Survival Guide To Soft Tissue Pathology: Series 1

PATHOLOGY SURVIVAL GUIDES
2 Series 1
Survival Guide to
Soft Tissue Pathology
Elizabeth A. Montgomery, MD
Alisha D. Ware, MD
Jerad M. Gardner, MD
~
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Innovative
Pathology
Pr@SS
Survival Guide to
Pathology Survival Guides
I. Innovative
{) Pathology
...l:. Press
EDITOR
Professor of Pathology, Oncology, and Orthopedic Su rgery
The Johns Hopkins Medical Institutions
Baltimore, Maryland
ASSOCIATE EDITOR
Dennis O'Malley, MD
Neogenomics, Aliso Viejo, California
Adjunct Associate Professor, MD Anderson Cancer Cente r, University of Texas
EDITORIAL BOARD
Jerad M. Gardner, MD
Associate Professor of Pathology and Dermatology
Dermatopathology, Bone and Soft Tissue Pathol ogy
Program Director, Dermatopathology Fellowship
University of Arkansas for Medical Sciences
Little Rock, Arkansas
Kiyoko Oshima, MD, Dr. Se.

Director of Clinical Hepatic Pathology
Assistant Professor of Pathology
Baltimore, Maryland
Lisa M . Rooper, MD
Baltimore, Maryland
Lysandra Voltaggio, MD
Director, Gastrointestinal Pathology Fellowship
Baltimore, Maryland
Available from the Innovative Pathology Press

www.innovativepathologypress.com
ISBN 1-933477-51-2
978-1-933477-51-0
Copyright © 2019 The Innovative Pathology Press
Printed in South Korea

First Series
Volu me 2
Survival Guide
to Soft Tissue Pathology
by
Professor of Pathology, Oncology, and Orthopedic Surgery
Baltimore, Maryland
Alisha D. Ware , MD
Department of Pathology
The Johns Hopkins University School of Medicine
Baltimo re, M aryland
Jerad M . Gardner, MD
Associate Professor of Pathology and Dermatology
Dermatopathology, Bone and Soft Tissue Pathology
Program Director, Dermatopathology Fellowship
University of Arkan sas for Medical Sciences
Little Rock, Arkansas
Published by t he
Innovative Patho logy Press
2019
i. Innovative
{)Pathology
..L. Press
Preface
Although there are many excellent sources for learning diagnostic pathology, those directed at
medical students are too simplified to be practical for daily work with diagnostic pathology, and many
other texts assume a foundation of more knowledge than many of us have as we begin to learn about a
new area of diagnostic pathology. This series is intended to help residents and colleagues w ho begin to
tackle an organ system that is unfamiliar to them . Further, in the interest of making the volumes
affordable to trainees and those beginning, we have chosen a soft cover format to contain costs but not
at the expense of the high-quality images, which will enhance the availability of the books to those who
will benefit most from them.
The second volume in our series, Survival Guide to Soft Tissue Pathology, like our initial volume
Survival Guide to Gl Mucosal Biopsies, is focu sed on mastering basic skills and concepts to tackle some of
the most difficult lesions encountered in diagnostic surgical pathology. This book is short, concise, rich in
high-quality images, and intended to offer a foundation or a refresher course in soft t issue lesions. We
have taken a novel approach, dividing the book into a brief introductory section that points out some
basic principles of reviewing mesenchymal lesions; then we delve into tumors that can be diagnosed on
routine hematoxylin and eosin only- in fact, the majority of soft tissue lesions- together with some for
which ancillary studies are helpful. We end with a discussion of lesions for which performing ancillary
studies can be important.
This book encourages taking diagnoses as far as possible by honing our foundational
morphology skills. lt will be a practical addition to the libraries of both trainees and practicing
pathologists.
Upcoming volumes will cover breast, liver, prostate, head and neck, frozen sections, skin,
pancreas, bone, soft tissue pathology, hematopathology, and cytopathology, and feature a host of
authors who are superb educators. On behalf of ourselves and the rest of the Editorial Board, we are
confident that many colleagues and residents will find the series usefu l and enjoyable to read.
Alisha D. Ware, MD
Jerad M. Ga rdner, MD
Acknowledgments and dedication
We acknowledge the team at Innovative Pathology Press and the Editorial Board members for
their expertise and advice.
We dedicate this volume to the residents, fellows, and colleagues who love diagnostic
pathology.
CONTENTS
1. Getting Started in Soft Tissue Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

2. Soft Tissue Lesions that Can be Diagnosed on Routine Hematoxylin and Eosin Staining . . 11
Adipose Tissue Neoplasms and a Few Mimics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Lipoblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Angiolipoma......... . ... . .. ......................................... 14
Spindle Cell and Pleomorphic Lipomas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Atypical Lipomatous Tumor/ Well-Differentiated Liposarcoma. . . . . . . . . . . . . . . . . . 16
Dedifferentiated Liposarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Pleomorphic Liposarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
Mixoid Liposarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Fibroblastic/Myofibroblastic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Nodular Fasciitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Proliferative Fasciitis and Myositis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Myositis Ossificans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Ischemic Fasciitis (Atypical Decubital Fibroplasia) . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Fibroma of Tendon Sheath. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Elastofibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Desmoplastic Fibroblastoma (Collagenous Fibroma) . . . . . . . . . . . . . . . . . . . . . . . . . 42
Calcifying Aponeurotic Fibroma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Inclusion Body Fibromatosis (Infantile Digital Fibromatosis). . . . . . . . . . . . . . . . . . . 45
Palmar and Plantar Fibromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Desmoid Type Fibromatosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Fibrous Hamartoma of Infancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Inflammatory Myofibroblastic Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Lipofibromatosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Fibrohistiocytic Tumors and Some Histiocytic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Tenosynovial Giant Cell Tumor, Localized and Diffuse Types . . . . . . . . . . . . . . . . . . 58
Dermatofibroma and Fibrous Histiocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Plexiform Fibrohistiocytic Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Dermatofibrosarcoma Protuberans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Giant Cell Fibroblastoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Rosai-Dorfman Disease, Langerhans Cell Histiocytosis, and Erdheim-Chester Disease . . 71

Smooth Muscle and Smooth Muscle-Related Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Leiomyoma and Leiomysarcoma ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Important Pitfalls Concerning Smooth Muscle Turners . . . . . . . . . . . . . . . . . . . . . . . 78
'Glomus Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Myofibroma/Myopericytoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Skeletal Muscle Turners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Embryonal Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Alveolar Rhabdomyosarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Gastrointestinal Stromal Tumor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Vascular Turners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
General Points Concerning Vascular Turners . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Capi llary Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Pyogenic Granuloma/Lobu lar Capillary Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . 89
Cavernous Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Anastomosing Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Epithelioid Hemangioma (Angiolymphoid Hyperplasia with Eosinophilia) . . . . . . . 91
Angiomatosis and Intramuscular Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Kaposi Sarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Epithelioid Hemangioendothelioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Neural-Related Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Schwannoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Neurofibroma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Granular Cell Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Malignant Peripheral Nerve Sheath Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Myxoid Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Cutaneous Myxoma (Superficial Angiomyxoma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Intramuscular Myxoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Myxoinflammatory Fibroblastic Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
Myxofibrosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Low-Grade Fibromyxoid Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Sclerosing Epithelioid Fibrosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Lesions with Unclear Differentiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
ii
Contents
Solitary Fibrous Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

Angiomatoid Fibrous Histiocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Ossifying Fibromyxoid Tumor........................ .. .. .......... . . . . . 121
Synovial Sarcoma.............................. . ...... .. . ...... ..... . . 124
Epithelioid Sarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Alveolar Soft Part Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Clear Cell Sarcoma............. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Extraskeletal Myxoid Chondrosarcoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Desmoplastic Small Round Cell Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
3. Soft Tissue Lesions for Which Ancillary Techniques are Important . . . . . . . . . . . . . . . . 147
Extrarenal Rhabdoid Tumor. .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Ewing Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ISO
Some Rhabdomyosarcomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Round Cell Sarcoma with Special Gene Fusions of All Sites . . . . . . . . . . . . . . . . . . . . . . 156
Some Hemangioendotheliomas................. ........ ................ . . . 157
Pleomorphic Bad Malignant Spindle Cell Neoplasms. . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Index ....... ....... .... . . .... ..... .... . . . ...... . ....... .......... . . . . . 165
iii
GETTING STARTED IN
SOFT TISSUE PATHOLOGY
This book is divided into this general section shows a pleomorphic malignant spindle cell
and two other sections that include: 1) lesions neoplasm for which the pathologist has con-
that can be diagnosed on routine hematoxylin sidered sarcomatoid carcinoma and melanoma,
and eosin (H&E)-stained slides and lesions for it makes sense to begin with an S-100 protein
which ancillary testing is needed, at least some and a pankeratin stain, order a few unstained
of the time; and 2) lesions for which ancillary sections, and wait for the results before ordering
testing is a key component (Tables 1-1-1-3). markers to address specific types of sarcomatoid
Fortunately, most soft tissue lesions fall into carcinomas. If the lesion is strongly reactive
the first category, but diagnosing many of them with S-100 protein, there is plenty of material
requires knowledge and practice, and takes time. left to either augment the interpretation (such
Our intent is to point out basic morphologic as with SOX10 and "melanoma markers") or to
features that led our patriarchs and matriarchs order studies to guide targeted therapy.
to describe these entities in the first place, even There is one important immunostain that
if, over time, ancillary techniques have expand- should NEVER be ordered when evaluating soft
ed the definitions of certain neoplasms. For tissue tumors and that is vimentin. Years ago,
those practicing in settings with fewer resources, there was an impression that vimentin staining
we hope to encourage confidence in using the was useful as a control of tissue integrity, but that
original techniques, and for those in practice assertion is no longer relevant with modern im-
settings with abundant resources, we hope to munohistochemistry. Vimentin immunolabeling
help refine their use. never provides information and wastes tissue and
If ancillary studies are used, it is important not time. Ordering vimentin is especially pointless for
to simply use a nondirected immunolabeling or needle biopsy samples since no tissue should be
molecular panel when confronting spindle cell waisted for noninformative testing. Do not order
lesions. Most soft tissue lesions are diagnosed with vimentin on an open biopsy or even think of
an H&E stain, or at least a differential diagnosis ordering vimentin on a needle biopsy. No soft
made that can be resolved with focused ancillary tissue pathologist ever does so; it is not useful.
studies. The key is that any panel of ancillary stud- When embarking on mastering the assessment
ies should be focused to answer a specific question of mesenchymal lesions, there are some practical
because different neoplasms can have overlapping ways to hone one's diagnostic "eye." These involve
immunolabeling characteristics and overlapping paying close attention to the size and chromatin
or identical gene alterations. pattern of endothelial cells in samples, studying
Ancillary tests should be chosen carefully, granulation tissue, and studying fat necrosis. These
especially for needle biopsies, for which it is simple helpful features are discussed with individ-
terrible to waste the limited tissue on a set of ual lesions in the coming sections.
studies that is unlikely to yield useful informa- Endothelial cell nuclei are nearly always present
tion. It is also wise to perform special studies in all types of samples and they are the "control
in steps rather than in a "shotgun" fashion. cell." Endothelial cell nuclei are usually paler than
Soft tissue needle biopsies are psychosocial those of malignant neoplasms and sometimes larg-
emergencies, but not medical emergencies. er than those of benign processes. Endothelial cells
Most surgeons and medical oncologists would and the vessels that they line are a real diagnostic
rather not subject the patient to another biop- clue in certain lesions (figs. 1-1, 1-2).
sy and would prefer to wait a few more days. Myxoid changes may also be seen in non-
For example, if a limited needle biopsy sample neoplastic connective tissue (fig. 1-3). Whether
1
Table 1-1
LESIONS THAT CAN BE DIAGNOSED WITH HEMATOXYLIN AND EOS IN (H&E) STAINING ALONE"
Lipoma Many leiomyosarcomas

Lipomatosis Glomus tumor
Lipomatosis of nerve (fibrolipomatous hamartoma of nerve) Myopericytoma/ myofibroma
Lipoblastoma Rhabdomyoma
Angiolipoma Some embryonal rhabdomyosarcomas
Myolipoma Some alveolar rhabdomyosarcomas
Spindle cell lipoma Hemangiomas
Pleomorphic lipoma Epithelioid hemangio ma
Atypical lipomatous tumor Angiomatosis
Massive localized lymphedema in the morbidly obese Lymphangioma
Some dedifferentiated liposarcomas Kaposiform hemangioendothelioma
Myxoid liposarcoma Retiform h emangioendothelioma
Pleomorphic liposarcoma Papillary intralymphatic angioendothelioma
Nodular fasciitis Composite hemangioendothelioma
Proliferative fasciitis Many Kaposi sarcomas
Myositis ossificans Some epithelioid hemangioendotheliomas
Ischemic fasciitis Some angiosarcomas
Fibromatosis colli Chondroma
Juvenile hyaline fibromatosis Extraskeletal osteosarcoma
Inclusion body fibrom atosis (in fantile digital fibromatosis) Some gastroin testinal stromal tumors
Fibroma of tendon sheath Schwannoma
Desmoplastic fibroblastoma (collagenous fibroma) Neurofibroma
Calcifying aponeurotic fibroma Granular cell tumor
Angiomyofibrob lastoma Some malignant peripheral nerve sheath tumors
Cellular angiofibroma Malignant granular cell tumor
Nuchal type fibroma Benign tri ton tumors
Calcifying fibrous tumor Some ectomesenchymomas
Palmar and plantar fibromatosis Acral fibromyxoma
Desmoid type fibromatosis Intramuscular myxoma
Lipofibromatosis Juxta-articular myxoma
Giant cell fibroblastoma Aggressive angiomyxoma
Dermatofibrosarcoma protuberans Ectopic hamartomatous thymoma
Some solitary fibrous tumors Some angiomatoid fibrous histiocytomas
Low grade myofibroblastic sarcoma Ossifying fibromyxoid tumor
Myxoinflammatory fibroblastic sarcoma Some myoepithelial carcinoma/mixed tumor
Myxofibrosarcoma Hem osiderotic fibrolipomatous tumor
Low-grade fibromyxoid sarcoma Phosphaturic mesench ymal tumor
Tenosynovial giant cell tumor, localized type Some synovial sarcomas
Tenosynovial giant cell tumor, diffuse type Some epithelioid sarcomas
Deep fibrous histiocytoma Some alveolar soft part sarcomas
Plexiform fibroh istiocytic tumor Some clear cell sarcomas
Leiomyoma Extraskeletal myxoid chondrosarcoma
Some desmoplastic small round cell tumors Some PEComas
Some intimal sarcom as
•some diagnoses require practice.
2
Getting Started in Soft Tissue Pathology
Table 1-2
LESIONS FOR WHICH ANCillARY STUDIES CAN BE IMPORTANT
TO ESTABLISH THE DIAGNOSIS OR DIRECT TREATMENT
Inflammatory myofibroblastic tumor Hybrid benign nerve sheath tumors

Some desmoid fibromatoses (small needle biopsies) Nerve sheath myxomas
Some examples of dermatofibrosarcoma protuberans (needle biopsies) Some malignant peripheral nerve sheath tumors
Some low grade fibromyxoid sarcomas (needle biopsies) Pleomorphic hyalinizing angiectatic tumor
Sclerosing epithelioid fibrosarcoma Atypical fibroxanthoma
Some leiomyosarcomas Some angiomatoid fibrous histiocytomas
Gastrointestinal stromal tumors Some ossifying fibromyxoid tumors
Embryonal rhabdomyosarcoma Myoepitheliomas/myoepithelial carcinomas
Some alveolar rhabdomyosarcomas Some synovial sarcomas
Some pleomorphic rhabdomyosarcomas Some solitary fibrous tumors
Sclerosing rhabdomyosarcomas Some epithelioid sarcomas
Some Kaposi sarcomas Some alveolar soft part sarcomas
Pseudomyogenic hemangioendothelioma Some clear cell sarcomas
Some epithelioid hemangioendotheliomas Desmoplastic small round cell tumor
Some PEComas Intimal sarcomas
myxoid change relates to the interstitium that Table 1-3

has been highlighted as a massive organ ex- LESIONS FOR WHICH ANCILlARY STUDIES CAN
tending throughout the body (1) or not, when BE ESSENTIAL TO ESTABLISH THE DIAGNOSIS
myxoid change is present, mast cells become Extrarenal rhabdoid tumor
easy to spot (fig. 1-4); this does not necessarily
Ewing sarcoma
mean that there is a neoplasm.
A good way to become comfortable and famil- Some alveolar rhabdomyosarcoma
iar with pseudosarcomas and not mistake them Some embryonal rhabdomyosarcomas
for sarcomas is to study the granulation tissue in Round cell sarcomas with special gene fusions of all sites
cases in which it is expected and in which there Poorly differentiated synovial sarcoma
is clearly tissue that is healing, such as bowel Some angiosarcomas
perforation specimens or re-excision specimens
Some hemangioendotheliomas
after breast needle biopsies. The appearance of
the nuclei and nucleoli in these samples mirrors Sarcomatoid carcinomas
that of several pseudosarcomatous processes, Spindle cell melanomas
some benign fibroblastic and myofibroblastic High-grade pleomorphic sarcomas
neoplasms, and fibromatoses (figs. 1-S-1-10).
Like tumors in the rest of the body, many soft
tissue lesions are diagnosed at low magnifica- mens (figs. 1-11, 1-12). Note the appearances of
tion, and the impression is confirmed by study- the histiocytes and their variety of shapes. This
ing selected areas at high magnification. This is skill is of great value in separating the nuclei that
especially applicable to tumors showing mature characterize areas of microscopic fat necrosis in
adipose tissue differentiation. These are diag- lipomas from the atypical nuclei that character-
nosed at 4X, and the diagnosis is confirmed at ize atypical lipomatous tumors (well-differenti-
higher magnification of selected foci. To practice ated liposarcomas, figs . 1-13-1-19).
evaluating such tumors, it is important to study Comfort in interpreting a few basic patterns
fat necrosis in samples in which it is expected, of tissue repair help in the diagnosis of a host of
such as resected biopsy sites in mammary speci- frequently encountered mesenchymal lesions.
3
Figure 1-1 Figure 1-2

HEMANGIOMA EPITHELIOID HEMANGIOENDOTHELIOMA OF LIVER
The lesion is well marginated, which allows us to In th is image, a normal endothelial cell is pointed out
compare the endothelial cells in the adjacent normal tissue (arrow). It has a smooth nuclear membrane and delicate
(arrows) with those in the lesion at the bottom. Note that ch romatin. There are many malignant nuclei in the image
the cells in the lesion (many of which show endothelial and they appear to be embedded in the tissue but devoid
differentiation) have similar sizes and degrees of nuclear of cytoplasm. Th is allows visualization of their irregular
hyperchromasia. nuclear membranes. The normal endothelial cell contains
a plump nucleus but many of the malignant cells (with
endothelial differen tiation) have larger nuclei than the
normal endothelial cell.
Figure 1-3
MYXOID CHANGE IN
BENIGN SOFT TISSUE
This appearance is common,
especially in con nective tissue
adjoining masses, presumably a
result of localized edema.
4

MAST CELL IN MYXOID TISSUE GRANULATION TISSUE
Note the amphophilic cytoplasm and tiny nucleus with Even at low magnification, the nuclei of the endothelial
a smooth nuclear membrane. cells are more hyperchromatic than those of the proliferating
myofibroblasts.
:
~ '
...... -
'~-,...
~·
~
· ·~'i ·"{··: ~
·'"' , ~
Figure 1-6
• GRANULATION TISSUE
The cytoplasm of the m yo-
fibroblasts is neither basophilic
nor full y eosinophilic in the
manner of collagen. The am -
phoph il ic appearance o f the
cytoplasm is characteristic of
myofibroblasts.
5
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GRANULATION TISSUE COLLAGENOU S FIBROMA
The endoth elia l cells are darker th an those of the (DESMOPLASTIC FIBROBLASTOMA)
m yofibrobl asts although they are smaller in this field. This is a ben ign fib roblastic/myofibroblastic neoplasm .
Several of the myofibroblast nuclei contain perfectly round Note that even at low magnification, the cytoplasm of the
red nucleoli and their nuclear mem branes are smooth. lesional cells appears stellate. This differs from desmoid type
Wisps of amphophilic cytoplasm are present. fibromatosis in its paucicell ularity but the basic cytologic
characteristics are similar to those of the myofibroblasts in
granulation tissue: smooth nuclear membranes, and bright
round nucleolus in almost every cell.
Figure 1-9
COLLAGENOUS FIBROMA
(DESMOPLASTIC
FIBROBLASTOMA)
This is a very high magnifica-
tion i nte nd e d to show the
stellate amphophilic cytoplasm
of t he ce ll s. The n ucleoli are
subtle in th is image, but once
spotted, perfectly round. Note
the smooth nuclear membranes.
6
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t,

COLLAGENOUS FIBROMA FAT NECROSIS
(DESMOPLASTIC FIBROBLASTOMA) There is damaged adipose tissue at the center of th e
Note the nucleoli. Also, com pare the amphophilic cyto- image and some granulation tissue at the bottom righ t. A
plasm in t he lesion al cell to the fibrillary eosinophi lic few foamy macrophages can be seen at the interface between
collagen that the cells have finally produced. the granulation tissue and the damaged adipose tissue.
I'
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Figure 1-13
LIPOMA WITH FAT NECROSIS
At 4X original magnification, the lipoma nuclei are tiny
dots. In lipomas, there are often zones of individual cell fa t
necrosis rather than the large expanses that are often seen
in surgical resections of injured tissue. The histiocytes that
react to the damaged adipose tissue cells have slightly larger
nuclei than those in the lesion itself and can have foamy
Figure 1-12 or eosinophilic cytoplasm. Such cells can mimic enlarged
lesion al nuclei or even lipoblasts. However, at 4x, these
FAT NECROSIS cells are far less conspicuous than the n uclei in atypical
Note the prominent foamy macrophages. lipomatous tumor (well-differentiated liposarcoma).
7
• '

LIPOMA WITH FAT NECROSIS LIPOMA WITH FAT NECROSIS
The cell with intranuclear lipid invaginations is not This is a small pocket of histiocytes, each with pale
a lipoblast but a so-called lochkern. This is a fak e and a eosinophilic cytoplasm. These cells are no cause for concern
common type of cell in lipomas, other mature adipocytic in lipomas.
proliferations, and even in normal adipose tissue. Notice
that it has delicate chromatin and a smooth nuclear
membrane.

LIPOMA WITH FAT NECROSIS LIPOMA WITH FAT NECROSIS
This is a high-magnification image of the cell highlighted This is a high magnification of some of the histiocytes
in figure 1-14. The ce ll has a very smooth nuclear in an area of fat necrosis. This image shows the nuclear
membrane. In this field there is an endothelial cell nucleus characteristics to advantage: smooth nuclear membranes
just to the right of the lochkern. The endoth elial cell has and delicate round nucleoli.
a small nucleus but the nucleus has a similar chromatin
pattern to that of the lipoma n ucleus.
8
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ATYPICAL LIPOMATOUS TUMOR ATYPICAL LIPOMATOUS TUMOR
(WELL-DIFFERENTIATED LIPOSARCOMA) (WELL-DIFFERENTIATED LIPOSARCOMA)
This image was taken at the same magnification as figure This image was taken at the same magnification as
1-13. Compare the two. Note that several nuclei are readily figures 1-16 and 1-1 7. The diagnosis is straightforward.
apparent at 4X, which is the magnification at which this The heterochromatin in this cell is strikingly dense and the
diagnosis is made, with confirmation at higher magnification. nucleolus has an irregular shape.
REFERENCE
1. Benias PC, Wells RG, Sackey-Aboagye B, et al.

Structure and distribution of an unrecognized in-
terstitium in human tissues. Sci Rep 2018;8:4947.
9
L
SOFT TISSUE LESIONS THAT CAN
BE DIAGNOSED ON ROUTINE
HEMATOXYLIN AND EOSIN STAINING
Chapter 1 showed that studying findings in but have included many. Our companion vol-
everyday samples (endothelial cells, fat necrosis, ume (Survival Guide to Bone Pathology) will
myxoid areas, and granulation tissue) can hone complement this material.
diagnostic skills in soft tissue pathology. This
applies particularly to identifying pseudosarco- ADIPOSE TISSUE NEOPLASMS
matous lesions and lipomas. Nevertheless, there AND A FEW MIMICS
are some neoplasms for which these principles Adipose tissue lesions show differentiation
do not apply, and these exceptions are noted, along the lines of fat, but the sarcomas "lumped"
but for most soft tissue tumors, they do. in this category are different in most cases. They
This chapter discusses lesions that can be are recognized with H&E staining, although some
diagnosed with hematoxylin and eosin (H&E) ancillary studies are very reassuring. The key points
stains, but note some issues that apply if an- of the adipose tissue sarcomas, before we discuss
cillary techniques are used. Comments on the various types of lipomas, are the following:
entities that are generally diagnosed in concert 1) Atypical lipomatous tumor and well-differ-
with ancillary studies as part of the discussion entiated liposarcoma are the same thing.
of entities that are readily diagnosed on H&E. 2) Atypical lipomatous tumor/well-differ-
We have roughly followed the World Health entiated liposarcoma is the low grade form of
Organization (WHO) classification system (1), dedifferentiated liposarcoma and has the same
although we cannot include every entity that root genetic alterations. MDM2 gene amplifica-
is described therein. Further, since that clas- tion is characteristic of both. These tumors lack
sification was published in 2013, additional a characteristic translocation/fusion.
information has become available as a result 3) Dedifferentiated liposarcoma has many
of emerging techniques. There are entities that appearances and it is the most common sarcoma
are not strictly soft tissue tumors (and therefore in the retroperitoneum.
not in the WHO classification) that pose major 4) Myxoid liposarcoma is genetically distinct
diagnostic pitfalls and they are indicated in the from the other liposarcomas and is a translo-
key sections. cation sarcoma, so it has monotonous nuclei
It is not our intention to state that ancillary and no atypical mitoses. It lacks MDM2 ampli-
testing should not be performed if there is a good fication, but instead has gene rearrangements/
reason to add it (such as assessing PAX-FOXOl translocations of FUS-DDIT3 or EWSR1-DDIT3.
status to prognosticate in alveolar rhabdomyosar- 5) Round cell liposarcoma is an old term for
coma); our point is that most diagnoses are made the high-grade form of myxoid liposarcoma; the
by H&E morphology and are merely confirmed term was eliminated in the 2013 WHO classifi-
or augmented by special testing. After all, most cation. However, it is still widely used.
entities (other than newly recognized round cell 6) Pleomorphic liposarcoma is unrelated to
sarcomas) were established by H&E diagnosis the others. It has a complex karyotype but not
and follow-up. Our point is that the approach MDM2 amplification. Rarely, however, dediffer-
should not be through "shotgun" ancillary test- entiated liposarcoma can show an overlapping
ing but rather through curated testing directed pattern (perhaps we could refer to that as "re-
by H&E morphology. We are unable to include differentiation" but it has been referred to as
and illustrate every entity in this slim volume, "homologous dedifferentiation") (2).
11
Figure 2-1
LIPOMA
A: Fat necrosis in lipomas often is seen as small spotty
foci rather than as large expanses, as manifes ted by multinu-
cleated histiocytes (arrow). At low magnifica tion, these can
mimic the atypical adipocyte nuclei of atypical lipomatous
tumor/well-differentiated liposarcoma.
B: Note the multinucleated histiocyte, which corresponds
to the indicated cell in figure A.
C: This is a loch kern, an adipocytic cell in which there
is an intranuclear lipid invagination (pseudoinclusion).
I
The nucleus itself is not hyperchromatic and has a sm ooth
nuclear membrane.
I •
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~ -
j,
..
~
I - .. ............
.. •_, I
- ~
c
....
~- ~
,~
, ••
/" I •
-- '
Lipoma
If your laboratory has MDM2 immunola-
Lipomas essentially resemble adipose tissue beling available, the pitfall is that histiocytes
except that they form masses. They are unusual can display nuclear labeling (fig. 2-4). If your
in children and young adults, especially deep laboratory has fluorescence in situ hybridization
lipomas. The main problem with lipomas, as (FISH) for MDM2, this is not an issue. Howev-
pointed out in chapter 1, is that they are prone er, most cases are easy to resolve with-guess
to fat necrosis. This fat necrosis results in nuclei what- H&:E staining.
that can be seen at 4X as individual large cells Another pitfall is that intramuscular heman-
(fig. 2-1) imparted either by histiocytes or by giomas and large vascular malformations, which
nuclei with intranuclear lipid invaginations tend to be encountered in children and young
(lochkerns; fig. 2-1C), which contrast with the adults, often have abundant overgrowth of ad-
atypical nuclei of atypical lipomatous tumor/ ipose tissue and can be mistaken for intramus-
well-differentiated liposarcoma (fig. 2-2) or with cular lipomas, which are unusual in children
actuallipoblasts (fig. 2-3). and young adults (fig. 2-5).
12
Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining
/' t: o
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ATYPICAL LIPOMATOUS TUMOR/ MYXOID LIPOSARCOMA
WELL-DIFFERENTIATED LIPOSARCOMA A lipoblast is present in the center of the image. Its
The nucleus in the center is lodged in a fibrous band, is nucleus is crisply indented by a bilobed lipid droplet.
dramatically hyperch romatic, and has an irregular nuclear
membrane.
' •
- I
•
MDM2 LABELING IN MULTINUCLEATED HISTIOCYTES INTRAMUSCULAR HEMANGIOMA
As with any immunostain, MDM2 labeling must be Note the overgrowth of adipose tissue, a featu re shared
interpreted with caution and, to confirm an interpretation of with vascular malformations and angiomatosis.
atypical lipomatous tumor/well-differentiated liposarcoma, it
is important that the correct type of nucleus shows labeling.
13
Figure 2-6
FIBROLIPOMATOUS HAMARTOMA OF NERVE
Left: The central n erve portions are cuffed by fibrous tissue. Fat enrobes the process but some fat is admixed with the
fibrous tissue that directly encases the nerve.
Right: The process is clearly benign and all three components (nerve, fibrous tissue, and fat) feature cytologically bland nuclei.
Another uncommon but characteristic lesion concerning cases are typically subjected instead
is the fibrolipomatous hamartoma of nerve. This to testing for DDIT3 rearrangements to exclude
is unequivocally a lesion that is diagnosed on myxoid liposarcoma. The patient should be
H&E alone. Tumors usually present in patients younger than 2 to 3 years (2 is better) for the
under 30 years of age, in the fingers, hand, or pathologist to be certain that H&E staining is
wrist, and some patients have macrodactyly enough to exclude myxoid liposarcoma.
(3,4). These lesions are often associated with Lipoblastomas are superficial lobulated le-
the median nerve and produce a swelling. Their sions consisting of a mixture of mature-appear-
microscopic features are characteristic: fat with ing fat and more primitive-appearing fat (fig.
fibrous strands is intimately wrapped around 2-7). The primitive areas are richly vascularized
nerves, with an onion skin appearance where and contain lipoblasts (adipocytic cells in which
the fatty component meets the nerve (fig. 2-6). the nuclei are crisply indented by lipid droplets).
Lipoblastomas are benign, whereas myxoid li-
lipoblastoma
posarcomas are sarcomas, and they are usually
Lipoblastoma is a tumor of babies. The trou- deep lesions. Exceptionally, lipoblastomas can
ble is that it can resemble myxoid liposarcoma fill an infant's lung or other deep spaces but
perfectly even though the genetics are different. this is a rare variant of an uncommon lesion. If
This tumor has rearrangements of PLAGl and lipoblastomas are not removed during infancy,
lacks any nuclear pleomorphism (5-7). In fact, they mature with the child and eventually re-
it can have areas that look exactly like myxoid semble lipomas, differing only by having a more
liposarcoma. It can be diagnosed with molecular lobulated appearance (fig. 2-8).
techniques, but these are usually not needed
Angiolipoma
because it is an H&E diagnosis in the correct
clinical setting. Since most lipoblastomas are easy These benign lesions typically arise in
to diagnose, commercial tests are not readily young adults and are superficial. They consist
available to confirm PLAG 1 rearrangements and of well-marginated small nodules composed
14
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Figure 2-7
LIPOBLASTOMA
Left: Note that the process is lobulated and that one of the lobules appears myxoid. Early lipoblastomas often have a
predom inance of the more primitive component, but as the patient matures, so too does the lipoblastoma.
Right: The presence of lipoblasts (some indicated with arrows) and prominent delicate capillaries makes these tumors
virtually identical to myxoid liposarcomas. Thei r gen etics differ, however, and FISH testing can be used to exclude myxoid
liposarcoma in doubtful cases.
of a mixture of fat and capillari~s that display

