Survival Guide To Soft Tissue Pathology: Series 1 [PDF]

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PATHOLOGY SURVIVAL GUIDES Series 1

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

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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.

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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

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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

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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.

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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

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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.

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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

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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

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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.

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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

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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

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MYXOID LIPOSARCOMA

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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

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