymoma (×200). D, High power pho-
tomicrograph showing dotlike and ringlike expression of epithelial membrane antigen as revealed by immunohistochemistry (×400).
(B and C, hematoxylin-eosin.)

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1012 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone
Radiographic Imaging
Radiographically, the lesions are lytic, but a narrow scle-
rotic zone may be present at the periphery (Fig. 14-18).
The bone contour may be expanded with no periosteal
reaction. The cortex may be thinned, but no true cortical
destruction or extension into soft tissue is present.
Although the lesions are primarily lytic, they may have
incomplete internal trabeculation or lobulation (Fig.
14-18). The radiographic appearance is usually inter-
preted as benign, but a specific diagnosis cannot be
made from radiographic findings alone. It is difficult to
differentiate intraosseous schwannoma on radiographs
from other conditions that have similar radiographic
features, such as solitary bone cyst, chondroblastoma,
chondromyxoid fibroma, and giant cell tumor.74-76,78,80,86
CT scans show sharp delineation of the tumor and may
disclose the dumbbell nature of the lesion (Figs. 14-19
and 14-20). On MRI, schwannomas appear as uniformly
contrast enhancing well-delineated lesions with an ana-
tomic relationship to the adjacent nerve structures
(Figs.14-19 and 14-20).
Gross Findings
Intraosseous schwannomas are soft, tan-gray lesions with
frequent yellowish patchy areas. Hemorrhage, myxoid,
and cystic changes are frequently present. When the
lesion is present in a neural canal or foramen, a capsule
may be discernible.
Microscopic Findings
The microscopic features of intraosseous schwannoma
are similar to those of their more common soft tissue
counterparts.77,79 The tumors have two basic patterns:
hypercellular (Antoni A) and hypocellular (Antoni B)
(Fig. 14-21). In Antoni A areas of schwannoma cells that
are compactly arranged form focally palisading structures
(Verocay bodies). In Antoni B areas, schwannoma cells
are widely separated by a loose intervening collagenous
matrix. Vessels with thick hyalinized walls are present
focally. Variable numbers of histiocytes, macrophages,
lymphocytes, and mast cells may be present. Some
intraosseous schwannomas are hypercellular and may
have less distinguishable Antoni A and B areas. These
lesions may exhibit some nuclear atypia, and occasional
mitoses may be present. These tumors are compatible
with so-called cellular schwannomas and should be care-
fully differentiated from malignant neoplasms.92
Special Techniques
Ultrastructural features of intraosseous schwannomas are
the same as those described for soft tissue schwanno-
mas.77,81,87,90 Spindle-shaped tumor cells with abundant
cytoplasmic processes are surrounded by bands of
basal lamina (Fig. 14-22). Occasionally, desmosome-like
junctions may be present. Multivesicular bodies and
long-spaced collagen fibers (Luse bodies) are also seen.
Immunohistochemically, the tumor cells are positive for
vimentin and S-100 protein (Fig. 14-21).
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Differential Diagnosis
Microscopically, intraosseous schwannoma should be dis-
tinguished from desmoplastic fibroma, well-differentiated
fibrosarcoma, fibrous dysplasia, and nonossifying fibroma.
In distinguishing cellular schwannoma from a malig-
nant spindle-cell neoplasm, it is important to remem-
ber that atypical mitoses are never present in benign
schwannoma. Atypia in benign schwannoma is of the
degenerative type. Moreover, a hypercellular tumor with
recognizable phenotypic features of Schwann cells is more
likely to represent a benign schwannoma than a malig-
nant spindle-cell neoplasm (also see the section on dif-
ferential diagnosis of malignant peripheral nerve sheath
tumor).92 The presence of specific radiographic and
microscopic features usually distinguishes schwannoma
from other benign intraosseous conditions such as nonos-
sifying fibroma and fibrous dysplasia.
In addition to its microscopic features, desmoplastic
fibroma can be ruled out by the absence of positivity for
S-100 protein in fibroblastic cells.
Treatment and Behavior
Intraosseous schwannomas are benign, and excision is
curative. Excision can be accomplished by enucleation or
curettage.
NEUROGENIC TUMOR
PREDISPOSITION SYNDROMES
A comprehensive description of all aspects of neurogenic
tumor predisposition syndromes is beyond the scope of
this chapter. Our description is restricted to the basic
clinical and pathologic features with emphasis on the
osseous manifestations. The clinical diagnostic criteria
for the three forms of neurofibromatosis, referred to as
types 1 to 3, are summarized in Table 14-3. These three
forms are clinically different and have distinct predispos-
ing genetic mechanisms.163,177,178,188 We also include in
this section description of the skeletal manifestations of
von Hippel-Lindau disease with its hallmark neoplasm,
hemangioblastoma.148,161,206
Neurofibromatosis Type 1
Neurofibromatosis type 1, traditionally referred to as
von Recklinghausen’s disease, is a congenital and familial
disorder with multiple manifestations that can involve
virtually any organ. Multiple soft tissue and cutaneous
neurofibromas and café au lait spots constitute the hall-
mark dermatologic features of this condition. Although
neurofibromatosis type 1 primarily involves tissues of
neural crest origin, it also affects the mesoderm and
endoderm.103,135,137,177,178,185,196 Neurofibromatosis type 1 is
diagnosed if two or more features listed in Table 14-3 are
present. Neurofibromatosis type 1 has an autosomal
dominant pattern of inheritance with 50% pene-
trance.114,115,118 Roughly half of neurofibromatosis type 1
patients have a documented family history of the disease,
Text continued on p. 1018
 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1013

A B

C D
FIGURE 14-18  ■  Intraosseous schwannoma: radiographic features. A, Lateral radiograph of mandible with lytic lesion produced by
expanding nerve sheath tumor arising in association with mandibular nerve. Note close relationship to mandibular canal and erosion
of root of molar. B, Radiograph of expansile tumor of pubic ramus in young adult with long history of groin pain. C, Anteroposterior
(AP) radiograph of sacrum showing expansile multiloculated lucent lesion. D, AP radiograph of sacrum showing expansile multi-
loculated lesion.

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1014 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-19  ■  Schwannoma: radiographic features. A, T1-weighted sagittal postcontrast magnetic resonance image (MRI) showing
supraorbital mass with uniform signal enhancement (arrow). Inset, Sagittal computed tomogram showing thinning of superior
orbital bone by schwannoma (arrow). B, T2-weighted coronal MRI showing brachial plexus schwannoma. C, T1-weighted axial
postcontrast MRI showing right intracanalicular schwannoma (arrow). D, T1-weighted axial postcontrast MRI showing right cerbel-
lopontine angle schwannoma.

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1015

B C

D E
FIGURE 14-20  ■  Schwannoma: radiographic features. A, Axial computed tomogram (CT) showing dumbbell schwannoma with widen-
ing of the intervertebral foramen. B, T1-weighted axial postcontrast magnetic resonance image (MRI) showing uniform signal
enhancing dumbbell schwannoma. Same case as in A. C, CT 3D reconstruction showing widening of the L2–L3 intervertebral foramen
(arrow). Same case as in A and B. D, Sagittal CT showing sacral schwannoma. E, T1-weighted sagittal postcontrast MRI showing
signal enhancement in sacral schwannoma. Same case as in D.

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1016 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-21  ■  Schwannoma: microscopic features. A, Low power photomicrograph showing densely cellular (Antoni type A) and
hypocellular (Antoni type B) components of schwannoma (×100). B, Low power photomicrograph showing plexiform schwannoma
(×50). C, Intermediate power photomicrograph showing nuclear palisades (Verocay bodies) in schwannoma (×200). D, Expression
of S-100 protein in schwannoma (Verocay bodies) revealed by immunohistochemistry (×200). (A-C, hematoxylin-eosin.)

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1017

B
FIGURE 14-22  ■  Schwannoma: ultrastructural features. A, Spindle cells with abundant cytoplasmic processes surrounded by basal
lamina (×4000). Inset, Long-spaced collagen (Luse bodies) in intercellular matrix (×28,000). B, Higher magnification of interdigitating
cytoplasmic processes with basal lamina. Note relationship of long-spaced collagen to basal lamina (×8,000).

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1018 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

TABLE 14-3  Neurofibromatoses: Clinical Diagnostic Criteria

Neurofibromatosis Type 1*
Six or more café au lait macules (over 5 mm in greatest diameter in prepubertal individuals or over 15 mm in greatest
diameter in postpubertal individuals)
Two or more neurofibromas of any type OR one plexiform neurofibroma
Freckling in the axillary or inguinal region
Optic glioma (pilocytic astrocytoma of the optic pathway)
Two or more Lisch nodules (iris hamartomas)
A distinctive osseous lesion, such as sphenoid dysplasia or tibial pseudarthrosis
A first-degree relative (parent, sibling, or offspring) with NF1 as defined by the above criteria

Neurofibromatosis Type 2†
Confirmed (Definite) NF2
Bilateral vestibular schwannoma (“acoustic neuroma”)
Presumptive (Probable) NF2
Family history of NF2
Unilateral vestibular schwannoma OR any 2 of the following: meningioma, glioma, schwannoma, juvenile posterior
subcapsular lenticular opacity, juvenile cortical cataract
Suspicious for NF2 (evaluation of the patient is needed if either of the conditions are present)
Unilateral vestibular schwannoma AND at least 2 of any of the following: meningioma, glioma, schwannoma, juvenile
posterior subcapsular lenticular opacities/juvenile cortical cataract
Two or more meningiomas AND either unilateral vestibular schwannoma or any 2 of the following: glioma, schwannoma,
juvenile posterior subcapsular lenticular opacities/juvenile cortical cataract

Neurofibromatosis Type 3‡
Confirmed (Definite) Schwannomatosis
Two or more nonintradermal, nonvestibular schwannomas (at least 1 with histologic confirmation) in a patient older than age
30 years
One histologically confirmed schwannoma AND a first-degree relative who meets the above criterion for definite
schwannomatosis (regardless of patient age)
Possible Schwannomatosis
• Patients younger than age 30 years: 2 or more nonintradermal, nonvestibular (confirmed by imaging) schwannomas (at least
1 with histologic confirmation)
• Patients older than age 45 years: 2 or more nonintradermal, nonvestibular schwannomas (at least 1 with histologic
confirmation), with no evidence of eighth nerve dysfunction (but magnetic resonance imaging confirmation of absence of
vestibular schwannoma is not required)
• Radiographic (imaging) evidence of a nonintradermal, nonvestibular schwannoma AND a first-degree relative meeting the
criteria for definite schwannomatosis
Segmental Schwannomatosis
Meets criteria for either definite or possible schwannomatosis, but the schwannomas are limited to one limb or to five or
fewer contiguous segments of the spine

*NIH diagnostic criteria for NF1 are met in patients who exhibit at least two of the seven features.
†Clinical diagnostic criteria for confirmed and presumptive NF2, as well as features suspicious for NF2 that warrant additional clinical
investigation.
‡Patients diagnosed with schwannomatosis must not meet any of the criteria for definite or probable NF2, and thus must not have
evidence of a vestibular schwannoma (confirmed by imaging), a constitutional NF2 mutation, or a first-degree relative with NF2.

and the remaining half are the result of new mutations.
Neurofibromatosis type 1 is linked to a very wide variety
of alterations (deletions, insertions, and mutations) as
well as alternate splicing of the neurofibromatosis 1
(NF1) gene located in the pericentromeric region of chro-
mosome 17 (Fig. 14-23).96,115,124,127,139,149,156,172,181,182,184,204 It
is one of the largest genes of the human genome, span-
ning a distance of 300 megabases (mb) and having a
complex exon-intron structure.158 The product of this
gene, neurofibromin, is a structural component of the
microtubular system and is ubiquitously expressed in all
human tissues.114 Neurofibromin represents a class of
guanosine triphosphatase–activating proteins that play a
role in signal transduction, modulation of cell differentia-
tion, and proliferation programs. NF1 cooperates with
Ras genes and has the overall biologic activity of a tumor
suppressor factor.154,208 NF1 encoded protein shows
extensive sequence similarities to two Saccharomyces cere-
visiae (yeast) genes encoding IRA1and IRA2 proteins that
are activating GTPase for yeast Ras and mammalian
Ras-GAP proteins.154 The NF1 mutations result in hyper-
activation of the Ras pathway similar to that caused by
Ras gene mutations (Fig. 14-23).93,191 It has been shown
that neurofibromas in this syndrome may develop because
of additional secondary hits within the NF1 locus, such
as a somatic deletion, that inactivate the normal allele of
the gene.115 It appears that the Schwann cell precursors
are the primary targets of loss of NF1 function. The
somatic loss of heterozygosity (LOH) in these cells
orchestrate the development of histologically complex
growth by inducing the co-proliferation of various cell
types involved in neural development by paracrine

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1019

NF1

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
Exon 17
Exon 18
Exon 19
Exon 20
Exon 22
Exon 23
Exon 24
Exon 25
Exon 26
Exon 27
Exon 28
Exon 29
Exon 30
Exon 31
Exon 32
Exon 33
Exon 34
Exon 35
Exon 36
Exon 37
Exon 38
Exon 39
Exon 40
Exon 41
Exon 42
Exon 43
Exon 44
Exon 45
Exon 46
Exon 47
Exon 48
Exon 49
Exon 50
Exon 51
Exon 52
Exon 53
Exon 54
Exon 55
Exon 56
Exon 57
Exon 58
Exon 1

Exon 2
Exon 3
Exon 4
Exon 5
Exon 6
Exon 7
Exon 8
Exon 9

Exon 1
Chr 17
13
12
11.2 11.1
11.1 NF1 NF1-NEUROFIBROMIN
12 11.2
21.2 21.1 1 2839 aa
21.3
22
23 Armadilo-type fold domain 278-2677
24
CSRD: cystein/serine-rich domain 543-909
25
TBD: tubulin-binding domain 1095-1194
GRD: GAP-related domain 1203-1549
Sec14/PH: Sec14-homologous domain 1560-1818
A NLS: nuclear localization sequence 2205-2785

INACTIVE
Ras stimulatory
Pi signal

GDP GEF

GAP blockage GTP

caused by
GDP
oncogenic
mutation

Ras

GTP

ACTIVE

+/-
Nf1
∆54 A1281 P1395 F1434 K1436 Schwann
E1264 cell
R1276 Q1426
N1430 LOH
K1423
C +/- -/- +/+
K1391 Nf1 Nf1 Nf1
mast Schwann mast
cell cell cell
α5c
N
R1413
NF91 L1425
recruitment of
G1404
fibroblasts and normal nerve
S1468 A1396
P1400
K1419
endothelial cells sheaths
ATCHSLLNKATVKEKKENKKS
Type II insert
B C neurofibroma

FIGURE 14-23  ■  Molecular mechanisms of neurofibromatosis Type 1. A, Chromosomal location, exonal structure, and functional
domains of the NF1 gene. B, The role of neurofibromin in the Ras signaling cycle. The Ras protein progresses the cycle, in which
it is activated by a guanine nucleotide exchange factor (GEF) and inactivated by a GTPase-activating protein (Ras-GAP). Neurofibro-
min (NF1) is one of the main Ras-GAPs that can stimulate Ras activity more than 1000-fold. The structure of the NF1 domain that
interacts with Ras, referred to as the arginine finger, is depicted. It carries an arginine (R1276) residue that is critical for the interac-
tion with the GTPase cleft of Ras. Mutations in the region that directly affect the R1276 residue and change the conformational status
of the domain activate the Ras pathway similar to oncogenic mutations directly affecting the Ras protein. (A and B, Modified and
reprinted with permission from Scheffzek K, et al: EMBO J 17:4313–4327, 1988; Weinberg RA: The biology of cancer, ed 2, New York,
2014, Garland Science.) C, The animal model data suggests that mast cells from bone marrow play an important role in the develop-
ing spinal cord where they contribute to the morphogenesis of the peripheral nerve. The absence of one copy of the NF1 gene
inactivated by the mutation makes them hypersensitive to signals released by the Schwann cells with NF1−/− genotype. This creates
a hypersensitive environment with aberrant morphogenesis of nerves and hyperproliferation of both fibroblasts and endothelial
cells. (C, Modified and reprinted with permission from Weinberg RA: The biology of cancer, ed 2, New York, 2014, Garland Science.)

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1020 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone
signaling. The loss of NF1 function (NF1−/− genotype)
is in the background of the NF1+/− genotype, which
might create a stimulatory hyperresponsive environment
(Fig. 14-23).214 It has been shown that the recruitment of
marrow cells, such as mast cells, plays a critical role in
the formation of plexiform neurofibromas.208,214 The
development of malignant peripheral nerve sheath tumors
is associated with additional genomic alterations such as
deletions of chromosome 17q and alterations of tumor
suppressor genes such as TP53.171,184 Molecular data
support the clonal origin of malignant peripheral nerve
sheath tumors in neurofibromatosis.132 Similar to neuro-
fibromas, malignant peripheral nerve sheath tumors
exhibit somatic deletions of the NF1 gene.156 These and
earlier data support the clinicopathologic observation
that malignant transformation in neurofibromatosis
typically occurs in a preexisting neurofibroma; that is,
malignant cells represent a subclone of an underlying
neurofibroma.132 These insights still do not address many
of the questions surrounding the formation of tumors
associated with neurofibromatosis type 1.
Clinical Symptoms
Clinical presentation of neurofibromatosis type 1 is
highly variable, but a combination of cardinal signs, listed
in Table 14-3, must be present to establish the diagnosis
of this syndrome. The severity and extent of the involve-
ment varies dramatically from patient to patient and
across families (Figs. 14-24 and 14-25). Although myriads
of genetic alterations have been discovered involving the
NF1 gene, mysteriously, the type of alteration cannot be
used to predict the various clinical manifestations of the
disorder. Typically, the disease becomes evident during
the first few years of life and is diagnosed by the presence
of dermatologic or ophthalmic lesions when café au lait
spots and Lisch nodules develop.116,145 The Lisch nodules
are pigmented hamartomas of the iris, asymptomatic
lesions that are helpful for establishing the diagnosis. Ini-
tially, the skin lesions resemble freckles, but they enlarge
with age and become darker, predominantly involving the
areas unexposed to sun. The typical presenting sign is the
so-called axillary freckle sign. The presence of multiple
skin neurofibromas is the hallmark of fibromatosis type 1
and they typically develop during childhood after the café
au lait spots become evident. Some of these tumors are
evident at birth; others continue to develop through late
adulthood. They involve both superficial and deep nerves,
and the symptoms may be related to the involvement of
nerves in various organs and anatomic sites. In addition
to neurofibromas, patients with neurofibromatosis also
develop central nervous system tumors, including optic
nerve glioma and astrocytoma (Fig. 14-27). Nearly half
of patients may have associated developmental skeletal
abnormalities varying from vertebral scalloping through
focal dysplasia to major disfiguring abnormalities (Figs.
14-26, 14-27, 14-39, and 14-40). Gynecomastia may
develop in male patients. The association of neurofi-
bromatosis type 1 with schwannoma, pheochromocy-
toma, ganglioneuroma, nephroblastoma, gastrointestinal
stromal tumor, and leukemia has been reported. In addi-
tion, such conditions as vascular aneurysms, fibrosing
ERRNVPHGLFRVRUJ
alveolitis, megacolon, lipoma, neuroblastoma, carcinoid
tumor, and Wilms’ tumor can occasionally be associated
with neurofibromatosis type 1.
Variants of neurofibromatosis type 1 with incomplete
or aberrant features in clinical presentation include
segmental manifestation, manifestation restricted to gas-
trointestinal or spinal involvement, and the so-called
“familial” café au lait spots.
Café Au Lait Spots.  Café au lait spots typically develop
first. They usually involve unexposed areas of the skin.
Initially, they are small and resemble freckles. They grad-
ually increase in size and become darker. Common loca-
tions are the trunk as well as the axillary and inguinal
regions (Fig. 14-17). Eventually, more than 30% of
patients with neurofibromatosis type 1 develop these
lesions. The number and size of café au lait spots cor-
respond to some extent to the severity of the disease.
Patients with less prominent skin pigmentation may have
a later or less severe onset of neurofibromatosis (i.e.,
palpable neurofibromas). The changes in these patients
may be restricted to one major anatomic region. Some
patients may prove to have neurofibromatosis type 2.
The borders of the pigmented areas are less irregular
than those associated with Albright-McCune syndrome
(“coast of California” rather than “coast of Maine”
contours). They occur most often over the trunk and
axillary regions. They do not become confluent to the
extent that skin lesions in Albright-McCune syndrome
do. Rarely, the macular pigmentations may have jagged
borders and become confluent. Microscopically, café au
lait spots are characterized by an increased level of pig-
mentation in the basal and peribasal layers of epidermis.
The presence of giant melanosomes (macromelano-
somes) is suggested by some authors to be pathogno-
monic for neurofibromatosis.146 However, they are not
always present, and their absence does not help to rule
out neurofibromatosis in the differential diagnosis of skin
pigmentations.194
Neurofibroma.  The presence of multiple neurofibro-
mas is a hallmark of neurofibromatosis. Several types of
neurofibromas may be present in neurofibromatosis.
Multiple localized neurofibromas that form discrete
nodules in the soft tissue are the most common lesions in
well-developed cases of neurofibromatosis type 1. These
are frequently present in the subcutaneous tissue and
dermis (Fig. 14-24). In fully developed cases, crops of
these tumors ranging from small nodules that measure
several millimeters to several centimeters can be seen
(Fig. 14-25). Nodular or localized neurofibromas do not
differ from solitary neurofibromas unassociated with
neurofibromatosis. They are therefore the least charac-
teristic lesions and are not absolutely pathognomonic for
neurofibromatosis. Nodular localized neurofibromas in
neurofibromatosis are usually larger than solitary neuro-
fibromas unassociated with neurofibromatosis.
Radiographically, especially on CT and MRI, neuro-
fibromas are well delineated signal-enhancing lesions
that may show association with the major neighboring
nerve structure (Figs. 14-26 and 14-27).
Text continued on p. 1025
 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1021

B
FIGURE 14-24  ■  Neurofibromatosis type 1: clinical features. A, Facial cutaneous and subcutaneous neurofibromas in young man with
relatively few skin lesions. B, Café au lait skin pigmentation in discrete, nonconfluent distribution over trunk. Note relatively smooth
borders around pigmented areas.

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1022 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

B
FIGURE 14-25  ■  Neurofibromatosis type 1: clinical features. A, Elderly woman with extensive cutaneous neurofibromas and malignant
peripheral nerve sheath tumor arising in left brachial plexus (arrow). B, Posterior trunk showing extensive cutaneous neurofibro-
matous involvement.

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1023

A B

C D
FIGURE 14-26  ■  Neurofibromatosis type 1: radiographic features. A, T1-weighted axial magnetic resonance image (MRI) showing a
plexiform neurofibroma involving the soft tissues of the head, sphenoid bone, and orbit. Note the characteristic “targetoid” pattern
of plexiform neuriofibroma. B, Anteroposterior radiograph of the head showing sphenoorbital dysplasia, which can occur alone or
in association with orbital neurofibroma. Same case as A. C, T1-weighted sagittal MRI showing characteristic scalloping of the
posterior aspects of the lumbosacral vertebral bodies that can be seen in NF1. D, Axial computed tomogram showing lumbar ver-
tebral body scalloping.

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1024 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-27  ■  Neurofibromatosis type 1: radiographic features. A, T1-weighted axial magnetic resonance image (MRI) showing foci
of abnormal T2 signal hyperintensity (“unidentified bright objects”) that are commonly seen in NF1. Bilateral basal ganglia lesions,
as illustrated here, are very common. B, T1-weighted axial postcontrast MRI showing bilateral gliomas of the optic pathway (optic
glioma). Optic gliomas are pilocytic astrocytomas. These can be unilateral or bilateral and can affect any part of the pregeniculate
optic pathway, including the optic nerves, chiasm, or tracts, or all of these components as seen here (double midbrain sign).
C, T2-weighted sagittal MRI showing multiple spinal neurofibromas arising at virtually every level of the spinal cord. D, T1-weighted
axial postcontrast MRI showing a biopsy-proven cerebellar glioblastoma. Diffuse gliomas are part of the spectrum of nervous system
tumors that can be seen in NF1.

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1025
Grossly, these lesions are encapsulated and tan-gray.
Neurofibromas growing within major nerves produce a
fusiform expansion. On longitudinal sections, a nerve and
its structures pass through the lesion, and this mass is
delineated by a perineurium.
Microscopically, the neurofibroma is composed of
haphazardly arranged spindle cells with an abundance of
extracellular stroma representing collagen and mucin
(Fig. 14-28). The cells are associated with strands of col-
lagen separated by myxoid matrix. The overall architec-
ture of neurofibroma is frequently described as being
patternless as opposed to neurilemmoma, which is com-
posed of bundles of palisaded cells. Various inflammatory
cells, such as mast cells, lymphocytes, and xanthomatous
histiocytes, are frequently present. Myxoid change may
be prominent, especially in larger lesions (Fig. 14-29).
Microscopically, these lesions may resemble soft tissue
myxoma. Schwann cells are usually present in neurofi-
bromas and predominate focally in some tumors. Neuro-
fibromas may contain heterologous elements, such as
glandular epithelial structures of various types, or even
foci resembling rhabdomyoma. Myelinated axons may be
demonstrated by neurofilament protein immunostaining
or Luxol fast blue myelin staining.
Immunohistochemically, neurofibroma cells are posi-
tive for vimentin and show variable focal positivity
for S-100 protein. Cells positive for S-100 protein may
in fact represent scattered individual Schwann cells.
Uniform, strong positivity of tumor cells for S-100
protein, typical in schwannoma, is not a feature of
neurofibroma.
Ultrastructurally, the majority of cells are consistent
with fibroblasts. Occasionally, Schwann cells surrounded
by basal lamina are present and are typically associated
with the axonal processes that traverse the lesion
(Fig. 14-32).90,110,155
Plexiform neurofibroma is pathognomonic for neurofi-
bromatosis if stringent gross criteria are applied to its
diagnosis. The plexiform variant of neurofibroma usually
develops in early childhood. It affects large segments of
a nerve, distorting its normal anatomic structures with
multiple nodules frequently described as “a bag of worms”
(Fig. 14-30). The identification of plexiform neurofi-
broma for the diagnosis of neurofibromatosis should
be confirmed by gross examination. The microscopic
features of a plexiform growth pattern alone are not
pathognomonic for neurofibromatosis. Fully developed
plexiform neurofibromas are large lesions that involve
one anatomic region or an entire extremity (elephantiasis
neuromatosa). The skin overlying the affected region is
loose, redundant, and hyperpigmented.
Microscopically, plexiform neurofibroma consists of
tortuous nerve branches expanded by nodules (Fig.
14-30). Nuclear pleomorphism and atypia with hyper-
chromatism are often seen in neurofibroma, especially in
larger, older lesions. These features do not indicate
malignant transformation. In plexiform lesions, individ-
ual nodules are delineated by perineural cells that are
positive for epithelial membrane antigen.
Diffuse neurofibroma is the rarest form of neurofi-
broma. It is not pathognomonic for neurofibromatosis;
that is, not all patients with this form of neurofibroma
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have neurofibromatosis. Enzinger and Weiss128 estimate
that at least 10% of patients with diffuse neurofibroma
have neurofibromatosis. On the other hand, large diffuse
lesions of this type involving the head region in chil-
dren are almost always associated with neurofibroma-
tosis. Microscopically, the tumor cells grow in a diffuse,
infiltrative pattern along fibrous septa and various
adnexal skin structures (Fig. 14-31). The adnexal dermal
and subcutaneous structures are not destroyed by the
tumor.
Schwannoma.  Schwannomas (neurilemmomas) are
almost always solitary lesions. They rarely occur in asso-
ciation with neurofibromatosis type 1. In his review,
Stout200 states that approximately 18% of patients with
neurilemmoma also have neurofibromatosis type 1. The
highly significant association of schwannoma and neuro-
fibromatosis is also confirmed by observations made by
Enzinger and Weiss.128 Rarely (approximately 5% of
cases), schwannoma may exhibit a plexiform or multi-
nodular growth pattern.95,128,213 This variant, however, is
not associated with neurofibromatosis.95,130,212 These
associations were established before the current under-
standing of the diversity of three forms of neurofibroma-
tosis was fully clinically developed. A more contemporary
view is primarily related to the clear separation of neu-
rofibromatosis type 2 and 3 with firm establishment of
the concept that neurofibromatosis type 3, also referred
to as schwannomatosis, is clinically distinct from neuro-
fibromatosis type 2. The large population based studies
of schwannomas indicate that nearly 90% of schwanno-
mas are solitary sporadic tumors and only 3% are associ-
ated with neurofibromatosis type 2. A distinct minority,
approximately 2% of schwannomas, are associated with
neurofibromatosis type 3. Overall, 5% of schwannomas
occur together with meningiomas. This last association
is seen in patients with and without neurofibromatosis
type 2. The alteration of the NF2 gene is a dominant
genetic abnormality in schwannomas regardless of
whether they are sporadic or are associated with neuro-
fibromatosis type 2.
Malignant Peripheral Nerve Sheath Tumor.  Malig-
nant peripheral nerve sheath tumor represents the most
serious and often fatal complication of neurofibromato-
sis. This term encompasses previously used designations
such as malignant schwannoma, neurofibrosarcoma, and neu-
rogenic sarcoma. These terms imply that the tumors reca-
pitulate or originate from specific cells of the nerve
sheath, such as Schwann cells, perineural fibroblasts, or
fibroblasts. Although this is true in some cases, many of
these neoplasms show only focal specific differentiation,
such as Schwann cells, whereas the majority of tumor
cells represent undifferentiated mesenchymal cells (Fig.
14-32). Phenotypic variation (divergent differentiation)
is frequently seen in these tumors, which can exhibit dif-
ferentiation toward nonneural elements such as rhabdo-
myoblasts, smooth muscle, adipose tissues, cartilage,
bone, and epithelial glandlike structures. In fact, many of
these lesions do not show neural differentiation and are
diagnosed as sarcomas of neural origin because of their
Text continued on p. 1031
1026 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-28  ■  Neurofibromatosis type 1: imaging, gross and microscopic features. A, Positron emission tomogram/computed
tomogram showing an FDG-avid tumor in the proximal upper arm. B, Gross photograph of neurofibroma resected en toto showing
prominent myxoid content as revealed by transillumination. C, Whole-mount cross-section of neurofibroma. D, Intermediate power
photomicrograph showing bland fusiform cells in myxoid background (×200). (C and D, hematoxylin-eosin.)

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1027

A B

C D
FIGURE 14-29  ■  Neurofibroma: microscopic features. A, Low power photomicrograph of neurofibroma showing prominent myxoid
content (×100). B, Intermediate power photomicrograph showing concentration of axons in the center of neurofibroma, same case
as A (×200). C, High power photomicrograph showing spindle cells and wavy collagen of neurofibroma with inconspicuous inter-
spersed axons (×400). D, High power photomicrograph highlighting entrapped myelinated axons within neurofibroma as revealed
with a Luxol fast blue stain (×400). (A-C, hematoxylin-eosin.)

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1028 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C
FIGURE 14-30  ■  Plexiform neurofibroma: microscopic features. A, Low power photomicrograph showing tangled mass of enlarged
nerves (“bag of worms”) characteristic of plexiform neurofibroma (×100). B, Intermediate power photomicrograph showing plexi-
form neurofibroma with prominent myxoid background and central concentration of axons, same case as A (×200). C, High power
photomicrograph showing centrally preserved axons, same case as A (×400). (A-C, hematoxylin-eosin.)

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1029

A B

C D
FIGURE 14-31  ■  Cutaneous (intradermal) neurofibroma: microscopic features. A, Low power photomicrograph of diffuse form of
cutaneous (intradermal) neurofibroma (×100). B, Intermediate power photomicrograph showing characteristic spindle cells of neu-
rofibroma (×200). C, Low power photomicrograph of cutaneous plexiform neurofibroma (×100). D, Intermediate power photomicro-
graph showing whorl formation in a cutaneous plexiform neurofibroma (×200). (A-C, hematoxylin-eosin.)

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1030 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

FIGURE 14-32  ■  Neurofibroma: ultrastructural features. A, Low magnification showing spindle cells in collagenous stroma (×3500).
B, Higher magnification of Schwann cell processes invested with basal lamina. Cytoplasm of Schwann cell contains myelin sheath
(dark ring) surrounding an axon (×10,500). Inset shows spindle cell with fibroblastic features at higher magnification. Note absence
of basal lamina and prominent rough endoplasmic reticulum (×7200).

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1031
association with major nerves or neurofibromatosis. For
all these reasons, the term malignant peripheral nerve
sheath tumor is preferred for the designation of a unique
set of tumors that arise in major nerves or occur in a
clinical setting of neurofibromatosis type 1.
Approximately 50% of all malignant peripheral nerve
sheath tumors are associated with neurofibromatosis type
1. The early concepts regarding the relationship between
these tumors and neurofibromatosis were complicated by
different sets of diagnostic criteria used by different
authors.142 The current consensus is that patients with
neurofibromatosis type 1 have a smaller risk of develop-
ing malignant peripheral nerve sheath tumors than the
24% risk originally estimated. It is now believed that less
than 5% of patients with neurofibromatosis type 1 even-
tually develop malignant peripheral nerve sheath tumors.
This serious complication is typically seen in patients
with long-term, fully developed disease (10 to 20 years)
and is occasionally multifocal. Malignant peripheral
nerve sheath tumors typically occur in patients between
ages 20 and 50 years. Malignant peripheral nerve sheath
tumors, both solitary and associated with neurofibroma-
tosis, are rare in children.3,169 The mean age of patients
diagnosed with these tumors in association with neurofi-
bromatosis is lower than the mean age of patients who
have sporadic malignant peripheral nerve sheath tumors.
The peak incidence of malignant peripheral nerve sheath
tumors in neurofibromatosis is during the third decade
of life. The peak incidence of sporadic malignant periph-
eral nerve sheath tumors is during the fifth decade of life.
The male-to-female ratio of malignant peripheral nerve
sheath tumors associated with neurofibromatosis is 4 : 1;
80% occur in neurofibromatosis-affected men. Sporadic
malignant peripheral nerve sheath tumors are almost
equally distributed between the sexes.
Most malignant peripheral nerve sheath tumors arise
in association with major nerves. The most frequently
affected nerves include the sciatic nerve and the sacral
and brachial plexus. Consequently, most cases are located
within the soft tissue of proximal parts of the extremities,
in the soft tissues of the buttocks, and in the shoulder
region.3,143,197 Skeletal involvement usually stems from
secondary invasion into the adjacent bone (Figs. 14-33
and 14-34).108 Primary malignant peripheral nerve sheath
tumors in bone are extremely rare. Bullock et al.104
reported such a primary tumor of the distal femur. After
reviewing the literature, they found only 18 examples in
bone, 15 of which occurred in the mandible or maxilla.
In view of these data, primary intraosseous malignant
peripheral nerve sheath tumor is one of the rarest neo-
plasms of bone.
Microscopically, a typical malignant peripheral nerve
sheath tumor is a spindle-cell sarcoma that resembles a
fibrosarcoma in regard to its overall cellular structure and
architectural organization. In contrast to typical fibrosar-
coma, most malignant peripheral nerve sheath tumors are
histologically of high grade and show prominent nuclear
atypia. On longitudinal sections, the tumor cells are spin-
dled, blunt ended, or comma shaped (Fig. 14-35). Per-
pendicularly cut nuclei are oval or round. Similar to
fibrosarcoma, the cells are arranged in fascicles with an
occasional herringbone pattern. Alternating hypocellular
ERRNVPHGLFRVRUJ
and hypercellular fascicles may be present. In addition,
various peculiar organizational patterns that most likely
reflect an attempt to recapitulate some neural structures
may be seen (Fig. 14-36). They include nodular, whorled,
and palisading structures. Focal divergent differentiation
is present in 10% to 15% of these tumors.125,126,128 Islands
of mature cartilage or bone are the most frequent
examples of this phenomenon. On rare occasions, foci
of skeletal muscle differentiation (malignant Triton
tumors) or glandular mucin-secreting structures can be
seen.117,131,174,212 Focal epithelioid features are frequently
seen, but a predominantly epithelioid appearance is a rare
phenomenon in these tumors.160 The spectrum of malig-
nant peripheral nerve sheath tumors ranges from tumors
with deceptively benign appearances that resemble neu-
rofibroma, except that they are hypercellular and show
mitotic activity, to highly pleomorphic tumors whose
neural origin cannot be identified microscopically. The
latter are diagnosed as malignant peripheral nerve sheath
tumors because they arise in major nerves or occur in a
setting of neurofibromatosis.
Immunohistochemically, malignant peripheral nerve
sheath tumors are focally positive for neural markers
such as S-100 protein, Leu-7, neurofilament protein,
and myelin basic protein.121,128,140,147,160,168,209,211 Although
immunohistochemical evidence of neural differentiation
can be documented in more than 50% of patients, it is
typically only focal. S-100 protein is the marker most
often used. Neuron-specific enolase cannot be used alone
as evidence of neural differentiation because it is fre-
quently positive in many other lesions. S-100 protein is
usually only focally positive, and strong uniform positiv-
ity for this marker is rare in malignant peripheral nerve
sheath tumors. In cases of strong uniform positivity for
S-100 protein, other spindle-cell neoplasms (primarily
cellular schwannoma) should be excluded before the
diagnosis of malignant peripheral nerve sheath tumor is
rendered.
Ultrastructurally, malignant peripheral nerve sheath
tumors have some of the features seen in benign periph-
eral nerve sheath tumors (Fig. 14-37).7,110-112,129,140,202
However, the ultrastructural examination of these lesions
often is disappointing and shows undifferentiated mesen-
chymal cells. Ultrastructural features suggestive of neural
differentiation include long, branching, and interdigitat-
ing cytoplasmic processes that contain microtubules and
neurofilaments. The extracellular matrix contains basal
lamina (frequently incomplete), collagen with focal fea-
tures of long-spaced collagen, and amianthoid fibers.
Malignant peripheral nerve sheath tumors are highly
aggressive and have a high propensity to metastasize to
distant sites, predominantly the lung, liver, and oddly
enough, bone. In fact, most malignant peripheral nerve
sheath tumors that involve the skeleton either are meta-
static or represent secondary involvement of bone by a
soft tissue lesion. Regional lymph node metastases are
extremely unusual in malignant peripheral nerve sheath
tumors. Several studies have shown that malignant
peripheral nerve sheath tumors associated with neurofi-
bromatosis are more aggressive than their sporadic coun-
terparts not associated with neurofibromatosis, but others
believe that the clinical behavior of both variants is
1032 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C
FIGURE 14-33  ■  Malignant peripheral nerve sheath tumor: radiographic features. A, T1-weighted coronal magnetic resonance image
(MRI) showing large malignant peripheral nerve sheath tumor of low signal intensity in brachial plexus. B, T1-weighted coronal
postcontrast MRI showing malignant peripheral nerve sheath tumor with heterogeneous signal enhancement in brachial plexus.
C, Axial computed tomogram showing large sacral malignant peripheral nerve sheath tumor.

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1033
A B
FIGURE 14-34  ■  Malignant peripheral nerve sheath tumor: radio-
graphic features. A and B, Anteroposterior and lateral radio-
graphs of tibia show erosion caused by malignant peripheral
nerve sheath tumor in the overlying soft tissue.
similar. In several reports, the survival rates of patients
with solitary malignant peripheral nerve sheath tumors
were approximately twice as high (approximately 40%
to 50% 5-year survival) as those for patients with malig-
nant peripheral nerve sheath tumors associated with
ERRNVPHGLFRVRUJ
neurofibromatosis (approximately 20% to 30% 5-year
survival).100,119,120,122,125,126,133,136,166,192,198,199,207,210
Skeletal Anomalies.  The skeleton is affected in approx-
imately 80% of patients with neurofibromatosis. Skeletal
changes range from minor erosive or pressure defects
through localized dysplasia to major disfiguring anoma-
lies caused by abnormal bone patterning (Figs. 14-19,
14-27, 14-38, and 14-40).106,107,141,144,150,157,179 The erosive
defects are caused by soft tissue neurofibromas develop-
ing within nerves pressing through bone foramina or
involving nerves in the vicinity of bone.107 These types of
abnormalities are typically seen in the vertebral column
(enlargement of intervertebral foramina, pressure defects
of vertebral bodies, or both conditions) and in the ribs
(Figs. 14-26 and 14-27).106,107 Such abnormalities may
also be present in other parts of the skeleton. Scoliosis is
a frequent axial anomaly and is present in approximately
50% of patients. Scoliosis in neurofibromatosis typically
involves the lower thoracic region and is associated with
sharp angulation that can cause paraplegia. Frequently, it
is associated with kyphosis predominantly affecting the
cervical segment.
The most frequent skeletal anomaly is macrocrania,
which can be documented in nearly 90% of children with
neurofibromatosis. More significant changes in these
regions include the congenital absence of a portion of the
orbit or sphenoid bone or a defect involving the cranial
vault. Congenital calvarial defects adjacent to the lamb-
doidal suture are most frequent and often involve the left
side (Fig. 14-38). Another frequent site of this anomaly
is the posterior aspect of the sagittal suture.
Gracile or twisted-ribbon bones are the typical anom-
alies observed in the long bones (Fig. 14-39). Other
anomalies of the appendicular skeleton include pseudar-
throsis, focal overgrowth (gigantism), or dwarfism. The
anomalies of the long tubular bones may be caused by
abnormal appositional growth.176 The periosteum seems
to show abnormal attachment to the bone surface. In
response to trauma and subperiosteal hemorrhage, it is
easily detached from the underlying bone, causing large
subperiosteal hematomas. Poor callus formation and fre-
quent pseudarthrosis of long tubular bones complicating
fractures can also be related to these peculiar features
of malfunctioning periosteum in neurofibromatosis. The
mechanism of pseudarthrosis in neurofibromatosis,
however, is not clear and cannot be related only to trauma
because many of these changes represent congenital
defects (Fig. 14-40). Congenital pseudarthrosis usually
occurs in the tibia and in the bones of the forearm.
Patients with neurofibromatosis tend to develop mul-
tiple nonossifying fibromas that predominantly affect
the metaphyseal parts of the long tubular bones (Fig.
14-41).165,176,192 Originally, Jaffe-Campanacci syndrome,
characterized by multifocal extensive nonossifying fibro-
mas that may involve the mandible and vertebrae and
are associated with café au lait pigmentation, various
nonskeletal anomalies, and mental retardation, was con-
sidered to be distinct from neurofibromatosis. More
recent clinical data, however, indicate that patients with
Jaffe-Campanacci syndrome may have other stigmata of
Text continued on p. 1038
1034 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-35  ■  Malignant peripheral nerve sheath tumor: microscopic features. A, Intermediate power photomicrograph showing
spindle-cell variant of malignant peripheral nerve sheath tumor (×200). B, High power photomicrograph showing compact fascicles
of malignant spindle cells with prominent mitotic activity (×400). C, Intermediate power photomicrograph showing epithelioid
malignant peripheral nerve sheath tumor (×200). D, High power photomicrograph showing epithelioid variant of malignant peripheral
nerve sheath tumor (×400) (A-D, hematoxylin-eosin).

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1035

A B

C D
FIGURE 14-36  ■  Triton variant of malignant peripheral nerve sheath tumor: microscopic features. A, Low power photomicrograph
showing pleomorphic malignant peripheral nerve sheath tumor (×100). B, Intermediate power photomicrograph showing pleomor-
phic malignant peripheral nerve sheath tumor with spindle and epithelioid components, same case as A (×200). C, Intermediate
power photomicrograph showing strong expression of Myo-D as revealed by immunohistochemistry (×200). D, Intermediate power
photomicrograph showing strong expression of desmin (×200). (A and B, hematoxylin-eosin.)

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1036 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

B
FIGURE 14-37  ■  Malignant peripheral nerve sheath tumor: ultrastructural features. A, Cytoplasm of malignant Schwann cell contain-
ing arrays of interdigitating cytoplasmic processes; (×7500). B, Higher magnification of A showing interdigitating cytoplasmic pro-
cesses. (×18,000).

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1037

B
FIGURE 14-38  ■  Neurofibromatosis: radiographic features. A, Lateral radiograph of skull in young adult shows geographic areas of
radiolucency in occipital region. B, Anteroposterior radiograph of skull shows large frontoparietal area of sharply defined radiolu-
cency representing absence of calvarial bone.

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1038 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B
FIGURE 14-39  ■  Neurofibromatosis: radiographic features. A and B, Anteroposterior and lateral radiographs of leg of child with con-
genital pseudarthrosis of tibia and lateral bowing deformity of fibula.

neurofibromatosis type 1.105,175 It may well be that this
syndrome represents a unique, previously unrecognized,
manifestation of neurofibromatosis. (See Chapter 9.)
Neurofibromatosis Type 2
Neurofibromatosis type 2 occurs less frequently than
type 1, making up approximately 10% of all neurofibro-
matosis patients. It has an autosomal dominant pattern
of transmission with a 95% penetrance.151,167 The gene
that predisposes to the condition is located on chromo-
some 22 and codes for a product designated merlin
(moesin-ezrin-radixin–like protein).94,151,201 The protein
plays a role in binding of the cytoskeleton matrix to the
cell membrane and may have the overall biologic activity
of a growth suppressor.151,162,190 Neurofibromatosis type 2
is linked to mutations that inactivate the NF2 gene (Fig.
14-42).94,101,102,152,203 Neurofibromatosis type 2 is diag-
nosed if an individual has bilateral masses in the eighth
cranial nerve (Fig. 14-43).98,123,134,153,163,164,173,187 It may also
be diagnosed if a first-degree relative has neurofibroma-
tosis type 2 and a unilateral vestibular nerve mass is
present, or if two of the following lesions can be identi-
fied: neurofibroma, meningioma, glioma, schwannoma,
ocular juvenile posterior subcapsular ventricular opacity,
or cerebral calcifications (Table 14-3).
The typical clinical presentation is the onset of tin-
nitus or hearing loss during adolescence or early adult
life because of the development of bilateral acoustic
schwannomas. They typically involve the vestibular
portion of the eighth cranial nerve. Café au lait spots and
neurofibromas are rare and less developed or even com-
pletely absent in neurofibromatosis type 2. Patients
affected with this syndrome also have an increased risk
for other central nervous system tumors. They include
schwannomas of other cranial nerves and cutaneous
tissue, meningioma, ependymoma, and glioma (Figs.
14-43 and 14-44). Schwannomas in neurofibromatosis
type 2 are similar to the more common solitary sporadic
schwannomas.
Neurofibromatosis Type 3
(Schwannomatosis)
Neurofibromatosis type 3 is the third recognized
form of neurofibromatosis characterized by multiple

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1039

A B
FIGURE 14-40  ■  Neurofibromatosis: radiographic features. A and B, Severe bowing deformity of radius and remnant of proximal ulna
in patient with congenital pseudarthrosis of forearm. C, Clinical photograph showing deformity of left forearm in patient with
neurofibromatosis.

nonvestibular, nonintradermal schwannomas.97,109,180 The
schwannomas may involve the spinal nerves (most
common), the peripheral soft tissues, or the nonvestibu-
lar cranial nerves (least common). Patients who exhibit a
SMARCB1 mutation may also develop meningiomas in
addition to schwannomas.170,189 In sharp contrast to the
other two, far more common, neurofibromatosis sub-
types, the vast majority of neurofibromatosis type 3 cases
result from new mutations, with only approximately 15%
having a verified familial history. The inactivation of two
genes on chromosome 22, the NF2 gene and its neighbor
gene SMARCB1, by four hits in three steps has been
proposed as a causative mechanism of neurofibromatosis
type 3 (Fig. 14-45).193 The predisposing event is a germ-
line mutation in SMARCB1 (hit 1), which represents the
first step of the sequence and is followed by a somatic loss
of a portion of chromosome 22 (step 2) that contains the
second SMARCB1 allele and one of the neighboring NF2
alleles (hits 2 and 3). The somatic mutation of the remain-
ing NF2 allele (hit 4) is the concluding third step that
causes the loss of function of the two involved genes. The
four hit, three step mechanism of SMARCB1 and NF2
inactivation is considered to be the dominant genetic
mechanism causing neurofibromatosis type 3.
Neurofibromatosis type 3 criteria are categorized as
either definitive or possible, with an additional set of cri-
teria for segmental schwannomatosis (Table 14-3).97,98,180
A diagnosis of definitive schwannomatosis requires
either two (or more) nonintradermal schwannomas (one
of which must be histologically confirmed) in a patient
older than age 30 years, or one histologically confirmed
schwannoma plus a first-degree relative with defini-
tive schannomatosis (by the first set of criteria). Pos-
sible schwannomatosis can be diagnosed if a patient
meets any one of three sets of criteria: (1) two (or more)
nonintradermal schwannomas (one of which must be

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1040 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A
FIGURE 14-41  ■  Neurofibromatosis: radiographic features. A, Plain radiograph of both knees of an 11-year-old girl with neurofibro-
matosis. Multiple radiolucent lesions in metaphyses of femora and tibiae bilaterally represent nonossifying fibromas. B, Lateral
radiograph of left knee of patient shown in A emphasizes eccentric location of nonossifying fibromas.

NF2
Exon 10

Exon 11
Exon 12
Exon 13
Exon 14

Exon 15
Exon 16
Exon 1
Exon 2
Exon 3
Exon 4

Exon 5
Exon 6
Exon 7
Exon 8

Exon 9

Chr 22
29999544

30079904

13
12
11.2 11.1 cen tel
11.1 11.2
12.1 NF2
12.3 12.2 NF2-MERLIN
13.2 13.1
13.3 1 595 aa
Unique N-terminal domain
FERM domain
Ezrin / radixin / moesin, C-terminal domain
FIGURE 14-42  ■  Molecular mechanisms of neurofibromatosis type 2. Chromosomal location, exonal structure, and functional domains
of the NF2 gene.

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1041

A B

C D
FIGURE 14-43  ■  Neurofibromatosis type 2: radiographic features. A, T1-weighted axial postcontrast magnetic resonance image (MRI)
showing the definitive bilateral vestibular schwannomas of neurofibromatosis type 2. Additional tumors seen in this image are a
middle fossa meningioma and a contralateral optic nerve sheath meningioma. B, T1-weighted coronal postcontrast MRI showing
multiple meningiomas, which are frequently seen in neurofibromatosis type 2. C, T1-weighted axial postcontrast MRI showing a
spinal cord ependymoma. Spinal cord ependymoma is the most common intramedullary spinal cord tumor in neurofibromatosis
type 2. D, T2-weighted axial MRI showing metallic artifact associated with a cochlear implant commonly seen in MRI of neurofibro-
matosis type 2 patients. The signature lesions of neurofibromatosis type 2, bilateral vestibular schwannomas, often lead to hearing
loss that can be treated via cochlear implants.

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1042 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-44  ■  Neurofibromatosis type 2: radiographic features. A, T1-weighted sagittal postcontrast magnetic resonance image
(MRI) showing multiple spinal meningiomas. B, T2-weighted sagittal MRI of the same patient as A, highlighting the dura-based
origin of spinal meningiomas. C, T1-weighted sagittal postcontrast MRI showing multiple spinal schwannomas. D, T1-weighted
coronal postcontrast MRI, same patient as C, highlighting the bilateral nature of the peripheral nerve sheath tumors in this patient.

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1043

cen
24129149 Germline Somatic
Exon 1
Exon 2
Exon 3 Hit 2
Exon 4
Exon 5 m – m

SMARCB1
Loss 22 NF2 mutation
Exon 6
Hit 3 Hit 4
Exon 7
Hit 1
Chr 22 + – m1
13 Exon 8
m +
12 Exon 9
11.2 11.1 24176705
11.1 SMARCB1 tel

6 Mb
12.1 11.2
12.3 NF2 cen
12.2 29999544 Schwannoma 1
13.2 13.1 Exon 1
13.3
Exon 2
Exon 3 + +
Exon 4
m – m
Exon 5
Exon 6 Loss 22 NF2 mutation
NF2

Exon 7
Exon 8
Exon 9
Exon 10
Exon 11 + – m2
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16
30079904 Schwannoma 2
A tel
B
FIGURE 14-45  ■  Molecular mechanisms of schwannomatosis (neurofibromatosis type 3). A, Chromosomal location and exonal struc-
tures of the vicinal SMARCB1 and NF2 genes on chromosome 22 involved in neurofibromatosis type 3. B, Four-hit mechanism
involving germline mutations of the SMARCB1 gene followed by somatic deletions of the remaining SMARCB1 copy and mutations
of NF2, combined with loss of the remaining NF2 allele, resulting in the complete inactivation of the two genes in multifocal
schwannomas.

histologically confirmed) in a patient younger than age
30 years; (2) two (or more) nonintradermal schwanno-
mas (one of which must be histologically confirmed) in a
patient older than age 45 years; or (3) imaging evidence of
a schwannoma plus a first-degree relative with definitive
schwannomatosis. A diagnosis of segmental schwanno-
matosis is appropriate when a patient meets the criteria
for either definitive or possible schwannomatosis, but the
schwannomas are confined to a single limb or to five or
fewer contiguous spine segmental levels.
Clinically the disease affects men and women with
equal frequency and presents with multiple, often painful,
schwannomas involving skin and soft tissue. Some patients
may present with a striking segmental involvement.
Although the development of multiple skin and soft tissue
schwannomas is a hallmark of the disease, some patients
may develop tumors in the central cranial and spinal
nerves (Fig. 14-46).
VON HIPPEL-LINDAU DISEASE
In 1894, Collins reported two siblings who, in retrospect,
were affected by a disorder now termed von Hippel-
Lindau disease.113 In 1904, von Hippel described similar
patients, and finally in 1927 Lindau proposed the sys-
temic nature of the disorder and provided the link
between the hereditary retinal angiomas and central
nervous system hemangioblastomas.159,205 Von Hippel-
Lindau disease is an autosomal dominant disorder char-
acterized by germline mutations of the VHL gene on
chromosome 3p25-26 (Fig. 14-47).148,186,206 Based on the
pattern of mutations in the VHL gene, the disease is
subdivided into von Hippel-Lindau disease subtype 1 and
2, characterized by deletions associated with nonsense
and missense mutations and pure missense mutations,
respectively. Type 2 is subdivided into A, B, and C forms
based on the patterns of missense mutations. The indi-
vidual subtypes have different risk levels for tumor devel-
opment at various topographic sites. Physiologically, the
VHL gene encodes two alternative proteins via different
inframe start codons. The longer form contains 213
amino acids and the short form consists of amino acid
residues 54 to 213 and lacks the acidic repeat domain.
The three dimensional structure of the VHL protein
reveals the presence of two structural subdomains termed
α and β. The α domain binds and activates elongin C,
cullin 2, elongin B, and Rbx1. The β domain is important

ERRNVPHGLFRVRUJ
1044 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-46  ■  Schwannomatosis (neurofibromatosis type 3): radiographic features. A-D, T1-weighted sagittal postcontrast mag-
netic resonance images showing spinal schwannomas at multiple vertebral levels in schwannomatosis.

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 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1045

A
Chr 3 VHL

Exon 1

Exon 2

Exon 3
26 25
24.3 VHL
24.2 10183318

10195354
24.1
22 23
21.3
21.2
21.1 VHL
14.3 14.2
14.1 1 213 aa
13
von Hippel-Lindau disease tumor suppressor, beta/alpha domain
12
11.1 11.2
11.2 11.1
12
13.1
13.2
13.3
21
B Normoxia PHD OH
22 VHL HIF
23 O2 OH
24
25.2
25.1
25.3 EloC Proteasome
26.1 Ubiquitylation
26.2
26.3 O2 HIF
27
28
29 VEGF
HIF PDGF
PHD VHL TGF
HIF EPO
Hypoxia EloC and others

Endothelial cells
C
Pericyte

PDGF

TGF-
VEGF, TGF- Blood vessel
?
?
EPO Nuclear HIF VHL+/-
tumor cell

MMPs ?
TIMPs SDF-1
FIGURE 14-47  ■  Molecular mechanisms of von Hippel-Lindau disease. A, Chromosomal location, exonal structure, and functional
domains of the VHL gene. B, Role of pVHL in the hypoxia inducible factor (HIF) pathway. The VHL protein is an essential part of an
ubiquitin ligase protein complex that includes elongin C (EloC) and other partners. Under normal oxygenation, HIFα is hydroxylated
on two proline residues by prolyl hydroxylase 2 (PHD2), then conjugates to pHVL. It targets the complex for ubiquitination and
proteasomal degradation. Under hypoxic conditions, HIFα is stabilized, binds to HIF1β, and stimulates the expression of downstream
targets such as vascular endothelial growth factor (VEGF), platelet-derived growth factor β (PDGFβ), transforming growth factor α
(TGFα), and erythropoietin (EPO). The VHL mutations block the degradation pathway and mimic the effects of the hypoxic condi-
tions, stimulating the expression of multiple growth factors. (A and B, Modified and reprinted with permission from Richard S, et al:
Semin Cancer Biol 23:26–37, 2013.) C, Altered expression of HIF-responsive growth factors and proteases in pVHL-defective cells. The
VHL mutations block the degradation pathway and mimic the effects of the hypoxic conditions, stimulating the expression of multiple
growth factors. (C, Modified and reprinted with permission from Kaelin WG Jr: Annu Rev Pathol Mech Dis 2:145–173, 2007.)

ERRNVPHGLFRVRUJ
1046 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone
for binding to hypoxia-inducible factor 1α (HIF1α). The
most significant binding substraits of the VHL protein
are the alpha subunits (HIF1-3α) of the heterodimeric
transcription factor HIF (Fig. 14-47). The deregulation
of the HIF pathway appears to be a major functionally
significant target of VHL mutations, but there are many
alternative interacting proteins, referred to as the pVHL-
associated proteins, that play contributory roles to its
biologic effects (Fig. 14-47).
Von Hippel-Lindau disease is characterized by the
frequent development of specific tumors in selected topo-
graphic sites. Affected individuals develop hemangioblas-
tomas in the central nervous system, clear cell carcinomas
of the kidney, pheochromocytomas of the adrenal gland,
extraadrenal paragangliomas, endolymphatic sac tumors,
pancreatic microcystic adenomas, and pancreatic neuro-
endocrine tumors. This description is restricted to skel-
etal manifestations of von Hippel-Lindau disease. The
hallmark neoplasm is hemangioblastoma. In addition,
another characteristic von Hippel-Lindau disease tumor,
papillary endolymphatic sac tumor, originates within the
petrous portion of the temporal bone; hence the rel-
evance of von Hippel-Lindau disease to the field of bone
pathology.138
Hemangioblastoma
Hemangioblastoma is the hallmark tumor of von Hippel-
Lindau disease and most commonly arises in the cerebel-
lum, spinal cord, and brain stem. They are significantly
less common in the supratentorial compartment (such as
the cerebral hemispheres and sellar region). Very rarely,
they may arise in extraneural sites.
Radiographic Imaging
The characteristic imaging presentation is that of a
spherical, avidly contrast-enhancing mass. Size varies
from minute, punctate lesions, most commonly seen in
the cerebellum, spinal cord, and spinal cord nerve root-
lets, to large tumors that are often accompanied by an
even larger cyst formation (Fig. 14-48). In the latter
instance, it is often the enlargement of the cyst that
incites clinical symptoms, secondary to mass effect com-
pression of adjacent structures, and leads the patient to
seek clinical attention.
In all anatomic locations, hemangioblastomas invari-
ably closely approach the pial surface at some point
along their circumference, and small tumors are invari-
ably located very superficially, immediately subjacent to
the pia.
Histologic Findings
Hemangioblastomas are highly vascular tumors that typi-
cally display the full range of blood vessel caliber, from
large to medium to small arteries and veins. However,
the signature vessel is the capillary (hence capillary heman-
gioblastoma), and all hemangioblastomas show a very rich
capillary bed. The relative prominence of the capillary
network varies depending on the degree of engorgement
present in tissue sections. The intervening spaces between
ERRNVPHGLFRVRUJ
blood vessels are occupied by lipidized stromal cells,
which constitute the neoplastic element of the tumor
(Fig. 14-49). This component of the tumor typically
exhibits reactivity for inhibin-α, which is often used as a
distinguishing marker to separate hemangioblastoma
from metastatic renal cell carcinoma, which is also a
highly vascular tumor with greatly increased incidence in
von Hippel-Lindau disease (Fig. 14-49).
Papillary Endolymphatic Sac Tumor
As the name implies, the endolymphatic sac tumor, also
referred to as Heffner tumor or aggressive middle ear papil-
lary tumor, originates in close association with the endo-
lymphatic sac, which, embryologically, is a neural crest
derivative and is located subjacent to the posteromedial
surface of the temporal bone.99,183,195 These two features
explain many of the most important aspects of endolym-
phatic sac tumor, such as clinical presentation, radio-
graphic features, and immunophenotype. Endolymphatic
sac tumors are locally aggressive, bone erosive tumors
and, by virtue of their origin in immediate proximity to
the inner ear structures, most commonly present with
hearing loss, tinnitus, and vertigo.
Radiographic Imaging
Papillary endolymphatic sac tumor, which originates
within the petrous portion of the temporal bone, erodes
the bone as it grows. Individual tumors may expand in
one or in several directions. One classical presentation is
erosive growth out of the temporal bone into the medi-
ally located cerebellopontine angle (Fig. 14-50). The dif-
ferential diagnosis of cerebello-pontine angle mass always
includes endolymphatic sac tumor.
Histologic Findings
Endolymphatic sac tumors typically exhibit a papil-
lary and glandular architecture, with a columnar epi-
thelium covering a fibrovascular stromal core.99,195 The
architecture is similar to that of choroid plexus papil-
loma, which can also present as a cerebellopontine angle
mass, leading to potential misdiagnosis of papillary
endolymphatic sac tumor as choroid plexus papilloma
(Fig. 14-50). Moreover, because papillary endolymphatic
sac tumor originates from the neural crest–derived endo-
lymphatic sac, the tumor can express neural antigens,
such as glial fibrillary acidic protein (GFAP), similar
to choroid plexus papilloma. Resolution of this dif-
ferential diagnosis is quite easy, however, and requires
only the examination of the preoperative CT and MRI
studies, which will show erosion of the temporal bone
in endolymphatic sac tumor, but not in choroid plexus
papilloma.
Treatment and Outcome
The treatment for endolymphatic sac tumor is surgical
resection, which can result in a cure in many cases. Local
recurrence can be treated with radiation therapy, with a
50% cure rate.
 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1047

A B

C D
FIGURE 14-48  ■  Hemangioblastoma: radiographic and microscopic features. A, T1-weighted axial postcontrast magnetic resonance
image (MRI) showing small hemangioblastoma of the right temporal lobe (arrow). B, T1-weighted coronal postcontrast MRI showing
classical “cyst with enhancing mural nodule” appearance of cerebellar hemangioblastoma. C, T1-weighted sagittal postcontrast MRI
showing multiple hemangioblastomas located in the sellar region, cerebellum, and brain stem. D, T1-weighted sagittal postcontrast
MRI showing multiple minute hemangioblastomas of the spinal cord.

ERRNVPHGLFRVRUJ
1048 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone

A B

C D
FIGURE 14-49  ■  Hemangioblastoma: microscopic features. A, Low power photomicrograph showing the characteristic highly vascular
architecture of hemangioblastoma with blood vessels of all sizes (×100). B, Intermediate power photomicrograph showing the dense
cellularity of hemangioblastoma (×200). C, High power photomicrograph showing characteristic foamy stromal cells interspersed
between a rich capillary network (×400). D, High power photomicrograph showing strong expression of inhibin-α by stromal cells
as revealed by immunohistochemistry (×400). (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone 1049

A B

C D
FIGURE 14-50  ■  Papillary endolymphatic sac tumor: radiographic and microscopic features. A, T1-weighted axial postcontrast mag-
netic resonance image (MRI) showing invasive tumor of the left sphenoid bone. B, Axial computed tomogram showing extensive
destruction of the left sphenoid bone. C, Intermediate power photomicrograph of endolymphatic sac tumor showing commonly
occurring papillary architecture (×100). D, Higher magnification photomicrographs showing expression of glial fibrillary acidic protein
(GFAP) in papillary endolymphatic sac tumor as revealed by immunohistochemistry (×200). (C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1050 14  Neurogenous Tumors and Neurofibromatosis Affecting Bone
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CHAPTER OUTLINE
ANEURYSMAL BONE CYST
Primary Aneurysmal Bone Cyst
Secondary Aneurysmal Bone Cyst
Soft Tissue Aneurysmal Bone Cyst
SOLITARY BONE CYST
Cystic lesions of bone represent a heterogeneous group
of entities in which the common feature is de novo for-
mation of unilocular or multilocular cavities filled with
blood, serous fluid, mucinous content, or keratin debris.
Secondary cystic changes in preexisting conditions, such
as in chondroblastoma, fibrous dysplasia, and giant-cell
tumor, are discussed in conjunction with those underly-
ing conditions. The development of secondary aneurys-
mal bone cyst engrafted on other lesions is also discussed
in this chapter.
ANEURYSMAL BONE CYST
The term aneurysmal bone cyst was introduced by Jaffe and
Lichtenstein.26,27,35 In their words “the term aneurysmal
relates to a sort of blowout distention of the contour
of the affected bone and the term bone cyst relates to
the fact that it represents mainly a blood-filled cavity.”
They defined this process in bone as a distinct lesion
separate from giant-cell tumor and other entities con-
taining giant cells.
Aneurysmal bone cyst is a multiloculated cystic lesion
that almost always arises in bone and is also, although
rarely, observed as a secondary phenomenon in certain
soft tissue lesions.6,50,68 Most likely, it is initiated by
an “injury” to the rich capillary network of the pre-
cursor lesion, culminating in an expansile destructive
process caused by capillary pressure of the extravasated
blood.11,30,34,35 Measurements of blood pressure in the
cysts, the absence of clotting in the venules, and veno-
graphic studies indicate that the cysts are actively con-
nected with the host capillary network.7,11,30 It has been
postulated that intraosseous hemorrhage can provoke
either a solid reactive lesion in the form of a giant-cell
reparative granuloma or an aneurysmal bone cyst. Hence,
some have proposed the term solid aneurysmal bone cyst
for lesions that have large areas of solid tissue with fea-
tures of giant-cell reparative granuloma and occur in sites
typical for aneurysmal bone cyst.16,28,55 Lesions that do
not develop a blowout component may represent an early
ERRNVPHGLFRVRUJ
C H A P T E R 1 5 
Cystic Lesions
INTRAOSSEOUS GANGLION
EPIDERMAL INCLUSION CYST AND
DERMOID CYST
stage of the process (i.e., are aneurysmal bone cysts in
statu nascendi). Both benign and malignant bone lesions
are prone to develop aneurysmal bone cysts as second-
ary phenomena superimposed on preexisting conditions.
These lesions are referred to as secondary aneurysmal
bone cysts.33,36
Cytogenetic studies demonstrating clonal rearrange-
ments of chromosomal bands 16q22 and 17p13 in at least
some aneurysmal bone cysts have raised doubts about the
reactive nature of these lesions.5,23,48,57,69,71 In fact, recent
molecular studies have shown that t(16;17) (q22;p13)
creates a chimeric gene in which a promoter region of
the osteoblast cadherin (CDH11) gene mapping to 16q22
is juxtaposed to the ubiquitin-specific protease (USP6)
gene mapping to 17p13 (Fig. 15-1). Several variants of
CDH11-USP6 fusion transcripts as well as alternative
rearrangements of these genes were identified in a subset
of primary aneurysmal bone cysts but not in secondary
aneurysmal bone cysts.44 The chimeric CDH11-USP6
gene consists of the noncoding exon 1 and 2 of CDH11
fused to the entire USP6 coding sequence. The fusion
breakpoints in various splicing variants are after the tran-
scription initiation site of the CDH11 gene. The break-
point of the second fusion partner is before the USP6
ATG transcription initiation signal, which results in
up-regulation of USP6 ubiquitin-specific protease. USP6
has a high degree of homology to TBCID3 and USP32
genes, from which it evolved.37,49 It has also been docu-
mented that the presence of TBC1D3 and TBC domains
is critical for the transforming activity of the USP6
protein.43 Several additional rearrangements of the
CDH11 gene with alternative fusion partners were sub-
sequently identified.18,29,45-47 They involve t(1;17)(p34.1-
34.3;p13) TRAP150-USP6; t(3;17)(q21;p13) ZNF9-USP6;
t(9;17)(q22;p13) OMD-USP6; and t(17;17)(p13;q21)
COL1A1-USP6. The mechanisms responsible for the
oncogenic effects of these fusion genes are similar to
those seen with CDH11-USP6. In all of these chimeric
genes, the USP6 coding sequences are juxtaposed to the
promoter regions of the alternative translocation part-
ners. In addition, rearrangements of the USP6 gene with
1055
1056 15  Cystic Lesions

16q22 CDH11
1 2

3 45 6 12 13
7 8 9 10 11

1 2 17p13 USP6
1 2

3 89 13 14 23 24 25 26 30
4 5 6 7 10 11 12 15 16 17 18 19 20 21 22 27 28 29

1 2

promoter

1 23 89 13 14 23 24 25 26 30
4 5 6 7 10 11 12 15 16 17 18 19 20 21 22 27 28 29

CDH11 portion USP6 portion

CDH11 protein CDH11-USP6

PFAM: Type 1 1 1 TBC UBP

CA CA CA CA CA Cadherin-C
Type 2 1 TBC UBP
Cadherin Cadherin-C
terminal Type 3 1 2 1 TBC UBP
USP6 protein Type 4 1 2 TBC UBP
TBC-RabGAP UCH-2-3 Type 5 1 2 1 TBC UBP

TBC/RabGAP Ubiquitin carboxyl-terminal hydrolases

B C
FIGURE 15-1  ■  Molecular structure of breakpoints associated with t(16;17) (q22; p13). A, Exon-intron structure of the CDH11 and
USP6 genes. Large solid arrows indicate the most frequent locations of the breakpoints within introns. The molecular structure of
the chimeric CDH11-USP6 gene, which include the promoter region and untranslated exon 1 and 2 of the CDH11 gene and the entire
coding sequence of the USP6 gene. The number indicates exon number. B, Functional domains of the two proteins involved in the
translocation. The CDH11 gene contributes its promoter region, resulting in transcriptional up-regulation of its fusion partner, the
USP6 gene. The USP6 protein contains TBC/GAP domain involved in Rab/Ypt GTPase signaling and the UBP domain with high
degree of homology to its ancestor genes, TBC1D3(PRC17) and USP32, respectively. C, Predicted structures of fusion transcripts
encoded by the chimeric CDH11-USP6 genes.