, I , ·~
fibrin thrombi. When they arise in the breast,
they always result in concern for a highly dif-
ferentiated angiosarcoma. This is especialy an
issue in examples that have a high proportion
of vessels (fig. 2-9). There can be mitoses in the
cells that support the capillaries but not in the
endothelial cells themselves.
Spindle Cell and Pleomorphic lipomas
Spindle cell and pleopmorphic lipomas are cous-
ins and they have a lot of overlapping features.
They were described years ago (with H&E) as tu-
mars of middle-aged adults, with a male predom-
inance and a proclivity for the neck and shoulder
region (8,9). They are superficial and well margin-
ated when they are found in their classic location
but they can be slightly infiltrative when found
in areas with little subcutaneous tissue such as
the shins. Spindle cell and pleomorphic lipomas Figure 2-8
can be confidently diagnosed on H&E when they
LIPOBLASTOMA
are in their classic presentation.
These tumors consist of spindle cells, wiry This lesion was exdsed about a year after a smaller biopsy
was diagnosed as a lipoblastoma. Other than the impressive
collagen ("kinky" collagen), mast cells, and lobulation, the tumor has the appearances of a li poma,
variable amounts of myxoid stroma . Sometimes which is usually a lesion of middle-aged adults.
15
Figure 2-9
ANGIOLIPOMA
A: At low magnification, angiolipomas with enhanced
vascularity can have an alarming appearance. The lesion is
overall well marginated and was superficial, both reassuring
features.
B: In the solid area, there is little fat and capillaries are
numerous. Many of them contain fi brin thrombi, a clue
to the diagnosis.
C: This image demonstrates the capillaries and fib rin
thrombi nicely.
they have striking cleft-like spaces (fig. 2-10). examples are diagnosed with an H&E stain.
Myxoid examples (fig. 2-11) result in concern These lesions consistently express CD34 but it
for myxoid liposarcoma (figs. 2-3, 2-12), but is generally not necessary to perform this stain.
these tumors are superficial wh ereas myxoid The spindle cells lack S-100 protein expression
liposarcoma is gen erally deep and the rich but h ave areas of fat. Both spindle cell and
vascularity of m yxoid liposarcoma is usually pleomorphic lipomas can contain lipoblasts (fig.
absent. Some examples have little fat ("low fat" 2-13C), the presence of which should not cause
or "fat free" spindle cell lipoma). alarm if the other features are present.
Pleomorphic lipoma has the same features as
Atypical Lipomatous Tumor/
spindle cell lipoma with the addition of multi-
Well-Differentiated Liposarcoma
n ucleated h yperchromatic "fleurette" cells (fig.
2-13). This can result in concern for atypical Atypical lipomatous tumor (ALD and well-differ-
lipomatous tumor (discussed below), but most entiated liposarcoma are the same thing. Tumors
16
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,
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I
Figure 2-10
SPINDLE CELL LIPOMA
A: The tu m or is well marginated and consists of adipose
tissue, spindle cells, and cords of wire-like collagen.
B: Note the prominent collagen.
C: Th is image shows the wiry appearance of the collagen.
D: A mast cell is present in the center of the image.
There is no fat in this area but the strands of wiry ("kinky")
collagen are a characteristic feature.
E: This example is quite cellular with scant fat (low fat
spindle cell lipoma). However, the prominent tissue clefts
are a clue to the diagnosis.
17
Figure 2-10, continued

SPINDLE CELL LIPOMA
F: Tissue clefts, spind le cells, and adipose tissue are all seen .
G: This field shows tissue clefts and an admixed mast cell is indicated (arrow).
.,.
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Figure 2-11
SPINDLE CELL LIPOMA
Left: Sometimes spindle cell lipomas are h ighly myxoid, which can suggest myxoid liposarcoma. Spindle cell lipomas
are superficial, affect the n eck and shoulders, and usually arise in middle-aged persons whereas myxoid liposarcomas are
deep an d generally affect young adults, arisi ng in the lower extremities. Add itionally, myxoid spindle cell lipomas lack the
gen erous componen t of capillaries that are foun d in myxoid liposarcomas.
Right: Even though th e lesion is quite myxoid, th e wiry collagen is a clue against a diagnosis of myxoid liposarcoma.
18
Figure 2-12
MYXOID LIPOSARCOMA
Left: At low magnification, cystic spaces are often a salient feature and the vascular pattern is apparent.
Right: The appearance of the capillary network has been likened to that of chicken wire. Each capillary is delicate and
small, with only enough space for a thin line of erythrocytes.
that were termed well-differentiated liposarco- Instead, search (at low magnification) in the
ma early on never metastasized, so in the late thick bands of collagen. These bands are not
1970s, Harry Evans proposed using the atypical the same as the "kinky" collagen encountered
lipomatous tumor terminology for lesions in in pleomorphic lipomas, and the bands should
the readily accessible soft tissues (10-12) and be punctuated by cells with enlarged hyper-
to reserve the liposarcoma terminology for ret- chromatic nuclei (fig. 2-14). It is also nice to
roperitoneal lesions, which were more likely to see the same hyperchromatic nuclei suspended
dedifferentiate (evolve to a higher grade form). "naked" in surrounding fat (fig. 2-15). Some
The 2013 WHO classification of soft tissue tu- tumors contain abundant lymphoid tissue and
mars went so far as to apply the term ALT to some examples are sclerotic, but the presence
retroperitoneal lesions but pointed out that the of atypical nuclei is the common denominator
term well-differentiated liposarcoma was also (fig. 2-16). In reality, in needle biopsies, it is
acceptable for neoplasms in the retroperitone- useful to test for MDM2 gene amplification or
um or mediastinum (1). protein overexpression but some needle biopsies
These are tumors of middle-aged and older contain the fatty component as well and such
adults. They are deep, either involving the deep testing is not necessary for the diagnosis.
muscles of the extremities or the mediastinum, There are a few pitfalls in diagnosing ALT. The
retroperitoneum, or abdomen. one that is seen more and more frequently in
ALT is diagnosed at 4X and confirmed at this era of obesity is massive localized lymph-
higher magnification. There is no need to hunt edema in the morbidly obese (13,14). It is not
for lipoblasts although it is fun to see them. clear why morbidly obese individuals acquire
19
Figure 2-13
PLEOMORPHIC LIPOMA
A: These are essentially spindle cell lipomas into which
pleo morphic cells are mixed . They oth erwise contain
the same wire-like collagen, myxoid zones, fat, and mast
cells.
B: Despite the alarming appearance of the lesion, wiry
collagen and mast cells that mirror those in spindle cell
lipomas are easy to spot. These are superficial tumors of
middle-aged persons, usually m en, with a fa vored location
of the neck or upper back.
C: This example even contains a few lipoblasts. This
is perfectly acceptable if the lesion is otherwise typical of
pleomorphic lipoma.
Figure 2-14
ATYPICAL LIPOMATOUS TUMOR/
WELL-DIFFERENTIATED LIPOSARCOMA
A: Atypical hyperch romatic n uclei are
in bands of coll agen. The collagen is not
as dense or wire-like as that in spindle cell
and p leomo rp hic lipoma. Furthermore,
atypical lipomatous tumor is nearly always
d eep. Th is lesion is di agn osed at low
magnification (4X) and the diagnosis is
confirmed at higher magnification. Compare
this low m agnification image to the low
magn ification image of a lipoma with fat
n ecrosis (fig. 2-1).
20
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4 ~
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E

B: The bands of collagen that traverse the adipose tissue (arrows) is where the atypical nuclei are most quickly found
when scanning samples.
C: This is a poor quality needle biopsy of a retroperitoneal mass that had imaging characteristics that suggested a prominent
adipose tissue component. At low magnification, several enlarged nuclei are present. In light of this history, atypical lipomatous
tumor/well-differentiated liposarcoma is the most likely interpretation even in this scant sample.
D: The diagnosis is suggested by knowing the location and imaging qualities. However, in general, imaging is of little
value in classifying soft tissue lesions other than to document the depth of the lesion.
E: This is an MDMZ immunostain from the lesion depicted in D. In light of the hematoxylin and eosin (H&E) features
and the imaging ones (retroperitoneal mass with imaging characteristics demonstrating prominent fat), it can be confidently
diagnosed as well-differentiated liposarcoma.
21
J ~
'
\-
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Figure 2-15
ATYPICAL LIPOMATOUS TUMOR/
WELL-DIFFERENTIATED LIPOSARCOMA
,#
Large hyperchro mati c nuclei plop-

ped in to zon es th at o therwise have
appea ran ces of fat are characteristic of ~·
atypical lipomatous tumor/well-differen-
tiated liposarcoma. If such zones can be
found in background fat associated with
a high-grade sarcoma, they confirm an
. ./
H&E interpretation of dedifferentiated

liposarcoma since zones like this cannot
be attributed to a high -grad e sarcoma
simply infiltrating adipose tissue.
-
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-•.. -·•:t; ;,... 1c· .
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Figure 2-16
ATYPICAL LIPOMATOUS TUMOR/ WELL-DIFFERENTIATED LIPOSARCOMA
Left: Some examples show prominent lymphohistiocytic infil tration so it is important to search for areas in the lesion
with fewer inflammatory elements to identify atypical ad ipocytic nuclei like the on e indicated in this case (arrow). When
inflammation is striking, sometimes immunolabeling or FISH for MDM2 is needed to con fi rm the diagnosis.
Right: Areas such as this can be difficult to diagn ose without ancillary studies, but a retroperitoneal mass with these
features is usually an atypical lipomatous tumor/well-differentiated liposarcoma.
22
Figure 2-17
MASSIVE LOCALIZED LYMPHEDEMA
IN THE MORBIDLY OBESE
A: The lesion is superficial, loosely marginated, and
features boggy edematous dermal and subcu ta neous
tissue.
B: The subcutaneous tissue is massively edematous with
slightly atypical stromal cells.
C: Note the wiry dermal collagen and the mildly atypical
fibroblasts.
localized mass-forming lymphedema but they there may be mildly atypical cells in the stroma
can; the process mimics liposarcoma but differs that are similar to the hyperchromatic cells that
in several ways. The lesions tend to arise in one characterize ALT (fig. 2-17C) (16). Attention to
of the patient's thighs, resulting in a pendulous, the superficial location and the boggy edematous
superficially-based mass that has overlying skin appearance of the process resolves the issue.
stasis changes with thickening of the skin and an Tumors with differentiation along the lines
elephantiasis-like appearance. Such lesions also of brown fat (hibemomas) are occasionally con-
arise in the scrotal area (15). Microscopically, there cerning. They arise in young adults rather than
is a superficial edematous process with plenty of middle-aged patients like ordinary lipomas. The
dilated lymphatic spaces. There is often inflam- brown fat appearance can suggest liposarcoma
mation of the overlying skin and perivascular and the rich vascularity typical of brown fat can
inflammation (fig. 2-17). The problem is that also be alarming (fig. 2-18).
23
Figure 2-18
HIBERNOMA
Left: These are lipomas with brown fat differentiation. They arise in young adults whereas usual lipomas a rise in middle-
aged adults. They are superficial.
Right: At high magnification, the brown fat adipocytes resemble lipoblasts but have a microvesicular pattern of fat droplets.
Brown fat has prom inent vessels, adding to the confusion.
Dedifferentiated Liposarcoma
differentiation (18). Some examples even show
The high-grade form of atypical lipomatous areas resembling pleomorphic liposarcoma (see
tumor/well-differentiated liposarcoma, dediffer- below) but they differ genetically fro m pleomor-
entiated liposarcoma, is easy to diagnose on H&E phic liposarcoma. This phenomenon has been
if there is both a low- and high-grade lesion in termed "homologous" dedifferentiation (2). A
the available tissue (fig. 2-19). Often, however, subset of cases shows a process that resembles a
ancillary testing is required to diagnose the low-grade fibrosarcoma, which has been termed
high-grade form on small samples (examples "low-grade dedifferentiation" (19). Examples of
are shown in chapter 3). t he various patterns of dedifferentiated liposar-
Dedifferentiated liposarcoma is a lesion of coma are seen in figure 2-20. Lesions that were
deep soft tissue (usually retroperitoneum, occa- regarded as "inflammatory malignant fibrous
sionally extremities) of adults. As it was initially histiocytoma" in the past are now known to be
described, dedifferentiated liposarcoma was a dedifferentiated liposarcomas (20) .
neoplasm in which a high-grade pleomorphic In many instances, dedifferent iated lipo-
sarcoma was seen arising in association with a sarcoma is an H&E diagnosis. In such cases,
well-differentiated liposarcoma (atypical lipo- the well-differentiated component is demon-
matous turner) (10,11). Certain mitotic counts strated together with the high-grade one. This
were expected and the lesion was described is true mostly in resection specimens but can
with a storiform pleomorphic pattern. Over sometimes be seen in needle biopsies if the
time, the definition has expanded and we now radiologist is knowledgeable enough to sample
realize that well-differentiated liposarco ma zones that have a fat-like appearances as well
can blast off into an y kind of high-grade comas solid areas. Importantly, there are forms of
ponent it fancies, whether with whorls (16), dedifferentiated liposarcoma that appear similar
smooth muscle d ifferentiation (17), or even to inflammatory myofibroblastic tumor (21),
skeletal muscle or osseous ("heterologous") and dedifferentiated liposarcomas that appear
24
'
." "
·' J..:
t.l 1
-4-.....t
.
'of
- ~
-<~-....-- . . _).-
l ~
Figure 2-19
DEDIFFERENTIATED LIPOSARCOMA
A: The part of the image at the right has the appearance
of a well-di fferentiated liposa rcoma but the remainder of
the neoplasm has a nonspecific appearance.
B: This is the adipose tissue component of the neoplasm
depicted in figure A. It shows a zone of fat punctuated by cells
with marked nucleomegaly and nuclear hyperchromasia.
C: This is the h igh-grade com ponent and it has the
appearance of an undifferentiated pleomorphic sarcoma.
D: MDMZ immunohistochem istry shows ab undant
n uclea r labeling.
E: This example shows mildly prominent inflammation.
.· . ,· .. ··. ...-.
. . ·.
... .,
. .
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t
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1- , 1. I
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....
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of
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.
• 0
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.'
.·. I ··.·
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.,.
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25
!
)'
Figure 2-20
A: This neoplasm has fea tures similar to those of
inflammatory myofibroblastic tumor.
B: This examp le, whi c h mimics inflammatory
m yofibroblastic tumor, even expressed smooth muscle
actin.
C: Calponin expression adds to mimicry of inflammatory
myo fibroblastic tumor.
D: This pleomorphic sarcoma contains many neutrophils
and arose in the retroperitoneum. Years ago, such tumors
were referred to as "inflammatory malignant fibrous
histiocytoma" but it is now known that most retroperitoneal
"inflammatory malignant fib rous hi stiocytomas" are
dedifferentiated liposarcomas.
E: Note that the nuclear characteristics in the cell in
the center of the field are similar to those of more classic
examples of dedifferentiated liposarcomas.
26
·, ;,.
., ,' •;.·
~
·~

F: Another example of an inflammatory dedifferentiated
liposarcoma.
G: MDM2 labeling can be helpful in confirming the
diagnosis in examples with prominent inflammation.
H: The presence of meningothelial-Iike whorls is one of
the many patterns that can be displayed by dedifferentiated
liposarcoma.
1: This lesion has both a prominen t inflammatory
backdrop and meningothelial-like whorls.
J: A meningothelial-Iike whorl is accompanied by a
hyperchromatic nucleus.
27

K: This example has an osteosarcoma component .
L: An osteosarcoma component shows both osteoid and
bone spicules.
M: MDM2 labeling is seen in an osteosarcoma
component.
. - ... . .-
...
.--....
.. ' • • 4
.
· ~·
,
.. \
.- <...-·
.,
<1 ~...
.:_ ... ,-
..' . ,.
'
,' .
~ ""..
~.
._
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.,;
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··-·, . ·
similar to myxofibrosarcoma with a myxoid

Pleomorphic Liposarcoma
appearance. In these cases, especially on needle
biopsies, ancillary studies are needed to establish In contrast to dedifferentiated liposarcoma,
the diagnosis. As a general rule, if a large retro- pleomorphic liposarcoma is an H&E diagnosis
peritoneal mass is a pleomorphic sarcoma on a because it is diagnosed by finding the areas of
small biopsy, the most likely interpretation is pleomorphic lipoblasts (22-25) an d it has no
dedifferentiated liposarcoma. Confirmatory im- characteristic molecular or immunolabeling
munolabeling or FISH testing for MDM2 can be signature. It is an aggressive sarcoma of older
helpful. Dedifferentiated liposarcoma is the least adults and typically arises in the deep thigh. It
aggressive of the pleomorphic sarcomas and the consists of undifferentiated areas and variable
5-year survival rate is 70 to 80 percent, although areas with extremely pleomorphic lipoblasts
the 10-year survival rate is less favorable. that contain some of the most bizarre nuclei
28
Figure 2-21
PLEOMORPHIC LIPOSARCOMA
A: These tumors feature pleomorphic lipoblasts, which may be present only focally. They lack a characteristic molecular
alteration and are nonreactive with MDM2 with one exception: rare dedifferentiated liposarcomas show "homologous
dedifferentiation" (as opposed to heterologous to-for example-osteosarcoma) and the latter subset shows MDM2 labeling.
B: This example is epithelioid.
C: This example contains sheets of lipoblasts.
D: This type of tumor features some of the most bizarre nuclei in human neoplasia.
29
Figure 2-22
MYXOID LIPOSARCOMA
A: Note the cystic spaces and rich network of delicate capillaries.
B: Even at low magnification, it is clear that the nuclei are small and uniform, a commonality of many neoplasms associated
with characteristic translocations and gene fusions.
in human neoplasia (fig. 2-21). There is also an network, which has been likened to chicken
epithelioid form (fig. 2-21B) (25). wire (fig. 2-23).
Pleomorphic liposarcoma can be difficult to If consideration is given to diagnosing a le-
diagnose in needle biopsies unless the pleomor- sion as myxoid liposarcoma and there is nuclear
phic lipoblasts, which can be focal, are sampled. pleomorphism, the lesion is probably instead
In this setting, MDM2 studies are nonreactive a myxofibrosarcoma, which features similar
because MDM2 amplification is not a feature of vessels, but is usually superficial and contains
pleomorphic liposarcoma. pleomorphic nuclei (fig. 2-24). Another pitfall
is fat atrophy, which can result in concern for
Myxoid Liposarcoma
myxoid liposarcoma because the atrophy of the
Myxoid liposarcoma is a tumor that arises in adipocytes results in accentuation of the exist-
the deep soft tissues (usually of the extremities) ing vessels (fig. 2-25). Additionally, sometimes
of young adults. There is a low-grade and high- damaged tissue has myxoid stroma and repara-
grade form. The high-grade form is also termed tive hypervascularity (fig. 2-26).
round cell liposarcoma. These tumors are un- The high-grade form of myxoid liposarcoma
usual because they have a proclivity to spread (round cell liposarcoma) features solid areas of
to other soft tissue sites and even to bone. cells that obscure the vascular pattern (fig. 2-27).
Since myxoid liposarcoma is a translocation Both the low- and high-grade forms are readily
sarcoma, it features uniform nuclei and lacks diagnosed on H&E alone. Most high-grade ex-
atypical mitoses (fig. 2-22). Myxoid liposarco- amples show a bit of the low-grade form in some
mas can have cystic spaces and loculation as areas; occasionally molecular analysis (for FUS-
well as areas with mature-appearing fat, but the DDIT3 or EWSR1-DDIT3) is needed (needle biop-
nuclei are uniform. Lipoblasts in these tumors sies). In general, surgeons and oncologists like to
tend to be found at the periphery of the tumor have a percentage of the high-grade component
lobules. The vascular pattern is characteristic, listed when reporting. Even a small percentage
consisting of delicate capillaries in a complex of the high-grade component (5 percent) can
30

C: Delicate capillaries, uniform nuclei, and lipoblasts
are all features.
0: Lipoblasts are not always numerous but they are easy
to find in this image (arrows). They contain small nuclei
a nd cytoplasm ic lipid that indents the nucleus. Note also
the delicate capillaries.
E: A lipoblast is indicated (arrow).
F: There is often increased cellularity at the edges of
lobules.
G: The nucleus of the li poblast (arrow) is smaller and
paler than those of the endothelial cells. Th e uniform small
nuclei do not indicate benignity in these translocation-
associated sarcomas.
31
figure 2-23 Figure 2-24

CHICKEN WIRE MYXOFIBROSARCOMA
This mimics the appearance of the vessels in myxoid The indicated cell is not a lipoblast of myxoid lipo-
liposarcoma. sarcoma, but rather it is a "pseudolipoblast." It is too pleo-
morphic and contains mucopolysaccharide matrix instead
of a lipid d roplet.
have a negative impact on outcome; pure myx-
oid liposarcoma is a grade 1 sarcoma (1). men, but no site is immune and no age off
limits. The process is generally associated with
FIBROBLASTIC/ MYOFIBROBLASTIC LESIONS fascia but it can be found in muscle (nodular
myositis). Lesions usually attain a size of about
Nodular Fasciitis
3 cm, but some are large and locally destructive.
Nodular fasciitis is the prototype pseudosar- Microscopically, nodular fasciitis displays a lot
coma and familiarity with its vascular pattern, of overlap with granulation tissue (fig. 2-28), but
range of appearances, and cytologic features is it differs by being more lobulated and lacking
the framework upon which other pseudosarco- hemosiderin despite containing many extrava-
matous lesions and benign fibroblastic lesions sated erythrocytes and plasma cells; neutrophils
are diagnosed. Nodular fasciitis was considered are unusual. The cells show the key features of
a reactive process in the past (26-28), but over myofibroblasts, namely smooth nuclear mem-
time, cytogenetic alterations were detected (29) branes and amphophilic (neither eosinophilic
and, finally, a characteristic fusion was identified nor basophilic) stellate cytoplasm. Each nucle-
(MYH9-USP6) (30). The latter is of great interest, us contains a delicate but readily identifiable
and confirms the interpretation in about 75 per- nucleolus, and the nuclear membranes are
cent of cases (31), but nodular fasciitis remains an smooth. The nuclei are usually similar in size
H&E diagnosis with a little practice. In exception- to endothelial cell nuclei and typically paler.
al cases, FISH for the fusion is of occasional use. Mitoses can be abundant but are not atypical
Nodular fasciitis is a lesion of young adults mitoses. In nearly every case, a careful search
and classically arises in the forearms of young demonstrates osteoclast-like giant cells.
32
Figure 2-25
FAT ATROPHY
A: The subcutaneous fat at the deep portion of this sample is shriveled.
B: The adipocytes are each small and deflated. This results in a false impression of prominent blood vessels.
C: This is fat from a patient with HIV/AIDS. Each adipocyte is less pl ump than usual, and the vessels appear prominent.
D: Cytomegalovirus viral cytopathic effect is presen t in some of th e cells, which has resulted in ischemic damage that
has contributed to the fat atrophy.
33
Figure 2-26
FAT ATROPHY AND STROMAL MYXOID CHANGE
A: There is no neoplasm in this tissue, which was from
a resection performed for an unrelated process.
B: The tissue here appears lobulated and myxoid but did
not correlate with a clinical mass.
C: Nonspecific edematous change in soft tissue. Such
findings can be ignored.
Fi~:ure 2-2 7
HIGH-GRADE MYXOID
LIPOSARCOMA (FORMERLY
ROUND CELL LIPOSARCOMA)
The nuclei are monotonous and the
only clue to the diagnosis is the presence
of a few lipoblasts (arrow).
34
Figure 2-28
NODULAR FASCIITIS
A: Thick strands of collagen, myxoid zones, hemorrhagic zones without hemosiderin, and an overall storiform architecture
are all features of this condition.
B: Note the prominent extravasated erythrocytes.
C: This image shows the nuclear features. Each nucleus has a delicate nucleolus and a smooth nuclear membrane.
D: Some of the cells have amphophilic cytoplasm, which is neither eosinophilic nor basophilic, with a stellate arrangement.
35

NODULAR FASCIITIS
E: Note the cystic spaces and scattered lymphocytes. Plasma cells are not a prominen t component of nodular fasciitis.
F: Osteoclast-like giant cells are present.
All cases show variable keloid-like collagen typically arises in older adults rather than in
deposition, myxoid stroma, cystic spaces, and young adults, and tracks along fascial planes
a loose storiform pattern. This pattern caused (33) . When it arises in children, it is especially
past researchers to liken the appearance to that cellular and can be easily mistaken for a high
of fibroblasts in tissue culture (32). The appear- grade sarcoma (34). It is infiltrative and usually
ance of the nuclei is important to know, since attains a size of 2 to 3 cm. When it is in muscle,
the same delicate nucleoli and smooth nuclear it tends to have a "checkerboard" distribution
membranes also characterize the fibromatoses, (figs. 2-29, 2-30). It seems to lack the MYH9-USP6
all of which have myofibroblastic differentiation fusion that characterizes nodular fasciitis (30,31),
despite divergent molecular underpinnings and but it seems like an analogous process.
pathologic features. For the colleague who is not Proliferative fasciitis contains a backdrop of
accustomed to diagnosing nodular fasciitis, it is cells that are essentially identical to those seen
worth knowing that it expresses smooth muscle in nodular fasciitis and another population of
actin but usually not desmin or caldesmon. It larger cells that have large round nuclei and
lacks nuclear beta-catenin labeling (which can macronucleoli that are smooth and round (fig.
be useful to confirm a diagnosis of desmoid fi- 2-29C,D). The cytoplasm in the large cells is
bromatosis). The expression of smooth muscle abundant and in the past was thought to be
actin in nodular fasciitis can easily lead to a ganglion cells. Thus, the term ganglion-like cells
misinterpretation as leiomyosarcoma. was used; however, the latter cells are fibroblasts.
Not surprisingly, proliferative fasciitis was often
Proliferative Fasciitis and Myositis
mistaken for sarcoma in the past, especially
Proliferative fasciitis is the entity that causes rhabdomyosarcoma in children, but modern
the most alarm among the pseudosarcomas. It immunolabeling with desmin and myogenin
36
Soft Tissue Lesions that Can Be Diagnosed on .Routine H&E Staining
• Figure 2-29
PROLIFERATIVE FASCIITIS
A: The lesion tracks along a connective tissue septum.
B: The process separates lobules of adipose tissue.
C: Note the ganglion-like cells, which are fibroblastic. The background cells and collagen pattern are similar to those of
nodular fasciitis.
D: The ganglion-like cells have abundant amphophilic cytoplasm and inclusion-like nucleoli.
37
.
. \ ·1..
.......,. .' ...
,.
r
Figure 2-30
PROLIFERATIVE MYOSITIS ... ' .• ' "
A: The lesion partitions the skeletal muscles into lobules, l.
"··.··.~ .·.
resulting in a checkerboard-like appearance.
B: The depth and cellularity result in concern for a , 0 •
I : '"
· :
·,
\
sarcoma.
C: The lesion is cellular. Note the damaged skeletal
..
myocyte entrapped in the lesion (arrow).
D: Each cell has abundant cytoplasm.
E: The lesional cells themselves appear bland, but
degenerating skeletal muscle (arrow) can produce an
alarming appearance; the nuclei become pressed together
in individual cells as the cytoplasm atrophies, imparting an
appearance akin to that of a pleomorphic nucleus. Note that
the cytoplasm of the atrophied skeletal myocyte is roughly
the same color as that of the normal skeletal muscle.
.. \ .. •
Q..
"""
....__ --- • ••
..
~
\
38
Figure 2-31
MYOSITIS OSSIFICANS
Left: This imaging study shows an early lesion, indicated by the arrow. The process has yet to fully ossify.
Right: This imaging study shows a fully developed lesion, with a shell of bone indicated by the arrow.
has eliminated this issue, at least in children. If

