(pathology Survival Guides Series 1) Elizabeth A. Montgomery, Md_ Kiyoko Oshima, Md, Dr. Sc._ Lysandra Voltaggio, Md (author), Elizabeth A. Montgomery, Md And Dennis O'malley, Md (series Editor) - Sur.pdf

2

PATHOLOGY SURVIVAL GUIDES Series 1

Survival Guide to Soft Tissue Pathology Elizabeth A. Montgomery, MD Alisha D. Ware, MD Jerad M. Gardner, MD

~

~ ....=.:... Innovative Pathology Pr@SS

Survival Guide to Soft Tissue Pathology

Pathology Survival Guides

I. Innovative

{) Pathology ...l:. Press

PATHOLOGY SURVIVAL GUIDES EDITOR Elizabeth A. Montgomery, MD 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 The Johns Hopkins Medical Institutions Baltimore, Maryland Lisa M . Rooper, MD Assistant Professor of Pathology The Johns Hopkins Medical Institutions Baltimore, Maryland Lysandra Voltaggio, MD Director, Gastrointestinal Pathology Fellowship Assistant Professor of Pathology The Johns Hopkins Medical Institutions 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

PATHOLOGY SURVIVAL GUIDES

First Series Volu me 2

Survival Guide to Soft Tissue Pathology by Elizabeth A. Montgomery, MD Professor of Pathology, Oncology, and Orthopedic Surgery The Johns Hopkins Medical Institutions 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.

Elizabeth A. Montgomery, MD 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

Soft Tissue Pathology

ii

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

Contents

3.

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

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 and two other sections that include: 1) lesions that can be diagnosed on routine hematoxylin and eosin (H&E)-stained slides and lesions for which ancillary testing is needed, at least some of the time; and 2) lesions for which ancillary testing is a key component (Tables 1-1-1-3). Fortunately, most soft tissue lesions fall into the first category, but diagnosing many of them requires knowledge and practice, and takes time. Our intent is to point out basic morphologic features that led our patriarchs and matriarchs to describe these entities in the first place, even if, over time, ancillary techniques have expanded the definitions of certain neoplasms. For those practicing in settings with fewer resources, we hope to encourage confidence in using the original techniques, and for those in practice settings with abundant resources, we hope to help refine their use. If ancillary studies are used, it is important not to simply use a nondirected immunolabeling or molecular panel when confronting spindle cell lesions. Most soft tissue lesions are diagnosed with an H&E stain, or at least a differential diagnosis made that can be resolved with focused ancillary studies. The key is that any panel of ancillary studies should be focused to answer a specific question because different neoplasms can have overlapping immunolabeling characteristics and overlapping or identical gene alterations. Ancillary tests should be chosen carefully, especially for needle biopsies, for which it is terrible to waste the limited tissue on a set of studies that is unlikely to yield useful information. It is also wise to perform special studies in steps rather than in a "shotgun" fashion. Soft tissue needle biopsies are psychosocial emergencies, but not medical emergencies. Most surgeons and medical oncologists would rather not subject the patient to another biopsy and would prefer to wait a few more days. For example, if a limited needle biopsy sample

shows a pleomorphic malignant spindle cell neoplasm for which the pathologist has considered sarcomatoid carcinoma and melanoma, it makes sense to begin with an S-100 protein and a pankeratin stain, order a few unstained sections, and wait for the results before ordering markers to address specific types of sarcomatoid carcinomas. If the lesion is strongly reactive with S-100 protein, there is plenty of material left to either augment the interpretation (such as with SOX10 and "melanoma markers") or to order studies to guide targeted therapy. There is one important immunostain that should NEVER be ordered when evaluating soft tissue tumors and that is vimentin. Years ago, there was an impression that vimentin staining was useful as a control of tissue integrity, but that assertion is no longer relevant with modern immunohistochemistry. Vimentin immunolabeling never provides information and wastes tissue and time. Ordering vimentin is especially pointless for needle biopsy samples since no tissue should be waisted for noninformative testing. Do not order vimentin on an open biopsy or even think of ordering vimentin on a needle biopsy. No soft tissue pathologist ever does so; it is not useful. When embarking on mastering the assessment of mesenchymal lesions, there are some practical ways to hone one's diagnostic "eye." These involve paying close attention to the size and chromatin pattern of endothelial cells in samples, studying granulation tissue, and studying fat necrosis. These simple helpful features are discussed with individual lesions in the coming sections. Endothelial cell nuclei are nearly always present in all types of samples and they are the "control cell." Endothelial cell nuclei are usually paler than those of malignant neoplasms and sometimes larger than those of benign processes. Endothelial cells and the vessels that they line are a real diagnostic clue in certain lesions (figs. 1-1, 1-2). Myxoid changes may also be seen in nonneoplastic connective tissue (fig. 1-3). Whether

1

Soft Tissue Pathology

Table 1-1 LESIONS THAT CAN BE DIAGNOSED WITH HEMATOXYLIN AND EOS IN (H&E) STAINING ALONE"

Lipoma Lipomatosis Lipomatosis of nerve (fibrolipomatous hamartoma of nerve) Lipoblastoma Angiolipoma Myolipoma Spindle cell lipoma Pleomorphic lipoma Atypical lipomatous tumor Massive localized lymphedema in the morbidly obese Some dedifferentiated liposarcomas Myxoid liposarcoma Pleomorphic liposarcoma Nodular fasciitis Proliferative fasciitis Myositis ossificans Ischemic fasciitis Fibromatosis colli Juvenile hyaline fibromatosis Inclusion body fibrom atosis (in fantile digital fibromatosis) Fibroma of tendon sheath Desmoplastic fibroblastoma (collagenous fibroma) Calcifying aponeurotic fibroma Angiomyofibrob lastoma Cellular angiofibroma Nuchal type fibroma Calcifying fibrous tumor Palmar and plantar fibromatosis Desmoid type fibromatosis Lipofibromatosis Giant cell fibroblastoma Dermatofibrosarcoma protuberans Some solitary fibrous tumors Low grade myofibroblastic sarcoma Myxoinflammatory fibroblastic sarcoma Myxofibrosarcoma Low-grade fibromyxoid sarcoma Tenosynovial giant cell tumor, localized type Tenosynovial giant cell tumor, diffuse type Deep fibrous histiocytoma Plexiform fibroh istiocytic tumor Leiomyoma Some desmoplastic small round cell tumors •some diagnoses require practice.

2

Many leiomyosarcomas Glomus tumor Myopericytoma/ myofibroma Rhabdomyoma Some embryonal rhabdomyosarcomas Some alveolar rhabdomyosarcomas Hemangiomas Epithelioid hemangio ma Angiomatosis Lymphangioma Kaposiform hemangioendothelioma Retiform h emangioendothelioma Papillary intralymphatic angioendothelioma Composite hemangioendothelioma Many Kaposi sarcomas Some epithelioid hemangioendotheliomas Some angiosarcomas Chondroma Extraskeletal osteosarcoma Some gastroin testinal stromal tumors Schwannoma Neurofibroma Granular cell tumor Some malignant peripheral nerve sheath tumors Malignant granular cell tumor Benign tri ton tumors Some ectomesenchymomas Acral fibromyxoma Intramuscular myxoma Juxta-articular myxoma Aggressive angiomyxoma Ectopic hamartomatous thymoma Some angiomatoid fibrous histiocytomas Ossifying fibromyxoid tumor Some myoepithelial carcinoma/mixed tumor Hem osiderotic fibrolipomatous tumor Phosphaturic mesench ymal tumor Some synovial sarcomas Some epithelioid sarcomas Some alveolar soft part sarcomas Some clear cell sarcomas Extraskeletal myxoid chondrosarcoma Some PEComas Some intimal sarcom as

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 has been highlighted as a massive organ extending throughout the body (1) or not, when myxoid change is present, mast cells become easy to spot (fig. 1-4); this does not necessarily mean that there is a neoplasm. A good way to become comfortable and familiar with pseudosarcomas and not mistake them for sarcomas is to study the granulation tissue in cases in which it is expected and in which there is clearly tissue that is healing, such as bowel perforation specimens or re-excision specimens after breast needle biopsies. The appearance of the nuclei and nucleoli in these samples mirrors that of several pseudosarcomatous processes, some benign fibroblastic and myofibroblastic neoplasms, and fibromatoses (figs. 1-S-1-10). Like tumors in the rest of the body, many soft tissue lesions are diagnosed at low magnification, and the impression is confirmed by studying selected areas at high magnification. This is especially applicable to tumors showing mature adipose tissue differentiation. These are diagnosed at 4X, and the diagnosis is confirmed at higher magnification of selected foci. To practice evaluating such tumors, it is important to study fat necrosis in samples in which it is expected, such as resected biopsy sites in mammary speci-

Table 1-3 LESIONS FOR WHICH ANCILlARY STUDIES CAN BE ESSENTIAL TO ESTABLISH THE DIAGNOSIS

Extrarenal rhabdoid tumor Ewing sarcoma Some alveolar rhabdomyosarcoma Some embryonal rhabdomyosarcomas Round cell sarcomas with special gene fusions of all sites Poorly differentiated synovial sarcoma Some angiosarcomas Some hemangioendotheliomas Sarcomatoid carcinomas Spindle cell melanomas High-grade pleomorphic sarcomas

mens (figs. 1-11, 1-12). Note the appearances of the histiocytes and their variety of shapes. This skill is of great value in separating the nuclei that characterize areas of microscopic fat necrosis in lipomas from the atypical nuclei that characterize atypical lipomatous tumors (well-differentiated liposarcomas, figs . 1-13-1-19). Comfort in interpreting a few basic patterns of tissue repair help in the diagnosis of a host of frequently encountered mesenchymal lesions.

3

Soft Tissue Pathology

Figure 1-1

Figure 1-2

HEMANGIOMA

EPITHELIOID HEMANGIOENDOTHELIOMA OF LIVER

The lesion is well marginated, which allows us to compare the endothelial cells in the adjacent normal tissue (arrows) with those in the lesion at the bottom. Note that the cells in the lesion (many of which show endothelial differentiation) have similar sizes and degrees of nuclear hyperchromasia.

In th is image, a normal endothelial cell is pointed out (arrow). It has a smooth nuclear membrane and delicate ch romatin. There are many malignant nuclei in the image and they appear to be embedded in the tissue but devoid of cytoplasm. Th is allows visualization of their irregular 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

Getting Started in Soft Tissue Pathology

Figure 1-4

Figure 1-5

MAST CELL IN MYXOID TISSUE

GRANULATION TISSUE

Note the amphophilic cytoplasm and tiny nucleus with a smooth nuclear membrane.

Even at low magnification, the nuclei of the endothelial cells are more hyperchromatic than those of the proliferating myofibroblasts.

:

...... -

'~-,... ~ '

· ·~'i

~·

~

·"{··:

~

·'"'

, ~

•

Figure 1-6 GRANULATION TISSUE

The cytoplasm of the m yofibroblasts 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

Soft Tissue Pathology

., .·

~-·

-. : -.. '

..

,

....·"'·

~

/

•

..' " ·. ' ·~

I

I •

.

"-"", .

,,

, I

\

... ·

'

~

" .

~

n,

, .~

. ·r ', ,.,. ·-.... .( ,

:

.

1 '\

·'

. -...

~

/· ,•

'

•}

~

,.,.

.

)

'

>

...

\

... . .• I.

Figure 1-7

Figure 1-8

GRANULATION TISSUE

COLLAGENOU S FIBROMA (DESMOPLASTIC FIBROBLASTOMA)

The endoth elia l cells are darker th an those of the m yofibrobl asts although they are smaller in this field. Several of the myofibroblast nuclei contain perfectly round red nucleoli and their nuclear mem branes are smooth. Wisps of amphophilic cytoplasm are present.

Figure 1-9 COLLAGENOUS FIBROMA (DESMOPLASTIC FIBROBLASTOMA)

This is a very high magnification 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

This is a ben ign fib roblastic/myofibroblastic neoplasm . Note that even at low magnification, the cytoplasm of the lesional cells appears stellate. This differs from desmoid type 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.

Getting Started in Soft Tissue Pathology

.

~I

... '. •

,, ...

"'

·I

..

,.

.

~

~

,~ ,, '

•r

\

., ...,

\

\

L

;

...,

I

t

•

··-

. ...

.... • ~ 't

,.·

' ~ -.;

"..,

.,V'

, t'

)>

~

'

--...

I

\,

'•

'- 1

---

" ...

..

~

...j

,•I

.,

\

. •

. , -

_,

•.

t,

Figure 1-10

Figure 1-11

COLLAGENOUS FIBROMA (DESMOPLASTIC FIBROBLASTOMA)

FAT NECROSIS

Note the nucleoli. Also, com pare the amphophilic cytoplasm in t he lesion al cell to the fibrillary eosinophi lic collagen that the cells have finally produced. I'

There is damaged adipose tissue at the center of th e image and some granulation tissue at the bottom righ t. A few foamy macrophages can be seen at the interface between the granulation tissue and the damaged adipose tissue.

,..•_. .

,·

I

,.

\

-

• .......\ .

....

r. . .... . ~ -

.1'

.

·. , (

' : •

.....

"·

. f ·."... ..,.

I ' ".; •

., ....

"

'\

_..,.,. . ... ~·

.

' ....

,(!#

• '

.

'\ \

.

:··'\1. ·;

.

.

'

..

..

' ,.~

.....

..

•.·.'.

•: Figure 1-13 LIPOMA WITH FAT NECROSIS

Figure 1-12 FAT NECROSIS

Note the prominent foamy macrophages.

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 or eosinophilic cytoplasm. Such cells can mimic enlarged lesion al nuclei or even lipoblasts. However, at 4x, these cells are far less conspicuous than the n uclei in atypical lipomatous tumor (well-differentiated liposarcoma).

7

Soft Tissue Pathology

'

•

/

Figure 1-14

Figure 1-15

LIPOMA WITH FAT NECROSIS

LIPOMA WITH FAT NECROSIS

The cell with intranuclear lipid invaginations is not a lipoblast but a so-called lochkern. This is a fak e and a common type of cell in lipomas, other mature adipocytic proliferations, and even in normal adipose tissue. Notice that it has delicate chromatin and a smooth nuclear membrane.

This is a small pocket of histiocytes, each with pale eosinophilic cytoplasm. These cells are no cause for concern in lipomas.

Figure 1-16

Figure 1-17

LIPOMA WITH FAT NECROSIS

LIPOMA WITH FAT NECROSIS

This is a high-magnification image of the cell highlighted in figure 1-14. The ce ll has a very smooth nuclear membrane. In this field there is an endothelial cell nucleus just to the right of the lochkern. The endoth elial cell has a small nucleus but the nucleus has a similar chromatin pattern to that of the lipoma n ucleus.

This is a high magnification of some of the histiocytes in an area of fat necrosis. This image shows the nuclear characteristics to advantage: smooth nuclear membranes and delicate round nucleoli.

8

Getting Started in Soft Tissue Pathology

,.

.

~

'

;

:

' ·... ·.·

' .

.: t

. . ,.

·.

"·

:. .~

)

·.- :: ~ ., ·- . ..... ,, 1 ·. ..... .

........ . .

... :r .... . ·, ·~

'"

)

:; -:. f .':' /_':·~, . ~. .

.

:,

·

.

. ..

..

..

'~

-~ :;>

., l

--f, . .

.... -

.. . ..

.

·i -

'

,

•.

···r ,r.

.;-· ~~-~·t. d· · } :· · ~ ( ·i!:i fl· . ·'~ . · ;~ -~·" ~-~- ~ j!> -: . ·, '• ,. . . .. · ;:~

~ . ~: ~ . /~:.. t_~ -.:~ · ..·:· . . ~ ... i?:J'.·. .

.

:. ~ • ·~. ~-¥..

, . ...

~

·:

.· ~ -

•

. ·.

.. :--

: ... --_ -:-· ......,.~ : . :"·

' .... . . . ~ , .•--. ~ -· • • . · ' /

',~ ·~ '..

-. ~ : ~- ...~. ~. ,:... ..

. '• . . _: • -1. .. .. ·~ ) . ~· · , ; ~. :·- . ·:~ •. ': ~ .;t

-~, ..,; · l,' ... . .--- ....

Figure 1-18

Figure 1-19

ATYPICAL LIPOMATOUS TUMOR (WELL-DIFFERENTIATED LIPOSARCOMA)

ATYPICAL LIPOMATOUS TUMOR (WELL-DIFFERENTIATED LIPOSARCOMA)

This image was taken at the same magnification as figure 1-13. Compare the two. Note that several nuclei are readily apparent at 4X, which is the magnification at which this diagnosis is made, with confirmation at higher magnification.

This image was taken at the same magnification as figures 1-16 and 1-1 7. The diagnosis is straightforward. The heterochromatin in this cell is strikingly dense and the nucleolus has an irregular shape.

REFERENCE

1. Benias PC, Wells RG, Sackey-Aboagye B, et al. Structure and distribution of an unrecognized interstitium 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 everyday samples (endothelial cells, fat necrosis, myxoid areas, and granulation tissue) can hone diagnostic skills in soft tissue pathology. This applies particularly to identifying pseudosarcomatous lesions and lipomas. Nevertheless, there are some neoplasms for which these principles do not apply, and these exceptions are noted, but for most soft tissue tumors, they do. This chapter discusses lesions that can be diagnosed with hematoxylin and eosin (H&E) stains, but note some issues that apply if ancillary techniques are used. Comments on entities that are generally diagnosed in concert with ancillary studies as part of the discussion of entities that are readily diagnosed on H&E. We have roughly followed the World Health Organization (WHO) classification system (1), although we cannot include every entity that is described therein. Further, since that classification was published in 2013, additional information has become available as a result of emerging techniques. There are entities that are not strictly soft tissue tumors (and therefore not in the WHO classification) that pose major diagnostic pitfalls and they are indicated in the key sections. It is not our intention to state that ancillary testing should not be performed if there is a good reason to add it (such as assessing PAX-FOXOl status to prognosticate in alveolar rhabdomyosarcoma); our point is that most diagnoses are made by H&E morphology and are merely confirmed or augmented by special testing. After all, most entities (other than newly recognized round cell sarcomas) were established by H&E diagnosis and follow-up. Our point is that the approach should not be through "shotgun" ancillary testing but rather through curated testing directed by H&E morphology. We are unable to include and illustrate every entity in this slim volume,

but have included many. Our companion volume (Survival Guide to Bone Pathology) will complement this material. ADIPOSE TISSUE NEOPLASMS AND A FEW MIMICS

Adipose tissue lesions show differentiation along the lines of fat, but the sarcomas "lumped" in this category are different in most cases. They are recognized with H&E staining, although some ancillary studies are very reassuring. The key points of the adipose tissue sarcomas, before we discuss the various types of lipomas, are the following: 1) Atypical lipomatous tumor and well-differentiated liposarcoma are the same thing. 2) Atypical lipomatous tumor/well-differentiated liposarcoma is the low grade form of dedifferentiated liposarcoma and has the same root genetic alterations. MDM2 gene amplification is characteristic of both. These tumors lack a characteristic translocation/fusion. 3) Dedifferentiated liposarcoma has many appearances and it is the most common sarcoma in the retroperitoneum. 4) Myxoid liposarcoma is genetically distinct from the other liposarcomas and is a translocation sarcoma, so it has monotonous nuclei and no atypical mitoses. It lacks MDM2 amplification, but instead has gene rearrangements/ translocations of FUS-DDIT3 or EWSR1-DDIT3. 5) Round cell liposarcoma is an old term for the high-grade form of myxoid liposarcoma; the term was eliminated in the 2013 WHO classification. However, it is still widely used. 6) Pleomorphic liposarcoma is unrelated to the others. It has a complex karyotype but not MDM2 amplification. Rarely, however, dedifferentiated liposarcoma can show an overlapping pattern (perhaps we could refer to that as "redifferentiation" but it has been referred to as "homologous dedifferentiation") (2).

11

Soft Tissue Pathology

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 multinucleated 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). The nucleus itself is not hyperchromatic and has a sm ooth nuclear membrane.

I A

I •

..

-

~

..

j,

I -

~

-

~

Lipoma

Lipomas essentially resemble adipose tissue except that they form masses. They are unusual in children and young adults, especially deep lipomas. The main problem with lipomas, as pointed out in chapter 1, is that they are prone to fat necrosis. This fat necrosis results in nuclei that can be seen at 4X as individual large cells (fig. 2-1) imparted either by histiocytes or by nuclei with intranuclear lipid invaginations (lochkerns; fig. 2-1C), which contrast with the atypical nuclei of atypical lipomatous tumor/ well-differentiated liposarcoma (fig. 2-2) or with actuallipoblasts (fig. 2-3).

12

.. ............

..

•_,

c

--

~- ~

....

,~

I

, ••

/" I •

'

If your laboratory has MDM2 immunolabeling available, the pitfall is that histiocytes can display nuclear labeling (fig. 2-4). If your laboratory has fluorescence in situ hybridization (FISH) for MDM2, this is not an issue. However, most cases are easy to resolve with-guess what- H&:E staining. Another pitfall is that intramuscular hemangiomas and large vascular malformations, which tend to be encountered in children and young adults, often have abundant overgrowth of adipose tissue and can be mistaken for intramuscular lipomas, which are unusual in children and young adults (fig. 2-5).

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

/'

t: o

\ ,I

n

,

,.

· _?

...

I ..

.

'

/

.. '

_(

I

/

Figure 2-2

Figure 2-3

ATYPICAL LIPOMATOUS TUMOR/ WELL-DIFFERENTIATED LIPOSARCOMA

MYXOID LIPOSARCOMA

The nucleus in the center is lodged in a fibrous band, is dramatically hyperch romatic, and has an irregular nuclear membrane.

'

•

-

A lipoblast is present in the center of the image. Its nucleus is crisply indented by a bilobed lipid droplet.

I

• Figure 2-4

Figure 2-5

MDM2 LABELING IN MULTINUCLEATED HISTIOCYTES

INTRAMUSCULAR HEMANGIOMA

As with any immunostain, MDM2 labeling must be interpreted with caution and, to confirm an interpretation of atypical lipomatous tumor/well-differentiated liposarcoma, it is important that the correct type of nucleus shows labeling.

Note the overgrowth of adipose tissue, a featu re shared with vascular malformations and angiomatosis.

13

Soft Tissue Pathology

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 is the fibrolipomatous hamartoma of nerve. This is unequivocally a lesion that is diagnosed on H&E alone. Tumors usually present in patients under 30 years of age, in the fingers, hand, or wrist, and some patients have macrodactyly (3,4). These lesions are often associated with the median nerve and produce a swelling. Their microscopic features are characteristic: fat with fibrous strands is intimately wrapped around nerves, with an onion skin appearance where the fatty component meets the nerve (fig. 2-6). lipoblastoma

Lipoblastoma is a tumor of babies. The trouble is that it can resemble myxoid liposarcoma perfectly even though the genetics are different. This tumor has rearrangements of PLAGl and lacks any nuclear pleomorphism (5-7). In fact, it can have areas that look exactly like myxoid liposarcoma. It can be diagnosed with molecular techniques, but these are usually not needed because it is an H&E diagnosis in the correct clinical setting. Since most lipoblastomas are easy to diagnose, commercial tests are not readily available to confirm PLAG 1 rearrangements and

14

concerning cases are typically subjected instead to testing for DDIT3 rearrangements to exclude myxoid liposarcoma. The patient should be younger than 2 to 3 years (2 is better) for the pathologist to be certain that H&E staining is enough to exclude myxoid liposarcoma. Lipoblastomas are superficial lobulated lesions consisting of a mixture of mature-appearing fat and more primitive-appearing fat (fig. 2-7). The primitive areas are richly vascularized and contain lipoblasts (adipocytic cells in which the nuclei are crisply indented by lipid droplets). Lipoblastomas are benign, whereas myxoid liposarcomas are sarcomas, and they are usually deep lesions. Exceptionally, lipoblastomas can fill an infant's lung or other deep spaces but this is a rare variant of an uncommon lesion. If lipoblastomas are not removed during infancy, they mature with the child and eventually resemble lipomas, differing only by having a more lobulated appearance (fig. 2-8). Angiolipoma

These benign lesions typically arise in young adults and are superficial. They consist of well-marginated small nodules composed

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

..

•

, •

,

$"'

, '*'' •

..

<#

,

,

.. .. ..

"' • • y

'

"' ,

•

-• ..

' :,.;

•

,

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 fibrin thrombi. When they arise in the breast, they always result in concern for a highly differentiated 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.

, I , ·~

Spindle Cell and Pleomorphic lipomas Spindle cell and pleopmorphic lipomas are cousins and they have a lot of overlapping features. They were described years ago (with H&E) as tumars of middle-aged adults, with a male predominance and a proclivity for the neck and shoulder region (8,9). They are superficial and well marginated 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 can be confidently diagnosed on H&E when they are in their classic presentation. These tumors consist of spindle cells, wiry collagen ("kinky" collagen), mast cells, and variable amounts of myxoid stroma . Sometimes

Figure 2-8 LIPOBLASTOMA

This lesion was exdsed about a year after a smaller biopsy was diagnosed as a lipoblastoma. Other than the impressive lobulation, the tumor has the appearances of a li poma, which is usually a lesion of middle-aged adults.

15

Soft Tissue Pathology

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). Myxoid examples (fig. 2-11) result in concern for myxoid liposarcoma (figs. 2-3, 2-12), but these tumors are superficial wh ereas myxoid liposarcoma is gen erally deep and the rich vascularity of m yxoid liposarcoma is usually absent. Some examples have little fat ("low fat" or "fat free" spindle cell lipoma). Pleomorphic lipoma has the same features as spindle cell lipoma with the addition of multin ucleated h yperchromatic "fleurette" cells (fig. 2-13). This can result in concern for atypical lipomatous tumor (discussed below), but most

16

examples are diagnosed with an H&E stain. These lesions consistently express CD34 but it is generally not necessary to perform this stain. The spindle cells lack S-100 protein expression but h ave areas of fat. Both spindle cell and pleomorphic lipomas can contain lipoblasts (fig. 2-13C), the presence of which should not cause alarm if the other features are present. Atypical Lipomatous Tumor/ Well-Differentiated Liposarcoma

Atypical lipomatous tumor (ALD and well-differentiated liposarcoma are the same thing. Tumors

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

I

'

,

,;

. , ....

4 •

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

Soft Tissue Pathology

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).

"

.,.

~

:.....

, ,

.

3.. ' ~I ,,

..

., <

'

., ,.

, I

c

.,,

--~

J

~4 ~ ~

t!'

'· ,::4, , ,.., '

-/{·~;; ~,.·

•

...

'

4

~.

,_

,

if

-

't

•

I

' -'

'Y,

-

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 liposarcoma early on never metastasized, so in the late 1970s, Harry Evans proposed using the atypical lipomatous tumor terminology for lesions in the readily accessible soft tissues (10-12) and to reserve the liposarcoma terminology for retroperitoneal lesions, which were more likely to dedifferentiate (evolve to a higher grade form). The 2013 WHO classification of soft tissue tumars went so far as to apply the term ALT to retroperitoneal lesions but pointed out that the term well-differentiated liposarcoma was also acceptable for neoplasms in the retroperitoneum or mediastinum (1). These are tumors of middle-aged and older adults. They are deep, either involving the deep muscles of the extremities or the mediastinum, retroperitoneum, or abdomen. ALT is diagnosed at 4X and confirmed at higher magnification. There is no need to hunt for lipoblasts although it is fun to see them.