SS18 typically involved in the development of synovial
sarcoma have also been reported in solid variants of aneu-
rysmal bone cysts.20 Some of these translocations modu-
late the production of matrix metalloproteinases and
upregulate NFκB. These findings clearly indicate that at
least some aneurysmal bone cysts are true neoplasms with
identifiable oncogene and promoter gene mechanisms of
development. 5,57
Primary Aneurysmal Bone Cyst
Definition
This term is used to describe a peculiar lesion of bone that
is characterized by the presence of spongy or multilocu-
lar cystic tissue filled with blood. The process is benign
in nature, but it is locally destructive and has a high
propensity for recurrence. Microscopically, cystic spaces
are bordered by septa composed of a well-vascularized,
loose, fibroconnective tissue with prominent giant-cell
reaction and focal reactive bone formation. In primary,
or de novo, aneurysmal bone cysts, no underlying condi-
tion can be identified radiographically or microscopically.
Incidence and Location
Aneurysmal bone cyst is relatively rare, accounting for
approximately 2.5% of all primary bone tumors. The
male-to-female sex ratio is approximately 1 : 1. The age
distribution is strikingly different from that of giant-cell
tumor, and almost 80% of the lesions occur in skeletally
immature patients who are younger than age 20 years
(Fig. 15-2). The peak incidence of this lesion is during
the second decade of life. An aneurysmal bone cyst may
affect any bone with similar frequency. Hence, its almost
uniform skeletal distribution is a unique feature among
bone tumors.8,13,14,21,30 Aneurysmal bone cyst has a slight
predilection for the craniofacial bones and vertebral

ERRNVPHGLFRVRUJ

45
40
35
Distribution (%)
30
25
20
15
10
0
1 2 3 4
Age in decades
FIGURE 15-2  ■  Age-related distribution of primary and secondary aneurysmal bone cyst. Note that peak incidence of both types of
aneurysmal bone cyst is during second decade of life. Lesions in patients older than age 50 years are extremely rare.
column, which are involved in 18% and 24% of cases,
respectively. The major long tubular bones of the upper
and lower extremities account for 20% of the cases.
Approximately 12% of cases are located in the small
bones of the hands and feet. Tarsal bones are more fre-
quently involved than carpal bones. The flat bones (the
pelvis and scapula) are also well-known locations for
aneurysmal bone cyst. In the long tubular bones, the
metaphyseal areas are preferentially involved. Lesions
that involve the ends and midshaft areas of long bones
occur less frequently. The typical sites of skeletal involve-
ment are presented in Figure 15-3.
Rare examples of multiple metachronous aneurysmal
bone cysts in as many as five different skeletal sites
have been reported.56,62 Recent observation of a familial
incidence of aneurysmal bone cysts have suggested a
hereditary factor in the pathogenesis of primary aneurys-
mal bone cyst.17,32
Clinical Symptoms
Pain and swelling (occasionally very pronounced) are the
typical symptoms, which may vary in duration from
weeks to several years. Occasionally the patient has a
relatively short history of pain and swelling that progres-
sively developed over a few weeks. The vertebral lesions
typically present with a full gamut of signs and symptoms
related to compression of the spinal cord and nerves.
Radiographic Imaging
The radiographic presentation is very distinctive, and in
most cases the diagnosis of aneurysmal bone cyst is
ERRNVPHGLFRVRUJ
15  Cystic Lesions 1057
Male 46
Female 0400
Total 86
Primary
Secondary
5 6 7 8 9
suggested on the basis of x-ray features.9,12,13,14,22,54,58,60,64,67
The most characteristic feature is a blowout or ballooned
distention of the periosteum outlined by a paper-thin
shell of subperiosteal bone. The blowout or expanded
component is found overlying an area of cortical disrup-
tion. The lesion is lytic and may have a “soap-bubble,”
multiloculated pattern (Figs. 15-4 and 15-5). The radio-
graphic features are best understood if the lesion is envi-
sioned as an expansile, multilocular balloon disrupting
the adjacent bone and elevating the periosteum. The
blowout character of the lesion is usually most strikingly
demonstrated in the long bones, but it is also evident in
other locations (Figs. 15-6 to 15-8). Although rare, reac-
tive bone in the lesion can be documented radiographi-
cally as lesional calcifications.59 The lesion is typically
eccentric and involves the metaphysis (Figs. 15-7 and
15-8). Involvement of the end of a bone and midshaft
location is less frequent (Figs. 15-8 to 15-10). Aneurys-
mal bone cysts can cross joints and involve several adja-
cent bones. This typically occurs in spinal lesions, where
several adjacent vertebrae and ribs can be affected. Aneu-
rysmal bone cyst of the vertebral column typically origi-
nates in the posterior neural arch and expands unilaterally
to produce an eccentric paravertebral blowout lesion. In
some cases, destruction of vertebral bodies with partial
or complete collapse occurs (Fig. 15-8, A).
Computed tomography and magnetic resonance
imaging are extremely valuable tools in the preoperative
evaluation of the lesion because they document the mul-
tilocular cystic nature of the lesion and the fluid-fluid
levels (Figs. 15-4 and 15-5). Magnetic resonance imaging
demonstrates the expansile nature of the lesion, which is
Text continued on p. 1066
1058 15  Cystic Lesions

10 20
Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 15-3  ■  Aneurysmal bone cyst: peak age incidence and frequent sites of skeletal involvement. Most frequent sites are indicated
by solid black arrows.

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1059

B C

D
FIGURE 15-4  ■  Aneurysmal bone cyst: radiographic features. A, Anteroposterior radiograph of chest of a 5-year-old boy with aneu-
rysmal bone cyst of thoracic spine. Note blowout lesion extending from right side of spinal column. B, Computed tomogram of
lesion shown in A. Large expansile cystic lesion extends from vertebral body and lateral elements to involve adjacent rib. C, Mag-
netic resonance image (MRI) of a 14-year-old girl with aneurysmal bone cyst of posterior neural arch of upper thoracic vertebra.
Note fluid level. D, Sagittal MRI of lesion shown in C reveals multiloculation and partial collapse of vertebral body.

ERRNVPHGLFRVRUJ
1060 15  Cystic Lesions

A B

C D
FIGURE 15-5  ■  Aneurysmal bone cyst: radiographic features. A and B, Anteroposterior and lateral radiographs of distal femoral
aneurysmal bone cyst in an 18-year-old woman shows ill-defined lucent area in distal shaft. Note posterior expansion of bone
contour in B. C, Axial T1-weighted magnetic resonance image (MRI) shows fluid levels within cystic lesion. D, Sagittal MRI demon-
strates loculation in T2-weighted image and posterior expansion into adjacent soft tissue.

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 15  Cystic Lesions 1061

A B

C D
FIGURE 15-6  ■  Aneurysmal bone cyst: radiographic features. A and B, Anteroposterior and lateral radiographs of eccentric lytic lesion
in proximal tibial metaphysis of female adolescent. Completely lytic lesion shows medial expansion and is limited proximally by
growth plate. C, Plain radiograph of shoulder of a 40-year-old woman shows aneurysmal bone cyst of scapula. Note that multilocu-
lated lytic lesion involves glenoid region of scapula. D, Computed tomogram of the lesion in C shows expansile radiolucent lesion
in scapula.

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1062 15  Cystic Lesions

A B

C
FIGURE 15-7  ■  Aneurysmal bone cyst: radiographic features. A and B, Oblique and anteroposterior radiographs of aneurysmal bone
cyst of proximal ulnar shaft. Note blowout expansion with partially delimiting shell of periosteal bone. C, Computed tomogram of
lesion shown in A and B. Note cortical disruption and large soft tissue component.

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1063

A B

C D
FIGURE 15-8  ■  Aneurysmal bone cyst: radiographic features. A, Radiograph of lumbar spine in adult with aneurysmal bone cyst that
led to partial collapse of vertebral body. B, Lateral radiograph of distal femur and knee of a 19-year-old woman with huge aneurys-
mal bone cyst replacing entire distal end of femur. Note narrow zone of transition proximally and inclusion of femoral shaft end in
expansile mass (“finger-in-the-balloon” sign). C, Subperiosteal aneurysmal bone cyst of ulnar shaft that developed 4 months after
direct trauma. D, Subperiosteal aneurysmal bone cyst of tibia.

ERRNVPHGLFRVRUJ
1064 15  Cystic Lesions

A B

C D E
FIGURE 15-9  ■  Aneurysmal bone cyst in short tubular bones: radiographic features. A, Aneurysmal bone cyst involving metacarpal
bone in child. B, Aneurysmal bone cyst involving metacarpal bone in adult. C, Aneurysmal bone cyst involving phalanx in child.
Note that unfused growth plate in A and C acts as barrier to metaphyseal lesion. In contrast, metacarpal lesion B in adult extends
to bone end. D and E, Metacarpal aneurysmal bone cyst shown in T1- and T2-weighted magnetic resonance images. Bright signal
in T2-weighted image shows multiloculation to better advantage.

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 15  Cystic Lesions 1065

A B

C D
FIGURE 15-10  ■  Aneurysmal bone cyst: radiographic features. A, Lateral plain radiograph of ankle of a 12-year-old girl shows lucent
lesion of talus. B and C, Sagittal and coronal T1-weighted magnetic resonance images (MRIs) of aneurysmal bone cyst of talus show
low signal intensity, sharp circumscription, and lateral eccentric expansion. D, Sagittal T2-weighted MRI of aneurysmal bone cyst
of talus shows high signal intensity.

ERRNVPHGLFRVRUJ
1066 15  Cystic Lesions
encircled by a thin rim of periosteal bone of low signal
intensity.
Gross Findings
Aneurysmal bone cyst examined in situ appears as a
spongy or multilocular cystic lesion filled with blood
(Figs. 15-11 to 15-13). The size of the cystic spaces ranges
from less than 1 mm (spongy areas) to large cavities that
measure several centimeters. The lesion contains only a
small amount of spongy, red-brown soft tissue or thin
membranous septa. The operating surgeon frequently
encounters what appears to be a hole containing blood.
The lesion has irregular, lobulated, but sharply demar-
cated borders. The more solid or spongy tissue is usually
found peripherally within the intramedullary component.
The central portion and especially the blowout extra-
medullary component are typically composed of large
cystic spaces and blood. The extramedullary component
is sharply delineated from the surrounding soft tissue by
an elevated and expanded periosteum that has a thin shell
of reactive bone.
Microscopic Findings
The microscopic features of aneurysmal bone cyst closely
parallel the gross findings. The multilocular cystic archi-
tecture of the lesion is evident under low-power examina-
tion (Figs. 15-14 to 15-16). When curetted material is
examined, the collapsed membranous septa of distended
cystic spaces and irregular spongy fragments of tissue are
present in a background of hemorrhagic material. The
septa and more solid areas are composed of loose, fibrous
tissue that has numerous capillary channels, multinucle-
ated giant cells, inflammatory cells, and extravasated red
blood cells. In general, it mimics young granulation
tissue. Occasionally, larger, better formed vascular chan-
nels (feeding vessels) that run parallel to the long axis of
the septum can be identified. The cystic spaces typically
do not have any clearly recognizable lining, but flattened
endothelial-like cells can be present focally.3 Focal pres-
ence of endothelial cells can be documented immunohis-
tochemically.4 However, ultrastructural studies do not
confirm the presence of an endothelial lining in the cystic
spaces.61 Giant osteoclast-like cells can dominate the
picture and form irregular clusters that are usually located
in the area of extravasated red blood cells. Reactive bone
formation is almost always present focally and occasion-
ally can be very prominent. Areas of immature reactive
osteoid with prominent plump osteoblasts often raise the
suspicion of a malignant, bone-forming tumor. Osteoid
is frequently deposited in the form of long strands that
may be partly mineralized; these strands are oriented
parallel to the long axis of the septum. At the periphery,
especially within the medullary canal, solid areas of tissue
with a prominent vasculature can be present. The sur-
rounding cancellous or cortical bone shows features of
resorption with prominent osteoclastic activity. The
blowout soft tissue component is delineated by a rim of
fibrous tissue representing elevated periosteum. On its
inner surface, a shell of reactive bone with prominent
osteoblastic activity is typically present.
ERRNVPHGLFRVRUJ
Differential Diagnosis
The overall diagnostic approach should be to rule out an
underlying condition (i.e., secondary aneurysmal bone
cyst). The lesion must be sampled extensively. Any solid
areas should be submitted completely for microscopic
examination because they are likely to contain elements
of a precursor condition.
Distinction from telangiectatic osteosarcoma is the most
important diagnostic problem and may be difficult
because these two conditions have overlapping clinical
and radiographic features. The problem is further ampli-
fied by the fact that an aggressive appearance on
radiographs may suggest the incorrect diagnosis of malig-
nancy. The distinction between aneurysmal bone cyst
and telangiectatic osteosarcoma is ultimately based on
microscopic features. The presence of highly anaplastic
sarcomatous cells with atypical mitoses producing tumor
osteoid is highly diagnostic of osteosarcoma. Some clini-
coradiographic clues that are helpful in distinguishing
these two conditions are as follows:
1. Telangiectatic osteosarcoma is uncommon and very
rarely involves the vertebral column, small bones of
the hands or feet, or craniofacial bones, where
aneurysmal bone cyst is common.
2. Aneurysmal bone cyst typically has a blowout
appearance on radiographs. Even expansile, highly
destructive lesions usually show an eggshell-like
rim of reactive periosteum.
Conventional osteosarcoma rarely exhibits focal fea-
tures of telangiectatic osteosarcoma. Moreover, a second-
ary aneurysmal bone cyst may be superimposed on a
conventional osteosarcoma. In such instances, pathologic-
radiologic correlation is extremely helpful to avoid a mis-
diagnosis. In the majority of cases, radiographs show a
bone-forming, radiodense lesion in addition to a lytic or
blowout component. The radiographs may also disclose
a discrepancy between the radiographic presentation of
the lesion and its microscopic appearance. In such
instances, another biopsy can be performed to sample a
portion of the tumor that shows the worrisome radio-
graphic features.
The more solid areas of an aneurysmal bone cyst,
because they contain numerous multinucleated giant
cells, may be confused with a giant cell tumor. An aneu-
rysmal bone cyst can also be engrafted on a preexisting
giant-cell tumor. Giant cell tumors may also cause an
aneurysmal bone cyst to develop as a secondary phenom-
enon. Distinction between a giant cell tumor with a sec-
ondary aneurysmal bone cyst and a primary aneurysmal
bone cyst on the basis of microscopic features alone can
be difficult. In such instances, involvement of the end of
the long bone, especially in the knee area of a skeletally
mature patient, suggests giant cell tumor. Epiphyseal
involvement by a similar lesion in a skeletally immature
patient suggests a chondroblastoma with a secondary
aneurysmal bone cyst superimposed.
Giant cell reparative granuloma is considered by some
authors as a common precursor lesion of aneurysmal
bone cyst that is synonymous with its solid variant. Giant
cell reparative granuloma is predominantly solid and
Text continued on p. 1073
 15  Cystic Lesions 1067

A B

C D
FIGURE 15-11  ■  Aneurysmal bone cyst: radiographic and gross features. A, Specimen radiograph of expansive lesion of the proximal
fibula. B, Bisected proximal segment of fibula shows aneurysmal bone cysts with hemorrhagic spongelike architecture. Same case
as shown in A. C, Enlarged photograph of resection specimen shown in B discloses multilocular cystic lesion. D, Low power pho-
tomicrograph shows hemorrhagic cysts and fibrous septations. (D, ×25) (D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1068 15  Cystic Lesions

A B

C D
FIGURE 15-12  ■  Aneurysmal bone cyst: gross features. A, Expansile hemorrhagic lesion of outer end of clavicle. Note blood-filled
cystic spaces in cut surface. B, Bisected aneurysmal bone cyst of ulna. Inner surfaces of cystic locules are discolored by old hemor-
rhage (hemosiderin). C, Resected segment of rib containing aneurysmal bone cyst that shows hemorrhagic, spongelike cut surface.
D, Specimen radiograph of lesion shown in C demonstrates ossification in septa.

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1069

A B

C D
FIGURE 15-13  ■  Aneurysmal bone cyst: gross and radiographic features. A, Specimen radiograph of humeral resection. Cyst is radio-
lucent, and shell of periosteal bone encloses soft tissue extension. B, Coronally sectioned proximal end of humerus containing
aneurysmal bone cyst in metaphysis and shaft shown in A. Note hemorrhagic intramedullary lesional tissue with destruction of
medial cortex and blowout expansion into soft tissue. C, Radiograph of right hip region showing a large, multiloculated blowout of
ischial ramus of a young adult; this lesion developed over 4 months. D, Gross specimen of lesion resected from ischial ramus shown
in C consisting of multiloculated fibrous sac with hemorrhagic staining of its walls.

ERRNVPHGLFRVRUJ
1070 15  Cystic Lesions

A B

C D
FIGURE 15-14  ■  Aneurysmal bone cyst: microscopic features. A, Parallel arrays of osteoid trabeculae along septum in typical aneu-
rysmal bone cyst. B, Higher power photomicrograph shows focus of osteoid formation in septum. C and D, Irregularly oriented
osteoid trabeculae in thickened septum of aneurysmal bone cyst. This early ossification is reactive in type. (A, ×100; B, ×200; C and
D, ×400.) (A-C, hematoxylin-eosin; D, trichrome.)

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1071

A B

C D
FIGURE 15-15  ■  Aneurysmal bone cyst: microscopic features. A-D, Examples of bone formation in septa of aneurysmal bone cysts.
Osteoid and woven bone trabeculae often are oriented along long axes of septa. Random orientation, however, is not uncommon
(A, ×50; B, ×100; C, ×100; D, ×200) (A-D, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
1072 15  Cystic Lesions

A B

C D
FIGURE 15-16  ■  Aneurysmal bone cyst: microscopic features. A, Low power photomicrograph shows irregular cystic space filled with
blood and bordered by thick septa. B and C, Higher magnification shows septa with spindle cells and numerous multinucleated
giant cells. D, Solid component of aneurysmal bone cyst with numerous multinucleated giant cells. Such areas of aneurysmal bone
cyst can be misdiagnosed as giant cell tumor. (A ×50, B-D, ×100) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

frequently contains microscopic foci of cystic change that
are consistent with those seen in an aneurysmal bone cyst;
however, the features of an expansile blowout lesion
are not seen on radiographs. The identification of USP6
gene rearrangement in giant cell reparative granulomas
of the appendicular skeleton, especially those involving
the bones of hands or the feet, further confirms the
relationship between these two entities. However, the
pathogenesis of giant cell reparative granulomas appears
to be heterogeneous; those affecting the craniofacial
bones are distinct from those in the appendicular skele-
ton and typically do not carry the USP6 gene rearrange-
ment. More complex description of the molecular
background of giant cell reparative granulomas is pro-
vided in Chapter 10. In general, the identification of the
clonal USP6 gene rearrangement in aneurysmal bone
cyst, giant cell reparative granulomas, and myositis ossi-
ficans provides important clues to the pathogenesis of
these conditions and may be useful in their differential
diagnosis.
A solitary bone cyst may occasionally be confused with
an aneurysmal bone cyst in biopsy material. Foci of hem-
orrhage associated with a pathologic fracture of a solitary
cyst may contain multinucleated giant cells and reactive
bone, which can closely simulate aneurysmal bone cyst.
In such instances, a review of radiographs is extremely
helpful. In addition, the mentioned giant cell–containing
areas are typically focal, and the remaining material
shows the bland-looking fibrous membrane of a solitary
bone cyst.
Treatment and Behavior
Aneurysmal bone cysts are locally destructive lesions
that may produce severe deformity and functional
impairment.53,54,64,67 Lesions located in the vertebral
column or in the craniofacial bones can compress vital
structures and cause serious disability or death, which
is unusual.12,24,41,51,65,70 The overall prognosis is good;
approximately 90% of patients have satisfactory long-
term treatment results. The kinetics of the lesion can vary
from case to case. Some lesions do not increase in size
and may develop radiographic features of intralesional
sclerosis.39 Most lesions, however, increase in size and
eventually require surgical intervention, other therapeu-
tic measures, or a combination of treatments to stabilize
the process and to prevent further damage.
The most effective treatment is complete surgical
excision of the lesion, but in many instances such an
approach may produce a major functional impairment.
Therefore most lesions are treated by curettage and bone
grafting. Unfortunately, this type of treatment is associ-
ated with a high recurrence rate that ranges from 20%
to 70% in different series.10,11,54,64 Recurrence typically
occurs within 6 months after treatment and almost never
occurs after 2 years.64 Cryotherapy has reduced the rate
of recurrence to 8% in one report.7 In some instances, in
situ transcatheter embolization can be performed.42
However, the clinical value of such treatment has not
been established in larger series. Percutaneous injection
of calcitonin, methylprednisolone, and sclerosing agents
such as Ethibloc have been reported to be effective in
ERRNVPHGLFRVRUJ
15  Cystic Lesions 1073
inducing shrinkage and healing.19,52 Adjuvant radiation
therapy is reserved for treatment of lesions that cannot
be completely excised because of their location and to
prevent damage to functionally important structures,
such as the spinal cord. Rare cases of high-grade sarcoma
(osteosarcoma and malignant fibrous histiocytoma)
developing at the site of a previously treated aneurysmal
bone cyst have been described.2,31 Most of these patients
received radiation therapy. Examples of spontaneous
malignant transformation without previous radiation
therapy also have been described.25,31
Secondary Aneurysmal Bone Cyst
Definition
The term secondary aneurysmal bone cyst is applied to aneu-
rysmal bone cysts that are superimposed on a preexisting
condition. The prognosis and behavior of these lesions
are generally determined by the biologic potential of the
underlying condition.
Incidence and Location
More than 50% of all aneurysmal bone cysts are
superimposed on a recognizable precursor condi-
tion.1,13,14,33,36,40,54,64,66,67,70,71 The age-related distribution
patterns of primary and secondary aneurysmal bone cysts
are similar and show a single peak during the second
decade of life (Fig. 15-2). Both variants of aneurysmal
bone cyst are rare in patients older than age 30 years.
This indicates that young individuals, especially those
who are skeletally immature, are more likely to develop
this process, either as a primary or secondary phenome-
non, compared with older individuals.16 In contrast to
primary aneurysmal bone cyst, secondary aneurysmal
bone cyst is more frequently found in weight-bearing
bones. On the other hand, there is no difference in pre-
dilection of primary versus secondary aneurysmal bone
cyst in non–weight-bearing sites.
Radiographic Imaging
The radiographic appearance of secondary aneurysmal
bone cyst reflects the superimposition of a blowout lesion
on the radiographic features of the preexisting condition
(Figs. 15-17 and 15-18). Quite frequently, the underlying
condition can be identified only microscopically. Because
of the anatomic location, involvement of specific areas of
bone, the age of the patient, and other factors, certain
preexisting conditions can be anticipated.13,14,21,33,36,41,63 In
the long tubular bones, involvement of the ends of bone
in skeletally immature patients and blowout lesions of
tarsal bones suggest that chondroblastoma could be the
predisposing condition. Chondroblastoma is almost
invariably a source of a blowout lesion that develops in
the calcaneus. It also should be suspected in the differen-
tial diagnosis of blowout lesions of the acetabulum. In
skeletally mature patients, giant cell tumor is the frequent
underlying condition of the blowout lesion in the end of
long bones, especially if it involves the knee area. Giant
cell reparative granuloma is a frequent predisposing
1074 15  Cystic Lesions

FIGURE 15-17  ■  Secondary aneurysmal bone cyst: radiographic features. A, Blowout lesion of proximal humeral end represents
secondary aneurysmal bone cyst superimposed on chondroblastoma. B, Expansile lytic lesion of intertrochanteric region of femur
represents secondary aneurysmal bone cyst superimposed on nonossifying fibroma. C, Expansile lesion involves distal end of
second metacarpal bone and is secondary aneurysmal bone cyst superimposed on giant cell reparative granuloma.

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1075

A B

C D
FIGURE 15-18  ■  Secondary aneurysmal bone cyst: gross, radiographic, and microscopic features. A, Bisected rib with large secondary
aneurysmal bone cyst engrafted on fibrous dysplasia. B, Specimen radiograph of A shows ground-glass appearance of more
solid area at top, which contains fibrous dysplasia, and lucent area of aneurysmal bone cyst below. C, Radiograph of chondroblas-
toma of glenoid region of scapula with superimposed aneurysmal bone cyst. D, Low power photomicrograph of curetted material
from C shows thickened septum of aneurysmal bone cyst with focus of chondroid matrix and sheets of chondroblasts. (D, ×100)
(D, hematoxylin-eosin).

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1076 15  Cystic Lesions
TABLE 15-1 Precursor Conditions for Secondary
Aneurysmal Bone Cyst
Giant cell tumor Eosinophilic granuloma
Chondroblastoma Hemangioma
Osteoblastoma Myositis ossificans
Nonossifying fibroma Osteosarcoma
Fibrous dysplasia Malignant fibrous histiocytoma
Giant cell reparative Metastatic carcinoma
granuloma
Chondromyxoid Miscellaneous lesions containing
fibroma rich vascular network
(hamartoma)
Fibrous histiocytoma
Solitary bone cyst
condition for the development of secondary aneurysmal
bone cyst in the small bones of the hands and feet and in
the mandible. Fibrous dysplasia should be considered in
reference to lesions located in the shafts of long bones
of the extremities, in the ribs, and in the craniofacial
region. In the metaphyseal parts of the long tubular
bones, especially in a lower extremity, lesions such as
nonossifying fibroma and, less frequently, chondromyx-
oid fibroma should be considered. The most frequent
underlying condition for secondary aneurysmal bone cyst
of the vertebral column is osteoblastoma. Osteoblastoma
should also be anticipated in sites such as the mandible
and the maxilla.63 An expansile, fluid-filled lesion of the
sacrum typically represents an aneurysmal bone cyst
superimposed on a giant cell tumor. The most frequent
underlying conditions for secondary aneurysmal bone
cyst are listed in Table 15-1. It must be remembered that
aneurysmal bone cyst is rarely superimposed on primary
or metastatic malignant tumors.15 All bone lesions
containing components with rich vasculature may occa-
sionally develop aneurysmal bone cysts as secondary phe-
nomena. Therefore it can be seen even in such conditions
as vascular cartilaginous hamartoma.38
Microscopic Findings
Microscopic features of secondary aneurysmal bone cyst
do not differ from those of primary aneurysmal bone
cyst. In addition, residual foci with microscopic features
of an underlying condition—chondroblastoma, giant
cell tumor, giant cell reparative granuloma—are present
(Figs. 15-19 and 15-20).
Differential Diagnosis
Differential diagnosis of a secondary aneurysmal bone
cyst is similar to that of a primary aneurysmal bone cyst.
Treatment and Behavior
The treatment and behavior of secondary and primary
aneurysmal bone cysts are similar. The prognosis is
related to the biology of the underlying condition. For
example, the patient with an aneurysmal bone cyst
ERRNVPHGLFRVRUJ
superimposed on a giant cell tumor may have all or some
of the complications related to both conditions.
Personal Comments
A useful radiologic feature of aneurysmal bone cyst, the
“finger-in-the-balloon” sign, has been observed by Dr.
Robert Freiberger (personal communication). This is the
preservation of a cortical bone cuff that penetrates for a
short distance into the expanded area of destructive
blowout. This sign is not present in telangiectatic osteo-
sarcoma or other aggressive malignant tumors of bone.
The most frequent histologic obstacle in the recogni-
tion of aneurysmal bone cyst is the presence of significant
amounts of reactive bone and osteoid within the septa
and even in solid areas of the lesion. Delicate osteoid
seams may be abundant in an aneurysmal bone cyst. They
are usually oriented along the septa, unlike the random
orientation of osteoid and tumor bone trabeculae of
osteosarcomas.
Microscopic features of an aneurysmal bone cysts are
often combined with those of giant cell reparative granu-
loma, especially in lesions found in the short tubular
bones of the hands and feet and in vertebral lesions. The
composite nature of these lesions suggests that aneurys-
mal bone cyst and giant cell reparative granuloma may
represent closely related but distinct reactions to intraos-
seous hemorrhage after trauma.
Soft Tissue Aneurysmal Bone Cyst
Aneurysmal bone cysts very rarely arise in extraosseous
sites, including the somatic soft tissue of the extremities,
most often in the thigh and shoulder regions.6,68 It has
also been reported in the larynx and in arterial walls.34,50
Some of these appear to have arisen within the hemor-
rhagic central zones of myositis ossificans lesions.6
SOLITARY BONE CYST
Similar to aneurysmal bone cyst, solitary bone cyst is not
a true neoplasm, but it is usually included in the discus-
sion of bone tumors. Sometimes, it is also referred to as
a simple or unicameral bone cyst. However, the term uni-
cameral is misleading because some of these lesions may
consist of several multilocular cavities.
Definition
Solitary bone cyst is typically a unilocular cystic lesion
that does not have a lining and is filled with serous fluid.
It arises most frequently in the metaphyseal portion of
the major long bones, such as the humerus or femur, in
skeletally immature patients.
Incidence and Location
Solitary bone cyst is typically diagnosed during the first
two decades of life.72,76,77,81,87 The peak incidence is
between ages 3 and 14 years, when nearly 80% of cases
are diagnosed. In several major series, the solitary bone
 15  Cystic Lesions 1077

A B

C D
FIGURE 15-19  ■  Secondary aneurysmal bone cyst engrafted on chondroblastoma: microscopic features. A and B, Low and intermedi-
ate power photomicrographs show aneurysmal cystic component of lesion. C and D, Low and intermediate power photomicrographs
show solid component of lesion consistent with chondroblastoma. Note focus of cartilaginous differentiation better seen in D.
(A and C, ×200; B and D, ×400) (A-D, hematoxylin-eosin)

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1078 15  Cystic Lesions

A B

C D
FIGURE 15-20  ■  Secondary aneurysmal bone cyst: microscopic features engrafted on osteoblastoma. A and B, Low power photomi-
crographs show aneurysmal cystic component of lesion. C, Low power photomicrograph shows osteoblastic lesion in wall of
cyst. D, Anastomosing pattern of bone trabeculae rimmed by osteoblasts in fibrovascular stroma consistent with osteoblastoma.
(A, B, and D, ×200; C, ×20.) (A-D, hematoxylin-eosin.)

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5 15
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 15-21  ■  Solitary bone cyst. Peak age incidence and frequent sites of skeletal involvement. Most frequent sites are indicated
by solid black arrows.
cyst had a predilection for male patients; the overall
male-to-female sex ratio is approximately 2 : 1.
Solitary bone cyst is relatively uncommon in patients
older than age 20 years. It has been noted that the lesion
preferentially involves the major long tubular bones, such
as the humerus and femur, during the first two decades
of life. Nearly 80% of cases are diagnosed in these ana-
tomic sites. On the other hand, rare cases diagnosed in
older patients usually involve the ilium, talus, and calca-
neus.72,75,87,88,103,107 In rare instances, a solitary bone cyst
may involve other anatomic sites, such as the spine,
sacrum, craniofacial bones, forearm, and acral skele-
ton.83,91-93,97,100,110 Peak age incidence and the most fre-
quent sites of skeletal involvement are presented in
Figure 15-21.
Clinical Symptoms
Pain in the area of the lesion is a common symptom.
Sometimes the lesion is discovered after pathologic
fracture. Swelling or deformity of the affected area
can also be a presenting symptom.72,75,87,107,114 Calcaneal
cysts, usually found in older patients, are usually asymp-
tomatic; however, the cyst’s large size in this weight-
bearing bone is associated with a significant risk of
fracture.
ERRNVPHGLFRVRUJ
15  Cystic Lesions 1079
7 8
Radiographic Imaging
Solitary bone cyst presents as a central lucency within
the medullary cavity of the shaft of the major long
bones.77,82,89,96,98,111,113 Fine trabeculation and scalloped
sclerotic borders are frequently seen (Figs. 15-22 to
15-26). Central involvement of the medullary cavity and
extension to the growth plate are typical (Fig. 15-26). The
cortex overlying the lesion is thinned and scalloped with
a distended bone contour. It is important to note that the
cortex is never completely disrupted and that the lesion
does not extend into soft tissue. Occasionally, it is possible
to document on serial radiographs that the epiphysis
grows away from the cyst. Pathologic fracture is fre-
quently the presenting symptom. Such fracture ranges
from a small cortical infarction to a complete fracture
with displacement. A fragment of displaced cortex can
drop to the distal part of the cyst and produce the so-called
fallen-fragment sign (Fig. 15-22).108 A shift in the position
of the fragment in the cyst confirms the nonsolid character
of the bone defect. Computed tomography and magnetic
resonance imaging accurately reveal the extent of the
lesion and disclose its cystic nature and water density
content. Occasionally, these scans reveal that several cystic
spaces are present (multilocular cyst). More typically, a
Text continued on p. 1085
1080 15  Cystic Lesions

A B
FIGURE 15-22  ■  Solitary bone cyst: radiographic features. A and B, External rotation view of proximal humerus of child shows patho-
logic fracture through large solitary bone cyst. Linear fragments of comminuted cortical bone (fallen-fragment sign) can be seen in
lower end of cyst in both views (arrows).

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1081

A B

C
FIGURE 15-23  ■  Solitary bone cyst: radiographic features. A and B, Well-demarcated lucent lesion in proximal femoral shaft of child.
Upper border of cyst is close to growth plate of greater trochanter. Parallel periosteal reaction on the cortical surface distally reflects
presence of pathologic fracture (arrow). C, Same lesion 5 years later. Note increased size with enlargement and involvement of
femoral neck.

ERRNVPHGLFRVRUJ
1082 15  Cystic Lesions

B C
FIGURE 15-24  ■  Solitary bone cyst: radiographic features. A, Anteroposterior (AP) radiograph of pelvis shows cystic lesion of superior
pubic ramus and acetabular area in adult. B, AP radiograph of right side of pelvis shows very large cyst occupying entire ilium of
adult and extending into both superior and inferior rami. Pelvic cysts of this type occur almost exclusively in adults. C, AP film of
foot of adult shows solitary bone cyst in very uncommon location in shaft of second metatarsal bone. Note extension into epiphysis,
which typically occurs in skeletally mature patients.

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1083

A B
FIGURE 15-25  ■  Solitary bone cyst: radiographic features. A and B, Anteroposterior and lateral radiographs show lytic lesion with
expansion of bone contour that involves distal end of fibula. Note prominent trabeculation.

ERRNVPHGLFRVRUJ
1084 15  Cystic Lesions

B C

FIGURE 15-26  ■  Solitary bone cyst: radiographic features. A, Lateral radiograph of ankle in young adult shows solitary bone cyst in
typical location within anterior half of calcaneus. B, Distal fibular lesion in young adult occupies diametaphyseal area of fibula with
expansion of bone contour. C, Bivalved solitary bone cyst of distal fibula in B shows single cavity with ridging of inner surface and
focal hemosiderin deposition.

ERRNVPHGLFRVRUJ

single, large cavity filled with fluid the density of water
is present. Extension to the end of bone is rare and, if
present, it is usually seen in skeletally mature patients.
Gross Findings
Evaluation of an intact solitary bone cyst is rarely possible
(Fig. 15-26). In such instances, it presents as a large
intramedullary cavity filled with a clear or yellowish fluid
that has a low viscosity. In general, it is similar to serous
effusions of body cavities. The lesion is usually composed
of a single cyst, but occasionally septations divide it into
several cavities. A spongy component composed of mul-
tiple smaller cysts can be present focally. This component
is usually located peripherally within the medullary cavity
and is attached to the wall of the cyst. The wall is com-
posed of a paper-thin, tan-yellow fibrous tissue with mul-
tiple bony ridges. Recent or old fractures create focal
nodularities related to the healing process.
Microscopic Findings
The wall of the cyst is composed of a thin layer of fibrous
tissue without any lining (Figs. 15-27 to 15-29). Dilated
vessels, scattered inflammatory cells, and multinucleated
giant cells are commonly present. Hemosiderin pigment
and foamy macrophages are seen focally. Fibrin deposits
in the wall of the cyst can become mineralized and produce
concentric lamellar structures that resemble cementum
(Figs. 15-29). Fibrous membranes curetted from the
bone cysts containing these cementoid bodies can be
confused with fibrous dysplasia or even an odontogenic
tumor.73,95,104,110 This accounts for reports of some cemen-
tomas of long bones in older literature. Prominent giant
cell reaction in the wall can occasionally be responsible
for its being confused with a giant cell lesion. Bone resorp-
tion with osteoclastic activities is seen in the tissue sur-
rounding the lesion. In addition, reactive bone formation
with prominent osteoblasts can be present, corresponding
to a site of pathologic fracture. Occasionally, septa sepa-
rating individual cysts can be seen and can have micro-
scopic features similar to those of aneurysmal bone cysts.
Differential Diagnosis
The problems in identifying a solitary bone cyst are pre-
dominantly related to the lack of radiologic and clinical
data—the pathologist is not aware of the cystic nature of
the lesion in question. Therefore the microscopic phe-
nomena observed in the curetted fibrous membrane are
interpreted to be an integral component of the solid
lesion. Moreover, although the cystic nature of the lesion
can be recognized, it is usually interpreted to be a second-
ary phenomenon (i.e., cystic degeneration of a preexist-
ing solid lesion). Thus the subsequent misdiagnosis of
solitary bone cyst as fibrous dysplasia, odontogenic tumor, or
giant cell lesion is a consequence of these two major errors.
Treatment and Behavior
In addition to dual-needle aspiration of the cyst and instil-
lation of methylprednisolone, which is now the treatment
of choice, the traditional method of curettage with bone
ERRNVPHGLFRVRUJ
15  Cystic Lesions 1085
grafting is frequently used to treat enlarging cysts of
weight-bearing bones.74,78,80,84,85,87,96,98,102,105 Other types
of treatment, including subtotal resection, allografting,
and packing with various synthetic materials; percutane-
ous injection of demineralized bone matrix; and autoge-
nous bone marrow transplant, have also been repor
ted.74,79,80,94,96,98,101,106,112 The recurrence rate after both
injection and curettage is approximately 20%. Repeat
injection or curettage is often necessary. Epiphyseal
involvement by solitary bone cysts is occasionally observed,
and these patients may exhibit growth arrest.99,109,112 Rare
instances of secondary malignancy in solitary bone cysts,
including a chondrosarcoma, have been reported.86,90
INTRAOSSEOUS GANGLION
Definition
An intraosseous ganglion cyst is identical to its soft tissue
counterpart. It is composed of a small cavity without
lining that is filled with mucoid viscous material. Typi-
cally, it occurs in the subchondral parts of bones near
joint surfaces. Similar to other cystic conditions discussed
in this chapter, it is not a true neoplasm. It probably
represents a degenerative change with development of a
cavity filled with mucoid material. To some extent, it is
similar to the so-called subchondral cyst frequently seen
in degenerative joint disease. In fact, the degenerative
mechanism that leads to the development of these condi-
tions could be similar. A lesion should be classified as an
intraosseous ganglion if it occurs as a solitary change that
is not associated with degenerative joint disease. By con-
vention, subchondral cystic lesions that occur in the pres-
ence of osteoarthritis should be considered as an integral
element of a degenerative disorder.122,123,124,126
Incidence and Location
The true incidence of this condition is unknown because
many of these lesions are asymptomatic and are inciden-
tally discovered on radiographs obtained for other reasons.
There are very few reported series of more than 10 cases
of intraosseous ganglion. On the basis of information from
the major reported series, it is possible to conclude that
the lesion is typically identified in skeletally mature patients
older than age 20 years (approximately 80% of cases). The
peak incidence is probably in the fourth or fifth decade of
life. In most series, there is a slight male predominance,
with a male-to-female ratio of approximately 1.2 : 1. Char-
acteristic sites are the juxtaarticular subchondral locations,
most frequently in the long tubular bones. The hip, knee,
and ankle regions are most frequently affected.155-117,120,123,
125,127-129
Other typical sites include the shoulder and wrist
regions. The joints of the lower extremities are more fre-
quently involved than those of the upper extremities. The
peak age incidence and the most frequent sites of skeletal
involvement are presented in Figure 15-30.
Clinical Symptoms
Some intraosseous ganglion cysts are asymptomatic, and
the lesions are discovered incidentally when a radiograph
is obtained for other reasons. The lesion is symptomatic
1086 15  Cystic Lesions

A B

C D
FIGURE 15-27  ■  Solitary bone cyst: microscopic features. A and B, Fibrous membrane without lining surrounding the solitary bone
cyst cavity. C, Delicate fibrous membrane showing sparse cellularity and deposits of eosinophilic fibrinlike material. D, Reactive
bone formation in the wall of solitary bone cyst (A-D, ×100) (A-D, hematoxylin-eosin.)

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 15  Cystic Lesions 1087

A B

C D
FIGURE 15-28  ■  Solitary bone cyst: microscopic features. A, Fibrous membrane with sparse cellularity showing myxoid change and
vascular proliferation. B, Fibrous membrane with eosinophilic fibrinlike deposits. C and D, Medium and higher power magnifications
of reactive bone formation in the wall of solitary bone cyst. (A-C, ×100; D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1088 15  Cystic Lesions

A B

C D
FIGURE 15-29  ■  Solitary bone cyst: microscopic features. A and B, Low power photomicrographs show multinucleated giant cell
reaction and osteoid formation in wall of cyst. C and D, Calcified fibrin deposits may undergo ossification, as shown in these pho-
tomicrographs of thickened cyst wall. (A and B, ×100; C and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

40
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 15-30  ■  Intraosseous ganglion. Peak age incidence and frequent sites of involvement. Most frequent sites are indicated by
solid black arrows.
in approximately 60% of cases. Pain of several months’
to several years’ duration is the most common symptom.
Symptoms can be aggravated by standing or exercise.
Radiographic Imaging
Radiographs reveal a well-defined lytic area with sclerotic
margins located eccentrically in the subchondral bone
(Fig. 15-31).115,116,120,122,127,128 The average size of the
lesion is 1 cm in diameter. Lesions larger than 2 cm in
diameter are extremely rare, but a few intraosseous gan-
glion cysts as large as 5 cm in diameter have been reported
(Fig. 15-31).115,118,124 The lesion is not connected with a
joint or adjacent synovial-lined structure. In typical cases,
the bone contours are not altered. Lesions exceeding
2 cm in diameter can expand into the adjacent cortex and
distort the articular cartilage. Rare cases of subperiosteal
ganglion cysts have also been reported.119
Gross Findings
Intraosseous ganglion cysts typically have a relatively
small cavity (less than 1 cm) and are surrounded by a thin,
fibrous capsule filled with gelatinous or mucoid fluid.
The bone and articular cartilage in the vicinity of the
lesion are not altered. Occasionally a thin sclerotic rim
of bone surrounds the cyst. In a majority of cases, gross
ERRNVPHGLFRVRUJ
15  Cystic Lesions 1089
60
7 8
examination of the lesion is based on curetted material.
In such instances, it represents a disrupted fibrous mem-
brane mixed with gelatinous fluid.
Microscopic Findings
As mentioned, the microscopic features of intraosseous
ganglion cysts are identical to the those of their soft tissue
counterparts. The wall of the cyst is composed of flat-
tened fibrous elements without lining (Fig. 15-32). The
capsule can have two distinct layers. The outer, or periph-
eral, layer is composed of more compact fibrous elements
(Fig. 15-32). In contrast, the inner portion is loose and
shows myxoid change and stellate-shaped cells. Areas of
myxoid change within the capsule can also be seen focally.
Scattered inflammatory cells and foamy macrophages
may be present. The gelatinous material represents
amorphous granular or membranous material with occa-
sional inflammatory and red blood cells (Fig. 15-33). The
surrounding tissue may contain reactive bone with osteo-
blastic rimming, focally resorptive changes with osteo-
clastic activity, or a combination of these features.
Differential Diagnosis
If the lesion is present in a typical location, it rarely causes
diagnostic problems. The diagnosis is usually established
1090 15  Cystic Lesions

B C D
FIGURE 15-31  ■  Intraosseous ganglion: radiographic features. A, Anteroposterior radiograph shows well-circumscribed, lucent lesion
in medial malleolus of tibia in young adult. Narrow zone of bone sclerosis forms margin of this loculated cyst. B, Radiograph shows
well demarcated area of lucency in distal portion of scaphoid. C and D, Unusually large ganglion cyst involves proximal end of
radius and most of its shaft. A and B were taken 2 years apart. (Courtesy Dr. T. Bauer, Cleveland.)

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1091

A B

C D
FIGURE 15-32  ■  Intraosseous ganglion: microscopic features. A, Low power photomicrograph of fibrous cyst. Note the absence
of specific lining. B, Fibrous membrane lining a ganglion cyst with prominent myxoid change. C and D, Low and higher
power photomicrographs of fibrous membrane lining a ganglion cyst with extensive myxoid change. (A-C, ×100; D, ×200.)
(A-D, hematoxylin-eosin.)

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1092 15  Cystic Lesions

A B

C D
FIGURE 15-33  ■  Intraosseous ganglion: microscopic features. A–C, Fibrous membrane lining the cyst. Note prominent stromal myxoid
change and the presence of proteinaceous myxoid material in the lumen. D, More cellular component of the fibrous cyst with myxoid
change (A-D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

preoperatively on the bases of radiographic features and
the location of the lesion. A subchondral cyst is microscopi-
cally indistinguishable from an intraosseous ganglion, but
the former is associated both microscopically and radio-
graphically with changes consistent with osteoarthri-
tis.121,126 Intraosseous ganglion also can be confused with
other myxoid lesions of bone, such as fibromyxoma or
chondromyxoid fibroma, but this is rare. Fibromyxoma and
chondromyxoid fibroma may contain free mucinous
material, but the periphery of the lesion usually contains
diagnostic cellular tissue.
Treatment and Behavior
Curettage and bone grafting are sufficient treatment for
the vast majority of cases. A small percentage of patients
may have recurrences, but these cases are successfully
treated by second curettage.
EPIDERMAL INCLUSION CYST
AND DERMOID CYST
Cysts of bone lined by squamous epithelium are relatively
rare. In the course of embryonal development, cells of
the epidermis may be displaced into bone and form cystic
Incidence
Phalanges
Skull
1 2 3 4 5 6
Age in decades
FIGURE 15-34  ■  Epidermal cyst. Peak age incidence and most frequent sites of skeletal involvement. Most frequent site is indicated
by solid black arrow.
ERRNVPHGLFRVRUJ
15  Cystic Lesions 1093
lesions lined by squamous epithelium. The displacement
theory (developmental or injury related) is frequently
postulated as a possible pathogenetic mechanism for the
development of epidermal cysts in bone and other organs.
Displacement is certainly a mechanism for lesions that
develop in association with a penetrating injury (inclusion
cysts). In many instances, such lesions arise by means of
aberrant squamous differentiation of mesenchymal cells
(developmental cysts) rather than by displacement. Inclu-
sion and developmental epidermal cysts of bone have
distinct age and skeletal distribution patterns.146 The age-
related distribution and the most frequent sites of skeletal
involvement are presented in Figure 15-34.
Epidermal inclusion inclusion cysts typically occur in
the acral skeleton and primarily involve the phalan-
ges.132,140,143,147 They are related to penetrating injuries
and frequently occur in the hands of skeletally mature
individuals. Involvement of a long bone is extraordinarily
rare.136 Radiographically, they represent well-demarcated
lytic defects with sclerotic margins (Fig. 15-35). The
bone contour can be expanded, but cortical disruption is
rarely seen. Pathologic fracture may be a presenting sign
(Fig. 15-35). Histologically, these lesions are cysts lined
by squamous epithelium and filled with keratin debris
(Fig. 15-36). Disruption of the cyst may result in a leak
of keratin material into the adjacent tissue, which causes
7 8
1094 15  Cystic Lesions

A B C

D
FIGURE 15-35  ■  Epidermal inclusion cyst: radiographic features. A, Cystic lucency in distal phalanx of man who sustained crush injury
of this finger 3 years previously. Slowly enlarging cyst expands bone contour and shows associated bone sclerosis proximally.
B, Pathologic fracture of distal phalanx through area of radiolucency. C, Expansile lytic lesion in distal phalanx of middle finger 1
year after a penetrating injury. D, Expansile lytic lesion of distal phalanx erodes cortex and is associated with soft tissue edema.

ERRNVPHGLFRVRUJ
 15  Cystic Lesions 1095

A B

C D
FIGURE 15-36  ■  Epidermal inclusion cyst: microscopic features. A, Cystic space filled with keratin and lined by stratified squamous
epithelium. B, Disrupted cyst with lumen partially lined by squamous epithelium exhibiting keratin debris in soft tissue. C and
D, Disrupted cysts showing keratin debris within soft tissue associated with inflammatory response. (A, C, and D, ×100; B, ×200.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1096 15  Cystic Lesions
an inflammatory response with foreign-body multinucle-
ated giant cells. The associated soft tissue edema may
clinically or radiographically raise suspicion of an aggres-
sive lesion.
Developmental epidermal cysts occur predominantly
in the skull and are most frequently diagnosed in
children during the first decade of life.139,145,149-151 Most of
these lesions are present at birth, but some may be
asymptomatic for many years and are eventually diag-
nosed during adulthood. Radiographically, they appear as
lytic defects with scalloped sclerotic margins. Epidermal
cysts may be encountered in any calvarial bone involving
outer and inner tables or diploe. Outward expansion can
produce a palpable mass. Inward growth may be asymp-
tomatic for a long period, but eventually it becomes
symptomatic.130,131,133,134,137,139,145
Dermoid cysts, or dermoids, are distinguished from
epidermal cysts by the presence of additional dermal
structures—skin adnexae (sebaceous glands, hair folli-
cles). They represent a form of mature cystic teratoma
and most frequently occur in the midline.135,141,142,144,148
These cysts usually occur in the regions of the anterior
fontanel and sacrum. Pathogenetically, they belong to the
family of germ-cell tumors, and their extensive descrip-
tion is beyond the scope of this text. Cholesteatoma is an
old descriptive term used to designate a cystic lesion filled
with grossly cheesy keratinous debris.104
Developmental epidermoid cysts, or dermoids, of the
skull may be associated with a malignant component.
Considering the relative rarity of these lesions, there are
quite a few reports of malignant transformation, which is
usually in the form of squamous carcinoma.138,152 To the
best of our knowledge, there is no report of malignant
transformation of epidermal inclusion cysts of the acral
skeleton. Squamous cell carcinomas of bone are typically
associated with epidermalization of sinus tracts of chronic
osteomyelitis and are discussed in Chapter 24.
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 C H A P T E R 1 6 

Miscellaneous Mesenchymal
Tumors

CHAPTER OUTLINE

LIPOMA PERIVASCULAR EPITHELIOID CELL TUMOR

Intramedullary Lipoma LEIOMYOSARCOMA
Intracortical and Subperiosteal Lipoma
Parosteal Lipoma RHABDOMYOSARCOMA

LIPOSARCOMA MULTIPOTENTIAL PRIMITIVE SARCOMA,

POLYHISTIOMA, AND MALIGNANT
VASCULAR-CARTILAGINOUS HAMARTOMA OF MESENCHYMOMA
THE CHEST WALL
MELANOTIC NEUROECTODERMAL TUMOR OF
INFANCY

LIPOMA (Figs. 16-2 and 16-3). Magnetic resonance imaging may

Definition
Lipoma is a rare primary tumor of bone composed
of mature adipose tissue. Lipomas involving bone
are divided into three types: intramedullary (intraosse-
ous), intracortical/subperiosteal, and parosteal. Lipomas
involving synovial tissue are described in Chapter 20.
Incidence and Location
Lipomas of bone are extremely rare; fewer than 50 cases
are described in the literature.
show no discernible signal alteration because lipoma is
composed of mature adipose tissue with signal character-
istics similar to normal fatty marrow (Fig. 16-1). Lipomas
with extensive fat necrosis may appear as low signal
density lesions with signal void in areas of calcifications
(Fig. 16-4).
Gross Findings
The gross appearance of lipoma is that of a well-
circumscribed, lobular mass of adipose tissue (see
Fig. 16-2).

Intramedullary Lipoma Microscopic Findings

Intramedullary lipomas usually occur in the metaphyseal
parts of major long bones of the lower extremity—the
femur, tibia, and fibula.3-6,8-14,16,17,20,21,23,25,26,28,29,34 The cal-
caneus is also a common site.1,12,19,21,22,27,31,33 Lipomas also
have been reported in the sacrum, coccyx, mandible,
maxilla, skull, ribs, and metatarsals.36,37 Pain and swelling
are the most frequent presenting symptoms, but most of
these lesions are asymptomatic and may only be inciden-
tally noted on radiographs.
Radiographic Imaging
Radiographically, intramedullary lipoma is seen as a lytic
lesion with trabeculation (Figs. 16-1 and 16-2). Bone
expansion with a thinned but intact cortex may be
present (Fig. 16-2). Central, niduslike calcification is a
frequent radiographic feature of intramedullary lipoma
Histologically, lipomas consist of mature adipose tissue
and do not differ from ordinary lipomas of soft tissue
(Fig. 16-4). The presence of fat necrosis with dystrophic
calcifications, which correspond to the central, niduslike
opacity seen radiographically, is frequently seen (Figs.
16-3 and 16-4).
Intracortical and Subperiosteal Lipoma
Intracortical and subperiosteal lipomas are extremely
rare.2,24,28,38 They radiographically present as intracortical
or subperiosteal lucent lesions with intralesional trabecu-
lations and foci of dotlike calcifications. Histologically,
these lesions consist of mature adipose tissue and, similar
to intramedullary lipomas, they do not differ from ordi-
nary lipomas of soft tissue.
Text continued on p. 1105

1100
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 16  Miscellaneous Mesenchymal Tumors 1101

C
FIGURE 16-1  ■  Intramedullary lipoma: radiographic features. A and B, Anteroposterior and lateral radiographs show lytic lobulated
lesion involving proximal tibial metaphysis in skeletally mature patient. Biopsy revealed mature adipose tissue. C, Coronal magnetic
resonance image of intramedullary lipoma of tibia shows no discernible marrow signal alteration because lipoma is composed
of mature adipose tissue. There is some expansion of contour of medial cortex overlying lesion. (Courtesy of Dr. German Steiner,
New York.)

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1102 16  Miscellaneous Mesenchymal Tumors

B
FIGURE 16-2  ■  Intramedullary lipoma: radiographic and gross features. A, Anteroposterior radiograph shows lytic lesion involving
distal end of fibula. Note bone contour expansion and central niduslike opacities corresponding to areas of fat necrosis. B, Fibular
resection specimen shows lesion composed of adipose tissue. (Courtesy Dr. Leonard Kahn, New York.)

ERRNVPHGLFRVRUJ
 16  Miscellaneous Mesenchymal Tumors 1103

A B

C D
FIGURE 16-3  ■  Lipoma of bone: cystic tumor of calcaneus with fat necrosis. A, Lateral radiograph of foot of a 40-year-old woman
who had pain for 1 year. Anterior portion of calcaneus shows lytic lesion with ringlike calcific density in its center. B, Coronal com-
puted tomogram shows lucent lesion in calcaneus that has central cyst; walls of cyst are calcified. C, On curettage, lesion was partly
cystic and contained calcified necrotic fat; fragment of cyst wall. D, Calcified necrotic fat in center of lipoma. (C, ×40; D, ×100) (C and
D, hematoxylin-eosin.) (Courtesy Dr. M. Nuovo, New York.)

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1104 16  Miscellaneous Mesenchymal Tumors

A B

C D
FIGURE 16-4  ■  Intramedullary lipoma: radiographic and microscopic features. A, Anteroposterior radiograph of proximal femur shows
lytic intertrochanteric lesion with well demarcated sclerotic margins. Note multifocal coalescent opacities corresponding to calcified
areas of fat necrosis. B, Magnetic resonance image (MRI) shows a well demarcated intramedullary lesion with signal void in areas
corresponding to calcifications. Inset, T2-weighted MRI shows signal enhancement with signal void in areas corresponding to cal-
cifications. C, Lesion is composed of mature adipose tissue. Note the absence of bone trabeculae, a feature helpful in distinguishing
this lesion from normal fatty bone marrow. D, Central portion of lesion exhibits features of fat necrosis and dystrophic calcification.
(C and D, ×50) (C and D, hematoxylin-eosin.)

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Parosteal Lipoma
Parosteal lipomas are not true bone tumors and belong
to the category of soft tissue lesions. Because of their
association with the bone surface, parosteal lipomas may
have some distinctive radiographic and microscopic
features. Similar to intramedullary lipomas, parosteal
lipomas of bone are extremely rare.7,15,17,18,20,30,32,35 They
usually involve the metaphyseal parts of long tubular
bones, but they may involve other bones, such as the flat
bones of the trunk and the bones of the upper extremities
(Fig. 16-5). A characteristic feature of parosteal lipoma
(not always seen) is a sclerotic, osseous pedicle that grows
from the surface of the bone into the adipose tissue. This
bony excrescence can dominate the lesion and can result
in radiographic misdiagnosis of the lesion as an osteo-
chondroma. Foci of cartilaginous metaplasia with forma-
tion of a cartilaginous cap may be present.
LIPOSARCOMA
Definition
Liposarcoma is an extremely rare primary sarcoma of
bone; it is composed of immature adipose tissue.
Incidence and Location
Liposarcoma of bone is one of the rarest of primary bone
tumors.39-48 In 1982, Addison and Payne accepted only six
examples of this entity in bone from previously published
reports.24 The patients ranged in age from 15 to 53 years
but usually had symptoms during the third and fourth
decades of life. Reported cases of intraosseous liposar-
coma involved the major long tubular bones, such as the
femur, tibia, and humerus.
Radiographic Imaging
Radiographic features are nonspecific and show a bone-
destructive process indicative of a malignant tumor.
Microscopic Findings
Microscopically, liposarcomas in bone represent high-
grade pleomorphic or round-cell (signet-ring) lesions.
Some of these tumors may have features of myxoid
liposarcoma.
Differential Diagnosis
The high-grade pleomorphic liposarcoma should be
differentiated from malignant fibrous histiocytoma. In the
evaluation of adipose tissue and differentiation of intraos-
seous lesions, the presence of residual nonneoplastic
tissue of fatty marrow infiltrated by a nonlipomatous
tumor should be ruled out before the lesion is classified
as a liposarcoma. It is our impression that at least some
of the cases previously reported as primary liposarcomas
of bone would be currently classified as malignant fibrous
histiocytomas.
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16  Miscellaneous Mesenchymal Tumors 1105
Clinical Behavior
Approximately 50% of patients who were reported to
have primary liposarcoma of bone had metastases after
amputation.
VASCULAR-CARTILAGINOUS
HAMARTOMA OF THE CHEST WALL
Definition
Vascular-cartilaginous hamartoma is a rare and distinct
clinical, radiologic, and pathologic entity that presents at
birth or early infancy as an expansile intraosseous lesion
involving the central portion of one or more ribs.
Incidence and Location
McLeod and Dahlin56 reported nine cases from the Mayo
Clinic’s consultation files. The lesion typically involves the
chest wall and most likely originates within the ribs.49-59
Gross Findings
The gross findings of these tumors are those of smooth,
well-circumscribed, red-brown masses that arise from the
surface of the rib. The cut surface is marked by the pres-
ence of many dilated channels filled with blood. These
spaces are separated by a friable, red-brown stroma that
contains variable amounts of gritty, shiny, white, carti-
laginous tissue.
Radiographic Imaging
Radiographically vascular-cartilaginous hamartoma pres-
ents as an expansile lesion of the rib. Magnetic reso-
nance imaging typically shows signal enhancement in
T2-weighted images corresponding to the high water
content in both cartilaginous and vascular components
of the lesion (Figs. 16-6 and 16-8).
Microscopic Findings
Microscopically, these lesions show a mixture of cellular
fibrous tissue that contains many blood-filled, endothelial-
lined vascular spaces; numerous islands of randomly dis-
tributed mature hyaline cartilage; and reactive new bone
(Figs. 16-6 and 16-7). The cartilage islands represent
well-developed nodules of cartilaginous tissue that are
well demarcated from the surrounding vascular compo-
nent and occasionally form irregular clusters. The vascu-
lar component is similar to conventional hemangioma
and may contain large, highly cellular areas composed of
spindle cells forming narrow vascular channels. The
spindle-cell areas may show prominent mitotic activity,
but atypical mitoses are absent. Larger-caliber vessels are
also present and may form clusters mimicking common
(cavernous) hemangioma. Vascular-cartilaginous hamar-
toma frequently shows features of superimposed second-
ary aneurysmal bone cyst.49,54-56 In fact, aneurysmal bone
Text continued on p. 1110
1106 16  Miscellaneous Mesenchymal Tumors

A B

C D
FIGURE 16-5  ■  Parosteal lipoma: radiographic, gross, and microscopic features. A, Lateral radiograph of femur shows multilobulated,
partially lucent parosteal tumor containing areas of mineralization. B, Corresponding magnetic resonance image demonstrates
parosteal location of tumor, which for the most part shows same signal intensity as marrow fat. C, Gross specimen of excised
tumor mass shown in A and B. It consists of lobulated adipose tissue covered by thin fibrous capsule. Bony spur was
present at point of attachment to cortex. D, Photomicrograph shows mature adipose tissue traversed by fibrous bands. (D, ×100)
(D, hematoxylin-eosin.)

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 16  Miscellaneous Mesenchymal Tumors 1107

A B

C D
FIGURE 16-6  ■  Vascular-cartilaginous hamartoma of rib in infancy. A, Chest radiograph shows large, ill-defined intrathoracic expansile
mass arising from the ninth and tenth ribs of a 7-month-old boy. B, Bulging encapsulated tumor mass compresses lung. Most of
this mass was composed of aneurysmal bone cyst component of cartilaginous hamartoma. C, Radiograph of resection specimen
of cartilaginous hamartoma that arose in rib with secondary aneurysmal bone cyst formation. Expansile lytic lesion with focal cal-
cification is seen in central rib. D, Whole-mount section of rib shows intramedullary cartilage lobules and dilated vascular channels
(hematoxylin-eosin).

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1108 16  Miscellaneous Mesenchymal Tumors

B
FIGURE 16-7  ■  Vascular-cartilaginous hamartoma of rib in infancy: microscopic features. A, Islands of mature cartilage within fibro-
vascular stroma containing numerous capillary-type vessels. B, Higher magnification of A shows islands of cartilage within spindle-
cell stroma with numerous capillary vessels. Inset, Higher magnification of spindle-cell area. Note focal brisk mitotic activity.
(A, ×100; B, ×200; Inset, ×400) (A, B, and Inset, hematoxylin-eosin)

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 16  Miscellaneous Mesenchymal Tumors 1109

C
FIGURE 16-8  ■  Vascular-cartilaginous hamartoma of rib in infancy: radiographic features. A and B, T1-weighted magnetic resonance
images (MRI) showing a well demarcated low signal lesion of the chest wall. C, T2-weighted MRI showing signal enhancement.

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1110 16  Miscellaneous Mesenchymal Tumors
cyst features can dominate the lesion. Some of the lesions
may contain coalescent nodules of mature hyaline carti-
lage that obscure the spindle and vascular component of
the lesion (Fig. 16-9).
Treatment and Behavior
These rare lesions are benign and may be cured by en
bloc excision of the mass in continuity with the involved
rib. Rapid enlargement of the lesion can be clinically
observed if vascular-cartilaginous hamartoma is compli-
cated by a superimposed aneurysmal bone cyst.49,54-56
MELANOTIC NEUROECTODERMAL
TUMOR OF INFANCY
Definition
Melanotic neuroectodermal tumor of infancy is a rare,
distinctive neoplasm that frequently affects children
younger than age 1 year. The tumor is composed of nests
of cells that have melanin pigment and is also referred to
as retinal anlage tumor, melanotic progonoma, or melanotic
ameloblastoma.
Incidence and Location
Melanotic neuroectodermal tumors usually involve the
maxilla or mandible but also occur in the soft tissue,
the epididymis, and the mediastinum or may present as
intracranial (dural or brain) masses.60,62-64,67-69,71,72,79,80,82,85
They may present as lesions in the long bones. The
lesion can be clinically associated with increased levels
of catecholamines and urinary excretion of vanillylman-
delic acid.61,70
Radiographic Imaging
Radiographically, the tumor presents as a well-
demarcated, lytic bone lesion.63,72,80 The preoperative
diagnosis can be suspected radiographically if the lesion
presents in typical locations—the maxilla or mandible—
in a child during the first year of life.
Gross Findings
The lesion is fibrous and tan, brown, or black, depending
on the proportion of the pigmented component.
Microscopic Findings
Microscopic features are characteristic and consist of two
basic cell populations: small neuroblastic cells and larger,
melanin-containing epithelial cells arranged in a distinct
architectural pattern.65,66,73-78,81 The tumor cells form
nests within a predominantly fibrous stroma. The nests
are delineated by epithelial, pigment-containing cells
(Figs. 16-10 to 16-14). The central portion of these struc-
tures with alveolar or tubular arrangements is filled by
small, loosely arranged neuroblastic cells in a neurofibril-
lary matrix (Fig. 16-13, B to D). The neuroblastic cells
occasionally form larger, more diffuse areas in which
ERRNVPHGLFRVRUJ
epithelial alveolar structures are loosely distributed. This
may create a more disorganized pattern of neuroblastic
cells and solid ephithelial proliferations. The presence
of heterologous elements (i.e., mesenchymal spindle
cells and woven bone) has also been described but is
extremely rare.83
The tumor cells, particularly the epithelial pigment–
containing cells, are positive for keratin and occasionally
positive for epithelial membrane antigen and the HMB-45
marker. In addition, both components (i.e., small neuro-
blastic cells and epithelial cells) are positive for neuron-
specific enolase and Leu-7 and occasionally are positive
for synaptophysin. Glial fibrillary acidic and S-100
proteins may be focally positive in a small-cell neuroblas-
tic component. This immunohistochemical pattern is
consistent with the postulated neuroectodermal deriva-
tion of these tumors.73,84,86,92,81
Treatment and Behavior
Melanotic neuroectodermal tumors of infancy generally
behave as benign lesions, but local recurrence is possible.
In addition, approximately 6% of patients develop distant
metastases. The development of distant metastases cannot
be correlated with any specific microscopic features,
the distribution of DNA ploidy, or tumor proliferation
parameters.
PERIVASCULAR EPITHELIOID
CELL TUMOR
Definition
Perivascular epithelioid cell tumor (PEComa) is a rare
distinct neoplasm of bone made up of epithelioid clear
cells rich in glycogen and characterized by coexpres-
sion of muscle and melanocytic markers. This term has
been applied to an expanding family of tumors that are
presumed to originate from microscopically and pheno-
typically unique perivascular epithelioid cells, although
there is no known normal cellular counterpart to these
cells, and precursor lesions for PEComas have not been
identified.88-91,99,101 It includes angiomyolipoma (both renal
and extrarenal), lymphangiomyomatosis, clear cell sugar
tumor of the lung, and a variety of spindled and epithe-
lioid neoplasms involving various organs, soft tissue, and
bone with a similar phenotype.88,92,93,96,98,100,105,108-110,114,116
The unifying concept proposed for this family of tumors
evolved over the past century and was developed by iden-
tifying unique clear cell features as well as the smooth
muscle and melanocytic characteristics of the tumor cells.
A distinct type of benign clear cell tumor referred to as
clear cell sugar tumor was described in the lung in 1963 by
Liebow and Castleman.107 The name refers to the clear
cytoplasm of the cells, which is rich in glycogen. Despite
their epithelioid appearance, the clear cells are negative
for epithelial markers and exhibit distinctive coexpression
of muscle and melanoma markers.88,89,97,100,105,106,112,115 The
same immunophenotypic features are also present in a
subset of cells in lymphangiomatosis and angiomyolipoma.
On the basis of the common and distinctive phenotype,
Text continued on p. 1117
 16  Miscellaneous Mesenchymal Tumors 1111

A B

C D
FIGURE 16-9  ■  Vascular-cartilaginous hamartoma of rib in infancy: microscopic features. A and B, Low power view of predominantly
cartilaginous component of the lesion with small islands of fibrovascular cores showing enlarged vascular channels. C and D, Higher
magnification showing mature hyaline cartilage and fibrous component with prominent vascular channels. (A and B, ×50; C and
D, ×100.) (A-D, hematoxylin-eosin.)

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1112 16  Miscellaneous Mesenchymal Tumors

A B

C D

FIGURE 16-10  ■  Melanotic neuroectodemal tumor of infancy: radiographic features. A and B, Axial and coronal magnetic resonance
images show variable signal intensity tumor involving left lateral orbit in the greater wing of sphenoid bone in a 3-month-old girl.
C and D, Axial computed tomograms of the lesion in A and B showing mixed sclerotic and lytic tumor involving left lateral orbit.

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 A

FIGURE 16-11  ■  Melanotic neuroectodermal tumor of infancy: microscopic features. A, Epithelial cells form tubular or alveolar struc-
tures in fibrous stroma. B, Central portions of epithelial-lined structures are filled with smaller, loosely arranged neuroblastic cells.
Inset (top), Higher magnification of A documents epithelial appearance of cells lining tubular structures that contain melanotic
granules. Inset (bottom), Higher magnification of B shows small neuroblastic cells filling larger alveolar spaces. Note loose fibrillar
intercellular matrix. (A and B, ×100; Insets, ×200) (A, B, and Insets, hematoxylin-eosin.) (Courtesy Dr. M.A. Luna, Houston.)