Ischemic Fasciitis (Atypical Decubital Fibroplasia)
immunolabeling is done, the cells lack expres-
sion of keratins, S-100 protein, desmin, and This condition was initially described as atyp-
myogenin such that the differential diagnosis is ical decubital fibroplasia (37), a unique form of
with pleomorphic sarcomas in adults; attention pressure sore that tends to arise in the elderly
to the morphology readily resolves the issue. in areas otherwise prone to decubitus ulcers
except that this lesion forms a mass. In fact, the
Myositis Ossificans
lesions were referred to informally as "nursing
Myositis ossificans is basically something that home lesions" while gathering data for the initial
looks like nodular fasciitis that ossifies. Like publication (3 7), terminology that does not lend
nodular fasciitis, it frequently has rearrange- itself to peer-reviewed medical publications. The
ments of USP6 (31,35,36). It tends to arise in term ischemic fasciitis was adopted even though
the thighs of young adults. Early on, it lacks the appearance is not inflammatory (38,39).
ossification, but over time, it develops a "shelr These tumors do not always arise in the
of bone" that can be seen on plain X rays (fig. elderly (38), but usually arise in areas prone
2-31). Skilled radiologists are generally able to poor blood flow, and they are somewhat
to recognize it. The trouble is that it is quite analogous to cyclists nodules encountered in
cellular early on and can be mistaken for ex- otherwise fit bicyclists in their perineal areas
traskeletal osteosarcoma. The key is to recognize (40,41). Ischemic fasciitis forms a subcutane-
that the nuclei are identical to those seen in ous tumor that can become large and mimic
nodular fasciitis and the presence of the bone is a liposarcoma since it contains subcutaneous
simply a distraction (fig. 2-32). The bone forms fat. Of course, liposarcomas are seldom subcu-
at the periphery of the lesion rather than fully taneous. The problem is compounded by the
intermingling within it. This pattern is referred fact that a wrong interpretation on H&E can
to as zonation, and is among the features that be falsely confirmed by expression of MDM2
allow for separation from extraskeletal osteo- and other proteins by immunostains known
sarcoma (fig. 2-33). to be reactive in atypical lipomatous tumor/
39
Figure 2-32
MYOSITIS OSSIFICANS
A: This needle biopsy shows ossification in a lesion that ot herwise mimics n odular fascii tis.
B: Note the stellate m yofibroblastic type cytoplasm.
C: Scattered osteoblastic cells are present.
D: The n uclei are like those of nodular fasciitis with smooth nuclear membranes a nd delicate nucleoli.
40
Figure 2-33
EXTRASKELETAL OSTEOSARCOMA
A: The lesion shows a random mixture of ossified and
nonossified zones.
B: Cytologically malignant cells are present in both the
osteoid and in the tissue between the newly formed bone.
C: High magnification demonstrates the malignant
cytologic features, which include macronuclei, clumped
heterochromatin, and irregular nuclear membranes.
well-differentiated liposarcoma, including p16, probably hypoxia-induced, atypical mitoses

TP53 (P53), and CDK4. However, if FISH testing may be encountered. In ischemic fasciitis, zones
for MDM2 is added, it is nonreactive (42) . Some of fibrinoid necrosis are present. At the edges of
genetic alterations have been detected but we the zones, there is ingrowth of plump fibroblastic
suspect that they don't mean much (43). Isch- cells with increased cytoplasm and nuclei with
emic fasciitis should be an H&E diagnosis. No enlarged round nucleoli. Additionally, there are
immunostaining is needed, and it can lead to clusters of capillaries that are in well-delineated
escalated molecular testing. zones . From these oxygenated areas, the fibro-
The key to diagnosing ischemic fasciitis is blasts sally forth into the pools of fibrinoid
noting the zonation and then noting that the necrosis. The nuclear to cytoplasmic ratio is low
lesional cells follow the rules of nodular and and the nuclei are not hyperchromatic like those
proliferative fasciitis (figs. 2-34, 2-35). The in atypical lipomatous tumor/well-differentiated
difference is, however, that since the lesion is liposarcoma (figs. 2-14A,B; 2-15).
41

ISCHEMIC FASCIITIS ISCHEMIC FASCIITIS
The center shows fibrinoid necrosis and there is ingrowth The cells between the capillaries are activated fibroblasts
of sprouts of capillaries. and myofibroblasts with stellate cytoplasm and prominent
but perfectly round nucleoli.
Fibroma of Tendon Sheath

nuclear cells can result in appearance similar to
Fibroma of tendon sheath looks benign. The that of nodular fasciitis. Confusing the two is of
only pitfall is that the early phase can appear no consequence since both are benign, except
identical to nodular fasciitis (44). It is a lesion that fibroma of tendon sheath is more likely to
of young adults (third to fifth decades) with a recur than nodular fasciitis.
slight male predominance. It usually arises in
Elastofibroma
association with the tendons and tendon sheaths
of the fingers, hand, and wrist. It usually presents Elastofibroma is a slowly growing fibroelastic
as insidiously growing masses associated with proliferation believed to result from mechanical
mild tenderness and pain in about one third friction between the scapula and the chest wall.
of patients. The finding of t(2;11)(q31-32;q12) It usually arises in middle-aged women. Bilater-
suggests that these are neoplasms rather than ality is also known. Elastofibromas are benign.
reactive lesions (45). This entity shares morpho- Microscopically, elastofibroma is hypocellular
logic features with desmoplastic fibroblastoma and contains thick elastic fibrils (fig. 2-3 7).
(collagenous fibroma, discussed below) but dif-
Desmoplastic Fibroblastoma
fers by lacking FOSLl immunolabeling, which
(Collagenous Fibroma)
is found in desmoplastic fibroblastoma (46,47).
Tumors are found attached to tendons and Desmoplastic fibroblastoma arises in adults
tendon sheaths, and are usually well circum- of wide age range (16 to 81 years in the largest
scribed, and lobulated, and sometimes encapsu- series) with a wide anatomic distribution (arm,
lated. It measures approximately 2 cm. Tumors shoulder, girdle, posterior neck and upper back,
are composed of myofibroblasts and fibroblasts feet and ankles, leg, hand, abdominal wall, and
associated with dense fibrous stroma and cleft- hip) (46-51) and a wide size range (1 to 20 centi-
like spaces (fig. 2-36). Myxoid degeneration, meters, median 3 cm). The lesion is benign. Even
extravasated erythrocytes, and scattered mono- incompletely excised tumors are not apt to recur.
42
Figure 2-36
FIBROMA OF TENDON SHEATH
A: This lesion of the hand arose in association with an
aponeurosis (arrow) and has a clefted zone in the center
of the image. ·
B: This early lesion is a bit cellular but pale at low
magnificati o n. A prominent ti ssue cleft is ind icated
(arrows).
C: This lesion ha s extremely low cellularity and no
fea tures to suggest malignancy.
.. .,
:.~ . ......
· ~ ·.. '
. ..... . .,
, ..··.... ·.. .. :...,./. ·~·:-..
::
. -·
1-.,; - •. ~
~- :;
.r.... · ·,
, ... ; '-~- :. ~
~ . "$ .
__
•• •l
Most examples are subcutaneous but some- fibromatosis on a needle biopsies, these fibro-
times skeletal muscle is involved, leading to con- mas lack beta-catenin nuclear labeling.
cern that the patient has desmoid fibromatosis.
Calcifying Aponeurotic Fibroma
The turnor can be quite infiltrative. These tumors
are paucicellular, consisting of bland stellate and Calcifying aponeurotic fibroma arises primar-
spindle-shaped fibroblasts in a densely collag- ily in the hands and feet of children between
enized matrix, sometimes with myxoid change. birth and 16 years (52). There are exceptions;
Mitotic activity is absent or minimal (fig. 2-38) . extra-acral examples may be observed (53). The
On immunolabeling, these tumors show a tumor usually presents as a slow-growing poor-
myofibroblastic signature. They have an llq12 ly circumscribed mass. Plain radiographs may
alteration related to the FOSLl gene (46,47). show calcific stippling. Calcifying aponeurotic
However, no ancillary testing is needed. For fibroma is a benign lesion, but aneuploidy has
those who are nervous about missing desmoid been reported (54). ins(2;4)(q35;q25) results in
43
Figure 2-37
ELASTOFIBROMA
A: The lesion (arrow) is present in the back.
B: The loosely marginated process has a nonspecific
macroscopic appearance (image courtesy of Dr. Christina
Arnold, Ohio Sta te University).
C: These tumors have low cellularity and are characterized
by eosinoph ilic coarse elastic fib ers.
D: Note the appearance of the elastic fi bers.
E: This is an elastic stain and it highlights the coarse
elastic fibers. In cross section, their appearance is remin-
iscent of a flower with plu m p stubby petals whereas they
resemble caterpillars when viewed in a sagittal fashion. They
have been referred to as "chenille" bodies; chenille is the
French word for caterpillar.
44
Figure 2-38
DESMOPLASTIC FIBROBLASTOMA (COLLAGENOUS FIBROMA)
Left: This lesion has an appearance similar to that of a "burned out" fibro ma of tendo n sheath (fig. 2-36C). The lesion is
hypocellular, and even at this low magnification, the stellate appearan ce of the cytoplasm is apparent.
Right: High magnification shows the stellate amphophilic cytoplasm and delicate nucleolus. This cytologic appearance
is common to all the benign fibroblastic neoplasms and pseudosarcomas.
fusion of the FNl and EGF genes, mapping to inance and the lesions have a median size of
the breakpoint regions on chromosomes 2 and 4, about 1 cm at the time they are removed.
respectively, that results in aberrant EGF protein, On H&E staining, inclusion body fibromatosis
which can be detected by immunolabeling (SS). appears similar to desmoid fibmomatosis (as de-
Calcifying aponeurotic fibroma has a tendency scribed below) with a key difference-the inclusion
for local recurrence. bodies. It can even display nuclear beta-catenin
These lesions can result in diagnostic difficulty labeling, but it lacks mutations in the CTNNBl
when they lack their characteristic appearance, gene that encodes beta-catenin (57). These lesions
but most are easily diagnosed by H&E alone do not seem to be syndromic and do not progress
(fig. 2-39). They show a mixture of chondroid to desmoid type fibromatosis. They can persist
cells and areas that resemble fibromatosis. The locally when incompletely excised.
chondroid areas become calcified in a serpiginous These lesions form superficial nodules (unlike
fashion. If the key calcified areas are missing, desmoid fibromatosis, which is almost always
sometimes adding a few recuts can reveal them. a larger deep mass). At low magnification, del-
The lesion is most likely to be biopsied from a icate blood vessels can be seen in a spindle cell
child's hand, which is the clue to consider it. lesion, with more or less uniformly spaced nuclei
present between deposited pale collagen. The
Inclusion Body Fibromatosis
treat is provided at high magnification because
(Infantile Digital Fibromatosis)
numerous cytoplasmic eosinophilic inclusions
This is a really delightful H&E diagnosis to are present (fig. 2-40). These are composed of
make. Do it early. Do it often. As the original actin filaments (58). Inclusion body fibromatosis
name implies, this tumor typically is encoun- is benign but can be locally persistent.
tered in infants and young children (mean age,
Palmar and Plantar Fibromatosis
12 months in the largest series) (56) and mostly
involves the toes or fingers, but occasionally the Palmar fibromatosis (Dupuytren contracture)
hands and feet. There is a slight male predom- is common, found in 1 to 2 percent of adults.
45
Figure 2-39
CALCIFYING APONEUROTIC FIBROMA
Left: Note the lobulation and pockets of chondro-osseous tissue.
Right: These tumors can be cellular but the overall cytologic features are benign. Mitotic activity, apparent in this image,
is acceptable.
Lesions present as slowly growing small subcuta- Plantar fibromatosis, like palmar fibromatosis,
neous nodules or plaques involving the dermis is a nodular fibrous proliferation. lt arises in
or underlying fascia/tendons which may lead plantar aponeuroses. It is less likely to result in
to contractures. They may be bilateral, familial, contractures than palmar fibromatosis and has
and multiple. These lesion s are associated with a higher recurrence rate. It is over-represented
alcoholism, epilepsy, diabetes, and chronic lung in patients with palmar or penile fibromatosis.
disease and can coexist with plantar but not Although the lesions may be asymptomatic,
with desmoid type fibromatosis. Some examples they may produce mild pain, or paraesthesia if
recur after local excision. there is superficial plantar nerve entrapment.
These lesions consist of multiple small nod- The histologic appearances of plantar fibro-
ular fibrovascular proliferations with delicate matoses are similar to those of palmar fibro-
blood vessels surrounded by a thin cuff of col- matoses (fig. 2-42). Some cases show striking
lagen situated near the center of the nodules. cellularity and numerous mitoses. Giant cells
The cells show the features of myofibroblasts may also be present (59).
delineated in the entities above (fig. 2-41 ).
Desmoid Type Fibromatosis
Newer lesions are more cellular, with plump
immature-appearing fibroblasts, and mitoses Desmoid type fibromatosis is a common lesion
are acceptable. Older lesions are less cellular and that has deceptively bland histomorphology but
contain increased dense collagen. Myxoid stro- a tendency to locally recur and infiltrate the sur-
ma is often present, and long-standing examples rounding tissue, hence, it is also called "aggressive
may show cartilagenous or osseous metaplasia. fibromatosis." It arises primarily in the connective
46
A B
Figure 2-40
INCLUSION BODY FIBROMATOSIS/ INFANTILE DIGITAL FIBROMATOSIS
A: This superficia l process usually arises in the fingers and toes of infants, as the old name implies. Note that the lesion
proliferates right up to the epidermis, leaving no spared zone.
B: The lesion is paler than the vessels that supply it.
C: One of the inclusion bodies is indicated (arrow), but there are severa l others in the field. Note the general cytologic
features of this fibroblastic and m yofibroblastic process. Each cell has a nucleus with a smooth nuclear membrane and a
perfectly round nucleolus.
0: Some inclusion bodies are indicated (arrows), and the presence of at least one capillary allows comparison between
the inclusion bodies and erythrocytes. The endothelial cells contain darker nuclei than the surrounding lesional cells. This
feature is helpful in confirming benignity in fibromas, nodular fasciitis, and the various fibromatoses.
47
Figure 2-41
PALMAR FIBROMATOSIS
A: This nodular lesion has arisen in a palmar tendon.
B: A mitosis is present in this field and is of no
consequence. There is also a capillary at the right side of the
field. Note the slightly darker endothelial cells compared to
the myofibroblasts that form the lesion.
C: This high magnification image highlights the nuclear
features. For comparison, a capillary is seen at the right of
the image.
tissue of muscle and the overlying fascia or apo- in children, in which case the lesions tend to be
neurosis (musculoaponeurotic fibromatosis). more cellular and may grow more aggressively,
In children, there is no gender predominance even encroaching on the trachea with destruc-
but there is a striking female predominance in tion of adjacent bone and a fatal outcome. Al-
young adults since these lesions are estrogen though these tumors do not metastasize, they
driven. The fema le predominance vanishes can be multicentric.
again in older persons. Organs can be involved, These tumors are easy to diagnose on H&E
such as breast, vulva, and spermatic cord, but (fig. 2-43). They have uniform cellularity and a
the most common location is the shoulder gir- characteristic appearance at low magnification
dle followed by chest wall and back, thigh, and in which tiny capillaries are easy to see since the
head and neck. Fibromatosis of the abdominal surrounding lesion is pale. Mesenteric examples
wall predilects to young women. Fibromatosis often have gaping thin-walled vessels that are
of the head and neck is seen more commonly easy to see at low magnification. The tumor has
48
Figure 2-42
PLANTAR FIBROMATOSIS
Left: Note the lobulated appearan ce.
Right: Mitotic activity can be striking and alarming, but the cell s have the same characteristics as those of the other
benign myofibroblastic lesio ns depicted.
long broad fascicles of spindle cells with evenly readily distinguishable on routine H&E-stained
spaced nuclei. The collagen is sometimes dense slides, pathologists should be aware that fibro-
and keloid-like. The nuclei and cytoplasm have matoses may react with some commercially
all the features of myofibroblasts, with smooth available CD11 7 antibodies if antigen retrieval is
nuclear membranes, delicate round nuclei in used (60). Staining is typically weaker than that
each cell, and cytoplasm that is stellate in areas seen with true GISTs but beta-catenin staining
where the tumor is a bit edematous. There is can be helpful, since nuclear staining is only
slight myxoid change in some examples. Im- seen in desmoid tumors (61). If this staining is
portantly, in zones in which skeletal muscle is performed, it is important to pay attention to
infiltrated, it is easy to be concerned that the internal controls on the slides (fig. 2-43D). The
entrapped atrophic skeletal muscle cells are nuclei of endothelial cells should be negative
pleomorphic cells (fig. 2-44). even though cytoplasmic staining is acceptable.
In patients with familial adenomatous pol- Strong cytoplasmic staining can be seen in a
yposis (FAP), intestinal and extraintestinal n eo- variety of tumors and reactive processes and is
plasms typically arise through bi-allelic (germ- completely non-specific. It may be difficult to
line then somatic) inactivation of the APC gene, determine if nuclei are staining when there is
whereas the corresponding tumors in non-FAP abundant background cytoplasmic staining. In
patients occur either through somatic bi-allelic the past, extremely aggressive resectio ns were
APC inactivation or somatic mutatio n of a single advocated for these lesions but the current
CTNNBl (the gene encoding for beta-catenin) approach is more of an active surveillance phi-
allele. A pitfall is with gastrointestinal stromal losophy, since these tumors tend to "burn out"
tumors (GISTs) . Although their features are as patients age.
49
.
.. ~ ' 1
_c
Figure 2-43
DESMOID TYPE FIBROMATOSIS/ DEEP FIBROMATOSIS/ AGGRESSIVE FIBROMATOSIS
A: Although there are slightly varying amounts of collagen in the tumor, the nuclei are overall spaced evenly throughout
the process. Since the tumor cells are pale, tiny capillaries (arrows) appear prominent at scanning magnification. Iden tifyi ng
the small capillaries that "pop out" is a diagnostic clue.
B: This mesenteric example features not only keloid-like collagen but also gaping vessels; th e latter are a fea ture of
mesenteric fibromatoses.
C: These perfect stellate myofibroblasts can be found in areas of the tumor that are less fascicula r. Their appearance in
isolation is identical to that of the cells in several other fibroblastic and myofibroblastic benign lesions even though the
various ones have different genetics and clinical presentations.
D: This is a beta-catenin immunostain. Only nuclear staining is relevant in confirming an interpretation of desmoid type
fibromatosis. Endothelial cells can be used as an internal control and their nuclei (sin gle arrow) sh ould lack staining. Not
every tumor cell stains, but nuclear staining (double arrows) is required.
so
Figure 2-44
DESMOID TYPE FIBROMATOSIS/ DEEP FIBROMATOSIS/ AGGRESSIVE FIBROMATOSIS
Left: Entrapped degenerated skeletal m uscle (arrows) in these lesions can produce an alarming appearance at low
magnification.
Right: Note the brightly eosinophilic degenerated skeletal myocytes and the interface of the fibromatosis and the skeleta l
muscle.
Fibrous Hamartoma of Infancy

appearing examples have not metastasized as
Fibrous hamartoma of infancy is an uncom- of this writing (63).
mon and nearly always benign fibroblastic and This lesion was initially termed hamarto-
myofibroblastic proliferation, which generally matous because it is composed of a mixture
arises in the axillary or shoulder region of males of three elements in varying proportions: 1)
in their first 2 years of life (groin is a "common fibrou s trabeculae or septa consisting of spin -
uncommon" site) (62). They usually present as dle cells separated by collagen, 2) myxoid foci
a solitary, small, rapidly growing soft to firm containing primitive round or stellate mesen-
mass. About 20 percent of cases are present chymal cells, and 3) mature adipose tissue (fig.
at birth. The lesion only rarely occurs on the 2-45). When fibrous hamartoma of infancy
hands and feet. Although the lesion is termed arises in the groin, the presence of the imma-
a hamartoma, the detection of several assorted ture-appearing cells can suggest the possibility
translocations and EGFR alterations as well as of embryonal rhabdomyosarcoma, especially
documentation of malignant transformation if frozen section s are performed. These turners
in rare cases, better supports a (usually benign) can have overlapping features with giant cell
neoplasm (63- 66). In the largest available case fibroblastoma (fig. 2-46), which can be regarded
series, the most common sites in descending as the pediatric variant of dermatofibrosarcoma
order were axilla, back, upper arm, scrotum, and protuberans, and both types of turners express
chest wall (63). The rare reported malignant- CD34, so morphology is the winner.
51
Figure 2-45
FIBROUS HAMARTOMA OF INFANCY
A: The lesion consists of th ree components in various
proportions, namely, fat, fibrous bands with a fib romatosis-
like appearance, and sma ll round cells.
B: This image demonstrates a collision of th e three
components. Do not let the fat entrap ment fool you into
call ing it dermatofibrosarcoma protuberans.
C: The primitive cell com ponent lacks mitotic activity.
Inflammatory Myofibroblastic Tumor

Occasional cases are found in the mediastinum,
Inflammatory myo(lbroblastic tumor (IMT) is abdominal wall, kidney, and liver but no site is
a lesion that is always tested using ancillary truly immune. Sometimes, patients experience
tech niques in parts of the world with plenty systemic symptoms. The tu mor can be solitary
of resources but it was initially described by its or multinodular (30 percent) and as large as 20
morph logy (67,68), and we use morphology cm in diameter.
to consider it in the hope of identifying an al- The tumors are composed of myofibroblasts
teration amenable to targeted therapy. It tends and fibroblasts in fascicles or in a loose storiform
to arise in the abdomen and pelvis (often m es- pattern, with variable background inflammation
entery) of children and young adults, without th at consists of plasma cells and lymphocytes
gender predilection, as well as the omentum with scattered eosinophils, but neutrophils are
and retroperitoneum (over 80 percent of cases). not common (fig. 2-47). Nuclear pleomorphism
52
Figure 2-46
GIANT CELL FIBROBLASTOMA
A: This is considered a juvenile form of dermatofibro-
sarcoma protuberans. It is very superficial, proliferating all
the way to the epidermis. It is not clear why some colleagues
include it in the differential diagnosis of fibrous hamartoma
of infancy. Perhaps because both arise in children.
B: Cleft-like spaces and scattered giant cells (arrow) are
the key features, although they a re not always prominent.
Note the otherwise monotonous appearance of the lesion.
C: This is a h igh-magnification image of the giant cells
in the lesion.
is moderate, but mitoses are infrequently seen. and are aggressive but most are treated surgically
Stromal fibrosis and calcification can be present. and have indolent behavior.
The nuclei, in the fashion of myofibroblastic A more aggressive form of inflammatory my-
cells, contain round red nucleoli. ofibroblastic tumor (fig. 2-48) has been termed
Immunostaining is positive for smooth mus- epithelioid inflammatory myofibroblastic sarcoma.
cle actin (SMA), and many examples express It is composed of mo notonous malignant nee-
cytokeratin especially where there is submeso- plastic cells with cherry red inclusion-like nu-
thelial involvement. By immunohistochemistry, cleoli. It tends to display strong desmin labeling
ALK is detected in 60 to 70 percent of cases, a and scattered neutrophils rather than plasma
finding that can be exploited for diagnosis and cells. If immunolabeling is performed, this type
possibly prognosis (positive cases may have a (essentially always of the mesentery) shows
better prognosis) (69). Th e tumors invade ad- strong desmin labeling and is characterized by
jacent viscera; occasional examples metastasize an unusual nuclear membrane or perinuclear
53
Figure 2-47
INFLAMMATORY MYOFIBROBLASTIC TUMOR

A: Th is example is composed of myofibroblastic cells with background inflammation.
B: The cytologic features overlap with those of nodular fasciitis and other strictly benign myofibroblastic lesions, but
there are generally macronucleoli. Because of the presence of the latter, these lesions were in itially described as inflammatory
fibrosarcoma even though most examples behave indolently following excision.
C: This image shows the amphophilic cytoplasmic myofibroblastic processes characteristic of myofibroblastic differentiation.
D: This ALK protein immunostain is strongly reactive.
54
Figure 2-48
EPITHELIOID INFLAMMATORY
MYOFIBROBLASTIC SARCOMA
A: This can be considered the high-grade form of
inflammatory myofibroblastic tumor.
B: Note the macronucleoli and the backdrop that
includes many neutrophils.
C: The ALK immunostain shows a peculiar perinuclear
pattern of labeling.
pattern of ALK expression and more aggressive since they sometimes harbor "targetable" ALK
clinical behavior than the classic form (70). The rearrangements, they can respond to treatment
high-grade form of IMT can be considered on with crizotinib and related compounds (71-75),
H&E but cannot be diagnosed as such purely on including the more aggressive epithelioid in-
H&E results whereas the low-grade form is more flammatory myofibroblastic sarcoma variant.
characteristic. Indeed, few colleagues in high About 10 percent of these tumors have alternate
resource practice environments would diagnose fusion of the ROSl gene (76,77); these tend to
inflammatory myofibroblastic tumor without be found in tumors from children and are also
performing ALK or ROS1 immunolabeling, but amenable to the same targeted therapy as tu-
it is important to remember that the entity was mors with ALKl rearrangements.
defined initially on the basis of H&E (68). Because IMTs are inflammatory, it is not sur-
IMTs are managed by surgery, with a fa- prising that colleagues have assessed them for
vorable outcome most of the time. However, IgG4, and plenty of IgG4-reactive plasma cells
ss
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0
,
..
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. ..... '. . .
"of* •
Figure 2-49
IGG4-RELATED FIBROSCLEROSING DISEASE
A: The low-power appearance overlaps with that of inflammatory myofibroblastic tumor, but the cells lack the macronucleoli
seen in inflamm atory m yofibroblastic tumo r.
B: This image shows the ob!iterative phlebitis. The artery in the field is unintlamed and intact whereas the vein is badly damaged.
C: This is a Movat sta in. Residual frayed elastic tissue in the obliterated vein is apparent. Such staining can be helpful in
detecting damaged veins that are otherwise inapparent.
D: This is an IgG4 stain. Plenty of plasma cells are labeled but the diagnosis was confirmed rather than made with the
staining. A diagnosis of IgG4-related fibrosclerosing disease should not be based on blind immunolabeling and coun ting
plasma cells. IgG4-expressing plasma cells can be a component of infectio ns, lymphomas, an d inflammatory myofibroblastic
tumor, among others.
can be found in them (78) and are not a specific Lipofibromatosis

finding. IgG4-related fibrosclerosing disease (fig. Lipofibromatosis is another pediatric confection
2-49) is diagnosed by morphology (storiform that is fun to diagnose and requires only H&E. It
fibrosis, inflammation, obliterative phlebitis), arises in the distal extremities of babies and young
and the diagnosis can be confirmed by adding children. It affects primarily male infants and boys
IgG4 immunolabeling (79). (median age, 1 year) . It usually involves the hand
56
Figure 2-50
LIPOFIBROMATOSIS
A: These tumors arise in th e distal extremities of babies
and children and consi st of lesions in which both fat and
fibrous tissue are integral parts.
B: The fibrous tissue component can be quite cellular.
C: The collision of the fat and fibrous tissue produces
an appearance of lipoblasts.
"""<. / ~ .. j
A.:- · L
r· ..
~
;.I _,
"',. ·~
-
. . ,,,,
.,. \ /
J - :~
f,.
/ ,-; ~ -
but the arm, leg, foot, chest, abdomen, and head Because lipofibromatosis is infiltrative between
can be affected. Some examples are congenital. vessels, nerves, skin adnexa, and skeletal mus-
Tumors are typically small (median, 2 cm) with cle, it is difficult to completely excise and thus
a yellowish or tan-white cut surface, often with recurs even though it is benign.
a fatty or fibrofatty appearance. With immunohistochemical staining (un-
Microscopically, lipofibromatosis is poorly necessary), the spindle cell component usually
marginated and composed of abundant fat with expresses CD99, CD34, and SMA, and variably ex-
an accompanying fibroblastic proliferation that presses BCL-2, S-1 00 protein, muscle specific actin,
spreads along fat septa (fig. 2-50). There is a vari- and epithelial membrane antigen (EMA). Keratin
able amount of collagen, and the tumor cells are and desmin are absent. Although no characteristic
uniform. In zones where the fibroblasts and fat gene fusion has been identified, alterations in the
merge, the collision results in univacuolated cells 1q21-22 area by FISH are found (80). This differs
reminiscent of lipoblasts. The tumors lack the from similar tumors termed "lipofibromatosis-like
"primitive cells" that characterize fibrous ham- neural tumors" (fig. 2-51), which have NIRK.l gene
artoma of infancy. Mitotic activity is minimal. fusions and express S-100 protein but not SOXlO.
57
Figure 2-51
LIPOFIBROMATOSIS-liKE NERVE SHEATH TUMOR
A: This process superficially resembles lipofibromatosis, but the nuclei are larger.
B: The nuclei lack the delicate nucleoli that characterize most fibromatoses.
C: This is a CD34 stain. CD34 labeling is present as a secondary component in most nerve sheath tumors.
D: This is an S-100 protein stain, which confirms the nerve sheath differentiation.
story for giant cell tumor of tendon sheath is a