Instead, search (at low magnification) in the thick bands of collagen. These bands are not the same as the "kinky" collagen encountered in pleomorphic lipomas, and the bands should be punctuated by cells with enlarged hyperchromatic nuclei (fig. 2-14). It is also nice to see the same hyperchromatic nuclei suspended "naked" in surrounding fat (fig. 2-15). Some tumors contain abundant lymphoid tissue and some examples are sclerotic, but the presence of atypical nuclei is the common denominator (fig. 2-16). In reality, in needle biopsies, it is useful to test for MDM2 gene amplification or protein overexpression but some needle biopsies contain the fatty component as well and such testing is not necessary for the diagnosis. There are a few pitfalls in diagnosing ALT. The one that is seen more and more frequently in this era of obesity is massive localized lymphedema in the morbidly obese (13,14). It is not clear why morbidly obese individuals acquire

19

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

.i .,

I .

"'

': • . ~

'

··...~,' .. i;·;.~ . '

. ··' ·'

f' .'.

c .-.

;

\.

I

-~-

.·

•

..

""' · .. •'l ....

.,.. . ~

.. -·.

4

.-,... • ~, ,

t

....

•

.

/

'.:.

. ... "

~

"·

-~·

..

,.:

E

.·

....

Figure 2-14, continued 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

Soft Tissue Pathology

J

\-

'

Figure 2-15

~

~

ATYPICAL LIPOMATOUS TUMOR/ WELL-DIFFERENTIATED LIPOSARCOMA

,#

Large hyperchro mati c nuclei plopped in to zon es th at o therwise have appea ran ces of fat are characteristic of atypical lipomatous tumor/well-differentiated 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.

~·

.

./

..

..

• •

-•.. -·•:t; . ..

..-

••..·

·'

'·. t

#

• , .·,"I,J"

. ..

I

·'~:

~,.

I

.. ..,... ...

·.

....

.

--

.· ·--<

-~

.

( :~

;,... 1c· . . ~ .. , . ·; ,.

,.

,' I'

\

• .

.. . . . ... , .•. .. ~

I • • •·

\: ... • I

• I

......-, •.

;~

I

·I

',

•

~

•

..

• :. . ,. i .l ..

.

of I

~

•

~ ...

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 can; the process mimics liposarcoma but differs in several ways. The lesions tend to arise in one of the patient's thighs, resulting in a pendulous, superficially-based mass that has overlying skin stasis changes with thickening of the skin and an elephantiasis-like appearance. Such lesions also arise in the scrotal area (15). Microscopically, there is a superficial edematous process with plenty of dilated lymphatic spaces. There is often inflammation of the overlying skin and perivascular inflammation (fig. 2-17). The problem is that

there may be mildly atypical cells in the stroma that are similar to the hyperchromatic cells that characterize ALT (fig. 2-17C) (16). Attention to the superficial location and the boggy edematous appearance of the process resolves the issue. Tumors with differentiation along the lines of brown fat (hibemomas) are occasionally concerning. They arise in young adults rather than middle-aged patients like ordinary lipomas. The brown fat appearance can suggest liposarcoma and the rich vascularity typical of brown fat can also be alarming (fig. 2-18).

23

Soft Tissue Pathology

Figure 2-18 HIBERNOMA

Left: These are lipomas with brown fat differentiation. They arise in young adults whereas usual lipomas a rise in middleaged 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

The high-grade form of atypical lipomatous tumor/well-differentiated liposarcoma, dedifferentiated liposarcoma, is easy to diagnose on H&E if there is both a low- and high-grade lesion in the available tissue (fig. 2-19). Often, however, ancillary testing is required to diagnose the high-grade form on small samples (examples are shown in chapter 3). Dedifferentiated liposarcoma is a lesion of deep soft tissue (usually retroperitoneum, occasionally extremities) of adults. As it was initially described, dedifferentiated liposarcoma was a neoplasm in which a high-grade pleomorphic sarcoma was seen arising in association with a well-differentiated liposarcoma (atypical lipomatous turner) (10,11). Certain mitotic counts were expected and the lesion was described with a storiform pleomorphic pattern. Over time, the definition has expanded and we now realize that well-differentiated liposarco ma can blast off into an y kind of high-grade component it fancies, whether with whorls (16), smooth muscle d ifferentiation (17), or even skeletal muscle or osseous ("heterologous")

24

differentiation (18). Some examples even show areas resembling pleomorphic liposarcoma (see below) but they differ genetically fro m pleomorphic liposarcoma. This phenomenon has been termed "homologous" dedifferentiation (2). A subset of cases shows a process that resembles a low-grade fibrosarcoma, which has been termed "low-grade dedifferentiation" (19). Examples of t he various patterns of dedifferentiated liposarcoma are seen in figure 2-20. Lesions that were regarded as "inflammatory malignant fibrous histiocytoma" in the past are now known to be dedifferentiated liposarcomas (20) . In many instances, dedifferent iated liposarcoma is an H&E diagnosis. In such cases, the well-differentiated component is demonstrated together with the high-grade one. This is true mostly in resection specimens but can sometimes be seen in needle biopsies if the radiologist is knowledgeable enough to sample zones that have a fat-like appearances as well as solid areas. Importantly, there are forms of dedifferentiated liposarcoma that appear similar to inflammatory myofibroblastic tumor (21), and dedifferentiated liposarcomas that appear

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

'

·'

."

" 1

t.l 'of

.

-

J..:

-4-.....t ~

. . _).-

-<~-....--

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.

.· . ,·

.

...

. ~­

:f

..-4

. .

.

o'

... ~.

' •'

....

. ·• •

...

... ..

. .....

•

•

~

\

, . . •

I

··Q ,.

.. I

.;

I

.

0

:~·

..

•

,,

.

0

'

~ "~ ,~

• .I

#

•I of

I

I

• •

.1.

i ,

l

'".·l' J •·

·:

•• • : o, , • •

. :

~ '

\ '

'

'.

I

. .. • ·' I

. ..

. /' : . ·' l .. . . '

•

I

• ,'

. • ., .

'

...-.

,...

,. . . \ ;

0

••' ,._,

: ' .•

f

r

• f

~0

, 1.

1-

..

...

•

. ,

\

.'

..

I

\

\'

-:

I

-~

I'

.

t

...

··.

,,'"'

'

...

)

: • .•

•

..

., .. . ... ..

·.

..· ..

.' .:~

.·. I ··.·

.

.. . ..,,..

, J!'

·, . ,

.,.

-.

25

Soft Tissue Pathology

! )' I

Figure 2-20 DEDIFFERENTIATED LIPOSARCOMA

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

·, ;,. ., ,' •;.· ·~

~

Figure 2-20, continued 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

Soft Tissue Pathology

Figure 2-20, continued DEDIFFERENTIATED LIPOSARCOMA

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.

...

similar to myxofibrosarcoma with a myxoid appearance. In these cases, especially on needle biopsies, ancillary studies are needed to establish the diagnosis. As a general rule, if a large retroperitoneal mass is a pleomorphic sarcoma on a small biopsy, the most likely interpretation is dedifferentiated liposarcoma. Confirmatory immunolabeling or FISH testing for MDM2 can be helpful. Dedifferentiated liposarcoma is the least aggressive of the pleomorphic sarcomas and the 5-year survival rate is 70 to 80 percent, although the 10-year survival rate is less favorable.

28

.--....

..

'

4

.

,

.

.. \ .- <...-· <1 ~... .:_ ... ,-

· ~·

• •

.,

..' . ,. ' ,' .

~ ""..

~.

- ... . .'

._

...-' .,;

,.._ .

. ~·· , . ·

··-·

Pleomorphic Liposarcoma

In contrast to dedifferentiated liposarcoma, pleomorphic liposarcoma is an H&E diagnosis because it is diagnosed by finding the areas of pleomorphic lipoblasts (22-25) an d it has no characteristic molecular or immunolabeling signature. It is an aggressive sarcoma of older adults and typically arises in the deep thigh. It consists of undifferentiated areas and variable areas with extremely pleomorphic lipoblasts that contain some of the most bizarre nuclei

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

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 epithelioid form (fig. 2-21B) (25). Pleomorphic liposarcoma can be difficult to diagnose in needle biopsies unless the pleomorphic lipoblasts, which can be focal, are sampled. In this setting, MDM2 studies are nonreactive because MDM2 amplification is not a feature of pleomorphic liposarcoma. Myxoid Liposarcoma

Myxoid liposarcoma is a tumor that arises in the deep soft tissues (usually of the extremities) of young adults. There is a low-grade and highgrade form. The high-grade form is also termed round cell liposarcoma. These tumors are unusual because they have a proclivity to spread to other soft tissue sites and even to bone. Since myxoid liposarcoma is a translocation sarcoma, it features uniform nuclei and lacks atypical mitoses (fig. 2-22). Myxoid liposarcomas can have cystic spaces and loculation as well as areas with mature-appearing fat, but the nuclei are uniform. Lipoblasts in these tumors tend to be found at the periphery of the tumor lobules. The vascular pattern is characteristic, consisting of delicate capillaries in a complex

30

network, which has been likened to chicken wire (fig. 2-23). If consideration is given to diagnosing a lesion as myxoid liposarcoma and there is nuclear pleomorphism, the lesion is probably instead a myxofibrosarcoma, which features similar vessels, but is usually superficial and contains pleomorphic nuclei (fig. 2-24). Another pitfall is fat atrophy, which can result in concern for myxoid liposarcoma because the atrophy of the adipocytes results in accentuation of the existing vessels (fig. 2-25). Additionally, sometimes damaged tissue has myxoid stroma and reparative hypervascularity (fig. 2-26). The high-grade form of myxoid liposarcoma (round cell liposarcoma) features solid areas of cells that obscure the vascular pattern (fig. 2-27). Both the low- and high-grade forms are readily diagnosed on H&E alone. Most high-grade examples show a bit of the low-grade form in some areas; occasionally molecular analysis (for FUSDDIT3 or EWSR1-DDIT3) is needed (needle biopsies). In general, surgeons and oncologists like to have a percentage of the high-grade component listed when reporting. Even a small percentage of the high-grade component (5 percent) can

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

D

Figure 2-22, continued 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 translocationassociated sarcomas.

31

Soft Tissue Pathology

figure 2-23

Figure 2-24

CHICKEN WIRE

MYXOFIBROSARCOMA

This mimics the appearance of the vessels in myxoid liposarcoma.

The indicated cell is not a lipoblast of myxoid liposarcoma, but rather it is a "pseudolipoblast." It is too pleomorphic and contains mucopolysaccharide matrix instead of a lipid d roplet.

have a negative impact on outcome; pure myxoid liposarcoma is a grade 1 sarcoma (1). FIBROBLASTIC/ MYOFIBROBLASTIC LESIONS

Nodular Fasciitis

Nodular fasciitis is the prototype pseudosarcoma and familiarity with its vascular pattern, range of appearances, and cytologic features is the framework upon which other pseudosarcomatous lesions and benign fibroblastic lesions are diagnosed. Nodular fasciitis was considered a reactive process in the past (26-28), but over time, cytogenetic alterations were detected (29) and, finally, a characteristic fusion was identified (MYH9-USP6) (30). The latter is of great interest, and confirms the interpretation in about 75 percent of cases (31), but nodular fasciitis remains an H&E diagnosis with a little practice. In exceptional cases, FISH for the fusion is of occasional use. Nodular fasciitis is a lesion of young adults and classically arises in the forearms of young

32

men, but no site is immune and no age off limits. The process is generally associated with fascia but it can be found in muscle (nodular myositis). Lesions usually attain a size of about 3 cm, but some are large and locally destructive. Microscopically, nodular fasciitis displays a lot of overlap with granulation tissue (fig. 2-28), but it differs by being more lobulated and lacking hemosiderin despite containing many extravasated erythrocytes and plasma cells; neutrophils are unusual. The cells show the key features of myofibroblasts, namely smooth nuclear membranes and amphophilic (neither eosinophilic nor basophilic) stellate cytoplasm. Each nucleus contains a delicate but readily identifiable nucleolus, and the nuclear membranes are smooth. The nuclei are usually similar in size to endothelial cell nuclei and typically paler. Mitoses can be abundant but are not atypical mitoses. In nearly every case, a careful search demonstrates osteoclast-like giant cells.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

Figure 2-28, continued 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 deposition, myxoid stroma, cystic spaces, and a loose storiform pattern. This pattern caused past researchers to liken the appearance to that of fibroblasts in tissue culture (32). The appearance of the nuclei is important to know, since the same delicate nucleoli and smooth nuclear membranes also characterize the fibromatoses, all of which have myofibroblastic differentiation despite divergent molecular underpinnings and pathologic features. For the colleague who is not accustomed to diagnosing nodular fasciitis, it is worth knowing that it expresses smooth muscle actin but usually not desmin or caldesmon. It lacks nuclear beta-catenin labeling (which can be useful to confirm a diagnosis of desmoid fibromatosis). The expression of smooth muscle actin in nodular fasciitis can easily lead to a misinterpretation as leiomyosarcoma. Proliferative Fasciitis and Myositis

Proliferative fasciitis is the entity that causes the most alarm among the pseudosarcomas. It

36

typically arises in older adults rather than in young adults, and tracks along fascial planes (33) . When it arises in children, it is especially cellular and can be easily mistaken for a high grade sarcoma (34). It is infiltrative and usually attains a size of 2 to 3 cm. When it is in muscle, it tends to have a "checkerboard" distribution (figs. 2-29, 2-30). It seems to lack the MYH9-USP6 fusion that characterizes nodular fasciitis (30,31), but it seems like an analogous process. Proliferative fasciitis contains a backdrop of cells that are essentially identical to those seen in nodular fasciitis and another population of larger cells that have large round nuclei and macronucleoli that are smooth and round (fig. 2-29C,D). The cytoplasm in the large cells is abundant and in the past was thought to be ganglion cells. Thus, the term ganglion-like cells was used; however, the latter cells are fibroblasts. Not surprisingly, proliferative fasciitis was often mistaken for sarcoma in the past, especially rhabdomyosarcoma in children, but modern immunolabeling with desmin and myogenin

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

Soft Tissue Pathology

.

Figure 2-30

A: The lesion partitions the skeletal muscles into lobules, resulting in a checkerboard-like appearance. B: The depth and cellularity result in concern for a 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

..

\

•

•• ~

..

'

...

PROLIFERATIVE MYOSITIS

..

.......,. .' ... r

. \ ·1..

• \

l.

"··.··.~ .·.

, \

..

0

•

· :

I : '"

·,

.• '

,.

"

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 immunolabeling is done, the cells lack expression of keratins, S-100 protein, desmin, and myogenin such that the differential diagnosis is with pleomorphic sarcomas in adults; attention to the morphology readily resolves the issue. Myositis Ossificans

Myositis ossificans is basically something that looks like nodular fasciitis that ossifies. Like nodular fasciitis, it frequently has rearrangements of USP6 (31,35,36). It tends to arise in the thighs of young adults. Early on, it lacks ossification, but over time, it develops a "shelr of bone" that can be seen on plain X rays (fig. 2-31). Skilled radiologists are generally able to recognize it. The trouble is that it is quite cellular early on and can be mistaken for extraskeletal osteosarcoma. The key is to recognize that the nuclei are identical to those seen in nodular fasciitis and the presence of the bone is simply a distraction (fig. 2-32). The bone forms at the periphery of the lesion rather than fully intermingling within it. This pattern is referred to as zonation, and is among the features that allow for separation from extraskeletal osteosarcoma (fig. 2-33).

Ischemic Fasciitis (Atypical Decubital Fibroplasia)

This condition was initially described as atypical decubital fibroplasia (37), a unique form of pressure sore that tends to arise in the elderly in areas otherwise prone to decubitus ulcers except that this lesion forms a mass. In fact, the lesions were referred to informally as "nursing home lesions" while gathering data for the initial publication (3 7), terminology that does not lend itself to peer-reviewed medical publications. The term ischemic fasciitis was adopted even though the appearance is not inflammatory (38,39). These tumors do not always arise in the elderly (38), but usually arise in areas prone to poor blood flow, and they are somewhat analogous to cyclists nodules encountered in otherwise fit bicyclists in their perineal areas (40,41). Ischemic fasciitis forms a subcutaneous tumor that can become large and mimic a liposarcoma since it contains subcutaneous fat. Of course, liposarcomas are seldom subcutaneous. The problem is compounded by the fact that a wrong interpretation on H&E can be falsely confirmed by expression of MDM2 and other proteins by immunostains known to be reactive in atypical lipomatous tumor/

39

Soft Tissue Pathology

A

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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, TP53 (P53), and CDK4. However, if FISH testing for MDM2 is added, it is nonreactive (42) . Some genetic alterations have been detected but we suspect that they don't mean much (43). Ischemic fasciitis should be an H&E diagnosis. No immunostaining is needed, and it can lead to escalated molecular testing. The key to diagnosing ischemic fasciitis is noting the zonation and then noting that the lesional cells follow the rules of nodular and proliferative fasciitis (figs. 2-34, 2-35). The difference is, however, that since the lesion is

probably hypoxia-induced, atypical mitoses may be encountered. In ischemic fasciitis, zones of fibrinoid necrosis are present. At the edges of the zones, there is ingrowth of plump fibroblastic cells with increased cytoplasm and nuclei with enlarged round nucleoli. Additionally, there are clusters of capillaries that are in well-delineated zones . From these oxygenated areas, the fibroblasts sally forth into the pools of fibrinoid necrosis. The nuclear to cytoplasmic ratio is low and the nuclei are not hyperchromatic like those in atypical lipomatous tumor/well-differentiated liposarcoma (figs. 2-14A,B; 2-15).

41

Soft Tissue Pathology

Figure 2-34

Figure 2-35

ISCHEMIC FASCIITIS The center shows fibrinoid necrosis and there is ingrowth of sprouts of capillaries.

ISCHEMIC FASCIITIS The cells between the capillaries are activated fibroblasts and myofibroblasts with stellate cytoplasm and prominent but perfectly round nucleoli.

Fibroma of Tendon Sheath

Fibroma of tendon sheath looks benign. The only pitfall is that the early phase can appear identical to nodular fasciitis (44). It is a lesion of young adults (third to fifth decades) with a slight male predominance. It usually arises in association with the tendons and tendon sheaths of the fingers, hand, and wrist. It usually presents as insidiously growing masses associated with mild tenderness and pain in about one third of patients. The finding of t(2;11)(q31-32;q12) suggests that these are neoplasms rather than reactive lesions (45). This entity shares morphologic features with desmoplastic fibroblastoma (collagenous fibroma, discussed below) but differs by lacking FOSLl immunolabeling, which is found in desmoplastic fibroblastoma (46,47). Tumors are found attached to tendons and tendon sheaths, and are usually well circumscribed, and lobulated, and sometimes encapsulated. It measures approximately 2 cm. Tumors are composed of myofibroblasts and fibroblasts associated with dense fibrous stroma and cleftlike spaces (fig. 2-36). Myxoid degeneration, extravasated erythrocytes, and scattered mono-

42

nuclear cells can result in appearance similar to that of nodular fasciitis. Confusing the two is of no consequence since both are benign, except that fibroma of tendon sheath is more likely to recur than nodular fasciitis. Elastofibroma

Elastofibroma is a slowly growing fibroelastic proliferation believed to result from mechanical friction between the scapula and the chest wall. It usually arises in middle-aged women. Bilaterality is also known. Elastofibromas are benign. Microscopically, elastofibroma is hypocellular and contains thick elastic fibrils (fig. 2-3 7). Desmoplastic Fibroblastoma (Collagenous Fibroma)

Desmoplastic fibroblastoma arises in adults of wide age range (16 to 81 years in the largest series) with a wide anatomic distribution (arm, shoulder, girdle, posterior neck and upper back, feet and ankles, leg, hand, abdominal wall, and hip) (46-51) and a wide size range (1 to 20 centimeters, median 3 cm). The lesion is benign. Even incompletely excised tumors are not apt to recur.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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.... · ·,

,

... ; '-~- :. ~ __

~ . "$ .

Most examples are subcutaneous but sometimes skeletal muscle is involved, leading to concern that the patient has desmoid fibromatosis. The turnor can be quite infiltrative. These tumors are paucicellular, consisting of bland stellate and spindle-shaped fibroblasts in a densely collagenized matrix, sometimes with myxoid change. Mitotic activity is absent or minimal (fig. 2-38) . On immunolabeling, these tumors show a myofibroblastic signature. They have an llq12 alteration related to the FOSLl gene (46,47). However, no ancillary testing is needed. For those who are nervous about missing desmoid

••

•l

fibromatosis on a needle biopsies, these fibromas lack beta-catenin nuclear labeling. Calcifying Aponeurotic Fibroma

Calcifying aponeurotic fibroma arises primarily in the hands and feet of children between birth and 16 years (52). There are exceptions; extra-acral examples may be observed (53). The tumor usually presents as a slow-growing poorly circumscribed mass. Plain radiographs may show calcific stippling. Calcifying aponeurotic fibroma is a benign lesion, but aneuploidy has been reported (54). ins(2;4)(q35;q25) results in

43

Soft Tissue Pathology

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 reminiscent 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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 the breakpoint regions on chromosomes 2 and 4, respectively, that results in aberrant EGF protein, which can be detected by immunolabeling (SS). Calcifying aponeurotic fibroma has a tendency for local recurrence. These lesions can result in diagnostic difficulty when they lack their characteristic appearance, but most are easily diagnosed by H&E alone (fig. 2-39). They show a mixture of chondroid cells and areas that resemble fibromatosis. The chondroid areas become calcified in a serpiginous fashion. If the key calcified areas are missing, sometimes adding a few recuts can reveal them. The lesion is most likely to be biopsied from a child's hand, which is the clue to consider it. Inclusion Body Fibromatosis (Infantile Digital Fibromatosis)

This is a really delightful H&E diagnosis to make. Do it early. Do it often. As the original name implies, this tumor typically is encountered in infants and young children (mean age, 12 months in the largest series) (56) and mostly involves the toes or fingers, but occasionally the hands and feet. There is a slight male predom-

inance and the lesions have a median size of about 1 cm at the time they are removed. On H&E staining, inclusion body fibromatosis appears similar to desmoid fibmomatosis (as described below) with a key difference-the inclusion bodies. It can even display nuclear beta-catenin labeling, but it lacks mutations in the CTNNBl gene that encodes beta-catenin (57). These lesions do not seem to be syndromic and do not progress to desmoid type fibromatosis. They can persist locally when incompletely excised. These lesions form superficial nodules (unlike desmoid fibromatosis, which is almost always a larger deep mass). At low magnification, delicate blood vessels can be seen in a spindle cell lesion, with more or less uniformly spaced nuclei present between deposited pale collagen. The treat is provided at high magnification because numerous cytoplasmic eosinophilic inclusions are present (fig. 2-40). These are composed of actin filaments (58). Inclusion body fibromatosis is benign but can be locally persistent. Palmar and Plantar Fibromatosis

Palmar fibromatosis (Dupuytren contracture) is common, found in 1 to 2 percent of adults.

45

Soft Tissue Pathology

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 subcutaneous nodules or plaques involving the dermis or underlying fascia/tendons which may lead to contractures. They may be bilateral, familial, and multiple. These lesion s are associated with alcoholism, epilepsy, diabetes, and chronic lung disease and can coexist with plantar but not with desmoid type fibromatosis. Some examples recur after local excision. These lesions consist of multiple small nodular fibrovascular proliferations with delicate blood vessels surrounded by a thin cuff of collagen situated near the center of the nodules. The cells show the features of myofibroblasts delineated in the entities above (fig. 2-41 ). Newer lesions are more cellular, with plump immature-appearing fibroblasts, and mitoses are acceptable. Older lesions are less cellular and contain increased dense collagen. Myxoid stroma is often present, and long-standing examples may show cartilagenous or osseous metaplasia.

46

Plantar fibromatosis, like palmar fibromatosis, is a nodular fibrous proliferation. lt arises in plantar aponeuroses. It is less likely to result in contractures than palmar fibromatosis and has a higher recurrence rate. It is over-represented in patients with palmar or penile fibromatosis. Although the lesions may be asymptomatic, they may produce mild pain, or paraesthesia if there is superficial plantar nerve entrapment. The histologic appearances of plantar fibromatoses are similar to those of palmar fibromatoses (fig. 2-42). Some cases show striking cellularity and numerous mitoses. Giant cells may also be present (59). Desmoid Type Fibromatosis

Desmoid type fibromatosis is a common lesion that has deceptively bland histomorphology but a tendency to locally recur and infiltrate the surrounding tissue, hence, it is also called "aggressive fibromatosis." It arises primarily in the connective

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

(

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

Soft Tissue Pathology

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 aponeurosis (musculoaponeurotic fibromatosis). In children, there is no gender predominance but there is a striking female predominance in young adults since these lesions are estrogen driven. The fema le predominance vanishes again in older persons. Organs can be involved, such as breast, vulva, and spermatic cord, but the most common location is the shoulder girdle followed by chest wall and back, thigh, and head and neck. Fibromatosis of the abdominal wall predilects to young women. Fibromatosis of the head and neck is seen more commonly

48

in children, in which case the lesions tend to be more cellular and may grow more aggressively, even encroaching on the trachea with destruction of adjacent bone and a fatal outcome. Although these tumors do not metastasize, they can be multicentric. These tumors are easy to diagnose on H&E (fig. 2-43). They have uniform cellularity and a characteristic appearance at low magnification in which tiny capillaries are easy to see since the surrounding lesion is pale. Mesenteric examples often have gaping thin-walled vessels that are easy to see at low magnification. The tumor has

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 spaced nuclei. The collagen is sometimes dense and keloid-like. The nuclei and cytoplasm have all the features of myofibroblasts, with smooth nuclear membranes, delicate round nuclei in each cell, and cytoplasm that is stellate in areas where the tumor is a bit edematous. There is slight myxoid change in some examples. Importantly, in zones in which skeletal muscle is infiltrated, it is easy to be concerned that the entrapped atrophic skeletal muscle cells are pleomorphic cells (fig. 2-44). In patients with familial adenomatous polyposis (FAP), intestinal and extraintestinal n eoplasms typically arise through bi-allelic (germline then somatic) inactivation of the APC gene, whereas the corresponding tumors in non-FAP patients occur either through somatic bi-allelic APC inactivation or somatic mutatio n of a single CTNNBl (the gene encoding for beta-catenin) allele. A pitfall is with gastrointestinal stromal tumors (GISTs) . Although their features are

readily distinguishable on routine H&E-stained slides, pathologists should be aware that fibromatoses may react with some commercially available CD11 7 antibodies if antigen retrieval is used (60). Staining is typically weaker than that seen with true GISTs but beta-catenin staining can be helpful, since nuclear staining is only seen in desmoid tumors (61). If this staining is performed, it is important to pay attention to internal controls on the slides (fig. 2-43D). The nuclei of endothelial cells should be negative even though cytoplasmic staining is acceptable. Strong cytoplasmic staining can be seen in a variety of tumors and reactive processes and is completely non-specific. It may be difficult to determine if nuclei are staining when there is abundant background cytoplasmic staining. In the past, extremely aggressive resectio ns were advocated for these lesions but the current approach is more of an active surveillance philosophy, since these tumors tend to "burn out" as patients age.

49

Soft Tissue Pathology

.