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1114 16  Miscellaneous Mesenchymal Tumors

A B

C D
FIGURE 16-12  ■  Melanotic neuroectodermal tumor of infancy: microscopic features. A, Low power magnification of complex tubular
structures in fibrous stroma. B, Higher power view of tubular structures lined by epithelial cells containing melanin pigment. C, Low
power magnification of large alveolar structures. D, Higher magnification of C shows small neuroblastic cells filling alveolar space.
(A and C, ×100; B, ×400; D, ×200) (A-D, hematoxylin-eosin). (Courtesy Dr. M.A. Luna, Houston.)

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 16  Miscellaneous Mesenchymal Tumors 1115

A B

C D
FIGURE 16-13  ■  Melanotic neuroectodemal tumor of infancy: microscopic features. A, Intermediate power view of a tumor showing
proliferation of small loosely arranged neuroblastic cells. B, Higher magnification of A showing proliferation of primitive neuroblastic
cells. C, Intermediate power view showing proliferation of epithelioid cells and small loosely arranged cluster of small neuroblastic
cells. D, Higher magnification of C showing clusters of small neuroblastic cells adjacent to areas of solid proliferations of epithelioid-
appearing cells. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

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1116 16  Miscellaneous Mesenchymal Tumors

B C
FIGURE 16-14  ■  Melanotic neuroectodemal tumor of infancy: microscopic features. A, Low power view showing strong positive
staining for cytokeratin in epithelioid cells. Small neuroblastic cells are negative. B, Higher magnification of A showing strong posi-
tive staining for keratin in the epithelioid component of the tumor. C, Coexpression of HMB-45 in the epithelioid component of the
tumor. (A, ×100; B and C, ×200)

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Bonetti et al, Pea et al, and Zamboni et al defined a family
of lesions characterized by the presence of this peculiar
cell type, the perivascular epithelioid cell (PEC), and
designated the group of tumors with similar features as
PEComas.88,89,90,118 These tumors have also been referred
to as PEST (primary extrapulmonary sugar tumors).114
Patients with one or more of the PEC family of lesions
may have the tuberous sclerosis complex. The tuber-
ous sclerosis complex is typically associated with angio-
myolipomas and lymphangiomyomatosis, but PEComas
in other anatomic sites can develop in this syndrome.91
Two-step inactivation of the TSC1 and TSC2 genes acti-
vating the Rheb/mTOR/p70S6K pathway underlie the
development of PEComas in tuberous sclerosis.101,117
Comparative genomic hybridization studies of PEComas
disclose frequent losses and gains of multiple chro-
mosomes, implicating major chromosomal rearrange-
ments.111 Some PEComas show rearrangements of the
transcription factor E3 (TFE3) gene and overexpression
of the TFE3 protein immunohistochemically.87,95,104,113
Incidence and Location
Our experience is restricted to four cases of primary clear
cell sugar tumor of bone seen in consultation. These pre-
sented in the calcaneus of a 9-year-old boy, the humerus
of a 10-year-old girl, the patella of a 29-year-old man, and
the proximal phalanx of the middle finger of the left hand
in a 33-year-old woman. One of the cases showed a clonal
cytogenetic abnormality consisting of reciprocal chromo-
somal translocation t(X;2) (q11-12; q34-35).
Radiographic Imaging
Radiographic features are nonspecific and consist of
a well-demarcated lucent lesion with a trabeculated
appearance and sclerotic margins (Figs. 16-15 and 16-
16). In general, the tumors arise in skeletal sites that are
relatively rare for primary bone tumors.
Microscopic Findings
Microscopically clear cell sugar tumors consist of clear
cells arranged in nests with prominent arborizing capil-
lary network demarcating the tumor cell nests (Figs.
16-17 and 16-18). The nuclei are uniform, oval or round,
with prominent nucleoli and fine granular chromatin.
Mitoses are rare and atypical mitoses are absent. Some
tumor cells contain pink granular cytoplasm but most
are vacuolated, which gives the tumor a clear cell appear-
ance. Reported cases of PEComas in bone display a spec-
trum of microscopic features ranging from clear cell
lesions, somewhat similar to those described for pulmo-
nary clear cell sugar tumors, to highly pleomorphic
lesions with necrosis and brisk mitotic activities reminis-
cent of those observed in a subset of epithelioid renal
angiomyolipomas.94,102,103,106,117
Special Techniques
The cytoplasm of clear cells is rich in glycogen and stains
positively with periodic acid–Schiff (PAS). Despite their
epithelioid appearance the clear cells are consistently
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16  Miscellaneous Mesenchymal Tumors 1117
negative for epithelial markers such as epithelial mem-
brane antigen and keratins (CAM5.2 and AE1:AE3) but
coexpress muscle markers (smooth muscle actin [SMA],
muscle-specific actin [MSA], and desmin) and melano-
cytic antigens (HMB45 and melanin A) (Fig. 16-18, D).
These lesions are also positive for neuron-specific enolase,
CD68, and sometimes for S-100. Ultrastructurally the
tumor cells form well-developed nests surrounded by
rudimentary basement membrane with prominent capil-
lary network encircling individual tumor cell nests. The
cytoplasm is rich in glycogen and contains multiple mito-
chondria. Premelanosomes and dense granules are often
observed but are not always present. Poorly developed
intercellular junctions are present but true desmosomes
are not found.
Treatment and Behavior
Long-term follow-up on the four cases indicates that
clear cell sugar tumors of bone are of uncertain malignant
potential. Three of our cases behaved as benign tumors
but one metastasized to the lung after many years of
follow-up. Reported cases of PEComas in bone indicate
that both primary and metastatic lesions can be found in
the skeleton. Clinical follow-up with primary cases is very
limited, but indicates a metastatic potential for those
tumors that originate as primary bone lesions.94,102,106,117
LEIOMYOSARCOMA
Definition
Leiomyosarcoma is a malignant mesenchymal tumor
composed predominantly of spindle cells that exhibit
smooth muscle differentiation.
Incidence and Location
Primary leiomyosarcoma in bone is extremely rare, and
fewer than 100 well-documented cases have been
described. The peak age incidence and most frequent
sites of skeletal involvement are shown in Figure 16-19.
Many bona fide primary leiomyosarcomas of bone may
prove to be metastatic, and the primary lesions are most
frequently located in the uterus and gastrointestinal
tract.123,129,142,154 Some of these lesions present many years
after excision of allegedly benign smooth muscle tumors
in the uterus or gastrointestinal tract. The ages of affected
patients are widely distributed, but primary leiomyosar-
coma of bone is rare during the first two decades of
life.120-122,126,132,145,150,155,159
The most common site is the distal femur followed
by the proximal tibia. These bones are involved in
almost 50% of reported cases, but any bone can be
affected.119,121,128,130-132,136,141,144,153,157 Other major long
tubular bones of the extremities are also frequently
involved. The pelvis is the most frequently involved trunk
bone. Leiomyosarcoma of bone also has been described
as one of the rare complications of radiation therapy.140
Leiomyosarcomas occur in immunocompromised
patients such as those who have undergone organ trans-
plants and patients with acquired immunodeficiency
Text continued on p. 1122
1118 16  Miscellaneous Mesenchymal Tumors

A B

C D
FIGURE 16-15  ■  Clear cell sugar tumor (PEComa): radiographic features. A, Well demarcated lucent lesion with a trabeculated appear-
ance and sclerotic margins involving the calcaneus of a 9-year-old boy. B, Intramedullary lucency with focal sclerosis and trabecula-
tion involving the proximal phalanx of the middle finger in a 33-year-old woman. C, Lucent lesion with trabeculation and focal
penetration of the cortex in the patella of a 29-year-old man. D, Sagittal magnetic resonance image of the lesion shown in C depict-
ing an intramedullary low signal intensity mass in the patella.

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 16  Miscellaneous Mesenchymal Tumors 1119

A B

C D
FIGURE 16-16  ■  Clear cell sugar tumor (PEComa): radiographic features. A and B, Anteroposterior and lateral views of the lesion
involving distal humerus of a 10-year-old girl. Note an expansile lytic lesion with trabeculations. The cortex shows thinning and
endosteal scalloping. C and D, T1- and T2-weighted axial magnetic resonance images showing an expansile intramedullary lesion
with thin but intact overlying cortex.

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1120 16  Miscellaneous Mesenchymal Tumors

A B

C D
FIGURE 16-17  ■  Clear cell sugar tumor (PEComa): microscopic features. A and B, Low and intermediate power view of PEComa
composed of clear cells arranged in nests with prominent capillary network. C and D, Higher magnification of PEComa showing
nests of tumor cells with clear cytoplasm and nuclei containing prominent typically singular nucleoli. (A, ×25; B, ×50; C, ×100;
D, ×400.) (A-D, hematoxylin-eosin.)

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 16  Miscellaneous Mesenchymal Tumors 1121

C D
FIGURE 16-18  ■  Clear cell sugar tumor (PEComa): microscopic features. A, Nests of primarily granular cells surrounded by prominent
capillary network. Inset, Higher magnification of a nest of tumor cells with predominantly granular cytoplasm and focal clear cell
features. B, Nests of clear cells demarcated by prominent capillary network. C, Higher magnification of B showing nests of clear
cells. D, Strong diffuse cytoplasmic stain of PEComa cells for HMB-45 protein. (A and B, ×100; Inset, C and D, x 200) (A-C and
inset, hematoxylin-eosin; D, DAB.)

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1122 16  Miscellaneous Mesenchymal Tumors
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 16-19  ■  Leiomyosarcoma of bone. Peak age incidence and most frequent sites of skeletal involvement. Most frequent sites
are indicated by solid black arrows.
syndrome (AIDS) with increased frequency as compared
to the general population.124,125,151,158,160 Leiomyosarcomas
associated with AIDS predominantly occur in children
and young adults. These tumors are often multifocal
and primarily involve the gastrointestinal tract, liver, and
lung.127,139,146,147,163 The development of leiomyosarco-
mas in immunocompromised patients is associated with
Epstein-Barr virus (EBV) infection; EBV surface antigen
(CD21) has been documented in these lesions.134,135,138
Although some rare examples of primary leiomyosarcoma
of bone occur in children, no association with immuno-
suppression and EBV infection has been reported for
these tumors. Leiomyosarcomas of the soft tissue and
bone may also develop in familial retinoblastoma syn-
drome caused by germline mutations of RB1 mapping to
13q14 locus (Figs. 16-24 and 16-29).
Radiographic Imaging
Radiographic features are nonspecific but are consis-
tent with those of a malignant lesion. On plain radio-
graphs, leiomyosarcoma presents as a destructive lytic
lesion with cortical disruption and extension into soft
tissue.122,126,149,152,162 The margins of the lesion are ill
defined with frequent moth-eaten patterns of bone
destruction (Figs. 16-20 to 16-24).
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7 8
Gross Findings
When the lesion is examined in situ, the cut surface is
gray to white with areas of necrosis (Fig. 16-25). The
tumor is usually well demarcated from the surrounding
bone or soft tissue, and this feature can be misleading. In
fact, microscopic margins show an infiltrative irregular
pattern of involvement of adjacent structures.
Microscopic Findings
The microscopic appearance of primary leiomyosarcoma
of bone does not differ from that of more common
uterine, gastrointestinal, or soft tissue leiomyosarco-
mas.150,159,161 The tumor is composed of interweaving fas-
cicles of spindle cells that have prominent eosinophilic
cytoplasm and elongated, blunt-ended nuclei (Figs. 16-27
and 16-28). The stroma can have variable amounts of
collagen, and the lesion may be focally or diffusely heavily
hyalinized. Large areas of necrosis can be present. Focally
the tumor cells may be more rounded with prominent
eosinophilic cytoplasm; that is, they may have a round-
cell or epithelioid appearance. Leiomyosarcomas in bone
frequently exhibit an associated giant-cell reaction. Occa-
sionally, aggregates of multinucleated, osteoclast-like
giant cells can be so prominent as to obscure the spindle
Text continued on p. 1129
 16  Miscellaneous Mesenchymal Tumors 1123

A B
FIGURE 16-20  ■  Leiomyosarcoma of bone: radiographic features. A and B, Anteroposterior and lateral radiographs of distal femoral
shaft of a 33-year-old man show lytic lesion with permeative destruction at margins and focal cortical erosion. Small amount of
periosteal new bone formation is seen along one border. Patient had experienced increasing pain in this area for 2 years.

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1124 16  Miscellaneous Mesenchymal Tumors

A B

D
FIGURE 16-21  ■  Leiomyosarcoma of bone: radiographic features. A, Lateral radiograph shows destructive lesion of proximal end of
fibula in a 32-year-old man. This well-differentiated leiomyosarcoma is sharply demarcated and expansile, without periosteal reac-
tion. B, Coronal magnetic resonance image (MRI) shows marrow replacement and cortical breakthrough laterally. C, Axial MRI shows
cortical thinning and disruption, with extension into soft tissue. D, Specimen radiograph demonstrates sharp circumscription of
proximal fibular leiomyosarcoma. Remnants of preexisting bone are seen in tumor, but reactive sclerosis is not apparent.

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 16  Miscellaneous Mesenchymal Tumors 1125

B
FIGURE 16-22  ■  Leiomyosarcoma of bone: radiographic features. A and B, Anteroposterior and lateral radiographs of knee of a
51-year-old man show ill-defined lesion in proximal tibial metaphysis. Tumor has produced permeative pattern of bone destruction
with no discernible periosteal reaction.

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1126 16  Miscellaneous Mesenchymal Tumors

C D
FIGURE 16-23  ■  Leiomyosarcoma of bone: radiographic features. A and B, Anteroposterior and lateral radiographs of ankle region of
a 68-year-old woman show ill-defined destructive lesion of distal tibial shaft with large mass in posterior soft tissue. C, Computed
tomogram shows intraosseous tibial tumor and large mass in posterior soft tissue. D, Coronal cut through distal tibia and ankle
(amputation specimen) shows gray-white, firm intraosseous tumor filling marrow cavity and eroding tibial cortex.

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 16  Miscellaneous Mesenchymal Tumors 1127

A B C
FIGURE 16-24  ■  Leiomyosarcoma of bone in familial retinoblastoma: radiographic features. A, Plain radiographic image showing
intramedullary diaphyseal lesion of the humerus with lytic destructive growth pattern and pathologic fracture in a 40-year-old woman
who had a son with bilateral retinoblastoma. B and C, T1- and T2-weighted magnetic resonance images of the lesion shown in
A showing a destructive intramedullary lesion with associated pathologic fracture. (For microscopic features, see Figure 16-26.)

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1128 16  Miscellaneous Mesenchymal Tumors

A C
FIGURE 16-25  ■  Leiomyosarcoma of bone: gross features. A, Sagittally sectioned tibial resection specimen with destructive gray to
white mass involving distal area. Note massive amount of cortical destruction, with circumferential extension into soft tissue.
B, Proximal tibial resection specimen shows destructive gray to white intramedullary mass. C, Coronal section of proximal tibial
resection shows intramedullary mass with central necrosis within fleshy site.

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cells and smooth muscle features of the tumor cells. Epi-
thelioid change can be focally present but is rarely a
dominant feature in primary leiomyosarcoma of bone.137
Therefore if such change is present, it suggests that the
lesion in question may be metastatic rather than primary
(Fig. 16-26). Pleomorphic or dedifferentiated leiomyo-
sarcoma is also extremely unusual in bone (Fig. 16-29),
and tumors with such features often are metastatic.
Special Techniques
Immunohistochemically, the tumor cells are strongly and
diffusely positive for SMA and MSA (Figs. 16-27, D and
16-29, C-D).121,133,143 Similar to other leiomyosarcomas,
especially those of the gastrointestinal tract, leiomyosar-
coma of bone can exhibit focal positivity for keratin.
Electron microscopic examination can provide supportive
evidence for the diagnosis of leiomyosarcoma (Fig. 16-30).
Ultrastructurally these tumors are composed of spindle
cells containing a centrally placed elongated nucleus with
blunt ends. Although the nuclei of smooth muscle cells
are oval under the light microscope, ultrastructurally they
may show multiple infoldings of the nuclear envelope.
The cytoplasm contains fine (6- to 80-nm thick) filaments
consistent with actin. Many electron-dense patches are
present within the filaments. These structures appear to
represent focal condensation of filaments. Smooth muscle
cells also contain numerous pinocytotic vesicles and are
surrounded by basal lamina. In well-differentiated tumors,
the described features are present in every tumor cell and
are easy to identify. On the other hand, in more undif-
ferentiated (high-grade) lesions, ultrastructural features
of smooth muscle differentiation can be focal. Leiomyo-
sarcomas show complex chromosomal aberrations with
frequent loss of 3p21-23, 8p21-pter, 13q12-13, and
13q32-qter and gain of the 1q21-31 region.148,156
Differential Diagnosis
In any case of leiomyosarcoma involving bone, a meta-
static lesion must be ruled out before the lesion in ques-
tion can be designated as a primary tumor. Microscopically
leiomyosarcoma must be differentiated from malignant
fibrous histiocytoma or fibrosarcoma and spindle-cell carcinoma.
These lesions have prominent herringbone or storiform
patterns that are typically not present in leiomyosarcoma.
Immunohistochemical staining for smooth muscle
markers can be somewhat confusing because some of the
malignant fibrous histiocytoma cells can be positive for
SMA and MSA. On the other hand, strong uniform posi-
tivity of tumor cells for these markers is rarely seen in
malignant fibrous histiocytomas or fibrosarcomas.
Differentiation from spindle-cell sarcomatoid carci-
noma can be accomplished in a majority of cases if clinical
data are available. In addition, most sarcomatoid carcino-
mas, at least focally, show strong positivity for epithelial
markers.
RHABDOMYOSARCOMA
Rhabdomyosarcoma is one of the rarest primary neo-
plasms of bone. The majority of rhabdomyosarcomas
ERRNVPHGLFRVRUJ
16  Miscellaneous Mesenchymal Tumors 1129
that involve bone in children are metastatic or represent
secondary involvement by contiguous growth of a soft
tissue lesion.169,170,171 The latter is typically seen in the
head and neck region (orbit). In patients older than age
50 years, the presence of rhabdomyoblastic differentia-
tion within a bone tumor is more likely to represent a
phenotypic switch (divergent differentiation) within a
high-grade sarcomatous component of dedifferentiated
chondrosarcoma rather than a pure primary rhabdomyo-
sarcoma of bone.164,166,167 However, there are extremely
rare, well-documented cases of pure primary rhabdomyo-
sarcomas of bone.165,168,172,173 Radiographic features are
nonspecific and show bone destruction by a lytic process
(Fig. 16-31). We have seen one case of a pure primary
rhabdomyosarcoma of bone.
The cases described in bone do not differ from rhab-
domyosarcomas of soft tissue, and both embryonal and
adult (pleomorphic) types of rhabdomyosarcoma can
occur in bone.
Typical microscopic features include round, ribbon-
shaped, and strap rhabdomyoblasts (Fig. 16-32). Large,
round, pleomorphic cells with dense eosinophilic cyto-
plasm, which are typical of the pleomorphic variant
of rhabdomyosarcoma, also may be present. In typical
cases, the tumor cells are positive for MyoD1, myo-
genin, myoglobin, and desmin, but the intensity of
staining is proportional to the degree of skeletal muscle
differentiation.
Cells with microscopically recognizable skeletal
muscle differentiation are typically strongly positive for
these markers. The staining is usually minimal or even
absent in less-differentiated round- or spindle-cell areas.
It is important to realize that MSA and desmin are also
positive in smooth muscle. Therefore the use of these
markers does not help in the determination between skel-
etal and smooth muscle differentiation.
The presence of other component,s such as cartilage,
bone, and undifferentiated sarcomatous elements, in
bone raise the suspicion that the lesion in question may
represent a dedifferentiation phenomenon rather than a
primary rhabdomyosarcoma of bone.
MULTIPOTENTIAL PRIMITIVE
SARCOMA, POLYHISTIOMA, AND
MALIGNANT MESENCHYMOMA
The term malignant mesenchymoma was proposed by
Stout184 to designate a group of malignant neoplasms that
had two or more distinct mesenchymal components
exhibiting divergent differentiation. Subsequently the
term was applied to a variety of neoplasms that involved
various organs. Rare cases of this questionable entity have
been reported in bone.174,178,181-184 In our opinion, most
lesions diagnosed as malignant mesenchymomas in bone
are better understood if they are classified as dedifferenti-
ated chondrosarcomas with divergent differentiation in
their high-grade sarcomatous components.179 Several
well documented cases of osteosarcoma combined with
rhabdomyosarcomatous differentiation have recently
been reported as primary bone lesions (Fig. 16-33).181,183,185
Text continued on p. 1138
 A

B
FIGURE 16-26  ■  Metastatic leiomyosarcoma of bone with epithelioid features. A and B, Low and intermediate power views of leio-
myosarcoma involving thoracic vertebrae. Note uniform epithelioid change of tumor cells and prominent hemangiopericytoma-like
pattern of branching vascular channels. This extent of epithelial change is rarely seen in primary leiomyosarcoma of bone and
suggests metastatic lesion. In this case, primary tumor was found in stomach. Inset (top) shows epithelioid features of tumor cells.
(A, ×100; B, ×200; Inset, ×400.) (A, B, and Inset, hematoxylin-eosin.)

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 16  Miscellaneous Mesenchymal Tumors 1131

A B

C D
FIGURE 16-27  ■  Leiomyosarcoma of bone: microscopic features. A, Interlacing bundles of spindle cells with inconspicuous nuclear
atypia. B and C, Features of smooth muscle are evident under higher magnification. Note bundles of cells with elongated endonuclei
and clearly darker dense, eosinophilic cytoplasm. D, Strong positivity of tumor cells for smooth muscle actin (A, ×100; B-D, ×200).

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1132 16  Miscellaneous Mesenchymal Tumors

A B

C D
FIGURE 16-28  ■  Leiomyosarcoma of bone: radiographic and microscopic features. A, Lytic lesion of distal tibia with cortical penetra-
tion in a 14-year-old girl. B, T1-weighted magnetic resonance image showing intramedullary lesion with low signal intensity. C, Low
power magnification of metastatic leiomyosarcoma in bone forming a subpleural nodule. D, Microscopic image of primary leiomyo-
sarcoma of the distal tibia showing interlacing bundles of spindle cells with prominent atypia. (C, ×4; D, ×100) (C and
D, hematoxylin-eosin.)

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 16  Miscellaneous Mesenchymal Tumors 1133

A B

C D
FIGURE 16-29  ■  Leiomyosarcoma of bone in familial retinoblastoma: microscopic features. A, Leiomyosarcoma composed of interlac-
ing spindle cells juxtaposed on areas with epithelioid appearance (×50). B, Highly pleomorphic dedifferentiated component of the
tumor shown in A (×200). C, Immunohistochemical stain for smooth muscle actin showing strong positive staining in spindle and
epithelioid areas and no staining in pleomorphic dedifferentiated component (×25). D, Immunohistochemical stain for desmin
showing strong positive staining of spindle cells and negative staining in pleomorphic areas (×50). Inset, Higher magnification of
pleomorphic component of the tumor with negative staining for desmin (×200). (A and B, hematoxylin-eosin; C, D, and Inset, DAB
with hematoxylin.) (Radiographic features of this case are shown in Figure 16-20.)

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1134 16  Miscellaneous Mesenchymal Tumors

B
FIGURE 16-30  ■  Leiomyosarcoma of bone: ultrastructural features. A, Low power magnification shows spindle-shaped tumor cells
with centrally placed oval nuclei. Note prominent bundles of actin filaments in peripheral areas of cytoplasm. B, Higher magnifica-
tion of A shows actin filaments with focal condensation forming patchy, electron-dense areas. Inset (top), Numerous pinocytotic
vesicles and presence of basal lamina are frequent features of cells exhibiting smooth muscle differentiation. Inset (bottom), Oval
nucleus of leiomyosarcoma with prominent nucleolus and irregular nuclear membrane forming deep infoldings. (A and bottom
Inset, ×3,500; B, ×12,000; top Inset, ×35,000)

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 16  Miscellaneous Mesenchymal Tumors 1135

B
FIGURE 16-31  ■  Rhabdomyosarcoma in bone: radiographic and gross features. A, Computed tomogram of pelvis of a 31-year-old
man with intraosseous radiolucent mass that has caused cortical destruction and has extended into soft tissue. B, Gross photograph
of wing of left ilium sectioned to show sarcoma that apparently arose in medullary cavity and penetrated cortex at several points.
Extension into soft tissue was noted during microscopic examination. (Courtesy Dr. M. Tsuneyoshi, Fukuoka, Japan.)

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1136 16  Miscellaneous Mesenchymal Tumors

A B

C D
FIGURE 16-32  ■  Rhabdomyosarcoma of bone: microscopic features. A-D, Spindle-cell malignant neoplasm with multiple strap cells
and occasional multinucleated large cells. (A-D, ×200) (A-D, hematoxylin-eosin.) (Courtesy Dr. M. Tsuneyoshi, Fukuoka, Japan.)

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 16  Miscellaneous Mesenchymal Tumors 1137

A B

C D

E F G
FIGURE 16-33  ■  Polyphenotypic sarcoma: radiographic and microscopic features. A, Computed tomogram scan of a destructive
osteoblastic lesion at the angle of the left mandible, with evidence of soft tissue extension. B, Areas of the osteosarcoma with
osteoblastic histology. There are pleomorphic tumor cells with extensive bone matrix production and osteoclasts. C, Areas of the
osteosarcoma with chondroblastic differentiation. There is extensive cartilaginous matrix production intermingled with osteoblastic
elements. D, Higher magnification of B showing osteoblastic differentiation and prominent osteoid deposition. E, Foci of tumor with
rhabdomyoblastic differentiation. The rhabdomyoblastic tumor cells have characteristic cross striations (arrow). F and G, Immuno-
phenotypic features support rhabdomyoblastic differentiation with positive staining for desmin and myogenin. (B and C, ×50;
D, F, and G, ×100; E, ×600) (B-E, hematoxylin-eosin.) (Reprinted with permission from Seethala RR, et al: Arch Pathol Lab Med 130:385–
388, 2006.)

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1138 16  Miscellaneous Mesenchymal Tumors
Some of these polyphenotypic sarcomas develop as com-
plications of radiotherapy.183
The terms primitive multipotential sarcoma and polyhis-
tioma were proposed by Hutter et al in 1966176 and
Jacobson in 1977,177 respectively. These terms were
used to designate a group of extremely rare primary
sarcomas of bone in which a population of primitive
undifferentiated cells, similar to those seen in Ewing’s
sarcoma, was accompanied by elements that exhibited
microscopically recognizable polyphenotypic differentia-
tion along several mesenchymal or even epithelial path-
ways (also see Chapter 11).175
Although a link between this neoplasm and a true
Ewing’s sarcoma was originally postulated and seems to
be logical, no consistent molecular data are available to
support this concept. On the other hand, some authors
say that review of a large series of small-cell tumors dis-
closes the presence of a new base of primitive sarcomas
with at least focal Ewing’s sarcoma–like features.180 Poly-
phenotypic differentiation, usually epithelial, muscular,
and neural, has been documented in some of these lesions
as well as the expression of MIC2 gene product.180
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 C H A P T E R 1 7 
Adamantinoma of Long Bone
CHAPTER OUTLINE
CLASSIC ADAMANTINOMA
DIFFERENTIATED (OSTEOFIBROUS
DYSPLASIA–LIKE) ADAMANTINOMA
An epithelial neoplasm originating in the long bones of
the skeleton, referred to as adamantinoma, which almost
exclusively affects the tibia and fibula, and its relationship
to a coexisting peculiar fibroosseus lesion, has been
intriguing both pathologists and clinicians for more than
a century. In 1913, Fischer17 described a peculiar tumor
occurring predominantly in the tibia and occasionally in
the fibula that was somewhat similar to a more common
odontogenic adamantinoma of the jaw bones. Despite
histologic similarity, there has been no proof that these
tumors—of the jaw bone and of the long bone—have a
similar histogenetic origin. Adamantinoma of long bones
is extremely rare; there are approximately 300 well-
documented cases published in the world literature.48-50
The largest individual series of long bone adamantinoma
was reported by a group from the Mayo Clinic.37,51,67,68
Long bone adamantinomas present with a wide range of
morphologic patterns that can mimic various primary or
even metastatic bone lesions. The morphologic diversity
of long bone adamantinomas also accounts for the con-
tinuing controversy regarding their histogenesis. Another
interesting phenomenon is the association of these tumors
with areas resembling osteofibrous dysplasia (ossifying
fibroma of long bones).
The first description of areas of rarefaction associ-
ated with long bone adamantinoma interpreted to be
osteitis fibrosa was provided in 1942 by Dockerty and
Myerding.15 In a subsequent article by Baker et al.,2 these
lesions were interpreted to be fibrous dysplasia. The first
comprehensive description of long bone adamantinoma
associated with areas resembling fibrous dysplasia was
provided in 1962 by Cohen et al.10 These authors stated
that the radiologic pattern of fibrous dysplasia associated
with adamantinoma was different from that of classic
fibrous dysplasia. Moreover, café au lait spots, which
are frequent in polyostotic fibrous dysplasia, were not
seen in association with adamantinomas. Therefore these
authors were the first to postulate that, despite the histo-
logic similarity to fibrous dysplasia, fibroosseous lesions
associated with adamantinoma may represent a distinc-
tive feature related to these tumors. The description of
ossifying fibroma of long bone by Kempson38 in 1966 and
the subsequent redesignation of this lesion as osteofibrous
dysplasia by Campanacci et al.7,8 provided a new basis for
1142
ERRNVPHGLFRVRUJ
OSTEOFIBROUS DYSPLASIA
studying the relationship between adamantinoma and
fibroosseous lesions of the long bones. Further studies
of such composite lesions showed that the histologic
and radiologic features of the fibroosseous components
were more consistent with those of osteofibrous dyspla-
sia.1,32,47,51 These studies also showed that although osteo-
fibrous dysplasia–like changes are frequently present
at the periphery of adamantinomas, in some instances
they may dominate the entire lesion.62,64-66 Most current
studies have shown that long bone adamantinoma, despite
the considerable range of its histologic patterns, appears
to be of an epithelial nature.11,52-58
The correlation of clinical, radiologic, and his-
tologic data of our 25 consultation cases showed that
long bone adamantinomas could be divided into two
main groups (Fig. 17-1).11 The first, defined as classic
adamantinoma, is characterized by an abundance of
tumor cells and destructive growth pattern radiographi-
cally. The second group is defined as differentiated
adamantinoma and is characterized histologically by a
predominance of an osteofibrous dysplasia–like pattern
with a small, inconspicuous component of epithelial
tumor elements. On radiographs, differentiated adaman-
tinomas are intracortical and often multicentric lesions.
The histogenesis of these peculiar neoplasms is still
unclear, and various concepts of their origin as derived
from eccrine gland, synovial, vascular, or pluripotential
mesenchyma have been postulated.9,12,16,28,29,38,43 The
current literature continues to subdivide adamantinomas
of long bones into the classic and differentiated osteofi-
brous dysplasia-like forms.13,19,26,41 A summary of clinical,
radiographic, and histologic features of the two subsets
of long bone adamantinoma is provided in Table 17-1. In
the description in this chapter, classic and differentiated
adamantinoma are discussed separately.
CLASSIC ADAMANTINOMA
Definition
Classic adamantinoma is a distinct, rare biphasic neo-
plasm of long bones that predominantly involves the tibia
and occasionally the fibula and is characterized by a
 17  Adamantinoma of Long Bone 1143

Differentiated
(osteofibrous dysplasia–like)
adamantinoma Classic adamantinoma

Beyond cortex

Intracortical

Age
of 0 10 20 30 40 50 60 70 80
patient
Predominance of Predominance of
Metastases
osteofibrous dysplasia tumor cells
FIGURE 17-1  ■  Separation of long bone adamantinomas into two main groups (differentiated and classic). Separation is based on
combination of clinical, radiologic, and microscopic data.

TABLE 17-1 Summary of Features Characteristic of Classic and Differentiated Types of Adamantinoma
of Long Bone
Feature Classic Differentiated
Age Usually after first 20 years First 20 years
Location Tibia or fibula Tibia or fibula
Radiograph Expand beyond periosteum or intracortical Intracortical
Histology Predominance of tumor cells forming basaloid, Predominance of osteofibrous dysplasia
spindled, tubular, or squamous pattern pattern
Immunohistochemistry Predominance of cytokeratin-positive cells Scattered elements positive for cytokeratin

variety of histologic patterns. It has an overall histologic Radiographic Imaging

similarity to the more common odontogenic adamanti-
noma of the jaw bones.
Incidence and Location
Classic adamantinoma is extremely rare; while its true
incidence is unknown, it clearly accounts for less than 1%
of all bone neoplasms.48,49 This tumor typically affects
patients older than age 20 years (Fig. 17-2), but occasion-
ally it may occur during the first two decades of life. The
youngest patient with classic adamantinoma in our series
was a 13-year-old boy who subsequently developed lung
metastases.11 More recently, a case of classic adamanti-
noma has been observed in the tibia of a 3-year-old boy.40
The involved bones are usually the tibia, fibula, or both.
Involvement of other skeletal sites is rare but has been
reported.49 According to our experience, the involvement
of other skeletal sites should make the clinician question
the diagnosis of adamantinoma and rule out other meta-
static neoplasms. Synchronous involvement of the tibia
and fibula by two independent foci or by contiguous foci
is typical of adamantinoma. The tibia and fibula are syn-
chronously involved in approximately 50% of cases.
Clinical Symptoms
Pain, bowing deformity of the tibia, or both of these
symptoms are the most frequent clinical findings, and
these may be present for decades before diagnosis. A
palpable mass may be present.
Features of classic adamantinoma on radiographs are dis-
tinct and often diagnostic.8,11,48,51 According to the radio-
graphic appearance, the lesion can be divided into two
major groups: intracortical and with radiologic evidence
of complete cortical disruption and involvement of the
medullary cavity, adjacent soft tissue, or both. Approxi-
mately 70% of lesions are located in the midshaft of the
tibia. The remaining 30% involve the proximal or distal
tibial regions. In the tibia, involvement of the anterolat-
eral cortex and the presence of a moderate to severe
bowing deformity are typical. The common appearance
is of mixed lytic and sclerotic lesions or multiple lucencies
with sclerosis of the intervening bone (Figs. 17-3 and
17-4). The lucent lesions have well-defined margins. Fea-
tures of a destructive growth pattern with cortical disrup-
tion are often seen. On radiographs, some lesions appear
as destructive lytic defects involving two adjacent bones,
the tibia and fibula. This is typically seen when the lesions
are located at the proximal or distal end of the tibia (Fig.
17-3). The synchronous involvement by separate foci in
the tibia and fibula is less frequent in this form of ada-
mantinoma (i.e., classic versus differentiated). The eccen-
tricity of the lesions is less evident in the fibula, in which
the lesions are more centrally located and represent
sharply demarcated lytic foci with sclerotic margins.
Expansion of the bone contour without bowing defor-
mity is typical of fibular lesions. A recent study of the role
of magnetic resonance imaging (MRI) characteristics
found that the method did not add to the specificity of

ERRNVPHGLFRVRUJ
1144 17  Adamantinoma of Long Bone
(osteofibrous dysplasia–like)
adamantinoma
Differentiated
Incidence
1 2
FIGURE 17-2  ■  Adamantinoma of long bones. Age distribution of classic and differentiated adamantinoma and most frequent sites
of skeletal involvement are indicated by a solid black arrow.
the distinction between histologic subtypes, but was
helpful in evaluating soft tissue and intramedullary
extension.69
Gross Findings
Classic adamantinoma evaluated in a resection specimen
presents as a fleshy, soft mass. The lesion can be multifo-
cal or can involve a large segment of the medullary cavity
(Figs. 17-5 and 17-6). Gradual transition from soft, fleshy
areas to gritty fibrous tissue can be seen. Complete corti-
cal disruption and contiguous involvement of adjacent
soft tissue or paired bone may be present.
Microscopic Findings
The histologic patterns of adamantinoma are extremely
variable within each case and among cases. However,
five basic patterns can be recognized: basaloid, spindle,
tubular, squamous, and osteofibrous dysplasia–like.70
The basaloid pattern consists of nests or large masses
of epithelioid tumor cells that have a peripheral layer of
cells oriented roughly at right angles to the inner masses
of cells (Figs. 17-7 and 17-8). Peripheral cuboid or
columnar cells with elongated nuclei occasionally produce
sharply demarcated palisading structures. Cystlike spaces
Classic adamantinoma
3 4 5 6 7 8
Age in decades
of various sizes within the masses of cells usually separate
the outer layer of cells from the inner masses. The solid
areas are composed of cells forming sheets with a roughly
parallel arrangement of their oval nuclei.
The spindle pattern is characterized by the presence
of spindle-shaped cells with elongated nuclei (Fig. 17-9).
This pattern also lacks the peripheral palisading orienta-
tion of the cells that is characteristic of the basaloid
pattern. The areas of pure spindle-cell pattern resemble
mesenchymal spindle-cell tumors such as fibrosarcoma,
even exhibiting a herring-bone pattern typical of that
tumor.
The tubular pattern consists of small, flattened or
cuboid cells that line spaces of varying sizes (Fig. 17-10).
In some areas the tubular pattern is produced by small
glandular spaces separating spindle cells. Sometimes,
tubular structures lined by one or several layers of cuboi-
dal cells or flattened cells are embedded in fibrous stroma.
Tubular structures give the impression of vascular chan-
nels of various sizes or resemble glandular structures.
Small tubular spaces occasionally resemble primitive
capillary channels. Careful examination, however, some-
times reveals the presence within these structures of
cells with features of epithelial differentiation or even
keratinization.
Text continued on p. 1153
ERRNVPHGLFRVRUJ
 17  Adamantinoma of Long Bone 1145

C
FIGURE 17-3  ■  Classic adamantinoma: radiographic features. A, Multifocal lytic lesions involving distal tibial shaft. Separate lesion
of distal fibula is present. B, Adamantinoma contiguously involves fibula and tibia. C, Lytic lesion of distal tibia involves fibula
contiguously.

ERRNVPHGLFRVRUJ
1146 17  Adamantinoma of Long Bone

A C
FIGURE 17-4  ■  Plain radiograph and corresponding computed tomograms of adamantinoma of tibia. A, Multifocal, predominantly
osteosclerotic lesions of tibial shaft. Note focal, lytic, intramedullary lesion. B, Axial computed tomogram (CT) shows dense sclerotic
lesion of tibial shaft. C, Axial CT from lytic focus shows expanded intramedullary lesion.

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 17  Adamantinoma of Long Bone 1147

B
FIGURE 17-5  ■  Classic adamantinoma: gross features. A, Coronal section of amputation specimen shows destructive fleshy lesion
that expanded contour of distal fibula and eroded tibia contiguously. Note separate intramedullary lesion in tibial shaft. Inset, Whole-
mount specimen showing destructive lesion in the tibial shaft. B, Coronal section of amputation specimen shows destructive lesion
of distal tibia that involves fibula contiguously. Same specimen as shown in A. Inset, Intramedullary extension of the lesion in fibula.

ERRNVPHGLFRVRUJ
1148 17  Adamantinoma of Long Bone

A B C

D E
FIGURE 17-6  ■  Classic adamantinoma: gross features. A, Bisected tibial resection specimen shows a destructive fleshy intramedullary
lesion that expanded contour of bone. B, Sagittal section of tibia showing multifocal intramedullary and intracortical lesions.
C, Expanded view of B showing multifocal cortical and medullary lesions consisting of fleshy tissue. Note sclerosis of the overlying
cortex and irregular corticomedullary border. D, Coronal section of tibial amputation specimen shows destructive fleshy lesions that
erodes overlying cortex. E, Whole-mount specimen showing an intramedullary extension of adamantinoma.

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 17  Adamantinoma of Long Bone 1149

A B

C D
FIGURE 17-7  ■  Classic adamantinoma: microscopic features. A, Basaloid pattern with peripheral layers of cuboidal cells oriented at
right angles to inner spindled cell mass. B, Solid proliferations of tumor cells outlined focally by basaloid patterns. C, Spindled
pattern of loosely arranged tumor cells. D, Nests of tumor cells in fibrous stroma (A-D, ×100) (A-D, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
1150 17  Adamantinoma of Long Bone

A B

C D
FIGURE 17-8  ■  Adamantinoma: microscopic features. A, Basaloid pattern with peripheral layers of cuboidal cells. B, Higher magnifica-
tion of A showing basaloid arrangement of cuboidal cells outlining the nests of tumor cells. C, Irregular nests of tumor cells in
fibrous stroma. D, Loose cluster of epithelial cells in fibrous stroma. (A, ×100; B-D, ×200) (A-D, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
 17  Adamantinoma of Long Bone 1151

A B

C D
FIGURE 17-9  ■  Classic adamantinoma: microscopic features. A, Solid proliferation of spindled tumor cells. B, Higher magnification
of A showing spindled tumor cells. C, Solid proliferation of spindled tumor cells. D, Higher magnification of C showing spindled
tumor cells. (A and C, ×100; B and D, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1152 17  Adamantinoma of Long Bone

B C
FIGURE 17-10  ■  Classic adamantinoma: microscopic variations of tubular pattern. A, Small open spaces (tubular) lined by flattened
or cuboidal cells. B, Irregular nests of tumor cells with small cystic spaces. C, Myriad small tubular spaces lined by flattened cells.
(A and C, ×200; B, ×100) (A-C, hematoxylin-eosin).

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The squamous pattern is characterized by areas that
show evidence of squamous differentiation, including
eosinophilic cytoplasm and the presence of round, oval,
or polygonal cytoplasm with occasional pyknosis of the
nucleus (Fig. 17-11). Cells with these features form areas
of various sizes embedded within solid masses of non-
squamous cells. Features of squamous differentiation also
are commonly seen in the peripheral parts of the solid
tumor nests, with individual squamous cells embedded in
surrounding stromal tissue.
The osteofibrous dysplasia–like pattern is seen at least
focally in all cases of adamantinoma with adequate sam-
pling of the tumor and its periphery. It represents areas
of loose fascicles of elongated fibroblast-like cells that
often have a storiform pattern. Trabeculae of bone sur-
rounded by rims of osteoblasts are present within this
tissue. The zonal architecture of the fibrous dysplasia–
like changes can be seen in adequately sampled lesions,
which show progressive maturation and increasing
numbers of bone trabeculae at the periphery of the lesion.
When examined with the aid of polarized light, the
increasing maturation from woven bone trabeculae in
the central parts to predominantly lamellar bone at the
periphery of the lesion is seen. The main feature differ-
entiating this pattern from typical osteofibrous dysplasia
is the presence of small nests of epithelial cells in
the fibroblastic stroma that show occasional squamous
differentiation. In addition to the solid epithelial nests,
small tubular structures lined by cuboidal or flattened
cells scattered in the fibrous stroma are commonly
found.
The classic adamantinomas are characterized micro-
scopically by the abundance of tumor cells and a frequent
mixture of several histologic patterns. The osteofibrous
dysplasia–like pattern is seen focally only and never dom-
inates the histologic picture.
Special Techniques
Ultrastructurally, adamantinoma is epithelial in nature
with prominent desmosomes, tubular structures, and fea-
tures of keratinization seen focally.16,39,52,57,58 Tumor cells
of basaloid, spindled, tubular, and squamous patterns are
consistently strongly positive for keratin (Figs. 17-12 and
17-13).3,11,30,58 The fibrous stroma and bone trabeculae of
the osteofibrous dysplasia–like pattern are negative for
keratin; however, small nests of epithelial cells and tubular
structures scattered in the stromal tissue are strongly
positive for keratin. More detailed studies reveal that
adamantinomas of long bone express classes of keratins
similar to those found in the basal layer of the epider-
mis.3,33,34,44,45 Typically the epithelial component shows
expression of keratins 5, 14, 9, 1, 13, and 17.23 Keratins
8 and 18 are not expressed. Interestingly, epithelial com-
ponents additionally coexpress epithelial membrane
antigen, p63, vimentin, and podoplanin indicative of a
mixed epithelial/mesenchymal phenotype.14,33,36,59 Stain-
ing for vimentin is uniformly strongly positive in tumor
cells of all patterns and in fibroblast-like stroma, includ-
ing blood vessels and osteoblasts. Staining for factor VIII,
Ulex europaeus, CD31, and CD34 is negative in all pat-
terns of tumor cells, fibrous stroma, and osteoblasts;
ERRNVPHGLFRVRUJ
17  Adamantinoma of Long Bone 1153
however, it is clearly positive in endothelial cells lining
the blood vessels. All tumor cells and various components
of the osteofibrous dysplasia–like pattern are uniformly
negative for S-100 protein. Staining for actin is negative
in all types of tumor cells. In contrast, fibroblast-like
stromal cells are focally weakly positive for this marker.
Classic adamantinomas express E-, P-, and N-cadherins,
which are typically not found in osteofibrous dysplasia–
like adamantinomas.44
Cytogenetic studies revealed numerical chromosomal
aberrations with extra copies of chromosomes 7, 8, 12,
19, and 21 that could be detected in both classic and
osteofibrous dysplasia–like adamantinomas.4,35 The simi-
larities of those aberrations in two subtypes of adaman-
tinomas further support the relationship between classic
and osteofibrous dysplasia–like adamantinomas.4 Struc-
tural chromosomal aberrations with translocations and
marker chromosomes resulting in complex karyotypes
are typically seen in classic adamantinoma and are not
observed in osteofibrous dysplasia–like adamantino-
mas.6,27,46,50 Taken together these observations support
the progressive nature of chromosomal aberrations when
disease evolves from osteofibrous dysplasia–like adaman-
tinoma to classic adamantinoma. Occasional transloca-
tions involving the 13q14 region of the tumor and
germline in the same patient have also been reported.60
In general, on total DNA measurements, the epithelial
component of adamantinoma is highly aneuploid and
osteofibrous dysplasia is euploid.22
Differential Diagnosis
Adamantinoma of long bones can be confused with a
variety of primary and metastatic epithelial and soft tissue
neoplasms.
In limited biopsy specimens, epithelial elements, espe-
cially basaloid/tubular or squamous patterns, can be mis-
diagnosed as metastatic carcinoma. Identification of a
peculiar mixture of various patterns present in the major-
ity of adamantinomas, as well as the location of the lesion
in the tibia, the fibula, or both areas, should help avoid
this error.
Dominant spindle-cell or small tubular patterns can
be misdiagnosed as fibrosarcoma or a vascular neoplasm.
Identification of the epithelial nature of cells by appropri-
ate immunohistochemical stains and radiographic data is
helpful in identifying the lesion as adamantinoma.
More difficult problems exist in biopsy specimens con-
taining predominantly fibroosseous areas that can be
confused with fibrous dysplasia or ossifying fibroma (osteo-
fibrous dysplasia). The distinction from fibrous dysplasia
can be easily made if radiographic features of the lesion
are considered. Fibrous dysplasia typically presents as an
intramedullary lesion. Scrupulous search and immuno-
histochemical stains can disclose inconspicuous epithelial
elements in a dominant osteofibrous dysplasia–like
pattern. In such instances, the distinction between
classic and differentiated adamantinoma should be made
(Table 17-1).
In rare instances, morphologic overlap has been
observed between adamantinoma and Ewing’s sarcoma.5,18,21
These perplexing cases have been referred to as both
1154 17  Adamantinoma of Long Bone

A B

C
FIGURE 17-11  ■  Spindled and squamous patterns of adamantinoma. A, Spindled pattern showing palisading of nuclei. B, Nests of
squamous differentiation in adamantinoma. C, Large areas of squamous differentiation in adamantinoma. (A and B, ×200; C, ×150)
(A-C, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
 17  Adamantinoma of Long Bone 1155

A B

C D
FIGURE 17-12  ■  Classic adamantinoma: immunohistochemical features. A, Solid areas of keratin positive tumor cells in fibrous
stroma. B, Higher magnification of A showing strong positivity of tumor cells for keratin. C, Solid nests of tumor cells positive for
vimentin. D, Scattered keratin positive cells in fibrous stroma. (A, ×100; B and C, ×200; D, ×150)

ERRNVPHGLFRVRUJ
1156 17  Adamantinoma of Long Bone

A B

C D
FIGURE 17-13  ■  Classic adamantinoma: immunohistochemical features. A, Solid nests of keratin-positive cells in fibrous stroma.
B, Small tubular structures with strong positivity for keratin in fibrous stroma. C, Keratin-positive tubular structures in fibrous stroma.
D, Scattered keratin-positive tumor cells in fibrous stroma. (A, C, and D, ×200; B, ×150)

ERRNVPHGLFRVRUJ

Ewing’s-like adamantinoma and as adamantinoma-like
Ewing’s because they may not only share phenotypic epi-
thelial features (cytokeratin immunoreactivity and well-
formed desmosomes ultrastructurally), but also O-13
antigen, S-100, and NSE immunoreactivity, dense core
granule presence ultrastructurally, as well as 11;22 trans-
location [t(11;22) (q24;q12)], resulting in the fusion of
EWSR1 and FLI1 genes. (See also discussion in Chapter
11.) Although such exceptional cases definitely enter into
the differential diagnosis of adamantinoma, they are
properly regarded as variants of Ewing’s sarcoma and not
the other way around, in our opinion.
DIFFERENTIATED (OSTEOFIBROUS
DYSPLASIA–LIKE) ADAMANTINOMA
Definition
Differentiated (osteofibrous dysplasia–like) adamanti-
noma is exclusively intracortical in the tibia with fre-
quent synchronous involvement of the ipsilateral fibula.
Microscopically, it is characterized by small nests of
epithelial neoplastic cells, scattered individual epithelial
cells, or both features, best documented by immuno-
histochemical staining for keratin in a dominant back-
ground of osteofibrous dysplasia–like pattern (Figs. 17-14
through 17-17). Sometimes these lesions are designated
as intracortical, juvenile, or osteofibrous dysplasia–like
adamantinomas.65,66
Incidence and Location
This form of adamantinoma is rare. In a series of 25
consultation cases, 8 could be classified as differentiated
adamantinoma. Typically it affects patients during the
first two decades of life. It seems that it is more frequent
during the second decade of life than in the first. The
lesion exclusively involves the tibia and the fibula. In 3 of
our cases, synchronous lesions in the tibia and the fibula
were present. The involvement of the anterolateral cortex
of the tibial midshaft is common.
Clinical Symptoms
The main symptom is a long history of dull pain in the
lower extremity. Clinically evident anterior bowing of the
tibia is frequently present.
Radiographic Imaging
On radiographs the lesions are indistinguishable from
conventional osteofibrous dysplasia. They present as
multiple lucencies, sclerotic foci, or both features, involv-
ing the anterolateral cortex of the tibia with associated
cortical expansion and sclerosis of the intervening cortex
(Figs. 17-14 and 17-15).11 Anterior bowing of the tibia is
frequently present. Although the cortex can be markedly
expanded, each focus is always delineated by a ring of
intact cortical bone. The intracortical location of this
form of adamantinoma is best evaluated by computed
tomography and MRI. The presence of complete cortical
ERRNVPHGLFRVRUJ
17  Adamantinoma of Long Bone 1157
disruption with involvement of the medullary cavity or
extension into adjacent soft tissue disqualifies the lesion
as a differentiated adamantinoma.
Gross Findings
Resection specimens show multiple areas of fibrous-
appearing tissue involving the anterolateral cortex of the
tibia. The lesions expand the cortex toward the medullary
cavity and anteriorly and are always delineated by a rim
of sclerotic cortical bone. True disruption of the cortex
with extension into the medullary cavity, soft tissue, or
both is not present. The bowing deformity of the resected
segment of bone is typically present.
Microscopic Findings
The microscopic hallmark of this form of adamantinoma
is its overall similarity to osteofibrous dysplasia. The
predominance of osteofibrous dysplasia–like changes is
characterized by the presence of fascicles of fibroblastic
cells with a storiform pattern (Figs. 17-17 and 17-18).
Trabeculae of bone with prominent rims of osteoblasts
are present within this tissue. The zonal architecture with
progressive trabeculation from woven to lamellar bone
and increasing numbers of bone trabeculae at the periph-
ery are seen in an appropriately sampled lesion or in the
resection specimens and are similar to the findings in de
novo osteofibrous dysplasia (Figs. 17-17 and 17-18). The
small nests of epithelial tumor cells along with individual
keratin-positive epithelial cells scattered in the fibrous
stroma are characteristic features (Figs. 17-16 through
17-18). A recent report cited a case of differentiated ada-
mantinoma with rhabdoid-like epithelial cell morphol-
ogy.38 Epithelial elements may be present only focally
and usually in the central portion of individual lucencies.
We postulated that the distinct histologic, radiologic, and
immunohistochemical features of this form of adaman-
tinoma are the result of indolent growth of tumor cells
and the predominance of a secondary reparative process
that overgrows the entire lesion. The reparative origin of
the osteofibrous dysplasia–like pattern in adamantinoma
is supported by its frequent location at the periphery of
the classic adamantinoma and by its zonal architecture
when it dominates the lesion in the differentiated type
of adamantinoma.
Treatment and Behavior (Classic and
Differentiated Adamantinoma)
Adamantinomas of long bones are slow-growing, locally
destructive tumors with a high recurrence rate after local
excision.13,24,51,63 It is estimated that metastases, most fre-
quently in the lungs, develop in approximately 25% of
patients with classic adamantinoma. Typically the metas-
tases occur late during the clinical course, often several
(2 to 5) years after diagnosis. The metastases develop
typically in regional lymph nodes and the lungs but any
site may be involved, including the skeleton, liver, and
brain, especially in the terminal phase. The available
incomplete follow-up data of our consultation cases
suggest that metastases occur exclusively in classic
1158 17  Adamantinoma of Long Bone

A B C D
FIGURE 17-14  ■  Radiographic features of adamantinoma: comparison of classic and differentiated (osteofibrous dysplasia–like) ada-
mantinoma. A, Differentiated adamantinoma involving anterolateral cortex of tibia. Note marked anterior bowing of tibial surface.
B, Differentiated adamantinoma showing multiple intracortical lesions in tibia and fibula of same extremity. C, Classic adamantinoma
represented by large expanding lesion in distal fibula. D, Classic adamantinoma represented by eccentric lytic lesion that has
expanded beyond cortex of tibia. Note sclerotic margins at its periphery. (From Czerniak B, Rojas-Corona RR, Dorfman HD: Cancer
64:2319–2333, 1989.)

adamantinoma. At the time of this writing, we have no Personal Comments

example of differentiated (osteofibrous dysplasia–like)
adamantinoma that metastasized. Therefore in addition
to microscopic and radiographic features, differentiated
adamantinoma may have clinical behavior that overlaps
with osteofibrous dysplasia.34 Several cases of differenti-
ated osteofibrous dysplasia–like adamantinoma that pro-
gressed to classic adamantinoma have been reported.20,61
In addition, in rare instances, classic adamantinoma
may evolve into the so-called dedifferentiated adamanti-
noma progressing to a highly pleomorphic sarcoma-like
malignancy.25,31
Because differentiated adamantinoma may initially
present as clinically indistinguishable from osteofibrous
dysplasia, it is essential to establish the diagnosis by
biopsy. Osteofibrous dysplasia lesions that have been
adequately sampled may be followed until puberty and
then treated by extraperiosteal excision or segmental
resection for larger lesions.42 Most adamantinomas, either
classic or differentiated, are now treated surgically, with
limb salvage as the standard. Wide operative margins can
be obtained in most cases, with a limb preservation rate
of more than 80% and a survival rate of close to 90% at
10 years.56
Describing the relationship between adamantinoma and
osteofibrous dysplasia of long bone, we have proposed
two distinct pathways that the tumor may follow (Fig.
17-19). The first is that exemplified by the classic ada-
mantinoma, in which the tumor grows progressively and
may, at least in some instances, invade the surrounding
tissue and metastasize. In the second, characterized by the
differentiated adamantinoma, an intracortically situated
adamantinoma becomes dominated by a secondary repar-
ative process with the histologic features of osteofibrous
dysplasia. It is possible that the continuation of this repar-
ative process may lead to the total elimination of recog-
nizable tumor cells from the lesion. At this stage, it may
no longer be possible to identify the underlying primary
condition. The notion that the differentiated type of ada-
mantinoma and osteofibrous dysplasia may represent dif-
ferent stages of the same process is supported by the
finding, in some cases, of inconspicuous focal remnants
of epithelial elements in a lesion otherwise indistinguish-
able from osteofibrous dysplasia. The close relationship
between these two lesions is further supported by their
similar anatomic location, age distribution, and tendency

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 17  Adamantinoma of Long Bone 1159

A B
FIGURE 17-15  ■  Similarity of radiographic features of differentiated adamantinoma and osteofibrous dysplasia. A and B, Differenti-
ated adamantinoma (A) and osteofibrous dysplasia (B) were located in anterolateral cortex of proximal shaft of tibia. Note that both
lesions have associated anterior bowing of tibia.

to grow intracortically. Indeed, the radiologic appearance
of these two entities is often identical.
The concept of differentiated adamantinoma implies
the existence of a continuum of lesions with classic ada-
mantinoma at one end and osteofibrous dysplasia at
the other. Therefore one can expect intermediate cases
exhibiting features of both subsets of adamantinoma.
The diagnosis of differentiated adamantinoma depends
on factors such as the intracortical location of the
entire lesion, uniform predominance of an osteofibrous
dysplasia–like pattern, and scattered positivity of epithe-
lial elements for cytokeratin. Focal predominance of an
osteofibrous dysplasia–like pattern is insufficient for a
diagnosis of differentiated adamantinoma. The lesion
may appear radiologically to be intracortical for the most
part; however, its focal expansion into the surrounding
tissue should be a warning signal of at least local aggres-
sion and indicates the primary site for biopsy. Such lesions
can contain large components of intracortically located
differentiated adamantinoma, with focal extension beyond
the cortex and histologic features of classic adamanti-
noma. In such instances, the diagnosis should be based
on the most aggressive portion of the tumor. It also
must be mentioned that our concept of differentiated

ERRNVPHGLFRVRUJ
1160 17  Adamantinoma of Long Bone

A B

C D

FIGURE 17-16  ■  Differentiated adamantinoma: microscopic features. A, Nests of epithelial cells in central portion of differentiated
adamantinoma. B, Higher magnification of A showing irregular nests of tumor cells in fibrous stroma. C, Residual nests of epithelial
cells in central portion of adamantinoma. D, Higher magnification of A showing inconspicuous nests of tumor cells in fibrous
stroma. Inset, Strong positivity of tumor cells for keratin in differentiated adamantinoma. (A and C, ×100; B and D, ×200)
(A-D, hematoxylin-eosin.)

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 17  Adamantinoma of Long Bone 1161

A B C D
FIGURE 17-17  ■  Differentiated adamantinoma of tibia and fibula: zonal architecture. A, Radiograph shows multilocular lesions in
anterolateral cortex of tibial shaft and in fibula. B-D, Osteofibrous dysplasia–like pattern in peripheral, intermediate, and central
zones of tibial lesion. Note progressive maturation of bone trabeculae from central to peripheral zone and few inconspicuous epi-
thelial nests present in central part of lesion (arrows). (B-D, ×50) (B-D, hematoxylin-eosin.)

adamantinoma and its proposed relationship to osteofi-
brous dysplasia does not rule out the possibility of
the existence of de novo osteofibrous dysplasia not related
to adamantinoma. It is also suggested that because of
its intracortical location and similarity to osteofibrous
dysplasia, the differentiated type of adamantinoma
may represent a prognostically more favorable variant
compared with the classic type of adamantinoma.
However, this statement remains unproved until suffi-
cient follow-up data on a representative number of cases
are available.
Since the publication of our concept of differentiated
adamantinoma and its relationship to osteofibrous
dysplasia–like change, several other groups have con-
firmed the existence of scattered epithelial elements in
some cases of osteofibrous dysplasia.30,41,66 Our original
concept was that the presence of osteofibrous dysplasia–
like areas in adamantinoma might indicate a healing or
regressive process. The relationship between these two
entities has become less controversial since we initially
proposed it in 1989, with a number of other authors
postulating the opposite pathway, suggesting that osteo-
fibrous dysplasia can be a precursor lesion for adamanti-
noma.20,22,62 It is not unusual for cases originally diagnosed
as osteofibrous dysplasia to be reclassified later as ada-
mantinoma61 (Fig. 17-20). In our opinion, such cases
represent a sampling problem or misdiagnosis rather
than the true evolution of the fibroosseous lesion into an
epithelial neoplasm.
OSTEOFIBROUS DYSPLASIA
Osteofibrous dysplasia is a rare lesion that occurs exclu-
sively in the tibia and fibula. Originally the lesion was
considered a variant of fibrous dysplasia or a process
analogous to ossifying fibroma of jaw bones.80,87 We
regard osteofibrous dysplasia of long bones to be patho-
genetically distinct from ossifying fibroma of the jaws and
from fibrous dysplasia. Initially this lesion was designated
as ossifying fibroma of long bones or intracortical fibrous dys-
plasia.81,87 These terms had the disadvantage of uninten-
tionally linking this lesion with other more common
fibroosseous disorders. In 1976, Campanacci78,79 intro-
duced the term osteofibrous dysplasia of long bones for
these lesions and proposed the concept of a self-healing
process that evolves until puberty and then stabilizes.
The relationship between osteofibrous dysplasia and

ERRNVPHGLFRVRUJ
1162 17  Adamantinoma of Long Bone

A B C D

FIGURE 17-18  ■  Osteofibrous dysplasia of tibia: zonal architecture. A, Radiograph shows multilocular lesion in anterolateral cortex
of proximal shaft of tibia. B-D, Osteofibrous dysplasia pattern in peripheral, intermediate, and central zones of lesion. Note progres-
sive maturation of bone trabeculae from central to peripheral zones. (B-D, ×50) (B-D, hematoxylin-eosin.)

adamantinoma of long bones, which is discussed in the
section on adamantinoma of long bone in this chapter, is
well documented in literature.72,75,76,83,85,91,93,95-98,100-102,104
However, there are unquestionable cases of de novo
osteofibrous dysplasia unrelated to adamantinoma.71,82,86
Rare forms of inherited familial osteofibrous dysplasia
have also been described.89 The following description
is restricted to this de novo variant of osteofibrous
dysplasia.
Definition
Osteofibrous dysplasia is a disorder characterized by the
presence of fibrous tissue and bone trabeculae rimmed by
osteoblasts. The lesion occurs exclusively in the tibia,
fibula, or both locations and predominantly affects infants
and children.
Incidence and Location
Osteofibrous dysplasia is a rare lesion, accounting for less
than 1% of all bone tumors. Although it typically occurs
during the first two decades of life, some cases have been
present at birth.71,81,94,99,103 There is no clear sex predilec-
tion. All reported cases have been located in the tibia,
fibula, or both locations. Synchronous involvement of the
tibia and fibula on one side is typical. The peak rate of
incidence and skeletal sites of involvement are shown in
Figure 17-21.
Radiographic Imaging
The lesion typically exhibits multiloculated radiolucent
expansion of the anterolateral cortex of the tibia (Figs.
17-22 and 17-23).74,88 Anterior bowing associated with
cortical thickening and sclerosis in the midshaft is very
characteristic. Additional synchronous, predominantly
lytic foci may be present near the distal or proximal end
or, less commonly in the fibula. The anterior bowing
deformity is usually present at the time of diagnosis and
may become more pronounced with progression of the
disease.
In young children, especially newborns, the lesion may
present as a purely lytic, sharply demarcated, expansile
defect in the tibial diaphysis (Figs. 17-24 and 17-25).
In this age group, the origin of the lesion in the antero-
lateral cortex may not be obvious on radiographs. Com-
puted tomography and MRI can be used to demonstrate
multiloculated anterolateral intracortical lesions with
cortical expansion and sclerosis of the intervening bone

ERRNVPHGLFRVRUJ

Progression
Fibroosseous
overgrowth
Further
fibroosseous
De novo
overgrowth
osteofibrous
dysplasia
FIGURE 17-19  ■  Adamantinoma: pathways of development.
Graphic presentation of concept of differentiated adamanti-
noma of long bones and its relationship to osteofibrous
dysplasia–like changes.
(Figs. 17-22 and 17-23). In extremely rare cases, osteofi-
brous dysplasia may involve both extremities and present
as bilateral tibial lesions (Fig. 17-25).
Gross Findings
Sections of resected segments of the tibial shaft show a
multilocular intracortical lesion in the anterolateral
cortex that is composed of gritty fibrous tissue. Expansion
of the cortex with sclerosis is usually clearly seen. Occa-
sionally the lesion may consist of a single larger focus of
fibrous tissue surrounded by an expanded shell of scle-
rotic cortex. Cortical disruption and invasion into soft
tissue are typically not present.
Microscopic Findings
The lesion is composed of loose bundles of fibroblast-like
cells that often show a storiform pattern. Within this
tissue, trabeculae of bone are present and are surrounded
by a row of rimming osteoblasts (Fig. 17-26). In appro-
priately sampled cases, zonal architecture can be observed
with progressive widening, maturation, and increased
numbers of mineralized bone trabeculae at the periphery
of the lesion. As the trabeculae become more numerous,
ERRNVPHGLFRVRUJ
17  Adamantinoma of Long Bone 1163
they anastomose and finally merge with the thickened
cortical bone. There is centrifugal maturation of woven
bone to lamellar bone. The central portion of the lesion
is predominantly fibrous and may exhibit myxomatous or
cystic changes. Pathologic fracture, hemorrhage, and
focal collections of multinucleated giant cells can alter
this classic pattern. Single, scattered, keratin-positive
cells that are verified ultrastructurally as epithelial ele-
ments are frequently present and support the concept
that osteofibrous dysplasia may represent an indolent
form of adamantinoma.73 In fact, in several resected spec-
imens, we found small epithelial nests in the fibrous
central zone in otherwise typical osteofibrous dysplasia.
This is not to deny the existence of cases in which a
scrupulous search is negative for any epithelial compo-
nent. The identification of clonal chromosomal abnor-
malities in osteofibrous dysplasia supports the concept
that an underlying indolent neoplastic process may be
involved in the pathogenesis of osteofibrous dysplasia.77
In the original description of this entity, Kempson90
used the term ossifying fibroma to distinguish it from
fibrous dysplasia. He postulated that this was an aggres-
sive lesion with a tendency for local recurrence and
progression. Campanacci and Laus79 designated the
same lesion as osteofibrous dysplasia and observed that it
initially grows in a locally aggressive way but that the
process has a tendency to stabilize at puberty. During
the second decade of life, at least some of these lesions
become stationary and develop gradual sclerosis, but the
deformities may persist. This observation necessitated a
more conservative approach to the treatment of osteofi-
brous dysplasia, which should be limited to corrective
procedures rather than radical excisions.
Differential Diagnosis
Clinically, radiographically, and microscopically, osteofi-
brous dysplasia must be differentiated from conventional
fibrous dysplasia and from both forms of adamantinoma:
classic and differentiated. Although the microscopic fea-
tures of fibrous dysplasia and osteofibrous dysplasia can
be somewhat overlapping, the distinct radiographic pre-
sentation, almost exclusive involvement of the tibia and
the absence of GNS mutations in this disorder distin-
guishes it pathogenetically from fibrous dysplasia.92 The
detailed differential diagnosis of osteofibrous dysplasia
and fibrous dysplasia is described in Chapter 8 in the
section on fibrous dysplasia. The differential diagnosis
between osteofibrous dysplasia and adamantinoma of
long bones is discussed in the section on osteofibrous
dysplasia–like adamantinoma in this chapter.
Our delineation of two subsets of adamantinoma,
namely the classic and differentiated (osteofibrous
dysplasia–like) types, suggests that the latter lesion,
despite focal presence of epithelial elements, pursues a
clinical course similar to that of conventional osteofi-
brous dysplasia.84 Other authors indicate that some cases
of osteofibrous dysplasia may progress to classic adaman-
tinoma.93 Hence, ruling out the possibility of adamanti-
noma continues to be a major problem in planning the
management of osteofibrous dysplasia–like lesions.
Text continued on p. 1171
1164 17  Adamantinoma of Long Bone

A B C
FIGURE 17-20  ■  Slow local growth of differentiated adamantinoma of tibia in an 18-year-old woman with diagnosis of osteofibrous
dysplasia 11 years previously. A, Multifocal lytic changes of tibia diagnosed as osteofibrous dysplasia when patient was 8 years
old. B, Persistent multifocal lesion 3 years later. Note slow progression of lesion, with sclerosis and mild anterior bowing of tibia.
C, Same lesion 11 years after original diagnosis. Note almost no progression compared with B remodeling of tibial cortex and partial
correction of bowing. At this time, biopsy with immunohistochemical studies revealed scattered epithelial elements, and lesion was
reclassified as differentiated adamantinoma.

ERRNVPHGLFRVRUJ
 17  Adamantinoma of Long Bone 1165

Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 17-21  ■  Osteofibrous dysplasia. Peak age incidence and typical sites of skeletal involvement are indicated by a solid black
arrow.

ERRNVPHGLFRVRUJ
1166 17  Adamantinoma of Long Bone

A C
FIGURE 17-22  ■  Osteofibrous dysplasia: radiographic features. A, Lateral radiograph of tibia of an 8-year-old boy with anterior bowing
deformity associated with intracortical lesion of tibia. B, T1-weighted magnetic resonance imaging shows cortical thickening.
C, Computed tomogram shows intracortical lesion narrowing medullary cavity.

ERRNVPHGLFRVRUJ
 17  Adamantinoma of Long Bone 1167

A B

C
FIGURE 17-23  ■  Osteofibrous dysplasia: radiographic features. A, Lateral view of tibia of young patient with anterior bowing deformity
and fusiform cortical expansion of anterior cortex. Fibula is not involved. B, Pathologic fracture ensured through tibial lesion shown
in A. C, Computed tomogram shows multilocular, low-signal defects in thickened anteromedial cortex of tibia.