FIBROHISTIOCYTIC TUMORS AND painless finger lump in a middle-aged woman,
SOME HISTIOCYTIC LESIONS but these tumors can be found over a wide age
range. The infiltrative type (pigmented villa-
Tenosynovial Giant Cell Tumor,
nodular tenosynovitis) is usually found in the
Localized and Diffuse Types
region of the knee joint in young women and
Tenosynovial giant cell tumors are also known produces tremendous morbidity as it impedes
as giant cell tumor of tendon sheath and pigmented joint function. The localized type, as the name
villonodular tenosynovitis. They are easy to diag- suggests, is a small lobulated lesion adjoining
nose on H&E in the proper setting. The classic a tendon sheath or aponeurosis. The diffuse
58
Figure 2-52
TENOSYNOVIAL GIANT CELL TUMOR, LOCALIZED
TYPE (GIANT CELL TUMOR OF TENDON SHEATH)
A: These are common lesions of the fingers in middle-
aged women. Note the prominent giant cells and small
nuclei at low magnification.
B: High magnification shows uniform nuclei with
slightly wrinkled nuclear membranes.
C: An iron stain shows a surprising amount of
hemosiderin.
type tends to grow into the joint space, produce can be expected. The key pitfall is with clear cell
symptoms, and be prone to local recurrence . sarcoma (fig. 2-54), which is S-100 protein and
Both types are composed of nests of round HMB45 (and other melanoma markers) reactive
cells in a background of variable numbers of and displays different morphology. Of course,
histiocytes (including multinucleated and the nervous pathologist can consider adding a
foamy ones), plasma cells, and lymphocytes, keratin and S-100 protein stain to nearly any
and variable amounts of hemosiderin, which mass of the hands to address clear cell sarcoma
accounts for the term "pigmented villonodular and epithelioid sarcoma, but this is not neces-
tenosnyovitis" for the infilatrative form. Some sary in most cases.
cases have few or even no giant cells, so learning
Dermatofibroma and Fibrous Histiocytoma
to diagnose this entity by its other features is
crucial. Most of the lesional cells have round nu- Dermatofibroma and fibrous histiocytoma are es-
clei and mitotic activity is acceptable and may sentially the same thing, but generally the former
be quite brisk (figs. 2-52, 2-53). Immunolabeling term is used for predominantly dermal lesions
is not necessary for diagnosis, but CD68labeling whereas larger lesions are usually designated as
59
Figure 2-53
TENOSYNOVIAL GIANT CELL TUMOR, DIFFUSE TYPE
(PIGMENTED VILLONODULAR TENOSYNOVITIS)
A: The prototypical history for such lesions is pain and
swelling of the knee joint area in a young woman. These
lesions can be quite debilitating. The microscopic appearance
is essentially the same as that of the localized type, so findings
on small samples must be correlated with history. Note the
giant cells and background mononuclear cells.
B: A coating of syn ovium is present at the right, beneath
which hemosiderin can be seen.
C: Note t he cytologic features. The mononuclear cells
often have eccentric nuclei with abundant cytoplasm,
imparting a plasmacytoid appearance. The multinucleated
giant cells are of the osteoclastic type.
Figure 2-54
CLEAR CELL SARCOMA
The prominent nucleoli in both the
giant cells and the mononuclear cells are
the clue to diagnosis. Immunolabeling can
be used to confirm that this is a clear cell
sarcoma rather than a tenosynovial giant
cell tumor. Clear cell sarcomas express
S-100 protein and label with melanoma-
associated an tibodies such as HMB45.
60
Figure 2-55
FIBROUS HISTIOCYTOMA (DEEP VERSION OF DERMATOFIBROMA)
A: This tumor has a variety of appearances. This example is in the deep dermis and abuts the subcutaneous tissue. It is
well marginated but not encapsulated. Trickling extension into adjacent dermis between reticular dermal collagen fibers and
focall y into the subcutaneous fat are both common and totally acceptable findings.
B: This example is som ewhat sclerotic and not particularly cellular.
C: The tumor has spread th rough skin appendages. Note the characteristic entrapment of dermal collagen bundles by
tumor cells (top of image).
0: This example has a storiform pattern and contains lymphocytes and plasma cells. This particular example shows overlap
with the cytologic features of nodular fasciitis.
fibrous histiocytomas. These lesions are com- leave a little space (the Grenz zone) for the
mon, arising in persons of all ages, but mostly papillary dermis, although this is sometimes
those in the fourth and fifth decades. The usual lost in excoriated/irritated lesions. They consist
location is the distal extremities. of spindle cells that are sometimes arranged in
Microscopically, they are well marginated but a storiform pattern (mat-like with intersecting
not excapsulated and associated with hyperplasia fascicles) similar to the pattern of dermatofibro-
in the overlying epidermis. The tumor cells do sarcoma protuberans. However, they contain
not proliferate right up to the epidermis, but various secondary components, namely, plasma
61

FIBROUS HISTIOCYTOMA (DEEP
VERSION OF DERMATOFIBROMA)
E: This is a CD34 stain. The unlabeled
lesion is at the center of the image. It
is surrounded by a thick cuff of CD34-
positive dermal dendrocytes that are
attempting to wall it off. Depending on the
plane of section, this natural barrier of cells
can be misinterpreted as lesional cell CD34
reactivity and lead to an incorrect diagnosis
of dermatofibrosarcoma protuberans.
cells, histiocytes (sometimes foamy), scattered above, it arises on the extremities of young
Touton giant cells, blood filled spaces, and adults, where it is in the dermis. There is often
hemosiderin. These secondary components are an epidermal collarette, but the characteristic
not a part of dermatofibrosarcoma protuberans. collagen trapping of fibrous histiocytoma is ab-
The lesional cells have overlapping features sent. Curiously, this type of tumor expresses ALK
with those of nodular fasciitis but the nuclei are protein and hasALK rearrangements, which can be
darker. The tumor cells often extend for a short exploited for diagnosis (fig. 2-59) (81,82), but recall
distance into the tissue at the interface of the that the original description was made using H&E.
lesion and the normal tissue, where they entrap Over time, rearrangements of the ALK gene are
collagen (fig. 2-55C). found in many tumor types of various malignant
The difficulty with these lesions is that, when potential, a story mirroring that with EWSRl,
they grow larger, they can show aneurysmal which is further mentioned in chapter 3.
features and pseudovascular spaces together In children, juvenile xanthogranuloma is
with some nuclear atypia and mitotic activity. It more likely than fibrous histiocytoma, and the
is the low-magnification architecture that saves head and neck is the favored site. These lesions
the day (figs. 2-56, 2-57). appear more solid than fibrous histiocytomas
The main pitfalls with fibrous histiocytomas and lack prominent collagen trapping (fig. 2-60).
happen when immunolabeling is added. Fibrous
Plexiform Fibrohistiocytic Tumor
histiocytomas are loaded with dendritic cells, so
S-100 protein often stains quite a few irrelevant Plexiform fibrohistiocytic tumor a subcutaneous
cells (fig. 2-58). However, the biggest pitfall occurs tumor of children and young adults that usu-
when CD34labeling is performed to differentiate ally arises in the upper extremity. It only rarely
fibrous histiocytoma from dermatofibrosarcoma metastasizes (83), and most patients have a fa-
protuberans. With nearly any tumor type, as the vocable outcome following complete excision.
body attempts to wall it off, a rind of CD34-posi- The name tells the story.
tive stromal cells coalesces at the periphery of the There are two patterns: in one, nodules of
tumor. If the plane of sectioning shows a lot of tumor with features similar to those of fibrous
this rind, it is easy to interpret the lesion as CD34 histiocytoma are arranged throughout the deep
positive, especially since the CD34-positive cells dermis and subcutaneous tissue in an infiltrative
grow into the outermost layer of the lesion (figs. pattern, and in another, these random nodules
2-55£, 2-58C). It is better not to have done the appear more fibroblastic (fig. 2-61). Although
CD34 than to be fooled by it. some have suggested that it is the same as cel-
There is an unusual lesion termed epithelioid lular neurothekeoma (84-86), the morphology
cell histiocytoma that, as suggested by the name, and immunolabeling patterns differ (fig. 2-62):
is composed of epithelioid cells. Like the lesion neurothekeomas express NKI-C3 and MiTF
62
Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Sta ining
Figure 2-56
ANEURYSMAL FIBROUS HISTIOCYTOMA (DEEP VERSION OF DERMATOFIBROMA)
A: There is epidermal (epithelial) hyperplasia overlying the process, wh ich has hemorrhage, dilated vessels, and hemosiderin
'-, deposition. Th ere is an unaffected zone just beneath the epithelium. Note the blunt flattened rete ridge tips in the epidermis
(tabling).
B: Note the hemosiderin deposition and dilated vessels.
C: Mitotic activity can be a prominent feature.
63
Figure 2-57
A: The lesion is well circumscribed. This example shows
aneurysmal features.
B: Dermal collagen that has become entrapped at the
periphery of the lesion.
C: This example features overlying epidermal hyperplasia
with pigmentation, and there is a spared zone just beneath
the squamous epithelium (Grenz zone). Note the foamy
multinucleated giant cells.
Figure 2-58
A: This lesion was "scooped out" in
fragmen ts by the surgeon.
64
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B: This is a high-magnificatio n image
showing collagen trapped in the periphery of the lesion
where it meets with normal tissue.
C: This CD34 stain shows the unstained lesion at the
top of the image and the labeled dermal dendrocytes at
the periphery.
0: This reactive factor XIIIA stain shows expression
within tumor cells in the center of the lesion.
E: The S-100 protein stain shows expression in numerous
dendritic ce'lls enmeshed in the lesion, but this is not
evidence of melanoma since the tumor cells themselves
are nonreactive.
F: This S-100 protein preparation stains plenty of cells
but not the key ones. The anxious pathologist can perform
a SOXlO in this situation; it will be negative.
65
,•
..·

EPITHELIOID CELL HISTIOCYTOMA JUVENILE XANTHOGRANULOMA
A: The tumor is dermal and is similar to fibrous A: These tumors appear very similar to fibrous histio-
histiocytoma, but the proliferating cells are epithelioid. cytomas but often contain numerous multinucleated
B: The center of the lesion consists of plump epithelioid cells. Touton giant cells and eosinophils.
C: These peculiar tumors have ALK gene rearrangements B: Note the abundance of multinucleated cells.
and express ALK protein by immunolabeling, as shown h ere. C: An eosinophil is present in the center of the image.
66
Figure 2-61
PLEXIFORM FIBROHISTIOCYTIC TUMOR
A: The tumor is seen as multiple small nodules scattered
throughout the dermis and subcutaneous fat.
B: The individual nodules have the appearance of fibrous
histiocytoma.
C: The cells are mildly atypical.
and plexiform fibrohistiocytic tumors do not and extremities (87). Its growth pattern is very
(84-86). A more difficult distinction is between infiltrative such that it can extend for several
myxoid neurothekeoma and nerve sheath myx- centimeters beyond where the surgeon palpates
oma (figs. 2-63, 2-64); at least for us this requires the lesion, a source of many microscopically
immunolabeling for S-100 protein, which is positive margins. It can be regarded as a very
only seen in nerve sheath myxoma (85,86). If low-grade sarcoma since metastases are rare, but
immunolabeling is not available, this is not a some examples transform to overt sarcomas and
disaster, since both tumors are benign. do spread, although this is uncommon.
Dermatofibrosarcoma protuberans harbors a
Dermatofibrosarcoma Protuberans
characteristic translocation that results in a CO-
Dermatofibrosarcoma protuberans is a lesion LlA-PDGFB fusion (88,89). Because of this, the
of young adults. It is superficial {dermal and tumor cells have a very monotonous appearance
subcutaneous) and usually arises on the trunk and advanced examples (rare) can be treated with
67
Figure 2-62
CELLULAR NEUROTHEKEOMA
Left: There is a slight plexiform pattern (pockets of tumor separated by n ormal tissue) but there is minim al normal tissue
between the nests of tumor. Even at low magnification, the cells have an epithelioid appearance.
Right: The tumor consists of plump epithelioid cells organized in nests. The nesting and epithelioid cytologic features can
sometimes cause confusion with Spitz nevus or melanoma, but it is negative for S-100, SOXlO, and othermelanocytic immunostains.
Figure 2-63
MYXOID VARIANT OF
CELLULAR NEUROTHEKEOMA
The tumor is composed of myxoid
nests and is difficult to distinguish from
nerve sheath myxoma without application
of immunolabeling. If any cellular areas
or nests of round cells are present, it is
probably a myxoid variant of cellu lar
neurothekeoma rather than a nerve sheath
myxoma.
tyrosine kinase inhibitors (90). In general, there is skin appendages. It slinks along connective tis-
no need to test for the characteristic gene fusion sue septa, extending far from the main lesion.
to diagnose dermatofibrosarcoma protuberans. The cells are very monotonous and no more
Dermatofibrosarcoma protuberans infiltrates than a few enmeshed inflammatory cells are
the subcutaneous adipose tissue and proliferates seen. Hemosiderin is not a component. Some-
right up to the epidermis and slides between times there is a repetitive storiform pattern (fig.
68
Figure 2-64
NERVE SHEATH MYXOMA
A: The lobulated appearance is very similar
to that of myxoid neurothekeoma.
B: The appearance is clearly benign at high
magnification.
C: This is an S-100 protein stain. SOX10
would also be positive. Despite the name,
neurothekeoma is not actually neural and is
negative for S-100 and SOXlO.
'
~ -.. \
2-65). Mitoses can be seen but are usually not Fibrous histiocytoma (see figs. 2-55-2-58) has
plentiful. No one counts them because it is not variable cells sizes and shapes, an admixture of
important. When the cells become larger and plasma cells, lymphocytes, histiocytes, including
mitoses are plentiful (no need to count), that is foamy ones, h~osiderin, and collagen trap-
when transition to fibrosarcoma is considered ping at the pemphery. Scattered nuclear atypia/
(fig. 2-66). However, even with this transition pleomorphism favors fibrous histiocytoma rather
to a high-grade form, most patients have a fa- than dermatofibrosarcoma protuberans. Diffuse
vorable outcome following wide excision (91). neurofibroma (fig. 2-67) has smaller nuclei de-
This tumor has a lot of morphologic overlap spite identical infiltrative pattern, lots of mast
with two benign lesions: fibrous histiocytoma cells, and sometimes tactoid (Wagner-Meissner)
and diffuse neurofibroma. The distinction is bodies. In any doubtful case, diffuse neurofibroma
easy on H&E with a little practice. expresses S-100 protein and dermatofibrosarcoma
69
Figure 2-65
DERMATOFIBROSARCOMA PROTUBERANS
A: Thi s monotonous lesion extends to the epidermis at the right side of the image and is composed of cells with uniform
nuclei.
B: Note the repetitive storiform pattern and cytologic monotony. There are also essentially no inflammatory cells enmeshed
in the lesion. Pleomorphism is almost never seen in this tumor.
C: Some examples contain cells with melanin pigment, particularly in persons with pigmented skin. These are eponymously
termed Bednar turners.
D: This is a very high magnification of a dermatofibrosarcoma protuberans with melanin pigment. There are n o
inflammatory cells in the field.
70
Figure 2-66
DERMATOFIBROSARCOMA PROTUBERANS WITH FIBROSARCOMATOUS TRANSFORMATION
Left: Note that the storiform pattern has given way to a purely fascicular pattern and that the nuclei have become enlarged
but not pleomorphic.
Right: Note the prominent mitotic activity.
protuberans does not. CD34 labeling is frequent Bone Pathology. The histiocytes in Rosai-Dorf-
in nerve sheath tumors and can be ignored (92). man disease and Langerhan s cell histiocytosis
typically express S-100 protein whereas those
Giant Cell Fibroblastoma
in Erdheim-Chester disease do so about half
The juvenile form of dermatofibrosarcoma the time. The one that is easiest to diagnose on
protuberans, giant cell fibroblastoma (88,93- 95), H&E is Rosai-Dorfman disease.
is easy to diagnose if it is considered, and has the The key finding in Rosai-Dorfman disease
same COLlA l-PDGFB gene fusion and the same is the presence of emperipolesis in which his-
immunolabeling pattern (CD34-positive) as tiocytes ingest 6fher cells without damaging
dermatofibrosarcoma protuberans. It typically them (96). Rosai-Dorfman disease was initially
arises in the first decade of life as a subcutaneous noted in lymph nodes in children and termed
lesion displaying a combination of spindle cells "sinus histiocytosis with massive adenopathy"
and multinucleated giant cells, myxoid areas, by Drs. Rosai and Dorfman (97,98), but later
and sinusoid-like spaces (see fig. 2-46) (95). it was described all over the body, to include
the soft tissues (99) and gastrointestinal tract
Rosai-Dorfman Disease, langerhans Cell
(100). The term "sinus histiocytosis with mas-
Histiocytosis, and Erdheim-Chester Disease
sive adenopathy" is a poor term for extranodal
These lesions are all histiocytic disorders. sites, so the term Rosai-Dorfman disease has
Langerhans cell histiocytosis and Erdheim-Chester been adopted. Rosai-Dorfman disease is usually
disease share BRAF mutations and all can be managed surgically, but some patients require
found in the soft tissues, but Langerhans cell immunodulatory therapy.
histiocytosis tends to be found in bone and The diagnosis is straightforward in enlarged
will be emphasized in the Survival Guide to lymph nodes because the emperipolesis is
71
Figure 2-67
DIFFU SE N EUROFIBROMA
A: At low magnification the lesion resembles dermatofibrosarcoma protuberans in that it infi ltrates between skin appendages
and fat rath er than destroying them, but it spares the zone just beneath the surface.
B: There is a tactoid (Wagner-Meissner) body in the center of the image (arrow), th e characteristic finding of diffuse
n eurofibrom a, a benign lesion.
C: The nuclei are tiny. The tumor slips between skin appendages.
0 : Many cells of the tumor express S-100 protein, unlike dermatofibrosarcoma protubera ns, which is S-100 negative.
Pitfall alert: CD34 is positive in both entities.
72
Figure 2-68
ROSAI-DORFMAN DISEASE
A: At low magn ification, the tumor cells appear pale. There are many lymphoid aggregates arranged in a checkerboard
pattern. The alternating pink and blue areas provide a usefu l low magni fication clue to the diagnosis.
B: Th ere is a storiform pattern but the cells have paler cytoplasm than those in IgG4-related fibrosclerosing disease or
inflammatory myofi broblastic tumo r.
C: A cell in th e lower right part of the image (arrow) has engulfed lymphocytes without destroyin g them (emperipolesis).
Note the characteristic histiocyte with large round nucleus, pale chromatin and prominent n ucleoli.
D: This is an S-100 protein stain. An abnormal histiocyte shows nuclear and cytoplasmic labeling and has engu lfed
inflammatory cells that do not stain.
73
. \ ·.
' '
,.
~
., .~.'
.
\ .._,.·.
. (
.)
··'
: ) ~.
Figure 2-69
LANGERHANS CEll HISTIOCYTOSIS
A: This example is dermal.
B: Note the nuclear grooves (arrows) and background eosinophils.
C: There is strong S-100 protein expression.
D: This is a CDla stain.
conspicuous in dilated sinuses. In extranodal appearance virtually identical to that of IgG4-as-

sites, the appearance is that of a fibroinflamma- sociated fibrosclerosing disease, namely, zones
tory process but the emperipolesis is apparent of storiform fibrosis and numerous plasma cells.
in areas that are less cellular (fig. 2-68). If an IgG4 stain is performed, this will result
For those nervous about diagnosing this in an incorrect diagnosis unless the absence of
condition, the abnormal histiocytes express obliterative venous changes is appreciated (79).
S-100 protein. However, extranodal Rosai-Dorf- Langerhans cell histiocytosis (fig. 2-69) often
man disease remains mostly an H&E diagnosis. requires confirmation with ancillary studies (S-
Rosai-Dorfman disease can have areas with an 100, CD1a, and Langerin/CD207 labeling (S-100
74
Figure 2-70
ERDHEIM·CHESTER DISEASE
A: The appearance is wholly nonspecific, with a tume-
factive mixture of fibrous tissue, histiocytes, and lymphocytes.
B: Multinucleated histiocytes are prominent in this field.
C: About half of cases shows S-100 protein expression
in the lesional histiocytes.
~". - t' · tt I • ~...,. .._ ' f
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protein labeling, COla labeling, langerin label- will not discuss them in detail. Nevertheless,
ing and BRAF mutational testing for targeted the core morphologic features of smooth muscle
therapy), whereas Erdheim-Chester disease is a turners are the same regardless of the malignant
clinicopathologic correlation diagnosis because potential. They are characterized by cells with
of its nonspecific histologic features (fig. 2-70). brightly eosinophilic cytoplasm arranged in
fascicles that are perfectly perpendicular to one
SMOOTH MUSCLE AND SMOOTH another. The cytoplasm does not extend in all
MUSCLE-RELATED LESIONS directions like the cytoplasm in myofibroblasts
(the cell type of fibromatosis and nodular fasci-
Leiomyoma and Leiomyosarcoma
itis) but forms a perfect line in continuity with
Since every pathologist gains familiarity with the long axis of the nucleus (figs. 2-71,2-72). Add
leiomyomas early on because they are frequently on nuclear hyperchromasia, increased cellularity,
encountered in hysterectomy specimens, we and mitoses, and the lesion is malignant.
75
.. i
"
..;·
( '
',.;
"
-~
Figure 2-71
LEIOMYOMA
A: This is a very rare type, the so-called "benign metastasizing leiomyoma" of the uterus, which is benign but extends into
uterine vessels and spreads to the lung. It is treated by metastasectomy and hormonal manipulation and is not malignant.
B: The cells have brightly eosinophilic cytoplasm containing delicate hair-like longitudinal striations. The nuclei are
blunt-ended, and the fascicles are perfectly perpendicular such that one fascicle sweeps across the image whereas the other
has been cut in a fashion that the nuclei appear round because they have been cut in coronal sections.
C: This is a desmin stain from the benign metastasizing leiomyoma depicted in figure A.
0: This is a progesterone receptor stain from the benign metastasizing leiomyoma depicted in figure A.
76
Figure 2-72
LEIOMYOSARCOMA
A: Like leiomyomas, leiomyosarcomas have brightly eosinophilic cytoplasm, blunt-ended nuclei, and perpendicular
fascicles. Mitotic activity is seen.
B: There is scattered nuclear pleomorphism.
C: Note the nuclear hyperchromasia.
D: Note the nuclear hyperchromasia and perpendicularly oriented fascicles. When retroperitoneal, these tumors often
arise in association with large veins.
77

LEIOMYOSARCOMA
E: This example h as myxoid change.
F: There is nuclear hyperchromasia, mitotic activity, and a paranuclear vacuole in one of the cells in the center of the image.
Leiomyosarcom as tend to arise in deep soft (104). Those who make the mistake of ordering
tissue, particularly in association with retroper- KIT or DOG 1 immunolabeling may regret it.
itoneal blood vessels. For skin lesions, tumors 3) If a patient with many cutaneous leiomyo-
restricted to the dermis with the same features mas is encountered (use H&E alone), consider he-
as leiomyosarcomas are diagnosed as "atypical reditary leiomyomatosis and renal cell carcinoma.
smooth muscle neoplasms" by some to under- These persons often manifest uterine leiomyomas
score their indolent behavior following excision as well. Here is a situation for which immunola-
(101). In contrast, when such tumors invade the beling can support the concern since such patients
subcutaneous tissue, some metastasize. have alterations in the gene that encodes for
fumarate hydratase, and an immunostain can
Important Pitfalls Concerning
address this (fig. 2-76) (105).
Smooth Muscle Tumor
For those who prefer to add immunolabeling,
1) Large retroperitoneal smooth muscle tu- leiomyomas generally strongly express desmin,
mors in women, especially young women, are smooth muscle actin, calponin, and caldesmon.
often leiomyomas despite teaching that retro- However, sometimes classic leiomyosarcomas
peritoneal smooth muscle tumors are usually lack desmin expression. This is acceptable.
leiomyosarcomas (102). Such tumors often ex- Of course, so me leiomyosarcomas require
press hormone receptors. Furthermore, they can immunolabeling for diagnosis, but many can
have an adipose tissue component (myolipoma be diagnosed without.
or lipoleiomyoma) (figs. 2-73, 2-74) (103).
Glomus Tumor
2) Leiomyomas of the gastrointestinal tract
often contain Cajal cells that are either entrapped In line with their monotonous cyt ologic fea-
or proliferate with the lesion. Spindled mast cells tures, glomus tumors harbor a MIR143-NOTCH
can be present in such leiomyomas (fig. 2-75) gene fusion. They most often arise in young
78
Figure 2-73
RETROPERITONEAL GYNECOLOGIC TYPE LEIOMYOMA
A: The nuclei are small and the cytoplasm brightly
eosinoph ilic.
B: Note the delicate nuclear chromatin and the smooth
nuclear m embranes. Compare the nuclei to those of
the endothelial cells in the capillary in the center of the
image. The endothelial cells have darker nuclei. Note also
the de lica te longitudinal cytoplasmic striations in the
leiomyoma cells.
C: There is strong nuclear labeling with an estrogen
receptor immunostain.
'1 / I - _. tt..- ; ,; ' •" 111 , I ,•

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adults and there is no gender predilection. They (but not chromogranin) such that they are easy
tend to arise in the distal extremities, where they to mistake for neuroendocrine tumors. Fortu-
produce pain. The "common uncommon" site nately, they lack keratin labeling. The basement
is the muscularis propria of the stomach. membrane encircling each cell can be highlight-
Glomus tumors are richly vascularized and ed with collagen type IV or laminin stains.
composed of little round cells separated by a
Myofi broma/ Myopericytoma
basement membrane that is easy to spot (fig.
2-77). Most are benign, but rare examples show Myofibroma and myopericytoma are within a
overtly m alignant features and can metastasize. morphologic spectrum with glomus tumors.
These tumors differentiate along the lines of Many have alterations in t he PDGFRB gene
modified perivascular smooth muscle cells (peri- (106-108), which can be exploited with targeted
cytes). As such, they express SMA but not desmin. therapy with i~atinib in the familial/extensive
A pitfall is that they can express synaptophysin form (myofibromatosis) (107).
79
Figure 2-74
MYOLIPOMA (LIPOLEIOMYOMA)
A: These tumors are often found in the pelvic soft tissue
of young women. The smooth muscle component resembles
retroperitoneal gynecologic type leiomyomas, but these
tumors contain adipose tissue.
B: There is a perfect collision between smooth muscle
and fat in this area.
C: There is strong expression of estrogen receptor by
immunolabeling.
These tumors were first described in babies neoplasms diagnosed as hemangiopericytoma

and children as multiple syndromic lesions years ago have been subsumed under the soli-
(109), but it was quickly noted that such tumors tary fibrous tumor category (111) .
are usually solitary, arising in adults (110) with
no gender predominance. Most are in the sub- SKELETAL MUSCLE TUMORS
cutis. Those in infants tend to be deeper.
Embryonal Rhabdomyosarcoma
These tumors are usually small (1 to 3 cm)
and well marginated . They have a biphasic In the correct clinical setting, embryonal rhab-
pattern consisting of myoid areas and richly domyosarcoma is easy to diagnose on H&E. There
vascular areas with more primitive cells and a is no confirmatory molecular test for it, but in
hemangiopericytoma-like vascular pattern (fig. modern practice, most colleagues would con-
2-78). In many respects, they can be regarded firm the H&E interpretation with desmin and
as the true hemangiopericytoma now that most myogenin (or available alternative staining).
80
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Figure 2-75
ESOPHAGEAL LEIOMYOMA
A: The tumor is clearly benign and has been present long enough to mineralize.
B: The tumor is h ypocellular and brightly eosinoph ilic.
C: This is a desmin stain. There was no need to do it- gastrointestinal stromal tumors are more cellular.
0: This DOG 1 stain labels mast cells and Cajal cells that are a component of the lesion. This scattered pattern of staining
should not be used to diagnose gastrointestinal stromal tumor.
81
,
'~ -, .
... ~-
..
r '
t.
.' ,' ,,, '\
.A;,'~
,. I f'~• .,. ,., _, ,~!-
. ·:;:• /: . . ''. ''"..