.. ~ ' 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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Fibrous hamartoma of infancy is an uncom-

mon and nearly always benign fibroblastic and myofibroblastic proliferation, which generally arises in the axillary or shoulder region of males in their first 2 years of life (groin is a "common uncommon" site) (62). They usually present as a solitary, small, rapidly growing soft to firm mass. About 20 percent of cases are present at birth. The lesion only rarely occurs on the hands and feet. Although the lesion is termed a hamartoma, the detection of several assorted translocations and EGFR alterations as well as documentation of malignant transformation in rare cases, better supports a (usually benign) neoplasm (63- 66). In the largest available case series, the most common sites in descending order were axilla, back, upper arm, scrotum, and chest wall (63). The rare reported malignant-

appearing examples have not metastasized as of this writing (63). This lesion was initially termed hamartomatous because it is composed of a mixture of three elements in varying proportions: 1) fibrou s trabeculae or septa consisting of spin dle cells separated by collagen, 2) myxoid foci containing primitive round or stellate mesenchymal cells, and 3) mature adipose tissue (fig. 2-45). When fibrous hamartoma of infancy arises in the groin, the presence of the immature-appearing cells can suggest the possibility of embryonal rhabdomyosarcoma, especially if frozen section s are performed. These turners can have overlapping features with giant cell fibroblastoma (fig. 2-46), which can be regarded as the pediatric variant of dermatofibrosarcoma protuberans, and both types of turners express CD34, so morphology is the winner.

51

Soft Tissue Pathology

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 romatosislike 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

Inflammatory myo(lbroblastic tumor (IMT) is a lesion that is always tested using ancillary tech niques in parts of the world with plenty of resources but it was initially described by its morph logy (67,68), and we use morphology to consider it in the hope of identifying an alteration amenable to targeted therapy. It tends to arise in the abdomen and pelvis (often m esentery) of children and young adults, without gender predilection, as well as the omentum and retroperitoneum (over 80 percent of cases).

52

Occasional cases are found in the mediastinum, abdominal wall, kidney, and liver but no site is truly immune. Sometimes, patients experience systemic symptoms. The tu mor can be solitary or multinodular (30 percent) and as large as 20 cm in diameter. The tumors are composed of myofibroblasts and fibroblasts in fascicles or in a loose storiform pattern, with variable background inflammation th at consists of plasma cells and lymphocytes with scattered eosinophils, but neutrophils are not common (fig. 2-47). Nuclear pleomorphism

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Figure 2-46 GIANT CELL FIBROBLASTOMA

A: This is considered a juvenile form of dermatofibrosarcoma 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. Stromal fibrosis and calcification can be present. The nuclei, in the fashion of myofibroblastic cells, contain round red nucleoli. Immunostaining is positive for smooth muscle actin (SMA), and many examples express cytokeratin especially where there is submesothelial involvement. By immunohistochemistry, ALK is detected in 60 to 70 percent of cases, a finding that can be exploited for diagnosis and possibly prognosis (positive cases may have a better prognosis) (69). Th e tumors invade adjacent viscera; occasional examples metastasize

and are aggressive but most are treated surgically and have indolent behavior. A more aggressive form of inflammatory myofibroblastic tumor (fig. 2-48) has been termed epithelioid inflammatory myofibroblastic sarcoma. It is composed of mo notonous malignant nee-

plastic cells with cherry red inclusion-like nucleoli. It tends to display strong desmin labeling and scattered neutrophils rather than plasma cells. If immunolabeling is performed, this type (essentially always of the mesentery) shows strong desmin labeling and is characterized by an unusual nuclear membrane or perinuclear

53

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 clinical behavior than the classic form (70). The high-grade form of IMT can be considered on H&E but cannot be diagnosed as such purely on H&E results whereas the low-grade form is more characteristic. Indeed, few colleagues in high resource practice environments would diagnose inflammatory myofibroblastic tumor without performing ALK or ROS1 immunolabeling, but it is important to remember that the entity was defined initially on the basis of H&E (68). IMTs are managed by surgery, with a favorable outcome most of the time. However,

since they sometimes harbor "targetable" ALK rearrangements, they can respond to treatment with crizotinib and related compounds (71-75), including the more aggressive epithelioid inflammatory myofibroblastic sarcoma variant. About 10 percent of these tumors have alternate fusion of the ROSl gene (76,77); these tend to be found in tumors from children and are also amenable to the same targeted therapy as tumors with ALKl rearrangements. Because IMTs are inflammatory, it is not surprising that colleagues have assessed them for IgG4, and plenty of IgG4-reactive plasma cells

ss

Soft Tissue Pathology

I

0

•

~· ' Ill'~· •

,

I'

.

..

• "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 finding. IgG4-related fibrosclerosing disease (fig. 2-49) is diagnosed by morphology (storiform fibrosis, inflammation, obliterative phlebitis), and the diagnosis can be confirmed by adding IgG4 immunolabeling (79).

56

Lipofibromatosis

Lipofibromatosis is another pediatric confection that is fun to diagnose and requires only H&E. It arises in the distal extremities of babies and young children. It affects primarily male infants and boys (median age, 1 year) . It usually involves the hand

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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.

~

"""<. /

A.:-

r·

..

·

.. j

L

~ ;.I .,. \ /

-

·~

_,

"',. . . ,,,,

J - :~ /

f,.

,-; ~ -

but the arm, leg, foot, chest, abdomen, and head can be affected. Some examples are congenital. Tumors are typically small (median, 2 cm) with a yellowish or tan-white cut surface, often with a fatty or fibrofatty appearance. Microscopically, lipofibromatosis is poorly marginated and composed of abundant fat with an accompanying fibroblastic proliferation that spreads along fat septa (fig. 2-50). There is a variable amount of collagen, and the tumor cells are uniform. In zones where the fibroblasts and fat merge, the collision results in univacuolated cells reminiscent of lipoblasts. The tumors lack the "primitive cells" that characterize fibrous hamartoma of infancy. Mitotic activity is minimal.

Because lipofibromatosis is infiltrative between vessels, nerves, skin adnexa, and skeletal muscle, it is difficult to completely excise and thus recurs even though it is benign. With immunohistochemical staining (unnecessary), the spindle cell component usually expresses CD99, CD34, and SMA, and variably expresses BCL-2, S-1 00 protein, muscle specific actin, and epithelial membrane antigen (EMA). Keratin and desmin are absent. Although no characteristic gene fusion has been identified, alterations in the 1q21-22 area by FISH are found (80). This differs from similar tumors termed "lipofibromatosis-like neural tumors" (fig. 2-51), which have NIRK.l gene fusions and express S-100 protein but not SOXlO.

57

Soft Tissue Pathology

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.

FIBROHISTIOCYTIC TUMORS AND SOME HISTIOCYTIC LESIONS Tenosynovial Giant Cell Tumor, Localized and Diffuse Types

Tenosynovial giant cell tumors are also known as giant cell tumor of tendon sheath and pigmented villonodular tenosynovitis. They are easy to diagnose on H&E in the proper setting. The classic

58

story for giant cell tumor of tendon sheath is a painless finger lump in a middle-aged woman, but these tumors can be found over a wide age range. The infiltrative type (pigmented villanodular tenosynovitis) is usually found in the region of the knee joint in young women and produces tremendous morbidity as it impedes joint function. The localized type, as the name suggests, is a small lobulated lesion adjoining a tendon sheath or aponeurosis. The diffuse

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Figure 2-52 TENOSYNOVIAL GIANT CELL TUMOR, LOCALIZED TYPE (GIANT CELL TUMOR OF TENDON SHEATH)

A: These are common lesions of the fingers in middleaged 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 symptoms, and be prone to local recurrence . Both types are composed of nests of round cells in a background of variable numbers of histiocytes (including multinucleated and foamy ones), plasma cells, and lymphocytes, and variable amounts of hemosiderin, which accounts for the term "pigmented villonodular tenosnyovitis" for the infilatrative form. Some cases have few or even no giant cells, so learning to diagnose this entity by its other features is crucial. Most of the lesional cells have round nuclei and mitotic activity is acceptable and may be quite brisk (figs. 2-52, 2-53). Immunolabeling is not necessary for diagnosis, but CD68labeling

can be expected. The key pitfall is with clear cell sarcoma (fig. 2-54), which is S-100 protein and HMB45 (and other melanoma markers) reactive and displays different morphology. Of course, the nervous pathologist can consider adding a keratin and S-100 protein stain to nearly any mass of the hands to address clear cell sarcoma and epithelioid sarcoma, but this is not necessary in most cases. Dermatofibroma and Fibrous Histiocytoma

Dermatofibroma and fibrous histiocytoma are essentially the same thing, but generally the former term is used for predominantly dermal lesions whereas larger lesions are usually designated as

59

Soft Tissue Pathology

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 melanomaassociated an tibodies such as HMB45.

60

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 common, arising in persons of all ages, but mostly those in the fourth and fifth decades. The usual location is the distal extremities. Microscopically, they are well marginated but not excapsulated and associated with hyperplasia in the overlying epidermis. The tumor cells do not proliferate right up to the epidermis, but

leave a little space (the Grenz zone) for the papillary dermis, although this is sometimes lost in excoriated/irritated lesions. They consist of spindle cells that are sometimes arranged in a storiform pattern (mat-like with intersecting fascicles) similar to the pattern of dermatofibrosarcoma protuberans. However, they contain various secondary components, namely, plasma

61

Soft Tissue Pathology

Figure 2-55, continued 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 CD34positive 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 Touton giant cells, blood filled spaces, and hemosiderin. These secondary components are not a part of dermatofibrosarcoma protuberans. The lesional cells have overlapping features with those of nodular fasciitis but the nuclei are darker. The tumor cells often extend for a short distance into the tissue at the interface of the lesion and the normal tissue, where they entrap collagen (fig. 2-55C). The difficulty with these lesions is that, when they grow larger, they can show aneurysmal features and pseudovascular spaces together with some nuclear atypia and mitotic activity. It is the low-magnification architecture that saves the day (figs. 2-56, 2-57). The main pitfalls with fibrous histiocytomas happen when immunolabeling is added. Fibrous histiocytomas are loaded with dendritic cells, so S-100 protein often stains quite a few irrelevant cells (fig. 2-58). However, the biggest pitfall occurs when CD34labeling is performed to differentiate fibrous histiocytoma from dermatofibrosarcoma protuberans. With nearly any tumor type, as the body attempts to wall it off, a rind of CD34-positive stromal cells coalesces at the periphery of the tumor. If the plane of sectioning shows a lot of this rind, it is easy to interpret the lesion as CD34 positive, especially since the CD34-positive cells grow into the outermost layer of the lesion (figs. 2-55£, 2-58C). It is better not to have done the CD34 than to be fooled by it. There is an unusual lesion termed epithelioid cell histiocytoma that, as suggested by the name, is composed of epithelioid cells. Like the lesion

62

above, it arises on the extremities of young adults, where it is in the dermis. There is often an epidermal collarette, but the characteristic collagen trapping of fibrous histiocytoma is absent. Curiously, this type of tumor expresses ALK protein and hasALK rearrangements, which can be exploited for diagnosis (fig. 2-59) (81,82), but recall that the original description was made using H&E. Over time, rearrangements of the ALK gene are found in many tumor types of various malignant potential, a story mirroring that with EWSRl, which is further mentioned in chapter 3. In children, juvenile xanthogranuloma is more likely than fibrous histiocytoma, and the head and neck is the favored site. These lesions appear more solid than fibrous histiocytomas and lack prominent collagen trapping (fig. 2-60). Plexiform Fibrohistiocytic Tumor

Plexiform fibrohistiocytic tumor a subcutaneous tumor of children and young adults that usually arises in the upper extremity. It only rarely metastasizes (83), and most patients have a favocable outcome following complete excision. The name tells the story. There are two patterns: in one, nodules of tumor with features similar to those of fibrous histiocytoma are arranged throughout the deep dermis and subcutaneous tissue in an infiltrative pattern, and in another, these random nodules appear more fibroblastic (fig. 2-61). Although some have suggested that it is the same as cellular neurothekeoma (84-86), the morphology and immunolabeling patterns differ (fig. 2-62): neurothekeomas express NKI-C3 and MiTF

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

Soft Tissue Pathology

Figure 2-57 FIBROUS HISTIOCYTOMA (DEEP VERSION OF DERMATOFIBROMA)

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 FIBROUS HISTIOCYTOMA (DEEP VERSION OF DERMATOFIBROMA)

A: This lesion was "scooped out" in fragmen ts by the surgeon.

64

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

'<'\

-~·

,

~

~ ~ '"'

" .. ---... .. . ~ '• .

t:

v

\,. """

T

'

J•

Qo

.r

~,1

.. ... -

Figure 2-58, continued 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

Soft Tissue Pathology

..·

,•

Figure 2-59

Figure 2-60

EPITHELIOID CELL HISTIOCYTOMA

JUVENILE XANTHOGRANULOMA

A: The tumor is dermal and is similar to fibrous histiocytoma, but the proliferating cells are epithelioid. B: The center of the lesion consists of plump epithelioid cells. C: These peculiar tumors have ALK gene rearrangements and express ALK protein by immunolabeling, as shown h ere.

A: These tumors appear very similar to fibrous histiocytomas but often contain numerous multinucleated Touton giant cells and eosinophils. B: Note the abundance of multinucleated cells. C: An eosinophil is present in the center of the image.

66

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 (84-86). A more difficult distinction is between myxoid neurothekeoma and nerve sheath myxoma (figs. 2-63, 2-64); at least for us this requires immunolabeling for S-100 protein, which is only seen in nerve sheath myxoma (85,86). If immunolabeling is not available, this is not a disaster, since both tumors are benign. Dermatofibrosarcoma Protuberans Dermatofibrosarcoma protuberans is a lesion of young adults. It is superficial {dermal and subcutaneous) and usually arises on the trunk

and extremities (87). Its growth pattern is very infiltrative such that it can extend for several centimeters beyond where the surgeon palpates the lesion, a source of many microscopically positive margins. It can be regarded as a very low-grade sarcoma since metastases are rare, but some examples transform to overt sarcomas and do spread, although this is uncommon. Dermatofibrosarcoma protuberans harbors a characteristic translocation that results in a COLlA-PDGFB fusion (88,89). Because of this, the tumor cells have a very monotonous appearance and advanced examples (rare) can be treated with

67

Soft Tissue Pathology

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 no need to test for the characteristic gene fusion to diagnose dermatofibrosarcoma protuberans. Dermatofibrosarcoma protuberans infiltrates the subcutaneous adipose tissue and proliferates right up to the epidermis and slides between

68

skin appendages. It slinks along connective tissue septa, extending far from the main lesion. The cells are very monotonous and no more than a few enmeshed inflammatory cells are seen. Hemosiderin is not a component. Sometimes there is a repetitive storiform pattern (fig.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 plentiful. No one counts them because it is not important. When the cells become larger and mitoses are plentiful (no need to count), that is when transition to fibrosarcoma is considered (fig. 2-66). However, even with this transition to a high-grade form, most patients have a favorable outcome following wide excision (91). This tumor has a lot of morphologic overlap with two benign lesions: fibrous histiocytoma and diffuse neurofibroma. The distinction is easy on H&E with a little practice.

-.. \

Fibrous histiocytoma (see figs. 2-55-2-58) has variable cells sizes and shapes, an admixture of plasma cells, lymphocytes, histiocytes, including foamy ones, h~osiderin, and collagen trapping at the pemphery. Scattered nuclear atypia/ pleomorphism favors fibrous histiocytoma rather than dermatofibrosarcoma protuberans. Diffuse neurofibroma (fig. 2-67) has smaller nuclei despite identical infiltrative pattern, lots of mast cells, and sometimes tactoid (Wagner-Meissner) bodies. In any doubtful case, diffuse neurofibroma expresses S-100 protein and dermatofibrosarcoma

69

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 in nerve sheath tumors and can be ignored (92). Giant Cell Fibroblastoma The juvenile form of dermatofibrosarcoma protuberans, giant cell fibroblastoma (88,93- 95), is easy to diagnose if it is considered, and has the same COLlA l-PDGFB gene fusion and the same immunolabeling pattern (CD34-positive) as dermatofibrosarcoma protuberans. It typically arises in the first decade of life as a subcutaneous lesion displaying a combination of spindle cells and multinucleated giant cells, myxoid areas, and sinusoid-like spaces (see fig. 2-46) (95). Rosai-Dorfman Disease, langerhans Cell Histiocytosis, and Erdheim-Chester Disease These lesions are all histiocytic disorders. Langerhans cell histiocytosis and Erdheim-Chester disease share BRAF mutations and all can be found in the soft tissues, but Langerhans cell histiocytosis tends to be found in bone and will be emphasized in the Survival Guide to

Bone Pathology. The histiocytes in Rosai-Dorfman disease and Langerhan s cell histiocytosis typically express S-100 protein whereas those in Erdheim-Chester disease do so about half the time. The one that is easiest to diagnose on H&E is Rosai-Dorfman disease. The key finding in Rosai-Dorfman disease is the presence of emperipolesis in which histiocytes ingest 6fher cells without damaging them (96). Rosai-Dorfman disease was initially noted in lymph nodes in children and termed "sinus histiocytosis with massive adenopathy" by Drs. Rosai and Dorfman (97,98), but later it was described all over the body, to include the soft tissues (99) and gastrointestinal tract (100). The term "sinus histiocytosis with massive adenopathy" is a poor term for extranodal sites, so the term Rosai-Dorfman disease has been adopted. Rosai-Dorfman disease is usually managed surgically, but some patients require immunodulatory therapy. The diagnosis is straightforward in enlarged lymph nodes because the emperipolesis is

71

Soft Tissue Pathology

A

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

. \ ·. '

'

,.

,

.

~ \

.._,.·.

.~.'

. ··'

:

)

.

(

.)

~.

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 sites, the appearance is that of a fibroinflammatory process but the emperipolesis is apparent in areas that are less cellular (fig. 2-68). For those nervous about diagnosing this condition, the abnormal histiocytes express S-100 protein. However, extranodal Rosai-Dorfman disease remains mostly an H&E diagnosis. Rosai-Dorfman disease can have areas with an

74

appearance virtually identical to that of IgG4-associated fibrosclerosing disease, namely, zones of storiform fibrosis and numerous plasma cells. If an IgG4 stain is performed, this will result in an incorrect diagnosis unless the absence of obliterative venous changes is appreciated (79). Langerhans cell histiocytosis (fig. 2-69) often requires confirmation with ancillary studies (S100, CD1a, and Langerin/CD207 labeling (S-100

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Figure 2-70 ERDHEIM·CHESTER DISEASE

A: The appearance is wholly nonspecific, with a tumefactive 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'

·

.• ·~· , "' ~' . . (., \ ~ ~

! .

\.

t '

• t'

•

;.

(

li:i''

·i

')I/

. . t•

/~

, .. .

• ~...,. .._ ' f '~ ... '.J • : . , ~ . I • , ' -

' ~... I . -: ~ ·· / d ·

• It

• • . · ..,·

•

tt I

,

.. ·l •

. ./ !

•

·,

,

•,' '

~

•• ... •

f•

·' . . ·' ' ~I: . ~ ......~ . ,4' · '

J '~ '

I '"1

' :

-

~,···, ~ ..

••• J

......

. ' \\) ••

.~

~· •

•

"' .

.

.

·- '·

..: • '. ·~·

.·c:·.....\·. ..·-<·

~

protein labeling, COla labeling, langerin labeling and BRAF mutational testing for targeted therapy), whereas Erdheim-Chester disease is a clinicopathologic correlation diagnosis because of its nonspecific histologic features (fig. 2-70). SMOOTH MUSCLE AND SMOOTH MUSCLE-RELATED LESIONS Leiomyoma and Leiomyosarcoma

Since every pathologist gains familiarity with leiomyomas early on because they are frequently

encountered in hysterectomy specimens, we

l

~

.

,

'(

4

\

~

•

I

,.,

,

/

'r/. t ." ,;, • '

• j

~

...- ··.

'

•

., '

". , '"

• . . • : .:

I•

~

ll

I

. : (.' J . •'

/' . ,

I • .1

I .'• · ,:

.•.

.,

'

··l

-

' :.•f.t. ;: ~\}~

·~ ~ /;

•

~~--~ ~:

\

. .. .

'

.,

~

..';-)·~-; '~.~ ., • .•

',

••

-~ . . ·~ . ·~· ·~ ~ ~ •• ' \ , #' .. ....

. t·.·· ·

f '.

1 ·•

. ; / •• •

i

.,.,. • . ; '

.... ..

. •.

. .·~

"' •

tl

/

'

'. ;t , .. . (' '., r-:,. ~ v., . ' ,I .

.. ~

.

0

""·;: .~~ ~· ... ..1'

' -...,

..

l ../ ., , / • I'" : •: I ' ' ro' • ~ •:

.,

.'

' .•

,., ,.

;

~~ . '< ,, · \' • . ~~~ · ·· '

..

•

.

will not discuss them in detail. Nevertheless, the core morphologic features of smooth muscle turners are the same regardless of the malignant potential. They are characterized by cells with brightly eosinophilic cytoplasm arranged in fascicles that are perfectly perpendicular to one another. The cytoplasm does not extend in all directions like the cytoplasm in myofibroblasts (the cell type of fibromatosis and nodular fasciitis) but forms a perfect line in continuity with the long axis of the nucleus (figs. 2-71,2-72). Add on nuclear hyperchromasia, increased cellularity, and mitoses, and the lesion is malignant.

75

Soft Tissue Pathology

.. ..;·

"

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

Figure 2-72, continued 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 tissue, particularly in association with retroperitoneal blood vessels. For skin lesions, tumors restricted to the dermis with the same features as leiomyosarcomas are diagnosed as "atypical smooth muscle neoplasms" by some to underscore their indolent behavior following excision (101). In contrast, when such tumors invade the subcutaneous tissue, some metastasize. Important Pitfalls Concerning Smooth Muscle Tumor

1) Large retroperitoneal smooth muscle tumors in women, especially young women, are often leiomyomas despite teaching that retroperitoneal smooth muscle tumors are usually leiomyosarcomas (102). Such tumors often express hormone receptors. Furthermore, they can have an adipose tissue component (myolipoma or lipoleiomyoma) (figs. 2-73, 2-74) (103). 2) Leiomyomas of the gastrointestinal tract often contain Cajal cells that are either entrapped or proliferate with the lesion. Spindled mast cells can be present in such leiomyomas (fig. 2-75)

78

(104). Those who make the mistake of ordering KIT or DOG 1 immunolabeling may regret it. 3) If a patient with many cutaneous leiomyomas is encountered (use H&E alone), consider hereditary leiomyomatosis and renal cell carcinoma. These persons often manifest uterine leiomyomas as well. Here is a situation for which immunolabeling can support the concern since such patients have alterations in the gene that encodes for fumarate hydratase, and an immunostain can address this (fig. 2-76) (105). For those who prefer to add immunolabeling, leiomyomas generally strongly express desmin, smooth muscle actin, calponin, and caldesmon. However, sometimes classic leiomyosarcomas lack desmin expression. This is acceptable. Of course, so me leiomyosarcomas require immunolabeling for diagnosis, but many can be diagnosed without. Glomus Tumor

In line with their monotonous cyt ologic features, glomus tumors harbor a MIR143-NOTCH gene fusion. They most often arise in young

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Jl'

. - . ' ..,. 7-

.,_t#

,~

,

tt..-

- _.

\

~

•

•

.... . . .

-

c

• ,

.. &. •

·~

~

'.

~

..: · • · ..

• •

...

,;

'

•"

,•

.

";o; . ' . .. \ ••• · · , ~ r~. ,· ~.. • .. ·'* - 1 -~,' ·. · ·'-~-:. ~- , • • (,.

..,...._. '\ ! '

.

.. .•

• - ""'" . 4 . • t . •• :

.•.•. .*•:. ..-"'. , '•

• , ••

111 , I

- . ,4 ... • • , .. • • ~ ~ #. . . _.. . .• • ; .. • . ..,. \ , ' ....... , ... . , . . • • •

"/

.•. ., , ... : ,. · ·

;

..." .

~-

~~' • •• , ~.....

\

~

~' ,

,

.J

'" Ill

..

.

•

,IJJ. •. ./. , . w, .... , . " .•..... ,, ' • .t . .. • ..., '..6;· , , .. · - - ~· ~· · · '.: · · . ·. t . Y",../ ..~ ..,.., '... - ·., .. ...: . .. '.- -, .,. .-, " ....,. ·• . . ·\~ · ·~ ~ " ~ -~ ~~; -~-· , ,:>1 ·,

t

.

,

. ..,._ •• '. '•

~

:~ ~:

•

1 •

~

,

•

•' •

...

•

.. ,,

~.... t

-

#I

·......

-

,

~

... • !'~ ... . .... ' ..,,

'-

... \.

~

"" _,. .. .....

......

' ,.. .. .,.. ., ........ ,.. .,..,..

. ... --.

~

•.. ...... ..... •

, ..

• '· •

-.... ,

'

~

6'

-r -:.~ ,.1 •

~.

.

'<~ I

, ~1

- ~~ ""\. - ,...

, ·~ ~ - ... . ' .......

'f ..

J,

._. ,.

t

..

•

; ...,4_;, • ~.t.• ; ,·!_· ·- , .,,._ . . . .. . . . • ~

-.... • ~

.

.. ·c

.. .. f ..__ .... '

•

'

. .. . ..,..·... ..... ~

r

•

~-.

-~

.. •

adults and there is no gender predilection. They tend to arise in the distal extremities, where they produce pain. The "common uncommon" site is the muscularis propria of the stomach. Glomus tumors are richly vascularized and composed of little round cells separated by a basement membrane that is easy to spot (fig. 2-77). Most are benign, but rare examples show overtly m alignant features and can metastasize. These tumors differentiate along the lines of modified perivascular smooth muscle cells (pericytes). As such, they express SMA but not desmin. A pitfall is that they can express synaptophysin

. ...

•

.

~

\

' -• "

•

•

,., ,._.

~.. ~

'~

. ..., .,.,... ,

-

• -;. ·~ .... . . ~ <"

. - •

- 2-

,

.... ,,.

~ ~

~

•

.

~ ·'"

..

.

1

..

• •. ,..• •

....... ~ ··

-

(but not chromogranin) such that they are easy to mistake for neuroendocrine tumors. Fortunately, they lack keratin labeling. The basement membrane encircling each cell can be highlighted with collagen type IV or laminin stains. Myofi broma/ Myopericytoma

Myofibroma and myopericytoma are within a morphologic spectrum with glomus tumors. Many have alterations in t he PDGFRB gene (106-108), which can be exploited with targeted therapy with i~atinib in the familial/extensive form (myofibromatosis) (107).

79

Soft Tissue Pathology

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 and children as multiple syndromic lesions (109), but it was quickly noted that such tumors are usually solitary, arising in adults (110) with no gender predominance. Most are in the subcutis. Those in infants tend to be deeper. These tumors are usually small (1 to 3 cm) and well marginated . They have a biphasic pattern consisting of myoid areas and richly vascular areas with more primitive cells and a hemangiopericytoma-like vascular pattern (fig. 2-78). In many respects, they can be regarded as the true hemangiopericytoma now that most

80

neoplasms diagnosed as hemangiopericytoma years ago have been subsumed under the solitary fibrous tumor category (111) . SKELETAL MUSCLE TUMORS

Embryonal Rhabdomyosarcoma

In the correct clinical setting, embryonal rhabdomyosarcoma is easy to diagnose on H&E. There is no confirmatory molecular test for it, but in modern practice, most colleagues would confirm the H&E interpretation with desmin and myogenin (or available alternative staining).

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

·-.

. •• .. .-.. ·~

..:. "

.. .. . ' ,,.

4.:.

,

,/

,

~.

:

1

""•·

-

.

r·~,

·-'' ...,;;;;

~i

-~

t ~-~--

.

....

......

. .. ., ....... "'~

.•.

..,

·,'

'.

l,•.

~

.-

. ..

...

I

r

''- " • f

•

''f ~

... -~·.. •

..........

I •

.._, . .. •c: •

-."

..

-: . ,

-~

A

•'

•

~~

"

:

~

J:~~•"-

11 ....

' . ·.