ERRNVPHGLFRVRUJ
1168 17  Adamantinoma of Long Bone

B
FIGURE 17-24  ■  Osteofibrous dysplasia: radiographic features. A, Bowing deformity of left tibia in a 4-month-old boy with large lytic,
expansile lesion in anterolateral cortex. B, Lateral view of lesion shown in A. Biopsy showed features of osteofibrous dysplasia.
Lesion was first discovered when boy was 1 month old.

ERRNVPHGLFRVRUJ
 17  Adamantinoma of Long Bone 1169

A B
FIGURE 17-25  ■  Osteofibrous dysplasia: radiographic features. A, Radiographs of left and right tibiae show bilateral involvement in
a young child. B, Lateral view of right tibia shown in A demonstrates marked anterior bowing deformity.

ERRNVPHGLFRVRUJ
1170 17  Adamantinoma of Long Bone

A B

C D
FIGURE 17-26  ■  Osteofibrous dysplasia (ossifying fibroma): microscopic features. A-C, Osteofibrous dysplasia with irregular, imma-
ture bone trabeculae surrounded by prominent osteoblastic rims. Note fibrous stroma. D, Example of typical fibrous dysplasia. Note
absence of osteoblastic rims and bone trabeculae. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

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 C H A P T E R 1 8 
Chordoma and Related Lesions
CHAPTER OUTLINE
NOTOCHORDAL RESTS AND BENIGN
NOTOCHORDAL TUMORS
CHORDOMA
In evolutionary biology, the notochord or chorda dorsalis
is typically discussed as a prototypic internal skeleton
of prevertebrate animals. In vertebrates, the notochord
exists transiently and in addition to providing structural
integrity to the embryo, it secretes factors that are essen-
tial for body patterning with respect to the dorsal-ventral
and left-right axes.10 These signals are required for posi-
tional orientation and fate information concerning the
development of several abdominal and thoracic organs as
well as the development of the central nervous system. In
human embryonal development, the notochord forms an
axial structure that attains its complete muturation in
the 10- to 11-mm embryo. Subsequently, it undergoes
gradual involution and fragmentation by the ossification
centers of the axial skeleton (Fig. 18-1).4,7,8 During the
second month of embryonal development, the notochord
is restricted to the intervertebral residues (Fig. 18-2). It
is generally received that in adults, it forms the nucleus
pulposus of the intervertebral disks, but recent data show
that the cells of the nucleus pulposus do not express
brachyury or epithelial markers, bringing into question
the notochord origin of the central portion of human
intervertebral disks.129 Occasionally, its remnants can be
found in the peripheral parts of the vertebral bodies.
They are also present in the sphenooccipital area and in
the sacrococcygeal region. They occasionally form larger
masses that are probably derived from the persistent
intravertebral notochord canal and are located more
centrally within the vertebral bodies.2,3,11,12,100 The rem-
nants of notochord tissue are referred to as ecchordosis
physaliphora.
Microscopically, the notochord tissue is somewhat
similar to immature cartilage and is composed of oval
cells with central nuclei and vacuolated cytoplasm embed-
ded in an eosinophilic myxomatous stroma2,3,4,7,9 (Fig.
18-2). The characteristic physaliphorous cells are focally
present. Immunohistochemically, the notochord cells
have some features of cartilage and epithelial cells and are
strongly positive for S-100 protein and keratin and epi-
thelial membrane antigen (EMA) and brachyury (Fig.
18-3).8 The coexpression of S-100 protein, epithelial
markers, and brachyury is a hallmark of notochord tissue
and is retained in chordoma.9 The molecular mechanisms
governing the development and involution of the noto-
chord are still poorly understood. The prelimary data
1174
ERRNVPHGLFRVRUJ
CHONDROID CHORDOMA
DEDIFFERENTIATED CHORDOMA
indicate that Rho-GTPase activity protein (XrGAP),
axial protocadherin, and antagonists of β-catenin are
critical mediators for notochord formation.1,2,4,6 It should
be viewed as a tissue that is evolutionary and functionally
related to cartilage and shares many features that are
common for notochord and cartilage cells. It expresses
such characteristic cartilage components as type II and
type IX collagen, aggrecan, Sox9, and chondromodulin.
In contrast to cartilage cells, notochord cells produce a
thick basement membrane and retain hydrated materials
in large vacuoles. The expression profiles characteristic
of chordoid and chondroid lesions that may have diag-
nostic significance are summarized in Table 18-1.129
NOTOCHORDAL RESTS AND BENIGN
NOTOCHORDAL TUMORS
In 1857, Luschka, Hasse, Zenker, and Virchow described
small gelatinous nodules projecting into the cranial cavity
from the clivus.2,5,19,31 Virchow considered these lesions
as cartilaginous and, because of the prominent vesicular
cytoplasmic change of their cells, designated them ecchor-
dosis physaliphora.27 In 1858, H. Muller performed a devel-
opmental study of human notochord and concluded that
the “ecchordoses” were derived from the notochordal
tissue.22 In 1894, Ribbert confirmed Muller’s opinion;
since then, it has been generally accepted that the gelati-
nous nodules occasionally found in the clivus or dorsum
sellae are “ecchordoses” composed of chordal tissue and
that chordomas arise from the remains of chordal tissue.24
Klebs in 1864 and Grahl in 1903 described the first large
“ecchordoses” causing symptoms.14,17,28
In the past notochord rests were identified as inciden-
tal autopsy findings or were found in vertebral biopsy
samples taken for other reasons. With the development
of modern computerized imaging techniques, they are
more often identified before surgery during the diag-
nostic workup of the axial skeleton.23,29 Several cases
recently presented, discussed at meetings of the Interna-
tional Skeletal Society, and published in reports provide
evidence that notochordal lesions represent a spectrum
of conditions ranging from occult microscopic remnants
to large symptomatic masses.13,15,16,18,20,21,25,29 Large noto-
chordal lesions with bland histologic appearance typically
 18  Chordoma and Related Lesions 1175

Residual
notochord
Somite

Noto-
chord
Intervertebral Residual
disk Vertebral notochord
body tissue

Residual
Neural Sclerotome notochord
tube
Notochord
A B C D
FIGURE 18-1  ■  Embryonal development of notochord and relationship to other structures of central axis. A, Fully developed noto-
chord forming axial structure located anteriorly to neural tube. B, Notochord surrounded by sclerotomes forming ossification centers
of vertebral column. C, Notochord obliterated by ossification centers of vertebral bodies. Note intravertebral notochord canal, which
may persist focally. D, Final stage of involution with residual notochordal tissue forming nucleus pulposus of intervertebral disks.

A B
FIGURE 18-2  ■  Development of notochord: microscopic features. A, Whole-mount photomicrograph of vertebral column from 3-month
human embryo showing vertebral ossification centers with residual notochord forming disklike structures within the intervertebral
cartilages. B, Higher magnification of residual notochordal tissue within an intervertebral cartilage. C and D, Residual notochordal
tissue located in place of future nucleus pulposus showing cordlike arrangement of cells within myxoid stroma. (A, ×4; B, ×20;
C, ×60; D, ×180.) (A-D, hematoxylin-eosin.)

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1176 18  Chordoma and Related Lesions

8 14%

7 Number of lesions
Frequency depending upon anatomical segments 12%

6
10%
Number of lesions

Frequency
8%
4
6%
3

4%
2

1 2%

0 0%
T5
C1
C2
C3
C4
C5
C6
C7
T1
T2
T3
T4

T6
T7

T9
T10
T11
T12

S1
S2
S3
S4
S5
T8

L5
L1
L2
L3
L4

Coccyx
Clivus

Cervical Thoracic Lumbar Sacro-coccygeal

FIGURE 18-3  ■  Anatomic distribution of intraosseous notochord rests. The lesions are most frequently found in the clivus and sacro-
coccygeal vertebra followed by the cervical and lumbar spine. The distribution, depending on anatomic segments, is identical to
that of classic chordomas. (Contributed by Yamaguchi T, et al, unpublished data.)

TABLE 18-1 Expression Profiles of Chordoid (Fig. 18-3). Microscopically such rests are composed of
and Chondroid Tumors solid areas of notochordal cells without nuclear atypia or
mitotic activity (Fig. 18-4). Small cystic spaces filled with
Common serous fluid can be present. The oval cytoplasm of the
SOX-9 notochordal cells shows various degree of vacuolization.
Collagen type II fibromodulin Typical physaliphorous cells are present focally. Some
Cartilage oligomeric matrix protein of such rests can be composed of cells with extensively
Aggrecan
Cartilage link protein 1
vacuolated cytoplasm that resemble fat or lipoma. The
S100 calcium-binding protein A1 trabecular bone of the medulla is intact and the nests of
Chondroitin sulfate proteoglycan 4 notochordal cells grow between the trabecular spaces.
Proline/arginine-rich end leucine-rich repeat protein The overall architecture is that of a stationary lesion
Chondroitin 6 focally surrounded by the embracing trabeculae of the
Chordoid medullary bone (Figs 18-5 and 18-6).
Brachyury The published reports and our own experience indi-
Keratin 8 cate that symtomatic notochordal rests typically measure
Keratin 15 at least 10 mm and may be multifocal involving several
Keratin 18 vertebral bodies. Microscopically such lesions are com-
Keratin 19
Discoidin domain receptor 1 posed of a uniform, sheetlike proliferation of notochordal
CD24 cells, which permeate and fill the intratrabecular spaces
(Fig. 18-7). The trabecular bone is preserved but may
Chondroid
show features of remodeling and sclorosis focally. Thick-
Collagen type X
Platelet-derived growth factor α
ened trabecular bone may have central cores of hyaline
Reticulocalbin-3 cartilage with peripheral seams of partially calcified or
ossified cartilage. The lesion has a nonagressive growth
pattern with pushing borders and is sharply delineated
measuring greater than 10 mm are designated as giant from the adjacent tissue. The notochordal cells are closely
notochordal rests or giant notochordal hamartomas. packed with no intercellular stroma. Most cells have clear
Detailed mapping studies of the axial skeleton indicates cytoplasm and resemble fat at low magnification.8,21,30 In
that the distribution of small notochordal rests measuring contrast, to adipocytes in the nuclei of notochordal cells
less than 5 mm is similar to that of conventional chordoma are frequently centrally located and are surrounded by

ERRNVPHGLFRVRUJ
 18  Chordoma and Related Lesions 1177

A B

FIGURE 18-4  ■  Notochord rest: microscopic features. A and B, Notochord rest of the clivus beneath sella turcica composed of uniform
cells filling intertrabecular spaces with preservation of the trabecular bone. C, Higher magnification of A and B showing sheetlike
proliferation of cells resembling fat with uniform mostly centrally located nuclei. Inset, Higher magnification of notochordal cells
with vacuolated cytoplasm. (A, ×4; B, ×16; C, ×200; Inset, ×400) (A-C and Inset, hematoxylin-eosin.)

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1178 18  Chordoma and Related Lesions

B C
FIGURE 18-5  ■  Notochord rest: gross and microscopic features. A, Whole-mount photomicrograph of vertebral column with a small
notochordal rest. B, Higher magnification of A showing overall architectural arrangement of the rest with preservation of the tra-
becular bone. Note pushing borders with trabecular bone partially outlining the rest. C, Higher magnification of A and
B showing sheetlike proliferation of notochordal cells with vacuolated cytoplasms resembling fat. (A, ×4; B, ×16; C, ×200)
(A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 18  Chordoma and Related Lesions 1179

A B
FIGURE 18-6  ■  Giant notochord rest: radiographic features. A, T1-weighted sagittal magnetic resonance image (MRI) () shows low-
signal lesion in the body of L3 (arrows). B, T2-weighted MRI of lesion shown in A exhibits signal enhancement (arrows).

the cytoplasm, which forms eosinophilic strands delineat-
ing vacuolar structures.
Immunohistochemically both small and giant noto-
chord rests retain phenotypic features of normal noto-
chord and stain positive for keratins AE1/AE3, CAM5.2,
EMA, S-100 protein, and brachyury (Fig. 18-8).13 They
are negative for p53 protein, Ki67 (MIB-1), and high
molecular weight keratin 34βE12 (keratin 903).18
Notochordal rests may progress to a conventional
chordoma. Chordomas associated with notochordal
rests range from incidental microscopic findings to
large destructive symptomatic lesions (Figs 18-9 and
18-10).26,30
Differential Diagnosis
It is important that notochordal rests not be confused
with chordoma. The correlation of microscopic features
with radiologic images helps avoid this error. Extensive
bone destruction with associated paravertebral soft tissue
mass is the hallmark of chordoma. Microscopically noto-
chordal rests lack the lobulation, mucinous stromal pools,
and syncytial cell chords characteristic of chordoma. In
addition, cellular atypia and heterogeneity is lacking in
benign notochordal lesions. The bone both trabecular
and cortical is typically destroyed in chordomas and is
intact or focally thickened in benign notochordal lesions.
CHORDOMA
Definition
Chordoma is a slow-growing neoplasm that exhibits
notochordal differentiation and most frequently arises in
the sacrococcygeal and sphenooccipital regions. Some
chordomas originate in the notochord rests, but it is
unclear whether all tumors of this type arise from the
persistent remnant of notochord tissue.
Incidence and Location
Chordoma is a relatively common tumor, accounting for
3% to 4% of primary malignant bone tumors in major
series. The peak age incidence and the frequent sites of
Text continued on p. 1184

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1180 18  Chordoma and Related Lesions

A B

C D
FIGURE 18-7  ■  Giant notochord rest: microscopic features. A, A uniform sheetlike proliferation of notochordal cells filling up the
intratrabecular spaces. Note preservation of the trabecular bone. B, Focus on thicken bone trabeculae with scallop borders forming
interconnecting network, signifying bone remodeling frequently seen in giant notochord rest. C, Solid sheetlike proliferation of
notochordal cells with clear cytoplasm resembling fat. D, Pushing border sharply delimiting the notochord cells from the adjacent,
uninvolved fatty marrow. Inset, Higher magnification of a physaliphorous cell typically present in notochord rests. (A and D, ×100;
B and C, ×60; Inset, ×600) (A-D and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 18  Chordoma and Related Lesions 1181

A B

C D
FIGURE 18-8  ■  Notochord rest: microscopic and immunohistochemical features. A, Notochord tissue with vacuolization of cytoplasm.
B, Physaliphorous cells in notochord rest. C, Strong positivity of notochord tissue for keratin. D, Positive staining for S-100 protein.
(A and C, ×300; B and D, ×600) (A and B, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1182 18  Chordoma and Related Lesions

A B

C D
FIGURE 18-9  ■  Chordoma developing in association with giant notochord rest: microscopic features. A and B, Whole-mount photo-
micrographs of coccyx showing a giant notochord rest and a focus of chordoma (arrows). Note that focus of chordoma shows
distinctive lobular architecture with myxoid stromal change and exhibits destructive growth pattern, breaking through the cortex
into the periosteal fibroadipose tissue. B, Higher magnifications of A and B showing a focus of chordoma with lobular architecture
and myxoid stroma. C, Higher magnification of A showing chordoma cells infiltrating periosteal stromal tissue. D, Higher magnifica-
tion of B showing chordoma cells infiltrating periosteal stromal tissue. Inset, Microscopic features of giant notochordal cells with
solid sheetlike proliferation of bland looking notochordal cells with clear cytoplasm resembling fat. (A and B, ×10; C and D, ×100;
Inset, ×100)

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 18  Chordoma and Related Lesions 1183

A B

C D
FIGURE 18-10  ■  Chordoma developing in association with giant notochord rest: radiographic, gross, and microscopic features.
A, Gadolinium-diethylenetriamine pentaacetic acid enhanced T1-weighted magnetic resonance image. Tumor protrudes anteriorly
from the coccyx and consists of intermediate density lobules separated by thin contrasted septations. Two intraosseous lesions of
low density corresponding to notochord rests are identified (arrows). B, Gross photograph of the resected specimen discloses a
lobulated tumor composed of gelatinous tissue with foci of hemorrhage. Two intraosseous lesions corresponding to multifocal giant
notochord rests are also present (arrows). C, Microscopic features of a giant notochord rest showing sheetlike solid proliferation
of cells with vacuolated cytoplasm. D, Microscopic features of notochordal rest (upper part) and chordoma (lower part).
Note myxoid appearance of stroma in chordoma and bland looking solid proliferation of benign notochord cells. (C and D, ×80)
(C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1184 18  Chordoma and Related Lesions
Sphenooccipital area
Incidence
50
1 2 3 4 5 6
Age in decades
FIGURE 18-11  ■  Chordoma. Peak age incidence and frequent sites of skeletal involvement. Most frequent sites are indicated by solid
black arrows.
skeletal involvement are shown in Figure 18-11. Chor-
doma appears to be the fourth most frequent primary
malignant tumor of bone after osteosarcoma, chondro-
sarcoma, and Ewing’s sarcoma. Approximately 8% of all
primary malignant bone tumors were reported as chor-
domas to the National Cancer Institute’s Surveillance,
Epidemiology, and End Results (SEER) Program. The
age-specific incidence and frequency distribution show
gradual increases and peak during the fifth and sixth
decades of life (Fig. 18-12). It must be mentioned that a
small number of chordomas occur during the first and
second decades of life.42,52 In this age group, the involve-
ment of the second cervical vertebra is typical. Very rare
cases of congenital chordoma have been described.89
Some of the major series report a male sex predominance.
However, SEER data show an almost equal male-to-
female sex distribution.57 It appears that, similar to
Ewing’s sarcoma, chordomas are less frequent in black
patients. In the SEER data, only 18 (2.1%) of 650 chor-
domas were reported in black patients.
Chordoma almost exclusively involves the axial
skeleton, which is in keeping with its notochordal
origin.55,7,12,20-22,59,95 Nearly 90% of cases occur in the
sacrococcygeal region and in the base of the skull.
The remaining cases are reported predominantly in the
cervical and lumbar spine. Involvement of the thoracic
ERRNVPHGLFRVRUJ
7 8
spine is rare. Extremely rare examples of multicentric
chordoma involving several anatomic sites have been
reported.34
Clinical Symptoms
Pain is a common symptom in chordoma and can last for
months to several years.58 Compression of the nerves in
the sacrococcygeal region and obstruction of the rectum
resulting in constipation are frequent presentations.
Sphenooccipital chordomas produce symptoms related to
compression or destruction of various adjacent struc-
tures, such as the optic nerves or pituitary gland.47,60,83
They also can present with symptoms characteristic of a
tumor of the pontocerebellar region. Spinal chordomas
frequently produce compression of the cord and
nerves.43,67 Cervical chordoma frequently presents as a
pharyngeal mass.53,81,90
Radiographic Imaging
On plain radiographs, chordoma typically presents as a
lytic lesion (Fig. 18-13).40,84,102,104,105 Scattered, discrete
opacities representing intralesional calcifications can be
present. Sphenooccipital lesions destroy the clivus, the
sella turcica, or both areas (Figs 18-14 and 18-15).
 18  Chordoma and Related Lesions 1185

0.25 12

10
Incidence Rate (per 1000,000)

0.2

Frequency %
0.15

0.1
4

0.05
2

0 0
4

+
0-

5-

-1

-1

-2

-2

-3

-3

-4

-4

-5

-5

-6

-6

-7

-7

-8

85
10

15

20

25

30

35

40

45

50

55

60

65

70

75

80
Age Group

Source: SEER Incidence Rate Frequency

FIGURE 18-12  ■  Epidemiology of chordoma. (Data from National Cancer Institute’s Surveillance, Epidemiology, and End Results Program,
1975-2010. Age-adjusted incidence rates and age-specific frequency, all races, both sexes, 650 cases.)

A B
FIGURE 18-13  ■  Chordoma: radiographic features. A, Anteroposterior radiograph of sacrum shows expansive lytic lesion of body of
sacrum. B, Lateral radiograph of lumbar spine shows unusual sclerotic appearance of body of L4 produced by vertebral
chordoma.

ERRNVPHGLFRVRUJ
1186 18  Chordoma and Related Lesions

FIGURE 18-14  ■  Intracranial chordoma: radiographic features. Lateral view of skull shows destruction of sella turcica region of base
produced by sphenooccipital chordoma (arrow).

FIGURE 18-15  ■  Chordoma: radiographic features. T2-weighted magnetic resonance image of chordoma at base of skull shows high
signal intensity mass in region of sphenoid bone (arrows).

ERRNVPHGLFRVRUJ

Sacrococcygeal lesions expand the bone contour and
obliterate normal markings (Fig. 18-16). Vertebral chor-
domas produce lytic lesions that may involve two or more
adjacent vertebral bodies. Chordomas of the vertebral
column and the sacrum originate in the vertebral bodies
and produce masses that grow anteriorly to the dural sac
(Figs 18-17 to 18-19). Lesions of the coccygeal region,
however, may grow both anteriorly and posteriorly to the
sacrum (Fig. 18-16). Chordoma may rarely present as a
sclerotic lesion (Fig. 18-13, B). Computed tomography
and magnetic resonance imaging are indispensable in
evaluating both the extent of the lesion and the involve-
ment of adjacent structures.72,74,75,91,97,103 Magnetic reso-
nance imaging, in particular, can reveal the lobulated
nature of the lesion, and T2-weighted images typically
show signal enhancement (Fig. 18-15).
Gross Findings
Chordomas are soft, gray-tan, multilobulated masses
(Fig. 18-20 to 18-22). They are frequently myxoid or
gelatinous in appearance and can mimic chondrosarcoma
or mucinous adenocarcinoma. The expanded bone
contour is frequently delineated by a thin rim of perios-
teum. The intraosseous borders are typically indistinct.
Despite good demarcation, the tumor usually extends
beyond its grossly recognizable borders. The recurrent
lesions are typically in the form of multiple nodules.
Chordomas often involve the medullary canal, compress-
ing the spinal cord and its nerves.
Histology
Chordomas are composed of cords or nests of solid
areas of cells that have vacuolated cytoplasm embed-
ded in a myxoid intercellular matrix (Fig. 18-23). The
nuclei are round or oval and have a prominent nucleolus.
Mitoses are rare, and atypical mitotic figures usually are
not present. The level of cellularity can vary consid-
erably among cases and in different areas of the same
tumor. Some tumors are highly cellular with minimal or
no intercellular matrix. More often, there is a moder-
ate amount of cellular tissue and clearly recognizable
intercellular myxoid stroma. In a typical case, the tumor
cells form an anastomosing pattern of cords with focal
solid areas separated by a prominent intercellular matrix
(Fig. 18-24). In general, most chordomas exhibit clearly
recognizable nuclear pleomorphism with occasional large
atypical cells.
Vacuolization of the cytoplasm is almost invariably
present (Figs. 18-24 to 18-28). Frequently, it is in the
form of large (single or several) vacuoles displacing the
nucleus peripherally and causing the so-called signet-
ring-like appearance of the tumor cells. It can also
be in the form of smaller (multivesicular) structures.
Occasionally, the vacuoles encircle the nucleus, which
remains centered in the cytoplasm and produces the
so-called physaliphorous appearance. The physaliphorous
cell is a hallmark of chordoma (Figs 18-29 and 18-30). It
must be mentioned, however, that classic physaliphorous
cells, as they are frequently illustrated in many pathology
ERRNVPHGLFRVRUJ
18  Chordoma and Related Lesions 1187
textbooks, are relatively sparse or may not be present
at all in otherwise typical chordoma. The classic large
physaliphorous cell has a centrally located nucleus sur-
rounded by a narrow rim of cytoplasm that in turn, is
encircled by a ring of more peripherally located cytoplas-
mic vacuoles. Extensive vacuolization of the cytoplasm
may cause a clear-cell appearance of the tumor (Fig.
18-28). Such lesions are descriptively referred to as
lipoma-like chordomas and may be confused with benign
or malignant lipomatous tumors. Some chordomas may
have a sarcoma-like appearance caused by elongation of
their nuclei and the presence of nuclear atypia (Fig.
18-23). On the other hand, highly cellular lesions with
minimal vacuolization and dense eosinophilic cytoplasm
may mimic epithelial neoplasms.
Chordoma may also exhibit cartilaginous differentia-
tion. Areas of cartilage can range from small microscopic
foci to large prominent areas. Therefore chordomas can
be occasionally difficult to distinguish from chondrosar-
coma. The term chondroid chordoma has been proposed to
designate hybrid lesions that exhibit features of both
lesions—chordoma and chondrosarcoma. The contro-
versy over this entity and its potential for clinical signifi-
cance are discussed separately.
Cytology
Fine-needle aspirates from chordoma usually are cellular
and contain abundant myxoid material admixed with
clear, vacuolated neoplastic cells33,38,54,68 (Fig. 18-31). The
presence of abnormal multivacuolated cytoplasm with
centrally placed, scalloped nucleus (that is, physalipho-
rous cells) is the hallmark of chordoma. Such classical
cells are, however, rare; in the vast majority, the cells
show dense eosinophilic cytoplasm or are lipoblast-like
with single or several larger cytoplasmic vacuoles displac-
ing the nucleus peripherally. Cytologic features com-
bined with radiologic and clinical presentation allow
correct cytologic diagnosis in most cases of chordoma.
The immunohistochemical features such as coexpression
of epithelial markers and S-100 protein can be also tested
in cytologic preparations.
Special Techniques
Ultrastructurally, the physaliphorous cells show numer-
ous vacuolated spaces that may occupy large portions
of the cytoplasm (Fig. 18-30).48,59,61,62,69,80,85,87,90,96,101,126 A
prominent Golgi center, rough endoplasmic reticulum,
and patchy areas of glycogen are present. Chordoma
cells contain intermediate filaments and are connected by
desmosome-like junctions. The extracellular matrix con-
sists of a fine, granular substance of low electron density.
Some chordomas may show prominent aggregates of
microtubules in their cytoplasm.
Immunohistochemically, chordomas coexpress S-100
protein, epithelial markers (i.e., cytokeratins, EMA) and
brachyury (Figs 18-32 and 18-33).32,73,76,92,98,115 They may
also be positive for neurofilaments and may express the
carcinoembryonic antigen (CEA). Chordomas also show
overexpression of cathepsin K and reduced expression of
1188 18  Chordoma and Related Lesions

B
FIGURE 18-16  ■  Sacrococcygeal chordoma: radiographic features. A, Computed tomography shows lobulated mass protruding pos-
teriorly and anteriorly from origin in sacrococcygeal junction. B, T1-weighted sagittal magnetic resonance image of chordoma shown
in A with larger posterior and anterior low signal mass (arrows).

ERRNVPHGLFRVRUJ

FIGURE 18-17  ■  Chordoma of cervical spine: radiographic features. Lateral radiograph of cervical spine shows destructive lesion of
body of C2 (arrows).
E-cadherin.64,79 The cytoplasm of tumor cells contains
material positive for periodic acid-Schiff, which is dia-
stase sensitive. In general chordoma recapitulate a gene
expression signature of notochordal cells.63,65,78,95 DNA
ploidy measurements show that chordoma may be aneu-
ploid or diploid, but DNA ploidy patterns do not cor-
relate with clinical outcome. Among all of the markers,
brachyury appears to be the most specific for chordoma
and notochordal tissue and is useful in the differential
diagnosis.41,93 Brachyury is an important transcriptional
regulator in the FGFR/MEK/ERK pathway, playing an
essential role in chordoma cell growth and sur-
vival.60,66,82,88,94,107 A more detailed description of the bio-
logic role of brachyury in notochord development and
chordoma is provided in Chapter 3.
Cytogenetic studies have been performed on a limited
number of cases.45,71,77,99 It seems that abnormalities of
chromosome 21, including loss or structural rearrange-
ment of 21(q22), are frequent in these tumors. The most
common cytogenetic abnormality is hypodiploidy with
loss of the short arm of chromosome 3, and loss of proxi-
mal 1p as well as monosomy of chromosome 10.99 Com-
parative genomic hybridization studies disclosed that
losses of 1p and 3p could be detected in 50% of chordo-
mas. Chordomas are also characterized by frequent gains
of genetic material on 5q, 7q, 12q, and 20q. The gains
on 17q appear to be a dominant event present in 70% of
tumors. The cytogenetic data suggests that tumor sup-
pressor genes on 1p and 3q as well as oncogenes mapping
ERRNVPHGLFRVRUJ
18  Chordoma and Related Lesions 1189
to 5q, 7q, 12q, and 20q may play a role in the develop-
ment of these tumors. A rare syndrome of familial chor-
doma was linked to chromosome 7q33.56,70
Differential Diagnosis
Chordoma must be distinguished from chondrosarcoma.
The presence of physaliphorous cells and a trabecular or
cordlike arrangement together with a myxoid matrix are
typical for chordoma. However, conventional chondro-
sarcoma occasionally may show a cordlike arrangement of
cells and myxoid stroma. In such instances, positivity for
S-100 protein and negative staining for epithelial markers
favor chondrosarcoma. Other myxoid bone tumors, such
as chondromyxoid fibroma, which rarely occurs in the axial
skeleton, are very unlikely to be confused with chordoma.
Highly cellular areas with cohesive solid cellular sheets
and prominent nuclear atypia can be confused, especially
in a limited biopsy specimen, with an epithelial neoplasm.
Extensive clear-cell change and the signet-ring appear-
ance of chordoma cells can lead to a misdiagnosis of meta-
static adenocarcinoma or less frequently lipomatous tumor.
On the other hand metastatic carcinomas can be misdiag-
nosed as chordoma. Among various epithelial tumors
metastatic to the skeleton a chromophobe variant of renal cell
carcinoma may superficially resemble a chordoma. Strict
adherence to clinical and radiographic data usually helps
to avoid this error. It must be mentioned that the
Text continued on p. 1206
1190 18  Chordoma and Related Lesions

A B
FIGURE 18-18  ■  Chordoma of cervical spine: radiographic features. A, T1-weighted magnetic resonance image (MRI) of cervical spine
shows expansive, low signal lesion of body of C2, with narrowing of spinal canal and compression of spinal cord. B, T2-weighted
MRI shows high signal intensity in lesion shown in A.

ERRNVPHGLFRVRUJ
 18  Chordoma and Related Lesions 1191

C
A
FIGURE 18-19  ■  Vertebral chordoma: radiographic features. A, Sagittal magnetic resonance image (MRI) of vertebral column shows
lesion of high signal intensity at thoracolumbar junction (T12-L1) (arrow). B and C, T1- and T2-weighted axial MRIs of lesion shown
in A that encircles vertebral body (arrows).

ERRNVPHGLFRVRUJ
1192 18  Chordoma and Related Lesions

A B

C D
FIGURE 18-20  ■  Chordoma: radiographic, gross, and microscopic features. A, Axial computed tomography shows destructive mass
protruding posteriorly and anteriorly from the sacrum (arrows). B, T1-weighted sagittal magnetic resonance image of chordoma
shown in A with predominantly anterior low signal mass (arrows). C, Sagitally cut resection specimen of the tumor shown in A and
B demonstrates a lobulated, fleshy tumor mass destroying the sacrum and extending to the soft tissue anteriorly and posteriorly.
D, Histologic section of same tumor shows cords of chordoma cells with multivesicular cytoplasm growing in a myxoid stroma.
(D, ×200) (D, hematoxylin-eosin.) (Reprinted with permission from Czerniak B, et al: Aspiration cytology of bone tumors. In: Koss LG, ed:
Diagnostic cytology and its histopathologic bases, ed 5. Lippincott Williams & Wilkins, New York, 2005.)

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 18  Chordoma and Related Lesions 1193

A B

C D
FIGURE 18-21  ■  Chordoma: gross features. A, Resection specimen of sacral chordoma showing a gelatinous tumor growing anteriorly
from the coccyx. Note extensive interstitial hemorrhage and areas of necrosis. B, Higher magnification of A showing a tumor growing
anteriorly out of coccyx. C, Gross photograph of a bisected lumbar (L5) vertebral resection specimen showing a gelatinous tumor
mass replacing almost the entire vertebral body. D, Specimen radiograph of tumor shown in C showing destructive lesion replacing
the vertebral body.

ERRNVPHGLFRVRUJ
1194 18  Chordoma and Related Lesions

A B

C D
FIGURE 18-22  ■  Chordoma: gross features. A, Bisected tumor from sacral region shows tan-gray soft tissue with myxoid appearance.
B, Bisected tumor mass from sacral region shows multilobulated myxoid tumor tissue with hemorrhagic areas. C, Autopsy specimen
shows recurrent chordoma of cervical spine invading medullary canal and compressing spinal cord (arrows). D, Sagittally cut resec-
tion specimen of recurrent sacrococcygeal chordoma shows multiple gray, fleshy nodules within coccyx and adjacent soft tissue
(arrows).

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 18  Chordoma and Related Lesions 1195

A B

C D
FIGURE 18-23  ■  Chordoma: microscopic features. A, Solid sheets of chordoma cells with vacuolated cytoplasm and areas of tumor
with more pronounced atypia. B, Higher magnification of A showing tumor cells with pronounced atypia. C, Higher magnification
of another area in A showing tumor cells with extensive vacuolated cytoplasms. D, Higher magnification of chordoma cells showing
pronounced atypia. Inset, Higher magnification of tumor cells showing vacuolated cytoplasm and physaliphorous features. (A, ×60;
B and C, ×100; D, ×200; Inset, ×300) (A-D and Inset, hematoxylin-eosin.)

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1196 18  Chordoma and Related Lesions

A B

C D
FIGURE 18-24  ■  Chordoma: microscopic features. A, Low power view of lobulated chordoma with mucinous stromal change. B, Higher
magnification of A showing nests and cords of highly atypical tumor cells loosely arranged in a myxoid stroma. C, View of chordoma
showing tumor cells loosely arranged in a myxoid stroma. D, Higher magnification of C showing predominantly cellular makeup of
the tumor. Note extensive vacuolization of the cytoplasm. Insets, Individual chordoma cells with pronounced nuclear atypia. (A and
C, ×60; B and D, ×120; Insets, ×200) (A-D and Insets, hematoxylin-eosin.)

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 18  Chordoma and Related Lesions 1197

C
FIGURE 18-25  ■  Chordoma: microscopic features. A, Solid area of highly vacuolated cells with occasional atypical nuclei. B, Intercon-
necting cords of small cells with prominent vacuolization and abundant myxoid stroma. C, Cords and trabeculae of large eosinophilic
cells with focal vacuolar changes. (A-C, ×200) (A-C, hematoxylin-eosin.)

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1198 18  Chordoma and Related Lesions

A B

C D
FIGURE 18-26  ■  Chordoma: microscopic features. A, Solid proliferation of chordoma cells with predominantly granular cytoplasms.
B, Solid nests of chordoma cells dispersed in a myxoid stroma. C, Cords of tumor cells growing in myxoid stroma. D, Unusual
microscopic appearance of chordoma with loosely connected predominantly spindled tumor cells separated by interstitial fluid.
(A-D, ×100) (A-D, hematoxylin-eosin.)

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 18  Chordoma and Related Lesions 1199

A B

C D
FIGURE 18-27  ■  Chordoma: microscopic features. A, Low magnification of chordoma showing lobular arrangement. Note increased
cellularity at the periphery of lobule. B, Cords of chordoma cells with epithelioid features. C, Loosely arranged tumor cells with
extensively vacuolated cytoplasm growing in a myxoid stroma. D, Solid area of tumor cells with granular cytoplasm and epithelioid
features. Tumors with such features can be confused with an epithelial neoplasm. Inset, Higher magnification of chordoma cells
with granular cytoplasms. (A, ×60; B-D, ×100; Inset, ×300) (A-D and Inset, hematoxylin-eosin.)

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1200 18  Chordoma and Related Lesions

A B

C D
FIGURE 18-28  ■  Chordoma: microscopic features. A and B, Unusual appearance of chordoma with tumor cells showing extensively
vacuolated cytoplasms resembling fat. Tumors with such features are referred to as lipoma-like chordomas and may be confused
with liposarcoma, especially when they involve the retroperitoneal tissue. C and D, Higher magnification of chordoma with exten-
sively vacuolated cytoplasm with pronounced nuclear atypia. (A and B, ×100; C and D, ×200) (A-D, hematoxlyin-eosin).

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 18  Chordoma and Related Lesions 1201

A B

C D
FIGURE 18-29  ■  Chordoma: physaliphorous cells. A-D, Microscopic appearances of physaliphorous cells. (A-D, ×600)
(A-D, hematoxylin-eosin)

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1202 18  Chordoma and Related Lesions

B
FIGURE 18-30  ■  Chordoma: ultrastructural features. A, Ultrastructure of physaliphorous cell. Multiple cytoplasmic vacuoles of low
electron density are present. B, Low power magnification of cord of chordoma cells connected by desmosome-like junctions. Light
microscopic appearance of physaliphorous cells. Inset left, light miscroscoptic features of physaliphorous cells. Inset right, higher
magnification of desmosome-like junction. (A, ×3000; B, ×2000; Inset, right, ×16,000; Inset, left, ×600).

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 18  Chordoma and Related Lesions 1203

A B

C D

FIGURE 18-31  ■  Chordoma: histologic and cytologic features. A and B, Histologic features of chordoma demonstrating tumor cells
with vacuolated cytoplasm growing in cords and trabeculae within loose myxoid stroma. B, A larger tumor cell with vacuolated
cytoplasm surrounding the nucleus (physaliphorous cell) (arrow). C, Fine-needle aspirate containing loosely arranged chordoma
cells with myxoid extracellular matrix. D, Higher magnification of chordoma cells with ill-defined cytoplasm and larger cell with a
prominent vacuolated cytoplasm corresponding to a physaliphorous cell (arrows). Inset, Higher magnification of chordoma cells
with vesicular cytoplasm and prominent nucleoli. (A, ×200; B, ×300; C, ×100; D, ×400; Inset, ×600) (A-D and Inset, hematoxylin-eosin.)
(Reprinted with permission from Czerniak B et al: Aspiration cytology of bone tumors. In: Koss LG, ed: Diagnostic cytology and its histo-
pathologic bases, ed 5. Lippincott Williams & Wilkins, New York, 2005.)

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1204 18  Chordoma and Related Lesions

A B

C D
FIGURE 18-32  ■  Chordoma: histologic and immunohistochemical features. A, Histologic features of chordoma demonstrating solid
tumor growth composed of cells with prominent eosinophilic and vacuolated cytoplasm. B, Strong positivity of chordoma cells for
pancytokeratin. C and D, Strong nuclear positivity of chordoma cells for brachyury. (A-D, ×100) (A, hematoxylin-eosin.)

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 18  Chordoma and Related Lesions 1205

A B

C D
FIGURE 18-33  ■  Chordoma: immunohistochemical features. A, Cords of chordoma cells in mucoid stroma. B, Positive staining for
S-100 protein. C, Positive staining for keratin (AE1/AE3) in chordoma cells. D, Positivity for periodic acid-Schiff reflects high content
of glycogen in chordoma cell cytoplasm. (A-D, ×400) (A, hematoxylin-eosin.)

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1206 18  Chordoma and Related Lesions
coexpression of S-100 protein and epithelial markers is
not specific for chordoma and is sometimes seen in various
neoplasms, including adenocarcinomas.
Treatment and Behavior
Chordoma is typically a locally aggressive tumor with
a high propensity for local recurrence. Because of its
unique location in the axial skeleton, it frequently affects
vital structures and causes death. Chordoma is associated
with a high delayed mortality rate and a mean survival
of approximately 4 years.44 Survival longer than 10 years
is extremely rare.44,90 A significant improvement in the
overall survival rate was noted in SEER data for 1973
to 1987. Over this period, the 5-year survival rates of
patients with chordoma improved from 40% to 65%.
Complete surgical excision, if possible, is the treatment of
choice. Unresectable tumors are treated by debulking and
adjuvant radiation therapy. The rate of metastases varies
widely among the series, with an average of 40%.46,49,50,51
The unusually high rates of metastases reported in some
series are probably the result of consideration in the anal-
ysis of the local or regional spread of recurrent tumors.
True distant metastases are relatively rare and most likely
occur in less than 10% of patients. Tumor recurrences
are typically in the form of multiple bone and soft tissue
masses or as subcutaneous nodules.35,36,39 Distant metas-
tases usually occur late during the course of disease and
typically involve the lungs (Fig. 18-34). Metastases in the
regional lymph nodes can also be seen. Chordoma may
occasionally exhibit unusually aggressive clinical behavior
with early distant metastases and massive vascular tumor
emboli involving multiple sites.37,86
CHONDROID CHORDOMA
Definition
Chondroid chordoma is a tumor that contains a mixture
of chondroid and cartilaginous elements. It predomi-
nantly occurs in the central axis and involves the skull
base, spine, or sacrococcygeal region (Figs 18-35 and
18-36).
Controversy over Chondroid Chordoma
Chondroid chordoma is relatively rare. The first report
published on this entity, by Heffelfinger et al.,112 identi-
fied 22 chondroid chordomas in a series of 155 conven-
tional chordomas. Since the original article in 1973, this
entity has become accepted, and the term chondroid chor-
doma has become a widely used designation for chondroid
tumors of the skull base.109,111,116,117,120,127,123,128,132 However,
advances in immunohistochemistry have caused a debate
over the existence of this entity.118,119,122,124 Both cartilage
cells and tumor cells of chordomas are positive for
S-100 protein. In addition to immunoreactivity for S-100
protein and vimentin, chordoma cells show positive
immunoreaction to epithelial markers such as cytokeratin
and EMA and occasionally to CEA.32,73,76,92,98,106,112,113,121
This immunophenotype of chordoma cells is useful in
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distinguishing it from cartilaginous tumors that show
negative immunoreactivity to the epithelial markers. In
addition, 58-nucleotidase can be histochemically docu-
mented in chordoma but not in chondroid chordoma or
chondrosarcoma.106
In 1986, Abenoza and Sibley32 reported that three
chondroid chordomas were positive for the epithelial
markers in both chondroid and chordoid areas, whereas
the chondrosarcomas they studied were negative for
cytokeratin and EMA. They concluded that immunohis-
tochemical studies were useful in the differential diag-
nosis between these tumors. In the late 1980s, Brooks
et al.107,108 reported totally discordant results because
cases previously classified as chondroid chordomas
were negative for cytokeratins and EMA, even in their
chordoma-like areas. As a result of their immunohisto-
chemical study and review of the literature on chondroid
chordomas, Brooks et al. concluded that chondroid chor-
doma did not exist and that the tumors at the skull base
with cartilaginous appearance were better classified as
low-grade chondrosarcoma. However, their “chondroid
chordomas” represented a peculiarly nonchordomatous
group of tumors. None of these tumors contained clear-
cut chordoid areas, and all were basically cartilaginous
or myxocartilaginous. In 1992, Wojno et al.130 repeated
their immunohistochemical study on 17 cases of car-
tilaginous tumors of the craniospinal axis. The chon-
droid differentiation in these tumors was confirmed not
only by light microscopic findings, but also by immu-
nohistochemical expression for type II collagen. A total
of 4 of 17 tumors were virtually indistinguishable from
chondrosarcomas. The remaining 13 tumors had areas
of recognizable conventional chordoma in addition to
the cartilaginous areas. The cells within the chondroid
components of most of these 13 tumors stained for the
epithelial markers. One of 4 tumors composed entirely
of cartilage was positive for the epithelial markers. The
remaining 3 tumors were negative for these markers and
were classified as low-grade chondrosarcomas. These
authors concluded that chordomas can contain cartilage
and that chordomas with cartilage (“chondroid chordo-
mas”) can be distinguished from chondrosarcomas. This
article appeared to reverse the trend of doubt about the
existence of chondroid chordoma. In modern literature,
chondroid chordomas continue to be listed mostly as
single case reports. A detailed molecular profiling dis-
closes, in spite of significant molecular overlap, distinct
profiles for chondroid and chordoid lesions, with brachy-
ury being a major discriminator.129 On the other hand,
it appears that cartilage-appearing components of chon-
droid chordomas express both keratins and brachyury
and are likely to be of notochordal origin.125,129
Personal Comments
Review of our consultation files of cartilaginous and
chordoid tumors of the skull base supported by the
immunohistochemical studies led us to the following
conclusions114:
1. Histologically, chondrosarcomas of the skull base
may show myxoid change of the matrix and a
linear arrangement of tumor cells.107,108,110,112 These
 18  Chordoma and Related Lesions 1207

B
FIGURE 18-34  ■  Metastatic chordoma in lung. A, Multiple tumor emboli in pulmonary vessels. B, High magnification showing
tumor embolus in peribronchial vessel. Inset, Microscopic details of tumor cells with clear cytoplasm. (A, ×40; B, ×100; Inset, ×200)
(A, B, and Inset, hematoxylin-eosin.)

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1208 18  Chordoma and Related Lesions

A B

C E
FIGURE 18-35  ■  Chondroid chordoma: microscopic features. A, Area of conventional chordoma with prominent vacuolization of tumor
cells. B, Cartilaginous differentiation in chondroid chordoma. C, Higher magnification of chondroid differentiation. D, Positive reac-
tivity of chondroid area for keratin. E, Positive reactivity of chondroid area for epithelial membrane antigen. (A and B, ×100;
C-E, ×200) (A-E, hematoxylin-eosin.)

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 18  Chordoma and Related Lesions 1209

A B

C D
FIGURE 18-36  ■  Comparison of microscopic features of conventional chordoma and chondroid chordoma. A, Conventional chordoma
with interconnecting cords of tumor cells in prominent mucoid stroma. B, Area of chondroid matrix in chondroid chordoma. C and
D, Physaliphorous cells showing prominent bubbly cytoplasmic change in conventional-appearing areas of chondroid chordoma.
(A and B, ×100; C, ×400; D, ×600). (A-D, hematoxylin-eosin.)

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1210 18  Chordoma and Related Lesions
findings are somewhat reminiscent of the cohesive
arrangement of chordoma cells. It is on the basis of
this histologic pattern that chondrosarcomas of the
skull base have been misinterpreted as chondroid
chordoma. However, the typical cords or nest for-
mation (two or more cells in thickness) usually
found in chordoma is lacking in chondrosarcomas.
It is important to recognize that a linear arrange-
ment of tumor cells can occur in chondrosarcomas
and that a strandlike appearance is insufficient evi-
dence for a diagnosis of chordoma.
2. Chondroid differentiation in chordomas appears
not to be such a rare phenomenon if tiny foci of
cartilage are included. Previously reported chon-
droid chordomas that were positive for cytokeratin
and EMA may represent tumors of this category.
The proportion of chondroid and chordoid areas
in such tumors may range from a predominance of
chordoma to an equal volume of each component.
This immunophenotype indicates that chordoma
cells have an ability to differentiate into cartilage
cells. Although chondroid chordomas were initially
considered to be confined to the sphenooccipital
region, 8 of 14 cytokeratin- and EMA-positive
chondroid chordomas reported by Wojno et al.130
arose from the spine or sacrococcygeal region. This
seems to indicate that chondroid differentiation in
chordomas is not limited to those that originate in
the sphenooccipital region.
3. It is also important to mention that some of the
reports concerning chondroid chordomas dealt
with tumors that were virtually cartilaginous or
myxocartilaginous in nature and were classified as
chondroid chordomas on the basis of microscopic
impressions. These tumors were consistently nega-
tive for cytokeratins and EMA.76,106,123
4. Although chondroid chordomas continue to be
reported in the literature as distinct entities,
the clinical significance of precise differentiation
between chordoma and chondroid chordoma
appears to be less significant than originally pro-
posed. Moreover, recent molecular profiling reports
suggest that cartilage-appearing components of
chondroid chordoma are notochordal in nature.
In summary, after more than four decades of debate the
identification of this specific subtype of chordoma con-
tinues to be controversial.
Clinical Significance
In the original report,112 mean survival of patients with
chondroid chordomas was about 6 to 10 years (3 times)
longer than the mean survival for conventional chordo-
mas. However, there has been no report in which
systematic follow-up study was performed on immuno-
histochemically classified cases. Therefore it is necessary
to investigate the long-range treatment results in the
major three categories of chondroid and cartilaginous
tumors of the central axis to evaluate the clinical signifi-
cance of chordoma with chondroid differentiation (so-
called chondroid chordoma).
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DEDIFFERENTIATED CHORDOMA
Definition
Dedifferentiated chordoma is a tumor composed of two
distinct elements: conventional chordoma and high-
grade spindle-cell or pleomorphic sarcoma. The phe-
nomenon of dedifferentiation in chordoma is similar to
that originally postulated for dedifferentiated chondro-
sarcoma. Chordomas with a high-grade sarcomatous
component were described as early as 1915 and 1923 by
Albert and Burrow, respectively.133,131 The term dediffer-
entiated chordoma was postulated by Meis et al. in 1987.141
Incidence and Location
Dedifferentiation in chordoma is rare, and only individ-
ual cases have been described in the literature. The age
and anatomic sites involved are similar to those seen in
conventional chordoma. All cases described are located
in the axial skeleton, predominantly in the sphenooccipi-
tal and sacrococcygeal regions.
Radiographic Imaging
Dedifferentiated chordoma presents as a destructive lytic
lesion. Identification of its components—conventional
chordoma and high-grade sarcoma—is not resolved by
conventional radiography. However, the possibility of
dedifferentiation can be suspected in a case of a rapidly
enlarging mass with progressive symptoms in a patient
with a history of conventional chordoma.
Gross Findings
The two components of the tumor can be distinguished
on gross examination. The conventional chordomatous
component has the typical gross appearance of a gray-tan
myxomatous mass and is present within or at the periph-
ery of a fleshy sarcomatous component. The two compo-
nents are typically well demarcated, but a small island of
chordoma can be embedded in the sarcomatous compo-
nent. Hemorrhage and necrosis are frequently present
within the dedifferentiated component.
Microscopic Findings
The hallmark of dedifferentiated chordoma is the coex-
istence of both conventional chordoma and high-grade
sarcoma (Figs 18-37 to 18-39).132,136-140,142,143-145 Typically,
there is a sharp separation between conventional chor-
doma and the dedifferentiated component. Sometimes,
small distinct nodules of chordoma are embedded in
a high-grade sarcoma. The dedifferentiated compo-
nent typically exhibits features of high-grade spindle-
cell or pleomorphic sarcoma with malignant fibrous
histiocytoma-like features. Similar to other dedifferenti-
ated tumors, the sarcomatous component of dediffer-
entiated chordoma may show a phenotypic switch to a
rhabdomyoblastic lineage and may exhibit features of
rhabdomyosarcoma.134
 18  Chordoma and Related Lesions 1211

B
FIGURE 18-37  ■  Dedifferentiated chordoma: microscopic features. A, Interface of two distinct tumor patterns in dedifferentiated
chordoma. Conventional chordoma (left) directly abuts highly cellular, pleomorphic spindle-cell sarcoma (right). B, Higher magnifi-
cation of high-grade sarcomatous component shown in A. Inset (left), Classic microscopic appearance of conventional chordoma
component. Inset (right), Whole-mount photomicrograph shows nodules of chordoma (arrows) within cellular sarcomatoid compo-
nents. (A and right Inset, ×50; B, ×80; left Inset, ×200) (A, B, and Insets, hematoxylin-eosin.)

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1212 18  Chordoma and Related Lesions

B
FIGURE 18-38  ■  Dedifferentiated chordoma: microscopic features. A, Sharp demarcation of two distinct tumor components: conven-
tional chordoma (left) and high-grade spindle-cell sarcoma (right). B, High magnification of dedifferentiated component. Inset, High
magnification of conventional chordoma component. (A, ×50; B and Inset, ×150) (A, B, and Inset, hematoxylin-eosin.)

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 18  Chordoma and Related Lesions 1213

A B

C D
FIGURE 18-39  ■  Dedifferentiated chordoma: microscopic features. A, Island of conventional chordoma within high-grade sarcoma.
B, High magnification showing area of conventional chordoma in A. C, High-grade sarcomatous component. D, High magnification
showing nuclear features of high-grade sarcoma in C. Inset, Higher magnification of physaliphorous cell in B. (A and C, ×100; B and
D, ×400; Inset, ×600) (A-D and Inset, hematoxylin-eosin.)

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1214 18  Chordoma and Related Lesions
Differential Diagnosis
Conventional chordoma may show prominent nuclear
atypia focally or diffusely or may mimic an epithelial
neoplasm. These features should not be confused with
dedifferentiation.
Dedifferentiated chondrosarcoma has very similar archi-
tectural features to conventional chordomas (i.e., the
clearly separated components). The difference is in a
low-grade precursor lesion that has features of conven-
tional chordoma and that coexpresses S-100 protein and
epithelial markers.
Because the dedifferentiation in chordoma has fea-
tures that mimic malignant fibrous histiocytoma, small
biopsy samples may be misinterpreted as malignant
fibrous histiocytoma when the chordomatous elements
are not found. Attention to the radiographic findings and
location of the lesion in the sites typical for chordoma
are essential in guiding the selection of a biopsy site that
would include both possible tumor components.
Treatment and Behavior
Dedifferentiation can occur in primary or recurrent chor-
domas.140,142 The behavior of dedifferentiated chordoma
is similar to that of dedifferentiated chondrosarcoma—
the tumor is highly lethal with almost no survivors 1
to 2 years after diagnosis. After diagnosis, widespread
metastases are the rule, and patients do not seem to
benefit significantly from chemotherapy or radiotherapy.
However, in some cases, a transient response to aggres-
sive chemotherapy protocols has been reported.135,139 The
relationship between irradiation and the transformation
of conventional chordoma into a high-grade sarcoma has
been postulated.
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Metastatic Tumors in Bone
CHAPTER OUTLINE
BIOLOGY OF METASTASES
GENERAL FEATURES OF SKELETAL METASTASES
SKELETAL METASTASES IN SELECTED COMMON
NEOPLASMS
Carcinoma of the Lung
Gastrointestinal Carcinoma
Carcinoma of the Breast
TUMORS WITH A UNIQUE PROPENSITY FOR
SKELETAL METASTASES
Carcinoma of the Prostate
Carcinoma of the Kidney
Bone is one of the most common anatomic sites for
metastases, along with the lungs and liver, and metastases
are the most commonly diagnosed neoplasms encoun-
tered in the skeleton. Although most metastases encoun-
tered in the adult skeleton are either carcinoma or
melanoma, sarcomas may also metastasize to bone, par-
ticularly in the pediatric population. The general surgical
pathologist is far more likely to encounter a skeletal focus
of metastatic cancer than any of the primary malignant
bone tumors. Patients frequently present with signs and
symptoms related to metastatic bone lesions before a
primary tumor has come to clinical attention, and severe
pain or a pathologic fracture is commonly the presenting
complaint. Despite the often extensive immunohisto-
chemical evaluation of metastatic deposits, a primary
source can be elusive and sometimes never located. The
incidence and localization, radiologic characteristics, pat-
terns of spread, and histologic and immunohistochemical
features of various metastatic lesions in bone are consid-
ered in some detail in this chapter. Because fine-needle
aspiration cytology plays a major role in diagnosing met-
astatic lesions affecting the skeleton, we include in this
chapter a brief description of cytologic features of meta-
static tumors in bone. First, however, it is important to
discuss some of the newer information on the biology of
tumor metastasis that has been derived from the methods
of molecular pathology. This information is important
for many reasons, including the understanding of the
pharmacologic strategies for treating bone metastases.
BIOLOGY OF METASTASES
The ability of tumor cells to invade within their host
organ and their ability to metastasize to distant sites are
ERRNVPHGLFRVRUJ
C H A P T E R 1 9 
John D. Reith, MD
Carcinoma of the Thyroid
Carcinoma of the Pancreas
METASTATIC MELANOMA
SKELETAL METASTASES IN SELECTED PEDIATRIC
TUMORS
Rhabdomyosarcoma
Neuroblastoma
Clear Cell Sarcoma of the Kidney
two biologic hallmarks of malignancy. To successfully
metastasize, tumor cells must (1) proliferate within the
host organ and gain the ability to invade the surrounding
tissue and matrix; (2) invade blood vessels, whether
induced by angiogenic properties of the tumor cells or
normal vessels at the site; (3) enter the circulatory system
and survive both intracellular and extracellular influences
attempting to destroy them; (4) adhere to and migrate
across sinusoidal walls at distant sites; and (5) form depos-
its capable of surviving in the new environment10 (Fig.
19-1, A). The basic biology, molecular mechanisms, and
genetic and epigenetic changes that drive these steps are
extremely complex and probably differ depending on the
source of the metastasis and specific type of tumor.
Before metastasizing, tumor cells prepare distant sites
to receive metastatic deposits by creating a premetastatic
niche.6,9 By modulating hematopoietic cells to increase
fibronectin production and by directly producing factors
that render the bone microenvironment receptive, tumors
are able to prepare the bone for metastases. Such factors
include osteopontin,2 matrix metalloproteinases, and
parathyroid hormone-related protein (PTHrP).5 Once
tumor cells have become disseminated, the local environ-
ment within the metastatic site, or metastatic niche, is
important in determining whether tumor cells are able to
survive.12,16
After induction neovascularization by tumor cells in
the primary organ, the tumor cells invade into the vessels
and are embolized to distant sites. Those tumor cells that
are able to survive in transit become lodged in capillaries
within a secondary site such as bone, adhere to the endo-
thelium, and eventually extravasate through the capillary
wall and into the stroma, where they proliferate and ulti-
mately form clinically significant masses. Tumor cells
home in to bone via the same protein interactions that
1217
1218 19  Metastatic Tumors in Bone

A B
FIGURE 19-1  ■  Major biologic phenomena associated with tumor progression and metastasis. A, To metastasize, tumor cells must
gain several unique biologic properties such as invasive growth, induction of vascular growth, vascular invasion, adherence to
endothelial cells or thrombosis of peripheral sinusoids, continuation of invasive growth with extravasation, and formation of primary
and secondary metastatic foci. Although biologic phenomena associated with tumor progression and metastasis are usually present
as sequence of orderly events, in reality tumor cells may develop these properties in a virtually haphazard pattern. Moreover, not
all tumor cells may develop all properties listed; some cell clones may subspecialize (e.g., have high invasive properties), whereas
other cells may take advantage of stromal and vascular destruction and metastasize. B, Summary of molecular changes associated
with tumor cell interaction with various stromal components essential for invasive growth and metastasis. See text for more specific
description.

hematopoietic stem cells use, relying on integrins, che-
mokines, bone morphogenetic proteins, and osteopontin,
among others, to settle in bone.18
An important element of metastasis is the ability of
tumor cells to both adhere to and degrade the extracel-
lular matrix, invade blood vessels, and evade cell death,
both within their primary organ and within bone.3,17 This
is achieved through a complex interaction between inte-
grins; extracellular matrix components such as type I col-
lagen and fibronectin; and proteolytic enzymes such as
matrix metalloproteinases (Fig. 19-2). Integrins, a super-
family of transmembrane receptors that modulate cell-to-
cell and cell-to-matrix interactions by binding with a
variety of ligands, play a key role in skeletal metastases
on many levels, matrix and blood vessel invasion, osteo-
clast signaling, neovascularization, and colonization of
bone.4,8,15,20 CD44, a hyaluronic acid receptor that has
been studied in a wide variety of tumors, appears to
be extremely important in the early development of
metastases.19
The tumor cells must invade and destroy the extracel-
lular matrix at several stages of the process to metastasize.
Thus the interaction of tumor cells with extracellular
matrix seems to be one of the major mechanisms of the
metastatic cascade.3,17 The extracellular matrix can be
divided into two main components: a basement mem-
brane and interstitial connective tissue. The basement
membrane is a sheetlike structure that separates epithelial
and endothelial cells from the interstitial matrix. It con-
tains type IV collagen and several distinct noncollagenous
proteins, such as laminin, heparan, and sulfated proteo-
glycan. Laminin, together with collagen IV, is a major
component of the basement membrane and serves as an
integration unit of the structure. Laminin also plays a
major role as a cellular adhesion molecule. This large
complex molecule has three short arms containing col-
lagen binding sites and a single long arm with a heparan
binding site. The central region of the molecule, where
all four arms are connected in a cross-shaped structure,
contains the laminin receptor binding site for cells.

ERRNVPHGLFRVRUJ
 19  Metastatic Tumors in Bone 1219

A B
FIGURE 19-2  ■  Regulation of bone resorption and bone formation. A, Both systemic factors and locally acting factors induce the
formation and activity of osteoclasts. Systemic hormones such as parathyroid hormone, 1,25-dihydroxyvitamin D3, and thyroxine
(T4), stimulate the formulation of osteoclasts by inducing the expression of receptor activator of nuclear factor-κB ligand (RANKL)
on marrow stromal cells and osteoblasts. In addition, osteoblasts produce interleukin-6, interleukin-1, prostaglandins, and colony-
stimulating factors (CSFs), which induce the formation of osteoclasts. Accessory cells such as T cells can produce cytokines that
can inhibit the formation of osteoclasts, such as interleukin-4, interleukin-18 and interferon-γ. TGF-β denotes transforming growth
factor-β. Plus signs indicate stimulation, and minus signs inhibition. B, Both systemic factors and locally acting factors can enhance
the proliferation and differentiation of osteoblasts. These include parathyroid hormone, prostaglandins, and cytokines as well as
growth factors such as platelet-derived growth factor (PDGF) produced by lymphocytes. In addition, bone matrix is a major source
of growth factors, which can enhance the proliferation and differentiation of osteoblasts. These include the bone morphogenetic
proteins (BMPs), TGF-β, insulin-like growth factors (IGFs), and fibroblast growth factors (FGFs). Corticosteroids can induce apoptosis
of osteoblasts and block bone formation. (Modified and reprinted with permission from Roodman GD: Mechanisms of bone metastasis.
N Engl J Med 350:1655–1664, 2004.)

Recent advancements have elucidated some additional
components of the so-called cell-to-cell and cell-to-
matrix adhesion system and its potential role in invasive
growth.8,13,15,17,20 A new class of transmembrane cell adhe-
sion receptors (integrins) that has a unique structure and
ability to bind fibronectin and laminin has been identi-
fied.13,15,17,20 These receptors integrate the extracellular
matrix anchorage with an intracytoplasmic cytoskeleton
and provide a pathway for signal transduction.
Collagen I and III are the most prominent compo-
nents of the interstitial extracellular matrix.3,17 Proteogly-
cans fill the interstitial space among the collagen fibers,
and their major role is to retain water and to maintain
the shape and volume of the interstitial space. Fibronec-
tin is one of the major noncollagenous components of the
interstitial matrix. It is biochemically distinct from
laminin but has a similar biologic function. It serves as a
major adhesion molecule in the intracellular matrix.
To invade the intercellular matrix and to penetrate the
vascular channels, the tumor cells have to follow three
general steps:
1. They must maintain some degree of their attach-
ment to the matrix components (mainly laminin
and fibronectin).
2. Degradation of the matrix components must
proceed through the action of proteolytic enzymes.
3. Tumor cells must continue to migrate into the
degraded area of the extracellular matrix.
Major molecular phenomena associated with the
development of the metastatic phenotype are summa-
rized in Figure 19-1, B.
Paradoxically, it has been shown that tumor cells
exhibiting increased levels of laminin and fibronectin
surface receptors have a higher metastatic potential com-
pared with those that have minimal levels of these recep-
tors. Thus to develop metastatic foci, the tumor cells

ERRNVPHGLFRVRUJ
1220 19  Metastatic Tumors in Bone
must maintain some degree of adherence to the intercel-
lular matrix elements. In general, some insufficiency of
cell adhesion and junction systems can be documented in
most cancers.3,13,15,17
For tumor cells to occupy a territory of the stromal
matrix, the existing elements of the stromal matrix have
to be at least partly destroyed or degraded. Tumor cells
that invade vessels have a higher capacity to degrade the
stromal matrix than other tumor cells. The enzymatic
activity of tumor cells plays an important role in the
development of metastases. The involvement of several
different proteases, including urokinase, plasminogen
activator, cathepsins B and D, and various metalloprote-
ases produced directly by tumor cells, play an important
role in the invasive growth and development of metasta-
sis.12 Virtually all proteases appear to be controlled by a
cascade of complex-activating and complex-inhibiting
factors. Therefore their roles in invasive growth and
metastasis depend not only on the level of the enzyme,
but also on the presence of adequate amounts of their
activators and inhibitors. The major component of the
basement membrane (type IV collagen) is degraded by a
specific metalloprotease known as type IV collagenase.
The activity of this enzyme can be correlated with the
metastatic potential of several experimental and human
tumors. Overall, an upregulation of multiple proteolytic
enzymes of the so-called plasminogen cascade have been
documented in malignant tumor cells and have been
linked to their invasive and metastatic potential.
The ability to induce vascular growth is another factor
that secures the survival of an enlarging tumor mass.13 It
appears that the tumors that induce a rich vascular
network have a higher metastatic potential. The ability
of tumor cells to induce proliferation of vascular cells via
a number of growth factors such as endothelial growth
factor and fibroblastic growth factor has recently been
extensively studied.3 It seems that tumors with higher
levels of these factors are more clinically aggressive com-
pared with those that have low levels of these factors. The
tumor cells that invade the vessels and circulate in the
lymph or blood interact with cellular and humoral com-
ponents of the environment. The interaction of tumor
cells with platelets and other blood clotting factors, both
circulating and cell fixed, is an important element in the
promotion of tumor cell thrombosis of peripheral sinu-
soids and growth of metastatic foci.13 In addition, the
retention on tumor cells of a unique class of carbohydrate
antigens that interact with endothelial surface antigens is
a critical factor for settlement in metastatic foci. More-
over, the tumor cells of a metastatic focus must retain
their stromal destructive activities and interact with other
cells of the new environment to survive and form clini-
cally detectable nodules.
Following the successful invasion and colonization of
the bone, metastatic deposits most commonly induce
osteolysis and less commonly new bone formation by
interacting with complex bone resorption and formation
regulatory pathways (Fig. 19-2). Osteolysis is driven by
osteoclastic resorption of bone, the control of which
comes under a variety of influences. For some metastatic
carcinomas, particularly breast cancer, osteoclastogenesis
is stimulated by a number of cytokines, one of the most
ERRNVPHGLFRVRUJ
important of which is PTHrP, an osteoclast activator.1,10
As osteoclasts resorb bone, TGFβ is released from bone
matrix, resulting in increased expression of PTHrP by
tumor cells13; PTHrP may also further increase tumor
cell proliferation and act as an angiogenic factor.
PTHrP and other factors stimulate osteoblasts to
produce the cytokine RANK-ligand (receptor activator of
nuclear factor-κβ ligand), a member of the tumor necrosis
factors, which binds to and activates the RANK receptor
on osteoclast precursors, inducing both differentiation
and activation of these bone resorbing cells. PTHrP
also down regulates osteoprotegerin, a decoy receptor
for RANKL.7 Blockade of the RANK-RANKL system
is the mechanism by which the monoclonal antibody
denosumab serves as an effective therapeutic agent in the
treatment of metastatic carcinoma.11,14 Bisphosphonates—
inhibitors of osteoclastic bone resorption—are also stan-
dard pharmacologic agents used for the care of patients
with bone metastases, among other conditions.
Not all types of metastatic carcinoma induce osteoly-
sis. Carcinomas of the prostate and breast, as well as
neuroendocrine tumors, can induce predominately blastic
or sclerotic metastases. The mechanisms that cause
blastic metastases are not as well understood as those for
osteolytic metastases. Factors such as endothelin-1,
platelet-derived growth factor (PDGF), TGFβ2, insulin-
like growth factor (IGF), and bone morphogenetic
proteins (BMPs) all stimulate bone formation and
are produced by various types of carcinomas. These
factors induce bone formation by inducing osteoclast
apoptosis while stimulating osteoblast differentiation and
proliferation.
GENERAL FEATURES OF
SKELETAL METASTASES
The skeleton is one of the most common sites for the
metastasis of virtually all common human malignant neo-
plasms, and almost every malignant neoplasm has been
described as being capable of metastasizing to bone.22,46
In general, metastatic neoplastic cells reach the bones
through the complex arterial and venous systems. The
blood supply to the skeleton represents a significant pro-
portion of the body’s vasculature. In addition, the verte-
bral plexus of veins is valveless, and the retrograde venous
pressure is often increased in the abdominal and chest
regions. This enables a retrograde flow of blood to bypass
the caval system and to reach the bones of the vertebral
column.24 These two basic anatomic and physiologic fea-
tures explain why metastases preferentially involve the
bones of the axial skeleton.25 From a biologic point of
view, it is very unlikely that the abundance of the vascular
network within bone is the only factor that predisposes
to metastasis because metastases rarely develop in other
tissues that have an equally rich vascular network, such
as the spleen. Thus the biologic conditions of bone tissue
must also be important factors in promoting the growth
of tumor cells that reach the marrow via the venous and
arterial blood network.
Autopsy reports of large series of patients have shown
that, with gross examination and limited sampling,

skeletal metastases can be documented in 30% of patients
who died of carcinoma, with particular carcinomas such
as breast or prostate cancer present in nearly 85% of
patients autopsied.21 These findings are supported by
bone scintigraphy studies, which suggest that approxi-
mately 85% of patients with common carcinomas have
skeletal involvement. This is in keeping with observations
by Jaffe, who stated that if extensive skeletal sampling
were to be performed, metastases could be documented
in 70% of patients who died of carcinoma.36
Conventional radiographs are not particularly sensi-
tive in identifying early metastatic lesions in the skele-
ton.53 Radioisotopic scanning can demonstrate abnormal
uptake of bone-seeking isotope approximately 4 months
on average before a lesion can be identified on plain
radiographs.37 Radioisotopic scans, however, are not
specific, and they identify an increased turnover state
associated with osteoblastic activity rather than the pro-
liferation of tumor cells. Therefore they may not detect
metastatic tumors that are primarily associated with bone
destruction and minimal or no osteoblastic activity.
Diffusion-weighted magnetic resonance imaging (MRI)
and whole-body fluorodeoxyglucose positron emission
tomography/computed tomography (FDG-PET/CT)
scans have been shown to be very sensitive and accurate
in identifying metastatic deposits in bone from a variety
of sources.33,51,52
Metastatic tumor in bone typically presents as a
destructive focus that has an aggressive pattern of bone
destruction (Fig. 19-3). Cortical disruption, extension
into soft tissue, and periosteal new bone formation can
be present.26,27,39,42,45 Some metastatic tumors can provoke
an osteoblastic reaction with new bone formation
and appear to be a densely sclerotic lesion32 (Fig. 19-4).
Often, focal sclerosis is seen within lytic lesions, and
therefore many skeletal metastases produce a mixture
of lytic and blastic appearances. In general, a lytic
versus blastic radiographic appearance of a metastatic
tumor in bone results from a prevalent bone resorptive
(destructive) or stimulating (osteoblastic) activity of the
tumor.28,30,31,40
Multiple lesions are a radiographic hallmark of meta-
static skeletal disease (Fig. 19-4). Although any skeletal
site can be affected by metastasis, the majority of lesions
involve the axial skeleton and proximal portions of the
appendicular skeleton (Fig. 19-5). Consequently, such
bones as the vertebrae, pelvis, ribs, skull, sternum, proxi-
mal femur, and humerus are most frequently involved.
These sites correspond to areas that contain hematopoi-
etic marrow, which has a rich sinusoidal vascular network.
This feature and the presence of venous plexus connected
with abdominal and thoracic organs may promote metas-
tasis in these regions. Metastases that predominantly
involve fatty marrow distal to elbow and knee joints and
the mandible are unusual in adults.
Occasionally a single metastatic focus of carcinoma
can be present. In some patients, it can be a presenting
sign of a clinically silent primary tumor that, most often,
is located within the thoracic or abdominal organs.29
Although a solitary skeletal metastasis can be a presenting
sign in any type of common carcinoma, it is most fre-
quent in carcinomas of the kidney, lung, breast, pancreas,
ERRNVPHGLFRVRUJ
19  Metastatic Tumors in Bone 1221
thyroid, and colon.50 Rarely, bilateral symmetric metas-
tases involving the left and right sides can be present.43,44
Bilateral, symmetric, osteoblastic metastases can simulate
osteopoikilosis. The small tubular bones of the hands and
feet are rarely affected by metastases34,38,41 (Fig. 19-6).
This rare phenomenon more often involves the bones of
the feet. Although it can occur in many common cancers,
carcinoma of the lung is the most frequent malignancy
in which so-called acral metastases occur. In general,
acral metastases are most often seen in the small bones
of the feet in highly aggressive malignant neoplasms of
visceral and thoracic organs. In extremely rare instances,
metastatic lesions can have a misleading radiographic
appearance; that is, their radiographic appearance may
support the diagnosis of a benign condition or a primary
bone lesion.
Tenderness, swelling, and pain are typical presenting
symptoms of skeletal metastases. The symptoms are
insidious in onset and gradually increase in intensity over
weeks to months, often preceding changes that are rec-
ognizable on conventional radiographs. An abrupt onset
of symptoms (typically severe pain) is usually associated
with pathologic fracture (Figs. 19-7 and 19-8). In general,
the presence of skeletal metastases is a sign of dissemi-
nated multisystem disease, and other organs are likely to
be involved. However, in a minority of patients, a solitary
metastatic focus in the skeleton can be the only identifi-
able site of the disease. In such cases, a metastasectomy
is advocated because it can significantly prolong a patient’s
life.23,49 The management of skeletal metastases typically
includes internal fixation or joint replacement for frac-
tures or impending fractures, radiation and chemother-
apy, and pain control. Pharmacologic therapy with
bisphosphonates inhibits bone resorption by blocking
osteoclastic activity and has become very important in the
management of patients with metastases. These drugs
improve bone stock in cases of metastatic carcinoma but
do not improve overall patient survival.35
Because a metastasis to the skeleton is often a patient’s
initial clinical manifestation of a carcinoma, the surgical
pathologist may be asked to assist in identifying the
source of the tumor. Although it is not possible to char-
acterize the site of origin in all cases of metastatic carci-
noma of unknown primary site (Fig. 19-9), some tumors,
such as metastatic renal cell carcinoma and metastatic
thyroid carcinomas, have characteristic light microscopic
features. In cases of metastatic carcinoma lacking charac-
teristic histologic findings, the use of a battery of com-
monly employed immunostains can often direct the
clinical team to investigate a limited number of potential
primary sites, if not identify the specific source for the
metastasis. Some tumors, such as squamous cell carci-
noma, lack a specific immunohistochemical profile that
allows the distinction of one primary site from another
with certainty. A focused history and physical examina-
tion coupled with a thorough radiographic evaluation of
the chest, abdomen, and pelvis are also extremely valu-
able in identifying the source of metastases to the skele-
ton.47,48 Figure 19-10 represents an algorithm for the
immunohistochemical evaluation of the commonly
encountered metastases in bone.
Text continued on p. 1230
1222 19  Metastatic Tumors in Bone

A B

C D
FIGURE 19-3  ■  Solitary metastasis: radiographic features. A, Anteroposterior view of a predominately lytic, destructive lesion in the
distal femur from a solitary metastatic deposit from a primary breast carcinoma. B, Coronal computed tomography (CT) scan allows
for easier visualization of the metastatic deposit. C, Radioisotope scan shows significant uptake in a solitary bone metastasis.
D, The gross appearance of the lesion correlates well with the radiographic findings, particularly those seen on CT scan.