Fumara'\:e hydratase · · ·
..
.. ·defident'leio~yoma
I ••
.. j (
1{
t, I
'·. ..
,/ '
'( I
(.
I •
~\
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.·
~- . ...."' .
Figure 2- 76
CUTANEOUS LEIOMYOMA ASSOCIATED WITH FUMARATE HYDRATASE DEFICIENCY
A: This was one of several leiomyomas biopsied from the same young adult patient. Th e lesion is indicated (arrow).
B: At h igh magnification, the find ings are like those of leiomyomas in other anatomic sites. The fascicles of cells are
perpendicularly align ed and brightly eosinophilic.
C: This is a fumarate hydratase immunostain. There are plenty of positive internal controls but the leiomyoma is negative.
D: This fumarate hydratase stain is annotated to show the lesion and an internal control.
82
Figure 2-77
GLOMUS TUMOR
A: The neoplasm is richly vascularized and consists of
perfectly round cells. There are prominent cell borders. The
chromatin is reminiscent of that seen in neuroendocrine
tumors.
B: The nuclei are round, and the cytoplasm is lightly
eosinophilic.
C: These tumors are composed of cells that differentiate
along the lines of modified smooth muscle cells such that
there is smooth muscle actin expression (shown) but not
desmin expression. Endothelial markers will be negative
in round tumor cells and stain only the vascular channels.
Embryonal rhabdomyosarcoma tends to arise rhabdomyosarcomas usually have focal rather

in the head and neck and genital regions of babies than diffuse myogenin expression, whereas the ex-
and small children, and can appear innocuous pression is diffuse in alveolar rhabdomyosarcomas.
histologically. Expect it on a pediatric bladder or The tumor cells tend to have densely eosin-
cervical biopsy, or from a head and neck lesion. ophilic cytoplasm. Rarely, cross striations are
The exotic site is the gallbladder. The key finding detected, but there is no need to look for them.
is the tendency of the tumor cells to condense Such cases are, as noted, easy to diagnose.
just under the surface, which has been referred to Unfortunately, sclerosil(g rhabdomyosar-
as a cambium layer since it has an arrangement coma, which also tends to arise in the head
similar to that of the cambium layer of a tree trunk and neck or genital region, often in adults,
sliced in cross section (figs. 2-79, 2-80). In general, often has a more nonspecific appearance and
babies do not get cystitis, so be worried if a biopsy immunolabeling is generally required to con-
is taken from a baby's bladder. Also, embryonal firm the interpretation (fig. 2-81).
83
.,
I
.
Figure 2-78
MYOFIBROMA
A: This tumor is biphasic with hypocellular myoid areas
and hypercellular hemangiopericytomatous areas. These
tumors are benign.
B: This image shows the juxtaposition between the
myoid lobules and hemangiopericytomatous component.
Different lesions have different proportions of the two
elements and some have areas that resemble glomus tumors
(glomangiomyofibroma).
C: The myoid areas feature a slight chondroid appearance
but the lesional cells have eosinophilic myoid cytoplasm.
D: This example is nearly purely hemangiopericytomatous.
E: This is a high magnification of the lesion seen in
figure D.
84
Figure 2-79
BOTRYOID
RHABDOMYOSARCOMA
Botryoid refers to the grape-
like clinical/gross appearance
of the tumor, which arises in
mucosal sites such as the genital
region or head and neck. This
example arose in the vagina.
The tumor tends to show
augmented cellularity just under
the epithelium (arrows), creating
a so-called cambium layer since
it is reminiscent of the rings in a
cut tree beneath the bark.
--.·-- ·r
/ . \
•
/
,
..,. .
/
•
D'
Figure 2-80
EMBRYONAL RHABDOMYOSARCOMA
A: There are hyperchromatic nuclei and eosinophilic cytoplasm. With this morphology, embryon al rhabdomyosarcoma
is the key consideration in a biopsy from the head and neck or genital region of a baby or young child.
B: Note the nuclear features and the suggestion of cytoplasmic cross striations.
C: Desmin immunolabeling is typically strongly reactive.
D: Do not expect to see diffuse myogenin labeling. In the context of the correct history and morphology, very focal
nuclear labeling (arrows) is confirmatory.
85
Figure 2-81
SCLEROSING RHABDOMYOSARCOMA
Left: lmmunolabeling is important in confirming this interpretation since the H&E findings can be nonspecific. The key
is to consider it in samples from adults with prominent sclerosis.
Right: This particular case is treacherous. There is low cellularity, and the presence of n uclear hyperchromasia is the only
clue to even consider a sarcoma. This is not an H&E diagnosis.
A somewhat macabre way to recall this: the

Alveolar Rhabdomyosarcoma
patient with a tumor with PAX3 fusions may
Alveolar rhabdomyosarcoma is a high-grade live 3 years, whereas the one whose tumor har-
round blue cell malignant neoplasm that arises bors the PAX7 fusions will enjoy 7 years. These
in adolescents and young adults in the deep soft figures are not accurate, but simply a construct
tissues, often the deep muscles of the thigh. to recall that patients with PAX7 fusions have
There is a male predominance. Many cases are a better outcome. ALK alterations have been
readily recognized on H&E and the diagnosis detected in both embryonal and alveolar rhab-
is simply confirmed by immunolabeling. Clas- domyosarcoma, but results of early studies ex-
sic lesions show spaces that contain cells with ploiting these targets have been disappointing
brightly eosinophilic rhabdomyoblasts (fig. (113,114).
2-82). Such zones, however, may not be appar-
Gastrointestinal Stromal Tumor
ent on small samples, and then immunolabel-
ing becomes critical, especially in separating An exhaustive discussion of gastrointestinal
malignant rhabdoid tumors and other round stromal tumors is beyond the scope of this slim
cell sarcomas, as shown in chapter 3. soft tissue volume, but it is important to recall
It has been known for years that molecular that these tumors are lesions of adults with one
testing prognosticates for alveolar rhabdomyo- exception and that they almost always have uni-
sarcoma far better than old fashioned methods form-appearing cells. They are easy to separate
(112): PAX3-FOX01-more aggressive; PAX7- from leiomyosarcomas and leiomyomas (fig. 2-83).
FOX01-1ess aggressive. The type of gastrointestinal stromal tumor found
86
Figure 2-82
ALVEOLAR RHABDOMYOSARCOMA
A: Other than the unusual gastrointestinal tract location,
this lesion shows classic features. There are spaces that
reminded our forefathers of lung alveoli; the tumor is
otherwise a round blue cell sarcoma.
B: This high-magnification image shows round blue cells
and rhabdomyoblasts (arrows).
C: Note the brightly eosinophilic appearance of the
cytoplasm of the rhab!Eyoblasts.
D: A mu ltinucle t ed rhabdomyoblast with cross
striations is surround d by round blue cells.
E: These tumors are desmin reactive and a majority
of nuclei label with myogenin antibodies. Nearly all the
cells label with myogenin, shown here, in contrast to focal
labeling in embryonal rhabdomysarcoma.
87
Figure 2-83
GASTROINTESTINAL STROMAL TUMOR
Left: Compare the cellularity of this small bowel gastrointestinal stromal tu m or to that of the fibromatosis in figure 2-43A
and to that of the esophagealleiomyoma in figure 2-?SA.
Right: Note the monotonous appearance of the nuclei. Nuclear pleomorphism is unusual in gastrointestinal stromal tumors.
in children is the succinate dehydrogenase-defi- cells but they lack the coating layer of nonen-
cient type. It is always in the stomach and has a dothelial cells in general.
plexiform growth pattern (fig. 2-84). The term "hemangioendothelioma" has been
over-used in the past to encompass exuberantly
VASCULAR TUMORS growing capillary hemangiomas in babies and
children, but it currently connotes a vascular
General Points Concerning Vascular Tumors
lesion that is malignant but conveys far less risk
There are numerous unimportant subtypes than an angiosarcoma.
of hemangiomas that have been described,
Capillary Hemangioma
and we will not attempt to elaborate on each
in detail but simply illustrate some of them Capillary hemangioma is the most common
and discuss separating them from malignant tumor of infancy, with an female:male ratio
vascular lesions. of 3:1. In children, capillary hemangiomas
Essentially, benign vascular lesions partici- are typically cellular and are thus referred to
pate in the overall program of creating tubes as infantile hemangioendothelioma, juvenile
lined by endothelial cells and cuffed by other hemangioma, strawberry nevus, and cellular
cells, including smooth muscle cells, through capillary hemangioma. Capillary hemangiomas
which erythrocytes or white blood cells can usually involve the skin or subcutis of the head
pass. Some well-differentiated angiosarcomas and neck. They typically proliferate in the first
make endothelial cell tubes that transport other few months of life, then regress and, in many
88
Figure 2-84
SUCCINATE DEHYDROGENASE-DEFICIENT
GASTROINTESTINAL STROMAL TUMOR
A: These are gastric tumors, arising in the muscularis
propria. At low magnification there is a prominent plexiform
pattern and the cytologic features are monotonous.
B: Note the epithelioid cytologic features and rich
vascularity. The nuclei of the tumor cells are larger than
those of the endothelial cells.
C: This is an SDHB stain, which is lost in the tumor cells.
Since succinate dehydrogenase is a component of the Krebs
cycle, it is present in most cells so the endothelial cells, nerves,
and smooth muscle cells are positive internal controls.
instances, completely involute. In half of un- vascular tumors or malformations (which do

treated patients, superficial lesions involute to not regress). GLUT1 also labels a variety of
normal skin by 5 years of life and from 70 to nonvascular neoplasms. The endothelial cells
90 percent of patients are "cured" by 7 years of in capillary hemangiomas express CD34 and
age (115). Capillary hemangiomas consist of CD31 but not podoplanin (DZ-40).
a mixture of endothelial cells, pericytes, and
Pyogenic Granuloma/
fibroblast-like cells. The endothelial cell nuclei
lobular Carillary Hemangioma
can have prominent nucleoli and pronounced
mitotic activity. Pyogenic granulomas (lobular capillary hemanio-
GLUT1 is usually expressed in the lesional mas) may involve mucosal, cutaneous, subcuta-
endothelial cells of most infantile hemangi- neous or even intravascular sites. When these
omas (which are likely to regress) during all tumors are found in children, there is a male
stages of their natural history but not in other predominance, whereas young adults are mostly
89
Figure 2-85
PYOGENIC GRANULOMA LOBULAR CAPILLARY HEMANGIOMA
A: Note the collarette of epidermis hugging the protuberant lesion.
B: In this example, larger vessels spill into progressively smaller ones in the manner of branches and leaves on a small bush.
C: The lesion is cellular but a cuff of other cells that support the endothelial cells surrounds each tiny vessel.
D: This high-magnification image shows a maturing capillary hemangioma. This process is clearly a vascular lesion and
is arranged in a lobular configuration.
females. There is equal gender incidence over Pyogenic granuloma is a well-marginated

40 (116). proliferation of small capillary-sized vessels
Approximately 1 percent of pregnant women arranged in a multilobular pattern, with larger
develop pyogenic granulomas in the oral mu- vesels branching into progressively smaller
cosa, especially the interdental regions of the ones. Polypoid or pedunculated lesion s often
gingiva. These typically appear in the first tri- have a collarette of hyperplastic epithelium (fig.
mester, and regress postpartum. Some pyogenic 2-85). The endothelial cells express CD34 and
granulomas are intravascular (117). CD31, but not GLUTl.
90
Cavernous Hemangioma
Cavernous hemangiomas are common in both
children and adults, without a gender predilec-
tion, and they usually arise in the upper half of
the body. They do not regress. Examples occur-
ring in deep soft tissue and organs (liver, bone,
intestines, lung) are also well known.
Cavernous hemangiomas consist of either
a lobulated or poorly marginated collection of
engorged thin-walled vascular channels lined
by flattened endothelium (fig. 2-86). Supporting
elements (pericytes, smooth muscle cells, and
fibroblastic cells) are less prominent than in
capillary hemangiomas but they are found.
Anastomosing Hemangioma
Anastomosing hemangioma is the hemangioma
type that is likely to cause anxiety concerning
angiosarcoma. This type was initially described
in the kidney and male genital tract, but it can
be detected anywhere (118-120). This heman-
gioma has been shown to harbor GNA14 and
GNAQ mutations (121).
Its features are those of a lesion with a sinusoidal Figure 2-86
pattern accompanied by endothelial cells with a
hobnail appearance (that means they poke out CAVERNOUS HEMANGIOMA
into the lumen of the vessel). Since both of these Note the gaping thin-walled vessels, each stuffed with
erythrocytes.
features are part of angiosarcoma, these lesions can
cause alarm. However, they are overall well-margi-
nated (even though necrosis can be seen) and they
basically consist of tubes through which blood Some atypical deep soft tissue and skele-
passes that are enrobed with a coating of cells that tal examples display fusions of FOSB (125),
are not endothelial cells (fig. 2-87). whereas cutaneous examples lack these fusions.
However, all epithelioid hemangiomas lack
Epithelioid Hemangioma (Angiolymphoid
the WWTRl-CAMTAl fusions that character-
Hyperplasia with Eosinophilia)
ize epithelioid hemangioendothelioma (126).
Epithelioid hemangioma is a lesion of adults Regardless, morphology separates epithelioid
(20 to 40 years) with no gender predominance hemangioma from epithelioid hemangioendo-
(122). They are most common in the head-neck thelioma in nearly every case.
region and present as papules (123).
Angiomatosis and Intramuscular Hemangioma
Subcutaneous examples are characterized by a
prominent proliferation of capillary-sized vessels These are strictly H&E diagnoses. No staining
that are lined by plump epithelioid (histiocytoid will help. Intramuscular hemangiomas/angiomas
[124]) endothelial cells. Mild cytologic atypia are uncommof». without gender predilection,
may be noted, but generally the nuclei have and most cases are identified in the first three
small nucleoli. The vascular proliferation is fre- decades of life (127-129). The lower extremi-
quently associated with a medium-sized artery or ty, in particular the quadriceps femoris, is the
vein that shows histologic evidence of damage main site, but any muscle may be involved. Soft
(fig. 2-88) (122). The process is commonly cuffed tissue swelling and pain are the most frequent
peripherally by lymphoid follicles. Eosinophils manifestations. Recurrences are common and
are usually present. attributable to incomplete excision.
91
Figure 2-87
ANASTOMOSING HEMANGIOMA
A: This type of capillary hemangioma can appea r alarming since the vessels are thin, lined by endothelial cells with
hobnail features (they protrude into the lumin a), and are seen in a sinusoidal pattern.
B: A ring of supporting nonendothelial cells surrounds each vessel.
C: The n uclei of the endothelial cells are small and dark.
D: These tumors sometimes con tain hyaline globules and extramedullary h ematopoiesis, particularly ren al examples.
Note t he multinucleated megakaryocyte.
92
Figure 2-88
EPITHELIOID HEMANGIOMA/
ANGIOLYMPHOID HYPERPLASIA
WITH EOSINOPHILIA
A: The tumor is well marginated,
lobulated, and surrounded by a lymphoid
cuff. There is a feeder vessel supplying the
process on the right.
B: The vessels are lined by plump
epithelioid endothelial cells and form a tube
through which erythrocytes can flow. A few
eosinophils are scattered in the background.
C: Sometimes the centers of these tumors
have areas in which the endothelial cells are
arranged in sheets. If there is vasoformation
at the periphery of the lesion, the solid
central areas can be ignored.
These vascular tumors can be histologically cat- Angiomatosis is a histologically benign vascular
egorized according to vessel size or type (capillary, proliferation growing contiguously in multiple
cavernous, arteriovenous, lymphatic) but some tissue planes or extensively in tissues of the
authors have suggested that all of these lesions, same type (e.g., apposed muscles) (130,131).
including capillary, cavernous, arteriovenous, The lesions are usually in the deep subcutaneous
lymphangiomatous, and complex malformation tissue and muscles, but more superficial tissues
types be regarded as intramuscular "angiomas" or underlying bone may also be involved. Most
(128), since most have mixed features and there patients are children, frequently in the first year
is no correlation between the predominant vessel of life (131). The most common symptoms are
type and the clinical outcome. Most important- persistent diffuse swelling, pain, and tenderness.
ly, all types of vessels can be accompanied by Limb hypertrophy is present only infrequently.
abundant fat. Atrophic skeletal muscle is often Angiomatosis shows a conglomerate of large
intermixed with the lesion. irregular venous segments with disorganized
./
93
affects the lower extremities of the elderly, the

endemic form was initially noted in sub-Saharan
Africa, and the immunosuppression-associated
type was encountered in association with trans-
plantation and during the AIDS epidemic. All
types are associated with human herpesvirus 8
(HHV8) and their histologic features are super-
imposable. Immunolabeling to detect HHV8
can be used to confirm a diagnosis of KS.
Although the core features of KS are the
same throughout the body, in the skin, there
are classically described stages of the lesions.
In the early, patch stage of KS (fig. 2-90), the
findings predominate in the upper half of the
reticular dermis, consisting of a proliferation
of capillaries around preexisting dermal vessels
and adnexa. The endothelial lining is flattened
or slightly plump. Some endothelial cells may
contain apoptotic nuclei. The protrusion of small
proliferating capillary channels into the vascular
lumen of a larger, preexisting dermal vessel has
been termed the "promontory" sign, and has
diagnotic importance (132). Bland-appearing
spindled cells tend to be a minor component.
Figure 2-89 A variable inflammatory infiltrate, dominated
by lymphocytes, with or without plasma cells,
ANGIOMATOSIS
is frequently present. Extravasated erythrocytes,
This lesion consists of disorganized vessels accompanied hemosiderin deposition, and intracytoplasmic
by adipose tissue.
PAS-positive, diastase-resistant, hyaline globules
may be noted.
muscular walls, cavernous vessels, and capillary In the plaque stage (fig. 2-91 ), the spindled
channels, scattered diffusely throughout tissue component of KS becomes readily evident.
planes and often associated with large amounts of These cells form slit-like spaces that frequently
adipose tissue (fig. 2-89). A characteristic feature is contain red blood cells. Plasma cells and hemo-
the presence of capillary-sized vessels proliferating siderin deposits are also usually apparent as well
adjacent to and within the walls of the disorga- as hyaline globules (fig. 2-92), which are various
nized veins. Similar extensive lesions composed stages of erythrophagolysosomes.
of lymphatic vessels are known as "lymphangio- Nodular (tumor stage) KS, which forms a
matosis" or "lymphatic malformation." clinical nodule, consists of spindle cells forming
fascicles and sheets. Extravasated erythrocytes,
Kaposi Sarcoma
siderophages, hyaline globules, and a peripheral
An exhaustive description of Kaposi sarcoma lyphoplasmacytic infiltrate are typically present
(KS) is beyond the scope of this slim volume. (fig. 2-93).
However, the most important thing to recall is
Epithelioid Hemangioendothelioma
that it is not terribly consequential to underdi-
agnose early lesions and they essentially neither Most of the time, epithelioid hemangioendo-
metastasize nor cause morbidity except those thelioma (EHE) is an H&E diagnosis, but modem
in the gastrointestinal tract that are associated techniques have made it easy to confirm this di-
with hemorrhage. In general, clinically import- agnosis using immunolabeling for CAMTA1 (133),
ant lesions are easy to diagnose, especially in which mirrors the known WWTRl-CAMTA 1 gene
the correct clinical setting. The "classic" form alteration (126) .
94
Figure 2-90
KAPOSI SARCOMA
Left: The earliest lesions (patch stage) show only subtle increases in dermal cellularity.
Right: In this early example, the process proliferates just beneath preexisting endoth elium causing a small mound to
bulge into the preexisting capillary. This h as been termed the "promontory sign."
Figure 2-91
KAPOSI SARCOMA
Left: At this stage (plaque stage), there is no question that a dermal lesion is present.
Right: A spindle lesion is present. Note that it is present in an area adjacent to a small preexisting vessel.
/
95
EHE is a malignant vascular tumor but is

less aggressive than angiosarcoma, hence the
"hemangioendothelioma" designation. It can
manifest at any age although it is rare in chil-
dren. The main sites of involvement are the soft
tissue, lungs, liver, and bones.
Soft tissue examples have no gender predilec-
tion (134-136). The median age at presentation
is in the fifth decade. Soft tissue epithelioid
hemangioendothelioma is usually solitary, aris-
ing in the extremities. About half of cases are
associated with a medium-sized or larger vessel,
usually a vein. Metastases and tumor related
deaths were reported in 31 and 13 percent of
patients, respectively, in the 1980s (134), figures
that have changed little over time. In a 2008
study, for example, 22 percent of patients had
metastases and 18 percent died of disease (136).
Intravascular bronchioloalveolar tumor (IVBAT),
sclerosing endothelial tumor, sclerosing interstitial
vascular sarcoma, primary chondrosarcoma of the
lung, and pulmonary deciduosis are outdated
terms for pulmonary EHE. Most patients (up to
Figure 2-92 80 percent) are women, and the median age at
KAPOSI SARCOMA presentation is 40 years. Multiple and bilateral
Note the hyaline globules (arrows), which are simply nodules are typically noted at presentation.
erythrophagolysosomes.
Figure 2-93
KAPOSI SARCOMA
Left: This lesion is at the nodular/tumor stage.
Right: This is an HHV8 immunostain (LANA stain). Most of the nuclei are reactive.
96
Over half of patients die of disease, often over immnolabeling (142). There is an immunostain
a long course. for CAMTA1 that can be helpful in confirming
Before the vascular nature of EHE was un- the interpretation, particularly in hepatic biopsies
derstood, hepatic examples were interpreted as (the pattern of infiltration can make the diagnosis
sclerosing hepatic carcinomas, cholangiocarci- difficult on a small needle biopsy) (133).
nomas, or calcifying mixed malignant tumors
Atypical Vascular Lesion and Angiosarcoma
(137). Hepatic involvement is often multifocal,
with a slight female predominance. The mean Atypical vascular lesion is a term used for
age at presentation is approximately 40 years. lesions that are usually encountered in mam-
Reported 1-year and 5-year patient survival rates mary skin following radiation for mammary
are 96 and 54.5 percent, respectively, after liver carcinoma. They appear as a single or several
transplant; 39.3 and 4.5 percent, respectively, small papules or patches in the irradiated site.
after no treatment; 73.3 and 30 percent, re- Most behave in a benign fashion, but a subset
spectively, after chemotherapy or radiotherapy; progresses to angiosarcoma, often after several
and 100 and 75 percent, respectively, after liver recurrences (143). These lesions are very difficult
resection (performed in patients deemed resect~ to distinguish from very well-differentiated an-
able and thus with less extensive disease) (138). giosarcomas, both clinically and histologically.
Epithelioid hemangioendothelioma (EHE) of As a rule of thumb, atypical vascular lesions are
bone may involve any bone. There is a slight small (<1 cm) whereas angiosarcomas have a
male predominance and a wide age distribution median size of about 7 cm (144).
extending from the second through the eighth Some resemble benign lymphangiomas,
decade of life. EHE of bone is multifocal about consisting of a well-demarcated proliferation of
half the time. It tends to have an indolent course. thin-walled vascular channels (fig. 2-95). These
EHEs are composed of epithelioid (histiocyt- channels have an interanastomosing pattern
oid) and, occasionally, spindle or dendritic cells, and bland flat or hobnail endothelium and lack
embedded singly, in cord-like arrangements, or erythrocytes. Others display a more infiltrative
clusters within a matrix variably described as pattern but feature bland-appearing endotheli-
"myxohyaline" or "chondromyxoid" (fig. 2-94). um. Despite "atypical" in the name, significant
The cells are present singly and not in groups that nuclear atypia is not usually seen. A subset, how-
form tubules through which blood passes. Many ever, has endothelium that appears as a lobular
of the cells contain vacuoles ("blister cells"). capillary proliferation. These cases may be more
Occasionally, the vacuoles contain intraluminal likely to progress to angiosarcoma although the
erythrocytes, a sign of "early" or "primitive" va- lymphatic types can progress as well (145).
soformative differentiation-or a manifestation The endothelial cells in these lesions express
of an artifact in which an erythrocyte happens CD34 and CD31. Those with lymphatic differ-
to have been pushed into the vacuole by chance. entiation express podoplanin (D2-40) (145). The
Features of soft tissue EHEs that correlate with presence of MYC amplification distinguishes
more aggressive behavior include finding greater angiosarcoma from atypical vascular lesion
than 3 mitotic figures per SO high-power fields in the post-irradiation setting, but is not
and size greater than 3.0 cm (136). as helpful in other situations since well-dif-
EHEs variably express CD31, CD34, ERG, and ferentiated angiosarcomas unassociated with
Fli1 (139) and may also express (usually focal- localized edema and radiation often lack MYC
ly) keratins as well as ERG. They lack VEGFR-3, amplification (146-148). Interestingly, the rare
which argues against lymphatic endothelial dif- angiosarcomas that arise in association with
ferentiation (140). Epithelioid sarcomas can show massive localized lymphedema in the morbidly
ERG labeling as well, which can be a diagnostic obese can display MYC amplification (146).
pitfall (141). These tumors have a fusion involv- Angiosarcoma, for the purposes of this discus-
ing WWTRl and CAMTAl in many cases (126) sion, are fully malignant neoplasms of endothe-
or an alternate fusion, YAP1-TFE3, that has been lial derivation, whether lymphatic (lymphan-
described in young patients with tumors that giosarcoma) or of blood vessels (hemangiosarco-
feature focal vasoformation and express TFE3 on ma), since there is no therapeutic or prognostic
97
Figure 2-94
EPITHELIOID HEMANGIOENDOTHELIOMA
A: These lesions are often infiltrative when they arise
in the liver. The tumor has produced a chondromyxoid
response but the tu m or cells do not really form vessels, but
instead they appear singly.
B: Note the epithelioid appearance of the malignant
cells. Some have vacuoles in their cytoplasm that seem to be
intracytoplasmic lumina created by individual cells (rath er
than cells working cooperatively to create lumina). The cells
with these lumina are sometim es termed "blister cells."
C: Note the nuclear hyperchromasia and the intracyto-
plasmic lumina.
D: Whether the degenerative erythrocyte in the center
is truly flowing through the cytoplasmic lumen or simply
artifactually pressed there during tissue processing is unknown.
E: This is an ERG stain, which labels the tum or cells (as
well as benign endothelial cells).
98
Figure 2-95
--
ATYPICAL VASCULAR LESION
Left: The process is small, superficial, and well circum scribed.
Right: The vessels track into spaces between collagen bundles and lack supporting elements such that some of these
lesions can be difficult to separate from highly differentiated angiosarcomas.
relevance to the distinction. Angiosarcomas are unaccompanied by a cuff of supporting cells

rare, comprising less than 1 percent of all sar- around the vessel. Some examples are hemangi-
comas, with a strong predilection for the skin oma-like, in which the only clues of malignancy
and subcutis. Superficial angiosarcoma has three are the interanastomosing and infiltrative nature
clinical settings: 1) the face and scalp of the el- of the process, the presence of mild nuclear hy-
derly, 2) the extremities of patients with chronic perchromasia, and occasional crowding or piling
lymphedema, and 3) sites previously subjected up of the endothelium, sometimes forming small
to radiation therapy. Other key primary sites papillations. The opposite end of the spectrum
for angiosarcoma are: breast parenchyma, liver, includes both a spindle cell pattern reminiscent
deep soft tissue, skeleton, heart, and spleen. of fibrosarcoma or KS and an "undifferentiated"
Angiosarcomas are also reported in association pattern consisting of plump epithelioid neoplas-
with foreign bodies, defunctionalized arterio- tic cells with prominent nucleoli and diffuse
venous fistulae in transplant recipients, and in sheet-like growth, suggestive of carcinoma or
neurofibromatosis (149). Arsenical compounds melanoma. This latter end of the spectrum can
(i.e., Fowler's solution, arsenical insecticides), require ancillary studies to diagnose.
vinyl chloride, and thorium dioxide (Thoro- Angiosarcomas variably express fa ctor
trast) exposure have been implicated in the VIII-related antigen, CD31, UEA-1, FKBP12,
development of approximately one fourth podoplanin (02-40), ERG, and Fli-1. CD31 is a
of angiosarcomas arising in the liver but not sensitive marker of endothelial differentiation
usually in other sites and this association is but it is important to recognize that histiocytes,
mainly a thing of the past. Deep angiosarcomas as well as plasma cells, can express CD31, to
are epithelioid over half the time and are often avoid overdiagnosis of angiosarcoma (150).
not readily diagnosed using H&E staining only. Cytokeratins can also be expressed, especially in
Angiosarcoma has a wide morphologic spec- epithelioid angiosarcoma. A pitfall is that over
trum (fig. 2-96) but can often be recognized on half of angiosarcomas express CD117 (c-kit) but
H&E with a bit of searching for vasoformation lack KIT mutations (151).
99
Figure 2-96
ANGIOSARCOMA
A: This malignant neoplasm is clearly vasoformative in some but not all areas.
B: Some of the turner is vasoformative and the vessels are lined by markedly atypical cells.
C: When such tumors are arranged in sheets of malignant cells, immunolabeling is needed to confirm the diagnosis.
D: The extension into subcutaneous adipose tissue supports the malignant diagnosis.
As a word of caution, don't be fooled by pap- NEURAL-RELATED LESIONS

illary endothelial hyperplasia (fig. 2-97), which
Schwannoma
is simply dramatic organization of thrombi.
It was first described in a hemorrhoid using Most schwannomas arise in the head and
alarming terminology (vegetant hemangioen- neck area (153) although they can be found
dothelioma) (152), but it is benign (unless it is associated with nerves anywhere in the body.
complicating a malignant vascular lesion with Although they can be slightly infiltrative in the
pools of hemorrhage). gastrointestinal tract, most examples elsewhere
100

E: Tumors like this can be confidently diagnosed on H&E since there is obvious vasoformation and the spaces are lined
by overtly malignant endothelial cells.
F: Vessels lined by atypical endothelial cells that lack cuffs of other types of cells extend between adipocytes.
Figure 2-97
PAPILLARY ENDOTHELIAL HYPERPLASIA
A: This example is present in thrombosed hemorrhoidal
vessels.
B: There is ingrowth of endothelial cells into a zone of
thrombus.
C: This process is inside a thrombosed vessel (intravascular
angiosarcoma is rare), and endothelial cells coat fibrin cores
in a monolayer. This lesion is simply an exuberant form of
organization of thrombi.
101
are well-marginated and have the usual compo- (fig. 2-106). The key pitfall is their association
nent of cells, namely, spindle cells with nuclear with pseudoepitheliomatous hyperplasia of
atypia out of proportion to mitotic activity, overlying skin or mucosa. Infiltrative growth
a lot of secondary change (lymphocytes and and perineural involvement are common and
plasma cells, foam cells, hemosiderin), areas totally benign findings. Criteria for malignan-
with nuclear palisading, and myxoid areas (figs. cy in these neoplasms are necrosis, spindling,
2-98-2-103). vesicular nuclei with large nucleoli, increased
In the day of needle biopsies of retroperi- mitotic activity (more than 2 mitoses per 10
toneal masses, they are a frequent source of high-power fields at 200X magnification), h igh
anxiety but are easy to diagnose on H&E with nuclear to cytoplasmic (N/C) ratio, and nuclear
a little practice. This is accomplished by pre- pleomorphism (156).
tending that only a small fraction of a typical
Malignant Peripheral Nerve Sheath Tumor
schwannoma can be seen while reviewing a
resection. Of course adding an S-100 protein Malignant peripheral nerve sheath tumor used
stain can help, since it is strongly reactive. If to be called "malignant schwannoma" except
it is negative, pleomorphic hyalinizing angiec- that colleagues realized that these usually arise
tatic tumor (fig. 2-104) should be considered. from neurofibromas rather than schwannomas.
There is, however, an important pitfall once These are easy to diagnose on H&E only if the
immunolabeling is performed: retroperitoneal preexisting benign nerve sheath tumor is pres-
schwannomas have a proclivity to express ker- ent and in the setting of neurofibromatosis but
atin (fig. 2-103C) (154). otherwise these are a real challenge to diagnose,
As a note of caution, while most schwanno- even with modern ancillary techniques. Exam-
mas are well-circumscribed, when cellular ex- ples are shown in figure 2-107.
amples (which have a predominance of Antoni Molecular techniques offer some help in
A areas) arise in the paranasal areas, they are some sporadic cases. These tumors often have
infiltrative and mimic sarcomas (155). However, mutations in SUZ12, resulting in downstream
they have strong diffuse S-100 protein expres- alterations in trimethylated H3K27 (157-159).
sion (in contrast to malignant nerve sheath The latter protein can be assessed with immu-
tumors, which have weak or even negative nolabeling methods and is lost in up to half
S-100 protein). If immunolabeling is added, of malignant peripheral nerve sheath tumors
most nerve sheath tumors (regardless of type) (fig. 2-107F) (157,158). However, it is not lost
contain lots of CD34-reactive supporting cells, in the remainder, so the diagnosis can only be
which can be ignored (92). S-100 protein beats confirmed some of the time. Overall, malignant
CD34 in this setting. peripheral nerve sheath tumors show far weaker
S-1 00 protein expression than benign ones and
Neurofibroma
the same holds for other markers such as SOX10.
Most neurofibromas are easy to diagnose with Loss of S-100 protein labeling is a clue that a
H&E. There is kinky collagen plastered against neurofibroma has progressed to malignant pe-
wavy nuclei in a myxoid backdrop; the thick- ripheral nerve sheath tumor
walled vessels, inflammation, and foamy cells The epithelioid variant of malignant pe-
of schwannomas are absent (fig. 2-105). If S-100 ripheral nerve sheath tumor is best confirmed
protein is added, the staining is not as intense with immunolabeling but has a characteristic
as that in schwannomas. Features that suggest appearance (fig. 2-108) . Additionally, in contrast
low-grade malignant peripheral nerve sheath to spindled malignant peripheral nerve sheath
tumor revolve around mitotic activity and loss tumor, the epithelioid form displays strong
of the kinky collagen. S-100 protein expression (160). It can also
display loss of SMARCB1 /INI1, a phenomenon
Granular Cell Tumor
that it shares with an ever-growing list of other
Granular cell tumors are readily diagnosed neoplasms, among which epithelioid sarcoma
on H&E based on the presence of the granular and malignant rhabdoid tumor are the key
appearance of the cells and the small nuclei players (161,162).
102
Figure 2-98
SCHWANNOMA
A: This image n icely demonstrates Antoni A (cellular) and Antoni B (myxoid) zones. Note that several of the cells are
enlarged and that the nuclei are hyperchromatic at this magnification . The lesion is very well marginated.
B: Cellular (Antoni A) and hypocellular (Antoni B) areas are nicely separated. Even at this relatively low magnification,
lymphocytes are sprinkled in the tumor.
C: A Verocay body is present. These are similar to tactoid (Wagner-Meissner) bodies as seen in diffuse neurofibroma (fig.
2-67B) but the nuclei are a bit larger and arranged in rows of elongated nuclei separated by fibrillary material. Additionally,
schwannomas are well marginated whereas diffuse neurofibromas are quite infiltrative. Note also that there are scattered
lymphocytes in the lesion.
D: This is high magnification of a Verocay body. The nuclei have variable sizes and shapes and several of them contain
intranuclear cytoplasmic pseudoinclusions.
103