,

"' ;,--

.~

.-. . .. 4 . . .. ...,.,_

":

"

.. . ... .

~

\'

.

.... ..

;

•. '

... '.\.

-

'· I

-.

I

'

' 1

·{

,( _.

-.. .:·. ' • .

'

·~

-· J ..:

-

'

,- -~. · f·

...

,.

" .,_..,..

. .-

..

~

. ..

/

J

t

'

.

...

*

"

...

p

·,-. ·

- ~

t;'

...

.] i I '

;1

~

.D

.·'" -

. b>+'"" I .

,·

·-

-·- l

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

Soft Tissue Pathology

,

-,

'~

. ...

.'

t.

~-

,'

,,,

'\

.A;,'~

I f'~•

,.

.,.

,.,

_,

,~!-

''"..

. ·:;:•

/: . . ''. Fumara'\:e hydratase · · ·

.. ·defident'leio~yoma .. j

,/ '(

I

(.

~\

'

..

I ••

(

1{

t,

r '

..

I

'·. .. •

I

' '

.· ~-

. ...."'

.

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 in the head and neck and genital regions of babies

and small children, and can appear innocuous histologically. Expect it on a pediatric bladder or cervical biopsy, or from a head and neck lesion. The exotic site is the gallbladder. The key finding is the tendency of the tumor cells to condense just under the surface, which has been referred to as a cambium layer since it has an arrangement similar to that of the cambium layer of a tree trunk sliced in cross section (figs. 2-79, 2-80). In general, babies do not get cystitis, so be worried if a biopsy is taken from a baby's bladder. Also, embryonal

rhabdomyosarcomas usually have focal rather than diffuse myogenin expression, whereas the expression is diffuse in alveolar rhabdomyosarcomas. The tumor cells tend to have densely eosinophilic cytoplasm. Rarely, cross striations are detected, but there is no need to look for them. Such cases are, as noted, easy to diagnose. Unfortunately, sclerosil(g rhabdomyosarcoma, which also tends to arise in the head and neck or genital region, often in adults, often has a more nonspecific appearance and immunolabeling is generally required to confirm the interpretation (fig. 2-81).

83

Soft Tissue Pathology

., 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

.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Figure 2-79

BOTRYOID RHABDOMYOSARCOMA

Botryoid refers to the grapelike 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

Soft Tissue Pathology

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.

Alveolar Rhabdomyosarcoma Alveolar rhabdomyosarcoma is a high-grade round blue cell malignant neoplasm that arises in adolescents and young adults in the deep soft tissues, often the deep muscles of the thigh. There is a male predominance. Many cases are readily recognized on H&E and the diagnosis is simply confirmed by immunolabeling. Classic lesions show spaces that contain cells with brightly eosinophilic rhabdomyoblasts (fig. 2-82). Such zones, however, may not be apparent on small samples, and then immunolabeling becomes critical, especially in separating malignant rhabdoid tumors and other round cell sarcomas, as shown in chapter 3. It has been known for years that molecular testing prognosticates for alveolar rhabdomyosarcoma far better than old fashioned methods (112): PAX3-FOX01-more aggressive; PAX7FOX01-1ess aggressive.

86

A somewhat macabre way to recall this: the patient with a tumor with PAX3 fusions may live 3 years, whereas the one whose tumor harbors the PAX7 fusions will enjoy 7 years. These figures are not accurate, but simply a construct to recall that patients with PAX7 fusions have a better outcome. ALK alterations have been detected in both embryonal and alveolar rhabdomyosarcoma, but results of early studies exploiting these targets have been disappointing (113,114). Gastrointestinal Stromal Tumor

An exhaustive discussion of gastrointestinal stromal tumors is beyond the scope of this slim soft tissue volume, but it is important to recall that these tumors are lesions of adults with one exception and that they almost always have uniform-appearing cells. They are easy to separate from leiomyosarcomas and leiomyomas (fig. 2-83). The type of gastrointestinal stromal tumor found

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

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-deficient type. It is always in the stomach and has a plexiform growth pattern (fig. 2-84). VASCULAR TUMORS General Points Concerning Vascular Tumors

There are numerous unimportant subtypes of hemangiomas that have been described, and we will not attempt to elaborate on each in detail but simply illustrate some of them and discuss separating them from malignant vascular lesions. Essentially, benign vascular lesions participate in the overall program of creating tubes lined by endothelial cells and cuffed by other cells, including smooth muscle cells, through which erythrocytes or white blood cells can pass. Some well-differentiated angiosarcomas make endothelial cell tubes that transport other

88

cells but they lack the coating layer of nonendothelial cells in general. The term "hemangioendothelioma" has been over-used in the past to encompass exuberantly growing capillary hemangiomas in babies and children, but it currently connotes a vascular lesion that is malignant but conveys far less risk than an angiosarcoma. Capillary Hemangioma

Capillary hemangioma is the most common tumor of infancy, with an female:male ratio of 3:1. In children, capillary hemangiomas are typically cellular and are thus referred to as infantile hemangioendothelioma, juvenile hemangioma, strawberry nevus, and cellular capillary hemangioma. Capillary hemangiomas usually involve the skin or subcutis of the head and neck. They typically proliferate in the first few months of life, then regress and, in many

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 untreated patients, superficial lesions involute to normal skin by 5 years of life and from 70 to 90 percent of patients are "cured" by 7 years of age (115). Capillary hemangiomas consist of a mixture of endothelial cells, pericytes, and fibroblast-like cells. The endothelial cell nuclei can have prominent nucleoli and pronounced mitotic activity. GLUT1 is usually expressed in the lesional endothelial cells of most infantile hemangiomas (which are likely to regress) during all stages of their natural history but not in other

vascular tumors or malformations (which do not regress). GLUT1 also labels a variety of nonvascular neoplasms. The endothelial cells in capillary hemangiomas express CD34 and CD31 but not podoplanin (DZ-40). Pyogenic Granuloma/ lobular Carillary Hemangioma

Pyogenic granulomas (lobular capillary hemaniomas) may involve mucosal, cutaneous, subcuta-

neous or even intravascular sites. When these tumors are found in children, there is a male predominance, whereas young adults are mostly

89

Soft Tissue Pathology

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 40 (116). Approximately 1 percent of pregnant women develop pyogenic granulomas in the oral mucosa, especially the interdental regions of the gingiva. These typically appear in the first trimester, and regress postpartum. Some pyogenic granulomas are intravascular (117).

90

Pyogenic granuloma is a well-marginated proliferation of small capillary-sized vessels arranged in a multilobular pattern, with larger vesels branching into progressively smaller ones. Polypoid or pedunculated lesion s often have a collarette of hyperplastic epithelium (fig. 2-85). The endothelial cells express CD34 and CD31, but not GLUTl.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Cavernous Hemangioma Cavernous hemangiomas are common in both children and adults, without a gender predilection, and they usually arise in the upper half of the body. They do not regress. Examples occurring 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 hemangioma has been shown to harbor GNA14 and GNAQ mutations (121). Its features are those of a lesion with a sinusoidal pattern accompanied by endothelial cells with a hobnail appearance (that means they poke out into the lumen of the vessel). Since both of these features are part of angiosarcoma, these lesions can cause alarm. However, they are overall well-marginated (even though necrosis can be seen) and they basically consist of tubes through which blood passes that are enrobed with a coating of cells that are not endothelial cells (fig. 2-87).

Epithelioid Hemangioma (Angiolymphoid Hyperplasia with Eosinophilia) Epithelioid hemangioma is a lesion of adults (20 to 40 years) with no gender predominance (122). They are most common in the head-neck region and present as papules (123). Subcutaneous examples are characterized by a prominent proliferation of capillary-sized vessels that are lined by plump epithelioid (histiocytoid [124]) endothelial cells. Mild cytologic atypia may be noted, but generally the nuclei have small nucleoli. The vascular proliferation is frequently associated with a medium-sized artery or vein that shows histologic evidence of damage (fig. 2-88) (122). The process is commonly cuffed peripherally by lymphoid follicles. Eosinophils are usually present.

Figure 2-86 CAVERNOUS HEMANGIOMA Note the gaping thin-walled vessels, each stuffed with erythrocytes.

Some atypical deep soft tissue and skeletal examples display fusions of FOSB (125), whereas cutaneous examples lack these fusions. However, all epithelioid hemangiomas lack the WWTRl-CAMTAl fusions that characterize epithelioid hemangioendothelioma (126). Regardless, morphology separates epithelioid hemangioma from epithelioid hemangioendothelioma in nearly every case. Angiomatosis and Intramuscular Hemangioma

These are strictly H&E diagnoses. No staining will help. Intramuscular hemangiomas/angiomas are uncommof». without gender predilection, and most cases are identified in the first three decades of life (127-129). The lower extremity, in particular the quadriceps femoris, is the main site, but any muscle may be involved. Soft tissue swelling and pain are the most frequent manifestations. Recurrences are common and attributable to incomplete excision.

91

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 categorized according to vessel size or type (capillary, cavernous, arteriovenous, lymphatic) but some authors have suggested that all of these lesions, including capillary, cavernous, arteriovenous, lymphangiomatous, and complex malformation types be regarded as intramuscular "angiomas" (128), since most have mixed features and there is no correlation between the predominant vessel type and the clinical outcome. Most importantly, all types of vessels can be accompanied by abundant fat. Atrophic skeletal muscle is often intermixed with the lesion.

Angiomatosis is a histologically benign vascular proliferation growing contiguously in multiple tissue planes or extensively in tissues of the same type (e.g., apposed muscles) (130,131). The lesions are usually in the deep subcutaneous tissue and muscles, but more superficial tissues or underlying bone may also be involved. Most patients are children, frequently in the first year of life (131). The most common symptoms are persistent diffuse swelling, pain, and tenderness. Limb hypertrophy is present only infrequently. Angiomatosis shows a conglomerate of large irregular venous segments with disorganized

./

93

Soft Tissue Pathology

Figure 2-89 ANGIOMATOSIS This lesion consists of disorganized vessels accompanied by adipose tissue.

muscular walls, cavernous vessels, and capillary channels, scattered diffusely throughout tissue planes and often associated with large amounts of adipose tissue (fig. 2-89). A characteristic feature is the presence of capillary-sized vessels proliferating adjacent to and within the walls of the disorganized veins. Similar extensive lesions composed of lymphatic vessels are known as "lymphangiomatosis" or "lymphatic malformation." Kaposi Sarcoma

An exhaustive description of Kaposi sarcoma (KS) is beyond the scope of this slim volume. However, the most important thing to recall is that it is not terribly consequential to underdiagnose early lesions and they essentially neither metastasize nor cause morbidity except those in the gastrointestinal tract that are associated with hemorrhage. In general, clinically important lesions are easy to diagnose, especially in the correct clinical setting. The "classic" form

94

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 transplantation and during the AIDS epidemic. All types are associated with human herpesvirus 8 (HHV8) and their histologic features are superimposable. 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. A variable inflammatory infiltrate, dominated by lymphocytes, with or without plasma cells, is frequently present. Extravasated erythrocytes, hemosiderin deposition, and intracytoplasmic PAS-positive, diastase-resistant, hyaline globules may be noted. In the plaque stage (fig. 2-91 ), the spindled component of KS becomes readily evident. These cells form slit-like spaces that frequently contain red blood cells. Plasma cells and hemosiderin deposits are also usually apparent as well as hyaline globules (fig. 2-92), which are various stages of erythrophagolysosomes. Nodular (tumor stage) KS, which forms a clinical nodule, consists of spindle cells forming fascicles and sheets. Extravasated erythrocytes, siderophages, hyaline globules, and a peripheral lyphoplasmacytic infiltrate are typically present (fig. 2-93). Epithelioid Hemangioendothelioma

Most of the time, epithelioid hemangioendothelioma (EHE) is an H&E diagnosis, but modem techniques have made it easy to confirm this diagnosis using immunolabeling for CAMTA1 (133), which mirrors the known WWTRl-CAMTA 1 gene alteration (126) .

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

Figure 2-92 KAPOSI SARCOMA Note the hyaline globules (arrows), which are simply erythrophagolysosomes.

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 children. The main sites of involvement are the soft tissue, lungs, liver, and bones. Soft tissue examples have no gender predilection (134-136). The median age at presentation is in the fifth decade. Soft tissue epithelioid hemangioendothelioma is usually solitary, arising 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 80 percent) are women, and the median age at presentation is 40 years. Multiple and bilateral nodules are typically noted at presentation.

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Over half of patients die of disease, often over a long course. Before the vascular nature of EHE was understood, hepatic examples were interpreted as sclerosing hepatic carcinomas, cholangiocarcinomas, or calcifying mixed malignant tumors (137). Hepatic involvement is often multifocal, with a slight female predominance. The mean age at presentation is approximately 40 years. Reported 1-year and 5-year patient survival rates are 96 and 54.5 percent, respectively, after liver transplant; 39.3 and 4.5 percent, respectively, after no treatment; 73.3 and 30 percent, respectively, after chemotherapy or radiotherapy; and 100 and 75 percent, respectively, after liver resection (performed in patients deemed resect~ able and thus with less extensive disease) (138). Epithelioid hemangioendothelioma (EHE) of bone may involve any bone. There is a slight male predominance and a wide age distribution extending from the second through the eighth decade of life. EHE of bone is multifocal about half the time. It tends to have an indolent course. EHEs are composed of epithelioid (histiocytoid) and, occasionally, spindle or dendritic cells, embedded singly, in cord-like arrangements, or clusters within a matrix variably described as "myxohyaline" or "chondromyxoid" (fig. 2-94). The cells are present singly and not in groups that form tubules through which blood passes. Many of the cells contain vacuoles ("blister cells"). Occasionally, the vacuoles contain intraluminal erythrocytes, a sign of "early" or "primitive" vasoformative differentiation-or a manifestation of an artifact in which an erythrocyte happens to have been pushed into the vacuole by chance. Features of soft tissue EHEs that correlate with more aggressive behavior include finding greater than 3 mitotic figures per SO high-power fields and size greater than 3.0 cm (136). EHEs variably express CD31, CD34, ERG, and Fli1 (139) and may also express (usually focally) keratins as well as ERG. They lack VEGFR-3, which argues against lymphatic endothelial differentiation (140). Epithelioid sarcomas can show ERG labeling as well, which can be a diagnostic pitfall (141). These tumors have a fusion involving WWTRl and CAMTAl in many cases (126) or an alternate fusion, YAP1-TFE3, that has been described in young patients with tumors that feature focal vasoformation and express TFE3 on

immnolabeling (142). There is an immunostain for CAMTA1 that can be helpful in confirming the interpretation, particularly in hepatic biopsies (the pattern of infiltration can make the diagnosis difficult on a small needle biopsy) (133). Atypical Vascular Lesion and Angiosarcoma

Atypical vascular lesion is a term used for lesions that are usually encountered in mammary skin following radiation for mammary carcinoma. They appear as a single or several small papules or patches in the irradiated site. Most behave in a benign fashion, but a subset progresses to angiosarcoma, often after several recurrences (143). These lesions are very difficult to distinguish from very well-differentiated angiosarcomas, both clinically and histologically. As a rule of thumb, atypical vascular lesions are small (<1 cm) whereas angiosarcomas have a median size of about 7 cm (144). Some resemble benign lymphangiomas, consisting of a well-demarcated proliferation of thin-walled vascular channels (fig. 2-95). These channels have an interanastomosing pattern and bland flat or hobnail endothelium and lack erythrocytes. Others display a more infiltrative pattern but feature bland-appearing endothelium. Despite "atypical" in the name, significant nuclear atypia is not usually seen. A subset, however, has endothelium that appears as a lobular capillary proliferation. These cases may be more likely to progress to angiosarcoma although the lymphatic types can progress as well (145). The endothelial cells in these lesions express CD34 and CD31. Those with lymphatic differentiation express podoplanin (D2-40) (145). The presence of MYC amplification distinguishes angiosarcoma from atypical vascular lesion in the post-irradiation setting, but is not as helpful in other situations since well-differentiated angiosarcomas unassociated with localized edema and radiation often lack MYC amplification (146-148). Interestingly, the rare angiosarcomas that arise in association with massive localized lymphedema in the morbidly obese can display MYC amplification (146). Angiosarcoma, for the purposes of this discussion, are fully malignant neoplasms of endothelial derivation, whether lymphatic (lymphangiosarcoma) or of blood vessels (hemangiosarcoma), since there is no therapeutic or prognostic

97

Soft Tissue Pathology

A 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 intracytoplasmic 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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

-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 rare, comprising less than 1 percent of all sarcomas, with a strong predilection for the skin and subcutis. Superficial angiosarcoma has three clinical settings: 1) the face and scalp of the elderly, 2) the extremities of patients with chronic lymphedema, and 3) sites previously subjected to radiation therapy. Other key primary sites for angiosarcoma are: breast parenchyma, liver, deep soft tissue, skeleton, heart, and spleen. Angiosarcomas are also reported in association with foreign bodies, defunctionalized arteriovenous fistulae in transplant recipients, and in neurofibromatosis (149). Arsenical compounds (i.e., Fowler's solution, arsenical insecticides), vinyl chloride, and thorium dioxide (Thorotrast) exposure have been implicated in the development of approximately one fourth of angiosarcomas arising in the liver but not usually in other sites and this association is mainly a thing of the past. Deep angiosarcomas are epithelioid over half the time and are often not readily diagnosed using H&E staining only. Angiosarcoma has a wide morphologic spectrum (fig. 2-96) but can often be recognized on H&E with a bit of searching for vasoformation

unaccompanied by a cuff of supporting cells around the vessel. Some examples are hemangioma-like, in which the only clues of malignancy are the interanastomosing and infiltrative nature of the process, the presence of mild nuclear hyperchromasia, and occasional crowding or piling up of the endothelium, sometimes forming small papillations. The opposite end of the spectrum includes both a spindle cell pattern reminiscent of fibrosarcoma or KS and an "undifferentiated" pattern consisting of plump epithelioid neoplastic cells with prominent nucleoli and diffuse sheet-like growth, suggestive of carcinoma or melanoma. This latter end of the spectrum can require ancillary studies to diagnose. Angiosarcomas variably express fa ctor VIII-related antigen, CD31, UEA-1, FKBP12, podoplanin (02-40), ERG, and Fli-1. CD31 is a sensitive marker of endothelial differentiation but it is important to recognize that histiocytes, as well as plasma cells, can express CD31, to avoid overdiagnosis of angiosarcoma (150). Cytokeratins can also be expressed, especially in epithelioid angiosarcoma. A pitfall is that over half of angiosarcomas express CD117 (c-kit) but lack KIT mutations (151).

99

Soft Tissue Pathology

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 papillary endothelial hyperplasia (fig. 2-97), which is simply dramatic organization of thrombi. It was first described in a hemorrhoid using alarming terminology (vegetant hemangioendothelioma) (152), but it is benign (unless it is complicating a malignant vascular lesion with pools of hemorrhage).

100

NEURAL-RELATED LESIONS

Schwannoma

Most schwannomas arise in the head and neck area (153) although they can be found associated with nerves anywhere in the body. Although they can be slightly infiltrative in the gastrointestinal tract, most examples elsewhere

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Figure 2-96, continued 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

Soft Tissue Pathology

are well-marginated and have the usual component of cells, namely, spindle cells with nuclear atypia out of proportion to mitotic activity, a lot of secondary change (lymphocytes and plasma cells, foam cells, hemosiderin), areas with nuclear palisading, and myxoid areas (figs. 2-98-2-103). In the day of needle biopsies of retroperitoneal masses, they are a frequent source of anxiety but are easy to diagnose on H&E with a little practice. This is accomplished by pretending that only a small fraction of a typical schwannoma can be seen while reviewing a resection. Of course adding an S-100 protein stain can help, since it is strongly reactive. If it is negative, pleomorphic hyalinizing angiectatic tumor (fig. 2-104) should be considered. There is, however, an important pitfall once immunolabeling is performed: retroperitoneal schwannomas have a proclivity to express keratin (fig. 2-103C) (154). As a note of caution, while most schwannomas are well-circumscribed, when cellular examples (which have a predominance of Antoni A areas) arise in the paranasal areas, they are infiltrative and mimic sarcomas (155). However, they have strong diffuse S-100 protein expression (in contrast to malignant nerve sheath tumors, which have weak or even negative S-100 protein). If immunolabeling is added, most nerve sheath tumors (regardless of type) contain lots of CD34-reactive supporting cells, which can be ignored (92). S-100 protein beats CD34 in this setting. Neurofibroma

Most neurofibromas are easy to diagnose with H&E. There is kinky collagen plastered against wavy nuclei in a myxoid backdrop; the thickwalled vessels, inflammation, and foamy cells of schwannomas are absent (fig. 2-105). If S-100 protein is added, the staining is not as intense as that in schwannomas. Features that suggest low-grade malignant peripheral nerve sheath tumor revolve around mitotic activity and loss of the kinky collagen. Granular Cell Tumor

Granular cell tumors are readily diagnosed on H&E based on the presence of the granular appearance of the cells and the small nuclei

102

(fig. 2-106). The key pitfall is their association with pseudoepitheliomatous hyperplasia of overlying skin or mucosa. Infiltrative growth and perineural involvement are common and totally benign findings. Criteria for malignancy in these neoplasms are necrosis, spindling, vesicular nuclei with large nucleoli, increased mitotic activity (more than 2 mitoses per 10 high-power fields at 200X magnification), h igh nuclear to cytoplasmic (N/C) ratio, and nuclear pleomorphism (156). Malignant Peripheral Nerve Sheath Tumor

Malignant peripheral nerve sheath tumor used to be called "malignant schwannoma" except that colleagues realized that these usually arise from neurofibromas rather than schwannomas. These are easy to diagnose on H&E only if the preexisting benign nerve sheath tumor is present and in the setting of neurofibromatosis but otherwise these are a real challenge to diagnose, even with modern ancillary techniques. Examples are shown in figure 2-107. Molecular techniques offer some help in some sporadic cases. These tumors often have mutations in SUZ12, resulting in downstream alterations in trimethylated H3K27 (157-159). The latter protein can be assessed with immunolabeling methods and is lost in up to half of malignant peripheral nerve sheath tumors (fig. 2-107F) (157,158). However, it is not lost in the remainder, so the diagnosis can only be confirmed some of the time. Overall, malignant peripheral nerve sheath tumors show far weaker S-1 00 protein expression than benign ones and the same holds for other markers such as SOX10. Loss of S-100 protein labeling is a clue that a neurofibroma has progressed to malignant peripheral nerve sheath tumor The epithelioid variant of malignant peripheral nerve sheath tumor is best confirmed with immunolabeling but has a characteristic appearance (fig. 2-108) . Additionally, in contrast to spindled malignant peripheral nerve sheath tumor, the epithelioid form displays strong S-100 protein expression (160). It can also display loss of SMARCB1 /INI1, a phenomenon that it shares with an ever-growing list of other neoplasms, among which epithelioid sarcoma and malignant rhabdoid tumor are the key players (161,162).

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

Figure 2-99

Figure 2-100

PLEXIFORM SCHWANNOMA So me of the nod ules are h ypercellular and so me a re hypocellu lar. Regardless, each n odu le of tumo r is surrounded by a slim ring of perin eurium.

SCHWANNOMA This area contains cells that have small round h yperchromatic nuclei. A sarcoma might be considered except that 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.

.. .. \

.

·'·•·'. ·'

' t

,., . ,, •J

,

. :+, • • .'

, '' ~

~

l, ••

't

' ~ •','!·

~...

•

•

I

I

f' •

.T

~·

~',

__.

,. J

~

., ,

•

•

•

1> I

,;

• •

,,

l.

,..•

.:~ , , ,~ • ·

r • •

' .,~

•

I

\

\

. .. " •'

•

t \.

• , . ., \

•

"•

~~ ....: •

' .~ "'

•

t

·,·' .., ...'.

.

'

.. ...

\

•

'\..'

' ' • ,......, .. t. . ~ ....

..

~ '

- . ·,

"t... .•" ' :f•., _, ,.... •' ·"'""--~ · - ~~ .' • " }I ·""'7 ... , ,..' ~1 , • 'tr.. ' .,) - - .,. •

. I

, I)_.,.. •

• '•

',

~;,~1

t ,.,: •

. ..

'

~

:_

,

... -f ~ ~ ~: ., ,. . }.-• ~ , ./

, ... t

•'

... ' .

. I "' \

'

•

I

''.. ~ ~'•, ,,

' ' X', • ·~ : .

~ \.\ 'A '•' I. ~ If 't :• ... ~ I. •. : I

.~

I'

'..B .. ..

104

•

~

t

'

~) •\

1: •

A.

....,.

• •' ,.. •" • '

• • .•

~

' • · , . ,.~

':

•

.. ~ .(;... t .

\. ._.. . ' t " ......, , •. I -~ :.. '

I

. ,, '

• ..

~

I

.i } ' '-

~

t

..(

f

"·'?. -~-- \

.,

~~

-

,

• ' .., ... ~1

"

A

f;. ...-.

I

-

I .,..,

c

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 hyperchromatic 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

Soft Tissue Pathology

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

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

.,.,

. •

•I

•

t

'

...,• I

'

' "'

•'

..

., •

~··

. ' .. . '

..

.

l

•

'

lt

..

If •

I

•

:

.

•

..

"

'\

I

I

•

,

•

0

." ..• ,,. .....

.. -

•

.• I'\ •

,

•• -

f.

•

•

•

I

o

•

•,' .. • , ., ;-; .. I , • f •..• • I'~ • •

I I •

,.

••

(

• •••

I

of

f

'

• t

...

•

'

I

•• I

•

..

I.

.' ·. . . I .. '

'; '' f ' '

(I

.. I

•

, /'

I

~· . .

I

~

•

•l . r. ·~

•

~

•• "11

, ••

~

'•

,·

'

I

f

.J

\

..

.. ":". I \.. ..

,.,. .

\

'

., l

t

I

,. ,

~ .

'

.

•

,

• • 1

.•.. ' .. . .. ,

.. ,

I

,

•

,

' '

•

•

.• I

. . ~f .

t

#

t

, .. f /

I

••

,. ·, .:

I

I f

.

.. ..'•

.,,'

'

,f .

\

: I 'P ,• · · ·' • I

.. ' ,' ,. . I ,~/I ',. '" '' '.t ',., • ••' '' • ' • • I

. ' •.; ' I I ' , •

, ,,

-.. . ...

·.~

I

, ... ' •

••

I • • ,

'

, J'

1

•

•

t

•

• 'I

• ~ .J • ·~ ..• •• ' . . 'i

.. \

~ ' ( ~\

• •

•

~

~

\ • • ,· •,' t

: .t

1

• ' •• '\

•

• •' ~. • ~ .. ·,. ,,

•'t . ' \# C•

~

J' '

• '• •

._

~

•

··'

t

•

.. ·. tl j

r •• •

' •.

I

"

'

•

~

'

Figure 2-107, continued 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.