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 19  Metastatic Tumors in Bone 1223

A B

C D
FIGURE 19-4  ■  Widespread osteoblastic skeletal metastases in prostate adenocarcinoma: radiographic features. A, Anteroposterior
view of several densely osteoblastic metastases in the proximal humerus and scapula. B, Coronal computed tomography (CT) scan
highlights osteoblastic lesions in the humerus and scapula. C, Radioisotope scan show multiple foci of increased uptake throughout
the axial and appendicular skeleton, including a large lesion in the proximal left femur. D, Coronal CT scan shows the destructive
lesion in the proximal femur, which has both lytic and blastic foci.

ERRNVPHGLFRVRUJ
1224 19  Metastatic Tumors in Bone

FIGURE 19-5  ■  Metastases in vertebral column: radiographic and gross features. A, Radiograph of sagittally bisected vertebral column
with multiple lytic destructive lesions in vertebral bodies taken during autopsy. B, Gross appearance of sagittally bisected vertebral
column with massive blastic metastases seen in vertebral bodies. C, Gross appearance of sagittally bisected lumbar spine and
sacrum with multifocal diffuse involvement by sclerotic metastatic foci of L3 and L5 and sacrum.

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 19  Metastatic Tumors in Bone 1225

A B C D

FIGURE 19-6  ■  Acral metastases: gross and radiographic features. A, Destructive lytic lesion of proximal phalanx of third toe repre-
sents metastasis from adenocarcinoma of lung. B, Closer oblique view of case shown in A. C and D, Destructive lytic lesion of middle
phalanx of thumb in non–small-cell carcinoma of the lung. E, Gross photograph shows metastatic renal cell carcinoma in talus.

ERRNVPHGLFRVRUJ
1226 19  Metastatic Tumors in Bone

B
FIGURE 19-7  ■  Metastatic carcinoma with pathologic fracture: radiographic and histologic features. A and B, Low and high power
photomicrographs of the lesion shown in the inset demonstrating characteristic histologic features of metastatic hepatocellular
carcinoma. Inset, Anteroposterior view of a pathologic fracture through a subtle radiolucent lesion involving the proximal diaphysis
of the humerus (A, ×100; B, ×400) (A and B, hematoxylin-eosin).

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 19  Metastatic Tumors in Bone 1227

A B

C
FIGURE 19-8  ■  Metastatic carcinoma: gross features. A, Metastatic renal cell carcinoma in proximal humerus. Note pathologic fracture
and extension into soft tissue. B, Metastatic renal cell carcinoma in proximal humerus. Tumor was embolized before surgery.
C, Metastatic breast carcinoma in femoral head.

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1228 19  Metastatic Tumors in Bone

A B

FIGURE 19-9  ■  Metastatic carcinoma to rib, unknown primary. A and B, Photomicrographs show a poorly differentiated carcinoma
composed of sheets and nests of atypical epithelioid cells, many of which have clear cytoplasm. The tumor elicits reactive
bone formation. C, Gross photograph of the metastasis to the rib, which has a heavily blastic appearance. Inset, An immunohisto-
chemical stain for CAM5.2 is strongly positive in tumor cells; immunohistochemical and radiographic evaluation failed to identify
a primary site, and the patient died with disseminated disease before a source could be located, (A, ×100; B and Inset, ×200; A and
B, hematoxylin-eosin.)

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 19  Metastatic Tumors in Bone 1229

Destructive skeletal lesion

Primary bone neoplasm Hematolymphoid process,

or myeloma

Keratin- Keratin+
Metastasis

S-100+, markers of Markers of

melanocytic differentiation neuroendocrine differentiation
Keratin- Screening Keratin+

Melanoma Sarcoma Carcinoma Small cell carcinoma TTF1+, variable CD56,

chromogranin+, synaptophysin+

Pheochromocytoma/ chromogranin+,
paraganglioma synaptophysin+

Neuroblastoma NFP+, chromogranin+,

(first r/o Ewing/PNET) synaptophysin+, CD56+

Prostatic PSA+, PSAP+

adenocarcinoma

CK7-/CK20- Renal cell CD10+, RCC+, PAX8+

Alveolar soft TFE3+, desmin+/-, muscle
carcinoma
part sarcoma specific actin+/-
Hepatocellular pCEA+, HepPar1+, AFP+
Angiosarcoma ERG+, CD31+
carcinoma
Leiomyosarcoma Smooth muscle actin+,
muscle specific actin+, Mammary ER+, GCDFP+,
desmin+, caldesmon+, adenocarcinoma mammaglobin+, GATA3+
EMA+/-
Pulmonary TTF1+, napsin A+
Liposarcoma S-100 protein+ (adipocytic adenocarcinoma
component/lipoblasts in all
liposarcoma subtypes), Well-differentiated TTF1+, thyroglobulin+
MDM2/CDK4+ thyroid carcinomas
(dedifferentiated liposarcoma)
CK7+/CK20- Gynecologic WT1+/ER-, PAX8+
Malignant S-100 protein+/- (50%) serous carcinomas
peripheral nerve
sheath tumor Gynecologic ER+/WT1-, PAX8+
endometrioid
Rhabdomyosarcoma Desmin+, myogenin+, carcinomas
CD99+/-
Pancreatic DPC4-
Synovial sarcoma Cytokeratin+ (positive in carcinoma
(SS) glandular component of
biphasic SS, patchy in Upper GI CDX2+, villin+
monophasic and poorly adenocarcinoma
differentiated SS), EMA+
(similar pattern to
cytokeratin), CD99+, BCL2+, Colorectal and CDX2+, villin+
CK7-/CK20+
TLE1+ some appendiceal
carcinomas
Undifferentiated Vimentin+, smooth muscle
pleomorphic actin+/-, CD68+/-
sarcoma Urothelial Uroplakin+, GATA3+
carcinoma

CK7+/CK20+ Some pancreatic MUC5+, CK19+

adenocarcinomas

Upper GI CDX2+, villin+

adenocarcinoma

FIGURE 19-10  ■  Algorithm for the immunohistochemical evaluation of a metastasis of unknown primary. (Modified and reprinted with
permission from Bhargava R, Dabbs DJ: Immunohistology of metastatic carcinomas of unknown primary. In Dabbs DJ, editor: Diagnostic
immunohistochemistry. Theranostic and genomic applications, Philadelphia, 2010, Saunders Elsevier, pp 206–255.)

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1230 19  Metastatic Tumors in Bone
SKELETAL METASTASES IN SELECTED
COMMON NEOPLASMS
In this section, some basic clinical, radiographic, and
pathologic features of bone involvement in the most
common malignant neoplasms are briefly discussed. The
entities discussed in this section represent only the
malignancies for which skeletal metastases are most fre-
quently a presenting sign or occur during the course of
the disease.
Carcinoma of the Lung
Lung cancer is a leading cause of death worldwide and
the most frequently occurring human malignancy that
has a high propensity to metastasize to a variety of distant
sites.76 All major histologic subtypes of lung cancer—
including small cell and non–small cell carcinomas—have
a high tendency to metastasize to the skeleton, particu-
larly the small cell types.70,77 Carcinoma of the lung typi-
cally produces lytic metastases (Fig. 19-11) and is the
most frequent human tumor to present as a solitary meta-
static lesion in bone; lung cancers are the most frequent
tumor that metastasizes to the acral skeleton. Bilateral
symmetric metastases that involve unusual sites, such as
the patella, can also occur.71 Finally, lung cancer is often
centered on the cortex of the appendicular skeleton and
may cause unusual radiographic presentations such as
entirely intracortical or subperiosteal lesions.
A great deal is known about the molecular alterations
in lung cancer, which can impact the use of targeted thera-
pies in the treatment of these patients. Epidermal growth
factor receptor (EGFR), the anaplastic lymphoma kinase
gene (ALK), and the K-RAS gene should all be evaluated
in lung cancers, including metastatic deposits when the
primary tumor has not been sampled. ALK gene rear-
rangements occur in young, nonsmoking patients with
adenocarcinoma. Metastatic pulmonary adenocarcinoma
may harbor mutations of the EGFR gene, and in such
cases patients frequently respond favorably to tyrosine
kinase inhibitors.63 Patients with K-RAS mutated adeno-
carcinoma may be resistant to tyrosine kinase inhibitors.
Aspirates from non–small cell metastatic lung cancer
are highly cellular and contain large epithelial cells with
pronounced atypia (Fig. 19-12, A). Keratinization and
extensive necrosis are frequently seen. Dispersed cells
with scanty cytoplasm, occasionally forming small three-
dimensional clusters, characterize metastatic small cell
carcinoma (Fig. 19-12, B). Nuclei of these cells have
coarsely granular chromatin with a few larger chromo-
centers and no visible nucleoli. Positive immunohisto-
chemical staining for thyroid transcription factor-1
(TTF-1) can be helpful to establish the origin of metas-
tasis from lung. Small cell carcinomas typically show neu-
roendocrine differentiation and are positive for a wide
range of neuroendocrine markers.
Gastrointestinal Carcinoma
Most carcinomas of the gastrointestinal tract are highly
aggressive lesions with a high propensity for metastasis.75
ERRNVPHGLFRVRUJ
Radioisotopic scans reveal abnormal uptake suggestive of
metastasis in approximately 45% of patients who have
stomach cancer.56 The sites most frequently involved are
similar to those affected by other common neoplasms:
the spine, ribs, pelvis, femur, and skull. Most metastases
occur approximately 1 year after diagnosis in patients
with stage III disease.73 Occasionally, skeletal metastasis,
either as a solitary lesion or as multiple lesions, can be a
presenting sign.67 This is more typical of poorly differ-
entiated gastric carcinoma such as a diffuse type of signet-
ringcell carcinoma or a small cell variant (Figs. 19-13
and 19-14).
Colorectal carcinoma is very common in developed
countries, but bone metastases from these tumors occur
less commonly than from gastric carcinomas.55 The inci-
dence of bone metastasis from colorectal cancer is
reported to be approximately 23% in autopsy cases.62
Cancers involving the rectum and cecum are more likely
to develop bone metastasis than tumors involving other
portions of the colon.69 Poorly differentiated carcinoma
and signet-ring cell carcinomas have a higher propensity
for metastasizing to bone than other histologic types of
colon cancer (i.e., conventional, well to moderately dif-
ferentiated adenocarcinoma of the colon). Skeletal metas-
tases typically coexist with lung and liver metastases.
Solitary skeletal metastasis can be a presenting sign in
colorectal cancer. In fact, colon carcinoma is the most
frequent gastrointestinal cancer in which solitary skeletal
metastasis can appear as the initial clinical event. Some
of these lesions may involve unusual sites such as the acral
skeleton, skull, or patella or even the temporomandibular
joint.59,65,72,74,78 Microscopically, these lesions have typical
features of gastrointestinal adenocarcinoma with variable
degrees of differentiation, mucin production, and signet-
ring cell features.
Aspirates from metastatic colon carcinoma are usually
very cellular and show cells organized in three-dimensional
clusters, large sheets, small groups, and dispersed singly.
Nuclei of cancer cells, arranged in palisade at borders of
the large sheet composed of columnar cancer cells, is a
characteristic feature of colon carcinoma (Fig. 19-15, A,
B). Necrosis is very frequent in cytologic preparations
from metastatic colon carcinoma. In many of the cases,
cytologic features of metastasis allow recognition of the
primary site even without clinical data.
Carcinoma of the Breast
Breast carcinomas have a high propensity for metastasiz-
ing to bone, and bone is the most common site of distant
(nonnodal) metastases for these tumors.54,57,58,61,64,66 They
occur in typical skeletal sites, such as the vertebral bodies,
pelvis, proximal femur, and humerus. Involvement of the
proximal femur (intertrochanteric area and femoral neck
with pathologic fracture) and the presence of cranial and
dural metastases are typical signs of advanced-stage breast
carcinoma. Carcinoma of the breast usually produces
osteolytic metastases, but some can be of mixed type; less
frequently, they are purely sclerotic60,68,79 (Fig. 19-16).
Cancers that produce lytic skeletal lesions destroy bone
with the assistance of bone-resorbing osteoclasts. The in
Text continued on p. 1237
 19  Metastatic Tumors in Bone 1231

C D
FIGURE 19-11  ■  Lytic pulmonary adenocarcinoma metastasis in humerus: radiographic, microscopic, and immunohistochemical
features. A, Anteroposterior radiograph showing a metastatic pulmonary adenocarcinoma resulting in a large radiolucent defect in
the humerus with cortical destruction and soft tissue extension. B, Positron emission tomography (PET) scan showing innumerable
PET-avid metastases throughout the skeleton. C and D, Microscopic features of the metastasis seen in A, showing a relatively poorly
differentiated adenocarcinoma with a small amount of adjacent reactive bone. Insets, The tumor was immunoreactive for cytokeratin
7 (left) and TTF-1 (right), supporting the lung as the source of the metastasis. (C and Insets, ×200; D, ×400.) (C, D, and Insets,
hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 A B

C D

FIGURE 19-12  ■  Metastatic carcinoma of the lung and follicular carcinoma of the thyroid: cytologic features. A, A cluster of the lung
adenocarcinoma cells showing obvious cytologic atypia. Inset, Higher magnification of individual cancer cells with hyperchromatic
dark nuclei. B, A cluster of poorly differentiated cancer cells with somewhat elongated nuclei, pronounced atypia, and brisk mitotic
activity in a case of small cell carcinoma metastatic to bone. C and D, Groups of loosely arranged cells forming small follicular
structures characteristic of thyroid cancer. Note traces of colloid substance in the background of the smears. Inset, Higher magni-
fication of thyroid follicular cancer cells with visible nucleoli. (A, C, and D, ×400; B and Insets, ×600.) (A-D and insets, hematoxylin-
eosin.) (Reprinted with permission from Czerniak B, et al: Bone tumors. In Koss LG, Melamed MR, editors: Koss’ diagnostic cytology and
its histopathologic bases, ed 5, Philadelphia, 2006, Lippincott Williams & Wilkins.)

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 19  Metastatic Tumors in Bone 1233

A B

C D

FIGURE 19-13  ■  Widespread blastic gastric adenocarcinoma metastases: radiographic, microscopic, and immunohistochemical fea-
tures. A, An axial computed tomography scan of the spine shows several osteoblastic foci of metastatic carcinoma within the
vertebral body. B, Radioisotope scan shows increased uptake in widespread metastases throughout the skeleton. C, Microscopic
features of metastatic poorly differentiated adenocarcinoma filling the intertrabecular spaces associated with reactive bone
formation. D, An immunohistochemical stain for cytokeratin AE1/3 is strongly reactive in tumor cells. (C and D, ×400;
hematoxylin-eosin.)

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1234 19  Metastatic Tumors in Bone

A B

C D
FIGURE 19-14  ■  Metastatic esophageal adenocarcinoma in femur: radiographic and microscopic features. A, Anteroposterior
radiograph shows a blastic metastatic focus from an esophageal adenocarcinoma. B and C, Coronal and axial computed tomog-
raphy scans highlight the blastic reaction to the metastatic deposits within the medullary cavity as well as periosteal reaction.
D, Microscopic features of metastatic, moderately differentiated adenocarcinoma that originated in the esophagus. (D, ×200)
(D, hematoxylin-eosin.)

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 19  Metastatic Tumors in Bone 1235

A B

C D

FIGURE 19-15  ■  Colonic and breast carcinomas metastatic to bone: cytologic features. A and B, Large sheets of colonic carcinoma
cells showing overlapping nuclei and focal peripheral palisading. Inset, Higher magnification of tumor cells. Note that individual
nuclei of tumor cells vary in size and contain coarse chromatin with prominent irregular nucleoli. C and D, Metastatic ductal breast
carcinoma of the breast with cells arranged in loose clusters. Inset, Details of nuclear morphology with coarse chromatin and
prominent irregular nucleoli (A-D, ×400; Insets, ×600) (A-D and insets, hematoxylin-eosin). (Reprinted with permission from Czerniak
B, et al: Bone tumors. In Koss LG, Melamed MR, editors: Koss’ diagnostic cytology and its histopathologic bases, ed 5, Philadelphia, 2006,
Lippincott Williams & Wilkins.)

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1236 19  Metastatic Tumors in Bone

A B

C D
FIGURE 19-16  ■  Metastatic breast carcinoma: radiographic and microscopic features. A and B, Axial computed tomography scans
show foci of metastatic carcinoma adjacent to the sacroiliac joint and within the iliac wing. C and D, Microscopically, this poorly
differentiated adenocarcinoma had foci with signet-ring cell features similar to the primary tumor within the breast (C, ×200; D, ×400)
(C and D, hematoxylin-eosin).

ERRNVPHGLFRVRUJ

vivo model of metastatic breast carcinoma supports the
concept that the ability of tumor cells to stimulate osteo-
clasts plays a role in bone destruction that is associated
with tumor deposits.1
Aspirates from metastatic breast carcinoma show
three-dimensional aggregates, small clusters and single,
dispersed cancer cells of various sizes. Differentiation
between ductal and lobular carcinoma in bone aspirates
is rarely possible.153 Ductal carcinomas are characterized
by the presence of large cancer cells with abundant cyto-
plasm containing highly atypical nuclei with a clumped
chromatin pattern and prominent nucleoli (Fig. 19-15,
C, D). These cells form irregular clusters with crowding
and overlapping nuclei. Aspirates from metastatic lobular
carcinoma are characterized by the presence of relatively
small, oval cells with eccentric, fairly monotonous hyper-
chromatic nuclei. Some of these cells contain a large
vacuole with central inclusion of condensed mucous
material. Nearly all patients have a past history of treated
mammary carcinoma. In the rare cases without this
history, the disease should be suspected in women of the
appropriate age group.
TUMORS WITH A UNIQUE PROPENSITY
FOR SKELETAL METASTASES
Some malignancies have unique biologic properties that
make them prone to metastasize to the skeleton. In fact,
for such malignancies, solitary or multiple skeletal metas-
tases are frequently an integral component of the clinical
picture at presentation, especially when the primary
tumor remains occult. Even if they are not evident at
presentation, skeletal metastases eventually develop later
during the course of the disease in this group of tumors.
Carcinoma of the Prostate
Carcinoma of the prostate is one of the most common
human cancers, accounting for nearly 25% of all malig-
nancies in males, and is a model for epithelial malignancy
that is likely to metastasize to bone.80,85,88,95,115 Not all
prostate cancers have this unique propensity, and some
prostate carcinomas will behave in indolent fashion. The
risk factors for dissemination of the disease and develop-
ment of metastases in distant sites such as the skeleton
include tumors with a high histologic grade (Gleason’s
combined score ≥7), high stage, large diameter, and
metastasis to pelvic lymph nodes.119,124,141,142 More precise
volumetric measurements of whole organ-embedded
specimens indicate that the volume of cancer is an impor-
tant prognostic factor for dissemination.142 Studies have
shown that nearly 90% of men who develop metastases
from prostate cancer will have bone involvement.136
Skeletal metastases of prostate carcinoma are typi-
cally osteoblastic (Fig. 19-4). Sclerotic lesions in the
pelvis and vertebral bodies are seen most often. In rare
instances, massive sclerotic metastases can develop within
major portions of the skeleton and are associated with
pronounced periosteal new bone formation. Osteo-
lytic metastases typically occur in poorly differentiated
prostate carcinomas (Gleason’s combined score of 9 to
ERRNVPHGLFRVRUJ
19  Metastatic Tumors in Bone 1237
10) or in small cell variants of prostate carcinoma. In
typical cases, the unique morphologic characteristics of
well-developed small glands of prostate carcinoma are
easy to recognize in metastases. In addition, the expres-
sion in metastatic sites of two organ-specific makers,
prostate-specific antigen (PSA) and prostate-specific acid
phosphatase (PSAP), which can be identified immuno-
histochemically, is a helpful feature for diagnosis. Some
poorly differentiated prostate carcinomas can be negative
for both PSA and PSAP. Some of these neoplasms can
have neuroendocrine features. The small cell carcinomas
of the prostate are microscopically indistinguishable from
other small cell carcinomas, such as those of lung origin.
A significant proportion of small cell carcinomas of the
prostate express TTF-1, and care must be taken to distin-
guish such lesions from metastatic small cell carcinoma
of pulmonary origin.136
The osteoblastic reaction associated with metastatic
neoplastic cells within the bone can be so pronounced
that it can overshadow cancer cells. In such cases, the
metastatic foci predominantly consist of sclerotic bone
with scattered small clusters of tumor cells. It is postu-
lated that prostate carcinoma stimulates new bone pro-
duction by secretion of several ubiquitous kinins and
pro-osteoblastic factors that drive osteoblast differentia-
tion and bone formation.81 Occasionally, painless scle-
rotic metastases of prostatic carcinoma that are negative
on biopsy samples (i.e., contain only sclerotic bone) can
be confused with nonneoplastic disorders such as osteo-
poikilosis and bone islands. Treated prostate carcinoma
can be very inconspicuous; that is, the tumor cells can
mimic nonneoplastic cells such as histiocytes. In such
cases, documentation of the epithelial nature of these
cells with epithelial markers such as cytokeratin can aid
the diagnosis. In addition to radiotherapy and bisphos-
phonates, a variety of radiopharmaceuticals have recently
been identified to specifically treat prostate carcinoma
bone metastases by homing in on bone lesions while
limiting local toxicity, thus providing both palliative and
survival benefits.84,96
Aspirates from metastatic prostatic adenocarcinoma
are cellular; cells may be dispersed singly or create sheets
and glandlike structures (Fig. 19-17, A, B). Cancer cells
have no distinguishing features and are usually large with
cytoplasmic borders and nuclei with clearly visible large
nucleoli. Cytologic preparations from well or moderately
differentiated prostate cancer may contain recognizable
microglandular structures that resemble small rosette-
like formations with nuclei at the periphery and a center
formed by amorphous cytoplasmic material. Immunohis-
tochemical stains for PSA and PSAP may be used to
confirm the prostatic origin of the lesion, if there is no
past history of the disease or if there is the possibility of
another primary tumor.
Carcinoma of the Kidney
Renal cell carcinoma is a prototype of a tumor that fre-
quently presents as a skeletal (often solitary) metastasis
with a clinically occult primary tumor.131,135 Nearly 30%
of patients with renal cell carcinomas have metastatic
disease at presentation.129 Dissemination in the form of
1238 19  Metastatic Tumors in Bone

C D

FIGURE 19-17  ■  Prostatic and renal carcinomas metastatic to bone: cytologic features. A and B, Large cohesive sheets of prostatic
carcinoma cells. Note that nuclei of tumor cells are uniform in size and display only minimal atypia. Inset, Higher magnification of
tumor cells showing details of nuclear morphology, which contain prominent nucleoli and evenly distributed chromatin. C and
D, Metastatic clear cell carcinoma of the kidney shows loosely arranged clusters of tumor cells with ill-defined clear and finely
granular cytoplasm. Inset, Tumor cells with clear cytoplasm. Note mild atypia of tumor cells characterized by the presence of round
to oval nuclei with clearly visible nucleoli (A-D, ×400; Inset A, ×600; Inset D, ×400) (A-D and insets, hematoxylin-eosin.) (Reprinted
with permission from Czerniak B et al: Bone tumors. In Koss LG, Melamed MR, editors: Koss’ diagnostic cytology and its histopathologic
bases, ed 5, Philadelphia, 2006, Lippincott Williams & Wilkins.)

ERRNVPHGLFRVRUJ

multiple or solitary skeletal metastases will eventually
develop in up to 50% of patients originally treated for
localized disease (Figs. 19-18 and 19-19).98,122 Occasion-
ally, partial or complete regression of metastatic renal cell
carcinoma is observed,91,100,106,114 which can be spontane-
ous or induced by the reduction of tumor burden.
Renal cell carcinomas are known to metastasize to
unusual distant sites such as the skin, tongue, eye, heart
muscle, acral skeleton, and breast.99,103,107,125,137 Autopsy
data reveal that approximately 8% of patients who died
of renal cell carcinoma have metastasis confined to one
organ. Renal cell carcinomas preferentially metastasize to
the femur, humerus, pelvis, and spine; although osteo-
blastic lesions have been described,128 the vast majority
are lytic.
Typically, metastatic renal cell carcinomas have clear
cell features, and the renal origin of skeletal metastasis is
suspected after microscopic examination of biopsy
samples (Fig. 19-19). Characterization of a metastatic
clear cell carcinoma as originating from the kidney is
easily achieved with commonly utilized immunohisto-
chemical markers such as RCCma, CD10, or PAX-8.
Approximately 10% of renal cell carcinomas dedifferenti-
ate into high-grade spindle-cell or pleomorphic sarcoma-
toid carcinoma. The sarcomatoid elements may be the
only components present in bone metastases. Some of
these lesions can have features suggesting an undifferen-
tiated spindle-cell or pleomorphic sarcoma, and can be
misdiagnosed as primary bone lesions. Review of clinical
data and identification of the epithelial nature of cells
with appropriate immunohistochemical markers are
helpful for classifying the lesion as a metastasis.
Resection of solitary skeletal metastasis significantly
prolongs life.89,110,127,130 Nephrectomy or metastasectomy
is sometimes performed in patients with disseminated
disease to reduce the tumor burden, with the hope that
remaining foci may stabilize or regress.132 Patients with a
solitary metastasis, metastatic deposits with low Fuhrman
histologic grade, and late onset of metastatic disease have
longer survival.92,129,138
Aspirates from metastatic renal cell carcinoma tend to
be bloody, with cancer cells lying singly or arranged in
small groups, and even occasionally larger three-
dimensional structures. Cancer cells have abundant clear
cytoplasm with multiple delicate vacuoles and ill-defined
borders (Fig. 19-17, C, D). Nuclei have delicate chroma-
tin and conspicuous nucleoli. Cytologic preparations
from the metastatic sarcomatoid variant of renal cell car-
cinoma show malignant spindle and pleomorphic cells
arranged in large sheets, small clusters, or singly that may
be very misleading. Nuclei show pronounced atypia char-
acterized by irregular chromatin clumping and promi-
nent nucleoli. In general, the cytologic features of
metastatic sarcomatoid carcinoma are indistinguishable
from those of primary malignant fibrous tumors of bone.
Immunohistochemical stains for keratin and vimentin,
combined with a clinical history of primary renal carci-
noma, are helpful to establish the correct diagnosis.
Carcinoma of the Thyroid
The behavior of carcinomas of the thyroid varies widely
from indolent, slow-growing, well-differentiated tumors
ERRNVPHGLFRVRUJ
19  Metastatic Tumors in Bone 1239
with a propensity for local recurrence and lymph node
metastases to highly malignant, undifferentiated (ana-
plastic) carcinoma.93,120,134 All variants of thyroid car-
cinoma can metastasize to bones (Fig. 19-20), but the
well-differentiated carcinomas (papillary, follicular, and
Hürthle cell types) have a unique propensity to metastasize
to the skeleton.90,94,97,108,109,111,112,116,118,123,126,132,133,139,140,143
Among the well-differentiated variants, follicular carci-
noma is particularly prone to metastasize to bone. Well-
differentiated thyroid carcinoma can present clinically
as skeletal metastases (either solitary or multiple lesions)
with an occult primary tumor.101 It appears that in thyroid
cancer, after metastases to the neck lymph nodes, the
skeleton and lungs are the most frequent site of metas-
tases.113 Skeletal metastases can occur even more than 20
years after treatment of the primary lesion. Thyroid car-
cinomas that affect younger individuals and children are
more aggressive and have a higher propensity to metas-
tasize to the skeleton and lungs, although age greater
than 55 years is a strong predictor of death following
disseminated disease.102
Radiographically, metastatic thyroid carcinoma typi-
cally presents as a destructive lytic lesion of bone.
Metastatic thyroid carcinoma in bone has easily recog­
nizable microscopic features and can be clinically associ-
ated with thyrotoxicosis105 (Figs. 19-20 and 19-21). The
microscopic diagnosis can be aided with appropriate
immunohistochemical stains for thyroglobulin or TTF-1
in follicular and papillary carcinomas, and calcitonin in
medullary carcinomas.
Aspirates from metastatic thyroid follicular carcinoma
show a uniform population of small cells lying singly in
three-dimensional clusters, sometimes forming follicles
with central colloid. Characteristically, the nuclei show
granular chromatin and clearly visible nucleoli (Fig.
19-12, C, D). Intranuclear cytoplasmic inclusions and
nuclear “creases” are commonly seen in the spherical
nuclei. Colloid can be seen as an amorphous substance
dispersed in a background of the smear or can be present
inside the core follicles. Cytologic features of metastatic
thyroid follicular cell carcinoma are very distinctive and
permit the identification of thyroid origin in the majority
of cases.49 Immunohistochemical stains for thyroglobulin
can be used as a marker in questionable cases.
Carcinoma of the Pancreas
Carcinoma of the pancreas is known for its poor progno-
sis. It is associated with the lowest 5-year survival rate
(10%) of all types of cancer surveyed in the National
Cancer Institute’s Surveillance, Epidemiology, and End
Results (SEER) Program.86 It seems that cancers that
arise in the body and the tail of the pancreas have a higher
tendency for distant metastasis compared with those that
arise in the head of the pancreas.104 In addition to regional
lymph nodes and liver, lung, and bone are the most favor-
able distant sites involved.82,87 Pancreatic carcinomas,
especially those that arise in the body or tail, can present
clinically as a solitary bone metastasis, and may produce
either lytic or osteoblastic lesions.83,117,121 The axial skel-
eton is more frequently affected by metastatic pancreatic
carcinoma than the bones of the extremities.
Text continued on p. 1244
1240 19  Metastatic Tumors in Bone

A B

C
FIGURE 19-18  ■  Multifocal metastatic renal cell carcinoma. A and B, T1- and T2-weighted coronal magnetic resonance images (MRIs)
show a large deposit of metastatic renal cell carcinoma that has destroyed the iliac wing, forming a large extraosseous mass. The
lesion is low signal intensity on T1-weighted images (A) and high-signal intensity on T2-weighted images (B). C, An axial computed
tomography scan shows the large lesion in the right ilium as well as a second lesion near the left sacroiliac joint.

ERRNVPHGLFRVRUJ
 19  Metastatic Tumors in Bone 1241

A B

C D
FIGURE 19-19  ■  Solitary renal cell carcinoma metastasis in humerus: radiographic, gross, and microscopic features. A, Anteroposte-
rior radiograph shows a solitary lytic lesion in the proximal humeral diaphysis. B, Radioisotope scan shows a solitary focus of uptake
corresponding to the lesion seen in A. Inset, Gross appearance of metastatic renal cell carcinoma. C and D, Microscopically, the
lesion is composed of nests of clear cells with intervening fine capillaries, typical of renal cell carcinoma (C, ×100; D, ×400) (C and
D, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
1242 19  Metastatic Tumors in Bone

A B

C D
FIGURE 19-20  ■  Lytic metastatic carcinoma of thyroid: radiographic features. A, Lytic destructive lesion of rib. B, Specimen radiograph
shows destructive lytic lesion with moth-eaten pattern. Note absence of sclerotic reaction. C, Gross photograph of bisected rib shows
intramedullary gray-tan lesion with cortical disruption. D, Photomicrograph shows characteristic follicular growth pattern with colloid
of metastatic follicular variant of papillary carcinoma of thyroid. (D, ×100) (D, hematoxylin-eosin.)

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 19  Metastatic Tumors in Bone 1243

A B

C D
FIGURE 19-21  ■  Metastatic anaplastic thyroid carcinoma to bone mimicking sarcoma. A and B, Low power photomicrographs show
a predominantly spindle-cell neoplasm with abundant collagenous stroma, interpreted on limited needle biopsy as undifferentiated
carcinoma. C, The sarcomatoid component adjacent to a focus with overt epithelial differentiation. D, The epithelial component
resembles the follicular variant of papillary carcinoma. (A, ×100; B-D, ×200.) (A-D, hematoxyin-eosin.)

ERRNVPHGLFRVRUJ
1244 19  Metastatic Tumors in Bone
Aspirates from metastatic pancreatic carcinoma show
clusters of obviously atypical adenocarcinoma cells with
prominent eosinophilic cytoplasm. The crowded sheets
of epithelial cells with a high ratio of nuclear variability
are typically present (Fig. 19-25, C, D).
METASTATIC MELANOMA
Melanoma is a relatively uncommon cutaneous malig-
nancy, accounting for fewer than 5% of all cancers. Mela-
noma most commonly metastasizes to regional lymph
nodes, but skeletal metastases also occur, most often
involving axial sites such as the ribs, jaw, pelvis, and
spine; appendicular metastases are encountered less
frequently.153,154
Radiographically, metastatic melanoma appears as a
lytic lesion with an aggressive pattern of bone destruction
(Fig. 19-22); however, a small percentage of metastatic
melanomas can have either a deceptively nonaggressive
pattern of bone destruction or can cause an osteoblas-
tic lesion.148 Metastatic melanoma may appear hyper-
intense on T1-weighted MRI due to the presence of
both melanin pigment and hemorrhage within the
lesion.150,152 MRI appears to be a more sensitive modal-
ity than CT for identifying metastatic melanoma in
bone.151
Metastatic melanoma can present the same wide array
of histologic appearances that is seen in primary melano-
mas (Fig. 19-23). Tumor cells can vary from epithelioid
to spindled in appearance, and may or may not contain
melanin pigment. While establishing a diagnosis of meta-
static melanoma is not difficult in the setting of a known
primary cutaneous tumor, the diagnosis can be extremely
challenging when the primary lesion has either not been
identified or has undergone regression. In such cases, a
battery of immunostains including S-100 protein, Melan-
A, HMB-45, microphthalmia-associated transcription
factor (MITF), or tyrosinase, is necessary to establish the
melanocytic nature of the tumor and distinguish the
lesion from other types of primary and secondary malig-
nant neoplasms.
In the setting of an unknown primary tumor, meta-
static melanoma must be distinguished from poorly dif-
ferentiated carcinoma; amelanotic tumors may also be
mistaken for poorly differentiated carcinoma or even sar-
comas when predominately spindled in appearance.147
This separation is usually possible with the use of a
battery of immunostains, including cytokeratins and
various melanocytic markers. Rare examples of HMB-45–
immunoreactive primary perivascular epithelioid cell
tumors (“PEComas”) of bone should be distinguished
from metastatic melanoma primarily by their lack of
cytologic atypia.146,155
After a diagnosis of metastatic melanoma, the surgical
pathologist may be asked to assess the tumor for either
BRAF, NRAS, or KIT mutations,144,149 particularly if such
testing has not been obtained on a primary tumor. The
status of these mutations can have implications for tar-
geted therapies. Survival following metastatic melanoma
to bone is poor. Patients with appendicular metastases
seem to have slightly better survival than those with axial
ERRNVPHGLFRVRUJ
metastases, owing in part to a shorter interval to metas-
tasis for the axial lesions.145
Aspirates of melanoma show the presence of cells with
oval densely eosinophilic cytoplasm and eccentrically
located nuclei showing obvious atypia and prominent
nucleoli. Melanin deposits are frequently present. Mela-
noma cells show a high degree of morphologic variability,
and cytologic presentation may vary from large pleomor-
phic to small inconspicuous cells as well spindle-cell vari-
ants (see Figs. 19-24, A and 19-25, A, B).
SKELETAL METASTASES IN SELECTED
PEDIATRIC TUMORS
Many extraskeletal pediatric tumors can metastasize to
bone. In general, most skeletal metastases that occur in
children are osteolytic. In addition, they more often
involve the appendicular skeleton compared with the
axial skeletal involvement seen in adults. However, metas-
tases from neoplasms such as medulloblastoma and other
glial tumors, osteosarcoma, carcinoid tumor, and some-
times retinoblastoma can induce prominent osteoblastic
reactions and present as sclerotic lesions on radio-
graphs165,171,198 (Fig. 19-26).
Rhabdomyosarcoma, neuroblastoma, and clear cell
sarcoma of the kidney are the three most notable exam-
ples of pediatric malignancies that have a particularly
high propensity for metastasizing to the skeleton, a
feature that represents an integral part of the clinical
behavior of these tumors. The first two tumors, together
with Ewing’s sarcoma, belong to the category of nonhe-
matologic small round-cell malignancies.
Rhabdomyosarcoma
Rhabdomyosarcoma can be classified into several differ-
ent subtypes. Embryonal and alveolar rhabdomyosar-
coma are seen mainly in the pediatric population, whereas
pleomorphic rhabdomyosarcoma, a relatively rare tumor,
occurs mainly in the adult population. Embryonal rhab-
domyosarcoma has a peak age incidence between ages 3
and 5 years. Occasionally, it may present in newborns as
an orbital or perineal mass. One subtype of embryonal
rhabdomyosarcoma that affects adolescents and is more
frequently located in the spermatic cord is the spindle-
cell variant. Overall, the head and neck region, genito-
urinary organs, and soft tissue of the extremities are the
most frequently affected sites. The alveolar variant of
rhabdomyosarcoma, which more commonly arises in the
extremities, has a poorer prognosis than either embryo-
nal rhabdomyosarcoma or fusion-negative alveolar rhab-
domyosarcomas193 (see below). Rhabdomyosarcoma is a
highly aggressive neoplasm; however, modern multimo-
dality treatment regimens have significantly improved
5-year survival to greater than 70%, and 5-year survival
for embryonal rhabdomyosarcoma approaches 90%.
Many rhabdomyosarcomas have clearly recognizable
rhabdomyoblastic microscopic features and can be diag-
nosed with the aid of appropriate immunostains and
Text continued on p. 1250
 19  Metastatic Tumors in Bone 1245

A B

C D
FIGURE 19-22  ■  Metastatic melanoma in femur: radiographic features. A, Lateral radiograph of the knee shows subtle disruption of
the posterior femoral cortex in the region of the lateral femoral condyle. B, Sagittal computed tomography scan more clearly shows
a radiolucent lesion in the distal femur with destruction of the posterior metaphyseal cortex. C, Sagittal, proton density magnetic
resonance image (MRI) and D, T2-weighted coronal MRI show the metastatic melanoma in the posterior portion of the lateral femoral
condyle.

ERRNVPHGLFRVRUJ
1246 19  Metastatic Tumors in Bone

B
FIGURE 19-23  ■  Metastatic melanoma: microscopic features. A and B, Photomicrographs of the lesion in Figure 19-18 showing nests
of pleomorphic, epithelioid cells typical of melanoma. Inset, Tumor cells are strongly immunoreactive for S-100 protein. (A and
Inset, ×200; B, ×400.) (A and B, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 19  Metastatic Tumors in Bone 1247

A B

C D
FIGURE 19-24  ■  Metastatic melanoma, neuroblastoma and rhabdomyosarcoma: cytologic features. A, Aspirates from metastatic
melanoma showing large epithelioid cells with eccentric nuclei. B, Metastatic neuroblastoma showing poorly differentiated small
cells in a background of delicate fibrillar matrix. C and D, Aspirate of metastatic alveolar rhabdomyosarcoma showing dispersed
rhabdoid cells with oval cytoplasm. (A, B, and D, ×600; C, ×400.) (A-D, hematoxylin-eosin.) (Courtesy of Dr. John Stewart, MD Anderson
Cancer Center, Houston, Texas.)

ERRNVPHGLFRVRUJ
1248 19  Metastatic Tumors in Bone

A B

C D
FIGURE 19-25  ■  Metastatic melanoma and pancreatic carcinoma: cytologic features. A, Aspirates of melanoma showing epithelioid
cells with dense eosinophilic cytoplasm and eccentric nuclei. Inset, Melanoma cells with melanin deposits. B, Spindle-cell melanoma
with extensive melanin deposits. C and D, Crowded sheets of epithelial cells with high nuclear size variability among tumor cells.
(A-D, ×400; Inset, ×600.) (A-D and Inset, hematoxylin-eosin.) (Courtesy of Dr. Gregory Starkel, MD Anderson Cancer Center, Houston,
Texas.)

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 19  Metastatic Tumors in Bone 1249

A B

C
FIGURE 19-26  ■  Lytic and osteoblastic metastases: radiographic features. A, Blowout destructive lytic lesion of second left rib (arrows)
confirmed by microscopic analysis to be metastatic carcinoma of thyroid. B, Computed tomogram of lesion in A documents destruc-
tive low-signal lesion in proximal portion of second left rib (arrows). Note residual patchy mineralization and thin line of expanded
periosteum. These features suggest that this metastatic carcinoma most likely contains a secondary aneurysmal bone cyst compo-
nent, which was confirmed microscopically. C, Anteroposterior radiograph of pelvis of a 9-year-old child shows multiple sclerotic
foci that represent widespread skeletal metastases of medulloblastoma.

ERRNVPHGLFRVRUJ
1250 19  Metastatic Tumors in Bone
molecular or molecular cytogenetic studies. Rhabdomyo-
sarcoma must be differentiated from a variety of other
hematologic and nonhematologic round-cell malignan-
cies. The skeleton is a relatively common site for meta-
static rhabdomyosarcoma, and skeletal metastases in
rhabdomyosarcoma are typically lytic167 (Fig. 19-27).
Diffuse involvement of bone with a permeative growth
pattern similar to that seen in other small cell malignan-
cies may be seen with alveolar rhabdomyosarcoma,182 and
pediatric patients typically undergo bone marrow biopsy
as a component of their staging studies.
Rhabdomyosarcoma is another example of a neoplasm
for which molecular techniques can be used as an adjunct
in diagnosis. Similar to neuroblastoma, these data can
provide some prognostic information. Alveolar rhabdo-
myosarcoma shows consistent chromosomal transloca-
tion t(2;13)(q35;q14), and less commonly t(1;13)(p36;q1
4).158,173,176,191,197,199,200 These cytogenetic abnormalities are
associated with the formation of PAX3-FOXO1 or PAX7-
FOXO1 gene fusions.159,161,170,192 The PAX3-FOXO1 gene
fusion occurs nearly four times as frequently in alveolar
rhabdomyosarcoma and is associated with a worse prog-
nosis than those tumors that harbor a PAX7-FOXO1
fusion.181 These abnormalities can be identified using
either reverse transcriptase polymerase chain reaction or
fluorescence in situ hybridization, valuable ancillary tests
that can be used to differentiate rhabdomyosarcoma from
other round-cell tumors.174 The amplification of the
MYCN gene is not entirely specific for neuroblastoma
and can occur in rhabdomyosarcoma, but it is typically
seen only in the alveolar variant.172,196
The smears from rhabdomyosarcoma are usually very
cellular and show a population of malignant small round
cells with scanty cytoplasm and round or oval nuclei (Fig.
19-24, C, D). The presence of larger cells with abundant
eosinophilic cytoplasm containing fibrils or showing
cross-striations indicates rhabdomyoblastic differentia-
tion. However, rhabdomyoblasts displaying unequivocal
cross-striation are difficult to find and, in most cases,
immunohistochemical stains are necessary to classify the
lesion.
Neuroblastoma
Solitary or multiple, typically lytic, bone lesions are fre-
quent presentations of neuroblastoma. This tumor has a
unique predilection to metastasize to the orbit, jaws, and
metaphyseal parts of long tubular bones.168 In fact, neu-
roblastoma is a prototypic pediatric malignancy that can
present as a solitary bone metastasis and a clinically occult
primary lesion. This tumor has a predilection to metas-
tasize to the orbit, jaws, and metaphyseal parts of long
bones. The latter presentation, due to similarity in clini-
cal symptoms, can be confused with osteomyelitis. In
typical cases, the presence of intercellular fibrillar matrix
separating the loosely arranged tumor cell nuclei is a
helpful feature in differentiating neuroblastomas from
other round-cell malignancies. The changes in the long
tubular bones can be similar to those seen with acute
leukemia, or they may be associated with periosteal reac-
tions and can be radiographically confused with osteomy-
elitis.156 Discrete diffuse involvement of bone marrow in
ERRNVPHGLFRVRUJ
biopsy samples is frequently seen and can be documented
in nearly 50% of neuroblastomas. On the other hand,
radiographically demonstrable destructive bone lesions
(Fig. 19-28) are seen less frequently in approximately
25% of children with neuroblastoma. In typical cases, the
presence of neuropil and ganglionic differentiation are
microscopic features diagnostic of neuroblastoma (Fig.
19-29). Neuroblastoma serves as an example of a tumor
for which molecular studies can not only aid the diagno-
sis, but are also of prognostic value. Clinically aggressive
tumors with a high propensity for dissemination and less
favorable response to treatment, as well as presenting in
an advanced stage, are characterized by MYCN amplifica-
tion, and loss of heterozygosity of 1p, 3p, and 11q, and
gains of 1q and 17q.160,162,163,175,178-180,188,190,195 MYCN also
regulates the expression of several micro-RNAs, which
play a role in the pathogenesis of neuroblastoma.166 The
PHOX2B and ALK genes have also been linked to familial
neuroblastomas. Low-risk neuroblastomas are character-
ized by hyperdiploidy or near triploidy, particularly in
patients younger than age 1.5 years.169
Aspirates from metastatic neuroblastoma are usually
very cellular and consist of small round cells occasionally
arranged in clusters and lying singly. Formation of
rosettes composed of spherically arranged nuclei with a
fibrillar center may also be present, but this is a rather
rare finding in cytologic preparations. The presentation
may be very similar to Ewing’s tumor (Fig. 19-25, B).
Clear Cell Sarcoma of the Kidney
Clear cell sarcoma of the kidney is a rare neoplasm
that represents the third most common pediatric renal
neoplasm after Wilms’ tumor and renal cell carci-
noma.157,177,185,201 This tumor primarily affects young chil-
dren and has a peak age incidence between age 2 and 3
years. Clear cell sarcoma of the kidney has a strong pro-
pensity to metastasize to the skeleton.157,189,194 Multiple
lytic osseous metastases during the clinical course of this
tumor represent a clinical hallmark of this rare tumor. In
fact, this unique feature was originally used to separate
this lesion from the Wilms’ tumor group. It frequently
presents with skeletal metastases and an occult primary
tumor. Microscopically, most tumors are composed of
nests of spindled or ovoid cells surrounded by fibrovas-
cular septa (Fig. 19-30); however, a small number of
tumors may have variant patterns described as myxoid,
sclerosing, cellular, epithelioid, palisading, spindle-cell,
storiform, or anaplastic.157 Clear cell sarcomas do not
have a characteristic immunohistochemical profile. A
unique translocation—t(10;17)(q22;p13)—has been iden-
tified in clear cell sarcoma164,183,184,186,187; however, the
molecular characteristics of the breakpoints have not
been defined.
Aspirates from metastatic clear cell sarcoma of the
kidney are usually cellular and show a large population
of pleomorphic sarcomatous cells. Deep nuclear indenta-
tions and nuclear grooves, as well as a granular cytoplasm,
are characteristic features. In some cases, aspirates may
show biphasic pattern with pleomorphic sarcomatous
cells admixed with spindle-shaped cells.
Text continued on p. 1255
 19  Metastatic Tumors in Bone 1251

A
B

C D

FIGURE 19-27  ■  Metastatic rhabdomyosarcoma in bone: radiographic, gross, and histologic features. A, Anteroposterior radiograph
showing a destructive lytic lesion with pathologic fracture. B, Coronally bisected gross photograph of the resected femur shown in
A with a destructive ill-defined fleshy tumor of the distal femur. Note cystic change within the center of the lesion filled with muci-
nous fluid related to treatment effect. C and D, Low power photomicrograph showing microscopic features of metastatic rhabdo-
myosarcoma infiltrating fatty marrow. Insets show microscopic details of metastatic rhabdomyosarcoma with maturation effect
induced by chemotherapy in C. (C and D, ×100; Insets, ×200.) (C, D and inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1252 19  Metastatic Tumors in Bone

C D
FIGURE 19-28  ■  Metastatic neuroblastoma: radiographic features. A, Lateral radiograph of the spine showing an osteoblastic lesion
in the S1 portion of the sacrum. B, Axial computed tomography scan of the spine through the S1 lesion seen in A. C, T1-weighted
sagittal magnetic resonance image (MRI) shows only the metastasis in S1, which appears dark (very low signal intensity).
D, However, T1-weighted sagittal postcontrast MRI reveals multiple lesions in the lower thoracic and lumbar vertebral bodies. Inset,
Radioisotope scan shows multiple areas of increased uptake in the lower spine.

ERRNVPHGLFRVRUJ
 19  Metastatic Tumors in Bone 1253

B
FIGURE 19-29  ■  Metstatic neuroblastoma: histologic and radiographic features. A and B, Photomicrographs show nests of round
cells deposited in an eosinophilic, fibrillary matrix. Ancillary tests are also useful in differentiating metastatic neuroblastoma from
other round cell malignancies. Inset, Axial computed tomography scan showing a metastatic neuroblastoma deposit within the
calvarium (A, ×200; B, ×400) (A and B, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
1254 19  Metastatic Tumors in Bone

B
FIGURE 19-30  ■  Metastatic clear cell sarcoma of kidney: microscopic features. A and B, Solid proliferation of round primitive cells
with clear cytoplasm is characteristic of this tumor (A, ×200; B, ×400) (A and B, hematoxylin-eosin).

ERRNVPHGLFRVRUJ

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CHAPTER OUTLINE
SYNOVIAL CHONDROMATOSIS
SYNOVIAL CHONDROSARCOMA
PIGMENTED VILLONODULAR SYNOVITIS
SYNOVIAL CHONDROMATOSIS
Definition
Synovial chondromatosis is a metaplastic condition
involving articular or tendon sheath synovial membranes
in which multiple nodules of cartilage are produced.
Many of the nodules subsequently become detached from
the synovial membrane and float in the joint. The process
typically involves the synovium diffusely, has a high pro-
pensity for recurrences, and may severely compromise
the function of a joint.
The exact pathogenesis of synovial chondromatosis is
unknown, but the involvement of chondroprogenitor
cells with dysregulation of the hedgehog signaling
pathway and overexpression of bone morphogenetic pro-
teins 2 and 4 (BMP2 and 4) has been postulated.6,11,23,24
Overexpression of fibroblast growth factor receptor 3
(FGFR3), an important regulator of chondroprogenitor
cells, and its specific ligand fibroblast growth factor 9
(FGF9) was identified in proliferating cells at the periph-
ery of cartilage nodules.28
Incidence and Location
Synovial chondromatosis is thought to occur rarely, but
data on its true incidence are not available. The peak
incidence is in the fifth decade of life, but the age range
varies widely from the first to seventh decades. Male
patients are predominantly affected, and the male-to-
female ratio is approximately 2 : 1.
Synovial chondromatosis preferentially involves the
major weight-bearing joints, but any joint may be
involved.4,5,7,10,13,15,18 Joints such as the knee, hip, and
elbow are typically involved. Approximately 70% of
cases involve the area around the knee. A few cases
involve joints of the shoulder and acral skeleton, the
intervertebral facet joint, and the temporomandibular
joint.1,2,14,16,17,29,31,40,41 Approximately 10% of cases, espe-
cially those involving the knee, hip, elbow, or shoulder,
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C H A P T E R 2 0 
Synovial Lesions
SYNOVIAL LIPOMA
SYNOVIAL HEMANGIOMA
are bilateral. The peak age incidence and the most fre-
quent joints involved are shown in Figure 20-1.
Clinical Symptoms
The clinical presentation consists of pain, swelling, and
limitation of motion. The patient may have a history of
symptoms lasting several months to several decades, but
usually symptoms have persisted for several years, with
the average being 5 years.
Radiographic Imaging
If the process is well developed (i.e., sufficient mineraliza-
tion of the cartilaginous matrix has occurred), the changes
shown on plain radiographs are characteristic, and the
diagnosis can be established preoperatively.8,22,25,38,39
However, in approximately 10% of synovial chondroma-
toses, no calcifications can be documented on plain films.
In typical cases involving a major joint, synovial chondro-
matosis presents as multifocal, articular, or periarticular
nodules with stippled or ringlike calcifications (Figs. 20-2
to 20-5). The level of mineralization gradually increases
if the lesions are untreated. Older lesions are heavily
calcified and easy to recognize on radiographs. Superim-
position of enchondral ossification is associated with the
development of linear calcifications. The nodules may
eventually develop ringlike or eggshell-like calcifications
with central lucencies (Fig. 20-2). These structures cor-
respond to well-developed ossified nodules that are com-
posed of a shell of bone with a central area mimicking a
medullary cavity. Occasionally the involvement may be
quite extensive, and the disease may pursue an aggressive
clinical course (Fig. 20-2). In such cases, there is extensive
involvement of tendons, multiple joints, or both tendons
and joints in the same anatomic region. Bone erosion can
be present and is not an indication of aggressive behav-
ior.17,25,26,28 Computed imaging techniques, especially
magnetic resonance imaging, are helpful in identifying
Text continued on p. 1264
1259
1260 20  Synovial Lesions

Incidence

1 2 3 4 5 6 7 8
Age in decades
FIGURE 20-1  ■  Synovial chondromatosis. Peak age incidence and most frequent joints involved. Most frequent sites are indicated by
solid black arrows.

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B
FIGURE 20-2  ■  Synovial chondromatosis: radiographic features. A and B, Lateral (A) and anteroposterior (B) radiographs of foot and
ankle show long-standing synovial chondromatosis involving tendon sheaths. Tarsal joints and ankle joint appear to be preserved.
Most nodules are of bony consistency. Note extensive involvement of extraarticular synovium of tendons and eggshell pattern of
mineralization with central lucency in some of the nodules.

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1262 20  Synovial Lesions

C
FIGURE 20-3  ■  Synovial chondromatosis: radiographic features. A, Lateral radiograph of knee shows stippled calcification in posterior
aspect. B, Computed tomogram documents multifocal calcification in periarticular soft tissue. C, Specimen radiograph of resected
synovial pad with multifocal calcified nodules representing areas of cartilaginous metaplasia.

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B
FIGURE 20-4  ■  Synovial osteochondromatosis: radiographic features. A, Sagittal magnetic resonance image shows high signal in
loose bodies with areas of signal void representing mineralization of cartilage and bone matrix. B, Lateral radiograph of knee shows
cartilaginous and bony loose bodies in knee joint below patella; joint space is preserved.

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1264 20  Synovial Lesions
FIGURE 20-5  ■  Synovial chondromatosis of ankle joint: radio-
graphic features. Lateral radiograph shows popcornlike calcifi-
cation in cartilaginous loose bodies and in synovium above
posterior aspect of calcaneus and overlying the distal end of
tibia, fibula, and talus. Note enlargement of tarsal sinus and
thinning of neck of talus secondary to pressure of intraarticular
bodies.
the lesion in its early stages when there is insufficient
mineralization to be documented in conventional radio-
graphs.4,12,36 In later stages, these techniques provide the
means to evaluate the extent of involvement of the joint
and its adjacent structures (Figs. 20-4, 20-6, and 20-7).
T1-weighted images typically show a punctate signal void
in the lesion involving the joint capsule. However,
T2-weighted images show signal enhancement and may
show the lesion to have a multinodular architecture.4,8,29
Lesions involving smaller joints become symptomatic in
earlier stages and may show discrete, ill-defined calcifica-
tions or no calcification on plain radiographs3 (Figs. 20-8
and 20-9). At the other end of the spectrum are long-
lasting lesions that present as a consolidated, heavily cal-
cified mass.30
Gross Findings
In advanced cases, the synovium is diffusely involved
and may be studded with multiple cartilage nodules
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(Fig. 20-10). Each cartilage nodule ranges in size from a
small focus (<1 mm) that requires a magnifying glass to
be seen to a larger lesion measuring more than 1 cm in
diameter. In well-established, diffuse lesions, there are
multiple free cartilaginous nodules, and the joint space
occasionally is packed with loose bodies that range in size
from 1 mm to 1 to 2 cm9,10 (Fig. 20-10). In addition to
individual nodules focally, larger cartilaginous areas rep-
resent coalescent smaller nodules of cartilage. These
larger cartilaginous masses have multinodular (granular)
surfaces, and their multifocal origin can still be seen
on cut surface. Occasionally in long-standing cases, the
adjacent bursae or tendons may be involved. On the
basis of gross features, synovial chondromatosis can be
divided into two forms: diffuse and localized. The diffuse
form is characterized by multiple nodules that involve
almost the entire synovium of the joint. In the localized
form a discrete mass is present and represents a coales-
cence of individual nodules of metaplastic cartilage
(Fig. 20-11). In rare cases a nodular form of synovial
chondromatosis can have a configuration of a polypoid
pedunculated mass protruding into the joint space. The
process typically involves synovial membranes of the joint
capsule. Exclusively extraarticular cases are rare.33,34
Extraarticular involvement is associated more often with
an articular form.
Microscopic Findings
Fully developed synovial chondromatosis consists of mul-
tiple, well-demarcated nodules of cartilage with hyaline
or myxoid features19,20,21,25,35,38-40 (Fig. 20-12). Early lesions
are composed of ill defined hypercellular nodules com-
posed of chondroblastic cells with minimal matrix forma-
tion (Figs. 20-13 and 20-14). In typical cases the cartilage
cells form loose clusters, but a uniform distribution of
cartilage cells can also be seen. The cellularity of cartilage
nodules is often increased. The nuclei of cartilage cells
have open chromatin and small nucleoli and may exhibit
significant nuclear atypia (Figs. 20-15 to 20-17). Binucle-
ated or larger cartilage cells are frequently present. The
microscopic features of cartilage atypia may be compat-
ible with those seen in grade 1 and 2 chondrosarcomas if
taken out of context of a metaplastic synovial condition.
These features should not be considered as indicative of
malignant transformation and cannot be correlated with
a more aggressive clinical behavior of the disease.
The development of cartilage nodules in this meta-
plastic process is somewhat similar to normal phases of
cartilage development. However, the majority of patients
have a long history of symptoms when they are first seen.
Therefore the early phases of this process are rarely seen.
The earliest phases of synovial cartilage metaplasia are
most frequently seen in smaller joints, such as the tem-
poromandibular joint or the small joints of the acral skel-
eton, in patients with a short history of symptoms. In the
earliest stages of synovial chondromatosis, small islands
of cartilage cells with chondroblastic features form. Indi-
vidual chondroblastic cells dispersed within the stromal
tissue of the joint capsule also can be seen (Fig. 20-18).
Loosely arranged clusters of immature cartilage cells may
Text continued on p. 1278
 20  Synovial Lesions 1265

FIGURE 20-6  ■  Localized synovial chondromatosis of hip joint: radiographic features. Computed tomogram of hip shows femoral
head within acetabulum. Note enlargement of acetabular fossa and calcified intrasynovial cartilaginous bodies characteristic of
localized synovial chondrometaplasia.

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1266 20  Synovial Lesions

B
FIGURE 20-7  ■  Synovial chondromatosis: radiographic features. A and B, Computed tomogram of skull shows involvement of tem-
poromandibular joint by synovial chondromatosis. Calcifications in loose bodies can be seen adjacent to mandibular condyle.
C, Magnetic resonance image of temporomandibular joint shown in A and B. Note expansion of joint and areas of signal void within
joint and in thickened synovium. These represent calcification in metaplastic cartilage.

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 20  Synovial Lesions 1267

B
FIGURE 20-8  ■  Synovial chondromatosis: radiographic features. A, Plain radiograph of wrist and hand shows soft tissue calcifications
in wrist joint overlying triquetrum, hamate, and distal end of ulna (arrows). B, Lateral view of wrist (same case as A) shows soft
tissue calcified bodies that are both dorsal and volar in location (arrows).

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B
FIGURE 20-9  ■  Synovial chondromatosis of tendon sheath: radiographic features. A, Anteroposterior radiograph of foot shows soft
tissue calcification between first and second metatarsals with ringlike and punctate appearance. B, Oblique radiograph shows soft
tissue calcifications representing loose cartilaginous bodies in tendon sheath. Note pressure erosions along inferolateral cortex of
first metatarsal.

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 20  Synovial Lesions 1269

A B

C D
FIGURE 20-10  ■  Synovial chondromatosis (diffuse form in major joints): gross features. A and B, Synovectomy specimen in case of
diffuse synovial chondromatosis of knee joint. Synovial membrane is studded with multiple cartilage nodules that vary in size.
C and D, Loose cartilaginous bodies and synovial membrane from two cases of synovial chondromatosis that diffusely involved
knee joint. Cartilage nodules are present in synovium and free in joint. Bodies vary in size, and some are conglomerated to form
larger masses.

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1270 20  Synovial Lesions

A B

C D
FIGURE 20-11  ■  Synovial chondromatosis (localized form): gross and radiographic features. A, Localized synovial chondromatosis
presents as conglomerate of individual cartilage nodules. B, Pedunculated polypoid lesion of knee joint is composed of individual
cartilage nodules and interlacing synovial membrane. C, Radiograph of shoulder showing a conglomerate of individual mineralized
nodules with punctate and ringlike calcification patterns. D, Central calcification in metaplastic chondroid nodule of synovium in
knee joint. (D, ×25) (D, hematoxylin-eosin.)

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 20  Synovial Lesions 1271

A B

C D
FIGURE 20-12  ■  Synovial chondromatosis: microscopic features. A, Low power photomicrograph of cross section through synovium
of knee joint in synovial chondromatosis. Most nodules are composed of hyaline cartilage. Some are calcified, and early endochon-
dral ossification is present in others. B, Medium power photomicrograph of typical chondroid metaplastic nodules in synovium
of knee joint. C, Low power photomicrograph of synovium with conversion of cartilage nodules to bone. This is late stage
of the phenomenon. D, Almost complete ossification of hyaline cartilage nodule in synovium to bone. (B, ×25; D, ×50)
(A-D, hematoxylin-eosin.)

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1272 20  Synovial Lesions

B
FIGURE 20-13  ■  Synovial chondromatosis: microscopic features. A, Ill defined nodules composed of chondroblastic cells in the syno-
vial membrane representing early phases of synovial chondromatosis. B, Higher magnification of A showing a ill defined subsynovial
nodule composed of chondroblastic cells with early evidence of matrix deposition in the center. Inset, Higher magnification showing
nuclear morphology of chondroblastic cell. (A, ×15; B, ×25; Inset, ×200) (A, B, and Inset, hematoxylin-eosin.)

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 20  Synovial Lesions 1273

B C
FIGURE 20-14  ■  Synovial chondromatosis: microscopic features. A, Low power view showing hypercellular ill defined nodules com-
posed of chondroblastic cells. Some of the nodules show cartilage matrix deposition. B, Higher magnification of A showing an ill
defined nodule composed of chondroblastic cells. C, Higher magnification of A showing a cartilage nodule. (A, ×15; B and C, ×25)
(A-C, hematoxylin-eosin.)

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1274 20  Synovial Lesions

B C
FIGURE 20-15  ■  Synovial chondromatosis: microscopic features. A, Medium power photomicrograph of chondroid metaplastic
nodules in synovium with clear cell features. B, Higher magnification of A showing cartilage nodules in the synovial membrane
with clear cell features and nuclear hyperchromasia. C, Higher magnification of metaplastic synovial cartilage nodules with clear
cell features and nuclear hyperchromasia. (A, ×15; B and C, ×50) (A-C, hematoxylin-eosin.)

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B
FIGURE 20-16  ■  Synovial chondromatosis: microscopic features. A, Low power photomicrograph of synovium containing nodules
of metaplastic cartilage with hyaline and myxoid features. B, Medium power photomicrograph shows hyaline cartilage arising
through metaplasia of synovial membrane. Inset on left shows early stage of development with myxoid differentiation of connective
tissue cells and intercellular matrix. Inset on right shows chondrocytes with open chromatin in hyaline matrix. (A, ×100; B and
left Inset, ×200; right Inset, ×400) (A, B, and Insets, hematoxylin-eosin.)

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1276 20  Synovial Lesions

A B

C D

FIGURE 20-17  ■  Synovial chondromatosis: microscopic features. A and B, Low power photomicrographs showing extensive cartilage
metaplasia of the synovial membrane with confluent cartilage nodules. C and D, Intermediate and high power photomicrographs
showing myxoid and hyaline chondroid matrix formation. Note pronounced cellular variability and nuclear hyperchromasia (A and
B, ×25; C, ×100; D, ×200) (A-D, hematoxylin-eosin).

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 20  Synovial Lesions 1277

A B

C D

FIGURE 20-18  ■  Synovial chondromatosis: microscopic features. A and B, Low and medium power photomicrographs of chondroid
metaplastic nodules in the synovium. C and D, Medium and high power photomicrographs showing loosely arranged cells with
chondroblastic features within myxoid areas adjacent to discrete cartilage nodules. Note variation in nuclear size and hyperchro-
matism, which should not be interpreted as indicative of malignancy (A, ×25; B, ×50; C, ×100; D, ×200) (A-D, hematoxylin-eosin).