PLEXIFORM SCHWANNOMA SCHWANNOMA
So me of the nod ules are h ypercellular and so me This area contains cells that have small round h yperchro-
a re hypocellu lar. Regardless, each n odu le of tumo r is matic nuclei. A sarcoma might be considered except that
surrounded by a slim ring of perin eurium. closer inspection would reveal only rare mitotic figures.
Figure 2-101
RETROPERITONEAL SCHWANNOMA,
NEEDLE BIOPSY
A: Even in this scant sample, hypocellular and
hypercellular zon es are present.
B: The thick walled vessels are a clue that this is
a schwannoma without adding immunolabeling,
but those with anxiety can seek reassurance in
the form of a positive S-100 protein stain.
C: This S-100 protein stain is strongly reactive
in both nuclei and cytoplasm. A
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104
Figure 2-102
SCHWANNOMA
Left: Note the variable cellularity, hemorrhage, and thick-walled vessels.
Right: Even in cellular areas, thick-walled vessels are a helpful clue that the lesion is benign.
Figure 2-103
RETROPERITONEAL SCHWANNOMA,
NEEDLE BIOPSY
A: Note that the nuclei are mildly hyperchro-
matic with some variability in size and shape.
B: This S-100 protein stain is strongly reactive.
For an S-100 protein stain to be considered positive,
both nuclei and cytoplasm should stain.
C: This is a cytokeratin stain. Retroperitoneal
schwannomas commonly express keratin, a pitfall
for the unwary. The nervous pathologist should
stick to S-100 protein to confirm a schwannoma
diagnosis.
105
Figure 2-104
PLEOMORPHIC HYALINIZING ANGIECTATIC TUMOR
A: These rare lesions superficially resemble schwannomas but have somewhat more atypical nuclei and more promin ent
hyalinized blood vessels with abundant hemosiderin. Rarely, sarcomas arise in association with pleomorphic hyalinizing
angiectatic tumor, a phen omenon still rarer than association with schwannomas.
B: Note the bizarre nuclei. These tumors are nonreactive with S- 100 protein and often express CD34.
C: The thick-walled vessels are a key feature. Often hemosiderin is prominent (not shown). Hyperchromatic pleomorphism
is present but mitoses are very scarce.
D: This is a CD34 stain.
106
Soft Tissue Lesions that Can Be D iagnosed on Routine H&E Staining
Figure 2-105
NEUROFIBROMA
Left: The lesion is well marginated, with a coating of perineurium in most cases other than the diffuse neurofibroma form,
which is infiltrative (fig. 2-67). Note that there is prominent wiry collagen that some liken to the appearance of shredded carrots.
Right: Note how the serpentine nuclei clasp the associated collagen. Mast cells are often present in the background.
Figure 2-106
GRANULAR CELL TUM OR
A: This example is associated with striking squamous
pseudoepitheliomatous hyperplasia. Our forefathers used
the term "epithelioma" to connote carcinoma so that
pseudoepitheliomatous indicates pseudocarcinomatous.
B: The reactive squamous epithelium is admixed with
the granular cell tumor.
C: The granular cells have plump granular cytoplasm
and a low nucleus to cytoplasmic ratio.
107
Figure 2-107
MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
A: This tumor is easy to diagnose on H&E since it is associated with a neurofibroma.
B: Alternating hypercellular and less cellular zones are a characteristic feature.
C: Large atypical nuclei are readily apparent at low magnification in this highly cellular malignant neoplasm.
D: Several of the nuclei are flat at one end and pointed at the other (bullet shaped).
108
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E: Although the feature is not specific, the proliferation of malignant cells just beneath the endothelial cells with no
separation is a characteristic feature of malignant peripheral nerve sheath tumor.
F: There is loss of trimethylated H3K2 7. Unfortunately, this only helps as a diagnostic test in less than half of the lesions.
Note that trimethylated H3K27 is present in the internal control endothelial cells.
with a slight male predominance. Lesions arise

MYXOID NEOPLASMS primarily on the trunk and lower extremity,
followed by the head and neck region and arm.
Cutaneous Myxoma
Carney complex (163) includes pigmented
(Superficial Angiomyxoma)
skin lesions (lentigines and epithelioid blue
Myxomas of the skin and subcutaneous tis- nevus/pigmented epithelioid melanocytoma),
sue are less well-characterized than the more endocrine disorders (primary pigmented nod-
frequently encountered deep intramuscular ular adrenocortical disease, a variety of stromal
myxomas and those arising in the jaw bones tumors of the testis, and growth hormone-pro-
and heart. However, they are easy to diagnose ducing pituitary adenoma), psammomatous
with H&E. A subset is associated with the Car- melanotic schwannoma, and myxomatous
ney complex of myxomas, including cutaneous tumors (cardiac myxoma, myxoid fibroadeno-
myxomas, spotty pigmentation, and endocrine ma of the breast, myxoma of the external ear
overactivity; such patients h ave been subse- canal, and cutaneous myxoma). The disorder is
quently shown to have various mutations in the autosomal dominant with"a slight female pre-
PRKARlA gene (163,164). Most cutaneous myx- dominance. Most patients lack the full spectrum
omas, however, are sporadic and some observers of lesions. However, as the cardiac myxoma and
have used the term "superficial angiomyxoma" the psammomatous melanotic schwannoma
to describe them (165,166). (now termed malignant melanotic schwannian
Superficial angiomyxoma/cutaneous myxoma tumor [167]) are the main causes of morbidity
unassociated with Carney complex presents as and mortality in this disorder, it is important
a painless, slow-growing, solitary skin nodule to identify patients at risk. Superficial myxomas
109
Figure 2-108
EPITHELIOID MALIGNANT PERIPHERAL NERVE SHEATH TUMOR
A: At low magnification, the process is overtly malignant.
B: Note the macronucleoli.
C: The tumor cell nuclei contain heterochromatin and have irregular nuclear membranes.
D: These lesions are strongly reactive with S-100 protein whereas usual malignant peripheral nerve sheath tumors often
show only focal S-100 protein expression. Epithelioid malignant peripheral nerve sheath tumors Jack labeling with so-called
melanoma markers. These tumors are most prudently diagnosed using immunolabeling confirmation.
associated with Carney complex are usually superficial angiomyxomas containing epithelial
multiple and vary from small sessile papules components (168).
to large pedunculated lesions. They most com- Microscopically, cutaneous myxomas involve
monly occur on the eyelid, as well as the nipple dermis and subcutaneous fat. The tumor consists
or ear." (163). Cutaneous myxomas are benign, of multiple, variably demarcated angiomyxoid
but local recurrence is common, especially with nodules. Prominent branching vessels are
110
commonly seen. The nodules are composed of

a hypo- to moderately cellular population of
bland-appearing, short spindled, stellate-shape,
and, occasionally, multinucleated cells scattered
haphazardly throughout a highly myxoid stro-
ma. Mitotic activity is negligible, and frequent-
ky there are scattered neutrophils. Epithelial
structures within the tumor can form nodules
or cysts (fig. 2-109).
The reported immunoprofile of myxomas is
broad with variable immunoreactivity reported
for CD34, muscle-specific and alpha-smooth
muscle actins, and factor XIIIa. S-100 protein
is negative (169).
As an aside, the Carney complex has myx-
omas, spotty pigmentation, and endocrine
overactivity. The Carney triad has epithelioid
gastroin testinal stromal tumor, functioning
extra-adrenal paraganglioma, and pulmonary
chondroma (170).
Intramuscular Myxoma
Intramuscular myxoma (IM) affects individuals
over a wide age range, but mostly middle-aged
females (171,172).The tumor develops in deep
skeletal muscle. The thigh and pelvic girdle, Figure 2-109
shoulder, and upper arm are the common sites
in decreasing order of frequency. The lesion usu- SUPERFICIAL ANGIOMYXOMA
(CUTANEOUS MYXOMA)
ally presents as a slow-growing, painless mass,
The lesion has entrapped skin appendages.
with less than 25 percent of tumors associated
with discomfort or pain. The rare presence
of multiple lesions is usually associated with uous with delicate strands of collagen that run
coexistent fibrous dysplasia of bone (173,17 4). haphazardly throughout the tumor. Mitotic
In most reported cases, the fibrous dysplasia activity is virtually nonexistent. The hyaluron-
involves more than one bone (polyostotic) and ic acid-rich, mucinous stroma often contains
sometimes is associated with McCune-Albright small cystic spaces. Occasionally, residual atro-
syndrome (polyostotic fibrous dysplasia, cafe phic skeletal muscle fibers, foamy histiocytes
au lait spots on the skin, and endocrine abnor- and, rarely, mast cells are identified within the
malities). The intramuscular myxomas typically myxoid matrix. Simple, nonarborizing, cap-
arise in the same general vicinity as the affected illary-sized vessels ~re scattered throughout.
bone(s). Intramuscular myxoma is a benign tu- At the periphery of the lesion, skeletal muscle
mor that rarely recurs following local excision. fibers adjacent to the tumor are atrophic and
Intramuscular myxoma is characterized by separated by edema fluid or infiltrating tumor
scattered, bland spindle- and stellate-shaped or myxoid matrix. Fat cells are commonly in-
cells, sparse small vessels, and numerous thin terspersed in the skeletal muscle.
collagen fibers suspended in a richly myxoid Routine immunolabeling is not of much
stromal matrix (fig. 2-110). The spindle- and stel- value; it is nonspecific other than that
late-shaped cells have small nuclei and a meager intramuscular myxomas lack keratin and
amount of pale, occasionally vacuolated, eosin- S-100 protein labeling. A third to half of spo-
ophilic cytoplasm. The ill-defined cytoplasmic radic cases have GNASl mutations (175). This
processes of the lesional cells are often contin- gene is also altered (germline) in patients with
111
Figure 2-11 0
INTRAMUSCULAR MYXOMA
A: This is one of the few soft tissue tumors that is more
common in women than in men. The cellularity is low and
the lesion is quite myxoid.
B: Note t he low cellularity.
C: The cytologic features are bland.
'\. t ..
I ,
i '
.. '" ... .
0
..
McCune-Albright syndrome (fibrous dysplasia about 40 years, with a range from children and
of bone), cafe-au-lait macules, and precocious teens to late in life. Most examples arise on the
puberty) (176). dorsal distal extremities as solitary, painless,
infiltrative masses (177-179).
Myxoinflammatory Fibroblastic Sarcoma
The tumors are infiltrative and multinod-
Acral myxoinflammatory (lbroblastic sarcoma u lar (fig. 2-111), characterized histologically
and inflammatory myxohyaline tumor (IMHT) are by dense inflammation merging with stroma
terms used to described the same entity. These varying from myxoid to hyalinized and con-
tumors are usually acral (hands and feet), but not taining sheets and small foci of epithelioid and
invariably, and thus the WHO classifies them as spindled cells. Some lesions contain foamy his-
"myxoinflammatory fibroblastic sarcoma" (1). tiocytes, giant cells, and hemosiderin. Amid the
Th ere is no gender predominance, but these in flammatory b ackdrop, scattered bizarre cells
are usually tumors of adults of a median age of having large vesicular nuclei and macron ucleoli
112
Figure 2-111
MYXOINFLAMMATORY FIBROBLASTIC SARCOMA
A: At low magnification, there is prominent inflammation.
B: Inflammatory cells are prominent and some of the
cells resemble Reed-Sternberg cells.
C: There are Reed-Sternberg-like cells in the center and
scattered neutrophils.
D: A perfect fa lse Reed-Sternberg cell is present. These
cells are fibroblasts rather than hematopoietic cells.
E: This tumor has both Reed-Sternberg-like cells and
abundant myxoid stroma.
E
I
113
..-·
~
/ '
Figure 2-112
HEMOSIDEROTIC FIBROLIPOMATOUS TUMOR
A: There are small spindle cells, inflammatory cells, and abundant hemosiderin infiltrating fat.
B: Note the quality of the spindle cells. The appearance is similar to that of fibrous histiocytoma but the infiltrative
appearance is different.
C: This example has abundant h emosiderin .
D: This is a CD34 stain.
reminiscent of Reed-Sternberg cells or virocytes TGFBR3 and MGEAS remains a subject of debate
are present. Despite the cytologic atypia, mitotic (180). These rearrangements have been report-
activity is usually minimal. ed in myxoinflammatory fibroblastic sarcoma,
On immunolabeling, expression of D2-40, and a relationship between it and pleomorphic
CD34, keratin(s), CD68, actin, desmin, S-100 hyalinizing angiectatic tumor (see fig. 2-104)
protein, and EMA have all been reported and hemosiderotic fibrolipomatous tumor (fig.
(177). Neither cytomegalovirus (CMV) nor 2-112) has been proposed. However, some col-
Epstein-Barr virus (EBV) are detected (179). leagues believe that pleomorphic hyalinizing
Whether or not they harbor rearrangements of angiectatic and hemosiderotic fibrolipomatous
114
Figure 2-113
MYXOFIBROSARCOMA
A: The vascular pattern is reminiscent of that of
myxoid liposarcoma but the vessels are larger and longer
here. Also, myxoid liposarcoma lacks pleomorphic nuclei.
B: This example shows myxoid stroma and scattered
enlarged atypical cells. These tumors are superficial and
pleomorphic, whereas myxoid liposarcomas are deep and
have monotonous cytologic features.
C: This lipoblast mimic contains mucopolysaccharide
material that presses against the nucleus and has the same
appearance as the myxoid material in the stroma. It is not lipid.
are related tumors that behave in a benign patients in the sixth to eighth d~cades, with a
fashion when they are in their initial state and slight male predominance. It involves mostly
that they harbor TGFBR3 and/or MGEAS rear- the lower extremities and limb girdles and is
rangements, and rarely progress to high-grade uncommon on the trunk. These tumors have
sarcomas with the same rearrangements. They also been termed myxoid malignant fibrous his-
believe that myxoinflammatory fibroblastic tiocytoma in the past (181).
sarcoma is a separate entity with genetics that There is a broad histologic spectrum de-
have yet to be elucidated. pending on tumor grade, but all lesions have
spindled to stellate cells, with varying degrees of
Myxofi brosarcoma
nuclear pleomorphism, embedded in abundant
Myxofibrosarcoma (182) is a frequently subcu- mucopolysaccharide matrix (fig. 2-113). At low
taneous (but it can be deep) multinodular tumor magnification, most lesions have a multinodular
of older adults or the elderly, found mainly in arrangement with incomplete fibrous septa.
115
Figure 2-114
LOW-GRADE FIBROMYXOID SARCOMA
Left: This needle biopsy shows a n eoplasm composed of small hyperchromatic nuclei. This example is not particularly
myxoid, but the cellularity is variable compared to that in the fibromatoses shown in figures 2-43, 2-44.
Right: Compare the tumor cell nuclei to those of the endoth elial cells in the capillary to the left. Th ey are as dark or
darker, different from the situation with fibromatosis. Nuclei are uniform; pleomorphism is rarely seen in this entity (unlike
myxofibrosarcoma).
Vascularity can be rich and similar to that in has uniform (not pleomorphic) cells (184,185).
myxoid liposarcoma (vessels are described as This lesion recurs, but many cases also metasta-
"curvilinear"). Some cells have markedly pleo- size (e.g., to lung).
morphic nuclei. Some contain abundant cyto- This tumor is not equivalent to low-grade
plasmic mucoid material and thus, superficially examples of myxofibrosarcoma, since the latter
mimic lipoblasts but this material, unlike lipid, occurs in older patients, is more pleomorphic
does not crisply indent the nucleus. and less fibrous, and seldom metastasizes when
By immunohistochemistry, there is variable superficial.
expression of actins, CD68, and CD34, but Hyalinizing spindle cell tumor with giant
no S-100 protein. These neoplasms have no rosettes (186) falls within the spectrum with
characteristic genetic alteration, yielding com- low-grade fibromyxoid sarcoma (187). These
plex karyotypes in keeping with their nuclear tumors have infiltrative borders and are com-
pleomorphism. posed of bland spindled cells in a hyalinized to
myxoid stroma, often with "cracking" artefact
Low-Grade Fibromyxoid Sarcoma
in the collagen. Characteristic scattered large
Low-grade fibromyxoid sarcoma is a tumor rosette-like structures often merge with serpig-
composed of bland, fibroblast-like cells with inous areas of dense h yalinization (fig. 2-115).
a swirling, whorled, vaguely storiform pat- The rosettes consist of a central collagen core
tern in a fibrous and focally myxoid stroma, surrounded by a rim of rounded cells morpho-
occasionally with plexiform vasculature. First logically and immunophenotypically different
reports highlighted the deceptive resemblance from the cells of the spindled stroma. These cells
to fibromatoses (figs. 2-114-2-116) (183). There express a number of antigens, including S-100
is little mitotic activity and minimal nuclear protein, neuron-specific enolase, and Leu 22,
pleomorphism. Since low-grade fibromyxoid in contrast to the stroma, which usually lacks
sarcoma is a translocation-associated sarcoma, it these antigens.
116
Figure 2-115
LOW-GRADE FIBROMYXOID SARCOMA/ HYALINIZING SPINDLE CEll TUMOR WITH GIANT ROSETTES
Left: There is a myxoid component and a cellular component that forms rosettes. The neoplastic nuclei are small but
hyperchromatic. The cellu larity is quite variable.
Right: This image shows both a rosette as well as the surrounding low-grade fibrom yxoid sarcoma.
Figure 2-116
LOW-GRADE FIBROMYXOID SARCOMA
Left: This is a MUC4 stain. This labeling can be very helpful for confirming the diagnosis in needle biopsies.
Right: The lesion appears to be transitioning to a high-grade form (sclerosing epithelioid fibrosarcoma).
11 7
Table 2-1
SURVIVAL CLUES TO KEY MYXOID LESIONS
Nuclear Ancillary Help

TumorType Who Gets It? How Deep? Pleomorphism? Beyond H&E?
Intramuscular myxoma Middle-aged women Intramuscular No No
Myxoid liposarcoma Young adults Intramuscular No Yes; assessment for

FUS-DDTT3, EWSRI-DDI T3
Myofibrosarcoma Elderly adults Subcutis Yes No
Low-grade fibro- Everyone Intramuscular No Yes; assessment for
myxoid sarcoma FUS-CREB3L2
FUS-CREB3L l
EWSRI-CREB3Ll
An identical characteristic translocation is patchy pattern of the reactivity. These tumors

found in both low-grade fibromyxoid sarcoma can behave quite aggressively.
and hyalinizing spindle cell tumor with rosettes:
t(7;16)(q33;pll) (188) fuses the FUS gene (also LESIONS WITH UNCLEAR DIFFERENTIATION
called TLS) to CREB3L2 (also called BBF2H7)
Solitary Fibrous Tumors
(189). MUC4 labeling is a characteristic feature
of low-grade fibromyxoid sarcoma (190). Table In early literature, solitary fibrous tumors were
2-1 shows clues for separating some key myxoid described as pleural-based lesions and consid-
soft tissue lesions. ered a benign localized counterpart of "fibrous"
mesotheliomas, an assertion supported by tissue
Sclerosing Epithelioid Fibrosarcoma
culture studies. They have been described in
Sclerosing epithelioid fibrosarcoma (191) is the many sites, including the soft tissues. Most be-
high-grade form of low-grade fibromyxoid sar- have in a benign fashion, but not all, and they
coma just as so-called "round cell liposarcoma" can transform to more aggressive tumors over
is the high-grade form of myxoid liposarcoma. time. Solit ary fibrous tumor is a good diagno-
It can mimic metastatic carcinoma, particularly sis to make since the pathologist can never be
lobular carcinoma of the breast. It can be diag- incorrect about the malignant potential.
nosed with H&E, but the availability of MUC4 Microscopically, solitary fibrous tumors char-
is a real improvement to our diagnostic arma- acteristically display a "patternless pattern" of
mentarium (192). These lesions affect primarily spindled fibroblast-like cells and collagen in
the deep musculature of adults, without gender varying proportions arranged in a disorderly
predilection, usually involving the lower limbs fashion (fig. 2-118). Classic examples can be di-
and limb girdles. Most are large. agnosed with H&E, but not all examples are clas-
These tumors consist of a uniform popula- sic. The individual cells have spindled to plump,
tion of small, slightly angulated, rounded cells ovoid nuclei and eosinophilic cytoplasm. They
with scant cytoplasm arranged in nests, cords, may also appear hemangiopericytoma-like with
and sometimes in a single file array (fig. 2-11 7). closely packed cells with amphophilic cyto-
There is a background of dense sclerosis, min- plasm arranged around staghorn-shaped vessels
imal inflammation, and sometimes zones of or they may have a myxoid appearance. Some
cartilage and mineralization. Mitotic activity is may contain mature fat.
scant. Patchy EMA, S-100 protein, and patchy On immunohistochemical staining, solitary
keratin have all been reported in these lesions. fibrous tumors consistently express CD34 and
Since the histologic differential diagnosis is with BCL2, and lack muscle markers (act ins and
carcinoma, the keratin and EMA can pose diag- desmin), keratins, and S-100 protein. A better
nostic problems if attention is not paid to the marker for them is STAT6 (193).
118
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t>
...,.'[.-
.. ~
'
, f'
.. "'--
Figure 2-117
SCLEROSING EPITHELIOI D FIBROSARCOMA
A: There is a sclerotic background and the cytologic features are monotonous. Their appearance is reminiscent of that of
metastatic lobular carcinoma, but none of the cells has cytoplasmic mucinous type material.
B: This neoplasm h as metastasized to the lung. Note the monotonous cytologic features.
C: The nuclei are round an d uniform.
D: A MUC4 stain labels the sarcoma, but lung tissue is unlabeled.
119
Figure 2-118
SOLITARY FIBROUS TUMOR
A: The neoplasm shows lobulations, variable cellularity, and thick-walled vessels arranged in staghorn-like configurations.
There are chunks of collagen also present in the stroma. These n eoplasms were diagnosed as hemangiopericytomas in the past.
B: Note the angulated vessels, some with thick walls. The vascular pattern is reminiscent of that of both synovial sarcoma
and nerve sheath turners, but the individual cells are arranged in a disorganized pattern rather than a fascicula r one. There
are few secondary changes (h emosiderin, foam cells, inflammatory cells).
C: The nuclei are randomly strewn about the lesion.
D: This is a STAT6 stain, which can be used to confirm the diagnosis in doubtful cases. This is a nuclear stain.
120
Angiomatoid Fibrous Histiocytoma

About 60 percent of AFHs express desmin,
Angiomatoid fibrous histocytoma (AFH) was either focally or diffusely, and sometimes calpo-
originally described as angiomatoid malignant nin and h-caldesmon but SMA and myogenin
fibrous histiocytoma and considered to be part of are negative. Other positive markers include
the malignant fibrous histiocytoma (MFH) family EMA, CD99, and CD68 . The lymphoid cuff
(194). The term "malignant" was removed from consists of a mixture of B and T cells as well as
its name in the 2002 WHO classification, and many plasma cells (polyclonal). Genetically,
the entity was recategorized as an intermediate AFH is characterized by several chromosomal
(rarely metastasizing) tumor of uncertain differ- rearrangements. The most common is t (2;22)
entiation (195). It has a distinctive morphology (q33;q12), associated withEWSRl-CREBl. Alter-.
and immunophenotype that is unrelated to natively, t(12;22)(ql3;q12) can result in EWSRl-
histiocytic differentiation or to fibrous histio- ATFl, and t(12;16) (ql3;pll) leads to a FUS-ATFl
cytoma (dermatofibroma), and is now known fusion gene. The first two translocations are of
to be characterized by specific chromosomal special interest because they are also found in
translocations (predominantly EWSRl-CREBl ) clear cell sarcoma of the gastrointestinal tract
in both primary and metastatic lesions (196). and soft tissues, respectively. The reasons for the
AFH occurs at any age but is most common different phenotypes in tumors with the same
in the first two decades, and is slightly more genotype are not known.
frequent in females. The favored sites are the
Ossifying Fibromyxoid Tumor
deep dermis/subcutis (or rarely skeletal muscle)
of the proximal limb girdle (espedally upper In 1989, Enzinger et al. (198) described the
limb), trunk, and head and neck, including clinicopathologic features of 59 examples of os-
sites of normal lymphoid tissue such as axilla, sifying fibromyxoid tumor of soft parts (OFT) based
antecubital fossa, and groin. Some cases are as- on H&E alone. OFT occurs over a wide age range
sociated with systemic clinical manifestations, with a peak incidence in the fifth decade but
including fever and anemia. Most are less than children can be affected (199). Men are affected
4 cm in maximum dimension, although exam- more often than women. The tumor clinically
ples have been reported exceeding 12 cm. Up presents as a slow-growing, asymptomatic nodule
to 15 percent recur, and wide local excision is or mass within the subcutaneous tissue or, less
appropriate management. Fewer than 3 percent often, skeletal muscle. Multiple lesions have been
have been reported to metastasize, usually to documented at presentation (200) and are usually
regional lymph nodes and exceptionally to lung grouped in the same general area. The shoulder,
and brain (194,197). Deep location, origin in upper arm, buttock, and thigh are the preferential-
head and neck region, and infiltrating histologic ly involved sites. The tumor arises less frequently
margins are risk factors for recurrence. in the head and neck region and trunk. The dura-
AFH is composed of multinodular sheets of tion of preoperative disease varied from less than
ovoid cells with mostly uniform vesicular nu- 1 year to over 20 years in the initial study (198).
clei, scanty cytoplasm, and low mitotic index OFT appears to have low-grade malignant
(fig. 2-119). Even though it is a translocation potential. In the original series (198), the local
neoplasm, this lesion is an exception in that recurrence rate was 27 percent, with multiple
some cases show focal nuclear pleomorphism recurrences documented in three patients. One
and occasional multinucleated giant cells. The patient with three recurrences developed a pre-
amount of hemorrhage is variable, and absent sumed metastasis to the opposite thigh 20 years
from some examples; others have extensive after initial excision. A subset of "atypical and
hemorrhage with large cysts that are lined by malignant" OFTs, characterized by increased
tumor cells, not endothelium. The tumor is cellularity and mitotic activity, has been reported
characteristically surrounded by a lymphoid and patients with such tumors are probably at in-
cuff. Based on this, these tumors can be recog- creased risk for metastatic disease (201). Surgery
nized at low magnification in the context of the is presently the mainstay of therapy.
correct clinical setting (distal extremity lesion Most tumors have calcified lamellar (some-
in a child). times with marrow) or woven bone within the
121
Figure 2-119
ANGIOMATOID (MALIGNANT)
FIBROUS HI STIOCYTOMA
A: At low magnification, cystic spaces and lymphoid
aggregates cuff the lesion. Most examples of this type of
tu m or are associated with a good outcome, but rarely these
tumors prove lethal.
B: The cystic spaces are not lined by endothelial cells,
but the tumor cells have coalesced around them. The spaces
may be filled with blood and/or serum.
C: This example shows monotonous nuclei, but some
examples contain scattered pleomorphic nuclei. This is an
exception to the general rule that neoplasms with characteristic
translocations/gene fusions lack pleomorphic cells.
D: Note the slightly increased cellularity around th e
cystic space.
E: Desmin expression can be useful in confirming
the diagnosis in the context of the correct morphologic
appearance, but not all examples are reactive with desmin.
122
Figure 2-120
OSSIFYING FIBROMYXOID TUMOR
A: A spectacular shell of bone is present. The tumor
itself consists of monotonous nuclei arranged in a lace-like
pattern.
B: The nuclei are perfectly round and small.
C: This field is somewhat solid, but there is myxoid
matrix in the background. The nuclei are round.
D: In this field, the nuclei are about the same size as
the endothelial cells in the capillary in the image. Most of
these neoplasms behave in a benign fashion, but malignant
examples are known.
E: S-100 protein expression is frequent but not invariable.
123
pseudocapsule (fig. 2-120). At low-power magnifi- closely resemble OfT. In line with their m onot-
cation, OfT is composed of uniform-appearing, onous cytologic features, OfTs show PHFl gene
small, round to polygonal-shaped cells embed- rearrangements in about half of cases, regardless
ded in a myxohyaline to collagenous stromal of their malignant potential (204).
matrix. The cells are arranged in lobules that vary
Synovial Sarcoma
in size and cellularity, and are partially separated
by fibrous bands. The tumor is surrounded by an Many cases of synovial sarcoma (SS) are easy
incomplete fibrous pseudocapsule composed of to diagnose on H&E. SS is the paradigm for the
dense fibrous and hyalinized connective tissue. discovery of a characteristic translocation and
Nests of tumor cells may be seen infiltrating elucidation of key molecular events in a solid
through rents in this fibrous shell. The prolif- tumor (20S). SS is a rare but distinctive soft
erating cells are small with lightly eosinophilic tissue neoplasm showing epithelial differentia-
to clear cytoplasm and a cytologically bland-ap- tion. The term has become well established, but
pearing, round to spindle-shaped nucle us is a misnomer. This tumor is wholly unrelated
containing a small nucleolus. The occasional to synovium.
presence of a clear space around the cell mimics Between S and 10 percent of all soft tissue sar-
the appearance of chondrocytic differentiation. comas are SS. These are mainly tumors of young
In zones with an abundant myxocollagenous adults, with a male predominance. SS presents
stromal matrix, the cells interconnect to form as an oth erwise asympt omatic deep-seated
anastomosing, thin cord-like arrangements. A slow-growing mass. About 90 percent occur on
vaguely fascicular growth pattern of spindled the extremities, with a third around the knee.
cells occurs in the more collageno us areas of the Origin within a joint or bursa represents fewer
tumor. In conventional examples, the mitotic than S percent of cases (206,207). A distinct
activity is low. In fact, many examples of this region of involvement is the head and neck,
tumor Jack bone in their capsule (nonossifying most commonly the paravertebral region with
variant) (201). pharyngeal presentation. There is local recur-
Tumors reported in the literature as "atypical" rence of tumor in up to half of cases. Metastases
or "malignant" OfTs show increased cellularity are usually blood-borne, to lungs and bone.
and are composed of a more pleomorphic cell However, perhaps reflecting the epithelial dif-
population exhibiting nuclear hyperchroma- ferentiation, they involve regional lymph nodes
sia and increased mitotic activity. Criteria for in over 20 percent of cases.
malignancy published by Folpe et al. (201) The usual course of SS is that of a high-grade
and validated in a subsequent study included sarcoma. However, patients with the calcifying
1) high nuclear grade or 2) high cellularity and variant have a better long-term prognosis. In
mitotic activity of more than 2 mitoses per SO contrast, poorly differentiated SS (PDSS) gener-
high-powerd fields (199,201). ally behaves more aggressively than the average,
The immunohistochemical profile of con- and metastasizes in a higher percentage of cases.
ventional OfT includes immunoreactivity for In one series of patients with PDSS, SO percent
neural and myogenic markers. Approximately died, with a mean survival of 33 months (208).
SO to 7S percent oftumors express S-100 protein Biphasic SS has an epithelial and a spindle
(201). In one study (202), 70 percent of tumors cell component while many monophasic tu-
expressed desmin. Limited expression of neu- mars consist only of spindle cells (figs. 2-121,
ron-specific enolase (NSE), GFAP, SMA, and MSA 2-122). The epithelial cells have round to oval
has also been documented (200,202,203). Some vesicular nuclei, abundant cytoplasm, and dis-
cases sh ow keratin expression and scattered tinct cell borders. Classically, they form glands
INil loss, features shared with epithelioid sar- with lumina, or prominent papillary structures
coma but the INil loss is not diffuse but rather with spindle cells rather than connective t issue
in a mosaic pattern. MUC4 expression, which in the papillary core. In both, there is usually
is generally an excellent marker for low-grade a single layer of uniform cells, but occasionally
fibromyxoid sarcoma, is also encountered in multilayering or tufting is seen, without nuclear
some cases (199). Myoepithelial neoplasms may pleomorphism. The n uclei of the spindle cells
124
Figure 2-121
SYNOVIAL SARCOMA
A: This is the biphasic form, consisting of glands and spindle cells. Note that the nuclei are monotonous in both zones.
In the spindle cell zone, the nuclei overlap and the cells have scarcely any cytoplasm.
B: Th is is the mon ophasic form. The cells are small, spin died, monotonous, and overlapping. Each cell has scant cytoplasm.
C: These tumors are rare in the gastrointestinal tract, and most gastrointestinal tract synovial sarcomas are encoun tered
in the stomach. This colonic example is monotonous-appearing and highly cellular. Of course, in this location, it would be
important to perform immunolabeling or molecular testing to confirm the diagnosis since gastrointesti nal stromal tumors
are far more likely.
D: This is high magnification of the lesion seen in figure C. It arose in a young adult and lacks a plexiform pattern. Since
most gastrointestinal stromal tumors arise in patients older than SO yea rs, synovial sarcoma was an immediate consideration
since the nuclei show prominent overlapping and the cells have minimal cytoplasm; the minimal mitotic activity d id not
match the cellularity.
125
...,. , --
•
~
.
. .... .
\
....
G . ._'
I
/
r
..- .. '1.•
..
E: This high-magnification image shows the monotonous cytologic features and nuclear overlap to advantage.
F: This monophasic synovial sarcoma shows a fascicular architecture and is highly cellular.
G: This scan t n eedle biopsy shows characteristic features of synovial sarcoma with overlapping nuclei. A mast cell has
flecked off the tissue fragment in the center of the image. The tumor cells are hyperchromatic, monotonous, and display
striking nuclear overlap.
H: This keratin stain labels some of the spindle cells. This is the characteristic keratin staining pattern for monophasic
synovial sarcoma. If a spindle cell lesion shows diffuse kera tin labeling, other interpretations should be considered.
126