MYXOID NEOPLASMS Cutaneous Myxoma (Superficial Angiomyxoma)

Myxomas of the skin and subcutaneous tissue are less well-characterized than the more frequently encountered deep intramuscular myxomas and those arising in the jaw bones and heart. However, they are easy to diagnose with H&E. A subset is associated with the Carney complex of myxomas, including cutaneous myxomas, spotty pigmentation, and endocrine overactivity; such patients h ave been subsequently shown to have various mutations in the PRKARlA gene (163,164). Most cutaneous myxomas, however, are sporadic and some observers have used the term "superficial angiomyxoma" to describe them (165,166). Superficial angiomyxoma/cutaneous myxoma unassociated with Carney complex presents as a painless, slow-growing, solitary skin nodule

with a slight male predominance. Lesions arise primarily on the trunk and lower extremity, followed by the head and neck region and arm. Carney complex (163) includes pigmented skin lesions (lentigines and epithelioid blue nevus/pigmented epithelioid melanocytoma), endocrine disorders (primary pigmented nodular adrenocortical disease, a variety of stromal tumors of the testis, and growth hormone-producing pituitary adenoma), psammomatous melanotic schwannoma, and myxomatous tumors (cardiac myxoma, myxoid fibroadenoma of the breast, myxoma of the external ear canal, and cutaneous myxoma). The disorder is autosomal dominant with"a slight female predominance. Most patients lack the full spectrum of lesions. However, as the cardiac myxoma and the psammomatous melanotic schwannoma (now termed malignant melanotic schwannian tumor [167]) are the main causes of morbidity and mortality in this disorder, it is important to identify patients at risk. Superficial myxomas

109

Soft Tissue Pathology

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 multiple and vary from small sessile papules to large pedunculated lesions. They most commonly occur on the eyelid, as well as the nipple or ear." (163). Cutaneous myxomas are benign, but local recurrence is common, especially with

110

superficial angiomyxomas containing epithelial components (168). Microscopically, cutaneous myxomas involve dermis and subcutaneous fat. The tumor consists of multiple, variably demarcated angiomyxoid nodules. Prominent branching vessels are

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 stroma. Mitotic activity is negligible, and frequentky 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 myxomas, 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, shoulder, and upper arm are the common sites in decreasing order of frequency. The lesion usually presents as a slow-growing, painless mass, with less than 25 percent of tumors associated with discomfort or pain. The rare presence of multiple lesions is usually associated with coexistent fibrous dysplasia of bone (173,17 4). In most reported cases, the fibrous dysplasia involves more than one bone (polyostotic) and sometimes is associated with McCune-Albright syndrome (polyostotic fibrous dysplasia, cafe au lait spots on the skin, and endocrine abnormalities). The intramuscular myxomas typically arise in the same general vicinity as the affected bone(s). Intramuscular myxoma is a benign tumor that rarely recurs following local excision. Intramuscular myxoma is characterized by scattered, bland spindle- and stellate-shaped cells, sparse small vessels, and numerous thin collagen fibers suspended in a richly myxoid stromal matrix (fig. 2-110). The spindle- and stellate-shaped cells have small nuclei and a meager amount of pale, occasionally vacuolated, eosinophilic cytoplasm. The ill-defined cytoplasmic processes of the lesional cells are often contin-

Figure 2-109 SUPERFICIAL ANGIOMYXOMA (CUTANEOUS MYXOMA)

The lesion has entrapped skin appendages.

uous with delicate strands of collagen that run haphazardly throughout the tumor. Mitotic activity is virtually nonexistent. The hyaluronic acid-rich, mucinous stroma often contains small cystic spaces. Occasionally, residual atrophic skeletal muscle fibers, foamy histiocytes and, rarely, mast cells are identified within the myxoid matrix. Simple, nonarborizing, capillary-sized vessels ~re scattered throughout. At the periphery of the lesion, skeletal muscle fibers adjacent to the tumor are atrophic and separated by edema fluid or infiltrating tumor or myxoid matrix. Fat cells are commonly interspersed in the skeletal muscle. Routine immunolabeling is not of much value; it is nonspecific other than that intramuscular myxomas lack keratin and S-100 protein labeling. A third to half of sporadic cases have GNASl mutations (175). This gene is also altered (germline) in patients with

111

Soft Tissue Pathology

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

B McCune-Albright syndrome (fibrous dysplasia of bone), cafe-au-lait macules, and precocious puberty) (176). Myxoinflammatory Fibroblastic Sarcoma Acral myxoinflammatory (lbroblastic sarcoma and inflammatory myxohyaline tumor (IMHT) are terms used to described the same entity. These tumors are usually acral (hands and feet), but not invariably, and thus the WHO classifies them as "myxoinflammatory fibroblastic sarcoma" (1). Th ere is no gender predominance, but these are usually tumors of adults of a median age of

112

about 40 years, with a range from children and teens to late in life. Most examples arise on the dorsal distal extremities as solitary, painless, infiltrative masses (177-179). The tumors are infiltrative and multinodu lar (fig. 2-111), characterized histologically by dense inflammation merging with stroma varying from myxoid to hyalinized and containing sheets and small foci of epithelioid and spindled cells. Some lesions contain foamy histiocytes, giant cells, and hemosiderin. Amid the in flammatory b ackdrop, scattered bizarre cells having large vesicular nuclei and macron ucleoli

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

..-· ~

/

'

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 are present. Despite the cytologic atypia, mitotic activity is usually minimal. On immunolabeling, expression of D2-40, CD34, keratin(s), CD68, actin, desmin, S-100 protein, and EMA have all been reported (177). Neither cytomegalovirus (CMV) nor Epstein-Barr virus (EBV) are detected (179). Whether or not they harbor rearrangements of

114

TGFBR3 and MGEAS remains a subject of debate

(180). These rearrangements have been reported in myxoinflammatory fibroblastic sarcoma, and a relationship between it and pleomorphic hyalinizing angiectatic tumor (see fig. 2-104) and hemosiderotic fibrolipomatous tumor (fig. 2-112) has been proposed. However, some colleagues believe that pleomorphic hyalinizing angiectatic and hemosiderotic fibrolipomatous

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 fashion when they are in their initial state and that they harbor TGFBR3 and/or MGEAS rearrangements, and rarely progress to high-grade sarcomas with the same rearrangements. They believe that myxoinflammatory fibroblastic sarcoma is a separate entity with genetics that have yet to be elucidated. Myxofi brosarcoma

Myxofibrosarcoma (182) is a frequently subcutaneous (but it can be deep) multinodular tumor of older adults or the elderly, found mainly in

patients in the sixth to eighth d~cades, with a slight male predominance. It involves mostly the lower extremities and limb girdles and is uncommon on the trunk. These tumors have also been termed myxoid malignant fibrous histiocytoma in the past (181). There is a broad histologic spectrum depending on tumor grade, but all lesions have spindled to stellate cells, with varying degrees of nuclear pleomorphism, embedded in abundant mucopolysaccharide matrix (fig. 2-113). At low magnification, most lesions have a multinodular arrangement with incomplete fibrous septa.

115

Soft Tissue Pathology

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 myxoid liposarcoma (vessels are described as "curvilinear"). Some cells have markedly pleomorphic nuclei. Some contain abundant cytoplasmic mucoid material and thus, superficially mimic lipoblasts but this material, unlike lipid, does not crisply indent the nucleus. By immunohistochemistry, there is variable expression of actins, CD68, and CD34, but no S-100 protein. These neoplasms have no characteristic genetic alteration, yielding complex karyotypes in keeping with their nuclear pleomorphism. Low-Grade Fibromyxoid Sarcoma

Low-grade fibromyxoid sarcoma is a tumor composed of bland, fibroblast-like cells with a swirling, whorled, vaguely storiform pattern in a fibrous and focally myxoid stroma, occasionally with plexiform vasculature. First reports highlighted the deceptive resemblance to fibromatoses (figs. 2-114-2-116) (183). There is little mitotic activity and minimal nuclear pleomorphism. Since low-grade fibromyxoid sarcoma is a translocation-associated sarcoma, it

116

has uniform (not pleomorphic) cells (184,185). This lesion recurs, but many cases also metastasize (e.g., to lung). This tumor is not equivalent to low-grade examples of myxofibrosarcoma, since the latter occurs in older patients, is more pleomorphic and less fibrous, and seldom metastasizes when superficial. Hyalinizing spindle cell tumor with giant rosettes (186) falls within the spectrum with low-grade fibromyxoid sarcoma (187). These tumors have infiltrative borders and are composed of bland spindled cells in a hyalinized to myxoid stroma, often with "cracking" artefact in the collagen. Characteristic scattered large rosette-like structures often merge with serpiginous areas of dense h yalinization (fig. 2-115). The rosettes consist of a central collagen core surrounded by a rim of rounded cells morphologically and immunophenotypically different from the cells of the spindled stroma. These cells express a number of antigens, including S-100 protein, neuron-specific enolase, and Leu 22, in contrast to the stroma, which usually lacks these antigens.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

Table 2-1 SURVIVAL CLUES TO KEY MYXOID LESIONS

TumorType

Who Gets It?

How Deep?

Nuclear Pleomorphism?

Intramuscular myxoma

Middle-aged women

Intramuscular

No

Myxoid liposarcoma

Young adults

Intramuscular

No

Ancillary Help Beyond H&E? No Yes; assessment for FUS-DDTT3, EWSRI-DDI T3

Myofibrosarcoma

Elderly adults

Subcutis

Yes

No

Low-grade fibromyxoid sarcoma

Everyone

Intramuscular

No

Yes; assessment for

An identical characteristic translocation is found in both low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with rosettes: t(7;16)(q33;pll) (188) fuses the FUS gene (also called TLS) to CREB3L2 (also called BBF2H7) (189). MUC4 labeling is a characteristic feature of low-grade fibromyxoid sarcoma (190). Table 2-1 shows clues for separating some key myxoid soft tissue lesions. Sclerosing Epithelioid Fibrosarcoma

Sclerosing epithelioid fibrosarcoma (191) is the high-grade form of low-grade fibromyxoid sarcoma just as so-called "round cell liposarcoma" is the high-grade form of myxoid liposarcoma. It can mimic metastatic carcinoma, particularly lobular carcinoma of the breast. It can be diagnosed with H&E, but the availability of MUC4 is a real improvement to our diagnostic armamentarium (192). These lesions affect primarily the deep musculature of adults, without gender predilection, usually involving the lower limbs and limb girdles. Most are large. These tumors consist of a uniform population of small, slightly angulated, rounded cells with scant cytoplasm arranged in nests, cords, and sometimes in a single file array (fig. 2-11 7). There is a background of dense sclerosis, minimal inflammation, and sometimes zones of cartilage and mineralization. Mitotic activity is scant. Patchy EMA, S-100 protein, and patchy keratin have all been reported in these lesions. Since the histologic differential diagnosis is with carcinoma, the keratin and EMA can pose diagnostic problems if attention is not paid to the

118

FUS-CREB3L2 FUS-CREB3L l EWSRI-CREB3Ll

patchy pattern of the reactivity. These tumors can behave quite aggressively. LESIONS WITH UNCLEAR DIFFERENTIATION Solitary Fibrous Tumors

In early literature, solitary fibrous tumors were described as pleural-based lesions and considered a benign localized counterpart of "fibrous" mesotheliomas, an assertion supported by tissue culture studies. They have been described in many sites, including the soft tissues. Most behave in a benign fashion, but not all, and they can transform to more aggressive tumors over time. Solit ary fibrous tumor is a good diagnosis to make since the pathologist can never be incorrect about the malignant potential. Microscopically, solitary fibrous tumors characteristically display a "patternless pattern" of spindled fibroblast-like cells and collagen in varying proportions arranged in a disorderly fashion (fig. 2-118). Classic examples can be diagnosed with H&E, but not all examples are classic. The individual cells have spindled to plump, ovoid nuclei and eosinophilic cytoplasm. They may also appear hemangiopericytoma-like with closely packed cells with amphophilic cytoplasm arranged around staghorn-shaped vessels or they may have a myxoid appearance. Some may contain mature fat. On immunohistochemical staining, solitary fibrous tumors consistently express CD34 and BCL2, and lack muscle markers (act ins and desmin), keratins, and S-100 protein. A better marker for them is STAT6 (193).

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

...,.'[.-

'

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

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Angiomatoid Fibrous Histiocytoma

Angiomatoid fibrous histocytoma (AFH) was

originally described as angiomatoid malignant fibrous histiocytoma and considered to be part of the malignant fibrous histiocytoma (MFH) family (194). The term "malignant" was removed from its name in the 2002 WHO classification, and the entity was recategorized as an intermediate (rarely metastasizing) tumor of uncertain differentiation (195). It has a distinctive morphology and immunophenotype that is unrelated to histiocytic differentiation or to fibrous histiocytoma (dermatofibroma), and is now known to be characterized by specific chromosomal translocations (predominantly EWSRl-CREBl ) in both primary and metastatic lesions (196). AFH occurs at any age but is most common in the first two decades, and is slightly more frequent in females. The favored sites are the deep dermis/subcutis (or rarely skeletal muscle) of the proximal limb girdle (espedally upper limb), trunk, and head and neck, including sites of normal lymphoid tissue such as axilla, antecubital fossa, and groin. Some cases are associated with systemic clinical manifestations, including fever and anemia. Most are less than 4 cm in maximum dimension, although examples have been reported exceeding 12 cm. Up to 15 percent recur, and wide local excision is appropriate management. Fewer than 3 percent have been reported to metastasize, usually to regional lymph nodes and exceptionally to lung and brain (194,197). Deep location, origin in head and neck region, and infiltrating histologic margins are risk factors for recurrence. AFH is composed of multinodular sheets of ovoid cells with mostly uniform vesicular nuclei, scanty cytoplasm, and low mitotic index (fig. 2-119). Even though it is a translocation neoplasm, this lesion is an exception in that some cases show focal nuclear pleomorphism and occasional multinucleated giant cells. The amount of hemorrhage is variable, and absent from some examples; others have extensive hemorrhage with large cysts that are lined by tumor cells, not endothelium. The tumor is characteristically surrounded by a lymphoid cuff. Based on this, these tumors can be recognized at low magnification in the context of the correct clinical setting (distal extremity lesion in a child).

About 60 percent of AFHs express desmin, either focally or diffusely, and sometimes calponin and h-caldesmon but SMA and myogenin are negative. Other positive markers include EMA, CD99, and CD68 . The lymphoid cuff consists of a mixture of B and T cells as well as many plasma cells (polyclonal). Genetically, AFH is characterized by several chromosomal rearrangements. The most common is t (2;22) (q33;q12), associated withEWSRl-CREBl. Alter-. natively, t(12;22)(ql3;q12) can result in EWSRlATFl, and t(12;16) (ql3;pll) leads to a FUS-ATFl fusion gene. The first two translocations are of special interest because they are also found in clear cell sarcoma of the gastrointestinal tract and soft tissues, respectively. The reasons for the different phenotypes in tumors with the same genotype are not known. Ossifying Fibromyxoid Tumor

In 1989, Enzinger et al. (198) described the clinicopathologic features of 59 examples of ossifying fibromyxoid tumor of soft parts (OFT) based on H&E alone. OFT occurs over a wide age range with a peak incidence in the fifth decade but children can be affected (199). Men are affected more often than women. The tumor clinically presents as a slow-growing, asymptomatic nodule or mass within the subcutaneous tissue or, less often, skeletal muscle. Multiple lesions have been documented at presentation (200) and are usually grouped in the same general area. The shoulder, upper arm, buttock, and thigh are the preferentially involved sites. The tumor arises less frequently in the head and neck region and trunk. The duration of preoperative disease varied from less than 1 year to over 20 years in the initial study (198). OFT appears to have low-grade malignant potential. In the original series (198), the local recurrence rate was 27 percent, with multiple recurrences documented in three patients. One patient with three recurrences developed a presumed metastasis to the opposite thigh 20 years after initial excision. A subset of "atypical and malignant" OFTs, characterized by increased cellularity and mitotic activity, has been reported and patients with such tumors are probably at increased risk for metastatic disease (201). Surgery is presently the mainstay of therapy. Most tumors have calcified lamellar (sometimes with marrow) or woven bone within the

121

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

pseudocapsule (fig. 2-120). At low-power magnification, OfT is composed of uniform-appearing, small, round to polygonal-shaped cells embedded in a myxohyaline to collagenous stromal matrix. The cells are arranged in lobules that vary in size and cellularity, and are partially separated by fibrous bands. The tumor is surrounded by an incomplete fibrous pseudocapsule composed of dense fibrous and hyalinized connective tissue. Nests of tumor cells may be seen infiltrating through rents in this fibrous shell. The proliferating cells are small with lightly eosinophilic to clear cytoplasm and a cytologically bland-appearing, round to spindle-shaped nucle us containing a small nucleolus. The occasional presence of a clear space around the cell mimics the appearance of chondrocytic differentiation. In zones with an abundant myxocollagenous stromal matrix, the cells interconnect to form anastomosing, thin cord-like arrangements. A vaguely fascicular growth pattern of spindled cells occurs in the more collageno us areas of the tumor. In conventional examples, the mitotic activity is low. In fact, many examples of this tumor Jack bone in their capsule (nonossifying variant) (201). Tumors reported in the literature as "atypical" or "malignant" OfTs show increased cellularity and are composed of a more pleomorphic cell population exhibiting nuclear hyperchromasia and increased mitotic activity. Criteria for malignancy published by Folpe et al. (201) and validated in a subsequent study included 1) high nuclear grade or 2) high cellularity and mitotic activity of more than 2 mitoses per SO high-powerd fields (199,201). The immunohistochemical profile of conventional OfT includes immunoreactivity for neural and myogenic markers. Approximately SO to 7S percent oftumors express S-100 protein (201). In one study (202), 70 percent of tumors expressed desmin. Limited expression of neuron-specific enolase (NSE), GFAP, SMA, and MSA has also been documented (200,202,203). Some cases sh ow keratin expression and scattered INil loss, features shared with epithelioid sarcoma but the INil loss is not diffuse but rather in a mosaic pattern. MUC4 expression, which is generally an excellent marker for low-grade fibromyxoid sarcoma, is also encountered in some cases (199). Myoepithelial neoplasms may

124

closely resemble OfT. In line with their m onotonous cytologic features, OfTs show PHFl gene rearrangements in about half of cases, regardless of their malignant potential (204). Synovial Sarcoma

Many cases of synovial sarcoma (SS) are easy to diagnose on H&E. SS is the paradigm for the discovery of a characteristic translocation and elucidation of key molecular events in a solid tumor (20S). SS is a rare but distinctive soft tissue neoplasm showing epithelial differentiation. The term has become well established, but is a misnomer. This tumor is wholly unrelated to synovium. Between S and 10 percent of all soft tissue sarcomas are SS. These are mainly tumors of young adults, with a male predominance. SS presents as an oth erwise asympt omatic deep-seated slow-growing mass. About 90 percent occur on the extremities, with a third around the knee. Origin within a joint or bursa represents fewer than S percent of cases (206,207). A distinct region of involvement is the head and neck, most commonly the paravertebral region with pharyngeal presentation. There is local recurrence of tumor in up to half of cases. Metastases are usually blood-borne, to lungs and bone. However, perhaps reflecting the epithelial differentiation, they involve regional lymph nodes in over 20 percent of cases. The usual course of SS is that of a high-grade sarcoma. However, patients with the calcifying variant have a better long-term prognosis. In contrast, poorly differentiated SS (PDSS) generally behaves more aggressively than the average, and metastasizes in a higher percentage of cases. In one series of patients with PDSS, SO percent died, with a mean survival of 33 months (208). Biphasic SS has an epithelial and a spindle cell component while many monophasic tumars consist only of spindle cells (figs. 2-121, 2-122). The epithelial cells have round to oval vesicular nuclei, abundant cytoplasm, and distinct cell borders. Classically, they form glands with lumina, or prominent papillary structures with spindle cells rather than connective t issue in the papillary core. In both, there is usually a single layer of uniform cells, but occasionally multilayering or tufting is seen, without nuclear pleomorphism. The n uclei of the spindle cells

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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

Soft Tissue Pathology

...,. ,

•

--

~

.

. .... . G . ._' \

....

I

/

..r

..

'1.•

..

Figure 2-121, continued 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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Figure 2-121, continued 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

Soft Tissue Pathology

are uniform, small, ovoid, and pale-staining with inconspicuous nucleoli. Cytoplasm is scant and the cell membranes are indistinct, so that nuclei overlap. Mitotic figures can be scarce despite the cellularity, but are more frequent in the poorly differentiated type. The spindle cell component can predominate or occur alone, and the term is monophasic synovial sarcoma (MSS). Many MSSs display, at least focally, a prominent hemangiopericytoma-like vascular architecture, with open, branching thinwalled vessels of variable caliber that do not allow their similar vascular pattern to cause confusion between MSS and solitary fibrous tumor. SS with a very prominent glandular component, in which the spindle cells are scarce, must be distinguished from purely glandular MSS (i.e., those without any discernible spindle cell component). About one third of SS have focal calcification, with or without ossification. In some tumors, however, calcification is extensive, and the improved prognosis in such cases merits their separation as a subtype. Many SSs (biphasic and monophasic) have poorly differentiated areas, characterized by high cellularity, numerous mitoses, and often necrosis but not by nuclear pleomorphism since SS is a translocation-associated sarcoma. PDSS has a similar range of immunohistologic and ultrastructural findings, and the same cytogenetic and molecular genetic abnormalities, as typical SS, but typically requires ancillary testing to diagnose. PDSS shows ~ets of darkly staining ovoid or rounded cells which resemble those in other small round cell tumors, especially Ewing sarcoma or peripheral primitive neuroectodermal tumor (ES/PNET) (fig. 2-122). Most synovial sarcomas show focal expression of cytokeratins and EMA. In biphasic SS, the epithelial component is strongly positive, as are scattered cells in the spindle cell component. CK-positive cells can usually be found in MSS, singly, in cords, or in small nests. S-100 protein positivity is detectable in nearly a third of synovial sarcomas including spindle cell MSS (209). CD99 is commonly positive in SSs, with a membranous or cytoplasmic pattern. Antibodies to TL~J are supposedly more specific for SS. TLE1 can also be expressed by some malignant peripheral nerve sheath tumors and some solitary fibrous tumors. On the other hand, lesions

128

lacking TLE1 expression are unlikely to be SSs. CD34 is virtually always negative in SS, but BCL-2 protein has been found in most SSs in a diffuse and strongly positive fashion. Staining for desmin is usually absent, but occasionally in otherwise typical MSS there is focal positivity for both muscle specific actin (represented by the HHF3S antibody) and alpha-smooth muscle actin. Calponin is also expressed by SS (210). A specific translocation involving chromosomes X and 18 has been described in SS (211). This balanced reciprocal translocation, t (x; 18) (p11.2;q11.2), is found in most reported SSs. The resultant fusion gene product, 5518-SSX, can be exploited for diagnosis. The breakpoints of the t(X;18) involve the fusion of the 5518 gene at 18q 11 to either of two highly homologous genes at Xp11 called SSX1 and SSX2. Epithelioid Sarcoma

These tumors were first described by Laskowski in 1961 (212). Enzinger subsequently coined the term epithelioid sarcoma (ES) (213), recognizing that this neoplasm was distinct from SS and, later, from clear cell sarcoma. ES is the most common primary sarcoma of the hand and wrist. The clinical and histologic features can mimic those of a non-neoplastic process, so that the sarcoma may be misdiagnosed until recurrence or metastasis reveals its true nature. The histogenesis of ES remains unknown. ES has been reported in almost all ages, but is most prevalent in patients between 10 and 39 years of age (214), with a male predominance. The flexor surface of the hand, fingers, and forearm are the most commonly involved sites, followed by the knee and lower leg, proximallower and upper extremity, ankle, and the feet and toes. The trunk and head and neck regions are the least commonly involved sites. Penile and vulvar cases have been reported. ES arising in the dermis most often presents as a slow-growing, painless, usually solitary, nodule or plaque. ES situated in the subcutaneous or fascia! tissue frequently presents as a fixed, hard nodu~e. Tumors of the hand and penis can clinically mimic superficial fibromatoses. Dermal and subcutaneous lesions characteristically develop a cleft of the overlying skin which eventually ulcerates. These innocuous clinical presentations sometimes lead the clinician to

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 neoplasm spreads proximally up the extremity, producing numerous cutaneous nodules and ulcerative lesions. Although these tumors were considered quite aggressive in the past, better recognition with early aggressive surgery has improved outcome. ES is characterized by a predominantly nodular growth pattern of epithelioid and plump spindled cells. The center of the nodule commonly undergoes degenerative change characterized by necrosis, hemorrhage, cyst formation, focal calcification, or replacement of tumor cells by a myxohyaline stroma (fig. 2-123) . At the periphery of the nodules, the epithelioid cells occasionally grow in a cord-like fashion and the spindled cells form vague fascicles as these elements mingle with dense, eosinophilic collagen. The nodules have a tendency to coalesce. When the tumor spreads

along fascial planes and aponeurotic connective tissue, the confluent nodules align themselves along the length of the tissue plane, resulting in a band of tumor cells surrounding hypocellular or necrotic zones (garland-like configuration). The proximal type of ES (21S), which arises primarily in axial sites as a large, generally deeply-seated mass, is composed of pleomorphic epithelioid cells (fig. 2-124) and this type is best diagnosed in the context of ancillary studies. This variant has histologic overlap with both extrarenal malignant rhabdoid tumor and carcinoma. ES characteristically expresses keratin. EMA is expressed in SO to96 percentoftumors (216-219) and its pattern of reactivity also demonstrates variability within the same lesion. CD34 is reportedly expressed in about SO percent of tumors (216,217,220). Carcinoembryonic antigen immunoreactivity can be focally identified in ES (221).

129

Soft Tissue Pathology

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 association with inactivation of a tumor suppressor gene SMARCBl / INJl although it lacks a characteristic translocation. The nuclear loss of INll protein by immunohistochemistry can be exploited for diagnosis in most cases of both the classic and proximal types of ES (162,222,223). Alveolar Soft Part Sarcoma

Alveolar soft part sarcoma (ASPS) accounts for fewer than 1 percent of all soft tissue sarcomas. It has a characteristic gene fusion such that it has monotonous nuclei. ASPS principally affects adolescents and young adults with a slight female predominance

130

(224-229), but pediatric cases are known (230) and older adults may be affected. The tumor arises primarily in th e deep soft tissues of the lower extremity, particularly the anterior thigh and the buttock (225), followed by the chest and abdominal wall. In children, ASPS has a proclivity for the head and neck region, especially the periorbital soft tissue and tongue. ASPS clinically presents as a slow-growing, painless mass which may be apparent for months to years before the patient seeks medical attention. Unfortunately, sometimes metastatic disease to the lung or brain heralds the presence of an occult primary sarcoma. Patients with ASPS have a poor long-term survival. The principal

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

metastatic sites are the lung, followed by the brain and bone (225). Children with ASPS fare better than adults; possibly earlier detection is a factor (228,230). At low magnification, ASPS displays a distinctive nested or organoid arrangement of large, polygonal cells with eosinophilic cytoplasm (fig . 2-125). The nests are separated from one another by thin-walled, sinusoidal vascular channels. Protrusion of nests of turner into these vessels, as well as frank vascular invasion, are common findings in ASPS. Loss of cellular cohesion results in intact and degenerat ed cells floating in the center of a tumor cell nest and imparts a pseudoalveolar appearance to the otherwise ball-like arrangement of cells. ASPS can also be composed of small, compact nests of cells without prominent vascularity, an architectural pattern seen mo re commonly in children. This pattern can vaguely resemble that of paraganglioma. The neoplastic cells have a uniform, oval to polygonal shape with distinct cell borders and an ample amount of finely granular, eosinophilic cytoplasm. The nuclei are uniform and nucleoli are prominent. Mitotic activity is ch aracteristically low. The immunohistochemical profile of ASPS is broad and nonspecific (although nuclear labeling with JF.E3 is characteristic). Most cases of ASPS exhibit some degree of desmin and muscle-specific actin expression, but myogenin is n egative. S-100 protein immunoreactivity has been observed in some turners but they are negative for more specific skeletal muscle markers and keratins. Clear Cell Sarcoma

Clear cell sarcoma was described by Enzinger in 1965 (231) as a unique sarcoma associated with tendons and aponeuroses of the hands and feet. The description was based on a clinical profile and H&E. At the time of Enzinger's initial description, the nature of this lesion was unclear although he suggested a melanocytic lesion. These turners mainly affect the distal extremities, particularly the feet and ankles, and they occur in young adults (231-234). Clear cell sarcomas are readily diagnosed on H&E manifest a packeted and fascicular arrangement of uniform round to spindled cells with

clear to eosinophilic cytoplasm, which often contains abundant glycogen (fig. 2-126). The individual cells have uniform and prominent nucleoli. Tumor giant cells with a peripheral wreath-like arrangement of nuclei are found in some cases. Melanin can occasionally be seen. Necrosis is found in a minority of cases. Most cases are reactive with S-100 protein and melanoma markers, both HMB45 (232-234) and newer ones. Some observers have speculated that these are simply melanomas of connective tissue. However, this is probably incorrect for several reasons: 1) their histologic features are very monotonous whereas skin melanomas feature more prominent cytologic pleomorphism; 2) their clinical behavior is also markedly different. Whereas an overall favorable prognosis would be expected for a 1 cm clear cell sarcoma, a nodular skin melanoma this size could be rapidly lethal. In fact, most patients with turners smaller than 2.5 cm fare well on follow-up (233); and 3) clear cell sarcoma has a characteristic characteristic 12;22 translocation resulting in an EWSRl-ATFl fusion; this can be detected for confirmation of the diagnosis if needed. In contrast, skin melanomas have complex karyotypes and/or BRAF mutations, but they lack the 12;22 translocation . Although melanomas are more so, clear cell sarcom as are aggressive turne rs. Survival rates of 67, 33, and 10 percent, at 5, 10, and 15 years, were reported (235). Chemotherapy has offered o nly limited success (236). Extraskeletal Myxoid Chondrosarcoma

Extraskeletal myxoid chondrosarcomas (EMCs) are rare soft tissue sarcomas that predominantly occur in adulthood (237,238). There is a slight male predilection. The turners most commonly occur in the deep soft tissues of the extremities. They usually present as a painless or minimally tender slow-growing mass. Most of the tumors are greater than 5 cm . In the original series, based on H&E, this tumor was considered relatively low grade, with a low incidence of metastasis and an indolent clinical course (237). Th e estimated 5-, 10-, and IS-year survival rates are 90, 70, and 60 percent, respectively (238). Older patient age, larger turner size, and tumor location in the proximal extremity or

131

Soft Tissue Pathology

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

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 identified by multivariate analysis. EMC has a unique clinical course, including a high rate of local recurrence, prolonged survival after metastasis in some cases, and eventually a high rate of d eath due to tumor. These features dis-

tinguish EMC from other low-grade sarcomas. Histologic grading is of no prognostic value in EMC because prognosis is dictated primarily by clinical features (238). EMCs are lobulated myxoid tumors that characteristically demonstrate low cellularity (fig.