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1278 20  Synovial Lesions
exhibit myxoid or clear-cell features. Occasionally, larger,
loose areas of cells with microscopically recognizable
chondroblastic features can be seen within the soft tissue
in the vicinity of more mature cartilage islands (Fig.
20-19). These foci are present beneath the synovial lining
and do not directly involve the synovium. Smaller, more
densely packed foci of chondroblastic cells with dense
eosinophilic cytoplasm and large hyperchromatic nuclei
may also be present within well-established cartilage
nodules (Fig. 20-20). It is our impression that immaturity
of cartilage cells is responsible for prominent atypia in a
majority of cases. Rarely is the formation of cartilage
nodules associated with prominent giant cell osteoclastic
reaction (Fig. 20-21).
Enchondral ossification of cartilage nodules is a fre-
quent feature of well-developed synovial chondromato-
sis. There are well-developed peripheral rings or eggshells
of lamellar bone (Fig. 20-12). Occasionally the nodules
consist of well-formed rings of lamellar bone with a
central, fatty bone marrow–like space. Lesions with well-
developed enchondral ossification are also referred to as
osteochondromatosis.
Lesions that present as a single cartilaginous nodule
within the joint capsule are sometimes referred to as
synovial chondromas.8,10,27,30,32,34,37 Single, isolated cartilage
nodules are typically seen in smaller joints of the acral
skeleton (Fig. 20-22) or in the temporomandibular joint.
These lesions typically show prominent mineralization of
cartilage matrix. It is still controversial whether a single
discrete nodule within synovium or periarticular soft
tissue is a clonal neoplastic proliferation of cartilage cells
(i.e., chondroma) or represents a localized unifocal variant
of a metaplastic process (i.e., synovial chondromatosis).
Differential Diagnosis
The most important consideration in differential diag-
nosis is chondrosarcoma. The cytologic atypia of carti-
lage cells is often worrisome and raises the suspicion of
chondrosarcoma. The approach used to evaluate synovial
chondromatosis is the same as that used to evaluate car-
tilage lesions of bone. Thus as with cartilage lesions, all
clinical and radiographic findings should be considered.
First, rare but well-known secondary involvement of
the joint by a chondrosarcoma of the adjacent bone, such
as the femur or tibia, must be clinically and radiographi-
cally ruled out. This dilemma arises most frequently in
evaluating hip lesions, in which the joint capsule may be
secondarily involved by a chondrosarcoma of the adjacent
pelvic and femoral bones. When the clinical, radio-
graphic, and gross findings are consistent with the
process confined to the joint capsule and space, the atypia
of cartilage cells can be discounted as a feature of malig-
nant transformation, and the lesion can be classified as
synovial chondromatosis. However, these cases must be
differentiated from extremely rare primary synovial
chondrosarcoma or chondrosarcoma developing in syno-
vial chondromatosis (see later section). In rare instances
synovial chondromatosis may develop in a bursa overly-
ing an osteochondroma. Such cases may, radiographi-
cally, mimic a secondary chondrosarcoma arising in the
cartilaginous cap of the osteochondroma.9
ERRNVPHGLFRVRUJ
Treatment and Behavior
Synovial chondromatosis is treated by removing the loose
bodies and the synovial membrane. In some cases, it
follows a self-limited course. After many years, these
lesions reach a quiescent stage in which only loose
intraarticular bodies are present and there is no active
process in the joint capsule. Extraarticular extension with
tendon involvement does not indicate aggressive behav-
ior. Synovial chondromatosis is a local, nonneoplastic,
self-limiting process. Removal of the loose bodies and of
the involved synovium is sufficient to control the disease
in the majority of cases. Multiple and often short-interval
recurrences raise suspicion of synovial chondrosarcoma.
SYNOVIAL CHONDROSARCOMA
Chondrosarcoma of the synovium is extremely rare.42-53
The largest series of 10 cases was published by research-
ers at the Mayo Clinic.43 Chondrosarcoma can develop
within the joint capsule as a de novo (primary) lesion or
may be secondary to preexisting synovial chondromato-
sis. Primary synovial chondrosarcoma is the rarest form.
In a series of 10 reported cases, only 2 were primary
lesions, and the remaining 8 developed in a setting of
synovial chondromatosis. The majority of reported cases
involve the major joints of the lower extremities. Knee
involvement is the most frequent, followed by involve-
ment of the ankle and hip. Synovial chondrosarcoma may
develop in other major joints of the upper extremities and
in the smaller joints of the acral skeleton. Our experience
is restricted to three cases that involved the knee, elbow,
and foot. In all three cases, the tumor developed in a
setting of synovial chondromatosis.
Radiographically, chondrosarcomas of the synovium
should be suspected if a consolidated calcified mass is
present in the joint area. In most cases, the presence
of a calcified consolidated mass is associated with bone
erosion. Grossly, the lesion represents a consolidated
cartilage mass and typically involves the adjacent bone
(Fig. 20-23).
Histologically, the lesions are typically grade 1 and 2
chondrosarcomas (Figs. 20-24 and 20-25). Sometimes,
the tumors are of myxoid type. Features such as loss of
clustered growth pattern of cartilage cells, prominent and
uniform myxoid appearance, necrosis, and presence of
spindling at the periphery of nodules should raise the
suspicion of malignancy.42,52,53 The diagnosis of chondro-
sarcoma of the synovium should be based on the analysis
of clinical, radiographic, and microscopic evidence.
The microscopic features described are valid if they
coincide with the radiographic and gross documentation
of a consolidated mass that is not a coalescence of indi-
vidual metaplastic nodules. It is common for the final
diagnosis of synovial chondrosarcoma to be made after
several local recurrences of lesions initially considered
to be synovial chondromatosis. Pulmonary metastases
develop in approximately 50% of patients with reported
cases of synovial chondrosarcomas, usually within 3 years
after initial diagnosis. Synovial chondrosarcomas are
Text continued on p. 1286
 20  Synovial Lesions 1279

A B

C D
FIGURE 20-19  ■  Synovial chondromatosis: microscopic features. A and B, Low and medium power photomicrographs showing con-
fluent cartilage nodules in the synovial membrane with hypercellular areas and hyperchromatism. C and D, Medium and high power
photomicrographs showing ill defined hypercellular cartilage nodules with clear cell features and nuclear hyperchromasia (A, ×25;
B, ×50; C and D, ×100) (A-D, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
1280 20  Synovial Lesions

B
FIGURE 20-20  ■  Synovial chondromatosis: microscopic features. A, Metaplastic chondroid nodule showing hypercellular metaplastic
cartilage nodule with nuclear hyperchromasia. B, Loosely arranged cells with chondroblastic features within myxoid area. Inset
shows variation in nuclear size and hyperchromasia, which should not be interpreted as indicative of malignancy. (A and B, ×200;
Inset, ×400) (A, B, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 20  Synovial Lesions 1281

B C
FIGURE 20-21  ■  Synovial chondromatosis: microscopic features. A, Low power photomicrograph showing an unusual association
of synovial chondroid cartilage metaplasia with prominent giant cell reaction. B and C, Interface between cartilage nodule
and hypercellular areas with prominent giant cell reaction with multinucleated osteoclastic cells (A, ×25; B and C, ×100)
(A-C, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
1282 20  Synovial Lesions

A B

C D

FIGURE 20-22  ■  Tenosynovial chondrometaplasia (localized nodular form): radiographic and microscopic features. A and B, Lateral
radiographs of synovial chondrometaplasia in dorsal and volar tendon sheath of fingers. Note pressure erosion of phalanx in A and
focal soft tissue calcification in B. C and D, Low power photomicrographs of tenosynovial chondrometaplasia (synovial chondroma-
tosis) in digits. There is nodular hyaline cartilage differentiation and patchy calcification. (C, × whole mount; D, ×25.) (C and
D, hematoxylin-eosin.)

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 20  Synovial Lesions 1283

FIGURE 20-23  ■  Synovial chondrosarcoma developing secondary to synovial chondromatosis: gross features. A, Gross photograph
of synovial chondrosarcoma developing in left elbow of a man with a 10-year history of synovial chondromatosis. Grade 2 chon-
drosarcoma arose in synovium of elbow and spread beyond joint into soft tissue and bone. Multiple recurrences were followed by
amputation. B, Gross photograph of sagittally cut ankle and foot of patient with 15-year history of recurrent tenosynovial chondro-
matosis who had a grade 1 chondrosarcoma that invaded tarsal and metatarsal bones.

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1284 20  Synovial Lesions

B
FIGURE 20-24  ■  Synovial chondrosarcoma arising in synovial chondromatosis: microscopic features. A and B, Medium power
photomicrographs show ill defined nodularity of malignant cartilage cells with nuclear irregularity and hyperchromatism.
Inset shows hyperchromatic malignant cartilage cells in hyaline cartilage matrix (A and B, ×100; Inset, ×200) (A, B, and
Inset, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
 20  Synovial Lesions 1285

B
FIGURE 20-25  ■  Synovial chondrosarcoma: microscopic features. A, Grade 2 chondrosarcoma that developed in synovium of elbow
(same case as Fig. 20-20, A). B, Higher magnification of A shows so-called open chromatin of cartilage cells and myxoid stroma.
Inset shows pronounced nuclear atypia of cartilage cells. (A, ×100; B, ×200; Inset, ×400) (A, B, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1286 20  Synovial Lesions
TABLE 20-1 Forms of Pigmented
Villonodular Synovitis
Intraarticular
Diffuse Diffuse involvement of joint synovium
Localized Localized (polypoid or nodular) joint synovial
lesion
Extraarticular
Diffuse Diffuse multifocal involvement of
extraarticular synovial membrane (tendons)
Nodular Localized extraarticular nodular lesion, also
referred to as giant cell tumor of the
tendon sheath
treated by aggressive surgery (i.e., amputation or extraar-
ticular resection with amputation).
PIGMENTED VILLONODULAR SYNOVITIS
The unified clinicopathologic concept of pigmented vil-
lonodular synovitis or tenosynovitis proposed by Jaffe et al.
in 194180 encompasses a diverse group of fibrohistiocytic
proliferations that can occur in several, sometimes over-
lapping, clinical settings (Table 20-1). The process may
involve joints, bursae, tendon sheaths, the adjacent fascial
and ligamentous tissue, or a combination of these areas.
Pigmented villonodular synovitis can be divided into
several forms on the basis of site and extent of involve-
ment: intraarticular versus extraarticular and diffuse
versus localized or nodular. It is common for a nodular
or more diffuse lesion to occur in the same case. Simi-
larly, intraarticular and extraarticular involvement can
coexist. At the time of initial presentation, most lesions
can be classified into the basic forms listed in Table 20-1.
In the past it was generally accepted that the process
represents a reactive inflammatory condition. However,
in some cases, the clinical aggressiveness—bone destruc-
tion, recurrences, or both—raised the suspicion of low-
grade, locally aggressive neoplasia. In fact, in some
lesions, especially in the nodular extra-articular form
(giant cell tumor of tendon sheaths), clonal chromosomal
aberrations and aneuploidy have been noted.54,67,72,91,102
Trisomies 5 and 7 appear to be dominant, nonrandom
alterations in this disorder.66,72 Translocations involving
chromosomes 1 and 2 and chromosomes 1 and 14 have
also been reported.77 In general, the cells involved in
pigmented villonodular synovitis express a wide range of
histiocyte/macrophage and osteoclast markers.55
Several reports indicate that clonal cytogenetic abnor-
malities involving 1p11-13 are most frequent in pig-
mented villonodular synovitis and may contribute to the
growth advantage in providing gene activation through a
balanced translocation.67,91,95,98,103,106 It was recently shown
that mononuclear and osteoclast-like giant cells in pig-
mented villonodular synovitis express high levels of colony
stimulating factor 1 receptor (CSF1R). In addition, the
colony stimulating factor 1 (CSF1) gene encoding ligand
for CSF1R is translocated in the majority of intraarticular
and extraarticular pigmented villonodular synovitis71,123
(Fig. 20-26). Surprisingly, only a minority of tumor cells
(<20%) carry the translocation and express CSF1.65,123 It
ERRNVPHGLFRVRUJ
appears that the polyclonal nonneoplastic histiocytic cells
are attracted to the lesion by overexpression of CSF1.
Cytogenetic studies also indicate that the most common
fusion partner for CSF1 should be located on 2q35-37,
resulting in 1p11-2q37 balanced translocation.123 In fact,
this translocation produces a CSF1-COL6A3 chimeric
gene65,123 reminiscent of the translocation that defines
dermatofibrosarcoma protuberans, in which t(17;22)
brings PDGF-β under control of the strong COL1A1
promoter.88 This data suggests that only a minority of
cells in pigmented villonodular synovitis are clonal and
neoplastic and that the majority of histiocytic cells in the
lesion are nonneoplastic. These observations are consis-
tent with the biology of CSF1, which mediates the pro-
liferation, differentiation, and function of macrophages
and their precursors. The clonal neoplastic cells, with the
CSF1 translocation and its overexpression, most likely
recruit CSF1R-expressing macrophages and induce the
formation of multinucleated giant cells (Fig. 20-26).
These findings explain the lack of evidence for clonality
in previous chromosome X inactivation studies.104
DNA microarray studies show that the genes differ-
entially expressed in pigmented villonodular synovitis
are involved in cell proliferation, apoptosis, matrix
degradation, and inflammation, in part explaining the
aggressive, occasionally bone destructive nature of the
disease.70,75,116,119,122 Occasional aneuploidy seen primarily
in the diffuse forms of the disease confirms the neo-
plastic nature of the disorder.55 The increased prolifera-
tive rate of monocyte-macrophage lineage (histiocytic)
cells with overexpression of fibroblast growth factor and
the tyrosine kinase receptors Tie-1/Tie-2 have been
documented in some cases of pigmented villonodular
synovitis.32,92,108,110,117
Definition
Pigmented villonodular synovitis is a destructive, fibro-
histiocytic proliferation with production of villous and
nodular protrusions of articular and extraarticular syno-
vial membranes. Microscopically the lesion is composed
of fibroblasts, histiocytic cells, and inflammatory cell
infiltrates and contains prominent hemosiderin deposi-
tion, which is responsible for its brown color.
Incidence and Location
The true incidence of this condition is unknown, but it
is relatively rare and accounts for less than 5% of all
primary soft tissue tumors. The peak age incidence and
most frequent sites of involvement are shown in Figure
20-27. The age of patients varies widely from the first to
seventh decades of life. The peak age incidence is in the
third and fourth decades of life. There are significant
differences in the skeletal locations and age distribution
patterns among the various forms of pigmented villon-
odular synovitis.78,99,100,101,117 The intraarticular forms,
both diffuse and localized, predominantly involve the
major weight-bearing joints of the lower extremities.
In the intraarticular form, the knee is involved in approxi-
mately 80% of cases, followed by the hip (15%). Rare
examples of intraarticular forms can be found in
the ankle, foot, elbow, shoulder, sacral, vertebral facet,
 Chr 1 CSF1

Exon 1

Exon 2

Exon 3

Exon 4

Exon 5

Exon 6

Exon 7
Exon 8

Exon 9
36.3
Chr 2 36.2

cds
36.1
25.3
25.1 25.2 35
24 34.3 34.2
34.1
23 33
32.3
22 32.2
21
32.1
31.3 CSF1
31.2
1 554 aa
16 31.1
15 22.3
14 22.2 Four-helical cytokine-like, core domain
13 22.1
12 21 B
11.2 13.3
11.1 11.1 CSF1
11.2 13.1 13.2
11
12
13
12
11
COL6A3
14.1 12
14.2

Exon 10
Exon 11
Exon 12
Exon 13
Exon 14
Exon 15
Exon 16

Exon 17
Exon 18
Exon 19
Exon 20
Exon 21
Exon 22
Exon 23
Exon 24
Exon 25
Exon 26
Exon 27
Exon 28
Exon 29
Exon 30
Exon 31
Exon 32
Exon 33
Exon 34
Exon 35
Exon 36
Exon 37
Exon 38
Exon 39
Exon 40
Exon 41
Exon 42
Exon 43
Exon 44
14.3

Exon 1
Exon 2
Exon 3

Exon 4

Exon 5
Exon 6
Exon 7
Exon 8
Exon 9
21.1 21.2 21.1
21.2 21.3 21.3

cds
22 22
23
23 24
24.1 24.2 25
24.3
31 31
32.1
32.2
COL6A3
32.3 32.1
33 32.2 1 3177 aa
32.3
34 41
35 42.1 von Willebrand factor, type A domain Immunoglobulin-like fold domain
36 42.2 42.3
43 Collagen triple helix repeat domains Proteinase inhibitor I2, Kunitz metazoa domain
37.1 44
37.2 COL6A6
37.3
C
A

D E F

G H I J

CSF1R
R

CSF1R
F1
1R
CS 1R
CSF1R

COL6A3:CSF1
C CSF1

CSF1R
1R

FIGURE 20-26  ■  Pigmented villonodular synovitis: activation of CSF1 by a translocation and its landscape effect. A, Positions of CSF1
and COL6A3 on chromosomes 1 and 2 involved in 1P13-2q37 balanced translocation are shown. The nature of the break-point and
the specific structure of the fusion gene are not known at this time. B, Exon-intron structure of the CSF1 gene and of its encoded
protein are shown. C, Exon-intron structure of the COL6A3 gene and of its encoded protein are shown. D, Fluorescence in situ
hybridization (FISH) with the CSF1-spanning BAC probe RP11–19F3B in extraarticular villonodular synovitis confirms that the CSF1
gene is split by the trans-location in TGCT. E, The fusion of CSF1 and COL6A3 confirmed by FISH. The COL6A3 locus is represented
by CTD–2344F21 (labeled in white), the region telomeric to CSF1 is represented by RP11–96F24 (labeled in green), and the region
centromeric to CSF1 is represented by RP11–354C7 (labeled in orange). F, FISH with BAC probe RP11–25803 that covers the region
telomeric to COL6A3 fails to split. G and H, Two nuclei with the fusion of CSF1 and COL6A3 demonstrated by FISH in extraarticular
villonodular synovitis. The COL6A3 locus is represented by CTD–2344F21 (labeled in white), the region telomeric to CSF1 is repre-
sented by RP11–96F24 (labeled in green), and the region centromeric to CSF1 is represented by RP11–354C7 (labeled in orange).
I, Lack of translocation in a nucleus from the same sample as D and E shows an intact CSF1 gene. J, Combined interphase FISH
with the region telomeric to CSF1 represented by RP11–96F24 (labeled in green) and the region centromeric to CSF1 represented
by RP11–354C7 (labeled in orange), and CSF1 immunohistochemistry (labeled in red) demonstrated that only the cells with the
translocation expressed CSF1. K, Autocrine and paracrine scheme for CSF1 landscaping effect. CSF1 is produced by neoplastic cells,
with translocation resulting in increased numbers of neoplastic cells through an autocrine loop with CSF1R. CSF1 also recruits non-
neoplastic CD163- and CSF1R-expressing cells of monocyte/macrophage lineage. (Modified and reprinted with permission from West
RB, et al: A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor
cells. PNAS 103(3):690–695, 2006.)
ERRNVPHGLFRVRUJ
1288 20  Synovial Lesions
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 20-27  ■  Pigmented villonodular synovitis. Peak age incidence and most frequent sites of involvement. Most frequent sites
are indicated by solid black arrows.
and temporomandibular joints.62,73,74,84,87,120 The nodular
extraarticular variant of pigmented villonodular tenosy-
novitis typically involves the sacral soft tissue and is pre-
dominantly found in the fingers and metacarpal and
carpal areas.100 Tendons of the forearm are rarely involved.
When all forms of the disease are analyzed, the fingers
are involved in nearly 60% of cases, whereas the knee is
involved in approximately 30% of cases.117 The toes are
involved in about 10% of cases. Involvement of several
joints or severe polyarticular forms are seen more often
in younger patients.56,64,118,121 In rare instances pigmented
villonodular tenosynovitis can coexist with other synovial
conditions such as synovial chondromatosis.81
Clinical Symptoms
Symptoms include pain, swelling of the joint, and limita-
tion of motion. The presence of hemorrhagic joint
effusion is frequent. The aspirated fluid is typically hem-
orrhagic. The patient usually has a relatively long history
of symptoms lasting from 2 to 3 years. The symptoms
can be intermittent or steadily progressive.
Radiographic Imaging
On plain radiographs, pigmented villonodular tenosy-
novitis presents as an ill-defined, periarticular soft tissue
ERRNVPHGLFRVRUJ
Extraarticular
Intraarticular
7 8
mass57,59,61,63,64,68,69,76,79,83,86,107,111 (Figs. 20-28 to 20-30). It
is frequently associated with degenerative joint disease
and multiple subchondral cysts in the bones around the
joint.57,107 The cysts are usually present on both sides
of the affected joint. Computed tomography and mag-
netic resonance imaging reveal the extent of involve-
ment and are particularly useful in documenting the
presence of localized pedunculated lesions within major
joints.58,82,85,90,112,113 T1-weighted magnetic resonance
images show low-signal inhomogeneous masses that
may reveal a punctate signal void related to hemosiderin
deposits (Figs. 20-31 and 20-32). Erosion of bone com-
pressing the affected joint is frequently present85,90,112,113
(Figs. 20-28, 20-30, and 20-31).
Gross Findings
The various forms of pigmented villonodular synovitis
are defined by a combination of clinical, gross, and
microscopic findings. Therefore gross examination of the
removed tissue is an important part of determining the
correct diagnosis. In diffuse intraarticular forms, most or
all of the synovium is involved. It is covered with tan to
brown, irregular papillary projections and larger nodular
protrusions (Fig. 20-33). The irregularity or heterogene-
ity of synovial projections is very prominent. They range
from slender villous structures to thick papillae to large
 20  Synovial Lesions 1289

B
FIGURE 20-28  ■  Pigmented villonodular synovitis: radiologic features. A, T1-weighted sagittal magnetic resonance image of knee
joint with diffuse pigmented vil-lonodular synovitis. Note nodular thickening of synovium with areas of signal void at sites of hemo-
siderin deposition and erosion in anterior part of tibial plateau. B, Lateral radiograph of knee. Note preservation of joint space and
anterior erosion of tibial plateau.

ERRNVPHGLFRVRUJ
1290 20  Synovial Lesions

A
FIGURE 20-29  ■  Localized nodular tenosynovitis: radiographic features. A, Radiograph of finger shows soft tissue mass devoid of
calcification alongside proximal phalanx. B, Corresponding T1-weighted magnetic resonance image of phalanx adjacent to soft
tissue mass shows nodular tenosynovitis (giant cell tumor of tendon sheath).

ERRNVPHGLFRVRUJ

FIGURE 20-30  ■  Localized nodular tenosynovitis: radiographic
features. Lateral radiograph of thumb shows pressure erosion
and reactive sclerosis of proximal phalanx produced by long-
standing, overlying tendon sheath nodule.
irregular nodules. The involved joint capsule is thick-
ened, and the lesion is poorly demarcated from the adja-
cent periarticular soft tissue. Cross sections reveal soft
tissue that varies in color. The areas with hemosiderin
deposition are tan to brown. The lighter or yellowish
regions correspond to lipid deposition in foamy histio-
cytes. The lesion has ill-defined borders that impercep-
tibly merge with the periarticular soft tissue and involve
the skeletal muscles. The articular cartilage and the adja-
cent bone may be eroded. The localized intraarticular
form presents as a discrete nodule protruding into the
joint space (Fig. 20-34). It can have a broad base of
ERRNVPHGLFRVRUJ
20  Synovial Lesions 1291
attachment to the synovial membrane or can present as
a pedunculated polypoid lesion. The nodule is frequently
necrotic because of mechanical injury or torsion of its
pedunculated stalk. Extraarticular pigmented villonodu-
lar synovitis can present as a diffuse or nodular disease
similar to the intraarticular form (Fig. 20-35). A nodular
growth pattern is typical for extra articular forms.
Microscopic Findings
The lesion is composed of several cell types that are
commonly found in a group of lesions identified as
fibrohistiocytic proliferations or reactions. The lesion is
composed of a variable number of mononuclear histio-
cytic cells and irregularly interspersed multinucleated
giant cells forming ill defined nodules or villous struc-
tures in the synovial membrane (Figs. 20-36 through
20-41).69,80,89,94,96,101,105 Hemosiderin deposits are promi-
nent. In addition, a variable number of foamy histiocytic
cells are individually interspersed or form clusters (Fig.
20-39). The villous structures are irregular and are
covered by a thickened synovial layer that merges with
an underlying cellular infiltrate (Fig. 20-37 to Fig. 20-40).
The overlying synovium can be denuded from the large
areas, and the stromal cellular infiltrate can be in direct
contact with synovial fluid. Cellularity varies in different
areas of the lesion. Ill-defined nodular aggregates of his-
tiocytic cells with enlarged nuclei and prominent, well-
defined eosinophilic cytoplasm are occasionally present
(Fig. 20-36). Mitotic figures are frequently seen, but the
atypical mitotic figures are absent. The mononuclear his-
tiocytic cells, as well as the multinucleated giant cells, are
positive for kinesin-like protein 1 (KP1 [CD68]), HAM56,
α1-antichymotrypsin, and MAC387 markers.55,89,93,96,105,108
The immunophenotype is consistent with the monocyte-
macrophage lineage origin. These findings are in keeping
with earlier electron microscopic observations that dis-
closed ultrastructural features consistent with the histio-
cytic origin of mononuclear and multinucleated giant
cells in this disorder.93,105 Results of staining for epithelial
membrane antigen and keratin are negative on cellular
infiltrates. More recent findings indicate that the vast
majority of cells in pigmented villonodular synovitis
express CSF1R.71,123 In contrast, only a small proportion
of cells (>20%) express CSF1. In some of the cases, these
CSF1 overexpressing cells show the clonal 1p11-2q37
translocation that produces CSF1-COL6A3 chimeric
gene.123 Preliminary data indicate that overexpression of
CSF1 is common in a wide range of reactive synovial
conditions, including reheumatoid arthritis, but the
translocations of CSF1 appeared to be specific for pig-
mented villonodular synovitis.65
Differential Diagnosis
Pigmented villonodular synovitis must be differentiated
from other reactive inflammatory conditions involving
synovial membranes that may be associated with villous
or nodular changes of the synovium, such as rheumatoid
arthritis, osteoarthritis, posttraumatic reactive synovitis, and
hemarthrosis associated with hemophilia.
Text continued on p. 1303
1292 20  Synovial Lesions

B
FIGURE 20-31  ■  Pigmented villonodular synovitis: radiographic features. A, T2-weighted magnetic resonance image shows intraspinal
mass arising from synovium of cervical facet joint, which is affected by pigmented villonodular synovitis. Note low-signal areas
corresponding to hemosiderin deposits. B, Computed tomogram of cervical spine of patient shown in A. Lamina is eroded and
expanded by synovium of facet joint, which is involved by pigmented villonodular synovitis.

ERRNVPHGLFRVRUJ
 20  Synovial Lesions 1293

B
FIGURE 20-32  ■  Diffuse pigmented villonodular synovitis of tendon sheaths of wrist and hand: radiographic and gross features.
A and B, Coronal and axial magnetic resonance images of hand show nodular masses in thenar eminence and wrist region. Irregular
areas of low signal represent hemosiderin deposition. C, Gross photograph of resected synovium of tendon sheath studded with
multiple nodules that range from rubbery gray-white and fibrous to soft yellow streaked with brown on cut section.

ERRNVPHGLFRVRUJ
1294 20  Synovial Lesions

A B

C D
FIGURE 20-33  ■  Pigmented villonodular synovitis of diffuse involvement with bone erosion: gross features. A, Lateral radiograph of
knee shows swelling of soft tissue and erosion of femur, tibia, and patella. B and C, Gross specimens of synovectomies of knee
performed for diffuse pigmented villonodular synovitis. Note chocolate-brown pigmentation produced by hemosiderin deposition.
Villous and nodular proliferation of synovium is evident. D, Low power photomicrograph shows villous architecture of the synovial
membrane with histiocytic infiltration. (D, ×15) (D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 20  Synovial Lesions 1295

A B

C D
FIGURE 20-34  ■  Pigmented villonodular synovitis of localized form in knee joint: gross features. A, Pedunculated mass attached to
inner surface of synovial fat pad of knee; meniscus is attached. Polypoid mass has been sectioned longitudinally. B, Pedunculated
nodular mass on inner surface of synovial fat pad of knee. C and D, Medium power photomicrographs show histiocytic infiltrate
with hemosiderin deposition and scattered osteoclast-like giant cells characteristic of pigmented villonodular synovitis. (C and
D, ×100) (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1296 20  Synovial Lesions

A B

C D
FIGURE 20-35  ■  Localized nodular tenosynovitis: radiographic and gross features. A, Plain radiograph of finger shows noncalcified
mass in soft tissue adjacent to proximal phalanx with pressure erosion of cortex. B, Bivalved tendon sheath nodule shows firm,
lipid-rich (yellow) mass with brown streaks. C, Whole-mount histologic section shows nodular infiltrates of histiocytes. Surface layer
of synovium is seen in D. D, Photomicrograph at low magnification of nodule shown in C. Note histiocytic infiltrate with hemosiderin
and multinucleated giant cells. (C and D, ×50) (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 20  Synovial Lesions 1297

C D

FIGURE 20-36  ■  Pigmented villonodular synovitis: microscopic features. A and B, Surface of synovial membrane with irregular villous
structures. C and D, Higher magnification of B shows villous structures infiltrated by histiocytic cells.(A and B, ×4; C, ×10; D, ×15.)
(A-D, hematoxylin-eosin.)

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1298 20  Synovial Lesions

B C
FIGURE 20-37  ■  Pigmented villonodular synovitis: microscopic features. A, Villous structures of the synovial membrane with extensive
histiocytic infiltrate. B and C, Medium-power photomicrographs showing extensive stromal histiocytic infiltrate and scattered
osteoclast-like giant cells. (A, ×50; B and C, ×200) (A-C, hematoxylin-eosin.)

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 20  Synovial Lesions 1299

B C
FIGURE 20-38  ■  Pigmented villonodular synovitis: microscopic features. A, Irregular villous structures of the synovial membrane
with stromal histiocytic infiltrate. B, Higher magnification of A showing irregular villous structures with stromal histiocytic
infiltrate. C, Medium power photomicrograph showing mixed lymphocytic and histiocytic infiltrate. (A, ×25; B, ×50; C, ×100)
(A-C, hematoxylin-eosin.)

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1300 20  Synovial Lesions

B C

FIGURE 20-39  ■  Pigmented villonodular synovitis: microscopic features. A, Synovial membrane with irregular villous structures.
B, Histiocytic infiltrate with focal aggregate of xanthomatous cells and scattered osteoclast-like giant cells. C, Histiocytic infiltrate
with occasional osteoclast-like giant cells. (A, ×25; B, ×50; C, ×100) (A-C, hematoxylin-eosin).

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 20  Synovial Lesions 1301

B C
FIGURE 20-40  ■  Pigmented villonodular synovitis: microscopic features. A, Surface of synovial membrane with irregular villous stru-
cures. B, Higher magnification of A showing extensive histiocytic infiltrate within the stroma of villous protrusions. C, Sheets of
histiocytes and osteoclast-like giant cells. (A, ×25; B, ×50; C, ×100) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1302 20  Synovial Lesions

A B

C D

E F
FIGURE 20-41  ■  Pigmented villonodular synovitis: microscopic features. A-F, Extensive stromal histiocytic infiltrate with hemosiderin
deposition and scattered osteoclast-like giant cells. (A-F, ×100) (A-F, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

Rheumatoid arthritis associated with villous synovial
changes usually shows prominent plasma cell infiltrates
and formation of lymphoid follicles, which are not fea-
tures of pigmented villonodular synovitis.
Posttraumatic synovitis can have villous change, but a
peculiar cellular infiltrate seen in pigmented villonodular
synovitis is not present.
Hemarthrosis in hemophilia usually does not show
hemosiderin deposits in the joint capsule. Detritic syno-
vitis associated with the dispersion of foreign material
related to prosthetic replacement joints is easily identified
under polarized light.
The extraarticular nodular form, especially in highly
cellular lesions with “epithelioid” histiocytes, must be
differentiated from epithelioid sarcoma (Fig. 20-42). As
mentioned, pigmented villonodular synovitis is negative
for epithelial markers. Geographic necrosis mimicking a
rheumatoid nodule is not a feature in this process, and
atypical mitoses are absent. In rare instances, pigmented
villonodular synovitis may show cords of epithelioid his-
tiocytic cells in hyalinized stroma. Such areas can be
misinterpreted as low-grade epithelioid sclerosing fibro-
sarcoma (Fig. 20-43).
Treatment and Behavior
Locally aggressive behavior with multiple recurrences is
typical for this disorder.59,78,97 Erosion of adjacent bone
and severe compromise of joint function can occur. The
treatment of choice is excision of the affected synovium.
The recurrence rate after surgical treatment ranges within
30%. Some cases with severe involvement of synovium
and adjacent bone require prostatic replacement.114,115 In
clinically aggressive cases, low-dose radiotherapy is some-
times used to control the process and has been shown to
be beneficial in preventing further destruction of the joint
and in reducing the risk of recurrences.97
In extremely rare cases, transformation to a spindle-
cell malignancy with metastases to the contralateral thigh
has been documented 40 years or more after initial pre-
sentation; it was preceded by multiple local recurrences.60
Unusually aggressive behavior with involvement of the
pelvic bone and subsequent extension into the peritoneal
cavity has also been reported.109 These cases are rare; in
most cases, locally destructive growth with recurrences is
typical. Cases with usually aggressive behavior are some-
times referred to as malignant giant cell tumor of synovium.93
SYNOVIAL LIPOMA
Lipomas involving the articular capsule and tendons
belong to the broad category of soft tissue lipomas. The
peak age incidence and the most frequent sites of involve-
ment are shown in Figure 20-44. A circumscribed lipoma
of the joint capsule is extremely rare. The tumor is micro-
scopically identical to an ordinary lipoma in soft tissue
and consists of mature adipose tissue. It may be pedun-
culated or polypoid and may protrude into the joint
space. Local excision is curative.
A more common variant of lipoma involving the joint
capsule is a diffuse adipose tissue overgrowth referred to
as lipoma arborescens124-129,130-132,134-138,144 (Fig. 20-45). It dif-
ERRNVPHGLFRVRUJ
20  Synovial Lesions 1303
fusely involves the synovial membrane and forms multi-
ple papillary excrescences composed of mature adipose
tissue lined by synovial cells (Fig. 20-46). The adipose
tissue is highly vascular, and often there is a noticeable
inflammatory cell infiltrate composed of lymphocytes
and plasma cells. In fact, some of the villous structures
may represent reactive change with inflammatory infil-
trates. Fibrosis within papillary projections and promi-
nant vascular channels are frequent findings in synovial
lipomas (Figs. 20-47 and 20-48). In extremely rare cases,
these may involve several joints.125,126,133,139,140,141 Most
lesions occur in the knee, but other large joints of the
extremities may also be involved.
Lipomas involving tendons occur less frequently than
those involving the articular capsule.142,145 The tendon
sheaths of the hands and wrists are common sites of involve-
ment. Multifocal tumors or bilateral involvement of both
hands may occur. Similar to lipomas of the joint capsule,
lipomas of the tendons can present as discrete circum-
scribed masses or may represent a diffuse, ill-defined over-
growth of adipose tissue. Lipomas of the tendons and joint
capsule may erode the adjacent bone, but complete excision
is curative with virtually no recurrences.
Plain radiographs are nonspecific and may disclose a
soft tissue or joint capsule swelling. Magnetic resonance
imaging is diagnostic and shows a typical pattern of
villous lipomatous proliferations of the synovium. T1–
weighted images show villous synovial proliferations of
similar density as subcutaneous fat. T2–weighted images
with fat-suppressed spin show the low signal intensity of
the lesion, similar to subcutaneous fat.126,130,133,143
SYNOVIAL HEMANGIOMA
Similar to synovial lipomas, hemangiomas involving the
synovium of a joint capsule, periarticular soft tissue, or
tendon sheath belong to the category of soft tissue
tumors.146-166 The peak age incidence and the most fre-
quently involved sites are shown in Figure 20-49. Extraar-
ticular synovial hemangiomas involving the tendon
sheath are rare and almost exclusively occur in the hand
or wrist.148,162,159 They are soft, nodular masses treated by
simple excision, which is curative.
Although hemangiomas involving articular synovium
occur more frequently than extraarticular hemangiomas
of tendons, they are still considered rare. Fewer than 200
cases of articular synovial hemangiomas have been
described in the world literature. These lesions almost
exclusively involve the knee and rarely involve the elbow
or the ankle. Some patients may have associated angioma-
tosis in another location. Typically the lesion manifests
during the second or third decade of life. Most patients
have a long history of dull pain, limitation of motion, and
a soft palpable mass. The mass decreases in size when the
extremity is elevated. Plain radiographs show an ill-
defined, periarticular mass, which may contain phlebo-
liths. An associated degenerative change in the affected
joint and cystic lesions in the adjacent bone may be present.
Microscopically, synovial hemangiomas do not differ
from ordinary hemangiomas of the soft tissue (Fig.
20-50). Typically, they are of capillary or mixed (capillary
Text continued on p. 1313
1304 20  Synovial Lesions

B
FIGURE 20-42  ■  Diffuse tenosynovial pigmented villonodular synovitis, extraarticular form: microscopic features. A, Low power
photomicrograph shows nodular infiltration of histiocytic cells with scattered multinucleated giant cells in synovium of tendon
sheath. B, High power photomicrograph shows sheets of histiocytes forming coalescent nodules. Cells containing vesicular nuclei
with prominent nucleoli but no cytologic atypia are noted. (A, ×10; B, ×200) (A and B, hematoxylin-eosin.)

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 20  Synovial Lesions 1305

B C
FIGURE 20-43  ■  Pigmented villonodular synovitis: microscopic features. A, Cords of histiocytic cells in hylanized stroma. B and
C, Higher magnification of A showing cords of epithelioid histiocytic cells in hyalinized fibrous stroma. This unique feature of
pigmented villonodular synovitis can be misinterpreted as diagnostic of low-grade epithelioid sclerosing fibrosarcoma. (A, ×100;
B and C, ×200) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1306 20  Synovial Lesions

Incidence

Tendons

Articular
synovium

1 2 3 4 5 6 7 8
Age in decades

FIGURE 20-44  ■  Synovial lipoma. Peak age incidence and most frequently involved sites. Most frequent site is indicated by solid black
arrow.

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 20  Synovial Lesions 1307

A B

C D

FIGURE 20-45  ■  Synovial lipoma. A, Gross specimen of excised pedunculated fatty tumor of synovium of knee joint. Tumor is covered
by thin layer of synovial lining. B, Lipoma arborescens representing broad-based polypoid fatty mass attached to synovium of knee
joint. Fine, villous fingerlike projections and clubbed fatty polyps are seen studding surface of tumor, which is composed of mature
fat. C, Diffuse lipomatosis of synovium of knee joint. Discrete polypoid masses of adipose tissue, each covered by a delicate synovial
lining, are seen with intervening zone of flat, uninvolved synovium. D, Higher magnification of specimen shown in C reveals discrete
polypoid masses of yellow adipose tissue.

ERRNVPHGLFRVRUJ
1308 20  Synovial Lesions

B
FIGURE 20-46  ■  Synovial lipoma: microscopic features. A, Lipoma arborescens of synovial membrane. Note multiple polypoid projec-
tions composed of adipose tissue. B, Some polypoid structures represent hyperplastic synovium with chronic inflammation.
Inset shows fingerlike projection, which represents chronically inflamed synovium. (A and B, ×25; Inset, ×50) (A, B, and
Inset, hematoxylin-eosin.)

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 20  Synovial Lesions 1309

B
FIGURE 20-47  ■  Synovial lipoma arborescens: microscopic features. A, Low power photomicrograph of polypoid projections of syno-
vial membrane. B, Higher magnification of A shows adipose tissue within one of polypoid projections. Inset shows pronounced
fibrosis, which is frequent in this type of lipoma. (A, ×10; B, ×25; Inset, ×50) (A, B, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1310 20  Synovial Lesions

FIGURE 20-48  ■  Synovial lipoma: microscopic features. A and B, Prominent vasculature is frequent feature of synovial lipomas
(A, ×50; B, ×100) (A and B, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
 20  Synovial Lesions 1311

Incidence

1 2 3 4 5 6 7 8
Age in decades

FIGURE 20-49  ■  Synovial hemangioma. Peak age incidence and most frequent involvement sites. Most frequent sites are indicated
by solid black arrows.

ERRNVPHGLFRVRUJ
1312 20  Synovial Lesions

A B

C D
FIGURE 20-50  ■  Synovial hemangioma: gross and microscopic features. A, Gross photograph of bivalved synovial nodule from knee
of patient who experienced recurrent hemorrhagic effusions without trauma. Note blood-filled dilated vascular channels embedded
in fat. B, Low power photomicrographs of cavernous hemangioma. C, Medium power photomicrograph of synovial hemangioma
showing cavernous and capillary vessels. D, Synovial hemangioma composed of small capillary-type vessels. (B, ×10; C and D, ×50)
(B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

and cavernous) type. Similar to hemangiomas in other
sites, synovial lesions may occasionally develop a papil-
lary endothelial hyperplasia of Masson’s type.152
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Sclerosing Bone Lesions
CHAPTER OUTLINE
OSTEOMA AND BONE ISLAND
Ivory Exostosis
Sinoorbital Osteoma
Bone Island (Enostosis)
Surface Osteoma of Long Bones
Sclerosing bone lesions represent a unique group of
dysplastic anomalies with a wide range of clinical presen-
tations, radiographic characteristics, and genetic back-
grounds.7 They can be separated into two major groups
with hereditary and nonhereditary clinical presentations.3
A comprehensive description of all conditions included
in the group is beyond the scope of this book. In this
chapter, we describe some of these conditions that may
occasionally simulate a neoplasm and may require micro-
scopic examination to confirm the diagnosis or to rule
out a neoplastic process.
In the radiologic literature, these conditions are
grouped into two major categories: those associated with
abnormal enchondral ossification and those primarily
affecting the sites of membranous bone formation. It is
generally accepted that the common feature of the condi-
tions described in this chapter is that they all arise from
defects in bone resorption or formation during the
process of skeletal development, maturation, and remod-
eling.1,5,8,10 Sometimes several such conditions can coexist,
resulting in the so-called overlapping dysplastic syndromes,
which further supports the concept of their unified
pathogenesis.5,6,9 An abbreviated list of sclerosing bone
dysplasias classified on the basis of the so-called target-
site approach originally proposed by Norman and
Greenspan5,10 (i.e., specific phase, site of skeletal develop-
ment affected, or both) is provided in Table 21-1. A
summary of clinical presentations, radiographic charac-
teristics, and genetic alterations implicated in the devel-
opment of hereditary bone dysplasia is provided in
Table 21-2.7
OSTEOMA AND BONE ISLAND
Several benign, slow-growing bony lesions are identified
under the general heading of osteoma (Fig. 21-1). They
can be divided into (1) calvarial and mandibular ivory
exostoses; (2) osteomas of the paranasal sinuses, facial
bones, and orbit (sino-orbital osteomas); (3) enostoses or
bone islands; and (4) surface (juxtacortical) osteomas of
long bones.
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C H A P T E R 2 1 
OSTEOPOIKILOSIS (SPOTTED BONE DISEASE)
OSTEOPETROSIS
MELORHEOSTOSIS
Some authors consider these lesions to be hamartoma-
tous or dysplastic in nature, but there is a rationale for
regarding those that affect the orbit, facial bones, and
paranasal sinuses (sinoorbital osteoma) as benign bone-
forming tumors.
Ivory Exostosis
Ivory exostoses represent a type of osteoma that affects
bones formed by membranous ossification, chiefly affect-
ing calvarial and mandibular surfaces2,4,6,10–12,20,22,28 (Fig.
21-2). Multiple osteomas of this type are frequently asso-
ciated with colonic polyposis and fibrous soft tissue
tumors, including mesenteric fibromatosis and epidermal
inclusion cysts in the familial disorder known as Gard-
ner’s syndrome.13,14,17,24,29 Some patients also had distinct
hyperplastic changes of the retinal pigmented epithe-
lium.22,32,33 The development of ocular lesions may
precede the development of colonic and osseous mani-
festations. The polyps of the gastrointestinal tract are
adenomatous and typically involve the colon but can also
be present in the duodenum and stomach. The adenoma-
tous polyps of the gastrointestinal tract have a high pro-
pensity for malignant transformation. In fact, colon
cancer develops in all affected individuals unless prophy-
lactic colectomy is performed.23 The disorder is transmit-
ted by an autosomal dominant pattern of inheritance.
Similar to other major familial colonic polyposis syn-
dromes, such as flat adenoma and Turcot’s syndrome
(colorectal polyposis with brain tumor), Gardner’s syn-
drome is linked to a malfunctioning adenomatous pol-
yposis coli (APC) gene mapped to chromosome 5q21.26
Mutations involving different regions of APC are associ-
ated with the severity of the clinical syndrome and the
extent of extracolonic manifestations. It has been shown
that mutations involving the 38 end around codon 1444
of the APC gene are associated with particularly severe
osseous manifestations.16 Patients with this type of APC
alteration also have a higher incidence of soft tissue fibro-
matosis. The soft tissue fibrous lesions range from aggres-
sive fibromatosis at one end of the spectrum to a lesion
which is histologically similar to nuchal-type fibroma.15,19,27
1317
1318 21  Sclerosing Bone Lesions

Bone island
(enostosis)

Sinoorbital
Ivory Surface
osteoma
exostosis osteoma
of long bones

Associated with
Gardner’s syndrome

FIGURE 21-1  ■  Clinicopathologic variants of osteoma. Lesions classified microscopically as osteomas can be separated into several
distinct clinicopathologic variants; ivory exostosis, sinoorbital osteoma, bone island, and surface osteoma of long bones.

stain positively for CD34 and CD99. Many of these

TABLE 21-1 Classification of Sclerosing
Dysplasias of Bone
Dysplasias of Enchondral Bone Formation
Affecting primary spongiosa (immature bone)
Osteopetrosis*
Affecting secondary spongiosa (mature bone)
Osteoma*
Bone islands*
Osteopoikilosis*
Dysplasias of Membranous Bone Formation
Progressive diaphyseal dysplasia
Hereditary multiple diaphyseal sclerosis
Endosteal hyperostosis
Mixed Sclerosing Dysplasias (Affecting Both Enchondral
and Membranous Ossification)
Melorheostosis (predominantly membranous ossification)*
*Described in this chapter.
Modified and used with permission from Greenspan A: Skelet
Radiol 20:561–583, 1991.
These fibromas of low cellularity have been designated
as Gardner fibromas, and their significance as early indi-
cators of the development of other manifestations of
Gardner’s syndrome such as desmoid-type fibromatosis
has been proposed.15,34 Unlike typical nuchal-type fibro-
mas, which most often affect patients in the third through
fifth decades of life, Gardner-associated fibromas arise in
younger patients and the majority of them present in the
first decade of life. The most common location is in the
back and paraspinal region followed by the head and neck
and extremities. Immunohistochemically, these lesions
lesions show positive nuclear immune-reactivity for
β-catenin.15,19 Approximately 50% of patients with
Gardner-associated fibromas eventually develop a
desmoid-type fibromatosis at the same site. Overall, 10%
to 15% of patients with Gardner’s syndrome develop
aggressive desmoid-type fibromatosis. They typically
develop intraabdominally spontaneously or more often
after surgery. Similar to Gardner-associated fibromas,
desmoid fibromatoses associated with this syndrome
harbor the inactivating mutations of the APC gene.
However, similar to sporadic fibromatoses, they are posi-
tive immunohistochemically for nuclear β-catenin.15,19 In
addition to osteomas, which are often multiple, dental
malformation or more diffuse sclerotic changes in the
craniofacial region may develop in patients with Gard-
ner’s syndrome.25 Osteomas in Gardner’s syndrome may
increase in size over time; that is, progressively more
severe malformation of the craniofacial bones may
develop.31 Osseous lesions in Gardner’s syndrome do not
behave as true neoplasms, and there is no evidence of
their evolution into malignant lesions. Moreover, the
presence of osteoblastoma-like areas, predominantly seen
in sporadic sinoorbital osteomas, is not a feature of
osseous lesions in Gardner’s syndrome.
Microscopically, ivory exostoses are button-like excres-
cences of mature lamellar bone limited to the cortical
surfaces and usually continuous with the outer table of
the skull or the mandibular cortex. The dense cortical
lamellar bone making up these exostoses contains osteons
with haversian canals. Rare cases of compact surface
osteoma have been reported in other flat bones as well as
on long bones.44

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TABLE 21-2 Summary of the Hereditary Sclerosing Bone Dysplasias

Dysplasia Inheritance Pattern Genetics Type of Dysplasia Age at Onset Osseous Findings Other Findings
Osteopetrosis AR, AD TCIRG1 (ATP6i), Endochondral (primary Stillbirth or infancy Diffusely increased Anemia, cranial nerve
CLCN7, GL spongiosa) to adulthood bone density; type deficits (rare with AD
(OSTM1), RANKL, 1: uniform sclerosis inheritance pattern)
CA2, PLEKHM1 of the skull, spine,
and long bones;
type 2: endobone
appearance
Pyknodysostosis AR Cathepsin K Endochondral (primary Infancy or early Hyperostosis of long Dwarfiism, acro-osteolysis,
spongiosa) childhood bones with wormian bones
preserved
medullary cavities
Osteopoikilosis AD LEMD3 Endochondral Childhood or Multiple enostoses Dermatofibrosis
(secondary spongiosa) adulthood lenticularis disseminate
Osteopathia striata X linked Unknown Endochondral Childhood or Dense striations in No other associated
(secondary spongiosa) adulthood metadiaphyses of abnormalities
(incidental finding) long bones
Progressive AD LAP of TGFB1 Intramembranous Childhood Bilateral/symmetric Gait disturbances, pain,
diaphyseal ossification periosteal and weakness
dysplasia endosteal cortical
thickening involving
long bones or
calvaria

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Hereditary multiple AR Unknown Intramembranous After puberty Unilateral/asymmetric Milder neuromuscular
diaphyseal ossification cortical thickening symptoms than with
sclerosis involving long progressive diaphyseal
bones only dysplasia
Hyperostosis AR (Van Buchem SOST (Wnt signaling Intramembranous Childhood Endosteal cortical Van Buchem disease:
corticalis disease, pathway), LRP5 ossification thickening involving facial nerve palsy;
generalisata sclerosteosis), AD (Wnt signaling the long bones, sclerosteosis: facial
(Worth disease) pathway) skull, and facial nerve palsy, syndactyly,
bones; mandible bone overgrowth; Worth
enlargement disease: no cranial nerve
palsy, torus palatinus

Note: AD, Autosomal dominant; AR, Autosomal recessive; ATP, Adenosine triphosphate; CA2, Carbonic anhydrase II; CLCN7, Chloride 7 channel; GL, Gray-lethal; LAP, Latency-associated
protein; LEMD3, LEM domain-containing protein 3; LRP5, Lipoprotein receptor-related protein 5; OSTM1, Osteopetrosis-associated transmembrane protein 1; PLEKHM1, Pleckstrin
homology domain-containing family M member 1; RANKL, Receptor activator of nuclear factor κ-B ligand; SOST, Sclerostin; TCIRG1, T-cell immune regulator 1; TGFB1, Transforming
growth factor β1.
Reprinted with permission from Ihde LL et al: RadioGraphics 31:1865–1882, 2011.
21  Sclerosing Bone Lesions
1319
1320 21  Sclerosing Bone Lesions

A B

C
FIGURE 21-2  ■  Ivory exostosis (parosteal osteoma) of skull: radiographic and histologic features. A, Lateral radiograph of skull shows
frontal region with buttonlike surface osteoma. B, Specimen radiograph of excised, ivory-like excrescence removed from frontal
regions of skull. C, Medium power photomicrograph of specimen shown in B. Compact bone with fibrous stroma shows focal
osteoclastic resorptive activity (C, ×25) (C, hematoxylin-eosin.)

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Sinoorbital Osteoma
Osteomas involving paranasal sinuses, orbit, and facial
bones tend to project into the sinus cavity from a broad
attachment to the affected bone (Figs. 21-3 and 21-
4).21,33,34,36,39,41,42,45,46 Some osteomas involving this region,
especially those that are multifocal, are associated with
Gardner’s syndrome. Microscopically, they are indistin-
guishable from ivory exostosis. In contrast, the so-called
sporadic sinoorbital osteomas (not associated with Gardner’s
syndrome) are usually composed of dense, immature
bone and may have osteoblastic rimming as well as signs
of bone resorption (Fig. 21-5). These lesions may contain
central or peripheral foci of spongy or cancellous appear-
ance (Figs. 21-6 and 21-7). Sometimes the latter areas
show active remodeling, with cellular fibrous tissue filling
the interstices, osteoblastic activity, and osteoclastic
resorption.33 In ethmoid and frontal sinus osteomas,
these lesions may occasionally contain radiolucent areas
that are histologically indistinguishable from conven-
tional osteoblastoma and even aggressive osteoblastoma
(Fig. 21-8).38,40,47 The latter cases sometimes resemble
multifocal osteoblastomas arising within osteomas. The
clinical behavior of these lesions is similar to that seen in
osteoblastomas and aggressive osteoblastoma groups;
that is, they exhibit a local destructive growth pattern and
recurrences. For this reason, we prefer to regard the
sporadic osteomas that arise in the orbit, paranasal
sinuses, and facial bones, especially those that contain
osteoblastoma-like foci or features of active bone produc-
tion and remodeling, as benign bone-forming neoplasms
rather than as hamartomas or dysplasias. Osteomas in this
region typically do not exceed 2 cm in diameter. Occa-
sionally, they attain a larger size (giant osteoma) that
compresses adjacent structures and cause a disfiguring
deformity.28,35,37,43
Bone Island (Enostosis)
Bone islands are foci of dense, compact bone within
the medullary cavity (i.e., within cancellous bone) (Fig.
21-9).48,50,51,54 Occasionally, they may be attached to the
inner surface of the cortex. They are ovoid, with the long
axis parallel to the cortex of the affected bone. Most bone
islands are small (less than 1 cm in diameter), and the
majority of lesions measure from 0.1 to 2.0 cm. Extremely
rare examples of giant bone islands that measure more
than 2.0 cm in diameter have been described (Figs. 21-10
and 21-11).18,30,49,52,57,60 The characteristic feature is the
presence of so-called thorny spicules or pseudopodia at
the periphery of the bone island.53,54,56
Microscopically, bone islands are composed of compact
(cortical) lamellar bone. The thornlike projections repre-
sent thickened trabeculae radiating from the main mass
and blending with the surrounding bone (Fig. 21-12).
The lesions show prominent haversian canals that may
contain osteoblasts and osteoclasts within Howship’s
lacunae. Features of active bone deposition and remodel-
ing are more often seen in larger lesions (Fig. 21-13).
This explains the increased amount of bone turnover in
bone islands, which can be demonstrated by skeletal scin-
tigraphy.48,50,58 In fact, some bone islands may slowly
increase in size (growing bone islands).48,50,55,59
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21  Sclerosing Bone Lesions 1321
Biopsy specimens from small bone islands are rarely
obtained, but larger lesions may raise the suspicion of a
neoplasm, such as a sclerotic variant of osteosarcoma. We
also have seen a giant bone island that was misinterpreted
microscopically as a low-grade intraosseous fibroblastic
osteosarcoma. Although some osteoblastic rimming may
be present within dilated haversian channels of giant bone
islands, the spindle-cell stroma and infiltrative pattern of
growth characteristic of low-grade intraosseous fibroblas-
tic osteosarcoma are not present in these lesions.
Surface Osteoma of Long Bones
Surface osteoma that involves the clavicle, pelvic, or long
bones of the extremities is the rarest form of osteoma.61-69
On radiographs, it appears to resemble ivory exostosis
(surface osteoma) of the craniofacial bones (Fig. 21-14).
Similar to other osteomas, this lesion is composed of
mature lamellar bone organized into osteons and haver-
sian canals. The outer surface is covered by a thin layer
of fibrous tissue. There is no cartilaginous cap covering
the lesion. The underlying cortex may be thickened but
is otherwise intact. No continuity between the lesion and
the underlying medullary cavity can be seen grossly or on
radiographs. Osteoma that involves the surface of a long
bone must be radiographically and microscopically dif-
ferentiated from parosteal osteosarcoma, melorheostosis, and
osteochondroma. The spindle-cell fibroblastic stroma that
is characteristic of parosteal osteosarcoma is not present
in osteoma. Moreover, the bone in osteoma is mature and
forms solid areas with recognizable haversian canals,
which are typically not present in parosteal osteosarcoma.
The distinction from melorheostosis is based mainly on
the radiographic pattern of the bone surface lesion. Mul-
tifocality and the so-called wax-dripping patterns are not
present in surface osteoma. In contrast to osteochon-
droma, parosteal osteoma is not covered by a cartilagi-
nous cap, and there is no continuation between the lesion
and the underlying medullary cavity.
OSTEOPOIKILOSIS (SPOTTED
BONE DISEASE)
Osteopoikilosis is closely related to osteomas and bone
islands. The difference is most likely related to the degree
of phenotypic penetration of the genetic defect. Some
investigators have suggested that a bone island represents
a unifocal minor form of osteopoikilosis.6,10 Osteopoiki-
losis is inherited in an autosomal dominant pattern by
inactivating mutations involving the LEM domain-
containing protein 3 gene. LEMD3 interacts with trans-
forming growth factor TGF-β and bone morphogenetic
protein signaling, causing focal deposit of compact lamel-
lar bone.7 On radiographs, osteopoikilosis presents as
multiple bone islands clustered at the ends of the
metaphyses.70–72 It is rare, with only about 400 cases
described in the literature. Osteopoikilosis can be associ-
ated with the hereditary dermatologic condition known
as dermatofibrosis lenticularis disseminata (Buschke-Ollendorff
syndrome), which is characterized by multiple papular
fibromas on the back, arms, and thighs.5,71
Text continued on p. 1333
1322 21  Sclerosing Bone Lesions

A
FIGURE 21-3  ■  Sinoorbital osteoma: radiographic and microscopic features. A, Large, sessile, radiodense mass within frontal sinus.
B, Computed tomogram of frontal sinus osteoma.

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 21  Sclerosing Bone Lesions 1323

B
FIGURE 21-4  ■  Sinoorbital osteoma: radiographic features. A, Plain radiograph of large, solid orbital mass composed of compact
bone. B, Computed tomogram of mass in A.

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1324 21  Sclerosing Bone Lesions

A B

C D
FIGURE 21-5  ■  Sinoorbital osteoma: mircroscopic features. A, Low power photomicrograph shows dense compact bone of osteoma.
B, Higher magnification of A shows compact bone with prominent haversion systems and focal resorption activity. C, Low power
photomicrograph shows compact bone of osteoma. D, Higher magnification of C showing compact sclerotic bone with prominent
haversian systems and accentuated ossification lines. Note irregularity of haversian systems due to resorptive activity. (A and C,
×20; B and D, ×50) (A-D, hematoxylin-eosin.)

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 21  Sclerosing Bone Lesions 1325

B
FIGURE 21-6  ■  Sinoorbital osteomas with osteoblastoma-like areas: radiographic and microscopic features. A, Low power photomi-
crograph shows compact bone with less dense areas showing bone remodeling that resembles osteoblastoma. B, Higher magnifica-
tion of A corresponding to less dense area shows loose bone trabeculae with osteoblastic lining and osteoclastic activity resembling
those seen in osteoblasoma. Inset, Computed tomogram shows radiodense oral mass composed of compact bone. (A, ×10; B, ×50)
(A and B, hematoxylin-eosin.)

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1326 21  Sclerosing Bone Lesions

A B

C D
FIGURE 21-7  ■  Sinoorbital osteoma: microscopic features. A, Low power photomicrograph shows dense compact bone. B, Less
mature pattern of woven bone and osteoblastic rimming that is seen in some osteomas. C and D, Periphery of osteoma shows loose
pattern of woven bone with osteoblastic rimming and cellular fibroblastic stromal tissue representing growing component of the
tumor. (A and B, ×25; C and D, ×50) (A-D, hematoxylin-eosin.)

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 21  Sclerosing Bone Lesions 1327

FIGURE 21-8  ■  Sinoorbital osteoma with areas of osteoblastoma: radiographic and microscopic features. A, Low power photomicro-
graph of a lesion corresponding to solid component shows compact, mature bone with resorptive activity. B, Osteoblastoma-like
area corresponding to low-signal area of A. Inset (top), Computed tomogram of lesion in maxillary sinus that is composed of solid
compact mass and has low-signal area with patchy mineralization corresponding to conventional osteoma and osteoblastoma com-
ponents, respectively. Inset (bottom), Higher magnification of B showing interconnected bone trabeculae with prominent osteoblasts
and engorged vasculature characteristic of osteoblastoma. The lesion recurred after the initial surgery, and the recurrent lesion
showed features of aggressive osteoblastoma. (A, ×50; B, ×200; Inset [bottom], ×100) (A, B, and Inset [bottom], hematoxylin-eosin.)
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1328 21  Sclerosing Bone Lesions

FIGURE 21-9  ■  Bone island (enostosis): radiographic features. A, Anteroposterior radiograph of right hip shows radiodense ovoid
intramedullary density in femoral neck. B, Computed tomogram of lesion in A reveals radiodense island of compact bone within
cancellous bone of femoral neck.

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 21  Sclerosing Bone Lesions 1329

A B
FIGURE 21-10  ■  Giant bone island: radiographic features. A, Anteroposterior radiograph shows large radiodense intramedullary mass
with irregular borders. B, Magnetic resonance image of lesion in A demonstrates absence of signal and irregular contour of large
intramedullary bone island.

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1330 21  Sclerosing Bone Lesions

C
FIGURE 21-11  ■  Giant bone island: radiographic features. A, Bone scintigram shows increased uptake of technetium 99 in large bone
island within medullary cavity of distal femur. B, Anteroposterior radiograph of intramedullary giant bone island of distal femoral
metaphysis; lesion was asymptomatic, incidentally discovered opacity. C, Axial computed tomogram shows ivory-like density and
sharp circumscription.

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 21  Sclerosing Bone Lesions 1331

C
FIGURE 21-12  ■  Bone island: microscopic features. A, Low power photomicrograph showing irregular contour with multiple pseudo-
podia and dense compact bone. B, Higher magnification of the edge of bone island showing long, projecting surface process con-
tinuous with dense bony focus. C, Detail of lamellar bone architecture with haversian canals within bone island. (A, ×5; B, ×20;
C, ×50) (A-C, hematoxylin-eosin.)

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1332 21  Sclerosing Bone Lesions

B
FIGURE 21-13  ■  Giant bone island: microscopic features. A, Low power photomicrograph shows thickened coarse trabeculae of lamel-
lar bone with interstices containing loose fibrous vascular tissue. B, Higher magnification shows lamellar architecture and loose
fibrous tissue stroma in narrow spaces. (A, ×25; B, ×50) (A and B, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

FIGURE 21-14  ■  Surface osteoma of long bone: radiographic fea-
tures. Anteroposterior radiograph of midshaft of fibula of young
adult with juxtacortical osteoma. This rare, benign tumor was
composed of mature compact bone without cartilage cap and
was treated by segmented resection.
The symmetric distribution of multiple bone islands
in the metaphyseal ends of the long tubular bones and in
the carpal or tarsal bones is a characteristic radiographic
feature (Figs. 21-15 and 21-16). Less frequently the
lesions may also be found in other parts of the skeleton
in the vicinity of joints (e.g., around the acetabulum or
glenoid fossa). The skull, spine, and ribs are extremely
rare sites of involvement.
The lesions in osteopoikilosis are intramedullary but
may also be attached to the inner surface of the cortex.
Microscopically, they are composed of lamellar bone
identical to that seen in bone islands (Fig. 21-16).
OSTEOPETROSIS
Osteopetrosis (Albers-Schönberg disease) occurs in two
basic clinical settings: as an autosomal recessive condition
with early manifestation and as an autosomal dominant
condition with delayed manifestation.77,81,82 These two
forms of osteopetrosis are referred to as congenital or
malignant osteopetrosis and adult osteopetrosis or osteopetro-
sis tarda. The autosomal recessive subtype, also referred
to as osteopetrosis type 1, has been linked to several
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21  Sclerosing Bone Lesions 1333
genetic defects, including inactivating mutations of T-cell
immune regulator 1 (TCIRG1); homozygous mutations
in the chloride 7 channel (CLCN7); a defect in the gray-
lethal or osteopetrosis-associated transmembrane protein
gene (GL); and mutations of the receptor activator of
nuclear factor κ-B ligand (RANKL).7,86,88,89 The autoso-
mal dominant subtype, referred to as osteopetrosis type
2, was linked to mutations inactivating one allele of the
chloride 7 channel gene (CLCN7), and mutations involv-
ing carbonic anhydrase II (CA2), T-cell immune regula-
tor 1 (TCIRG1), osteopetrosis-associated transmembrane
protein 1 (OSTM1), and pleckstrin homology domain-
containing family M member 1 (PLEKHM1).7,76,86,88,89 At
least eight subtypes of osteopetrosis, each with unique
clinical presentation and mode of transmission, have been
described in humans.73,74,77 Deficiency of the carbonic
anhydrase II isoenzyme is associated with autosomal
recessive osteopetrosis. The majority of malignant auto-
somal recessive osteopetrosis is caused by mutations in
the TCIRG1 gene, whereas mutations in the gene encod-
ing the CLCN7 chlorine channel pump are responsible
for the majority of the most common autosomal domi-
nant osteopetrosis.75,78,80,83,84,85,86,88,89
The adult form occurs more frequently than the con-
genital form. Under normal conditions, the primary
spongiosa is resorbed by osteoclasts. Focal ineffective
resorption of primary spongiosa results in accumulated
masses of calcified cartilage in the medullary cavity. Con-
genital osteopetrosis is typically fatal and in many
instances results in stillbirth. When a child is born alive,
the disease rapidly progresses, and most patients die in
early infancy after manifesting profound anemia and
other sequelae of bone marrow compromise. Adults with
osteopetrosis usually live a long time. Many patients are
asymptomatic, and the diagnosis is based on incidental
findings on radiographs made for other reasons or as a
result of pathologic fractures.
The radiologic hallmark of all variants of osteopetrosis
is generalized opacification of bone (Figs. 21-17 and
21-18). The skeletal sites that are formed by membranous
ossification are usually unaffected. Thus in the skull, scle-
rosis is more prominent at the base. In the long bones,
the metaphyseal parts typically show prominent sclerosis.
In the spine, the sclerosis of the end plates gives the
vertebrae a “sandwiched” appearance. The metaphyseal
regions of long bones appear clublike without the normal
flare (Erlenmeyer flask deformity). The metaphyses may
also show horizontal striations of lucent and sclerotic
areas.
Microscopically, the sclerotic areas of bone show an
accumulation of cartilage with an interconnecting
network of bone trabeculae87 (Figs. 21-18 and 21-19).
Osteoclasts may be present on bone surfaces, but they do
not show Howship’s lacunae and lack ruffled borders.
These features indicate that the basic defect in this dis-
order involves osteoclastic cells that cannot resorb bone.
This is consistent with the observation that the metaphy-
seal region closest to the growth plate is packed with
thickened trabeculae of woven bone that has a central
core of calcified cartilage (i.e., lack of resorption of
primary spongiosa). This concept is further supported by
Text continued on p. 1339
1334 21  Sclerosing Bone Lesions

B
FIGURE 21-15  ■  Osteopoikilosis: radiographic features. A, Incidentally discovered speckled, pea-sized densities within cancellous bone
of proximal femur, pelvis, and sacrum. B, Distal tibiae and fibulae showing multiple small islands of compact bone.

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 21  Sclerosing Bone Lesions 1335

A B

FIGURE 21-16  ■  Osteopoikilosis: radiographic and histologic features. A, Plain radiograph showing punctate radiodensities in pha-
langes. B, Anteroposterior radiograph of left hip of a 21-year-old man in whom speckled radiodensities were incidentally discovered
in pelvis, sacrum, and proximal femur. C, Whole-mount photomicrograph of femoral head showing multiple small islands of compact
bone within cancellous bone (C, hematoxylin-eosin.)

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1336 21  Sclerosing Bone Lesions

B C D

FIGURE 21-17  ■  Osteopetrosis (Albers-Schönberg disease): radiographic features. A, Anteroposterior radiograph of pelvis and hips
of child with marble bone disease. Note diffuse ivory-like density of bones, including epiphyses. B, Erlenmeyer flask deformities
seen in distal femoral shaft. Note ill-defined delineation of cortical and cancellous bone borders. C, Distal ends of tibia and fibula
showing increased density adjacent to growth plates and horizontal striations in distal tibial shaft. D, Lateral radiograph of lumbar
spine showing ivory density in upper and lower borders of each vertebral body.

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 21  Sclerosing Bone Lesions 1337

B C
FIGURE 21-18  ■  Osteopetrosis: radiographic and microscopic features. A, Lateral radiograph of skull shows thickening of base with
ivory density of bone preformed in cartilage. B, “Bone-within-a-bone” appearance of first metatarsal with diffuse osteosclerosis.
C, Low-power photomicrograph of osteopetrotic bone shows persistence of calcified cartilage cores in cancellous bone trabeculae
(primary spongiosa) as well as absence of normal marrow spaces. (C, ×100) (C, hematoxylin-eosin)

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1338 21  Sclerosing Bone Lesions

A B

C D
FIGURE 21-19  ■  Osteopetrosis: microscopic features. A-D, Lower and corresponding intermediate power microphotographs show
persistence of prominent calcified cartilage cores in bone trabeculae of primary spongiosa and the fibrosis of marrow spaces with
the absence of hematopoetic element. (A and C, ×100; B and D, ×200.) (A-D, hematoxylin-eosin.)