1: This is an S-100 protein stain. Patchy S-100 protein la beling is common in synovial sarcomas and should n ot be mistaken
for evidence of a ben ign nerve sheath tumor. If it results in misinterpretation as a malignant peripheral n erve sheath tumor,
this is of lesser consequence.
J: This example is calcified and has a few staghorn-shaped vessels. The cytologic features, however, differ from those of
solitary fibrous tumor. Additionally, CD34 is positive in solitary fibrous tumor but is almost always negative in synovial sarcoma.
Figure 2-122
POORLY DIFFERENTIATED SYNOVIAL SARCOMA
Left: The poorly differentiated form may require molecular techniqu es to diagnose but often reta ins the basic
immunolabeling profile for synovial sarcoma (focal keratin expression, focal S-100 protein expression, BCL2 and CD99
expression, and negative CD34 and WT1 expression). The poorly differentiated form of synovial sarcoma retains the presence
of staghorn-shaped vessels.
Right: This example shows many stagh orn-shaped vessels. Note the round blue cell morphology th at is common in the
poorly differentiated form of synovial sarcoma.
127
are uniform, small, ovoid, and pale-staining lacking TLE1 expression are unlikely to be SSs.
with inconspicuous nucleoli. Cytoplasm is scant CD34 is virtually always negative in SS, but
and the cell membranes are indistinct, so that BCL-2 protein has been found in most SSs in a
nuclei overlap. Mitotic figures can be scarce diffuse and strongly positive fashion. Staining
despite the cellularity, but are more frequent for desmin is usually absent, but occasionally
in the poorly differentiated type. in otherwise typical MSS there is focal positivity
The spindle cell component can predominate for both muscle specific actin (represented by
or occur alone, and the term is monophasic syno- the HHF3S antibody) and alpha-smooth muscle
vial sarcoma (MSS). Many MSSs display, at least actin. Calponin is also expressed by SS (210).
focally, a prominent hemangiopericytoma-like A specific translocation involving chromo-
vascular architecture, with open, branching thin- somes X and 18 has been described in SS (211).
walled vessels of variable caliber that do not allow This balanced reciprocal translocation, t (x; 18)
their similar vascular pattern to cause confusion (p11.2;q11.2), is found in most reported SSs. The
between MSS and solitary fibrous tumor. resultant fusion gene product, 5518-SSX, can be
SS with a very prominent glandular compo- exploited for diagnosis. The breakpoints of the
nent, in which the spindle cells are scarce, must t(X;18) involve the fusion of the 5518 gene at
be distinguished from purely glandular MSS 18q 11 to either of two highly homologous genes
(i.e., those without any discernible spindle cell at Xp11 called SSX1 and SSX2.
component). About one third of SS have focal
Epithelioid Sarcoma
calcification, with or without ossification. In
some tumors, however, calcification is exten- These tumors were first described by Laskow-
sive, and the improved prognosis in such cases ski in 1961 (212). Enzinger subsequently coined
merits their separation as a subtype. the term epithelioid sarcoma (ES) (213), recog-
Many SSs (biphasic and monophasic) have nizing that this neoplasm was distinct from SS
poorly differentiated areas, characterized by and, later, from clear cell sarcoma.
high cellularity, numerous mitoses, and often ES is the most common primary sarcoma of
necrosis but not by nuclear pleomorphism since the hand and wrist. The clinical and histologic
SS is a translocation-associated sarcoma. features can mimic those of a non-neoplastic
PDSS has a similar range of immunohisto- process, so that the sarcoma may be misdiag-
logic and ultrastructural findings, and the same nosed until recurrence or metastasis reveals its
cytogenetic and molecular genetic abnormali- true nature. The histogenesis of ES remains un-
ties, as typical SS, but typically requires ancillary known. ES has been reported in almost all ages,
testing to diagnose. PDSS shows ~ets of darkly but is most prevalent in patients between 10
staining ovoid or rounded cells which resemble and 39 years of age (214), with a male predom-
those in other small round cell tumors, espe- inance. The flexor surface of the hand, fingers,
cially Ewing sarcoma or peripheral primitive and forearm are the most commonly involved
neuroectodermal tumor (ES/PNET) (fig. 2-122). sites, followed by the knee and lower leg, prox-
Most synovial sarcomas show focal expres- imallower and upper extremity, ankle, and the
sion of cytokeratins and EMA. In biphasic SS, feet and toes. The trunk and head and neck
the epithelial component is strongly positive, regions are the least commonly involved sites.
as are scattered cells in the spindle cell compo- Penile and vulvar cases have been reported.
nent. CK-positive cells can usually be found in ES arising in the dermis most often presents as
MSS, singly, in cords, or in small nests. S-100 a slow-growing, painless, usually solitary, nod-
protein positivity is detectable in nearly a third ule or plaque. ES situated in the subcutaneous
of synovial sarcomas including spindle cell MSS or fascia! tissue frequently presents as a fixed,
(209). CD99 is commonly positive in SSs, with a hard nodu~e. Tumors of the hand and penis
membranous or cytoplasmic pattern. Antibod- can clinically mimic superficial fibromatoses.
ies to TL~J are supposedly more specific for SS. Dermal and subcutaneous lesions characteristi-
TLE1 can also be expressed by some malignant cally develop a cleft of the overlying skin which
peripheral nerve sheath tumors and some soli- eventually ulcerates. These innocuous clinical
tary fibrous tumors. On the other hand, lesions presentations sometimes lead the clinician to
128
Figure 2-123
EPITHELIOID SARCOMA
Left: The malignant cells surround a zone of necrosis, imparting an appearance reminiscent of that of necrotizing
granulomas from infection or of rheumatoid nodules. This appearance led to underdiagnoses and aggressive behavior in the
past but the survival has vastly improved over time with better recognition of these neoplasms.
Right: The nuclei in th is example are not particularly pleomorphic but the cytologic features differ from those of histiocytes
in granulomas. Note the abundant dense eosinophilic cytoplasm , a common finding.
an erroneous diagnosis of a benign lesion. The along fascial planes and aponeurotic connective
neoplasm spreads proximally up the extremity, tissue, the confluent nodules align themselves
producing numerous cutaneous nodules and along the length of the tissue plane, resulting in
ulcerative lesions. Although these tumors were a band of tumor cells surrounding hypocellular
considered quite aggressive in the past, better or necrotic zones (garland-like configuration).
recognition with early aggressive surgery has The proximal type of ES (21S), which arises
improved outcome. primarily in axial sites as a large, generally
ES is characterized by a predominantly nod- deeply-seated mass, is composed of pleomorphic
ular growth pattern of epithelioid and plump epithelioid cells (fig. 2-124) and this type is best
spindled cells. The center of the nodule commonly diagnosed in the context of ancillary studies. This
undergoes degenerative change characterized variant has histologic overlap with both extrarenal
by necrosis, hemorrhage, cyst formation, focal malignant rhabdoid tumor and carcinoma.
calcification, or replacement of tumor cells by a ES characteristically expresses keratin. EMA is
myxohyaline stroma (fig. 2-123) . At the periphery expressed in SO to96 percentoftumors (216-219)
of the nodules, the epithelioid cells occasionally and its pattern of reactivity also demonstrates
grow in a cord-like fashion and the spindled cells variability within the same lesion. CD34 is re-
form vague fascicles as these elements mingle with portedly expressed in about SO percent of tumors
dense, eosinophilic collagen. The nodules have a (216,217,220). Carcinoembryonic antigen immu-
tendency to coalesce. When the tumor spreads noreactivity can be focally identified in ES (221).
129
Figure 2-124
PROXIMAL TYPE EPITHELIOID SARCOMA
A: This is a highly ce llul ar malignant neoplasm
with abundant necrosis. These n eoplasms often require
immunolabeling for diagnosis as the differential diagnosis is
with metastatic poorly differentiated carcinoma, melanoma,
or epithelioid angiosarcoma.
B: The tumor consists of pleomorphic epit helioid cells.
C: This is an !Nil (SMARCBl) stain. Inflammatory cells
within the lesion show nuclear labeling, but the neoplastic
cells are nonreactive. Several types of neoplasms are
SMARCBl-deficient so the diagnosis must be made in the
appropriate context.
ES harbors abnormalities of 22q or 18q with (224-229), but pediatric cases are known (230)
association with inactivation of a tumor sup- and older adults may be affected. The tumor
pressor gene SMARCBl / INJl although it lacks a arises primarily in th e deep soft tissues of the
characteristic translocation. The nuclear loss of lower extremity, particularly the anterior thigh
INll protein by immunohistochemistry can be and the buttock (225), followed by the chest
exploited for diagnosis in most cases of both the and abdominal wall. In children, ASPS has a
classic and proximal types of ES (162,222,223). proclivity for the head and neck region, espe-
cially the periorbital soft tissue and tongue. ASPS
Alveolar Soft Part Sarcoma
clinically presents as a slow-growing, painless
Alveolar soft part sarcoma (ASPS) accounts for mass which may be apparent for months to
fewer than 1 percent of all soft tissue sarcomas. years before the patient seeks medical attention.
It has a characteristic gene fusion such that it Unfortunately, sometimes metastatic disease
has monotonous nuclei. to the lung or brain heralds the presence of
ASPS principally affects adolescents and an occult primary sarcoma. Patients with ASPS
young adults with a slight female predominance have a poor long-term survival. The principal
130
metastatic sites are the lung, followed by the clear to eosinophilic cytoplasm, which often
brain and bone (225). Children with ASPS fare contains abundant glycogen (fig. 2-126). The
better than adults; possibly earlier detection is individual cells have uniform and prominent
a factor (228,230). nucleoli. Tumor giant cells with a peripheral
At low magnification, ASPS displays a distinc- wreath-like arrangement of nuclei are found
tive nested or organoid arrangement of large, in some cases. Melanin can occasionally be
polygonal cells with eosinophilic cytoplasm seen. Necrosis is found in a minority of cases.
(fig . 2-125). The nests are separated from one Most cases are reactive with S-100 protein and
another by thin-walled, sinusoidal vascular melanoma markers, both HMB45 (232-234)
channels. Protrusion of nests of turner into and newer ones.
these vessels, as well as frank vascular invasion, Some observers have speculated that these
are common findings in ASPS. Loss of cellular are simply melanomas of connective tissue.
cohesion results in intact and degenerat ed However, this is probably incorrect for several
cells floating in the center of a tumor cell nest reasons: 1) their histologic features are very
and imparts a pseudoalveolar appearance to monotonous whereas skin melanomas feature
the otherwise ball-like arrangement of cells. more prominent cytologic pleomorphism; 2)
ASPS can also be composed of small, compact their clinical behavior is also markedly different.
nests of cells without prominent vascularity, Whereas an overall favorable prognosis would
an architectural pattern seen mo re commonly be expected for a 1 cm clear cell sarcoma, a
in children. This pattern can vaguely resemble nodular skin melanoma this size could be rap-
that of paraganglioma. idly lethal. In fact, most patients with turners
The neoplastic cells have a uniform, oval smaller than 2.5 cm fare well on follow-up (233);
to polygonal shape with distinct cell borders and 3) clear cell sarcoma has a characteristic
and an ample amount of finely granular, eo- characteristic 12;22 translocation resulting in
sinophilic cytoplasm. The nuclei are uniform an EWSRl-ATFl fusion; this can be detected
and nucleoli are prominent. Mitotic activity is for confirmation of the diagnosis if needed. In
ch aracteristically low. contrast, skin melanomas have complex karyo-
The immunohistochemical profile of ASPS types and/or BRAF mutations, but they lack the
is broad and nonspecific (although nuclear la- 12;22 translocation .
beling with JF.E3 is characteristic). Most cases Although melanomas are more so, clear cell
of ASPS exhibit some degree of desmin and sarcom as are aggressive turne rs. Survival rates
muscle-specific actin expression, but myogenin of 67, 33, and 10 percent, at 5, 10, and 15 years,
is n egative. S-100 protein immunoreactivity were reported (235). Chemotherapy has offered
has been observed in some turners but they o nly limited success (236).
are negative for more specific skeletal muscle
Extraskeletal Myxoid Chondrosarcoma
markers and keratins.
Extraskeletal myxoid chondrosarcomas (EMCs)
Clear Cell Sarcoma
are rare soft tissue sarcomas that predominantly
Clear cell sarcoma was described by Enzinger occur in adulthood (237,238). There is a slight
in 1965 (231) as a unique sarcoma associated male predilection. The turners most commonly
with tendons and aponeuroses of the hands occur in the deep soft tissues of the extremities.
and feet. The description was based on a clin- They usually present as a painless or minimally
ical profile and H&E. At the time of Enzinger's tender slow-growing mass. Most of the tumors
initial description, the nature of this lesion was are greater than 5 cm . In the original series,
unclear although he suggested a melanocytic based on H&E, this tumor was considered
lesion. These turners mainly affect the distal relatively low grade, with a low incidence of
extremities, particularly the feet and ankles, and metastasis and an indolent clinical course (237).
they occur in young adults (231-234). Th e estimated 5-, 10-, and IS-year survival
Clear cell sarcomas are readily diagnosed on rates are 90, 70, and 60 percent, respectively
H&E manifest a packeted and fascicular arrange- (238). Older patient age, larger turner size, and
ment of uniform round to spindled cells with tumor location in the proximal extremity or
131
Figure 2-125
ALVEOLAR SOFT PART SARCOMA

A: Note that this tumor is rich ly vascular and partitioned
into nests that reminded our forefathers of lung alveoli.
B: The tumor cells have plenty of cytoplasm and unusual
but uniform nucleoli.
C: Each nucleus has a large nucleolus and the cytoplasm
is eosinophilic.
D: Some examples have PAS-positive cytoplasmic
crystalline inclusions.
E: TFE3 immunolabeling can be confirmatory but is not
specific, as granular cell tumors can also show TF£3 staining.
132
Figure 2-126
ClEAR CELL SARCOMA
A: The tumor has arisen in a tendon and has a nested appearance.
B: This example features wreath-like tumor giant cells. Each cell has a large nucleolus and pale cytoplasm. Some examples
are more spindled. Most arise in the distal extremities of young adults.
C: Note the strong S-100 protein labeling. These neoplasms are translocation sarcomas such that the nuclei are not
pleomorphic, a finding that helps separate them from melanoma. Despite their melanocytic differentiation, clear cell sarcomas
behave as high-grade sarcomas rather than as melanomas.
0: HMB4S labeling is strong in this example.
limb girdle were adverse prognostic factors tinguish EMC from other low-grade sarcomas.
identified by multivariate analysis. EMC has Histologic grading is of no prognostic value in
a unique clinical course, including a high rate EMC because prognosis is dictated primarily by
of local recurrence, prolonged survival after clinical features (238).
metastasis in some cases, and eventually a high EMCs are lobulated myxoid tumors that char-
rate of d eath due to tumor. These features dis- acteristically demonstrate low cellularity (fig.
133
Figure 2-127
EXTRASKELETAL MYXOID CHONDROSARCOMA
A: These neoplasms lack the rich vascularity that typifies myxoid liposarcomas, and they often con tain prominent
hemosiderin. The cells are plumper than those of ossifying fibromyxoid tumor, but are monoton ous since extraskeletal
myxoid chondrosarcoma has a characteristic translocation/gene fusion.
B: Uniform cells are present in a myxoid background.
C: The cells have eosinophilic cytoplasm and delicate nucleoli.
D: This area has a lace-like appearance but the cells are larger than those in ossifying fib romyxoid tumor.
2-127). The individual tumor cells are small and tumor cells are embedded within a hypovascular
oval, and have small amounts of eosinophilic basophilic flocculent matrix. Hemosiderin is
cytoplasm surrounding the nucleus. The nuclei often prominent. In low-grade tumors, there is
are central, dark staining, and usually lack visi- low cellularity and higher-grade tumors typical- .
ble nucleoli. Tumor cells are arranged in linear ly show greater cellularity with less extracellular
arrays that appear as straight lines or curves. matrix. Hyaline cartilage is not found in EMC.
Mitotic figures are usually inconspicuous. The Additionally, a subset of cases has zones that
134
Figure 2-128
EXTRASKELETAL MYXOID CHONDROSARCOMA
A: This example has particularly prominent hemosiderin
deposition.
- B: Some tumors have solid areas, as seen in the lower
h alf of the field.
C: Solid areas such as this can be diagnosed as
extraskeletal myxoid chondrosarcoma by searching for the
more typical less cellular zones.
are solid, consisting of sheets of small round and t(9;15)(q22;q21), with TAF1168-NR4A3 and
uniform cells (fig. 2-128). TCF12-NR4A3 fusion genes, respectively.
Immunohistochemical stains demonstrate
Desmoplastic Small Round Cell Tumor
S-100 protein expression (e-fig. 21.57) in the
majority of cases. Interestingly, many tumors Desmoplastic small round cell tumor (DSRCT) is
express endocrine markers, including synapto- a descriptively named malignancy that primarily
physin and INSM1 (239). affects adolescents and young adults and arises
Cytogenetic analysis of EMC shows a con- within the peritoneal cavity and retroperitoneum
sistent translocation between chromosomes 9 (240). DSRTC is an aggressive, malignant neoplasm
and 22, t(9;22)(q22-31;qll-12), which serves that responds poorly to treatment. Its peritoneal
as a diagnostic marker for this neoplasm since seeding, abdominal adhesion, and omental cake
it results in a specific fusion product, EWSR1- formation are all reminiscent of mesothelioma
NR4A3 (238) that can be exploited for diagnosis. and ovarian surface carcinomas. Treatment at-
Variant translocations include t(9; 17)(q22;q 11) tempts have been largely unsuccessful.
135
Figure 2-129
DESMOPLASTIC SMALL ROUND CELL TUMOR
A: Note the small nests separated by hypocellular areas containing myofibroblasts. These are highly lethal tumors.
In children and young adults they are easy to consider, but in older adults the first consideration would be h igh-grade
neuroendocrine ca rcinoma (small cell type) and immunolabeling or even molecular testing is needed fo r a confiden t diagnosis.
B: Note the prominent necrosis.
In its typical intra-abdominal location, DS- desmin, EMA, cytokeratin, neuron-specific eno-
RCT occurs as a sclerotic, locally invasive mass lase, S-100 protein, synaptophysin, and CDS7.
that may arise anywhere from the surface of the WT1 immunolabeling shows nuclear staining.
ovary to the pancreas, with frequent peritoneal DSRCT is genetically characterized by a fusion
spread. The tumor consists of nests of primitive of the WTl gene on chromosome 11 and the
small cells encircled by dense fibrotic tissue (fig. EWSRl gene on chromosome 22, karyotypically
2-129). The small cell foci may contain vague expressed by a reciprocal translocation, t (11;22)
rosettes or have epithelioid features, and often (p13;q12). Although similar chromosomes are
have a rhabdoid appearance, raising a differen- involved, the breakpoint on chromosome 11
tial diagnosis of alveolar rhabdomyosarcoma differs from that of the Ewing family of tumors.
because of their abundant pinkish cytoplasm As with Ewing tumors and alveolar rhabdo-
containing hyaline inclusions. myosarcomas, RT-PCR or FISH can be used to
These tumors display a range of markers by support the diagnosis by demonstration of this
immunohistochemistry. Tumors often express chimeric gene.
136

C: The tumor cells are small but overtly malignant.
D: This examp le has uniform cells that are not
particularly hyperchromatic and any of several round cell
sarcomas could be considered.
E: This is a desmin stain. Nuclear WTl labeling would
also be confirmatory together with negative myogenin.
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146
SOFT TISSUE lESIONS
FOR WHICH ANCillARY
TECHNIQUES ARE IMPORTANT
In chapter 2 we pointed out issues with enti- much we test. Every single day, a new report ap-
ties that are sometimes readily diagnosed with pears of another strange primitive round cell ma-
hematoxylin and eosin (H&E) staining alone lignant neoplasm with a new gene fusion with or
but, some examples of those same entities are without a therapeutic target. We will not pretend
difficult to diagnose and immunolabeling or to be able to present all those entities. However,
molecular studies are reassuring and sensible to some are already well-defined entities and some
add. Furthermore, the challenge of tiny samples display unusual features and are difficult to even
is often resolved with ancillary testing, for which consider based on the H&E (fig. 3-2).
we are grateful. In this section, we illustrate some
Extrarenal Rhabdoid Tumor
entities for which it is important to use ancillary
testing. We realize that ancillary testing is not Malignant rhabdoid tumor was initially
available to all colleagues and that morphology characterized as a highly aggressive renal neo-
directs it. Modern molecular pathology is a plasm affecting children under 2 years of age
valuable tool for both diagnosis and choosing (1). The tumor derives its name from the early
the best treatment, but it is only as good as the observation that the cells resembled those of
underlying morphology. Table 3-1 shows some rhabdomyosarcoma. Most extrarenal rhabdoid
tumors with very different biologic potentials tumors (ERTs) arise in infants and young chil-
that can have the same fusions. Of course, dren, altho ugh they may affect adolescents and
sometimes, there are simply surprises in our adults. ERTs have been described in the soft tis-
diagnoses, as seen in figure 3-1. sues of the head and neck, paravertebral region,
There are some neoplasms that we are unable to shoulder, trunk, extremities, mediastinum, and
classify, regardless of how much we try and how retroperitoneum (2,3) as well as multiple other
Table 3-1
SOME NEOPLASMS THAT SHARE GENE FUSIONS
Gene or Fusion(s) Neoplasms Involved/Malignant Potential
MALATl-GLil Gastroblastoma/ malignant
Plexiform fibromyxoma/benign
EWSRl-ATFl and EWSRl-CREBl Clear cell sarcoma and gastrointestinal tract variant/malignant, high grade
Angiomatoid (malignant) fibrous histiocytoma/low grade
ALKl rearrangements Inflammatory myofibroblastic tumor/malignant (sometimes)
Epithelioid cell histiocytoma/benign
Some lung carcinomas/malignant
Some colorectal carcinomas/malignant
Some lymphomas/malignant
EWSRl rearrangements Desmoplastic small round cell tumor
Ewing sarcoma/ Primitive neuroectodermal tumor
Myoepithelioma (mixed tumor) of soft tissue
Myxoid chondrosarcoma
Myxoid liposarcoma (some)
Hyalinizing clear cell carcinoma of salivary glands
Clear cell odontogenic carcinoma
147
Figure 3-1
EPITHELIOID GASTROINTESTINAL STROMAL TUMOR OF OM ENTUM ASSOCIATED W ITH ENDOMETRIOSIS
A: In the setting of endometriosis, the anticipated lesion would be endometrial stromal sarcoma but the cells are too
epithelioid, which led to the consideration of gastrointestinal stromal tumor, an in terpretation that was confirmed by
immunolabeling. This case demonstrated that gastrointestinal stromal tumor should at least be considered for any monotonous
neoplasm arising in the abdomen or pelvis.
B: Note the cytologic features. The cytoplasm is plump and epithelioid and the neoplasm contains many small capillaries.
C: This DOG 1 stain labels the neoplasm but not the endometriosis.
0 : This estrogen receptor stain labels the endometriosis but not the neoplasm.
148
Soft Tissue Lesions for which A ncillary Techniques are Important
Figure 3-2
SYNOVIAL SARCOMA WITH UNUSUAL FEATURES
A: This neoplasm has epithelioid features and was diagnosed as a malignant ossifying fibromyxoid tumor in the "pre-
molecular" era but is a synovial sarcoma. However, the morphology was unusual for either in terpretation. Molecular testing
was done and showed an 5518-55X rearrangement.
B: Note the epithelioid cytologic appearance. The nuclei appear malign ant, but the cytoplasm is quite abundant.
C: Focal keratin expression is present, a clue to consider a peculiar synovial sarcoma.
D: There is a mosaic pattern of loss using INil /SMARCBl immunolabeli ng, the significa nce of which is unclear.
149
sites. The clinical course of ERT is marked by nodules that frequently coalesce and exhibit
early dissemination and death (2,3). central necrosis. The proximal type of epithelioid
Nearly all of the turners arising in the soft sarcoma is composed of large epithelioid cells,
tissues of the neck, thorax, and extremities are including a significant component of rhab-
deep, intramuscular lesions. doid-appearing cells, arranged in large, bulky
Microscopically, the malignant cells are round nodules. In some instances, the number of rhab-
to polygonal, with amphophilic to lightly baso- doid-appearing cells in this variant of epithelioid
philic cytoplasm, a paranuclear globoid inclu- sarcoma make the separation from ERT almost
sions with a pale eosinophilic, glassy appearance. impossible. Although expression of keratin is a
The cells have large, eccentrically-positioned feature shared by both epithelioid sarcoma and
nuclei with a round to reniform configuration ERT, the former neoplasm demonstrates CD34
and prominent nucleoli (fig. 3-3). The cells are immunoreactivity in SO percent of cases.
generally noncohesive, but may focally grow in The discovery of alterations of chromosome
a trabecular pattern or adhere to vessel walls or 22 and deletions in the SMARCBl (also called
fibrous septa. Mitotic figures are easily observed, !Nil) gene in malignant rhabdoid turners has
but atypical mitotic figures are infrequent. The led to the possibility of immunohistochemical
cells form bulky, ill-defined sheets or large and molecular diagnosis of these tumors. INil
irregular nests. The stromal matrix is usually loss can be sought by immunolabeling (5-11),
edematous but may be myxoid. Lymphatic and a feature shared with epithelioid sarcoma, as
blood vessel invasion are frequently identified. described above (8,9) . The loss of INil in epi-
ERT shows consistent immunoexpression thelioid sarcoma is less likely to be associated
of keratin and epithelial membrane antigen with DNA alterations in SMARCBl. Several other
(EMA). In one study, over half of turners ex- turner types can show loss of INI1/SMARCB1,
pressed CD99, synaptophysin, _Leu-7 (CDS7), including extraskeletal myxoid chondrosar-
and neuron-specific enolase (NSE) (4). Focal coma, epithelioid malignant peripheral nerve
immunoreactivity has been reported for desmin sheath turner, ossifying fibromyxoid turner,
and muscle-specific actin. and various carcinomas, but these have either
In the correct clinical context, it is important different morphology or a completely different
to consider ERT but many neoplasms, includ- clinical presentation (10,12).
ing carcinomas, melanomas, and soft tissue
Ewing Sarcoma
sarcomas, may have foci exhibiting the cyto-
morphologic features of a malignant rhabdoid It is only within the past couple of decades
turner, and ERT is thus a diagnosis of exclusion. that we have realized that two histologically dis-
Poorly differentiated foci of synovial sarcoma, tinct neoplasms, Ewing sarcoma and peripheral
epithelioid malignant peripheral nerve sheath primitive neuroectodermal turner (PNET; also
tumor, extraskeletal myxoid chondrosarcoma, referred to as peripheral neuroepithelioma), are
mesothelioma, myoepithelial neoplasms, and the same and now we simply regard them all as
intra-abdominal desmoplastic small round cell Ewing sarcoma.]ames Ewing described a peculiar
tumor are some of the soft tissue sarcomas that undifferentiated round cell turn or of bone in ado-
can demonstrate rhabdoid features . Also, several lescents in 1921 (13), and--Ewing sarcoma became
carcinoma types can have a rhabdoid phenotype. a standard diagnosis by the 1950s whereas PNET
Rhabdomyosarcoma, like ERT, arises princi- was largely unrecognized until Askin et al. (14)
pally in the deep soft tissues and mostly affects described a peculiar small cell turn or of the chest
children. Rhabdomyoblasts express desmin and wall in adolescents (Askin tumor). Subsequently,
Myo01, but not keratin or EMA (although focal based on cytogenetic, ultrastructural, and bio-
cytokeratin may sometimes be seen). Epitheli- logic studies, the commonality of these three
oid sarcoma can also have cells with rhabdoid lesions, Ewing sarcoma, PNET, and Askin turners,
features. In contrast to ERT, epithelioid sarcoma became apparent. Soft tissue examples of these
affects mostly adolescents and young adults and neoplasms are now recognized as the second
predilects to the hand and forearm area. The most common pediatric soft tissue sarcoma,
tumor cells of epithelioid sarcoma form cohesive following rhabdomyosarcoma. Ewing sarcoma
150
Soft Tissue Lesions for which Ancillary Techniques are Important
Figure 3-3
MALIGNANT RHABDOID TUMOR
A: In the context of a pediatric malignant neoplasm, the consideration of malignant rhabdoid tumor is obvious but many
malignant neoplasms can have rhabdoid features, especially in adults. As such, it is always prudent to use ancillary studies
in the diagnosis of such neoplasms.
B: Note the dense eosinophilic cytoplasm. The large nucleoli are not typical of rhabdomyosarcoma but are typical of
malignant rhabdoid tumor in a pediatric sample.
C: Strong cytokeratin labeling is characteristic of these tumors. It is also characteristic of epithelioid sarcoma, but the
cytologic features of the latter tumor differ. In addition, the clinical presentation is quite different.
D: Loss of INil/SMARCBl confirms the interpretation in the correct context (young child, often intra-abdominal). A few
lymphocytes and endothelial cells serve as internal controls.
151
Figure 3-4
EXTRASKELETAL EWING SARCOMA
A: This high-grade round cell sarcoma is best diagnosed with immunolabeling and/or molecular confirmation.
B: The tumor consists of primitive malignant cells. Even leukemia should be considered before di agnosing such a tumor
as Ewing sarcoma.
C: Ewing sarcoma often contains glycogen. This PAS stain demonstrates it.
0 : This is a PAS preparation with diastase digestion (amylase, salivary type), which has removed the glycogen in the
cells. In the era before immuno labeling and molecular testing existed, this stain was helpful for confirmi ng the diagnosis.
is primarily a bone tumor and will be further lary cores. On the other end of the differentiation
covered in Survival Guide to Bone Tumors. spectrum lies typical Ewing sarcoma, which is the
!::!Q_mer-Wright rosettes are the hallmark of quintessential "small round blue cell" tumor (fig.
primitive neuroectodermal tumors (whereas 3-4). These are composed of highly compressed
Ewing sarcomas lack these). These microscopic cellular masses that usually occur in diffuse
structures contain wreaths of dark, oval nuclei sheets. The turnor cell nuclei typically possess
that circumscribe wispy, lightly pink, neurofibril- round, even contours and smooth chromatin
152