133

Soft Tissue Pathology

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 oval, and have small amounts of eosinophilic cytoplasm surrounding the nucleus. The nuclei are central, dark staining, and usually lack visible nucleoli. Tumor cells are arranged in linear arrays that appear as straight lines or curves. Mitotic figures are usually inconspicuous. The

134

tumor cells are embedded within a hypovascular basophilic flocculent matrix. Hemosiderin is often prominent. In low-grade tumors, there is low cellularity and higher-grade tumors typical- . ly show greater cellularity with less extracellular matrix. Hyaline cartilage is not found in EMC. Additionally, a subset of cases has zones that

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

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 uniform cells (fig. 2-128). Immunohistochemical stains demonstrate S-100 protein expression (e-fig. 21.57) in the majority of cases. Interestingly, many tumors express endocrine markers, including synaptophysin and INSM1 (239). Cytogenetic analysis of EMC shows a consistent translocation between chromosomes 9 and 22, t(9;22)(q22-31;qll-12), which serves as a diagnostic marker for this neoplasm since it results in a specific fusion product, EWSR1NR4A3 (238) that can be exploited for diagnosis. Variant translocations include t(9; 17)(q22;q 11)

and t(9;15)(q22;q21), with TAF1168-NR4A3 and TCF12-NR4A3 fusion genes, respectively. Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is a descriptively named malignancy that primarily affects adolescents and young adults and arises within the peritoneal cavity and retroperitoneum (240). DSRTC is an aggressive, malignant neoplasm that responds poorly to treatment. Its peritoneal seeding, abdominal adhesion, and omental cake formation are all reminiscent of mesothelioma and ovarian surface carcinomas. Treatment attempts have been largely unsuccessful.

135

Soft Tissue Pathology

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, DSRCT occurs as a sclerotic, locally invasive mass that may arise anywhere from the surface of the ovary to the pancreas, with frequent peritoneal spread. The tumor consists of nests of primitive small cells encircled by dense fibrotic tissue (fig. 2-129). The small cell foci may contain vague rosettes or have epithelioid features, and often have a rhabdoid appearance, raising a differential diagnosis of alveolar rhabdomyosarcoma because of their abundant pinkish cytoplasm containing hyaline inclusions. These tumors display a range of markers by immunohistochemistry. Tumors often express

136

desmin, EMA, cytokeratin, neuron-specific enolase, S-100 protein, synaptophysin, and CDS7. WT1 immunolabeling shows nuclear staining. DSRCT is genetically characterized by a fusion of the WTl gene on chromosome 11 and the EWSRl gene on chromosome 22, karyotypically expressed by a reciprocal translocation, t (11;22) (p13;q12). Although similar chromosomes are involved, the breakpoint on chromosome 11 differs from that of the Ewing family of tumors. As with Ewing tumors and alveolar rhabdomyosarcomas, RT-PCR or FISH can be used to support the diagnosis by demonstration of this chimeric gene.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

Figure 2-129, continued 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.

REFERENCES

1. 2.

Fletcher C, Bridge J, Hogendoorn PC, Mertens FE. WHO Classification of tumours of soft tissue and bone. Geneva: WHO Press; 2013. Marino-Enriquez A, Fletcher CD, Dal Cin P, HornickJL. Dedifferentiated liposarcoma with "homologous" lipoblastic (pleomorphic liposarcoma-like) differentiation: clinicopathologic and molecular analysis of a series suggesting

3.

4.

revised diagnostic criteria. Am J Surg Pathol 2010;34:1122-31. Plaza JA, Kazakov DV, Casas G, et al. Fibrolipomatous hamartoma of the nerve: a clinicopathologic report of 13 cases. J Am Acad Dermatol 2014;70:736-42. Silverman TA, Enzinger FM. Fibrolipomatous hamartoma of nerve. A clinicopathologic analysis of 26 cases. Am) Surg Pathol1985;9:7-14.

137

Soft Tissue Pathology

s. 6. 7.

8. 9.

10. 11. 12.

13.

14.

15.

16.

17. 18.

19.

138

Chung EB, En zinger FM. Be nign lipoblastomatosis. An analysis of 35 cases. Cancer 1973;32:482-92. Hibbard MK, Kozakewich HP, Dal Cin P, et al. PLAG1 fusion oncogenes in lipoblastoma. Cancer Res 2000;60:4869-72. Mentzel T, Calonje E, Fletcher CD. Lipoblastoma and lipoblastomatosis: a clinicopathological study of 14 cases. Histopathology 1993;23:52733. Enzinger FM, Harvey DA. Spindle cell lipoma. Cancer 1975;36:1852-9. Shmookler BM, Enzinger FM. Pleomorphic lipoma: a benign tumor simulating liposarcoma. A clinicopathologic analysis of 48 cases. Cancer 1981;47:126-33. Evans H. Liposarcomas and atypical lipomatous tumors: a study of 66 cases followed for a minimum of 10 years. Surg Pathol1988;1 :41-S4. Evans HL. Liposarcoma: a study of SS cases with a reassessment of its classification. Am J Surg Pathol 1979;3:507-23. Evans HL, Soule EH, Winkelmann RK. Atypical lipoma, atypical intramuscular lipo ma, and well differentiated retroperitoneal liposarcoma: a reappraisal of 30 cases formerly classified as well differentiated liposarcoma. Can cer 1979;43:574-84. Farshid G, Weiss SW. Massive localized lymphedema in the morbidly obese: a histologically distinct reactive lesion simulating liposarcoma. AmJ Surg Pathol1998;22:1277-83. Manduch M, Oliveira AM, Nascimento AG, Folpe AL. Massive localised lymphoedema: a clinicopathological study of 22 cases and review of the literature. J Clin Pathol2009;62:808-11. Lee S, Han JS, Ross HM, Epstein JI. Massive localized lymphedema of the male external genitalia: a clinicopathologic study of 6 cases. Hum Pathol2013;44:277-81. Fanburg-Smith ] C, Miettinen M. Liposarcoma with meningothelial-like whorls: a study of 17 cases of a distinctive histological pattern associated with dedifferentiated liposarcoma. Histopathology 1998;33:414-24. Evans HL. Smooth muscle in atypical lipomatous tumors. A report of three cases. Am J Surg Pathol1990;14:714-8. Evans HL, Khurana KK, Kemp BL, Ayala AG. Heterologous elements in the dedifferentiated component of dedifferentiated liposarcoma. Am J Surg Pathol 1994;18:1150-7. Henricks WH, Chu YC, GoldblumJR, Weiss SW. Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol 1997;21:271-81.

20.

21.

22.

23.

24.

25.

26.

27. 28. 29.

30.

31.

32. 33.

CoindreJM, Hostein I, Maire G, et al. Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas: histological review, genomic profile, and MDM2 and CDK4 status favour a single entity.] Pathol2004;203:822-30. Lucas DR, Shukla A, Thomas DG, Pate! RM, Kubat AJ, McHugh JB. Dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features. Am J Surg Pathol 2010;34:844-S 1. Downes KA, Goldblum JR, Montgomery EA, Fisher C. Pleomorphic liposarcoma: a clinicopathologic analysis of 19 cases. Mod Pathol 2001;14:179-84. Gardner ]M, Dandekar M, Thomas D, et al. Cutaneous and subcutaneous pleomorphic liposarcoma: a clinicopathologic study of 29 cases with evaluation of MDM2 gene amplification in 26. Am J Surg Pathol 2012;36: 104 7-51. Hornick JL, Bosenberg MW, Mentzel T, MeMenamin ME, Oliveira AM, Fletcher CD. Pleomorphic liposarcoma: clinicopathologic analysis of 57 cases. ArnJ Surg Pathol 2004;28:1257-67. Miettinen M, Enzinger FM. Epithelioid variant of pleomorphic liposarcoma: a study of 12 cases of a distinctive variant of high-grade liposarcoma. Mod Pathol 1999;12: 722-8. Meister P, Konrad EA, Buckmann FW. Nodular fasciitis and proliferative myositis as variants of one disease entity. Invest Cell Pathol 1979;2:277-81. Montgomery EA, MeisJM. Nodular fasciitis. Its morphologic spectrum and immunohistochemical profile. Am J Surg Pathol 1991;15:942-48. Shimizu S, Hashimoto H, Enjoji M. Nodular fasciitis: an analysis of 250 patients. Pathology 1984;16:161-6. Birdsall SH, Shipley JM, Summersgill BM, et al. Cytogenetic findings in a case of nodular fasciitis of the breast. Cancer Genet Cytogenet 1995;81:166-8. Erickson-Johnson MR, Chou MM, Evers BR, et al. Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. Lab Invest 2011;91:1427-33. Erber R, Agaimy A. Misses and near misses in diagnosing nodular fasciitis and morphologically related reactive myofibroblastic proliferations: experience of a referral center with emphasis on frequency of USP6 gene rearrangements. Virchows Arch 2018. [Epub ahead of print] Konwaler B, Keasbey L, Kaplan L. Subcutaneous pseudosarcom atous fibromatosis (fasciitis). Am J Clin Pathol1955;25:241-S2. Chung EB, Enzinger FM. Proliferative fasciitis. Cancer 1975;36:1450-8.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

34. 35.

36.

37.

38.

39.

40.

41. 42.

43.

44. 45. 46.

Meis ]M, Enzinger FM. Proliferative fasciitis and myositis of childhood. Am J Surg Pathol 1992; 16:364-72. Bekers EM, Eijkelenboom A, Grunberg K, et al. Myositis ossificans - An other condition with USP6 rearrangement, providing evidence of a relationship with nodular fasciitis and aneurysmal bone cyst. Ann Diagn Pathol2018;34:56-9. Sukov WR, Franco MF, Erickson-Johnson M, et al. Frequency of USP6 rearrangements in myositis ossificans, brown tumor, and cherubism: molecular cytogenetic evidence that a subset of "myositis ossificans-like lesions" are the early phases in the formation of soft-tissue aneurysmal bone cyst. Skeletal Radio! 2008;37:321-7. Montgomery EA, Meis ]M, Mitchell MS, Enzinger FM. Atypical decubital fibroplasia. A distinctive fibroblastic pseudotumor occurring in debilitated patients. Am J Surg Pathol 1992;16:708-15. Liegl B, Fletcher CD. Ischemic fasciitis: analysis of 44 cases indicating an inconsistent association with immobility or debilitation. Am] Surg Pathol 2008;32: 1546-52. Perosio PM, Weiss SW. Ischemic fasciitis: a juxta-skeletal fibroblastic proliferation with a predilection for elderly patients. Mod Pathol 1993;6:69-72. McCluggage WG, Smith ]H. Reactive fibroblastic and myofibroblastic proliferation of the vulva (Cyclist's nodule): a hitherto poorly described vulva! lesio n occurring in cyclists. Am J Surg Pathol 2011;35:110-14. Stoneham A, Thway K, Messiou C, Smith M. Cyclist's nodule: no smooth ride. BMJ Case Rep 2016;2016. Yamada Y, Kinoshita I, Kohashi K, et al. HIF-1alpha, MDM2, CDK4, and p 16 expression in ischemic fasciitis, focusing on its ischemic condition. Virchows Arch 2017;471:11 7-22. Sachak T, Heerema NA, Mayerson ], Payne JE, Parwani A, Iwenofu O H. Novel t (1;2) (p36.1;q23) and t(7; 19)(q32;q13.3) chromosoma! translocations in isch emic fasciitis: expanding the spectrum of pseudosarcomatous lesions with clonal pathogenetic link. Diagn Pathol 20 18; 13:18. Chung EB, Enzinger FM. Fibroma of tendon sheath. Cancer. Nov 1979;44(5):1945-1954. Dal Cin P, Sciot R, De Smet L, Van den Berghe H. Translocation 2;11 in a fibroma of tendon sheath. Histopathology 1998;32:433-435. Kato I, Yoshida A, Ikegami M, et al. FOSLl immuno histochemistry clarifies the distinction between desmoplastic fibroblastoma and fibroma of tendon sheath. Histopathology 2016;69: 1012-20.

47.

48. 49.

so.

51.

52.

53.

54.

ss. 56.

57.

58. 59. 60.

Macchia G, Trombetta D, Moller E, et al. FOSLl as a candidate target gene for 11q12 rearrangements in desmoplastic fibroblastoma. Lab Invest 2012;92:735-43. Evans HL. Desmoplastic fibroblastoma. A report of seven cases. Am] Surg Pathol1995;19:1077-81. Fukunaga M, Ushigome S. Collagenous fibroma (desmoplastic fibroblastoma): a distinctive fibroblastic soft tissue tumor. Adv Anat Pathol 1999;6:275-80. Hasegawa T, Shimoda T, Hirohashi S, Hizawa K, Sano T. Collagenous fibroma (desmoplastic fibroblastoma): report of four cases and review of the literature. Arch Pathol Lab Med 1998; 122:455-60. Miettinen M, Fetsch ]F. Collagenous fibroma (desmoplastic fibroblastoma): a clinicopathologic analysis of 63 cases of a distinctive soft tissue lesion with stellate- shaped fibroblasts. Hum Pathol1998;29:676-82. Keasbey L. juvenile aponeurotic fibroma (ea!cifying fibroma): A distinctive tumor arising in the palms and soles of young children. Cancer 1953;6:338-46. Fetsch ]F, Miettinen M. Calcifying aponeurotic fibroma: a clinicopathologic study of 22 cases arising in uncommon sites. Hum Pathol 1998;29:1504-10. Alho A, Skjeldal S, Pettersen EO, Melvik JE, Larsen TE. An euploidy in benign tumors and nonneoplastic lesions of musculoskeletal tissues. Cancer 1994;73:1200-5. Puls F, Hofvander ], Magnusson L, et al. FN1EGF gene fusions are recurrent in calcifyi ng aponeurotic fibroma. J Pathol2016;238:502-7. Laskin WB, Miettinen M, Fetsch JF. Infantile digital fibroma /fibromatosis: a clinicopathologic and immunoh istochemical study of 69 tumors from 57 patients with long-term follow-up. Am J Surg Pathol 2009;33:1-13. Montgomery E, Lee JH , Abraham SC, Wu TT. Superficial fibromatoses are genetically distinct from deep fibromatoses. Mod Pathol 2001;14:695-701. Yun K. Infantile digital fibromatosis. lmmunohistochemical and ultrastructural observations of cytoplasmic inclusions. Cancer 1988;61 :500-7. Evans HL. Multinucleated giant cells in plantar fibromatosis. Am J Surg Pathol 2002;26:244-8. Yantiss RK, Spiro I], Compton CC, Rosenberg AE. Gastrointestinal stromal tumor versus intea-abdominal fibromatosis of the bowel wall: a clinically important differential diagnosis. Am J Surg Pathol 2000;24:947-57.

139

Soft Tissue Pathology

61.

62. 63.

64.

65 .

66.

67.

68.

69.

70.

71.

72.

73.

140

Montgomery E, Torbenson MS, Kaushal M, Fisher C, Abraham SC. Beta-Catenin immunohistoch emistry separates m esenteric fibromatosis from gastrointestinal stromal tumor and sclerosing mesenteritis. Am J Surg Pathol 2002;26: 1296-301. Popek EJ, Montgomery EA, Fourcroy JL. Fibrous hamartoma of infancy in the genital region: findings in 15 cases. J Urol1994;152:990-3. Al-lbraheemi A, Martinez A, Weiss SW, et al. Fibrous hamartoma of infancy: a clinicopathologic study of 145 cases, including 2 with sarcomatous features. Mod Pathol2017;30:474-85. Lakshminarayanan R, Konia T, Welborn ]. Fibrous hamartoma of infancy: a case report with associated cytogenetic findings. Arch Pathol Lab Med 2005;129:520-2. ParkJY, Cohen C, Lopez D, RamosE, Wagenfuehr ], Rakheja D. EGFR exon 20 insertion/duplication mutations characterize fibrous hamartoma of infancy. Am J Surg Pathol2016;40:1713-8. Rougemont AL, Fetni R, Murthy S, Fournet]C. A complex translocation (6;12;8)(q25;q24.3;q1 3) in a fibrous hamartoma of infancy. Can cer Genet Cytogenet 2006; 171:115-8. Coffin CM, Watterson ], Priest JR, Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol 1995;19:859-72. Meis JM, Enzinger FM. Inflammatory fibrosarcoma of the mesentery and retroperitoneum. A tumor closely simulating inflammatory pseudotumor. Am J Surg Pathol1991;15:1146-56. Coffin CM, Hornick JL, Fletcher CD. Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol2007;31:509-20. Marino-Enriquez A, Wang WL, Roy A, et al. Epithelioid inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol2011;35:135-44. Butrynski JE, D' Adamo DR, Hornick JL, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med 2010;363:1727-33. Gaudichon ], Jeanne-Pasquier C, Deparis M, et al. Complete and Repeated response of a metastatic ALK-rearranged inflammatory myofibroblastic tumor to Crizotinib in a Teenage girl. J Pediatr Hematol Oncol 2016;38:308-11. Liu Q, Kan Y, Zhao Y, He H, Kong L. Epithelioid inflammatory myofibroblastic sarcoma treated

74. 75.

76.

77.

78.

79. 80.

81.

82.

83.

84.

85. 86.

with ALK inhibitor: a case report and review of literature. IntJ Clin Exp Pathol 2015;8:15328-32. Murga-Zamalloa C, Lim MS. ALK-driven tumors and targeted therapy: focus on crizotinib. Pharmacogenomics Pers Med 2014;7:87-94. Subbiah V, McMahon C, Pate! S, et al. STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflamm atory myofibroblastic tumor with myxoid features harboring DCTNlALK fusion. J Hematol Oncol 2015;8:66. Antonescu CR, Suurmeijer A], Zhang L, et al. Molecular characterization of inflammatory myofibroblastic tum o rs with freq uent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am] Surg Pathol2015;39:957-7. Hornick]L, Sholl LM, Dal Cin P, Childress MA, Lovly CM. Expression of ROS1 predicts ROSl gene rearrangement in inflammatory myofibroblastic tumors. Mod Pathol 2015;28:732-9. Saab ST, Hornick JL, Fletcher CD, Olson SJ, Coffin CM. IgG4 plasma cells in inflammatory myofibroblastic tu m or: inflammatory marker or pathogenic link? Mod Pathol 2011;24:606-12. Deshpande V, Zen Y, Ch an ]K, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181-92. Agaram NP, Zhang L, Sung YS, et al. Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis-like neural tumors. Am J Surg Pathol2016;40:1407-16. Dickson BC, Swanson D, Charames GS, Fletcher CD, HornickJL. Epithelioid fibrous histiocytoma: molecular characterization of ALK fusion partners in 23 cases. Mod Pathol2018;31:753-62. Doyle LA, Marino-Enriquez A, Fletcher CD, HornickJL. ALK rearrangement and overexpression in epithelioid fibrous histiocytoma. Mod Path ol 2015;28:904-12. Enzinger FM, Zhang RY. Plexifo rm fibrohistiocytic tumor presenting in children and young adults. An analysis of 65 cases. Am] Surg Pathol 1988;12:818-26. Fox MD, Billings SD, Gleason BC, et al. Expression of MiTF may be helpful in differentiating cellular neuro thekeoma from plexifor m fibrohistiocytic tumor (histiocytoid predominant) in a partial biopsy specimen . Am] Dermatopathol 2012;34:157-60. HornickJL, Fletcher CD. Cellular neurothekeoma: detailed characterization in a series of 133 cases. Am] Surg Pathol2007;31:329-40. Laskin WB, Fetsch JF, Miettinen M. The "neurothekeoma": immunohistochemical analysis distinguishes the true n erve sheath m yxoma from its mimics. Hum Pathol2000;31:1230-41.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

87. 88.

89.

90.

91.

92.

93.

94.

95 .

96. 97.

98.

Laskin WB. Dermatofibrosarcoma protuberans. CA Cancer J Clin 1992;42:116-25. O'Brien KP, Seroussi E, Dal Cin P, et al. Various regions within the alpha-helical domain of the COL1A1 gene are fused to the second exon of the PDGFB gene in dermatofibrosarcomas and giant-cell fibroblastomas. Genes Chromosomes Cancer 1998;23:187-93. Zhang Z, Ch en H, Chen M, He X, Wang Y, Zhang H. Applica tio n of COL1Al-PDGFB fusion gene detection by fluorescence in situ hybridization in biopsy tissue of dermatofibrosarcoma protuberans. J Dermatol 2017;44:798802. Xiao W, Qu e Y, Peng R, et al. A favo rable outcome of advanced dermatofibrosarcoma protuberans under treatment with sunitinib after imatinib failure. Onco Targets Ther 2018;11 :2439-43. Goldblum JR, Reith JD, Weiss SW. Sarcomas arising in dermatofibrosarcoma protuberans: a reappraisal of biologic behavior in eighteen cases treated by wide local excision with extended clinical follow up. Am ] Surg Pathol 2000;24: 1125-30. Kh alifa MA, Montgomery EA, Ismiil N, Azumi N. What are the CD34+ cells in benign periphera! nerve sheath tumors? Double immunostaining study of CD34 and S-100 protein. Am J Clin Pathol 2000;114:123-6. Ellington N, ParkJY, King K, josephs S, Rakheja D. EGFR exon 20 insertion/du plication mutation in fibrous hamartoma of infancy with predominantly pseudoangiomatous pattern mimicking giant cell fibroblastoma. Int J Surg Pathol 2017;25:421-4. Macarenco RS, Zamolyi R, Franco MF, et al. Genomic gains of COLlAl-PDFGB occur in the histologic evolution of giant cell fibroblastoma into dermatofibrosarcoma protuberans. Genes Chromosomes Cancer 2008;47:260-5. Shmookler BM, Enzinger FM, Weiss SW. Giant cell fibroblasto ma. A juven ile form of dermatofibrosarcoma protuberans. Can cer 1989;64:2154-61. Detlefsen S, Fagerberg CR, Ousager LB, et al. Histiocytic disorders of the gastrointestinal tract. Hum Pathol 2013;44:683-96. Rosai ], Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch Pathol 1969;87:63-70. Rosai ], Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder. Analysis of 34 cases. Cancer 1972;30:11 74-88.

99. 100.

101.

102.

103. 104. 105.

106.

107.

108.

109. 110. 111. 112.

Montgomery EA, Meis JM, Frizzera G. Rosai-Dorfman disease of soft tissue. Am J Surg Pathol1992;16:122-9. La uwe rs GY, Perez-Atayde A, Dorfman RF, Rosai J . The digestive system manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy): review of 11 cases. Hum Pathol 2000;31:380-5. Kraft S, Fletcher CD. Atypical intradermal smooth muscle neoplasms: clinicopathologic analysis of 84 cases and a reappraisal of cutan eous "leiomyosarcoma." Am J Surg Pathol 2011;35:599-607. Billings SD, Folpe AL, Weiss SW. Do leiomyomas of deep soft tissue exist? An analysis of highly differentiated smooth m uscle tumors of deep soft tissue supporting two distinct subtypes. Am J Surg Pathol 2001;25:1134-42. Meis JM, Enzinger FM. Myolipoma of soft tissue. Am] SurgPathol. Feb 1991;15(2):121-125. Ye ] X, Liu Y, Qin Y, et al. Mast cells or not? CD11 7 positive cells in esophageal leiomyoma. Histol Histopathol 2015;30:581-8. Carter CS, Skala SL, Chinnaiyan AM, et al. Immunohistoch emical characterization of fumarate hydratase (FH) and succinate dehydrogenase (SOH) in cutaneous leiomyomas for detection of familial cancer syndromes. Am J Surg Pathol201 7;41:801-9. Agaimy A, Bieg M, Michal M, et al. Recurrent Somatic PDGFRB mu tations in sporadic infantile/solitary adult myofibromas but not in angioleiomyomas and myopericytomas. Am J Surg Pathol201 7;41:195-203. Arts FA, Chand D, Pecquet C, et al. PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. Oncogene 2016;35:3239-48. Arts FA, Sciot R, Brichard B, et al. PDGFRB gain-of-function mutatio ns in sporadic infantile m yofibromatosis. Hum Mol Genet 201 7;26:1801-10. Chung EB, Enzinger FM. Infantile myofibromatosis. Cancer 1981;48:1807-18. Smith KJ, Skelton HG, Barrett TL, Lupton GP, Graham ]H. Cutaneous m yofibroma. Mod Pathol 1989;2:603-9. Gengler C, Guillou L. Solitary fibrous tumour and haemangiopericytoma: evolution of a concept. Histopathology 2006;48:63-74. Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 2002;20:2672-9.

141

Soft Tissue Pathology

113.

114.

115. 116.

117. 118.

119.

120.

121.

122.

123.

124.

125.