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 21  Sclerosing Bone Lesions 1339

A B
FIGURE 21-20  ■  Melorheostosis: radiographic features. A and B, Anteroposterior and lateral radiographs of leg show cortical thicken-
ing of fibular diaphysis resembling candle dripping, characteristic of melorheostosis.

the significant normalization of skeletal density and the
reversal of bone opacification that can be induced by
bone marrow transplantation in patients with congenital
osteopetrosis.79,89
MELORHEOSTOSIS
Melorheostosis is a rare condition characterized by a
localized, diffuse thickening of the cortical bone (Figs.
21-20 through 21-23). The lesions frequently are
described radiographically as resembling wax dripping
down the side of a candle (guttering).90,92,93,96,102 The
condition may involve one bone (monostotic form) or
may affect multiple bones in one extremity (monomelic
form). Rarely, it presents as a disseminated skeletal dis-
order that involves more than one limb (polyostotic
polymelic form) (Fig. 21-23).91 The most prominent
hyperostosis is usually at the site developmentally con-
sidered to be formed by membranous ossification (shafts
in the long tubular bones). In the polyostotic involvement
of one limb, the distribution of lesions in melorheostosis
seems to correlate with the anatomic distribution of
sclerotomes.101 It can also be associated with other lesions
such as arteriovenous aneurysms and scleroderma.99,100,103
Microscopically, these lesions represent hyperostosis of
compact cortical bone similar to that seen in osteomas,
bone islands, and osteopoikilosis (Fig. 21-24). Features
of immaturity (absence of well-organized osteons and a
woven bone appearance) can be present. Melorheostosis
typically involves the surface of bone but in rare cases can
also involve the medullary cavity. It is believed that
hyperostosis tends to progress through childhood into
adult life. It is characterized by periods of exacerbation
and arrest.95,98 Overlying soft tissues and nearby joints
may be involved with fibrous thickening and contrac-
tures. Radioisotopic bone scans are usually positive in
melorheostosis and show increased uptake at the sites of
lesions. Mineralized soft tissue masses may occur in as
many as 27% of patients with melorheostosis.101 These
may be found adjacent to areas of cortical hyperostosis
or at a distance, usually in paraarticular location.97 His-
tologically, these bony and cartilaginous soft tissue masses
often contain a core of mature osseous tissue with a
peripheral cap of hyaline cartilage.94
Text continued on p. 1344

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1340 21  Sclerosing Bone Lesions

FIGURE 21-21  ■  Melorheostosis: radiographic features. Anteroposterior radiograph of tibia shows thickening of medial cortex in upper
diaphysis. Lucent defect represents biopsy site.

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 21  Sclerosing Bone Lesions 1341

B
FIGURE 21-22  ■  Melorheostosis: radiographic features. A and B, Lateral radiographs of calcaneus of a 46-year-old woman show
sclerotic changes within bone and on dorsal surface.

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1342 21  Sclerosing Bone Lesions

A B

C D
FIGURE 21-23  ■  Melorheostosis, polyostotic (polymelic form): radiographic features. A and B, Anteroposterior radiographs of shoul-
der and elbow of a 35-year-old woman show surface thickening of cortex of humerus and soft tissue bony densities. C, Technetium
99 radioisotope scan shows markedly increased uptake in shoulder and humeral shaft. D, Radiograph of wrist and hand of patient
in A and C. Note sclerotic lesions of second metacarpal and carpal bones and phalanx.

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 21  Sclerosing Bone Lesions 1343

B C
FIGURE 21-24  ■  Melorheostosis: microscopic features. A, Low power photomicrograph of cortex and intramedullary dense bone
in calcaneus shown in Figure 21-22. Note that cortex (right) is thickened, and intramedullary sclerotic bone (left) is immature.
B and C, Intermediate and high power photomicrographs of intramedullary dense immature bone. (A, ×50; B and C, ×100.)
(A-C, hematoxylin-eosin.)

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1344 21  Sclerosing Bone Lesions
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 C H A P T E R 2 2 
Tumor-Induced Osteomalacia
and Rickets
Modern understanding of rachitic syndromes, originally
referred to as vitamin D-resistant rickets, is based on the
identification of a novel phosphate-regulating homeo-
static system and its underlying diverse genetic back-
ground.7,10 Essential to this understanding were discoveries
of two mutated genes involved in the development of
somewhat overlapping yet distinct phosphaturic disor-
ders. The first one involved the identification of phos-
phate regulating endopeptidase homolog on chromosome
X (PHEX) as the mutated gene in X-linked phosphate-
mia.56 The second was the discovery that a mutant fibro-
blast growth factor 23 (FGF23) plays a role in the
development of tumor induced osteomalacia and rickets
as well as an autosomal dominant X-linked variant of
hypophosphatemic rickets. A more complete list of phos-
phatemic disorders with their genetic background and
biochemistry is provided in Table 22-1.7 Their detailed
description is beyond the scope of this book, and this
chapter focuses primarily on tumor-induced osteomalacia
and rickets.
The cause-and-effect relationship between certain
mesenchymal tumors and severe osteomalacia or rickets
was first recognized in 1959 by Prader et al.54 The origi-
nal description of this peculiar paraneoplastic syndrome
was provided in 1947 by McCance,41 who reported a case
of resolution of vitamin D-resistant rickets after removal
of “degenerated osteoid tissue.”
TUMOR-INDUCED OSTEOMALACIA
Tumor-induced osteomalacia (oncogenic osteomalacia) is
a clinicopathologic entity in which vitamin D-resistant
osteomalacia or rickets occurs in association with a bone
or soft tissue tumor.1,64,72 These tumors have exhibited a
wide spectrum of histologic features that have only
recently been gathered under a unifying concept of phos-
phaturic mesenchymal tumors.20,82,83 Overlapping clinical
presentation and biochemical abnormalities can be
present in X-linked hypophosphatemia and autosomal
dominant hyphosphatemia.7,37 A similar syndrome has
also been reported in association with the linear seba-
ceous nevus syndrome and fibrous dysplasia.2,15,25,29
Clinical Data
The majority of patients with tumor-induced osteo­
malacia are adults; two thirds are age 30 years or
older.36,45,55,58,63,74,89 The ages of reported patients range
from 7 to 73 years, and the male-to-female ratio is 1.2 : 1.
1346
ERRNVPHGLFRVRUJ
The typical presentation is a gradual onset of bone pain
in weight bearing areas such as the legs, ankles, hips, and
back. Some patients have pathologic fractures. The pain
is frequently accompanied by generalized muscular weak-
ness, leading to a severely debilitated state in which the
patient is bedridden. Hence, in some patients an initial
misdiagnosis of a primary muscular disorder is made.
Symptoms are usually present anywhere from 3 months
to 17 years before diagnosis. In some cases, a mass was
noted up to 20 years before the onset of generalized
symptoms. Occasionally an asymptomatic bone tumor is
identified in radiographs in a patient with a diagnosis of
vitamin-D resistant rickets.40 Children may initially have
malaise, gait disturbance, swollen joints, and genu valgum
or varum.
Characteristic metabolic abnormalities include a low
serum phosphorus level (2.2 to 0.33 mg/dL), normal or
slightly low serum calcium level, and variably elevated
alkaline phosphatase activity (occasionally up to 1700 to
2300 IU). The urinary phosphate level is usually ele-
vated, and most cases exhibit decreased tubular reabsorp-
tion of phosphate (23% to 70%). Urinary calcium levels
tend to be low. Serum levels of 1,25-dihydroxyvitamin
D3 are low or detectable, whereas serum levels of
25-hydroxyvitamin D3 are generally normal. In addition,
aminoaciduria and glycosuria with normal serum glucose
levels may be present.
Radiographic Imaging
In skeletally immature patients, radiographs show wid­
ening of growth plates and radiolucent zones in the
metaphyses consistent with rachitic changes (Fig. 22-1).
Lower-extremity long bones may show bowing deformi-
ties. In skeletally mature patients, radiographic features
consist of generalized osteopenia with Milkman’s pseu-
dofractures or Looser’s lines, characteristic of osteomala-
cia. In addition, skeletal radiographs may reveal the
presence of an asymptomatic or symptomatic tumor.11
Pathologic fractures in adults, particularly of the femoral
neck, are relatively common.
Pathologic Findings
Histomorphometry on undecalcified bone sections shows
hyperosteoidosis with increased osteoid volume and
increased width of osteoid seams. In approximately 50%
of cases, the tumor is primary in bone.49 Half of the cases
involving bone occurred in the long bones of the lower
extremities, particularly in the femur and tibia. The
 22  Tumor-Induced Osteomalacia and Rickets 1347

TABLE 22-1 Biochemistry and Genetics of Hypophosphatemic Disorders

Phosphate Vitamin D
Calcium Metabolism Metabolism Metabolism Mutation
SERUM URINE SERUM GI CALCIUM SERUM SERUM
CALCIUM CALCIUM PTH ABSORPTION PHOSPHATE TMP/GFR 1,25(OH)2D GENE

FGF23-mediated
  XLH N ↓ N, ↑ ↓ ↓ ↓ (↓) PHEX
  ADHR N ↓ N ↓ ↓ ↓ (↓) FGF23
  ARHR1 N N, ↓ N, ↑ ? ↓ ↓ (↓) DMP1
  TIO N N, ↓ N, ↓, ↑ ↓ ↓ ↓ ↓ FGF23
  ARHR2 N N, ↓ N ? ↓ ↓ (↓) ENPP1
  McCune-Albright N, ↑ N N, ↑ ? N, ↓ N, ↓ N, ↓ GNAS1
  ENS N, ↑ N, ↓ N, ↑ ? N, ↓ N, ↓ (↓) ? FGFR3*
  NF N, ↓ N, ↓ N ? N, ↓ N, ↓ N, (↓) NF1
  OGD N N N ? ↓ ↓ (↓) FGFR1
  HRHPT N, ↑ N, ↑ ↑ ? ↓ ↓ (↓) KL (klotho)
Non-FGF23-mediated
  XLRH N ↑ N, ↓, ↑ N, ↑ ↓ ↓ ↑ CLCN5
  HHRH N, ↑ ↑ N, ↓ ↑ ↓ ↓ ↑ SLC34A3
  Fanconi N, ↓, ↑ N, ↑ N ? N, ↓ N, ↓ N, ↓ Various (SLC34A1)
  NHERF1 N ? (stones) N ? ↓ ↓ N, ↑ NHERF1

Reprinted with permission from Carpenter TO, et al: J Bone Miner Metab 30:1–9, 2012.
ADHR, autosomal dominant hypophosphatemic rickets; ARHR, autosomal recessive hypophosphatemic rickets; ENS, epidermal
nevus syndrome; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; HRHPT, hypophosphatemic rickets with
hyperparathyroidism; NF neurofibromatosis; N, normal; NHERF, Na+/H+ exchanger regulatory factor; OGD, osteoglophonic dysplasia;,
TIO, tumor-induced osteomalacia; XLH, X-linked hypophosphatemia; XLRH, X-linked recessive hypophosphatemia (Dent’s disease);
↓, decreased; (↓), decreased relative to the serum phosphorus concentration; ↑, increased; ?, not well documented.
*Mosaic FGF23 mutations account for some cases of ENS; however, in reported cases due to this mutation hypophosphatemia is not
reported.

second most common location of osseous tumors is in the
craniofacial bones.31,47 Soft tissue tumors comprise the
other half of all cases and follow the same pattern of
anatomic distribution as skeletal tumors—they occur in
the soft tissues of the lower extremities and craniofacial
region.
Histologically, 40% of reported cases are vascular
tumors (Table 22-2). Of these, hemangiopericytoma
is the most common, representing about half of the vas-
cular tumors and approximately 20% of the total (Fig.
22-2).6,24,26,42,60,65,77,83,84,89 Primary hemangiopericytoma of
bone is extremely rare and comprises 0.08% of all primary
tumors of bone.79 Other vascular tumors include heman-
gioma, angiofibroma, low-grade hemangioendothelioma,
and very rarely, high-grade angiosarcoma.1,13,39,43,63,81,89
The second group of tumors associated with rickets
or osteomalacia can be histologically classified as having
features of fibrohistiocytic and giant cell lesions exhibit-
ing prominent vasculature (Fig. 22-3). The specific
lesions of this group are nonossifying fibromas and giant
cell reparative granuloma, giant cell tumor, and pig-
mented villonodular synovitis.3 A small proportion of
reported tumors represent malignant lesions, which
include osteosarcoma and mesenchymal chondrosar-
coma.28,46,48,75,76,87 Some of the tumors defy clear-cut clas-
sifications and are descriptively designated as fibrovascular
or mesenchymal. The majority of tumors are relatively
small—within the range of 1 to 4 cm—but occasionally
measure 7 cm or larger. Rarely malignant tumors such as
osteosarcoma are associated with rickets or osteomalacia
(Fig. 22-4).
Ultrastructurally or immunohistochemically, the
tumors inducing rickets or osteomalacia do not differ
histologically from similar lesions not associated with this
syndrome (see Fig. 22-2).
It was recognized by several authors that many of these
tumors show a distinctive morphology and have micro-
scopic features in common.8,18,50,63 In 1987, Weidner and
Santa Cruz first introduced the term phosphaturic mesen-
chymal tumor, mixed connective tissue variant, proposing
that these tumors of wide-ranging histologic patterns had
common features of spindle cells, prominent blood
vessels, osteoclast-like giant cells, cystic spaces, metaplas-
tic bone, and cartilage-like matrix, which indicated that
they represent a distinct clinicopathologic entity.83
A collaborative multiinstitutional study of 32 examples
of phosphaturic mesenchymal tumors in which reverse
transcription polymerase chain reaction (RT-PCR) dem-
onstration of FGF23 gene expression in two cases and
immunohistochemical demonstration of FGF23 protein
expression in 17 cases has strengthened the concept of a
recognizable clinicopathologic entity with a demonstra-
ble phosphaturic factor in the tumor cells. These authors
pointed out that wider recognition of the histologic fea-
tures of phosphaturic mesenchymal tumors could occa-
sionally identify patients with previously undiagnosed
osteomalacia.22
Treatment and Behavior
Conventional treatment for rickets or osteomalacia con-
sisting of increasing doses of vitamin D or phosphate
provides only transient improvement in approximately
15% of patients with oncogenic osteomalacia.3,4,12,51,52
Removal of the tumor is required and results in complete
cure of osteomalacia or rickets in approximately 80% of

ERRNVPHGLFRVRUJ
1348 22  Tumor-Induced Osteomalacia and Rickets

B
FIGURE 22-1  ■  Oncogenic rickets: radiographic features. A, Radiograph of knee of same case in A showing radiolucent zones on
metaphyseal sides of growth plates and circumscribed eccentric lesion of distal femur diagnosed as hemangiopericytoma. B, Radio-
graph of wrist with radiolucent zones on metaphyseal sides of the growth plates and flaring of the metaphyses characteristic of
rachitic changes.

ERRNVPHGLFRVRUJ
 22  Tumor-Induced Osteomalacia and Rickets 1349

sarcomatosis.38,59,83 Another death occurred in the case

TABLE 22-2 Types of Tumors Producing
of nasal hemangiopericytoma and was attributed to per-
Osteomalacia and Rickets
sistent bleeding.9 A reported complication of medical
Histologic Type No. of Cases therapy with calcitriol and phosphates is the development
of parathyroid autonomy (tertiary hyperparathyroidism).
Vascular tumors 31
  Hemangiopericytomas 14
  Hemangiomas 7 Pathogenesis
  “Fibrovascular” lesions 6
  Angiosarcomas 2 A wide variety of causes may give rise to osteomalacia or
  Hemangioendothelioma 1
  Angiolipoma 1
rickets, and their description is beyond the scope of this
Giant cell lesions 9 book. In developed countries, however, given that inad-
  GCT of bone 2 equate nutrition is infrequent, some of the rare causes are
  Soft tissue GCT 2 X-linked hypophosphatemia and autosomal dominant
  Other 5 hypophosphatemia.7,10,17 Oncogenic osteomalacia pres-
  Malignant GCT
  PVNS ents with analogous symptoms and chemical abnormali-
  GCRG ties requiring large doses of vitamin D and phosphate for
  Giant cell variant of soft-part chondroma mild, transitory improvement.21 However, serum calcium
  Giant cell MFH levels usually are normal in contrast to other forms of
Nonossifying fibromas 8
osteomalacia.
“Mesenchymal” tumors (malignant) 9
Osteoblastomas 4 After the tumor is excised, a dramatic reversion to
Cartilaginous 2 normal bone metabolism implies that the tumor is directly
  Chondroma 1 responsible for skeletal changes. Immunoassays per-
  Mesenchymal chondrosarcoma 1 formed on saline tumor extracts show no evidence of
Odontogenic 2
Undifferentiated sarcomas 2
parathyroid hormone or calcitonin.61,62 Elaboration by
Other 5 the tumor of a “phosphaturic substance” that would act
  “Degenerate osteoid tissue” on the proximal renal tubule and cause a renal phosphate
  Neuroma leak has been proposed.35,43,50,61,62 Some investigators were
  Osteosarcoma able to induce phosphaturia in experimental animals by
  Fibrous xanthoma
  “Vascular” fibrous histiocytoma injection of saline tumor extract that did not contain
parathyroid hormone or calcitonin.2,34,53 A substance
Modified from Nuovo MA, et al: Am J Surg Pathol 13:588–599, affecting phosphaturia alone would not explain the low
1989. or undetectable levels of 1,25-dihydroxyvitamin D3.16 It
GCT, Giant-cell tumor; GCRG, giant-cell reparative granuloma;
PVNS, pigmented villonodular tenosynovitis; MFH, malignant has been postulated that the decreased levels of 1,25
fibrous histiocytoma. dihydroxyvitamin D3 are due to elaboration and secretion
by the tumor of a factor that would inhibit the hydroxy-
lase, which acts on the mitochondria of the proximal
patients.14,84 If the tumor cannot be completely removed renal tubule. Phosphaturia would be a direct effect
because of its location, partial removal is necessary to of 1,25-dihydroxyvitamin D3 deficiency, because it has
support the medical treatment to reverse symptoms been proved that the latter increases renal phosphate
and skeletal changes. Recurrence of the original tumor resorption.32 Transplantation of soft tissue hemangioperi-
(benign or malignant) results in the reappearance of the cytoma causing osteomalacia into athymic mice resulted
chemical findings with or without accompanying clinical in hyperphosphatemia, high serum alkaline phosphate
symptoms or skeletal changes. In fact, chemical monitor- levels, and increased urinary phosphorus excretion.45 On
ing can be used for identification of local recurrence or the other hand, decreased levels of the metabolically
metastasis. active form of vitamin D3 alone do not fully account for
Correction of the laboratory abnormalities usually the phosphate depletion because increasing the dosage
occurs from 1 day to 20 months after surgery. Symptoms does not correct the defect.23,62,63,73,80,86
may disappear from the first day to 1 year after resec- The circulating phosphaturic factor secreted by the
tion.43,55,67,71 Continuation of medical treatment (vitamin tumor cells was originally termed phosphatonin but is now
D, phosphate) is required in patients with advanced skel- recognized to represent fibroblast growth factor-23
etal changes and persistent symptoms.13,44 In some cases (FGF23).17,22,32,33,70 Missense mutations in the gene encod-
the persistence of symptoms, chemical abnormalities, and ing FGF23 are associated with the development of
skeletal changes can be attributed to incomplete removal tumor-induced osteomalacia and rickets in the majority
of the tumor.18,57 In malignant tumors, local recurrence of cases. They also play a role in autosomal dominant
and metastases are associated with reappearance of chem- hypophosphatemic rickets, which has clinical manifesta-
ical changes, skeletal abnormalities, and clinical symp- tions virtually identical to those of X-linked hypophos-
toms of rickets or osteomalacia.38,61,62 phatemic rickets and tumor-induced osteomalacia.
Follow-up of reported cases varies from 3 days to Mutations of the PHEX gene are believed to play a role
30 years. In eight cases, the asymptomatic patients in the development of X-linked hypophosphatemia. The
were followed for more than 5 years. Among the 10 FGF23 gene, located on human chromosome 12p1,3 is
histologically malignant tumors, only 1 recurred and 2 one of 23 known members of the FGF family.68,70 The
metastasized, leading to death as a result of generalized full-length FGF23 is an 26-kDa (251 amino acids) protein

ERRNVPHGLFRVRUJ
1350 22  Tumor-Induced Osteomalacia and Rickets

A B

C D
FIGURE 22-2  ■  Hemangiopericytoma associated with osteomalacia: radiographic and microscopic features. A, Radiograph of chest
showing an expansile lesion involving the rib. Inset, T2- weighted magnetic resonance image of the same lesion. Note high signal
intensity of the tumor. B, Photomicrograph of tumor composed of oval and spindle cells with branching stag-horn pattern of vascular
spaces. C, Different area of tumor shown in B with tightly packed parieytic cells and prominent cystic vascular spaces. D, Higher
magnification of C showing solid area of pericytic cells. (B and C, ×100; D, ×400) (B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 22  Tumor-Induced Osteomalacia and Rickets 1351

A B C

D E

FIGURE 22-3  ■  Nonossifying fibroma associated with rickets: radiographic and microscopic features. A and B, Radiograph of the
knee showing radiolucent zones on the metaphyseal sides of growth plates. Note an inconspicuous eccentric lesion with sclerotic
margins involving the femoral metastasis diagnosed as nonossifying fibroma (arrows). C-E, Photomicrographs of nonossifying
fibroma showing proliferation of spindle cells arranged in storiform pattern with interstitial hemorrhage and scattered osteoclast-like
multinucleated giant cells. (C-E, ×200) (C-E, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1352 22  Tumor-Induced Osteomalacia and Rickets

B C

D E

FIGURE 22-4  ■  Intracortical osteosarcoma associated with rickets: radiographic and microscopic features. A, Radiograph of tibia
showing radiolucent intracortical lesion involving the proximal metaphysis. Note radiolucent zones on metaphyseal sides of growth
plates characteristic of rickets. B, Magnetic resonance image of same case as A showing eccentric intracortical lesions of low signal
intensity. C, Gross photograph of case shown in A and B, showing expansile intracortical lesion with heavily mineralized matrix.
D, Low power photomicrograph showing intracortical lesion with prominent production of tumor osteoid. E, Higher magnification
of D showing tumor osteoid production and its deposition on the preexisting host bone. Inset, Atypia of tumor cells producing
osteoid. (D, ×40; E and Inset, ×400) (D, E, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 22  Tumor-Induced Osteomalacia and Rickets 1353

Chr12 FGF23
13.3 FGF23

Exon 1

Exon 2

Exon 3
13.1 13.2
12.3

cds
12.2 12.1
11.2
11 11.1
12
13.1
tel cen
13.3 13.2
14
15 FGF23

4
21.1
21.2
21.3 1 251 aa
22 176 RXXR 179
23
Missense substitution
24.1
Substitution - coding silent
24.2
24.31 24.32
24.33
A

Osteoblast Fi
PHEX PHEX
Calcium in diet and Phosphate in diet and
1,25-(OH)2D Fa
serum increases serum increases
Osteocyte

FGF23 FGF23a FGF23i

PT DCT
3Na
Klotho
FGFR1

2Pi
Tubular reabsorption
PTH FGF23 of phosphate 1a–hydroxylase 1,25–(OH)2D

B C
FIGURE 22-5  ■  The FGF23 gene and its regulatory pathway. A, Chromosomal location of the FGF23 gene on the short arm of chro-
mosome 12 (left diagram). The exon-intron structure of the FGF23 gene is shown (upper right diagram). The linear structure of the
encoded FGF23 protein with the position of the mutations in the RXXR motif are shown (lower right diagram). B, Regulatory pathway
of FGF23. Solid lines represent promotion and dotted lines represent inhibition. Calcium, phosphorus, and 1,25-(OH)2D in food and
serum can stimulate the synthesis of FGF23. FGF23 directly inhibits the secretion of 1,25-(OH)2D, and inhibits parathyroid hormone
and blocks the synthesis of 1,25(OH)2D. In contrast, FGF23 inhibits the reabsorption of phosphorus in the renal tubules to decrease
serum phosphate levels, whereas hypophosphatemia stimulates secretion of 1,25(OH)2D. As a result, the serum level of 1,25(OH)2D
depends on both FGF23 and the phosphate level. C, Interaction of FGF23 and PHEX, and their influence on serum 1,25(OH)2D and
phosphate levels. FGF23 secreted from osteocytes binds to FGFR1, and inhibits the NaPi symporter and the activity of 1α-hydroxylase
(CPT27B1). PHEX from osteoblasts activates inactive factor (Fi) to produce active factor (Fa), which exists upstream of FGF23. Fa
inactivates FGF23. Elevation of 1,25(OH)2D inhibits PHEX activity through a negative feedback pathway. (B and C, Adapted and reprinted
with permission from Liao E: Front Med 27:65–80, 2013.)

with an NH2-terminal region containing the FGF
homology domain and a novel 71-amino acid COOH
terminus.70 Cleavage of FGF23 at the 176-RXXR-179
motif generates biologically inactive NH2- and COOH-
terminal fragments.76 The basic physiologic defects in
tumor-induced osteomalacia and rickets depends on
increased activity of circulating mutant FGF23 produced
by tumor cells that cannot be cleaved into inactive frag-
ments.69 The increased FGF23 activity reduces the
expression of NaPi-2α and β (type 2 sodium phosphate
cotransporters) on the apical surface of renal proximal
tubules.37 The signal transduction of FGF23 is accom-
plished by forming a complex with FGF receptors
(FGFR1c and FGFR3c) interacting with the klotho
protein.27 In physiologic states, FGF23 plays a central
role in phosphate homeostasis, interacting with 1,25-
(OH)2D, parathyroid hormone, and tubular reabsorption
of phosphate (Fig. 22-5). It is also a PHEX substrate that
provides a functional link between FGF23-mediated
phosphaturic syndrome and PHEX mutations in X-linked
phosphatemia.5 Its primary hyperactivation by mutations
that prevent degradation of the active protein or by over-
expression by the upstream regulatory factors decreases
the mineralization of bone and inhibits renal tubular
reabsorption of phosphate, causing the phosphate waste
related syndromes (Fig. 22-6).

ERRNVPHGLFRVRUJ
1354 22  Tumor-Induced Osteomalacia and Rickets

PHEX
Mutations
inhibit
proteolysis Oligopeptide Substrates
Subtilisin-like
proprotein convertase
RXXR
FGF23 MEPE
N FGF-like domain C N FGF-like domain C
1 176 179 251 1 176 179 251

Inactive FGF23N- and C-

Terminal Fragments

Proliferative
FGFR3C
Hypertrophic
Chondrocytes
PHEX

Proximal
tubule
25(OH)D
Osteoblasts
O s
1a hydroxylase 1,25(OH)2D
Abnormal
1,25–(OH)2D3
Na+ PTHr
NaPi2 Phex Rickets / Osteomalacia
R
PTH
PO43– FGFR2C
Phosphaturia PTH
FGFR3C

Kidney Skeleton
FIGURE 22-6  ■  Biologic effects of FGF23 and PHEX, explaining the pathogenesis of autosomal dominant phosphatemic rickets,
X-linked hypophosphatemia, and sporadic oncogenic rickets and osteomalacia. In this model, mutations of PHEX and FGF23 are
linked to autosomal dominant phosphatemic rickets, X-linked hypophosphatemia, and the tumor-induced rickets and osteomalacia.
Increased levels of mutant uncleaved FGF23, by interaction with FGF receptors (FGFRs) 2C and 3C in kidney and skeleton, and MEPE
or its fragments acting to modulate mineralization of extracellular matrix, are responsible for the phosphaturia and rickets/
osteomalacia. (Modified and reprinted with permission from Quarles DL: Am J Physiol Endocrinol Metab 285:E1–E9, 2003.)

The RXXR motif of FGF23 is similar to the consensus
recognition site for precursor convertases, which belong
to the family of serine proteases of the subtilisin/kexin
type. The increased level of uncleaved FGF23 in periph-
eral blood can be used to confirm preoperative diagnosis
of tumor-induced osteomalacia and to monitor the treat-
ment.78,85,88 The demonstration that some of the tumors
involved in the syndrome may express somatostatin
receptors has led to the use of octreotide imaging using
labeling with indium-111 to detect occult phosphaturic
mesenchymal tumors and in some cases to treat overpro-
duction of FGF23 secretion by these tumors.19,22,30,66
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Reactive and Metabolic Conditions
Simulating Neoplasms of Bone
CHAPTER OUTLINE
MYOSITIS OSSIFICANS
MYOSITIS OSSIFICANS PROGRESSIVA
REACTIVE LESIONS OF THE BONE SURFACE
Florid Reactive Periostitis
Bizarre Parosteal Osteochondromatous
Proliferation (Nora’s Lesion)
Acquired Osteochondroma (Turret Exostosis)
Subungual (Dupuytren’s) Exostosis
EXUBERANT FRACTURE CALLUS
AVULSION AND STRESS INJURIES
Avulsion Injuries
MYOSITIS OSSIFICANS
Definition
Myositis ossificans is a reactive, self-limiting condition
characterized by prominent heterotopic ossification. It
predominantly occurs deep in soft tissue, and it undergoes
zonal maturation. If the lesion is located in the vicinity
of bone (i.e., involves the structures of the bone surface),
a periosteal reaction contributes to its formation. This
may alter the classic clinicopathologic presentation of the
lesion. For this reason, we distinguish the classic (soft
tissue) and bone surface forms of myositis ossificans (par-
osteal myositis ossificans) (Fig. 23-1). The pathogenesis
of myositis ossificans is unknown, but it is generally con-
sidered a reactive process. Chromosome X inactivation
analysis indicates that it is a polyclonal disorder, but some
recent studies show rearrangement of the USP6 gene in
a subset of myositis ossificans, which affects only a minor
population of the stromal cells within the lesion.17,30
Incidence and Location
Myositis ossificans predominantly affects adolescents and
young, athletically active adults. Typically, it develops at
a site of clearly identifiable trauma, but in some cases, no
history of injury can be obtained.1,4,5,16,22,24,26,29 The peak
age incidence is during the second and third decades of
life, and nearly 50% of patients with this diagnosis are in
this age group. It is usually found deep in soft tissue
within the muscles of the lower or upper extremities (Fig.
23-2). However, it may also involve fasciae, tendons, or
ERRNVPHGLFRVRUJ
C H A P T E R 2 3 
Cortical Irregularity Syndrome
(Periosteal Desmoid)
Stress Fractures
PUBIC OSTEOLYSIS
TUMORAL CALCINOSIS
TOPHACEOUS PSEUDOGOUT
TOPHACEOUS GOUT
CHRONIC RECURRENT MULTIFOCAL
OSTEOMYELITIS
AMYLOIDOSIS OF BONE
subcutaneous tissue.12,13,15 Rare examples of intraabdomi-
nal myositis ossificans have been also reported.35 A lesion
located deep in soft tissue may present radiographically
and clinically as a lesion of the bone surface. Some lesions
that originate in the parosteal soft tissue and do not
involve the bone surface de novo may eventually, in the
process of their evolution, adhere to the adjacent bone.
This typically occurs in the later stages of the lesion’s
evolution.
Most intramuscular lesions that involve deep soft
tissue are located in the lower extremities, whereas more
superficial lesions typically affect the upper extremities
and occur more frequently in women than in men. A
similar process seen predominantly in the acral parts has
been designated fibroosseous pseudotumor of the digits. It is
described in this chapter under the term florid reactive
periostitis in the section on reactive lesions of the bone
surface.
A peculiar form of heterotopic bone formation that
resembles myositis ossificans occurs in comatose patients
who have sustained head injuries.8 It is typically located
in the soft tissue around the hip joints, but other major
joints such as the shoulder area also can be affected.
Heterotopic ossification of the soft tissue has also been
described as a complication of many neurologic disor-
ders, including tetanus, myelodysplasia, poliomyelitis,
spinal cord injury, anoxic brain damage, and stroke.19,27,32,33
These lesions resemble myositis ossificans in the sense
that the fundamental soft tissue reaction is that of het-
erotopic bone formation. However, they show no radio-
graphic or microscopic evidence of a zonal architecture
nor do they ultimately form a peripheral shell of bone.
1357
1358 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

Periosteum

Cortex
With periosteal With focal attachment
Medullary cavity reaction and no bone to bone surface
attachment

Soft tissue Parosteal

FIGURE 23-1  ■  Myositis ossificans in relation to bone surface. Parosteal lesions may induce periosteal reaction without true bone
attachment. Lesions located closer to bone may show focal or broad-based attachment to bone surface. Note that lesions attached
to bone surface do not show continuous fusion with underlying cortex. Prominent cartilage metaplasia (blue) within lesion and in
periosteal new bone formation can be present in the region corresponding to bone attachment.

Soft
Incidence

tissue

1 2 3 4 5 6 7 8
Age in decades

FIGURE 23-2  ■  Myositis ossificans. Peak age incidence and most frequently involved sites are indicated by arrows.

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1359
Radiographic Imaging
Myositis ossificans has several ill-defined phases that may,
to some extent, be identified on radiographs.7,9,14,21,31
These evolutionary phases follow an orderly time
sequence and reflect maturation and then regression. Ini-
tially, radiographs show an ill-defined mass in the soft
tissue. A well-developed zonal calcification pattern, char-
acteristic of the mature lesion, is typically seen 4 to 6
weeks after an injury (Figs. 23-3 and 23-4). The mature
phase of myositis ossificans presents radiographically as
a well-demarcated, calcified mass. The calcifications are
accentuated at the periphery of the lesion and may form
a shell at its periphery (Figs. 23-3 to 23-5). Less evident
faint, flocculent, irregular opacities, referred to as a
dotted veil, can be seen much earlier. A regressive phase
is associated with some reduction in size and increased
mineralization at the periphery. Zonal architecture and
mineralization pattern are particularly well documented
by computed tomography and magnetic resonance
imaging.7,14 T1-weighted images show shell-like signal
void of the periphery of the lesion (Figs. 23-3 and 23-5).
Central portions of the lesion show varying degrees of
signal enhancement on T2-weighted images (Figs. 23-3
and 23-5).
Myositis ossificans developing in the vicinity of bone
(parosteal myositis ossificans) can be accompanied by a
periosteal new bone formation that typically has a multi-
layered onion-skin pattern (Figs. 23-4 and 23-6). The
presence of a radiolucent cleft (space) that separates the
lesion from the periosteum helps distinguish the lesions
that affect the soft tissue from those that primarily affect
a bone surface (Figs. 23-4 and 23-8).20,21 The lesion may
show a focal attachment to the bone surface (see Fig.
23-6). In areas of attachment, especially in a lesion of
long duration, it may be difficult to demonstrate a fibrous
zone that separates the lesion from the adjacent cortex.
However, even if there is radiographic evidence of attach-
ment, microscopically there is usually a narrow fibrous
zone that separates the lesion from the cortex. Occasion-
ally, myositis ossificans presents as a convex lesion
attached to the surface of the bone by a broad base
(Figs. 23-7 and 23-8). Long-standing lesions show a
linear pattern of mineralization at the periphery and may
show a broad, bony stalk attached to the bone surface,
which is fused with its cortex (Figs. 23-5, 23-9, and
23-10). This phase of myositis ossificans somewhat over-
laps radiographically and microscopically with acquired
osteochondroma or the so-called turret exostosis that is
seen predominantly in the acral skeleton.
Myositis ossificans occasionally involves the soft tissues
of the trunk or the head and neck region (Fig. 23-11). If
these sites are involved in patients younger than age 20
years and especially if multifocal ossifications are present
in the soft tissue, myositis ossificans progressiva (fibro-
dysplasia ossificans progressiva) must be ruled out.
Gross Findings
The gross appearance of myositis ossificans corresponds
to the radiographic presentation of the lesion: a zonal
architecture with a hemorrhagic, more cellular, center
ERRNVPHGLFRVRUJ
and a peripheral shell of reactive bone (Figs. 23-12 to
23-14). The outer surface of the reactive shell of the bone
is more sclerotic and better delineated from the adjacent
soft tissue than its inner surface. The inner border of the
sclerotic rim merges imperceptibly with a softer, often
hemorrhagic, center. The hemorrhagic center is seen in
younger lesions. More mature, older lesions show tan,
fibrous, sometimes prominently vascularized tissue.
Myxoid or cystic changes are frequently seen in fully
matured or regressing older lesions. Initially the shell of
the bone is ill-defined and sparsely mineralized with a
gritty consistency. At the other end of the spectrum are
well-developed lesions that have a well-mineralized and
clearly demarcated peripheral shell of bone, which
requires decalcification for specimen processing. The
lesions are typically less than 10 cm in size, and most are
relatively small, measuring 3 to 6 cm.
Microscopic Findings
The distinct zonal architecture with predominantly
peripheral heterotopic ossification is a hallmark of myo-
sitis ossificans (Figs. 23-12 to 23-14).1,2,3,6,11,16,18,31,34 This
feature is most evident in mature, fully developed lesions
at least 4 weeks old. The inner central portion of the
lesion is composed of loose fibrovascular tissue. It resem-
bles, to some extent, granulation tissue or a type of
spindle-cell proliferation seen in nodular fasciitis (Fig.
23-15). Ultrastructural analyses show that the proliferat-
ing spindle cells in this process are myofibroblasts.25
Areas with ganglion-like giant mesenchymal cells that
have prominent nucleoli, similar to those seen in prolif-
erative myositis, also may be present. These usually are
seen in younger, evolving lesions. Lesions with a pre-
dominance of these types of cells are sometimes referred
to as proliferative fasciitis. Evidence of fresh and old hem-
orrhage with deposition of hemosiderin may be present.
Prominent histiocytic and giant-cell reactions may also
be seen and are usually concentrated in the areas of hem-
orrhage. Degenerated, entrapped skeletal muscle cells are
seen focally. The peripheral parts of the lesion contain a
network of reactive bone that shows prominent osteo-
blastic rimming (Fig. 23-15). The amount of osteoid and
its maturation increases toward the periphery. Early
lesions are dominated by florid stromal cell proliferations
with nuclear atypia showing various stages of osteoid
matrix deposition and mineralization (Figs. 23-16 and
23-17). Fully developed lesions are outlined by a clearly
defined shell of mature bone. In well-developed lesions,
progressive maturation from woven to lamellar bone may
be identified under polarized light. The outer edges of
the lesion are separated from the surrounding skeletal
muscle by a loose fibrous capsule. Foci of metaplastic
cartilage with enchondral ossification evolving into bone
trabeculae may occasionally be seen (Figs. 23-18 and 23-
19). Metaplastic cartilage is more likely to be present in
deeply sited lesions and often corresponds to the
areas of bone surface attachment (parosteal myositis ossi-
ficans). In this area a clear zonal architecture may be
disturbed by a periosteal reaction that contains foci
of cartilage. In such cases, metaplastic hypercellular
cartilage can dominate the lesion focally. In areas of
1360 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-3  ■  Myositis ossificans: radiographic features. A, Plain radiograph shows ringlike calcification delineating mass in soft
tissue of medial aspect of proximal thigh (arrows). B, Computed tomogram of lesion in A shows well-circumscribed mass in soft
tissue with incomplete ring of peripheral calcification. C and D, Magnetic resonance images of same lesion show well-circumscribed
mass. Note that peripheral ring-shaped signal void corresponds to mineralization of bone within lesion.

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 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1361

A B

C D
FIGURE 23-4  ■  Myositis ossificans: radiographic features. A, Ill-defined soft tissue mass with parallel periosteal reaction on surface
of adjacent bone. B, Same lesion as shown in A, x-rayed approximately 1 month later, shows distinct mineralization without typical
shell-like structure at the periphery. C, Juxtacortical myositis ossificans shows prominent peripheral maturation 6 months after direct
trauma. Note continuous radiolucent zone between cortex and bony parosteal mass. D, Specimen radiograph (slab x-ray film) of
lesion shown in A. Note mature bony shell and central lucency.

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1362 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A C

D E
FIGURE 23-5  ■  Myositis ossificans: radiographic features. A and B, Ill-defined soft tissue mass of the proximal thigh with mineraliza-
tion pattern accentuated at the periphery of the lesion. Note the attachment of the lesion to the underlying bone surface. C and
D, T1-weighted axial and coronal magnetic resonance images (MRI) show shell-like signal void at the periphery of the lesion.
E. Strong signal enhancement of the lesion on T2-weighted MRI.

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 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1363
FIGURE 23-6  ■  Parosteal myositis ossificans of scapula: specimen radiograph. Note focal attachment of lesion to surface of adjacent
bone (left) and parallel periosteal new bone formation (arrows) on surface of adjacent bone (right).
attachment to a bone’s surface, focal proliferation of bone
and metaplastic cartilage can mimic the areas seen in
florid reactive periostitis or bizarre osteochondromatous
proliferation (Fig. 23-18) (also see the section on reactive
lesions of the bone surface in this chapter). Early lesions
may show less evident zonal architecture, and the level of
cellularity can be very high. In such lesions, florid prolif-
eration of spindle cells with giant cells may be the domi-
nant feature.
Differential Diagnosis
Distinguishing myositis ossificans from extraskeletal osteo-
sarcoma and osteosarcoma of a bone surface is of para-
mount importance.5,11,16,21,31 The zonal architecture in
myositis ossificans is the single most important feature
helpful in distinguishing this lesion from malignant
bone-forming tumors. The zonal architecture of the
lesion can be seen on radiographs and in gross and micro-
scopic examinations and provides important clues to the
correct diagnosis. The microscopic features of immature
bone trabeculae with osteoblastic rimming and progres-
sion to more mature bone are not seen in osteosarcoma.
Moreover, extraskeletal osteosarcomas involving soft
tissue are usually high-grade lesions with obvious nuclear
atypia. Atypical mitoses are not present in myositis
ossificans.
ERRNVPHGLFRVRUJ
It is occasionally difficult to distinguish parosteal myo-
sitis ossificans from osteosarcoma (parosteal and periosteal
osteosarcoma) of a bone surface, especially when the lesion
is located near the surface of a major long tubular bone
of the lower extremities. Lesions located on the poste-
rior aspect of the distal femoral shaft and superior to
the popliteal fossa should be carefully evaluated because
parosteal osteosarcoma frequently is found at this site.
Parosteal myositis ossificans usually shows a clear zone
of separation from the underlying cortical bone that can
be seen on radiographs. Lesions that show wide, broad
fusion with the underlying bone in this location should be
considered suspicious. Microscopically, parosteal osteo-
sarcoma has unique features of hypercellular, fibroblas-
tic stroma and a network of relatively well-developed
tumor bone. Paradoxically, the level of bone matura-
tion in parosteal osteosarcoma often exceeds the level
of bone maturation in myositis ossificans. The overall
radiographic pattern of mineralization in parosteal osteo-
sarcoma is different from that seen in myositis ossificans
because parosteal osteosarcoma has a heavily mineralized
central or basal portion that is fused with the underlying
cortex.
The occasional presence of cartilage with hypercellu-
larity and nuclear atypia may require differentiation
between myositis ossificans and periosteal osteosarcoma.
Text continued on p. 1377
1364 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B
FIGURE 23-7  ■  Parosteal myositis ossificans: radiographic features. A, Lateral radiograph of ankle of young adult shows partly calci-
fied mass in soft tissue adjacent to distal end of tibia. Peripheral density and central radiolucency indicate zonal maturation.
B, Juxtacortical mineralized mass adjacent to posterior cortex of femoral shaft. The lesion is in early stage of evolution and does
not yet show zonal maturation.

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 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1365

A C
FIGURE 23-8  ■  Parosteal myositis ossificans: radiographic features. A, Lateral plain radiograph shows convex bony lesion on bone
surface of distal femur. Note lucent zone of separation from underlying cortex. B and C, Computed tomograms show lesion that
involves bone surface of anterolateral aspect of femoral shaft. Note line of separation in B. Underlying cortex is intact. Focal attach-
ment in central portion of base is seen in C.

ERRNVPHGLFRVRUJ
1366 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B
FIGURE 23-9  ■  Parosteal myositis ossificans, late phase: radiographic features. A and B, Lateral and oblique plain radiographs of
distal femur with exostosis-like lesion of bone surface.

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 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1367

A
FIGURE 23-10  ■  Parosteal myositis ossificans, late phase: radiographic features. A, Exostosis-like bony outcropping on cortical surface
of humeral shaft in young adult with history of trauma. B, Computed tomogram shows cortically based, mature, bony excrescence,
which represents late stage of development (posttraumatic exostosis).

ERRNVPHGLFRVRUJ
1368 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

B
FIGURE 23-11  ■  Myositis ossificans: radiographic features A and B, Anteroposterior and lateral views of cervical spine show mineral-
ized mass in soft tissue anterolateral to C4 to C5 within paraspinal musculature (arrows). There is suggestion of peripheral matura-
tion and central lucency.

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1369

A B

C D

FIGURE 23-12  ■  Myositis ossificans: microscopic features. A and B, Whole-mount photomicrographs of myositis ossificans demon-
strate zonal maturation of bone peripherally. C and D, Low power photomicrographs demonstrate zonal maturation of osteoid and
bone formation peripherally. (A and B, ×3; C and D, ×10.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1370 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D E
FIGURE 23-13  ■  Myositis ossificans, mature phase: microscopic features. A and B, Whole-mount photomicrographs of myositis ossi-
ficans demonstrate zonal maturation of bone peripherally. C, Well-developed shallow bone at periphery of lesion. D, Intermediate
zone showing well-organized trabeculae of bone rimmed by osteblasts. E, Central less ossified part of lesion is composed of thin
bone trabeculae and loose fibroblastic tissue with prominent vasculature. (A and B, ×3; C-E, ×25.) (A-E, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1371

B C

FIGURE 23-14  ■  Myositis ossificans, mature phase: microscopic features. A, Fragment of whole-mount section of entire lesion with
mature, well-developed shell of bone delineating its periphery. B, Central nonossified part of lesion is composed of loose fibroblastic
tissue that resembles nodular fasciitis. C, Well-developed shell of bone is seen at periphery of lesion. Note sharp delineation of
outer surface from surrounding soft tissue. (A, ×3; B, ×50; C, ×25) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1372 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

D
FIGURE 23-15  ■  Myositis ossificans: microscopic features. A-D, Zonal maturation of bone formation. A, Central nonossified part of
lesion is composed of loose fibroblastic proliferation and fresh hemorrhage that resembles nodular fasciitis or proliferative myositis.
B, Early phases of osteoid formation in the intermediate zone. C, Well-organized irregular trabeculae of osteoid rimmed by osteo-
blasts. D, Well-developed shell of bone at periphery of the lesion. Note sharp delineation of outer surface from surrounding soft
tissue. (A-D, ×5) (A-D, hematoxylin-eosin.)

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 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1373

D
FIGURE 23-16  ■  Myositis ossificans, early phase: miscroscopic features. A-D, Early phases of osteoid formation in myositis ossificans
(A-D, ×100) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1374 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-17  ■  Myositis ossificans, early phase: microscopic features. A, Early osteoid formation. B, Florid proliferation of
fibroblastic cells in central zone of myositis ossificans. C, Early osteoid formation. D, Florid proliferation of plump spindle cells
in central portion of the lesion. Note cellular variability and some degree of hyperchromatism. (A and B, ×100; C and D, ×200)
(A-D, hematoxylin-eosin.)

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 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1375

B C
FIGURE 23-18  ■  Parosteal myositis ossificans: microscopic features. A-C, Bizarre osteochondromatous proliferation dominates area
of bone surface attachment in parosteal myositis ossificans (A-C, ×25) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1376 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-19  ■  Parosteal myositis ossificans: microscopic features. A and B, Bizarre osteochondromatous proliferation dominates
area of bone surface attachment in parosteal myositis ossificans. C and D, Anastomosing pattern of osteoid deposition with promi-
nent osteoblastic rimming in areas of bone surface attachment in periosteal myositis ossificans. (A and C, ×25; B and D, ×50.)
(A-D, hematoxylin-eosin.)

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 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1377
The overall radiographic appearance of periosteal osteo-
sarcoma is different from that of myositis ossificans. Peri-
osteal osteosarcoma is a true lesion of the bone surface
and has an associated periosteal reaction that is usually in
the form of perpendicular striations on the bone surface.
In addition, true sarcomatous elements with direct tumor
bone formation are a classic feature of periosteal osteo-
sarcoma. Moreover, periosteal osteosarcoma shows a
seamless fusion with the underlying cortex, which is rela-
tively uniform over the entire length of the lesion.
Treatment and Behavior
Myositis ossificans is a benign, self-limiting condition.
Conservative excision of the lesion is curative. This is
best performed during the mature phase of the disease,
when the lesion is well delineated and a mass is clearly
identifiable. Incompletely excised lesions, especially those
in the early phase of development, continue to grow for
a limited period (several weeks to months). Eventually,
these lesions stabilize and may undergo partial or com-
plete regression.
Myositis ossificans is one of the rare extraskeletal con-
ditions that may be complicated by a superimposed sec-
ondary aneurysmal bone cyst.2 Several reports on
secondary malignant transformation in myositis ossifi-
cans are not convincing.10,23,28 Most likely, they represent
lesions that were originally misdiagnosed and were de
novo malignant lesion of the soft tissue.
A more recently published case by E. Konishi et al
may represent an extremely rare true example of an
osteosarcoma that has developed in association with a
long-standing myositis ossificans.13
MYOSITIS OSSIFICANS PROGRESSIVA
Definition
Myositis ossificans progressiva (fibrodysplasia ossificans
progressiva) represents an extremely rare, multifocal,
generalized chronic progressive disease of heterotopic
ossification within the body’s musculature and frequently
shows a familial pattern of occurrence.38,41,42,57,63 It pre-
dominantly affects children during the first decade of life,
primarily between birth and age 6 years.
Myositis ossificans progressiva is an autosomal domi-
nant disorder caused by germline mutations of the activin
A type 1 receptor (bone morphogenetic protein type 1
receptor) gene mapping to the 2q23-34 chromosomal
region in both inherited and sporatic cases.58,59 The
majority of patients carry a germline (617G→A; R206H)
mutation in the glycine-serine (Gs) activation domain of
the ACVR1 gene. Other less frequent mutations such as
(1067G→A; G356D) also involving the ACVR1 gene
have been identified.46,47 Another predisposing locus
mapping to the 17q21-32 region with mutations of the
noggin (NOG) gene may be involved in a subset of
patients with myositis ossificans progressiva.45,55
It is postulated that the mutations of ACVR1 cause
destabilization of the GS domain and permanently acti-
vate ACVR1, which in turn trigger exuberant ectopic
chondrogenesis and osteogenesis, a hallmark of myositis
ERRNVPHGLFRVRUJ
ossificans progressiva. Upregulation of the RUNX2/
CBFA1 gene in stromal cells of myositis ossificans pro-
gressiva increases the recruitment of chondroprogenitor
and osteoprogenitor cells from the pool of uncom-
mitted primitive mesenchymal cells.48 The resulting
downstream deregulation of the bone morphogenetic
protein network through the SMAD and MAPK kinase
pathways causes ligand-independent activation of bone
morphogenetic protein signaling and ligand-dependent
hyper-responsiveness to bone morphogenetic protein
stimulation.36,44,64 Animal model studies indicate that
hematopoietic stem cells contribute to early phases of
heterotopic ossification induced by BMP-4.51 Although
the genetic defects causing fibrodysplasia ossificans pro-
gressiva are not completely understood, the clinical and
animal models implicate mutations in bone morphoge-
netic proteins, their receptors, and activin receptor type
IA (ACVR1) as well as mutations of the noggin (NOG)
gene in the development of this disorder.56
Clinical Symptoms
Multifocal involvement of soft tissues, predominantly of
the trunk, a progressive chronic clinical course, and
a familial incidence and occurrence in young children
distinguish this disease from the more common, local-
ized, and solitary (posttraumatic) form of myositis
ossificans.37,38,40,41,43,52,57
The first clinical manifestation is a localized, painful
swelling in the soft tissue. The onset is often precipitated
by a minor injury or an infectious disease. The lesion
typically appears first within the muscles of the trunk (the
back, shoulder, and paravertebral region). The head and
neck region is also a frequent site of initial presentation.
Lesions of the head and neck are most often located in
the scalp and within the sternocleidomastoid muscle. As
it progresses, the disease moves into the proximal parts
of the extremities until it eventually involves their distal
parts, which is typical of a more advanced, long-term
process.40,41
The disorder is often associated with abnormalities of
bone and joint formation that principally affect the acral
skeleton.60 The changes predominantly consist of bilat-
eral microdactyly and the absence of both thumbs and
great toes. If great toes are present, they frequently show
deviation (bilateral hallux valgus). Deafness and sexual
infantilism can also be present.
Radiographic Imaging
On radiographs, the disorder presents as multifocal ossi-
fications of soft tissue that progress to form a network of
interconnecting bridges between adjacent bones and
joints, causing ankylosis, muscle stiffness, and ultimately,
heterotopic bone formation at the affected sites (Fig.
23-20).39,54,61,62
Microscopic Findings
The early lesions consist of multifocal proliferations
of plump fibroblasts within the skeletal muscle, similar
to those seen in fibromatosis. In fact, early lesions of
1378 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

B
FIGURE 23-20  ■  Myositis ossificans progressiva (fibrodysplasia ossificans progressiva): radiographic features. A, Multiple foci of
heterotopic ossification of soft tissue in forearm. Some foci are attached to adjacent bone surfaces. B, Lesion’s progression is shown
by formation of multiple bridges between ulna and radius.

myositis ossificans progressiva, especially in the sterno-
cleidomastoid muscle, are often confused with juvenile
fibromatosis. The lesions undergo mineralization and
develop extensive bone metaplasia with formation of
fusing bridges between adjacent bones and joints. The
development of bone can be associated with cartilage
metaplasia and can have features of enchondral ossifica-
tion.53 The zonal architecture typical of common solitary
myositis ossificans is not present (Fig. 23-21).
Pathogenetically, the disease has three main phases
that somewhat parallel those of conventional solitary
myositis ossificans. The first phase consists of a prolifera-
tion of loose fibroblastic cells that are somewhat similar
to those seen in fasciitis or fibromatosis. In the second
phase, thick collagen fibers appear among the fibroblasts
before osteoid deposition, mineralization, and the meta-
plastic change into bone and cartilage. In the third
(regressing) phase, there is some reduction in size, and
maturation is identified by the network of lamellar bone
and the formation of firm bridges among individual
lesions and adjacent structures (articular ankylosis). Con-
trary to localized solitary myositis ossificans, this process
is multifocal, and the ossifications develop in the centers
of individual lesions rather than at their periphery.

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 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1379

A B

C D
FIGURE 23-21  ■  Myositis ossificans progressiva (fibrodysplasia ossificans progressiva): microscopic features. A, Multiple foci of het-
erotopic ossification within soft tissue. B, Focus of ossification within fibrous area. C and D, Higher power magnification shows
maturation of heterotopic bone with formation of interconnecting network of lamellar bone trabeculae. Note absence of zonal
architecture and tendency toward uniform ossification pattern that preferentially involves central portion of lesion. (A and B, ×5;
C and D, ×25.) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1380 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone
Differential Diagnosis
Myositis ossificans progressiva should be differentiated
microscopically from fibromatosis and the localized
common form of myositis ossificans. The analysis of the
entire clinical and radiographic picture is usually very
helpful: occurrence during the first decade of life, initial
involvement of trunk musculature, and presence of mul-
tifocal proliferations. Radiographic and microscopic evi-
dence of bone formation helps differentiate the lesions
from fibromatosis. In addition, the clinical differential
diagnosis includes battered child syndrome, ectopic bone
formation with multiple congenital anomalies, and
pseudohypoparathyroidism.
Treatment and Behavior
Typically the disease is fatal and causes death after 10 to
15 years of prolonged progressive illness with transient
spontaneous remissions.37,40,41,49,50,57,61 The fatal outcome
frequently results from the progressive immobilization of
the thorax, which causes severe respiratory insufficiency.
Biopsy, trauma, and infections can exacerbate the process
and lead to the development of new lesions.
REACTIVE LESIONS OF
THE BONE SURFACE
Periosteal (bone surface) reactive lesions that mimic
primary neoplasms of bone occur in several distinct clini-
copathologic settings and are designated as florid reactive
periostitis, bizarre parosteal osteochondromatous proliferation,
acquired osteochondroma (turret exostosis), and subungual
(Dupuytren’s) exostosis.77,95,100 In the pathology literature
concerning soft tissue, these lesions are designated
descriptively as fibroosseous pseudotumors.76,78,97 Common
to all these lesions is an initial hemorrhagic subperiosteal
collection that often can be related to trauma.
The lesion undergoes organization referred to as mat-
uration. Because of its peculiar localization, a periosteal
reaction (i.e., new bone and cartilage of periosteal origin)
participates in the process. Initially, spindle and giant
cells, as well as hemorrhage with minimal bone and car-
tilage proliferation, dominate the lesion (florid reactive
periostitis). Later, periosteal new bone formation and
metaplastic cartilage proliferation are dominant elements
(bizarre parosteal osteochondromatous proliferation, or
Nora’s lesion). Finally, the focus of ossification matures
with the formation of a bony base that is incorporated
into the underlying cortex and that more peripherally is
covered with a cartilaginous cap (acquired osteochon-
droma, turret exostosis, subungual exostosis).
All these lesions predominantly affect the phalanges of
the hands and feet and have their peak incidence in the
third and fourth decades of life (Fig. 23-22). They rarely
involve the long tubular bones of the extremities. The
bones of the forearm are more often affected than other
long bones. In extremely rare instances, the lesions can
involve other bones.
It is postulated that the radiologic and histologic
features of these lesions depend on their stages of
ERRNVPHGLFRVRUJ
maturation and organization rather than on a distinct
pathogenesis.107 The basic architectural features of these
conditions are summarized in Figure 23-23. Although
the radiographic and microscopic data of these condi-
tions clearly overlap, recent cytogenetic studies have
identified distinctive chromosomal rearrangements in
subungual (Dupuytren’s) exostosis and bizarre parosteal
ostechondromatous prolifereration (Nora’s lesion), which
suggests that these lesions are in fact neoplastic and may
evolve via different molecular mechanisms.79,86,94,101,108
Several reports indicate that Nora’s lesion is charac-
terized by a clonal balanced translocation t(1;17)(q32;
q21) or variant translocations involving 1q32 or t(1:17)
(q42:q23) (Fig 23-24).79,94 Conversely, the cells in subun-
gual exostosis carry a balanced clonal translocation t(x;6)
(q13-14;q22).86,91,101,108 The chromosomal breakpoints of
subungual exostosis cluster in 6q13-14 and Xq22 harbor-
ing the collagen genes CoL12A1 and COL4A5, respec-
tively.101 The exact structure of putative chimeric gene(s)
and their fusion transcripts in subungual exostosis are
unknown at this time.
Florid Reactive Periostitis
The term florid reactive periostitis was proposed by Spjut
and Dorfman100 in 1981 to designate a rare lesion on the
bone surface that most frequently affects the short tubular
bones of the hands and, less commonly, the feet.80,82,96,103
The peak incidence is during the third and fourth decades
of life. Nearly 70% of cases are diagnosed in patients
between ages 20 and 40 years, at a mean age of 34 years.
There is no sex predilection. The lesions usually involve
the proximal and middle phalanges and less frequently,
the metatarsals and the metacarpals but have also been
reported in the long bones.68
Radiographically, there is a critical difference between
these proliferations and ordinary cartilage-capped osteo-
chondromas. There is no flaring out of the cortex of
the adjacent bone or continuity of the central part of
the lesion with the underlying osseous medulla, as is seen
in typical osteochondroma. The lesion appears to arise
from the surface of the bone without disturbing the
architecture of the adjacent bony structure. The overall
shape of the lesion is that of a pedunculated or, more
often, flat cap attached to the bone surface (Fig. 23-25).
Early lesions present as an ill-defined density of soft
tissue that is attached to the bone surface and contains
varying amounts of calcific material. Sometimes, rapid
growth is noted over several days or weeks. Most symp-
toms are related to the mechanics of the lesion, such as
discomfort from wearing shoes or pain when flexing
digits.
The size of the lesions varies from 0.5 to 3.0 cm. Most
lesions are grossly described as resembling osteochon-
dromas because they have a bony matrix covered by car-
tilage. Microscopically, an irregular cartilage cap covers
the outer surface of the lesion. The cartilage exhibits
marked proliferative activity. The osteocartilaginous
interface is irregular and strongly resembles a callus. Car-
tilage cells are numerous and have enlarged nuclei.
Spindle-cell fibroblastic proliferation with giant-cell
reaction and fresh hemorrhage can dominate the lesion
focally.
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1381

Predominantly florid periostitis

Incidence

and bizarre
osteochondromatous
proliferations

1 2 3 4 5 6 7 8
Age in decades

Predominantly subungual
exostosis

FIGURE 23-22  ■  Reactive lesions of bone surface. Peak age incidence and most frequent sites of skeletal involvement are indicated
by solid black arrow.

Cartilage
Metaplastic cap
Periosteum
cartilage (blue)
Cortex
Medullary cavity

Florid reactive Bizarre Reactive

periostitis osteocartilaginous osteoochondroma
proliferation (Nora's lesion) (turret exostosis)
FIGURE 23-23  ■  Unified concept of reactive lesions of bone surface. It is postulated that several separately described entities (florid
reactive periostitis, bizarre osteochondromatous proliferation, acquired osteochondroma, and subungual exostosis) represent dif-
ferent phases of reactive processes initiated by trauma and subperiosteal hemorrhage with subsequent organization and maturation.
End stage of these processes and final common pathway is acquired exostosis (turret exostosis).

ERRNVPHGLFRVRUJ
1382 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

1 2 3 4 5

6 7 8 9 10 11 12

13 14 15 16 17 18

19 20 21 22 X Y
A

der(1)
I

1 der(1)

17 der(17) der(17)
B C 1

der(1)
1
17

D der(17) E F G H J
FIGURE 23-24  ■  Bizarre parosteal osteocartilaginous proliferation (Nora’s lesion): cytogenetic abnormalities. A, G-banding karyogram
showing reciprocal 1;17 translocation. (A, Case courtesy of Dr. Nina Tatevian, Texas Children’s Hospital, Houston, TX) B, Partial karyo-
gram showing reciprocal 1;17 translocation. Breakpoints are indicated by arrows. C, Three-color metaphase fluorescent in situ
hybridization (FISH) using BAC probes 99A19 (green), 145I20 (red), and 351B8 (yellow). Signals from all three probes are present in
the der(17)t(1;17), whereas the reciprocal der(1) has a signal from only the proximal probe 99A19. The insert presents only green
signals to demonstrate the uneven split of 99A19. D, Split of BAC probe 219F9 (yellow). Signals are seen on der(1), der(17), and
chromosome 17. Signals from the more proximal probe 243D13 (red) are present on der(17) and chromosome 17. The whole chro-
mosome 1 paint probe (green) demonstrates the presence of chromosome 1 material. E, Interphase nucleus (case 1) showing a split
in the 1q probes. Chromosome 1 is indicated by joined red and green signals (arrow), der(1) is indicated by a red signal (black
arrowhead), and der(17) is indicated by a green signal (white arrowhead). F, Interphase nucleus showing a split in the 17q probes.
Chromosome 17 is indicated by joined red and green signals (arrow), der(17) is indicated by a red signal (black arrowhead), and
der(1) is indicated by a green signal (white arrowhead). G, Interphase nucleus (case 2a) showing fusion of the proximal 1q and distal
17q probes. The fusion and der(1) are indicated by joined red and green signals (arrow), chromosome 1 is indicated by a red signal
(black arrowhead), and chromosome 17 is indicated by a green signal (white arrowhead). H, Normal tissue hybridized with the 1q
probes, where red and green signals are seen together on chromosome 1 (arrows). I and J, FISH probes used for detecting break-
points in chromosomes 1 and 17. BAC clones are represented by vertical lines. Probes that were split by the 1;17translocation are
marked with stars, and those used in interphase FISH analyses are shown in bold type. Probes situated on the proximal side and
on the distal side of the breakpoints are labeled red and green, respectively. The localization and size of BAC clones are given
according to the UCSC Genome Browser and NCBI Map Viewer. (B-J, Modified and reprinted with permission from Nilsson M, et al:
Human Pathol 35:1063–1069, 2004.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1383

A B

C D
FIGURE 23-25  ■  Florid reactive periostitis: radiographic and microscopic features. A, Swelling of soft tissue adjacent to proximal
phalanx of fifth finger shortly after injury. B, One month later, there is ill-defined calcification of soft tissue and periosteal new bone
formation. C and D, Low and intermediate power photomicrographs show proliferation of spindle cells and trabeculae of woven
bone. (C, ×25; D, ×50.) (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1384 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone
Bizarre Parosteal Osteochondromatous
Proliferation (Nora’s Lesion)
Bizarre parosteal osteochondromatous proliferation pre-
dominantly involving the bones of the hands and feet has
been described by Nora et al.95 The peak age incidence
is during the third and fourth decades of life, and the
lesion predominantly affects the short tubular bones of
the hands and feet.65,71,74,75,85,87,90,105 The peak age inci-
dence and the anatomic sites involved closely overlap
with those of florid reactive periostitis. In fact, the lesion
is closely related to other reactive lesions of the bone
surface and most likely represents an intermediate step
between florid reactive periostitis and acquired osteo-
chondroma that is either subungual or the so-called
turret exostosis found on the shafts of phalanges and
metacarpals.
Radiographically, Nora’s lesion presents as a well-
delineated, cap-shaped lesion attached to the bone
surface. Plain radiographs typically disclose a well-
developed patchy or linear mineralization pattern
(Figs. 23-26 and 23-27).
Prominent periosteal new bone and cartilage forma-
tion is a dominant feature of the lesion (Figs. 23-27 and
23-28). The cartilage shows hypercellularity, an open
chromatin structure, and binucleated cartilage cells. In
summary, the lesion exhibits striking architectural and
cytologic atypia that may lead to the diagnosis of malig-
nancy if microscopic features are evaluated without
knowledge of the entire clinicoradiologic presentation.
Despite pronounced cytologic atypia of both osseous and
cartilaginous elements, a low power examination dis-
closes a peculiar zonal architecture—the bony elements
are located within the central/basal region, and the car-
tilage forms irregular, caplike structures toward the
periphery. In some cases, a more organized, somewhat
parallel arrangement of reactive bone trabeculae can be
seen at low power magnification.
Acquired Osteochondroma
(Turret Exostosis)
The term turret exostosis was proposed by Wissinger
et al.106 in 1966 in reference to reactive lesions on the
bone surface of the phalanges that they descriptively des-
ignated as ossifying hematoma of the phalanges.83,92 The
clinicoradiologic features of this condition overlap with
the two other reactive lesions of the bone surface
described in this section: florid reactive periostitis and
bizarre parosteal osteochondromatous proliferation.
Radiographically, acquired osteochondroma is typi-
cally well delineated and has a well-developed linear min-
eralization pattern at the base, which is fused with the
cortex (Fig. 23-29). Microscopically, the lesion consists
of an ossified core or base attached to the underlying
cortex. The periphery of the lesion is covered by a carti-
laginous cap.
Depending on the level of maturation of osseous and
cartilaginous elements, the lesion may exhibit more or
less architectural and cytologic atypia. Typically the zonal
architecture is well developed; that is, it has cartilage at
the periphery and bone at the base (Fig. 23-30). The
ERRNVPHGLFRVRUJ
proliferation of cartilage is less evident, and the cartilage
cap is thinner and more regular and exhibits less cytologic
atypia. In contradiction to ordinary osteochondroma or
osteocartilaginous exostosis, the underlying cortex is
intact, and there is no continuity between the center of
the lesion and the medullary cavity of the affected bone.
In summary, the microscopic features overlap with those
of so-called subungual exostosis.
Subungual (Dupuytren’s) Exostosis
Subungual exostosis is an osteocartilaginous reactive
lesion similar to acquired osteochondroma but arising
from a distal phalanx.66,67,69,70,72,73,81,84,88,89,93,98,99,102,104 It was
first described by Dupuytren in 1847 as a bony growth
of the distal phalanx of the great toe.77 In fact, this is the
most frequent location of the lesion. The peak incidence
is in the second and third decades of life, at a mean age
of 24 years. Nearly 80% of reported cases involve the
great toe, and the remaining cases involve other toes.
Subungual exostosis rarely involves the fingers.
The radiographic features are typical. Frequently, the
exostosis arises from the dorsal aspect of the tip of the
distal phalanx (Figs. 23-31 and 23-32). In mature, well-
developed lesions, there is a clear trabecular pattern at
the base that connects the lesion to the underlying pha-
langeal bone tuft. The peripheral parts of the exostosis
have ill-defined margins and a hazy density in the soft
tissue, which is the typical presentation of an early lesion.
As these lesions mature, they develop calcification and
trabecular patterns (compare photographs in Fig. 23-32).
In the early stages of development, the lesion consists
of proliferating fibroblasts in direct continuity with the
nail bed, where cartilaginous metaplasia can be seen
(Figs. 23-33 and 23-34). The cartilage gradually under-
goes calcification, increases in volume, and develops
enchondral ossification. The areas of enchondral ossifica-
tion gradually progress to woven bone and then lamellar
bone. Eventually the bone forms the core, or base, of the
lesion and is covered by a thick cartilaginous cap (Figs.
23-33 and 23-34). During evolution of the lesion, the
continuity between the bony stalk and the underlying
cortex is established. The cartilage cap may show striking
cellularity with plump nuclei and binucleated and multi-
nucleated chondrocytes. The surrounding proliferating
fibrous tissue can be hypercellular, and it is composed of
myofibroblasts. In the initial phase, the proliferation of
cartilage contributes to the exophytic growth of the
lesion. In later phases, an interconnecting network of
mature lamellar bone dominates the lesion (Fig. 23-35).
Limited biopsy samples taken from the periphery of the
lesion may create the impression of a malignant cartilage
tumor. The microscopic features of this condition should
be evaluated with the clinicopathologic presentation: the
anatomic site and radiographic features of a lesion at the
bone surface. An associated infection can cause a consid-
erably acute and chronic inflammatory infiltrate.
Subungual exostosis is a benign condition with self-
limited growth potential. These lesions usually develop
during the course of several months, but we have seen
cases in which the lesion had been present for 10 years
before the patient sought help. The growth causes only
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1385

A B

C D
FIGURE 23-26  ■  Bizarre parosteal osteocartilaginous proliferation (Nora’s lesion): radiographic and microscopic features. A and
B, Two examples of bony and cartilaginous exostotic lesions of phalanx and metacarpal bone in a 38-year-old man and a 61-year-
old woman, respectively. C, Photomicrograph of lesion of phalanx shown in A demonstrates island of hyaline cartilage that blends
with woven bone in fibrous background. D, Basophilic bone elsewhere in C. This type of immature bone is found in both florid
reactive periostitis and Nora’s lesion. (C and D, ×100) (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1386 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-27  ■  Bizarre parosteal osteochondromatous proliferation (Nora’s lesion): radiographic and microscopic features. A, Cir-
cumscribed bony and cartilaginous excrescence attached to surface of distal ulnar shaft is shown in this lateral radiograph.
B, Computed tomogram shows exostotic mass composed of bone and cartilage attached to cortical surface of ulna. C, Photomicro-
graph of exostosis shows disorganized pattern of bone and cartilage in fibrous matrix. D, Basophilic bone in fibrous stroma.
(C, ×50; D, ×100) (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1387

B C

FIGURE 23-28  ■  Bizarre parosteal osteochondromatous proliferation (Nora’s lesion): microscopic features. A, Low power photomi-
crograph shows proliferation of disorganized metaplastic cartilage with enchondral ossification. Note that formation of irregular
cartilage cap is evident at periphery (top). B, Higher magnification of A shows atypical features of cartilage cells. C, Higher magni-
fication of A showing hypercellular spindle-cell proliferation and osteoid deposition adjacent to cartilaginous areas. (A, ×100; B and
C, ×200) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1388 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A
FIGURE 23-29  ■  Acquired, posttraumatic exostosis (turret exostosis): radiographic features. A and B, Anteroposterior and lateral
radiographs of third finger of adult who sustained injury to middle phalanx 1 year previously. Note broad-based, well-circumscribed
exostosis and intact underlying cortex. In some cases, this lesion represents end stage of florid reactive periostitis.

local discomfort. Consequently, it is not surprising that a EXUBERANT FRACTURE CALLUS

patient may wait several years before seeking medical
attention. Treatment is usually prompted by superim-
posed infection. The recurrence rate is not well docu-
mented, but a partial biopsy and incomplete excision
stimulate further growth in approximately 50% of
patients. Definitive excision is curative. A permanent cure
is usually accomplished if complete excision is performed
on mature, well-established exostoses. The gradual
merging of the fibrocartilage cap with the nail bed, most
evident in early lesions, makes it impossible to develop a
cleavage plane. Therefore if excision is attempted before
the lesion is mature, the overlying nail bed must be
removed. Although the deformity of the nail after this
procedure rarely presents a problem in the toe, the
patient whose lesion is in a finger may require a nail bed
graft. The best cosmetic results are accomplished if the
lesion becomes a purely osseous structure and cleavage
planes are more easily identified.
The intensity and extent of repair are a complex process
regulated by multiple growth factors and modified by the
severity of injury and underlying pathologic condi-
tions.109,112,114,115 Submitted tissue from fracture callus
rarely presents a diagnostic problem for a pathologist.
However, occasionally it can be so exuberant that, radio-
graphically and clinically, it raises the suspicion of a neo-
plastic process. The development of an exuberant callus
typically follows major trauma with or without fracture
(Fig. 23-36). Some rare conditions, such as osteogenesis
imperfecta and osteopetrosis, predispose to the develop-
ment of exuberant fracture callus even after minor
trauma.110,111,113
Typical fracture callus shows a gradual transition from
hypercellular areas containing spindle cells with early
osteoid formation of an interconnecting network of
reactive bone with prominent osteoblastic rimming

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1389

B
FIGURE 23-30  ■  Acquired exostosis: microscopic features. A, Note well-organized ossification pattern, which is linear and forms
interconnecting trabeculae (lower aspect of photograph). Peripheral parts are covered by cartilaginous cap. B, Higher magnification
of A shows hypercellularity of cartilaginous cap. (A, ×50; B, ×100) (A and B, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1390 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

C
FIGURE 23-31  ■  Subungual exostosis: radiographic features. A and B, Anteroposterior and lateral radiographs of great toe show very
large mature bony excrescence attached to dorsomedial surface of distal phalanx by narrow base. C, Clinical photograph of fungat-
ing, ulcerated mass arising in nail bed of 11-year-old boy 5 months after treatment for paronychia. Excision revealed subungual
exostosis (same case as in A and B).