E: This CD99 stain shows strong membranous labeling. With the correct morphology and negative studies for other
pertinent proteins (desmin, myogenin, WTl, TdT), this stain is confirmatory.
F: This neoplasm has pseudorosettes and the term primitive neuroectodermal tumor can be applied to describe the findings.
The genetics, however, are the same as those for classic Ewing sarcoma, with EWSRl-FLJJ rearrangements.
G: This is a high magnification of a pseudorosette.
H: This CD99 stain is strongly reactive.
with inconspicuous nucleoli, similar to but sionally are also positive, although generally in a
larger than lymphoid cells. focal cytoplasmic or nuclear pattern of reactivity.
_Q299., formerly known as the MICZ antigen, is Thus, as with the other markers, CD99 stains are
expressed in over 95 percent of Ewing/PNET cases best interpreted within the context of a diagnostic
with a distinctive diffuse membranous pattern of panel of immunostains. An antibody to the Fill
immunoreactivity. However, being derived from a protein product of the EWSRl-FLJl fusion gene
lymphoblastic cell line, this antigen may react with (15-17) is hardly specific and is an excellent marker
lymphoblastic tumors. Rhabdomyosarcomas occa- for vascular neoplasms as well (18).
153
Figure 3-5
SPINDLE CELL/ SCLEROSING
RHABDOMYOSARCOMA
A: This neoplasm could be any of
a number of high-grade spindle cell
sarco mas . The cells are more pleo-
morphic than those in synovial sarcoma.
This was a neck lesion in an adult such
that a peculiar rhabdomyosarcoma
should be considered.
When we encounter these neoplasms, we of acute lymphoblastic leukemia is particularly

perform a panel of keratin, WT1, desmin, S-100 difficult because of its react ivity with CD99 and
protein, BCL2, TdT, NKX2.2, and CD99. If the frequent nonreactivity with CD45, the common
CD99 and NKX2.2 are strongly reactive and leukocyte antigen. As above, attention to cyto-
nothing else is, we can relatively confidently logic detail is thus important, as well as use of
diagnose Ewing sarcoma, but if anything is off, a panel that includes neural, muscle, and lym-
then molecular testing is in order. phoid antigens. Poorly differentiated synovial
Ewing sarcoma usually harbors a gene fu- sarcoma can have a great deal of labeling over-
sion between the FL/l gene on chromosome lap with Ewing sarcoma as well, and molecular
11 and the EWSRl gene on chromosome 22. assessment for it is also important.
Karyotypically, this is expressed by the recipro-
Some Rhabdomyosarcomas
cal translocation, t(11;22)(q24;q12). However,
several alternate fusio ns are described-the key Most rhabdomyosarcomas are easy to con-
one is EWSRl-ERG. Unlike alveolar rhabdomyo- sider and diagnose (u sually with ancillary
sarcoma, which has a single reproducible fusion t echniques t ogether with H&E) when they
point, a variety of fusions may occur in Ewing are found in children and adolescents. The
sarcoma, all of which fuse the two translated rhabdomyosarcomas that result in issues are
protein molecules. In this chimeric protein, a spindle/sclerosing rhabdomyosarcomas of
DNA transcription factor (EWSR1) is joined to adults that arise in the head and neck. They
a RNA binding factor (FLil ) causing abnormal are very aggressive and really don't have an
DNA regulation and leading to tumorigenesis. appearance that suggests rhabdomyosarcoma
A common mimic of tumors in the Ewing except that they are often sclerosing. The first
family is the solid variant of alveolar rhabdo- issue is to consider them in any odd-looking
myosarcoma. These two tumor entities occur spindle cell neoplasm of the head and neck of
in identical locations and affect identical age an adult and add immunolabeling that includes
groups of patients, with the caveat that Ewing desmin. The second issue is to realize that on
tumors are rare in African-American children. immunolabeling, myogenin labeling is likely to
Most cases can be resolved using immunohis- be sparse and the preparation must be assessed
tochemistry. Lymphoma is less of a problem, at high magnification (fig. 3-5). Such sclerosing
given its usual presentation in lymph nodes, but rhabdomyosarcomas are aggressive and harbor
soft tissue examples are well-known. Diagnosis MYODl mutations (19-21).
154

SPINDLE CELL/SCLEROSING
RHABDOMYOSARCOMA
B: The tumor is overtly malignant but lacks the cyto-
plasmic eosinophilia that typifies embryonal rhabdo-
myosarcoma.
C: Desmin expression can be focal.
D: Do not expect diffuse myogenin labeling. It is
important to scan the slide at intermediate magnification
and not expect a "brown slide."
E: This is a sclerosing rhabdomyosarcoma. The findings
are subtle and the diagnosis must be considered.
F: This sclerosing rhabdomyosarcoma shows dense
sclerosis.
155
Figure 3-6
ROUND CELL SARCOMA WITH C/C REARRANGEMENT$
A: The neoplasm is Ewing sarcoma-like but is unusual
in that it is superficial. The appearance is similar to that of
extraskeletal Ewing sarcoma but CD99 expression is likely
to be weak.
B: The nuclei are round and there is pale cytoplasm.
C: The appearance is nonspecific but the pale cyto-
plasm is characteristic of round cell sarcomas with C/C
rearrangements.
pale cytoplasm (fig. 3-6). Sometimes there is

Round Cell Sarcomas with
myxoid stroma. CD99 staining is usually patchy
Special Gene Fusions of All Sites
and WTl and keratins are frequently reactive.
Sarcomas that have the appearances of Ew- A smaller subset of primitive sarcomas are
ing sarcoma with weak or negative CD99 and BCOR-rearranged sarcomas, most of which har-
NKX2.2 are often CJC-rearranged tumors. The bor BCOR-CCNB3 fusions. These are mostly in
majority have CIC-DUX4 fusions but some have
~
adolescent males in the bone (about 60 percent)
~IC-FOX04 rearrangements. They arise in young and soft tissues or the trunk and extremities.
adults in the deep soft tissues of the extremities They are less aggressive than CJC-rearranged
and trunk, and are highly aggressive compared tumors. They have small round nuclei with in-
to Ewing sarcoma, although presently they are conspicuous nucleoli and scant cytoplasm. There
treated similarly. They are composed of round can be myxoid stroma and delicate capillaries
cells, some with prominent nucleoli, and scant (fig. 3-7). On immunolabeling, CD99 expression
156
Figure 3-7
ROUND CELL SARCOMA WITH BCOR REARRANGEMENT$
A: Like round cell sarcoma with CIC rearrangements, tumors with BCOR rearrangemen ts show pri mitive round cell
features. CD99 labeling is typically weak.
B: The tumor is monotonous appearing with slight myxoid stromal changes.
C: At high magnification, t he findings are similar to those in Ewing sarcoma and in CJC-rearranged sarcomas.
D: This is a BCOR immunolabeling; note the nuclear expression.
Some Hemangioendotheliomas
is variable, but nuclear BCOR protein can be
detected. These also express cyclin Dl, SATB2, Most hemangioendotheliomas are easy to
and TLEl. Although BCOR is an excellent marker consider on H&E, but there is one type that
for these neoplasms, it can also label synovial takes some practice to even consider as a vas-
sarcoma, clear cell sarcoma of kidney, and some cular lesion, but it is actually characteristic. In
high-grade endometrial stromal sarcomas. Our the original series (26), this lesion was termed
understanding of the relationship between "epithelioid sarcoma-like hemangioendothelio-
some of these neoplasms is evolving (22-25). ma" and the patients (four male; three female)
157
... ,,.. ..
~
Figure 3-8
PSEUDOMYOGENIC HEMANGIOENDOTHEUOMA ( EPITHELIOID SARCOMA-LIKE HEMANGIOENDOTHEUOMA)
A: This example is superficial. The lesion is pale at low magnification, cellular, and contains scattered inflammation.
B: Although the tumor cells have large nuclei, they are n ot hyperchromatic in this field and there is some overlap with
nodular fasciitis. Note the background neutrophils, which would be unusual in nodular fasciitis.
ranged in age from 17 to 54 years (median, 23 These tumors express cytokeratin, CD31 ,
years). Their tumors were small (1.0 to 3.5 cm), ERG, and FLI-1, but often lack CD34 (26). They
and involved the extremities (n = 5), scalp (n = show retained INil/SMARCBl. A characteristic
1), and chest wall (n = 1), both in deep (n = 3) translocation and fusion gene (SERPINEl-FOSB)
and superficial (n = 3) soft tissue or both (n = 1). has been described th at can also be exploited
In the original series, local (but not systemic) for diagnosis together with an immunostain for
metastases were reported, but not tumor-asso- FOSB (29,30).
ciated deaths. The tumors had been regarded
Pleomorphic Bad Malignant
as a variant of epithelioid sarcoma before their
Spindle Cell Neoplasm s
recognition as vascular lesions (27). The findings
were confirmed in a larger series (28) using the It is important to remember that anything
name pseudomyogenic hemangioendothelioma, can have spindle cell morphology. This includes
in which a striking male predominance and sarcomatoid carcinomas, spindle cell melano-
young age was reported. Tumors tended to be mas and lymphomas, and undifferentiated
multifocal, involving both soft tissues and bone, pleomorphic sarcomas. When the latter are
and had a proclivity to recur locally but metas- very superficial in the skin (dermis in the head/
tases and tumor-associated deaths were unusual. neck of a sun-damaged elderly person), they
Pseudomyogenic hemangioendothelioma shows are termed atypical fibroxanthoma (in light
sheets, ill-defined nodules, or fascicles of deeply of their indolent behavior) whereas as soon as
eosinophilic cells set within a desmoplastic stro- they extend into the subcutaneous fat, they
ma (fig. 3-8). Overt vascular channel formation become pleomorphic dermal sarcoma (the old
and hemorrhage are absent. Some cases display "superficial malignant fibrous histiocytoma"),
cells with vacuolization suggestive of intracyto- in light of their potential for aggressive behavior
plasmic vascular lumen formation. The tumor once they involve subcutis. Deeper lesions that
cells are large and rounded to spindled. Mitotic have the same characteristics are undifferentiat-
activity is low, nuclear pleomorphism is mild to ed pleomorphic sarcomas (the old "malignant
moderate, and necrosis is absent. fibrous histiocytomas"). When dealing with
158
Figure 3-8, continu ed

C: In this example, the nuclei are slightly hyperchromatic.
The tu m or cell nuclei are larger than those in the endothelial
cells of the small capillaries that are supplying blood to
the tumor.
D: At high magnification, the tumor cells show nuclear
membrane irregularities. Note the abundant deep ly
eosinophilic cytoplasm.
E: There is strong expression of cytokeratin.
F: This ERG immunostai ning shows strong nuclear
labeling.
G: This is an INll /SMARCB l stain. There is intact
expression of the protein, which is against a diagnosis of
epithelioid sarcoma. The overlying squamous epithelium
serves as an internal control.
..
159
Figure 3-9
A: Lesions such as this can be difficult to diagnose without
ancillary techniques. There is prominent inflammation and
the overt adipose tissue lacks enlarged hyperchromatic nuclei.
However, dedifferentiated liposarcoma should always be a
consideration when retroperitoneal lesions are encountered.
B: This pleomorphic spindle cell lesion contains many
eosinophilic cells and could be a sarcomatoid carcinoma,
a pleomorphic rhabdomyosarcoma, a vascular lesion, or
epithelioid sarcoma (the latter two less likely). Adding an
immunolabeling panel can be helpful in evaluating such
lesions. This one is a dedifferentiated liposarcoma.
C: This is an MDM2 stain from the lesion shown in B.
• .
"..,... 1 . .
f .J •
~~ ..
' t
... ' .. .' "
skin lesions, always check the surface for in obvious vascular channel formation particularly
situ melanoma or carcinoma; if present, the on a small shave biopsy.
diagnosis can be made and then the diagnosis 2) Pleomorphic spindle cell lesions of the
can be made wthout immunolabeling. A few retroperitoneum in adults are often dediffer-
tips apply here: entiated liposarcomas (fig. 3-9). Although some
1) In spindle cell lesions of skin, always con- observers believe that MDM2 immunolabeling
sider spindle cell melanoma and sarcomatoid is not sensitive and specific, in the correct
carcinoma (spindled squamous cell carcinoma) context, it is quite useful. A good starter panel
before anything else, especially if the skin shows in the retroperitoneum when confronted with
solar damage. Use an initial panel that includes a a modest amount of tissue is ~s=.lQOJ protein
pankeratin and/orp63/p40, S-100 protein, and/or for schwannoma and melanoma, ~Z.1 for
SOXlO. If that fails, begin to consider sarcomas. dedifferentiated liposarcoma, and keratin1for
Including a vascular marker like _ERG or CD31 mesothelioma and sarcomatoid carcinoma as
is a good idea as some angiosarcomas can lack well as some unstained slides. The panel can be
160
Figure 3-10
DIFFUSE LARGE B-CEll lYMPHOMA
A: This example contains numerous spindle cells as well
as smaller lymphoid type cells.
B: This is predominantly a spindle cell lesion. Extranodal
diffuse large B-celllymphomas are not uncommon.
C: An apoptotic cell is present in the upper center part
of the field; prominent apoptotic bodies are a feature of
higher grade lymphomas.
D: Note the background small lymphoid cells and spindle
cells. Such an appearance can be seen with dedifferentiated
liposarcoma as well. However, apoptotic bodies are easy to
find, a clue to the correct interpretation.
E: Left: There are prominent spindle cells. Right: This is
a P63 stain. Such labeling is common in diffuse large B-cell
lymphomas.
161
Figure 3-11
SARCOMATOID RENAL
CELL CARCINOMA
A: The malignant cells are brightly
eos inophilic, a clue t o co n sider the
diagnosis.
B: Note the nuclear pleomo rphism.
C: This is a keratin stain (CAM 5.2).
expanded after the "first pass." In cases where lack CD45 labeling. If there is strong concern
the MDM2 stain is difficult to interpret, FISH for lymphoma, additional markers such asmJOJ
can be used to clarify the issue. and/or plasma cell markers, can be added. Keep
3) Sarcomatoid carcinomas and spindle cell CD20 in your panel in those sites and remember
lymphomas are the big contenders in organs that several m arkers (such as P63, GATA3) often
(figs. 3-10, 3-11). Kidney and lung are the homes labellyrnphocytes.
of sarcomatoid carcinomas and the pancreas is 4) Don't forget to consider p leomorphic
the home of anaplastic carcinomas with giant rhabdomyosarcoma when dealing with undif-
cells. The liver and spleen are the home of large ferentiated pleomorphic sarcomas (fig. 3-12).
B cell lymphomas, which can be spind ly and
162
Figure 3-12
PLEOMORPHIC RHABDOMYOSARCOMA
Left: This overtly malignant neoplasm of the deep soft tissue has overlapping features with sarcomatoid carcinoma as
well as several sarcoma types. For such cases, immunolabeling is important.
Right: This is a des m in stain, which labels most of the cells strongly. Pleomorphic rhabdomyosarcomas also display strong
(but focal) nuclear myogenin expression.
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Index*
Desmoplastic fibroblastoma, 7, 42
A Desmoplastic small round cell tumor, 135
Adipose tissue neoplasms, 11 Diffuse large B-celllymphoma, 161
Angiolipoma, 14 Diffuse neurofibroma, 69
Atypical lipomatous tumor/we ll-differentiated
liposarcoma, 16
E
Dedifferentiated liposarcoma, 24 Elastofibroma, 42
Lipoblastoma, 14 Embryonal rhabdomyosarcoma, 80
Lipoma, 11 Epithelioid cell histiocytoma, 66
Myxoid liposarcoma, 30 Epithelioid gastrointestinal stromal tumor, 148
Pleomorphic lipoma, 15 Epithelioid hemangioendothelioma, 94
Pleomorphic liposarcoma, 28 Epithelioid hemangioma, 91
Spindle cell lipoma, 15 Epithelioid sarcoma, 128
Alveolar soft part sarcoma, 130 Erdh eim-Chester disease, 71
Alveolar rhabdomyosarcoma, 86 Ewing sarcoma, 150
Anastomosing hemangioma, 91 Extrarenal rhabdoid tumor, 147
Ancillary testing, 3, 147 Extraskeletal myxoid chondrosarcoma 131
I
Angiolipoma, 14
Angiolymphoid hyperplasia with eosinophilia, 91 F
Angiomatoid fibrous histiocytoma, 121 Fat atrophy, 33
Angiomatosis, 91 Fat necrosis, 7
Angiosarcoma, 97 Fibroblastic lesions, 32
Askin tumor, 150 Calcifying aponeurotic fibroma, 43
Atypical decubital fib roplasia, 39 Desmoid type fibromatosis, 46
Atypical lipomatous tumor/well-differentiated Desmoplastic fibroblastoma, 42
liposarcoma, 10, 13, 16 Elastofibroma, 42
Atypical vascular lesion, 97 Fibroma of tendon sheath, 42
B Fibrous h amartoma of infancy, 51
IgG4-related fibrosclerosing disease, 56
BCOR-rearranged round cell sarcoma, 157 Inclusion body fibromatosis, 45
Botryoid rhabdomyosarcoma, 85 Ischemic fasciitis, 39
Inflammatory myofibroblastic tumor, 52
Lipofibromatosis, 56
Calcifying aponeurotic fibroma, 43 Nodular fasciitis, 32
Capillary hemangioma, 88 Palmar/plantar fibromatosis, 46
Cavernous hemangioma, 91 Proliferative fasciitis, 36
CJC-rearranged round cell sarcoma, 156 Proliferative myositis, 36
Clear cell sarcoma, 131 Myositis ossificans, 39
Collagenous fibroma, 42 Fibrohistiocytic/histiocytic lesions, 58
Cutaneous myxoma, 109 Dermatofibroma/fibrous histiocytoma, 59
Dermatofibroma protuberans, 67
Erdheim-Chester disease, 71
Dedifferentiated liposarcoma, 24, 160 Giant cell fibroblastoma, 69
Dermatofibroma, 59 Langerhans cell histiocytosis, 71
Dermatofibrosarcoma protuberans, 67 Plexiform fibrohistiocytic tumor, 62
Desmoid type fibromatosis, 46
*In a series of numbers, those in boldface indicate the main discussion of the entity.
165
Rosai-Dorfman disease, 71 Lipoma, 9, 11

Tenosynovial giant cell tumor, 58 With fat necrosis, 7
Fibroma of tendon sheath, 42 Lobular capillary hemangioma, 89
Fibrous hamartoma of infancy, 51 Low-grade fibromyxoid sarcoma, 116
Fibrous histiocytoma, 59, 69 Lymphedema, 23
G M
Gastrointestinal stromal tumor, 86 Malignant peripheral nerve sheath tumor, 102
Succinate dehydrogenase-deficient, 89 Epithelioid, 110
Gene fusions, shared, 147 Malignant rhabdoid tumor, 147
Giant cell fibroblastoma, 69 Myofibroblastic lesions, 32, see also Fibroblastic
Giant cell tumor of tendon sheath, 58 lesions
Glomus tumor, 78 Myofibroma, 79
Granular cell tumor, 102 Myolipoma, 79
Granulation tissue, 5 Myopericytoma, 79
Myositis ossificans, 39
H Myxofibrosarcoma, 32, 115
Hemangioendotheliomas, 15 7 Myxoid changes, 3, 4
Pseudomyogenic hemangioendothelioma, 158 Myxoid lesions, 109
Hematoxylin and eosin staining, 2, 3, 147 Cutaneous myxoma/superficial angiomyxoma,
Lesions diagnosed with stain alone, 2 109
Lesions needing ancillary testing, 3, 147 Intramuscular myxoma, 111
Hibernoma, 24 Low-grade fibromyxoid sarcoma, 116
Histiocytic lesions, see Fibrohistiocytic/histiocytic Myxofibrosarcoma, 115
lesions Myxoinflammatory fibroblastic sarcoma, 112
Hyalinizing spindle cell tumor with giant rosettes, 116 Sclerosing epithelioid fibrosarcoma, 118
Myxoid liposarcoma, 19, 30
Myxoinflammatory fibroblastic sarcoma, 112
IgG4-related fibrosclerosing disease, 56
Inclusion body fibromatosis, 45 N
Inflammatory myofibroblastic tumor, 52 Neural lesions, 102
Epithelioid type, SS Granular cell tumor, 102
Inflammatory myxohyaline tumor, 112 Malignant peripheral nerve sheath tumor, 102
Infantile digital fibromatosis, 45 Neurofibroma, 102
Intramuscular hemangioma, 91 Schwannoma, 102
Intramuscular myxoma, 111 Neurofibroma, 102
Ischemic fasciitis, 39 Nodular fasciitis, 32
J 0
Juvenile xanthogranuloma, 66 Ossifying fibromyxoid tumor, 121
K p
Kaposi sarcoma, 94 Palmar fibromatosis, 46
Peripheral primitive neuroectodermal tumor, 150
L Pigmented villonodular tenosynovitis, 58
Langerhans cell histiocytosis, 71 Plantar fibromatosis, 46
Leiomyoma, 75 Pleomorphic lipoma, 15
Leiomyosarcoma, 75 Pleomorphic liposarcoma, 28
Lipoblastoma, 14 Pleomorphic rhabdomyosarcoma, 163
Lipofibromatosis, 56 Plexiform fibrohistiocytic tumor, 62
Lipoleiomyoma, 80 Poorly differentiated synovial sarcoma, 128
166
Index
Proliferative fasciitis, 36 Spindle cell neoplasms, malignant, 158

Proliferative fasciitis, 36 Spindle/sclerosing rhabdomyosarcoma, 143
Pseudomyogenic hemangioendothelioma, 158 Superficial angiomyxoma, 109
Pyogenic granuloma, 89 Synovial sarcoma, 124
Poorly differentiated, 128
R
With unusual features, 149
Rhabdomyosarcoma, 150, 154
Spindle/sclerosing, 154 T
Rosai-Dorfman disease, 71 Tenosynovial giant cell tumor, 58
Round cell sarcomas, 156
V
BCOR rearrangement, 157
CIC rearrangement, 156 Vascular tumors, 88
Anastomosing hemangioma, 91
s Angiomatosis, 91
Sarcomatoid renal cell carcinoma, 162 Angiosarcoma, 97
Schwannoma, 102 Atypical vascular lesion, 97
Sclerosing epithelioid fibrosarcoma, 118 Capillary hemangioma, 88
Skeletal muscle tumors, 80 Cavernous hemangioma, 91
Alveolar rhabdomyosarcoma, 86 Epithelioid h emangioendothelioma, 94
Embryonal rhabdomyosarcoma, 80 Epithelioid hemangioma, 91
Gastrointestinal stromal turner, 86 Intramuscular hemangioma, 91
Smooth muscle lesions, 75 Kaposi sarcoma, 94
Diagnostic pitfalls, 78 Pyogenic granuloma, 89
Glomus turner, 78 Vimentin, 1
Leiomyoma, 75
Leiomyosarcoma, 75
w
Myofibroma, 79 Well-differentiated liposarcoma, see Atypical
Myopericytoma, 79 lipomatous tumor/well-differentiated liposarcoma
Solitary fibrous tumors, 118
Spindle cell lipoma, 15
167
ISBN- 13 : 978- 1- 9334n-S1-Q
ISBN-10: 1- 933477- 51- 2
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Montgomery, Ware, Gardner 1~i

Survival Guide To Soft Tissue Pathology: Series 1

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PATHOLOGY SURVIVAL GUIDES

Pathology Survival Guides

Kiyoko Oshima, MD, Dr. Se.

Available from the Innovative Pathology Press

Printed in South Korea

1. Getting Started in Soft Tissue Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Rosai-Dorfman Disease, Langerhans Cell Histiocytosis, and Erdheim-Chester Disease . . 71

Solitary Fibrous Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

Lipoma Many leiomyosarcomas

Inflammatory myofibroblastic tumor Hybrid benign nerve sheath tumors

myxoid change relates to the interstitium that Table 1-3

Figure 1-1 Figure 1-2

Figure 1-4 Figure 1-5

Figure 1-7 Figure 1-8

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Figure 1-18 Figure 1-19

1. Benias PC, Wells RG, Sackey-Aboagye B, et al.

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of a mixture of fat and capillari~s that display

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Figure 2-14, continued

Large hyperchro mati c nuclei plop-

H&E interpretation of dedifferentiated

Figure 2-20, continued

Figure 2-20, continued

similar to myxofibrosarcoma with a myxoid

Figure 2-22, continued

figure 2-23 Figure 2-24

Figure 2-28, continued

has eliminated this issue, at least in children. If

well-differentiated liposarcoma, including p16, probably hypoxia-induced, atypical mitoses

Figure 2-34 Figure 2-35

Fibroma of Tendon Sheath

Fibrous Hamartoma of Infancy

Inflammatory Myofibroblastic Tumor

INFLAMMATORY MYOFIBROBLASTIC TUMOR

can be found in them (78) and are not a specific Lipofibromatosis

story for giant cell tumor of tendon sheath is a

Figure 2-55, continued

Figure 2-58, continued

Figure 2-59 Figure 2-60

conspicuous in dilated sinuses. In extranodal appearance virtually identical to that of IgG4-as-

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These tumors were first described in babies neoplasms diagnosed as hemangiopericytoma

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