142

Gasparini P, Casanova M, Villa R, et al. Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma. Oncotarget 2016;7:58903-14. Schoffski P, Wozniak A, Leahy MG, et al. The tyrosine kinase inhibitor crizotinib does not have clinically meaningful activity in heavily pre-treated patients with advanced alveolar rhabdomyosarcoma with FOXO rearrangement: European Organisation for Research and Treatment of Cancer phase 2 trial 90101 'CREATE'. Eur J Cancer 2018;94:156-67. Sachatello CR, McSwain B. Regression of cutaneous capillary hemangioma. Am J Surg 1968;116:113-4. Mills SE, Cooper PH, Fechner RE. Lobular capillary hemangioma: the underlying lesion of pyogenic granuloma. A study of 73 cases from the oral and nasal mucous membranes. Am J Surg Pathol 1980;4:4 70-9. Cooper PH, McAllister HA, Helwig EB. Intravenous pyogenic granuloma. A study of 18 cases. Am J Surg Pathol 1979;3:221-8. John I, Folpe AL. Anastomosing hemangiomas arising in unusual locations: a clinicopathologic study of 17 soft tissue cases showing a predilection for the paraspinal region. Am J Surg Pathol 2016;40:1084-9. Lin ], Bigge J, Ulbright TM, Montgomery E. Anastomosing hemangioma of the liver and gastrointestinal tract : an unusual variant histologically mimicking angiosarcoma. Am J Surg Pathol2013;37:1761 -S. Montgomery E, Epstein JI. Anastomosing hemangioma of the genitourinary tract: a lesion mimicking angiosarcoma. Am J Surg Pathol 2009;33:1364-9. Bean GR, joseph NM, Folpe AL, Horvai AE, Umetsu SE. Recurrent GNA14 mutations in anastomosing haemangiomas. Histopathology 2018;73:354-7. Fetsch JF, Weiss SW. Observations concerning the pathogenesis of epithelioid hemangioma (angiolymphoid hyperplasia). Mod Pathol 1991;4:449-55. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia. A clinicopathologic study of 116 patients. J Am Acad Dermatol 1985;12(Pt 1):781-96. Rosai J. Angiolymphoid hyperplasia with eosinophilia of the skin. Its nosological position in the spectrum of histiocytoid hemangioma. Am J Dermatopathol 1982;4:175-84. Huang SC, Zhang L, Sung YS, et al. Frequent FOS gene rearrangements in epithelioid hemangioma: a molecular study of 58 cases

with morphologic reappraisal. Am J Surg Pathol 2015;39:1313-21. 126. Errani C, Sung YS, Zhang L, Healey JH, Antonescu CR. Monoclonality of multifocal epithelioid hemangioendothelioma of the liver by analysis of WWTR1-CAMTA1 breakpoints. Cancer Genet 2012;205:12-7. 127. Alien PW, Enzinger FM. Hemangioma of skeletal muscle. An analysis of 89 cases. Cancer 1972;29:8-22. 128. Beham A, Fletcher CD. Intramuscular angioma: a clinicopathological analysis of 74 cases. Histopathology 1991; 18:53-9. 129. Watson W, McCarthy W. Blood and blood vessel tumors: 1056 cases. Surg Gyn ecol Obstet 1940;71:569-88. 130. Howat AJ, Campbell PE. Angiomatosis: a vascular malformation of infancy and childhood. Report of 17 cases. Pathology 1987;19:3i7-82. 131. Rao VK, Weiss SW. Angiomatosis of soft tissue. An analysis of the histologic features and clinical outcome in 51 cases. Am J Surg Pathol 1992;16:764-71. 132. Gottlieb GJ, Ackerman AB. Kaposi's sarcoma: an extensively disseminated form in young homosexual men. Hum Pathol 1982;13:882-92. 133. Doyle LA, Fletcher CD, Hornick JL. Nuclear expression of CAMTA1 distinguishes epithelioid hemangioendothelioma from histologic mimics. Am J Surg Pathol 2016;40:94-102. 134. Weiss SW, Ishak KG, Dail DH, Sweet DE, Enzinger FM. Epithelioid hemangioendothel ioma and related lesions. Semin Diagn Pathol 1986;3:259-87. 135. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970-81. 136. Deyrup AT, Tighiouart M, Montag AG, Weiss SW. Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases. Am J Surg Pathol 2008;32:924-7. 137. Ishak KG, Sesterhenn lA, Goodman ZD, Rabin L, Stromeyer FW. Epithelioid h emangioendothelioma of the liver: a clinicopathologic and follow-up study of 32 cases. Hum Pathol 1984;15:839-52. 138. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on th e surgical therapy. Cancer 1 2006;107:2108-21. 139. Folpe AL, Chand EM, Goldblum JR, Weiss SW. Expression of Fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. Am J Surg Pathol 2001;25:1061-6.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

Folpe AL, Hill CE, Parham DM, O'Shea PA, Weiss SW. Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor. Am J Surg Pathol 2000;24: 165 7-62. Miettinen M, Wang Z, Sarlomo-Rikala M, Abdullaev Z, Pack SO, Fetsch ]F. ERG expression in epithelioid sarcoma: a diagnostic pitfall. Am J Surg Pathol2013;37:1580-5. Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer 2013;52:775-84. Gengler C, Coindre ]M, Leroux A, et al. Vascular proliferations of the skin aft er radiation therapy for breast cancer: clinicopathologic analysis of a series in favor of a benign process: a study from the French Sarcoma Group. Cancer 2007;109:1584-98. Brenn T, Fletcher CD. Radiation-associated cutaneous atypical vascular lesions and angiosarcoma: clinicopathologic analysis of 42 cases. Am J Surg Pathol 2005;29:983-96. Patton KT, Deyrup AT, Weiss SW. Atypical vascular lesions after surgery and radiation of the breast: a clinicopathologic study of 32 cases analyzing histologic heterogeneity and association with angiosarcoma. Am J Surg Pathol 2008;32:943-50. Harker D, jennings M, McDonough P, et al. MYC amplification in angiosarcomas arising in the setting of chronic lymphedema of m orbid obesity. J Cutan Pathol 2017;44:15-9. Shon W, Sukov WR, )enkins SM, Folpe AL. MYC amplification and overexpression in primary cutaneous angiosarcoma: a fluorescence in-situ hybridization and immunohistochemical study. Mod Pathol 2014;27:509-15. Udager AM, Ishikawa MK, Lucas OR, McHughJB, Pate! RM. MYC immunohistochemistry in angiosarcoma and atypical vascular lesions: practical considerations based on a single institutional experience. Pathology 2016;48:697-704. Mentzel T, Katenkamp D. Intraneural angiosarcoma and angiosarcoma arising in benign and malignant peripheral nerve sheath tumours: clinicopathological and immunohistochemical analysis of four cases. Histopathology 1999;35:114-20. McKenney JK, Weiss SW, Folpe AL. CD31 expression in intratumoral macrophages: a potential diagnostic pitfall. Am J Surg Pathol 2001;25:1167-73. Miettinen M, Sarlomo-Rikala M, Lasotaj. KIT expression in angiosarcomas and fetal endo-

152. 153. 154.

155. 156.

157.

158.

159. 160.

161. 162.

163.

164.

165.

thelia! cells: lack of mutations of exon 11 and exon 17 of C-kit. Mod Pathol 2000; 13:536-41. Masson P. Hemangioendotheliome vegetant intravasculaire. Bull Soc Anat Paris 1923;93:517-23. Das Gupta TK, Brasfield RD, Strong EW, Hajdu SI. Benign solitary Schwannomas (neurilemamas). Cancer 1969;24:355-66. Fanburg-Smith ] C, Majidi M, Miettinen M. Keratin expression in schwannoma; a study of 115 retroperitoneal and 22 peripheral schwannomas. Mod Pathol 2006;19:115-21. Hasegawa SL, Mentzel T, Fletcher CD. Schwannomas of the sinonasal tract and nasopharynx. Mod Pathol1997;10:777-84. Fanburg-Smith JC, Meis-Kindblom ]M, Fante R, Kindblom LG. Malignant granular cell tumor of soft tissue: diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol 1998;22:779-94. Cleven AH, Sannaa GA, Briaire-de Bruijn I, et al. Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival. Mod Pathol 2016;29:582-90. Schaefer IM, Fletcher CD, Hornick JL. Loss of H3K27 trimethylation distinguishes malignant peripheral nerve sheath tumors from histologic mimics. Mod Pathol2016;29:4-13. Zhang M, Wang Y, ]ones S, et al. Somatic m utations of SUZ12 in malignant peripheral nerve sheath tumors. Nat Genet 2014;46:1170-2. Laskin WB, Weiss SW, Bratthauer GL. Epithelioid variant of malignant peripheral nerve sheath tumor (malignant epithelioid schwannom a). Am J Surg Pathol 1991;15:1136-45. Hollmann TJ, Hornick JL. !Nil-deficient tumors: diagnostic features and molecular genetics. Am] Surg Pathol2011;35:e47-63. HornickJL, Dal Cin P, Fletcher CD. Loss ofiNil expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol 2009;33:542-50. Carney ]A, Gordon H, Carpenter PC, Shenoy BV, Go VL. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine 1985;64:270-83. Kirschner LS, Carney JA, Pack SO, et al. Mutations of the gene encoding the protein kinase A type !-alpha regulatory subunit in patients with the Carney complex. Nat Genet 2000;26:89-92. Allen PW, Dymock RB, MacCormac LB. Superficial angiomyxomas with and without epithelial components. Report of 30 tumors in 28 patients. Am] Surg Pathol1988;12:519-30.

143

Soft Tissue Pathology

Calonje E, Guerin D, McCormick D, Fletcher CD. Superficial angiomyxoma: clinicopathologic analysis of a series of distinctive but poorly recogni zed cutaneous tumors with tendency for recurrence. Am J Surg Path ol 1999;23:910-7. 167. Torres-Mora ], Dry S, Li X, Binder S, Amin M, Folpe AL. Malignant m elan otic schwannian tumor: a clinicopathologic, immuno histochemical, and gene expression profiling study of 40 cases, with a proposal for the reclassification of "melanotic schwannoma." Am J Surg Pathol 2014;38:94-105. 168. Alien PW, Dymock RB, MacCormac LB. Superficial angiomyxomas with and without epithelial components. Report of 30 tumors in 28 patients. Amj Surg Patholl988;12:519-30. 169. Fetsch ]F, Laskin WB, Tavassoli FA. Superficial angiomyxoma (cutaneous myxoma): a clinicopathologic study of 17 cases arising in the genital region. Int J Gynecol Pathol 1997;16:325-34. 170. Carney ] A. The triad of gastric epithelioid leiomyosarcoma, functioning extra- adrenal paraganglioma, and pulmonary chondrom a. Cancer 1979;43:374-82. 171. Kindblom LG, Stener B, Angervall L. Intramuscular myxoma. Cancer 1974;34:1737-44. 172. Nielsen GP, O'Connell]X, Rosenberg AE. Intramuscular m yxoma: a clinicopathologic study of 51 cases with emphasis on hypercellular and hypervascular varia nts. Am] Surg Pathol 1998;22:1222-7. 173. Ireland DC, Soule EH, Ivins ]C. Myxoma of somatic soft tissues. A report of 58 patients, 3 with multiple tumors and fibrous dysplasia of bone. Mayo Clin Proc 19 73;48:401-10. 174. Wirth WA, Leavitt D, Enzinger FM. Multiple intramuscular myxomas. Another extraskeletal manifestation of fibrous dysplasia. Cancer 1971;27:1167-73. 175. Delaney D, Diss TC, Presneau N, et al. GNAS1 mutation s occur more commonly than previously thought in intramuscular myxoma. Mod Pathol 2009;22:718-24. 176. Weinstein LS, Shenker A, Gejman PV, Merino M], Friedman E, Spiegel AM. Activating mutations of the stimulatory G protein in th e McCune-Albright syndrome. N Engl J Med 1991;325:1 688-95. 177. Laskin WB, Fetsch JF, Miettinen M. Myxoinflammatory fibroblastic sarcoma: a clinicopathologic analysis of 104 cases, with emphasis on predictors of outcome. Am] Surg Pathol 2014;38:1-12. 178. Meis-Kindblom JM, Kindblom LG . Acral m yxoinflammatory fibrob lastic sarcoma: a 166.

144

low-grade tumor of the hands and feet. Am] Surg Pathol 1998;22:911-24. 179. Montgomery EA, Devaney KO, Giordano TJ, Weiss SW. Inflammatory myxohyaline tumo r of distal extremities with virocyte or Reed-Sternberg-like cells: a distinctive lesion with features simulating inflammatory conditio ns, Hodgkin's disease, and va rious sarcomas. Mod Pathol 1998;11:384-91. 180. Boland ]M, Folpe AL. Hemosiderotic Fibrolipomatous Tumor, Pleomorphic Hyalinizing Angiectatic Tumor, and Myxoinflammatory Fibroblastic Sarco m a: Related or Not? Adv Anat Pathol2017;24:268-77. 181. Weiss SW, Enzinger FM. Myxoid variant of malignant fibrous histiocytoma . Ca n cer 1977;39:1672-85. 182. Angervall L, Kindblom LG, Merck C. Myxofibrosarcoma. A study of 30 cases. Acta Pathol Microbial Scand A 1977;85A(2):127-40. 183. Evans HL. Low-grade fibromyxoid sarcoma. A report of two metastasizing neoplasms having a deceptively benign appearance. Am J Clin Pathol 1987;88:615-9. 184. Montgomery E, Argani P, Hicks JL, DeMarzo AM, Meeker AK. Telomere lengths of translocation-associated and nontranslocation-associated sarcomas differ dramatically. Amj Pathol 2004;164:1523-9. 185. Montgomery E, Wilentz RE, Argani P, et al. Analysis of anaphase figures in routine histologic sections distinguishes chromosomally unstable from chrom osom ally stable malignancies. Cancer Bioi Ther 2003;2:248-52. 186. Lane KL, Shannon RJ, Weiss SW. Hyalinizing spindle ceJl tumor with giant rosettes: a distinctive tumor closely resembling low-grade fibromyxoid sarcoma. Am J Surg Patho l 1997;21:1481-8. 187. Folpe AL, Lane KL, Paull G, Weiss SW. Lowgrade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes: a clinicopathologic study of 73 cases supporting their identity and assessing the impact of highgrade areas. Am] Surg Pathol2000;24:13S3-60. 188. Reid R, de Silva MV, Paterson L, Ryan E, Fisher C. Low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes share a common t(7;16)(q34;pll) translocation. Am J Surg Pathol 2003;27:1229-36. 189. Mertens F, Fletcher CD, Antonescu CR, et al. Clinicopathologic and molecular genetic cha racterizatio n of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3Ll fusion gene. Lab Invest 2005;85:408-15.

Soft Tissue Lesions that Can Be Diagnosed on Routine H&E Staining

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

202.

Doyle LA, Moller E, Dal Cin P, Fletcher CD, Mertens F, Hornick JL. MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma. Am J Surg Pathol 2011;35:733-41. Meis-Kindblom JM, Kindblom LG, Enzinger FM. Sclerosing epithelioid fib rosarcoma. A variant of fibrosarcoma simulating carcinoma. Am] Surg Pathol1995;19:979-93. Doyle LA, Wang WL, Dal Cin P, et al. MUC4 is a sensitive and extremely useful marker for sclerosing epithelioid fibrosarcoma: association with FUS gene rearrangement. Am] Surg Pathol2012;36:1444-Sl. Yoshida A, Tsuta K, Ohno M, et al. STAT6 immunohistochemistry is helpful in the diagnosis of solitary fibrous tumors. Am J Surg Pathol 2014;38:552-9. Enzinger FM. Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of chfldren and you ng adults simulating a vascular neoplasm. Cancer 1979;44:2147-57. Fletcher CD, Unni KK, Mertens FE, eds. Pathology and genetics of tumours of soft tissue and bone. World Health Organization classification of tumours. Lyon: IACR Press; 2002. Antonescu CR, Dal Cin P, Nafa K, et al. EWSR1CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer 2007;46:1051 -60. Costa MJ, Weiss SW. Angiomatoid malignant fibrous histiocytoma. A follow-up study of 108 cases with evaluation of possible histologic predictors of outcome. Am] Surg Pathol 1990;14:1126-32. Enzinger FM, Weiss SW, Liang CY. Ossifying fibromyxoid tu m or of soft parts. A clinicopathological analysis of 59 cases. Am] Surg Pathol 1989;13:817-27. Graham RP, Dry S, Li X, et al. Ossifying fibromyxoid tumor of soft parts: a clinicopathologic, proteomic, and genomic study. Am J Surg Pathol 2011;35:1615-25. Miettinen M. Ossifying fibromyxoid tumor of soft parts. Additional observations of a distinctive soft tissue tumor. Am J Clin Pathol 1991;95:142-9. Folpe AL, Weiss SW. Ossifying fibromyxoid tumor of soft parts: a clinicopath o logic study of 70 cases with emphasis on atypical and malignant variants. Am J Surg Pathol 2003;27:421-31. SchofieldJB, Krausz T, Stamp GW, Fletcher CD, Fisher C, Azzopardi]G. Ossifying fibromyxoid tumour of soft parts: immunohistochemical and ultrastructural analysis. Histopathology 1993;22:101-12.

203.

204.

205. 206.

207. 208.

209. 210. 211.

212. 213. 214. 215.

216.

Williams SB, Ellis GL, Meis ]M, Heffner OK. Ossifying fibromyxoid tumour (of soft parts) of the head and neck: a clinicopathological and immunohistochemical study of nine cases. J Laryngol Otol 1993;107:75-80. Gra ham RP, Weiss SW, Sukov WR, et al. PHF1 rearrangements in ossifying fibromyxoid tumors of soft parts: a fluorescence in situ hybridization study of 41 cases with emphasis on the malignant variant. Am J Surg Pathol 2013;37:1751-5. Fisher C. Synovial sarcoma. Ann Diagn Pathol 1998;2:401-21. Dardick I, O'Brien PK, jeans MT, Massiah KA. Synovial sarcoma arising in an anatomical bursa. Virchows Arch A Pathol Anat Histol 1982;397:93-101. McKinney CD, Mills SE, Fechner RE. Intraarticular synovial sarcoma. Am J Surg Pathol 1992;16:1017-20. van de Rijn M, Barr FG, Xiong QB, Hedges M, Shipley ], Fisher C. Poorly differentiated synovial sarcoma: an analysis of clinical, pathologic, and molecular genetic features. Am J Surg Pathol 1999;23:106-12. Fisher C, Schofield ]B . S-100 protein positive synovial sarcoma. Histopathology 1991;19:375-7. Healy V, Fisher C. Calpo nin and h-caldesmon expression in synovial sarcoma. Mod Pathol 2002; 15:16A. Sm ith S, Reeves BR, Wong L, Fisher C. A consistent chromosome translocation in synovial sarcoma. Cancer Genet Cytogenet 1987;26:179-80. Laskowski J. Sarcoma aponeuroticum. Nowotwary 1961; 11:61-67. Enzinger F. Epithelioid sarcoma. A sarcoma simulating a granu loma or a carcinoma. Cancer 1970;26: 1029-41. Chase OR, Enzinger FM. Epithelioid sarcoma. Diagnosis, prognostic indicators, and treatment. Am J Surg Pathol 1985;9:241-63. Guillou L, Wadden C, Coindre JM, Krausz T, Fletcher CD. "Proximal-type" epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series. Am] Surg Pathol1997;21:130-46. Miettinen M, Fanburg-SmithJC, Virolainen M, Shmookler BM, Fetsch JF. Epithelioid sarcoma: an immunohistochemical analysis of 112 classical and variant cases and a discussion of the differential diagnosis. Hum Pathol 1999;30:934-42.

145

Soft Tissue Pathology

217.

Daimaru Y, Hashimoto H, Tsuneyoshi M, Enjo-

229.

ji M. Epithelial profile of epithelioid sarcoma.

218.

219.

220.

221. 222.

223.

224. 225.

226.

227.

228.

146

An immunohistochemical analysis of eight cases. Cancer 1987;59:134-41. Wick MR, Manivel)C. Epithelioid sarcoma and isolated necrobiotic granuloma: a comparative immunocytochemical study. J Cutan Pathol 1986; 13:253-60. Wick MR, Manivel JC. Epithelioid sarcoma and epithelioid hemangioendothelioma: an immunocytochemical and lectin-histochemical comparison. Virchows Arch A Pathol Anat Histopathol 1987;410:309-16. Arber DA, Kandalaft PL, Mehta P, Battifora H. Vimentin-negative epithelioid sarcoma. The value of an immunohistochemical panel that includes CD34. Am) Surg Pathol 1993;17:302-7. Engel JD, Kuzel TM, Moceanu MC, Oefelein MG, Schaeffer AJ. Angiosarcoma of the bladder: a review. Urology 1998;52:778-84. Kohashi K, Izumi T, Oda Y, et al. Infrequent SMARCB1/INI1 gene alteration in epithelioid sarcoma: a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor. Hum Pathol 2009;40:349-SS. Raoux D, Peoc'h M, Pedeutour F, Vaunois B, Decouvelaere AV, Folpe AL. Primary epithelioid sarcoma of bone: report of a unique case, with immunohistochemical and fluorescent in situ hybridization confirmation of INll deletion. Am J Surg Pathol 2009;33:954-8. van Ruth S, van Coevorden F, Peterse]L, Kroon BB. Alveolar soft part sarcoma. a report of 15 cases. Eur J Cancer 2002;38:1324-8. Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin-Chesa P, Flehinger BY. AIveolar soft-part sarcoma. A clinico-pathologic study of half a century. Cancer 1989;63:1-13. Eva ns HL. Alveolar soft-part sarcoma . A study of 13 typical examples and one with a histologically atypical component. Cancer 1985;55:912-7. Portera CA, Jr., Ho V, Pate! SR, et al. Alveolar soft part sarcoma: clinical course and patterns of metastasis in 70 patients treated at a single institution. Cancer 2001;91:585-91. Matsuno Y, Mukai K, ltabashi M, et al. Alveolar soft part sarcoma. A clinicopathologic and immunohistochemical study of 12 cases. Acta Pathol Jpn 1990;40:199-205.

230.

231. 232.

233.

234. 235.

236. 237. 238.

239.

240.

Auerbach HE, Brooks)). Alveolar soft part sarcoma. A clinicopathologic and immunohistochemical study. Cancer 1987;60:66-73. Pappo AS, Parham DM, Cain A, et al. Alveolar soft part sarcoma in children and adolescents: clinical features and outcome of 11 patients. Med Pediatr Oncol 1996;26:81-4. Enzinger F. Clear cell sarcoma of tendons and aponeuroses: an analysis of 21 cases. Cancer 1965;18:1163-74. Lucas DR, Nascimento AG, Sim FH. Clear cell sarcoma of soft tissues. Mayo Clinic experience with 35 cases. Am) Surg Pathol1992;16:119704. Montgomery E, Meis ), Ramos A, Frisman D, Martz K. Clear cell sarcoma of tendons and aponeuroses. A clinicopathologic study of 58 cases with analysis of prognostic factors. lnt J Surg Pathol1993;1:89-100. Chung EB, Enzinger FM. Malignant melanoma of soft parts. A reassessment of clear cell sarcoma. Am J Surg Pathol 1983;7:405-13. Clark MA, Johnson MB, Thway K, Fisher C, Thomas JM, Ha yes AJ. Clear cell sarcoma (melanoma of soft parts): the Royal Marsden Hospital experience. Eur J Surg Oncol 2008;34:800-4. ]ones RL, Constantinidou A, Thway K, et al. Chemotherapy in clear cell sarcoma. Med Oncol 2011;28:859-63. Enzinger FM, Shiraki M. Extraskeletal myxoid chondrosarcoma. An analysis of 34 cases. Hum Pathol 1972;3:421-35. Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom LG. Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol 1999;23:636-50. Yoshida A, Makise N, Wakai S, Kawai A, Hiraoka N. INSM1 expression and its diagnostic significance in extraskeletal myxoid chondrosarcoma. Mod Pathol 2018;31:744-52. Gerald WL, Miller HK, Battifora H, Miettinen M, Silva EG, Rosai ]. Intra-abdominal desmoplastic small round-cell tumor. Report of 19 cases of a distinctive type of high-grade polyphenotypic malignancy affecting young individuals. Am J Surg Pathol 1991;15:499513.

SOFT TISSUE lESIONS FOR WHICH ANCillARY TECHNIQUES ARE IMPORTANT In chapter 2 we pointed out issues with entities that are sometimes readily diagnosed with hematoxylin and eosin (H&E) staining alone but, some examples of those same entities are difficult to diagnose and immunolabeling or molecular studies are reassuring and sensible to add. Furthermore, the challenge of tiny samples is often resolved with ancillary testing, for which we are grateful. In this section, we illustrate some entities for which it is important to use ancillary testing. We realize that ancillary testing is not available to all colleagues and that morphology directs it. Modern molecular pathology is a valuable tool for both diagnosis and choosing the best treatment, but it is only as good as the underlying morphology. Table 3-1 shows some tumors with very different biologic potentials that can have the same fusions. Of course, sometimes, there are simply surprises in our diagnoses, as seen in figure 3-1. There are some neoplasms that we are unable to classify, regardless of how much we try and how

much we test. Every single day, a new report appears of another strange primitive round cell malignant neoplasm with a new gene fusion with or without a therapeutic target. We will not pretend to be able to present all those entities. However, some are already well-defined entities and some display unusual features and are difficult to even consider based on the H&E (fig. 3-2). Extrarenal Rhabdoid Tumor Malignant rhabdoid tumor was initially characterized as a highly aggressive renal neoplasm affecting children under 2 years of age (1). The tumor derives its name from the early observation that the cells resembled those of rhabdomyosarcoma. Most extrarenal rhabdoid tumors (ERTs) arise in infants and young children, altho ugh they may affect adolescents and adults. ERTs have been described in the soft tissues of the head and neck, paravertebral region, shoulder, trunk, extremities, mediastinum, and 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

Soft Tissue Pathology

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 "premolecular" 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

Soft Tissue Pathology

sites. The clinical course of ERT is marked by early dissemination and death (2,3). Nearly all of the turners arising in the soft tissues of the neck, thorax, and extremities are deep, intramuscular lesions. Microscopically, the malignant cells are round to polygonal, with amphophilic to lightly basophilic cytoplasm, a paranuclear globoid inclusions with a pale eosinophilic, glassy appearance. The cells have large, eccentrically-positioned nuclei with a round to reniform configuration and prominent nucleoli (fig. 3-3). The cells are generally noncohesive, but may focally grow in a trabecular pattern or adhere to vessel walls or fibrous septa. Mitotic figures are easily observed, but atypical mitotic figures are infrequent. The cells form bulky, ill-defined sheets or large irregular nests. The stromal matrix is usually edematous but may be myxoid. Lymphatic and blood vessel invasion are frequently identified. ERT shows consistent immunoexpression of keratin and epithelial membrane antigen (EMA). In one study, over half of turners expressed CD99, synaptophysin, _Leu-7 (CDS7), and neuron-specific enolase (NSE) (4). Focal immunoreactivity has been reported for desmin and muscle-specific actin. In the correct clinical context, it is important to consider ERT but many neoplasms, including carcinomas, melanomas, and soft tissue sarcomas, may have foci exhibiting the cytomorphologic features of a malignant rhabdoid turner, and ERT is thus a diagnosis of exclusion. Poorly differentiated foci of synovial sarcoma, epithelioid malignant peripheral nerve sheath tumor, extraskeletal myxoid chondrosarcoma, mesothelioma, myoepithelial neoplasms, and intra-abdominal desmoplastic small round cell tumor are some of the soft tissue sarcomas that can demonstrate rhabdoid features . Also, several carcinoma types can have a rhabdoid phenotype. Rhabdomyosarcoma, like ERT, arises principally in the deep soft tissues and mostly affects children. Rhabdomyoblasts express desmin and Myo01, but not keratin or EMA (although focal cytokeratin may sometimes be seen). Epithelioid sarcoma can also have cells with rhabdoid features. In contrast to ERT, epithelioid sarcoma affects mostly adolescents and young adults and predilects to the hand and forearm area. The tumor cells of epithelioid sarcoma form cohesive

150

nodules that frequently coalesce and exhibit central necrosis. The proximal type of epithelioid sarcoma is composed of large epithelioid cells, including a significant component of rhabdoid-appearing cells, arranged in large, bulky nodules. In some instances, the number of rhabdoid-appearing cells in this variant of epithelioid sarcoma make the separation from ERT almost impossible. Although expression of keratin is a feature shared by both epithelioid sarcoma and ERT, the former neoplasm demonstrates CD34 immunoreactivity in SO percent of cases. The discovery of alterations of chromosome 22 and deletions in the SMARCBl (also called !Nil) gene in malignant rhabdoid turners has led to the possibility of immunohistochemical and molecular diagnosis of these tumors. INil loss can be sought by immunolabeling (5-11), a feature shared with epithelioid sarcoma, as described above (8,9) . The loss of INil in epithelioid sarcoma is less likely to be associated with DNA alterations in SMARCBl. Several other turner types can show loss of INI1/SMARCB1, including extraskeletal myxoid chondrosarcoma, epithelioid malignant peripheral nerve sheath turner, ossifying fibromyxoid turner, and various carcinomas, but these have either different morphology or a completely different clinical presentation (10,12). Ewing Sarcoma

It is only within the past couple of decades that we have realized that two histologically distinct neoplasms, Ewing sarcoma and peripheral primitive neuroectodermal turner (PNET; also referred to as peripheral neuroepithelioma), are the same and now we simply regard them all as Ewing sarcoma.]ames Ewing described a peculiar undifferentiated round cell turn or of bone in adolescents in 1921 (13), and--Ewing sarcoma became a standard diagnosis by the 1950s whereas PNET was largely unrecognized until Askin et al. (14) described a peculiar small cell turn or of the chest wall in adolescents (Askin tumor). Subsequently, based on cytogenetic, ultrastructural, and biologic studies, the commonality of these three lesions, Ewing sarcoma, PNET, and Askin turners, became apparent. Soft tissue examples of these neoplasms are now recognized as the second most common pediatric soft tissue sarcoma, following rhabdomyosarcoma. Ewing sarcoma

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

Soft Tissue Pathology

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 covered in Survival Guide to Bone Tumors. !::!Q_mer-Wright rosettes are the hallmark of primitive neuroectodermal tumors (whereas Ewing sarcomas lack these). These microscopic structures contain wreaths of dark, oval nuclei that circumscribe wispy, lightly pink, neurofibril-

152

lary cores. On the other end of the differentiation spectrum lies typical Ewing sarcoma, which is the quintessential "small round blue cell" tumor (fig. 3-4). These are composed of highly compressed cellular masses that usually occur in diffuse sheets. The turnor cell nuclei typically possess round, even contours and smooth chromatin

Soft Tissue Lesions for which Ancillary Techniques are Important

Figure 3-4, continued 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 larger than lymphoid cells. _Q299., formerly known as the MICZ antigen, is expressed in over 95 percent of Ewing/PNET cases with a distinctive diffuse membranous pattern of immunoreactivity. However, being derived from a lymphoblastic cell line, this antigen may react with lymphoblastic tumors. Rhabdomyosarcomas occa-

sionally are also positive, although generally in a focal cytoplasmic or nuclear pattern of reactivity. Thus, as with the other markers, CD99 stains are best interpreted within the context of a diagnostic panel of immunostains. An antibody to the Fill protein product of the EWSRl-FLJl fusion gene (15-17) is hardly specific and is an excellent marker for vascular neoplasms as well (18).