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1391

A B

C D
FIGURE 23-32  ■  Subungual exostosis: radiographic features. A, Anteroposterior radiograph of foot shows ill-defined exostotic bony
mass on medial aspect of distal phalanx of great toe with swelling of surrounding soft tissue. B, More mature subungual exostosis
of distal phalanx of great toe. Mass is attached to phalangeal cortex, and its periphery is sharply defined. C, Lateral view of mature
subungual exostosis shown in B. D, Lateral view of great toe with maturing subungual exostosis.

(Figs. 23-37 and 23-38). In more chronic proliferation,
such as that initiated by prolonged repeated trauma (i.e.,
unrecognized malunited fracture), disorganized fibrocar-
tilaginous proliferation can be a dominant feature of
the process (Fig. 23-39). More mature lesions show pro-
gressive maturation to lamellar bone. The peculiar dis-
tinctive architecture of a fracture callus is best evaluated
under low power magnification. The continuity among
various microscopic elements of callus tissue is the most
helpful microscopic feature in distinguishing this reactive
process from a neoplasm.
Osteogenesis imperfecta is a rare condition that predis-
poses a bone to fracture. Moreover, patients with this
disorder are particularly prone to the development of
florid exuberant callus tissue in response to even mild
trauma; this evolution may not be evident clinically
or may not be documented radiographically. Radio­
graphically and clinically, these reactions can simulate
a bone-forming neoplastic process. They typically occur
in the parosteal soft tissue without an evident frac-
ture, presenting on radiographs as a mass on the bone
surface or in the soft tissue (Fig. 23-40). A fracture
superimposed on osteopetrosis can result in the forma-
tion of an exuberant callus with abundant cartilage that
exhibits highly atypical features. Microscopically, these
reactions show a fracture callus that lacks maturation
patterns into lamellar bone and shows the disorga-
nized florid formation of metaplastic cartilage and early
osteoid (Figs. 23-40 to 23-42). These lesions may contain
areas of young granulation or fibroblastic tissue with
hemorrhage and an occasional giant-cell reaction. Meta-
plastic cartilage with irregular zones of enchondral ossi-
fication is present. These zones show continuity with
areas of reactive bone formation rimmed by palisading
osteoblasts.
Text continued on p. 1402

ERRNVPHGLFRVRUJ
1392 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

B
FIGURE 23-33  ■  Subungual exostosis: microscopic features. A, Low power photomicrograph shows cellular chondroid tissue merging
with peripheral zone of proliferating fibrous tissue in nail bed. Cartilage matrix calcification and early stages of enchondral ossifica-
tion are seen below. Inset, Higher magnification of cartilaginous cap showing hypercellularity and atypia of cartilage cells. B, Higher
magnification of an area of A below the cartilaginous cap showing early phases of enchondral ossification and hypercellular fibro-
blastic stroma. (A, ×25; Inset, ×50; B, ×100) (A, B, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1393

B
FIGURE 23-34  ■  Subungual exostosis: microscopic features. A, Low power photomicrograph shows metaplastic cartilage cap overly-
ing zone of enchondral ossification. Inset, Higher magnification of cartilaginous cap with hypercellularity and atypia. B, Somewhat
disorderly zone of enchondral ossification is evolving into subungual exostosis. (A and B, ×100; Inset, ×200) (A, B, and Inset,
hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1394 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

B
FIGURE 23-35  ■  Subungual exostosis: microscopic features. A, Low power photomicrograph of late stage in development of subun-
gual exostosis shows it projecting into nail bed (below). The cartilage cap has been almost completely replaced, through enchondral
ossification, to form bony mass with lamellar maturation. B, Higher power magnification of A shows trabecular bone with lamellar
architecture and almost complete replacement of cartilaginous cap. The bone blends with fibrous tissue of nail bed. Inset, Higher
magnification shows irregular trabecular bone with osteoblastic rimming blending with fibrous tissue of nail bed. (A, ×15; B, ×25;
Inset, ×100) (A, B, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1395

B
FIGURE 23-36  ■  Exuberant fracture callus: radiographic features. A and B, Anteroposterior and lateral radiographs of foot in young
man with metatarsal shaft fracture exhibiting excessive callus formation that can be mistaken for bone-forming tumor.

ERRNVPHGLFRVRUJ
1396 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-37  ■  Hyperplastic fracture callus: microscopic features. A and B, Low power views of abandoned callus growth in unrec-
ognized fracture composed of well-organized woven and lamellar bone trabeculae. C, Higher magnification of abandoned callus
growth showing well-developed trabecular bone formation arranged in plexiform pattern with zoning. D, Higher magnification of
fracture callus composed of mixture of hyaline cartilage and both woven and lamellar bone trabeculae. (A and B, ×15; C and D, ×20.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1397

B
FIGURE 23-38  ■  Fracture callus: microscopic features. A and B, Anastomosing weblike pattern of woven bone trabeculae with promi-
nent osteoblastic rimming in fracture callus. Inset, Anastomosing woven bone trabeculae rimmed by prominent osteoblastic cells.
(A and B, ×100; Inset, ×200.) (A, B, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1398 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-39  ■  Hyperplastic fracture callus: microscopic features. A, Low power view of abundant callus growth in unrecognized
fracture of rib; growth is composed of mixture of hyaline cartilage and both woven and lamellar bone trabeculae. Note that trabeculae
are arranged in plexiform pattern with zoning. B, Chondroid and chondromyxoid areas in long-term fracture callus.
C, Juxtaposed hyaline cartilage and trabecular bone in long-term persistent fracture callus. D, Granulation tissue and relatively
mature bone trabeculae with osteoclastic remodeling. (A, ×10; B and D, ×50; C, ×200) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1399

A B C

D
FIGURE 23-40  ■  Exuberant hyperplastic callus in osteogenesis imperfecta: radiographic features. A, Fluffy mineralization is noted
juxtacortically at midshaft of femur (arrows) in a 13-year-old boy known to have osteogenesis imperfecta. He had history of multiple
long bone fractures since age 2. No definite history of trauma could be obtained, and fracture line is very indistinct. B, Circumfer-
ential new bone formation involving midshaft (arrows) of a 4-year-old child who has osteogenesis imperfecta and history of several
fractures sustained after minor injuries. No recent history of trauma could be obtained. Note bony deformation and thickening of
posterior cortex. C, Mass on medial aspect of surface of right femoral shaft in child with osteogenesis imperfecta. There is no
radiographic evidence of fracture, and no recent history of significant trauma could be obtained. D, Microscopic features of florid
fracture callus with early osteoid and metaplastic cartilage matrix deposition of the lesion shown in C (200; hematoxylin-eosin).

ERRNVPHGLFRVRUJ
1400 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

B
FIGURE 23-41  ■  Exuberant fracture callus in osteogenesis imperfecta: microscopic features. A, Low power view of periosteal mass
in soft tissue shows florid fracture callus with extensive cartilage metaplasia and early osteoid formation. B, Area of metaplastic
cartilage with nuclear atypia. Inset, Early deposition of osteoid. (A, ×25; B and Inset, ×100) (A, B, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1401

B
FIGURE 23-42  ■  Exuberant fracture callus in osteogenesis imperfecta: microscopic features. A, Low power view showing florid frac-
ture callus with extensive areas of cartilage metaplasia. B, Area of metaplastic cartilage with hypercelluarity and nuclear atypia.
Inset, Early osteoid deposition in florid callus. (A, ×25; B and Inset, ×100) (A, B, and Inset, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1402 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone
AVULSION AND STRESS INJURIES
Avulsion and stress injuries are caused by distinct trau-
matic episodes that may synergistically contribute to the
development of a single lesion. Microscopically, these
conditions are characterized by the presence of a fracture
callus in different phases of formation. They can be sepa-
rated into specific clinicoradiologic entities if clinical
history (type of injury or physical activity involved) and
radiologic features are considered. Occasionally, these
conditions clinically and radiographically simulate a neo-
plasm and may require a biopsy to rule out a malignant
process. The most typical sites of avulsion and stress
injuries, as well as their peak age incidence, are shown in
Figure 23-43.
Avulsion Injuries
Avulsion injuries are caused by a traumatic episode of
muscle spasm or traction causing the detachment of the
muscle’s tendinous attachment.120,122,125,126,136,139,140,150,155
Acute avulsion is recognized by the displacement of a
bone that frequently corresponds to the site of insertion.
Acute injuries are typically not subjected to microscopic
evaluation. More insidious or chronic lesions are associ-
ated with repeated stress or represent the healing phase
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 23-43  ■  Avulsive and stress injuries. Peak age incidence and typical sites of skeletal involvement are indicated by arrows.
ERRNVPHGLFRVRUJ
of previously unrecognized acute episodes. Chronic avul-
sions are characterized by the formation of callus and
organized bone in relation to a separated osseous frag-
ment. The bone prominences in the lower extremities,
particularly around the pelvis and hip, are particularly
susceptible to avulsion injuries.120,122,125,136,137,147,156 The
most frequent sites of involvement include the ischial
apophysis, the anterior/inferior iliac spine, and the lesser
and greater trochanters of the femur. In the upper
extremities the insertion of the deltoid muscle tendon
(lateral aspect of proximal humeral shaft) is the most
typical site of an avulsion injury.125,152 The chronic
variant of this injury may clinically and radiographically
raise the suspicion of a neoplasm, prompting biopsy and
microscopic evaluation (Fig. 23-44). Lesions involving
areas of ligament insertion can predispose to avulsion
injuries.127,152
Microscopically, the lesion shows fracture callus in
different phases of formation. Long-standing lesions may
show well-developed woven or lamellar bone, but more
typically, repeated stress stimulates florid proliferations
of fibroblastic and granulation tissue with prominent for-
mation of reactive woven bone and cartilage metaplasia;
that is, features overlap with those seen in the tissue
of bizarre parosteal osteochondromatous proliferation
(Figs. 23-45 and 23-46).
Avulsion
injury
Avulsion
injuries
7 8
Stress
injuries
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1403
FIGURE 23-44  ■  Avulsive injury to ischial apophysis: radiographic features. Note irregularity of ischial apophysis in teenage boy with
groin pain and stiffness (arrows).
Cortical Irregularity Syndrome
(Periosteal Desmoid)
In the past the term periosteal desmoid has been inappro-
priately applied to this avulsive lesion, which involves
the insertion of the adductor muscle tendon on the
posteromedial aspect of the distal end of the femur
(Fig. 23-47).117,124,132,134,135,148,149,153,157 Cortical irregularity
syndrome especially affects young, athletic individuals,
predominantly boys, before adolescence. Bony irregulari-
ties and excavations in relation to the medial side of the
distal end of the femur are common and characteristic of
this lesion.76,81,101-103,110,111,146 In rare circumstances, this
lesion, as it appears on radiographs, can raise suspicion
of a neoplastic disorder.107 In such cases, biopsy samples
shows young, fibroblastic tissue without cytologic atypia
(Fig. 23-48). The presence of thick collagen fibers
with parallel arrangement consistent with tendinous or
ligamentous tissue can be seen. If the microscopic fea-
tures are evaluated without clinicoradiologic correlation,
the lesion may be confused with fibromatosis or even
fibrosarcoma.
Stress Fractures
Stress fractures are traumatic lesions that are the result
of prolonged minor, repeated traumas usually associated
with athletic or occupational activities.116,119,127-130,133,144
These lesions usually occur in young, athletically active
adults. There also is some association between this type of
injury and osteoporosis in elderly patients. The repeated
stress finally culminates in an acute fracture of the bone.
Stress fractures usually involve the bones of the lower
extremities.121,123,129,130,133,138 The frequent involvement of
ERRNVPHGLFRVRUJ
the second or third metatarsal neck region, which com-
monly affects soldiers in training, is popularly referred to
as march fracture.116,127,131,143,145 Long-distance running
(jogging) typically causes stress fractures involving the
distal fibula and the tibial shaft.122,143 Underlying skeletal
disorders, such as osteoporosis, can predispose to fatigue
(stress) fractures even in relation to normal activities.142,145
On radiographs, the lesion may show a transverse frac-
ture or sclerosis with associated periosteal reaction (Fig.
23-49). The actual fracture may not be revealed by
computed tomography or even magnetic resonance
imaging.151,154 The so-called gray cortex represents focal
density and can be an early radiographic sign of stress
fracture.141 In such cases, the lesion presents only as peri-
osteal new bone formation on radiographs. Some of these
lesions may raise the suspicion of a neoplasm on the bone
surface, and biopsy should be performed. Microscopic
examination reveals fracture callus in various phases of
development.
PUBIC OSTEOLYSIS
Pubic osteolysis is a rare lesion characterized by a
rapidly progressive osteolysis in and around the pubis.
The condition usually affects middle-aged to elderly
osteopenic women. The major diagnostic significance
of pubic osteolysis is that it may have radiographic and
microscopic features that overlap with those of chon-
drosarcoma.158,161,164,165,167,170 Our consultation practice
indicates that most cases of pubic osteolysis are submit-
ted for second opinion with the preliminary diagnosis of
chondrosarcoma.118
Text continued on p. 1409
1404 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-45  ■  Chronic avulsive injury: microscopic features. A and B, Low power magnification of atypical pattern of callus seen
in longstanding or persistent avulsive injury consisting of alternating zones of metaplastic hyaline cartilage and woven bone tra-
beculae. C, Prominent hyaline cartilage differentiation in fracture callus with focal conversion to bone. D, Anastomosing pattern of
woven bone trabeculae in fracture callus (A-D, ×25) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1405

A B

C D
FIGURE 23-46  ■  Chronic avulsive injury: microscopic features. A, Anastomosing weblike pattern of woven bone trabeculae in fracture
callus. B, Chondroid and chondromyxoid areas juxtaposed on woven bone in long-term fracture callus. C, Chondroid areas with
disorganized enchondral ossification pattern in persistent fracture callus. D, Juxtaposed hyaline cartilage and trabecular bone in
long-term persistent fracture callus. (A, C, and D, ×25; B, ×50) (A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1406 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

C D
FIGURE 23-47  ■  Cortical irregularity syndrome: radiographic features. A, Lateral radiograph of knee shows roughening of supracon-
dylar ridge and overlying shadow of soft tissue, which represents chronic avulsive lesion of insertion of adductor magnus
muscle (arrows). B, Computed tomogram shows concave erosion of linea aspera, into which adductor magnus tendon inserts
(arrow). C, Photomicrograph showing proliferation of myofibroblastic cells without cytologic atypia. D, Proliferation of
fibroblast-like spindle cells in fibrous stroma resembling fibromitosis frequently seen in this reactive process. (C and D, ×25) (C and
D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1407

B C
FIGURE 23-48  ■  Cortical irregularity syndrome: radiographic features. A-C, Proliferation of myofibroblastic cells without cytologic
atypia in dense fibrous stroma resembling fibromatosis (A-C, ×100) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1408 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B
FIGURE 23-49  ■  Stress fracture: radiographic features. A and B, Anteroposterior and lateral radiographs of tibia in child show posterior
cortical disruption in upper third of shaft, with periosteal new bone formation and surrounding bone sclerosis. Such injuries can
mimic osteoid osteoma or even osteosarcoma.

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1409
The exact pathogenesis of this condition is not known.
It is generally postulated that trauma and osteopenia are
the two major predisposing factors.159,160,162,163,168,169,171
Similar lesions have been described in athletes and in
association with urologic surgery, renal failure, and
obesity.162,166,169,170 The presence of radiographically doc-
umented pathologic fracture was evident in only one of
our cases.
On radiographs the lesion represents a lysis of the
bone in the pubic area (Fig. 23-50). Development of
fracture, fragmentation, or both frequently occur later in
the course of the disease. An area of lysis is usually sur-
rounded by swelling of the adjacent soft tissue. Virtually
all lesions eventually develop calcification (sclerosis)
within lytic areas of the affected bone and in the adjacent
soft tissue.
Microscopically, the lesion shows ineffective and exu-
berant bony callus. Prominent areas of metaplastic carti-
lage are always present and may dominate the lesion
(Fig. 23-51). Occasional binucleate chondrocytes, a high
degree of cellularity, and myxoid changes are seen within
cartilaginous areas. Bone metaplasia is also frequently
present with the production of abundant immature woven
bone. The bone metaplasia is identical to that seen in
lesions of exuberant callus formation secondary to frac-
ture healing or in active myositis ossificans. The risk of
misdiagnosis is compounded if this fracture callus extends
into soft tissue. The osteocartilaginous material may also
show focal bone necrosis, fibrosis of the marrow, and
proliferation of capillary vessels with hemosiderin depos-
its. The angiomatoid pattern of granulation tissue might
suggest angioma, but this is typically seen in fracture
healing. Neuropathic change is suggested by the occa-
sional presence of fragments of necrotic bone and carti-
lage debris that result from fragmentation of the fracture
site. There is loosely textured edematous chondroid and
fibrous intervening tissue with vascular proliferation and
a granulation-like tissue appearance. Inflammatory cells
are typically not present; thus confusion with osteitis
pubis does not arise.
TUMORAL CALCINOSIS
Definition
Tumoral calcinosis is a distinct clinicopathologic entity
characterized by a tumorlike deposition of calcium
without an obvious associated metabolic calcium disorder.
Incidence and Location
Tumoral calcinosis is very rare and seems to affect Afri-
cans and African-Americans predominantly, but it can
also affect other ethnic groups.129,171,183,185,190,193,201,205,206,214
It typically occurs in otherwise healthy children, adoles-
cents, and young adults.202 The lesions are often multiple,
and they may affect two or more siblings in the same
family. Calcifications are usually located in the periarticu-
lar soft tissue in the vicinity of major joints, such as the
hips, shoulders, and posterior elbows. Occasionally, they
may affect the knee and spine regions.108 Tumoral calci-
nosis is extremely rare in the hands and feet. Examples
ERRNVPHGLFRVRUJ
of this condition involving the temporomandibular joint
also have been described.209 Bilateral symmetric involve-
ment of corresponding anatomic regions is frequent. The
peak age incidence and the most frequently affected sites
are shown in Figure 23-52. Familial occurrences have also
been reported. Lesions have been described in siblings
and in several generations of one family. An autosomal
dominant pattern of inheritance with variable clinical
expressivity is postulated in familial cases.199 Germline
mutations of several genes, such as fibroblast growth factor
23 (FGF23), UDP-N-acetyl-alpha-d-galactosamine: poly-
peptide N-acetylgalactosaminyl transferase 3 (GALNT3),
sterile alpha motif domain containing 9 (SAMD9), and
klotho (KL), have been identified in familial forms of
tumoral calcinosis.175-182,186-189,196,197,213,216,218 Some of these
familial syndromes (e.g., associated with mutations of
GALNT3) are clinically presenting with widespread
ectopic calcifications and severe phosphatemia.175,179
Clinical Symptoms
The mass is typically asymptomatic. It may cause local
discomfort such as tenderness or pain. Laboratory data
show no evidence of abnormal calcium levels. However,
many patients may have mild to moderate hyperphospha-
temia.169,198,199,216 Calcitriol (1, 25-dihydroxyvitamin D3)
levels may also be elevated.200,207,211 Serum uric acid and
alkaline phosphatase levels are normal.
Radiographic Imaging
Plain radiographs reveal conglomerates of well-
demarcated opacities in soft tissue near a major joint
(Fig. 23-53, A and B).170,173,194,195,210,217 Occasionally, fluid
levels can be documented on plain radiographs.194 They
can usually be seen in larger, long-lasting lesions. The
foci of calcification range in size from several millimeters
to 1 to 2 cm. Computed tomography or magnetic reso-
nance imaging shows multifocal lesions. In some of the
larger calcified nodules, cystic changes with fluid levels
can be documented using these techniques.
Gross Findings
Tumoral calcinosis consists of an encapsulated firm mass
of multiple calcified nodules that focally coalesce into
larger, lobulated masses. Cystic changes are frequently
present in some of the nodules. The nodules are filled
with yellow-gray, pasty masses or a milky fluid that can
be washed out from individual lesions.
Microscopic Findings
Microscopically, the lesion consists of large areas of amor-
phous or granular calcium masses with occasional inter-
spersed, concentrically laminated calcospherites172,185,215
(Fig. 23-53, C and D). Chemical and ultrastructural
analysis of this substance reveals calcium crystals con-
sistent with hydroxyapatite.192,208 The active phase of
the disorder is associated with a prominent infiltration
by macrophages, osteoclast-like giant cells, and other
inflammatory cells that border and encircle calcium
1410 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

B
FIGURE 23-50  ■  Pubic osteolysis: radiographic features. A, Lysis of bones in pubic area and widening of pubic symphysis. B, Lysis
of pubic bone with fracture and fragmentation.

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1411

A B

C D
FIGURE 23-51  ■  Pubic osteolysis: microscopic features. A and B, Proliferation of spindle cells with prominent vasculature. C, Reactive
bone with osteoblastic rimming. D, Metaplastic cartilage with hypercellularity and nuclear atypia. (A and C, ×50; B, ×100; D, ×200.)
(A-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1412 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 23-52  ■  Tumoral calcinosis. Peak age incidence and most frequent sites of skeletal involvement are indicated by solid black
arrows.
deposits. The inactive or mature phase merely shows
calcified deposits in a dense fibrous stroma.
Differential Diagnosis
Similar tumoral calcifications can be found in patients
with several underlying metabolic calcium disorders,
such as chronic renal disease or secondary hyperparathy-
roidism.174,184,203 The patients with such conditions are
typically older, have a history of an underlying disorder,
or exhibit features of generalized metabolic calcium dis-
order. In addition, they show disseminated calcification
in visceral organs. Lesions similar to tumoral calcinosis
can occur in patients with primary hyperparathyroidism,
hypervitaminosis D, milk-alkali syndrome, and sclero-
derma.191 However, these lesions are typically associated
with abnormal serum levels of calcium.
Treatment and Behavior
Surgical removal of the lesion is the treatment of choice.
Incompletely excised lesions recur. Long-standing lesions
may develop secondary infection with abscess formation.
It is recommended that lesions be surgically removed as
early as possible, when they are small and amenable to
complete excision. Calcium deprivation and PO4-binding
ERRNVPHGLFRVRUJ
Periarticular
soft tissue
7 8
antacids have been used and offer an alternative mode of
conservative therapy for lesions that cannot be surgically
removed for technical reasons.204 Other modes of non-
surgical therapy (radiotherapy, cortisone, low-phosphorus
diet, aluminum hydroxide gels) have been shown to be
ineffective.204,212
TOPHACEOUS PSEUDOGOUT
Definition
Tophaceous pseudogout (tumoral calcium pyrophosphate
dihydrate crystal deposition disease) was first described in
1962 by McCarty et al.226 The crystals were identified in
the synovial fluid of patients who had goutlike symptoms
without sodium urate crystals. Consequently the entity
was designated as pseudogout. The terms chondrocalcinosis
and calcium pyrophosphate crystal deposition arthropathy were
independently applied to the same condition, which is
characterized on radiographs by prominent multifocal
calcification in the cartilages of joints and intervertebral
disks.225,228 The condition is now designated as calcium
pyrophosphate dihydrate crystal deposition disease. The term
encompasses pseudogout, chondrocalcinosis, and pyro-
phosphate arthropathy.219,220,222-225,227
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1413

C D
FIGURE 23-53  ■  Tumoral calcinosis: radiographic and microscopic features. A, Lateral radiograph of elbow shows coarse deposits of
calcific material in region of olecranon bursa. B, Massive calcinosis in soft tissue around parascapular area and axilla in teenage
boy. C, Low power photomicrograph shows circumscribed foci of calcific material with central cystification and peripheral foreign-
body giant-cell reaction in tumoral calcinosis. D, Higher power magnification shows calcified bodies and more finely dispersed,
noncrystalline calcifications. (C, ×50; D, ×25) (C-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1414 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone
Calcium pyrophosphate dihydrate deposition com-
monly occurs in the articular and periarticular tissue.
However, tophaceous calcium pyrophosphate dihydrate
deposition (i.e., tumoral or massive calcium pyrophos-
phate dihydrate crystal deposition) is very rare.221,229,230
Because of the unusual location and prominent cartilage
formation, the tumorlike masses in calcium pyrophos-
phate dihydrate crystal deposition disease may be misin-
terpreted as a benign or even a malignant cartilage
neoplasm, especially chondrosarcoma.
Clinical Data
We have seen seven cases of tophaceous pseudogout in
consultation. The ages of the patients ranged from 31 to
86 years (average, 60.7 years). One patient was a man,
and six were women. The temporomandibular joint was
involved in three patients, and the metatarsophalangeal
joint of the great toe was involved in two patients. The
hip joint and cervical spine were involved in one patient
each. Long-standing swelling of the affected area was
noted in two patients with temporomandibular joint
involvement. Two patients had a painful mass of the great
toe, which was clinically considered to be gouty tophus.
One patient noticed increasing hip pain over 18 months.
Rapid, progressive myelopathy at an upper cervical level
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 23-54  ■  Tophaceous pseudogout (tumoral calcium pyrophosphate dihydrate crystal deposition disease). Peak age incidence
and most frequent sites of skeletal invovlement.
ERRNVPHGLFRVRUJ
developed in another patient. One patient was asymp-
tomatic, and the lesion was discovered incidentally on
imaging studies done for other reasons. No patient’s
serum tests showed an abnormal level of calcium or phos-
phate. None of the patients in our series had radiographic
evidence of chondrocalcinosis or clinical symptoms in
any other joints. The peak age incidence and sites of
skeletal involvement of our consultation cases are shown
in Figure 23-54.
Radiographic Imaging
Radiographically, the lesion appears to be a slightly or
densely calcified mass; the pattern of calcification is gran-
ular or fluffy (Figs. 23-55 and 23-56). Unlike myositis
ossificans, peripheral density is not observed. The bone
adjacent to the calcified mass shows pressure erosion in
some cases. The calcification itself and its pattern are
demonstrated well on computed tomograms and mag-
netic resonance images (Fig. 23-57).
Gross Findings
The lesion is a circumscribed, white-gray mass with a
more or less chalky appearance. The sizes of the lesions
in our series ranged from 2 to 4 cm.
7 8
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1415
A which calcium pyrophosphate dihydrate crystals are lost,
B Synovial chondromatosis and chondromas in soft
FIGURE 23-55  ■  Calcium pyrophosphate dihydrate deposition
disease (tophaceous pseudogout): radiographic features.
A, Radiograph of right hip shows calcified mass in soft tissue
adjacent to acetabular margin; this mass represents deposits of
calcium pyrophosphate dihydrate in capsule of hip joint
(arrows). B, Computed tomogram of case shown in A demon-
strates circumscribed calcification in soft tissue that is adjacent
to acetabular labium (arrows). (From Ishida T, Dorfman HD,
Bullough PG: Hum Pathol 26:587–593, 1995.)
Microscopic Findings
Histologically, the lesion consists of cellular or less
cellular tissues containing small to large islands of
intensely basophilic calcified crystalline material (Fig.
23-58). The crystals are short rhomboid or, rarely,
needle shaped, similar to urate crystals. Under compen-
sated polarized light microscopy, the crystals exhibit the
weak positive birefringence characteristic of calcium
ERRNVPHGLFRVRUJ
pyrophosphate dihydrate crystals (Fig. 23-58). The cel-
lular tissues contain large numbers of histiocytes and
foreign body–type giant cells surrounding the calcified
areas and representing a foreign body granulomatous
reaction, whereas the less cellular tissues consist of meta-
plastic chondroid tissues. The chondroid cells can be
atypical, with variable nuclear size and shape, and can
mimic a malignant cartilage tumor. The chondroid
cells can be seen in and around the calcified areas (see
Fig. 23-58).
The calcium pyrophosphate dihydrate crystals are
removable by decalcification, and their basophilic fea-
tures are lost in demineralized sections. Moreover, in
decalcified sections, the amorphous intercellular matrix,
which is somewhat similar to the chondroid matrix, is left
behind in the areas of calcium pyrophosphate dihydrate
deposition (Fig. 23-59).
Differential Diagnosis
The metaplastic chondrocytes found in our series of
patients sometimes showed cytologic atypia (three
patients) analogous to that seen in some patients with
synovial chondromatosis and superficially resembled
chondrosarcoma. Particularly in decalcified sections from
atypical features in metaplastic chondrocytes and the
presence of myxoid stroma may lead to the histologic
misdiagnosis of chondrosarcoma. Grossly, tophaceous
pseudogout is a calcified, chalky mass unlike the calcifica-
tion seen in chondrosarcoma. A foreign body–type gran-
ulomatous reaction containing histiocytes and giant cells
is a helpful finding to distinguish it from chondrosar-
coma. More important, however, is the identification by
polarized light microscopy of birefringent crystals char-
acteristic of calcium pyrophosphate dihydrate. The exact
nature of these crystals can be determined by radio-
graphic diffraction or electron probe analysis. Even in the
decalcified sections, empty outlines of crystals in the
chondroid matrix can be seen, although birefringent
crystals are not identified directly.
tissue are the other lesions that can be confused with
tophaceous pseudogout, especially in the conditions in
which a heavily calcified cartilage matrix may obscure the
cartilaginous nature. However, the calcified areas of
synovial chondromatosis do not contain the rhomboid
crystals characteristic of calcium pyrophosphate dihy-
drate deposition. Indeed, radiographic diffraction studies
in both synovial chondromatosis and chondroma of
soft tissue show that the mineral deposits represent
hydroxyapatite.
Treatment and Behavior
Tophaceous pseudogout may recur after complete or
incomplete surgical excision. Six cases that recurred 11
months to 6 years after surgery have been reported.
Three recurrences were noted in one patient. One of the
patients in our series had two recurrences during a
20-year span.
Text continued on p. 1420
1416 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

FIGURE 23-56  ■  Calcium pyrophosphate dihydrate deposition disease (tophaceous pseudogout): radiographic features. A and
B, Anteroposterior and lateral radiographs of foot show massive calcification of soft tissue around metatarsophalangeal joint of
great toe resulting from localized deposit of calcium pyrophosphate dihydrate crystals. (From Ishida T, Dorfman HD, Bullough PG:
Hum Pathol 26:587–593, 1995.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1417

B
FIGURE 23-57  ■  Calcium pyrophosphate deposition disease (tophaceous pseudogout): radiographic features. A, Sagittal magnetic
resonance image (MRI) of skull and cervical spine of elderly woman who had calcified extradural mass at junction of C1 and C2
with posterior displacement and kinking of dural sac and cord (arrow). B, Computed tomogram of cervical spine of patient shown
in A reveals extradural calcific mass compressing dural sac (arrows). Inset, T2-weighted axial MRI of skull of 55-year-old woman
shows tumorous mass of infratemporal fossa adjacent to temporomandibular joint on left side of photograph. (From Ishida T, Dorfman
HD, Bullough PG: Hum Pathol 26:587–593, 1995.)

ERRNVPHGLFRVRUJ
1418 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-58  ■  Calcium pyrophosphate dihydrate deposition disease (tophaceous pseudogout): gross and microscopic features.
A, Calcified tophaceous deposit from plantar aspect of foot shows whitish chalky appearance similar to that seen in monosodium
urate tophus. B, Metaplastic chondroid change surrounds islands of basophilic calcified crystalline calcium pyrophosphate dihydrate.
C, Some basophilic calcified deposits provoke foreign body–type, giant-cell reaction without chondroid metaplasia. D, Compensated
polarization microscopy demonstrates positive birefringence of rhomboid calcium pyrophosphate dihydrate crystals. (B and C, ×100;
D, ×200) (B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1419

A B

C D
FIGURE 23-59  ■  Tumoral calcium pyrophosphate dihydrate crystal deposition disease (tophaceous pseudogout): radiographic and
microscopic features. A, Computed tomogram (CT) of the skull showing a calcified soft tissue mass in the area of the right tem-
poromandibular joint. B, 3-D CT reconstruction image showing a mass in the right temporomandibular joint. C, Photomicrograph
of decalcified specimen showing lobules of myxoid material corresponding to areas of metaplastic cartilage and crystalline material
deposits. D, Higher magnification of C showing an interface between hypercellular stroma and myxoid areas with prominent plump
histiocytic cells exhibiting nuclear atypia. (C, ×100; D, ×200) (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1420 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone
TOPHACEOUS GOUT
A comprehensive description of the various forms of gout
and their pathogenesis is beyond the scope of this book.
This description is restricted to the tophaceous form
of gout and the basic microscopic features that are
helpful in distinguishing this metabolic disorder from a
neoplasm.
Clinical Data
In general, gout is characterized by hyperuricemia and
the deposition of monosodium urate crystals in synovial
tissues.232,233,235,236
Nearly 90% of cases of gout occur in men, and the
peak incidence is in patients older than age 50 years. It
is rare in women, but when it does affect a female patient,
the onset of symptoms typically occurs in the postmeno-
pausal period. Many patients with hyperuricemia are
asymptomatic. About 20% have renal lithiasis or episodes
of acute gouty arthritis. Acute gout can present as a
monoarticular or oligoarticular arthritis. The disease
usually involves the joints of the foot and ankle. The knee
joint is also frequently involved. The involvement of the
small joints of the hands is next in frequency. The periods
Incidence
1 2 3 4 5 6
Age in decades
FIGURE 23-60  ■  Tophaceous gout. Peak age incidence and typical sites of skeletal involvement. Solid black arrows indicate most
frequent sites of involvement.
ERRNVPHGLFRVRUJ
of acute attacks increase in duration and become more
frequent. Approximately 50% of the patients with gouty
arthritis have nodular deposition of monosodium urate
crystals that are referred to as tophi. Patients who have
higher levels of uric acid have a high propensity for the
development of tophi. The peak age incidence and the
most frequent sites of skeletal involvement are shown in
Figure 23-60.
Radiographic Imaging
The formation of tophi occurs 3 to 40 years (average, 12
years) after the first attack of gout. Radiographically,
tophaceous gout typically presents as a periarticular non-
calcified mass with frequent erosion of the adjacent bones
(Figs. 23-61 and 23-62). Early lesions present as ill-
defined swelling in the soft tissue. Approximately 20% to
30% of tophi show calcifications. Occasionally, topha-
ceous gout can produce large calcified periarticular
masses (Fig. 23-63).231,234,237,238
Gross Findings
Tophaceous deposits in gout appear as white to yellow
chalky nodular areas surrounded by an intervening
7 8
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1421
FIGURE 23-61  ■  Tophaceous gout: radiographic features. Mar-
ginal erosions of tarsal bones and metatarsals are sharply out-
lined and completely radiolucent (arrows).
fibrous tissue. Smaller lesions predominantly show
deposits of urate crystals. Larger, older lesions may
exhibit multilobular architecture with prominent fibrosis
and calcifications (Fig. 23-64).
Microscopic Findings
Microscopically, monosodium urate crystals are needle
shaped and demonstrate strongly negative birefringence
under compensated polarization microscopy. They are
found floating freely and intracellularly in leukocytes.
Monosodium urate crystals are also found in tophi, where
they form multicentric, radially oriented deposits sur-
rounded by a matrix of amorphous material, lipids, and
proteinaceous debris. They show a multilobular or
nodular pattern of deposition that may undergo calcifica-
ERRNVPHGLFRVRUJ
tion (Fig. 23-65). The intervening stromal tissue shows
histiocytic and multinucleated giant-cell reaction.
CHRONIC RECURRENT
MULTIFOCAL OSTEOMYELITIS
Chronic recurrent multifocal osteomyelitis is a more
recently described rare variant of osteomyelitis that pri-
marily affects children and young adults. Clinically, it is
characterized by an insidious onset of fever, local swell-
ing, and pain in the affected bones.239,243,252-261 The disease
mainly affects the metaphyses of the long tubular bones
and the clavicle. Sometimes, it has a symmetric distribu-
tion; that is, similar sites in both extremities are involved
(Fig. 23-66).245,246 The most commonly involved skeletal
sites are the tibia, femur, clavicle, and fibula. On radio-
graphs the lesion presents as lytic foci with associated
sclerosis (Figs. 23-66 to 23-68).245,249,253,256-258
The presence of associated autoimmune disorders
and familial clustering with linkage to a predisposing
locus at 18q21-22 suggests an autoimmune etiology
and genetic predisposition.248 In fact, mutations of the
LPIN2 gene cause a familial form of chronic recurrent
multifocal osteomyelitis known as Majeed syndrome
while mutations in Pstpip2 cause a murine form of the
disorder.244,251 The roles of LPIN2 and of the human
homolog of Pstpip2 (PSTPIP2) in the etiology of chronic
recurrent multifocal osteomyelitis are uncertain at the
time of this writing.
Microscopically, early lesions contain polymorpho-
nuclear (neutrophilic) leukocytic infiltrate in the
marrow.241 Collections of neutrophils that mimic bone
marrow abscesses can be present and are sometimes sur-
rounded by a collar of lymphocytic infiltrates. Bone
resorption with prominent osteoclasts is a common
feature. Long-standing lesions show fibrosis with pre-
dominantly lymphocytic infiltrates (Fig. 23-67, D, and
Fig. 23-68, D). Prominent formation of new reactive
bone can be a dominant feature in later phases of the
disease. Peculiar granulomas made up of collections
of neutrophils surrounded by a rim of epithelioid histio-
cytes can be present, but there is no caseous necrosis.
Results of bacterial, viral, and fungal cultures, as well as
special stains for infectious organisms, are consistently
negative.
Some patients may have associated recurrent skin
lesions (pustolosis palmoplantaris).239,240 Typically, the
emergence of skin changes parallels exacerbations of the
skeletal lesions. In fact, it is postulated that chronic recur-
rent multifocal osteomyelitis is a manifestation of the
spectrum of disorders characterized by sterile neutro-
philic infiltrate primarily in the skin referred to as neu-
trophilic dermatoses. They include palmoplantar pustulosis,
psoriasis, acne fulminans, neutrophilic eccrine hidradeni-
tis, acute febrile netrophilic dermatosis, and pyoderma
gangrenosum. The frequent association of chronic recur-
rent multifocal osteomyelitis with synovitis, acne, pustu-
losis, hyperostosis, and osteitis has been defined as a new
(SAPHO) syndrome.262
In most cases the erythrocyte sedimentation rate is
elevated. Some authors have reported a high incidence
1422 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B
FIGURE 23-62  ■  Tophaceous gout: radiographic features. A and B, Anteroposterior and lateral views of knee of patient with long-
standing gout show bone erosion by tophaceous deposits of monosodium urate (arrows). Note radiolucent defects with sclerotic
borders in femoral condyle, tibial plateau, patella, and fibular head. Subchondral erosions show typical overhanging edge.

of prior throat infections and elevation of antistreptoly-
sin O titers. Clinical outcome of patients with chronic
recurrent multifocal osteomyelitis is generally good,
but some patients may have persistent disease after a
long follow-up.242,247,250 A minority of patients can have a
severe and prolonged disease course.242
Because of the involvement of the metaphyseal parts
of the long bones in young patients and the sclerotic
radiographic appearance, chronic recurrent multifocal
osteomyelitis must be differentiated from more common
bone-forming lesions that affect the same sites in young
patients (i.e., osteosarcoma). Lesions of the clavicle
may simulate Ewing’s sarcoma. Biopsy of the lesions is
performed to confirm the inflammatory nature of the
process, and the lesions are rarely confused with a non-
hematologic neoplasm. However, the late phases of the
process, characterized by the predominant lymphoid
infiltrate, can be confused with lymphoma of the bone. We
have also seen lymphoma of the bone misclassified as
chronic osteomyelitis. It is helpful to consider in the
differential diagnosis the entire clinical picture and
radiographic presentation of the lesion. Lymphoma of
the bone almost never occurs in young patients whose
disease presents with multifocal involvement of metaphy-
seal parts. On the other hand, a destructive (permeative)
lesion that occurs in a patient older than age 40 years and
that is shown under a microscope to contain lymphoid
cells is very unlikely to represent chronic osteomyelitis.
AMYLOIDOSIS OF BONE
Two basic forms of amyloidosis—secondary and
primary—can affect the skeleton. Primary amyloidosis,
with no associated generalized disorder, is very rare in the
skeleton.
The most frequent form of amyloidosis involving the
skeleton is associated with multiple myeloma. It can
affect the skeleton diffusely as a part of disseminated
multiorgan disorder. Disseminated and tumoral forms
can coexist. Tumoral amyloidosis is defined by focal
deposition of amyloid in a sufficient quantity to produce

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1423

FIGURE 23-63  ■  Tophaceous gout: radiographic features. Olecranon deposit of monosodium urate crystals (tophus) shows sufficient
calcium deposits to render it radiopaque. This phenomenon occurs in only one third of gouty tophi, which are usually
radiolucent.

a lytic tumorlike lesion that can be detected on radio-
graphs (Fig. 23-69). Less frequently diffuse or tumoral
amyloidosis can be associated with chronic autoimmune
disorder. In older textbooks, secondary amyloidosis, such
as that associated with tuberculosis or chronic infectious
osteomyelitis, has been emphasized. These types of amy-
loidosis are now exceedingly rare. A new form of skeletal
amyloidosis has been described in patients receiving
long-term dialysis.263,265,267,269,273,274,281,284,287 In this instance,
the deposits represent β2-microglobulin and may form
lytic lesions several centimeters in diameter.279,282 This
form of skeletal amyloidosis appears to occur second
most frequently, following skeletal amyloidosis associated
with multiple myeloma. Several cases of tumorlike amy-
loidosis associated with Bence Jones proteinuria and
other laboratory parameters of plasma cell dyscrasias
have been described. Extremely rare cases of tumoral
amyloid deposition in bone without any other associated
disorders have been also described in the skele-
ton.264,266,268,270,272,285 However, the type of amyloid has not
been characterized in these cases.265 These lesions seem
to be similar to solitary amyloids that occasionally are
identified in other organs and soft tissue.271,275,277,280,288
Tumoral deposition of amyloid in bone predisposes a
person to pathologic fracture, especially in weight-
bearing bones, and may compress adjacent vital struc-
tures such as the spinal cord.264-268,276
Microscopically, amyloid represents amorphous eosin-
ophilic deposits within stromal tissue and around blood
vessels. Tumoral amyloidosis is typically associated with
an abundance of amyloid deposits in well-demarcated
areas associated with interspersed multinucleated giant
cells of the foreign body type, mononuclear histiocytes,
and plasma cells (Fig. 23-70). Tumoral deposition of
amyloid in bone is frequently associated with cystic
degeneration.278,286 Amyloid deposits are typically meta-
chromatic and stain positively with Congo red and
crystal violet. Congo red preparations show distinct
green birefringence under polarized light. Minimal
amounts of amyloid deposit may not be recognizable on
conventional histologic preparations. The presence of
amyloidosis in such cases can be disclosed by all or some
of the mentioned special stains.265,266,274,281,283 Congo red
preparations examined under polarized light appear to be
the most sensitive stains.
Text continued on p. 1431

ERRNVPHGLFRVRUJ
1424 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D

FIGURE 23-64  ■  Tophaceous gout: gross and microscopic features. A, Tophaceous gout forming large mass in olecranon area.
B, Bisected tophus shows areas of chalky material surrounded by fibrous tissue. C, Whole-mount specimen of tophaceous gout
involving interphalangeal joint. Note that tophaceous deposit of chalky material erodes bone and disrupts joint surfaces. D, Higher
power magnification of C depicts tophaceous deposit and disruption of interphalangeal joint surface and deposition of material in
adjacent medullary cavity. (C and D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1425

A B

C D
FIGURE 23-65  ■  Tophaceous gout: radiographic and microscopic features. A, Plain radiograph of right hand shows multiple lytic
periarticular defects with overhanging edges typical of tophaceous gout. B, Nodular (tophaceous) deposition of monosodium urate
crystals surrounded by fibrosis with reactive changes such as mononuclear cells and multinucleated giant cells. C, Polarized micros-
copy of tissue processed and fixed in nonaqueous solution shows strong birefringence of needle-shaped monosodium urate crystals.
D, Higher power photomicrograph under compensated polarization microscopy shows negatively birefringent needle-shaped mono-
sodium urate crystals. (B and C, ×50; D, ×100) (B-D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1426 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-66  ■  Chronic recurrent multifocal osteomyelitis: radiographic features. A, Lytic and sclerotic changes in proximal metaphy-
sis of tibia in patient with episodes of fever and bone pain. B, Radioisotopic bone scan shows increased uptake in both femoral and
tibial metaphyses. C, Lytic sclerotic changes in distal fibular and tibial metaphysis (same patient as in A and B). D, Radioisotopic
bone scan shows increased uptake in both distal tibial metaphyses.

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1427

A B

C D
FIGURE 23-67  ■  Chronic recurrent multifocal osteomyelitis: radiographic and microscopic features. A, Mixed sclerotic and lytic lesion
involving middle phalanx of second finger. B, Radioisotopic scan of same patient shows increased uptake in middle phalanx of
second finger as well as radius. C, Sclerotic lesion involving distal radial metaphysis (same patient as in A and B). D, Chronic inflam-
matory cell infiltrate with fibrosis corresponding to late phase of disease. (D, ×200) (D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1428 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

D
FIGURE 23-68  ■  Chronic recurrent multifocal osteomyelitis: radiographic and microscopic features. A, Multifocal lytic and sclerotic
lesion involving both clavicles and third right rib. B, Radioisotopic bone scan of same patient as shown in A shows multifocal
increased uptake in right third rib and both clavicles. C, Diffuse lytic and sclerotic process with bone expansion involving left
clavicle (same patient as in A and B). D, Chronic inflammatory infiltrate with predominance of lymphocytes and associated fibrosis.
(D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1429

C
FIGURE 23-69  ■  Tumoral amyloidosis: radiographic features. A, Lytic lesion involving proximal humerus. Note well-demarcated scle-
rotic margins and incomplete trabeculation. No other underlying condition was identified. B, T2-weighted magnetic resonance image
shows high signal intensity in central (cystic) portion of lesion. Note peripheral rim of signal void (same lesion as in A). Lesion
represents cyst with extensive deposits of amyloid in its wall. C, Pathologic fracture through tumor amyloidosis involving distal
femoral end in patient with plasma cell dyscrasia and associated disseminated amyloidosis.

ERRNVPHGLFRVRUJ
1430 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone

A B

C D
FIGURE 23-70  ■  Tumoral amyloidosis of bone: microscopic features. A, Extensive deposit of eosinophilic masses. B, Crystal violet
stain of amyloid deposit. C, Congo red stain of amyloid deposit. D, Apple-green birefringence of amyloid stained with Congo red
and examined under polarized light (A-D, ×50) (A, hematoxylin-eosin; B, crystal violet; C and D, Congo red)

ERRNVPHGLFRVRUJ
 23  Reactive and Metabolic Conditions Simulating Neoplasms of Bone 1431
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256. Probst FP: Chronic multifocal cleido-metaphyseal osteomy-
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257. Probst FP, Bjorksten B, Gustavson KH: Radiological aspects of
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258. Ravelli A, Marseglia GL, Viola S, et al: Chronic recurrent multi-
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259. Segev E, Hayek S, Lokiec F, et al: Primary chronic sclerosing
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multifocal osteomyelitis (CRMO) and synovitis, acne, pustulosis,
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268. Dickman CA, Sonntag VK, Johnson P, et al: Amyloidoma of the
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Precancerous Conditions
CHAPTER OUTLINE
PAGET’S DISEASE OF BONE
OSTEOMYELITIS
BONE INFARCTS
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 trans-
formation 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 malig-
nant tumors of bone generally reach substantial dimen-
sions 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 diag-
nostic 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 cat-
egory. 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
ERRNVPHGLFRVRUJ
C H A P T E R 2 4 
OSTEOGENESIS IMPERFECTA
SYNDROMES PREDISPOSING TO MALIGNANCY
IN BONE
Rothmund-Thomson Syndrome
Li-Fraumeni Syndrome
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, rep-
resents a prototype skeletal disorder that predisposes to
the development of sarcoma in bone.12,13 A comprehen-
sive 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 oste-
itis deformans that are relevant for its recognition when
it is associated with sarcoma of bone. From the pathoge-
netic point of view, the disease can be explained by
increased transient but progressive and multifocal osteo-
clastic 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 infec-
tion.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 transforma-
tion. 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 dem-
onstrate the presence of a paramyxoviral genome in
1437
1438 24  Precancerous Conditions
TABLE 24-1 Neoplastic and Nonneoplastic
Precursors of Malignancy in Bone
Nonneoplastic
Conditions Benign Tumors
Paget’s disease* Osteochondroma
(see Chapter 6)
Chronic osteomyelitis* Enchondroma (see Chapter 6)
Bone infarct* Ollier’s disease and Maffucci’s
syndrome (see Chapter 6)
Metallic implants* Chondromyxoid fibroma
(see Chapter 6)
Radiation, osteitis* Giant cell tumor
(see Chapter 10)
Osteogenesis Metaphyseal fibrous defect
imperfecta* (see Chapter 8)
Fibrous dysplasia Osteoblastoma (see Chapter 4)
(see Chapter 8)
Bone cysts Osteofibrous dysplasia and
(see Chapter 15) adamantinoma of long bones
(see Chapters 8 and 17)
Synoval chondromatosis
(see Chapter 20)
*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 etiol-
ogy 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) encod-
ing the p62 protein.5 All mutations involving p62 identi-
fied 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 osteo-
clastic cells but are insufficient to induce full pagetic
phenotype, and additional genetic as well as environmen-
tal factors are needed for full expression of the pagetic
phenotype. The scaffold p62 protein has specific interac-
tions 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, neuro-
degenerative disorders in which there is previously unrec-
ognized coexistence with Paget’s disease of bone.16 The
mutations in these disorders can overlap with those iden-
tified in Paget’s disease, but some of them appear to be
specific for the neurodegenerative disease. These find-
ings 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 (promyelo-
cytic leukemia [PML] and golgin A6 family, member
ERRNVPHGLFRVRUJ
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 trans-
mission 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 deformi-
ties 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 involve-
ment 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,
 SQSTM1
Chr 5

Exon 1

Exon 2

Exon 3
Exon 4
Exon 5
Exon 6

Exon 7
Exon 8

Exon 9
15.3

cds
15.2
15.1
14
13.3
13.1 13.2
12
11 11.1
11.2

P392L
12
13.1
13.3 13.2 SQSTM1
14
15
21 1 440 aa
22
23.1
3 PB1 102 122 ZZ 167 LIR KIR 387 UBA 436
23.2
23.3 B
31.1
31.2
31.3
33.1 32
33.3 33.2
34
35.1 35.2
35.3 SQSTM1
A

PB1 Phox/Bem1p domain

ZZ Zinc finger type domain
LIR LC3-interacting region
KIR Keap1-interacting region
UBA Ubiquitin associated domain

Synonymous substitution
Missense substitution
Substitution - coding silent
Deletion frameshift

p65 NF-κB
Activation & IL-6 gene expression

NF-κB activation
1,25-(OH)2D3 signaling
D 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.)
ERRNVPHGLFRVRUJ
1440 24  Precancerous Conditions

28

Peak age 31
incidence
of Paget's
sarcoma
11
1

76
Incidence

14
Peak age 31
incidence
of Paget's
disease

1 2 3 4 5 6 7 8
Age in decades 14

FIGURE 24-2  ■  Paget’s disease and sarcomatoid transformation. Skeletal sites most frequently involved by Paget’s disease are indi-
cated 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.
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 promi-
nent bony deformities (Fig. 24-4). In the long bones, the
disease typically starts within the end portion and pro-
gresses toward the shaft (Fig. 24-5). When the disease is
confined to the epiphyses of long bones, it can be con-
fused 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 osteo-
porosis circumscripta (Figs. 24-6 and 24-8). Characteristi-
cally, 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.
Bowing deformities and pathologic fractures are typically
seen in weight-bearing sites.
Microscopic Findings
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 for-
mation 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 irregu-
lar 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,
Text continued on p. 1450

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 24  Precancerous Conditions 1441

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

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1442 24  Precancerous Conditions

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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 24  Precancerous Conditions 1443

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.

ERRNVPHGLFRVRUJ
1444 24  Precancerous Conditions

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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 24  Precancerous Conditions 1445

A B

C D
FIGURE 24-7  ■  Paget’s disease of long bones: radiographic features. A, Early localized phase of Paget’s disease of radius with patho-
logic 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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1446 24  Precancerous Conditions

A B

C D
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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 24  Precancerous Conditions 1447

A B

C D
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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1448 24  Precancerous Conditions

A B

C D
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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 24  Precancerous Conditions 1449

A B

C D
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 corticomedul-
lary 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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1450 24  Precancerous Conditions
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 com-
plicating 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 local-
ized 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 distri-
bution 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). Typi-
cally 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 fibro-
sarcoma, 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 dis-
crepancy.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 com-
plete 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
ERRNVPHGLFRVRUJ
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 fre-
quently, squamous cell carcinoma develops in the epithe-
lialized lining of the bone defect.24
Atypical pseudoepitheliomatous hyperplasia heralds
the transformation into squamous cell carcinoma. Some-
times it is difficult to separate the two conditions in the
limited, small, and superficial biopsy material. Differen-
tial diagnosis between florid pseudoepitheliomatous pro-
liferation 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 fol-
lowed by evaluation of large tissue sections from postop-
erative 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 osteo-
myelitis, 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 assess-
ment of the affected tissues. The histologic features of
malignancy include cellular atypia, abnormal mitosis,
Text continued on p. 1462
 24  Precancerous Conditions 1451

A B

C D
FIGURE 24-12  ■  Paget’s sarcoma: gross features. A, Destructive tumor mass of proximal humerus with pathologic fracture. B, Tan-
white 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.

ERRNVPHGLFRVRUJ
1452 24  Precancerous Conditions

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.

ERRNVPHGLFRVRUJ
 24  Precancerous Conditions 1453

B C

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 min-
eralized mass at its proximal end. D, Microscopically the tumor is high-grade osteosarcoma (D, ×200) (D, hematoxylin-eosin).

ERRNVPHGLFRVRUJ
1454 24  Precancerous Conditions

B C

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 mineraliza-
tion juxtaposed on the preexisting host bone. C, Higher magnification showing atypical osteoblastic cells and tumor osteoid deposi-
tion. (A, ×50; B, ×100; C, ×400) (A-C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 24  Precancerous Conditions 1455

A B

C D
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, Photo-
micrographs 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.)

ERRNVPHGLFRVRUJ
1456 24  Precancerous Conditions

A B

C D
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, Photomi-
crograph of tumor shown in C reveals grade 2 myxoid chondrosarcoma. (D, ×400) (D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
 24  Precancerous Conditions 1457

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.

ERRNVPHGLFRVRUJ
1458 24  Precancerous Conditions

A B

C D
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)

ERRNVPHGLFRVRUJ
 24  Precancerous Conditions 1459

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.

ERRNVPHGLFRVRUJ
1460 24  Precancerous Conditions

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 squa-
mous 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.)

ERRNVPHGLFRVRUJ
 24  Precancerous Conditions 1461

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 inter-
connecting 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.)

ERRNVPHGLFRVRUJ
1462 24  Precancerous Conditions
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 car-
cinoma 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 sec-
tions. 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 squa-
mous 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, rhab-
domyosarcoma, and lymphoma.22,24-26 Because the sarco-
mas 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 typi-
cally 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 dialy-
sis; exposure to compressed air, such as occurs in caisson
workers and divers; Legg-Calvé-Perthes disease; hemo-
globinopathies, 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 infarct-
related 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 previ-
ous 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 chemo-
therapy.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
ERRNVPHGLFRVRUJ
in the fourth and fifth decades of life (5 cases each), fol-
lowed 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 tender-
ness, 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 clini-
cal 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 metaph-
ysis with focal areas of calcification at the periphery,
which correspond to bone infarct.
Text continued on p. 1469
 24  Precancerous Conditions 1463

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.)

ERRNVPHGLFRVRUJ
1464 24  Precancerous Conditions

6 1
Males 13

Females 9
5
TOTAL 22

4
Incidence

2
3
1

2 6

7
1

0
3
1 2 3 4 5 6 7 8 9
Age in decades
FIGURE 24-24  ■  Sarcomas associated with bone infarcts. Age-specific and skeletal distribution patterns of 22 sarcomas associated
with bone infarcts.

ERRNVPHGLFRVRUJ
 24  Precancerous Conditions 1465

A B

D
C

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.)

ERRNVPHGLFRVRUJ
1466 24  Precancerous Conditions

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.)

ERRNVPHGLFRVRUJ
 24  Precancerous Conditions 1467

A B

C D

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, Microscopi-
cally, tumor represents malignant fibrous histiocytoma (D, ×100) (D, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ
1468 24  Precancerous Conditions

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 associ-
ated with high-grade sarcomatoid neoplasm. C, Microsocopically, tumor represents malignant fibrous histiocytoma. (B, ×25; C, ×100)
(B and C, hematoxylin-eosin.)

ERRNVPHGLFRVRUJ

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 med-
ullary tissue and often erode or destroy the cortex while
infiltrating into the adjoining muscle and fascia. Hemor-
rhage and necrosis are usually obvious.
Microscopic Findings
Histologic examination of the bone infarcts shows irregu-
lar 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 histio-
cytes in Gaucher’s disease (Fig. 24-30) or sickled eryth-
rocytes in patients with sickle cell disease.
The peripheral areas of bone infarction in the transi-
tion zone adjacent to frank sarcoma contain focal resorp-
tion 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 inter-
lacing spindle-cell fascicles. The fascicles of these cells
are sometimes arranged in a storiform pattern with des-
moplastic collagen. Farther from the infarct, atypical
spindle cells merge into a high-grade, spindle-cell sarco-
matous component.
Infarct-associated sarcomas show the typical micro-
scopic features of malignant fibrous histiocytoma,
low-grade osteosarcoma, and conventional high-grade
osteosarcoma.18,36,39,40,44 Low-grade osteosarcomas associ-
ated with bone infarcts are mostly composed of interlac-
ing 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
ERRNVPHGLFRVRUJ
24  Precancerous Conditions 1469
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 attrib-
uted to the fact that many conditions that predispose to
bone infarction are predominantly related to male-
oriented 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 calci-
fied matrix in enchondroma are discrete and scattered
diffusely throughout the lesion and have punctate to pop-
cornlike 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 adja-
cent 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 repara-
tive 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 revas-
cularization and increased accumulation of the radioiso-
tope.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 malig-
nant fibrous histiocytoma as the tumor most commonly
1470 24  Precancerous Conditions

A B

C D
FIGURE 24-29  ■  Sarcoma associated with bone infarct: microscopic features. A and B, Periphery of infarct shows regenerative granu-
lation 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.)

ERRNVPHGLFRVRUJ
 24  Precancerous Conditions 1471

B
FIGURE 24-30  ■  Malignant fibrous histiocytoma associated with Gaucher’s disease: radiographic and microscopic features. A, Low-
power 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.)

ERRNVPHGLFRVRUJ
1472 24  Precancerous Conditions
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., fibro-
blasts, osteoblasts, and endothelial cells). Thus it seems
clear that a close pathogenetic relationship exists between
bone infarcts and the associated sarcomas. The repara-
tive, predominantly fibroblastic tissue, which has a rela-
tively 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 asso-
ciation 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-and-
effect 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 environ-
ment and the implanted metal sets the background for
potential production of corrosive products. The rate of
corrosion varies according to particle size; metal solubil-
ity; 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 pleomor-
phic 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 osteo-
sarcoma, chondrosarcoma, and malignant fibrous histio-
cytoma. 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
ERRNVPHGLFRVRUJ
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 devel-
oped in patients treated with radiotherapy with other
modalities for previous malignancies and in patients who
had genetic predispositions, the latency period was short-
ened by the use of adjuvant chemotherapy.68 Typically
postradiation sarcoma develops 5 to 10 years after expo-
sure (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 techni-
cians. 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 develop-
ment 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 auto-
somal 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 paradoxi-
cal 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
 24  Precancerous Conditions 1473

A B

C D
FIGURE 24-31  ■  Sarcoma of bone associated with metallic implant. A, Radiograph of resection specimen shows femoral head pros-
thesis 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.)

ERRNVPHGLFRVRUJ
1474 24  Precancerous Conditions
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 syn-
dromes 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 surveil-
lance, 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 retinoblastoma-
associated 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
ERRNVPHGLFRVRUJ
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 sus-
pected when (1) clusters of cancer occur in one family,
regardless of whether the tumors are the same or differ-
ent 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
This extremely rare syndrome is an autosomal recessive
disorder that consists of skin lesions (atrophy, hyper-
pigmentation, subepidermal fibrosis, and telangiecta-
sias referred to as poikiloderma), cataracts, and skeletal
abnormalities such as dysostoses and dysplasias that
result in abnormally shaped bones (Figs. 24-35 and 24-
36).91,92,107,112,116,119,120 Abnormal developmental anoma-
lies 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 Rothmund-
Thomson syndrome (Fig. 24-37).85,93,105,109,121 In contrast,
mutations of RECQL4 are infrequent in sporadic osteo-
sarcoma.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 sarco-
mas. The members of these families were less frequently
Text continued on p. 1480
 24  Precancerous Conditions 1475

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, pro-
truding 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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1476 24  Precancerous Conditions

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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 24  Precancerous Conditions 1477

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 19p13 Spondyloenchondrodysplasia AR Enchondromas
ACVR1 2q24 Fibrodysplasia ossificans Sporadic/AD Progressive heterotopic ossification
progressiva (myositis ossificans progressiva),
proximal tibial osteochondromas
ANTXR2 4q21 Fibromatosis, juvenile hyaline AR Fibromatosis
APC 5q21 Desmoid disease, hereditary AD Desmoid tumors
Familial adenomatous polyposis 1 AD Craniofacial osteomas, desmoid tumors,
(Gardner’s syndrome included) Gardner fibromas
BRAF 7q34 Cardiofaciocutaneous syndrome AD Giant cell lesions of small bones (central)
BUB1B 15q15 Mosaic variegated aneuploidy AR Embryonal rhabdomyosarcomas
syndrome 1
TP53 17p13 Li-Fraumeni syndrome 1 AD Osteosarcomas, rhabdomyosarcomas,
and other soft tissue sarcomas
CHEK2 22q12 Li-Fraumeni syndrome 2 AD Osteosarcomas, rhabdomyosarcomas,
and other soft tissue sarcomas
EXT1 8q24 Multiple osteochondromas AD Osteochondromas, secondary peripheral
chondrosarcomas
Trichorhinophalangeal syndrome Sporadic Osteochondromas, secondary peripheral
type 2 chondrosarcomas
EXT2 11p11 Multiple osteochondromas AD Osteochondromas, secondary peripheral
chondrosarcomas
Potocki-Shaffer syndrome Sporadic Osteochondromas, secondary peripheral
chondrosarcomas
GLMN 1p22 Glomovenous malformations AD Glomus tumors
GNAS 20q13 Pseudohypoparathyroidism, type 1A AD Cutaneous osteomas
McCune-Albright syndrome, incl. Sporadic Polyostotic fibrous dysplasia,
Mazabraud syndrome osteosarcomas (Mazabraud syndrome:
intramuscular myxomas)
Osseous heteroplasia, progressive AD Cutaneous osteomas
Pseudopseudohypoparathyroidism AD Cutaneous osteomas
IDH1 2q34 Enchondromatosis Sporadic Enchondromas, chondrosarcomas
IDH2 15q26 (Ollier’s disease and Maffucci’s (Maffucci’s syndrome: hemangiomas,
PTH1R 3p21 syndrome) angiosarcomas)
LEMD3 12q14 Buschke-Ollendorff (osteopoikilosis AD Enostoses
isolated incl.)
MID1 Xp22 Opitz GBBB syndrome, X-linked XR Cranial osteomas
PORCN Xp11 Focal dermal hypoplasia XD Giant cell tumors of bone
PRKAR1A 17q24 Carney complex, type 1 AD Osteochondromyxomas, cardiac and
other myxomas, melanocytic
schwannomas
PTPN11 12q24 LEOPARD syndrome 1 AD Granular cell tumors
Metachondromatosis AD Enchondromas, osteochondroma-like
lesions
Noonan syndrome 1 AD Granular cell tumors, giant cell lesions of
small bones (central)
RB1 13q14 Retinoblastoma AD Osteosarcomas, soft tissue sarcomas
RECQL4 8q24 Baller-Gerold syndrome AR Osteosarcomas
RAPADILINO syndrome AR Osteosarcomas
Rothmund-Thomson syndrome AR Osteosarcomas
WRN 8p12 Werner syndrome AR Bone and soft tissue sarcomas
BLM 15q26 Bloom syndrome AR Osteosarcomas
SH3BP2 4p16 Cherubism AD Giant cell lesions
T 6q27 Chordoma, familial AD Chordomas
TNFRSF11A 18q22 Paget’s disease of bone AD Osteosarcomas
Polyostotic osteolytic dysplasia, AD Osteosarcomas
hereditary expansile

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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1478 24  Precancerous Conditions

A D

B 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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 24  Precancerous Conditions 1479

A B 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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1480 24  Precancerous Conditions

Chr 8 RECQL4
23.3 23.2
23.1

Exon 10
Exon 11

Exon 12

Exon 13

Exon 14

Exon 15

Exon 16
Exon 17
Exon 18

Exon 19

Exon 20

Exon 21
Exon 1
Exon 2
Exon 3

Exon 4

Exon 5

Exon 6

Exon 7
Exon 8
Exon 9
22
21.3 21.2

cds
21.1
12
11.2 11.1
11.1
11.22 11.21
12 11.23 Helicase region Splicing mutation
13 Intronic deletion
21.1
21.2
21.3 RECQL4

5
22.1
22.2
22.3
23 1 1208 aa
24.1
24.2 24.3 Zinc finger CCHC-type domain Missense substitution
RECQL4 P-loop containing nucleoside triphosphate hydrolase domains Frameshift mutation
Helicase superfamily 1/2 ATP-binding domain Nonsense mutation
A Helicase C-terminal domain
B

N-End Rule Base Excision

Pathway Repair

UBR1/2 PARP1

RECQL4

Rad51 Cut5

RECQL4-interacting Partners

Repair of DNA
DSBs 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 chromo-
some 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 malig-
nant 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 condi-
tion 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 fami-
lies. 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 develop-
ment of sarcoma in the absence of TP53 mutations is
uncertain at the time of this writing.83,86,108,111,115
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