153

Soft Tissue Pathology

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 pleomorphic 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 perform a panel of keratin, WT1, desmin, S-100 protein, BCL2, TdT, NKX2.2, and CD99. If the CD99 and NKX2.2 are strongly reactive and nothing else is, we can relatively confidently diagnose Ewing sarcoma, but if anything is off, then molecular testing is in order. Ewing sarcoma usually harbors a gene fusion between the FL/l gene on chromosome 11 and the EWSRl gene on chromosome 22. Karyotypically, this is expressed by the reciprocal translocation, t(11;22)(q24;q12). However, several alternate fusio ns are described-the key one is EWSRl-ERG. Unlike alveolar rhabdomyosarcoma, which has a single reproducible fusion point, a variety of fusions may occur in Ewing sarcoma, all of which fuse the two translated protein molecules. In this chimeric protein, a DNA transcription factor (EWSR1) is joined to a RNA binding factor (FLil ) causing abnormal DNA regulation and leading to tumorigenesis. A common mimic of tumors in the Ewing family is the solid variant of alveolar rhabdomyosarcoma. These two tumor entities occur in identical locations and affect identical age groups of patients, with the caveat that Ewing tumors are rare in African-American children. Most cases can be resolved using immunohistochemistry. Lymphoma is less of a problem, given its usual presentation in lymph nodes, but soft tissue examples are well-known. Diagnosis

154

of acute lymphoblastic leukemia is particularly difficult because of its react ivity with CD99 and frequent nonreactivity with CD45, the common leukocyte antigen. As above, attention to cytologic detail is thus important, as well as use of a panel that includes neural, muscle, and lymphoid antigens. Poorly differentiated synovial sarcoma can have a great deal of labeling overlap with Ewing sarcoma as well, and molecular assessment for it is also important. Some Rhabdomyosarcomas

Most rhabdomyosarcomas are easy to consider and diagnose (u sually with ancillary t echniques t ogether with H&E) when they are found in children and adolescents. The rhabdomyosarcomas that result in issues are spindle/sclerosing rhabdomyosarcomas of adults that arise in the head and neck. They are very aggressive and really don't have an appearance that suggests rhabdomyosarcoma except that they are often sclerosing. The first issue is to consider them in any odd-looking spindle cell neoplasm of the head and neck of an adult and add immunolabeling that includes desmin. The second issue is to realize that on immunolabeling, myogenin labeling is likely to be sparse and the preparation must be assessed at high magnification (fig. 3-5). Such sclerosing rhabdomyosarcomas are aggressive and harbor MYODl mutations (19-21).

Soft Tissue Lesions for which Ancillary Techniques are Important

Figure 3-5, continued SPINDLE CELL/SCLEROSING RHABDOMYOSARCOMA

B: The tumor is overtly malignant but lacks the cytoplasmic eosinophilia that typifies embryonal rhabdomyosarcoma. 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

Soft Tissue Pathology

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 cytoplasm is characteristic of round cell sarcomas with C/C rearrangements.

Round Cell Sarcomas with Special Gene Fusions of All Sites

Sarcomas that have the appearances of Ewing sarcoma with weak or negative CD99 and NKX2.2 are often CJC-rearranged tumors. The majority have CIC-DUX4 fusions but some have ~IC-FOX04 rearrangements. They arise in young adults in the deep soft tissues of the extremities and trunk, and are highly aggressive compared to Ewing sarcoma, although presently they are treated similarly. They are composed of round cells, some with prominent nucleoli, and scant ~

156

pale cytoplasm (fig. 3-6). Sometimes there is myxoid stroma. CD99 staining is usually patchy and WTl and keratins are frequently reactive. A smaller subset of primitive sarcomas are BCOR-rearranged sarcomas, most of which harbor BCOR-CCNB3 fusions. These are mostly in adolescent males in the bone (about 60 percent) and soft tissues or the trunk and extremities. They are less aggressive than CJC-rearranged tumors. They have small round nuclei with inconspicuous nucleoli and scant cytoplasm. There can be myxoid stroma and delicate capillaries (fig. 3-7). On immunolabeling, CD99 expression

Soft Tissue Lesions for which Ancillary Techniques are Important

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.

is variable, but nuclear BCOR protein can be detected. These also express cyclin Dl, SATB2, and TLEl. Although BCOR is an excellent marker for these neoplasms, it can also label synovial sarcoma, clear cell sarcoma of kidney, and some high-grade endometrial stromal sarcomas. Our understanding of the relationship between some of these neoplasms is evolving (22-25).

Some Hemangioendotheliomas

Most hemangioendotheliomas are easy to consider on H&E, but there is one type that takes some practice to even consider as a vascular lesion, but it is actually characteristic. In the original series (26), this lesion was termed "epithelioid sarcoma-like hemangioendothelioma" and the patients (four male; three female)

157

Soft Tissue Pathology

... ,,.. .. ~

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 years). Their tumors were small (1.0 to 3.5 cm), and involved the extremities (n = 5), scalp (n = 1), and chest wall (n = 1), both in deep (n = 3) and superficial (n = 3) soft tissue or both (n = 1). In the original series, local (but not systemic) metastases were reported, but not tumor-associated deaths. The tumors had been regarded as a variant of epithelioid sarcoma before their recognition as vascular lesions (27). The findings were confirmed in a larger series (28) using the name pseudomyogenic hemangioendothelioma, in which a striking male predominance and young age was reported. Tumors tended to be multifocal, involving both soft tissues and bone, and had a proclivity to recur locally but metastases and tumor-associated deaths were unusual. Pseudomyogenic hemangioendothelioma shows sheets, ill-defined nodules, or fascicles of deeply eosinophilic cells set within a desmoplastic stroma (fig. 3-8). Overt vascular channel formation and hemorrhage are absent. Some cases display cells with vacuolization suggestive of intracytoplasmic vascular lumen formation. The tumor cells are large and rounded to spindled. Mitotic activity is low, nuclear pleomorphism is mild to moderate, and necrosis is absent.

158

These tumors express cytokeratin, CD31 , ERG, and FLI-1, but often lack CD34 (26). They show retained INil/SMARCBl. A characteristic translocation and fusion gene (SERPINEl-FOSB) has been described th at can also be exploited for diagnosis together with an immunostain for FOSB (29,30). Pleomorphic Bad Malignant Spindle Cell Neoplasm s It is important to remember that anything can have spindle cell morphology. This includes sarcomatoid carcinomas, spindle cell melanomas and lymphomas, and undifferentiated pleomorphic sarcomas. When the latter are very superficial in the skin (dermis in the head/ neck of a sun-damaged elderly person), they are termed atypical fibroxanthoma (in light of their indolent behavior) whereas as soon as they extend into the subcutaneous fat, they become pleomorphic dermal sarcoma (the old "superficial malignant fibrous histiocytoma"), in light of their potential for aggressive behavior once they involve subcutis. Deeper lesions that have the same characteristics are undifferentiated pleomorphic sarcomas (the old "malignant fibrous histiocytomas"). When dealing with

Soft Tissue Lesions for which Ancillary Techniques are Important

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

Soft Tissue Pathology

Figure 3-9 DEDIFFERENTIATED LIPOSARCOMA

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 •

'

... ' skin lesions, always check the surface for in situ melanoma or carcinoma; if present, the diagnosis can be made and then the diagnosis can be made wthout immunolabeling. A few tips apply here: 1) In spindle cell lesions of skin, always consider spindle cell melanoma and sarcomatoid carcinoma (spindled squamous cell carcinoma) before anything else, especially if the skin shows solar damage. Use an initial panel that includes a pankeratin and/orp63/p40, S-100 protein, and/or SOXlO. If that fails, begin to consider sarcomas. Including a vascular marker like _ERG or CD31 is a good idea as some angiosarcomas can lack

160

..

.'

t

"

obvious vascular channel formation particularly on a small shave biopsy. 2) Pleomorphic spindle cell lesions of the retroperitoneum in adults are often dedifferentiated liposarcomas (fig. 3-9). Although some observers believe that MDM2 immunolabeling is not sensitive and specific, in the correct context, it is quite useful. A good starter panel in the retroperitoneum when confronted with a modest amount of tissue is ~s=.lQOJ protein for schwannoma and melanoma, ~Z.1 for dedifferentiated liposarcoma, and keratin1for mesothelioma and sarcomatoid carcinoma as well as some unstained slides. The panel can be

Soft Tissue Lesions for which Ancillary Techniques are Important

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

Soft Tissue Pathology

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 the MDM2 stain is difficult to interpret, FISH can be used to clarify the issue. 3) Sarcomatoid carcinomas and spindle cell lymphomas are the big contenders in organs (figs. 3-10, 3-11). Kidney and lung are the homes of sarcomatoid carcinomas and the pancreas is the home of anaplastic carcinomas with giant cells. The liver and spleen are the home of large B cell lymphomas, which can be spind ly and

162

lack CD45 labeling. If there is strong concern for lymphoma, additional markers such asmJOJ and/or plasma cell markers, can be added. Keep CD20 in your panel in those sites and remember that several m arkers (such as P63, GATA3) often labellyrnphocytes. 4) Don't forget to consider p leomorphic rhabdomyosarcoma when dealing with undifferentiated pleomorphic sarcomas (fig. 3-12).

Soft Tissue Lesions for which Ancillary Techniques are Important

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.

REFERENCES

1. Weeks DA, Beckwith ]B, Mierau GW, Luckey DW. Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms' Tumor Study Pathology Center. Am] Surg Pathol1989;13:439-58. 2. Kodet R, Newton WAJr, Sachs N, et al. Rhabdoid tumors of soft tissues: a clinicopathologic study of 26 cases enrolled on the Intergroup Rhabdomyosarcoma Study. Hum Pathol1991;22:674-84. 3. White FV, Dehner LP, Belchis DA, et al. Congenital disseminated malignant rhabdoid tumor: a distinct clinicopathologic entity demonstrating abnormalities of chromosome 22q11. Am J Surg Pathol 1999;23:249-56. 4. Fanburg-Smith]C, Hengge M, Hengge UR, Smith ]S]r, Miettinen M. Extrarenal rhabdoid tumors of soft tissue: a clinicopathologic and immunohistochemical study of 18 cases. Ann Diagn Pathol 1998;2:351-62.

5. Haberler C, Laggner U, Slave I, et al. Immunohistochemical analysis of !Nil protein in malignant pediatric CNS tumors: lack of !Nil in atypical teratoid/rhabdoid tumors and in a fraction of primitive neuroectodermal tumors without rhabdoid phenotype. Am] Surg Pathol 2006;30:1462-8. 6. Hasselblatt M, Gesk S, Oyen F, et al. Nonsense mutation and inactivation of SMARCA4 (BRG 1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (!Nil) expression. Am] Surg Pathol 2011;35:933-5. 7. Hoot AC, Russo P, Judkins AR, Perlman EJ, Biegel ]A. Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am] Surg Pathol2004;28:1485-91.

163

Soft Tissue Pathology

8. HornickJL, Dal Cin P, Fletcher CD. Loss of !Nil expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol 2009;33:542-50. 9. Kohashi K, Izumi T, Oda Y, et al. Infrequent SMARCB1/ INI1 gene alteration in epithelioid sarcoma: a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tu mor. Hum Pathol 2009;40:349-55. 10. Kohashi K, Oda Y, Yamamoto H, et al. SMARCBl/ INil protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/ INll negative variant extraskeletal myxoid chondrosarcoma. Amj Surg Pathol2008;32:1168-74. 11. Kusafuka T, Miao J, Yoneda A, Kuroda S, Fukuzawa M. Novel germ-line deletion of SNF5/INI1/ SMARCB1 gene in neonate presenting with congenital malignant rhabdoid tu m or of kidney and brain primitive neuroectodermal tumor. Genes Chromosomes Cancer 2004;40:133-9. 12. Graham RP, Dry S, Li X, et al. Ossifying fibromyxoid tumor of soft parts: a clinicopathologic, proteomic, and genomic study. Am J Surg Pathol 2011;35:1615-25. 13. Ewing J. Diffuse endothelioma of bone. Proc NY Pathol Soc 1921;21:17-24. 14. Askin FB, Rosaij, Sibley RK, Dehner LP, McAlister WH. Malignant small cell tumor of the thoracopulmonary region in childhood: a distinctive clinicopathologic entity of uncertain histogenesis. Cancer 1979;43:2438-5 1. 15. Weidner N, Tjoe ]. Immunohistochemical profile of monodonal antibody 013: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma. Am ] Surg Pathol1994;18:486-94. 16. Folpe AL, Hill CE, Parham DM, O'Shea PA, Weiss SW. Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor. Am J Surg Pathol 2000;24:1657-62. 17. jimenez RE, Folpe AL, Lap ham RL, et al. Primary Ewing's sarcoma/primitive neuroectodermal tumor of the kidney: a clinicopathologic and immunohistochemical analysis of 11 cases. Am J Surg Pathol2002;26:320-7. 18. Folpe AL, Chand EM, Goldblum JR, Weiss SW. Expression of Fli-1, a nuclear transcription factor, distinguishes vascular neoplasms from potential mimics. Am J Surg Pathol 2001;25:1061-6. 19. Agaram NP, Chen CL, Zhang L, LaQuaglia MP, Wexler L, Antonescu CR. Recurrent MYOD1 mutation s in pediatric and adult sclerosi ng and

164

20.

21.

22.

23.

24.

25.

26. 27.

28.

29.

30.

spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 2014;53:779-87. Owosho AA, Huang SC, Chen SM, et al. A clinicopathologic study of head and neck rhabdomyosarcomas showing FOX01 fusion-positive alveolar and MYOD1-mutant sclerosing are associated with unfavorable outcome. Oral Oncol 2016;61 :89-97. Rekhi B, Upadhyay P, Ramteke MP, Dutt A. MYOD1 (Ll22R) mutations are associated with spindle cell and sclerosing rhabdomyosarcomas with aggressive clinical outcomes. Mod Pathol 2016;29:1532-40. Argani P, Pawel B, Szabo S, Reyes-Mugica M, Timmons C, Antonescu CR. Diffuse strong BCOR immunoreactivity is a sensitive and specific marker for clear cell sarcoma of the kidney (CCSK) in pediatric ren al neoplasia. Am J Surg Pathol 2018;42:11 28-31. Chiang S, Lee CH, Stewart C], et al. BCOR is a robust diagnostic immunohistochemical marker of genetically diverse high-grade endometrial stromal sarcoma, including tumors exhibiting variant morphology. Mod Pathol2017;30:1251-61. Kao YC, Owosho AA, Sung YS, et al. BCORCCNB3 fusion positive sarcomas: a clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas. Am J Surg Pathol 2018;42:604-15 . Kao YC, Sung YS, Zhang L, et al. BCOR overexpression is a highly sensitive marker in round cell sarcomas with BCOR genetic abnormalities. Am J Surg Pathol 2016;40:1670-8. Billings SD, Folpe AL, Weiss SW. Epithelioid sarcoma-like hemangioendothelioma. Am] Surg Pathol 2003;27:48-57. Mirra ]M, Kessler S, Bhuta S, Eckardt J. The fibroma-like variant of epithelioid sarcoma. A fibrohistiocytic/myoid cell lesion often confused with benign and malignant spindle cell tumors. Can cer 1992;69:1382-95. Hornick JL, Fletcher CD. Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. Am J Surg Pathol 2011;35:190-201. Hung YP, Fletcher CD, Hornick JL. FOSS is a Useful diagnostic marker fo r pseudomyogenic hemangioendothelioma. Am J Surg Pathol 2017;41:596-606. Trombetta D, Magnusson L, von Steyern FV, Hornick JL, Fletcher CD, Mertens F. Translocation t(7;19)(q22;q13)-a recurrent chromosome aberration in pseudomyogenic hemangioendothelioma? Cancer Genet 2011;204:211-5.

Index*

A Adipose tissue neoplasms, 11 Angiolipoma, 14 Atypical lipomatous tumor/we ll-differentiated liposarcoma, 16 Dedifferentiated liposarcoma, 24 Lipoblastoma, 14 Lipoma, 11 Myxoid liposarcoma, 30 Pleomorphic lipoma, 15 Pleomorphic liposarcoma, 28 Spindle cell lipoma, 15 Alveolar soft part sarcoma, 130 Alveolar rhabdomyosarcoma, 86 Anastomosing hemangioma, 91 Ancillary testing, 3, 147 Angiolipoma, 14 Angiolymphoid hyperplasia with eosinophilia, 91 Angiomatoid fibrous histiocytoma, 121 Angiomatosis, 91 Angiosarcoma, 97 Askin tumor, 150 Atypical decubital fib roplasia, 39 Atypical lipomatous tumor/well-differentiated liposarcoma, 10, 13, 16 Atypical vascular lesion, 97

B BCOR-rearranged round cell sarcoma, 157 Botryoid rhabdomyosarcoma, 85

Calcifying aponeurotic fibroma, 43 Capillary hemangioma, 88 Cavernous hemangioma, 91 CJC-rearranged round cell sarcoma, 156 Clear cell sarcoma, 131 Collagenous fibroma, 42 Cutaneous myxoma, 109

Dedifferentiated liposarcoma, 24, 160 Dermatofibroma, 59 Dermatofibrosarcoma protuberans, 67 Desmoid type fibromatosis, 46

Desmoplastic fibroblastoma, 7, 42 Desmoplastic small round cell tumor, 135 Diffuse large B-celllymphoma, 161 Diffuse neurofibroma, 69

E Elastofibroma, 42 Embryonal rhabdomyosarcoma, 80 Epithelioid cell histiocytoma, 66 Epithelioid gastrointestinal stromal tumor, 148 Epithelioid hemangioendothelioma, 94 Epithelioid hemangioma, 91 Epithelioid sarcoma, 128 Erdh eim-Chester disease, 71 Ewing sarcoma, 150 Extrarenal rhabdoid tumor, 147 Extraskeletal myxoid chondrosarcoma 131 I

F Fat atrophy, 33 Fat necrosis, 7 Fibroblastic lesions, 32 Calcifying aponeurotic fibroma, 43 Desmoid type fibromatosis, 46 Desmoplastic fibroblastoma, 42 Elastofibroma, 42 Fibroma of tendon sheath, 42 Fibrous h amartoma of infancy, 51 IgG4-related fibrosclerosing disease, 56 Inclusion body fibromatosis, 45 Ischemic fasciitis, 39 Inflammatory myofibroblastic tumor, 52 Lipofibromatosis, 56 Nodular fasciitis, 32 Palmar/plantar fibromatosis, 46 Proliferative fasciitis, 36 Proliferative myositis, 36 Myositis ossificans, 39 Fibrohistiocytic/histiocytic lesions, 58 Dermatofibroma/fibrous histiocytoma, 59 Dermatofibroma protuberans, 67 Erdheim-Chester disease, 71 Giant cell fibroblastoma, 69 Langerhans cell histiocytosis, 71 Plexiform fibrohistiocytic tumor, 62

*In a series of numbers, those in boldface indicate the main discussion of the entity.

165

Soft Tissue Pathology

Rosai-Dorfman disease, 71 Tenosynovial giant cell tumor, 58 Fibroma of tendon sheath, 42 Fibrous hamartoma of infancy, 51 Fibrous histiocytoma, 59, 69

G Gastrointestinal stromal tumor, 86 Succinate dehydrogenase-deficient, 89 Gene fusions, shared, 147 Giant cell fibroblastoma, 69 Giant cell tumor of tendon sheath, 58 Glomus tumor, 78 Granular cell tumor, 102 Granulation tissue, 5

H Hemangioendotheliomas, 15 7 Pseudomyogenic hemangioendothelioma, 158 Hematoxylin and eosin staining, 2, 3, 147 Lesions diagnosed with stain alone, 2 Lesions needing ancillary testing, 3, 147 Hibernoma, 24 Histiocytic lesions, see Fibrohistiocytic/histiocytic lesions Hyalinizing spindle cell tumor with giant rosettes, 116

IgG4-related fibrosclerosing disease, 56 Inclusion body fibromatosis, 45 Inflammatory myofibroblastic tumor, 52 Epithelioid type, SS Inflammatory myxohyaline tumor, 112 Infantile digital fibromatosis, 45 Intramuscular hemangioma, 91 Intramuscular myxoma, 111 Ischemic fasciitis, 39

J Juvenile xanthogranuloma, 66

K Kaposi sarcoma, 94

L Langerhans cell histiocytosis, 71 Leiomyoma, 75 Leiomyosarcoma, 75 Lipoblastoma, 14 Lipofibromatosis, 56 Lipoleiomyoma, 80

166

Lipoma, 9, 11 With fat necrosis, 7 Lobular capillary hemangioma, 89 Low-grade fibromyxoid sarcoma, 116 Lymphedema, 23

M Malignant peripheral nerve sheath tumor, 102 Epithelioid, 110 Malignant rhabdoid tumor, 147 Myofibroblastic lesions, 32, see also Fibroblastic lesions Myofibroma, 79 Myolipoma, 79 Myopericytoma, 79 Myositis ossificans, 39 Myxofibrosarcoma, 32, 115 Myxoid changes, 3, 4 Myxoid lesions, 109 Cutaneous myxoma/superficial angiomyxoma, 109 Intramuscular myxoma, 111 Low-grade fibromyxoid sarcoma, 116 Myxofibrosarcoma, 115 Myxoinflammatory fibroblastic sarcoma, 112 Sclerosing epithelioid fibrosarcoma, 118 Myxoid liposarcoma, 19, 30 Myxoinflammatory fibroblastic sarcoma, 112

N Neural lesions, 102 Granular cell tumor, 102 Malignant peripheral nerve sheath tumor, 102 Neurofibroma, 102 Schwannoma, 102 Neurofibroma, 102 Nodular fasciitis, 32

0 Ossifying fibromyxoid tumor, 121

p Palmar fibromatosis, 46 Peripheral primitive neuroectodermal tumor, 150 Pigmented villonodular tenosynovitis, 58 Plantar fibromatosis, 46 Pleomorphic lipoma, 15 Pleomorphic liposarcoma, 28 Pleomorphic rhabdomyosarcoma, 163 Plexiform fibrohistiocytic tumor, 62 Poorly differentiated synovial sarcoma, 128

Index

Proliferative fasciitis, 36 Proliferative fasciitis, 36 Pseudomyogenic hemangioendothelioma, 158 Pyogenic granuloma, 89

R Rhabdomyosarcoma, 150, 154 Spindle/sclerosing, 154 Rosai-Dorfman disease, 71 Round cell sarcomas, 156 BCOR rearrangement, 157 CIC rearrangement, 156

s Sarcomatoid renal cell carcinoma, 162 Schwannoma, 102 Sclerosing epithelioid fibrosarcoma, 118 Skeletal muscle tumors, 80 Alveolar rhabdomyosarcoma, 86 Embryonal rhabdomyosarcoma, 80 Gastrointestinal stromal turner, 86 Smooth muscle lesions, 75 Diagnostic pitfalls, 78 Glomus turner, 78 Leiomyoma, 75 Leiomyosarcoma, 75 Myofibroma, 79 Myopericytoma, 79 Solitary fibrous tumors, 118 Spindle cell lipoma, 15

Spindle cell neoplasms, malignant, 158 Spindle/sclerosing rhabdomyosarcoma, 143 Superficial angiomyxoma, 109 Synovial sarcoma, 124 Poorly differentiated, 128 With unusual features, 149

T Tenosynovial giant cell tumor, 58

V Vascular tumors, 88 Anastomosing hemangioma, 91 Angiomatosis, 91 Angiosarcoma, 97 Atypical vascular lesion, 97 Capillary hemangioma, 88 Cavernous hemangioma, 91 Epithelioid h emangioendothelioma, 94 Epithelioid hemangioma, 91 Intramuscular hemangioma, 91 Kaposi sarcoma, 94 Pyogenic granuloma, 89 Vimentin, 1

w Well-differentiated liposarcoma, see Atypical lipomatous tumor/well-differentiated liposarcoma

167

ISBN- 13 : 978- 1- 9334n-S1-Q ISBN-10: 1- 933477- 51- 2

..

m

z

Montgomery, Ware, Gardner

l
if.